WO2024062090A1 - Pcsk9 inhibitors and methods of use thereof - Google Patents

Pcsk9 inhibitors and methods of use thereof Download PDF

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Publication number
WO2024062090A1
WO2024062090A1 PCT/EP2023/076197 EP2023076197W WO2024062090A1 WO 2024062090 A1 WO2024062090 A1 WO 2024062090A1 EP 2023076197 W EP2023076197 W EP 2023076197W WO 2024062090 A1 WO2024062090 A1 WO 2024062090A1
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optionally substituted
methyl
alkyl
compound
mmol
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PCT/EP2023/076197
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French (fr)
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Gavin Donal O’MAHONY
Olaf Panknin
Andrey Frolov
Anna TOMBERG
Erik Weis
Hans Fredrik BERGSTRÖM
Jan Åke LINDBERG
Karl Thomas Antonsson
Jens Patrik JOHANSSON
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Astrazeneca Ab
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Publication of WO2024062090A1 publication Critical patent/WO2024062090A1/en

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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

Definitions

  • the present disclosure relates to compounds which inhibit PCSK9 and their use in methods of treatment.
  • the application claims the benefit of priority to US application No. 63/376,791, filed on 23rd September 2022, US application No. 63/483,797 filed on 8th February 2023, and US application No. 63/580,500 filed on 5 September 2023, which are incorporated herein by reference in their entirety.
  • PCSK9 also referred to as “proprotein convertase subtilisin/kexin 9”
  • PCSK9 increases the levels of circulating LDL cholesterol (LDL-C) via the enhanced degradation of the LDLRs independently of its catalytic activity.
  • Secreted PCSK9 binds to the Epidermal Growth Factor domain A (EGFA) of the LDL receptor (LDLR) at the cell surface and the PCSK9/LDLR complex is internalized into endosomal/lysosomal compartments.
  • EGFA Epidermal Growth Factor domain A
  • PCSK9 The enhanced binding affinity of PCSK9 to the LDLR at the acidic pH of late endosomes/lysosomes reduces LDLR recycling and instead targets LDLR for lysosomal degradation.
  • Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with low plasma LDL-C levels and a reduction in the incidence of adverse cardiovascular events.
  • PCSK9 For cardiovascular disease, few options exist for inhibiting PCSK9.
  • Statins actually upregulate PCSK9 in HepG2 cells and in human primary hepatocytes through the increased expression of SREBP-2, a transcription factor that upregulates both the LDLR and PCSK9 genes. Since an elevated level of PCSK9 decreases the abundance of LDLR on the cell surface, increasing doses of statins have failed to achieve proportional LDL-C lowering effects.
  • mAbs Two monoclonal antibodies (mAbs) that bind selectively to extracellular PCSK9 and prevent its interaction with the LDLR, alirocumab and evolocumab, have recently received FDA approval for lowering LDL-C levels.
  • alirocumab showed an about 50% decrease in LDL levels compared to placebo (Elbitar 2016).
  • Patients taking evolocumab showed an about 60- 75% decrease in LDL levels.
  • the potency of these drugs demonstrates the potential for inhibitors of PCSK9 to be effective treatments for those with hypercholesterolemia and other cardiovascular diseases.
  • both antibody drugs require intravenous administration and can cause allergic reactions or other deleterious immune responses in the body.
  • WO 2020/150473 A2 relates to heteroaryl compounds and pharmaceutical preparations thereof. It also relates to methods of treating or preventing cardiovascular diseases, and methods of treating sepsis or septic shock, using the described novel heterocyclic compounds.
  • WO 2020/150474 A1 relates to an inhibitor pharmacophore of PCSK9 and heteroaryl compounds that bind the PCSK9 protein.
  • a first aspect provides a compound with the Formula (I): A-B-C (I) or a pharmaceutically acceptable salt and tautomeric forms or stereoisomers thereof, wherein A is of the following formula: wherein the wavy line indicates the point of attachment to B; X 1 is N; 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) C1-6 alkoxy, optionally substituted by OH, C1-6 alkyl amido, or one or more halo groups; (vi) C1-6 acyl amido (wherein the acyl is optionally substituted by H or methyl); (vii) C1-6 thioalkyl; (viii) C1-6 alkyl ester; (ix) C 1-6 alkyl acyl; (x) C 4-5 heterocyclyl
  • a second aspect provides a pharmaceutical composition comprising the compound of the first aspect and a pharmaceutically acceptable diluent, carrier or excipient.
  • the third aspect provides the compound of the first aspect for use in a method of therapy.
  • the third aspect also provides the use of a compound of the first aspect in the manufacture of a medicament for treating a cardiovascular disease.
  • the third aspect also provides a compound of the first aspect for use in the treatment of a cardiovascular disease.
  • the third aspect also provides a method of treating a cardiovascular disease comprising administering a therapeutically effective amount of a compound of the first aspect or a composition according to the second aspect to a patient in need thereof.
  • the disclosure includes the combination of the aspects and features described except where such a combination is clearly impermissible or expressly avoided.
  • the compounds disclosed herein are PCSK9 inhibitors.
  • the compounds may have higher inhibition of PCSK9, lower hERG activity, improved secondary pharmacology profile including GSK3 ⁇ and/or other kinases, good stability, and/or improved activity in the treatment of cardiovascular diseases.
  • 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.
  • halo is selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), such as fluoro.
  • Oxo: O (oxygen double bonded to the rest of the molecule).
  • 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.
  • C 1-4 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 iso-propyl (C 3 ), iso-butyl (C 4 ), sec-butyl (C 4 ), tert-butyl (C 4 ), iso-pentyl (C 5 ), and neo-pentyl (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.
  • C1-6 alkoxy The term C1-6 alkoxy as used herein, pertains to an OR group, wherein R is an C1-6 hydrocarbon group.
  • C16 alkoxy groups include, but are not limited to, OMe, OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (isopropoxy), O(nBu) (n-butoxy), O(sBu) (sec-butoxy), O(iBu) (isobutoxy), and O(tBu) (tert-butoxy).
  • Amino groups may be primary (-NH2), secondary (-NHR 1 ), or tertiary (-NHR 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 , -NHC(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , and -NHPh.
  • 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 groups.
  • C1-6 thioalkyl The term C1-6 thioalkyl as used herein, pertains to an -SR, wherein R is a C1-6 hydrocarbon group. Examples of C1-6 alkylthio groups include, but are not limited to, -SCH3 and -SCH2CH3.
  • Carboxy (carboxylic acid): -C( O)OH.
  • C 3-12 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
  • C3-10 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 heterocycloalkyl ring may be linked via either a carbon atom or a heteroatom.
  • heteroatom means O, S, N, Si or B (Boron).
  • 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: N 1 : aziridine (C 3 ), azetidine (C 4 ), pyrrolidine (tetrahydropyrrole) (C 5 ), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C 5 ), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C 5 ), piperidine (C 6 ), dihydropyridine (C 6 ), tetrahydropyridine (C 6 ), azepine (C 7 ); O1: oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane (tetrahydropyran) (C6), dihydropyran (C6), pyran (
  • bicyclic heterocyclyl groups include, but are not limited to those derived from: C 6-10 carboaryl:
  • C 6-10 carboaryl refers 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.
  • Examples of 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.
  • the term “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).
  • Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: N1: pyrrole (azole) (C5), pyridine (azine) (C6); O1: furan (oxole) (C5); S1: thiophene (thiole) (C5); N1O1: oxazole (C5), isoxazole (C5), isoxazine (C6); N2O1: oxadiazole (furazan) (C5); N 3 O 1 : oxatriazole (C 5 ); N 1 S 1 : thiazole (C 5 ), isothiazole (C 5 ); N2: imidazole (1,3-diazole) (C5), pyrazole (1,2-diazole) (C5), pyridazine (1,2-diazine) (C6), pyrimidine (1,3-diazine) (C 6 ) (e
  • heteroaryl which comprise fused rings, include, but are not limited to Cw (with 2 fused rings) derived from:
  • Spiro C6-i2 carbocyclyl The term Spiro C6-i2carbocyclyl 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 Ce- i2carbocyclyl 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 Ce-12 heterocyclyl The term Spiro C6-i2heterocyclyl 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 C6-i2heterocyclyl 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.
  • 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.
  • 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 methanesulfonic acid salt.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof where the pharmaceutically acceptable salt is a mono- methanesulfonic acid salt, i.e. the stoichiometry of the compound of the compound of Formula (I) to methanesulfonic acid is 1:1.
  • 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 kinase 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%.
  • 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 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.
  • tautomeric forms of some of the exemplified compounds where R A3 is OH can be shown as follows.
  • Compounds and salts described in this specification may be crystalline and may exhibit one or more crystalline forms.
  • the compound of Formula (I) encompasses any crystalline or amorphous form of a compound of Formula (I), or mixture of such forms, which possesses PCSK9 inhibitory activity.
  • crystalline materials may be characterised using conventional techniques such as X-Ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis (TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy.
  • XRPD X-Ray Powder Diffraction
  • DSC Differential Scanning Calorimetry
  • TGA Thermal Gravimetric Analysis
  • DRIFT Diffuse Reflectance Infrared Fourier Transform
  • NIR Near Infrared
  • solution and/or solid state nuclear magnetic resonance spectroscopy solution and/or solid state nuclear magnetic resonance spectroscopy.
  • the water content of crystalline materials may be determined by Karl Fischer analysis.
  • 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.
  • the compounds of Formula (I), and pharmaceutically acceptable salts thereof, may be administered as pharmaceutical compositions, comprising one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition 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. As persons skilled in the art will appreciate, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.
  • compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing), or as a suppository for rectal dosing.
  • the compositions may be obtained by conventional procedures well known in the art.
  • Compositions intended for oral use may contain additional components, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable daily doses of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, in therapeutic treatment of humans are about 0.0001-100 mg/kg body weight.
  • Pharmaceutical formulations as described herein may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.1 mg to 1000 mg.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, any therapies being co-administered, and the severity of the illness being treated. Accordingly, the practitioner who is treating any particular patient may determine the optimum dosage.
  • 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.
  • the compounds described herein may be used in a method of therapy. Also provided is a method of treatment, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I.
  • a 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 timecourse of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the responsibility of general practitioners and other medical doctors.
  • a compound may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) for use in therapy.
  • a method of treatment comprising administering to a subject the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I).
  • the compounds described herein are PCSK9 inhibitors.
  • 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 LDLRs 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;
  • the method of inhibiting PCSK9 occurs in a subject in need thereof, thereby treating a disease or disorder mediated by PCSK9. Also, disclosed herein are methods of treating or preventing a disease or a disorder mediated by PCSK9 comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • disclosed herein are methods of treating a disease or a disorder mediated by PCSK9 comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, disclosed herein are methods of preventing a disease or a disorder mediated by PCSK9 comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the prevention of cardiovascular events through the inhibition of PCSK9 has been described, e.g., in Robinson 2015.
  • 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.
  • Exemplary cardiovascular diseases and conditions include, but are not limited to, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dimensia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure or congestive heart failure.
  • exemplary cardiovascular diseases and conditions include, but are not limited to, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery 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.
  • 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.
  • such 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) a 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) citrate lyase inhibitor; 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).
  • additional active ingredient selected from Ezetimibe, Rosuvastatin, Dapagliflozin and Ticagrelor.
  • 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.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof and at least one additional active ingredient for use in the simultaneous, separate or sequential treatment of a cardiovascular disease.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cardiovascular disease where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one an additional active substance selected from Ezetimibe, Rosuvastatin, Dapagliflozin and Ticagrelor.
  • a method of treating a cardiovascular disease in a subject which comprises administering to said subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional active substance, wherein the at least one additional active substance is selected from Ezetimibe, Rosuvastatin, Dapagliflozin and Ticagrelor.
  • the at least one additional active substance is selected from Ezetimibe, Rosuvastatin, Dapagliflozin and Ticagrelor.
  • 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) C1-6 alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups; (vi) C1-6 acyl amido (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) 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 heterocyclyl, C 1-3 alkyl which alkyl is optionally substituted with
  • 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 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) C1-6 acyl amido (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) C5heteroaryl; (xii) C1-6 alkyl amido optionally substituted by C1-3alkyl amido, CN, C2-3 alkynyl, C4-6 heterocyclyl, C1-3 alkyl which alkyl is optionally substituted with one or more
  • R A2 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6acyl, C1-6alkoxy or one or more halo groups; (v) OH; (vi) C1-6 alkoxy, optionally substituted by OH, C1-6 alkyl amido, or one or more halo groups; (vii) C1-6 alkyl ester; (viii) C1-6 alkyl acyl; (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; and (x) C 1-6 alkylamino In further embodiments R A2 is selected from the group consisting of: (i) H; (ii) halo; (iii)
  • 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) 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 C1-3alkyl 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) C1-6 hydrocarbon; (v) C1-6 alkyl amido optionally substituted by C1-3 alkyl amido, C2-3 alkynyl, C4-6 heterocyclyl, or C1- 3alkyl which alkyl is optionally substituted with one or more halo or OH groups; (vi) C1-6 thioalkyl; (vii)C1-6 alkyl acyl; (viii) C 5 heteroaryl; or (ix) C 1-6 alkylamino.
  • R A2 is halo, in some embodiments it is Br or Cl.
  • R A2 is a C1-6 hydrocarbon it is an optionally substituted C1-6 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 C1-6 alkyl, in some embodiments 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 C1-6alkoxy, 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 or 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 C 1-6 alkoxy it is difluoromethoxy (OCHF 2 ).
  • R A2 is C 1-6 alkyl amido
  • the optional substituents are selected from one or more methyl groups, an oxetane ring, a C 2 alkylamido, ethyl which ethyl is optionally substituted by OH or one or more halo groups.
  • the optional substituent is OH.
  • These groups are as shown in the table below:
  • R A2 is selected from the following groups:
  • R A2 is selected from the following groups:
  • 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 a C1-6hydrocarbon it is an optionally substituted C1-6 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 C1-6 alkyl, in some embodiments the optionally 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. In some embodiments R A3 is OH.
  • R A3 is optionally substituted C 1-6 alkoxy, in some embodiments it is optionally substituted OMe or ethoxy. In further embodiments it is OMe.
  • R A3 is optionally substituted C 1-6 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, CF 3 , CN, C 1-2 alkyl, NH 2 and halo. In other embodiments R A3 is selected from H, methyl, CN and Cl.
