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WO2025133338A1 - Dérivés de quinolone contre le cancer - Google Patents

Dérivés de quinolone contre le cancer Download PDF

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Publication number
WO2025133338A1
WO2025133338A1 PCT/EP2024/088233 EP2024088233W WO2025133338A1 WO 2025133338 A1 WO2025133338 A1 WO 2025133338A1 EP 2024088233 W EP2024088233 W EP 2024088233W WO 2025133338 A1 WO2025133338 A1 WO 2025133338A1
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group
hydrocarbyl group
independently selected
optionally
groups
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English (en)
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Paul Meo
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Genome Therapeutics Ltd
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Genome Therapeutics Ltd
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Priority claimed from GBGB2319820.3A external-priority patent/GB202319820D0/en
Priority claimed from GBGB2417508.5A external-priority patent/GB202417508D0/en
Application filed by Genome Therapeutics Ltd filed Critical Genome Therapeutics Ltd
Publication of WO2025133338A1 publication Critical patent/WO2025133338A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the present invention relates to fused tetracyclic heteroaromatic compounds and antibody-drug conjugates (ADCs) comprising the compounds.
  • ADCs antibody-drug conjugates
  • the present invention also relates to processes for the preparation of the compounds and ADCs, and to pharmaceutical compositions containing them and their use in therapy, particularly for use in treating cancers.
  • Background of the Invention Small molecules have a long history of use in cancer chemotherapy (e.g. cisplatin family and anthracyclines). 1
  • CX-5461 entered clinical trials for solid tumours with HR-deficiency mutations (NCT02719977) 2 .
  • the molecule was overall well tolerated, but displayed dose-limiting phototoxicity.
  • each of the four rings in the fused tetracyclic ring system of Formula (I) is aromatic.
  • X 1 , X 2 , X 3 , X 4 , A 1 , A 2 , A 3 , A 4 , A 5 , A 6 and Q 1 are selected such that each ring of the fused tetracyclic ring system of Formula (I) is aromatic.
  • a “hydrocarbyl” substituent group or a hydrocarbyl moiety in a substituent group only includes carbon and hydrogen atoms but, unless stated otherwise, does not include any heteroatoms, such as N, O or S, in its carbon skeleton.
  • a hydrocarbyl group/moiety may be saturated or unsaturated (including aromatic), and may be straight-chained or branched, or be or include cyclic groups wherein, unless stated otherwise, the cyclic group does not include any heteroatoms, such as N, O or S, in its carbon skeleton.
  • hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups/moieties and combinations of all of these groups/moieties.
  • a hydrocarbyl group is a C1-C20 hydrocarbyl group. More typically a hydrocarbyl group is a C1-C15 hydrocarbyl group.
  • hydrocarbyl group is a C1-C10 hydrocarbyl group.
  • a “hydrocarbylene” group is similarly defined as a divalent hydrocarbyl group.
  • An “alkyl” substituent group or an alkyl moiety in a substituent group may be linear (i.e. straight-chained) or branched. Examples of alkyl groups/moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and n-pentyl groups/moieties. Unless stated otherwise, the term “alkyl” does not include “cycloalkyl”.
  • an alkyl group is a C1-C12 alkyl group. More typically an alkyl group is a C1-C6 alkyl group.
  • An “alkylene” group is similarly defined as a divalent alkyl group.
  • An “alkenyl” substituent group or an alkenyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon double bonds.
  • alkenyl groups/moieties examples include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1,4- hexadienyl groups/moieties.
  • alkenyl does not include “cycloalkenyl”.
  • an alkenyl group is a C2-C12 alkenyl group. More typically an alkenyl group is a C2-C6 alkenyl group.
  • An “alkenylene” group is similarly defined as a divalent alkenyl group.
  • alkynyl substituent group or an alkynyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon triple bonds.
  • alkynyl groups/moieties include ethynyl, propargyl, but-1-ynyl and but-2- ynyl groups/moieties.
  • an alkynyl group is a C2-C12 alkynyl group. More typically an alkynyl group is a C2-C6 alkynyl group.
  • An “alkynylene” group is similarly defined as a divalent alkynyl group.
  • a “cyclic” substituent group or a cyclic moiety in a substituent group refers to any hydrocarbyl ring, wherein the hydrocarbyl ring may be saturated or unsaturated (including aromatic) and may include one or more heteroatoms, e.g. N, O or S, in its carbon skeleton.
  • Examples of cyclic groups include cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl groups as discussed below.
  • a cyclic group may be monocyclic, bicyclic (e.g. bridged, fused or spiro), or polycyclic.
  • a cyclic group is a 3- to 12-membered cyclic group, which means it contains from 3 to 12 ring atoms.
  • a cyclic group is a 3- to 7-membered monocyclic group, which means it contains from 3 to 7 ring atoms.
  • a bicyclic or polycyclic group is “saturated” it is to be understood that all of the ring systems within the bicyclic or polycyclic group (excluding any ring systems which are part of or formed by optional substituents) are saturated.
  • a “heterocyclic” substituent group or a heterocyclic moiety in a substituent group refers to a cyclic group or moiety including one or more carbon atoms and one or more (such as one, two, three or four) heteroatoms, e.g. N, O or S, in the ring structure.
  • heterocyclic groups include heteroaryl groups as discussed below and non-aromatic heterocyclic groups such as azetinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl and thiomorpholinyl groups.
  • non-aromatic heterocyclic groups such as azetinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazo
  • a “cycloalkyl” substituent group or a cycloalkyl moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless stated otherwise, a cycloalkyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
  • a “cycloalkenyl” substituent group or a cycloalkenyl moiety in a substituent group refers to a non-aromatic unsaturated hydrocarbyl ring having one or more carbon- carbon double bonds and containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl and cyclohex-1,3- dien-1-yl. Unless stated otherwise, a cycloalkenyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
  • An “aryl” substituent group or an aryl moiety in a substituent group refers to an aromatic hydrocarbyl ring.
  • aryl refers to monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic.
  • aryl groups/moieties include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless stated otherwise, the term “aryl” does not include “heteroaryl”.
  • a “heteroaryl” substituent group or a heteroaryl moiety in a substituent group refers to an aromatic heterocyclic group or moiety.
  • heteroaryl refers to monocyclic aromatic heterocycles and polycyclic fused ring aromatic heterocycles wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic.
  • a cyclic group or moiety is stated to be non-aromatic, such as a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group, it is to be understood that each ring system within the group or moiety (excluding any ring systems which are part of or formed by optional substituents) is non-aromatic.
  • a combination of moieties is referred to as one group, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule.
  • an arylalkyl group is benzyl.
  • each hydrogen atom may optionally be replaced by any specified monovalent substituent; - any two hydrogen atoms attached to the same carbon or nitrogen atom may optionally be replaced by any specified ⁇ -bonded substituent; - any sulphur atom may optionally be substituted with one or two of any specified ⁇ -bonded substituents; and - any two hydrogen atoms attached to the same or different atoms, within the same optionally substituted group or moiety, may optionally be replaced by any specified divalent bridging substituent.
  • a substituted group comprises 1, 2, 3 or 4 substituents, more typically 1, 2 or 3 substituents, more typically 1 or 2 substituents, and more typically 1 substituent.
  • any divalent bridging substituent e.g. -O-, -S-, -NH-, -CH2-, -CH2-CH2-, etc.
  • R 1 an optionally substituted group or moiety
  • R 2 a second group or moiety
  • halo includes fluoro, chloro, bromo and iodo.
  • halo such as a haloalkyl or halomethyl group
  • the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo and iodo.
  • the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the corresponding group without the halo prefix.
  • a halomethyl group may contain one, two or three halo substituents.
  • a haloethyl or halophenyl group may contain one, two, three, four or five halo substituents.
  • halomethyl refers to a methyl group substituted with one, two or three fluoro groups.
  • halo-substituted it is to be understood that the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo and iodo.
  • the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the group said to be halo-substituted.
  • a halo-substituted methyl group may contain one, two or three halo substituents.
  • a halo-substituted ethyl or halo-substituted phenyl group may contain one, two, three, four or five halo substituents.
  • any reference to an element is to be considered a reference to all isotopes of that element.
  • any reference to hydrogen is considered to encompass all isotopes of hydrogen including deuterium and tritium.
  • any reference to a compound or group is to be considered a reference to all tautomers of that compound or group.
  • methoxy, dimethylamino and aminoethyl groups are considered to be hydrocarbyl groups including one or more heteroatoms N, O or S in their carbon skeleton.
  • the compounds of the invention contain no more than one quaternary ammonium group. More typically, the compounds of the invention contain no quaternary ammonium groups.
  • a Cx-Cy group is defined as a group containing from x to y carbon atoms.
  • a C1-C4 alkyl group is defined as an alkyl group containing from 1 to 4 carbon atoms.
  • optional substituents are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituents.
  • replacement heteroatoms e.g. N, O or S
  • a morpholinyl group is to be considered a C4 heterocyclic group, not a C6 heterocyclic group.
  • the hydrocarbyl group of R X includes at least one heteroatom independently selected from N, O and S in its carbon skeleton.
  • the hydrocarbyl group is a C1- C12 group.
  • the hydrocarbyl group includes no more than five heteroatoms selected from N, O and S in its carbon skeleton. More typically in such an embodiment, the hydrocarbyl group includes no more than four heteroatoms selected from N, O and S in its carbon skeleton.
  • the hydrocarbyl group includes no more than three cyclic groups. More typically, the hydrocarbyl group includes no more than two cyclic groups.
  • the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a nitrogen, oxygen or sulphur atom, more typically a nitrogen or oxygen atom, and most typically a nitrogen atom.
  • the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a carbon atom.
  • the hydrocarbyl group of R X includes at least two heteroatoms each independently selected from N, O and S in its carbon skeleton.
  • the hydrocarbyl group is a C2-C12 group.
  • the hydrocarbyl group includes two, three, four or five heteroatoms each independently selected from N, O and S in its carbon skeleton. More typically in such an embodiment, the hydrocarbyl group includes two, three or four heteroatoms each independently selected from N, O and S in its carbon skeleton.
  • the hydrocarbyl group includes no more than three cyclic groups. More typically, the hydrocarbyl group includes no more than two cyclic groups.
  • the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a nitrogen or oxygen atom.
  • R X is a C1-C24 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo and/or -NO2 groups, and wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N and O in its carbon skeleton.
  • the hydrocarbyl group of R X includes at least one heteroatom independently selected from N and O in its carbon skeleton.
  • R X may be a C1-C24 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo and/or -NO2 groups, wherein the hydrocarbyl group includes one or more heteroatoms each independently selected from N and O in its carbon skeleton.
  • the hydrocarbyl group is a C1-C12 group.
  • the hydrocarbyl group includes no more than five heteroatoms selected from N and O in its carbon skeleton.
  • the hydrocarbyl group includes no more than four heteroatoms selected from N and O in its carbon skeleton. Typically in such an embodiment, the hydrocarbyl group includes no more than three cyclic groups. More typically, the hydrocarbyl group includes no more than two cyclic groups.
  • the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a nitrogen or oxygen atom, more typically a nitrogen atom. In another aspect of such an embodiment, the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a carbon atom.
  • R X may be a C1-C12 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or two cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo and/or -NO2 groups, and wherein the hydrocarbyl group includes one, two, three or four heteroatoms each independently selected from N and O in its carbon skeleton.
  • the hydrocarbyl group of R X includes at least two heteroatoms each independently selected from N and O in its carbon skeleton.
  • R X may be a C2-C24 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo and/or -NO2 groups, wherein the hydrocarbyl group includes two or more heteroatoms each independently selected from N and O in its carbon skeleton, and wherein the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a nitrogen or oxygen atom.
  • the hydrocarbyl group is a C2-C12 group.
