WO2017001853A1 - Composés antiviraux - Google Patents

Composés antiviraux Download PDF

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Publication number
WO2017001853A1
WO2017001853A1 PCT/GB2016/051964 GB2016051964W WO2017001853A1 WO 2017001853 A1 WO2017001853 A1 WO 2017001853A1 GB 2016051964 W GB2016051964 W GB 2016051964W WO 2017001853 A1 WO2017001853 A1 WO 2017001853A1
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compound
alkyl
mmol
independently
heteroaryl
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PCT/GB2016/051964
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English (en)
Inventor
Richard GREENHOUGH
Jon FINLAYSON
Katie GIBSON
Adam BUNT
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Redx Pharma Plc
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Publication of WO2017001853A1 publication Critical patent/WO2017001853A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • This invention relates to a series of tricyclic compounds comprising a pteridinone core linked to a third heterocycloalkyl ring.
  • the compounds stimulate interferon-a (IFN-a) production useful in the treatment of Hepatitis B viral infections.
  • IFN-a interferon-a
  • the invention also relates to pharmaceutical compositions comprising these compounds and methods of using the compound in treatment.
  • HBV hepatitis B virus
  • CHB chronic hepatitis B
  • HCC liver cirrhosis and hepatocellular carcinoma
  • nucleoside/nucleotide analogues or interferon-a / pegylated interferon-a (IFN-a/peg IFN-a). Nucleoside/nucleotide analogues, can be effective at inhibiting viral replication, however not all patients respond and viral resistance is an emerging problem.
  • IFN-a/peg IFN-a is indicated in patients with a very high viral load (chronic active infection), and although IFN-a/peg IFN-a displays a higher rate of seroconversion compared to nucleo(s)tide analogues, they are poorly tolerated and carry a risk of adverse events.
  • TLRs Tolllike receptors
  • GS- 9620 The most advanced TLR agonist program in development for HBV is Gilead's GS- 9620, which is currently in Phase II trials as an oral treatment for HBV infection.
  • the drug has a reported high clearance rate.
  • Oral administration and gut absorption results in direct impact at the site of infection, the liver, and reduces the risk of potential side effects due to systemic IFN-a or cytokine production.
  • high inter-patient variability in uptake has been observed with GS-9620, which may be a result of its low permeability and because it is a potential substrate for efflux pumps within the gut.
  • Data also show that GS-9620 may induce tumour necrosis factor alpha (TNF-a) production from human PBMCs (Turnas et al.
  • TNF-a tumour necrosis factor alpha
  • -L 1 - is independently selected from: a bond, -0-, -NR 6 -, -C(O)-, -S(0) y - (where y is 0, 1 or 2), -C(0)0-, -OC(O)-, -C(0)NR 6 -, -NR 6 C(0)-, -S(0) 2 NR 6 - and -NR 6 S(0) 2 -;
  • X 1 , X 2 and X 3 are each independently selected from a bond, a carbon atom, a nitrogen atom, -O- and -S(0)y-(where y is 0, 1 or 2); provided that no more than two of X 1 , X 2 and X 3 are a bond and provided that no more than one of X 1 , X 2 and X 3 is selected from a nitrogen atom, -O- and -S(0)y-;
  • R 1 is independently selected from Ci-Cio-alkyl, Ci-Cio-haloalkyl, C2-Cio-alkenyl, C2-C10- alkynyl, C3-Cs-cycloalkyl, 4-12-heterocycloalkyl, aryl, heteroaryl and -d-Cs-alkylene-R 7 ; wherein R 7 is independently selected from C3-Cs-cycloalkyl, 4-12-heterocycloalkyl, aryl and heteroaryl, -0-Ci-C 4 alkyl, -S-Ci-C 4 alkyl and -NR 6 Ci-C 4 -alkyl;
  • R 2 and R 9 are each independently at each occurrence selected from: H , Ci-C4-alkyl, -C(O)- Ci-C 4 -alkyl and -S(0) 2 -Ci-C 4 -alkyl;