  • R A3 is selected from H, OMe, CF 3 , CN, C 1-2 alkyl, NH 2 and halo. 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 or 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 C6 carboaromatic ring or C5-7 heteroaromatic ring they form an optionally substituted benzene ring or an optionally substituted pyridine 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 methyl, ethyl, OMe, NH2, F, Cl and Br.
  • the optional substituents are selected from methyl, NH2, 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 C5-7 heteroaromatic ring, they form an optionally substituted pyridine. In some embodiments the optional substituent is NH 2 . 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.
  • the optional substituents are selected from Ci-ealkyl, Ci-e 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.
  • the 5 membered ring contains one N.
  • the 5 membered ring contains one N and one O.
  • 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.
  • the optional substituents are selected from NH2, Ci-ealkyl, Ci- ealkoxy and halo. In other embodiments the optional substituents are selected from methyl, ethyl, OMe, ethoxy, NH2, 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:
  • R A3 and R A2 together with the carbon atoms to which they are bound form an optionally substituted Ce carboaromatic ring or C5-7 heteroaromatic ring wherein the optional substituents are selected from Ci-ealkyl, and halo.
  • R A2 and R A3 together form an unsubstituted 2-pyrazole, a 2-pyrrole substituted by methyl, pyridine optionally substituted by NH2, or a phenyl optionally substituted by Cl, F or OMe.
  • R A2 and R A3 together form a ring selected from:
  • R B1 is H.
  • B is of the formula (B-1 a):
  • B is of the formula (B-1 b):
  • the compounds of Formula (I) is the S,S-enantiomer.
  • B is of formula (B-2): wherein the wavy line indicates the point of attachment to A and C; R B2 is C 1-2 alkyl-OH, CH 2 CONHMe or C 1-3 alkyl. In some of these embodiments, R B2 is C 1-2 alkyl-OH, or C 1-3 alkyl In some embodiments when B is of the formula (B-2) it is of the following formula (B-2a) wherein the wavy line indicates the point of attachment to A and C; and R B2 is C 1-2 alkyl-OH, CH 2 CONHMe or C 1-2 alkyl; (B-2a). In some embodiments B is of the following formula: . In further embodiments B is of the following formula: .
  • C is an optionally substituted C 5-6 heteroaryl in some embodiments it is an optionally substituted C 6 heteroaryl. In other embodiments it is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl. In other embodiments it is an optionally substituted pyridinyl.
  • C is substituted by C6-10 carboaryl, C5-10 heteroaryl or C5-10 heterocyclyl, it may bear a number of substituent groups.
  • one substituent of C is at the para position.
  • the optional substituents are selected from C 1-6 alkyl and halo.
  • the optional substituent is methyl.
  • C is substituted by methyl at the meta position.
  • C is substituted by an optionally substituted C 6-10 carboaryl, C 5-10 heteroaryl or C5-10 heterocyclyl, it may be substituted by an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted imidazolidinyl, an optionally substituted dihydroquinolinyl, an optionally substituted benzimidazolyl or an optionally substituted imidazopyridinyl.
  • C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl it may bear a number of substituent groups.
  • the substituents are an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted imidazolidine, an optionally substituted dihydroquinoline, an optionally substituted benzimidazolyl or an optionally substituted imidazopyridinyl.
  • C is an optionally substituted pyridinyl wherein the optional substituents are selected from phenyl and pyridyl which are themselves optionally substituted by methyl or CN.
  • C is an optionally substituted pyridinyl wherein the optional substituent is phenyl or pyridyl which are themselves optionally substituted by one or more groups selected from the following: a) one or more OMe groups; b) one or more F groups; c) CN; d) tetrazole; or e) carboxy.
  • C is an optionally substituted pyridinyl wherein the optional substituent is a C5 heteroaryl or C5 heterocyclyl which are themselves optionally substituted by one or more substituents selected from methyl and CN.
  • C is an optionally substituted pyridinyl wherein the optional substituent is a pyrazole, triazole, imidazole or an oxazole which are themselves optionally substituted by one or more substituents selected from methyl and CN.
  • the pyrazole, triazole, imidazole or oxazole are substituted by two methyl groups and optionally one CN group.
  • C is an optionally substituted pyridinyl wherein the optional substituent is an unsubstituted C9 membered heterocyclyl containing 2 or 3 nitrogen atoms.
  • C is (C-1) in some embodiments D is an optionally substituted pyridin-2-one.
  • the pyridine-2-one is unsubstituted.
  • the pyridin-2-one is pyridin-2(1H)- one.
  • C is of the formula (C-1) and D is an optionally substituted phenyl or piperidyl wherein there are one or two optional substituents selected from F, OMe and CN.
  • C is of the formula (C-1) and D is an optionally substituted phenyl or pyridyl wherein there are one or two optional substituents selected from F, OMe and CN.
  • D is an optionally substituted C 5 heterocyclyl or C 5 heteroaryl, wherein the optional substituents are selected from methyl and CN.
  • D is an optionally substituted pyrazole, imidazole, triazole or oxazole wherein the optional substituents are selected from methyl and CN.
  • D is a triazole substituted with two methyl groups. In further embodiments D is a pyrazole substituted by two methyl groups. In further embodiments D is an imidazole substituted by two methyl groups and CN. In further embodiments D is an oxazole substituted by two methyl groups. In some embodiments D is a C9 heterocyclyl or C9 heteroaryl comprising 2 or 3 nitrogen atoms. In further embodiments D is 1H-pyrazolo[3,4-b]pyridiyl, indazol-1-yl or indazol-2-yl. In some embodiments D is optionally substituted by 1, 2 or 3 substituents.
  • R D1 , R D2 , R D3 and R D4 are selected from C1-6 alkyl optionally substituted by one or more halo groups, C1-6 alkoxy optionally substituted by one or more halo groups, C5-6 heterocyclyl or C5-6heteroaryl with an optional methyl substituent, carboxy halo, CN, or phenyl optionally substituted by one or more halo atoms, and the rest are H.
  • D is of the formula (D-1) and one or two of R D1 , R D2 , R D3 and R D4 are selected from: i) methyl; ii) OMe; iii) Cl; iv) CN; v) CF 3 ; vi) F; vii) pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl; viii) O-CF 3 ix) O-CHF2 and the rest of R D1 , R D2 , R D3 and R D4 are H.
  • R D1 , R D2 , R D3 and R D4 are H.
  • R D3 is selected from H, CN, OMe, Cl, pyrazole optionally substituted by methyl, tetrazole, methyl, OCHF2, or triazole and wherein R D1 , R D2 and R D4 are all H.
  • R D3 is selected from H, CN, OMe, Cl, pyrazole, tetrazole, methyl, OCHF2, or triazole and wherein R D1 , R D2 and R D4 are all H.
  • R D2 is selected from H, OMe, Cl and CN and wherein R D1 , R D3 and R D4 are all H.
  • R D1 is selected from H, methyl, OMe, Cl, CF3, OCF3, OCHF2 and CN and R D2 , R D3 and R D4 are all H.
  • R D1 is selected from H, OMe, Cl, CF3, OCF3, OCHF2, CN, F, triazole and pyrazole optionally substituted by methyl, and R D2 , R D3 and R D4 are all H.
  • R D3 and R D4 form an optionally substituted benzene ring or an optionally substituted pyridine ring.