  • the hydrocarbyl group includes two, three, four or five heteroatoms each independently selected from N and O in its carbon skeleton. More typically in such an embodiment, the hydrocarbyl group includes two, three or four heteroatoms each independently selected from N and O in its carbon skeleton. Typically, the hydrocarbyl group includes one nitrogen atom in its carbon skeleton and one, two or three further heteroatoms each independently selected from N and O in its carbon skeleton. Typically in such an embodiment, the hydrocarbyl group includes no more than three cyclic groups. More typically, the hydrocarbyl group includes no more than two cyclic groups.
  • R X may be a C2-C12 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or two cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo and/or -NO2 groups, wherein the hydrocarbyl group includes two, three or four heteroatoms each independently selected from N and O in its carbon skeleton, and wherein the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a nitrogen or oxygen atom.
  • the hydrocarbyl group of R X includes at least one heteroatom independently selected from N and O in its carbon skeleton.
  • the hydrocarbyl group is a C1-C12 group.
  • the hydrocarbyl group includes no more than five heteroatoms selected from N and O in its carbon skeleton.
  • the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a nitrogen or oxygen atom, more typically a nitrogen atom. In another aspect of such an embodiment, the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a carbon atom.
  • the saturated hydrocarbyl group of R X includes at least two heteroatoms each independently selected from N and O in its carbon skeleton.
  • the hydrocarbyl group is a C2-C12 group.
  • the hydrocarbyl group includes two, three, four or five heteroatoms each independently selected from N and O in its carbon skeleton. More typically in such an embodiment, the hydrocarbyl group includes two, three or four heteroatoms each independently selected from N and O in its carbon skeleton. Typically, the hydrocarbyl group includes one nitrogen atom in its carbon skeleton and one, two or three further heteroatoms each independently selected from N and O in its carbon skeleton. Typically in such an embodiment, the hydrocarbyl group includes no more than three cyclic groups. More typically, the hydrocarbyl group includes no more than two cyclic groups.
  • the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a nitrogen atom.
  • R X is a C1-C24 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro groups, and wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N and O in its carbon skeleton.
  • the hydrocarbyl group of R X includes at least one heteroatom independently selected from N and O in its carbon skeleton.
  • R X may be selected from a C1-C24 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro groups, wherein the hydrocarbyl group includes one or more heteroatoms each independently selected from N and O in its carbon skeleton.
  • the hydrocarbyl group is a C1-C12 group.
  • the hydrocarbyl group includes no more than five heteroatoms selected from N and O in its carbon skeleton.
  • the hydrocarbyl group includes no more than four heteroatoms selected from N and O in its carbon skeleton. Typically in such an embodiment, the hydrocarbyl group includes no more than three cyclic groups. More typically, the hydrocarbyl group includes no more than two cyclic groups.
  • the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a nitrogen or oxygen atom, more typically a nitrogen atom. In another aspect of such an embodiment, the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a carbon atom.
  • R X may be a C1-C12 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or two cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro groups, and wherein the hydrocarbyl group includes one, two, three or four heteroatoms each independently selected from N and O in its carbon skeleton.
  • the saturated hydrocarbyl group of R X includes at least two heteroatoms each independently selected from N and O in its carbon skeleton.
  • R X may be a C2-C24 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro groups, wherein the hydrocarbyl group includes two or more heteroatoms each independently selected from N and O in its carbon skeleton, and wherein the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a nitrogen or oxygen atom.
  • the hydrocarbyl group is a C2-C12 group.
  • the hydrocarbyl group includes two, three, four or five heteroatoms each independently selected from N and O in its carbon skeleton. More typically in such an embodiment, the hydrocarbyl group includes two, three or four heteroatoms each independently selected from N and O in its carbon skeleton. Typically, the hydrocarbyl group includes one nitrogen atom in its carbon skeleton and one, two or three further heteroatoms each independently selected from N and O in its carbon skeleton. Typically in such an embodiment, the hydrocarbyl group includes no more than three cyclic groups. More typically, the hydrocarbyl group includes no more than two cyclic groups.
  • R X may be a C2-C12 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or two cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro groups, wherein the hydrocarbyl group includes two, three or four heteroatoms each independently selected from N and O in its carbon skeleton, and wherein the atom of R X that is directly attached to the remainder of the compound of Formula (I) is a nitrogen or oxygen atom.
  • the group -NR 1 R 2 contains no more than 18 carbon atoms. More typically, the group -NR 1 R 2 contains no more than 12 carbon atoms.
  • R 1 and R 2 are each independently selected from hydrogen or a C1-C8 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a single cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo and/or -NO2 groups, and wherein the hydrocarbyl group may optionally include one, two, three or four heteroatoms each independently selected from N and O in its carbon skeleton.
  • R 1 may be a C1-C8 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a single cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo and/or -NO2 groups, and wherein the hydrocarbyl group may optionally include one, two, three or four heteroatoms each independently selected from N and O in its carbon skeleton, and R 2 may be selected from hydrogen or a C1-C4 alkyl or C1-C4 haloalkyl group.
  • R 1 is selected from a methyl, ethyl, isopropyl or cyclopropyl group, any of which may optionally be fluoro substituted
  • R 2 is selected from hydrogen or a methyl or fluoromethyl group.
  • -NR 1 R 2 may have the formula -NMe2.
  • R 1 is a C2-C8 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a single cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro groups, wherein the hydrocarbyl group includes one or two heteroatoms each independently selected from N and O in its carbon skeleton, and R 2 is selected from hydrogen or a C1-C3 alkyl or C1-C3 fluoroalkyl group.
  • R 1 may be selected from a -(C(R 101 )2)e-X 10 -R 102 or -(C(R 101 )2)e-X 10 -(C(R 101 )2)f-X 11 -R 102 group
  • R 2 may be selected from hydrogen or a methyl or fluoromethyl group
  • X 10 is selected from O or NR 103
  • X 11 is selected from O or NR 104
  • e is 2, 3 or 4
  • f is 2, 3 or 4
  • each R 101 is hydrogen
  • R 102 is selected from a hydrogen or a methyl, ethyl, isopropyl or cyclopropyl group, any of which may optionally be fluoro substituted
  • R 103 is selected from hydrogen or a methyl or fluoromethyl group
  • R 104 is selected from hydrogen or a methyl or fluoromethyl group; or a single R 101 and R 103 , or a single R 101 and R 104 , or R 103 and
  • R 1 is a -(C(R 101 )2)e-NR 102 R 103 group
  • R 2 is selected from hydrogen or a methyl or fluoromethyl group, wherein: e is 2, 3 or 4; a single R 101 and R 103 , or two R 101 , together form a -(CH2)2- group; each remaining R 101 is hydrogen; R 102 is selected from a methyl, ethyl, isopropyl or cyclopropyl group, any of which may optionally be fluoro substituted; and R 103 , if not part of a -(CH2)2- group, is selected from hydrogen or a methyl or fluoromethyl group.
  • -NR 1 R 2 may have a formula selected from:
  • R 1 has the formula -L 1 -R 10 , wherein L 1 is a C1-C2 alkylene or C1-C2 fluoroalkylene group, and R 10 is a 5- or 6-membered heteroaryl group, such as an imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl group, and R 2 is selected from hydrogen or a C1-C3 alkyl or C1-C3 fluoroalkyl group. Typically in such an embodiment, R 2 is selected from hydrogen or a methyl or fluoromethyl group.
  • -NR 1 R 2 has a formula selected from: .
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered cyclic group
  • the resultant cyclic group is a heterocyclic group.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered monocyclic group or a 6- to 12- membered (e.g.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered monocyclic group typically the monocyclic group is a saturated monocyclic group.
  • the compound is a compound of Formula (III):
  • m is 0.
  • X 12 is O.
  • -NR 1 R 2 may have the formula: .
  • X 12 is NR 12 .
  • R 12 is selected from hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl, fluorocyclopropylmethyl or -CO-R 120 group, wherein R 120 is selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • R 12 is selected from hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group.
  • R 12 may be selected from hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3-C4 fluorocycloalkyl group. More typically still, R 12 is selected from hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • R 12 is selected from hydrogen or a methyl or fluoromethyl group.
  • -NR 1 R 2 has a formula selected from:
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group, wherein the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group is substituted with a -NR 13 R 14 group such that the nitrogen atom of the -NR 13 R 14 group is not directly attached to a carbon atom that in turn is directly attached to the ring nitrogen atom of the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group, wherein R 13 and R 14 are each independently selected from hydrogen or a methyl or fluoromethyl group, and wherein the azetidinyl, pyrrol
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group, wherein the pyrrolidinyl or piperidinyl group is substituted with a -NR 13 R 14 group such that the nitrogen atom of the -NR 13 R 14 group is not directly attached to a carbon atom that in turn is directly attached to the ring nitrogen atom of the pyrrolidinyl or piperidinyl group, wherein R 13 and R 14 are each independently selected from hydrogen or a methyl or fluoromethyl group.
  • -NR 1 R 2 has the formula: .
  • the compounds of the invention where R 1 and R 2 together with the nitrogen atom to which they are attached form a bicyclic group offer particular steric and electronic properties that are advantageous to the pharmacological profile of the molecule.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 6- to 12-membered bicyclic group
  • typically the bicyclic group is a saturated bicyclic group.
  • R 1 and R 2 may together with the nitrogen atom to which they are attached form a 6- to 12-membered (e.g.
  • the saturated hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group
  • the saturated hydrocarbyl group may optionally be substituted with
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 6- to 12-membered bicyclic group
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 8- to 10-membered fused bicyclic group, such that the nitrogen atom of -NR 1 R 2 is a ring atom of a first 5- or 6- membered ring of the fused bicyclic group, and the first 5- or 6-membered ring is fused to a second 5- or 6-membered ring of the fused bicyclic group.
  • substituents each independently selected from a fluoro, chloro, bromo, -OH, -NH2, or a C1-C4 saturated hydrocarbyl group, wherein the saturated hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group
  • the first 5- or 6-membered ring is not aromatic and is unsubstituted
  • the second 5- or 6-membered ring is an unsubstituted 5- membered heteroaryl ring comprising a NH group.
  • -NR 1 R 2 has the formula: .
  • the first 5- or 6-membered ring is saturated and the second 5- or 6- membered ring is saturated.
  • the second 5- or 6-membered ring comprises at least one ring nitrogen atom.
  • said ring nitrogen atom is not directly attached to a sp 2 hybridised carbon atom.
  • the first 5- or 6-membered ring is saturated and the second 5- or 6-membered ring is saturated.
  • the compound is a compound of Formula (IV): Formula (IV) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 15 , R 16 , j, k, p, q, r and s are as defined in accordance with Formula (I).
  • j is 1 or 2 and k is 1 or 2. More typically, j is 1 and k is 1.
  • p is 0, 1 or 2 and q is 1 or 2. More typically, p is 1 or 2 and q is 1 or 2. More typically still, p is 1 and q is 1.
  • r is 0 and s is 0.
  • j + k 2.
  • R 15 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group. More typically, R 15 is a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group.
  • R 15 is a methyl, ethyl or cyclopropylmethyl group.
  • -NR 1 R 2 may have a formula selected from: .
  • -NR 1 R 2 has the formula: wherein: r is 0, 1 or 2; s is 0, 1 or 2; t is 1 or 2; and each R 16 is independently selected from a methyl or fluoromethyl group.
  • the compound is a compound of Formula (V):
  • Formula (V) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 16 , r, s and t are as defined in accordance with Formula (I).
  • r is 0 and s is 0.
  • t is 1.
  • -NR 1 R 2 may have the formula: .
  • the compound is a compound of Formula (VI): Formula (VI) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 16 , j, k, r, s and v are as defined in accordance with Formula (I).
  • j is 1 or 2 and k is 1 or 2. More typically, j is 1 and k is 1.
  • v is 1.
  • r is 0 and s is 0.
  • -NR 1 R 2 may have the formula: .
  • a first 5- or 6-membered ring is fused to a second 5- or 6-membered ring across two sp 3 hybridised ring carbon atoms, e.g. across two ring carbon atoms in a saturated fused bicyclic ring system
  • the second ring may be fused cis- or trans- to the first ring.
  • -NR 1 R 2 may have the formula: .
  • -NR 1 R 2 may have the formula: .
