WO2012175991A1 - Composés pentacycliques fusionnés anti-prolifératifs - Google Patents

Composés pentacycliques fusionnés anti-prolifératifs Download PDF

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WO2012175991A1
WO2012175991A1 PCT/GB2012/051467 GB2012051467W WO2012175991A1 WO 2012175991 A1 WO2012175991 A1 WO 2012175991A1 GB 2012051467 W GB2012051467 W GB 2012051467W WO 2012175991 A1 WO2012175991 A1 WO 2012175991A1
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ium
phenanthridin
methylchromeno
methyl
alkyl
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David Cousin
Mark Frigerio
Marc Geoffery Hummersone
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Pharminox Ltd
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Pharminox Ltd
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Priority claimed from GBGB1110727.3A external-priority patent/GB201110727D0/en
Priority claimed from GBGB1205504.2A external-priority patent/GB201205504D0/en
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    • 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
    • C07D495/06—Peri-condensed systems
    • 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
    • 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
    • C07D491/06—Peri-condensed systems

Definitions

  • the present invention relates to novel compounds that function as inhibitors of the activity of the enzyme telomerase, either directly or indirectly via interaction with the telomere itself. More specifically, the present invention relates to novel compounds which are potentially useful therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their therapeutic uses.
  • Cancer is caused by uncontrolled and unregulated cellular proliferation. Precisely what causes a cell to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intense research over recent decades. This research has led to the identification of numerous tumour- specific or tumour-associated targets, which can then be targeted by anticancer agents.
  • telomere enzyme catalyses the synthesis of telomeres.
  • Telomeres are nucleoprotein structures at the ends of linear chromosomes which consist of DNA sequences arranged in tandemly repeated units which extend from less than 100 to several thousands of bases. With each cell division cycle, bases are lost from the ends of the chromosomes and, as these telomeres shorten in length, the cell eventually reaches a point at which apoptosis is triggered.
  • Telomerase is a ribonucleoprotein reverse transcriptase that functions to maintain the telomere length above the point at which apoptosis is triggered by utilising its internal RNA template to synthesize telomeric DNA sequences, which compensate for the loss of telomeric DNA (see Blackburn; Annu. Rev.
  • telomerase is present in stem and germ line cells of normal tissues, but is absent in most other cells.
  • telomerase activity and the associated shortened but stabilized telomeres, have been detected in the majority of tumours examined (and in over 90% of all human cancers examined).
  • the telomerase enzyme is a particularly interesting target for anti-cancer therapy.
  • the absence of telomerase in most normal cells makes this enzyme a particularly attractive target because its inhibition would be expected to cause minimal damage to normal healthy cells and tissues.
  • tumour cells have shorter telomeres and higher proliferation rates than normal replicative cell populations suggests that a therapeutic telomerase inhibitor may cause tumour cell death well before damage to regenerative tissues occurs, thereby minimising undesirable side effects.
  • telomeres and telomerase A more detailed discussion of telomeres and telomerase, and their role as anti-proliferative targets is provided in, for example, Sharma et al, Annals of Oncology, 1997, Vol. 8, pp 689-685; Urquidi et al, Ann. Med., 1998, Vol. 30, pp 419-430; Perry etal, Exp. Opin. Ther. Patents, 1998, Vol. 8, No. 12, pp 1567-1586; Autexier, Chemistry & Biology, 1999, Vol. 6, pp R299-R303; andNeidle i3 ⁇ 4a/., Anti-Cancer Drug Design, 1999, Vol. 14, pp 341-347.
  • telomere enzyme Certain compounds that target the telomerase enzyme are known.
  • WO 02/30932 describes certain N 8 , N 13 -disubstituted quino[4,3,2-KL]acridium salts that function as inhibitors of telomerase.
  • telomerase inhibitors that possess one or more advantageous pharmaceutical properties and which are potentially useful therapeutic agents for the treatment of proliferative disorders such as cancer.
  • telomerase inhibitors which exhibit good selectivity for the target as well as reduced non-target activity.
  • telomerase inhibitors that can be used as pharmaceutical agents for use in the treatment of proliferative disorders such as cancer.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in admixture with a pharmaceutically acceptable diluent or carrier.
  • the present invention provides a method of inhibiting telomerase in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, as defined herein.
  • the present invention provides a method of inhibiting cell proliferation in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, as defined herein.
  • the present invention provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a compound, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
  • the present invention provides a compound, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition.
  • the present invention provides a compound, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer.
  • the cancer is a human cancer.
  • the present invention provides a compound, or a pharmaceutically acceptable salt or solvate thereof, as defined herein for use in the production of a telomerase inhibitory effect.
  • the present invention provides the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for use in the treatment of a proliferative condition.
  • the present invention provides the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for use in the treatment of cancer.
  • the medicament is for use in the treatment of human cancers.
  • the present invention provides the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for use in the production of a telomerase inhibitory effect.
  • the present invention further provides a method of synthesising a compound, or a pharmaceutically acceptable salt or solvate thereof, as defined herein.
  • the present invention provides a compound, or a pharmaceutically acceptable salt or solvate thereof, obtainable by, or obtained by, or directly obtained by a method of synthesis as defined herein.
  • the present invention provides novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.
  • references to "treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.
  • Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • alkyl includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only.
  • (l-6C)alkyl includes (l-4C)alkyl, (l-3C)alkyl, propyl, isopropyl and i-butyl.
  • phenyl(l-6C)alkyl includes phenyl(l-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.
  • (m-nC) or "(m-nC) group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • alkylene is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to connect two other chemical groups.
  • (1- 6C)alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
  • (2-6C)alkenylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, for example, as in ethenylene, 2,4-pentadienylene, and the like.
  • (2-6C)alkynylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, for example, as in ethynylene, propynylene, and butynylene and the like.
  • (3-8C)cycloalkyl means a hydrocarbon ring containing from 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.
  • (3-8C)cycloalkenyl means a hydrocarbon ring containing at least one double bond, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, such as 3-cyclohexen-l- yl, or cyclooctenyl.
  • (3-8C)cycloalkyl-(l-6C)alkylene means a (3-8C)cycloalkyl group covalently attached to a (l-6C)alkylene group, both of which are defined herein.
  • halo refers to fluoro, chloro, bromo and iodo.
  • heterocyclyl means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s).
  • heterocyclyl includes both monovalent species and divalent species.
  • Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring.
  • Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring.
  • Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems.
  • heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers.
  • Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like.
  • Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-l ,3-dithiol, tetrahydro- 2H-thiopyran, and hexahydrothiepine.
  • Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
  • heterocycles containing sulfur the oxidized sulfur heterocycles containing SO or S0 2 groups are also included.
  • examples include the sulfoxide and sulfone forms of tetrahydrothienyl and fhiomorpholinyl such as tetrahydrothiene 1,1 -dioxide and thiomorpholinyl 1,1 -dioxide.
  • heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1 -dioxide, thiomorpholinyl, thiomorpholinyl 1,1 -dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl.
  • any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom.
  • reference herein to piperidino or morpholino refers to a piperidin-l-yl or morpholin-4-yl ring that is linked via the ring nitrogen.
  • bridged ring systems is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992.
  • bridged heterocyclyl ring systems include, aza- bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo [3.2.1] octane and quinuclidine.
  • Heterocyclyl(l-6C)alkyl means a heterocyclyl group covalently attached to a (1- 6C)alkylene group, both of which are defined herein.
  • heteroaryl or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur.
  • heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members.
  • the heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non- basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • heteroaryl examples include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridin
  • Heteroaryl also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur.
  • partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo- 1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro- benzo[l,4]dioxinyl, benzo[l,3]dioxolyl, 2,2-dioxo-l,3-dihydro-2-benzothienyl, 4,5,6,7- tetrahydrobenzofuranyl, indolinyl, l,2,3,4-tetrahydro-l,8-naphthyridinyl, l,2,3,4-tetrahydropyrido[2,3- ?]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-Z?] [l,4]oxazinyl
  • heteroaryl groups examples include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • heteroaryl groups examples include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • a bicyclic heteroaryl group may be, for example, a group selected from:
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
  • bicyclic heteroaryl groups containing two fused six membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.
  • Heteroaryl(l-6C)alkyl means a heteroaryl group covalently attached to a (1- 6C)alkylene group, both of which are defined herein.
  • heteroaralkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.
  • aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms.
  • aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In particular embodiment, an aryl is phenyl.
  • aryl(l-6C)alkyl means an aryl group covalently attached to a (l-6C)alkylene group, both of which are defined herein.
