WO2025008516A2 - Nouveaux composés - Google Patents

Nouveaux composés Download PDF

Info

Publication number
WO2025008516A2
WO2025008516A2 PCT/EP2024/069024 EP2024069024W WO2025008516A2 WO 2025008516 A2 WO2025008516 A2 WO 2025008516A2 EP 2024069024 W EP2024069024 W EP 2024069024W WO 2025008516 A2 WO2025008516 A2 WO 2025008516A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
optionally
independently selected
substituted
groups
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.)
Ceased
Application number
PCT/EP2024/069024
Other languages
English (en)
Other versions
WO2025008516A3 (fr
Inventor
John Andrew Christopher
Paul Graham Wyatt
Thomas William HORNSBY
Martin Edward Cooper
Mark Mills
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.)
Sitala Bio Ltd
Original Assignee
Sitala Bio 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 GBGB2316974.1A external-priority patent/GB202316974D0/en
Application filed by Sitala Bio Ltd filed Critical Sitala Bio Ltd
Priority to EP24740851.1A priority Critical patent/EP4739667A2/fr
Publication of WO2025008516A2 publication Critical patent/WO2025008516A2/fr
Publication of WO2025008516A3 publication Critical patent/WO2025008516A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings

Definitions

  • the present invention relates to active esters of Factor B inhibitors, and to associated salts, solvates, prodrugs and pharmaceutical compositions.
  • the present invention further relates to methods of synthesising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by Factor B inhibition.
  • Background of the Invention The complement system is a critical part of the innate immune system and serves to help the body fight against infection from pathogens, ultimately leading to inflammation and phagocytic removal of pathogens or foreign particles.
  • the complement system is comprised of multiple proteins, including zymogens which undergo proteolytic cleavage to become activated and facilitate the activation of further zymogens in the cascade.
  • the proteins may be zymogens or proteins without potential for enzymatic activity that change conformation revealing binding sites for other components of the system. These successive enzymatic cleavages lead to a large, amplified response and many regulatory components exist in this system to prevent uncontrolled activation.
  • the complement system can be activated via three pathways: classical, lectin, and alternative.
  • the classical pathway is triggered by antigen:antibody complexes and connects the innate to the adaptive immune system.
  • the lectin pathway is triggered directly by the pathogen when serum protein mannan-binding lectin, collectins or ficolins bind to bacterial or viral mannose-containing carbohydrates.
  • the alternative pathway (also known as the alternate pathway) is initiated by activation of the central complement component, C3, either through spontaneous hydrolysis or enzymatic cleavage.
  • the alternative pathway also serves as a critical amplification loop of all three pathways of complement activation.
  • all of these pathways lead to the generation of C3 convertase which cleaves and activates further C3 molecules to promote: 1) opsonization of pathogens so they can be engulfed by phagocytes that recognise key receptors, 2) the recruitment of inflammatory cells by generating chemoattractants at the site of activation, and 3) formation of the C5 convertase resulting in production of C5a and C5b, the latter of which induces direct killing of pathogens by assembling terminal complement components to create membrane attack complex (MAC) pores in the membrane of bacteria or other target cells (Janeway, C.
  • MAC membrane attack complex
  • Factor B a trypsin-like serine protease
  • Spontaneous steady-state hydrolysis of C3 leads to the formation of C3(H 2 O).
  • Factor B can bind to the active forms of C3: C3(H2O) and C3b, generating the proenzyme C3bB (or C3(H2O)B), a target for activation by Factor D.
  • C3(H2O) and C3b Upon cleavage by Factor D, two fragments are generated: Ba and Bb (Schwaeble, W. J., Ali, Y. M., and Sim, R. B., (2020) Chapter 14 - The Roles and Contributions of the Complement System in the Pathophysiology of Autoimmune Diseases, in The Autoimmune Diseases (Sixth Edition) (Rose, N. R., and Mackay, I. R. eds.), Academic Press).
  • C5 convertase cleaves C5 to generate the anaphylatoxin C5a, and C5b which serves as a platform for the formation of the membrane attack complex.
  • Dysregulation of the alternative complement pathway due to genetics or the presence of autoantibodies can lead to many different diseases.
  • Inhibition of Factor B is therefore a key therapeutic target for modulation of the alternative pathway and hence the treatment of numerous diseases, disorders and conditions.
  • Iptacopan (LNP023), disclosed in Mainolfi et al., J. Med. Chem., 2020, vol.63, pp. 5697-5722, is a known Factor B inhibitor having the following structure:
  • Iptacopan is highly selective for Factor B, showing no inhibition of Factor D or the classical or lectin complement pathways. Also, no significant effects have been observed in a broad assay panel of receptors, ion channels, kinases, and proteases (Schubart, A. et al, Proc. Natl. Acad. Sci. U.S.A.2019, 116, 7926-7931).
  • a first aspect of the invention provides a compound of Formula (I):
  • R 1 is hydrogen;
  • R 2 is selected from hydrogen or a halo group;
  • R 4 is selected from hydrogen or a halo, -OH, -NH2, -SO2NH2, or a
  • R 1 is hydrogen;
  • R 2 is selected from hydrogen or a halo group;
  • R 3 is selected from hydrogen or a halo, -CN, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 1 -C 4 fluoroalkyl or C 3 -C 4 fluorocycloalkyl group;
  • R 4 is selected from hydrogen or a halo, -OH, -NH2, -SO2NH2, or a C1-C8 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups
  • R 1 is hydrogen;
  • R 5 is selected from hydrogen or a halo group;
  • R 6 is selected from hydrogen or a halo, -R 60 or
  • R 1 is hydrogen;
  • R 2 is selected from hydrogen or a halo group;
  • R 4 is selected from hydrogen or a halo, -OH, -NH2, -SO2NH2, or a
  • R 1 is hydrogen;
  • R 2 is selected from hydrogen or a halo group;
  • R 3 is selected from hydrogen or a halo, -CN, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C 3 -C 4 fluorocycloalkyl group;
  • R 4 is selected from hydrogen or a halo, -OH, -NH2, -SO2NH2, or a C1-C8 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, wherein the hydrocarbyl group may optionally include one or more heteroatoms each independently selected from N, O and S in its carbon skeleton, and wherein any -S- moiety may optionally be substituted with one or two groups each independently selected
  • R 1 is hydrogen;
  • R 5 is selected from hydrogen or a halo group;
  • R 6 is selected from hydrogen or a halo, -R 60 or -
  • hydrocarbyl substituent group or a hydrocarbyl moiety in a substituent group only includes carbon and hydrogen atoms but, unless stated otherwise, does not include any heteroatoms, such as N, O or S, in its carbon skeleton.
  • a hydrocarbyl group/moiety may be saturated or unsaturated (including aromatic), and may be straight-chained or branched, or be or include cyclic groups wherein, unless stated otherwise, the cyclic group does not include any heteroatoms, such as N, O or S, in its carbon skeleton.
  • hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups/moieties and combinations of all of these groups/moieties.
  • a hydrocarbyl group is a C1-C20 hydrocarbyl group. More typically a hydrocarbyl group is a C1-C15 hydrocarbyl group. More typically a hydrocarbyl group is a C 1 -C 10 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.
  • alkyl groups/moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and n-pentyl groups/moieties.
  • 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.
  • 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 include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1- pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1,4- hexadienyl groups/moieties.
  • alkenyl does not include “cycloalkenyl”.
  • an alkenyl group is a C2-C12 alkenyl group.
  • an alkenyl group is a C2-C6 alkenyl group.
  • An “alkenylene” group is similarly defined as a divalent alkenyl group.
  • An “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. Examples of alkynyl groups/moieties include ethynyl, propargyl, but-1-ynyl and but-2- ynyl groups/moieties.
  • an alkynyl group is a C2-C12 alkynyl group. More typically an alkynyl group is a C2-C6 alkynyl group.
  • alkynylene is similarly defined as a divalent alkynyl group.
  • a “cyclic” substituent group or a cyclic moiety in a substituent group refers to any hydrocarbyl ring, wherein the hydrocarbyl ring may be saturated or unsaturated (including aromatic) and may include one or more heteroatoms, e.g. N, O or S, in its carbon skeleton. Examples of cyclic groups include cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl groups as discussed below.
  • a cyclic group may be monocyclic, bicyclic (e.g. bridged, fused or spiro), or polycyclic.
  • a cyclic group is a 3- to 12-membered cyclic group, which means it contains from 3 to 12 ring atoms. More typically, a cyclic group is a 3- to 7-membered monocyclic group, which means it contains from 3 to 7 ring atoms.
  • a bicyclic or polycyclic group or moiety is “saturated” it is to be understood that all of the ring systems within the bicyclic or polycyclic group or moiety (excluding any ring systems which are part of or formed by optional substituents) are saturated.
  • heterocyclic substituent group or a heterocyclic moiety in a substituent group refers to a cyclic group or moiety including one or more carbon atoms and one or more (such as one, two, three or four) heteroatoms, e.g. N, O or S, in the ring structure.
  • heterocyclic groups include heteroaryl groups as discussed below and non-aromatic heterocyclic groups such as azetinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl and thiomorpholinyl groups.
  • non-aromatic heterocyclic groups such as azetinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazo
  • a “cycloalkyl” substituent group or a cycloalkyl moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless stated otherwise, a cycloalkyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
  • a “cycloalkenyl” substituent group or a cycloalkenyl moiety in a substituent group refers to a non-aromatic unsaturated hydrocarbyl ring having one or more carbon- carbon double bonds and containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl and cyclohex-1,3-dien-1-yl. Unless stated otherwise, a cycloalkenyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
  • An “aryl” substituent group or an aryl moiety in a substituent group refers to an aromatic hydrocarbyl ring.
  • aryl refers to monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic.
  • aryl groups/moieties include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless stated otherwise, the term “aryl” does not include “heteroaryl”.
  • a “heteroaryl” substituent group or a heteroaryl moiety in a substituent group refers to an aromatic heterocyclic group or moiety.
  • heteroaryl refers to monocyclic aromatic heterocycles and polycyclic fused ring aromatic heterocycles wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic.
  • heteroaryl groups/moieties include the following:
  • G O, S or NH.
  • 5- or 6-membered heteroaryl groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl groups.
  • bicyclic or polycyclic group or moiety is stated to be aromatic, such as an aryl or a heteroaryl group, it is to be understood that all of the ring systems within the bicyclic or polycyclic group or moiety (excluding any ring systems which are part of or formed by optional substituents) are aromatic.
  • a bicyclic or polycyclic 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 all of the ring systems within the bicyclic or polycyclic group or moiety (excluding any ring systems which are part of or formed by optional substituents) are non-aromatic.
  • arylalkyl arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl
  • the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule.
  • An example of an arylalkyl group is benzyl.
  • each hydrogen atom may optionally be replaced by any specified monovalent substituent; - any two hydrogen atoms attached to the same carbon or nitrogen atom may optionally be replaced by any specified ⁇ -bonded substituent; - any sulphur atom may optionally be substituted with one or two of any specified ⁇ -bonded substituents; and - any two hydrogen atoms attached to the same or different atoms, within the same optionally substituted group or moiety, may optionally be replaced by any specified divalent bridging substituent.
  • a substituted group comprises 1, 2, 3 or 4 substituents, more typically 1, 2 or 3 substituents, more typically 1 or 2 substituents, and more typically 1 substituent.
  • any divalent bridging substituent e.g. -O-, -S-, -NH-, -CH2-, -CH 2 -CH 2 -, etc.
  • an optionally substituted group or moiety e.g. R 1
  • R 2 a second group or moiety
  • halo includes fluoro, chloro, bromo and iodo.
  • halo such as a haloalkyl or halomethyl group
  • the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo and iodo.
  • the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the corresponding group without the halo prefix.
  • a halomethyl group may contain one, two or three halo substituents.
  • a haloethyl or halophenyl group may contain one, two, three, four or five halo substituents.
  • halomethyl refers to a methyl group substituted with one, two or three fluoro groups.
  • halo-substituted it is to be understood that the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo and iodo.
  • the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the group said to be halo-substituted.
  • a halo- substituted methyl group may contain one, two or three halo substituents.
  • a halo- substituted ethyl or halo-substituted phenyl group may contain one, two, three, four or five halo substituents.
  • any reference to an element is to be considered a reference to all isotopes of that element.
  • any reference to hydrogen is considered to encompass all isotopes of hydrogen including deuterium and tritium.
  • any reference to a compound or group is to be considered a reference to all tautomers of that compound or group.
  • methoxy, dimethylamino and aminoethyl groups are considered to be hydrocarbyl groups including one or more heteroatoms N, O or S in their carbon skeleton.
  • the compounds of the invention contain no more than one quaternary ammonium group. More typically, the compounds of the invention contain no quaternary ammonium groups.
  • a C x -C y group is defined as a group containing from x to y carbon atoms.
  • a C 1 -C 4 alkyl group is defined as an alkyl group containing from 1 to 4 carbon atoms.
  • optional substituents are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituents.
  • replacement heteroatoms e.g. N, O or S
  • a morpholinyl group is to be considered a C4 heterocyclic group, not a C6 heterocyclic group.
  • R 2 is selected from hydrogen or a halo group.
  • R 2 is selected from hydrogen or a fluoro, chloro or bromo group. Most typically, R 2 is hydrogen.
  • R 3 is selected from hydrogen or a halo (e.g. fluoro, chloro or bromo), -R 30 , -CN, -CHO, -COR 30 , -CO 2 H or -CO 2 R 30 group, wherein R 30 is selected from a C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl or -R 31 group, wherein R 31 is a 3- to 6-membered monocyclic group, wherein the 3- to 6- membered monocyclic group may optionally be substituted with one or more halo (e.g.
  • each R 32 is independently selected from a methyl or a fluoromethyl group, provided that the group R 3 , including any optional substituents, contains no more than 8 carbon atoms.
  • R 3 is selected from hydrogen or a fluoro, chloro, bromo, -R 30 , -CN, -CHO, -COR 30 , -CO 2 H or -CO 2 R 30 group, wherein R 30 is selected from a C1-C4 alkyl, C1-C4 fluoroalkyl or -R 31 group, wherein R 31 is selected from a C3-C6 cycloalkyl group, a 4- to 6-membered saturated heterocyclic group, or a phenyl or a 5- or 6-membered heteroaryl group, wherein the C3-C6 cycloalkyl group and the 4- to 6- membered saturated heterocyclic group may optionally be substituted with one or more fluoro groups and/or with one or two groups R 32 , and wherein the phenyl or the 5- or 6- membered heteroaryl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/
  • R 3 is selected from hydrogen or a fluoro, chloro, bromo, -R 30 , -R 31 , -CN, -CHO, -COR 30 , -CO2H or -CO2R 30 group, wherein R 30 is selected from a methyl or fluoromethyl group, and wherein R 31 is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/or with one or two groups R 32 .
  • R 3 is selected from hydrogen or a halo (e.g.
  • R 30 is selected from a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3-C4 fluorocycloalkyl group.
  • R 3 is selected from hydrogen or a fluoro, chloro, bromo -R 30 , -CN, -CHO, -COR 30 , -CO 2 H or -CO 2 R 30 group, wherein R 30 is selected from a methyl or fluoromethyl group.
  • R 3 is selected from hydrogen or a halo (e.g. fluoro, chloro or bromo), -CN, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 1 -C 4 fluoroalkyl or C 3 -C 4 fluorocycloalkyl group.
  • R 3 is selected from hydrogen or a fluoro, chloro, bromo, -CN or methyl group, wherein the methyl group may optionally be fluoro substituted. More typically, R 3 is selected from hydrogen or a fluoro, chloro or bromo group. Most typically, R 3 is hydrogen.
  • R 4 is selected from hydrogen or a fluoro, chloro, bromo, -OH, -NH2, -SO2NH2, -SO2-R 40 or -R 40 group, wherein R 40 is selected from a C1- C6 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and wherein the hydrocarbyl group may optionally include one, two or three heteroatoms each independently selected from N and O in its carbon skeleton.
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 )2, -SO2-R 41 , -SO2-N(R 42 )2, -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 )2, -L 4 -SO2-R 41 , -L 4 -SO2-N(R 42 )2, -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 )2, -O-L 4 -SO2-R 41 , -O-L 4 -SO 2 -N(R 42 ) 2 , -NR 43 -L 4 -OH, -NR 43 -L 4 -OR 41 , -NR 43 -L 4 -N(R 42 ) 2 , -NR 43 -L 4 -OH, -NR 43 -L 4 -OR
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 )2, -SO2-R 41 , -SO2-N(R 42 )2, -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 )2, -L 4 -SO2-R 41 , -L 4 -SO2-N(R 42 )2, -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 ) 2 , -O-L 4 -SO 2 -R 41 , -O-L 4 -SO 2 -N(R 42 ) 2 , -NR 43 -L 4 -OH, -NR 43 -L 4 -OR 41 , -NR 43 -L 4 -N(R 42 )2, -NR 43 -L 4 -SO2-R 41 , -NR 43
  • R 4 may be a bromo or a chloro group, or a -R 44 group such as a methyl, -CF3 or cyclopropyl group, or a -OR 41 group such as a -OMe, -OCD3, -OCHF2 or -OCH2CHF2 group, or a -SO2-R 41 group such as a -SO2Me or -SO2Et group, or a -O-L 4 -N(R 42 ) 2 group such as a -OCH 2 CH 2 NHMe group, or a -L 4 -N(R 42 ) 2 group such as a -CONHMe group.
  • a -R 44 group such as a methyl, -CF3 or cyclopropyl group
  • a -OR 41 group such as a -OMe, -OCD3, -OCHF2 or -OCH2CHF2 group
  • a -SO2-R 41 group such as
  • R 4 contains no more than 6 carbon atoms.
  • the total number of nitrogen, oxygen and sulphur atoms in R 4 , including any optional substituents is no more than four. More typically, the total number of nitrogen, oxygen and sulphur atoms in R 4 , including any optional substituents, is no more than three.
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 44 , -N(R 42 ) 2 , -COOH, -COOR 44 , -CON(R 42 ) 2 , -SO 2 -R 44 , -SO 2 -N(R 42 ) 2 , -O-L 4 -OH, -O-L 4 -OR 44 , -O-L 4 -N(R 42 )2, -NR 43 -L 4 -OH, -NR 43 -L 4 -OR 44 , -NR 43 -L 4 -N(R 42 )2, or -R 44 group, wherein: each R 42 is independently selected from hydrogen or a -R 44 group; R 43 is selected from hydrogen or a -R 44 group; each R 44 is independently selected from a C1-C4 alkyl or C3-C6 cycloalkyl group, wherein the C1-C4
  • R 4 is selected from a fluoro, chloro, bromo, -OR 44 , -CON(R 42 )2, -SO2-R 44 , -SO2-N(R 42 )2, -O-CH2-CH2-OR 44 , -O-CH2-CH2-N(R 42 )2, or -R 44 group.
  • each R 44 is independently selected from a C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl group, wherein the C1-C4 alkyl or C3-C6 cycloalkyl group may optionally be substituted with one or more fluoro groups.
  • each R 44 is independently selected from a C 1 -C 3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group.
  • R 4 is selected from a fluoro, chloro, bromo, -OR 44 -SO2-R 44 , -SO2-N(R 42 )2, -O-CH2-CH2-N(R 42 )2, or -R 44 group. More typically, R 4 is selected from a fluoro, chloro, bromo, -R 44 or -OR 44 group.
  • R 44 is selected from a C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group.
  • R 4 is selected from a fluoro, chloro, bromo, methyl (Me) or -OMe group, wherein any methyl group may optionally be fluoro substituted.
  • R 4 is selected from a methyl (Me) or -OMe group, wherein any methyl group may optionally be fluoro substituted.
  • R 4 is -OMe.
  • R 5 is selected from hydrogen or a halo group.
  • R 5 is selected from hydrogen or a fluoro, chloro or bromo group. More typically, R 5 is selected from hydrogen or a fluoro group. Most typically, R 5 is hydrogen.
  • R 6 is selected from hydrogen or a halo, -R 60 or -OR 60 group, wherein R 60 is selected from a C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 1 -C 4 fluoroalkyl or C 3 -C 4 fluorocycloalkyl group. More typically, R 6 is selected from a fluoro, chloro, bromo, -R 60 or -OR 60 group.
  • R 6 is selected from a chloro, bromo, -R 60 or -OR 60 group. Yet more typically, R 6 is selected from a -R 60 or -OR 60 group. In one embodiment, R 60 is selected from a C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group. For example, R 6 may be selected from a -R 60 or -OR 60 group, and R 60 may be selected from a C 1 -C 3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group.