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 6- to 12-membered bicyclic group
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 6- to 12-membered spiro bicyclic group, such that the nitrogen atom of -NR 1 R 2 is a ring atom of a first 4- to 7- membered ring of the spiro bicyclic group, and the first 4 to 7-membered ring shares a spiro ring atom with a second 3- to 7-membered ring of the spiro bicyclic group.
  • the first 4- to 7-membered ring is saturated and the second 3- to 7-membered ring is saturated.
  • the second 3- to 7-membered ring is a 4- to 7- membered ring that comprises at least one ring nitrogen or ring oxygen atom.
  • said ring nitrogen or ring oxygen atom is not directly attached to a sp 2 hybridised carbon atom.
  • the second 4- to 7-membered ring comprises at least one ring nitrogen atom or at least one ring oxygen atom, the first 4- to 7- membered ring is saturated and the second 4- to 7-membered ring is saturated.
  • the compound is a compound of Formula (VII): Formula (VII) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , X 15 , R 16 , j, k, p, q, r and s are as defined in accordance with Formula (I).
  • j is 1 or 2 and k is 1 or 2. More typically, j is 1 and k is 2.
  • p is 0, 1 or 2 and q is 1, 2 or 3. More typically, p is 0, 1 or 2 and q is 2 or 3. More typically still, p is 2 and q is 2.
  • r is 0 and s is 0.
  • R 15 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1- C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group. More typically, R 15 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group. More typically still, R 15 is hydrogen or a methyl or fluoromethyl group. Yet more typically, R 15 is hydrogen or a methyl group.
  • -NR 1 R 2 may have a formula selected from:
  • Formula (VIII) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 15 , R 16 , j, k, p, q, r and s are as defined in accordance with Formula (I).
  • j is 1 or 2 and k is 1 or 2.
  • p is 1 or 2 and q is 1 or 2.
  • r is 0 and s is 0.
  • R 15 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group. More typically, R 15 is hydrogen or a methyl or fluoromethyl group.
  • R 15 is hydrogen.
  • -NR 1 R 2 may have the formula: .
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 6- to 12-membered bicyclic group
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 7- to 9-membered bridged bicyclic group.
  • the 7- to 9-membered bridged bicyclic group is saturated.
  • the 7- to 9-membered bridged bicyclic group comprises a least one further ring nitrogen or ring oxygen atom.
  • said further ring nitrogen or ring oxygen atom is not directly attached to a sp 2 hybridised carbon atom.
  • the 7- to 9-membered bridged bicyclic group comprises a least one further ring nitrogen or ring oxygen atom, the 7- to 9-membered bridged bicyclic group is saturated.
  • -NR 1 R 2 has the formula: wherein: w is 1 or 2; X 15 is O or NR 15 ; R 15 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl, fluorocyclopropylmethyl or -CO-R 150 group, wherein R 150 is selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; one R 17 and one R 18 together form a -CH2- or -CH2CH2- group; and each remaining R 17 and R 18 is hydrogen.
  • the compound is a compound of Formula (IX): Formula (IX) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , X 15 , R 17 , R 18 and w are as defined in accordance with Formula (I).
  • w is 1.
  • X 15 is NR 15 .
  • R 15 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1- C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group.
  • R 15 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group. More typically still, R 15 is hydrogen or a methyl or fluoromethyl group. Yet more typically, R 15 is a methyl or fluoromethyl group. Typically in such an embodiment, one R 17 and one R 18 together form a -CH2CH2- group. For example, -NR 1 R 2 may have the formula: .
  • R 3 is selected from hydrogen or a C1-C12 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained
  • the compound is a compound of Formula (X): Formula (X) wherein R 3 , X 1 -X 4 , A 1 -A 6 and Q 1 are as defined in accordance with Formula (I).
  • R 3 is C1-C8 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a single cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo and/or -NO2 groups, and wherein the hydrocarbyl group may optionally include one, two, three or four heteroatoms each independently selected from N and O in its carbon skeleton.
  • R 3 is a C2-C8 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a single cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro groups, and wherein the hydrocarbyl group includes one or two heteroatoms each independently selected from N and O in its carbon skeleton.
  • R 3 may be selected from a -(C(R 105 )2)e-Q 10 -R 106 or -(C(R 105 )2)e-Q 10 -(C(R 105 )2)f-Q 11 -R 106 group, wherein: Q 10 is selected from O or NR 107 ; Q 11 is selected from O or NR 108 ; e is 2, 3 or 4; f is 2, 3 or 4; each R 105 is hydrogen; R 106 is selected from a hydrogen or a methyl, ethyl, isopropyl or cyclopropyl group, any of which may optionally be fluoro substituted; R 107 is selected from hydrogen or a methyl or fluoromethyl group; and R 108 is selected from hydrogen or a methyl or fluoromethyl group; or a single R 105 and R 107 , or a single R 105 and R 108 , or R 107 and R 108 , or two R 105 , together form a
  • R 3 is a -(CH2)2-NR 106 R 107 group, wherein: R 106 is selected from a methyl, ethyl, isopropyl or cyclopropyl group, any of which may optionally be fluoro substituted; and R 107 is selected from hydrogen or a methyl or fluoromethyl group.
  • -OR 3 may have the formula: .
  • the fused bicyclic heterocyclic group contains no more than 12 carbon atoms.
  • the fused bicyclic heterocyclic group, including any optional substituents contains in total no more than four nitrogen and oxygen atoms.
  • the second ring system contains a ring nitrogen atom.
  • the fused bicyclic heterocyclic group contains no more than three ring heteroatoms. More typically, the fused bicyclic heterocyclic group contains no more than two ring heteroatoms.
  • the first ring system is a 4- to 7-membered ring and the second ring system is a 4- to 7-membered ring.
  • the first ring system is a 5- or 6-membered ring and the second ring system is a 5- or 6-membered ring.
  • each R 40 may be independently selected from a -OH, -NH2, -R 41 , -CO-R 42 , -OR 41 , -NHR 41 or -N(R 41 )2 group, wherein each R 41 is independently selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group, or any two R 41 attached to the same nitrogen atom may together form a C2-C4 alkylene or a C2-C4 fluoroalkylene group, provided that the group -N(R 41 )2 contains no more than four carbon atoms, and wherein each R 42 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • each R 40 is independently selected from a -NH2, -R 41 , -CO-R 42 , -NHR 41 or -N(R 41 )2 group, wherein each R 41 is independently selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group, or any two R 41 attached to the same nitrogen atom may together form a C2-C4 alkylene or a C2-C4 fluoroalkylene group, provided that the group -N(R 41 )2 contains no more than four carbon atoms, and wherein each R 42 is independently selected from a C1-C3 alkyl, C1-C3 fluor
  • the saturated fused bicyclic heterocyclic group is substituted, it is substituted with one or more fluoro groups and/or a single group selected from -R 41 or -CO-R 42 , wherein if present -R 41 or -CO-R 42 is directly attached to a ring nitrogen atom of the saturated fused bicyclic heterocyclic group, wherein R 41 is selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group, and wherein R 42 is selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • the compound is a compound of Formula (XI): wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 15 , R 16 , j, k, p, q, r and s are as defined in accordance with Formula (I).
  • X 1 -X 4 , A 1 -A 6 , Q 1 , R 15 , R 16 , j, k, p, q, r and s are as defined in accordance with Formula (I).
  • j 0, q is 1, 2 or 3
  • k 0, p is 1, 2 or 3
  • p 0, k is 1, 2 or 3
  • q 0, j is 1, 2 or 3
  • j is 1 or 2 and k is 1 or 2.
  • p is 0, 1 or 2 and q is 1 or 2.
  • R 15 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1- C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group. More typically, R 15 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • R X may have the formula: .
  • R x is a 5- or 6-membered heteroaryl or a bicyclic fused heteroaryl group, wherein the 5- or 6-membered heteroaryl or the bicyclic fused heteroaryl group contains at least one ring nitrogen atom; and/or (ii) the phenyl, naphthyl, 5- or 6-membered heteroaryl or bicyclic fused heteroaryl group is substituted with at least one substituent that comprises a nitrogen atom.
  • each R 5 is independently selected from a -OH, -NH2, -R 51 , -CO-R 52 , -OR 51 , -NHR 51 or -N(R 51 )2 group, wherein each R 51 is independently selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group, or any two R 51 attached to the same nitrogen atom may together form a C2-C4 alkylene or a C2-C4 fluoroalkylene group, provided that the group -N(R 51 )2 contains no more than four carbon atoms, and wherein each R 52 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • each R 5 is independently selected from a -NH2, -R 51 , -CO-R 52 , -NHR 51 or -N(R 51 )2 group, wherein each R 51 is independently selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group, or any two R 51 attached to the same nitrogen atom may together form a C2-C4 alkylene or a C2-C4 fluoroalkylene group, provided that the group -N(R 51 )2 contains no more than four carbon atoms, and wherein each R 52 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • each R 5 is independently selected from a -NH2, -R 51 , -NHR 51 or -N(R 51 )2 group, wherein each R 51 is independently selected from a methyl or fluoromethyl group.
  • R x is selected from a 5- or 6-membered heteroaryl or a bicyclic fused heteroaryl group, wherein the ring atoms of the 5- or 6-membered heteroaryl group or the bicyclic fused heteroaryl group are selected from the group consisting of nitrogen and carbon atoms, and wherein the 5- or 6-membered heteroaryl group or the bicyclic fused heteroaryl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/or with a single group R 5 , wherein R 5 is selected from a -NH2, -R 51 , -NHR 51 or -N(R 51 )2 group, wherein each R 51 is independently selected from a methyl or fluoromethyl
  • the 5- or 6-membered heteroaryl group or the bicyclic fused heteroaryl group is unsubstituted, i.e.
  • R x is selected from a 5- or 6-membered heteroaryl or a bicyclic fused heteroaryl group, wherein the ring atoms of the 5- or 6-membered heteroaryl group or the bicyclic fused heteroaryl group are selected from the group consisting of nitrogen and carbon atoms.
  • R X may have the formula:
  • the phenyl or the 5- or 6-membered heteroaryl group is substituted with a first substituent selected from a -NH2, -NHR 53 , -N(R 53 )2, -CH2-NH2, -CH2-NHR 53 or -CH2-N(R 53 )2 group, wherein each R 53 is independently selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group, or any two R 53 attached to the same nitrogen atom may together form a C2-C5 alkylene or a C2-C5 fluoroalkylene group, provided that the group -N(R 53 )2 contains no more than five carbon atoms, and wherein the phenyl or the 5- or 6-membered heteroaryl group may optionally be further substituted with a single R 53 ,
  • each R 53 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group, or any two R 53 attached to the same nitrogen atom may together form a C3-C4 alkylene or a C3-C4 fluoroalkylene group, provided that the group -N(R 53 )2 contains no more than four carbon atoms.
  • R x is selected from a phenyl or a pyridinyl group, wherein the phenyl or the pyridinyl group is substituted with a -NH2, -NHR 53 , -N(R 53 )2, -CH2-NH2, -CH2-NHR 53 or -CH2-N(R 53 )2 group, wherein each R 53 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group, or any two R 53 attached to the same nitrogen atom may together form a C3-C4 alkylene or a C3-C4 fluoroalkylene group, provided that the group -N(R 53 )2 contains no more than four carbon atoms.
  • R X may have the formula: As stated in accordance with the first aspect of the invention: X 1 is N, C-H, C-Hal or C-R X1 ; X 2 is N, C-H, C-Hal or C-R X2 ; X 3 is N, C-H, C-Hal or C-R X3 ; and X 4 is N or C; provided that at least one of X 1 , X 2 , X 3 and X 4 is N, and that no more than three of X 1 , X 2 , X 3 and X 4 are N; and R X1 , R X2 and R X3 are each independently selected from -OH, -SH, -NH2, -SO2H, -SO3H, -SO2NH2, -NO2, or a C1-C4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include
  • X 4 is N
  • a 6 is C
  • a 6 is N
  • at least one of X 1 , X 2 , X 3 and X 4 is N.
