WO2025196155A1 - Inhibiteurs de pcsk9 et leurs procédés d'utilisation - Google Patents

Inhibiteurs de pcsk9 et leurs procédés d'utilisation

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Publication number
WO2025196155A1
WO2025196155A1 PCT/EP2025/057561 EP2025057561W WO2025196155A1 WO 2025196155 A1 WO2025196155 A1 WO 2025196155A1 EP 2025057561 W EP2025057561 W EP 2025057561W WO 2025196155 A1 WO2025196155 A1 WO 2025196155A1
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Prior art keywords
alkyl
optionally substituted
compound
pharmaceutically acceptable
halo
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English (en)
Inventor
Olaf Panknin
Gavin Donal O'MAHONY
Andrey Frolov
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AstraZeneca AB
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AstraZeneca AB
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Publication of WO2025196155A1 publication Critical patent/WO2025196155A1/fr
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Z8 and Z9 are independently selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C 1-6 hydrocarbon, optionally substituted by OH, CN, C 1-6 alkyl acyl, C 1-6 alkoxy or one or more halo groups; (v) C 1-6 alkoxy, optionally substituted by C 1-6 alkyl amido, C 1-6 alkyl phosphonyl, or one or more halo groups; (vi) C 1-6 alkylamino (vii) C 1-6 thioalkyl, (viii) C 1-6 alkyl phosphinyl; and (ix) C 1-6 alkyl phosphonyl; R A8 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6 thioalkyl, C1-6 alkoxy, C1-6
  • the compounds may have an improved secondary pharmacology profile or an improved off-target profile.
  • Substituents The phrase “optionally substituted” as used herein, pertains to a parent group which may be unsubstituted or which may be substituted. Unless otherwise specified, the term “substituted” as used herein, pertains to a parent group which bears one or more substituents.
  • substituted is used herein in the conventional sense and refers to a chemical moiety which is covalently attached to, or if appropriate, fused to, a parent group.
  • substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known. Examples of substituents are described in more detail below.
  • C1-6 hydrocarbon The term “C1-6 hydrocarbon” as used herein pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 6 carbon atoms, which may be aliphatic or alicyclic, which may be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated) and may also be branched.
  • hydrocarbon includes the terms alkyl, alkenyl, alkynyl, cycloalkyl, etc., discussed below.
  • C1-6 alkyl The term “C1-6 alkyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 6 carbon atoms, which are saturated and may also be branched.
  • C1-4 alkyl as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 4 carbon atoms, which are saturated.
  • saturated alkyl groups include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ), butyl (C 4 ), pentyl (C 5 ) and hexyl (C 6 ).
  • saturated linear alkyl groups include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), n-butyl (C 4 ), n-pentyl (amyl) (C 5 ) and n-hexyl (C 6 ).
  • saturated branched alkyl groups include isopropyl (C 3 ), iso-butyl (C 4 ), sec-butyl (C 4 ), tert-butyl (C 4 ), iso-pentyl (C 5 ), and neopentyl (C 5 ).
  • C 2-6 Alkenyl The term “C 2-6 alkenyl” as used herein, pertains to a hydrocarbon group having one or more carbon-carbon double bonds.
  • C2-6 alkynyl The term “C2-6 alkynyl” as used herein, pertains to a hydrocarbon group having one or more carbon-carbon triple bonds.
  • Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH) and 2- propynyl (propargyl, -CH2C ⁇ CH).
  • C1-6 alkoxy The term C1-6 alkoxy as used herein, pertains to an OR group, wherein R is an C1-6 hydrocarbon group.
  • C1-6 alkoxy groups include, but are not limited to, OMe, OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (iso-propoxy), O(nBu) (n-butoxy), O(sBu) (sec-butoxy), O(iBu) (iso-butoxy), and O(tBu) (tert-butoxy).
  • Amino groups may be primary (-NH 2 ), secondary (-NHR 1 ), or tertiary (-NR 1 R 2 ), and in cationic form, may be quaternary (- + NR 1 R 2 R 3 ).
  • amino groups include, but are not limited to NH 2 , NHCH 3 , NHCH(CH 3 ) 2 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , and NHPh.
  • Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.
  • R 1 and R 2 may together form a cyclic or bicyclic structure and form a cyclic acylamido group.
  • C 1-6 thioalkyl The term C 1-6 thioalkyl as used herein, pertains to an SR, wherein R is a C 1-6 hydrocarbon group. Examples of C 1-6 alkylthio groups include, but are not limited to, SCH 3 and SCH 2 CH 3 .
  • C3-12 cycloalkyl refers to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 7 carbon atoms, including from 3 to 7 ring atoms.
  • the carbocyclic ring may be saturated or unsaturated and may be bridged or unbridged.
  • the ring may be a fused ring or a single ring.
  • cycloalkyl groups include, but are not limited to, those derived from: saturated monocyclic hydrocarbon compounds: cyclopropane (C3), cyclobutane (C4), cyclopentane (C5), cyclohexane (C6), cycloheptane (C7), methylcyclopropane (C4), dimethylcyclopropane (C5), methylcyclobutane (C5), dimethylcyclobutane (C6), methylcyclopentane (C6), dimethylcyclopentane (C7) and methylcyclohexane (C7); unsaturated monocyclic hydrocarbon compounds: cyclopropene (C3), cyclobutene (C4), cyclopentene (C5), cyclohexene (C6), methylcyclopropene (C4), dimethylcyclopropene (C5), methylcyclobutene (C5), dimethylcyclobutene (C6), methyl
  • C 3-10 heterocyclyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 10 ring atoms, of which from 1 to 5 are ring heteroatoms. In certain embodiments, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
  • the ring may be saturated or unsaturated, and may be bridged or unbridged.
  • the ring may be a fused ring or a single ring. For the avoidance of doubt, substituents on the heterocyclyl ring may be linked via either a carbon atom or a heteroatom.
  • heteroatom means O, S, N, Si or B (Boron). More commonly in a pharmaceutical context, the term ‘heteroatom’ means O, S or N.
  • prefixes e.g. C 3-10 C 3-7 , C 5-6 , etc.
  • C 5-6 heterocyclyl as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms.
  • Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from: N1: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g.2,5-dihydro- 1H-pyrrole) (C5), 2H-pyrrole or 3H-pyrrole, isoazole (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), azepine (C7); O1: oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane (tetrahydropyran) (C6), dihydropyran (C6), pyran (C6), oxepin (C7); S1: thiiran
  • bicyclic heterocyclyl groups include, but are not limited to those derived from: Compound Structure Compound Structure 7-azabicyclo[4.2.0]octane 3-azabicyclo[3.1.0]hexane (N 1 ) C 8 (N 1 ) C 6 6-azabicyclo[3.2.0]heptane 2,3,3a,4,5,6,7,7a- (N1) C7 octahydrofuro[2,3- c]pyridine (N1O1) C9 C 6-10 carboaryl:
  • the term “C 6-10 carboaryl”, as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 6 to 10 ring atoms and the ring atoms are all carbon atoms, as in “carboaryl groups”.
  • the ring may be a fused ring or a single ring.
  • carboaryl groups include, but are not limited to, those derived from benzene (i.e. phenyl) (C 6 ), naphthalene (C 10 ) and azulene (C 10 ).
  • the prefixes e.g. C 5-7 , C 5-6 , C 5-10 , etc.
  • C5-6 aryl as used herein, pertains to an aryl group having 5 or 6 ring atoms.
  • carboaryl groups which comprise fused rings, at least one of which is an aromatic ring, include, but are not limited to, groups derived from indane (e.g.2,3-dihydro-1H-indene) (C9), indene (C9), isoindene (C9) and tetraline (1,2,3,4-tetrahydronaphthalene) (C10).
  • C5-10 heteroaryl The term “C5-10 heteroaryl”, as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 5 to 10 ring atoms of which from 1 to 5 are ring heteroatoms.
  • each ring has from 5 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
  • substituents on the heteroaryl ring may be linked via either a carbon atom or a heteroatom.
  • the ring may be a fused ring or a single ring.
  • heteroatom means O, S, N, Si or B (Boron). More commonly in a pharmaceutical context, the term ‘heteroatom’ means O, S or N.
  • Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: N 1 : pyrrole (azole) (C 5 ), pyridine (azine) (C 6 ); O 1 : furan (oxole) (C 5 ); S 1 : thiophene (thiole) (C 5 ); N 1 O 1 : oxazole (C 5 ), isoxazole (C 5 ), isoxazine (C 6 ); N 2 O 1 : oxadiazole (furazan) (C 5 ); N 3 O 1 : oxatriazole (C 5 ); N 1 S 1 : thiazole (C 5 ), isothiazole (C 5 ); N 2 : 1H-imidazole (1,3-diazole) (C 5 ), 1H-pyrazole (1,2-diazole) (C 5 ), pyridazine (1,2-diazine) (C 6
  • heteroaryl which comprise fused rings
  • heteroaryl or heterocyclic compounds include but are not limited to those derived from: Spiro C 6-12 carbocyclyl:
  • Spiro C 6-12 carbocyclyl as used herein pertains to a moiety that has at least two molecular rings with only one common atom.
  • the simplest spiro compounds are bicyclic (having just two rings), or have a bicyclic portion as part of the larger ring system, in either case with the two rings connected through the defining single common atom.
  • Spiro C 6-12 carbocyclyl pertains to a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 6 to 12 carbon atoms, including from 3 to 7 ring atoms wherein the rings share a common atom.
  • Spiro C 6-12 heterocyclyl The term Spiro C 6-12 heterocyclyl as used herein pertains to a moiety that has at least two molecular rings with only one common atom.
  • the simplest spiro compounds are bicyclic (having just two rings), or have a bicyclic portion as part of the larger ring system, in either case with the two rings connected through the defining single common atom.
  • the spiro C 6-12 heterocyclyl moiety pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 8 to 12 ring atoms of which from 1 to 3 are ring heteroatoms wherein the rings share a common atom.
  • each ring has from 9 to 11 ring atoms, of which from 1 to 2 are ring heteroatoms.
  • substituents on the heteroaryl ring may be linked via either a carbon atom or a heteroatom.
  • the selected substituents may comprise the same substituents or different substituents from within the given group.
  • Pharmaceutically acceptable salt The term “pharmaceutically acceptable” is used to specify that an object (for example a salt, dosage form or excipient) is suitable for use in patients. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim/Zürich: Wiley-VCH/VHCA, 2002.
  • a suitable pharmaceutically acceptable salt of a compound of Formula (I) is, for example, an acid addition salt.
  • An acid addition salt of a compound of Formula (I) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person.
  • An acid addition salt may for example be formed using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid.
  • An acid addition salt may also be formed using an organic acid selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.
  • Another suitable pharmaceutically acceptable salt of a compound of Formula (I) is, for example, a base addition salt.
  • a base addition salt of a compound of Formula (I) may be formed by bringing the compound into contact with a suitable inorganic or organic base under conditions known to the skilled person.
  • a base addition salt may for example be formed using an inorganic base selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide and calcium hydroxide.
  • a base addition salt may also be formed using an organic base selected from the group consisting of L-arginine, choline, L- lysine, t-butylamine, ethylenediamine, ammonia, dimethylaminoethanol, N-methylglucamine, tromethamine and hydroxyethylmorpholine.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof where the pharmaceutically acceptable salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or para- toluenesulfonic acid salt.
  • the pharmaceutically acceptable salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulf
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof where the pharmaceutically acceptable salt is a lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, L-arginine salt, choline salt, L-lysine salt, t-butylamine salt, ethylenediamine salt, ammonia salt, dimethylaminoethanol salt, N-methylglucamine salt, tromethamine salt or hydroxyethylmorpholine salt.
  • the pharmaceutically acceptable salt is a lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, L-arginine salt, choline salt, L-lysine salt, t-butylamine salt, ethylenediamine salt, ammonia salt, dimethylaminoethanol salt, N-methylglucamine salt, tromethamine salt or hydroxyethylmorpholine salt.
  • Other forms Compounds and salts described in this specification may exist in solvated forms and unsolvated forms.
  • a solvated form may be a hydrated form, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate or an alternative quantity thereof.
  • the compounds of Formula (I) encompass all such solvated and unsolvated forms of compounds of Formula (I), particularly to the extent that such forms possess PCSK9 inhibitory activity, as for example measured using the tests described herein.
  • Compounds and salts described in this specification include one or more chiral (i.e. asymmetric) centres. To the extent a structure or chemical name in this specification does not indicate the chirality, the structure or name is intended to encompass any single stereoisomer (i.e.
  • any single chiral isomer corresponding to that structure or name, as well as any mixture of stereoisomers (e.g. a racemate).
  • a single stereoisomer is obtained by isolating it from a mixture of isomers (e.g. a racemate) using, for example, chiral chromatographic separation.
  • a single stereoisomer is obtained through direct synthesis from, for example, a chiral starting material.
  • a particular enantiomer of a compound described herein may be more active than other enantiomers of the same compound.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof which is a single enantiomer being in an enantiomeric excess (%ee) of ⁇ 95, ⁇ 98% or ⁇ 99%.
  • the single enantiomer is present in an enantiomeric excess (%ee) of ⁇ 99%.
  • a pharmaceutical composition which comprises a compound of Formula (I), which is a single enantiomer being in an enantiomeric excess (%ee) of ⁇ 95, ⁇ 98% or ⁇ 99% or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable excipients.
  • the single enantiomer is present in an enantiomeric excess (%ee) of ⁇ 99%.
  • Isotopes Atoms of the compounds and salts described in this specification may exist as their isotopes.
