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WO2025242908A2 - Nouveaux composés - Google Patents

Nouveaux composés

Info

Publication number
WO2025242908A2
WO2025242908A2 PCT/EP2025/064379 EP2025064379W WO2025242908A2 WO 2025242908 A2 WO2025242908 A2 WO 2025242908A2 EP 2025064379 W EP2025064379 W EP 2025064379W WO 2025242908 A2 WO2025242908 A2 WO 2025242908A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
groups
optionally
oxo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/064379
Other languages
English (en)
Inventor
Shankar Balasubramanian
Paul Meo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genome Therapeutics Ltd
Original Assignee
Genome Therapeutics Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB2407455.1A external-priority patent/GB202407455D0/en
Priority claimed from GBGB2417511.9A external-priority patent/GB202417511D0/en
Application filed by Genome Therapeutics Ltd filed Critical Genome Therapeutics Ltd
Publication of WO2025242908A2 publication Critical patent/WO2025242908A2/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—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 5 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.
  • Small molecules that interact with genomic DNA have a long history of use in cancer chemotherapy (e.g. cisplatin family and anthracyclines). 1 Such molecules target DNA indiscriminately and display broad toxicity in patients owing to their lack of molecular and biological specificity. Despite adverse toxicity, these drugs are still widely 15 deployed in the clinic.
  • G-quadruplexes are four-stranded, non-canonical nucleic acid secondary structures which can form in guanine-rich DNA and RNA sequences.
  • G4 motifs are 20 particularly enriched at repetitive elements of the genome, e.g. telomeres, and at gene regulatory regions of protein-coding genes including many oncogenes.
  • Folded DNA and RNA G4s have been visualized in human cells and tissues, 6–8 mapped in human chromatin and the human transcripome, 9–12 and overall been found to be 25 more abundant in cancer-like cells and tissues 7,9 .
  • G4s have been implicated in several key genome functions such as transcription, replication, translation, telomere maintenance and epigenetic regulation. 13 Many G4s are likely transient and readily resolved by helicases 14 . Unresolved DNA G4s can 30 impede DNA polymerases causing DNA damage and requiring homologous recombination (HR) repair 15,16 . Some compounds, named G4 ligands (G4L), have been shown to interact with and stabilise G4s in vitro and in human chromatin 17–19 .
  • G4Ls have been explored as therapeutic agents and shown antiproliferative and chemosensitizing effects against cancer cell lines and tumour models 18,20–22 .
  • DNA G4 stabilization may interfere with replication and transcription, affect epigenetic - 2 - modifications, promote DNA damage, affect the biogenesis and interactions of coding and non-coding RNA or impair telomerase and thereby inhibit tumour growth.
  • Different G4L chemotypes have been described to mediate genome-wide perturbations, target a subset of G4 topologies and particular G4s in certain 5 oncogenes.
  • G4Ls are synthetic lethal with loss of various10 cellular functions 24 , in particular DNA damage repair 25–28 , suggesting a biomarker- driven therapeutic approach as well as combination treatment with other agents.
  • Some G4Ls have shown activity in HR-deficient cells and tumour models that were resistant to PARP inhibitor treatment as well as gemcitabine-resistant pancreatic cancer cells, indicating that some G4Ls may be used to target difficult to treat certain 15 tumours with acquired resistances.
  • 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 20 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 25 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, 30 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. 35
  • 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- - 6 - 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 10 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 15 (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 20 atoms. More typically, a cyclic group is a 3- to 7-membered monocyclic group, which means it contains from 3 to 7 ring atoms.
  • 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 25 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, 30 piperazinyl, dioxanyl, morpholinyl and thiomorpholinyl groups.
  • non-aromatic heterocyclic groups such as azetinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imid
  • 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 35 stated otherwise, a cycloalkyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
  • 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- 5 dien-1-yl.
  • a cycloalkenyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
  • aryl substituent group or an aryl moiety in a substituent group refers to an aromatic hydrocarbyl ring.
  • aryl refers to monocyclic aromatic hydrocarbons 10 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. Examples of aryl groups/moieties include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless stated otherwise, the term “aryl” does not include “heteroaryl”. 15 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.
  • 5- or 6-membered heteroaryl groups 25 include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl groups.
  • a cyclic group or moiety is stated to be aromatic, such 30 as an aryl or a heteroaryl 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 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 - 8 - (excluding any ring systems which are part of or formed by optional substituents) is non-aromatic.
  • a cyclic group or moiety is stated to be saturated, 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 5 substituents) is saturated.
  • 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 10 group is attached to the rest of the molecule.
  • An example of an arylalkyl group is benzyl.
  • each hydrogen atom may optionally be replaced by any specified monovalent 15 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 20 - 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 25 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.
  • an optionally substituted group or moiety e.g. R 1
  • R 2 a second group 30 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 - 9 - 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.
  • a group 5 is prefixed by a specific halo group, it is to be understood that the group in question is substituted with one or more of the specific halo groups.
  • fluoromethyl 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.
  • halo substituents typically, 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.
  • 15 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 20 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 25 reference to all tautomers of that compound or group.
  • ⁇ is replaced by N ⁇ ; provided that the resultant group comprises at least one carbon atom.
  • methoxy, dimethylamino and aminoethyl groups are considered to be hydrocarbyl 5 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.
  • 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 15 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 are not to be counted as carbon atoms when calculating the number of carbon atoms in a Cx-Cy group.
  • a morpholinyl group is to be considered a C4 heterocyclic group, not a C6 heterocyclic group. 20
  • a first atom or group is “directly attached” to a second atom or group it is to be understood that the first atom or group is covalently bonded to the second atom or group with no intervening atom(s) or group(s) being present.
  • the carbon atom of each methyl group is directly attached to the nitrogen atom and the carbon atom of the carbonyl group is directly attached to the nitrogen atom, but the carbon atom of the carbonyl group is not directly attached to the carbon atom of either methyl group.
  • the bicyclic or tricyclic group of R 1 may be a fused, spiro or bridged bicyclic or tricyclic group, or in the case of a tricyclic group any combination thereof.
  • the bicyclic or tricyclic group of R 1 is a fused or spiro bicyclic or a fused or spiro tricyclic group, or a fused and spiro tricyclic group. More typically, the bicyclic or tricyclic group of R 1 is a fused bicyclic or a fused tricyclic group. 10
  • the bicyclic or tricyclic group of R 1 is a bicyclic group.
  • the bicyclic or tricyclic group of R 1 may be a fused, spiro or bridged bicyclic group.
  • the bicyclic or tricyclic group of R 1 is a fused or spiro bicyclic group.
  • the bicyclic or tricyclic group of R 1 is a bicyclic group, typically the bicyclic group is a 6- to 13-membered bicyclic group. More typically, the bicyclic group is a 7- to 12-membered bicyclic group.
  • the bicyclic or tricyclic group of R 1 is a heterocyclic group. 20 Typically, the bicyclic or tricyclic group of R 1 is saturated.
  • the ring atom of the bicyclic or tricyclic group of R 1 that is directly attached to the remainder of the molecule is a nitrogen atom.
  • the bicyclic or tricyclic group of R 1 contains at least one ring nitrogen or ring oxygen atom that is not directly attached to the remainder of the molecule. More typically, the bicyclic or tricyclic group of R 1 contains at least one ring nitrogen atom that is not directly attached to the remainder of the molecule.
  • the fused bicyclic heterocyclic group comprises a first ring system that is directly attached to the remainder of the molecule and a second ring system that is fused to the first ring system, wherein both 5 the first and the second ring system are non-aromatic.
  • at least one of the first and the second ring systems is saturated. More typically, both the first and the second ring systems are saturated.
  • the first ring system contains a ring nitrogen atom that is directly attached to the remainder of the molecule.
  • the second ring system contains a ring nitrogen atom.
  • the fused bicyclic 10 heterocyclic group contains no more than three ring heteroatoms.
  • 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. More typically, 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 11 may be independently selected from a -OH, -NH2, -R 110 , -CO-R 111 , -OR 110 , -NHR 110 or -N(R 110 )2 group, wherein each R 110 is independently selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or 35 fluorocyclopropylmethyl group, or any two R 110 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 110 )2 contains no more than four carbon atoms, and wherein each R 111 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or - 14 - fluorocyclopropyl group.
  • each R 11 is independently selected from a -OH, -NH2, -R 110 , -OR 110 , -NHR 110 or -N(R 110 )2 group, wherein each R 110 is independently selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl or C3-C4 fluorocycloalkyl group, or any two R 110 attached to the same nitrogen atom may together form a C2-C4 5 alkylene or a C2-C4 fluoroalkylene group, provided that the group -N(R 110 )2 contains no more than four carbon atoms.
  • the fused bicyclic heterocyclic group comprises a first ring system that is 20 directly attached to the remainder of the molecule and a second ring system that is fused to the first ring system, wherein both the first and the second ring system are saturated.
  • the first ring system contains a ring nitrogen atom that is directly attached to the remainder of the molecule.
  • the second ring system contains a ring nitrogen atom.
  • the fused bicyclic heterocyclic group contains no more 25 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. More typically, 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 11 may be independently selected from a -OH, -NH2, -R 110 , -CO-R 111 , -OR 110 , -NHR 110 or -N(R 110 )2 group, wherein each R 110 is independently - 15 - selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group, or any two R 110 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 110 )2 contains no more than four carbon atoms, 5 and wherein each R 111 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • each R 11 is independently selected from a -OH, -NH2, -R 110 , -OR 110 , -NHR 110 or -N(R 110 )2 group, wherein each R 110 is independently selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl or C3-C4 fluorocycloalkyl group, or any two R 110 attached to the same nitrogen atom may 10 together form a C2-C4 alkylene or a C2-C4 fluoroalkylene group, provided that the group -N(R 110 )2 contains no more than four carbon atoms.
  • each R 11 is independently selected from a -NH2, -R 110 , -CO-R 111 , -NHR 110 or -N(R 110 )2 group, wherein each R 110 is 15 independently selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group, or any two R 110 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 110 )2 contains no more than four carbon atoms, and wherein each R 111 is independently selected from a C1-C3 alkyl, C1- 20
  • each R 11 may be independently selected from a -NH2, -R 110 , -NHR 110 or -N(R 110 )2 group, wherein each R 110 is independently selected from a methyl or fluoromethyl group. More typically, where 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 110 or -CO-R 111 , 25 wherein if present -R 110 or -CO-R 111 is directly attached to a ring nitrogen atom of the saturated fused bicyclic heterocyclic group, wherein R 110 is selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group, and wherein R 111 is selected from a C1-C3 alkyl, C1-C3 al
  • the compound is a compound of Formula (Ia): 25 Formula (Ia) - 17 - wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 2 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • m is 1 or 2 and n is 1 or 2. More typically, m is 1 5 and n 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.
  • r is 0 and s is 0.
  • R 12 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group. More typically, R 12 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group. More typically still, R 12 is hydrogen or a methyl or 10 fluoromethyl group.
  • R 1 may have a formula selected from: 15
  • R 1 has the formula: wherein: 20 r is 0, 1 or 2; s is 0, 1 or 2; t is 1 or 2; and each R 13 is independently selected from a methyl or fluoromethyl group.
  • the compound is a compound of Formula (Ib): - 19 - Formula (Ib) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 2 , R 3 , R 13 , r, s and t are as defined in accordance with Formula (I). 5
  • r is 0 and s is 0.
  • t is 1.
  • R 1 may have the formula: .
  • the compound is a compound of Formula (Ic): Formula (Ic) 5 wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 2 , R 3 , R 13 , m, n, r, s and v are as defined in accordance with Formula (I).
  • m is 1 or 2 and n is 1 or 2. More typically, m is 1 and n is 1. 10
  • v is 1.
  • r is 0 and s is 0. 15
  • R 1 may have the formula: .
  • R 1 may have the formula: .
  • 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 15 heteroatoms.
  • the first ring system is a 4- to 7-membered ring and the second ring system is a 4- to 7-membered ring. More typically, 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 11 may be independently selected from a -OH, -NH2, -R 110 , -CO-R 111 , -OR 110 , -NHR 110 or -N(R 110 )2 group, wherein each R 110 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 110 attached to the same nitrogen atom 30 may together form a C2-C4 alkylene or a C2-C4 fluoroalkylene group, provided that the group -N(R 110 )2 contains no more than four carbon atoms, and wherein each R 111 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • each R 11 is independently selected from a -NH2, -R 110 , -CO-R 111 , -NHR 110 or -N(R 110 )2 group, wherein each R 110 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 110 attached to the - 22 - same nitrogen atom may together form a C2-C4 alkylene or a C2-C4 fluoroalkylene group, provided that the group -N(R 110 )2 contains no more than four carbon atoms, and wherein each R 111 is independently selected from a C1-C3 alkyl
  • the saturated fused 5 bicyclic heterocyclic group is substituted, it is substituted with one or more fluoro groups and/or a single group selected from -R 110 or -CO-R 111 , wherein if present -R 110 or -CO-R 111 is directly attached to a ring nitrogen atom of the saturated fused bicyclic heterocyclic group, wherein R 110 is selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group, 10 and wherein R 111 is selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • the compound is a compound of Formula (Id): 5 Formula (Id) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 2 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • p is 0, 1 or 2 and q is 1 or 2. More typically, p is 1 20 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.