  • at least one of X 2 , X 3 and X 4 is N.
  • at least one of X 2 and X 3 is N.
  • X 2 is N.
  • X 1 is N.
  • X 1 is also N.
  • at least one of X 1 and X 2 is N. More typically, at least X 2 is N. More typically still, X 1 is N and X 2 is N. Typically, no more than two of X 1 , X 2 , X 3 and X 4 are N.
  • X 1 is N, C-H, C-Hal or C-R X1 ;
  • X 2 is N, C-H, C-Hal or C-R X2 ;
  • X 3 is N, C-H, C-Hal or C-R X3 ; and
  • X 4 is C; provided that at least one of X 1 , X 2 and X 3 is N and that no more than two of X 1 , X 2 and X 3 are N.
  • at least one of X 2 and X 3 is N.
  • at least X 1 is N.
  • X 1 is N, C-H, C-Hal or C-R X1 ;
  • X 2 is N, C-H, C-Hal or C-R X2 ;
  • X 3 is C-H, C-Hal or C-R X3 ;
  • X 4 is N or C; provided that at least one of X 1 , X 2 and X 4 is N, and that no more than two of X 1 , X 2 and X 4 are N.
  • X 2 is N.
  • X 1 is N, C-H, C-Hal or C-R X1 ;
  • X 2 is N, C-H, C-Hal or C-R X2 ;
  • X 3 is C-H, C-Hal or C-R X3 ; and
  • X 4 is C. provided that at least one of X 1 and X 2 is N.
  • X 1 is N.
  • X 2 is N. More typically in such an embodiment, X 1 is N and X 2 is N.
  • X 1 is N, C-H or C-R X1 ;
  • X 2 is N, C-H or C-R X2 ;
  • X 3 is N, C-H or C-R X3 ;
  • X 4 is N or C; provided that at least one of X 1 , X 2 , X 3 and X 4 is N, and that no more than three of X 1 , X 2 , X 3 and X 4 are N.
  • no more than two of X 1 , X 2 , X 3 and X 4 are N.
  • at least one of X 2 , X 3 and X 4 is N.
  • X 2 and X 3 are N. More typically, at least one of X 2 and X 3 is N. Most typically, X 2 is N. In one embodiment: X 1 is N, C-H or C-R X1 ; X 2 is N, C-H or C-R X2 ; X 3 is N, C-H or C-R X3 ; and X 4 is C; provided that at least one of X 1 , X 2 and X 3 is N and that no more than two of X 1 , X 2 and X 3 are N. Typically in such an embodiment, at least one of X 2 and X 3 is N. Typically in such an embodiment, at least X 1 is N.
  • X 1 is N, C-H or C-R X1 ;
  • X 2 is N, C-H or C-R X2 ;
  • X 3 is C-H or C-R X3 ; and
  • X 4 is N or C; provided that at least one of X 1 , X 2 and X 4 is N, and that no more than two of X 1 , X 2 and X 4 are N.
  • X 1 is N.
  • X 2 is N. More typically in such an embodiment, X 1 is N and X 2 is N.
  • X 1 is N, C-H or C-R X1 ;
  • X 2 is N, C-H or C-R X2 ;
  • X 3 is C-H or C-R X3 ; and
  • X 4 is C; provided that at least one of X 1 and X 2 is N.
  • X 1 is N.
  • X 2 is N or C-H. More typically, X 2 is N. More typically still in such an embodiment, X 1 is N and X 2 is N. Yet more typically, X 1 is N, X 2 is N, and X 3 is C-H.
  • R X1 , R X2 and R X3 are each independently selected from -OH, -SH, -NH2, -SO2H, -SO3H, -SO2NH2 or a C1-C4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one or two heteroatoms each independently selected from N and O in its carbon skeleton.
  • R X1 , R X2 and R X3 are each independently selected from -OH, -SH, -NH2, or a C1-C4 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one or two heteroatoms each independently selected from N, O and S in its carbon skeleton.
  • R X1 , R X2 and R X3 are each independently selected from a C1-C3 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro groups, and wherein the hydrocarbyl group may optionally include a single heteroatom selected from N and O in its carbon skeleton.
  • R X2 is selected from -OH, -SH, -NH2, or a C1-C4 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or two heteroatoms each independently selected from N, O and S in its carbon skeleton.
  • R X2 is a C1-C3 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, and wherein the hydrocarbyl group may optionally include a single heteroatom selected from N and O in its carbon skeleton. More typically still in such an embodiment, R X2 is a methyl group. In one embodiment, X 2 is not C-Hal. For example, X 2 may be N, C-H or C-R X2 , wherein R X2 is selected from -OH, -SH, -NH2, or a C1-C4 saturated hydrocarbyl group as described above.
  • R X1 , R X2 and R X3 are each independently selected from a methyl or fluoromethyl group.
  • X 1 is N, C-H or C-Hal
  • X 2 is N, C-H or C-Hal
  • X 3 is N, C-H or C-Hal
  • X 4 is C; provided that at least one of X 1 , X 2 and X 3 is N and that no more than two of X 1 , X 2 and X 3 are N.
  • Q 1 is O, S, N, N-H, N-R Q1 , C-H, C-Hal, or C-R Q2 ;
  • R Q1 and R Q2 are each independently selected from a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl, fluorocyclopropylmethyl or -CO-R Q3 group, wherein R Q3 is selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • Q 1 is O, S, N-H, N-R Q1 , C-H, C-Hal, or C-R Q2 . More typically, Q 1 is O, S, N-H or N-R Q1 .
  • Q 1 may be O, S or NH, or Q 1 may be O, S, N-H or N-R Q1 , wherein R Q1 is selected from a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl, fluorocyclopropylmethyl or -CO-R Q3 group, wherein R Q3 is selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • no more than two of A 1 , A 2 , A 3 , A 4 and A 5 are N. More typically, no more than one of A 1 , A 2 , A 3 , A 4 and A 5 is N.
  • a 5 is N
  • X 4 is N
  • a 6 is C and Q 1 is N, C-H, C-Hal, or C-R Q2 . More typically, when A 5 is N, X 4 is N, A 6 is C and Q 1 is C-H, C-Hal, or C-R Q2 .
  • Q 1 is O, S, N-H or N-R Q1 , A 5 is C.
  • a 1 is N, C-H, C-Hal or C-R A1 ;
  • a 2 is N, C-H, C-Hal or C-R A2 ;
  • a 3 is N, C-H, C-Hal or C-R A3 ;
  • a 4 is N, C-H, C-Hal or C-R A4 ;
  • a 5 is C; provided that no more than two of A 1 , A 2 , A 3 and A 4 are N.
  • no more than one of A 1 , A 2 , A 3 and A 4 is N.
  • a 2 is N or A 3 is N. More typically, A 3 is N.
  • R A1 , R A2 , R A3 and R A4 are each independently selected from -OH, -SH, -NH2, -SO2H, -SO3H, -SO2NH2 or a C1-C4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one or two heteroatoms each independently selected from N and O in its carbon skeleton.
  • R A1 , R A2 , R A3 and R A4 are each independently selected from a methyl or fluoromethyl group.
  • a 1 is N, C-H or C-Hal;
  • a 2 is N, C-H or C-Hal;
  • a 3 is N, C-H or C-Hal;
  • a 4 is N, C-H or C-Hal; and
  • a 5 is C; provided that no more than two of A 1 , A 2 , A 3 and A 4 are N.
  • no more than one of A 1 , A 2 , A 3 and A 4 is N.
  • a 2 is N or A 3 is N.
  • a 3 is N.
  • a 1 is C-H or C-Hal; A 2 is C-H or C-Hal; A 3 is C-H or C-Hal; A 4 is C-H or C-Hal; and A 5 is C.
  • a 1 is C-H, A 2 is C-H, A 3 is C-H, A 4 is C-H and A 5 is C.
  • a 6 is N or C. Typically, A 6 is N.
  • each Hal is independently selected from a fluoro, chloro, bromo or iodo group.
  • each Hal is independently selected from a fluoro, chloro or bromo group.
  • the compound is a compound of Formula (Ia): wherein R X , X 1 , X 2 and Q 1 are as defined in accordance with Formula (I).
  • X 2 is N.
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (IIa): Formula (IIa) wherein R 1 , R 2 , X 1 , X 2 and Q 1 are as defined in accordance with Formula (II).
  • X 2 is N.
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (IIIa):
  • Formula (IIIa) wherein X 1 , X 2 , Q 1 , R 11 , X 12 , m and n are as defined in accordance with Formula (III).
  • X 2 is N.
  • X 1 is N
  • X 2 is N.
  • the compound is a compound of Formula (IVa): Formula (IVa) wherein X 1 , X 2 , Q 1 , R 15 , R 16 , j, k, p, q, r and s are as defined in accordance with Formula (IV).
  • X 2 is N.
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (Va): Formula (Va) wherein X 1 , X 2 , Q 1 , R 16 , r, s and t are as defined in accordance with Formula (V).
  • X 2 is N.
  • X 1 is N
  • X 2 is N.
  • the compound is a compound of Formula (VIa): wherein X 1 , X 2 , Q 1 , R 16 , j, k, r, s and v are as defined in accordance with Formula (VI).
  • X 2 is N.
  • the compound is a compound of Formula (VIIa): wherein X 1 , X 2 , Q 1 , X 15 , R 16 , j, k, p, q, r and s are as defined in accordance with Formula (VII).
  • X 2 is N.
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (VIIIa):
  • X 1 , X 2 , Q 1 , R 15 , R 16 , j, k, p, q, r and s are as defined in accordance with Formula (VIII).
  • X 2 is N.
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (IXa): Formula (IXa) wherein X 1 , X 2 , Q 1 , X 15 , R 17 , R 18 and w are as defined in accordance with Formula (IX).
  • X 2 is N.
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (Xa): Formula (Xa) wherein R 3 , X 1 , X 2 and Q 1 are as defined in accordance with Formula (X).
  • X 2 is N.
  • X 1 is N
  • X 2 is N.
  • the compound is a compound of Formula (XIa): Formula (XIa) wherein X 1 , X 2 , Q 1 , R 15 , R 16 , j, k, p, q, r and s are as defined in accordance with Formula (XI).
  • X 2 is N.
  • X 1 is N and X 2 is N.
  • the compound is not: .
  • embodiments directed to one substituent or moiety may be read in conjunction with embodiments directed to a different substituent or moiety.
  • R X is a C1-C12 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or two cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo and/or -NO2 groups, and wherein the hydrocarbyl group includes one, two, three or four heteroatoms each independently selected from N and O in its carbon skeleton;
  • X 1 is N, C-H, C-Hal or C-R X1 ;
  • X 2 is N, C-H, C-Hal or C-R X2 ;
  • X 3 is N, C-H, C-Hal or C-R X3 ; and
  • X 4 is C; provided that at least one of X 1 , X 2 and X 3 is N and that no more than two of X 1 ,
  • At least one of X 2 and X 3 is N.
  • X 2 is N.
  • Q 1 is S, or N-H.
  • Q 1 is NH.
  • At least one of X 2 and X 3 is N.
  • X 2 is N.
  • Q 1 is S, or N-H.
  • Q 1 is NH.
  • X 2 and X 3 are N.
  • X 2 is N.
  • Q 1 is S, or N-H.
  • Q 1 is NH.
  • R 3 is a C2-C8 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a single cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro groups, and wherein the hydrocarbyl group includes one or two heteroatoms each independently selected from N and O in its carbon skeleton.
  • X 1 is N, C-H, C-Hal or C-R X1 ;
  • X 2 is N, C-H, C-Hal or C-R X2 ;
  • X 3 is N, C-H, C-Hal or C-R X3 ; and
  • X 4 is C;
  • At least one of X 2 and X 3 is N.
  • X 2 is N.
  • Q 1 is S, or N-H.
  • Q 1 is NH.
  • At least one of X 2 and X 3 is N.
  • X 2 is N.
  • Q 1 is S, or N-H.
  • Q 1 is NH.