  • R D3 and R D4 form an unsubstituted benzene ring or an unsubstituted pyridine ring.
  • D is of the formula (D-2):
  • X D is NR D5a or CR D5a R D5b ;
  • R D5a is selected from H or methyl; either R D5b and R D6b are both H or together they are -CH2-;
  • C is of the formula (C-1) and D is of the formula (D-2) and X D is N and R D5a is methyl.
  • R D6a and R D7a form an unsubstituted benzene ring and R D6b and R D7b are absent. In some embodiments R D6a and R D7a form an unsubstituted pyridine ring and R D6b and R D7b are absent.
  • X D is N and R D5a is H or methyl.
  • X D is C and R D5a is H or methyl and R D5b is H. In further embodiments both R D5a and R D5b are H.
  • D is selected from the following table:
  • C has the formula (C-1) and all of R C7 , R C8 , R C9 and R c10 are H.
  • R C7 , R C8 , R C9 and R C1 ° are selected from methyl, OMe, Cl, CN, CF3, F; pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl; O- CF 3 , O-CHF 2 and the rest of R D1 , R D2 , R D3 and R D4 are H.
  • R C9 is selected from H, CN, OMe, Cl, pyrazole optionally substituted by methyl, tetrazole, methyl, OCHF2, or triazole and R C7 , R C8 and R C1 ° are all H.
  • R C7 is selected from H, methyl, OMe, Cl, F, CF3, -OCF3 and CN and R C8 , R C9 and R C1 ° are all H. In some embodiments R C7 is selected from H, OMe, Cl, CF3, OCF3,
  • R C8 is selected from H, OMe, Cl and CN and wherein R C7 , R C9 and R C1 ° are all H.
  • C is selected from the group consisting of the groups 1-48 listed in the following table:
  • C is selected from the group consisting of the 49-80 listed in the following table:
  • the compound of formula A-B-C is of the Formula (l-A): wherein X 1 is N.
  • R A2 is selected from the group consisting of:
  • Ci-6 alkyl amido optionally substituted by C1.3 alkyl amido, C ⁇ alkynyl, C4-6 heterocyclyl, or C1.3 alkyl which alkyl is optionally substituted with one or more halo or OH groups;
  • R A3 is selected from the group consisting of CN, Br, Cl, OH, H, CF 3 , Ci- 2 alkyl, Ci. 2 alkoxy, NH 2 . In further embodiments R A3 is selected from H, methyl and CN. In some embodiments R A3 is selected from H, methyl or OH.
  • R A3 and R A2 together with the carbon atoms to which they are bound form an optionally substituted Ce carboaromatic ring or C5-7 heteroaromatic ring, the optional substituents are selected from NH 2 , C1-6 alkyl, Ci-e alkoxy and halo. In other embodiments the optional substituents are selected from NH 2 , methyl, ethyl, OMe, F, Cl and Br.
  • 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 and R A3 together form an unsubstituted 2-pyrazole, a 2- pyrrole substituted by methyl, pyridine optionally substituted by NH 2 or benzene optionally substituted by Cl, F or OMe.
  • C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl.
  • the optional substituents are selected from:
  • the compound of formula A-B-C is of the Formula (I-B): wherein X 1 , R A2 and R A3 are as defined (I-A).
  • Formula (I-B) can be Formula (I-Ba) or (I-Bb) as shown below:
  • D is an optionally substituted pyridine-2-one.
  • the pyridine- 2-one is unsubstituted.
  • the pyridine-2-one is pyridin-2(1H)-one.
  • D is an optionally substituted C5 heterocycle or C5 heteroaryl, wherein the optional substituents are selected from methyl and CN.
  • D is an optionally substituted pyrazole, imidazole, triazole or oxazole wherein the optional substituents are selected from methyl.
  • D is a triazole substituted with two methyl groups.
  • D is a pyrazole substituted by two methyl groups.
  • D is an imidazole substituted by two methyl groups and CN.
  • D is an oxazole substituted by two methyl groups.
  • D is a C 9 heterocyclyl or C 9 heteroaryl comprising 2 or 3 nitrogen atoms.
  • D is 1H-pyrazolo[3,4-b]pyridiyl, indazol-1-yl or indazol-2-yl.
  • the compound of formula A-B-C is of the Formula (l-C): wherein X 1 , R A2 and R A3 are as defined (l-A).
  • R D1 , R D2 , R D3 and R D4 are H.
  • R D3 and R D4 form an unsubstituted benzene ring or an unsubstituted pyridine ring.
  • the compound of formula A-B-C is of Formula (l-D):
  • X 1 , R A2 and R A3 are as defined (l-A).
  • X D is NR D5a or CR D5a R D5b ;
  • R D5a is selected from H or methyl; either R D5b and R D6b are both H or together they are -CH2-;
  • the compound of formula A-B-C is of the Formula (l-E):
  • R A2 is selected from: (i) H; (ii) halo; (iii) CN; (iv) C 1-6 hydrocarbon, optionally substituted by OH, CN, C 1-6 acyl, C 1-6 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) carboxy; (viii) C1-6alkyl 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 or OH groups.
  • R A2 is selected from the group consisting of: (i) H; (ii) halo; (iii) C1-6 alkyl ester; (iv) C1-6 hydrocarbon; (v) C1-6 alkyl amido optionally substituted by C1-3 alkyl amido, C2-3 alkynyl, C4-6 heterocyclyl, or C1-3 alkyl which alkyl is optionally substituted with one or more halo or OH groups; (vi) C1-6 thioalkyl; (vii)C1-6 alkyl acyl; (viii) C5 heteroaryl; or (ix) alkylamino.
  • the compound is of the Formula (I-E) and D is an optionally substituted pyridin-2-one.
  • the compound is of the Formula (I-E) and D is an optionally substituted pyridin-2-one or pyridin-2(1H)-one.
  • the pyridine-2-one is unsubstituted.
  • the pyridine-2-one is pyridin-2(1H)-one.
  • the compound is of the Formula (I-E) and D is an optionally substituted C5 heterocycle or C5 heteroaryl, wherein the optional substituents are selected from methyl and CN.
  • D is an optionally substituted pyrazole, imidazole, triazole or oxazole wherein the optional substituents are selected from methyl.
  • D is a triazole substituted with two methyl groups.
  • D is a pyrazole substituted by two methyl groups.
  • D is an imidazole substituted by two methyl groups and CN.
  • D is an oxazole substituted by two methyl groups.
  • D is a C9 heterocyclyl or C9 heteroaryl comprising 2 or 3 nitrogen atoms.
  • D is 1H-pyrazolo[3,4-b]pyridiyl, indazol-1-yl or indazol-2-yl.
  • D is optionally substituted by 1, 2 or 3 substituents.
  • the compound is of Formula (I-Ea): (I-Ea) wherein D and R A3 are a defined above for Formula (I-E).
  • the compound is of Formula (I-Eb):
  • the compound is of Formula (I) A-B-C (I) or a pharmaceutically acceptable salt, tautomeric forms or stereoisomers thereof, wherein A is of the following: wherein the wavy line indicates the point of attachment to B; X 1 is N; 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) C 1-6 alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups; (vi) C 1-6 acyl amido (wherein the acyl is optionally substituted by H or methyl); (vii) C 1-6 thioalkyl; (viii) C 1-6 alkyl ester; (
  • the compound is of Formula (I) A-B-C (I) or a pharmaceutically acceptable salt, tautomeric forms or stereoisomers thereof, wherein A is of the following: wherein the wavy line indicates the point of attachment to B; R A2 is C1-6 alkylamino; X 1 , R A3, B and C are as defined above.