  • R 60 is selected from a methyl, fluoromethyl, ethyl or fluoroethyl group. More typically still, R 60 is selected from a methyl or fluoromethyl group. In a further embodiment, R 6 is a methyl or a fluoromethyl group. More typically, R 6 is a methyl group.
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro or a C 1 -C 6 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and wherein the hydrocarbyl group may optionally include one, two or three heteroatoms each independently selected from N and O in its carbon skeleton, provided that the atom of any hydrocarbyl group of R 7 or R 8 that is directly attached to the reminder of the molecule is a carbon atom.
  • R 7 may be selected from hydrogen or a fluoro or a C1-C6 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight- chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and wherein the hydrocarbyl group may optionally include one, two or three heteroatoms each independently selected from N and O in its carbon skeleton, provided that the atom of any hydrocarbyl group of R 7 that is directly attached to the reminder of the molecule is a carbon atom, and R 8 may be selected from hydrogen or a fluoro, methyl or fluoromethyl group.
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro, -CN, -COOH, -COOR 71 , -CO-N(R 72 )2, -L 7 -COOH, -L 7 -COOR 71 , -L 7 -CO-N(R 72 )2, -L 7 -OH, -L 7 -OR 71 , -L 7 -N(R 72 )2, -R 73 , -R 74 or -L 7 -R 74 group, wherein: each R 71 is independently selected from a -R 73 or -R 74 group; each R 72 is independently selected from hydrogen or a -R 73 or -R 74 group, or any two R 72 may, together with the nitrogen atom to which they are attached, form a 3- to 6- membered saturated monocyclic heterocyclic group, wherein the 3- to 6-membered saturated monocyclic heterocyclic group may optionally be substituted with one or
  • R 7 is selected from hydrogen or a fluoro, -CN, -COOH, -COOR 71 , -CO-N(R 72 ) 2 , -L 7 -COOH, -L 7 -COOR 71 , -L 7 -CO-N(R 72 ) 2 , -L 7 -OH, -L 7 -OR 71 , -L 7 -N(R 72 ) 2 , -R 73 , -R 74 or -L 7 -R 74 group, and R 8 is selected from a hydrogen or a fluoro, methyl or fluoromethyl group.
  • L 7 may be seen as a straight-chained alkylene group substituted with two R L7 groups, wherein the two R L7 together form a -CH2CH2-, -CH2- or -CF2- group respectively, such that the two R L7 and the carbon atom or atoms to which they are attached together form a cyclopropyl or fluorocyclopropyl group.
  • L 7 may be seen as a straight-chained alkylene group substituted with a single R L7 group, wherein the R L7 and one R 72 group together form a -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - group respectively, such that the R L7 and the R 72 together with the atoms of the -L 7 -N(R 72 )2 group to which they are attached together form a saturated 5- or 6- membered monocyclic heterocyclic group.
  • any R 7 or R 8 group including any optional substituents, contains no more than 10 carbon atoms.
  • any R 7 or R 8 group contains no more than 8 carbon atoms.
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro, -CN, -COOH, -COOR 71 , -L 7 -COOH, -L 7 -COOR 71 , -L 7 -OH, -L 7 -OR 71 , -L 7 -N(R 72 )2, -R 73 , -R 74 or -L 7 -R 74 group, wherein: each R 71 is independently selected from a -R 73 or -R 74 group; each R 72 is independently selected from hydrogen or a -R 73 or -R 74 group, or any two R 72 may, together with the nitrogen atom to which they are attached, form a 3- to 6- membered saturated monocyclic heterocyclic group, wherein the 3- to 6-membered saturated monocyclic heterocyclic group may optionally be substituted
  • R 7 is selected from hydrogen or a fluoro, -CN, -COOH, -COOR 71 , -L 7 -COOH, -L 7 -COOR 71 , -L 7 -OH, -L 7 -OR 71 , -L 7 -N(R 72 )2, -R 73 , -R 74 or -L 7 -R 74 group, and R 8 is selected from a hydrogen or a fluoro, methyl or fluoromethyl group.
  • R 7 is selected from hydrogen or a fluoro, -CN, -COOH, -L 7 -COOH, -L 7 -OH, -L 7 -OR 71 , -L 7 -N(R 72 ) 2 , -R 73 , -R 74 or -L 7 -R 74 group, and R 8 is selected from a hydrogen or a fluoro, methyl or fluoromethyl group.
  • any R 7 or R 8 group, including any optional substituents contains no more than 6 carbon atoms.
  • the total number of nitrogen, oxygen and sulphur atoms in any R 7 or R 8 group, including any optional substituents is no more than four. More typically, the total number of nitrogen, oxygen and sulphur atoms in any R 7 or R 8 group, including any optional substituents, is no more than three.
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro, -COOH, -COOR 75 , -CONH 2 , -CONHR 75 , -CON(R 75 ) 2 , -L 71 -COOH, -L 71 -COOR 75 , -L 71 -CONH2, -L 71 -CONHR 75 , -L 71 -CON(R 75 )2, -L 71 -OH, -L 71 -OR 75 or -R 75 group, wherein: each -L 71 - is independently selected from a -CH2-, -CHMe-, -CMe2-, , -CH 2 -CH 2 -, -CH 2 -CHMe-, -CH 2 -CMe 2 -, -CHMe-CH 2 -, -CHMe-CHMe-, -CHMe-CMe 2 -, -CMe2-CH
  • R 7 is selected from from hydrogen or a fluoro, -COOH, -COOR 75 , -CONH2, -CONHR 75 , -CON(R 75 )2, -L 71 -COOH, -L 71 -COOR 75 , -L 71 -CONH 2 , -L 71 -CONHR 75 , -L 71 -CON(R 75 ) 2 , -L 71 -OH, -L 71 -OR 75 or -R 75 group, and R 8 is selected from a hydrogen or a fluoro, methyl or fluoromethyl group. More typically, R 8 is hydrogen.
  • R 7 is selected from from hydrogen or a fluoro, -COOH, -COOR 75 , -CONH2, -CONHR 75 , -CON(R 75 )2, -L 71 -COOH, -L 71 -COOR 75 , -L 71 -CONH2, -L 71 -CONHR 75 , -L 71 -CON(R 75 )2, -L 71 -OH, -L 71 -OR 75 or -R 75 group
  • R 7 (including any optional substituents) contains no more than 10 carbon atoms.
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro, -COOH, -COOR 75 , -L 71 -COOH, -L 71 -COOR 75 , -L 71 -OH, -L 71 -OR 75 or -R 75 group, wherein: each -L 71 - is independently selected from a -CH 2 -, -CHMe-, -CMe 2 -, -CH 2 -CH 2 -, -CH2-CHMe-, -CH2-CMe2-, -CHMe-CH2-, -CHMe-CHMe-, -CHMe-CMe2-, -CMe2-CH2-, -CMe2-CHMe- or -CMe2-CMe2- group, wherein any -CH2-, -CHMe- or -CMe2- group may optionally be fluoro substituted; and each R 75 is independently selected from a C 1 -C 4 alky
  • R 7 is selected from hydrogen or a fluoro, -COOH, -COOR 75 , -L 71 -COOH, -L 71 -COOR 75 , -L 71 -OH, -L 71 -OR 75 or -R 75 group
  • R 8 is selected from a hydrogen or a fluoro, methyl or fluoromethyl group.
  • each -L 71 - is independently selected from a -CH 2 -, -CHMe-, -CMe2-, -CH2-CH2-, -CH2-CHMe-, -CH2-CMe2-, -CHMe-CH2-, -CHMe-CHMe- or -CMe2-CH2- group, wherein any -CH2-, -CHMe- or -CMe2- group may optionally be fluoro substituted.
  • R 7 including any optional substituents contains no more than 6 carbon atoms
  • R 8 is selected from a hydrogen or a fluoro, methyl or fluoromethyl group.
  • R 7 including any optional substituents contains no more than 5 carbon atoms
  • R 8 is selected from a hydrogen or a fluoro, methyl or fluoromethyl group.
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro, -L 71 -COOH, -L 71 -COOR 75 , -L 71 -OH, -L 71 -OR 75 or -R 75 group, wherein: each -L 71 - is independently selected from a -CH2-, -CHMe- or -CMe2- group, wherein any -CH2-, -CHMe- or -CMe2- group may optionally be fluoro substituted; and each R 75 is independently selected from a C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group.
  • R 7 is selected from hydrogen or a fluoro, -L 71 -COOH, -L 71 -COOR 75 , -L 71 -OH, -L 71 -OR 75 or -R 75 group
  • R 8 is selected from a hydrogen or a fluoro, methyl or fluoromethyl group.
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro, methyl or fluoromethyl group.
  • R 7 may be selected from hydrogen or a fluoro, methyl or fluoromethyl group
  • R 8 may be hydrogen or a fluoro group.
  • at least one of R 7 and R 8 is hydrogen.
  • R 8 is hydrogen.
  • R 7 and R 8 are both hydrogen.
  • -L 78 - is selected from a -CH2-CH2-, -
  • ring A is a phenyl or a 5- or 6-membered heteroaryl ring.
  • ring A may be a phenyl or a 6-membered heteroaryl ring, wherein the group R 9 OOC- is attached to the phenyl or the 6-membered heteroaryl ring at the 3-, 4- or 5-position, relative to the point of attachment of the phenyl or the 6-membered heteroaryl ring to the remainder of the molecule.
  • ring A may be a 5-membered heteroaryl ring, wherein the group R 9 OOC- is attached to the 5-membered heteroaryl ring at the 3- or 4-position, relative to the point of attachment of the 5-membered heteroaryl ring to the remainder of the molecule.
  • ring A may be a phenyl or a 6-membered heteroaryl ring, wherein the group R 19 CON(R 18 )OOC- is attached to the phenyl or the 6-membered heteroaryl ring at the 3-, 4- or 5-position, relative to the point of attachment of the phenyl or the 6-membered heteroaryl ring to the remainder of the molecule.
  • ring A may be a 5-membered heteroaryl ring, wherein the group R 19 CON(R 18 )OOC- is attached to the 5-membered heteroaryl ring at the 3- or 4-position, relative to the point of attachment of the 5-membered heteroaryl ring to the remainder of the molecule.
  • R 19 CON(R 18 )OOC-
  • the compound is a compound of Formula (Ia): Formula (Ia) wherein: X A1 is N, C-H or C-R 10 ; X A2 is N, C-H or C-R 10 ; X A3 is N, C-H or C-R 10 ; and X A4 is N, C-H or C-R 10 ; provided that no more than three of X A1 , X A2 , X A3 and X A4 are N; and R 1 to R 11 , X 12 , R 13 , m, n and q are as defined in accordance with Formula (I).
  • the compound is a compound of Formula (IIa): wherein: X A1 is N, C-H or C-R 10 ; X A2 is N, C-H or C-R 10 ; X A3 is N, C-H or C-R 10 ; and X A4 is N, C-H or C-R 10 ; provided that no more than three of X A1 , X A2 , X A3 and X A4 are N; and R 1 , R 4 to R 11 , X 12 , R 13 to R 17 , m, n and q are as defined in accordance with Formula (II).
  • the compound is a compound of Formula (IIIa):
  • X A1 is N, C-H or C-R 10 ;
  • X A2 is N, C-H or C-R 10 ;
  • X A3 is N, C-H or C-R 10 ;
  • X A4 is N, C-H or C-R 10 ; provided that no more than three of X A1 , X A2 , X A3 and X A4 are N; and R 1 to R 8 , R 10 , R 11 , X 12 , R 13 , R 18 , R 19 , m, n and q are as defined in accordance with Formula (III).
  • the compound is a compound of Formula (IVa):
  • X A1 is N, C-H or C-R 10 ;
  • X A2 is N, C-H or C-R 10 ;
  • X A3 is N, C-H or C-R 10 ;
  • X A4 is N, C-H or C-R 10 ; provided that no more than three of X A1 , X A2 , X A3 and X A4 are N; and R 1 , R 4 to R 8 , R 10 , R 11 , X 12 , R 13 to R 19 , m, n and q are as defined in accordance with Formula (IV).
  • no more than two of X A1 , X A2 , X A3 and X A4 are N.
  • no more than one of X A1 , X A2 , X A3 and X A4 is N.
  • no more than two of X A1 , X A2 , X A3 and X A4 are C-R 10 .
  • no more than one of X A1 , X A2 , X A3 and X A4 is C-R 10 .
  • X A1 is C-H or C-R 10
  • X A2 is C-H or C-R 10
  • X A3 is C-H or C-R 10
  • X A4 is C-H or C-R 10
  • X A1 is C-H
  • X A2 is C-H
  • X A3 is C-H
  • X A4 is C-H.
  • R 9 is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is a monocylic group or a fused bicyclic or fused tricyclic group, and wherein the aryl or the heteroaryl group may optionally be substituted with one or more substituents each independently selected from a halo, -OH, -NH 2 , -NO 2 , -SH, -SO 2 H, -SO 3 H, -SO 2 NH 2 , -R 90 or -SO 2 R 90 group, wherein each R 90 is independently selected from a C1-C4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight- chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one or two hetero
  • R 9 is a monocylic group or a fused bicyclic group.
  • R 9 is a phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or the 5- or 6-membered heteroaryl group may optionally be substituted with one or more substituents each independently selected from a halo, -OH, -NH2, -NO 2 , -SH, -SO 2 H, -SO 3 H, -SO 2 NH 2 , -R 90 or -SO 2 R 90 group, wherein each R 90 is independently selected from a C1-C4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one or two heteroatoms each
  • R 9 is a phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or the 5- or 6-membered heteroaryl group may optionally be substituted with one or more substituents each independently selected from fluoro, chloro and bromo, and/or with one or two substituents each independently selected from a -OH, -NH 2 , -NO 2 , -SH, -SO 2 H, -SO 3 H, -SO 2 NH 2 , -R 90 or -SO 2 R 90 group.
  • the phenyl or the 5- or 6-membered heteroaryl group is substituted with at least one substitutent.
  • each R 90 is independently selected from a C 1 -C 4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one or two heteroatoms each independently selected from N and O in its carbon skeleton.
  • R 9 is a phenyl or a 6-membered heteroaryl group, such as a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, wherein the phenyl or the 6- membered heteroaryl group is: (i) substituted with at least one fluoro group; and/or (ii) substituted with one or two substituents each independently selected from a fluoromethyl, fluoroethyl or -R 91 group, wherein each R 91 group is independently selected from a -NO 2 , -SO 3 H, -OR 92 , -CHO, -COR 92 , -COOH, -COOR 92 , -CONH 2 , -CONHR 92 , -CON(R 92 )2, -SO2R 92 , -SO2NH2, -SO2NHR 92 or -SO2N(R 92 )2 group
  • each R 91 group is independently selected from a -NO2, -SO3H, -OR 92 , -COR 92 , -COOR 92 , -CONH2, -CONHR 92 , -CON(R 92 )2, -SO2R 92 , -SO 2 NH 2 , -SO 2 NHR 92 or -SO 2 N(R 92 ) 2 group.
  • R 9 is selected from:
  • R 9 is selected from: or .
  • p is 0, 1, 2, 3 or 4. Accordingly, ring A may optionally be substituted with from one to four groups R 10 . Typically, p is 0, 1 or 2. More typically, p is 0 or 1. More typically still, p is 0.
  • each R 10 is independently selected from a halo, -OH, -NH2 or a C1-C4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one, two or three heteroatoms each independently selected from N and O in its carbon skeleton, or any two adjacent R 10 may together form a C1-C6 saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbylene group may optionally be substituted with one or more groups R 101 , wherein each R 101 is independently selected from a halo group, and wherein the hydrocarbylene group may optionally include one
  • each R 10 is independently selected from a halo, -OH, -NH2 or a C1-C4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one, two or three heteroatoms each independently selected from N and O in its carbon skeleton.
  • one R 10 is selected from a fluoro, chloro, bromo, -OH or a C1-C3 saturated hydrocarbyl group, wherein the saturated hydrocarbyl group may be straight-chained or branched, wherein the saturated hydrocarbyl group may optionally be substituted with one or more fluoro groups, and wherein the saturated hydrocarbyl group may optionally include a single heteroatom O in its carbon skeleton, and each remaining R 10 (if present) is independently selected from a fluoro, chloro or bromo group.
  • one R 10 is selected from a fluoro, -OH, methyl (Me), ethyl (Et), -OMe, -OEt, -CH2OH, -CH2OMe or -CH2OEt group, wherein any methyl (Me), ethyl (Et) or methylene (-CH2-) group of R 10 may optionally be fluoro substituted, and each remaining R 10 (if present) is a fluoro group.
  • one R 10 (if present) is selected from a fluoro, methyl or fluoromethyl group, and each remaining R 10 (if present) is a fluoro group.
  • two adjacent R 10 together form a C1-C6 saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight- chained or branched, or be or include a cyclic group, wherein the hydrocarbylene group may optionally be substituted with one or more groups R 101 , wherein each R 101 is independently selected from a halo group, and wherein the hydrocarbylene group may optionally include one, two or three heteroatoms each independently selected from N and O in its carbon skeleton.
  • the hydrocarbylene group together with the atoms to which it is attached forms a ring that is fused to ring A.
  • the hydrocarbylene group has a chain length of 3 or 4 atoms.
  • the hydrocarbylene group together with the atoms to which it is attached forms a 5- or 6-membered ring that is fused to ring A.
  • two adjacent R 10 may together form a C 2 -C 4 saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group is straight-chained, wherein the hydrocarbylene group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/or with a single methyl, fluoromethyl, methoxy or fluoromethoxy group, and wherein the hydrocarbylene group may optionally include a single heteroatom selected from N and O in its carbon skeleton, such that the hydrocarbylene group has a chain length of 3 or 4 atoms.
  • each remaining R 10 is independently selected from a fluoro, chloro or bromo group. More typically, each remaining R 10 (if present) is a fluoro group.
  • X 12 is NR 121 or C(R 122 )(R 123 ). In one embodiment, X 12 is NR 121 . In a further embodiment, X 12 is C(R 122 )(R 123 ).
  • m is 0, 1 or 2
  • n is 0, 1 or 2, provided that (i) m + n ⁇ 4, and (ii) when X 12 is NR 121 , m is 1 or 2 and n is 1 or 2.
  • X 12 is NR 121
  • m is 1 and n is 1.
  • X 12 is C(R 122 )(R 123 ), and (i) m is 0 and n is 0, or (ii) m is 0 and n is 1, or (iii) m is 1 and n is 0, or (iv) m is 1 and n is 1, or (v) m is 1 and n is 2, or (vi) m is 2 and n is 1.
  • (i) m is 0 and n is 1, or (ii) m is 1 and n is 0, or (iii) m is 1 and n is 1. More typically in such an embodiment, m is 1 and n is 1.
  • the compound is a compound of Formula (Ib): wherein R 1 to R 9 , R 11 , X 12 , R 13 , X A1 , X A2 , X A3 , X A4 and q are as defined in accordance with Formula (Ia).
  • the compound is a compound of Formula (IIb):
  • R 1 , R 4 to R 9 , R 11 , X 12 , R 13 to R 17 , X A1 , X A2 , X A3 , X A4 and q are as defined in accordance with Formula (IIa).
  • the compound is a compound of Formula (IIIb): Formula (IIIb) wherein R 1 to R 8 , R 11 , X 12 , R 13 , R 18 , R 19 , X A1 , X A2 , X A3 , X A4 and q are as defined in accordance with Formula (IIIa).
  • the compound is a compound of Formula (IVb):
  • R 1 , R 4 to R 8 , R 11 , X 12 , R 13 to R 19 , X A1 , X A2 , X A3 , X A4 and q are as defined in accordance with Formula (IVa). As stated in accordance with each of the first to the fourth aspects of the invention, q is 0, 1, 2, 3, 4, 5, 6, 7 or 8.
  • q is 0, 1 or 2;
  • m is 0 and n is 1, or m is 1 and n is 0, q is 0, 1, 2, 3 or 4;
  • m is 1 and n is 1, or m is 0 and n is 2, or m is 2 and n is 0, q is 0, 1, 2, 3, 4, 5 or 6; and
  • m is 1 and n is 2, or m is 2 and n is 1, q is 0, 1, 2, 3, 4, 5, 6, 7 or 8.
  • q is 0, 1 or 2.
  • q is 0 or 1. More typically, q is 0.
  • R 11 is a hydrocarbyl group
  • the hydrocarbyl group, including any optional substituents contains no more than six carbon atoms. More typically, the hydrocarbyl group, including any optional substituents, contains no more than four carbon atoms.
  • the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 11 , including any optional substituents is no more than four. More typically, the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 11 , including any optional substituents, is no more than three.
  • R 11 is selected from hydrogen or a fluoro, methyl (Me), ethyl (Et), -CH 2 OH, -CH 2 OMe or -CH 2 OEt group, wherein any methyl (Me), ethyl (Et) or methylene (-CH 2 -) group of R 11 may optionally be fluoro substituted.
  • R 11 is selected from hydrogen or a fluoro group. More typically, R 11 is hydrogen.
  • R 121 is a hydrocarbyl group
  • the hydrocarbyl group, including any optional substituents contains no more than six carbon atoms. More typically, the hydrocarbyl group, including any optional substituents, contains no more than four carbon atoms.
  • the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 121 , including any optional substituents is no more than four. More typically, the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 121 , including any optional substituents, is no more than three.
  • R 121 is selected from hydrogen or a -R 124 group.
  • R 121 is selected from hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3-C4 fluorocycloalkyl group.
  • R 121 is selected from a C 1 -C 3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group.
  • R 122 is a hydrocarbyl group
  • the hydrocarbyl group, including any optional substituents contains no more than six carbon atoms. More typically, the hydrocarbyl group, including any optional substituents, contains no more than four carbon atoms.
  • the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 122 , including any optional substituents is no more than four. More typically, the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 122 , including any optional substituents, is no more than three.
  • R 122 is selected from hydrogen or a fluoro, -OH, -NH2 or -R 126 group.
  • R 122 is selected from hydrogen or a fluoro, -R 128 or -OR 128 group, wherein R 128 is selected from a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C 3 -C 4 fluorocycloalkyl group.
  • R 122 may be a -OR 128 group, such as a -OMe or OEt group, wherein the methyl (Me) or ethyl (Et) group may optionally be fluoro substituted.
  • R 122 is -OEt.
  • R 123 is a hydrocarbyl group
  • the hydrocarbyl group, including any optional substituents contains no more than six carbon atoms. More typically, the hydrocarbyl group, including any optional substituents, contains no more than four carbon atoms.
  • the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 123 , including any optional substituents is no more than four. More typically, the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 123 , including any optional substituents, is no more than three.
  • R 123 is selected from hydrogen or a fluoro, C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group.
  • R 123 may be hydrogen or a fluoro, methyl or fluoromethyl group. In a typical embodiment, R 123 is hydrogen.
  • the compound is a compound of Formula (Ic): wherein R 1 to R 9 , R 11 , R 122 , R 13 , X A1 , X A2 , X A3 , X A4 and q are as defined in accordance with Formula (Ia).
  • the compound is a compound of Formula (IIc): Formula (IIc) wherein R 1 , R 4 to R 9 , R 11 , R 122 , R 13 to R 17 , X A1 , X A2 , X A3 , X A4 and q are as defined in accordance with Formula (IIa).
  • the compound is a compound of Formula (IIIc): Formula (IIIc) wherein R 1 to R 8 , R 11 , R 122 , R 13 , R 18 , R 19 , X A1 , X A2 , X A3 , X A4 and q are as defined in accordance with Formula (IIIa).