  • a compound of Formula (IIa) as defined above wherein: R 1 is selected from a methyl, ethyl, isopropyl or cyclopropyl group, any of which may optionally be fluoro substituted; R 2 is selected from hydrogen or a methyl or fluoromethyl group; X 1 is N or C-H; and X 2 is N or C-H; provided that at least one of X 1 and X 2 is N; Q 1 is O, S, N-H or N-R Q1 ; and R Q1 is a methyl or fluoromethyl group.
  • R 1 is selected from a methyl or fluoromethyl group and R 2 is selected from a methyl or fluoromethyl group.
  • X 2 is N. More typically, X 1 is N and X 2 is N.
  • Q 1 is S, or N-H. In one aspect, Q 1 is NH.
  • R 1 is selected from a -(C(R 101 )2)e-X 10 -R 102 or -(C(R 101 )2)e-X 10 -(C(R 101 )2)f-X 11 -R 102 group, provided that any -(C(R 101 )2)e-X 10 -R 102 or -(C(R 101 )2)e-X 10 -(C(R 101 )2)f-X 11 -R 102 group contains no more than 8 carbon atoms; R 2 is selected from hydrogen or a methyl or fluoromethyl group; X 10 is selected from O or NR 103 ; X 11 is selected from O or NR 104 ; e is 2, 3 or 4; f is 2, 3 or 4; each R 101 is hydrogen; R 102 is selected from a hydrogen or a methyl, ethyl, isopropyl or cyclo
  • R 1 is a -(C(R 101 )2)e-NR 102 R 103 group
  • R 2 is selected from hydrogen or a methyl or fluoromethyl group
  • e is 2, 3 or 4
  • each remaining R 101 is hydrogen
  • R 102 is selected from a methyl, ethyl, isopropyl or cyclopropyl group, any of which may optionally be fluoro substituted
  • R 103 if not part of a -(CH2)2- group, is selected from hydrogen or a methyl or fluoromethyl group.
  • X 2 is N. More typically, X 1 is N and X 2 is N. Typically in accordance with the seventh exemplary embodiment, Q 1 is S, or N-H. In one aspect, Q 1 is NH.
  • X 12 is O or NR 12 ;
  • R 12 is selected from hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl, fluorocyclopropylmethyl or -CO-R 120 group;
  • R 120 is selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group;
  • X 1 is N, C-H or C-Hal; and
  • X 2 is N, C-
  • X 1 is N or C-H and X 2 is N or C-H. More typically, X 1 is N or C-H and X 2 is N. More typically still, X 1 is N and X 2 is N.
  • Q 1 is S, or N-H.
  • Q 1 is NH.
  • X 12 is O and m is 0. Typically in such an aspect, n is 1.
  • X 12 is NR 12 . Where X 12 is NR 12 , typically m is 0.
  • X 12 is NR 12
  • R 12 is selected from hydrogen or a methyl or fluoromethyl group. More typically, R 12 is selected from hydrogen or a methyl group.
  • X 12 is NR 12
  • typically X 1 is N or C-H and X 2 is N. Most typically, X 1 is N and X 2 is N. Most typically where X 12 is NR 12 , n is 1.
  • n is 1; m is 0; X 12 is NR 12 ; R 12 is selected from hydrogen or a methyl or fluoromethyl group; X 1 is N; X 2 is N; and Q 1 is S or N-H.
  • R 12 is selected from hydrogen or a methyl group.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group, wherein the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group is substituted with a -NR 13 R 14 group such that the nitrogen atom of the -NR 13 R 14 group is not directly attached to a carbon atom that in turn is directly attached to the ring nitrogen atom of the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group, wherein R 13 and R 14 are each independently selected from hydrogen or a methyl or fluoromethyl group, and wherein the azetidinyl, pyr
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group, wherein the pyrrolidinyl or piperidinyl group is substituted with a -NR 13 R 14 group such that the nitrogen atom of the -NR 13 R 14 group is not directly attached to a carbon atom that in turn is directly attached to the ring nitrogen atom of the pyrrolidinyl or piperidinyl group, wherein R 13 and R 14 are each independently selected from hydrogen or a methyl or fluoromethyl group.
  • X 2 is N. More typically, X 1 is N and X 2 is N.
  • Q 1 is S, or N-H.
  • Q 1 is NH.
  • j is 1 or 2; k is 1 or 2; p is 0, 1 or 2; q is 1 or 2; r is 0; and s is 0. More typically in accordance with the tenth exemplary embodiment: j is 1; k is 1; p is 1 or 2; q is 1 or 2; r is 0; and s is 0.
  • R 15 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group.
  • R 15 is a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group. More typically still, R 15 is a methyl, ethyl or cyclopropylmethyl group.
  • the compound is a compound of Formula (IVa) as defined above, wherein X 1 , X 2 , Q 1 , R 15 , R 16 , j, k, p, q, r and s are as defined above.
  • X 2 is N. More typically, X 1 is N and X 2 is N. Typically in accordance with the tenth exemplary embodiment, Q 1 is S, or N-H. In one aspect, Q 1 is NH.
  • R 15 is a methyl, ethyl or cyclopropylmethyl group.
  • a compound of Formula (Va) as defined above wherein: r is 0, 1 or 2; s is 0, 1 or 2; t is 1 or 2; each R 16 is independently selected from a methyl or fluoromethyl group; X 1 is N or C-H; and X 2 is N or C-H; provided that at least one of X 1 and X 2 is N; Q 1 is O, S, N-H or N-R Q1 ; and R Q1 is a methyl or fluoromethyl group.
  • r is 0, s is 0 and t is 1.
  • X 2 is N. More typically, X 1 is N and X 2 is N.
  • Q 1 is S, or N-H. In one aspect, Q 1 is NH.
  • j is 1, k is 1, v is 1, r is 0 and s is 0.
  • X 2 is N. More typically, X 1 is N and X 2 is N.
  • Q 1 is S, or N-H. In one aspect, Q 1 is NH.
  • j is 1 or 2; k is 1 or 2; p is 0, 1 or 2; q is 1, 2 or 3; r is 0; and s is 0. More typically in accordance with the thirteenth exemplary embodiment: j is 1; k is 2; p is 2; q is 2; r is 0; and s is 0.
  • R 15 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group.
  • R 15 is hydrogen or a methyl or fluoromethyl group. Yet more typically, R 15 is hydrogen or a methyl group.
  • X 2 is N. More typically, X 1 is N and X 2 is N.
  • Q 1 is S, or N-H. In one aspect, Q 1 is NH.
  • a compound of Formula (VIIa) as defined above wherein: X 15 is O or NR 15 ; j is 1; k is 2; p is 2; q is 2; r is 0; s is 0; R 15 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group; X 1 is N; X 2 is N; and Q 1 is S or N-H. Typically in such an aspect, R 15 is hydrogen or a methyl group.
  • j is 1 or 2; k is 1 or 2; p is 1 or 2; q is 1 or 2; r is 0; and s is 0. More typically in accordance with the fourteenth exemplary embodiment: j is 2; k is 2; p is 1; q is 1; r is 0; and s is 0.
  • R 15 is hydrogen or a methyl or fluoromethyl group. More typically, R 15 is hydrogen.
  • X 2 is N. More typically, X 1 is N and X 2 is N.
  • Q 1 is S, or N-H.
  • Q 1 is NH.
  • a compound of Formula (VIIIa) as defined above wherein: j is 2; k is 2; p is 1; q is 1; r is 0; s is 0; R 15 is hydrogen or a methyl or fluoromethyl group; X 1 is N; X 2 is N; and Q 1 is S or N-H.
  • R 15 is hydrogen.
  • a compound of Formula (IXa) as defined above wherein: w is 1 or 2; X 15 is O or NR 15 ; R 15 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl, fluorocyclopropylmethyl or -CO-R 150 group; R 150 is selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; one R 17 and one R 18 together form a -CH2- or -CH2CH2- group; each remaining R 17 and R 18 is hydrogen; X 1 is N or C-H; and X 2 is N or C-H; provided that at least one of X 1 and X 2 is N; Q 1 is O, S, N-H or N
  • R 15 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group. More typically, R 15 is hydrogen or a methyl or fluoromethyl group.
  • X 2 is N. More typically, X 1 is N and X 2 is N.
  • Q 1 is S, or N-H. In one aspect, Q 1 is NH.
  • R 3 is selected from a -(C(R 105 )2)e-Q 10 -R 106 or -(C(R 105 )2)e-Q 10 -(C(R 105 )2)f-Q 11 -R 106 group, provided that any -(C(R 105 )2)e-Q 10 -R 106 or -(C(R 105 )2)e-Q 10 -(C(R 105 )2)f-Q 11 -R 106 group contains no more than 8 carbon atoms
  • Q 10 is selected from O or NR 107 ;
  • Q 11 is selected from O or NR 108 ;
  • e is 2, 3 or 4;
  • f is 2, 3 or 4;
  • each R 105 is hydrogen;
  • R 106 is selected from a hydrogen or a methyl, ethyl, isopropyl or cyclopropyl group, any of which may optionally be fluor
  • R 3 is a -(CH2)2-NR 106 R 107 group, wherein: R 106 is selected from a methyl, ethyl, isopropyl or cyclopropyl group, any of which may optionally be fluoro substituted; and R 107 is selected from hydrogen or a methyl or fluoromethyl group.
  • X 2 is N. More typically, X 1 is N and X 2 is N.
  • Q 1 is S, or N-H. In one aspect, Q 1 is NH.
  • j is 1 or 2; k is 1 or 2; p is 1 or 2; q is 1 or 2; r is 0; and s is 0.
  • R 15 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group. More typically, R 15 is hydrogen or a methyl or fluoromethyl group.
  • X 2 is N. More typically, X 1 is N and X 2 is N.
  • Q 1 is S, or N-H.
  • Q 1 is NH.
  • R x is selected from a 5- or 6-membered heteroaryl or a bicyclic fused heteroaryl group, wherein the ring atoms of the 5- or 6-membered heteroaryl group or the bicyclic fused heteroaryl group are selected from the group consisting of nitrogen and carbon atoms, and wherein the 5- or 6-membered heteroaryl group or the bicyclic fused heteroaryl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/or with a single group R 5 ;
  • R 5 is selected from a -NH2, -R 51 , -NHR 51 or -N(R 51 )2 group; each R 51 is independently selected from a methyl or fluoromethyl group;
  • X 1 is
  • the 5- or 6- membered heteroaryl group or the bicyclic fused heteroaryl group is unsubstituted
  • X 2 is N. More typically, X 1 is N and X 2 is N.
  • Q 1 is S, or N-H. In one aspect, Q 1 is NH.
  • R x is selected from a phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or the 5- or 6-membered heteroaryl group is substituted with a first substituent selected from a -NH2, -NHR 53 , -N(R 53 )2, -CH2-NH2, -CH2-NHR 53 or -CH2-N(R 53 )2 group, provided that the group -N(R 53 )2 contains no more than five carbon atoms, and wherein the phenyl or the 5- or 6-membered heteroaryl group may optionally be further substituted with a single methyl or fluoromethyl group and/or with one or more fluoro, chloro and/or bromo groups; each R 53 is independently selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalky
  • R x is selected from a phenyl or a pyridinyl group, wherein the phenyl or the pyridinyl group is substituted with a -NH2, -NHR 53 , -N(R 53 )2, -CH2-NH2, -CH2-NHR 53 or -CH2-N(R 53 )2 group, wherein each R 53 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group, or any two R 53 attached to the same nitrogen atom may together form a C3-C4 alkylene or a C3-C4 fluoroalkylene group, provided that the group -N(R 53 )2 contains no more than four carbon atoms.
  • X 2 is N. More typically, X 1 is N and X 2 is N.
  • Q 1 is S, or N-H. In one aspect, Q 1 is NH.
  • the compound of the first aspect of the invention has a molecular weight of from 250 to 1000 Da. Typically, the compound of the first aspect of the invention has a molecular weight of from 300 to 750 Da. More typically, the compound of the first aspect of the invention has a molecular weight of from 350 to 600 Da.