  • the compound of Formula (I) is selected from the following in Table 1. Table 1.
  • the compound is selected from 50, 57, 129, 132 and 136. In some embodiments the compound is 132.
  • the compounds according to general formula (l-B) can be prepared according to the following schemes 1 , 2, 3, 4 and 5.
  • the schemes and procedures described below illustrate synthetic routes to the compounds of general formula (l-B) and are not intended to be limiting. It is clear that the order of transformations as exemplified in schemes 1, 2, 3, 4 and 5 can be modified in various ways. The order of transformations exemplified in these schemes is therefore not intended to be limiting.
  • Scheme 1 Routes for the preparation of compounds of general formula (l-B) in which X is a leaving group, PG is a protective group and D, X 1 , R A2 and R A3 have the meaning as given for general formula (l-B), supra.
  • Monoarylated diamines of general formula (A3) can be obtained via nucleophilic aromatic substitution (SnAr) or palladium catalyzed Buchwald-Hartwig amination between monoprotected diamines (A1) or their corresponding salts and heteroaryls (A2a) with X being a leaving group like halogen or -S(O)Me as depicted in Scheme 1.
  • diamines (A1) may be reacted with (A2a) in the presence of inorganic bases like K2CO3 or Na2COs 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 (A1) may be reacted with (A2a) in the presence of a palladium catalyst like Pd PEPPSI-IpentCl [CAS 1612891-29-8], Pd 2 (dba) 3 or tBuXPhos Pd G3 [1447963-75-8] and a base like Cs 2 CO 3 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.
  • Diamines of general formula (A1) and heteroaryls of general formula (A2a) are either commercially available or can be prepared according to procedures available from the public domain.
  • Arylated diamines of general formula (A6) can be obtained from (A3) via copper catalyzed Ullmann couplings with heterocycles (A4) or via palladium catalyzed Suzuki couplings with boronic acid derivatives (A5).
  • Ullmann couplings all methods that are known in the art may be applied.
  • (A3) may be reacted with (A4) 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 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.
  • (A3) may be reacted with boronic acid derivatives (A5) in the presence of a palladium catalyst like 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride [CAS 95408-45-0] or 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride [CAS 72287-26-4] and a base like Cs2CO3, K2CO3 or K3PO4 in polar solvents such as 1,4-dioxane, THF and water or mixtures thereof at temperatures between room temperature and 120 °C for 2-15 hours.
  • a palladium catalyst like 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride [CAS 95408-45-0] or 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride [CAS 72287-26-4]
  • a base like Cs2CO3, K2
  • Heterocycles of general formula (A4) and boronic acid derivatives of general formula (A5) are either commercially available or can be prepared according to procedures available from the public domain.
  • Primary amines of general formula (A7) can be obtained from monoprotected diamines of general formula (A6) 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 Wuts 2014.
  • Final compounds of general formula (l-B) can be synthesized from primary amines of general formula (A7) via nucleophilic aromatic substitution (SNAr) or palladium catalyzed Buchwald- Hartwig amination.
  • Primary amines of general formula (A7) can be reacted with heteroaryls of general formula (A8) with X being a leaving group like halogen such as chlorine or -S(O)Me applying procedures in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.
  • Heteroaryls of general formula (A8) are either commercially available or can be prepared according to procedures available from the public domain.
  • Monoarylated diamines of general formula (A12) can be obtained via nucleophilic aromatic substitution (SNA ⁇ or palladium catalyzed Buchwald-Hartwig amination between monoprotected diamines (A1) or their corresponding salts and heteroaryls (A8) with X being a leaving group such as halogen or -S(O)Me.
  • SNA ⁇ nucleophilic aromatic substitution
  • X being a leaving group such as halogen or -S(O)Me.
  • the procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.
  • Carboxylic acid derivatives of general formula (A21) may be synthesized according to the route depicted in Scheme 3.
  • Nitro compounds of general formula (A15) can be obtained from reacting monoprotected diamines (A1) or their corresponding salts and nitroaryls (A14) with X being a leaving group like chlorine in a nucleophilic aromatic substitution (SNAr).
  • SNAr nucleophilic aromatic substitution
  • the reaction can be carried out in the presence of inorganic bases like K2CO3 in polar solvents such as for example DMSO at temperatures between room temperature and the boiling point of the solvent for 2- 12 h.
  • Nitroaryls of general formula (A14) are either commercially available or can be prepared according to procedures available from the public domain.
  • Anilines of general formula (A16) may be obtained from nitro compounds of general formula (A15) by reduction.
  • All methods that are known in the art may be applied.
  • nitro compounds of general formula (A15) can be reacted in the presence of a metal catalyst like palladium on charcoal under an atmosphere of hydrogen gas (1-5 bar) in polar, protic solvents like methanol or ethanol at temperatures between 0 °C and the boiling point of the solvent for 15-24 h.
  • Pyridones of general formula (A18) may be obtained from anilines (A16) by condensation with oxo-pyranes of general formula (A17) with Aik being methyl or ethyl in polar, protic solvents like ethanol at temperatures between room temperature and the boiling point of the solvent for 2- 12 h.
  • Oxo-pyranes of general formula (A17) are either commercially available or can be prepared according to procedures available from the public domain.
  • Primary amines of general formula (A19) may be synthesized from (A18) via removal of the protective group.
  • the same procedures apply as described for the synthesis of (A 7) from (A6) in Scheme 1.
  • Carboxylic esters of general formula (A20) can be obtained from primary amines (A19) and heteroaryls (A8) via nucleophilic aromatic substitution (SNA ⁇ or palladium catalyzed Buchwald- Hartwig amination applying procedures in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.
  • Carboxylic acid derivatives of general formula (A21) may be synthesized from carboxylic esters of general formula (A20) by ester hydrolysis. For saponification all methods that are known in the art may be applied. For example, esters (A20) may be reacted with bases like sodium hydroxide in polar, protic solvents like methanol, water or mixtures thereof at temperatures between 0 °C and the boiling point of the solvent for 0.5-2 h.
  • 1,2,4-Triazines of general formula (A29) may be synthesized according to the routes depicted in Scheme 4.
  • the methyl-thioether moiety of 3-(methylthio)-1 ,2,4-triazine (A22) [CAS 28735-21-9] might be activated for nucleophilic displacement by oxidation for which all methods that are known in the art may be applied.
  • (A22) can be reacted with mCPBA or Oxone® in inert solvents like dichloromethane at temperatures between 0 °C and the boiling point of the solvent for 0.5-2 h.
  • the crude oxidation product may be directly converted to monoarylated diamines of general formula (A23) in a nucleophilic aromatic substitution (SNAr) by reacting it with primary amines of general formula (A1) in polar solvents such as for example nBuOH at temperatures between room temperature and the boiling point of the solvent for 2-18 hours.
  • SNAr nucleophilic aromatic substitution
  • Aryl bromides of general formula (A24) can be obtained from triazines of general formula (A23) by bromination.