  • the compound is a compound of Formula (IVc): Formula (IVc) wherein R 1 , R 4 to R 8 , R 11 , R 122 , R 13 to R 19 , X A1 , X A2 , X A3 , X A4 and q are as defined in accordance with Formula (IVa).
  • R 13 is a hydrocarbyl group
  • the hydrocarbyl group, including any optional substituents contains no more than six carbon atoms. More typically, the hydrocarbyl group, including any optional substituents, contains no more than four carbon atoms.
  • the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 13 , including any optional substituents is no more than four. More typically, the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 13 , including any optional substituents, is no more than three.
  • one R 13 (if present) that is not directly attached to a carbon atom which in turn is directly attached to a nitrogen atom is selected from a fluoro, methyl (Me), ethyl (Et), -OH, -OMe, -OEt, -CH2OH, -CH2OMe or -CH2OEt group, wherein any methyl (Me), ethyl (Et) or methylene (-CH2-) group of R 13 may optionally be fluoro substituted, or one R 13 (if present) that is directly attached to a carbon atom which in turn is directly attached to a nitrogen atom is selected from a fluoro, methyl (Me), ethyl (Et), -CH2OH, -CH2OMe or -CH2OEt group, wherein any methyl (Me), ethyl (Et) or methylene (-CH2-) group of R 13 may optionally be fluoro substituted, and each remaining
  • R 11 and R 121 , or R 11 and R 122 , or R 11 and R 123 , or R 11 and any R 13 , or R 121 and any R 13 , or R 122 and R 123 , or R 122 and any R 13 , or R 123 and any R 13 , or any two R 13 together form a hydrocarbylene group
  • the hydrocarbylene group, including any optional substituents contains no more than six carbon atoms. More typically, the hydrocarbylene group, including any optional substituents, contains no more than four carbon atoms.
  • the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbylene group (including any optional substituents) formed by any of R 11 and R 121 , or R 11 and R 122 , or R 11 and R 123 , or R 11 and any R 13 , or R 121 and any R 13 , or R 122 and R 123 , or R 122 and any R 13 , or R 123 and any R 13 , or any two R 13 is no more than four.
  • the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbylene group (including any optional substituents) formed by any of R 11 and R 121 , or R 11 and R 122 , or R 11 and R 123 , or R 11 and any R 13 , or R 121 and any R 13 , or R 122 and R 123 , or R 122 and any R 13 , or R 123 and any R 13 , or any two R 13 is no more than three.
  • R 11 and R 121 , or R 11 and R 122 , or R 11 and R 123 , or R 11 and any R 13 together form a hydrocarbylene group
  • the atom of the hydrocarbylene group that is directly attached to the carbon atom to which ring A is attached is a carbon atom.
  • R 11 and R 121 , or R 121 and any R 13 together form a hydrocarbylene group
  • the atom of the hydrocarbylene group that is directly attached to the nitrogen atom of NR 121 is a carbon atom.
  • R 11 and R 123 , or R 123 and any R 13 together form a hydrocarbylene group the atom of the hydrocarbylene group that is directly attached to the carbon atom of C(R 122 )(R 123 ) is a carbon atom.
  • R 122 and R 123 together form a hydrocarbylene group two atoms of the hydrocarbylene group are directly attached to the carbon atom of C(R 122 )(R 123 ).
  • at least one of the two atoms is a carbon atom.
  • R 11 and any R 13 , or R 121 and any R 13 , or R 122 and any R 13 , or R 123 and any R 13 , or any two R 13 together form a hydrocarbylene group, and the carbon atom of a CR 13 moiety through which the hydrocarbylene group is attached to the remainder of the molecule is in turn directly attached to an oxygen, nitrogen or sulphur atom, the atom of the hydrocarbylene group that is directly attached to the carbon atom of the CR 13 moiety is a carbon atom.
  • the hydrocarbylene group is attached to the remainder of the molecule as a spiro ring structure.
  • R 122 and R 123 or only two R 13 attached to the same carbon atom, together form a hydrocarbylene group. More typically in such an embodiment, only R 122 and R 123 together form a hydrocarbylene group.
  • R 122 and R 123 together form a C 2 -C 4 saturated hydrocarbylene group, wherein the hydrocarbylene group is straight-chained, wherein the saturated hydrocarbylene group may optionally include a single heteroatom N or O in its carbon skeleton, wherein the hydrocarbylene group may optionally be substituted with one or more substitutents each independently selected from a fluoro, methyl (Me), ethyl (Et), -OH, -OMe, -OEt, -CH 2 OH, -CH 2 OMe, -CH 2 OEt or -COMe group, wherein any methyl (Me), ethyl (Et) or methylene (-CH 2 -) group of such a substituent may optionally be fluoro substituted, and wherein the hydrocarbylene group, including any optional substituents, contains no more than 5 carbon atoms.
  • the hydrocarbylene group is attached to the remainder of the molecule as a fused ring structure.
  • no more than one of (i) R 11 and R 121 , or (ii) R 11 and R 122 , or (iii) R 11 and R 123 , or (iv) R 11 and any single R 13 , or (v) R 121 and any single R 13 , or (vi) R 122 and any single R 13 , or (vii) R 123 and any single R 13 , or (viii) any two R 13 together form a hydrocarbylene group.
  • R 11 and any single R 13 , or R 122 and any single R 13 , or R 123 and any single R 13 , or any two R 13 when attached to adjacent ring carbon atoms, together form a C1-C3 saturated hydrocarbylene group, wherein the hydrocarbylene group is straight-chained, wherein the saturated hydrocarbylene group may optionally include a single heteroatom N or O in its carbon skeleton, wherein the hydrocarbylene group may optionally be substituted with one or more substitutents each independently selected from a fluoro, methyl (Me), ethyl (Et), -OH, -OMe, -OEt, -CH2OH, -CH2OMe, -CH2OEt or -COMe group, wherein any methyl (Me), ethyl (Et) or methylene (-CH 2 -) group of such a substituent may optionally be fluoro
  • non- adjacent ring carbon atoms or non-adjacent ring carbon and nitrogen atoms), together form a C1-C4 saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group is straight-chained, wherein the hydrocarbylene group may optionally include one or two heteroatoms each independently selected from N and O in its carbon skeleton, wherein the hydrocarbylene group may optionally be substituted with one or more substitutents each independently selected from a fluoro, chloro, bromo, methyl (Me), ethyl (Et), -OH, -OMe, -OEt, -CH 2 OH, -CH 2 OMe, -CH 2 OEt, -NH 2 , -NHMe, -N(Me)2, -CH2NH2, -CH2NHMe, -CH2N(Me)2, oxo ( O), -CN, -CH2-, or -COMe group, wherein any
  • the hydrocarbylene group is attached to the remainder of the molecule as a bridged ring structure.
  • no more than one of (i) R 11 and R 121 , or (ii) R 11 and R 122 , or (iii) R 11 and R 123 , or (iv) R 11 and any single R 13 , or (v) R 121 and any single R 13 , or (vi) R 122 and any single R 13 , or (vii) R 123 and any single R 13 , or (viii) any two R 13 together form a hydrocarbylene group.
  • R 11 and R 122 or (ii) R 11 and R 123 , or (iii) R 11 and any single R 13 , or (iv) R 122 and any single R 13 , or (v) R 123 and any single R 13 , or (vi) any two R 13 , together form a hydrocarbylene group.
  • R 11 and R 122 , or R 11 and R 123 , or R 11 and any single R 13 , or R 122 and any single R 13 , or R 123 and any single R 13 , or any two R 13 when attached to non-adjacent ring carbon atoms, together form a C1-C3 saturated hydrocarbylene group, wherein the hydrocarbylene group is straight-chained, wherein the saturated hydrocarbylene group may optionally include a single heteroatom N or O in its carbon skeleton, wherein the hydrocarbylene group may optionally be substituted with one or more substitutents each independently selected from a fluoro, methyl (Me), ethyl (Et), -OH, -OMe, -OEt, -CH2OH, -CH2OMe, -CH2OEt or -COMe group, wherein any methyl (Me), ethyl (Et) or
  • each R 14 and R 15 is independently selected from hydrogen or a C1- C 4 alkyl, C 3 -C 4 cycloalkyl, C 1 -C 4 fluoroalkyl or C 3 -C 4 fluorocycloalkyl group.
  • R 14 may be hydrogen and R 15 may be selected from hydrogen or a C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3-C4 fluorocycloalkyl group.
  • each R 14 and R 15 is independently selected from hydrogen or a C1-C3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group.
  • R 14 may be hydrogen and R 15 may be selected from hydrogen or a C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group.
  • each R 14 and R 15 is independently selected from hydrogen or a methyl or fluoromethyl group.
  • R 14 may be hydrogen and R 15 may be selected from hydrogen or a methyl or fluoromethyl group.
  • R 14 and R 15 are both hydrogen.
  • R 14 and R 15 together with the carbon atom to which they are attached may form a cyclopropyl or a cyclobutyl group, wherein the cyclopropyl or cyclobutyl group may optionally be substituted with one or more fluoro groups.
  • R 16 is selected from hydrogen or a fluoro, -R 160 , -CN, -CHO, -COR 160 , -CO 2 H or -CO 2 R 160 group, wherein R 160 is selected from a C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl or -R 161 group, wherein R 161 is a 3- to 6-membered monocyclic group, wherein the 3- to 6-membered monocyclic group may optionally be substituted with one or more halo (e.g.
  • each R 162 is independently selected from a methyl or a fluoromethyl group, provided that the group R 16 , including any optional substituents, contains no more than 8 carbon atoms.
  • R 16 is selected from hydrogen or a fluoro, -R 160 , -CN, -CHO, -COR 160 , -CO2H or -CO2R 160 group, wherein R 160 is selected from a C1-C4 alkyl, C1-C4 fluoroalkyl or -R 161 group, wherein R 161 is selected from a C 3 -C 6 cycloalkyl group, a 4- to 6- membered saturated heterocyclic group, or a phenyl or a 5- or 6-membered heteroaryl group, wherein the C3-C6 cycloalkyl group and the 4- to 6-membered saturated heterocyclic group may optionally be substituted with one or more fluoro groups and/or with one or two groups R 162 , and wherein the phenyl or the 5- or 6-membered heteroaryl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/or with one
  • R 16 is selected from hydrogen or a fluoro, -R 160 , -R 161 , -CN, -CHO, -COR 160 , -CO2H or -CO2R 160 group, wherein R 160 is selected from a methyl or fluoromethyl group, and wherein R 161 is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/or with one or two groups R 162 .
  • R 17 is selected from hydrogen or a fluoro, C1-C4 alkyl, C3- C 4 cycloalkyl, C 1 -C 4 fluoroalkyl or C 3 -C 4 fluorocycloalkyl group. More typically, R 17 is selected from hydrogen or a fluoro, C 1 -C 3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group. Most typically, R 17 is hydrogen.
  • R 16 is selected from hydrogen or a fluoro, -R 160 , -CN, -CHO, -COR 160 , -CO 2 H or -CO 2 R 160 group, wherein R 160 is selected from a C 1 - C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3-C4 fluorocycloalkyl group, and R 17 is selected from hydrogen or a fluoro, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3- C 4 fluorocycloalkyl group.
  • R 17 is selected from hydrogen or a fluoro, C 1 -C 3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group.
  • R 16 may be selected from hydrogen or a fluoro, -R 160 , -CN, -CHO, -COR 160 , -CO2H or -CO2R 160 group, wherein R 160 is selected from a methyl or fluoromethyl group, and R 17 may be hydrogen.
  • R 16 is selected from hydrogen or a fluoro, -CN, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3-C4 fluorocycloalkyl group
  • R 16 is selected from hydrogen or a fluoro, -CN, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3-C4 fluorocycloalkyl group
  • R 17 is selected from hydrogen or a fluoro, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 1 -C 4 fluoroalkyl or C 3 -C 4 fluorocycloalkyl group.
  • R 16 may be selected from hydrogen or a fluoro, -CN, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3-C4 fluorocycloalkyl group, and R 17 may be hydrogen.
  • R 16 is selected from hydrogen or a fluoro, -CN, C 1 -C 3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group
  • R 17 is selected from hydrogen or a fluoro, C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group.
  • R 16 may be selected from hydrogen or a fluoro, -CN, C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group, and R 17 may be hydrogen. More typically in such an embodiment, each R 16 and R 17 is independently selected from hydrogen or a methyl or fluoromethyl group. For example, R 16 may be selected from hydrogen or a methyl or fluoromethyl group and R 17 may be hydrogen. In one embodiment, R 16 and R 17 are both hydrogen.
  • R 16 and R 17 together with the carbon atom to which they are attached may form a cyclopropyl or a cyclobutyl group, wherein the cyclopropyl or cyclobutyl group may optionally be substituted with one or more fluoro groups.
  • R 16 is selected from hydrogen or a fluoro, -CN, C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group
  • R 17 is selected from hydrogen or a fluoro, C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group
  • R 16 and R 17 together with the carbon atom to which they are attached form a cyclopropyl or a cyclobutyl group, wherein the cyclopropyl or cyclobutyl group may optionally be substituted with one or more fluoro groups.
  • any hydrocarbylene group (including any optional substituents) formed by any of R 3 and R 7 , or R 17 and R 7 , or R 4 and R 7 , or R 4 and any R 10 , or R 4 and any R 101 , or R 4 and R 11 , or R 4 and R 121 , or R 4 and R 122 , or R 4 and R 123 , or R 4 and any R 13 , or R 7 and any R 10 , or R 7 and any R 101 , or R 7 and R 11 , or R 7 and R 121 , or R 7 and R 122 , or R 7 and R 123 , or R 7 and any R 13 , or any R 10 and R 11 , or any R 10 and R 121 , or any R 10 and R 122 , or any R 10 and R 123 , or any R 10 and any R 13 , or any R 101 and R 11 , or any R 10 and R 121 , or any R 10 and R 122 , or any R 10 and R 123 , or
  • any hydrocarbylene group (including any optional substituents) formed by any of R 3 and R 7 , or R 17 and R 7 , or R 4 and R 7 , or R 4 and any R 10 , or R 4 and any R 101 , or R 4 and R 11 , or R 4 and R 121 , or R 4 and R 122 , or R 4 and R 123 , or R 4 and any R 13 , or R 7 and any R 10 , or R 7 and any R 101 , or R 7 and R 11 , or R 7 and R 121 , or R 7 and R 122 , or R 7 and R 123 , or R 7 and any R 13 , or any R 10 and R 11 , or any R 10 and R 121 , or any R 10 and R 122 , or any R 10 and R 123 , or any R 10 and any R 13 , or any R 101 and R 11 , or any R 10 and R 121 , or any R 10 and R 122 , or any R 10 and R 123 , or
  • R 3 and R 7 , or R 4 and R 7 , or R 7 and any R 10 , or R 7 and any R 101 , or R 7 and R 11 , or R 7 and R 121 , or R 7 and R 122 , or R 7 and R 123 , or R 7 and any R 13 , or R 17 and R 7 together form a hydrocarbylene group, the atom of the hydrocarbylene group that is directly attached to the carbon atom to which R 8 is attached is a carbon atom.
  • R 4 and R 11 , or R 7 and R 11 , or any R 10 and R 11 , or any R 101 and R 11 together form a hydrocarbylene group
  • the atom of the hydrocarbylene group that is directly attached to the carbon atom to which ring A is attached is a carbon atom.
  • R 4 and R 121 , or R 7 and R 121 , or any R 10 and R 121 , or any R 101 and R 121 together form a hydrocarbylene group
  • the atom of the hydrocarbylene group that is directly attached to the nitrogen atom of NR 121 is a carbon atom.
  • R 4 and R 123 , or R 7 and R 123 , or any R 10 and R 123 , or any R 101 and R 123 together form a hydrocarbylene group
  • the atom of the hydrocarbylene group that is directly attached to the carbon atom of C(R 122 )(R 123 ) is a carbon atom.
  • R 4 and any R 13 , or R 7 and any R 13 , or any R 10 and any R 13 , or any R 101 and any R 13 together form a hydrocarbylene group, and the carbon atom of the CR 13 moiety through which the hydrocarbylene group is attached to the remainder of the molecule is in turn directly attached to an oxygen, nitrogen or sulphur atom, the atom of the hydrocarbylene group that is directly attached to the carbon atom of the CR 13 moiety is a carbon atom.
  • R 3 and R 7 together form a C1-C6 saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbylene group may optionally be substituted with one or more halo groups, wherein the hydrocarbylene group may optionally include one or more (e.g.
  • R 17 and R 7 together form a C1-C6 saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbylene group may optionally be substituted with one or more halo groups, wherein the hydrocarbylene group may optionally include one or more (e.g.
  • R 3 and R 7 , or R 17 and R 7 together form a C 1 -C 4 saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbylene group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and wherein the hydrocarbylene group may optionally include one or two heteroatoms each independently selected from N and O in its carbon skeleton, provided that the atom of the hydrocarbylene group that is directly attached to the carbon atom to which R 8 is attached is a carbon atom.
  • R 3 and R 7 , or R 17 and R 7 together form a hydrocarbylene group
  • R 8 is selected from hydrogen or a fluoro, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 1 -C 4 fluoroalkyl or C 3 - C 4 fluorocycloalkyl group. More typically, where R 3 and R 7 , or R 17 and R 7 , together form a hydrocarbylene group, R 8 is selected from hydrogen or a fluoro, methyl or fluoromethyl group. More typically still, where R 3 and R 7 , or R 17 and R 7 , together form a hydrocarbylene group, R 8 is hydrogen.
  • R 16 is selected from hydrogen or a fluoro, -CN, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3-C4 fluorocycloalkyl group. More typically, where R 17 and R 7 together form a hydrocarbylene group, R 16 is selected from hydrogen or a fluoro, -CN, C 1 -C 3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group.
  • R 17 and R 7 together form a hydrocarbylene group R 16 is selected from hydrogen or a methyl or fluoromethyl group. Yet more typically, where R 17 and R 7 together form a hydrocarbylene group, R 16 is hydrogen.
  • R 4 and R 7 together form a C1-C6 saturated or unsaturated hydrocarbylene group wherein the hydrocarbylene group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbylene group may optionally be substituted with one or more halo groups, wherein the hydrocarbylene group may optionally include one or more (e.g.
  • R 4 and R 7 together form a C1-C4 saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight- chained or branched, or be or include a cyclic group, wherein the hydrocarbylene group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and wherein the hydrocarbylene group may optionally include one or two heteroatoms each independently selected from N and O in its carbon skeleton, provided that the atom of the hydrocarbylene group that is directly attached to the carbon atom to which R 8 is attached is a carbon atom.
  • R 4 and R 7 together form a hydrocarbylene group
  • the hydrocarbylene group has a chain length of from 2 to 4 atoms. More typically, the hydrocarbylene group has a chain length of 2 or 3 atoms. More typically, where R 4 and R 7 together form a hydrocarbylene group, the hydrocarbylene group is selected from -CH2-CH2-, -CH2-O-, -O-CH2-, -CH2-CH2-CH2-, -O-CH2-CH2-, -CH2-CH2-O- or -CH2-O-CH2-, provided that the atom of the hydrocarbylene group that is directly attached to the carbon atom to which R 8 is attached is a carbon atom.
  • R 8 is selected from hydrogen or a fluoro, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 fluoroalkyl or C3-C4 fluorocycloalkyl group. More typically, where R 4 and R 7 together form a hydrocarbylene group, R 8 is selected from hydrogen or a fluoro, methyl or fluoromethyl group. More typically still, where R 4 and R 7 together form a hydrocarbylene group, R 8 is hydrogen.
  • one R 10 and R 11 together form a C1-C6 saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbylene group may optionally be substituted with one or more halo groups, wherein the hydrocarbylene group may optionally include one or more (e.g.
  • one R 10 and R 11 together form a C 1 -C 4 saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight- chained or branched, or be or include a cyclic group, wherein the hydrocarbylene group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and wherein the hydrocarbylene group may optionally include one or two heteroatoms each independently selected from N and O in its carbon skeleton, provided that the atom of the hydrocarbylene group that is directly attached to the carbon atom to which ring A is attached is a carbon atom.
  • the hydrocarbylene group has a chain length of from 2 to 4 atoms. More typically, the hydrocarbylene group has a chain length of 2 or 3 atoms. More typically, where one R 10 and R 11 together form a hydrocarbylene group, the hydrocarbylene group is selected from -CH2-CH2-, -CH2-O-, -O-CH2-, -CH2-CH2-CH2-, -O-CH2-CH2-, -CH2-CH2-O- or -CH2-O-CH2-, provided that the atom of the hydrocarbylene group that is directly attached to the carbon atom to which ring A is attached is a carbon atom.
  • ring A is a phenyl or a 6-membered heteroaryl ring
  • one R 10 and R 11 together form a hydrocarbylene group
  • the R 10 that forms part of the hydrocarbylene group is attached to the phenyl or the 6-membered heteroaryl ring at the 2- or the 6- position, relative to the point of attachment of the phenyl or the 6-membered heteroaryl ring to the remainder of the molecule.
  • ring A is a 5-membered heteroaryl ring
  • one R 10 and R 11 together form a hydrocarbylene group
  • the R 10 that forms part of the hydrocarbylene group is attached to the 5-membered heteroaryl ring at the 2- or the 5-position, relative to the point of attachment of the 5-membered heteroaryl ring to the remainder of the molecule.
  • R 18 is a hydrocarbyl group
  • the hydrocarbyl group, including any optional substituents contains no more than eight carbon atoms. More typically, the hydrocarbyl group, including any optional substituents, contains no more than six carbon atoms.