  • a second aspect of the invention provides a compound selected from the group consisting of:
  • a third aspect of the invention provides a pharmaceutically acceptable salt and/or solvate and/or prodrug of any compound of the first or second aspect of the invention.
  • the third aspect of the invention provides a pharmaceutically acceptable salt and/or solvate of any compound of the first or second aspect of the invention.
  • the third aspect of the invention may provide (i) a pharmaceutically acceptable salt of any compound of the first or second aspect of the invention, or (ii) a pharmaceutically acceptable solvate of any compound of the first or second aspect of the invention, or (iii) a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of any compound of the first or second aspect of the invention.
  • the compounds of the present invention can be used both, in their free base form and their acid addition salt form.
  • a “salt” of a compound of the present invention includes an acid addition salt.
  • Acid addition salts are preferably pharmaceutically acceptable, non-toxic addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulfuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, trifluoroacetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethan
  • the acid addition salt may be a mono-, di-, tri- or multi-acid addition salt.
  • a preferred salt is a hydrohalogenic, sulfuric, phosphoric or organic acid addition salt.
  • a preferred salt is a hydrochloric acid addition salt.
  • a compound of the invention includes a quaternary ammonium group, typically the compound is used in its salt form.
  • the counter ion to the quaternary ammonium group may be any pharmaceutically acceptable, non-toxic counter ion. Examples of suitable counter ions include the conjugate bases of the protic acids discussed above in relation to acid addition salts.
  • the compounds of the present invention can also be used both, in their free acid form and their salt form.
  • a “salt” of a compound of the present invention includes one formed between a protic acid functionality (such as a carboxylic acid group) of a compound of the present invention and a suitable cation. Suitable cations include, but are not limited to lithium, sodium, potassium, magnesium, calcium and ammonium.
  • the salt may be a mono-, di-, tri- or multi-salt.
  • the salt is a mono- or di-lithium, sodium, potassium, magnesium, calcium or ammonium salt. More preferably the salt is a mono-sodium salt or a mono- potassium salt.
  • any salt is a pharmaceutically acceptable non-toxic salt.
  • the compounds and/or salts of the present invention may be anhydrous or in the form of a hydrate (e.g. a hemihydrate, monohydrate, dihydrate or trihydrate) or other solvate.
  • Such other solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
  • the third aspect of the invention provides a prodrug of any compound of the first or second aspect of the invention.
  • the third aspect of the invention may provide a pharmaceutically acceptable salt and/or solvate of such a prodrug.
  • the third aspect of the invention may provide (i) a pharmaceutically acceptable salt of a prodrug, or (ii) a pharmaceutically acceptable solvate of a prodrug, or (iii) a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of a prodrug.
  • therapeutically inactive prodrugs are provided.
  • Prodrugs are compounds which, when administered to a subject such as a human, are converted in whole or in part to a compound of the invention.
  • the prodrugs are pharmacologically inert chemical derivatives that can be converted in vivo to the active drug molecules to exert a therapeutic effect.
  • Any of the compounds described herein can be administered as a prodrug to increase the activity, bioavailability, or stability of the compound or to otherwise alter the properties of the compound.
  • Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs include, but are not limited to, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, and/or dephosphorylated to produce the active compound.
  • the present invention also encompasses salts and solvates of such prodrugs as described above.
  • the compounds, salts, solvates and prodrugs of the present invention may be obtained in all grades of purity, for example via conventional techniques such as recrystallisation and/or column chromatography.
  • the compounds, salts, solvates and prodrugs of the present invention may be at least 90% pure, at least 95% pure, at least 99% pure, at least 99.5% pure or at least 99.9% pure, as measured by HPLC.
  • the compounds, salts, solvates and prodrugs of the present invention may be at least 90% pure, at least 95% pure, at least 99% pure, at least 99.5% pure or at least 99.9% pure, as measured by LCMS.
  • the compounds, salts, solvates and prodrugs of the present invention may be at least 90% pure, at least 95% pure, at least 99% pure, at least 99.5% pure or at least 99.9% pure, as measured by 1 H NMR.
  • the compounds, salts, solvates and prodrugs of the present invention may contain any stable isotope including, but not limited to 12 C, 13 C, 1 H, 2 H (D), 14 N, 15 N, 16 O, 17 O, 18 O, 19 F and 127 I, and any radioisotope including, but not limited to 11 C, 14 C, 3 H (T), 13 N, 15 O, 18 F, 123 I, 124 I, 125 I and 131 I.
  • the compounds, salts, solvates and prodrugs of the present invention may be in any polymorphic or amorphous form.
  • a fourth aspect of the invention provides an antibody-drug conjugate comprising a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug of the third aspect of the invention.
  • the compound, salt, solvate or prodrug needs to lose at least one atom such as a hydrogen atom in order to form the link to the antibody.
  • the compound, salt, solvate or prodrug of the present invention comprises a a -NH- group, a -NH2 group, a -OH group, or a -SH group, each of which can be used to link the compound, salt, solvate or prodrug to an antibody, with the loss of a hydrogen atom from the -NH-, NH2, -OH or -SH group.
  • the antibody- drug conjugate can have the Formula (I-AB), (II-AB), (III-AB), (IV-AB), (VII-AB), (VIII-AB) or (X-AB): Formula (II-AB)
  • Typical antibodies that may be used to prepare the antibody-drug conjugate of the fourth aspect of the invention are: ⁇ Cetuximab ⁇ Trastuzumab ⁇ Brentuximab ⁇ ado-Trastuzumab ⁇ Polatuzumab ⁇ Inotuzumab ⁇ Gemtuzumab ⁇ Sacituzumab ⁇ Enfortumab ⁇ Loncastuximab ⁇ fam-Trastuzumab ⁇ Tisotumab ⁇ Belantamab ⁇ Mirvetuximab ⁇ Amivantamab
  • the antibody-drug conjugate has the Formula (I-AB), (II-AB), (III-AB), (IV-AB), (VII-AB), (VIII-AB) or (X-AB)
  • the antibody AB may be selected from any of the above.
  • the linker L AB comprises a maleimide moiety, one or more PEG spacers, optionally a BCN moiety, a valine-citrulline (Val-Cit) dipeptide, and a para- aminobenzyl (PAB) spacer.
  • the hydrocarbylene group of linker L AB has a chain length of from 20 to 80 atoms. More typically, the hydrocarbylene group has a chain length of from 30 to 70 atoms, or from 40 to 60 atoms.
  • chain length of a hydrocarbylene group refers to the number of atoms of the hydrocarbylene group that are bonded to each other in a continuous chain between the two points of attachment of the hydrocarbylene group to the remainder of the molecule, as measured by the shortest route.
  • Typical linkers that may be used to link a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug of the third aspect of the invention, to an antibody to prepare the antibody-drug conjugate of the fourth aspect of the invention are: ⁇ maleimide-valine-citruline-PABC, including those comprising PEG and/or a BCN-derived moiety ⁇ thioether ⁇ hydrazone and disulfide ⁇ CL2a linker ⁇ maleimide-valine-alanine-PABC ⁇ maleimide tetrapeptide linker (GGFG) ⁇ Maleidocaproic linker ⁇ Sulfo-SPDB disulfide
  • the antibody-drug conjugate has the Formula (I-AB), (II-AB), (III
  • the antibody-drug conjugate is Cetuximab-mal-vc-4-(1,4-Diazepan-1-yl)-8-oxo-11-thia-1,3,5- triazatetracyclo[8.7.0.02 , 7.012 , 17]heptadeca-2(7),3,5,9,12,14,16-heptaene-9- carboxylic acid or a pharmaceutically acceptable salt and/or solvate thereof.
  • a fifth aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug of the third aspect of the invention, or an antibody-drug conjugate of the fourth aspect of the invention, and a pharmaceutically acceptable excipient.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Aulton’s Pharmaceutics - The Design and Manufacture of Medicines”, M. E. Aulton and K. M. G. Taylor, Churchill Livingstone Elsevier, 4 th Ed., 2013.
  • compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • the pharmaceutical composition comprises a compound of the first aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein X 2 is not C-F and wherein R X2 is not -NO2.
  • Q 1 is O, S or NH.
  • a pharmaceutical composition comprising a compound of the first aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein X 2 is C-H or C-R X2 , wherein R X2 is selected from -OH, -SH, -NH2, or a C1-C4 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or two heteroatoms each independently selected from N, O and S in its carbon skeleton.
  • R X2 is a C1-C3 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, and wherein the hydrocarbyl group may optionally include a single heteroatom selected from N and O in its carbon skeleton.
  • Q 1 is O, S or NH.
  • X 1 is N.
  • the compound of the first aspect of the invention, or the pharmaceutically acceptable salt and/or solvate and/or prodrug thereof may be such that X 1 is N, X 2 is C-H, and Q 1 is O, S or NH.
  • the pharmaceutical composition comprises a compound of the first aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein: X 1 is N, C-H or C-R X1 ; X 2 is N, C-H or C-R X2 ; X 3 is N, C-H or C-R X3 ; and X 4 is C; provided that at least one of X 1 , X 2 and X 3 is N and that no more than two of X 1 , X 2 and X 3 are N; and wherein R X1 , R X2 and R X3 are each independently selected from -OH, -SH, -NH2, or a C1-C4 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more
  • the pharmaceutical composition may comprise a compound of any of the first to fifth exemplary embodiments of the first aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein: X 1 is N, C-H or C-R X1 ; X 2 is N, C-H or C-R X2 ; X 3 is N, C-H or C-R X3 ; and X 4 is C.
  • the pharmaceutical composition may comprise a compound of the eighth exemplary embodiment of the first aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein X 1 is N or C-H and X 2 is N or C-H.
  • the pharmaceutical composition comprises a compound of the first aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein -R X is -OR 3 .
  • a sixth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug of the third aspect of the invention, or an antibody-drug conjugate of the fourth aspect of the invention, or a pharmaceutical composition of the fifth aspect of the invention, for use in medicine, and/or for use in the treatment or prevention of a disease, disorder or condition.
  • the use comprises the administration of the compound, salt, solvate, prodrug, antibody-drug conjugate or pharmaceutical composition to a subject.
  • treatment refers equally to curative therapy, and ameliorating or palliative therapy.
  • the term includes obtaining beneficial or desired physiological results, which may or may not be established clinically.
  • beneficial or desired clinical results include, but are not limited to, the alleviation of symptoms, the prevention of symptoms, the diminishment of extent of disease, the stabilisation (i.e., not worsening) of a condition, the delay or slowing of progression/worsening of a condition/symptom, the amelioration or palliation of a condition/symptom, and remission (whether partial or total), whether detectable or undetectable.
  • prevention means that the extent and/or undesirable manifestations of a physiological condition or symptom are lessened and/or time course of the progression is slowed or lengthened, as compared to not administering a compound, salt, solvate, prodrug, antibody-drug conjugate or pharmaceutical composition of the present invention.
  • prevention as used herein in relation to a disease, disorder or condition, relates to prophylactic or preventative therapy, as well as therapy to reduce the risk of developing the disease, disorder or condition.
  • prevention includes both the avoidance of occurrence of the disease, disorder or condition, and the delay in onset of the disease, disorder or condition.
  • a seventh aspect of the invention provides the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug of the third aspect of the invention, or an antibody-drug conjugate of the fourth aspect of the invention, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition.
  • the treatment or prevention comprises the administration of the compound, salt, solvate, prodrug, antibody-drug conjugate or medicament to a subject.
  • An eighth aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the step of administering an effective amount of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug of the third aspect of the invention, or an antibody-drug conjugate of the fourth aspect of the invention, or a pharmaceutical composition of the fifth aspect of the invention, to thereby treat or prevent the disease, disorder or condition.
  • the administration is to a subject in need thereof.
  • the compound of the first aspect of the invention, or the pharmaceutically acceptable salt and/or solvate and/or prodrug thereof is a compound of Formula (I), or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein X 2 is not C-F and wherein R X2 is not -NO2.
  • Q 1 is O, S or NH.