  • triazines (A23) can be reacted with bromine or /V-bromosuccinimide (NBS) in solvents like methanol, water, DMF or mixtures thereof at temperatures between 0 °C and the boiling point of the solvent for 4-15 h.
  • NBS bromine or /V-bromosuccinimide
  • 3,6-Disubstituted triazines of general formula (A27) may be synthesized from aryl bromides (A24) via Suzuki coupling for which all methods that are known in the art may be applied.
  • (A24) may be reacted with potassium trifluoroborates (A25) or trioxatriborinanes (A26) in the presence of a palladium catalyst like CataCXium A Pd G3 [CAS 1651823-59-4] or 1,1'- bis(di-terf-butylphosphino)ferrocene palladium dichloride [CAS 95408-45-0] and a base like CS2CO3, K2CO3 or K3PO4 in polar solvents such as 1 ,4-dioxane, THF and water or mixtures thereof at temperatures between room temperature and 120 °C for 8-15 hours.
  • Trifluoroborates of general formula (A25) or trioxatriborinanes (A26) are either commercially
  • Scheme 4 Routes for the preparation of compounds of general formula (A29) in which X is a leaving group, PG is a protective group, Aik is methyl or ethyl, X 2 and X 3 are CH or N (provided that when X 2 is N, X 3 is CH and vice versa), R A2 is alkyl or cycloalkyl and D has the meaning as given for general formula (l-B), supra.
  • Primary amines of general formula (A28) may be obtained from (A27) via removal of the protective group.
  • the same procedures apply as described for the synthesis of (A 7) from (A6) in Scheme 1 .
  • Final compounds of general formula (A29) can be synthesized from primary amines (A28) or their corresponding salts and preassembled heteroaryls (A11) with X being a leaving group like halogen via nucleophilic aromatic substitution (SNA ⁇ or palladium catalyzed Buchwald-Hartwig amination.
  • SNA ⁇ or palladium catalyzed Buchwald-Hartwig amination The procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.
  • Heteroaryls of general formula (A11) are either commercially available or can be prepared according to procedures available from the public domain. Specific examples of (A11) are described in the subsequent paragraphs.
  • primary amines (A28) or their corresponding salts may be first reacted with heteroaryls (A2) with X being a leaving group like halogen via nucleophilic aromatic substitution (SNAr) or palladium catalyzed Buchwald-Hartwig amination to give aryl iodides of general formula (A30).
  • SNAr nucleophilic aromatic substitution
  • aryl iodides of general formula (A30) The procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.
  • Heteroaryls of general formula (A2) are either commercially available or can be prepared according to procedures available from the public domain.
  • ketoacetals of general formula (A31) may be reacted with methyl hydrazinecarbimidothioate (A32) or its corresponding salts in polar solvents such as for example methanol at temperatures between room temperature and the boiling point of the solvent for 5-12 h to give triazine thioethers of general formula (A33) [for a similar approach to triazine thioethers see Duan 2012], Ketoacetals of general formula (A31) and methyl hydrazinecarbimidothioate (A32) are either commercially available or can be prepared according to procedures available from the public domain.
  • polar solvents such as for example methanol
  • Triazine thioethers of general formula (A33) in turn could be transferred to 3,6-disubstituted triazines of general formula (A27) by a two-step approach including oxidation of (A33) followed by nucleophilic aromatic substitution (SNA ⁇ with primary amines of general formula (A1) applying procedures in analogy to those described for the synthesis of compounds (A23) from (A22) in Scheme 4.
  • SNA ⁇ nucleophilic aromatic substitution
  • Carboxylic ester or amide derivatives of general formulae (A35) and (A37) may be synthesized according to the routes depicted in Scheme 5.
  • Carboxylic esters of general formula (A35) may be obtained from primary amines (A7) [see Scheme 1] and triazines of general formula (A34) via nucleophilic aromatic substitution (SNA ⁇ applying procedures in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.
  • SNA ⁇ nucleophilic aromatic substitution
  • (A 7) and (A34) can be reacted in the presence of an organic base like DIPEA in polar solvents such as NMP at temperatures between room temperature and the boiling point of the solvent for 0.5-2 h applying microwave heating.
  • Triazines of general formula (A34) are either commercially available or can be prepared according to procedures available from the public domain.
  • Carboxamides of general formula (A37) can be obtained from carboxylic esters (A35) via direct amidation.
  • esters (A35) can be reacted with amines (A36) in polar solvents such as methanol, ethanol or THF at temperatures between room temperature and the boiling point of the solvent for 1-5 hours. If an amine (A36) of limited nucleophilicity is used it is possible to increase the temperature and prolong the reaction time and/or to add Lewis acids like AIMes.
  • esters (A35) may first be hydrolyzed to carboxylic acids of general formula (A38). For saponification all methods that are known in the art may be applied. For example, esters (A35) may be reacted with bases like sodium hydroxide, lithium hydroxide or potassium hydroxide in polar, protic solvents like water or methanol or mixtures thereof at temperatures between 0 °C and the boiling point of the solvent for 0.5-24 hours. In certain cases it might be beneficial to add ethers like THF or 1,4-dioxane to the reaction mixture.
  • Carboxamides of general formula (A37) in turn can be obtained from carboxylic acids (A38) via amide coupling with appropriate amines (A36).
  • A36 amide coupling
  • acids (A38) may be reacted with amines (A36) in polar, aprotic solvents like DMF, acetonitrile or NMP via an activated acid derivative.
  • activated derivatives can be obtained from acids (A38) with reagents such as HOBt, HOAt or /V-hydroxysuccinimide and a carbodiimide such as DCC or EDC or else with preformed reagents like HATLI, PyBOP or T3P®.
  • a suitable base such as DIPEA or triethylamine can be used.
  • the activated acid derivative might be isolated prior to the reaction with the amine (A36).
  • Amide formation might also be accomplished via the acid halide (which can be formed from a carboxylic acid by reaction with e.g. oxalyl chloride, thionyl chloride or sulfuryl chloride), mixed anhydride (which can be formed from a carboxylic acid by reaction with e.g. isobutylchloroformate), imidazolide (which can be formed from a carboxylic acid by reaction with e.g. GDI) or azide (which can be formed from a carboxylic acid by reaction with DPPA).
  • the acid halide which can be formed from a carboxylic acid by reaction with e.g. oxalyl chloride, thionyl chloride or sulfuryl chloride
  • mixed anhydride which can be formed from a carboxylic acid by reaction with
  • Diamines of general formula (A39) are either commercially available or can be prepared according to procedures available from the public domain.
  • Scheme 6 Routes for the preparation of compounds of general formula (A43) in which X is a leaving group, PG is a protective group and D, X 1 , R A2 , R A3 and R B2 have the meaning as given for general formulae (l-B) and (B-2), supra.
  • Scheme 7 Routes for the preparation of compounds of general formula (A43) in which X is a leaving group, PG is a protective group and D, X 1 , R A2 , R A3 and R B2 have the meaning as given for general formulae (l-B) and (B-2), supra.
  • NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
  • CataCXium A Di(adamantan-1-yl)(butyl)phosphane (CAS Registry Number 321921-71-5)
  • HATU (1-(Bis(dimethylamino)methylene]-1/7-1 ,2,3-triazolo[4,5- b]pyridinium-3-oxo hexafluorophosphate
  • 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 LIPLC, acquiring either positive and negative ion data, and generally, only ions relating to the parent structure are reported;
  • ChemDraw is using labels in the graphical representation of stereocenters such and 'or' to describe the configuration of the stereochemical centers present in the structure. A number following the and 'or 1 flag is assigned to each stereocenter present.