  • aryl-(l-6C)alkyl groups include benzyl, phenylethyl, and the like
  • heterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted by
  • heterocyclyl refers to either groups, structures, or molecules that are substituted and those that are not substituted.
  • X is O, S, SO or S0 2 ;
  • Q is selected from O , (l-6C)alkyl, (l-6C)alkoxy, (2-6C)alkenyl, (2-6C)alkynyl, or Q is group of the formula:
  • L 1 is absent or (l-6C)alkylene, (2-6C)alkenylene or (2-6C)alkynylene, each of which is optionally substituted with one or more (l-4C)alkyl groups;
  • Q 1 is selected from -OR 9 , -NR9R1 0 , -S(0) p R 9 (wherein p is 0, 1 or 2), -C(0)R 9 , -C(0)OR 9 , -OC(0)R 9 , -C(O)NR 9 R 10 , -N(R 10 )C(O)R 9 , -N(R 10 )CON(R 10 )R 9 -, -S0 2 N(R 9 )-, -N(R 9 )S0 2 -, (3-8C)cycloalkyl, aryl, heterocyclyl, heteroaryl, and wherein a (3-8C)cycloalkyl, aryl, heterocyclyl, heteroaryl group is optionally substituted by one or more substituents independently selected from halogeno, cyano, nitro, hydroxy, amino or (l-4C)alkoxy;
  • R is selected from hydrogen, (l-6C)alkyl, (3-8C)cycloalkyl, aryl, heterocyclyl, heteroaryl, and wherein a (l-6C)alkyl, (3-8C)cycloalkyl, aryl, heterocyclyl, heteroaryl group is optionally substituted by one or more substituents independently selected from halogeno, cyano, nitro, hydroxy, amino or (1- 4C)alkoxy;
  • Rio is selected from hydrogen or (l-6C)alkyl
  • Ri, R2, R3, R4, R5, R 6 , R7 Re, R21, R22 and R23 are each independently selected from hydrogen, halogeno, trifluoromethyl, cyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, ureido, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
  • L 2 is absent or a (l-6C)alkylene, (2-6C)alkenylene or (2-6C)alkynylene;
  • L 3 is absent or is selected from O, S, SO, S0 2 , OS(0) 2 , N(Ri 3 ), C(O), CH(ORi 3 ),
  • R 13 and R J4 are each independently selected from hydrogen or (l-4C)alkyl
  • R20 is hydrogen, (l-6C)alkyl, aryl, aryl-(l-6C)alkyl, (3-6C)cycloalkyl, (3- 6C)cycloalkyl-(l-6C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl and wherein R 2 o is optionally further substituted by one or more substituents independently selected from oxo, halogeno, cyano, nitro, hydroxy, amino, (1-4C) alkyl (l-4C)alkoxy, or a group of the formula:
  • L 4 is absent or is selected from O, S, SO, S0 2 , N(R 25 ), C(O), CH(OR 25 ), C(0)0, OC(O), C(0)N(R 25 ), N(R 25 )C(0), N(R 25 )C(0)N(R 2 6), S(0) 2 N(R 25 ), or N(R25)S0 2 , wherein R 2 5 and R 2 6 are each independently selected from hydrogen or (l-4C)alkyl; and
  • R 24 is hydrogen, (l-6C)alkyl, aryl, aryl-(l-6C)alkyl, (3-6C)cycloalkyl, (3- 6C)cycloalkyl-(l-6C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl and wherein R 2 4 is optionally further substituted by one or more substituents independently selected from halogeno, cyano, nitro, hydroxy, amino, (1-4C) alkyl or (l-4C)alkoxy;
  • any nitrogen atoms present in any of the groups R l5 R 2 , R 3 , R4, R5, R6, R7 Rs, R21, R22 and R2 3 are optionally in the form of an N-oxide;
  • X is O, S, SO or S0 2 ;
  • Q is selected from O , (l-6C)alkyl, (l-6C)alkoxy, (2-6C)alkenyl or (2-6C)alkynyl, or Q is a group of the formula:
  • L 1 is absent or (l-6C)alkylene, (2-6C)alkenylene or (2-6C)alkynylene, each of which is optionally substituted with one or more (l-4C)alkyl groups;
  • Q 1 is selected from -OR9, -NR9R1 0 , -S(0) p R 9 (wherein p is 0, 1 or 2), -C(0)R 9 , -C(0)OR 9 , -OC(0)R 9 , -C(0)NR 9 Rio, -N(Ri 0 )C(O)R 9 , -N(R 10 )CON(R 10 )R 9 -, -S0 2 N(R 9 )-, -N(R 9 )S0 2 -, (3-8C)cycloalkyl, aryl, heterocyclyl, heteroaryl, and wherein a (3-8C)cycloalkyl, aryl, heterocyclyl, heteroaryl, and wherein a (3-8C)cyclo
  • R 9 is selected from hydrogen, (l-6C)alkyl, (3-8C)cycloalkyl, aryl, heterocyclyl, heteroaryl, and wherein a (l-6C)alkyl, (3-8C)cycloalkyl, aryl, heterocyclyl, heteroaryl group is optionally substituted by one or more substituents independently selected from halogeno, cyano, nitro, hydroxy, amino or (1- 4C)alkoxy;
  • Rio is selected from hydrogen or (l-6C)alkyl
  • Ri, R 2 , R3, R4, R5, R 6 , R7 and Rg are each independently selected from hydrogen, halogeno, trifluoromefhyl, cyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, ureido, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
  • L 2 is absent or a (l-6C)alkylene, (2-6C)alkenylene or (2-6C)alkynylene;
  • L 3 is absent or is selected from O, S, SO, S0 2 , N(Ri 3 ), C(O), CH(ORi 3 ), C(0)0, OC(O), C(0)N(R 13 ), N(Ri 3 )C(0), N(R 13 )C(0)N(R 14 ), S(0) 2 N(R 13 ), or
  • Ri 3 and R14 are each independently selected from hydrogen or (l-4C)alkyl
  • R 20 is (l-6C)alkyl, aryl, aryl-(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(l-
  • R 20 is optionally further substituted by one or more substituents independently selected from halogeno, cyano, nitro, hydroxy, amino, (1-4C) alkyl or (1- 4C)alkoxy;
  • novel compounds of the invention include, for example, compounds of the formula I, or pharmaceutically acceptable salts or solvates thereof, wherein, unless otherwise stated, each of X, Q, R 1; R2, R 3 , R4, R5, R 6 , R7, Rs, R21, R22 and R23 has any of the meanings defined hereinbefore or in any of paragraphs (1) to (41) hereinafter: -
  • X is O, S or S0 2 ;
  • Q is selected from O , (l-6C)alkyl, (l-6C)alkoxy, (2-6C)alkenyl or (2-6C)alkynyl, or Q is a group of the formula: wherein:
  • L 1 is (l-6C)alkylene which is optionally substituted with one or more (l-4C)alkyl groups;
  • Q 1 is selected from -OR 9 , -NR 9 R 10 , -S(0) p R 9 (wherein p is 0, 1 or 2), -C(0)R 9 ,
  • -C(0)OR 9 -OC(0)R 9 , -C(0)NR 9 Rio, -N(R 10 )C(O)R 9 , -N(Ri 0 )CON(Ri 0 )R 9 -, -S0 2 N(R 9 )-, -N(R 9 )S0 2 -, (3-8C)cycloalkyl, aryl, heterocyclyl, heteroaryl, and wherein a (3- 8C)cycloalkyl, aryl, heterocyclyl or heteroaryl group is optionally substituted by one or more substituents independently selected from halogeno, cyano, nitro, hydroxy, amino or (l-4C)alkoxy;
  • R 9 is selected from hydrogen, (l-6C)alkyl, (3-8C)cycloalkyl, aryl, heterocyclyl, heteroaryl, and wherein a (l-6C)alkyl, (3-8C)cycloalkyl, aryl, heterocyclyl, heteroaryl group is optionally substituted by one or more substituents independently selected from halogeno, cyano, nitro, hydroxy, amino or (l-4C)alkoxy;
  • Rio is selected from hydrogen or (l-6C)alkyl
  • Q is selected from O , (l-6C)alkyl, (l-6C)alkoxy, (2-6C)alkenyl or (2-6C)alkynyl, or Q is a group of the formula:
  • L 1 is (l-4C)alkylene which is optionally substituted with one or more (l-2C)alkyl groups;
  • Q 1 is selected from -OR 9 , -NR 9 Rio, -S(0) p R 9 (wherein p is 0, 1 or 2), -C(0)R 9 ,
  • -C(0)OR 9 , -OC(0)R 9 , -C(O)NR 9 R 10 , -N(R 10 )C(O)R 9 , -N(R 10 )CON(R 10 )R 9 -, -S0 2 N(R 9 )-, -N(R 9 )S0 2 -, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, and wherein a (3- 6C)cycloalkyl, aryl, heterocyclyl or heteroaryl group is optionally substituted by one or more substituents independently selected from halogeno, cyano, nitro, hydroxy, amino or (l-4C)alkoxy;
  • R 9 is selected from hydrogen, (l-4C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, and wherein a (l-4C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl group is optionally substituted by one or more substituents independently selected from halogeno, cyano, nitro, hydroxy, amino or (l-4C)alkoxy;
  • Rio is selected from hydrogen or (l-2C)alkyl
  • Q is selected from 0 ⁇ , (l-6C)alkyl, (l-6C)alkoxy, or Q is a group of the formula: wherein:
  • L 1 is (l-2C)alkylene
  • Q 1 is selected from -OR 9 , -NR 9 Ri 0 , -S(0) p R 9 (wherein p is 0, 1 or 2), -C(0)R 9 ,
  • -C(0)OR 9 -OC(0)R 9 , -C(0)NR 9 Rio, -N(Ri 0 )C(O)R 9 , -N(Ri 0 )CON(Ri 0 )R 9 -, -S0 2 N(R 9 )-, -N(R 9 )S0 2 -, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, and wherein a (3- 6C)cycloalkyl, aryl, heterocyclyl or heteroaryl group is optionally substituted by one or more substituents independently selected from halogeno, cyano, nitro, hydroxy, amino or (l-4C)alkoxy;
  • R9 is selected from hydrogen or (l-4C)alkyl
  • L and Q have any one of the definitions set out herein;
  • Q is selected from O , (l-6C)alkyl, or (l-6C)alkoxy;
  • Q is selected from O , (l-4C)alkyl, or (l-4C)alkoxy;
  • Q is selected from O , (l-2C)alkyl, (l-2C)alkoxy;
  • Q is O ⁇ or (l-6C)alkyl.