  • R 3 , R 6 , R 8 and R 11 are each independently at each occurrence selected from: H and C1-C4 -alkyl;
  • -L 4 - is independently selected from: -(CR 10 R 10 ) r - (where r is 1 , 2 or 3), aryl, heteroaryl, C3- Cs-cycloalkyl, 4-i 2 -heterocycloalkyl;
  • -L 5 - is independently selected from: a bond, -0-, -S-, -NR 6 -, -C(O)-, -S(0) 2 -, -C(0)0-, - OC(O)-, -C(0)NR 6 -, -NR 6 C(0)-, -S(0) 2 NR 6 - and -NR 6 S(0) 2 -;
  • R 5 is independently selected from: H, Ci-C6-alkyl, C 2 -C6-alkenyl, C 2 -C6-alkynyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, 4 -i 2 -heterocycloalkyl, Ci-C 6 -haloalkyl and -(CR 10 R 10 ) S -NR 11 R 12 (where s is 0, 1 , 2 or 3); wherein when -L 2 -, -L 3 - and -L 4 - are selected such that R 5 is directly attached to a nitrogen or oxygen atom, R 5 is not attached to the rest of the molecule through a nitrogen atom;
  • R 10 is independently at each occurrence selected from: H, F and Ci-C 4 -alkyl;
  • R 12 is independently selected from H, Ci-C6-alkyl, C 2 -C6-alkenyl, C 2 -C6-alkynyl, aryl, heteroaryl, C3-Cs-cycloalkyl, 4 -i 2 -heterocycloalkyl, -d-Cs-alkylene-R 13 ; wherein R 13 is independently selected from C3-Cs-cycloalkyl, 4 -i 2 -heterocycloalkyl, aryl and heteroaryl; or R 11 and R 12 together with the nitrogen to which they are attached form a 4 -i 2 heterocycloalkyi group;
  • x is an integer selected from 0, 1 , 2, 3 and 4;
  • any aryl, heteroaryl or heterocycloalkyi group may be monocyclic- or bicyclic; where a heterocycloalkyi group is bicyclic it comprises a 4-, 5-, 6- or 7-membered heterocycloalkyi ring fused to a ring selected from phenyl, 5- or 6- membered heteroaryl, C3-Cs-cycloalkyl, 4-, 5-, 6- or 7-membered heterocycloalkyi ring;
  • R 4 and -L 2 - may be attached to any position, where chemically possible, on the 5-, 6- or 7-membered ring that comprises X 1 , X 2 and X 3 .
  • X 1 , X 2 or X 3 is a carbon atom or a nitrogen atom
  • that carbon atom or a nitrogen atom may be the point of attachment of one or more R 4 groups and/or -L 2 -. Otherwise, that carbon atom or nitrogen atom is attached to two or one hydrogen atoms respectively.
  • the compound of formula (I) is a compound of formula (II):
  • R 1 , R 4 , R 5 , -L 1 -, -L 2 -, -L 3 -, X 3 and x are as described above for formula (I).
  • the compound of formula (I) is a compound of formula (III):
  • R 1 , R 4 , R 10 , R 11 , R 12 , -L 1 -, -L 3 -, s and x are as described above for formula (I); wherein -L 2 - is independently selected from -C(O)- and -S(0)2-.
  • the compound of formula (I) is a compound of formula (IV):
  • R 10 S NR 11 R 12 (IV) wherein R 1 , R 4 , R 10 , R 1 1 , R 12 , -L 5 -, x and s are as described above for formula (I); wherein - L 2 - is independently selected from -C(O)- and -S(0)2-; and wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are each carbon or nitrogen; wherein no more than two of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are nitrogen; R 14 is independently at each occurrence selected from the group consisting of: halo, nitro, cyano, NR a R a , NR a S(0) 2 R a , NR a C(0)R a , NR a CONR a R a , NR a C0 2 R a , OR a , SR a , S(0)R a , S(0) 2 OR a , S(0) 2 R a
  • the compound of formula (I) is a compound of formula (V):
  • R 10 R 10 S NR 11 R 12 (V) wherein R 1 , R 4 , R 10 , R 1 1 , R 12 , -L 5 -, x and s are as described above for formula (I); wherein - L 2 - is independently selected from -C(O)- and -S(0) 2 -; and wherein Z 1 , Z 2 , Z 4 , Z 5 , R 14 and a are as described above for formula (IV).
  • the compound of formula (I) is a compound of formula (VI):
  • R 1 , R 4 , R 10 , R 11 , R 12 , x and s are as described above for formula (I); wherein -L 2 - is independently selected from -C(O)- and -S(0) 2 -; and wherein R 14 and a are as described above for formula (IV).