  • the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 18 , including any optional substituents is no more than five. More typically, the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 18 , including any optional substituents, is no more than three.
  • R 18 is selected from hydrogen or a -R 181 or -COR 181 group, wherein R 181 is a C 1 -C 8 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and wherein the hydrocarbyl group may optionally include one, two, three or four heteroatoms each independently selected from N and O in its carbon skeleton, provided that where R 18 is -R 181 , the atom of the hydrocarbyl group of R 181 that is directly attached to the reminder of the molecule is a carbon atom.
  • R 18 is a -COR 181 group. In a further embodiment of the third or the fourth aspects of the invention, R 18 is hydrogen.
  • R 19 is a hydrocarbyl group
  • the hydrocarbyl group, including any optional substituents contains no more than eight carbon atoms. More typically, the hydrocarbyl group, including any optional substituents, contains no more than six carbon atoms.
  • the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 19 , including any optional substituents is no more than five. More typically, the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbyl group of R 19 , including any optional substituents, is no more than three.
  • R 19 is a C1- C 8 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and wherein the hydrocarbyl group may optionally include one, two, three or four heteroatoms each independently selected from N and O in its carbon skeleton.
  • R 19 is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is a monocylic group or a fused bicyclic or fused tricyclic group, and wherein the aryl or the heteroaryl group may optionally be substituted with one or more substituents each independently selected from a halo, -OH, -NH2, -NO2, -SH, -SO2H, -SO3H, -SO2NH2, -R 191 or -SO2R 191 group, wherein each R 191 is independently selected from a C1-C4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one or two heteroatoms each independently selected from a halo, -OH, -NH
  • the aryl or the heteroaryl group is a monocylic group or a fused bicyclic group.
  • R 19 is a phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or the 5- or 6-membered heteroaryl group may optionally be substituted with one or more substituents each independently selected from a halo, -OH, -NH2, -NO 2 , -SH, -SO 2 H, -SO 3 H, -SO 2 NH 2 , -R 191 or -SO 2 R 191 group, wherein each R 191 is independently selected from a C 1 -C 4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one
  • R 19 is a phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or the 5- or 6-membered heteroaryl group may optionally be substituted with one or more substituents each independently selected from fluoro, chloro and bromo, and/or with one or two substituents each independently selected from a -OH, -NH 2 , -NO 2 , -SH, -SO 2 H, -SO 3 H, -SO 2 NH 2 , -R 191 or -SO 2 R 191 group, provided that R 19 , including any optional substituents, contains no more than 10 carbon atoms.
  • R 19 is a phenyl or a 6-membered heteroaryl group, such as a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group.
  • each R 191 is independently selected from a C1-C4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more halo groups, and wherein the hydrocarbyl group may optionally include one or two heteroatoms each independently selected from N and O in its carbon skeleton.
  • R 19 is an aryl or a heteroaryl group, such as a phenyl or a 5- or 6- membered heteroaryl group
  • R 19 including any optional substituents, contains no more than eight carbon atoms.
  • R 19 is an aryl or a heteroaryl group
  • R 19 contains no more than six carbon atoms.
  • R 19 is: .
  • the hydrocarbylene group, including any optional substituents contains no more than eight carbon atoms. More typically, the hydrocarbylene group, including any optional substituents, contains no more than six carbon atoms. Typically, the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbylene group formed by R 18 and R 19 , including any optional substituents, is no more than five. More typically, the total number of nitrogen, oxygen and sulphur atoms in any hydrocarbylene group formed by R 18 and R 19 , including any optional substituents, is no more than three.
  • R 18 and R 19 together form a group -L 189 -, wherein -L 189 - is a C2-C4 straight chained alkylene or alkenylene group, wherein the alkylene or alkenylene group may optionally include a nitrogen atom in its carbon skeleton, wherein the alkylene or alkenylene group has a chain length of 3 or 4 atoms, and wherein the alkylene or alkenylene group may optionally be substituted with one or more groups -R 189 , wherein each R 189 is independently selected from a fluoro, chloro, bromo, -OH, -NH2, -SH, -SO2H, -SO3H, -SO 2 NH 2 , -R 190 or -SO 2 R 190 group, wherein each R 190 is independently selected from a C 1 -C 4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl
  • the group R 19 CON(R 18 )- has the formula (V): Formula (V) wherein each X V is independently selected from N, C-H, C-Hal or C-R 183 , wherein each Hal is independently selected from a fluoro, chloro or bromo group, and wherein each R 183 is independently selected from a -OH, -NH 2 , -SH, -SO 2 H, -SO 3 H, -SO 2 NH 2 , -R 193 or -SO2R 193 group, wherein each R 193 is independently selected from a C1-C4 saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight- chained or branched, or be
  • the group of Formula (V), including any optional substituents contains no more than eight carbon atoms. More typically, the group of Formula (V), including any optional substituents, contains no more than six carbon atoms.
  • the group R 19 CON(R 18 )- has the formula (Va): Formula (Va)
  • the group R 19 CON(R 18 )- has the formula (VI): Formula (VI) wherein: is a single or double bond; where is a single bond, t is 0, 1, 2, 3 or 4; where is a double bond, t is 0, 1 or 2; and each R 185 is independently selected from a fluoro, chloro, bromo, -SO 3 H, -SO2NH2, -R 195 or -SO2R 195 group, and/or any two R 185 attached to the same or different carbon atoms may, together with carbon atom or atoms to which they are attached,
  • t is 0, 1 or 2.
  • each R 185 is independently selected from a fluoro, -SO 3 H, -R 196 , -OR 196 or -SO2R 196 group, provided that no more than one -SO3H, -OR 196 or -SO2R 196 group is present, or two R 185 attached to adjacent carbon atoms may, together with carbon atoms to which they are attached, form a 5- to 7-membered fused cyclic group, wherein the 5- to 7-membered fused cyclic group may optionally be substituted with one or more fluoro groups and/or with one or two substituents each independently selected from a -SO3H, -R 196 , -OR 196 or -SO2R 196 group, provided that no more than one -SO3H, -OR 196 or -SO 2 R 196 group is present; and each R 196 is independently selected from a fluoro, -SO 3 H, -R 196 ,
  • the group of Formula (VI), including any optional substituents contains no more than eight carbon atoms. More typically, the group of Formula (VI), including any optional substituents, contains no more than six carbon atoms.
  • the group R 19 CON(R 18 )- of Formula (VI) is selected from: In a further embodiment of the third or the fourth aspects of the invention, the group R 19 CON(R 18 )- of Formula (VI) is selected from: .
  • R 1 is hydrogen
  • R 2 is selected from hydrogen or a halo group
  • R 4 is selected from hydrogen
  • R 1 is hydrogen
  • R 5 is selected from hydrogen or a halo group
  • R 6 is selected from hydrogen or a halo group
  • R 1 is hydrogen;
  • R 2 is selected from hydrogen or a halo group;
  • R 4 is selected from hydrogen or a
  • R 1 is hydrogen
  • R 5 is selected from hydrogen or a halo group
  • R 6 is selected from hydrogen or a halo group
  • R 1 is hydrogen
  • R 2 is selected from hydrogen or a fluoro, chloro or bromo group
  • R 3 is selected from hydrogen or a fluoro, chloro, bromo, -R 30 , -CN, -CHO, -COR 30 , -CO 2 H or -CO 2 R 30 group, provided that R 3 , including any optional substituents, contains no more than 8 carbon atoms
  • R 30 is selected from a C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl or -R 31 group
  • R 31 is a 3- to 6-membered monocyclic group, wherein the 3- to 6-membered monocyclic group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/or with one or two groups R 32 ; each R 32 is
  • R 3 is selected from hydrogen or a fluoro, chloro, bromo, -CN or methyl group, wherein the methyl group may optionally be fluoro substituted;
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 ) 2 , -SO 2 -R 41 , -SO2-N(R 42 )2, -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 )2, -L 4 -SO2-R 41 , -L 4 -SO2-N(R 42 )2, -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 )2, -O-L 4 -SO2-R 41 , -O-L 4 -OR 41 , -O-L 4 -N(R 42 )2, -O-L 4 -SO2-R 41
  • R 3 is selected from hydrogen or a fluoro, chloro, bromo, -CN or methyl group, wherein the methyl group may optionally be fluoro substituted;
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 )2, -SO2-R 41 , -SO 2 -N(R 42 ) 2 , -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 ) 2 , -L 4 -SO 2 -R 41 , -L 4 -SO 2 -N(R 42 ) 2 , -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 ) 2 , -O-L 4 -SO 2 -R 41 , -O-L 4 -SO 2 -R 41 , -O-L 4 -SO 2
  • R 1 is hydrogen
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 )2, -SO2-R 41 , -SO 2 -N(R 42 ) 2 , -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 ) 2 , -L 4 -SO 2 -R 41 , -L 4 -SO 2 -N(R 42 ) 2 , -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 ) 2 , -O-L 4 -SO 2 -R 41 , -O-L 4 -SO 2 -R 41 , -O-L 4 -SO 2 -R 41 , -O-L 4 -SO 2 -N(R 42 ) 2 , -NR 43 -L 4 -OH, -
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 )2, -SO2-R 41 , -SO 2 -N(R 42 ) 2 , -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 ) 2 , -L 4 -SO 2 -R 41 , -L 4 -SO 2 -N(R 42 ) 2 , -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 )2, -O-L 4 -SO2-R 41 , -O-L 4 -SO2-N(R 42 )2, -NR 43 -L 4 -OH, -NR 43 -L 4 -OR 41 , -NR 43 -L 4 -OH, -NR 43 -L 4 -OR 41 , -NR 43 -L 4
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 )2, -SO2-R 41 , -SO2-N(R 42 )2, -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 )2, -L 4 -SO2-R 41 , -L 4 -SO2-N(R 42 )2, -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 ) 2 , -O-L 4 -SO 2 -R 41 , -O-L 4 -SO 2 -N(R 42 ) 2 , -NR 43 -L 4 -OH, -NR 43 -L 4 -OR 41 , -NR 43 -L 4 -N(R 42 ) 2 , -NR 43 -L 4 -OR 41 , -NR 43
  • R 1 is hydrogen
  • R 2 is selected from hydrogen or a fluoro, chloro or bromo group
  • R 3 is selected from hydrogen or a fluoro, chloro, bromo, -R 30 , -CN, -CHO, -COR 30 , -CO2H or -CO2R 30 group, provided that R 3 , including any optional substituents, contains no more than 8 carbon atoms
  • R 30 is selected from a C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl or -R 31 group
  • R 31 is a 3- to 6-membered monocyclic group, wherein the 3- to 6-membered monocyclic group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and/or with one or two groups
  • R 32 is selected from a C 1 -C 6 alkyl, C 1 -C
  • R 5 is selected from hydrogen or a fluoro, chloro or bromo group
  • R 6 is selected from a chloro, bromo, -R 60 or -OR 60 group;
  • R 60 is selected from a Ci-C 3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group;
  • R 7 is selected from hydrogen or a fluoro, -CN, -COOH, -COOR 71 , -CO-N(R 72 ) 2 , -L 7 -COOH, -L7-COOR 71 , -L 7 -CO-N(R 72 ) 2 , -L 7 -OH, -L 7 -OR 71 , -L 7 -N(R 72 ) 2 , -R 73 , -R 74 or -L 7 -R 74 group, provided that R 7 , including any optional substituents, contains no more than 10 carbon atoms, and that the atom of R 7 that is directly attached to the reminder of the molecule is a carbon, hydrogen or fluorine atom;
  • X A1 is N, C-H or C-R 10 ;
  • X A2 is N, C-H or C-R 10 ;
  • X A3 is N, C-H or C-R 10 ;
  • X 12 is NR 121 , and m is 1 and n is 1; or X 12 is C(R 122 )(R 123 ), and (i) m is o and n is 1, or (ii) m is 1 and n is o, or (iii) m is 1 and n is 1; q is o, t or 2;
  • R 121 is selected from hydrogen or a -R 124 , -R 125 or -L 121 -R 125 group, provided that any R 121 group, including any optional substituents, contains no more than 8 carbon atoms, and that any atom of -R 124 , -R 125 or -L 121 -R 125 that is directly attached to the reminder of the molecule is
  • R 125 is selected from a phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or the 5- or 6-membered heteroaryl group may optionally be substituted with one or more groups each independently selected from fluoro, chloro and bromo;
  • R 122 is selected from hydrogen or a fluoro, -OH, -NH 2 , -R 126 , -SO 2 R 126 , -R 127 or
  • R 122 group including any optional substituents, contains no more than 8 carbon atoms
  • R 127 is selected from a phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or the 5- or 6-membered heteroaryl group may optionally be substituted with one or more groups each independently selected from fluoro, chloro and bromo, and/or with a single methyl, fluoro methyl, -CN or -S0 2 Me group, wherein the -S0 2 Me group may optionally be fluoro substituted;
  • R 18 is selected from hydrogen or a -R 181 or -COR 181 group, provided that where R 18 is -R 181 , the atom of the hydrocarbyl group of R 181 that is directly attached to the reminder of the molecule is a carbon atom;
  • R 181 is a Ci-Cs saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and wherein the hydrocarbyl group may optionally include one, two, three or four heteroatoms each independently selected from N and O in its carbon skeleton; and
  • R 19 is a Ci-Cs saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include a cyclic group, wherein the hydrocarbyl group may optionally be substituted with one or more fluoro, chloro and/or bromo groups, and wherein the hydrocarbyl group may optionally include one, two, three or four heteroatoms each independently selected from N and O in its carbon skeleton; or R 18 and R 19 together form a group -L 189 -, wherein -L 189 - is a C 2 -C 4 straight chained alkylene or alkenylene group, wherein the alkylene or alkenylene group may optionally include a nitrogen atom in its carbon skeleton, wherein the alkylene or alkenylene group has a chain length of 3 or 4 atoms, and wherein the alkylene or alkenylene group may optionally be substituted with one or more groups -R 189
  • R 3 is selected from hydrogen or a fluoro, chloro, bromo, -CN or methyl group, wherein the methyl group may optionally be fluoro substituted;
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 )2, -SO2-R 41 , -SO2-N(R 42 )2, -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 )2, -L 4 -SO2-R 41 , -L 4 -SO2-N(R 42 )2, -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 ) 2 , -O-L 4 -SO 2 -R 41 , -O-L 4 -SO 2 -N(R 42 ) 2 , -NR 43 -L 4 -OH
  • R 3 is selected from hydrogen or a fluoro, chloro, bromo, -CN or methyl group, wherein the methyl group may optionally be fluoro substituted;
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 ) 2 , -SO 2 -R 41 , -SO2-N(R 42 )2, -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 )2, -L 4 -SO2-R 41 , -L 4 -SO2-N(R 42 )2, -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 )2, -O-L 4 -SO2-R 41 , -O-L 4 -OR 41 , -O-L 4 -N(R 42 )2, -O-L 4 -SO2-R 41
  • R 1 is hydrogen
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 ) 2 , -SO 2 -R 41 , -SO2-N(R 42 )2, -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 )2, -L 4 -SO2-R 41 , -L 4 -SO2-N(R 42 )2, -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 )2, -O-L 4 -SO2-R 41 , -O-L 4 -SO2-R 41 , -O-L 4 -SO2-N(R 42 )2, -NR 43 -L 4 -OH, -NR 43 -L 4 -OR 41 , -NR 43 -L 4 -OH, -NR 43 -L 4 -
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 )2, -SO2-R 41 , -SO2-N(R 42 )2, -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 )2, -L 4 -SO2-R 41 , -L 4 -SO2-N(R 42 )2, -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 ) 2 , -O-L 4 -SO 2 -R 41 , -O-L 4 -SO 2 -N(R 42 ) 2 , -NR 43 -L 4 -OH, -NR 43 -L 4 -OR 41 , -NR 43 -L 4 -N(R 42 ) 2 , -NR 43 -L 4 -OR 41 , -NR 43
  • R 4 is selected from a fluoro, chloro, bromo, -OH, -OR 41 , -N(R 42 ) 2 , -SO 2 -R 41 , -SO2-N(R 42 )2, -L 4 -OH, -L 4 -OR 41 , -L 4 -N(R 42 )2, -L 4 -SO2-R 41 , -L 4 -SO2-N(R 42 )2, -O-L 4 -OH, -O-L 4 -OR 41 , -O-L 4 -N(R 42 )2, -O-L 4 -SO2-R 41 , -O-L 4 -SO2-N(R 42 )2, -NR 43 -L 4 -OH, -NR 43 -L 4 -OR 41 , -NR 43 -L 4 -OH, -NR 43 -L 4 -OR 41 , -NR 43 -L 4 -OH, -NR 43
  • R 3 is selected from hydrogen or a fluoro, chloro or bromo group
  • R 4 is selected from a fluoro, chloro, bromo, -R 44 or -OR 44 group
  • R 44 is selected from a C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group
  • R 6 is a methyl or a fluoromethyl group
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro, methyl or fluoromethyl group
  • R 9 is a phenyl or a 6-membered heteroaryl group, wherein the phenyl or the 6- membered heteroaryl group is (i) substituted with at least one fluoro group, and/or (ii) substituted with one or two substituents each independently selected from a fluoromethyl, fluoroethyl or -R
  • each R 91 group is independently selected from a -NO 2 , -SO 3 H, -OR 92 , -COR 92 , -COOR 92 , -CONH 2 , -CONHR 92 , -CON(R 92 ) 2 , -SO 2 R 92 , -SO 2 NH 2 , -SO 2 NHR 92 or -SO 2 N(R 92 ) 2 group.
  • R 4 is selected from a fluoro, chloro, bromo, -R 44 or -OR 44 group;
  • R 44 is selected from a C 1 -C 3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group;
  • R 6 is a methyl or a fluoromethyl group;
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro, methyl or fluoromethyl group;
  • R 9 is a phenyl or a 6-membered heteroaryl group, wherein the phenyl or the 6- membered heteroaryl group is (i) substituted with at least one fluoro group, and/or (ii) substituted with one or two substituents each independently selected from a fluoromethyl, fluoroethyl or -R 91 group, provided that where the phenyl or the 6- membered heteroaryl group of R 9 is substituted with one or two -R
  • each R 91 group is independently selected from a -NO2, -SO3H, -OR 92 , -COR 92 , -COOR 92 , -CONH2, -CONHR 92 , -CON(R 92 )2, -SO2R 92 , -SO2NH2, -SO2NHR 92 or -SO2N(R 92 )2 group.
  • R 3 is selected from hydrogen or a fluoro, chloro or bromo group
  • R 4 is selected from a fluoro, chloro, bromo, -R 44 or -OR 44 group
  • R 44 is selected from a C 1 -C 3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group
  • R 6 is a methyl or a fluoromethyl group
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro, methyl or fluoromethyl group
  • X A1 is N, C-H or C-R 10
  • X A2 is N, C-H or C-R 10
  • X A3 is N, C-H or C-R 10
  • X A4 is N, C-H or C-R 10 ; provided that no more than two of X A1 , X A2 , X A3 and X A4 are N, and that no more than two of X A
  • R 4 is selected from a fluoro, chloro, bromo, -R 44 or -OR 44 group; R 44 is selected from a C 1 -C 3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group; R 6 is a methyl or a fluoromethyl group; R 7 and R 8 are each independently selected from hydrogen or a fluoro, methyl or fluoromethyl group; X A1 is N, C-H or C-R 10 ; X A2 is N, C-H or C-R 10 ; X A3 is N, C-H or C-R 10 ; and X A4 is N, C-H or C-R 10 ; provided that no more than two of X A1 , X A2 , X A3 and X A4 are N, and that no more than two of X A1 , X A2 , X A3 and X A4 are N, and that no more
  • R 3 is selected from hydrogen or a fluoro, chloro or bromo group
  • R 4 is selected from a fluoro, chloro, bromo, -R 44 or -OR 44 group
  • R 44 is selected from a C 1 -C 3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group
  • R 6 is a methyl or a fluoromethyl group
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro, methyl or fluoromethyl group
  • X A1 is N, C-H or C-R 10
  • X A2 is N, C-H or C-R 10
  • X A3 is N, C-H or C-R 10
  • X A4 is N, C-H or C-R 10 ; provided that no more than two of X A1 , X A2 , X A3 and X A4 are N, and that no more than two of X A
  • R 4 is selected from a fluoro, chloro, bromo, -R 44 or -OR 44 group; R 44 is selected from a C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group; R 6 is a methyl or a fluoromethyl group; R 7 and R 8 are each independently selected from hydrogen or a fluoro, methyl or fluoromethyl group; X A1 is N, C-H or C-R 10 ; X A2 is N, C-H or C-R 10 ; X A3 is N, C-H or C-R 10 ; and X A4 is N, C-H or C-R 10 ; provided that no more than two of X A1 , X A2 , X A3 and X A4 are N, and that no more than two of X A1 , X A2 , X A3 and X A4 are C-R 10 ;
  • R 3 is selected from hydrogen or a fluoro, chloro or bromo group
  • R 4 is selected from a fluoro, chloro, bromo, -R 44 or -OR 44 group
  • R 44 is selected from a C 1 -C 3 alkyl, cyclopropyl, C 1 -C 3 fluoroalkyl or fluorocyclopropyl group
  • R 6 is a methyl or a fluoromethyl group
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro, methyl or fluoromethyl group
  • R 19 is a phenyl or a 6-membered heteroaryl group, wherein the phenyl or the 6- membered heteroaryl group may optionally be substituted with one or more substituents each independently selected from fluoro, chloro and bromo, and/or with one or two substituents each independently selected from a -OH, -NH2, -NO2, -SH, -SO2H, -SO3H
  • R 4 is selected from a fluoro, chloro, bromo, -R 44 or -OR 44 group;
  • R 44 is selected from a C1-C3 alkyl, cyclopropyl, C1-C3 fluoroalkyl or fluorocyclopropyl group;
  • R 6 is a methyl or a fluoromethyl group;
  • R 7 and R 8 are each independently selected from hydrogen or a fluoro, methyl or fluoromethyl group;
  • R 19 is a phenyl or a 6-membered heteroaryl group, wherein the phenyl or the 6- membered heteroaryl group may optionally be substituted with one or more substituents each independently selected from fluoro, chloro and bromo, and/or with one or two substituents each independently selected from a -OH, -NH 2 , -NO 2 , -SH, -SO2H, -SO3H, -SO2NH2, -R 191 or -SO
  • a fifth aspect of the invention provides a compound, wherein the compound is an active ester of a Factor B inhibitor, wherein the Factor B inhibitor comprises a carboxylic acid (-COOH) group.