  • Q is O " ,or (l-2C)alkyl.
  • Q is O , or methyl.
  • Ri, R2, R3, R4, R5, R 6 , R7 and Rs are each independently selected from hydrogen,
  • halogeno trifluoromethyl, cyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, ureido, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, or a group of the formula:
  • L 2 is absent or (l-6C)alkylene, (2-6C)alkenylene or (2-6C)alkynylene;
  • L 3 is absent or is selected from O, S, SO, S0 2 , N(R i3 ), C(O), CH(ORi 3 ), C(0)0,
  • Ri 3 and R14 are each independently selected from hydrogen or (l-2C)alkyl
  • R 20 is (l-6C)alkyl, aryl, aryl-(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(l- 6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l- 6C)alkyl and wherein R 20 is optionally further substituted by one or more substituents independently selected from oxo, halogeno, cyano, nitro, hydroxy, amino or (l-4C)alkoxy;
  • Ri, R2, R3, R4, R5, R 6 , 7 and R 8 are each independently selected from hydrogen, halogeno, trifluoromethyl, cyano, nitro, hydroxy, mercapto, amino, carboxy, carbamoyl, ureido, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, or a group of the formula:
  • L 2 is absent or a (l-6C)alkylene, (2-6C)alkenylene or (2-6C)alkynylene;
  • L 3 is absent or is selected from O, S, SO, S0 2 , N(Ri 3 ), C(O), CH(ORi 3 ), C(0)N(Ri 3 ), N(Ri 3 )C(0), S(0) 2 N(Ri 3 ), or N(Ri 3 )S0 2 , wherein R i3 and R i4 are each independently selected from hydrogen or (l-2C)alkyl; and
  • R 20 is (l-6C)alkyl, aryl, aryl-(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(l- 6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l- 6C)alkyl and wherein R2 0 is optionally further substituted by one or more substituents independently selected from oxo, halogeno, cyano, nitro, hydroxy, amino or (l-4C)alkoxy;
  • R 2 i, R22 and R 23 are hydrogen
  • Ri, R2, R 3 , R4, R5, R 6 , R7 and Rg are each independently selected from hydrogen,
  • L 3 is absent or is selected from O, S, SO, S0 2 , N(R i3 ), C(O), CH(ORi 3 ), C(0)N(Ri 3 ), N(Ri 3 )C(0), N(R 13 )C(0)N(R 14 ), S(0) 2 N(Ri 3 ), or N(Ri 3 )S0 2 , wherein Ri 3 and R14 are each independently selected from hydrogen or (1- 2C)alkyl; and
  • R2 0 is (l-6C)alkyl or (3-6C)cycloalkyl, and wherein R 2 o is optionally further substituted by one or more substituents independently selected from oxo, halogeno, cyano, nitro, hydroxy, amino or (l-2C)alkoxy;
  • R 2 i, R 22 and R 23 are hydrogen
  • Ri, R 2 , R 3 , R4, R5, R 6 , R7 and R 8 are each independently selected from hydrogen
  • L 3 is absent or is selected from O, S, SO, S0 2 , N(Ri 3 ), C(O), CH(ORi 3 ), C(0)N(Ri 3 ), N(Ri 3 )C(0), S(0) 2 N(Ri 3 ), or N(Ri 3 )S0 2 , wherein R i3 and R i4 are each independently selected from hydrogen or (l-2C)alkyl; and
  • R2 0 is (l-4C)alkyl which is optionally further substituted by one or more substituents independently selected from oxo, halogeno, cyano, nitro, hydroxy, amino or (l-2C)alkoxy;
  • R21, R22 and R 23 are hydrogen
  • Ri, R2, R 3 , R4, R5, R 6 , R7 Re, R21, R22 and R2 3 are each independently selected from hydrogen, halogeno, hydroxy, or a group of the formula:
  • L 2 is absent or a (l-6C)alkylene or (2-6C)alkynylene;
  • L 3 is absent or is selected from O, OS(0) 2 , N(Ri 3 ), C(0)0, C(0)N(Ri 3 ),
  • R i3 is selected from hydrogen or (l-4C)alkyl
  • R2 0 is hydrogen, (l-6C)alkyl, heteroaryl, or heterocyclyl and wherein R2 0 is optionally further substituted by one or more substituents independently selected from oxo, halogeno, hydroxy, (l-4C)alkoxy, or a group of the formula:
  • L 4 is N(R 25 ), wherein R25 is independently selected from hydrogen or (1- 4C)alkyl;
  • R 24 is (l-6C)alkyl
  • any nitrogen atoms present in any of the groups Ri, R2, R 3 , R 4 , R5, R6, R ? ,Rs R21, R22 and R2 3 are optionally in the form of a N-oxide;
  • Ri, R2, R 3 , R4, R5, R 6 , 7 s, R21, R22 and R2 3 are each independently selected from hydrogen, halogeno, hydroxy, or a group of the formula:
  • L 2 is absent or a (l-3C)alkylene or (2-3C)alkynylene;
  • L 3 is absent or is selected from O, OS(0) 2 , N(Ri 3 ), C(0)0, C(0)N(Ri 3 ),
  • Ri 3 is selected from hydrogen or (l-2C)alkyl
  • R2 0 is hydrogen, (l-3C)alkyl, heteroaryl, or heterocyclyl and wherein R 2 o is optionally further substituted by one or more substituents independently selected from oxo, halogeno, hydroxy, (l-2C)alkoxy, or a group of the formula:
  • L is N(R 25 ), wherein R 25 is (l-2C)alkyl
  • R 24 is (l-2C)alkyl
  • any nitrogen atoms present in any of the groups Ri, R2, R3, R4, R5, R6, R7, Re, R21, R22 and R2 3 are optionally in the form of a N-oxide;
  • Ri, R2, R 3 , R4, R5, R 6 , R7 Rs, R21, R22 and R 2 3 are each independently selected from hydrogen, fluoro, hydroxy, or a group of the formula:
  • L 2 is absent or a (l-3C)alkylene or (2-3C)alkynylene;
  • L 3 is absent or is selected from O, OS(0) 2 , N(R 13 ), C(0)0, C(0)N(Ri 3 ), N(Ri 3 )C(0), wherein R1 3 is selected from hydrogen or (l-2C)alkyl; and R20 is hydrogen, (l-3C)alkyl, heteroaryl, or heterocyclyl and wherein R20 is optionally further substituted by one or more substituents independently selected from fluoro, hydroxy, (l-2C)alkoxy, or a group of the formula:
  • L 4 is N(R 25 ), wherein R 25 is (l-2C)alkyl
  • R 24 is (l-2C)alkyl
  • any nitrogen atoms present in any of the groups Ri, R2, R 3 , R4, R5, R6, R7, Re, R21, R22 and R2 3 are optionally in the form of a N-oxide;
  • Ri, R 2 , R 3 , R4, R5, R 6 , R7 R8, R21, R22 and R2 3 are each independently selected from hydrogen, halogeno, hydroxy, or a group of the formula:
  • L 2 is absent or a (l-3C)alkylene or (2-3C)alkynylene;
  • L 3 is absent or is selected from O, OS(0) 2 , N(Ri 3 ), C(0)0, N(Ri 3 )C(0), wherein Ri 3 is selected from hydrogen or (l-2C)alkyl; and R2 0 is (l-3C)alkyl, heteroaryl, or heterocyclyl and wherein R 2 o is optionally further substituted by one or more substituents independently selected from oxo, halogeno, hydroxy, (l-2C)alkoxy, or a group of the formula:
  • L is N(R 25 ), wherein R 25 is (l-2C)alkyl
  • R 24 is (l-2C)alkyl
  • any nitrogen atoms present in any of the groups Ri, R2, R3, R4, R5, R6, R7, Re, R21, R22 and R2 3 are optionally in the form of a N-oxide;
  • Ri, R2, R3, R4, R5, R 6 , 7 s, R21, R22 and R 2 3 are each independently selected from
  • L 2 is absent or a (l-3C)alkylene or (2-3C)alkynylene;
  • L 3 is absent or is selected from O, OS(0) 2 , N(Ri 3 ), C(0)0, N(Ri 3 )C(0), wherein Ri 3 is selected from hydrogen or (l-2C)alkyl;
  • R20 is (l-3C)alkyl, heteroaryl, or heterocyclyl and wherein R20 is optionally further substituted by one or more substituents independently selected from oxo, halogeno, hydroxy, (l-2C)alkoxy,
  • Rg, R21, R22 and R2 3 are optionally in the form of a N-oxide
  • Ri, R2, R3, R4, R5, R 6 , 7 s, R21, R22 and R 2 3 are each independently selected from hydrogen, halogeno, trifluoromethyl, cyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, ureido, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
  • L 2 is absent or a (l-6C)alkylene, (2-6C)alkenylene or (2-6C)alkynylene;
  • L 3 is absent or is selected from O, S, SO, S0 2 , OS(0) 2 , N(R i3 ), C(O), CH(ORi 3 ), C(0)0, OC(O), C(0)N(R 13 ), N(R 13 )C(0), N(R 13 )C(0)N(R 14 ), S(0) 2 N(R 13 ), or
  • R i3 and R J4 are each independently selected from hydrogen or (l-4C)alkyl
  • R 20 is hydrogen, (l-6C)alkyl, aryl, aryl-(l-6C)alkyl, (3-6C)cycloalkyl, (3- 6C)cycloalkyl-(l-6C)alkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl and wherein R 2 o is optionally further substituted by one or more substituents independently selected from oxo, halogeno, cyano, nitro, hydroxy, amino, (1-4C) alkyl (l-4C)alkoxy
  • any nitrogen atoms present in any of the groups Ri, R 2 , R 3 , R4, R5, R5, R7, Rg, R21, R 22 and R 2 3 are optionally in the form of a N-oxide;
  • Ri, R 2 , R 3 , R4, R5, R 6 , 7 s, R 2 i, 22 and R 23 are each independently selected from hydrogen, halogeno, hydroxy, or a group of the formula:
  • L 2 is absent or a (l-6C)alkylene, or (2-6C)alkynylene;
  • L 3 is absent or is selected from O, OS(0) 2 , N(Ri 3 ), C(0)0, C(0)N(Ri 3 ),
  • Ri 3 is selected from hydrogen or (l-4C)alkyl
  • R2 0 is hydrogen, (l-6C)alkyl, heteroaryl, or heterocyclyl and wherein R 2 o is optionally further substituted by one or more substituents independently selected from oxo, halogeno, hydroxy, (l-4C)alkoxy
  • Rg, R 2 i, R 22 and R 23 are optionally in the form of a N-oxide
  • Ri, R 2 , R 3 , R4, R5, R 6 , 7 s, 2 i, R 22 and R 23 are each independently selected from hydrogen, halogeno, hydroxy, or a group of the formula:
  • L 2 is absent or a (l-3C)alkylene, or (2-3C)alkynylene;
  • L 3 is absent or is selected from O, OS(0) 2 , N(Ri 3 ), C(0)0, C(0)N(Ri 3 ),
  • R1 3 is selected from hydrogen or (l-2C)alkyl
  • R 2 o is hydrogen, (l-3C)alkyl, heteroaryl, or heterocyclyl and wherein R 2 o is optionally further substituted by one or more substituents independently selected from oxo, halogeno, hydroxy, (l-2C)alkoxy;
  • Rg, R21, R22 and R 2 3 are optionally in the form of a N-oxide
  • Ri, R2, R 3 , R4, R5, R 6 , 7 s, 2 i > R 22 and R 23 are each independently selected from hydrogen, fluoro, hydroxy, or a group of the formula:
  • L 2 is absent or a (l-3C)alkylene, or (2-3C)alkynylene;
  • L 3 is absent or is selected from O, OS(0) 2 , N(Ri 3 ), C(0)0, C(0)N(Ri 3 ),
  • R2 0 is hydrogen, (l-3C)alkyl, heteroaryl, or heterocyclyl and wherein R2 0 is optionally further substituted by one or more substituents independently selected from oxo, fluoro, hydroxy, or methoxy;
  • any nitrogen atoms present in any of the groups R l5 R 2 , R3, R4, R5, R , R7 Rs, R21, R22 and R23 are optionally in the form of a N-oxide;
  • Ri and R2 are each independently a substituent group as defined hereinbefore (in
  • R3, R4, R5, R 6 , R7, Re, R21, R22 and R2 3 are each independently selected from hydrogen, fluoro, CF 3 , OCF 3 or (l-2C)alkoxy.
  • one of Ri and R2 is a substituent group other than hydrogen as defined hereinbefore (in particular a substituent group as defined in any one of paragraphs (17) to (29) above) and the other is hydrogen; and R 3 , R4, R5, R5, R 7 R 8 , R 2 i, R22 and R 2 3 are each independently selected from hydrogen, fluoro, CF 3 , OCF 3 or (l-2C)alkoxy.
  • Ri and R2 is a substituent group other than hydrogen as defined hereinbefore (in particular a substituent group as defined in any one of paragraphs (17) to (29) above) and the other is hydrogen; and upto four of R 3 , R4, R5, R 6 , R 7 R 8 , R 2 i, R22 and R 2 3 are each independently selected from fluoro, CF 3 , OCF 3 or (l-2C)alkoxy and the others are hydrogen.
  • Ri and R 2 is a substituent group other than hydrogen as defined hereinbefore (in particular a substituent group as defined in any one of paragraphs (17) to (29) above) and the other is hydrogen; and upto three of R3, R4, R5, R6, R 7 Rs, R21, R22 and R2 3 are each independently selected from fluoro, CF 3 , OCF 3 or (l-2C)alkoxy and the others are hydrogen.
  • Ri and R 2 are each independently a substituent group as defined hereinbefore (in
  • R 3 , R4, R5, R6, R7 Re, R 21 , R 22 and R 2 3 are each independently selected from hydrogen, fluoro, CF 3 or OCF 3 .
  • Ri and R 2 are a substituent group other than hydrogen as defined hereinbefore (in particular a substituent group as defined in any one of paragraphs (17) to (29) above) and the other is hydrogen; and R3, R4, R5, R6, R 7 Rs, R21, R22 and R2 3 are each independently selected from hydrogen, fluoro, CF 3 or OCF 3 .
  • one of Ri and R 2 is a substituent group other than hydrogen as defined hereinbefore (in particular a substituent group as defined in any one of paragraphs (17) to (29) above) and the other is hydrogen; and upto four of R 3 , R4, R5, R6, R7 R 8 , R 2 i, R22 and R2 3 are each independently selected from fluoro, CF 3 or OCF 3 and the others are hydrogen.