  • the compound of the first aspect of the invention may be a compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein X 2 is C-H or C-R X2 , wherein R X2 is selected from -OH, -SH, -NH2, or a C1-C4 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one or two heteroatoms each independently selected from N, O and S in its carbon skeleton.
  • X 2 is C-H or C-R X2
  • R X2 is selected from -OH, -SH, -NH2, or a C1-C4 saturated hydrocarbyl group
  • the hydrocarbyl group may be straight-chained or branched,
  • R X2 is a C1-C3 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, and wherein the hydrocarbyl group may optionally include a single heteroatom selected from N and O in its carbon skeleton.
  • Q 1 is O, S or NH.
  • X 1 is N.
  • the compound of the first aspect of the invention, or the pharmaceutically acceptable salt and/or solvate and/or prodrug thereof may be such that X 1 is N, X 2 is C-H, and Q 1 is O, S or NH.
  • the compound of the first aspect of the invention, or the pharmaceutically acceptable salt and/or solvate and/or prodrug thereof is a compound of Formula (I), or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein: X 1 is N, C-H or C-R X1 ; X 2 is N, C-H or C-R X2 ; X 3 is N, C-H or C-R X3 ; and X 4 is C; provided that at least one of X 1 , X 2 and X 3 is N and that no more than two of X 1 , X 2 and X 3 are N; and wherein R X1 , R X2 and R X3 are each independently selected from -OH, -SH, -NH2, or a C1-C4 saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be
  • the compound of the first aspect of the invention, or the pharmaceutically acceptable salt and/or solvate and/or prodrug thereof may be a compound of any of the first to fifth exemplary embodiments of the first aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein: X 1 is N, C-H or C-R X1 ; X 2 is N, C-H or C-R X2 ; X 3 is N, C-H or C-R X3 ; and X 4 is C.
  • the compound of the first aspect of the invention, or the pharmaceutically acceptable salt and/or solvate and/or prodrug thereof may be a compound of the eighth exemplary embodiment of the first aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, wherein X 1 is N or C-H and X 2 is N or C-H.
  • a ninth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug of the third aspect of the invention, or an antibody-drug conjugate of the fourth aspect of the invention, or a pharmaceutical composition of the fifth aspect of the invention, for use in the treatment or prevention of a cancer.
  • the use comprises the administration of the compound, salt, solvate, prodrug, antibody-drug conjugate or pharmaceutical composition to a subject.
  • a tenth aspect of the invention provides the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug of the third aspect of the invention, or an antibody-drug conjugate of the fourth aspect of the invention, in the manufacture of a medicament for the treatment or prevention of a cancer.
  • the treatment or prevention comprises the administration of the compound, salt, solvate, prodrug, antibody-drug conjugate or medicament to a subject.
  • An eleventh aspect of the invention provides a method of treatment or prevention of a cancer, the method comprising the step of administering an effective amount of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug of the third aspect of the invention, or an antibody-drug conjugate of the fourth aspect of the invention, or a pharmaceutical composition of the fifth aspect of the invention, to thereby treat or prevent the cancer.
  • the administration is to a subject in need thereof.
  • the compound of the first or second aspect of the invention, or the pharmaceutically acceptable salt and/or solvate and/or prodrug of the third aspect of the invention, or the antibody-drug conjugate of the fourth aspect of the invention, or the pharmaceutical composition of the fifth aspect of the invention can be combined with other therapeutic agents and treatments, for example, to exploit synergies and enhance the cytotoxic activity in cancer treatment.
  • the compound, salt, solvate, prodrug, antibody-drug conjugate or pharmaceutical composition can used in combination with X-ray radiation; DNA alkylating agents like cisplatin; NU7441, an inhibitor of DNA repair regulating kinase DNA-PK; MK1775, an inhibitor of the cell cycle regulator WEE1 kinase; Pimozide, an inhibitor of the deubiquitinylation enzyme USP1; NSC697923, an inhibitor of ubiquitin conjugating enzyme UBE2N; APR-246, a P53 activator; PARP inhibitors; topoisomerase 1 knockdown; HDAC inhibitors; lysosome inhibitors; and immunomodulators.
  • DNA alkylating agents like cisplatin
  • NU7441 an inhibitor of DNA repair regulating kinase DNA-PK
  • MK1775 an inhibitor of the cell cycle regulator WEE1 kinase
  • Pimozide an inhibitor of the deubiquitinylation enzyme USP1
  • the subject may be any human or other animal.
  • the subject is a mammal, more typically a human or a domesticated mammal such as a cow, pig, lamb, sheep, goat, horse, cat, dog, rabbit, mouse etc. Most typically, the subject is a human.
  • any of the medicaments employed in the present invention can be administered by oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), airway (aerosol), rectal, vaginal, ocular or topical (including transdermal, buccal, mucosal, sublingual and topical ocular) administration.
  • parenteral including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural
  • airway asperaerosol
  • rectal rectal
  • vaginal ocular
  • topical including transdermal, buccal, mucosal, sublingual and topical ocular
  • the mode of administration selected is that most appropriate to the disorder, disease or condition to be treated or prevented.
  • the compounds, salts, solvates, prodrugs or antibody-drug conjugates of the present invention will generally be provided in the form of tablets, capsules, hard or soft gelatine capsules, caplets, troches or lozenges, as a powder or granules, or as an aqueous solution, suspension or dispersion.
  • Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose.
  • Binding agents may include starch and gelatine.
  • the lubricating agent if present, may be magnesium stearate, stearic acid or talc.
  • the tablets may be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Tablets may also be effervescent and/or dissolving tablets.
  • Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent, and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • Powders or granules for oral use may be provided in sachets or tubs.
  • Aqueous solutions, suspensions or dispersions may be prepared by the addition of water to powders, granules or tablets.
  • Any form suitable for oral administration may optionally include sweetening agents such as sugar, flavouring agents, colouring agents and/or preservatives.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds, salts, solvates, prodrugs or antibody-drug conjugates of the present invention will generally be provided in a sterile aqueous solution or suspension, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer’s solution and isotonic sodium chloride or glucose.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • the compounds of the invention may also be presented as liposome formulations.
  • the compounds, salts, solvates, prodrugs or antibody-drug conjugates of the invention will generally be provided in a form suitable for topical administration, e.g. as eye drops.
  • suitable forms may include ophthalmic solutions, gel-forming solutions, sterile powders for reconstitution, ophthalmic suspensions, ophthalmic ointments, ophthalmic emulsions, ophthalmic gels and ocular inserts.
  • the compounds, salts, solvates or prodrugs of the invention may be provided in a form suitable for other types of ocular administration, for example as intraocular preparations (including as irrigating solutions, as intraocular, intravitreal or juxtascleral injection formulations, or as intravitreal implants), as packs or corneal shields, as intracameral, subconjunctival or retrobulbar injection formulations, or as iontophoresis formulations.
  • intraocular preparations including as irrigating solutions, as intraocular, intravitreal or juxtascleral injection formulations, or as intravitreal implants
  • packs or corneal shields as intracameral, subconjunctival or retrobulbar injection formulations, or as iontophoresis formulations.
  • the compounds, salts, solvates, prodrugs or antibody-drug conjugates of the invention will generally be provided in the form of ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters or patches. Suitable suspensions and solutions can be used in inhalers for airway (aerosol) administration.
  • the dose of the compounds, salts, solvates, prodrugs or antibody-drug conjugates of the present invention will, of course, vary with the disease, disorder or condition to be treated or prevented. In general, a suitable dose will be in the range of 0.01 to 500 mg per kilogram body weight of the recipient per day.
  • the desired dose may be presented at an appropriate interval such as once every other day, once a day, twice a day, three times a day or four times a day.
  • the desired dose may be administered in unit dosage form, for example, containing 1 mg to 50 g of active ingredient per unit dosage form. All citations are incorporated herein by reference in their entirety. For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention. In addition, insofar as is practicable it is to be understood that any preferred, typical or optional embodiment of any aspect of the present invention should also be considered as a preferred, typical or optional embodiment of any other aspect of the present invention. References 1. Silverman, R. B.
  • LCMS method All final compounds were purified to ⁇ 95% purity as determined Shimadzu LC-20AD XR&MS 2020 with UV detection at 220 nm using the following method: Halo C18 column (5.0 ⁇ m, 3.0 mm ⁇ 30 mm), eluting with binary solvent systems A and B using a 5 ⁇ 95% B over 3.0 minutes gradient elution [A, H2O with 0.04% TFA; B, CH3CN with 0.02% TFA]; flow rate 1.0 mL/min. Mass spectral data were recorded on an Shimadzu LC-20AD XR&MS 2020 with UV detection, ESI.
  • Preparative HPLC method TFA as buffer: Preparative reversed-phase high pressure liquid chromatography (RP- HPLC) was performed using a Gilson 281 Semi-preparative HPLC system and Phenomenex Luna C18 column (5 ⁇ m, 100 mm ⁇ 40 mm), eluting with binary solvent systems A and B using a gradient elution [A, H2O with 0.1% TFA; B, CH3CN] with UV detection at 220 nm.
  • RP- HPLC reversed-phase high pressure liquid chromatography
  • HCl as buffer Preparative reversed-phase high pressure liquid chromatography (RP- HPLC) was performed using a Gilson 281 Semi-preparative HPLC system and Phenomenex Luna C18 column (5 ⁇ m, 100 mm ⁇ 40 mm), eluting with binary solvent systems A and B using a gradient elution [A, H2O with 0.04% HCl; B, CH3CN] with UV detection at 220 nm.
  • NH4HCO3 as buffer Preparative reversed-phase high pressure liquid chromatography (RP-HPLC) was performed using a Gilson 281 Semi-preparative HPLC system and Waters Xbridge Prep OBD C18 (10 ⁇ m, 150 mm ⁇ 40 mm), eluting with binary solvent systems A and B using a gradient elution [A, H2O with 10mM NH4HCO3; B, CH3CN] with UV detection at 220 nm.
  • RP-HPLC Reparative reversed-phase high pressure liquid chromatography
  • Ethyl 2-chloro-5-oxo-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3-b]- pyrazine-6-carboxylate To a solution of ethyl 2-(1,3-benzothiazol-2-yl)acetate (5 g, 22.60 mmol, 1 eq) and MgCl2 (3.23 g, 33.89 mmol, 1.39 mL, 1.5 eq) in THF (50 mL) was added 3,5-dichloropyrazine-2-carbonyl chloride (6.21 g, 29.38 mmol, 1.3 eq) and DIEA (11.68 g, 90.39 mmol, 15.74 mL, 4 eq) at 0 °C.
  • TEA 4.35 g, 43.01 mmol, 5.99 mL, 2 eq
  • TEA 4.30 g, 42.50 mmol, 5.92 mL, 2 eq
  • the reaction mixture was concentrated in vacuo and the crude product was triturated with H2O at 25°C for 20 min, filtered and filter cake was further triturated with MeCN at 25°C for 20 min before being filtered.
  • the filter cake was dried under vacuum to give the title compound (7.1 g, 20.74 mmol, 97.60% yield) as a purple solid.
  • the mixture was stirred at 25°C for 1 h.
  • the reaction mixture was concentrated under reduced pressure and to the mixture was added water (40 mL).
  • the pH was adjusted to pH 1-2 with HCl, the mixture filtered and the filter cake was concentrated in vacuo.
  • the crude product was purified by reversed- phase HPLC (column: CD18-Welch Utimate C18 150*40*7 ⁇ m; mobile phase: [H2O (0.1%TFA)-ACN]; gradient:0%-29% B over 10.0 min) to give the title compound (340 mg, 628.85 ⁇ mol, 37.11% yield, 98.86% purity, TFA) as a yellow solid.
  • the reaction mixture was filtered and the filter cake was concentrated under reduce pressure.
  • the crude product was purified by prep-HPLC (column: CD24- WePure Biotech XPT C18 150*25*7 ⁇ m; mobile phase: [H2O (0.05%HCl)-ACN]; gradient: 0%-28% B over 10.0 min) to give an eluent and the eluent was concentrated under reduce pressure to remove MeCN then lyophilized to give the title compound (24.5 mg, 53.98 ⁇ mol, 4.68% yield, 97.36% purity, HCl) as a yellow solid.