  • the Factor B inhibitor is known in the art, e.g. from any of Mainolfi et al., J. Med.
  • the active ester is prepared by or preparable by the esterification of the carboxylic acid of the Factor B inhibitor with an alcohol of formula R 9 OH, wherein R 9 is as defined in accordance with the first or second aspect of the invention.
  • the active ester is prepared by or preparable by the esterification of the carboxylic acid of the Factor B inhibitor with an alcohol of formula R 19 CON(R 18 )OH, wherein R 18 and R 19 are as defined in accordance with the third or fourth aspect of the invention.
  • the compound of formula (I), (II), (III) or (IV), or the active ester of the fifth aspect of the invention has a molecular weight of from 352 to 900 Da.
  • the compound of formula (I), (II), (III) or (IV), or the active ester of the fifth aspect of the invention has a molecular weight of from 375 to 800 Da. More typically, the compound of formula (I), (II), (III) or (IV), or the active ester of the fifth aspect of the invention, has a molecular weight of from 400 to 700 Da.
  • a sixth aspect of the invention provides a compound selected from the group consisting of:
  • a seventh aspect of the invention provides a pharmaceutically acceptable salt and/or solvate and/or prodrug of any compound of the first, second, third, fourth, fifth or sixth aspect of the invention.
  • the seventh aspect of the invention provides a pharmaceutically acceptable salt and/or solvate of any compound of the first, second, third, fourth, fifth or sixth aspect of the invention.
  • the seventh aspect of the invention may provide (i) a pharmaceutically acceptable salt of any compound of the first, second, third, fourth, fifth or sixth aspect of the invention, or (ii) a pharmaceutically acceptable solvate of any compound of the first, second, third, fourth, fifth or sixth aspect of the invention, or (iii) a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of any compound of the first, second, third, fourth, fifth or sixth aspect of the invention.
  • the compounds of the present invention can be used both, in their free base form and their acid addition salt form.
  • a “salt” of a compound of the present invention includes an acid addition salt.
  • Acid addition salts are preferably pharmaceutically acceptable, non-toxic addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulfuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, toluene-p-
  • the acid addition salt may be a mono-, di-, tri- or multi-acid addition salt.
  • a preferred salt is a hydrohalogenic, sulfuric, phosphoric or organic acid addition salt.
  • a preferred salt is a hydrochloric acid addition salt.
  • a compound of the invention includes a quaternary ammonium group, typically the compound is used in its salt form.
  • the counter ion to the quaternary ammonium group may be any pharmaceutically acceptable, non-toxic counter ion. Examples of suitable counter ions include the conjugate bases of the protic acids discussed above in relation to acid addition salts.
  • the compounds of the present invention can also be used both, in their free acid form and their salt form.
  • a “salt” of a compound of the present invention includes one formed between a protic acid functionality (such as a carboxylic acid group) of a compound of the present invention and a suitable cation. Suitable cations include, but are not limited to lithium, sodium, potassium, magnesium, calcium and ammonium.
  • the salt may be a mono-, di-, tri- or multi-salt.
  • the salt is a mono- or di-lithium, sodium, potassium, magnesium, calcium or ammonium salt. More preferably the salt is a mono-sodium salt or a mono-potassium salt.
  • any salt is a pharmaceutically acceptable non-toxic salt.
  • salts are included in the present invention, since they have potential to serve as intermediates in the purification or 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 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 seventh aspect of the invention provides a prodrug of any compound of the first, second, third, fourth, fifth or sixth aspect of the invention.
  • the seventh aspect of the invention may provide a pharmaceutically acceptable salt and/or solvate of such a prodrug.
  • the seventh aspect of the invention may provide (i) a pharmaceutically acceptable salt of a prodrug, or (ii) a pharmaceutically acceptable solvate of a prodrug, or (iii) a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of a prodrug.
  • therapeutically inactive prodrugs are provided.
  • Prodrugs are compounds which, when administered to a subject such as a human, are converted in whole or in part to a compound of the invention.
  • the prodrugs are pharmacologically inert chemical derivatives that can be converted in vivo to the active drug molecules to exert a therapeutic effect. Any of the compounds described herein can be administered as a prodrug to increase the activity, bioavailability, or stability of the compound or to otherwise alter the properties of the compound.
  • Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs include, but are not limited to, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, and/or dephosphorylated to produce the active compound.
  • the present invention also encompasses salts and solvates of such prodrugs as described above.
  • the compounds, salts, solvates and prodrugs of the present invention may be obtained in all grades of purity, for example via conventional techniques such as recrystallisation and/or column chromatography.
  • the compounds, salts, solvates and prodrugs of the present invention may be at least 90% pure, at least 95% pure, at least 99% pure, at least 99.5% pure or at least 99.9% pure, as measured by HPLC.
  • the compounds, salts, solvates and prodrugs of the present invention may be at least 90% pure, at least 95% pure, at least 99% pure, at least 99.5% pure or at least 99.9% pure, as measured by LCMS.
  • the compounds, salts, solvates and prodrugs of the present invention may be at least 90% pure, at least 95% pure, at least 99% pure, at least 99.5% pure or at least 99.9% pure, as measured by 1 H NMR.
  • the compounds, salts, solvates and prodrugs of the present invention may contain 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 any stable isotope including, but not limited to 12 C, 13 C, 1 H, 2 H (D), 14 N, 15 N, 16 O, 17 O, 18 O, 19 F and 127 I, and any radioisotope including, but not limited to 11 C, 14 C, 3 H (T), 13 N, 15 O, 18 F, 123 I, 124 I, 125 I and 131 I.
  • the compounds, salts, solvates and prodrugs of the present invention may be in any polymorphic or amorphous form.
  • An eighth aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the first, second, third, fourth, fifth or sixth aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug of the seventh aspect of the invention, and a pharmaceutically acceptable excipient.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Aulton’s Pharmaceutics - The Design and Manufacture of Medicines”, M. E. Aulton and K. M. G. Taylor, Churchill Livingstone Elsevier, 4 th Ed., 2013.
  • compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • a ninth aspect of the invention provides a compound of the first, second, third, fourth, fifth or sixth aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the seventh aspect of the invention, or a pharmaceutical composition of the eighth 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 or pharmaceutical composition to a subject.
  • treatment refers equally to curative therapy, and ameliorating or palliative therapy. The term includes obtaining beneficial or desired physiological results, which may or may not be established clinically.
  • Beneficial or desired clinical results include, but are not limited to, the alleviation of symptoms, the prevention of symptoms, the diminishment of extent of disease, the stabilisation (i.e., not worsening) of a condition, the delay or slowing of progression/worsening of a condition/symptom, the amelioration or palliation of a condition/symptom, and remission (whether partial or total), whether detectable or undetectable.
  • the term “palliation”, and variations thereof, as used herein, means that the extent and/or undesirable manifestations of a physiological condition or symptom are lessened and/or time course of the progression is slowed or lengthened, as compared to not administering a compound, salt, solvate, prodrug or pharmaceutical composition of the present invention.
  • prevention 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. Any statistically significant (p ⁇ 0.05) avoidance of occurrence, delay in onset or reduction in risk as measured by a controlled clinical trial may be deemed a prevention of the disease, disorder or condition.
  • Subjects amenable to prevention include those at heightened risk of a disease, disorder or condition as identified by genetic or biochemical markers.
  • the genetic or biochemical markers are appropriate to the disease, disorder or condition under consideration and may include for example, inflammatory biomarkers such as C-reactive protein (CRP) and monocyte chemoattractant protein 1 (MCP-1) in the case of inflammation, as well as biomarkers associated with the complement system, such as C5a, terminal complement complex, Factor B, fragments Ba and Bb, Complement C3 fragments C3a and C3b, and downstream degradation products iC3b, C3c and C3d(g).
  • CRP C-reactive protein
  • MCP-1 monocyte chemoattractant protein 1
  • a tenth aspect of the invention provides the use of a compound of the first, second, third, fourth, fifth or sixth aspect, or a pharmaceutically effective salt, solvate or prodrug of the seventh aspect, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition.
  • the treatment or prevention comprises the administration of the compound, salt, solvate, prodrug or medicament to a subject.
  • An eleventh aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the step of administering an effective amount of a compound of the first, second, third, fourth, fifth or sixth aspect, or a pharmaceutically acceptable salt, solvate or prodrug of the seventh aspect, or a pharmaceutical composition of the eighth aspect, to thereby treat or prevent the disease, disorder or condition.
  • the administration is to a subject in need thereof.
  • Dysregulation of the alternative complement pathway due to genetics or the presence of autoantibodies can lead to many different diseases. Common polymorphisms in complement proteins or rare mutations can cause dysfunction or dysregulation of the complement system due to over-activation or under-regulation.
  • Autoantibodies can bind to self-cells and drive the complement system such that the capacity of the natural regulators to protect is overwhelmed.
  • the cells natural defence mechanism, such as shedding of active complexes, can cause symptoms due to loss of critical molecules from the cell surface, such as the acetylcholine receptor.
  • the complement system is not the primary trigger of disease but acts secondarily to other disease-causing triggers to set up a vicious cycle of inflammation that is propagated by the complement system. In these diseases, inhibition of the complement system can bring about a treatment effect.
  • gain of function Complement C3 and/or Factor B mutations, and/or the loss of function in the regulatory proteins eventuate in uncontrolled C3 activation (Garred, P., Tenner, A. J., and Mollnes, T. E. Pharmacol. Rev.2021, 73, 792-827).
  • common polymorphisms or rare mutations can lead to distinctive phenotypes due to specific impact on function, such as the ability to bind membranes.
  • Some genetic changes result in proteins with altered ability to bind to certain structures (such as glycosaminoglycans or disease-associated epitopes), resulting in tissue-specific diseases.
  • the domain in which the mutation or polymorphism resides can impact disease phenotype.
  • a twelfth aspect of the invention provides a compound of the first, second, third, fourth, fifth or sixth aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the seventh aspect of the invention, or a pharmaceutical composition of the eighth aspect of the invention, for use in the treatment or prevention of a disease, disorder or condition in an individual, wherein the individual has a germline or somatic mutation in Complement C3 or Factor B, or a germline or somatic mutation in a regulator of the alternate pathway, or a germline or somatic mutation in an enzyme that directly or indirectly causes the production or activation of Factor B.
  • the mutation may be, for example, a gain-of-function or other mutation of Factor B resulting in increased Factor B or C3/C5 convertase activity.
  • the mutation may be a gain-of-function or other mutation of Complement C3 resulting in increased Factor B or C3/C5 convertase activity.
  • the mutation may be a loss of function in a negative regulator (such as Factor H) resulting in increased alternate pathway activity, a gain of function in a positive regulator (such as properdin) resulting in increased alternate pathway activity, or a gain of function in an enzyme that causes the production or activation of Factor B.
  • the use comprises the administration of the compound, salt, solvate, prodrug or pharmaceutical composition to the individual.
  • the use may also comprise the diagnosis of an individual having a germline or somatic mutation in (i) Complement C3, (ii) Factor B, (iii) a regulator of the alternate pathway, or (iv) an enzyme that directly or indirectly causes the production or activation of Factor B, wherein the compound, salt, solvate, prodrug or pharmaceutical composition is administered to an individual on the basis of a positive diagnosis for the mutation.
  • a thirteenth aspect of the invention provides the use of a compound of the first, second, third, fourth, fifth or sixth aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the seventh aspect of the invention, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition in an individual, wherein the individual has a germline or somatic mutation in Complement C3 or Factor B, or a germline or somatic mutation in a regulator of the alternate pathway, or a germline or somatic mutation in an enzyme that directly or indirectly causes the production or activation of Factor B.
  • the mutation may be, for example, a gain-of-function or other mutation of Factor B resulting in increased Factor B or C3/C5 convertase activity.
  • the mutation may be a gain-of-function or other mutation of Complement C3 resulting in increased Factor B or C3/C5 convertase activity.
  • the mutation may be a loss of function in a negative regulator (such as Factor H) resulting in increased alternate pathway activity, a gain of function in a positive regulator (such as properdin) resulting in increased alternate pathway activity, or a gain of function in an enzyme that causes the production or activation of Factor B.
  • the treatment or prevention comprises the administration of the compound, salt, solvate, prodrug or medicament to the individual.
  • the treatment or prevention may also comprise the diagnosis of an individual having a germline or somatic mutation in (i) Complement C3, (ii) Factor B, (iii) a regulator of the alternate pathway, or (iv) an enzyme that directly or indirectly causes the production or activation of Factor B, wherein the compound, salt, solvate, prodrug or medicament is administered to an individual on the basis of a positive diagnosis for the mutation.
  • identification of the mutation in Complement C3, Factor B, the regulator or the enzyme in the individual may be by any suitable genetic or biochemical means.
  • a fourteenth aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the steps of diagnosing of an individual having a germline or somatic mutation in (i) Complement C3, (ii) Factor B, (iii) a regulator of the alternate pathway, or (iv) an enzyme that directly or indirectly causes the production or activation of Factor B, and administering an effective amount of a compound of the first, second, third, fourth, fifth or sixth aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the seventh aspect of the invention, or a pharmaceutical composition of the eighth aspect of the invention, to the positively diagnosed individual, to thereby treat or prevent the disease, disorder or condition.
  • the administration is to a subject in need thereof.
  • the disease, disorder or condition may be a disease, disorder or condition of the immune system, the cardiovascular system, the renal system, the respiratory system, the central nervous system, the reproductive system, the ocular system, the metabolic system, the haematological system, may be a cancer or other malignancy, and/or may be caused by or associated with a pathogen.
  • these general embodiments defined according to broad categories of diseases, disorders and conditions are not mutually exclusive.
  • any particular disease, disorder or condition may be categorized according to more than one of the above general embodiments.
  • a non-limiting example is type I diabetes which is an autoimmune disease and a disease of the endocrine system.
  • the disease, disorder or condition is responsive to Factor B inhibition.
  • Factor B inhibition refers to the complete or partial reduction in the level of activity of Factor B, either unbound or in complex with C3b/C3(H 2 O), and includes, for example, (i) the inhibition of active Factor B or Bb, (ii) the inhibition of latent Factor B (the zymogen) and/or (iii) the inhibition of the conversion of latent Factor B into active Factor B.
  • Factor B A number of ocular conditions have been shown to involve Factor B including, in particular, age-related macular degeneration (Schramm, E. C. et al, Mol. Immunol. 2014, 61, 118-125), retinal detachment (Sweigard, J. H. et al, Sci. Transl. Med.2015, 7, 297ra116-297ra116), Doyne honeycomb retinal dystrophy, also known as malattia leventinese (DHRD/ML) (Crowley, M. A. et al, Hum. Mol. Genet.2023, ddac187), diabetic macular oedema and diabetic retinopathy (Murray, H. et al, Investig.
  • age-related macular degeneration Schom, E. C. et al, Mol. Immunol. 2014, 61, 118-125
  • retinal detachment Sweigard, J. H. et al, Sci. Trans
  • Immunol.2021, 6, eabg0833 Covid-19 (Fujimura, Y., and Holland, L. Z. Int. J. Hematol.2022, 115, 457- 469), smoke-induced mucosal damage (Davis, K. S. et al, Otolaryngol. Head Neck Surg. 2010, 143, 152-158), airway hyperresponsiveness allergic asthma (Herbert, C. et al, Clin. Sci. (Lond) 2017, 131, 499-509), idiopathic pulmonary fibrosis (Meliconi, R. et al, Clin. Immunol.
  • ITP idiopathic thrombocytopenic purpura
  • PNH paroxysmal nocturnal hemoglobinuria
  • Factor B has been implicated in the pathogenesis of various cancers, including pancreatic cancer (Shimazaki, R. et al, Cell Oncol.2021, 44, 937-950), photocarcinogenesis (Byrne, S. N. et al, Photochem. Photobiol. Sci.2015, 14, 801-806), breast cancer (Suman, S. et al, J. Proteomics 2016, 148, 183-193), gastro-oesophageal cancer (Wu, C.
  • C3 glomerulopathy including dense deposit disease and C3 glomerulonephritis
  • FSGS focal segmental glomerulosclerosis
  • Factor B has been suggested to have a role in a number of metabolic conditions, including diabetes related conditions including, in particular, gestational diabetes (Shen, Y. et al, Gynecol. Endocrinol.2022, 38, 158-163), cardiometabolic disease (Coan, P. M. et al, Hypertension, 2017, 70, 624-633), diabetic macular oedema and diabetic retinopathy as discussed above, diabetic kidney disease (Lu, Q. et al, JCI Insight 2021, 6, e147716), and metabolic disorders including diet-induced steatosis and dyslipidemia (Sadana, P. et al, Int. J. Mol. Sci.2020, 21, 7472).
  • diabetes related conditions including, in particular, gestational diabetes (Shen, Y. et al, Gynecol. Endocrinol.2022, 38, 158-163), cardiometabolic disease (Coan, P. M. et al, Hyper
  • Factor B has been linked to infertility (Sim, Y. J., Ryu, A. R., and Lee, M. Y. Biotechnol. Appl. Biochem.2022, 69, 289-295), inflammation during pregnancy (Livson, S. et al, Front. Immunol.2022, 13, 925630), spontaneous preterm birth (Lynch, A. M. et al, Am. J. Obstet. Gynecol.2008, 199, 354.e1-8), pregnancy loss in antiphospholipid syndrome (Breen, K. A. et al, Thromb. Haemost. 2012, 107(3), 423-429; Salmon, J. E.
  • Factor B has also been linked to several pathogenic diseases, including dengue- associated DHF (dengue hemorrhagic fever) and DSS (dengue shock syndrome) (Cabezas-Falcon, S. et al, J. Gen. Virol.2021, 102, 001547; and Dalrymple, N. A. et al, J. Virol.2012, 86(12), 6408-6415), hyper-inflammatory complications of severe sepsis (Li, D. et al, Crit. Care Med.2016, 44, e289-299; and Zou, L.
  • DHF dengue hemorrhagic fever
  • DSS dengue shock syndrome
  • Nephrol.2020, 31, 829-840 Other diseases, disorders or conditions in which Factor B has been implicated or shown to be involved include: - liver diseases including chronic hepatitis B (Chen, H. et al, Aliment. Pharmacol. Ther.2020, 51, 469-478; Seo, T. Y. et al, BMC Med. Genet.2020, 21(1), 241; and Jiang, D-K. et al, Hepatology, 2015, 62(1), 118-128), acute alcohol-associated hepatitis (Fan, X. et al, Hepatology 2021, 73, 983-997) and large duct biliary obstruction and viral hepatitis (Potter, B. J.
  • any of the diseases, disorders or conditions listed above may be treated or prevented in accordance with the ninth, tenth, eleventh, twelfth, thirteenth or fourteenth aspect of the present invention.
  • diseases, disorders or conditions which may be responsive to Factor B inhibition and which may be treated or prevented in accordance with the sixth, seventh, eighth, ninth, tenth or eleventh aspect of the present invention include: (i) ocular diseases, disorders or conditions, such as age-related macular degeneration, retinal detachment, Doyne honeycomb retinal dystrophy (also known as malattia leventinese) (DHRD/ML), retinal ischemia reperfusion, non-infectious uveitis, and diabetic retinopathy and diabetic macular oedema; (ii) haematological diseases, disorders or conditions, such as cold agglutinin disease, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic ure