  • R 12 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1- 25 C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group.
  • R 12 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • R 1 may have the formula: - 24 - .
  • the 15 spiro bicyclic heterocyclic group comprises a first ring system that is directly attached to the remainder of the molecule and a second ring system that shares a spiro ring atom with the first ring system, wherein both the first and the second ring system are non-aromatic.
  • at least one of the first and the second ring systems is saturated. More typically, both the first and the second ring systems are saturated.
  • the first ring system contains a ring nitrogen atom that is directly attached to the remainder of the molecule.
  • the second ring system contains a ring nitrogen or a ring oxygen atom. More typically, the second ring system contains a ring nitrogen atom.
  • the spiro bicyclic heterocyclic group contains no more than three ring heteroatoms. More typically, the spiro bicyclic heterocyclic group contains25 no more than two ring heteroatoms.
  • the first ring system is a 4- to 7- membered ring and the second ring system is a 3- to 7-membered ring. More typically, 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 11 may be independently selected from a -OH, -NH2, 10 -R 110 , -CO-R 111 , -OR 110 , -NHR 110 or -N(R 110 )2 group, wherein each R 110 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 110 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 110 )2 contains no more than four carbon atoms, 15 and wherein each R 111 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • the spiro bicyclic heterocyclic group comprises a first ring system that is 30 directly attached to the remainder of the molecule and a second ring system that shares a spiro ring atom with the first ring system, wherein both the first and the second ring system are saturated.
  • the first ring system contains a ring nitrogen atom that is directly attached to the remainder of the molecule.
  • the second ring system contains a ring nitrogen or a ring oxygen atom. More typically, the 35 second ring system contains a ring nitrogen atom.
  • the spiro bicyclic heterocyclic group contains no more than three ring heteroatoms.
  • the spiro 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 3- to - 26 - 7-membered ring. More typically, 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 11 may be independently selected from a -OH, -NH2, -R 110 , -CO-R 111 , -OR 110 , -NHR 110 or -N(R 110 )2 group, wherein each R 110 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 110 attached to the same nitrogen atom 15 may together form a C2-C4 alkylene or a C2-C4 fluoroalkylene group, provided that the group -N(R 110 )2 contains no more than four carbon atoms, and wherein each R 111 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • the ring nitrogen atom is a ring nitrogen atom of the second ring system.
  • the compound is a compound of Formula (Ie): - 28 - Formula (Ie) wherein X 1 -X 4 , X 12 , A 1 -A 6 , Q 1 , R 2 , R 3 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • m is 1 or 2 and n is 1 or 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.
  • r is 0 and s is 0.
  • R 12 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1- C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl 15 group. More typically, R 12 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group. More typically, R 12 is hydrogen or a methyl or fluoromethyl group.
  • R 1 may have a formula selected from: 20
  • m is 1, n is 1, p is 1 or 2, q is 1, r is 0 and s is 0.
  • R 12 is hydrogen.
  • the compound is a compound of Formula (If): Formula (If) 25 wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 2 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • - 30 Typically in such an embodiment, m is 1 or 2 and n is 1 or 2. More typically, m is 2 and n is 2. 5 Typically in such an embodiment, p is 1 or 2 and q is 1 or 2. More typically, p is 1 and q is 1. Typically in such an embodiment, r is 0 and s is 0.
  • R 12 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group. More typically, R 12 is hydrogen or a methyl or fluoromethyl group. More typically still, R 12 is hydrogen.
  • R 1 may have the formula: 15 .
  • the non-aromatic bridged bicyclic heterocyclic group is saturated.
  • the non-aromatic bridged 30 bicyclic heterocyclic group contains a ring nitrogen atom that is directly attached to the remainder of the molecule.
  • the non-aromatic bridged bicyclic heterocyclic group contains at least one further ring nitrogen or a ring oxygen atom. More typically, the non-aromatic bridged bicyclic heterocyclic group contains at least one further ring nitrogen atom.
  • the non-aromatic bridged bicyclic 35 heterocyclic group contains no more than three ring heteroatoms. More typically, the - 31 - non-aromatic bridged bicyclic heterocyclic group contains no more than two ring heteroatoms.
  • R 1 is a non-aromatic bridged bicyclic heterocyclic group
  • the group is a 7- to 9-membered bridged bicyclic group. More typically, the group is a 7- or 8-membered bridged bicyclic group.
  • each R 11 may be independently selected from a -OH, -NH2, -R 110 , -CO-R 111 , -OR 110 , -NHR 110 or -N(R 110 )2 group, wherein each R 110 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 110 attached to the 25 same nitrogen atom may together form a C2-C4 alkylene or a C2-C4 fluoroalkylene group, provided that the group -N(R 110 )2 contains no more than four carbon atoms, and wherein each R 111 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • the ring nitrogen atom of the saturated bridged bicyclic heterocyclic group is directly attached to the remainder of the molecule.
  • the saturated bridged bicyclic heterocyclic group contains at 5 least one further ring nitrogen or a ring oxygen atom. More typically, the saturated bridged bicyclic heterocyclic group contains at least one further ring nitrogen atom.
  • the saturated bridged bicyclic heterocyclic group contains no more than three ring heteroatoms. More typically, the saturated bridged bicyclic heterocyclic group contains no more than two ring heteroatoms.
  • R 1 is a saturated 10 bridged bicyclic heterocyclic group
  • the group is a 7- to 9-membered bridged bicyclic group.
  • the group is a 7- or 8-membered bridged bicyclic group.
  • each R 11 may be independently selected from a -OH, -NH2, -R 110 , -CO-R 111 , -OR 110 , -NHR 110 or -N(R 110 )2 group, wherein each R 110 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 110 attached to the same nitrogen atom may together form a C2-C4 alkylene or a C2-C4 fluoroalkylene 25 group, provided that the group -N(R 110 )2 contains no more than four carbon atoms, and wherein each R 111 is independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • R 1 has the formula: wherein: 10 w is 1 or 2; X 12 is O or NR 12 ; R 12 is 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 15 fluorocyclopropyl group; one R 14 and one R 15 together form a -CH2- or -CH2CH2- group; and each remaining R 14 and R 15 is hydrogen.
  • the compound is a compound of 20 Formula (Ig): Formula (Ig) wherein X 1 -X 4 , X 12 , A 1 -A 6 , Q 1 , R 2 , R 3 , R 14 , R 15 and w are as defined in accordance with Formula (I). 25 Typically in such an embodiment, w is 1. - 34 - Typically in such an embodiment, X 12 is NR 12 .
  • R 12 is hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1- 5 C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group. More typically, R 12 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group. More typically still, R 12 is hydrogen or a methyl or fluoromethyl group. Yet more typically, R 12 is a methyl or fluoromethyl group.
  • R 14 and one R 15 together form a -CH2CH2- group.
  • R 1 may have the formula: . 15
  • R 3 is selected from hydrogen or a C1-C4 alkyl, C1- C4 fluoroalkyl, C3-C4 cycloalkyl or C3-C4 fluorocycloalkyl group. More typically, R 3 is selected from hydrogen or a methyl, ethyl, fluoromethyl or fluoroethyl group. More typically still, R 3 is selected from hydrogen or a methyl or fluoromethyl group. Most 35 typically, R 3 is hydrogen.
  • the hydrocarbyl group of R 2 includes at least one heteroatom selected from N, O and S in its carbon skeleton.
  • the - 37 - hydrocarbyl group of R 2 includes at least one heteroatom selected from N and O in its carbon skeleton.
  • the hydrocarbyl group of R 2 may comprise a primary, secondary or tertiary amine, wherein the nitrogen atom of the primary, secondary or tertiary amine is not directly attached to a sp 2 hybridised carbon atom.
  • R 3 is 25 selected from hydrogen or a methyl, ethyl, fluoromethyl or fluoroethyl group. More typically, R 3 is selected from hydrogen or a methyl or fluoromethyl group. More typically still, R 3 is hydrogen.
  • the hydrocarbyl group of R 2 includes at least 30 one nitrogen atom in its carbon skeleton, wherein said nitrogen atom is a nitrogen atom of a tertiary amine and wherein said nitrogen atom is not directly attached to a sp 2 hybridised carbon atom.
  • R 3 is selected from hydrogen or a methyl, ethyl, fluoromethyl or fluoroethyl group. More typically, R 3 is selected from hydrogen or a methyl or fluoromethyl group. More typically still, R 3 is hydrogen.
  • the hydrocarbyl group of R 2 may include at least one oxygen atom in its 20 carbon skeleton, wherein said oxygen atom is not directly attached to a sp 2 hybridised carbon atom.
  • R 3 is selected from hydrogen or a methyl, ethyl, fluoromethyl or fluoroethyl group. More typically, R 3 is selected from hydrogen or a methyl or fluoromethyl group. More 5 typically still, R 3 is hydrogen.
  • the hydrocarbyl group of R 2 may include at least one oxygen atom in its carbon skeleton, wherein said oxygen atom is an oxygen atom of an ether and wherein said oxygen atom is not directly attached to a sp 2 10 hybridised carbon atom.
  • R 3 is selected from hydrogen or a methyl, ethyl, fluoromethyl or fluoroethyl group. More typically, R 3 is selected from hydrogen or a methyl or fluoromethyl group. More typically still, R 3 is hydrogen. 35 Alternatively still, the hydrocarbyl group of R 2 may include at least one sulphur atom in its carbon skeleton, wherein said sulphur atom is not directly attached to a sp 2 hybridised carbon atom.
  • R 3 is selected from hydrogen or a methyl, 20 ethyl, fluoromethyl or fluoroethyl group. More typically, R 3 is selected from hydrogen or a methyl or fluoromethyl group. More typically still, R 3 is hydrogen.
  • the hydrocarbyl group of R 2 may include at least one sulphur atom in its carbon skeleton, wherein said sulphur atom is a sulphur 25 atom of a thioether and wherein said sulphur atom is not directly attached to a sp 2 hybridised carbon atom.
  • R 3 is selected from hydrogen 10 or a methyl, ethyl, fluoromethyl or fluoroethyl group. More typically, R 3 is selected from hydrogen or a methyl or fluoromethyl group. More typically still, R 3 is hydrogen.
  • the group -CONR 2 R 3 is acyclic, i.e. the group -CONR 2 R 3 does not contain any cyclic moieties or groups. 15 In other embodiments, the group -CONR 2 R 3 contains at least one cyclic moiety or group.
  • the resultant cyclic 35 group is a saturated heterocyclic group.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl or piperidinyl group.
  • R 2 and R 3 together with the nitrogen atom to which they are attached 10 form a 6- or 7-membered saturated monocyclic group or a 8- or 9-membered saturated fused bicyclic group. More typically in such an embodiment, R 2 and R 3 together with the nitrogen atom to which they are attached form a 6- or 7-membered saturated monocyclic group.
  • said further ring nitrogen atom is substituted with a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl or C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group. More typically in such an aspect, said further ring nitrogen atom is substituted with a C1-C4 5 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl or C3-C4 fluorocycloalkyl group.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a 6- or 7-membered saturated monocyclic group or a 8- or 9-membered saturated fused bicyclic group. More typically in such an aspect, R 2 and R 3 together with the nitrogen atom to which they are attached form a 6- or 7-membered saturated 10 monocyclic group.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a 6- or 7-membered saturated monocyclic group.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated monocyclic group or a 7- to 10- 30 membered saturated bicyclic group, wherein the monocyclic group or the bicyclic group is substituted with a -N(R 25 )2 group, wherein each R 25 is independently selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group, or wherein any two R 25 together form a C2-C4 allkylene or C2-C4 fluoroallkylene group, and wherein 35 the monocyclic group or the bicyclic group may optionally be further substituted
  • each R 25 is independently selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl or C3-C4 fluorocycloalkyl group, such as a methyl, fluoromethyl, ethyl or fluoroethyl group, or any two R 25 together form a C2-C4 allkylene or C2-C4 fluoroallkylene group.
  • R 2 and R 3 together with the nitrogen atom to which they are attached 10 form a 4- to 7-membered saturated monocyclic group.
  • each R 25 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 25 together form a C2-C4 allkylene or C2-C4 15 fluoroallkylene group.
  • each R 25 is independently selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl or C3-C4 fluorocycloalkyl group, such as a methyl, fluoromethyl, ethyl or fluoroethyl group, or any two R 25 together form a C2-C4 allkylene or C2-C4 fluoroallkylene group.
  • R 25 is selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 35 cycloalkyl or C3-C4 fluorocycloalkyl group.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated monocyclic group.
  • R 25 is selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl or C3-C4 fluorocycloalkyl group.
  • R 25 is selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl or C3-C4 fluorocycloalkyl group, such as a methyl, fluoromethyl, ethyl or fluoroethyl group.
  • each R 24 is independently selected from a -OH, -NH2, -R 240 , -OR 240 , -NHR 240 or -N(R 240 )2 group, wherein each R 240 is independently selected from a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group (more typically a C1-C4 alkyl, C1- 10 C4 fluoroalkyl, C3-C4 cycloalkyl or C3-C4 fluorocycloalkyl group) provided that the group -N(R 240 )2 contains no more than four carbon atoms, or any two R 240 attached to the same nitrogen atom may together form a C2-C4 alkylene or a C2-C4 fluoroalkylene group.