  • the compound of Formula (I) encompasses all compounds of Formula (I) where an atom is replaced by one or more of its isotopes (for example a compound of Formula (I) where one or more carbon atom is an 11 C or 13 C carbon isotope, or where one or more hydrogen atoms is a 2 H or 3 H isotope).
  • Tautomers Compounds and salts described in this specification may exist as a mixture of tautomers.
  • “Tautomers” are structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom.
  • the compound of Formula (I) includes all tautomers of compounds of Formula (I) particularly to the extent that such tautomers possess PCSK9 inhibitory activity.
  • Therapy, prophylaxis and related terms The term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.
  • prophylaxis is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • treatment is used synonymously with “therapy”.
  • treat can be regarded as “applying therapy” where “therapy” is as defined herein.
  • subject to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a paediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys.
  • Preferred subjects are humans.
  • an “effective amount”, as used herein, refers to an amount that is sufficient to achieve a desired biological effect.
  • a “therapeutically effective amount”, as used herein refers to an amount that is sufficient to achieve a desired therapeutic effect.
  • a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of the disease to be treated.
  • Pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, carriers, stabilisers, flavourings, colorants, fillers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents.
  • compositions described herein comprise compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and are therefore expected to be useful in therapy.
  • a pharmaceutical composition for use in therapy comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition for use in the treatment of a disease in which inhibition of PCSK9 is beneficial comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition for use in the treatment of a cardiovascular disease comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition for use in the treatment of a cardiovascular disease in which inhibition of PCSK9 is beneficial comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition for use in the treatment of a cardiovascular disease in which inhibition of PCSK9 is beneficial comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • the compounds described herein may be used in a method of therapy.
  • a method of treatment comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I).
  • therapeutically effective amount is an amount sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom.
  • the actual amount administered, and rate and time- course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g.
  • the PCSK9 gene was identified using genetic mapping techniques on DNA from subjects with autosomal dominant hypercholesterolemia (Abifadel 2003).
  • the encoded protein is a serine protease that is mostly expressed in the liver, gut, kidney, and nervous system and circulates in plasma. While not wishing to be bound by any particular theory, studies on mutations in the gene indicated that its putative role was in reducing LDLR at the cell surface independently of its catalytic activity (Abifadel 2010). Binding of PCSK9 to the LDLR results in their lysosomal degradation. This enhanced LDLR degradation results in increases in the amount of circulating low-density lipoprotein (LDL).
  • LDL low-density lipoprotein
  • PCSK9 is upregulated by statins, SREBP-1a and SREBP-2, LXR agonist, and insulin, but downregulated by dietary cholesterol, glucagon, ethinylestradiol, chenodeoxycholic acid and the bile acid-activated farnesoid X receptor (FXR) (Maxwell 2003; Persson 2009; Langhi 2008). Since an elevated level of PCSK9 decreases the abundance of LDLR on the cell surface, increasing doses of statins fail to achieve proportional LDL-C lowering results. Thus, disclosed herein are methods for treating a wide range of cardiovascular diseases and conditions that benefit from inhibiting PCSK9 thereby lowering LDL-C.
  • a method of treating a cardiovascular disease comprising administering to a subject a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) for use in the treatment of a cardiovascular disease comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) for the manufacture of a medicament for the treatment of a cardiovascular disease.
  • the disease is hypercholesterolemia, such as familial hypercholesterolemia or autosomal dominant hypercholesterolemia.
  • the disease is hyperlipidemia.
  • the disease is coronary artery disease.
  • the disclosed methods of treatment can decrease high levels of circulating serum cholesterol, such as LDL-C and VLDL-Cholesterol.
  • the disclosed methods are useful for decreasing circulating serum triglycerides, circulating serum lipoprotein A, circulating serum LDL-C and atherogenic lipoproteins.
  • the diseases or conditions treated with the disclosed compounds and compositions include atherosclerosis and atherosclerotic plaque formation.
  • Subjects having a gain-of-function mutation in the PCSK9 gene also benefit with treatment with the disclosed compounds and compositions counteracting the mutation through their inhibition of PCSK9.
  • a method of treating a kidney disease comprising administering to a subject a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) for the manufacture of a medicament for the treatment of a kidney disease are examples of the manufacture of a medicament for the treatment of a kidney disease.
  • the kidney disease is a chronic kidney disease.
  • Combination treatments Disclosed compounds and compositions may be conjointly administered with other therapeutic agents, such as other agents suitable for the treatment of high levels of LDL-C and triglycerides.
  • conjointly administering one or more additional therapeutic agents with a compound described herein provides a synergistic effect.
  • conjointly administering one or more additional therapeutic agents provides an additive effect.
  • the amount of the compound or salt described in this specification and the amount of the other pharmaceutically active agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the animal patient.
  • the combined amounts are “therapeutically effective amounts” if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; or reduce the risk of the disorder getting worse.
  • amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the compound or salt and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).
  • a pharmaceutical composition of the specification may comprise one or more further active ingredients, as appropriate, examples of combinations of a compound of the specification (or a pharmaceutically acceptable salt thereof) and one or more additional active ingredients are described herein.
  • the specification further relates to a combination therapy wherein a compound of the specification, or a pharmaceutically acceptable salt thereof, and a second active ingredient are administered concurrently, sequentially or in admixture, for the treatment of one or more of the conditions listed above.
  • a combination may be used in combination with one or more further active ingredients.
  • a combination for example, for use as a medicament for the treatment of one of the diseases or conditions listed herein, such as a cardiovascular disease
  • a combination comprising a compound of the specification, or a pharmaceutically acceptable salt thereof, and at least one active ingredient selected from: i) a statin; ii) a cholesterol absorption inhibitor; iii) a SGLT2 inhibitor; iv) a P2Y12 inhibitor; v) an ATP-citrate lyase inhibitor; and vi) anti-hypertensive drugs.
  • a pharmaceutical composition for example, for use as a medicament for the treatment of one of the diseases or conditions listed herein, such as a cardiovascular disease
  • a pharmaceutical composition comprising a compound of the specification, or a pharmaceutically acceptable salt thereof, and at least one active ingredient selected from: i) a statin; ii) a cholesterol absorption inhibitor; iii) a SGLT2 inhibitor; iv) a P2Y12 inhibitor; v) an ATP-citrate lyase inhibitor; and vi) anti-hypertensive drugs.
  • the statin is Rosuvastatin (Crestor).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from a SGLT2 inhibitor wherein the SGLT2 inhibitor is selected from Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, Ipragliflozin, Luseogliflozin, Remogliflozin etabonate, Sergliflozin etabonate, Sotagliflozin or Tofogliflozin.
  • the SGLT2 inhibitor is selected from Dapagliflozin (Farxiga or Forxiga).
  • the additional active ingredient is Ezetimibe, Rosuvastatin, Dapagliflozin or Ticagrelor.
  • the additional two active ingredients are Ezetimibe and Rosuvastatin or Dapagliflozin and Rosuvastatin.
  • the antihypertensive drug is selected from Valsartan (Diovan), Metoprolol (Lopressor), HCTZ (Hydrochlorothiazide), Olmesartan (Benicar), Lisinopril (Prinivil, Zestril), Amlodipine besylate (Norvasc), Candesartan, or a calcium channel blocker or a combination thereof.
  • US5273995 discloses certain 6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones such as atorvastatin and any pharmaceutically acceptable form thereof (i.e. LIPITOR®).
  • Atorvastatin calcium i.e., atorvastatin hemicalcium
  • US RE37,314 E discloses rosuvastatin and rosuvastatin calcium.
  • EP0304063 and US5011930 disclose pitivastatin.
  • US3983140 discloses mevastatin.
  • US4448784 and US4450171 disclose velostatin.
  • US4804770 discloses compactin.
  • EP0738510A2 discloses dalvastatin.
  • EP0363934A1 discloses fluindostatin.
  • US4450171 discloses dihydrocompactin.
  • the statin is selected from atorvastatin, rosuvastatin, lovastatin, pravastatin, simvastatin and fluvastatin; and pharmaceutically acceptable salts thereof.
  • the statin is rosuvastatin or a pharmaceutically acceptable salt thereof.
  • the statin is rosuvastatin or rosuvastatin calcium.
  • the statin dosing regimen is a moderate-intensity dosing according to the ACC (American College of Cardiology)/AHA (American Heart Association) (Grundy 2018).
  • This moderate-intensity dosing may be: Dosing regimen A torvastatin 10 to 20 mg once daily Fluvastatin 40 mg twice daily; or 80 mg once daily Lovastatin 40 to 80 mg once daily Pitavastatin 1 to 4 mg once daily Pravastatin 40 to 80 mg once daily Rosuvastatin 5 to 10 mg once daily Simvastatin 20 to 40 mg once daily
  • the rosuvastatin may be dosed as rosuvastatin calcium, where the dose given is calculated as rosuvastatin in its free form.
  • the atorvastatin may be dosed as atorvastatin calcium or atorvastatin calcium trihydrate, where the dose given is calculated as atorvastatin in its free form.
  • the pravastatin may be dosed as pravastatin calcium, where the dose given is calculated as pravastatin in its free form.
  • the pitavastatin may be dosed as pitavastatin calcium, where the dose given is calculated as pitavastatin in its free form.
  • the statin dosing regimen is a high-intensity dosing according to the ACC (American College of Cardiology)/AHA (American Heart Association) (Grundy 2018).
  • This high-intensity dosing may be: Dosing regimen A torvastatin 40 to 80 mg once daily Rosuvastatin 20 to 40 mg once daily
  • the rosuvastatin may be dosed as rosuvastatin calcium, where the dose given is calculated as rosuvastatin in its free form.
  • the atorvastatin may be dosed as atorvastatin calcium or atorvastatin calcium trihydrate, where the dose given is calculated as atorvastatin in its free form.
  • the statin dosing regimen is one appropriate to patients from, for example, Japan: Dosing regimen A torvastatin 10 to 40 mg once daily Fluvastatin 60 mg once daily Pitavastatin 1 to 4 mg once daily Rosuvastatin 2.5 to 20 mg once daily Simvastatin 10 to 20 mg once daily
  • the rosuvastatin may be dosed as rosuvastatin calcium, where the dose given is calculated as rosuvastatin in its free form.
  • the atorvastatin may be dosed as atorvastatin calcium or atorvastatin calcium trihydrate, where the dose given is calculated as atorvastatin in its free form.
  • the pitavastatin may be dosed as pitavastatin calcium, where the dose given is calculated as pitavastatin in its free form.
  • Ezetimibe refers to a compound with the chemical name (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3- (4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one and the structure shown below: Ezetimibe inhibits the absorption of cholesterol from the small intestine and decreases the amount of cholesterol normally available to liver cells. The lower levels of cholesterol in the liver cells leads them to absorb more cholesterol from circulation and thus lowering the levels of circulating cholesterol.
  • ezetimibe reduces plasma LDL-C levels by up to 20% when used alone, and that it lowered plasma levels of lipoprotein(a) by about 7%.
  • ezetimibe is administered in a dose of 5 to 15 mg per day. The daily dose may be up to 10 mg, 11 mg, 12 mg, 13 mg, 14 mg or 15 mg.
  • the daily dose may be at least 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.
  • ezetimibe is administered in a dose of 10 mg per day.
  • ezetimibe is administered as a free base, i.e. not in salt form.
  • ezetimibe is administered as a pharmaceutically acceptable salt thereof, where the dosage is that of ezetimibe not in a salt form.
  • any reference in this disclosure to an amount of ezetimibe, or pharmaceutically acceptable salt thereof is based on the ezetimibe free base equivalent weight.
  • “wt%” refers to weight % based on ezetimibe free base equivalent weight.
  • Bempedoic acid refers to a compound also known as 8-hydroxy-2,2,14,14- tetramethylpentadecanedioic acid and the structure shown below: . Bempedoic acid targets the cholesterol biosynthesis pathway in the liver. Bempedoic acid inhibits ATP-citrate lyase (ACL), two steps upstream of HMG CoA reductase.
  • ACL ATP-citrate lyase
  • Bempedoic acid is converted to active coenzyme A form by enzymes found only in the liver and not in muscles (Agarwala and Goldberg 2020) Bempedoic acid has been approved for use in combination with a statin or statin with other lipid- lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or, alone or in combination with other lipid-lowering therapies in patients who are statin intolerant, or for whom a statin is contraindicated.
  • bempedoic acid is administered in a dose of 150 to 200 mg per day.
  • the daily dose may be up to 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.
  • the daily dose may be at least 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg or 180 mg.
  • bempedoic acid is administered in a dose of 180 mg per day.
  • bempedoic acid is administered as a free acid, i.e. not in salt form.
  • bempedoic acid is administered as a pharmaceutically acceptable salt thereof, where the dosage is that of bempedoic acid not in a salt form.
  • any reference in this disclosure to an amount of bempedoic acid, or pharmaceutically acceptable salt thereof is based on the bempedoic acid free acid equivalent weight.
  • “wt%” refers to weight % based on bempedoic acid free acid equivalent weight.
  • A is (A1a).
  • X 1 is N.
  • X 1 is C-R A3 .
  • A is of formula (A1); .
  • R A1 is selected from the group consisting of: (i) H (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by one or more OH, CN, C1-6 alkyl acyl, C1-6 alkoxy or one or more halo groups; (v) C1-6 alkoxy, optionally substituted by OH, one or more halo groups, C1-6 alkyl amido; (vi) C1-6 alkyl ester; (vii) C1-6 alkyl acyl; and (viii) OH.
  • R A1 is selected from the group consisting of: (i) H (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by one or more OH, CN, C1-6 alkyl acyl, C1-6 alkoxy or one or more halo groups; and (v) C 1-6 alkoxy, optionally substituted by OH, halo or C 1-6 alkyl amido.