  • Ri and R2 is a substituent group other than hydrogen as defined hereinbefore (in particular a substituent group as defined in any one of paragraphs (17) to (29) above) and the other is hydrogen; and upto three of R 3 , R 4 , R5, R 6 , R 7 R 8 , R 2 i, R22 and R 2 3 are each independently selected from fluoro, CF 3 or OCF 3 and the others are hydrogen.
  • Ri and R2 are each independently a substituent group as defined hereinbefore (in
  • R 3 , R4, R5, R 6 , R 7 Rs, R21, R22 and R2 3 are each independently selected from hydrogen, fluoro, CF 3 or OCF 3 .
  • Ri and R2 is a substituent group other than hydrogen as defined hereinbefore (in particular a substituent group as defined in any one of paragraphs (17) to (29) above) and the other is hydrogen; and R 3 , R4, R5, R5, R 7 Rs, R21, R22 and R 2 3 are each independently selected from hydrogen or fluoro.
  • one of Ri and R 2 is a substituent group other than hydrogen as defined hereinbefore (in particular a substituent group as defined in any one of paragraphs (17) to (29) above) and the other is hydrogen; and upto four of R 3 , R4, R5, R 6 , R 7 R 8 , R 2i , R 22 and R 23 are fluoro and the others are hydrogen.
  • one of Ri and R 2 is a substituent group other than hydrogen as defined hereinbefore (in particular a substituent group as defined in any one of paragraphs (17) to (29) above) and the other is hydrogen; and upto three of R 3 , R 4 , R5, R 6 , R 7 Rs, R21, R22 and R2 3 are fluoro and the others are hydrogen.
  • X is as defined in any one of paragraphs 1 to 4 above.
  • X is O or S.
  • Q is as defined in any one of paragraphs 5 to 16 above.
  • Q is O " or methyl.
  • Ri, R 2 , R3, R 4 , R5, R 6 , R7 Rs, R 21 , R 22 and R 2 3 have any one of the definitions set out in paragraphs 17 to 41 above.
  • R l5 R 2 , R 3 , R4, R5, R6, R 7 R 8 , R 2 i, R 22 and R 23 have any one of the definitions set out in paragraphs 29 to 41 above.
  • Ri, R 2 , R 3 , R ⁇ , R5, R 6 , R 7 Rs, R 2 i, R 22 and R2 3 have any one of the definitions set out in paragraphs 30 to 41 above.
  • up to four of R l 5 R 2 , R3, R4, R5, R 6 , R7, Re, R21, R22 and R2 3 are a substituent group other than hydrogen.
  • Ri, R2, R3, R 4 , R5, R6, R7, Re, R21, R22 and R2 3 are a substituent group other than hydrogen.
  • one or two of Ri, R2, R3, R 4 , R5, R 6 , R7, Rg, R21, R22 and R 2 3 is/are a substituent group other than hydrogen.
  • R l 5 R 2 , R3, R4, R5, R6, R7, Rs, 21 5 R22 and R23 is a substituent group other than hydrogen.
  • Rg, R21, R22 and R2 3 are hydrogen, i.e. the compounds have the structural formula II shown below:
  • X, Q, Ri, R2, R3, R4, R5, R6 and R7 have any one of the meanings defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof.
  • one of Ri or R 2 is hydrogen.
  • X is as defined herein before (and is particularly as described in any one of paragarphs (1) to (4) above);
  • Q is O " or (l-6C)alkyl (and is particularly O " or methyl);
  • Ri, R 2 and R 3 each independently have any one of the definitions set out hereinbefore (and in particular are as defined in any one of paragraphs (17) to (41) above);
  • R 4 , R5, R 6 , R 7 , Re, R21, R22 and R23 each have any one of the definitions set out hereinbefore;
  • X is O, S or S0 2 ;
  • R 2 , R3, R4, R5, R6, R7, Rs, R21, R22 and R23 each have any one of the definitions set out in paragraphs (30) to (41) above;
  • the various functional groups and substituents making up the compounds of the invention are typically chosen such that the molecular weight of the compound does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525 and, for example, is 500 or less.
  • Particular compounds of the invention include any one of the following:
  • Suitable pharmaceutically acceptable anions include, for example,
  • the compounds of the invention may be present in any pharmaceutically acceptable salt form.
  • the compounds of the invention are positively charged, they are suitably associated with one or more pharmaceutically acceptable anions.
  • the compound of the invention will suitably possess a +1 charge, although other charged substituent groups could be present.
  • the associated anion may carry a -1 charge, in which case the molar ratio of anionrcation is 1:1, or , alternatively, the anion may carry a -2 or -3 charge, in which case the molar ratio of anion ation is will be 1:2 or 1:3, respectively.
  • the anion is independently derived from one or more of the following acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, phosphorous acetic, propionic, succinic, gycolic, stearic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetyoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, isethionic, and valeric.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess telomerase inhibitory activity.
  • the present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 3 ⁇ 4, 2 H(D), and 3 H (T);
  • C may be in any isotopic form, including 12 C, 13 C, and 14 C;
  • O may be in any isotopic form, including 16 0 and 18 0; and the like.
  • tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • N-oxides Compounds of the invention containing an amine function may also form N-oxides.
  • a reference herein to a compound of the invention that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g.
  • N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
  • MCPBA m-chloroperoxybenzoic acid
  • the compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the invention and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the invention.
  • the present invention includes those compounds of the invention as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the invention that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the invention may be a
  • a suitable pharmaceutically acceptable pro-drug of a compound of the invention is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);
  • a suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the invention containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically acceptable esters for carboxy include
  • Ci_ 6 alkyl esters such as methyl, ethyl and ieri-butyl
  • Ci- 6 alkoxymethyl esters such as
  • Ci- 6 alkanoyloxymethyl esters such as pivaloyloxymethyl esters
  • 2-oxo-l,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and Ci ealkoxycarbonyloxy- Ci ⁇ alkyl esters such as methoxycarbonyloxymethyl and
  • a suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the invention containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include Ci ioalkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci_ioalkoxycarbonyl groups such as ethoxycarbonyl, N,N -(Ci-6)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci- 4 alkylamine such as methylamine, a (Ci_ 4 alkyl) 2 amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a Ci_ 4 alkoxy- C 2 - 4 alkylamine such as 2-methoxyethylamine, a phenyl-Ci_ 4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a Ci- 4 alkylamine such as methylamine
  • a (Ci_ 4 alkyl) 2 amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine
  • a suitable pharmaceutically acceptable pro-drug of a compound of the invention that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with Ci-ioalkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl,
  • the in vivo effects of a compound of the invention may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the invention. As stated herein before, the in vivo effects of a compound of the invention may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • compounds of invention may also be covalently linked (at any suitable position) to other groups such as, for example, solubilising moieties (for example, PEG polymers), moieties that enable them to be bound to a solid support (such as, for example, biotin-containing moieties), and targeting ligands (such as antibodies or antibody fragments).
  • solubilising moieties for example, PEG polymers
  • moieties that enable them to be bound to a solid support such as, for example, biotin-containing moieties
  • targeting ligands such as antibodies or antibody fragments
  • protecting groups see one of the many general texts on the subject, for example, 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons).
  • Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.
  • reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or i-butoxycarbonyl group, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or i-butoxycarbonyl group, an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or i-butoxycarbonyl group, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or i-butoxycarbonyl
  • arylmethoxycarbonyl group for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or
  • alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a teri-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a i-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a i-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • Resins may also be used as a protecting group.
  • the present invention provides a process for the production of a compound of the formula I, or a pharmaceutically acceptable salt or solvate thereof, which comprises:
  • Q-L where Q has any one of the definitions set out hereinbefore and L is a leaving group; and optionally thereafter, and if necessary:
  • L is halo (e.g. fluoro, chloro or bromo, particularly chloro or bromo) or another suitable leaving group such as trifluoromethanesulfonate, Meerwein salt or methyl sulfate.
  • halo e.g. fluoro, chloro or bromo, particularly chloro or bromo
  • another suitable leaving group such as trifluoromethanesulfonate, Meerwein salt or methyl sulfate.
  • the reaction is carried out in the presence of a suitable solvent.
  • Any suitable solvent or solvent mixture may be used for this reaction.
  • a person skilled in the art will know how to select suitable solvents or solvent mixtures for use in these reactions.
  • Particular examples of suitable solvents for this reaction include dichloromethane or chloroform.
  • the reaction is carried out in a sealed vessel.
  • the reaction is carried out in the presence of a carbonate, for example, potassium carbonate.
  • a carbonate for example, potassium carbonate.