  • the compound of formula (I) is a compound of formula (VII): wherein R 1 , R 4 , R 10 , R 11 , R 12 , s and x are as described above for formula (I); wherein -L 2 - is independently selected from -C(O)- and -S(0)2-.
  • R 2 and R 3 are H.
  • R 2 and R 3 are each H.
  • -L 1 - may be selected from -0-, -NR 6 - and -S-. Preferably, -L 1 - is -0-.
  • R 1 is independently selected from Ci-Cio-alkyl, C2-Cio-alkenyl, C2- Cio-alkynyl. It may be that the groups of which R 1 is comprised are unsubstituted. Preferably, R 1 is unsubstituted Ci-Cio-alkyl. Thus, R 1 may be unsubstituted C2-C8 alkyl. R 1 may be unsubstituted C3-C5 alkyl . In certain specific embodiments, R 1 is n-butyl.
  • R 1 may be -Ci-C 5 -alkylene-0-Ci-C 4 alkyl.
  • X 3 is selected from a carbon atom and a nitrogen atom. It may be that X 3 is carbon. In certain preferred embodiments, X 3 is nitrogen.
  • X 2 is a bond. In certain preferred embodiments, X 2 is carbon.
  • X 1 is a bond. In certain preferred embodiments, X 1 is carbon.
  • X 1 , X 2 and X 3 are a bond.
  • the ring comprising X 1 , X 2 and X 3 is therefore preferably a 7-membered ring.
  • R 4 may at each occurrence be selected from Ci-C6-alkyl, e.g. methyl.
  • x is 0.
  • x is 2. Where x is 2, it may be that both R 4 groups are attached to the same carbon atom. R 4 may at both occurrences be selected from Ci-C6-alkyl, e.g. methyl. In these embodiments, it may be that X 1 is a carbon atom and both R 4 groups are attached to X 1 .
  • -L 2 -, -L 3 - and R 5 are selected such that -L 2 -L 3 -R 5 comprises at least one (e.g. a single) nitrogen atom.
  • -L 2 -, -L 3 - and R 5 are selected such that -L 2 - L 3 -R 5 comprises at least one (e.g. a single) tertiary amine.
  • -L 2 -L 3 -R 5 is preferably attached to the rest of the molecule at X 3 .
  • X 3 will be selected from a carbon atom and a nitrogen atom.
  • -L 2 - may be selected from -C(O)- or -S(0)2-.
  • -L 2 - may however be -(CR 10 R 10 ) Z - (e.g. -CR 10 CR 10 or -CH 2 -).
  • -L 2 - is -C(O)-.
  • -L 3 - may be a bond. It may be that -L 3 - is a bond and R 5 is -(CR 10 R 10 ) S -N R 1 1 R 12 . In these embodiments, it may be that s is selected from 1 , 2 and 3. It may be that -L 2 - is selected from -C(O)- or -S(0)2-, that -L 3 - is a bond and s is selected from 1 , 2 and 3. In these embodiments, it may be that s is 1 or it may be that s is 2.
  • -L 3 - may be -L 4 -L 5 -.
  • -L 4 - may be independently selected from: -(CR 10 R 10 ) r - (where r is 1 , 2 or 3), aryl, heteroaryl, C3-Cs-cycloalkyl, 4-12-heterocycloalkyl.
  • -L 4 - may be independently selected from aryl, heteroaryl, C3-Cs-cycloalkyl, 4-12-heterocycloalkyl.
  • -L 4 - may be independently selected from aryl and heteroaryl, e.g. -L 4 - may be selected from phenyl and 6-membered heteroaryl.
  • -L 4 - is phenyl.
  • -L 4 - is 6-membered heteroaryl, e.g. a pyridinyl.
  • -L 5 - may be independently selected from: a bond, -0-, -S-, -N R 6 -, -C(O)- and - S(0)2-.
  • -L 5 - may be independently selected from: a bond, -0-, -S- and -N R 6 -.
  • -L 5 - may be independently selected from -C(O)- and -S(0)2-.
  • -L 5 - is a bond.
  • -L 5 - is -0-.
  • -L 4 - is independently selected from aryl and heteroaryl
  • -L 5 - is independently selected from: a bond, -0-, -S- and -N R 6 - and R 5 is -(CR 10 R 10 ) S -N R 1 1 R 1 2 .
  • s is selected from 1 , 2 and 3.
  • L 2 is selected from -C(O)- or -S(0) 2 -.