  • R A1 is selected from the group consisting of: (i) H (ii) halo; (iii) CN; (iv) C 1-6 hydrocarbon, optionally substituted by one or more OH, CN, C 1-6 alkyl acyl, C 1-6 alkoxy or one or more halo groups; (v) C 1-6 alkoxy, optionally substituted by OH, one or more halo groups or C 1-6 alkyl amido; and (vi) OH.
  • R A1 is an optionally substituted C 1-6 hydrocarbon it is an optionally substituted C 1-6 alkyl. In some embodiments it is optionally substituted methyl or optionally substituted ethyl.
  • R A1 is optionally substituted methyl. In further embodiments, it is unsubstituted methyl.
  • R A1 is optionally substituted C 1-6 alkyl
  • the optional substituents are selected from OH, CN, and one or more halo groups. In further embodiments the optional substituents are selected from OH, F and Br.
  • R A1 is optionally substituted C 1-6 alkoxy, in some embodiments it is optionally substituted OMe or ethoxy. In some embodiments R A1 is unsubstituted OMe.
  • R A1 is optionally substituted C 1-6 alkoxy
  • the optional substituents are selected from C 1-6 alkyl amido and one or more halo groups.
  • the optional substituents are selected from one, two or three F atoms.
  • R A1 is halo, in some embodiments it is F, Br or Cl. In other embodiments it is Br or Cl.
  • R A1 is H.
  • R A1 is OH.
  • R A1 is CN.
  • R A1 is methyl.
  • R A1 is -OCF2H.
  • R A1 is selected from H, Br, Cl, CN, OMe, ethoxy, methyl and ethyl.
  • R A1 is selected from H, -OCF2H, Br and Cl.
  • R A1 is selected from H, Br and Cl.
  • R A1 is H or -OCF2H. In some embodiments R A1 is selected from the group consisting of H, OH, Br, Cl, CN, -OCF2H, OMe, ethoxy, methyl and ethyl. In some embodiments R A1 is selected from the group consisting of H, Br, Cl, CN, -OCF2H, OMe, ethoxy, methyl and ethyl. In some embodiments R A1 is selected from the group consisting of H, OH, -OCF2H, Br and Cl. In some embodiments R A1 is selected from the group consisting of H, -OCF2H, Br and Cl. In some embodiments R A1 is H.
  • R A1 is OH or H.
  • R A2 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C 1-6 hydrocarbon, optionally substituted by OH, CN, C 1-6 alkyl acyl, C 1-6 alkoxy or one or more halo groups; (v) C 1-6 alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups; (vi) C 1-6 acylamido (where acyl substituent is H or Me); (vii) C 1-6 thioalkyl, (viii) C 1-6 alkyl ester; (ix) C 1-6 alkyl acyl, (x) C 4-5 heterocyclyl; (xi) C 5 heteroaryl; (xii) C 1-6 alkyl amido optionally substituted by C 1-3 alkyl amido, CN, OH, C 2-3 alkynyl
  • R A2 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6 alkyl acyl, C1-6 alkoxy or one or more halo groups; (v) C1-6 alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups; (vi) C1-6 acylamido (where acyl substituent is H or Me); (vii) C1-6 thioalkyl, (viii) C1-6 alkyl ester; (ix) C1-6 alkyl acyl, (x) C4-5 heterocyclyl; (xi) C5 heteroaryl; (xii) C1-6 alkyl amido optionally substituted by C1-3 alkyl amido, CN, C2-3 alkynyl, C4-6 heterocyclyl, C1-3 alkyl which alkyl is optionally substituted with one or more halo
  • R A2 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6 acyl, C1-6 alkoxy or one or more halo groups; (v) OH; (vi) C 1-6 alkoxy, optionally substituted by OH, C 1-6 alkyl amido, or one or more halo groups; (vii) C 1-6 alkyl ester; (viii) C 1-6 alkyl acyl; (ix) C 1-6 alkyl amido optionally substituted by C 1-3 alkyl amido, CN, C 2-3 alkynyl, C 4-6 heterocyclyl, or C 1-3 alkyl which alkyl is optionally substituted with one or more halo or OH groups; and (x) C 1-6 alkylamino In further embodiments R A2 is selected from the group consisting of: (i) H; (ii)
  • R A2 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6 alkyl acyl, C1-6 alkoxy or one or more halo groups; (v) C1-6 alkoxy, optionally substituted by OH, C1-6 alkyl amido, or one or more halo groups; (vi) C1-6 thioalkyl; (viii) C1-6 alkyl ester; and (ix) C1-6 alkyl amido optionally substituted by C1-3 alkyl amido, CN, C2-3 alkynyl, C4-6 heterocyclyl, or C1-3 alkyl which alkyl is optionally substituted with one or more halo or OH groups.
  • R A2 is selected from the group consisting of: (i) H; (ii) halo; (iii) C1-6 alkyl ester; (iv) C 1-6 hydrocarbon; (v) C 1-6 alkyl amido optionally substituted by C 1-3 alkyl amido, C 2-3 alkynyl, C 4-6 heterocyclyl, or C 1-3 alkyl which alkyl is optionally substituted with one or more halo or OH groups; (vi) C 1-6 thioalkyl; (vii)C 1-6 alkyl acyl; (viii) C 5 heteroaryl; and (ix) C 1-6 alkylamino.
  • R A2 is selected from the group consisting of: (i) H; (ii) halo; (iii) C 1-3 alkyl, optionally substituted by OH, or one or more halo groups; (v) C 1-3 alkoxy, optionally substituted by OH, or one or more halo groups; and (vi) cyclopropyl.
  • R A2 is halo, in some embodiments it is Br or Cl. In further embodiments it is Cl.
  • R A2 is selected from CF 3 , CN, Cl, OMe, methyl, cyclopropyl, -OCHF 2 , - OCF 3 and optionally substituted C 1-6 alkylamido.
  • R A2 is selected from CN, Cl, OMe, methyl, cyclopropyl, -OCHF2, -OCF3 and optionally substituted C1-6 alkylamido.
  • R A2 is an optionally substituted C 1-6 hydrocarbon it is an optionally substituted C 1-6 alkyl. In some embodiments it is optionally substituted methyl, optionally substituted ethyl or optionally substituted cyclopropyl. In further embodiments, it is optionally substituted methyl. In further embodiments, it is unsubstituted methyl. In other embodiments it is unsubstituted cyclopropyl.
  • R A2 is optionally substituted C 1-6 alkyl
  • the optional substituents are selected from OH, CN, or one or more halo groups. In further embodiments the optional substituents are selected from OH, F and Br.
  • R A2 is optionally substituted C 1-6 alkoxy, in some embodiments it is optionally substituted OMe or ethoxy.
  • R A2 is optionally substituted C 1-6 alkoxy, in some embodiments the optional substituents are selected from alkyl amido and one or more halo groups. In another embodiment the optional substituents are selected from one or more F. In another embodiment where R A2 is optionally substituted C1-6 alkoxy it is difluoromethoxy (-OCHF2).
  • R A2 is C1-6 alkyl amido, in some embodiments the optional substituents are selected from one or more methyl groups, an oxetane ring, a C2 alkylamido and ethyl which ethyl is optionally substituted by OH or one or more halo groups.
  • R A2 is C1-6 alkyl amido, in some embodiments the optional substituent is OH.
  • R A2 is C1-6 alkylamino in some embodiments it is NHCH3, NHCH(CH3)2, N(CH2CH3)2, or N(CH3)2.
  • These groups are as shown in the table below:
  • R A2 is selected from the following groups: In some embodiments R A2 is selected from the following groups: In some embodiments R A2 is selected from the following groups: In some embodiments R A2 is selected from the following groups: In some embodiments R A2 is selected from the following groups: In some embodiments RA2 is selected from halo, C1-6 hydrocarbon and C1-6 alkoxy optionally substituted by one or more halo. In some embodiments RA2 is selected from chloro, bromo, C1-6alkyl and C1-6 alkoxy optionally substituted by one, two or three halo. In some embodiments R A2 is selected from H, chloro, methyl, OCF 2 H, CF 3 and cyclopropyl.
  • R A2 is selected from chloro, methyl, OCF 2 H, and CF 3 . In some embodiments, R A2 is selected from methyl, CF 3 and OCF 2 H. In some embodiments, R A2 is selected from OCF2H and methyl. In some embodiments R A2 is selected from chloro, methyl and OCF2H. In some embodiments R A2 is selected from chloro and OCF2H.
  • R A3 is halo, in some embodiments it is Br or Cl. In some embodiments it is Cl. In further embodiments R A3 is Br. Where R A3 is an optionally substituted C 1-6 hydrocarbon it is an optionally substituted C 1-6 alkyl. In some embodiments it is optionally substituted methyl or optionally substituted ethyl. In further embodiments, it is optionally substituted methyl. In further embodiments, it is unsubstituted methyl. When R A3 is optionally substituted C 1-6 alkyl, in some embodiments the optionally substituents are selected from OH, CN, and one or more halo groups. In further embodiments the optional substituents are selected from OH, F and Br.
  • R A3 is OH.
  • R A3 is optionally substituted C1-6 alkoxy, in some embodiments it is optionally substituted OMe or ethoxy. In further embodiments it is OMe.
  • R A3 is optionally substituted C1-6 alkoxy, in some embodiments the optional substituents are selected from alkyl amido or one or more halo groups. In another embodiment the optional substituents are selected from one or more F.
  • R A3 is selected from H, CF3, CN, C1-2 alkyl, NH2 and halo. In other embodiments R A3 is selected from H, methyl, CN and Cl.
  • R A3 is selected from H, OMe, CF3, CN, C1-2 alkyl, NH2 and halo. In some embodiments, R A3 is selected from the group consisting of H, methyl and OH. In some embodiments R A3 is CN. In some embodiments R A3 is H. In some embodiments R A3 is methyl. In some embodiments R A3 is OMe. In some embodiments R A3 is selected from methyl, H and CN. In some embodiments R A3 is selected from H, methyl and OH.
  • R A2 and R A3 When R A3 and R A2 together with the carbon atoms to which they are bound form an optionally substituted C 6 carboaromatic ring or C 5-7 heteroaromatic ring they form an optionally substituted benzene ring or an optionally substituted pyridine ring.
  • the optional substituents are selected from NH 2 , C 1-6 alkyl, C 1-6 alkoxy and halo. In other embodiments the optional substituents are selected from methyl, ethyl, OMe, NH 2 , F, Cl and Br.
  • the optional substituents are selected from methyl, NH 2 , Cl, F and OMe. In other embodiments the optional substituent is methyl. In one embodiment when R A2 and R A3 together with the carbon atoms to which they are bound form an optionally substituted C 5-7 heteroaromatic ring, they form an optionally substituted pyridine. In some embodiments the optional substituent is NH2. In another embodiment R A2 and R A3 together with the carbon atoms to which they are bound form an unsubstituted pyridine. In another embodiment R A2 and R A3 together form an optionally substituted pyrazole, an optionally substituted pyrrole or an optionally substituted thiazole. In some embodiments the optional substituent is methyl.
  • R A3 and R A2 together with the carbon atoms to which they are bound form an optionally substituted C5-7 heteroaromatic ring the optional substituents are selected from C1-6 alkyl, C1-6 alkoxy, NH2 and halo. In other embodiments the optional substituents are selected from methyl, ethyl, OMe, ethoxy, NH2 and halo. In other embodiments the optional substituents are selected from NH2 and methyl.
  • R A3 and R A2 together with the carbon atoms to which they are bound form an optionally substituted C5-7 heterocycle ring they form a 5 membered ring which comprises one or two atoms selected from N, O and S.
  • the 5 membered ring contains one N and one S. In other embodiments the 5 membered ring contains one N. In other embodiments the 5 membered ring contains one N and one O. In other embodiments the 5 membered ring contains two Ns.
  • R A3 and R A2 together with the carbon atoms to which they are bound form an optionally substituted pyrrole or pyrazole. When R A3 and R A2 together with the carbon atoms to which they are bound form an optionally substituted C 5-7 heterocycle ring, the optional substituents are selected from NH 2 , C 1-6 alkyl, C 1-6 alkoxy and halo.
  • the optional substituents are selected from methyl, ethyl, OMe, ethoxy, NH 2 , F, Cl and Br. In other embodiments the optional substituent is methyl.
  • R A2 and R A3 together with the carbon atoms to which they are bound form: (i) optionally substituted C 6 heteroaromatic ring; wherein the optional substituent is NH 2 ; (ii) optionally substituted C 6 carboaromatic ring; wherein the optional substituent is F, OMe, Cl; (iii) optionally substituted C 5 heteroaromatic or C 5 heterocycle ring wherein the optional substituent is methyl.
  • R A3 and R A2 together with the carbon atoms to which they are bound form an optionally substituted C 6 carboaromatic ring or C 5-7 heteroaromatic ring wherein the optional substituents are selected from C 1-6 alkyl, and halo.
  • R A2 and R A3 together form an unsubstituted 2-pyrazole, a 2-pyrrole substituted by methyl, pyridine optionally substituted by NH 2 , or a phenyl optionally substituted by Cl, F or OMe.
  • R A2 and R A3 together form a ring selected from: , In some embodiments, A is selected from one of the following formulae: In some embodiments, A is selected from one of the following formulae: , . In some embodiments, A1a is selected from one of the following formulae: In some embodiments A is selected from one of the following formulae: In some embodiments A is selected from one of the following formulae: In some embodiments A is selected from one of the following formulae: . In some embodiments A is selected from one of the following formulae: . In some embodiments A is selected from one of the following formulae: . In some embodiments A is selected from one of the following formulae: . (A2a) In some embodiments, A is (A2a). wherein the wavy line indicates the point of attachment to B.