  • the reaction is carried out an elevated temperature, suitably within the range of 60 to 160 °C or, more suitably 100 to 140 °C, for a suitable time period of, for example, 6 hours to 2 days.
  • an elevated temperature suitably within the range of 60 to 160 °C or, more suitably 100 to 140 °C, for a suitable time period of, for example, 6 hours to 2 days.
  • a person skilled in the art will be able to select appropriate reaction conditions to use in order to facilitate this reaction.
  • the process defined herein may further comprise the step of subjecting the compound of formula I to a salt exchange, particularly in situations where the compound of formula I is formed as a mixture of different salt forms.
  • the salt exchange suitably comprises immobilising the compound of formula I on a suitable solid support or resin, and eluting the compounds with an appropriate acid to yield a single salt of the compound of formula I.
  • the compounds of formula A can be prepared by processes known in the art.
  • the compound of formula A can be prepared by the intra-molecular cyclisation of a compound of formula B
  • X, Ri, R2, R3, R4, R5, R 6 , R7, Rs, R21, R22 and R23 each have any one of the meanings defined hereinbefore, and L2 is a leaving group (e.g. bromine);
  • L2 is fluoro, chloro or bromo, particularly chloro or bromo or another suitable leaving group such as trifluoromthanesulfonate.
  • the intra-molecular cyclisation reaction is a palladium catalysed reaction which is suitably carried out using a strong base (such as sodium ierf-butoxide) and a ligand such as PhDavePhos (2-Diphenylphosphino-2'-(N,N-dimethylamino)biphenyl).
  • a strong base such as sodium ierf-butoxide
  • a ligand such as PhDavePhos (2-Diphenylphosphino-2'-(N,N-dimethylamino)biphenyl).
  • Any suitable solvent may be used for the cyclisation reaction.
  • suitable solvents include dimethylacetamide (DMA) and dimethylformamide (DMF).
  • reaction mixture is heated in some way.
  • the reaction is heated in a microwave for between 5 minutes and 30 minutes.
  • the compound of formula B is prepared by reacting a compound of formula C:
  • the reaction may be carried out in any suitable solvent.
  • suitable solvents include toluene and pyridine.
  • reaction is suitably carried out in the presence of a Lewis acid, such as titanium tetrachloride.
  • a Lewis acid such as titanium tetrachloride.
  • the reaction is carried out in anhydrous conditions and in the presence of an inert atmosphere, such as argon or nitrogen.
  • an inert atmosphere such as argon or nitrogen.
  • the reaction may be carried out at room temperature or at an elevated temperature, for example at the reflux temperature of the solvent used.
  • the resultant compound of formula B can be isolated and purified using techniques well known in the art.
  • a compound of formula A can be prepared by the intra-molecular cyclisation of a compound of formula E
  • X, Ri, R2, R3, R4, R5, R 6 , R7, Rs, R21, R22 and R23 each have any one of the meanings defined hereinbefore;
  • Y is halo and Z is a leaving group.
  • Y is bromo .
  • Z may be any suitable suitable leaving group.
  • Z is fluoro.
  • the intra-molecular cyclisation reaction takes place in the presence of an organolithium reagent such as t-butyl-lithium.
  • Any suitable solvent may be used for the cyclisation reaction.
  • suitable solvents include THF.
  • reaction is treated with i-butyl-lithium at low temperature.
  • the resultant compound of formula A can be isolated and purified using techniques well known in the art.
  • SPR Surface Plasmon Resonance Assay
  • Biosensor experiments were conducted in filtered, degassed HEPES buffer (10 mM HEPES, 100 mM KC1, 3 mM EDTA, 0.000 05 v/v of 10% P20 BIACORE surfactant, pH 7.3) at 25 °C.
  • the 5'-biotin labeled DNA sequences (Integrated DNA Technologies) were HPLC
  • test compounds were solubilised at lOmM in dimethyl sulfoxide (DMSO), diluted in tissue culture media and added to cells at final concentrations of 30, 10, 3, 1, 0.3, 0.1 , 0.03 and 0.01 ⁇ in triplicate. Following an incubation period of 96 hr MTT was added to a final concentration of 400 g/ml and the plates incubated for a further 4 hr. The media/MTT was then aspirated and 150 ⁇ DMSO added. Plates were shaken briefly and the absorbance at 550nm read using a Labtech LT-4000 plate reader. An extra plate was seeded and the MTT assay was carried out on this plate at the time of drug addition to ascertain an initial absorbance value.
  • DMSO dimethyl sulfoxide
  • the compounds of formula I demonstrate a quadraplexrduplex ratio in the SPR assay of greater than 2.
  • the quadraplex: duplex ratio in the SPR assay of the compound of Example 2 herein is greater than 15.
  • antiproliferative activity possessed by compounds of the formula I may be demonstrated in the growth inhibition assay by a GI 50 value of less than 40 ⁇ (preferred compounds have an GI 50 of less than 15 ⁇ , more preferably less than 10 ⁇ ).
  • the compound is not one the above-identified compounds.
  • Pharmaceutical Compositions are not one the above-identified compounds.
  • composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • An effective amount of a compound of the present invention for use in therapy of infection is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the symptoms of infection, to slow the progression of infection, or to reduce in patients with symptoms of infection the risk of getting worse.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg kg to 30 mg kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg kg body weight will be used.
  • Oral administration may also be suitable, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • the present invention provides a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.
  • the compounds of the invention are capable of inhibiting telomerase activity.
  • the present invention provides a method of inhibiting telomerase activity in a cell, the method comprising administering to said cell compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides the use of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the inhibition of telomerase in a cell (in vivo or ex vivo) .
  • the present invention provides a method of inhibiting telomerase activity in a human or animal subject in need of such inhibition, the method comprising administering to said subject an effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of disease or condition associated with telomerase activity.
  • the present invention provides the use of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of disease or condition associated with telomerase activity.
  • the present invention provides a method of treating a proliferative disorder in a human or animal subject, the method comprising administering to said subject a therapeutically acceptable amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a proliferative disorder.
  • the present invention provides the use of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of a proliferative disorder.
  • proliferative disorder are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
  • proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and
  • any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin.
  • the anti-proliferative effects of the compounds of the present invention have particular application in the treatment of human cancers by virtue of their telomerase inhibitory properties.
  • the anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).
  • the invention further provides a method of treatment of the human or animal body, the method comprising administering to a subject in need of treatment a therapeutically-effective amount of an active compound, preferably in the form of a pharmaceutical composition.
  • Telomerase targeting agents are also known to be useful for inhibiting cancer stem cells (see, for example, US2008/0279961).
  • the present invention also provides a method of inhibiting a cancer stem cell, the method comprising administering to said cell an effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the inhibition and/or treatment of cancer stem cells.
  • the present invention provides the use of a compound of the invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the inhibition and/or treatment of cancer stem cells.
  • the compounds of the invention or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (ie., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, infraarterlal, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratrache
  • the antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents :-
  • alkylating agents for example cis-platin, oxaliplatin, carboplatin,
  • cyclophosphamide nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas
  • antimetabolites for example gemcitabine and antifolates such as
  • fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea
  • antitumour antibiotics for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin
  • antimitotic agents for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors
  • topoisomerase inhibitors for example irinotecan, etoposide, teniposide, amsacrine, topotecan and camptothecin
  • PARP inhibitors for example irinotecan, etoposide, teniposide, amsacrine, topotecan and camptothecin
  • irinotecan for example irinotecan, etoposide, teniposide, amsacrine, topotecan and camptothecin
  • PARP inhibitors for example irinotecan, etoposide, teniposide, amsacrine, topotecan and camptothecin
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a- reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), N-(2-chloro-6- methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-l-yl]-2-methylpyrimidin-4-ylamino ⁇ thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med.
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyr
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM] , the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the insulin growth
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-l- ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669,
  • an endothelin receptor antagonist for example zibotentan (ZD4054) or atrasentan;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • (ix) gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • (x) immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • Particular combinations of interest include the compounds of the invention with a topioisomerase inhibitor (such as irinotecan) and/or a PARP inhibitor.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically- active agent within its approved dosage range.
  • a combination suitable for use in the treatment of a cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof, and another anti-tumour agent.
  • a combination suitable for use in the treatment of a cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof, and any one of the anti-tumour agents listed under (i) - (ix) above.
  • a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof in combination with an anti-tumour agent selected from one listed under (i) - (ix) herein above, in association with a pharmaceutically acceptable diluent or carrier.