  • -L 3 -R 5 may be:
  • Z 2 , Z 3 , Z 4 and Z 5 are each carbon or nitrogen; wherein no more than two of Z Z 2 , Z 3 , Z 4 and Z 5 are nitrogen;
  • R 14 is independently at each occurrence selected from the group consisting of: halo, nitro, cyano, NR a R a , NR a S(0)2R a , NR a C(0)R a , NR a CONR a R a , NR a C0 2 R a , OR a , SR a , S(0)R a , S(0) 2 OR a , S(0) 2 R a , S(0) 2 NR a R a , C0 2 R a , C(0)R a , CONR a R a , Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl and Ci- -haloalkyl; and a is an integer selected from
  • Z 2 , Z 3 , Z 4 and Z 5 are each carbon.
  • -L 3 -R 5 may be:
  • . -L 5 - may be a bond, a may be 0.
  • R 5 is not H.
  • R 5 may be independently selected from: Ci-ds- alkyl, C 2 -C6-alkenyl, C 2 -C6-alkynyl, aryl, heteroaryl, d-Cs-cycloalkyl, 4 -i 2 -heterocycloalkyl, d-Ce-haloalkyl and -(CR 10 R 10 ) S -NR 1 1 R 12 (where s is 0, 1 , 2 or 3);
  • R 5 is selected such that R 5 comprises at least one (e.g. a single) nitrogen atom.
  • R 5 is selected such that R 5 comprises at least one (e.g. a single) tertiary amine.
  • R 5 is -(CR 10 R 10 ) S -NR 1 1 R 12 .
  • s may be selected from 1 , 2 and 3. Thus, it may be that s is selected from 1 and 2.
  • R 1 1 may be Ci-C -alkyl.
  • R 12 may be selected from d-Ce-alkyl, C 2 -C 6 -alkenyl, C 2 - C6-alkynyl, aryl, heteroaryl, d-Cs-cycloalkyl, 4 -i 2 -heterocycloalkyl, -d-Cs-alkylene-R 13 .
  • R 1 1 is Ci-C 4 -alkyl
  • R 12 is selected from Ci-C6-alkyl d-d-alkenyl, C 2 -C6-alkynyl, aryl, heteroaryl, d-Cs-cycloalkyl, 4 -i 2 -heterocycloalkyl, -d-d-alkylene-R 13 ; or that R 11 and R 12 together with the nitrogen to which they are attached form a 4-12 heterocycloalkyi group which may be monocyclic- or bicyclic; where a heterocycloalkyi group is bicyclic it comprises a 4-, 5-, 6- or 7-membered heterocycloalkyi ring fused to a ring selected from phenyl, 5-or 6- membered heteroaryl, C3-C8 cycloalkyl, 4-, 5-, 6- or 7- membered heterocycloalkyi ring.
  • R 5 is -(CR 10 R 10 ) S -NR 11 R 12 it may be that R 11 and R 12 together with the nitrogen to which they are attached form a 4-12 heterocycloalkyi group which may be monocyclic- or bicyclic; where a heterocycloalkyi group is bicyclic it comprises a 4-, 5-, 6- or 7-membered heterocycloalkyi ring fused to a ring selected from phenyl, 5-or 6- membered heteroaryl, C3-C8 cycloalkyl, 4-, 5-, 6- or 7-membered heterocycloalkyi ring. It may be that R 11 and R 12 together with the nitrogen to which they are attached form a pyrrolidine ring which optionally forms part of a bicyclic heterocycloalkyi group.
  • Exemplary NR 11 R 12 groups include:
  • R 5 may be selected from heteroaryl or 4-12-heterocycloalkyl, wherein the heteroaryl group or heterocycloalkyi group comprise at least one ring nitrogen.
  • R 5 may be imidazole, pyrrole or pyrazole, e.g. pyrazol-2-yl.
  • R 5 is a heterocycloalkyi group comprising a heterocycloalkyi ring and a phenyl ring, it may be that the group is attached
  • R 5 may also be In these embodiments, it may be that -L 3 - is a bond. It may also be that -L 2 - is selected from C(O)- and -S(0) 2 -.
  • Exemplary -L 2 -L 3 -R 5 groups include: 11
  • C m -C n refers to a group with m to n carbon atoms.
  • alkyl refers to a monovalent linear or branched hydrocarbon chain.
  • Ci-C6-alkyl may refer to methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, sec-butyl, te/f-butyl, n-pentyl and n-hexyl.