  • Z 1 is selected from O or S. In some embodiments, Z 1 is O. In some embodiments, Z 1 is S.
  • R A5 R A5 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C 1 alkyl optionally substituted by one or more OH, CN, or one or more halo groups; and (v) C 1 alkoxy, optionally substituted by one or more halo groups; In some embodiments, R A5 is selected from H, halo, CN, or methyl optionally substituted by one or more OH groups or one or more halo groups. In some embodiments, R A5 is H.
  • R A6 R A6 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C 1-6 hydrocarbon, optionally substituted by OH, CN, C 1-6 alkyl acyl, C 1-6 alkoxy or one or more halo groups; (v) C1-6 alkoxy, optionally substituted by C1-6 alkyl amido, C1-6 alkyl phosphonyl, or one or more halo groups; (vi) C1-6 alkylamino; (vii) C1-6 thioalkyl; (viii) C1-6 alkyl phosphinyl; and (ix) C1-6 alkyl phosphonyl; In some embodiments R A6 is selected from the group consisting of: (i) H; (ii) halo; (iii) C1-6 alkyl, optionally substituted by one or more OH or one or more halo groups; (iv) C1-6 alkoxy, optionally substituted by one or
  • R A6 is selected from the group consisting of: (i) H; (ii) halo; (iii) C 1-3 alkyl, optionally substituted by one or more OH or one or more halo groups; and (iv) C 1-3 alkoxy, optionally substituted by one or more halo groups. In some embodiments, R A6 is H.
  • A is selected from one of the following formulae: , wherein the wavy line indicates the point of attachment to B and wherein R A5 , R A6 and R A7 are as defined in any other embodiment herein. In some embodiments, A is selected from one of the following formulae: , wherein the wavy line indicates the point of attachment to B. In some embodiments, A is of the formula A2a7: In some embodiments, A is selected from one of formula A2a1, A2a3, and A2a5. In some embodiments, A2a is formula A2a5. (A2b) In some embodiments, A is A2b: Z 6 In some embodiments Z 6 is N. In some embodiments Z 6 is CH.
  • Z 7 In some embodiments Z 7 is N. In some embodiments Z 7 is C-R A8 . Z 6 and Z 7 In some embodiments, Z 6 is C-H, and Z 7 is C-R A8 . In some of these embodiments, R A8 is H. In some embodiments, Z 6 is N and Z 7 is C-H.
  • Z 8 and Z 9 are independently selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6 alkyl acyl, C1-6 alkoxy or one or more halo groups; (v) C1-6 alkoxy, optionally substituted by C1-6 alkyl amido, C1-6 alkyl phosphonyl, or one or more halo groups; (vi) C1-6 alkylamino (vii) C1-6 thioalkyl, (viii) C1-6 alkyl phosphinyl; and (ix) C1-6 alkyl phosphonyl.
  • Z 8 and Z 9 are independently selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6 alkyl acyl, C1-6 alkoxy or one or more halo groups; (v) C1-6 alkoxy, optionally substituted by C1-6 alkyl amido, or one or more halo groups; (vi) C1-6 alkylamino; (vii) C1-6 thioalkyl, and (viii) C1-6 alkyl phosphinyl.
  • Z 8 and Z 9 are independently selected from: (i) H; (ii) halo; (iii) C 1-6 alkyl, optionally substituted by one or more OH or one or more halo groups; (iv) C 1-6 alkoxy, optionally substituted by one or more halo groups; (v) C 3-5 cycloalkyl; (vi) C 1-6 thioalkyl; and (vii) C 1-6 alkyl phosphinyl.
  • Z 8 and Z 9 are H.
  • Z 6 and Z 7 are C-H
  • Z 8 and Z 9 are H. In some embodiments when one or both of Z 8 and Z 9 are halo it is F, Cl or Br.
  • Z 8 and Z 9 when one or both of Z 8 and Z 9 are optionally substituted C 1-6 alkyl it is a methyl, ethyl, propyl, CH 2 OH, CH 2 F, CHF 2 , CF 3 . In further embodiments it is methyl, ethyl, CH 2 OH or CF 3. In some embodiments when one or both of Z 8 and Z 9 are an optionally substituted C 1-6 alkoxy it is OMe, O-ethyl, O-propyl, OCF2H, OCF3, OCFH2. In further embodiments it is OMe, OCF3, OCF2H.
  • R A8 is selected from: (i) H; (ii) halo (iii) CN; (iv) C 1-6 alkyl optionally substituted by OH, or one or more halo groups; (v) C 2-6 alkenyl optionally substituted by OH, or one or more halo groups; (vi) C 2-6 alkynyl optionally substituted by OH, or one or more halo groups; and (vii) C 1-6 alkoxy, optionally substituted by one or more halo groups.
  • R A8 is H.
  • R A8 is CN.
  • R A8 when R A8 is halo it is selected from Cl, Br and F.
  • R A8 when R A8 is an optionally substituted C 1-6 alkyl it is methyl, ethyl, propyl, CF3, CF2H, CH2-CF2H or CH2-cyclopropyl. In further embodiments it is CF3, CH2-CF2H, CF2H or CH 2 -cyclopropyl.
  • R A8 when R A8 is C2-6 alkynyl it is propargyl, acetylene or 1-butyne. In some embodiments it is propargyl.
  • R A8 when R A8 is optionally substituted C1-6 alkoxy it is OCF3, OCF2H or OMe.
  • R A8 is selected from H, Cl, Br and OMe.
  • A is selected from one of the following formulae: , , wherein the wavy line indicates the point of attachment to B and wherein Z 7 , Z 8 , and Z 9 are as defined in any other embodiment herein.
  • A is selected from one of the following formulae: , wherein the wavy line indicates the point of attachment to B, and Z 6 is as defined in any other embodiment herein.
  • A is formula A2b7.
  • A is selected from one of the following formulae: (A3a) and (A3b)
  • A is (A3a) or (A3b):
  • A is (A3a).
  • A is (A3b).
  • R A9 In some embodiments, R A9 is selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, 1- methylcyclopropyl and 2-methylcyclopropyl.
  • R A9 is selected from methyl, cyclopropyl, 1-methylcyclopropyl and 2- methylcyclopropyl. In some embodiments, R A9 is selected from methyl and 1-methylcyclopropyl. In some embodiments, R A9 is methyl.
  • A is: R A4 R A4 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6 alkyl acyl, C1-6 alkoxy or one or more halo groups; (v) C1-6 alkoxy, optionally substituted by OH, C1-6 alkyl amido, or one or more halo groups; (vi) C1-6 acylamido (wherein the acyl is optionally substituted by H or methyl); (vii) C1-6 thioalkyl; (viii) C 1-6 alkyl ester; (ix) C 1-6 alkyl acyl; (x) C 4-5 heterocyclyl; (xi) C 5 heteroaryl; (xii) C 1-6 alkyl amido, optionally substituted by C 1-3 alkyl amido, CN, OH, C 2-3 alkynyl, C 4-6 heterocycl
  • R A4 is CN. In some embodiments R A4 is H. In some embodiments R A4 is -OCHF2. In some embodiments R A4 is cyclopropyl. In some embodiments R A4 is Cl. In some embodiments R A4 is methyl. In some embodiments, R A4 is selected from H, CN, -OCF2H, cyclopropyl, Cl, and methyl. In some embodiments, A is one of formulae (A1a), (A2b), (A3a), and (A3b). In some embodiments, A is of formulae (A1a) or (A2b). In some embodiments, A is selected from one of the following formulae: .
  • C-1a In some embodiments, C is (C-1a).
  • X is H.
  • X is F.
  • C is (C-1):
  • R N is H, methyl or benzyl optionally substituted with a C 1-3 alkoxy group.
  • R N is H, methyl or benzyl substituted with a C 1-3 alkoxy group.
  • R N is H, methyl or para-methoxybenzyl.
  • R N is H or methyl.
  • R N is H or benzyl optionally substituted with a C 1-3 alkoxy group.
  • R N is benzyl optionally substituted with a C1-3 alkoxy group.
  • R N is benzyl substituted with a C1-3 alkoxy group. In some embodiments, R N is para-methoxybenzyl. In some embodiments, R N is H. In some embodiments, R N is methyl. In some embodiments, R C1 and R C2 together with the carbon atoms to which they are bound form a benzene ring or a pyridine ring, which rings are optionally substituted by one or more R C3 groups. In some embodiments, R C1 and R C2 together with the carbon atoms to which they are bound form a benzene ring which is optionally substituted by one or more R C3 groups.
  • R C1 and R C2 together with the carbon atoms to which they are bound form a pyridine ring which is optionally substituted by one or more R C3 groups. In some embodiments, R C1 and R C2 together with the carbon atoms to which they are bound form an unsubstituted benzene ring or an unsubstituted pyridine ring. In some embodiments, R C1 and R C2 together with the carbon atoms to which they are bound form an unsubstituted benzene ring. In some embodiments, R C1 and R C2 together with the carbon atoms to which they are bound form an unsubstituted pyridine ring.
  • C is selected from one of the formulae listed in the following table: wherein the wavy line indicates the point of attachment to B, and X is hydrogen or fluorine. In some of these embodiments, X is H. In some of these embodiments, X is F. In some embodiments, C is selected from one of the following formulae: . wherein the wavy line indicates the point of attachment to B, R N is as defined in any other embodiment herein, and X is hydrogen or fluorine. In some of these embodiments, X is H. In some of these embodiments, X is F. In some embodiments, C is selected from one of the following formulae: wherein X is hydrogen or fluorine. In some of these embodiments, X is H.
  • X is F.
  • C is selected from one of the following formulae: A and C
  • A is:
  • X is hydrogen.
  • A is selected from: wherein the wavy line indicates the point of attachment to B, and wherein R A9 , R A1 , R A2 , Z 8 , Z 9 , X and R N are as defined in any other embodiment herein.
  • X is H.
  • X is F.
  • A is selected from: wherein the wavy line indicates the point of attachment to B.
  • A is selected from: wherein the wavy line indicates the point of attachment to B.
  • A-B-C (A1a)
  • the compound of formula A-B-C is of the formula (I-Ax): wherein R A1 , R A2 , X 1 , X, R C1 , R C2 and R N are as defined in any other embodiment herein.
  • R A1 is H, OH, CN, Br, Cl, optionally substituted -OMe, -O-ethyl, methyl or ethyl, where the optional substituents on the -OMe, O-ethyl, methyl or ethyl groups are selected from OH, CN, and one or more halo groups.
  • R A1 is H, CN, OH, Br, Cl, optionally substituted -OMe, -O-ethyl, methyl or ethyl, where the optional substituents on the - OMe, O-ethyl, methyl or ethyl groups are selected from OH, CN, and one or more halo groups.
  • R A1 is optionally substituted O-methyl wherein the optional substituents are one or more F groups.
  • R A1 is H.
  • R A1 is OH.
  • R A3 is selected from the group consisting of CN, Br, Cl, OH, H, CF3, C1-2 alkyl, C1-2 alkoxy and NH2.
  • R A3 is selected from H, methyl and CN.
  • R A3 and R A2 together with the carbon atoms to which they are bound form an optionally substituted C6 carboaromatic ring or C5-7 heteroaromatic ring the optional substituents are selected from NH2, C1-6 alkyl, C1-6 alkoxy and halo. In other embodiments the optional substituents are selected from NH2, methyl, ethyl, OMe, F, Cl and Br. In some embodiments R A3 and R A2 together with the carbon atoms to which they are bound form an optionally substituted pyridine, an optionally substituted benzene, a pyrrole or a pyrazole.
  • R A2 in formula (I-Cx) is selected from fluoro, chloro, bromo and iodo.
  • formula (I-Cx) can be any one of formulae (I-Cax) to (I-Cgx) as shown below: 7 5 A-B-C (A2a)
  • the compound of formula A-B-C is of the formula (IV-A): wherein Z 1 , R A5 , R A6 , R A7 , X, R C1 , R C2 , and R N are as defined in any other embodiment herein.
  • Z 1 is S.
  • Z 1 is O.
  • R A5 is selected from the group consisting of H, halo, CN, C1 alkyl optionally substituted by one or more OH, CN, or one or more halo groups, and C1 alkoxy, optionally substituted by one or more halo groups. In some embodiments, R A5 is selected from H, halo, CN, or methyl optionally substituted by one or more OH groups or one or more halo groups. In some embodiments, R A5 is H.
  • R A6 is selected from the group consisting of H, halo, CN, C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6 alkyl acyl, C1-6 alkoxy or one or more halo groups, C1-6 alkoxy, optionally substituted by C1-6 alkyl amido, C1-6 alkyl phosphonyl, or one or more halo groups, C1-6 alkylamino, C1-6 thioalkyl, C1-6 alkyl phosphinyl, and C1-6 alkyl phosphonyl.
  • R A6 is selected from the group consisting of H, halo, C1-3 alkyl, optionally substituted by one or more OH or one or more halo groups, and C1-3 alkoxy, optionally substituted by one or more halo groups. In some embodiments, R A6 is H.
  • R A7 is selected from H, Cl, Br and OMe.
  • R A7 is H.
  • formula (IV-A) can be any one of formulae (IV-Aa), (IV-Ab), (IV-Ac), (IV- Ad), (IV-Ae), or (IV-Af) as shown below: wherein R A5 , R A6 , R A7 , X, R C1 , R C2 , and R N are as defined in any other embodiment herein.
  • the compound of formula A-B-C is of the formula (IV-B): wherein Z 1 , R A5 , R A6 , X, Q 1 , Q 2 , Q 3 , Q 4 , and R N are as defined in any other embodiment herein.