  • PNH paroxysmal nocturnal hemoglob
  • the disease, disorder or condition is selected from: (i) an ocular disease, disorder or condition; (ii) a haematological disease, disorder or condition; (iii) a renal disease, disorder or condition; (iv) a cancer; or (v) an auto-immune disease, disorder or condition.
  • the disease, disorder or condition is selected from: (i) acute kidney injury; (ii) age-related macular degeneration; (iii) airway hyperresponsiveness with inflammation; (iv) Alzheimer’s disease; (v) amyotrophic lateral sclerosis; (vi) ANCA vasculitis; (vii) antiphospholipid syndrome; (viii) aortic stenosis; (ix) atypical hemolytic uremic syndrome; (x) acquired thrombotic thrombocytopenic purpura; (xi) bullous pemphigoid; (xii) C3 glomerulopathy; (xiii) immune complex-mediated membranoproliferative glomerulonephritis (IC- MPGN) (xiv) cardiac ischemia and reperfusion; (xv) cardiac remodelling; (xvi) cardiometabolic disease; (xvii) coeliac disease; (xviii) cold agglutinin disease; (xix) a respiratory condition caused by S
  • diseases, disorders or conditions which may be responsive to Factor B inhibition and which may be treated or prevented in accordance with ninth, tenth, eleventh, twelfth, thirteenth or fourteenth aspect of the present invention are listed above.
  • some of the diseases, disorders or conditions mentioned above arise due to mutations in (i) Complement C3, (ii) Factor B, (iii) a direct or indirect regulator of Factor B, or (iv) an enzyme that directly or indirectly causes the production or activation of Factor B.
  • Such mutations may give rise to an increase in alternative pathway activity which may be effectively treated by Factor B inhibition.
  • a fifteenth aspect of the invention provides a method of inhibiting Factor B, the method comprising the use of a compound of the first, second, third, fourth, fifth or sixth aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the seventh aspect of the invention, or a pharmaceutical composition of the eighth aspect of the invention, to inhibit Factor B.
  • the method is performed ex vivo or in vitro, for example in order to analyse the effect on cells of Factor B inhibition.
  • the method is not a method of treatment of the human or animal body.
  • the method is performed in vivo.
  • the method may comprise the step of administering an effective amount of a compound of the first, second, third, fourth, fifth or sixth aspect, or a pharmaceutically acceptable salt, solvate or prodrug of the seventh aspect, or a pharmaceutical composition of the eighth aspect, to thereby inhibit Factor B.
  • the administration is to a subject in need thereof.
  • the method of the fifteenth aspect of the invention may be a method of inhibiting Factor B in a non-human animal subject, the method comprising the steps of administering the compound, salt, solvate, prodrug or pharmaceutical composition to the non-human animal subject and optionally subsequently mutilating or sacrificing the non-human animal subject.
  • a method further comprises the step of analysing one or more tissue or fluid samples from the optionally mutilated or sacrificed non-human animal subject.
  • a sixteenth aspect of the invention provides a compound of the first, second, third, fourth, fifth or sixth aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the seventh aspect of the invention, or a pharmaceutical composition of the eighth aspect, for use in the inhibition of Factor B.
  • the use comprises the administration of the compound, salt, solvate, prodrug or pharmaceutical composition to a subject.
  • a seventeenth aspect of the invention provides the use of a compound of the first, second, third, fourth, fifth or sixth aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the seventh aspect of the invention, in the manufacture of a medicament for the inhibition of Factor B.
  • the inhibition comprises the administration of the compound, salt, solvate, prodrug or medicament to a subject.
  • the subject may be any human or other animal.
  • the subject is a mammal, more typically a human or a domesticated mammal such as a cow, pig, lamb, sheep, goat, horse, cat, dog, rabbit, mouse etc. Most typically, the subject is a human.
  • any of the medicaments employed in the present invention can be administered by oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), airway (aerosol), rectal, vaginal, ocular or topical (including transdermal, buccal, mucosal, sublingual and topical ocular) administration.
  • parenteral including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural
  • airway asperaerosol
  • rectal rectal
  • vaginal ocular
  • topical including transdermal, buccal, mucosal, sublingual and topical ocular
  • the mode of administration selected is that most appropriate to the disorder, disease or condition to be treated or prevented.
  • the compounds, salts, solvates or prodrugs 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. Corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatine.
  • the lubricating agent if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Tablets may also be effervescent and/or dissolving tablets.
  • Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent, and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil. Powders or granules for oral use may be provided in sachets or tubs.
  • Aqueous solutions, suspensions or dispersions may be prepared by the addition of water to powders, granules or tablets.
  • Any form suitable for oral administration may optionally include sweetening agents such as sugar, flavouring agents, colouring agents and/or preservatives.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds, salts, solvates or prodrugs 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 or prodrugs of the invention will generally be provided in a form suitable for topical administration, e.g. as eye drops.
  • suitable forms may include ophthalmic solutions, gel-forming solutions, sterile powders for reconstitution, ophthalmic suspensions, ophthalmic ointments, ophthalmic emulsions, ophthalmic gels and ocular inserts.
  • the compounds, salts, solvates or prodrugs of the invention may be provided in a form suitable for other types of ocular administration, for example as intraocular preparations (including as irrigating solutions, as intraocular, intravitreal or juxtascleral injection formulations, or as intravitreal implants), as packs or corneal shields, as intracameral, subconjunctival or retrobulbar injection formulations, or as iontophoresis formulations.
  • the compounds, salts, solvates or prodrugs of the invention will generally be provided in the form of ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters or patches.
  • Suitable suspensions and solutions can be used in inhalers for airway (aerosol) administration.
  • the dose of the compounds, salts, solvates or prodrugs of the present invention will, of course, vary with the disease, disorder or condition to be treated or prevented. In general, a suitable dose will be in the range of 0.01 to 500 mg per kilogram body weight of the recipient per day.
  • the desired dose may be presented at an appropriate interval such as once every other day, once a day, twice a day, three times a day or four times a day.
  • the desired dose may be administered in unit dosage form, for example, containing 1 mg to 50 g of active ingredient per unit dosage form.
  • An eighteenth aspect of the invention provides a method of synthesising a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, the method comprising the step of: (i) reacting a compound of Formula (SM-1) with a compound of Formula R 9 OH to produce a compound of Formula (I), or a pharmaceutically acceptable salt and/or solvate thereof:
  • a nineteenth aspect of the invention provides a method of synthesising a compound according to the second aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, the method comprising the step of: (i) reacting a compound of Formula (SM-2) with a compound of Formula R 9 OH to produce a compound of Formula (II), or a pharmaceutically acceptable salt and/or solvate thereof: Formula (SM-2) Formula (II) wherein ring A, R 1 , R 4 to R 11 , X 12 , R 13 to R 17 , m, n, p and q are as defined in accordance with the second aspect of the invention.
  • a twentieth aspect of the invention provides a method of synthesising a compound according to the third aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, the method comprising the step of: (i) reacting a compound of Formula (SM-1) with a compound of Formula R 19 CON(R 18 )OH to produce a compound of Formula (III), or a pharmaceutically acceptable salt and/or solvate thereof: Formula (SM-1) Formula (III) wherein ring A, R 1 to R 8 , R 10 , R 11 , X 12 , R 13 , R 18 , R 19 , m, n, p and q are as defined in accordance with the third aspect of the invention.
  • a twenty-first aspect of the invention provides a method of synthesising a compound according to the fourth aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, the method comprising the step of: (i) reacting a compound of Formula (SM-2) with a compound of Formula R 19 CON(R 18 )OH to produce a compound of Formula (IV), or a pharmaceutically acceptable salt and/or solvate thereof:
  • a twenty-second aspect of the invention provides a method of synthesising a compound according to the fifth aspect of the invention, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, the method comprising the step of reacting a Factor B inhibitor comprising a carboxylic acid group with an alcohol to form an active ester.
  • the alcohol has the formula R 9 OH, where R 9 is as defined in accordance with the first or second aspect of the invention, or the alcohol has the formula R 19 CON(R 18 )OH, wherein R 18 and R 19 are as defined in accordance with the third or fourth aspect of the invention.
  • the reaction with the alcohol is performed in the presence of a carbodiimide such as N,N'-dicyclohexylcarbodiimide (DCCI), N,N'- diisopropylcarbodiimide (DIC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).
  • a carbodiimide such as N,N'-dicyclohexylcarbodiimide (DCCI), N,N'- diisopropylcarbodiimide (DIC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).
  • DCCI N,N'-dicyclohexylcarbodiimide
  • DIC N,N'- diisopropylcarbodiimide
  • EDCC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • EDCCI 1-ethyl-3-
  • a 4-dialkylaminopyridine is used as a catalyst. More typically, 4- dimethylaminopyridine (DMAP) is used as a catalyst.
  • DMAP 4- dimethylaminopyridine
  • a base is also present.
  • the base is a tertiary amine base such as N,N-diisopropylethylamine (DIPEA) or triethylamine (TEA), More typically, the base is N,N-diisopropylethylamine (DIPEA).
  • the reaction with the alcohol is performed in the presence of a dipolar aprotic solvent, such as such as dimethyl sulfoxide, N,N- dimethylformamide, N,N′-dimethylpropyleneurea, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, or N-methyl pyrrolidone. More typically, the solvent is N,N-dimethylformamide (DMF).
  • a dipolar aprotic solvent such as such as dimethyl sulfoxide, N,N- dimethylformamide, N,N′-dimethylpropyleneurea, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, or N-methyl pyrrolidone. More typically, the solvent is N,N-dimethylformamide (DMF).
  • the reaction with the alcohol is performed in the presence of a carbodiimide (such as 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC)), a 4-dialkylaminopyridine catalyst (such as 4-dimethylaminopyridine (DMAP)), a tertiary amine base (such as N,N- diisopropylethylamine (DIPEA)) and a dipolar aprotic solvent (such as N,N- dimethylformamide (DMF)).
  • a carbodiimide such as 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC)
  • EDC 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • DMAP 4-dialkylaminopyridine
  • DIPEA tertiary amine base
  • DIPEA dipolar aprotic solvent
  • the method of the eighteenth aspect of the invention further comprises the step of converting the compound of Formula (I) into a different compound of Formula (I), or a pharmaceutically acceptable salt and/or solvate thereof.
  • the method of the ninteenth aspect of the invention further comprises the step of converting the compound of Formula (II) into a different compound of Formula (II), or a pharmaceutically acceptable salt and/or solvate thereof.
  • the method of the twentieth aspect of the invention further comprises the step of converting the compound of Formula (III) into a different compound of Formula (III), or a pharmaceutically acceptable salt and/or solvate thereof.
  • the method of the twenty-first aspect of the invention further comprises the step of converting the compound of Formula (IV) into a different compound of Formula (IV), or a pharmaceutically acceptable salt and/or solvate thereof.
  • All citations are incorporated herein by reference in their entirety. For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention. In addition, insofar as is practicable it is to be understood that any preferred, typical or optional embodiment of any aspect of the present invention should also be considered as a preferred, typical or optional embodiment of any other aspect of the present invention.
  • Chromatography refers to column chromatography performed using silica or C18 silica and executed under positive pressure (flash chromatography) conditions.
  • LCMS Methods Instruments Waters H-Class with Binary Solvent Pump, Sample Manager with Flow- Through Needle, CMA Column Manager, Photodiode array detector, QDa mass detector (methods A1, A3, B3) or Agilent 1260 with Binary Pump, HiP Sampler, Column Compartment, diodearray detector, G6150 mass selective detector (methods C1, C3).
  • Methods A1, A3 Column: Waters ACQUITY UPLC CSH C18, 2.1 x 30 mm, 1.7 ⁇ m, at 40 °C; Solvents: A: 0.1% HCO2H in water, B: MeCN; Gradient [time (min)/solvent B in A (%)]: 0.00/2, 0.65/100, 1.00/100 (Method A1) or 0.00/2, 2.50/100, 3.00/100 (Method A3); Flow rate: 1 mL/min (Method A1) or 0.77 mL/min (Method A3); Detection: UV at 210-400 nm, MS by electrospray ionisation.
  • Method B3 Column: Waters ACQUITY UPLC BEH C18, 2.1 x 30 mm, 1.7 ⁇ m, at 40 °C; Solvents: A: 0.1% NH 3 in water, B: MeCN; Gradient [time (min)/solvent B in A (%)]: 0.00/2, 2.50/100, 3.00/100; Flow rate: 0.77 mL/min; Detection: UV at 210-400 nm, MS by electrospray ionisation.
  • Methods C1, C3 Column: Waters Cortecs C18, 30 x 2.1 mm, 2.7 ⁇ m, at 40 °C; Solvents: A: 0.1% HCO2H in water, B: MeCN; Gradient [time (min)/solvent B in A (%)]: 0.00/2, 0.65/100, 1.00/100 (Method C1) or 0.00/2, 2.50/100, 3.00/100 (Method C3); Flow rate: 1 mL/min (Method C1) or 1.35 mL/min (Method C3); Detection: UV at 260 nm +/- 90 nm, MS by electrospray ionisation.
  • Step 2 To a solution of 5-methoxy-7-methyl-1H-indole-4-carbaldehyde (2.80 g, 14.8 mmol) in DMF (60 mL) at 0 °C was added sodium hydride (888 mg, 60 % dispersion in mineral oil, 22.2 mmol) portion wise. The reaction was warmed to rt and stirred for 30 min. The reaction was cooled to 0 °C and 4-methylbenzenesulfonyl chloride (4.23 g, 22.2 mmol) in DMF (5 mL) was added drop-wise, and the reaction was stirred at rt for 14 h before the addition of water (40 mL) at 0 °C.
  • sodium hydride 888 mg, 60 % dispersion in mineral oil, 22.2 mmol
  • Step 2 TFA (6.34 mL, 82.9 mmol) was added to a solution of tert-butyl 4-((5-methoxy- 7-methyl-1-tosyl-1H-indol-4-yl)methyl)-3-(4-(methoxycarbonyl)phenyl)piperazine-1- carboxylate (5.90 g, 91 % pure by LCMS, 8.29 mmol) in DCM (80 mL) and the reaction was stirred at rt for 16 h before concentration in vacuo. DCM (150 mL) was added and the organic phase was washed with aq.
  • DCM 150 mL
  • Step 3 To a solution of methyl 4-(1-((5-methoxy-7-methyl-1-tosyl-1H-indol-4-yl)- methyl)piperazin-2-yl)benzoate (2.00 g, 3.62 mmol) in THF (30 mL) was added formaldehyde (1.35 mL, 37 % aq. solution, 18.1 mmol). After stirring for 5 min at rt, STAB (1.15 g, 5.42 mmol) was added and the reaction mixture was stirred for 6 h at rt. Water (50 mL) and EtOAc (50 mL) were added and the phases separated.
  • Step 4 KOH (0.30 g, 5.35 mmol) was added to a solution of methyl 4-(1-((5-methoxy-7- methyl-1-tosyl-1H-indol-4-yl)methyl)-4-methylpiperazin-2-yl)benzoate (0.30 g, 0.53 mmol) in EtOH (1 mL) and the reaction stirred at 80 °C for 12 h. After cooling to rt the reaction mixture was loaded on to celite and purified by reverse phase column chromatography on a 12g Flash C18 cartridge, eluting with 0-50% MeCN in 10 mM aq.
  • the first eluting product was concentrated in vacuo and lyophilized to yield (R)-tert-butyl 3-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (Intermediate 3, 14.5 g, 45.3 mmol, 36 % yield) as an off-white solid
  • the second eluting product was concentrated in vacuo to yield (S)-tert-butyl 3-(4-(methoxycarbonyl)phenyl)- piperazine-1-carboxylate (Intermediate 4, 14.5 g, 45.3 mmol, 36 % yield) as a white solid
  • Step 1 5-methoxy-7-methyl-1-tosyl-1H-indole-4-carbaldehyde (Intermediate 1, 2.36 g, 6.87 mmol) was added to a solution of (R)-tert-butyl 3-(4-(methoxycarbonyl)- phenyl)piperazine-1-carboxylate (Intermediate 3, 2.00 g, 6.24 mmol) in THF (80 mL) and the reaction mixture was stirred for 5 min at rt.
  • Step 2 TFA (3.28 mL, 42.8 mmol) was added to a solution of tert-butyl (R)-4-((5- methoxy-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-3-(4-(methoxycarbonyl)phenyl)- piperazine-1-carboxylate (3.05 g, 4.71 mmol) in DCM (70 mL) and the reaction was stirred at rt for 16 h concentration in vacuo. DCM (150 mL) was added and the organic phase was washed with aq. NaHCO3 (100 mL) and water (100 mL).
  • Step 3 Triethylamine (160 ⁇ L, 1.15 mmol) and 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate (616 ⁇ L, 3.83 mmol) were added to a solution of methyl (R)- 4-(1-((5-methoxy-7-methyl-1-tosyl-1H-indol-4-yl)methyl)piperazin-2-yl)benzoate (210 mg, 0.38 mol) in MeCN (1 mL), and the reaction mixture was heated at 70 °C for 2 h then concentrated in vacuo.
  • Step 4 KOH (170 mg, 3.02 mmol) was added to a solution of methyl (R)-4-(1-((5- methoxy-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-4-(2,2,3,3-tetrafluoropropyl)- piperazin-2-yl)benzoate (200 mg, 302 ⁇ mol) in EtOH (4 mL) and the reaction mixture was stirred at 80 °C for 20 h before cooling to rt and loading onto a 2 g SCX cartridge in MeOH. The cartridge was washed with MeOH and then eluted with 0.7N ammonia in MeOH.
  • reaction mixture was stirred at rt for 12 h then diluted with EtOAc (50 mL) and washed with water (3 x 50 mL) and 5% aq. CuSO4 solution (3 x 50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo.
  • Table 1 The examples shown in the table below were prepared by the methods described for Examples 1-3 from 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)piperidin-2-yl)benzoic acid (for Examples 4-15 and 19), or Intermediate 6 (for Example 16), or Intermediate 5 (for Examples 17, 18), and the corresponding alcohol.
  • Example 20 4-((4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)- methyl)piperidin-2-yl)benzoyl)oxy)benzoic acid
  • Step 1 4-(Tert-butoxycarbonyl)phenyl 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl- 1H-indol-4-yl)methyl)piperidin-2-yl)benzoate was prepared from tert-butyl 4-hydroxy- benzoate (115 mg, 592 ⁇ mol), DMAP (7.2 mg, 59 ⁇ mol), DIPEA (258 ⁇ L, 1.48 mmol) and EDC (202 mg, 0.89 mmol) and 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)piperidin-2-yl)benz
  • Step 2 TFA (0.59 mL, 7.65 mmol) was added to a solution of 4-(tert-butoxycarbonyl)- phenyl 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoate (229 mg, 0.38 mmol) in DCM (2 mL). After stirring at rt for 4 h the reaction mixture was concentrated in vacuo and azeotroped with MeCN (2 x 5 mL).
  • glycerol was added to a final concentration of 20 % (v/v), and preparations were stored until use at 4°C.
  • Enzyme assays were performed in 384 well format, in which compounds were prepared as 1:5 serial dilutions (8-point curves) in DMSO and 150 nL of compound was stamped to an assay plate (384-well OptiPlate, Perkin Elmer 6007299) at 100x final assay concentration (FAC). The final assay DMSO concentration was 1% (v/v).
  • the compound preincubation step was initiated by addition of 7.5 ⁇ l biochemical assay buffer containing CVF:Bb complex (5 nM FAC unless stated otherwise), based on input FB concentration and pre-equilibrated to rt) for 30 min at rt. Subsequently, 7.5 ⁇ l biochemical assay buffer containing purified C3 substrate (Complement Technology A113c, to 0.1 ⁇ M FAC) was added and CVF:Bb mediated cleavage was allowed to proceed for 60 min at rt. Reactions were terminated by addition of 3.75 ⁇ l 10x Halt protease inhibitor cocktail (Fisher 78437) in assay buffer, and cooling on ice.
  • CVF:Bb complex 5 nM FAC unless stated otherwise
  • Inhibitor data were normalized to DMSO vehicle, 0 % inhibition) and reference maximum inhibition (10 ⁇ M Iptacopan, 100 % inhibition) plate controls, and compound inhibition curves were fitted to a 4-parameter equation with variable slope to determine IC 50 estimates.
  • the results of the factor B biochemical ELISA assay are summarised in Table 2 below as IC 50 values.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des esters actifs d'inhibiteurs du facteur B, ainsi que des sels, des solvates, des promédicaments et des compositions pharmaceutiques associés. La présente invention concerne en outre des procédés de synthèse de tels composés, et l'utilisation de tels composés dans le traitement et la prévention de troubles et de troubles médicaux, plus particulièrement par inhibition du facteur B.
PCT/EP2024/069024 2023-07-06 2024-07-05 Nouveaux composés Ceased WO2025008516A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP24740851.1A EP4739667A2 (fr) 2023-07-06 2024-07-05 Derives de l'indole ayant une activite inhibitrice du facteur b