  • the alkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkyl group independently may be fluorine, OR a or NHR a .
  • alkylene refers to a bivalent linear hydrocarbon chain.
  • Ci-C3-alkylene may mean a methylene group (-CH2-), an ethylene group (-CH2CH2-) or a propylene group.
  • the alkylene groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkylene group independently may be C1-C4 alkyl, oxo or fluorine.
  • haloalkyl refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence from: fluorine, chlorine, bromine and iodine.
  • the halogen atom may be present at any position on the hydrocarbon chain.
  • Ci-C6-haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1 -chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.
  • a halo alkyl group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at least one halogen atom.
  • alkenyl refers to a branched or linear hydrocarbon chain containing at least one double bond.
  • the double bond(s) may be present as the E or Z isomer.
  • the double bond may be at any possible position of the hydrocarbon chain.
  • C2- C6-alkenyl may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
  • the alkenyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkenyl group independently may be fluorine, OR a or NHR a .
  • alkynyl refers to a branched or linear hydrocarbon chain containing at least one triple bond.
  • the triple bond may be at any possible position of the hydrocarbon chain.
  • C2-C6-alkynyl may refer to ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • the alkynyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkynyl group independently may be fluorine, OR a or NHR a .
  • cycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms.
  • C3-C6-cycloalkyl may refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • the cycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each cycloalkyl group independently may be Ci-C4-alkyl, oxo, fluorine, OR a or NHR a .
  • aromatic when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated ⁇ system within the ring or ring system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • aryl refers to an aromatic hydrocarbon ring system.
  • the ring system has 4n +2 electrons in a conjugated ⁇ system within a ring where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the "aryl” may be phenyl and naphthyl.
  • the aryl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each aryl group independently may be Ci-C4-alkyl, Ci-C4-haloalkyl, cyano, halogen, OR a or NHR a .
  • heteroaryl may refer to any aromatic (i.e. a ring system containing (4n + 2) TT- electrons or n- electrons in the ⁇ -system) 5-10 membered ring system comprising from 1 to 4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring system are selected from O, S and N).
  • any heteroaryl groups may be independently selected from: 5 membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-4 heteroatoms independently selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 (e.g.1-2) nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 heteroatoms independently selected from O, S and N; 10-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 nitrogen atoms.
  • heteroaryl groups may be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole; pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine.
  • Heteroaryl groups may also be 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1 heteroatomic group independently selected from O, S and NH and the ring also comprises a carbonyl group. Such groups include pyridones and pyranones.
  • the heteroaryl system itself may be substituted with other groups.
  • the heteroaryl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each heteroaryl group independently may be C1-C4- alkyl, Ci-C4-haloalkyl, cyano, halogen, OR a or NHR a .
  • m -nheterocycloalkyl refers to a m to n membered monocyclic or bicyclic saturated or partially saturated group comprising 1 or 2 heteroatoms independently selected from O, S and N in the ring system (in other words 1 or 2 of the atoms forming the ring system are selected from O, S and N).
  • a Vi2heterocycloalkyl is a 4 to 12 membered monocyclic or bicyclic saturated or partially saturated group comprising 1 or 2 heteroatoms independently selected from O, S and N in the ring system (in other words 1 or 2 of the atoms forming the ring system are selected from O, S and N).
  • the ring may comprise one or two double bonds. This applies particularly to monocyclic rings with from 5 to 8 members.
  • the double bond will typically be between two carbon atoms but may be between a carbon atom and a nitrogen atom.
  • heterocycloalkyl groups include; piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, azepine.
  • Bicyclic systems may be spiro-fused, i.e.
  • heterocycloalkyl groups may be unsubstituted or substituted by one or more substituents.
  • Specific substituents for any saturated carbon atom in each heterocycloalkyl group may independently be Ci-C4-alkyl, oxo, fluorine, OR a or NHR a .
  • the compound of formula (I) is an N-oxide
  • it will typically be a pyridine N- oxide, i.e. where the compound of formula (I) comprises a pyridine ring, the nitrogen of that pyridine may be N + -0 " .
  • the compound of the invention is not an N-oxide.
  • tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety.
  • racemate or a racemic precursor
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1- phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1- phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted into the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine.
  • racemic compound true racemate
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, 1994).