  • each R 24 is independently selected from a -NH2, -R 240 , -NHR 240 or -N(R 240 )2 group, wherein each R 240 is independently selected from a methyl or 15 fluoromethyl group. More typically still, each R 24 is independently selected from a methyl or fluoromethyl group.
  • the group -CONR 2 R 3 contains no more than 12 carbon atoms. More typically, the group -CONR 2 R 3 contains no more than 10 carbon 20 atoms. More typically still, the group -CONR 2 R 3 contains no more than 8 carbon atoms.
  • R 2 is selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 25 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group
  • R 3 is selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group; or 30 R 2 and R 3 together with the nitrogen atom to which they are attached form a azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group, any of which may optionally be fluoro-substituted.
  • R 2 is selected from hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl or cyclopropylmethyl group
  • R 3 is selected from hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl or cyclopropylmethyl group
  • - 47 - R 2 and R 3 together with the nitrogen atom to which they are attached form a azetidinyl, pyrrolidinyl or piperidinyl group.
  • R 2 is selected from hydrogen or a methyl or ethyl group
  • R 3 is selected from hydrogen or a methyl or ethyl group
  • -CONR 2 R 3 may have the formula -CONH2, -CONHMe, -CON(Me)2, .
  • R 3 is hydrogen.
  • -CONR 2 R 3 may have the formula -CONH2, -CONHMe or -CONHEt. 15
  • -CONR 2 R 3 has the formula -CONH 2 .
  • the compound is a compound of Formula (II): Formula (II) 20 wherein R 1 , X 1 -X 4 , A 1 -A 6 and Q 1 are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (III): 10 Formula (III) wherein R 1 , X 1 -X 4 , A 1 -A 6 , Q 1 , Q 2 , R 3 , L 2 and R 21 are as defined in accordance with Formula (I).
  • R 1 , X 1 -X 4 , A 1 -A 6 , Q 1 , Q 2 , R 3 , L 2 and R 21 are as defined in accordance with Formula (I).
  • the two or more groups may together form a single ring atom or more than one ring atom of the cyclic group.
  • L 2 may have the formula: .
  • the group -CO-N(R 3 )-L 2 -Q 2 -R 21 contains no more than 10 carbon atoms. More typically, the group -CO-N(R 3 )-L 2 -Q 2 -R 21 contains no more than 8 carbon atoms.
  • Q 2 is O or NR 22 . More typically, Q 2 is NR 22 .
  • the atom of the alkylene group of L 2 that is directly attached to the nitrogen atom of N-R 3 is a carbon atom.
  • L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-O-CH2CH2-, -CH2CH2CH2-O-CH2CH2-, -CH2CH2-O-CH2CH2CH2-, -CH2CH2-NH-CH2CH2-, -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the -CH2CH2-O-CH2CH2-, the -CH2CH2CH2-O-CH2CH2-, the 20 -CH2CH2-O-CH2CH2CH2-, the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group may optionally be substituted with one or more fluoro groups and/or one or two groups R L2 .
  • L 2 may be a C2-C4 straight- chained alkylene group, wherein the alkylene group may optionally be substituted with one or more fluoro groups and/or one or two groups R L2 . More typically still in such an 25 embodiment, L 2 is a C2-C3 straight-chained alkylene group, wherein the alkylene group may optionally be substituted with one or more fluoro groups and/or one or two groups R L2 .
  • -CONR 2 R 3 has the formula -CO-N(R 3 )-L 2 -Q 2 -R 21 , the atom of R 3 that is 30 directly attached to the nitrogen atom of N-R 3 is a hydrogen atom or a carbon atom.
  • R 22 is hydrogen or a C1-C4 alkyl group, wherein the alkyl group may be straight-chained or branched, or be or include a single cyclic group, and wherein the alkyl group may optionally be 5 substituted with one or more fluoro groups. More typically in such an embodiment, R 22 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group. In another embodiment, the atom of R 22 that is directly attached to the nitrogen atom of -NR 21 R 22 is the carbon atom of a carbonyl group or the sulphur atom of a -SO- or 10 -SO2- group.
  • the atom of R 220 that is directly attached to the carbon atom of the -CO-R 220 group or that is directly attached to the sulphur atom of the SO-R 220 or -SO2-R 220 group is a sp 3 hybridised carbon atom.
  • R 220 is a C1-C4 alkyl group, wherein the alkyl group may be straight- chained or branched, or be or include a single cyclic group, and wherein the alkyl group may optionally be substituted with one or more fluoro groups.
  • R 220 is a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group. 25
  • -CONR 2 R 3 has the formula -CO-N(R 3 )-L 2 -Q 2 -R 21 , R 21 is not hydrogen and, if present, R 22 is not hydrogen.
  • R 3 and any R L2 may, together with the atoms to which they are attached, form a 5- to 7-membered saturated monocyclic heterocyclic group, - 55 - wherein the 5- to 7-membered saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 .
  • R 3 and R 21 together with the atoms to which they are attached form a 5 6- or 7-membered saturated monocyclic heterocyclic group
  • a 6- or 7-membered saturated monocyclic heterocyclic group such as a morpholinyl, 10 piperazinyl or diazepanyl group
  • the 6- or 7-membered saturated monocyclic heterocyclic group may optionally be substituted with one or more
  • R 3 and R 21 may, together with the atoms to which they are attached, form a 6- or 7-membered saturated monocyclic heterocyclic 20 group, wherein the 6- or 7-membered saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 .
  • each R L2 is independently selected from a methyl or a fluoromethyl 35 group, or any two R L2 may, together with the atom or atoms to which they are attached, form a C3-C6 cycloalkylene group or a 4- to 7-membered saturated heterocyclic group, wherein the C3-C6 cycloalkylene group or the 4- to 7-membered saturated heterocyclic group may optionally be substituted with one or more fluoro - 56 - groups and/or one or two groups R L3 .
  • each R L2 may be independently selected from a methyl or a fluoromethyl group, or any two R L2 may, together with the carbon atom or carbon atoms to which they are attached, form a C3-C5 cycloalkylene group, wherein the C3-C5 cycloalkylene group may optionally be substituted with one 5 or more fluoro groups and/or one or two groups R L3 . More typically in such an embodiment, each R L2 is independently selected from a methyl or a fluoromethyl group.
  • a 4- to 7-membered saturated monocyclic heterocyclic group such as15 an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group
  • any R L2 and R 21 may, together with the atoms to which they are attached, form a 5- to 7-membered saturated monocyclic heterocyclic group, wherein the 5- to 7-membered saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 .
  • R 21 and R 22 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated monocyclic heterocyclic group
  • a 3- to 6-membered saturated monocyclic heterocyclic group such as an aziridinyl, azetidinyl, pyrrolidinyl, piperidin
  • R 21 and R 22 may together with the nitrogen atom to which they are attached form a 3- to 5-membered saturated monocyclic heterocyclic group, such as an aziridinyl, azetidinyl, or pyrrolidinyl group, wherein the 3- to 5-membered saturated monocyclic heterocyclic group may optionally be substituted with one or 5 more fluoro groups and/or one or two groups R L3 .
  • R 3 and any two R L2 may, together 15 with the atoms to which they are attached, form a 8- to 10-membered saturated fused bicyclic heterocyclic group, wherein the 8- to 10-membered saturated fused bicyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 .
  • R 3 , R 21 and any R L2 may, together with the atoms to which they are attached, form a 8- to35 10-membered saturated fused bicyclic heterocyclic group, wherein the 8- to 10- membered saturated fused bicyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 .
  • R 3 , R 21 and R 22 may, together with the atoms to which they are attached, form a 9- or 10-membered saturated fused bicyclic heterocyclic group, wherein the 9- or 10-membered saturated fused bicyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 .
  • any two R L2 and R 21 may, together with the atoms to which they are attached, form a 8- to 10-membered saturated fused bicyclic heterocyclic group, wherein the 8- to 10-membered saturated fused bicyclic heterocyclic group may 35 optionally be substituted with one or more fluoro groups and/or one or two groups R L3 .
  • any R L2 , R 21 and R 22 may, together with the atoms to which they are attached, form a 8- to 10-membered saturated fused bicyclic heterocyclic group, wherein the 8- to 10-membered saturated fused bicyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 .
  • -CONR 2 R 3 has the formula: wherein: L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-O-CH2CH2-, 20 -CH2CH2CH2-O-CH2CH2-, -CH2CH2-O-CH2CH2CH2-, -CH2CH2-NH-CH2CH2-, -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the -CH 2 CH 2 -O-CH 2 CH 2 -, the -CH 2 CH 2 CH 2 -O-CH 2 CH 2 -, the -CH 2 CH 2 -O-CH 2 CH 2 CH 2 -, the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group may optional
  • the compound is a compound of 25 Formula (IV): Formula (IV) wherein R 1 , X 1 -X 4 , A 1 -A 6 , Q 1 , R 3 , L 2 , R 21 and R 22 are as defined in accordance with Formula (I).
  • -CONR 2 R 3 has the formula: 20 wherein: L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-O-CH2CH2-, -CH 2 CH 2 CH 2 -O-CH 2 CH 2 -, -CH 2 CH 2 -O-CH 2 CH 2 CH 2 -, -CH 2 CH 2 -NH-CH 2 CH 2 -, -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the -CH2CH2-O-CH2CH2-, the -CH2CH2CH2-O-CH2CH2-, the -CH2CH2-O-CH2CH2CH2-, the 25 -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group may optionally be substituted with one or more fluoro
  • L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group may 30 optionally be substituted with one or more fluoro groups and/or one or two groups R L2 ;
  • R 22 is not selected from a -CO-R 220 , -SO-R 220 or -SO2-R 220 group; and each R L2 is independently selected from a methyl or fluoromethyl group; or R 3 and any R L2 may, together with the atoms to which they are attached, 35 form a 5- to 7-membered saturated monocyclic heterocyclic group, wherein the 5- to 7-membered saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 ; - 66 - or any R L2 and R 21 may, together with the atoms to which they are attached, form a 5- to 7-membered saturated monocyclic heterocyclic group, wherein the 5- to 7-
  • L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group may 15 optionally be substituted with one or more fluoro groups and/or one or two groups R L2 ; each R L2 is independently selected from a methyl or a fluoromethyl group; R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; 20 R 21 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; and R 22 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or
  • R 3 is hydrogen.
  • -CONR 2 R 3 may have the formula: 35 - 67 -
  • L 2 is a C2-C4 straight-chained alkylene group
  • 5 R 3 is hydrogen
  • R 21 is hydrogen or a methyl group
  • R 22 is hydrogen or a C1-C3 alkyl or cyclopropyl group.
  • 10 L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group is substituted with one group R L2 , and wherein the alkylene group may optionally be further substituted with one or more fluoro groups;
  • R 3 and R L2 together with the atoms to which they are attached, form a 5- to 7- membered saturated monocyclic heterocyclic group, wherein the 5- to 7-membered 15 saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 ;
  • R 21 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; or R 3 , R 21 and R L2 may, together with the atoms to which they are attached, 20 form a 8- to 10-membered saturated fused bicyclic heterocyclic group, wherein the 8- to 10-membered saturated
  • -CONR 2 R 3 may have the formula: 30 .
  • - 68 - R 3 and R L2 together with the atoms to which they are attached, form a 5- to 7- membered saturated monocyclic heterocyclic group, wherein the 5- to 7-membered saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 ; and 5 R 21 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • R 22 is hydrogen or a methyl group. Most typically, R 22 is hydrogen.
  • L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group is substituted with two groups R L2 , and wherein the alkylene group may optionally be further substituted with one or more fluoro groups; 15 the two R L2 , together with the carbon atom or carbon atoms to which they are attached, form a C3-C6 cycloalkylene group, wherein the C3-C6 cycloalkylene group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 ; R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or 20 fluorocyclopropyl group; R 21 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; R 22 is hydrogen or a -CO-R 220
  • R 3 is hydrogen.
  • R 21 is hydrogen or a methyl group
  • 35 is hydrogen or a -CO-R 220 , C1-C3 alkyl or cyclopropyl group
  • R 220 is a C1-C3 alkyl or cyclopropyl group.
  • -CONR 2 R 3 may have the formula: - 69 - .
  • 5 L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-NH-CH2CH2-, -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group is substituted with one group R L2 , and wherein the alkylene, the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the 10 -CH2CH2-NH-CH2CH2CH2- group may optionally be further substituted with one or more fluoro groups; R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; R 22 is
  • -CONR 2 R 3 may have the formula: - 70 - 5
  • L 2 is a C 2 -C 4 straight-chained alkylene group, wherein the alkylene group is substituted with one group R L2 , and wherein the alkylene group may optionally be further substituted with one or more fluoro groups
  • 10 R 22 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group is 15 substituted with one group R L2 ; and R 22 is hydrogen or a methyl group.
  • R 3 is hydrogen.
  • -CONR 2 R 3 has the formula: wherein: L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-O-CH2CH2-, -CH2CH2CH2-O-CH2CH2-, -CH2CH2-O-CH2CH2CH2-, -CH2CH2-NH-CH2CH2-, 25 -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the - 71 - -CH2CH2-O-CH2CH2-, the -CH2CH2CH2-O-CH2CH2-, the -CH2CH2-O-CH2CH2CH2-, the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group may optionally be substituted with one or more fluoro groups
  • the compound is a compound of Formula (V): - 73 - Formula (V) wherein R 1 , X 1 -X 4 , A 1 -A 6 , Q 1 , R 3 , L 2 and R 21 are as defined in accordance with Formula (I).