  • formula (IV-B) can be any one of the formulae (IV-Ba), (IV-Bb), (IV-Bc), (IV-Bd), and (IV-Be) as shown below: A-B-C (A2b)
  • the compound of formula A-B-C is of the formula (II-Ax): wherein Z 6 , Z 7 , Z 8 , Z 9 , X, R C1 , R C2 and R N are as defined in any other embodiment herein.
  • Z 8 and Z 9 are independently selected from the group consisting of H, one or more halo groups, CN, C 1-6 hydrocarbon, optionally substituted by OH, CN, C 1-6 alkyl acyl, C 1-6 alkoxy or one or more halo groups, C 1-6 alkoxy, optionally substituted by C 1-6 alkyl amido, or one or more halo groups, C 1-6 alkylamino, C 1-6 thioalkyl, and C 1-6 alkyl phosphinyl.
  • R A8 is selected from H, halo, CN, C 1-6 alkyl optionally substituted by OH or one or more halo groups, C 2-6 alkenyl optionally substituted by OH or one or more halo groups, C 2-6 alkynyl optionally substituted by OH or one or more halo groups, and C 1-6 alkoxy, optionally substituted by one or more halo groups.
  • R A8 is selected from H, Cl, Br and OMe.
  • formula (II-Ax) can be any one of formulae (II-Aax), (II-Abx), (II-Acx) and (II-Adx) as shown below: wherein Z 7 , Z 8 , Z 9 , X, R C1 , R C2 , and R N are as defined in any other embodiment herein.
  • the compound of formula A-B-C is of the formula (II-Bx): wherein Z 6 , X, R C1 , R C2 , and R N are as defined in any other embodiment herein.
  • formula (II-Bx) can be any one of formulae (II-Bax) and (II-Bbx) shown below: wherein X, R C1 , R C2 , and R N are as defined in any other embodiment herein.
  • the compound of formula A-B-C is of the formula (II-Cx): wherein Z 6 , Z 7 , Z 8 , Z 9 , X and R N are as defined in any other embodiment herein, and Q1, Q2, Q3 and Q4 are either all C-H or one of Q1, Q2, Q3 and Q4 is selected from N, C-CN and C-PO(Me)2 and the remaining three are C-H.
  • Z 8 and/or Z 9 in formula (II-Cx) is selected from fluoro, chloro, bromo or iodo.
  • formula (II-Cx) can be any one of formulae (II-Cax) to (II-Cgx) as shown below: wherein Z 6 , Z 7 , Z 8 , Z 9 , X, and R N are as defined in any other embodiment herein.
  • A-B-C (A3a) and (A3b) In other embodiments the compound of formula A-B-C is of the formula (III-Ax): (III-Ax), wherein R A9 , X, R C1 , R C2 and R N are as defined in any other embodiment herein.
  • the compound of formula A-B-C is of the formula (III-Bx): wherein X, R C1 , R C2 and R N are as defined in any other embodiment herein.
  • R A9 in formula (III-Cx) is selected from fluoro, chloro, bromo and iodo.
  • formula (III-Cx) can be any one of formulae (III-Cax) to (III-Cgx) as shown below: wherein R A9 , X, and R N are as defined in any other embodiment herein.
  • the compound of formula (I) is selected from the following in Table 1.
  • the compound is a pharmaceutically acceptable salt of a compound selected from the following in Table 1.
  • Table 1. Examples 1 to 19 Example No Structure Example Name 1-(6-(((1S,3S)-3-(Oxazolo[5,4-b]pyridin- 2-ylamino)cyclopentyl)amino)pyridin-3- 1 yl)-1,3-dihydro-2H-benzo[d]imidazol-2- one 1-(6-(((1S,3S)-3-(Thiazolo[5,4-b]pyridin- 2-ylamino)cyclopentyl)amino)pyridin-3- 2 yl)-1,3-dihydro-2H-benzo[d]imidazol-2- one 1-(6-(((1S,3S)-3-((5- (Difluoromethoxy)pyrimidin-2- 3 yl)amin
  • the compound is a pharmaceutically acceptable salt of a compound selected from Examples 1, 2, 3, 5, 8, 10 and 12. In some embodiments the compound is selected from Examples 3, 8, 10 and 12. In some embodiments, the compound is a pharmaceutically acceptable salt of a compound selected from Examples 3, 8, 10 and 12. In some embodiments the compound is selected from Examples 3, and 12. In some embodiments, the compound is a pharmaceutically acceptable salt of a compound selected from Examples 3, and 12. In some embodiments the compound is selected from Examples 12, 16, 23, 28, 30, and 32. In some embodiments, the compound is a pharmaceutically acceptable salt of a compound selected from Examples 12, 16, 23, 28, 30, and 32. In some embodiments the compound is selected from Examples 12 and 16. In some embodiments the compound is a pharmaceutically acceptable salt of a compound selected from Examples 12 and 16.
  • the compound is a pharmaceutically acceptable salt of a compound selected from Examples 3 to 8, 10 to 19, and 23 to 27. Any definitions herein relating to formula (A1a) and its substituents may be understood as being equally applicable to formula (A1), and vice versa.
  • a compound of formula (I) A-B-C (I) or a pharmaceutically acceptable salt and tautomeric forms or stereoisomers thereof wherein A is of one of the following formulae: wherein the wavy line indicates the point of attachment to B;
  • R A1 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C 1-6 hydrocarbon, optionally substituted by one or more OH, CN, C 1-6 alkyl acyl, C 1-6 alkoxy or one or more halo groups; (v) C 1-6 alkoxy, optionally substituted by OH, one or more halo groups, C 1-6 alkyl amido; (vi) C 1-6 alkyl ester; (vii) C 1-6 alkyl acyl; and (viii) OH;
  • R A2 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (i
  • the compound of formula (I) is not according to one or more of the specific compounds described in WO 2024078620 A1. In some embodiments, the compound of formula (I) is not according to one or more of the specific compounds described in WO 2025021188 A1. In some embodiments, the compound of formula (I) is not according to one or more of the specific compounds described in WO 2025007915 A1.
  • General synthesis The compounds according to general formula (I-G), (G9) and (G17) can be prepared according to the following schemes 1, 2, 3, 4, 5 and 6. The schemes and procedures described below illustrate synthetic routes to the compounds of general formula (I-G), (G9) and (G17) and are not intended to be limiting.
  • Monoarylated diamines of general formula (G3) can be obtained via nucleophilic aromatic substitution (S N Ar) or palladium catalyzed Buchwald-Hartwig amination between monoprotected diamines (G1) or their corresponding salts and heteroaryls (G2a) with X being a leaving group like halogen or -S(O)Me as depicted in Scheme 1.
  • diamines (G1) may be reacted with (G2a) in the presence of inorganic bases like K 2 CO 3 or Na 2 CO 3 or in the presence of organic bases like triethylamine or DIPEA or without any additional base in polar solvents such as for example DMSO, NMP or nBuOH at temperatures between 100-130 °C.
  • the reaction times may vary between 1 hour and 24 hours.
  • diamines (G1) may be reacted with (G2a) in the presence of a palladium catalyst like Pd PEPPSI-IpentCl [CAS Reg. No.1612891-29-8], Pd2(dba)3 or tBuXPhos Pd G3 [1447963-75-8] and a base like Cs2CO3 or NaOtBu in aprotic solvents like 1,4- dioxane, DMF, toluene or DMA at temperatures between room temperature and 130 °C, preferably at 65-100 °C, for 15-24 h.
  • a palladium catalyst like Pd PEPPSI-IpentCl [CAS Reg. No.1612891-29-8]
  • Pd2(dba)3 or tBuXPhos Pd G3 [1447963-75-8]
  • a base like Cs2CO3 or NaOtBu
  • aprotic solvents like 1,4- dioxane, DMF, toluen
  • Diamines of general formula (G1) and heteroaryls of general formula (G2a) are either commercially available or can be prepared according to procedures available from the public domain.
  • Arylated diamines of general formula (G6) can be obtained from (G3) via copper catalyzed Ullmann couplings with heterocycles (G4) or via palladium catalyzed Suzuki couplings with boronic acid derivatives (G5).
  • Ullmann couplings all methods that are known in the art may be applied.
  • (G3) may be reacted with (G4) in the presence of a copper catalyst like Cu(I)I, Cu(Otf) 2 or Cu(Oac) 2 and a base like Cs 2 CO 3 or K 2 CO 3 in polar, aprotic solvents like 1,4-dioxane, DMF or pyridine at temperatures between room temperature and 120 °C, preferably at 100 °C for 15-20 h.
  • a ligand like N 1 ,N 2 -dimethylcyclohexane- 1,2-diamine, TMEDA, N 1 ,N 2 -dimethylethane-1,2-diamine or N,N-dimethylglycine might be added to the reaction mixture.
  • (G3) may be reacted with boronic acid derivatives (G5) in the presence of a palladium catalyst like 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride [CAS Reg. No.95408- 45-0] or 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride [CAS Reg.
  • Heterocycles of general formula (G4) and boronic acid derivatives of general formula (G5) are either commercially available or can be prepared according to procedures available from the public domain.
  • Primary amines of general formula (G7) can be obtained from monoprotected diamines of general formula (G6) via deprotection methods. Depending on the protective group applied these can be for example acidic, basic, oxidative or hydrogenation methods.
  • Heteroaryls of general formula (G8) are either commercially available or can be prepared according to procedures available from the public domain.
  • An analogous general scheme involves oxadiazoles of general formula (G8a) and its isomers.
  • An alternative route to compounds of general formula (I-G) starts with deprotection of diamines of general formula (G3) to give primary amines of general formula (G9) as depicted in Scheme 1.
  • deprotection the same procedures apply as described for the synthesis of (G7) from (G6).
  • Monoarylated diamines of general formula (G12) can be obtained via nucleophilic aromatic substitution (SNAr) or palladium catalyzed Buchwald-Hartwig amination between monoprotected diamines (G1) or their corresponding salts and heteroaryls (G8) with X being a leaving group such as halogen or -S(O)Me.
  • SNAr nucleophilic aromatic substitution
  • G8a palladium catalyzed Buchwald-Hartwig amination between monoprotected diamines (G1) or their corresponding salts and heteroaryls
  • X being a leaving group such as halogen or -S(O)Me.
  • An analogous general scheme involves oxadiazoles of general formula (G8a) and its isomers. Deprotection of diamines of general formula (G12) can give primary amines of general formula (G13).
  • diamines (G1) may be reacted with (G2) in the presence of inorganic bases like K 2 CO 3 , Na 2 CO 3 or Cs 2 CO 3 or in the presence of organic bases like TEA or DIPEA, or without any additional base in polar solvents such as for example DMSO, NMP, nBuOH or 1,4-dioxane at temperatures between 100-130 °C.
  • the reaction times may vary between 1 h and 24 h.
  • diamines (G1) may be reacted with (G2) in the presence of a palladium catalyst like Pd PEPPSI-IpentCl [CAS Reg. No.1612891-29-8], Pd 2 (dba) 3 , tBuXPhos Pd G3 [1447963-75-8] or tBuBrettPhos G3 and a base like Cs 2 CO 3 , NaOtBu or MTBD in aprotic solvents like 1,4-dioxane, DMF, toluene, NMP or DMA at temperatures between room temperature and 130 °C, preferably at 65-100 °C, for 15-24 h.
  • a palladium catalyst like Pd PEPPSI-IpentCl [CAS Reg. No.1612891-29-8]
  • Pd 2 (dba) 3 Pd 2 (dba) 3
  • tBuXPhos Pd G3 [1447963-75-8]
  • Diamines of general formula (G1) and heteroaryls of general formula (G2) are either commercially available or can be prepared according to procedures available from the public domain.
  • Arylated diamines of general formula (G6) can be obtained from (G3) via copper catalyzed Ullmann couplings with heterocycles (G4) or via palladium catalyzed Suzuki couplings with boronic acid derivatives (G5).
  • Ullmann couplings all methods that are known in the art may be applied.
  • (G3) may be reacted with (G4) in the presence of a copper catalyst like Cu(I)I, Cu(OTf)2 or Cu(Oac)2 and a base like Cs2CO3 or K2CO3 in polar, aprotic solvents like 1,4-dioxane, DMF or pyridine at temperatures between room temperature and 120 °C, preferably at 100 °C for 15-20 h.
  • a ligand like DMCDA, TMEDA, N 1 ,N 2 - dimethylethane-1,2-diamine or N,N-dimethylglycine might be added to the reaction mixture.
  • Suzuki couplings towards (G6) all methods that are known in the art may be applied.
  • Primary amines of general formula (G7) can be obtained from monoprotected diamines of general formula (G6) via deprotection methods. Depending on the protective group applied these can be for example acidic, basic, oxidative or hydrogenation methods. Appropriate protective moieties for amino groups and their introduction and cleavage are well-known in the art. For an overview of protective group chemistry see for example P.G.M. Wuts, T.W. Greene, Greene’s Protective Groups in Organic Synthesis 4 th ed., J. Wiley & Sons, 2006. Final compounds of general formula (G9) can be synthesized from primary amines of general formula (G7) via S N Ar or palladium catalyzed Buchwald-Hartwig amination.
  • Primary amines of general formula (G7) can be reacted with heteroaryls of general formula (G8) with LG being a leaving group like halogen, such as chlorine or bromine, or -S(O) 2 Me applying procedures in analogy to those described for the synthesis of (G3) from (G1) and (G2) in Scheme 3.
  • Heteroaryls of general formula (G8) are either commercially available or can be prepared according to procedures available from the public domain.