  • the present invention also includes the synthesis of all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (VII) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Certain isotopically-labelled compounds for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
  • the compounds of the invention promote IFN-a production and will therefore be useful in the treatment of any indication which can be treated by stimulation of IFN-a. Stimulation of IFN-a boosts the immune system. It can be used to treat viral infections.
  • the compounds of the invention are particularly useful in the treatment of Hepatitis B viral infections.
  • a compound for use in the preparation of a medicament may be for use in the treatment of any of the diseases, infections and indications mentioned in this specification.
  • a compound of the invention for medical use.
  • the compound may be used in the treatment of any of the diseases, infections and indications mentioned in this specification.
  • a method of treating a disease in a subject in need thereof comprises administering a therapeutic amount of a compound of the invention to a subject in need thereof.
  • the invention provides a method of promoting IFN-a production in a subject in need thereof, the method comprising administering a therapeutic amount of a compound of the invention.
  • the invention also provides a method of boosting the immune system in a subject in need thereof, the method comprising administering a therapeutic amount of a compound of the invention.
  • a pharmaceutical formulation comprising a compound of the invention and at least one pharmaceutically acceptable excipient.
  • the compounds of the invention can be used to treat viral infections.
  • Illustrative viral infections include: HIV, Hepatitis B, Hepatitis C, herpes, norovirus, Epstein-Barr, chicken pox, smallpox, dengue fever, viral meningitis, cytomegalovirus, monkeypox, vaccinia, Ebola, Newcastle disease virus, Sendai virus, influenza, vesicular stomatis virus, west nile virus, herpes simplex viruses 1 and 2 and rotavirus.
  • the compounds of the invention are particularly useful in the treatment of Hepatitis B infections.
  • the compounds of the invention can be used to treat cancer.
  • IFN-a is used to treat cancer of the kidney, malignant melanoma, multiple myeloma, carcinoid tumours, lymphoma and leukaemia.
  • IFN-a has been around for many years, we still do not know how it exerts its anticancer effects.
  • IFN-a modulates gene expression, promotes cell differentiation and apoptosis, directly inhibits cell growth and proliferation, restores regulation by the bone marrow microenvironment and induces an immunomodulatory response.
  • Microarray analyses have shown that IFN-a IFN-a can induce expression of over 300 different genes.
  • apoptotic proteins i.e., TRAIL, Fas, caspase-4, caspase-8 and XAF-1
  • anti-viral proteins that is, PKR, 20 50 A oligoadenylate synthetase and Mx proteins
  • immunomodulatory proteins that is, MHC I and II, LMP-2 and C1 inhibitor
  • host defense proteins that is, PKR, IRF 1- 9, interleukin- 15 and interleukin-6
  • transcription factors that is, signal transducer and activator of transcription 1 , signal transducer and activator of transcription 2, ISGF3-g and IRF1-7.
  • IFN-a directly targets key regulators of the cell cycle, including retinoblastoma protein, cdc25A, cyclins (cyclin D3, cyclin E and cyclin A) and cyclindependent kinases (cdk4 and cdk6).
  • retinoblastoma protein cdc25A
  • cyclins cyclin D3, cyclin E and cyclin A
  • cyclindependent kinases cdk4 and cdk6
  • the compounds of the invention have been shown to stimulate IFN-a production and it would thus be expected that they could be used in the treatment of cancer.
  • the compounds of the invention may be useful in treatment of allergic diseases. Allergies are the result of aberrant immune reactivity to innocuous environmental proteins (allergens).
  • a pivotal component of allergic pathogenesis is the generation of effector Type 2 helper T (Th2) cells, which secrete cytokines that drive the synthesis of allergen- specific Immunoglobulin E and activation of pro-inflammatory cells, leading to manifestation of symptoms.
  • Th2 Type 2 helper T
  • Most current therapies for allergic diseases alleviate symptoms by reducing either the activity of mediators of the allergic cascade or the degree of local inflammation. Though beneficial, this approach does not alter the underlying allergic immune pathology and therefore does not promote long-term disease remission.
  • Th1 helper T Type 1 helper T
  • IFNs interferons [IFNs] and interleukin [IL]-12
  • TLRs toll-like receptors
  • the compounds of the invention may be obtained, stored and/or administered in the form of a pharmaceutically acceptable salt.
  • suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, toluenesulfonic, benzenesulfonic, salicylic, sulfanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids
  • Suitable base salts are formed from bases which form nontoxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.
  • Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous.
  • compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • a compound of the invention, or pharmaceutically acceptable salt thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the compounds of the invention may be administered in combination with other active compounds (e.g. antifungal compounds, oncology compounds, antibacterial compounds, other modulators of the immune system) and, in particular, with antiviral compounds.
  • active compounds e.g. antifungal compounds, oncology compounds, antibacterial compounds, other modulators of the immune system
  • antiviral compounds e.g. antifungal compounds, oncology compounds, antibacterial compounds, other modulators of the immune system
  • the compound of the invention and the other active may be administered in different pharmaceutical formulations either simultaneously or sequentially with the other active. Alternatively, the compound of the invention and the other active may form part of the same pharmaceutical formulation.
  • the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.
  • compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders, suspensions, solutions or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories; or by inhalation (i.e. in the form of an aerosol or by nebulisation).
  • the compounds of the invention will be administered orally.
  • the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in the art.
  • the compounds of the invention may be administered as a sterile aqueous or oily solution.
  • the size of the dose for therapeutic purposes of compounds 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.
  • Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient.
  • the standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.
  • Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein.
  • NMR spectra were obtained on a LC Bruker AV400 using a 5 mm QNP probe (Method A) or Bruker AVIII 400 Nanobay using a 5 mm BBFQ with z-gradients (Method B).
  • MS was carried out on a Waters Alliance ZQ MS (Methods A, B, D, E, F and G) or Acquity UPLC-SQD2#LCA081 (Method C) using H 2 0 and CH 3 CN mobile phase with pH modification as detailed under each method. Wavelengths were 254 and 210 nM.
  • Preparative HPLC was performed using column: XBridgeTM prep C18 5 ⁇ OBD 19 mm. Flow rate: 20 mL/min.
  • reaction was quenched by addition of saturated aqueous solution of NaHCC>3 (50 ml_).
  • the phases were separated and the aqueous phase extracted with DCM (2 x 50 ml_).
  • the combined organic phases were dried over MgSCU and the solvent removed in vacuo.
  • the reaction was quenched by addition of a saturated aqueous solution of NaHCC>3 (50 mL).
  • the phases were separated and the aqueous phase extracted with DCM (2 x 50 mL).
  • the combined organic phases were dried over MgS0 4 and the solvent removed in vacuo.
  • 6-[2-(Pyrrolidin-1-yl)ethoxy]pyridine-3-carboxylic acid XE To a solution of 6-[2-(pyrrolidin-1-yl)ethoxy]pyridine-3-carbonitrile (0.18 g, 0.85 mmol) XD in EtOH:water (2 ml_:12 mL) was added NaOH (0.53 mL, 8.50 mmol) and the resultant solution was heated at reflux for 6 h. The reaction mixture was cooled to room temperature then EtOH was removed in vacuo. The remaining solution was acidified to pH 8 using aqueous HCI (1 M) and the solution was concentrated in vacuo to a white salt.
  • reaction mixture was diluted with DCM (50 mL), washed with saturated NaHCC solution (50 mL), water (50 mL) and brine (50 mL), dried over MgSCU and concentrated in vacuo.
  • the resulting residue was purified by flash column chromatography eluting with 10% MeOH in DCM to provide ethyl 1-(6-amino-2-butoxy-5-nitropyrimidin-4-yl)-4-(2- ⁇ 3-azabicyclo[3.1.0]hexan-3-yl ⁇ acetyl)-1 ,4- diazepane-2-carboxylate (72 mg, 68%) as a yellow solid; LC-MS (Method F) 506.6 [MH + ]; 3.04 RT min.
  • reaction was quenched by addition of a saturated aqueous solution of NH4CI (50 ml_).
  • the phases were separated and the aqueous phase extracted with DCM (2 x 40 ml_).
  • the combined organic phases were dried over MgS0 4 and the solvent removed in vacuo.
  • Assays were performed to investigate cytokine production from human peripheral blood mononuclear cells (PBMCs) after being stimulated for 24 hours with compounds of the present invention.
  • PBMCs peripheral blood mononuclear cells
  • Cryo-preserved human PBMCs were thawed and seeded in 96 well plates at 5 x 10 5 cells/well in 225 ⁇ _ RPMI 1640 media (supplemented with 0.5% foetal bovine serum, 2 mM sodium pyruvate and 2 mM Glutamax). The cells were then incubated for 1 h at 37°C and 5% CO2, following which 25 ⁇ _ of compound was added.