  • -CONR 2 R 3 has the formula: wherein: L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-O-CH2CH2-, -CH2CH2CH2-O-CH2CH2-, -CH2CH2-O-CH2CH2CH2-, -CH2CH2-NH-CH2CH2-, 25 -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the -CH2CH2-O-CH2CH2-, the -CH2CH2CH2-O-CH2CH2-, the -CH2CH2-O-CH2CH2CH2-, the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group may optionally be substituted with one or more fluoro groups and/or one or two groups R L2
  • L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group may optionally be substituted with one or more fluoro groups and/or one or two groups 25 R L2 ; and each R L2 is independently selected from a methyl or fluoromethyl group; or R 3 and any R L2 may, together with the atoms to which they are attached, form a 5- to 7-membered saturated monocyclic heterocyclic group, wherein the 5- to 7-membered saturated monocyclic heterocyclic group may optionally be substituted 30 with one or more fluoro groups and/or one or two groups R L3 ; or any R L2 and R 21 may, together with the atoms to which they are attached, form a 5- to 7-membered saturated monocyclic heterocyclic group, wherein the 5- to 7-membered saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 ; and 35 each
  • R 21 is not hydrogen.
  • L 2 is a C2-C5 or a C2-C4 straight-chained alkylene group, wherein the alkylene group is substituted with one group R L2 , and wherein the alkylene group may 5 optionally be further substituted with one or more fluoro groups;
  • R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group;
  • R L2 and R 21 together with the atoms to which they are attached, form a 5- to 7-membered saturated monocyclic heterocyclic group, wherein the 5- to 7-membered 10 saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 ; and each R L3 is
  • R 3 is hydrogen.
  • -CONR 2 R 3 may have the formula: 20
  • -CONR 2 R 3 has the formula: wherein: L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-O-CH2CH2-, 25 -CH2CH2CH2-O-CH2CH2-, -CH2CH2-O-CH2CH2CH2-, -CH2CH2-NH-CH2CH2-, -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the -CH2CH2-O-CH2CH2-, the -CH2CH2CH2-O-CH2CH2-, the -CH2CH2-O-CH2CH2CH2-, the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH
  • the compound is a compound of Formula (VI): - 79 - Formula (VI) wherein R 1 , X 1 -X 4 , A 1 -A 6 , Q 1 , R 3 , L 2 and R 21 are as defined in accordance with Formula (I).
  • L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group may optionally be substituted with one or more fluoro groups and/or one or two groups R L2 ; 20 each R L2 is independently selected from a methyl or a fluoromethyl group; R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; and R 21 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; 25 provided that the group -CO-N(R 3 )-L 2 -SR 21 contains no more than 10 carbon atoms.
  • R 3 is hydrogen.
  • -CONR 2 R 3 may have the formula: .
  • the compound is a compound of Formula (IIa): - 81 - Formula (IIa) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IIb): Formula (IIb) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 13 , r, s and t are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IId): Formula (IId) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with 15 Formula (I).
  • the compound is a compound of Formula (IIe): - 82 - Formula (IIe) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , X 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IIf): wherein X 1 -X 4 , A 1 -A 6 , Q 1 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with 10 Formula (I).
  • the compound is a compound of Formula (IIIa): Formula (IIIa) 15 wherein X 1 -X 4 , A 1 -A 6 , Q 1 , Q 2 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IIIb): Formula (IIIb) 5 wherein X 1 -X 4 , A 1 -A 6 , Q 1 , Q 2 , L 2 , R 21 , R 3 , R 13 , r, s and t are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IIId): 10 Formula (IIId) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , Q 2 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IIIe): 15 Formula (IIIe) - 84 - wherein X 1 -X 4 , A 1 -A 6 , Q 1 , Q 2 , L 2 , R 21 , R 3 , X 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IIIf): 5 Formula (IIIf) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , Q 2 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IVa): Formula (IVa) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 22 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IVb): - 85 - Formula (IVb) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 22 , R 3 , R 13 , r, s and t are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IVd): Formula (IVd) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 22 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in 10 accordance with Formula (I).
  • the compound is a compound of Formula (IVe): Formula (IVe) 15 wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 22 , R 3 , X 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IVf): Formula (IVf) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 22 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in 5 accordance with Formula (I).
  • the compound is a compound of Formula (Va): Formula (Va) 10 wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (Vb): 15 Formula (Vb) - 87 - wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 3 , R 13 , r, s and t are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (Vd): 5 Formula (Vd) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I). 10
  • the compound is a compound of Formula (Ve): Formula (Ve) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 3 , X 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (Vf): - 88 - Formula (Vf) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (VIa): Formula (VIa) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in 10 accordance with Formula (I).
  • the compound is a compound of Formula (VIb): Formula (VIb) 15 wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 3 , R 13 , r, s and t are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (VId): Formula (VId) 5 wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (VIe): 10 Formula (VIe) wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 3 , X 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (VIf): 15 Formula (VIf) - 90 - wherein X 1 -X 4 , A 1 -A 6 , Q 1 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • 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
  • X 4 is N or C; provided that no more than three of X 1 , X 2 , X 3 and X 4 are N
  • 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 a single cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo and/or -NO2 groups
  • X 4 is N
  • a 6 is C.
  • X 4 is C.
  • a 6 is N.
  • no more than two of X 1 , X 2 , X 3 and X 4 are N.
  • at least one of X 1 , X 2 , X 3 and X 4 is N.
  • at least one of X 2 and X 3 is N.
  • X 2 is N.
  • 35 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; - 91 - 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.
  • at least X 1 is N.
  • X 1 is N, C-H, C-Hal or C-R X1 ;
  • X 2 is N;
  • X 3 is C-H, C-Hal or C-R X3 ;
  • X 4 is N or C; provided that no more than two of X 1 , X 2 and X 4 are N.
  • X 4 is C.
  • 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 15 X 4 is C; provided that no more than two of X 1 , X 2 and X 3 are N.
  • at least one of X 1 , X 2 and X 3 is N.
  • at least one of X 2 and X 3 is N.
  • X 2 is N and 20 X 3 is C-H, C-Hal or C-R X3 , or X 3 is N and X 2 is C-H, C-Hal or C-R X2 . Most typically, X 2 is N. Typically in such an embodiment, X 1 is N and at least one of X 2 and X 3 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; 30 provided that at least one of X 1 and X 2 is N.
  • at least X 1 is N.
  • X 1 is N, C-H, C-Hal or C-R X1 ;
  • X 2 is N;
  • 35 X 3 is C-H, C-Hal or C-R X3 ; and
  • X 4 is C.
  • 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 5 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 a methyl or fluoromethyl group.
  • X 1 is N, C-H or C-Hal; 20
  • X 2 is N, C-H or C-Hal;
  • X 3 is N, C-H or C-Hal;
  • X 4 is N or C; provided 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 and X 3 is N. More particularly, X 2 is N.
  • At least one of X 1 , X 2 , X 3 and X 4 is N.
  • at least X 1 is N.
  • X 1 is N, C-H or C-Hal; 30
  • X 2 is N;
  • X 3 is N, C-H or C-Hal;
  • X 4 is N or C; provided 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.
  • X 4 is C.
  • X 1 is N, C-H or C-Hal
  • X 2 is N, C-H or C-Hal
  • - 93 - X 3 is N, C-H or C-Hal
  • X 4 is C; provided that no more than two of X 1 , X 2 and X 3 are N.
  • at least one of X 1 , X 2 and X 3 is N.
  • at least one of X 2 and X 3 is N.
  • X 2 is N and X 3 is C-H or C-Hal, or X 3 is N and X 2 is C-H or C-Hal.
  • X 2 is N.
  • X 1 is N and at least one of X 2 and X 3 is N. 10
  • X 1 is N, C-H or C-Hal
  • X 2 is N, C-H or C-Hal
  • X 3 is C-H or C-Hal
  • 15 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.
  • at least X 1 is N.
  • X 1 is N, C-H or C-Hal; X 2 is N; X 3 is C-H or C-Hal; and X 4 is N or C; provided that no more than two of X 1 , X 2 and X 4 are N.
  • X 1 is N, C-H or C-Hal; X 2 is N, C-H or C-Hal; X 3 is C-H or C-Hal; and 30 X 4 is C; provided that at least one of X 1 and X 2 is N.
  • at least X 1 is N.
  • X 1 is N, C-H or C-Hal; 35 X 2 is N; X 3 is C-H or C-Hal; and X 4 is C. - 94 - More typically in such an embodiment, X 1 is N and X 2 is N. More typically still, X 1 is N, X 2 is N and X 3 is C-H. In a further embodiment: 5 X 1 is N or C-H; X 2 is N or C-H; X 3 is N or C-H; and X 4 is C; provided that no more than two of X 1 , X 2 and X 3 are N. Typically in such an 10 embodiment, at least one of X 1 , X 2 and X 3 is N.
  • At least one of X 2 and X 3 is N.
  • X 2 is N and X 3 is C-H, or X 3 is N and X 2 is C-H.
  • Most typically, X 2 is N.
  • X 1 is N and at least one of X 2 and X 3 is N. Most typically, X 1 is N, X 2 is N and X 3 is C-H.
  • 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, 5 wherein R Q3 is selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group.
  • R Q1 and R Q2 are each independently selected from a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group. More typically still, R Q1 and R Q2 are each independently selected from a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or 10 fluorocyclopropyl group. Yet more typically, R Q1 and R Q2 are each independently selected from a methyl or fluoromethyl 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, N-H or N-R Q1 , wherein R Q1 is selected from a 15 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 S, N-H or N-R Q1 .
  • R Q1 is a methyl or fluoromethyl group.
  • Q 1 is S or N-H. 20
  • Q 1 is S.
  • Q 1 is O. 25
  • Q 1 is N-H or N-R Q1 , wherein R Q1 is a methyl or fluoromethyl group.
  • Q 1 is N-H.
  • a 1 is N, C-H, C-Hal or C-R A1 ; 30 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 ; and A 5 is N or C; provided that no more than three of A 1 , A 2 , A 3 , A 4 and A 5 are N; and 35 R A1 , R A2 , R A3 and R A4 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 a single cyclic group, wherein the hydrocarbyl group may optionally be substitute
  • 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. 10
  • 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.
  • a 1 is C-H C-Hal or C-R A1 ;
  • a 2 is C-H, C-Hal or C-R A2 ;
  • a 3 is C-H, C-Hal or C-R A3 ;
  • a 4 is C-H, C-Hal or C-R A4 ;
  • a 5 is C.
  • no more than two of A 1 , A 2 , A 3 and A 4 are C-R A1 , C-R A2 , C-R A3 or C-R A4 .
  • 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 - 97 - 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 5 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
  • 20 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. 25
  • 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
  • a 5 is C.
  • a 1 is C-H
  • a 2 is C-H
  • a 3 is C-H
  • a 4 is C-H or C-Hal
  • a 5 is C.
  • a 1 is C-H
  • a 2 is C-H
  • a 3 is C-H
  • a 4 is C-H
  • a 5 is C. 35
  • a 6 is N or C.
  • a 6 is N. - 98 -
  • 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 (VII): Formula (VII) wherein Q 1 is O, S, N-H or N-R Q1 , and R 1 , R 2 , R 3 , X 1 -X 3 , A 1 -A 4 and R Q1 are as defined in 10 accordance with Formula (I).
  • the compound is a compound of Formula (VIIa): 15 Formula (VIIa) wherein Q 1 is O, S, N-H or N-R Q1 , and R 2 , R 3 , X 1 -X 3 , A 1 -A 4 , R Q1 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a 20 compound of Formula (VIIb): - 99 - Formula (VIIb) wherein Q 1 is O, S, N-H or N-R Q1 , and R 2 , R 3 , X 1 -X 3 , A 1 -A 4 , R Q1 , R 13 , r, s and t are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (VIId): Formula (VIId) 10 wherein Q 1 is O, S, N-H or N-R Q1 , and R 2 , R 3 , X 1 -X 3 , A 1 -A 4 , R Q1 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (VIIe): 15 Formula (VIIe) - 100 - wherein Q 1 is O, S, N-H or N-R Q1 , and R 2 , R 3 , X 1 -X 3 , A 1 -A 4 , R Q1 , X 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a 5 compound of Formula (VIIf): wherein and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (VIII): 15 Formula (VIII) wherein Q 1 is O, S, N-H or N-R Q1 , and R 1 , X 1 -X 3 , A 1 -A 4 and R Q1 are as defined in accordance with Formula (I).
  • the compound is a 20 compound of Formula (VIIIa): - 101 - Formula (VIIIa) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (VIIIb): Formula (VIIIb) 10 wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , R 13 , r, s and t are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (VIIId): 15 Formula (VIIId) - 102 - wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a 5 compound of Formula (VIIIe): Formula (VIIIe) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , X 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (VIIIf): Formula (VIIIf) 15 wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IX): - 103 - Formula (IX) wherein Q 1 is O, S, N-H or N-R Q1 , and R 1 , X 1 -X 3 , A 1 -A 4 , R Q1 , Q 2 , L 2 , R 21 and R 3 are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IXa): Formula (IXa) 10 wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , Q 2 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IXb): 15 Formula (IXb) - 104 - wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , Q 2 , L 2 , R 21 , R 3 , R 13 , r, s and t are as defined in accordance with Formula (I).