  • the purification methods as described above can provide those compounds of Formula (I) which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of Formula (I) which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of Formula (I) which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known in the art or be used as salt in subsequent biological assays. It is to be understood the specific form (e.g. salt, free base etc.) of a compound of Formula (I) as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
  • PrepMethod A The compound was purified by preparative HPLC on a XbridgeTM C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeOH in a H2O/NH4HCO3 (10 mM)/NH3 (0.1 %, aq) buffer system as mobile phase;
  • PrepMethod B The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NH3 (0.1 %, aq) buffer system as mobile phase;
  • PrepMethod C The compound was purified by preparative HPLC on a XbridgeTM Shield RP18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.1 %, aq) buffer system as mobile phase;
  • PrepMethod D The compound was purified by preparative HPLC on a XbridgeTM C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NHs (0.1 %, aq) buffer system as mobile phase;
  • PrepMethod E The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/FA (0.1 %) buffer system as mobile phase;
  • PrepMethod F The compound was purified by preparative HPLC on a XbridgeTM C18 column (10 pm, 250x50 mm ID) using a gradient of MeCN in H2O/MeCN/NH3 (95/5/0.2) buffer system as mobile phase;
  • PrepMethod G The compound was purified by preparative HPLC on a Kromasil C8 column (10 pm, 250x20 mm ID) using a gradient of MeCN in H2O/MeCN/FA (95/5/0.2) buffer system as mobile phase;
  • PrepMethod H The compound was purified by preparative HPLC on a XbridgeTM C18 column (10 pm, 250x19 mm ID) using a gradient of MeCN in H2O/MeCN/NH3 (95/5/0.2) buffer system as mobile phase;
  • PrepMethod I The compound was purified by preparative HPLC on a XbridgeTM C18 ODB column (5 pm, 150x19 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM, pH 9) buffer system as mobile phase;
  • PrepMethod J The compound was purified by preparative HPLC on a WatersTM SunfireTM C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/FA (0.1%) as mobile phase;
  • PrepMethod K The compound was purified by preparative HPLC on a YMC-Actus Triart C18 column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
  • PrepMethod L The compound was purified by preparative HPLC on a WatersTM SunfireTM C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NHs (0.1 %, aq) buffer system as mobile phase;
  • PrepMethod M The compound was purified by preparative HPLC on a YMC-Actus Triart C18 column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NH3 (0.1%, aq) buffer system as mobile phase;
  • PrepMethod N The compound was purified by preparative HPLC on a XbridgeTM OBD Phenyl column (5 pm, 150x19 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NHs (0.1 %, aq) buffer system as mobile phase;
  • PrepMethod O The compound was purified by preparative HPLC on a XbridgeTM C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
  • PrepMethod P The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O as mobile phase;
  • PrepMethod Q The compound was purified by preparative HPLC on a XbridgeTM Shield RP18 OBD column (5 pm, 250x19 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
  • PrepMethod R The compound was purified by preparative HPLC on a WatersTM SunfireTM C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/FA (10mM) as mobile phase;
  • PrepMethod S The compound was purified by preparative HPLC on a XbridgeTM C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM) buffer system as mobile phase;
  • PrepMethod T The compound was purified by preparative HPLC on a XbridgeTM C18 OBD column (5 pm, 150x30 mm ID) using a gradient of 20 mM NaOH + 10% MeCN in a H2O/NH4HCO3 (10 mM)/NH3 (0.05%, aq) buffer system as mobile phase;
  • PrepMethod U The compound was purified by preparative HPLC on a XbridgeTM OBD Phenyl column (5 pm, 250x19 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
  • PrepMethod V The compound was purified by preparative HPLC on a XbridgeTM OBD Phenyl column (5 pm, 250x19 mm ID) using a gradient of MeCN in a H20/TFA (0.05%) buffer system as mobile phase;
  • PrepMethod X The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
  • PrepMethod Y The compound was purified by preparative HPLC on a XbridgeTM Shield RP18 OBD column (5 pm, 100x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
  • PrepMethod Z The compound was purified by preparative HPLC on a Waters Xselect Peptide CSH C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/FA (0.1%) buffer system as mobile phase;
  • PrepMethod Z1 The compound was purified by preparative HPLC on a Waters Xselect Peptide CSH C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NH3 (0.1 %, aq) buffer system as mobile phase;
  • PrepMethod Z2 The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NH3 (0.05%, aq) buffer system as mobile phase;
  • PrepMethod Z3 The compound was purified by preparative HPLC on a XbridgeTM C18 OBD column (5 pm, 100x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
  • PrepMethod Z4 The compound was purified by preparative HPLC on a XbridgeTM C18 OBD column (5 pm, 250x19 mm ID) using a gradient of MeCN in a H2O/TFA (0.005%) buffer system as mobile phase;
  • PrepMethod Z5 The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 pm, 250x19 mm ID) using a gradient of MeOH in a H2O/NH4HCO3 (10 mM)/NH3 (0.05%, aq) buffer system as mobile phase;
  • PrepMethod Z6 The compound was purified by preparative HPLC on a XbridgeTM Shield RP18 OBD column (5 pm, 100x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.1 %, aq) buffer system as mobile phase;
  • PrepMethod Z7 The compound was purified by preparative HPLC on a XbridgeTM C18 OBD column (5 pm, 100x50 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.1%, aq) buffer system as mobile phase;
  • PrepMethod Z8 The compound was purified by preparative HPLC on a XbridgeTM RP18 OBD column (5 pm, 100x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.1%, aq) buffer system as mobile phase.
  • PrepMethod Z9 The compound was purified by preparative HPLC on a XbridgeTM C8 column (5 pm, 250x20 mm ID) using a gradient of MeCN in H2O/MeCN/NH3 (95/5/0.2) buffer system as mobile phase;
  • PrepMethod Z10 The compound was purified by preparative HPLC on a XbridgeTM C8 column (5 pm, 250x50 mm ID) using a gradient of MeCN in H2O/MeCN/NH3 (95/5/0.2) buffer system as mobile phase.
  • PrepMethod SFC-A The compound was purified by preparative SFC on a WatersTM BEH (5 pm, 250x30 mm ID) using MeOH/H2O (NH3, 50 mM) (97/3) in CO2 as mobile phase;
  • PrepMethod SFC-B The compound was purified by preparative SFC on a Phenomenex Luna Hilic (3.5 pm, 100x3 mm ID) using MeOH/NHs 20 mM in CO2 as mobile phase;
  • PrepMethod SFC-C The compound was purified by preparative SFC on a WatersTM Acquity UPC2 BEH (3.5 pm, 100x3 mm ID) using MeOH/H 2 O (NH 3 , 50 mM) (97/3) in CO 2 as mobile phase;
  • PrepMethod SFC-D The compound was purified by preparative SFC on a WatersTM BEH (5 pm, 250x30 mm ID) using MeOH/NHs (20 mM) in CO2 as mobile phase;
  • PrepMethod SFC-E The compound was purified by preparative SFC on a Phenomenex Luna Hilic (5 pm, 250x30 mm ID) using MeOH/NHs 20 mM in CO2 as mobile phase.