  • the supernatant was assayed for interferon alpha (IFN-a) and tumour necrosis factor alpha (TNF-a) in two separate ELISAs.
  • MabTech's pan IFN-a kit was used to determine IFN-a levels. The kit will detect native and recombinant human IFN-a subtypes 1/13, 2, 4, 5, 6, 7, 8, 10, 14, 16 and 17. The assay was carried out following manufacturer's instructions. In brief, in a 96 well plate 100 ⁇ _ ⁇ / ⁇ of capture antibody was added and incubated overnight at 4°C. After washing 2 x with PBS, the plate was blocked with 200 ⁇ _ incubation buffer for 1 h at room temperature.
  • PBS-T PBS containing 0.05% Tween20
  • 100 ⁇ _ standard or sample was added for 2 h at room temperature.
  • the PBS-T wash step was then repeated and 100 ⁇ _ ⁇ / ⁇ of detection antibody was added for 1 h at room temperature.
  • the PBS-T wash step was repeated, followed by the addition of 100 ⁇ _ ⁇ / ⁇ of Streptavidin-HRP.
  • 100 ⁇ _ ⁇ / ⁇ of TMB substrate solution was added, then stopped after a suitable development time using 100 ⁇ _ ⁇ / ⁇ of 0.5 M HCI and the optical density was read at 450 nM.
  • the human TNF-a ELISA Ready-SET-Go! kit from eBioscience was used for TNF-a determination.
  • the assay was carried out following manufacturer's instructions. In brief, in a 96 well plate 100 ⁇ _ ⁇ / ⁇ of capture antibody was added and incubated overnight at 4°C. After washing 5 x with wash buffer, the plate was blocked with 200 ⁇ _ assay diluent for 1 h at room temperature. After washing 5 x with wash buffer, 100 ⁇ _ standard or sample was added for 2 h at room temperature. The wash step was then repeated and 100 ⁇ _ ⁇ / ⁇ of detection antibody was added for 1 h at room temperature. Again, the wash step was repeated, followed by the addition of 100 ⁇ _ ⁇ / ⁇ of Avidin-HRP. After a final wash 100 ⁇ _ ⁇ / ⁇ of substrate solution was added, then stopped after a suitable development time using 50 ⁇ _ ⁇ / ⁇ of 0.5 M HCI and the optical density was read at 450 nM.
  • MEC minimum effective concentration
  • Table 1 A denotes an MEC of between 0.0001 and 1 ; B denotes an MEC of between 1 and 10 and C denotes an MEC of greater than 10. Grey shading indicates the cytokine level has not been determined.
  • IFN-a stimulators Many of the compounds of the invention have been shown to be effective as IFN-a stimulators. Many of the compounds that are effective as IFN-a stimulators are considerably less effective as stimulators of TNF-a, in contrast to GS-9620.
  • the passive permeability of the compounds of the present invention was determined using confluent MDR1-MDCKII cells growing on 24 well plates with transwell inserts.
  • Donor solutions Hank's balanced salt solution [HBSS] with 10 mM HEPES, 10 ⁇ compound and 100 ⁇ Lucifer yellow
  • receiver solution HBSS buffer with 10 mM HEPES and 0.1 % DMSO
  • HBSS buffer with 10 mM HEPES and 0.1 % DMSO
  • TEER transepithelial electrical resistance
  • MDCK permeability - A denotes a permeability of between 2 x 10 "6 and 5 x 10 "6 cm/sec; B denotes a permeability of between 0.5 x 10 "6 and 2 x 10 "6 cm/sec .and C denotes a permeability of between 0.01 x 10 "6 and 0.5 x 10 "6 cm/sec; MDCK efflux ratio - A denotes a ratio of less than 5; B denotes a ratio of between 5 and 25; and C denotes a ratio of greater than 25.

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Abstract

Cette invention se rapporte à une série de composés tricycliques comprenant un noyau ptéridinone lié à un troisième anneau hétérocycloalkyle. Les composés sont utiles dans le traitement des infections virales par le virus de l'hépatite C. La présente invention concerne également des compositions pharmaceutiques contenant les composés, ainsi que des méthodes d'utilisation des composés dans le traitement.
PCT/GB2016/051964 2015-06-30 2016-06-30 Composés antiviraux WO2017001853A1 (fr)

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