  • LCMS data were obtained using an Agilent 1200 series LC/MS with an Agilent 6110 quadropole MS, with Electrospray ionisation. The following three methods were used:
  • Mobile phase A 0.1% Acetic acid in water.
  • Mobile Phase B 0.1% acetic acid in acetonitrile. Flow rate of l.OOml/min. Gradient from 2% B over 3 minutes to 20%B for 0.2 minutes, up to 95% B for 1.8 minutes and then back down to 2%B. Total run time of 6 minutes.
  • Mass Spectra were achieved using the MS in positive mode.
  • Mobile phase A 0.1% ammonia solution in water.
  • Mobile phase B 0.1% ammonia solution in acetonitrile. Flow rate of 0.500ml/min. Gradient from 5% B over 3 minutes to 95%B, remaining at 95%B until 4.1 minutes, when it returns down to 5%B until the 7 minute run is over.
  • Mass Spectra were achieved using the MS in positive mode.
  • reversed-phase silica was used with a flow rate of about 1 ml per minute and detection was by Electrospray Mass Spectrometry and by UV absorbance at a wavelength of 254 nm.
  • Silica bound trimethylammonium chloride resin (1 g) was stirred in degassed water and was filtered. This process was repeated three times and the resin was added to 1L of a 0.1M aqueous solution of 2:1 methanesulfonic acid: sodium methanesulfonate. The mixture was stirred for 10 min. and decantated. This was repeated two more times and the silica was filtered and transferred to a small column.
  • silica bound resin was washed successively with two column volume of 0.1M aqueous solution of 2:1 methanesulfonic acid: sodium methanesulfonate, two column volume of 0.01M aqueous solution of 2:1 methanesulfonic acid: sodium methanesulfonate, and two column volume of water to give silica bound trimethyl ammonium mesylate.
  • Acetic anhydride (3.24 mL, 34.3 mmol, 1.1 equ) was added dropwise to a solution of propargyl amine (2 mL, 31.2 mmol), pyridine (2.76 mL, 34.3 mmol, 1.1 equ) and N,N dimethylaminopyridine (few crystals, catalytic amount) in dichloromethane (50 mL) at 0°C and the mixture was stirred overnight. The mixture was diluted with dichloromethane and transferred into a separating funnel. Water was added and the product was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate. The product was absorbed on silica and purified by flash chromatography (Hexane:EtOAc 30%-20 ) to give the title compound as an off white crystalline solid (1.45 g, 49% yield).
  • An air condenser (50 cm length) loosely packed with glass wool was attached to the reaction vessel. The outlet of the air condenser was connected to a Dewar condenser filled with dry ice-acetone connected to a receiving flask (250 mL) cooled in a dry ice-acetone bath.
  • the receiving flask was also connected in series to a second dry ice-acetone cold trap, a trap containing potassium iodide solution, and a vacuum was placed on the apparatus.
  • Oxone was added in portions (10-15 g) over approximately 0.5h while the acetone-water mixture was simultaneously added dropwise and the reaction mixture was stirred vigorously throughout the addition of reagents.
  • a yellow solution of 3,3-dimethyldioxirane in acetone collected in the receiving flask. Vigorous stirring was continued for an additional 15 min while a vacuum was applied to the cold trap.
  • the yellow dioxirane solution was dried over sodium sulfate, filtered and stored in the freezer (-25 °C) over activated molecular sieves.
  • the overall yield was 65mL.
  • a microwave vial was charged with 2-bromo-N-(9H-xanthen-9-ylidene)aniline (250 mg, 1.43 mmol), sodium ie/t-butoxide (274 mg, 2.86 mmol, 2.0 equ), a catalytic amount of tris(dibenzylideneacetone)dipalladium, followed by a catalytic amount of diphenylphosphino-2- (N,N-dimethylamino)biphenyl.
  • the RM was diluted with anhydrous dimethylacetamide (5 mL) and then heated under microwave radiation at 180°C (300W, 200psi, 5 mins). This reaction was repeated in duplicate.
  • Step 1 Preparation of 2',3-difluoro-4'-methoxybiphenyl-2-carbonitrile
  • N,N- diisopropylethylamine 100 mg, 0.76 mmol, 2 equ
  • N-phenyl bis-trifluoromethane sulfonimide 207 mg, 0.58 mmol, 1.5 equ
  • the reaction mixture was then evaporated to dryness, and purified by flash chromatography (chloroform) to give the title compound as pale yellow solid (100 mg, 62% yield).
  • reaction mixture was concentrated in vacuo, dissolved in 95% DCM:MeOH and purified by flash column chromatography (gradient elution DCM:MeOH 98%-90%). The combined pure fractions were concentrated in vacuo, and dissolved in DCM:MeOH 90% (10 mL). This was stirred with silica bound trimethylammonium- mesylate (400 mg) for 2 h and filtered through Celite. The filtrate was evaporated to dryness to give the title compound as a yellow solid (39 mg, 0.0875 mmol, 36% yield).
  • a mixture 13-methyl-2-(trifluoromethylsulfonyloxy)chromeno[4,3,2-g/i]phenanthridin-13-ium trifluoromethanesulfonate (100 mg, 0.240 mmol; Example 4), tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.0240 mmol, 0.1 equ), potassium carbonate (67 mg, 0.480 mmol, 2 equ) and 3-furanyl boronic acid (54 mg, 0.480 mmol, 2 equ) in 1 :1 DME:H 2 0 (6 mL) was heated at 80°C under microwave irradiation (300 W, 300 psi) for 10 min.
  • the reaction mixture was concentrated in vacuo, dissolved in 95% DCM:MeOH and purified by flash column chromatography (gradient elution DCM:MeOH 98%-90%). The combined pure fractions were concentrated in vacuo, dissolved in DCM:MeOH 90% (10 mL) and stirred with silica bound trimethylammonium-mesylate (750 mg) for 2 h. The mixture was filtered through Celite and the filtrate was evaporated to dryness to give the title compound as a yellow solid (86 mg, 0.193 mmol, 80% yield).
  • reaction mixture was dissolved in DCM:MeOH 90% (8 mL) and purified by column chromatography (gradient elution DCM:MeOH 90%-80%). The combined pure fractions were concentrated in vacuo, dissolved in 90% DCM:MeOH (10 mL) and was stirred with silica bound trimethylammonium-mesylate (1.5 g) for 2 h. The mixture was filtered through Celite and the filtrate was evaporated to dryness in vacuo to give the title compound as a yellow solid (145 mg, 0.330 mmol, 91% yield).
  • 2-Bromo-5-nitroaniline (4.43 g, 20.4 mmol, 2 equ) was added portionwise to a stirring solution of xanthone (2.00 g, 10.2 mmol), 1.0 M titanium chloride in toluene (10.2 mL, 10.2 mmol, 1 equ) and N,N-diisopropylethylamine (13.2 g, 102 mmol, 10 equ) in toluene (300 mL). The mixture was refluxed under nitrogen for 2 h and 1.0 M titanium chloride in toluene (10.2 mL, 10.2 mmol, 1 equ) was added. The reaction mixture was refluxed under nitrogen for 16 h and was allowed to cool to room temperature.
  • Phthaloyl dichlonde (88 mg, 0.422 mmol, 1.5 equ) was added to a stirring solution of chromeno[4,3,2-g/z]phenanthridin-2-amine (80 mg, 0.282 mmol), pyridine (112 mg, 1.408 mmol, 5 equ) and N, N dimethylaminopyridine ( ⁇ 1 mg, catalytic amount) in dichloromethane (40 mL).
  • the reaction mixture was allowed to stir under nitrogen at room temperature for 10 min and then concentrated in vacuo.
  • the solid residue was triturated with 0.5 M HC1 (aq) (20 mL) and the resulting precipitate was collected by filtration.
  • Acetyl chloride (22 mg, 0.280 mmol, 6.3 equ) was added to a stirring solution of 2-amino-13- methylchromeno[4,3,2-g/z]phenanthridin-13-ium trifluoromethanesulfonate (20 mg, 0.0446 mmol) and pyridine (24 mg, 0.281 mmol, 6.3 equ) in dichloromethane (2 mL) for 1 h at room temperature.
  • the reaction mixture was evaporated to dryness in vacuo, dissolved in DCM/MeOH 90% (3 mL) and purified by flash column chromatography (gradient elution 90%- 85%).