  • Ethyl 2-(4-methyl-1,4-diazepan-1-yl)-5-oxo-5H-benzo[4,5]thiazolo[3,2-a]- [1,8]naphthyridine-6-carboxylate A mixture of ethyl 2-chloro-5-oxo-[1,3]- benzothiazolo[3,2-a][1,8]naphthyridine-6-carboxylate (550 mg, 1.53 mmol, 1 eq) and 1-methyl-1,4-diazepane (0.350 g, 3.06 mmol, 0.381 mL, 2 eq) in MeCN (10.00 mL) was stirred at 80°C for 2 h.
  • Ethyl 2-chloro-5-oxo-[1,3]benzothiazolo[3,2-a][1,6]naphthyridine-6- carboxylate To a solution of ethyl 2-(1,3-benzothiazol-2-yl)acetate (5 g, 22.6 mmol, 1 eq) and MgCl2 (3.23 g, 33.8 mmol, 1.39 mL, 1.5 eq) in ACN (50 mL) was added 4,6- dichloropyridine-3-carbonyl chloride (6.18 g, 29.3 mmol, 1.3 eq) and TEA (9.14 g, 90.2 mmol, 4 eq) slowly at -10°C.
  • Ethyl 2-chloro-5-oxo-7H-benzimidazolo[1,2-a][1,6]naphthyridine-6- carboxylate To a solution of ethyl 3-(4,6-dichloro-3-pyridyl)-2-(1,3- dihydrobenzimidazol-2-ylidene)-3-oxo-propanoate (11 g, 29.08 mmol, 1 eq) in THF (100 mL) was added TEA (5.89 g, 58.17 mmol, 8.10 mL, 2 eq). The mixture was stirred at 80°C for 12h. The reaction mixture was concentrated under reduced pressure to remove solvent.
  • Example 63 4-(2,8-Diazaspiro[4.5]decan-2-yl)-8-oxo-1,3,5,11- tetrazatetracyclo[8.7.0.0 2,7 .0 12,17 ]heptadeca-2,4,6,9,12(17),13,15-heptaene- 9-carboxylic acid
  • 4-(8-tert-butoxycarbonyl-2,8-diazaspiro[4.5]decan-2-yl)-8-oxo- 1,3,5,11-tetrazatetracyclo [8.7.0.0 2,7 .0 12,17 ]heptadeca-2,4,6,9,12(17),13,15- heptaene-9-carboxylic acid 150 mg
  • tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,6,6a- tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate To a solution of tert-butyl 5- (trifluoromethylsulfonyloxy)-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2- carboxylate (5 g, 13.99 mmol, 1 eq) and bis(pinacolato)diboron (BPD) (4.26 g, 16.79 mmol, 1.2 eq) in dioxane (100 mL) was added KOAc (4.12 g, 41.98 mmol, 3 eq), Pd(dppf)Cl2 (307.14 mg, 419.76 ⁇ mol, 0.03 eq) and dppf (232.71 mg, 419.
  • Example 67 4-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl)-8-oxo- 11-thia-1,3,5-triazatetracyclo[8.7.0.0 2,7 .0 12,17 ]heptadeca- 2,4,6,9,12(17),13,15-heptaene-9-carboxylic acid
  • ethyl 4-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl)-8-oxo- 11-thia-1,3,5-triazatetracyclo[8.7.0.0 2,7 .0 12,17 ]heptadeca-2,4,6,9,12(17),13,15- heptaene-9-carboxylate (200 mg, 460.29 ⁇ mol, 1 eq) in THF (2 mL) and MeOH (2 mL) was added LiOH
  • Flash chromatographic purifications were carried out using CombiFlash Rf (Teledyne Isco) with a Interchim column (PF-15C18HP-F0025), with H2O-Acetonitrile gradient.
  • 1 H NMR spectra were recorded at ambient temperature using an internal deuterium lock on Bruker DPX (400 MHz; 1 H DUL probe) and Bruker Avance III HD (400 MHz; Smart probe). Excess solvents were removed either by rotary evaporation on Buchi Rotavapor R-114 or Genevac EZ-2 Elite.
  • Bioconjugation Small molecules, drugs and fluorophores were removed from antibodies/bioconjugates via ZebaTM Spin Desalting Columns and Plates, 7K and 40K MWCO, 0.5 mL–5 mL, unless otherwise stated. Equivalents of drugs added to antibodies/bioconjugates are reported as 1:1 antibody:drug (i.e. not accounting number of available cysteine residues for reaction).
  • UV-vis spectra were recorded over a range of 220 – 650 nm on a Thermo ScientificTM NanoDropTM One Microvolume UV-vis spectrophotometer and was used to determine concentration of bioconjugates, and FAR (Fluorophore-to- Antibody Ratio).
  • SPR sulfhydryl per protein ratio
  • Typical conditions were capillary voltage 1.6-2.2 kV, cone voltage 160– 190 V, Trap 40 ⁇ 50 V, Transfer 140 V with backing pressure 3–4 mbar and source temperature of 20 °C.
  • Data acquisition and processing were performed using MassLynx 4.1. The raw data was converted to zero charge mass spectra using a maximum entropy deconvolution algorithm, over the full peak regions as identified via the LC trace. All full antibody samples were deglycosylated with PNGase F enzyme treatment prior to LC-MS analysis. A 2-step protocol was utilised for Cetuximab antibody and respective conjugates to efficiently remove Fab and Fc region N-glycans.
  • ADC Synthetic Route Example ADC-1 Cetuximab-mal-vc-4-(1,4-Diazepan-1-yl)-8-oxo-11-thia- 1,3,5-triazatetracyclo[8.7.0.02 , 7.012 , 17]heptadeca-2(7),3,5,9,12,14,16- heptaene-9-carboxylic acid
  • Intermediate 1 4-(1,4-Diazepan-1-yl)-8-oxo-11-thia-1,3,5-triazatetracyclo- [8.7.0.02 , 7.012 , 17]heptadeca-2(7),3,5,9,12,14,16-heptaene-9-carboxylic acid (0.028 mmol.1 eq.) and DIPEA (0.028 mmol, 1.1 eq.) were added to a solution of azido- PEG3-Val-Cit-PAB-PNP (20 mg, 0.026 mmol) in DMF (5
  • P53 (-/-) were seeded at 150 cells/mL and 184-hTERT-L9 83.86 (P53 (-/-) BRCA1 (-/-) were seeded at 250 cells/mL in supplemented MEBM media into 12-well tissue culture plates and incubated overnight at 37 °C in a humidified 5% CO2 atmosphere. Following overnight incubation cells were dosed with serial diluted compounds or DMSO vehicle and incubated for a further 7 days at 37 °C in a humidified 5% CO2 atmosphere. Colonies were stained with Crystal violet (0.05% w/v) after fixation with 90% methanol.
  • Liver Hepatocyte Assay Test compounds are incubated at 37°C with cryopreserved liver hepatocytes (pooled from multiple donors) at 0.5 ⁇ 10 6 cells per mL. The reaction samples will be removed at multiple time points (0, 15, 30, 60, and 90 minutes), and medium control samples without cells at 0 and 90 minutes will be incubated. All samples will be immediately mixed with cold organic solution containing internal standard (IS) to stop the reaction.
  • IS internal standard
  • test compounds or positive control warfarin will be spiked into frozen plasma (commercial vendors, pooled from multiple individuals) at the final concentration of 2 ⁇ M.
  • An aliquot of 150 ⁇ L of the compound-spiked plasma sample will be added to one side of the chamber in a 96-well equilibrium dialysis plate (HTD dialysis) and an equal volume of dialysis buffer (100 mM sodium phosphate and 150 mM NaCl, 7.4 ⁇ 0.1) will be added to the other side of the chamber.
  • Plasma sample will be harvested before the incubation and used as T0 samples for recovery calculation. Triplicate incubations will be performed. The plate will then be incubated in a humidified incubator with 5% CO2 at 37°C for 4 hours. After incubation, 50 ⁇ L samples will be taken from the plasma side as well as the buffer side. The plasma sample will be mixed with an equal volume of blank buffer; buffer samples will be mixed with an equal volume of blank plasma. The matrix-matched samples will be quenched with stop solution containing internal standard (IS). Samples are analyzed by LC-MS/MS. Test compound concentrations in plasma and buffer samples will be determined based on peak area ratio of analyte to IS without a standard curve. Cell Titre Glow Data IC50 ( ⁇ M) values:

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Abstract

La présente invention concerne des composés de formule (I) et des sels, solvates et promédicaments pharmaceutiquement acceptables de ceux-ci : Formule (I) dans laquelle RX, X1, X2, X3, X4, Q1, A1, A2, A3, A4, A5 et A6 sont tels que définis dans la description, et des conjugués anticorps-médicament (ADC) comprenant les composés. La présente invention concerne également des procédés de préparation des composés et des ADC, des compositions pharmaceutiques les contenant et leur utilisation en thérapie, en particulier pour une utilisation dans le traitement de cancers.
PCT/EP2024/088233 2023-12-21 2024-12-20 Dérivés de quinolone contre le cancer Pending WO2025133338A1 (fr)

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GB2319820.3 2023-12-21
GBGB2417508.5A GB202417508D0 (en) 2024-11-28 2024-11-28 Novel compounds
GB2417508.5 2024-11-28

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA852769B (en) * 1984-04-26 1985-11-27 Abbott Lab Benzothiazolo-quinoline antibacterial compounds
WO2009046383A1 (fr) * 2007-10-05 2009-04-09 Cylene Pharmaceuticals, Inc. Analogues de quinolone et procédés associés
CN104177379A (zh) * 2013-05-22 2014-12-03 中国科学院上海药物研究所 一种喹诺酮类化合物或其立体化学异构体、包含该化合物的药物组合物及其用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA852769B (en) * 1984-04-26 1985-11-27 Abbott Lab Benzothiazolo-quinoline antibacterial compounds
WO2009046383A1 (fr) * 2007-10-05 2009-04-09 Cylene Pharmaceuticals, Inc. Analogues de quinolone et procédés associés
CN104177379A (zh) * 2013-05-22 2014-12-03 中国科学院上海药物研究所 一种喹诺酮类化合物或其立体化学异构体、包含该化合物的药物组合物及其用途

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] Chemical Abstract Service, Columbus, Ohio, US; 1 January 1987 (1987-01-01), CHU DANIEL TIM WO: "5H-Benzothiazolo[3,2-a]quinoline-6-carboxylate antibacterial compounds", XP093254598, retrieved from https://stn.org/stn/# Database accession no. 1987:18529 *
DINAKARAN M ET AL: "Antitubercular activities of novel benzothiazolo naphthyridone carboxylic acid derivatives endowed with high activity toward multi-drug resistant tuberculosis", BIOMEDICINE & PHARMACOTHERAPY, ELSEVIER, FR, vol. 63, no. 1, 1 January 2009 (2009-01-01), pages 11 - 18, XP025845765, ISSN: 0753-3322, [retrieved on 20071120], DOI: 10.1016/J.BIOPHA.2007.10.009 *
FU ZHIWEN ET AL: "Antibody drug conjugate: the "biological missile" for targeted cancer therapy", SIGNAL TRANSDUCTION AND TARGETED THERAPY, vol. 7, no. 1, 1 December 2022 (2022-12-01), XP093049353, ISSN: 2095-9907, DOI: 10.1038/s41392-022-00947-7 *
HILTON, J ET AL.: "Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies", NAT. COMMUN., vol. 13, 2022, pages 3607
KHOT, A ET AL.: "First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study", CANCER DISCOV., vol. 9, 2019, pages 1036 - 1049
M. E. AULTONK. M. G. TAYLOR: "Aulton's Pharmaceutics - The Design and Manufacture of Medicines", 2013, ELSEVIER
SILVERMAN, R. B.HOLLADAY, M. W.: "The Organic Chemistry of Drug Design and Drug Action", 2014, ELSEVIER

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