  • the compound is a 5 compound of Formula (IXd): Formula (IXd) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , Q 2 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IXe): Formula (IXe) 15 wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , Q 2 , L 2 , R 21 , R 3 , X 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IXf): - 105 - wherein p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (X): Formula (X) 10 wherein Q 1 is O, S, N-H or N-R Q1 , and R 1 , X 1 -X 3 , A 1 -A 4 , R Q1 , L 2 , R 21 , R 22 and R 3 are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (Xa): 15 Formula (Xa) - 106 - wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , L 2 , R 21 , R 22 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a 5 compound of Formula (Xb): wherein r, s and t are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (Xd): Formula (Xd) 15 wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , L 2 , R 21 , R 22 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (Xe): - 107 - Formula (Xe) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , L 2 , R 21 , R 22 , R 3 , X 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (Xf): 10 wherein p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (XI): 15 Formula (XI) - 108 - wherein Q 1 is O, S, N-H or N-R Q1 , and R 1 , X 1 -X 3 , A 1 -A 4 , R Q1 , L 2 , R 21 and R 3 are as defined in accordance with Formula (I).
  • the compound is a 5 compound of Formula (XIa): Formula (XIa) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (XIb): 15 wherein and t are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (XId): - 109 - Formula (XId) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (XIe): Formula (XIe) 10 wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , L 2 , R 21 , R 3 , X 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (XIf): 15 Formula (XIf) - 110 - wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 -X 3 , A 1 -A 4 , R Q1 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound 5 of Formula (XII): Formula (XII) wherein Q 1 is O, S, N-H or N-R Q1 , and R 1 , R 2 , R 3 , X 1 , X 2 and R Q1 are as defined in accordance with Formula (I).
  • X 1 is N 10 and X 2 is N.
  • the compound is a compound of Formula (XIIa): 15 wherein and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIIb): - 111 - Formula (XIIb) wherein Q 1 is O, S, N-H or N-R Q1 , and R 2 , R 3 , X 1 , X 2 , R Q1 , R 13 , r, s and t are as defined in accordance with Formula (I).
  • X 1 is N 5 and X 2 is N.
  • the compound is a compound of Formula (XIId): 10 wherein and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIIe): - 112 - Formula (XIIe) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , R 2 , R 3 , X 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIIf): 10 Formula (XIIf) wherein Q 1 is O, S, N-H or N-R Q1 , and R 2 , R 3 , X 1 , X 2 , R Q1 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIII): - 113 - Formula (XIII) wherein Q 1 is O, S, N-H or N-R Q1 , and R 1 , X 1 , X 2 and R Q1 are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIIIa): Formula (XIIIa) 10 wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a 15 compound of Formula (XIIIb): Formula (XIIIb) - 114 - wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , R 13 , r, s and t are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIIId): wherein are as 10 defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIIIe): 15 wherein are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIIIf): - 115 - Formula (XIIIf) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (XIV): 10 Formula (XIV) wherein Q 1 is O, S, N-H or N-R Q1 , and R 1 , L 2 , Q 2 , R 21 , R 3 , X 1 , X 2 and R Q1 are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIVa): - 116 - wherein and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIVb): 10 wherein t are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIVd): Formula (XIVd) - 117 - wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , L 2 , Q 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIVe): Formula (XIVe) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , L 2 , Q 2 , R 21 , R 3 , X 12 , R 13 , m, n, p, q, r 10 and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XIVf): 15 Formula (XIVf) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , Q 2 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XV): - 118 - Formula (XV) wherein Q 1 is O, S, N-H or N-R Q1 , and R 1 , L 2 , R 21 , R 22 , R 3 , X 1 , X 2 and R Q1 are as defined in accordance with Formula (I).
  • X 1 is N 5 and X 2 is N.
  • the compound is a compound of Formula (XVa): 10 wherein and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XVb): Formula (XVb) - 119 - wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , L 2 , R 21 , R 22 , R 3 , R 13 , r, s and t are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XVd): Formula (XVd) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , L 2 , R 21 , R 22 , R 3 , R 12 , R 13 , m, n, p, q, r 10 and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XVe): 15 Formula (XVe) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , L 2 , R 21 , R 22 , R 3 , X 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XVf): - 120 - Formula (XVf) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , L 2 , R 21 , R 22 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XVI): 10 Formula (XVI) wherein Q 1 is O, S, N-H or N-R Q1 , and R 1 , L 2 , R 21 , R 3 , X 1 , X 2 and R Q1 are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XVIa): - 121 - wherein p, q, r and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XVIb): 10 wherein are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XVId): Formula (XVId) - 122 - wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N. 5
  • the compound is a compound of Formula (XVIe): Formula (XVIe) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , L 2 , R 21 , R 3 , X 12 , R 13 , m, n, p, q, r and 10 s are as defined in accordance with Formula (I).
  • X 1 is N and X 2 is N.
  • the compound is a compound of Formula (XVIf): 15 Formula (XVIf) wherein Q 1 is O, S, N-H or N-R Q1 , and X 1 , X 2 , R Q1 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • Q 1 is O, S, N-H or N-R Q1
  • X 1 , X 2 , R Q1 , L 2 , R 21 , R 3 , R 12 , R 13 , m, n, p, q, r and s are as defined in accordance with Formula (I).
  • At least one of X 2 and X 3 is N. Most typically, X 2 is N.
  • at least one of X 2 and X 3 is N. Most typically, X 2 is N.
  • at least one of 30 X 2 and X 3 is N. Most typically, X 2 is N.
  • at least one of X 2 and X 3 is N. Most typically, X 2 is N.
  • a compound of Formula (VIIa) as defined above wherein: R 2 is selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group; 5 and R 3 is selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group; or R 2 and R 3 together with the nitrogen atom to which they are attached form a azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group, any of which may optionally be 10 fluoro-substituted;
  • X 2 and X 3 are N. Most typically, X 2 is N.
  • X 2 is N.
  • the compound is a compound of 20 Formula (VIIIa) as defined above.
  • at least one of X 2 and X 3 is N.
  • X 2 is N.
  • the compound is a compound of Formula (XIIa) as defined above.
  • R 2 is selected from hydrogen or a methyl or ethyl group
  • R 3 is selected from hydrogen or a methyl or ethyl group
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a azetidinyl, pyrrolidinyl or piperidinyl group
  • X 1 is N
  • X 2 is N or C-H
  • Q 1 is S or N-H
  • m is 1 or 2
  • n 1 or 2
  • p is 0, 1 or 2
  • - 127 - r is 0; s is 0
  • R 12 is hydrogen or a methyl or fluoromethyl group.
  • X 2 is N.
  • the compound is a compound of Formula (XIIIa) as defined above.
  • X 2 is N.
  • R 2 is selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group; and 30 R 3 is selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group; or R 2 and R 3 together with the nitrogen atom to which they are attached form a azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group, any of which may optionally be fluoro-substituted; 35 X 1 is N
  • the compound is a compound of 20 Formula (VIIIb) as defined above. Typically in such an aspect at least one of X 2 and X 3 is N. Most typically, X 2 is N. In another aspect of the third exemplary embodiment the compound is a compound of Formula (XIIb) as defined above.
  • R 2 is selected from hydrogen or a methyl or ethyl group
  • R 3 is selected from hydrogen or a methyl or ethyl group
  • X 1 is N
  • 30 is N or C-H
  • Q 1 is S or N-H
  • r is 0
  • s is 0
  • t is 1 or 2.
  • X 2 is N. - 129 -
  • the compound is a compound of Formula (XIIIb) as defined above.
  • X 2 is N.
  • a compound of Formula (VIIe) as defined above wherein: R 2 is selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 15 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group; and R 3 is selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group; or R 2 and R 3 together with the nitrogen atom to which they are attached form a 20 azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group, any of which may optionally be fluoro-substituted; X 1 is N,
  • the compound is a compound of Formula (VIIIe) as defined above.
  • at least one of X 2 and X 3 is N.
  • X 2 is N.
  • the compound is a compound of Formula (XIIe) as defined above.
  • R 2 is selected from hydrogen or a methyl or ethyl group
  • R 3 is selected from hydrogen or a methyl or ethyl group; or - 131 - R 2 and R 3 together with the nitrogen atom to which they are attached form a azetidinyl, pyrrolidinyl or piperidinyl group
  • X 1 is N
  • X 2 is N or C-H
  • 5 Q 1 is S or N-H
  • m is 1 or 2
  • n is 1 or 2
  • p is 0, 1 or 2
  • q 2 or 3
  • r is 0; s is 0;
  • 15 is hydrogen or a methyl or fluoromethyl group.
  • X 2 is N.
  • the compound is a compound 20 of Formula (XIIIe) as defined above.
  • X 1 is N; X 2 is N or C-H; Q 1 is S or N-H; m is 2; 25 n is 1 or 2; p is 1 or 2; q is 2; r is 0; s is 0; and 30 R 12 is hydrogen or a methyl or fluoromethyl group.
  • X 2 is N.
  • a compound of Formula (VIIf) as 35 defined above wherein: R 2 is selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group; and - 132 - R 3 is selected from hydrogen or a C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, C3-C4 fluorocycloalkyl, cyclopropylmethyl or fluorocyclopropylmethyl group; or R 2 and R 3 together with the nitrogen atom to which they are attached form a azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group, any of which may optionally be 5 fluoro-substituted;
  • the compound is a compound of Formula (VIIIf) as defined above.
  • at least one of X 2 and X 3 is N.
  • X 2 is N.
  • the compound is a compound of Formula (XIIf) as defined above.
  • R 2 is selected from hydrogen or a methyl or ethyl group; and R 3 is selected from hydrogen or a methyl or ethyl group; or R 2 and R 3 together with the nitrogen atom to which they are attached form a 20 azetidinyl, pyrrolidinyl or piperidinyl group;
  • X 1 is N;
  • X 2 is N or C-H;
  • Q 1 is S or N-H;
  • m is 2; 25 n is 2; p is 1; q is 1; r is 0; s is 0;
  • R 12 is hydrogen or a methyl or fluoromethyl group.
  • X 2 is N.
  • the compound is a compound of 35 Formula (XIIIf) as defined above.
  • X 1 is N; X 2 is N or C-H; Q 1 is S or N-H; - 134 - m is 2; n is 2; p is 1; q is 1; 5 r is 0; s is 0; and R 12 is hydrogen or a methyl or fluoromethyl group.
  • X 2 is N.
  • at least 20 one of X 2 and X 3 is N. Most typically, X 2 is N.
  • at least one of X 2 and X 3 is N. Most typically, X 2 is N.
  • at least one of X 2 and X 3 is N. Most typically, X 2 is N.
  • a compound of Formula (Xa) as defined above wherein: X 1 is N, C-H or C-Hal; - 138 - X 2 is N, C-H or C-Hal; and X 3 is N, C-H or C-Hal; provided that no more than two of X 1 , X 2 and X 3 are N; Q 1 is O, S, N-H or N-R Q1 ; 5 R Q1 is 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; and A 4 is N, C-H or C-Hal; 10 provided that no more than one of A 1 , A 2 , A 3 and A 4 is N; each Hal is independently selected from a fluoro, chloro or bromo group; m is 0, 1, 2 or 3; n is 0, 1, 2 or
  • L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group may optionally be substituted with one or more fluoro groups and/or one or two groups 15 R L2 ; each R L2 is independently selected from a methyl or a fluoromethyl group; R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; R 21 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or 20 fluorocyclopropyl group; and R 22 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; or R 21 and R 22 may, together with the nitrogen atom to which they are attached, form a 3- to 5-membered saturated monocyclic hetero
  • L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group is 35 substituted with one group R L2 , and wherein the alkylene group may optionally be further substituted with one or more fluoro groups; R 3 and R L2 , together with the atoms to which they are attached, form a 5- to 7- membered saturated monocyclic heterocyclic group, wherein the 5- to 7-membered - 142 - saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 ; and R 21 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluor
  • L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group is substituted with two groups R L2 , and wherein the alkylene group may optionally be 15 further substituted with one or more fluoro groups; the two R L2 , together with the carbon atom or carbon atoms to which they are attached, form a C3-C6 cycloalkylene group, wherein the C3-C6 cycloalkylene group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 ; 20 R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl
  • L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-NH-CH2CH2-, -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the - 146 - -CH2CH2-NH-CH2CH2CH2- group is substituted with one group R L2 , and wherein the alkylene, the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2CH
  • X 1 and X 2 are N. More typically, X 1 is N or 20 C-H and X 2 is N. Most typically, X 1 is N and X 2 is N.
  • X 1 is N and X 2 is N.