  • An alternative route to compounds of general formula (G9) starts with deprotection of diamines of general formula (G3) to give primary amines of general formula (G10) as depicted in Scheme 3. For deprotection the same procedures apply as described for the synthesis of (G7) from (G6).
  • Final compounds of general formula (G9) can be synthesized from aryl iodides of general formula (G11) via copper catalyzed Ullmann couplings with heterocycles H-D (G4) or via palladium catalyzed Suzuki couplings with boronic acid derivatives (G5) applying procedures in analogy to those described for the synthesis of compounds (G6) from (G3) in Scheme 3.
  • Yet another approach to compounds of general formula (G9) starts from monoprotected diamines (G1) or their corresponding salts and preassembled heteroaryls (G12) with LG being a leaving group like halogen, e.g.
  • Scheme 4 Routes for the preparation of compounds of general formula (G9) and intermediates (G11) are described in the scheme in which LG is a leaving group, PG is a protective group, and Z 6 , Z 7 , Z 8 and Z 9 have the meaning as given for general formula (A2b), supra. D is defined above.
  • Monoarylated diamines of general formula (G13) can be obtained via S N Ar or palladium catalyzed Buchwald-Hartwig amination between monoprotected diamines (G1) or their corresponding salts and heteroaryls (G8) with LG being a leaving group like halogen, such as chlorine or bromine, or -S(O) 2 Me.
  • Primary amines of general formula (G7) or their corresponding salts can be reacted with one carbon equivalents like CDI or TCDI in the presence of inorganic bases like sodium hydroxide or in the presence of organic bases like TEA or DIPEA, or without any additional base in polar, aprotic solvents like DMF at temperatures between rt and the boiling point of the solvent, preferably at 100 °C for 1-2 h to give an acylimidazole intermediate.
  • This intermediate may be reacted in situ with 1,2-dianilines (G15) in the presence of a carbodiimide reagent like EDC at temperatures between rt and the boiling point of the solvent, preferably at 100 °C for 15-24 h to give (G17).
  • Scheme 5 Scheme 5: Routes for the preparation of compounds of general formula (G17) in which Z 6 , Z 7 , Z 8 and Z 9 have the meaning as given for general formula (A2b), supra. D is defined above.
  • protected intermediates of general formula (G16) prepared according to the routes depicted in Schemes 3 or 4, may be deprotected to give compounds of general formula (G17). Depending on the protective group applied these can be for example acidic, basic, oxidative or hydrogenation methods.
  • Suitable protective groups may be groups such as para- methoxybenzyl (PMB), 4-methylbenzenesulfonyl (Ts) or benzyl (Bn).
  • PMB para- methoxybenzyl
  • Ts 4-methylbenzenesulfonyl
  • Bn benzyl
  • Deprotection of a PMB group for example could be achieved by reaction with acids such as TFA in solvents like DCM, or without any additional solvent, at temperatures between rt and the boiling point of the solvent, preferably at 60-100 °C for 15 min to 18 h.
  • Deprotection of a Ts group may be performed by reaction with a base such as K 2 CO 3 or Na 2 CO 3 in polar, protic solvent such as MeOH or EtOH at temperatures between rt and the boiling point of the solvent, preferably at 60 °C for 1-4 h.
  • Aryl bromides of general formula (G18), prepared according to the procedures depicted in Schemes 3-5, can be functionalized under metal or metallaphotoredox catalysis (see for exampleChan 2022), e.g. via late-stage functionalisation, with nucleophiles of general formula (G19) (see for example Ley and Thomas 2003) or boronic acid derivatives (G20) (see for example Miyaura and Suzuki 1995) or stannanes (G21) (see for exampleCordovilla 2015) to give final compounds of general formula (G9).
  • metal or metallaphotoredox catalysis all methods that are known in the art may be applied.
  • Nucleophiles of general formula (G19) and boronic acid derivatives of general formula (G20) and stannanes (G21) are either commercially available or can be prepared according to procedures available from the public domain.
  • Stereo centers may also be introduced by asymmetric synthesis. All stereoisomers are included within the scope of the disclosure. Persons skilled in the art will appreciate that starting materials for any of the above processes can in some cases be commercially available. Persons skilled in the art will appreciate that processes for some starting materials above could be found in the general common knowledge. It will also be understood that some of the compounds described in the processes above may exhibit the phenomenon of tautomerism and the processes described above include any tautomeric form. All novel intermediates form a further aspect of the disclosure. EXPERIMENTAL SECTION NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. The following table lists the abbreviations used in this paragraph and in the examples section as far as they are not explained within the text body.
  • PrepMethod G The compound was purified by preparative HPLC on a Waters Xselect CSH Prep Fluoro-phenyl OBD column (5 ⁇ m, 150 ⁇ 30 mm ID) using a gradient of MeCN in H 2 O/FA (0.1%) buffer system as mobile phase.
  • PrepMethod H The compound was purified by preparative HPLC on a XBridge C18 OBD column (3.5 ⁇ m, 75 ⁇ 30 mm ID) using a gradient of MeCN in a H 2 O/NH 4 HCO 3 (10 mM)/NH 3 (0.05%, aq) buffer system as mobile phase.
  • PrepMethod I The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRs column (5 ⁇ m, 150 ⁇ 30 mm ID) using a gradient of MeCN in H 2 O/NH 4 HCO 3 (10 mM)/NH 3 (0.05%, aq) buffer system as mobile phase.
  • PrepMethod J The compound was purified by preparative HPLC on a XBridgeTM C18 OBD column (5 ⁇ m, 150 ⁇ 30 mm ID) using a gradient of MeCN in a H 2 O/NH 4 HCO 3 (10 mM)/NH 3 (0.05%, aq) buffer system as mobile phase.
  • PrepMethod K The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 ⁇ m, 250 ⁇ 19 mm ID) using a gradient of MeCN in a H 2 O/NH 4 HCO 3 (10 mM)/NH 3 (0.05%, aq) buffer system as mobile phase; Relevant fractions were collected, combined, and freeze-dried or evaporated to give the purified compound or relevant fractions were collected, combined, and concentrated at reduced pressure, the aqueous layer was extracted with DCM or EtOAc, and the organic layer was dried, either over Na2SO4 or by using a phase-separator, and then concentrated at reduced pressure and when needed dried in vacuo, to give the purified compound.
  • (xi) yields, where present, are not necessarily the maximum attainable, and when necessary, reactions were repeated if a larger amount of the reaction product was required; (xii) where certain compounds were obtained as an acid-addition salt, for example a mono-hydrochloride salt or a di-hydrochloride salt, the stoichiometry of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the salt was generally not determined, for example by means of elemental analysis data; where stated the salts were treated according to literature-known processes to generate the corresponding free base prior to being used; (xiii) in general, the structures of the end-products of the Formula (I) were confirmed by NMR and/or mass spectral techniques; proton NMR chemical shift values were measured on the delta scale using Bruker Avance III 300, 400, 500 and 600 spectrometers, operating at 1 H frequencies of 300, 400, 500 and 600 MHz, respectively.
  • compounds of Formula (I) appear as tautomers in the NMR-spectrum, in which instances only peaks of the major tautomer are reported. In some cases, compounds of Formula (I) appear as tautomers in a more equal relationship, in such instances the peaks of such tautomers are either reported as multiplets, if the signals of said tautomer are partially overlapping with other peaks, or as individual peaks, if the signals of said tautomers are well separated. The integral of such peaks are reported as fractions of protons, indicating the ratio of the tautomer in the mixture.
  • Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar equipment, acquiring both positive and negative ion data, and generally, only ions relating to the parent structure are reported; high resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or similar equipment, coupled to a Waters Acquity UPLC, acquiring either positive and negative ion data, and generally, only ions relating to the parent structure are reported; (xv) intermediates were not necessarily fully purified but their structures and purity were assessed by TLC, analytical HPLC/UPLC, and/or NMR analysis and/or mass spectrometry; (xvi) in general Examples and intermediate compounds are named using ChemDraw Professional version 20.1.1.125 or version 21.0.0 from PerkinElmer.
  • ChemDraw Professional version 20.1.1.125 or version 21.0.0 generates the names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules as closely as possible when generating chemical names. Stereoisomers are differentiated from each other by stereodescriptors cited in names and assigned in accordance with the CIP rules.
  • No.67579-81-1) (0.388 g, 2.73 mmol) was added to tert-butyl ((1S,3S)-3- ((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (1.10 g, 2.73 mmol), 1,3- dihydro-2H-benzo[d]imidazol-2-one (CAS Reg. No.615-16-7) (0.549 g, 4.09 mmol),Cs2CO3 (2.67 g, 8.18 mmol) and CuI (0.519 g, 2.73 mmol) in 1,4-dioxane (15 mL) at rt.
  • Zinc powder (7.83 g, 120 mmol) was added to N-(6-chloropyridin-3-yl)-3-nitropyridin-2-amine intermediate 4 (5 g, 20 mmol) and NH4Cl (10.7 g, 200 mmol) in a mixture of EtOH (50 mL) and EtOAc (50 mL) at 20 °C and the mixture stirred at 60 °C for 15 h.
  • No.32315-10-9) (1.936 g, 6.53 mmol) was added in portions to N 3 -(6-chloropyridin-3-yl)pyridine-2,3-diamine intermediate 12 (1.2 g, 5.44 mmol), Et3N (7.6 mL, 54 mmol) and DMAP (0.332 g, 2.72 mmol) in THF (100 mL) at 0 °C. The solution was stirred at 60 °C for 15 h. The reaction was poured into sat NaHCO3 (250 mL) and extracted with EtOAc (3 x 200 mL). The organic layer was dried over Na2SO4, filtered and evaporated.
  • No.171197-80-1 (203 mg, 0.91 mmol) was added to a mixture of the 2HCl salt of (1S,3S)-N 1 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine intermediate 21 (220 mg, 0.83 mmol) and Na2CO3 (263 mg, 2.48 mmol) in DMSO (15 mL). The resulting mixture was stirred at 100 °C for 15 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the obtained material was taken up with EtOAc (300 mL).
  • Example 5 1-(6-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,3- dihydro-2H-benzo[d]imidazol-2-one – compound 5 (1S,3S)-N 1 -(5-Iodopyridin-2-yl)-N 3 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine intermediate 22 (57 mg, 0.14 mmol), 1,3-dihydro-2H-benzo[d]imidazol-2-one (23.2 mg, 0.17 mmol), CuI (27 mg, 0.14 mmol), K2CO3 (60 mg, 0.43 mmol), 1,4-dioxane (1 mL) and DMCDA (0.023 mL, 0.14 mmol) was mixed in a vial
  • Example 8 1-(6-(((1S,3S)-3-([1,2,4]Triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)pyridin-3-yl)- 1,3-dihydro-2H-benzo[d]imidazol-2-one – compound 8 (1S,3S)-N 1 -([1,2,4]Triazolo[1,5-a]pyridin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine intermediate 25 (66 mg, 0.16 mmol), 1,3-dihydro-2H-benzo[d]imidazol-2-one (26 mg, 0.19 mmol), CuI (30 mg, 0.16 mmol), K2CO3 (66 mg, 0.48 mmol), dioxane (1 mL) and DMCDA (0.025 mL, 0.16 mmol) was mixed in
  • the vial was capped, evacuated, and filled with N2 (g) (x 2). The mixture was stirred at 100 °C for 20 h under a N2 (g) atmosphere. The reaction was cooled to rt and EtOAc was added. The mixture was filtered through Celite, the plug washed with EtOAc and MeOH and the combined filtrates were concentrated under reduced pressure. The crude material was purified by preparative HPLC (PrepMethod C, gradient: 20- 60%) and the solid obtained after lyophilization was re-dissolved in a mixture of EtOAc/MeOH (1:2).
  • Example 21 1-(4-Methoxybenzyl)-3-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclo- pentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one – compound 21 Pd-PEPPSI-lpentCl 2-methylpyridine (19 mg, 0.02 mmol) was added to a mixture of (1S,3S)-N 1 - (6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine intermediate 21 as 2TsOH salt (748 mg, 1.39 mmol), 3-(6-chloropyridin-3-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin- 2-one intermediate 7 (170 mg, 0.46 mmol)
  • Example 24 1-(6-(((1S,3S)-3-((5-(Trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one – compound 24 Pd-PEPPSI-lpentCl 2-methylpyridine (58 mg, 0.07 mmol) was added to a mixture of 1-(6- chloropyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 13 (170 mg, 0.69 mmol), (1S,3S)-N 1 -(5-(trifluoromethyl)pyrimidin-2-yl)cyclopentane-1,3-diamine intermediate 28 as 2TFA salt (392 mg, 0.83 mmol) and Cs 2 CO 3 (674 mg, 2.07 mmol) in 1,4- dioxan
  • Example 26 1-(6-(((1S,3S)-3-([1,2,4]Triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)pyridin-3-yl)- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one – compound 26 Pd-PEPPSI-lpentCl 2-methylpyridine (26 mg, 0.03 mmol) was added to a mixture of 1-(6- chloropyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 13 (150 mg, 0.61 mmol), (1S,3S)-N 1 -([1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine intermediate 24 as 3HCl salt (238 mg, 0.73 mmol) and Cs2CO3 (1.19 g, 3.65
  • Example 27 1-(6-(((1S,3S)-3-((5-(Difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3- yl)-N,N-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxamide – compound 27 Ethyl 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)- 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate intermediate 48 (230 mg, 0.44 mmol) was added to solution of dimethylamine in MeOH (30%, 20 mL) at 20 °C and the mixture sealed in a microwave tube.