  • Acetyl chloride (8 mg, 0.0983 mmol) was added to the mixture of 13-methyl-2- (methylamino)chromeno[4,3,2- z]phenanthridin-13-ium trifluoromethanesulfonate and 2- (dimethylamino)-13-methylchromeno[4,3,2-g z]phenanthridin-13-ium trifluoromethanesulfonate obtained above (21 mg) and pyridine (11 mg, 0.131 mmol) in dichloromethane (2 mL) and stirred under nitrogen at room temperature for 1 h.
  • reaction mixture was concentrated in vacuo and dissolved in DCM:MeOH 90% (5 mL) and purified by flash column chromatography (gradient elution DCM:MeOH 90%-86%) giving two separate product fractions.
  • the first combined pure fractions were concentrated in vacuo to give 13-mefhyl-2-(N- methylacetamido)chromeno[4,3,2-g/z]phenanthridin-13-ium 1/3 trifluoromethanesulfonate 2/3 acetate as a yellow solid (10 mg, 0.0198 mmol).
  • 2-acetamido- 13-methylchromeno[4,3,2-gA]phenanthridin- 13-ium methanesulfonate could be obtained by palladium catalysed cross-coupling of acetamide with 13-methyl-2-(trifluoromethylsulfonyloxy)chromeno[4,3,2- z]phenanthridin-13-ium
  • a second portion of caesium carbonate (14 mg, 0.240 mmol, 3 equ) was added and the mixture was heated at 80 °C under microwave irradiation (300 W, 300 psi) for 5 min.
  • the reaction mixture was filtered through Celite, evaporated to dryness in vacuo, dissolved in DCM:MeOH 95% (4 mL) and purified by flash column chromatography (gradient elution DCM:MeOH 95%-90%). The combined pure fractions were concentrated in vacuo and the resulting orange solid was then stirred in DCM:MeOH (90%, 20 ml) when polymer supported trialkylammonium mesylate resin (0.500 g) was added.
  • Acetyl chloride (4.6 ⁇ L, 0.0646 mmol, 1.5 equ) was added to a suspension of 2-amino-13- methylthiochromeno[4,3,2- z]phenanthridin-13-ium trifluoromethanesulfonate (20 mg, 0.04431 mmol) and N,N-Diisopropylethylamine (9 ⁇ L , 0.0517 mmol, 1.2 equ) in dichloromethane (1 mL) at 0°C and the mixture was stirred at 0°C for 45 min.
  • the mixture was basified at 0°C to pH 13 with 5N NaOH and a saturated solution of potassium sulfite was added.
  • the product was extracted with dichloromethane and the combined organic extracts were dried over magnesium sulfate then concentrated in vacuo.
  • the product was dissolved in dichloromethane and the solution was loaded on a short column packed with silica.
  • the product was eluted with DCM to give the title compound as a yellow/pale brown solid (75 mg, 69% yield).
  • Step 1 Preparation of 3, 6-dihydroxy-9H-xanthen-9-one (synthesized by modification of a procedure reported in Grover, P. K.; Shah, G. D.; Shah, R. C. /. Chem. Soc. 1955, 3982-3985)
  • a suspension of bis(2,4-dihydroxyphenyl)methanone (6 g, 24.4 mmol) in water was heated at 190°C for 48 hours.
  • the reaction mixture was cooled to room temperature and the resulting precipitate was filtered, washed with acetonitrile and diethyl ether to give the title compound as pale yellow solid (5.56 g, 100% yield).
  • Step 2 Preparation of 6,10-bis(2-hydroxyethoxy)-13-methylchromeno[4,3,2- gft]phenanthridin-13-ium bromide
  • the mixture was stirred at 100°C for 2 h and was allowed to cool to room temperature.
  • the mixture was diluted with N,N-dimethylformamide and filtered through a syringe filter.
  • the filtrate was concentrated in vacuo and the product was dissolved in DCM:MeOH.
  • the product was absorbed on silica and purified by flash chromatography (gradient elution DCM:MeOH 95%-90 -85%) to give the title compound as a yellow/orange solid (13 mg, 54% yield).
  • reaction mixture was quenched with methanol and filtered; the filtrate was concentrated to dryness and the solid residue was absorbed on silica and purified by flash chromatography (gradient elution DCM:MeOH 100%-95%) to give the title compound as a solid (13 mg, 45% yield).
  • Step 1 Preparati -difluoro-4-methoxyphenylboronic acid
  • Methyl iodide (1.56 mL, 25.1 mmol, 1.5 equ) was added dropwise to a suspension of 4-bromo- 2,3-difluorophenol (3.5 g, 16.7 mmol) and potassium carbonate (2.77 g, 20.0 mmol, 1.2 equ) in N,N-dimethylformamide (30 mL) and the mixture was stirred for 3 days. The precipitate was removed by filtration and the filtrate was concentrated to dryness in vacuo. Dichloromethane and water were added and the product was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give l-bromo-2,3- difluoro-4-methoxybenzene as a white crystalline solid (3.8 g, quantitative).
  • Nitrogen was bubbled through a suspension of 2-bromo-6-fhiorobenzonitrile (2.39 g, 12.0 mmol), 2,3-difluoro-4-methoxyphenylboronic acid (2.7 g, 14.4 mmol, 1.2 equ) and potassium fluoride (2.3 g, 39.6 mmol, 3.3 equ) in tetrahydrofuran (45 mL) for 10 min. before the addition of bis(tri-iert-butylphosphine)palladium (123 mg, 0.24 mmol, 0.02 equ). The mixture was immersed into a pre-heating oil bath at 55°C and the mixture was stirred at 55°C for 45 min.
  • reaction was quenched with acetic acid and 1M NaOH, followed by sat. NaHCC>3 were added.
  • the resulting bright yellow suspension was transferred into a separating funnel and the product was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate.
  • a reaction mixture from a separate experiment carried out on 85 mg scale was combined and the mixture was absorbed on silica.
  • the product was purified by flash chromatography (gradient elution CHCl 3 :Hexane 25%-50%-100% then DCM:MeOH 97.5%- 95%) to give the title compound as a yellow solid (565 mg, 50% yield).
  • the product could be only partially purified as some impurities co-eluted with the product during the purification by flash chromatography. The product was used without further purification in the next steps.
  • Step 5 Preparation of l,ll-difluoro-2-methoxy-13-methylchromeno[4,3,2- gA]phenanthridin-13-ium trifluoromethanesulfonate
  • Methyl triflate (98 iL, 0.895 mmol, 10 equ ) was added to a suspension of l,l l-difluoro-2- methoxychromeno[4,3,2-g/z]phenanthridine (30 mg, 0.0895 mmol) and potassium carbonate (124 mg, 0.895 mmol, 10 equ) in chloroform (3 mL) and the mixture was heated at 110°C m a sealed tube overnight. The mixture was cooled to room temperature and the reaction was quenched with methanol. The mixture was stirred for ⁇ 30min. and was filtered.
  • Step 1 Preparation of l,ll-difluorochromeno[4,3,2- ⁇ ]phenanthridin-2-yl
  • Step 2 Preparation of l,ll-difluoro-13-methyl-2-(lH-pyrazol-4-yl)chromeno[4,3,2- g/i]phenanthridin-13-ium trifluoromethanesulfonate
  • Methyl triflate (532 ⁇ , 4.85 mmol, 10 equ) was added to a suspension of 1,11- difluorochromeno[4,3,2-g3 ⁇ 4phenanthridin-2-yl trifluoromethanesulfonate (220 mg, 0.485 mmol) and potassium carbonate (670 mg, 4.85 mmol, 10 equ) in chloroform (5 mL) and the mixture was heated in a sealed tube at 100°C overnight. The mixture was cooled to room temperature and methanol was added. The precipitate was removed by filtration and the filtrate was absorbed on silica. The product was purified by flash chromatography (gradient elution DCM:MeOH 100%- 98%-97%-96%-92%) to give l,l l-difluoro-13-methyl-2-
  • the resulting solid was dissolved in DCMrMeOH, absorbed on silica and purified by flash chromatography (gradient elution DCMrMeOH 100%-98%-97%-96%-94%-92%-90%) to give 26 mg of an orange solid.
  • the material was triturated with 3N HCl, filtered, washed successively with water and diethyl ether, then dried under suction to give the title compound as an orange solid (15 mg, 24% yield).

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Abstract

La présente invention concerne de nouveaux composés de formule (I) dans laquelle: X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R21, R22 et R23 sont tels que définis dans la description. Les composés de formule (I) sont inhibiteurs de la fonction enzymatique de la télomérase et sont donc utiles pour le traitement de troubles de la prolifération cellulaire, tel que le cancer.
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US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US12404272B2 (en) 2020-11-06 2025-09-02 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor

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