  • a compound of Formula (Xb) as defined above wherein: X 1 is N, C-H or C-Hal; 25 X 2 is N, C-H or C-Hal; and X 3 is N, C-H or C-Hal; provided that no more than two of X 1 , X 2 and X 3 are N; Q 1 is O, S, N-H or N-R Q1 ; R Q1 is selected from a methyl or fluoromethyl group; 30 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; and A 4 is N, C-H or C-Hal; provided that no more than one of A 1 ,
  • L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group may 15 optionally be substituted with one or more fluoro groups and/or one or two groups R L2 ; each R L2 is independently selected from a methyl or a fluoromethyl group; R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; 20 R 21 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; and R 22 is hydrogen or a C1-C3 alkyl, C1
  • the compound may be a compound of Formula (XVb) as defined above, wherein: X 1 is N or C-H; 35 X 2 is N or C-H; Q 1 is O, S, N-H or N-R Q1 ; R Q1 is selected from a methyl or fluoromethyl group; r is 0; - 150 - s is 0; t is 0; L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group may optionally be substituted with one or more fluoro groups and/or one or two groups 5 R L2 ; each R L2 is independently selected from a methyl or a fluoromethyl group; R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; R 21 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl,
  • X 1 and X 2 are N. More typically, X 1 is N or C-H and X 2 is N. Most typically, X 1 is N and X 2 is N.
  • 25 L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-NH-CH2CH2-, -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group is substituted with one group R L2 , and wherein the alkylene, the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the 30 -CH2CH2-NH-CH2CH2CH2- group may optionally
  • the compound may be a compound of Formula (XVb) as defined above, wherein: X 1 is N or C-H; 10 X 2 is N or C-H; Q 1 is O, S, N-H or N-R Q1 ; R Q1 is selected from a methyl or fluoromethyl group; r is 0; s is 0; 15 t is 0; L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-NH-CH2CH2-, -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group is substituted with one group R L2 , and wherein the 20 alkylene, the -CH2CH2-NH-CH2CH2-, the -(-
  • X 1 and X 2 are N. More typically, X 1 is N or C-H and X 2 is N. Most typically, X 1 is N and X 2 is N. - 152 -
  • a compound of Formula (Xd) as defined above wherein: X 1 is N, C-H or C-Hal; X 2 is N, C-H or C-Hal; and 5 X 3 is N, C-H or C-Hal; provided that no more than two of X 1 , X 2 and X 3 are N; Q 1 is O, S, N-H or N-R Q1 ; R Q1 is selected from a methyl or fluoromethyl group; A 1 is N, C-H or C-Hal; 10 A 2 is N, C-H or C-Hal; A 3 is N, C-H or C-Hal; and A 4 is N, C-H or C-Hal; provided that no more
  • L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-O-CH2CH2-, -CH2CH2CH2-O-CH2CH2-, -CH2CH2-O-CH2CH2CH2-, -CH2CH2-NH-CH2CH2-, -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the -CH2CH2-O-CH2CH2-, the -CH2CH2CH2-O-CH2CH2-, the -CH2CH2-O-CH2CH2CH2-, the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- 35 group may optionally be substituted with one or more fluoro groups and/or one or two groups R L2 ; R 3 is hydrogen or a C1-C3 alkyl, C1-C
  • X 2 and 35 X 3 is N. Most typically, X 2 is N.
  • X 2 is N.
  • L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-NH-CH2CH2-, -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group is substituted with one group R L2 , and wherein the 15 alkylene, the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group may optionally be further substituted with one or more fluoro groups; R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl
  • X 1 and X 2 are N. More typically, X 1 is N or C-H and X 2 is N. Most typically, X 1 is N and X 2 is N. 35
  • a compound of Formula (Xe) as defined above wherein: X 1 is N, C-H or C-Hal; X 2 is N, C-H or C-Hal; and - 156 - X 3 is N, C-H or C-Hal; provided that no more than two of X 1 , X 2 and X 3 are N; Q 1 is O, S, N-H or N-R Q1 ; R Q1 is selected from a methyl or fluoromethyl group; 5 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; and A 4 is N, C-H or C-Hal; provided that no
  • L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-NH-CH2CH2-, -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the 15 the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group is substituted with one group R L2 , and wherein the alkylene, the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group may optionally be further substituted with one or more fluoro groups;
  • R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocycloprop
  • X 1 and X 2 are N. More typically, X 1 is N or C-H and X 2 is N. Most typically, X 1 is N and X 2 is N. - 160 -
  • a compound of Formula (Xf) as defined above wherein: X 1 is N, C-H or C-Hal; X 2 is N, C-H or C-Hal; and 5 X 3 is N, C-H or C-Hal; provided that no more than two of X 1 , X 2 and X 3 are N; Q 1 is O, S, N-H or N-R Q1 ; R Q1 is selected from a methyl or fluoromethyl group; A 1 is N, C-H or C-Hal; 10 A 2 is N, C-H or C-Hal; A 3 is N, C-H or C-Hal; and A 4 is N, C-H or C-Hal; provided that no more than
  • L 2 is a C2-C4 straight-chained alkylene group, wherein the alkylene group may optionally be substituted with one or more fluoro groups and/or one or two groups 15 R L2 ; each R L2 is independently selected from a methyl or a fluoromethyl group; R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; R 21 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or 20 fluorocyclopropyl group; and R 22 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group; or R 21 and R 22 may, together with the nitrogen atom to which they are attached, form a 3- to 5-membered saturated monocyclic
  • L 2 is a C2-C6 straight-chained alkylene group or a -CH2CH2-NH-CH2CH2-, -CH2CH2CH2-NH-CH2CH2- or -CH2CH2-NH-CH2CH2CH2- group, wherein the alkylene, the the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the 35 -CH2CH2-NH-CH2CH2CH2- group is substituted with one group R L2 , and wherein the alkylene, the -CH2CH2-NH-CH2CH2-, the -CH2CH2CH2-NH-CH2CH2- or the -CH2CH2-NH-CH2CH2CH2- group may optionally
  • X 1 and X 2 are N. More typically, X 1 is N or 15 C-H and X 2 is N. Most typically, X 1 is N and X 2 is N.
  • XIa a compound of Formula (XIa) as defined above, wherein: X 1 is N, C-H or C-Hal; 20 X 2 is N, C-H or C-Hal; and X 3 is N, C-H or C-Hal; provided that no more than two of X 1 , X 2 and X 3 are N; Q 1 is O, S, N-H or N-R Q1 ; R Q1 is selected from a methyl or fluoromethyl group; 25 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; and A 4 is N, C-H or C-Hal; provided that no more than
  • X 2 and X 3 are N. Most typically, X 2 is N.
  • X 2 is N.
  • L 2 is a C2-C5 straight-chained alkylene group, wherein the alkylene group is substituted with one group R L2 , and wherein the alkylene group may optionally be 25 further substituted with one or more fluoro groups;
  • R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group;
  • R L2 and R 21 together with the atoms to which they are attached, form a 5- to 7-membered saturated monocyclic heterocyclic group, wherein the 5- to 7-membered 30 saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 ; and each R L3 is independently selected from a methyl or a fluoromethyl group; provided that the group -CO-N(R 3 )-L 2 -OR 21 contains no more than 10 carbon
  • X 1 and X 2 are N. More typically, X 1 is N or C-H and X 2 is N. Most typically, X 1 is N and X 2 is N.
  • a compound of Formula (XIf) as defined above wherein: 35 X 1 is N, C-H or C-Hal; X 2 is N, C-H or C-Hal; and X 3 is N, C-H or C-Hal; provided that no more than two of X 1 , X 2 and X 3 are N; - 169 - Q 1 is O, S, N-H or N-R Q1 ; R Q1 is 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; 5 A 3 is N, C-H or C-Hal; and A 4 is N, C-H or C-Hal; provided that no
  • X 2 and X 3 are N. Most typically, X 2 is N.
  • X 2 is N.
  • L 2 is a C2-C5 straight-chained alkylene group, wherein the alkylene group is substituted with one group R L2 , and wherein the alkylene group may optionally be further substituted with one or more fluoro groups;
  • - 171 - R 3 is hydrogen or a C1-C3 alkyl, C1-C3 fluoroalkyl, cyclopropyl or fluorocyclopropyl group;
  • R L2 and R 21 together with the atoms to which they are attached, form a 5- to 7-membered saturated monocyclic heterocyclic group, wherein the 5- to 7-membered 5 saturated monocyclic heterocyclic group may optionally be substituted with one or more fluoro groups and/or one or two groups R L3 ; and each R L3 is independently selected from a methyl or a fluoromethyl group; provided that the group -CO-N(R 3 )-L 2 -OR 21 contains no more than
  • the compound of the first aspect of the invention has a molecular weight of from 250 to 1000 Da.
  • the compound 10 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 400 to 650 Da.
  • a second aspect of the invention provides a compound selected from the group 15 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 10 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 15 pharmaceutically acceptable salt of any compound of the first or second aspect of the invention.
  • 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, 5 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, 10 tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric,
  • the acid addition salt may be a 15 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 20 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. 25
  • 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, 30 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.
  • salts are included in the present invention, since they have potential to serve as intermediates in the purification or - 190 - preparation of other, for example, pharmaceutically acceptable salts, or are useful for identification, characterisation or purification of the free acid or base.
  • the compounds and/or salts of the present invention may be anhydrous or in the form 5 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 10 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 15 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 25 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 30 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. - 191 - Alternately, 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 at least one chiral centre. The compounds, salts, solvates and prodrugs may therefore exist in at least two isomeric forms.
  • the present invention encompasses racemic mixtures of the compounds, salts, solvates and prodrugs of the present invention as well as enantiomerically enriched and substantially enantiomerically pure isomers.
  • a “substantially enantiomerically pure” isomer of a compound comprises less than 5% of other isomers of the same compound, more typically less than 2%, and most typically less than 0.5% by weight.
  • the compounds, salts, solvates and prodrugs of the present invention may contain 20 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, 1 8 O, 19 F and 127 I, and any radioisotope including, but not limited to 11 C, 14 C, 3 H (T), 1 3 N, 15 O, 18 F, 123 I, 124 I, 125 I and 131 I.
  • 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 35 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), (Ia-AB-i), (Id-AB-i), (Ie-AB-i), (If-AB-i), - 192 - (Ia-AB-ii), (Ib-AB-ii), (Id-AB-ii), (Ie-AB-ii), (If-AB-ii), (III-AB), (IIIa-AB-i), (IIId-AB-i), (IIIe-AB-i), (IIIf-AB-i), (IIIa-AB-ii), (IIIb-AB-ii), (IIId-AB-ii), (IIIe-AB-ii), (IIIf-AB-ii), (IV-AB), (IVa-AB-i), (IVd-AB-i), (IVe-AB-i), (IVf-AB-i), (IVa-AB-i), (IVf-AB-i), (IVa-AB-i), (IVe-AB-i), (IVf-AB-i
  • the various substituents including the fused tetracyclic ring system may be further defined in the same manner as for the first aspect of the invention.
  • the fused tetracyclic ring system may be replaced by that of Formula (VII) or of Formula (XII)
  • the fused tetracyclic ring system may be replaced by that of Formula (Xa) or of Formula (XVa), etc.
  • the above discussed exemplary embodiments apply equally to the antibody-drug conjugates of the above formulae.
  • Typical antibodies that may be used to prepare the antibody-drug conjugate of the fourth aspect of the invention are: • Cetuximab • Trastuzumab 20 • Brentuximab • ado-Trastuzumab • Polatuzumab • Inotuzumab • Gemtuzumab 25 • Sacituzumab • Enfortumab • Loncastuximab • fam-Trastuzumab • Tisotumab 30 • Belantamab - 206 - • Mirvetuximab • Amivantamab
  • the antibody-drug conjugate has the Formula (I-AB), (Ia-AB-i), (Id-AB-i), 5 (Ie-AB-i), (If-AB-i), (Ia-AB-ii), (Ib-AB-ii), (Id-AB-ii), (Ie-AB-ii), (If-AB-ii), (III-AB), (IIIa-AB),
  • 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.
  • the “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 5 to the remainder of the molecule, as measured by the shortest route.
  • structure (C) has a chain length between A and B of 3 atoms
  • structure (D) has a chain length between A and B of 5 atoms: 10
  • 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 15 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 20 • CL2a linker • maleimide-valine-alanine-PABC • maleimide tetrapeptide linker (GGFG) • Maleidocaproic linker • Sulfo-SPDB disulfide 25
  • the antibody-drug conjugate has the Formula (I-AB), (Ia-AB-i), (Id-
  • a fifth aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a 35 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 - 208 - 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 5 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 15 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 20 glycol and wool fat.
  • 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 25 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., 35 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 - 209 - 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 5 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 20 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 25 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 30 prevent the disease, disorder or condition.
  • the administration is to a subject in need thereof.
  • 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 35 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 - 210 - 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 5 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 10 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 15 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 25 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 30 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 30 USP1
  • the 35 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, 5 sublingual and topical ocular) administration.
  • parenteral including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural
  • airway asperaerosol
  • rectal rectal
  • vaginal including transdermal, buccal, mucosal, 5 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 35 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, 20 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 25 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 25 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 30 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. 35
  • 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 - 213 - 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 5 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 10 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. 15 References 1. Silverman, R.
  • LCMS method All final compounds were purified to ⁇ 95% purity as determined using a Shimadzu LC- 20AD XR&MS 2020 with UV detection at 220 nm using the following method: Halo C18 30 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 - 216 - 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- 5 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.