  • Example 28 1-(5-Fluoro-6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one – compound 28 Pd-PEPPSI-lpentCl 2-methylpyridine (24 mg, 0.03 mmol) was added to a mixture of (1S,3S)-N 1 - (6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine intermediate 21 as 3TsOH salt (485 mg, 0.68 mmol), 1-(6-chloro-5-fluoropyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one intermediate 29 (150 mg, 0.57 mmol) and Cs2CO3 (927 mg, 2.84 mmol)
  • Example 32 1-(6-(((1S,3S)-3-((5-(Difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3- yl)-5-methyl-3,5-dihydro-1H-imidazo[4,5-c]pyridine-2,4-dione – compound 32 Pd-PEPPSI-lpentCl 2-methylpyridine (91 mg, 0.11 mmol) was added to a mixture of (1S,3S)-N 1 - (5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine intermediate 31 as 3HCl salt (256 mg, 0.72 mmol), 1-(6-chloropyridin-3-yl)-5-methyl-3,5-dihydro-1H-imidazo[4,5-c]pyridine- 2,4-dione intermediate 41 (100 mg, 0.36 mmol) and Cs2CO3 (5
  • Assay 1 - Biochemical human PCSK9 assay This assay measures binding of compounds to PCSK9 by homogenous time-resolved fluorescence resonance energy transfer (TR-FRET). To determine the IC 50 of inhibitors of the interaction between the human PCSK9 and Alexa647 labelled small molecule, fluorescent probe displacement was monitored by homogenous TR- FRET technology.
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • Tb terbium
  • mAb Anti-6His Tb cryptate Gold Cisbio
  • Recombinantly expressed and purified PCSK9-TEV-His6 (1 nM) was mixed with a fluorescent probe (5 nM) and anti His-Tb-cryptate antibody (0.2 nM) in assay buffer (10 mM HEPES/NaOH, pH 7.4, 150 mM NaCl, 0.005 (v/v) % Tween 20).6 ⁇ L were subsequently added to an assay- ready plate containing 0.06 ⁇ L of controls and test compound 10 dose-response serial dilutions starting at a concentration of 10 mM (with 100 ⁇ M top and 3.2 nM lowest final concentration) by using Certus flex dispenser.
  • the plate was sealed, and the reaction was incubated overnight (18-24h) at RT in the dark.
  • FRET signal quantification was achieved by PHERAstar FSX (BMG) plate reader.
  • the created data file contained the emission of FRET acceptor channel (665 nm, probe), FRET donor channel (620 nm, Tb-cryptate, excitation at 337 nm) and the FRET ratio (665 nm/620 nm signal x 10.000) which was used for calculation of a test compound ⁇ s IC50.
  • Assays 2 and 2a - Biophysical human PCSK9 assays These assays measure binding of compounds to PCSK9 by SPR (“surface plasmon resonance”, a biophysical method) at plasma and a representative endosomal pH (7.4 and 5.6 respectively).
  • the pH 7.4 (Assay 2) SPR binding experiments were performed on a Biacore S200 optical biosensor unit at 30 °C.
  • a Series S Sensor Chip SA that is designed to bind biotinylated molecules for interaction analysis in Biacore systems was equilibrated at room temperature prior to use.
  • the running buffer for protein tethering and subsequent ligand binding experiments was 10mM HEPES pH 7.4, 150mM NaCl, 0.05% (v/v) Tween 20 pH 7.4.
  • biotinylated human PCSK9 (31-692)-Avi-His6 (Charles River Laboratories) at a concentration of 0.5mg/mL was used.
  • the surface Prior to the surface tethering, the surface was exposed to a solution of 50mM NaOH, 500mM NaCl via 3 consecutive injections of this solution with a contact time of 60 s and a flowrate of 10 ⁇ L min -1 to remove non-conjugated streptavidin.
  • the PCSK9 protein was diluted to a concentration of 20 ⁇ g/mL using running buffer and injected with a contact time of 180-300 s and a flowrate of 10 ⁇ L min -1 over a single flow channel (typically flow channel 2 or flow channel 4) with the aim to achieve protein capture levels of > 5000 response units (RU).
  • Remaining biotin binding sites were blocked via 2 consecutive injections of a 10 ⁇ M D-biotin solution in running buffer with a contact time of 60 s and a flowrate of 10 ⁇ L min -1 over all flow-channels.
  • Flow-channels 1 and 3 typically served as a reference surface throughout the subsequent binding experiments.
  • the binding experiments were all performed at a flow rate of 30 ⁇ L min -1 and by employing the method of single-cycle kinetics. This approach involves the sequential injection of a compound concentration series without regeneration steps. A contact time between 90-150 s was selected, which was followed by a 40 min dissociation phase to allow for a proper estimation of the dissociation rate constant.
  • Test compounds were delivered in DMSO at a concentration of 10 mM and a digital dispenser HP D300 was used to set up the compound concentration series using 6 concentrations. The tested concentrations have been 30, 100, 300, 1000, 3000 and 10000 nM. Prior to injecting any compound, the surfaces were equilibrated by injecting running buffer over them in three separate pulses. The data collection rate was set to 10 Hz.
  • the raw sensorgrams of the compound injections were first subjected to reference subtraction (subtracting the signal from flow channel 1 and/or 3 from the signal from channels 2 and/or 4 respectively) and then blank subtraction (subtracting the signal from injecting DMSO controls from the reference subtracted data).
  • the resulting double-referenced sensorgrams were then fitted using a 1:1 binding interaction model using the manufactures software package to extract kinetic- and affinity data.
  • Active compounds have been defined by creating a detectable binding signal at the highest compound concentration (10mM) of ⁇ 3 RUs.
  • Buffer A for protein tethering was 10 mM Hepes, 150 mM NaCl, 0.05% (v/v) Tween 20 pH 7.4. (Cytiva, Product#BR100671). Buffer B used for the subsequent ligand binding experiments was 20 mM Cacodylate, 150 mM NaCl, 0.05% (v/v) Tween 20, pH 5.60.
  • the biotinylated human PCSK9 (31-692)-Avi-His6 (Charles River Laboratories) at a concentration of 0.5 mg/mL was diluted to a concentration of 20 ⁇ g/mL using Buffer A and injected over flow cell 2 with a contact time of 600 s and a flowrate of 5 ⁇ L.min- 1 with the aim to achieve protein capture levels of 6000-7000 RU. Remaining biotin binding sites were blocked with a single injections of a 10 ⁇ M D-biotin solution (Avidity, Product#BIO200) in running buffer with a contact time of 60 s and a flowrate of 10 ⁇ L.min -1 over all flow cells.
  • a 10 ⁇ M D-biotin solution (Avidity, Product#BIO200) in running buffer with a contact time of 60 s and a flowrate of 10 ⁇ L.min -1 over all flow cells.
  • Flow cells 1 served as a reference surface during the subsequent ligand binding experiments.
  • the protein surface was stabilised over night using standby flow, and Buffer A was exchanged with Buffer B by priming the system the next day prior to the ligand binding experiments
  • the binding experiments were all performed at a flow rate of 30 ⁇ L.min -1 and by employing the method of single-cycle kinetics. This approach involves the sequential injection of a compound concentration series without regeneration steps. A contact time of 120 s was used, which was followed by a 40 min dissociation phase to allow for a proper estimation of the dissociation rate constant.
  • Compounds have been tested in a concentration series using 6 concentrations. The tested concentrations have been 30, 100, 300, 1000, 3000 and 10000 nM.
  • the raw sensorgrams of the compound injections were first subjected to reference subtraction (subtracting the signal from flow-channel 1 from signal from channel 2) and then blank subtraction (subtracting the signal from injecting 2 DMSO controls from the reference subtracted data).
  • the resulting double-referenced sensorgrams were then fitted using a 1:1 binding interaction model using the manufactures software package (BIAcore Insight Evaluation software V 5.0.18.22102) to extract kinetic- and affinity data.
  • the comparator compound used in Assays 2 and 2a is example 493 in WO 2020/150473 A2. .
  • Table 3 SPR Data Assay 2 Assay 2 Assay 2 Assay 2 (PCSK9 Assay 2a (PCSK9 (PCSK9 Assay 2a Assay 2a BIAcore pH 5.6 BIAcore BIAcore DBA pH 5.6 SPR pH 5.6 SPR DBA SPR Example No.
  • the assay is based on exogenous PCSK9 protein (WT, assay 3 or D374Y mutant, assay 3a) and LDL complexed with a pH-sensitive dye (pHrodoTM Red-LDL). Outside the cells, at neutral pH, the pHrodoTM Red-LDL is dimly fluorescent but upon LDLR mediated endocytosis it fluoresces brightly.
  • PCSK9 trafficks the LDL receptor (LDLR) to intrecellular degradation and reduces uptake of LDL. Inhibition of PCSK9 reduces LDLR degradation and the increased LDL uptake is quantified by fluorescence microscopy.
  • Assay medium OptiMem (Gibco #51985) + Penicilin/Streptomycin (Gibco #15140122, 1:100 dilution) Labelled LDL: Low Density Lipoprotein From Human Plasma, pHrodoTM Red (pHrodoTM Red- LDL) (Invitrogen #L34356) Cells: HepG2 (ATCC #HB-8065) WT PCSK9 protein: In-house.
  • Assay 3 Neutral Control DMSO (100%) Assay 3 Inhibitor Control: 6'-(((1S,3S)-3-((3H-Imidazo[4,5-b]pyridin-2- yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one (10 ⁇ M) Synthesis of Assay 3 Inhibitor Control 6'-(((1S,3S)-3-((3H-Imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2- one A mixture of 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2- yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one and 6
  • Test compounds were prepared in concentration response in DMSO with a half-log dilution factor in DMSO in Echo 384 LDV plates (Labcyte LP-#0200) starting at 10 mM. 2. 30 nL of above test compounds were dispensed with Echo 655 (Labcyte) to cells for a top concentration of 10 ⁇ M (Assay 3) or single concentration of 0.1 ⁇ M (Assay 3a). 3. Assay 3: WT PCSK9 protein was diluted to 375 nM with assay medium and dispensed to cells with Multidrop Combi (ThermoFisher), 10 ⁇ L per well, for a final concentration of 125 nM.
  • Assay 3a PCSK9 protein (D374Y mutant) was diluted to 6 nM with assay medium and dispensed to cells with Multidrop Combi (ThermoFisher), 10 ⁇ L per well, for a final concentration of 2 nM. 4. Plates were incubated at 37 °C, 5% CO2 for 24 h. Day 3 1. 6 ⁇ g/mL pHrodoTM Red-LDL in assay medium was dispensed to cells with Multidrop Combi (ThermoFisher), 10 ⁇ L per well. 2.
  • the comparator compound used in Assays 3 and 3a is example 493 in WO 2020/150473 A2.
  • Assay 4 - hERG assay human Ether-á-go-go-Related Gene
  • This assay human Ether-á-go-go-Related Gene measures activity of the compounds at the potassium ion channel hERG (human Ether-á-go-go-Related Gene).
  • hERG human Ether-á-go-go-Related Gene
  • hERG Chinese hamster ovary K1 (CHO) cell lines over- expressing the ion channel of choice (hERG) were used from live culture. All solutions were stored at 4 °C or -20 °C. All compounds were dispensed as 10 or 50mM DMSO stocks, in 96 well plates and diluted to a format that allowed testing in a 6 point cumulative assay (final DMSO concentration 2% or 0.4% DMSO). Only wells that passed previously agreed acceptance criteria for this platform were used in this analysis (500 MegaOhm seal resistance and current size >0.2 nA, with positive controls including Verapamil and DMSO being consistent).
  • Assay 5 GSK3 ⁇ Assay (ThermoFisher assay) This assay measures the activity of the compounds at GSK3 ⁇ (Glycogen synthase kinase-3 beta). The test compounds were screened in 1% DMSO (final) in the well. For 10-point titrations, 3- fold serial dilutions are conducted from the starting concentration of 10 ⁇ M.
  • Assay Protocol Bar-coded Corning, low volume NBS, black 384-well plate 1.2.5 ⁇ L – 4X Test Compound or 100 nL 100X plus 2.4 ⁇ L kinase buffer 2.5 ⁇ L – 2X Peptide/Kinase Mixture 3.2.5 ⁇ L – 4X ATP Solution 4.30-second plate shake 5.60-minute Kinase Reaction incubation at room temperature 6.5 ⁇ L – Development Reagent Solution 7.30-second plate shake 8.60-minute Development Reaction incubation at room temperature 9.
  • step 2 the 2X GSK3 ⁇ (GSK3 beta) / Ser/Thr (Glycogen synthase kinase-3 beta/ Serine/ Threonine) 09 mixture is prepared in 50 mM HEPES (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid) pH 7.5, 0.01% BRIJ-35, 10 mM MgCl 2 , 1 mM EGTA (egtazic acid).
  • HEPES 4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid
  • the final 10 ⁇ L Kinase Reaction consists of 0.22 - 0.92 ng GSK3 ⁇ (GSK3 beta) and 2 ⁇ M Ser/Thr 09 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl 2 , 1 mM EGTA.
  • the ATP Solution is diluted to a 4X working concentration in Kinase Buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA).
  • Step 6 the Development Reagent is diluted 1:512 in Development Buffer (10X Novel PKC Lipid Mix: 2 mg/mL Phosphatidyl Serine, 0.2 mg/mL DAG in 20 mM HEPES, pH 7.4, 0.3% CHAPS).
  • Development Buffer 10X Novel PKC Lipid Mix: 2 mg/mL Phosphatidyl Serine, 0.2 mg/mL DAG in 20 mM HEPES, pH 7.4, 0.3% CHAPS.
  • Graphing Software SelectScreen® Kinase Profiling Service uses XLfit from IDBS.