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB202310422 2023-07-06
GB2310422.7 2023-07-06
GBGB2316974.1A GB202316974D0 (en) 2023-11-06 2023-11-06 Novel compounds
GB2316974.1 2023-11-06

Publications (2)

Publication Number Publication Date
WO2025008516A2 true WO2025008516A2 (fr) 2025-01-09
WO2025008516A3 WO2025008516A3 (fr) 2025-02-13

Family

ID=91899194

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/069024 Ceased WO2025008516A2 (fr) 2023-07-06 2024-07-05 Nouveaux composés

Country Status (2)

Country Link
EP (1) EP4739667A2 (fr)
WO (1) WO2025008516A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025172535A1 (fr) 2024-02-15 2025-08-21 Sitala Bio Ltd Composés indole et benzimidazole utilisés en tant qu'inhibiteurs du facteur b

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130296377A1 (en) 2012-05-04 2013-11-07 Christopher Michael ADAMS Complement pathway modulators and uses thereof
WO2013164802A1 (fr) 2012-05-04 2013-11-07 Novartis Ag Modulateurs des voies du complément et leurs utilisations
WO2014143638A1 (fr) 2013-03-14 2014-09-18 Novartis Ag Dérivés de 2-(1h-indol-4-ylméthyl)-3h-imidazo[4,5-b]pyridine-6-carbonitrile comme inhibiteurs du facteur b du complément utiles pour le traitement de maladies ophtalmiques
WO2015009616A1 (fr) 2013-07-15 2015-01-22 Novartis Ag Dérivés de pipéridinyl-indole et leur utilisation en tant qu'inhibiteurs du facteur b du complément
WO2022028507A1 (fr) 2020-08-07 2022-02-10 上海美悦生物科技发展有限公司 Composé hétérocyclique, son procédé de préparation et son utilisation
WO2022028527A1 (fr) 2020-08-07 2022-02-10 上海美悦生物科技发展有限公司 Inhibiteur du facteur b du complément et composition pharmaceutique de celui-ci, procédé de préparation correspondant et utilisation associée
WO2022143845A1 (fr) 2020-12-30 2022-07-07 江苏恒瑞医药股份有限公司 Composé hétérocyclique ponté contenant de l'azote, son procédé de préparation et son utilisation médicale
WO2022143940A1 (fr) 2020-12-30 2022-07-07 南京明德新药研发有限公司 Série de composés d'acide benzoïque substitués par pipéridine et leur utilisation
WO2022155294A1 (fr) 2021-01-14 2022-07-21 Alexion Pharmaceuticals, Inc. Inhibiteurs macrocycliques du facteur b du complément
WO2022218429A1 (fr) 2021-04-16 2022-10-20 正大天晴药业集团股份有限公司 Composés d'acide carboxylique aromatique substitués bicycliques
WO2022256586A2 (fr) 2021-06-03 2022-12-08 Chinook Therapeutics, Inc. Composés d'indole substitués et leurs procédés d'utilisation
WO2023278698A1 (fr) 2021-06-30 2023-01-05 Apellis Pharmaceuticals, Inc. Inhibition du complément
WO2023020566A1 (fr) 2021-08-18 2023-02-23 四川海思科制药有限公司 Dérivé de cycle hétéroaromatique contenant de l'azote benzo et son utilisation en médecine
WO2023072197A1 (fr) 2021-10-27 2023-05-04 Hansoh Bio Llc Dérivés de pipéridinyl indole, leurs procédés de préparation et leurs utilisations médicales
WO2023139534A1 (fr) 2022-01-24 2023-07-27 Novartis Ag Dérivés de pipéridinyle spirocycliques en tant qu'inhibiteurs du facteur b du complément et leurs utilisations
WO2023187715A1 (fr) 2022-04-01 2023-10-05 Novartis Ag Inhibiteurs du facteur b du complément et leurs utilisations
WO2024049977A1 (fr) 2022-08-31 2024-03-07 Chinook Therapeutics, Inc. Composés d'indole substitués et leurs procédés d'utilisation

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130296377A1 (en) 2012-05-04 2013-11-07 Christopher Michael ADAMS Complement pathway modulators and uses thereof
WO2013164802A1 (fr) 2012-05-04 2013-11-07 Novartis Ag Modulateurs des voies du complément et leurs utilisations
WO2014143638A1 (fr) 2013-03-14 2014-09-18 Novartis Ag Dérivés de 2-(1h-indol-4-ylméthyl)-3h-imidazo[4,5-b]pyridine-6-carbonitrile comme inhibiteurs du facteur b du complément utiles pour le traitement de maladies ophtalmiques
WO2015009616A1 (fr) 2013-07-15 2015-01-22 Novartis Ag Dérivés de pipéridinyl-indole et leur utilisation en tant qu'inhibiteurs du facteur b du complément
WO2022028507A1 (fr) 2020-08-07 2022-02-10 上海美悦生物科技发展有限公司 Composé hétérocyclique, son procédé de préparation et son utilisation
WO2022028527A1 (fr) 2020-08-07 2022-02-10 上海美悦生物科技发展有限公司 Inhibiteur du facteur b du complément et composition pharmaceutique de celui-ci, procédé de préparation correspondant et utilisation associée
WO2022143845A1 (fr) 2020-12-30 2022-07-07 江苏恒瑞医药股份有限公司 Composé hétérocyclique ponté contenant de l'azote, son procédé de préparation et son utilisation médicale
WO2022143940A1 (fr) 2020-12-30 2022-07-07 南京明德新药研发有限公司 Série de composés d'acide benzoïque substitués par pipéridine et leur utilisation
WO2022155294A1 (fr) 2021-01-14 2022-07-21 Alexion Pharmaceuticals, Inc. Inhibiteurs macrocycliques du facteur b du complément
WO2022218429A1 (fr) 2021-04-16 2022-10-20 正大天晴药业集团股份有限公司 Composés d'acide carboxylique aromatique substitués bicycliques
WO2022256586A2 (fr) 2021-06-03 2022-12-08 Chinook Therapeutics, Inc. Composés d'indole substitués et leurs procédés d'utilisation
WO2023278698A1 (fr) 2021-06-30 2023-01-05 Apellis Pharmaceuticals, Inc. Inhibition du complément
WO2023020566A1 (fr) 2021-08-18 2023-02-23 四川海思科制药有限公司 Dérivé de cycle hétéroaromatique contenant de l'azote benzo et son utilisation en médecine
WO2023072197A1 (fr) 2021-10-27 2023-05-04 Hansoh Bio Llc Dérivés de pipéridinyl indole, leurs procédés de préparation et leurs utilisations médicales
WO2023139534A1 (fr) 2022-01-24 2023-07-27 Novartis Ag Dérivés de pipéridinyle spirocycliques en tant qu'inhibiteurs du facteur b du complément et leurs utilisations
WO2023187715A1 (fr) 2022-04-01 2023-10-05 Novartis Ag Inhibiteurs du facteur b du complément et leurs utilisations
WO2024049977A1 (fr) 2022-08-31 2024-03-07 Chinook Therapeutics, Inc. Composés d'indole substitués et leurs procédés d'utilisation

Non-Patent Citations (146)