  • Example 2 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5- yl)-N-[(1-methylpyrrolidin-2-yl)methyl]-8-oxo-11-thia-1,3,5-30 triazatetracyclo[8.7.0.0 2,7 .0 12,17 ]heptadeca-2,4,6,9,12(17),13,15-heptaene- 9-carboxamide - 219 - Yield: 33%. Isolated as HCl salt.
  • Example 4 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5- yl)-N-(1-methyl-4-piperidyl)-8-oxo-11-thia-1,3,5-triazatetracyclo- 25 [8.7.0.0 2,7 .0 12,17 ]heptadeca-2,4,6,9,12(17),13,15-heptaene-9-carboxamide - 220 - Yield: 34%. Isolated as HCl salt. LCMS (ESI+): m/z 518.3 (M+H) + , Rt: 1.916 min.
  • Example 38 N-(4-(dimethylamino)cyclohexyl)-2-(5-15 methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-5-oxo-5H- benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxamide Yield: 12%. Isolated as HCl salt. LCMS (ESI+): m/z 546.3 (M+H) + , Rt: 1.378 min.
  • Example 41 N-((1-isopropylpiperidin-4-yl)methyl)-2-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxo-5H-benzo[4',5']- 25 thiazolo[3',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxamide Yield: 39%. Isolated as HCl salt. LCMS (ESI+): Rt: 1.401 min, m/z 560.3 (M+H) + .
  • Example 42 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)- 5 N-[3-(1-methyl-4-piperidyl)propyl]-8-oxo-11-thia-1,3,5-triazatetracyclo- [8.7.0.0 2,7 .0 12,17 ]heptadeca-2(7),3,5,9,12(17),13,15-heptaene-9-carboxamide Yield: 12%. Isolated as HCl salt. LCMS (ESI+): m/z 560.3 (M+H) + , Rt: 2.242 min.
  • Example 44 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)- N-[(1-methylpyrrolidin-3-yl)methyl]-8-oxo-11-thia-1,3,5-triazatetracyclo- 30 [8.7.0.0 2,7 .0 12,17 ]heptadeca-2,4,6,9,12(17),13,15-heptaene-9-carboxamide - 224 - Yield: 12%. Isolated as HCl salt. LCMS (ESI+): m/z 518.1 (M+H) + , Rt: 1.199 min.
  • Example 45 N-(1-isopropylpiperidin-4-yl)-2-(5-methylhexahydropyrrolo[3,4- 10 c]pyrrol-2(1H)-yl)-5-oxo-5H-benzo[4',5'] thiazolo[3',2':1,6] pyrido [2,3-d] pyrimidine-6-carboxamide Yield: 18%. Isolated as HCl salt. 15 LCMS (ESI+): m/z 546.3 (M+H) + , Rt: 1.361 min.
  • Example 48 N-(1-isopropylpiperidin-4-yl)-2-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxo-5H-benzo[4',5']- thiazolo[3',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxamide Yield: 6%. Isolated as HCl salt. 20 LCMS (ESI+): m/z 546.3 (M+H) + , Rt: 1.366 min.
  • Example 50 N-[(1-isopropyl-4-piperidyl)methyl]-4-(2-methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-yl)-8-oxo-11-thia-1,3,5-triazatetracyclo- [8.7.0.0 2,7 .0 12,17 ]heptadeca-2(7),3,5,9,12(17),13,15-heptaene-9-carboxamide Yield: 5%. Isolated as HCl salt. 15 LCMS (ESI+): m/z 560.3 (M+H) + , Rt: 2.058 min.
  • Example 53 N-((1s,4s)-4-(dimethylamino)cyclohexyl)-2-(5-15 methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxo-5H-benzo[4',5']- thiazolo[3',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxamide Yield: 7%. Isolated as HCl salt. LCMS (ESI+): m/z 546.4 (M+H) + , Rt: 1.384 min.
  • Example 160 2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-oxo-N-(2-10 (pyrrolidin-1-yl)ethyl)-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3- d]pyrimidine-6-carboxamide Yield: 34%. Isolated as HCl salt. 15 LCMS (ESI+): m/z 518.1 (M+H) + , Rt: 1.314 min.
  • Example 163 N-(2-(dimethylamino)ethyl)-5-oxo-2-(3-oxo-2,8-15 diazaspiro[4.5]decan-8-yl)-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3- d]pyrimidine-6-carboxamide Yield: 15%. Isolated as HCl salt. 20 LCMS (ESI+): m/z 520.3 (M+H) + , Rt: 1.514 min.
  • Example 164 N-((1-methylpiperidin-4- yl)methyl)-5-oxo-2-(3-oxo-2,8- diazaspiro[4.5]decan-8-yl)-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3- d]pyrimidine-6-carboxamide - 230 - Yield: 21%. Isolated as HCl salt. LCMS (ESI+): m/z 560.3 (M+H) + , Rt: 1.585 min.
  • Example 165 5-oxo-2-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)-N-(tetrahydro-10 2H-pyran-4-yl)-5H-benzo [4',5']thiazolo[3',2':1,6]pyrido[2,3-d]pyrimidine - 6-carboxamide Yield: 3%.
  • Example 8 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)- 5 N-[(1-methylpyrrolidin-2-yl)methyl]-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-carboxamide Yield: 42.22%. Isolated as HCl salt.
  • Example 9 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)-20 N-(1-methylpyrrolidin-3-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-carboxamide Yield: 30.32% LCMS (ESI+): m/z 487.3 (M+H) + , Rt: 2.661 min.
  • Example 11 2-(5-methylhexahydropyrrolo[3, 4-c]pyrrol-2(1H)-yl)-5-oxo-N- (tetrahydro-2H-pyran-4-yl)-5,7-dihydrobenzo[4',5']imidazo[1',2':1,6]pyrido- [2,3-d]pyrimidine-6-carboxamide 15 Yield: 14%. Isolated as HCl salt. LCMS (ESI+): m/z 488.3 (M+H) + , Rt: 1.476 min.
  • Example 12 N-(2-(dimethylamino)ethyl)-2-(5-methylhexahydropyrrolo[3,4-25 c]pyrrol-2(1H)-yl)-5-oxo-5,7-dihydrobenzo[4',5']imidazo[1',2':1,6]pyrido- [2,3-d]pyrimidine-6-carboxamide - 235 - Yield: 22%. Isolated as HCl salt. LCMS (ESI+): m/z 475.2 (M+H) + , Rt: 2.475 min.
  • Example 13 2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxo-N-10 (2-(pyrrolidin-1-yl)ethyl)-5,7-dihydrobenzo[4',5']imidazo[1',2':1,6]pyrido- [2,3-d]pyrimidine-6-carboxamide Yield: 19%. Isolated as HCl salt. LCMS (ESI+): m/z 501.2 (M+H) + , Rt: 2.578 min.
  • Example 55 2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-(1- methylpiperidin-4-yl)ethyl)-5-oxo-5,7-dihydrobenzo[4',5']imidazo- [1',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxamide 10 Yield: 19%. Isolated as HCl salt. LCMS (ESI+): m/z 528.3 (M+H) + , Rt: 2.767 min.
  • Example 56 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)-20 8-oxo-N-(2-tetrahydropyran-4-ylethyl)-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-carboxamide Yield: 19%. Isolated as HCl salt. LCMS (ESI+): m/z 516.3 (M+H) + , Rt: 2.623 min.
  • Example 58 N-(1-isopropyl-4-piperidyl)-4-(2-methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-5-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-carboxamide Yield: 10%. Isolated as HCl salt. 15 LCMS (ESI+): m/z 529.3 (M+H) + , Rt: 1.765 min.
  • Example 61 N-(1-cyclopropylpiperidin-4-yl)-2-(5- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxo-5,7-dihydrobenzo- [4',5']imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxamide 20 Yield: 12%. Isolated as HCl salt. LCMS (ESI+): Rt: 1.891 min, m/z 527.3 (M+H) + .
  • Example 62 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5- yl)-N-(1-methylsulfonyl-4-piperidyl)-8-oxo-1,3,5,11-tetrazatetracyclo- 30 [8.7.0.0 2,7 .0 12,17 ]heptadeca-2,4,6,9,12(17),13,15-heptaene-9-carboxamide - 239 - Yield: 10%. Isolated as HCl salt. LCMS (ESI+): m/z 565.2 (M+H) + , Rt: 2.420 min.
  • Example 15 2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxo-N- 5 (pyrrolidin-2-ylmethyl)-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3-d]- pyrimidine-6-carboxamide
  • Example 15 was separated into isomer 1 (Example 15A) and isomer 2 (Example 15B):
  • Example 15A 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5- yl)-8-oxo-N-[[(2S)-pyrrolidin-2-yl]methyl]-11-thia-1,3,5-triazatetracyclo- 25 [8.7.0.0 2,7 .0 12,17 ]heptadeca-2,4,6,9,12(17),13,15-heptaene-9-carboxamide Yield: 29% LCMS (ESI+): m/z 504.3 (M+H)+, Rt: 1.926 min.
  • Example 15B 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5- 5 yl)-8-oxo-N-[[(2R)-pyrrolidin-2-yl]methyl]-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-carboxamide Yield: 38% LCMS (ESI+): m/z 504.3 (M+H)+, Rt: 2.014 min.
  • Example 16 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)- 8-oxo-N-(4-piperidylmethyl)-11-thia-1,3,5-triazatetracyclo[8.7.0.0 2,7 .0 12,17 ]- 20 heptadeca-2,4,6,9,12(17),13,15-heptaene-9-carboxamide Yield: 45% LCMS (ESI+): m/z 518.3 (M+H) + , Rt: 1.933 min.
  • Example 18 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)- 8-oxo-N-pyrrolidin-3-yl-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-carboxamide 15 Yield: 11% LCMS (ESI+): m/z 490.3 (M+H) + , Rt: 1.867 min.
  • Example 19 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)- 8-oxo-N-(4-piperidyl)-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-carboxamide 25 Yield: 18% - 244 - LCMS (ESI+): m/z 504.3 (M+H) + , Rt: 1.844 min.
  • Example 20 N-(2-(methylamino)ethyl)-2-(5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-5-oxo-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3-d]- pyrimidine-6-carboxamide 10 Yield: 71%. Isolated as HCl salt. LCMS (ESI+): m/z 478.2 (M+H) + , Rt: 1.272 min.
  • Example 64 2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxo-N- (pyrrolidin-3-ylmethyl)-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3-d]- 20 pyrimidine-6-carboxamide Yield: 48%. Isolated as HCl salt. LCMS (ESI+): m/z 504.1 (M+H) + , Rt: 2.718 min.
  • Example 23 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)- 8-oxo-N-(4-piperidylmethyl)-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-carboxamide - 247 - Yield: 54%. Isolated as HCl salt.
  • Example 24 N-(aminomethyl)-4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo- [3,4-c]pyrrol-5-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-carboxamide Yield: 38%. Isolated as HCl salt. 15 LCMS (ESI+): m/z 447.3 (M+H) + , Rt: 1.523 min.
  • Example 25 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)- 8-oxo-N-pyrrolidin-3-yl-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-carboxamide 25 Yield: 58%. Isolated as HCl salt. - 248 - LCMS (ESI+): m/z 473.3 (M+H) + , Rt: 1.758 min.
  • Example 26 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)-10 8-oxo-N-(4-piperidyl)-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-carboxamide Yield: 62.50%. Isolated as HCl salt. LCMS (ESI+): m/z 487.3 (M+H) + , Rt: 1.812 min.
  • Example 27 N-(2-(methylamino)ethyl)-2-(5-methylhexahydropyrrolo[3,4-c]- pyrrol-2(1H)-yl)-5-oxo-5,7-dihydrobenzo[4',5']imidazo[1',2':1,6]pyrido-[2,3- d]pyrimidine-6-carboxamide 25 Yield: 36%. Isolated as HCl salt. LCMS (ESI+): m/z 461.2 (M+H) + , Rt: 1.719 min.
  • Example 29 4-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl)-8- 15 oxo-N-(pyrrolidin-2-ylmethyl)-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-carboxamide
  • tert-butyl 2-[9-[(1-tert-butoxycarbonylpyrrolidin-2-yl)methyl- carbamoyl]-8-oxo-11-thia-1,3,5-triazatetracyclo[8.7.0.0 2,7 .0 12,17 ]heptadeca-20 2,4,6,9,12(17),13,15-heptaen-4-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]
  • Example 30 4-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl)-8- oxo-N-(pyrrolidin-2-ylmethyl)-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-carboxamide 5 Yield: 32% LCMS (ESI+): m/z 473.3 (M+H) + , Rt: 1.765 min.
  • Example 66 N-ethyl-2-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]- pyrrol-5-yl)-5-oxo-[1,3]benzothiazolo[3,2-a][1,8]naphthyridine-6- carboxamide 10 Yield: 21%. Isolated as HCl salt. LCMS (ESI+): m/z 448.1 (M+H) + , Rt: 2.887 min.
  • Example 35 2-(5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxo-N- (piperidin-4-yl)-5H-benzo [4',5']thiazolo[3',2':1,6]pyrido[2,3-d]pyrimidine- 10 6-carboxamide
  • Example 68 2-(5-(cyclopropylmethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)-N-(1-methylpiperidin-4-yl)-5-oxo-5H-benzo[4',5']thiazolo[3',2':1,6]- pyrido[2,3-d]pyrimidine-6-carboxamide 10 Yield: 21%. Isolated as HCl salt. LCMS (ESI+): Rt: 1.385 min, m/z 558.4 (M+H) + .