  • the dose response curve is curve fit to model number 205 (sigmoidal dose-response model). If the bottom of the curve does not fit between -20% & 20% inhibition, it is set to 0% inhibition. If the top of the curve does not fit between 70% and 130% inhibition, it is set to 100% inhibition.
  • MMTr-protected oligonucleotide (MMTr-ON) with the above sequence was synthesised on an ⁇ KTA OligoPilot Plus 100 synthesizer (GE Healthcare), on a 940 ⁇ mol scale, using a standard synthesis cycle of detritylation (3% dichloroacetic acid in toluene), coupling (coupling agent: 0.25 M 5-[3,5-bis(trifluoromethyl)phenyl]-1H-tetrazole solution in acetonitrile), capping (Cap A: 20% N-methylimidazole and 80% acetonitrile; Cap B: 20% pyridine, 20% acetic anhydride and 60% acetonitrile), oxidation (0.05 M iodine in pyridine and water) or thiolation (0.2 M xanthane hydride in pyridine), and solid supports (UNY Primer Support 5G ⁇ 353 ⁇ mol/g, GE Healthcare).
  • the solution was filtered, and the MMTr-ON product was purified using HPLC (XBridge C18, 10 ⁇ m 50x250 mm column; 5-45% acetonitrile in aqueous NH 4 HCO 3 (50 mM). Fractions containing the MMTr-ON product were combined, and volatiles were removed on a Speedvac. The residue was dissolved in water (4 mL) and the MMTr group was removed by treating the obtained solution with acetic acid 10% (1 mL) at 40 °C for 60 min. NaOAc (3 M aq, 0.6 mL) and EtOH (95%, 20 mL) were sequentially added. The mixture was stored at -20 °C for 120 min and centrifuged for 15 min at 4 °C.
  • HA-oligonucleotide (1074 mg) was dissolved in water (11.176 mL), TEA (0.38 mL) was added and the pH was immediately checked, then 765 mg of GalNAc ligand 1-OPfp ester (Kim 2024, dissolved in 2.79 mL of ACN) was added to the tube. The mixture was shaken for 4 h, at room temperature.
  • the fractions were concentrated (ammonia buffer), and the oligo was precipitated with NaOAc in EtOH (10% NaOAc in 20 mL 80% EtOH) overnight. Then, the fractions were centrifuged and immediately submitted to desalt.
  • the ASO was desalted using an ⁇ KTA system using WorkBeads Dsalt (50 mL) column at a flowrate of 10mL/min of water over 20 mins. Injected in 15 mL of 1 M aq NaCl and fractions were collected based on absorbance at 260 nm. The pure fraction was collected and freeze- dried overnight. A sample was taken to check absorbance with nanodrop.
  • mice Heterozygous male human PCSK9 knock-in (hPCSK9-KI) mice (Carreras 2019) were fed a regular chow diet throughout and dosed via subcutaneous injections with murine Pcsk9 GalNAc-ASO (Mouse GalNAc ASO for in vivo above) at 5 mg/kg/week formulated in PBS for 4 weeks with one additional loading dose in week 1 to ablate endogenous hepatic murine Pcsk9 expression levels prior to compound dosing.
  • murine Pcsk9 GalNAc-ASO Mae GalNAc ASO for in vivo above
  • the comparator compound used in Assay 6 is example 493 in WO 2020/150473 A2. .
  • Table 4 – in vivo data Dose LDL-C reduction Example No. (mg/kg/day) (%) Comparative Example 493 30 -27.5% in WO 2020/150473 A2 12 100 -35
  • A a compound of Formula (I) A-B-C (I) or a pharmaceutically acceptable salt thereof, wherein A is of one of the following formulae: wherein the wavy line indicates the point of attachment to B;
  • R A1 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6 alkyl acyl, C1-6 alkoxy or one or more halo groups; (v) C1-6 alkoxy, optionally substituted by OH, one or more halo groups, or C1-6 alkyl amido; (vi) C1-6 alkyl ester; (vii) C1-6 alkyl acyl; and (viii) OH;
  • R A2 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C
  • A-B-C is of the formulae (I-A), (I-B), (I-Ba), (I-Bb), (I-C), (I-Ca), (I-Cb), (I-Cc), (I-Cd) and (I-Ce) wherein all definitions are according to statement A1; A11.
  • A-B-C is of the formula (III-A), (III-B), (III-C), (III-Ca), (III-Cb), (III-Cc), (III-Cd) and (III-Ce) wherein all definitions are according to statement A1: 20137788--WWO- PPCT 1711 H pharmaceutically acceptable salt thereof.
  • A14 A compound listed in Table 1 or a pharmaceutically acceptable salt thereof.
  • A15 The compound of any one of statements A1 to A14 or a pharmaceutically acceptable salt thereof, for use in therapy.
  • a pharmaceutical composition comprising the compound of any one of statements A1 to A14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.
  • A17. The compound of any one of statements A1 to A14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to statement A16 for use in the treatment of a cardiovascular disease.
  • the compound for use according to statement A17 wherein the compound is administered simultaneously, separately or sequentially in combination with an additional active ingredient selected from the group consisting of: i) a statin; ii) a cholesterol absorption inhibitor; iii) a SGLT2 inhibitor; iv) a P2Y12 inhibitor; v) a ATP-citrate lyase inhibitor; and vi) anti-hypertensive drugs.
  • an additional active ingredient selected from the group consisting of: i) a statin; ii) a cholesterol absorption inhibitor; iii) a SGLT2 inhibitor; iv) a P2Y12 inhibitor; v) a ATP-citrate lyase inhibitor; and vi) anti-hypertensive drugs.
  • cardiovascular disease is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease heart failure and congestive heart failure.
  • cardiovascular disease is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease heart failure and congestive heart failure.
  • A20 Use of a compound of any one of statements A1 to A14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to statement 16 in a method of medical treatment.
  • A21. A method of medical treatment comprising administering to the patient the pharmaceutical
  • a method of treating PCSK9-mediated disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of statements A1 to A14 or the pharmaceutical composition according to statement A16.
  • A24. The method according to statement A23, wherein the disease or disorder is a cardiovascular disease or disorder.
  • cardiovascular disease or disorder is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease heart failure or congestive heart failure.
  • A is of one of the following formulae: wherein the wavy line indicates the point of attachment to B;
  • X 1 is N or C-R A3 ;
  • R A1 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C 1-6 hydrocarbon, optionally substituted by OH, CN, C 1-6 alkyl acyl, C 1-6 alkoxy or one or more halo groups; (v) C1-6 alkoxy, optionally substituted by OH, one or more halo groups, or C1-6 alkyl amido; (vi) C1-6 alkyl ester; (vii) C1-6 alkyl acyl; and (viii) OH;
  • R A2 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C
  • B25 The compound of any one of statements B1 to B20, or a pharmaceutically acceptable salt thereof, wherein C is selected from one of the following formulae: B26.
  • A-B-C is of the formulae (I-Ax), (I-Bx), (I-By), (I-Bax), (I-Bay), (I-Bbx), and (I-Bcx) wherein all definitions are according to statement B1; B30.
  • A-B-C is of the formulae (I-Cx), (I-Cax), (I-Cbx), (I-Ccx), (I-Cdx), (I-Cex), (I-Cfx), and (I-Cgx) wherein all definitions are according to statement B1 or formula (C-2a);
  • A-B-C is of the formulae (IV-A), or (IV-B) wherein all definitions are according to statement B1 or formula (C-2a): B32.
  • A-B-C is of the formulae (II-Cx), (II-Cax), (II-Cbx), (II-Ccx), (II-Cfx) and (II-Cgx) wherein all definitions are according to statement B1 or formula (C-2a); B34.
  • A-B-C is of the formulae (III-Ax), (III-Bx), (III-Cx), (III-Cax), (III-Cbx), (III-Ccx), (III-Cfx) and (III- Cgx) wherein all definitions are according to statement B1 or formula (C-2a); B35.
  • B36 The compound any one of statements B1 to B20, B22 to B26, and B28 to B34, or pharmaceutically acceptable salts thereof, wherein X is H. B37.
  • the compound or pharmaceutically acceptable salt thereof for use according to statement B41 wherein the compound is administered simultaneously, separately or sequentially in combination with an additional active ingredient selected from the group consisting of: i) a statin or pharmaceutically acceptable salt thereof; ii) a cholesterol absorption inhibitor or pharmaceutically acceptable salt thereof; iii) a SGLT2 inhibitor or pharmaceutically acceptable salt thereof; iv) a P2Y12 inhibitor or pharmaceutically acceptable salt thereof; v) a ATP-citrate lyase inhibitor or pharmaceutically acceptable salt thereof; and vi) anti-hypertensive drugs or pharmaceutically acceptable salt thereof.
  • an additional active ingredient selected from the group consisting of: i) a statin or pharmaceutically acceptable salt thereof; ii) a cholesterol absorption inhibitor or pharmaceutically acceptable salt thereof; iii) a SGLT2 inhibitor or pharmaceutically acceptable salt thereof; iv) a P2Y12 inhibitor or pharmaceutically acceptable salt thereof; v) a ATP-citrate lyase inhibitor or pharmaceutically
  • the compound or pharmaceutically acceptable salt thereof for use according to statement B41 wherein the treatment comprises administering to a subject in need thereof, a first amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof and a second amount of at least one additional active ingredient, wherein the first amount and the second amount together comprise a therapeutically effective amount.
  • the compound or pharmaceutically acceptable salt thereof for use according to statement B43, wherein the at least one additional active ingredient may be selected from (a) a statin or pharmaceutically acceptable salt thereof, (b) ezetimibe or a pharmaceutically acceptable salt thereof, and/or (c) bempedoic acid or a pharmaceutically acceptable salt thereof.
  • statin is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, velostatin, compactin, dihydrocompactin, dalvastatin, fluindostatin, rosuvastatin, and simvastatin; and pharmaceutically acceptable salts thereof.
  • statin is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, velostatin, compactin, dihydrocompactin, dalvastatin, fluindostatin, rosuvastatin, and simvastatin; and pharmaceutically acceptable salts thereof.
  • B49 The compound or pharmaceutically acceptable salt thereof for use according to statement B48, wherein the statin is rosuvastatin or a pharmaceutically acceptable salt thereof.
  • B50 The compound or pharmaceutically acceptable salt thereof for use according to any one of statements B45 to B49, wherein the statin is administered in a moderate-intensity dosing.
  • B51 The compound or pharmaceutically acceptable salt thereof for use according to any one of statements B45 to B49, wherein the statin is administered in a high-intensity dosing.
  • B52 The compound or pharmaceutically acceptable salt thereof for use according to statement B44, wherein the at least one additional active ingredient is ezetimibe or a pharmaceutically acceptable salt thereof.
  • B61 A method of medical treatment comprising administering to the patient the pharmaceutical composition of statement B40.
  • B62 Use of a compound of any one of statements B1 to B38 in the manufacture of a medicament for use in therapy.
  • B63 Use of a compound according to statement B62, wherein the medicament is for use in the treatment of a cardiovascular disease.
  • B64 Use of a compound according to statement B63, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof and ii) at least one additional active ingredient to a subject in need thereof.
  • B66 A method of treating PCSK9-mediated disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of statements B1 to B38 or the pharmaceutical composition according to statement B40.
  • B67 The method according to statement B66, further comprising the separate, sequential or simultaneous administration of at least one additional active ingredient to a subject in need thereof.
  • the method according to statement B67 further comprising administering to a subject in need thereof, a first amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof and a second amount of the at least one additional active ingredient, wherein the first amount and the second amount together comprise a therapeutically effective amount.
  • B69. The method according to statement B68, wherein the at least one additional active ingredient may be selected from (a) a statin or pharmaceutically acceptable salt thereof, (b) ezetimibe or a pharmaceutically acceptable salt thereof, and/or (c) bempedoic acid or a pharmaceutically acceptable salt thereof.
  • B70 The method according to statement B69, wherein the at least one additional active ingredient is a statin or pharmaceutically acceptable salt thereof.
  • statin is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, velostatin, compactin, dihydrocompactin, dalvastatin, fluindostatin, rosuvastatin, and simvastatin; and pharmaceutically acceptable salts thereof.
  • statin is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, velostatin, compactin, dihydrocompactin, dalvastatin, fluindostatin, rosuvastatin, and simvastatin; and pharmaceutically acceptable salts thereof.
  • statin is selected from atorvastatin, rosuvastatin, lovastatin, pravastatin, simvastatin and fluvastatin; and pharmaceutically acceptable salts thereof.
  • statin is rosuvastatin or a pharmaceutically acceptable salt thereof.
  • B75 The method according to any one of statements B69 to B74, wherein the statin is administered in a moderate-intensity dosing.
  • B76 The method according to any one of statements B69 to B74, wherein the statin or pharmaceutically acceptable salt thereof is administered in a high-intensity dosing.
  • B83 The method according to any one of statements B66 to B82, wherein the disease or disorder is a cardiovascular disease or disorder.
  • B84. The method according to statement B83, wherein the cardiovascular disease or disorder is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease heart failure or congestive heart failure.
  • B85 The method according to statement B84, wherein the cardiovascular disease or disorder is dyslipidemia.

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne un composé de formule (I) : A-B-C (I) ou un sel pharmaceutiquement acceptable et des formes tautomères ou des stéréoisomères de celui-ci, A étant de l'une des formules suivantes : (A1a), (A2a), (A2b), (A3a), (A3b) et (A4) ; B étant de formule : (B-1) ; et C étant de formule : (C-1a).
PCT/EP2025/057561 2024-03-20 2025-03-19 Inhibiteurs de pcsk9 et leurs procédés d'utilisation Pending WO2025196155A1 (fr)

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