* Cited by examiner, † Cited by third party
Title
"Novartis iptacopan meets primary endpoints in Phase II study in rare kidney disease C3 glomerulopathy (C3G", 4 November 2021, NOVARTIS PRESS RELEASE
"Novartis Phase III APPOINT-PNH trial shows investigational oral monotherapy iptacopan improves hemoglobin to near-normal levels, leading to transfusion independence in all treatment-naive PNH patients", NOVARTIS PRESS RELEASE, 26 April 2023 (2023-04-26)
ALAWIEH, A. ET AL., J. NEUROSCI, vol. 38, no. 10, 2018, pages 2519 - 2532
ALEXANDER, J. J. ET AL., EUR. J. IMMUNOL, vol. 37, 2007, pages 1691 - 1701
ASSIRELLI, E ET AL., FRONT. IMMUNOL, vol. 11, 2020, pages 535010
BALDAN-MARTIN, M. ET AL., ADV. WOUND CARE (NEW ROCHELLE, vol. 9, 2020, pages 277 - 294
BARBOUR, T. D. ET AL., NEPHROL. DIAL. TRANSPLANT, vol. 28, 2013, pages 1685 - 1693
BERENTSEN, S, SEMIN. HEMATOL, vol. 55, 2018, pages 141 - 149
BLAKEY, H ET AL., PREGNANCY HYPERTENS, vol. 32, 2023, pages 43 - 49
BOMBACK, A. S. ET AL., KIDNEY INT. REP
BOUDHABHAY, I ET AL., KIDNEY INT, vol. 99, no. 3, 2021, pages 581 - 597
BOYAJYAN, A ET AL., NEUROCHEMICAL RESEARCH, vol. 35, 2010, pages 894 - 898
BRANDTZAEG, P ET AL., J. INFECT. DIS, vol. 173, 1996, pages 647 - 655
BREEN, K. A ET AL., THROMB. HAEMOST, vol. 107, no. 3, 2012, pages 423 - 429
BRODSKY, R. A, BLOOD, vol. 124, 2014, pages 2804 - 2811
BYRNE, S. N. ET AL., PHOTOCHEM. PHOTOBIOL. SCI, vol. 201, no. 14, pages 801 - 806
CABEZAS-FALCON, S ET AL., J. GEN. VIROL, vol. 102, 2021, pages 001547
CAMPBELL, C. I ET AL., BRAIN COMMUN, vol. 4, no. 6, 2022, pages fcac3061
CAO, W. ET AL., HAEMATOLOGICA, vol. 101, 2016, pages 1319 - 1326
CHAUVET, S ET AL., J. AM. SOC. NEPHROL, vol. 31, 2020, pages 829 - 840
CHEN, C ET AL., MED. MICROBIOL. IMMUNOL, vol. 209, 2020, pages 81 - 94
CHEN, H ET AL., ALIMENT. PHARMACOL. THER, vol. 51, 2020, pages 469 - 478
CHEN, K ET AL., BIOMED. PHARMACOTHER, vol. 153, 2022, pages 113433
CHUDWIN, D. S. ET AL., CLIN. IMMUNOL. IMMUNOPATHOL, vol. 71, no. 2, 1994, pages 199 - 202
CHUN, N. ET AL., PLOS ONE, vol. 12, 2017, pages 0179450
COAN, P. M. ET AL., HYPERTENSION, vol. 201, no. 70, pages 624 - 633
COAN, P. M. ET AL., HYPERTENSION, vol. 70, 2017, pages 624 - 633
COUSER, W. G, CLIN. J. AM. SOC. NEPHROL, vol. 201, no. 12, 2017, pages 983 - 997
CROWLEY, M. A. ET AL., HUM. MOL. GENET, 2023, pages ddac187
DA ROSA UTIYAMA, S. R ET AL., INT. J. IMMUNOGENET, vol. 32, 2005, pages 307 - 314
DAHA, M. R. ET AL., J. NEPHROL, vol. 29, no. 1, 2016, pages 1 - 4
DALRYMPLE, N. A., J. VIROL, vol. 86, no. 12, 2012, pages 6408 - 6415
DAVIS, K. S. ET AL., OTOLARYNGOL. HEAD NECK SURG, vol. 143, 2010, pages 152 - 158
DEMIR, S ET AL., DIAGNOSTICS (BASEL, vol. 13, no. 10, 2023, pages 1729
EKDAHL, K. N. ET AL., IMMUNOL. REV, vol. 313, no. 1, 2023, pages 91 - 103
EL IDRISSI, N. B ET AL., ACTA NEUROPATHOL., vol. 129, no. 5, 2015, pages 653 - 667
EL IDRISSI, N. B ET AL., CLIN. EXP. IMMUNOL, vol. 184, no. 3, 2016, pages 338 - 346
ELVINGTON, A. ET AL., J. IMMUNOL., vol. 189, no. 9, 2012, pages 4640 - 4647
ESKANDARPOUR, PATHOL., vol. 191, no. 2, 2021, pages 320 - 334
FAN, X ET AL., HEPATOLOGY, vol. 73, 2021, pages 983 - 997
FRENETTE, J ET AL., AM. J. PATHOL, vol. 156, 2000, pages 2103 - 2110
FUJIMURA, YHOLLAND, L. Z, INT. J. HEMATOL, vol. 115, 2022, pages 457 - 469
GERL ET AL., INVEST. OPTHALMOL. VIS. SCI, vol. 43, no. 4, 2002, pages 1104 - 1108
GHAFOURI, B ET AL., BMC MUSCULOSKELET. DISORD, vol. 17, 2016, pages 206
GIAMARELLOS-BOURBOULIS, E. J ET AL., BR. J. DERMATOL, vol. 183, no. 1, 2020, pages 176 - 178
GOICOECHEA DE JORGE, E. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 104, no. 1, 2007, pages 240 - 245
GUZZO, G. ET AL., BMC NEPHROL, vol. 22, 2021, pages 252
HALSTEAD, S. K ET AL., BRAIN, vol. 127, no. 9, 2004, pages 2109 - 2123
HERBERT, C, CLIN. SCI. (LOND, vol. 131, 2017, pages 499 - 509
HOLERS, V. M ET AL., FRONT. IMMUNOL, vol. 9, 2018, pages 1057
HOLT, M. F ET AL., FRONT. IMMUNOL, vol. 12, 2021, pages 800978
IATROPOULOS, P ET AL., J. A. SOC. NEPHROL, vol. 29, no. 1, 2018, pages 283 - 294
INAFUKU, SKLOKMAN, GCONNOR, K. M, FRONT. MOL. NEUROSCI, vol. 11, 2018, pages 278
J. IMMUNOLOGY, vol. 193, 2014, pages 5567 - 5575
JAGER, N. M. ET AL., FRONT, vol. 10, 2019, pages 2538
JANEWAY, C. A. JR ET AL.: "Immunobiology: The Immune System in Health and Disease", 2001, GARLAND SCIENCE, article "The complement system and innate immunity"
JIA, K ET AL., MED. SCI. MONIT, vol. 25, 2019, pages 7087 - 7093
JIANG, D-K ET AL., HEPATOLOGY, vol. 62, no. 1, 2015, pages 118 - 128
KIM, M. Y. ET AL., ANN. RHEUM. DIS, vol. 77, no. 4, 2018, pages 549 - 555
KLEIN, M. A. ET AL., MAT. MED, vol. 7, no. 4, 2001, pages 488 - 492
KONO, D. H.: "Systemic Lupus Erythematosus", 2011, ACADEMIC PRESS, article "Chapter 4 - Genetics of Lupus in Mice"
KOUSER ET AL., FRONT. IMMUNOL, vol. 4, no. 93, 2013, pages 1 - 12
KRICK, E. H ET AL., CLIN. EXP. IMMUNOL, vol. 34, 1978, pages 1 - 9
LARSSEN, E. ET AL., SAGE OPEN MED, vol. 7, 2019, pages 2050312119850390
LASKOWSKI, J ET AL., AM. J., vol. 317, 2019, pages F650 - F657
LEE, J. D ET AL., J. NEUROINFLAMMATION, vol. 15, 2018, pages 171
LENDERINK, A. M ET AL., AM. J. PHYSIOL. RENAL PHYSIOL., vol. 293, no. 2, 2007, pages F555 - F564
LI, D ET AL., CRIT. CARE MED, vol. 44, 2016, pages 289 - 299
LINDBLAD, C. ET AL., CRIT. CARE, vol. 25, 2021, pages 103
LIVSON, S. ET AL., FRONT. IMMUNOL, vol. 13, 2022, pages 1054159
LU, Q., INSIGHT, vol. 6, 2021, pages 147716
LYNCH, A. M ET AL., AM. J. OBSTET. GYNECOL, vol. 198, no. 4, 2008, pages 385 - 8
MAINOLFI ET AL., J. MED. CHEM, vol. 63, 2020, pages 5697 - 5722
MAINOLFI ET AL., J. MED. CHEM., vol. 63, 2020, pages 697 - 5722
MALLAH, K. ET AL., ACTA NEUROPATHOL. COMMUN, vol. 9, no. 1, 2021, pages 72
MAYILYAN, KRWEINBERGER, DRSIM, R. B, DRUG NEWS PERSPECT, vol. 21, 2008, pages 200
MELICONI, R. ET AL., CLIN. IMMUNOL. IMMUNOPATHOL, vol. 57, 1990, pages 64 - 73
MERLE, N. S. ET AL., TRANSFUS. CLIN. BIOL, vol. 26, no. 2, 2019, pages 116 - 124
MORGAN, A. R. ET AL., ALZHEIMERS DEMENT, vol. 15, 2019, pages 776 - 787
MURRAY, H. ET AL., INVESTIG. OPHTHALMOL. VIS. SCI, vol. 59, 2018, pages 5476 - 5476
MURRAY, H., J. MOL. SCI., vol. 22, 2021, pages 9580
NELSON, K. C ET AL., J. CLIN. INVEST, vol. 116, 2006, pages 2892 - 2900
OHSHIRO, K. ET AL., INT. J. ONCOL, vol. 30, 2007, pages 743 - 749
PALACE, J ET AL., CLINICAL TRIAL, vol. 47, 2021, pages 102641
PANDEY, M. K ET AL., NATURE, vol. 543, no. 7643, 2017, pages 108 - 112
PENG, Y. ET AL., FRONT. PEDIATR, vol. 11, 2023, pages 1137375
PICCELI, V. F ET AL., LUPUS, vol. 25, no. 4, 2016, pages 412 - 417
PICKERING, M. C. ET AL., KIDNEY INT, vol. 83, no. 2, 2013, pages 1079 - 1089
POPPELAARS, F ET AL., J. CLIN. MED, vol. 10, no. 20, 2021, pages 4715
POTTER, B. J ET AL., DIGESTION, vol. 18, 1978, pages 371 - 383
QIAO, F. ET AL., AM. J. PATHOL, vol. 177, no. 6, 2010, pages 3061 - 3070
QUEROL, L, PERIPHER. NERV. SYST, vol. 28, no. 2, 2023, pages 276 - 285
REDDY, P. V. ET AL., CLIN. PSYCHOPHARMACOL. NEUROSCI, vol. 21, no. 2, 2023, pages 313 - 319
RIIHILD, P. ET AL., AM. J. PATHOL, vol. 187, 2017, pages 1186 - 1197
RIZK, D. V. ET AL., KIDNEY INT. REP, vol. 8, no. 5, 2023, pages 968 - 979
RODRIGUEZ DE CORDOBA, IMMUNOLOGICAL REVIEWS, vol. 313, 2023, pages 71 - 90
RODRIGUEZ DE CORDOBA, S. ET AL., SEMIN. THROMB. HEMOST, vol. 40, 2014, pages 422 - 430
SADANA, P. ET AL., INT. J. MOL. SCI, vol. 21, 2020, pages 7472
SALMON, J. E ET AL., LUPUS, vol. 12, no. 7, 2012, pages 535 - 538
SALMON, J. E ET AL.: "7", CURR. DIR. AUTOIMMUN, 2004, pages 133 - 148
SARTAIN, S ET AL., PEDIATR. BLOOD CANCER, vol. 67, 2020, pages 28070
SCHRAMM, E. C ET AL., MOL. IMMUNOL, vol. 61, 2014, pages 118 - 125
SCHUBART, A. ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 116, 2019, pages 7926 - 7931
SCHUBART, A. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 116, no. 6, 2019, pages 7926 - 7931
SCHWAEBLE, W. J., ALI, Y. M., SIM, R. B.: "The Autoimmune Diseases", 2020, ACADEMIC PRESS, article "The Roles and Contributions of the Complement System in the Pathophysiology of Autoimmune Diseases"
SEGERS, F. M ET AL., PLOS ONE, vol. 9, no. 10, 2014, pages 110053
SEO, T. Y ET AL., BMC MED. GENET, vol. 21, no. 1, 2020, pages 241
SERFECZ, J. C ET AL., INT. J. MOL. SCI, vol. 22, no. 18, 2021, pages 9912
SHADRINA, A ET AL., GENE, vol. 659, 2018, pages 93 - 99
SHAHINI, N. ET AL., J. IMMUNOL., vol. 203, 2019, pages 1973 - 1980
SHEN, Y. ET AL., GYNECOL. ENDOCRINOL, vol. 38, no. 1, 2022, pages 158 - 163
SHI, D ET AL., J. HUM. GENET, vol. 65, 2020, pages 241 - 249
SHIMAZAKI, R. ET AL., CELL ONCOL., vol. 44, 2021, pages 937 - 950
SHINDO, R. ET AL., IMMUNOL. MED, 9 January 2023 (2023-01-09)
SIM, Y. J.RYU, A. RLEE, M. Y, BIOTECHNOL. APPL. BIOCHEM., vol. 69, 2022, pages 289 - 295
SOLMAZ, I. ET AL., J. NEUROIMMUNOL, vol. 348, 2020, pages 577359
SOTO, E ET AL., J. MATERN. FETAL NEONATAL MED, vol. 23, 2010, pages 1085 - 1090
STROHMEYER, R. ET AL., BRAIN RES. MOL. BRAIN RES, vol. 81, no. 1-2, 2000, pages 7 - 18
SU, Z ET AL., J. INTERN. MED, 6 February 2014 (2014-02-06), pages 470 - 485
SUMAN, S. ET AL., J. PROTEOMICS, vol. 148, 2016, pages 183 - 193
SWEIGARD, J. H ET AL., SCI. TRANSL. MED, vol. 7, 2015, pages 297ra116 - 297ra116
TANAKA ET AL., BMC OPTHALMOL, vol. 14, 2014, pages 83
TAUBE, C. ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 103, 2006, pages 8084 - 8089
TUREK-JAKUBOWSKA, A. ET AL., J. CLIN. MED, vol. 11, 2022, pages 339
TURNBERG, D. ET AL., J. IMMUNOL., vol. 1, no. 6, 2006, pages 4094 - 4102
UNLII, M. ET AL., NEUROSCI. LETT, vol. 282, 2000, pages 149 - 152
VAISBUCH, E ET AL., J. MATERN. FETAL NEONATAL MED, vol. 22, 2009, pages 905 - 916
WAHLEN, K. ET AL., FRONT. PSYCHOL, vol. 9, 2018, pages 2400
WAN, K. C ET AL., BURNS, vol. 24, 1998, pages 241 - 244
WANG, F.M., FRONT. GENET, vol. 12, 2021, pages 690952
WANG, Q. ET AL., PSYCHIATRY RESEARCH, vol. 272, 2019, pages 404 - 410
WEITZ, I. C., J. HAEMATOL, vol. 203, no. 1, 2023, pages 96 - 100
WILSON, M. R ET AL., CLIN. EXP. IMMUNOL, vol. 26, no. 1, 1976, pages 11 - 20
WU, C. ET AL., BR. J. CANCER, vol. 113, 2015, pages 220 - 225
XIAO, H ET AL., AM. J. PATHOL, vol. 170, no. 0, 2007, pages 52 - 64
XU ET AL., EUR. J. PHARMACOL., vol. 787, 2016, pages 94 - 104
YAN, B ET AL., SCI. IMMUNOL, vol. 6, 2021, pages abg0833
YANG, M. ET AL., IMMUNOL. RES, vol. 64, 2016, pages 610 - 618
YANG, Y. ET AL., EUR. J. IMMUNOL, vol. 50, 2020, pages 220 - 233
ZANCHI, C ET AL., MOL. IMMUNOL, vol. 161, no. 10, 2023, pages 25 - 32
ZHANG ET AL., DIABETES, vol. 51, no. 12, 2002, pages 3499 - 3504
ZHANG, Y ET AL., CLIN. J. AM. SOC, vol. 7, 2012, pages 265 - 274
ZHANG, Y. ET AL., J. PROTEOMICS, vol. 201, no. 123, 2015, pages 89 - 100
ZHANG, Y. ET AL., NEPHROL. DIAL. TRANSPLANT, vol. 36, 2021, pages 1222 - 1233
ZHOU, X. J. ET AL., CLIN. J. AM. SOC. NEPHROL, vol. 16, 2021, pages 213 - 224
ZOU, L ET AL., J. IMMUNOL., vol. 191, no. 11, 2013, pages 5625 - 5635

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025172535A1 (fr) 2024-02-15 2025-08-21 Sitala Bio Ltd Composés indole et benzimidazole utilisés en tant qu'inhibiteurs du facteur b

Also Published As

Publication number Publication date
EP4739667A2 (fr) 2026-05-13
WO2025008516A3 (fr) 2025-02-13

Similar Documents

Publication Publication Date Title
JP7254082B2 (ja) Ｃ５ａＲ阻害剤としてのジアリール置換６，５－縮合環化合物
KR101680818B1 (ko) Ｃ5ａｒ 길항제
CN110997674B (zh) 作为C5a抑制剂的6-5稠合环类
AU2020266529B2 (en) 3-amino-4H-benzo[E][1,2,4]thiadiazine 1,1-dioxide derivatives as inhibitors of MRGX2
CN111032658B (zh) 作为C5a抑制剂的5-5稠合环类
KR20190121399A (ko) 파네소이드 x 수용체 효능제 및 이의 용도
PT1849773E (pt) Derivados de piperazina para o tratamento de dor e de incontinência urinária
AU2024290587A1 (en) 2-(1h-indol-4-yl)methyl)-isoindoline derivatives as factor b inhibitors
WO2025008451A1 (fr) Dérivés de 2-(1h-indol-4-yl)méthyl)2h-indazole utilisés en tant qu'inhibiteurs du facteur b
WO2025158284A1 (fr) Polythérapie utilisant des composés antagonistes du récepteur de polypeptide insulinotropique glucose-dépendant et des peptides agonistes du récepteur glp-1
EP4739667A2 (fr) Derives de l'indole ayant une activite inhibitrice du facteur b
EP3597634B1 (fr) Acides sulfoniques oxygénés contenant de l'ammonium et leur utilisation médicale
EP2875025A1 (fr) Dérivés de triazole fusionnés en tant que modulateurs de gamma sécrétase
TW201002716A (en) Fused pyrazine compounds useful for the treatment of degenerative and inflammatory diseases
JP6172143B2 (ja) 含窒素二環式芳香族へテロ環化合物
EP4739675A1 (fr) Dérivés d'indole à activité inhibitrice du facteur b
TW202045505A (zh) 用於疾病之治療之新穎化合物及其醫藥組合物
WO2025172535A1 (fr) Composés indole et benzimidazole utilisés en tant qu'inhibiteurs du facteur b
RU2780338C2 (ru) 6-5 КОНДЕНСИРОВАННЫЕ КОЛЬЦА КАК ИНГИБИТОРЫ С5а
RU2780322C2 (ru) 5-5 КОНДЕНСИРОВАННЫЕ КОЛЬЦА КАК ИНГИБИТОРЫ С5а
US20240391940A1 (en) Fused ring-containing compound, application thereof, and composition containing same
BR112020012270B1 (pt) Compostos de anel 6,5-fundido substituído por diarila, composição farmacêutica, e usos dos mesmos
HK1204602B (en) Oxygenated amino- or ammonium-containing sulfonic acid, phosphonic acid and carboxylic acid derivatives and their medical use

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24740851

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 2024740851

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2024740851

Country of ref document: EP

Effective date: 20260206

WWP Wipo information: published in national office

Ref document number: 2024740851

Country of ref document: EP