  • Example 70 9-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5- carbonyl)-4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)- 11-thia-1,3,5-triazatetracyclo[8.7.0.02,7.012,17]heptadeca- 2,4,6,9,12(17),13,15-heptaen-8-one - 259 - Yield: 20%. Isolated as HCl salt.
  • Example 72 2-(5-Ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxo-N- (piperidin-4-yl)-5,7-dihydrobenzo[4',5']imidazo[1',2':1,6]pyrido[2,3-d]- 5 pyrimidine-6-carboxamide
  • Example 74 2-(5-(cyclopropylmethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- 5 yl)-N-(1-methylpiperidin-4-yl)-5-oxo-5,7-dihydrobenzo[4',5']imidazo [1',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxamide Yield: 22%. Isolated as HCl salt. LCMS (ESI+): Rt: 1.330 min, m/z 541.5 (M+H) + .
  • Example 77 2-(1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-oxo-N- (piperidin-4-yl)-5H-benzo[4',5'] thiazolo[3',2':1,6]pyrido[2,3-d]pyrimidine- 20 6-carboxamide Yield: 40%. Isolated as HCl salt. LCMS (ESI+): m/z 504.1 (M+H) + , Rt: 1.725 min.
  • Example 79 2-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-10 oxo-N-(piperidin-4-yl)-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3-d]- pyrimidine-6-carboxamide Yield: 58%. Isolated as HCl salt. LCMS (ESI+): m/z 504.4 (M+H) + , Rt: 1.281 min.
  • Example 81 4-(5-methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin- 2-yl)-8-oxo-N-(4-piperidyl)-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-carboxamide 20 4-(5-Methyl-3,3a,4,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-2-yl)-8-oxo- N-(4-piperidyl)-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-carboxamide: A solution of tert-buty
  • Example 85 N-methyl-4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]- pyrrol-5-yl)-N-(1-methyl-4-piperidyl)-8-oxo-11-thia-1,3,5-triazatetracyclo- 30 [8.7.0.0 2,7 .0 12,17 ]heptadeca-2,4,6,9,12(17),13,15-heptaene-9-carboxamide - 271 - Yield: 3%.
  • Example 87 N-methyl-4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]- pyrrol-5-yl)-8-oxo-N-(4-piperidyl)-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-carboxamide 20
  • N-(4-aminocyclohexyl)-N-methyl-acetamide A mixture of tert-butyl N-[4- 20 [acetyl(methyl)amino]cyclohexyl]carbamate (1.1 g, 4.07 mmol, 1 eq) in HCl/dioxane (2 M, 11 mL, 5.41 eq) was degassed and purged with N2 (x 3). The mixture was stirred at 20 °C for 12h under N2 atmosphere. The reaction mixture was concentrated in vacuo and the crude product (1.3 g, crude) was used in the next step without further purification.
  • Example 91 4-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)-8-oxo-N-(4- piperidyl)-11-thia-1,3,5-triazatetracyclo[8.7.0.0 2,7 .0 12,17 ]heptadeca- 20 2,4,6,9,12(17),13,15-heptaene-9-carboxamide
  • Example 94 4-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)-N-(1-methyl-4- piperidyl)-8-oxo-11-thia-1,3,5-triazatetracyclo[8.7.0.0 2,7 .0 12,17 ]heptadeca- 30 2,4,6,9,12(17),13,15-heptaene-9-carboxamide - 280 - Yield: 6%. Isolated as HCl salt. LCMS (ESI+): m/z 532.2 (M+H) + , Rt: 2.037 min.
  • Example 96 4-(2-methyl-2,8-diazaspiro[4.5]decan-8-yl)-N-(1-methyl-4-20 piperidyl)-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-carboxamide Yield: 18%. Isolated as HCl salt. LCMS (ESI+): m/z 546.3 (M+H) + , Rt: 2.072 min.
  • Example 97 4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-N-(1-methyl-4-30 piperidyl)-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-carboxamide - 281 - Yield: 15%. Isolated as HCl salt. LCMS (ESI+): m/z 560.2 (M+H)+, Rt: 2.137 min.
  • Example 100 2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(1- 5 methylpiperidin-4-yl)-5-oxo-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3-d]- pyrimidine-6-carboxamide Yield: 15%. Isolated as HCl salt. LCMS (ESI+): m/z 518.1 (M+H) + , Rt: 2.676min.
  • Example 101 N-(1-methylpiperidin-4-yl)-5-oxo-2-(3-oxo-2,8-diazaspiro- [4.5]decan-8-yl)-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3-d]pyrimidine- 6-carboxamide Yield: 10%. Isolated as HCl salt. 20 LCMS (ESI+): m/z 546.3 (M+H) + , Rt: 1.538 min.
  • Example 102 N-(1-methyl-4-piperidyl)-4-(3-oxa-9-azaspiro[5.5]undecan-9- 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-carboxamide - 283 - Yield: 16%. Isolated as HCl salt. LCMS (ESI+): m/z 547.2 (M+H) + , Rt: 3.040 min.
  • Example 103 2-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-(1-10 methylpiperidin-4-yl)-5-oxo-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3-d]- pyrimidine-6-carboxamide Yield: 16%. Isolated as HCl salt. LCMS (ESI+): m/z 503.3 (M+H) + , Rt: 2.047 min.
  • Example 107 4-(2,8-diazaspiro[4.5]decan-2-yl)-N-(1-methyl-4-piperidyl)-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-carboxamide 35 - 286 - Yield: 10%. Isolated as HCl salt. LCMS (ESI+): m/z 532.2 (M+H) + , Rt: 2.143 min.
  • Example 116 2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(1- methylpiperidin-4-yl)-5-oxo-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3-b]- pyrazine-6-carboxamide 15
  • 3,5-Dichloropyrazine-2-carbonyl chloride A mixture of 3,5-dichloropyrazine-2- carboxylic acid (10 g, 51.82 mmol, 1 eq) and SOCl2 (100 mL) was stirred at 65 °C for 12 hrs.
  • Example 121 N-(1-acetylpiperidin-4-yl)-2-(5-methylhexahydropyrrolo[3,4- 5 c]pyrrol-2(1H)-yl)-5-oxo-5,7-dihydrobenzo[4',5']imidazo[1',2':1,6] pyrido[2,3-d]pyrimidine-6-carboxamide 10
  • 2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxo-N- (piperidin-4-yl)-5,7-dihydrobenzo[4',5']imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6- carboxamide (Example 26) (100 mg, 205.52 ⁇ mol, 1 eq) in DCM (2 mL) was added DIEA (79
  • Example 124 2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxo-N- (2-(pyrrolidin-1-yl)ethyl)-5H-benzo[4,5]thiazolo[3,2-a][1,8]naphthyridine- 6-carboxamide 20 Yield: 12%. Isolated as HCl salt. LCMS (ESI+): Rt: 1.367 min, m/z 517.3 (M+H) + .
  • TEA (.11 g, 40.58 mmol, 5.65 mL, 2 eq) at -5°C under N2 was 25 added and the resultant mixture was stirred at -5°C for 2 h.
  • TEA (4.07 g, 40.26 mmol, 5.60 mL, 2 eq) was added and the mixture was stirred at 65°C for a further 12 h.
  • the reaction mixture was filtered and water (50 mL) was added to the filtrate.
  • the 15 aqueous phase was extracted with DCM (40 mL ⁇ 3).
  • the combined organic phases were washed with brine (80 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo.
  • the crude product was triturated with MTBE (20 mL) at 25°C for 1 h, filtered and the solid was dried under vacuum.
  • the product was purified by silica gel column chromatography (0 ⁇ 10% MeOH in DCM) to give the title compound 20 (1.1 g, 2.46 mmol, 49.43% yield) as a yellow solid.
  • Example 131 2-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5- yl)-5-oxo-N-(4-piperidyl)-[1,3]benzothiazolo[3,2-a]quinoline-6-carboxamide 25
  • Example 136 7-Methyl-2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)- N-(1-methylpiperidin-4-yl)-5-oxo-5,7-dihydrobenzo[4',5']imidazo[1',2':1,6 ]pyrido[2,3-d]pyrimidine-6-carboxamide 25 Yield: 14%. Isolated as HCl salt. LCMS (ESI+): m/z 515.5 (M+H) + , Rt: 1.157 min.
  • the reaction mixture was filtered and the filter cake was 25 concentrated under reduced pressure to give the crude product.
  • 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% 30 purity, HCl) as a yellow solid.
  • Example 138 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5- yl)-8-oxo-N-(4-piperidyl)-11-oxa-1,3,5-triazatetracyclo[8.7.0.0 2,7 .0 12,17 ]- heptadeca-2,4,6,9,12(17),13,15-heptaene-9-carboxamide 20
  • tert-butyl 4-[[4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]- pyrrol-5-yl)-8-oxo-11-oxa-1,3,5-triazatetracyclo[8.7.0.0 2,7 .0 12,17 ]heptadeca- 2,4,6,9,12(17),13,15-heptaene-9-carbonyl]amino]piperidine-1-carboxy
  • Example 139 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5- yl)-N-(1-methyl-4-piperidyl)-8-oxo-11-oxa-1,3,5-triazatetracyclo [8.7.0.0 2,7 .0 12,17 ]heptadeca-2,4,6,9,12(17),13,15-heptaene-9-carboxamide 10 Yield: 14%. Isolated as HCl salt.
  • Example 142 4-(2-oxa-8-aza-8-spiro[4.5]decyl)-8-oxo-11-thia-1,3,5- triazatetracyclo[8.7.0.0 2,7 .0 12,17 ]heptadeca-2(7),3,5,9,12(17),13,15- heptaene-9-carboxamide 10 Yield: 19%.
  • Example 143 4-(8-oxa-2-aza-2-spiro[4.5]decyl)-8-oxo-11-thia-1,3,5- triazatetracyclo[8.7.0.0 2,7 .0 12,17 ]heptadeca-2(7),3,5,9,12(17),13,15- heptaene-9-carboxamide 20 Yield: 32%.
  • Example 144 2-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-5-oxo- 5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxamide - 325 - Yield: 32%. Isolated as HCl salt. LCMS (ESI+): m/z 435.1 (M+H) + , Rt: 1.413 min.
  • Example 152 2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-6- 5 (pyrrolidine-1-carbonyl)-5H-benzo [4',5']thiazolo[3',2':1,6]pyrido[2,3- d]pyrimidin-5-one Yield: 12%. Isolated as HCl salt. LCMS (ESI+): m/z 475.2 (M+H) + , Rt: 1.465 min.
  • Example 153 N-methyl-2-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2- yl)-5-oxo-5H-benzo[4',5']thiazolo[3',2':1,6]pyrido[2,3-d]pyrimidine-6- carboxamide 20 Yield: 12%. Isolated as HCl salt. LCMS (ESI+): m/z 449.2 (M+H) + , Rt: 1.429 min.
  • Example 154 N-(2-(dimethylamino)ethyl)-N-ethyl-2-(5- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-oxo-5H-benzo[4',5'] thiazolo[3',2':1,6]pyrido[2,3-d]pyrimidine-6-carboxamide - 334 - Yield: 33%. Isolated as HCl salt. LCMS (ESI+): m/z 520.2 (M+H) + , Rt: 1.275 min.
  • the mixture was stirred at 25°C for 12 h.
  • the reaction mixture was filtered and the filter cake was concentrated under reduced 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 12.0 min) to give an eluent and 20 the eluent was concentrated under reduce pressure to remove MeCN, then lyophilized to give the title compound (30.2 mg, 52.80 ⁇ mol, 11.10% yield, 96.7% purity, HCl salt) as a yellow solid.
  • the reaction mixture was filtered and the filter cake was concentrated under reduced 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: 9%-39% B over 12.0 min) to give an eluent and the eluent was concentrated under reduced pressure to 15 remove MeCN, then lyophilized to give the title compound (40.1 mg, 64.39 ⁇ mol, 20.41% yield, 97.65% purity, HCl salt) as a yellow solid.
  • the reaction was warmed to 25°C and stirred for 2 h.
  • the reaction was quenched with NH4Cl (aq, 5 mL) and extracted with DCM (3 x 5 mL).
  • the combined organics were washed with saturated brine solution (2 x 3 mL), dried over anhydrous sodium sulfate and concentrated in vacuo.
  • the crude product was purified by prep-HPLC (column: 10 Phenomenex luna C18 100*40mm*5 ⁇ m;mobile phase: [H2O(0.04% HCl)-ACN]; gradient:5%-35% B over 8.0 min) to give the title compound (19.6 mg, 39.85 ⁇ mol, 5.99% yield) as a yellow solid.
  • Example 171 2-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-N-((1- methylpiperidin-4-yl)methyl)-5-oxo-5H-benzo[4',5'] thiazolo[3',2':1,6]- pyrido[2,3-d]pyrimidine-6-carboxamide 25 Yield: 3%. Isolated as HCl salt. LCMS (ESI+): m/z 546.3 (M+H) + , Rt: 1.340 min.

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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, dans laquelle R1, R2, R3, 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.
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