  • PrepMethod Parallel A The compound was purified by preparative HPLC on a WatersTM XbridgeTM C18 column (5 pm, 100x10 mm ID) using a gradient (2-94%) of MeCN in H2O/NH3 (pH 10) buffer system as mobile phase;
  • PrepMethod Parallel B The compound was purified by preparative HPLC on a WatersTM XselectTM CSH Fluoro Phenyl column (5 pm, 100x10 mm ID) using a gradient (2-94%) of MeCN in H2O/FA (pH 3) buffer system as mobile phase;
  • PrepMethod Parallel C The compound was purified by preparative HPLC on a WatersTM XbridgeTM C18 OBD column (5 pm, 150x19 mm ID) using a gradient (5-95%) of MeCN in H2O/MeCN/NHs (95/5/0.2) (pH 10) buffer system as mobile phase;
  • PrepMethod Parallel D The compound was purified by preparative HPLC on a XbridgeTM C18 OBD column (5 pm, 150x19 mm ID) using a gradient (5-95%) of MeCN in a H2O/NH4HCO3 (10 mM) (pH 9) buffer system as mobile phase.
  • a solution of the respective amine nucleophile or its salt (1 eq.) in 1 ,4-dioxane under nitrogen at rt is treated with the respective heteroaryl electrophile (0.5-4 eq.), CS2CO3 (1.2-5 eq.) and Pd PEPPSI-lpentCI [CAS 1612891-29-8] (3-7 mol%) and the reaction mixture stirred under heating (100 °C) until TLC and/or LCMS indicate complete consumption of the starting material (typically overnight).
  • the reaction mixture is either filtered through a pad of Celite or silica, the filter cake washed with EtOAc and the combined filtrates concentrated under reduced pressure.
  • the obtained crude material is either triturated with PE/EtOAc or subjected to prep. TLC and/or prep. HPLC to give the desired aniline product.
  • reaction mixture is concentrated under reduced pressure and the residue partitioned between EtOAc and water. The phases are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with water and/or brine, dried over Na2SO4, filtered and evaporated and the obtained crude material subjected to prep. TLC and/or prep. HPLC to give the desired aniline product.
  • reaction mixture is diluted with EtOAc and washed sequentially with water and brine.
  • reaction mixture is diluted with water or brine and the aqueous layer extracted with EtOAc.
  • the organic layer is dried over Na2SC>4, filtered and evaporated.
  • the obtained crude material is either triturated with PE/EtOAc or subjected to prep. TLC and/or prep. HPLC to give the desired coupling product.
  • reaction mixture is filtered through a pad of Celite, the filter cake washed with DCM and the combined filtrates concentrated under reduced pressure.
  • the obtained crude material is subjected to prep. TLC and/or prep. HPLC to give the desired coupling product.
  • a solution of the respective aryl halide (1 eq.) in a mixture of 1 ,4-dioxane and water under nitrogen at rt is treated with the respective boronic acid derivative (A5) (1.5-2 eq.) or (A26) (10 eq.), CS2CO3 (3 eq.) or K2CO3 (3 eq.) or K3PO4 (2-3 eq.) and 1 , 1 '-bis(di-fert- butylphosphino)ferrocene palladium dichloride [CAS 95408-45-0] (5-10 mol%) or 1 ,T- bis(diphenylphosphino)ferrocene palladium dichloride [CAS 72287-26-4] (10 mol%) and the reaction mixture stirred under heating (80-100 °C) until TLC and/or LCMS indicate complete consumption of the starting material (2-18).
  • the reaction mixture is filtered through a pad of Celite, the filter cake washed with DCM and
  • reaction mixture is diluted with water, the phases separated and the aqueous phase extracted with EtOAc.
  • the combined organic layers are dried over Na2SC>4, filtered and evaporated and the obtained crude material subjected to prep. TLC and/or C18-flash chromatography or prep. HPLC to give the desired coupling product.
  • a solution of the respective ester (A35) in MeOH is treated with the respective amine or its salt (A36) (4-100 eq., neat or as a solution in THF) and where applicable additionally with DI PEA (4-8 eq.) at rt.
  • the vial is capped, and the reaction mixture stirred at rt or heating (60-70 °C) until TLC and/or LCMS indicate complete consumption of the starting material (3).
  • the reaction mixture is concentrated under reduced pressure and the obtained crude material subjected to preparative HPLC to give the desired amide.
  • reaction mixture is concentrated under reduced pressure and the obtained crude material is subjected to flash chromatography on silica to give the desired oxidation product.
  • Step A i-1 a tert-Butyl ((1 S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate
  • Step B i-1 b tert-Butyl ((1 S,3S)-3-((2-oxo-2H-[1 ,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate
  • Step B i-3b 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one x 2 HCI
  • GM5 (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (1.29 g, 8.21 mmol), 1 ,8-naphthyridin-2(1/7)-one (CAS Reg. No.
  • GM4A 6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (301 mg, 1.91 mmol), 3-bromo-1-methylpyridin-2(1/7)-one (81971-38-2 ) (200 mg, 1.06 mmol), CS2CO3 (1.04 g, 3.19 mmol) and 1 ,1'-bis(di-terf-butylphosphino)ferrocene palladium dichloride (CAS Reg. No.
  • GM3 2-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (560 mg, 2.51 mmol), 3-chloropyridin-2(1/7)-one (CAS Reg. No. 13466-35-8) (651 mg, 5.02 mmol), potassium phosphate, tribasic (1.60 g, 7.53 mmol), Cu(l)l (478 mg, 2.51 mmol) and re/-(1R,2R)- /V ⁇ A ⁇ -dimethylcyclohexane-l ⁇ -diamine (357 mg, 2.51 mmol) were reacted in 1 ,4-dioxane (60 mL) at 100 °C for 18 h.
  • Step B i-17b (1S,3S)-A/ 1 -(5-Chloropyrazin-2-yl)-A/ 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine i-17b
  • GM1A (1 S,3S)-/V 1 -(5-iodopyridin-2-yl)cyclopentane-1 ,3-diamine compound i-17a (1.26 g, 3.05 mmol), 2,5-dichloropyrazine (CAS Reg. No. 19745-07-4) (0.910 g, 6.11 mmol) and Na2CC>3 (1.62 g, 15.3 mmol) were reacted in DMSO (25 mL) at 120 °C for 15 h.
  • Step B i-21 b tert-Butyl ((1 S,3S)-3-((5-(2-oxoquinolin-1 (2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate According to GM2 1-(6-chloropyridin-3-yl)quinolin-2(1/7)-one compound i-21 a (90 mg, 0.35 mmol), tert-butyl ((1 S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No.
  • Step C i-21 c 1-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one
  • Step A i-22a tert-Butyl ((1 S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate m-CPBA (5.60 g, 25.95 mmol) was added in small portions to a solution of 3-(methylthio)-1 ,2,4- triazine (CAS Reg. No. 28735-21-9) (3.0 g, 23.6 mmol) in DCM (80 mL) at 0 °C and the resulting suspension was stirred at 20 °C for 2 h.
  • 3-(methylthio)-1 ,2,4- triazine CAS Reg. No. 28735-21-9
  • Step B i-22b tert-Butyl ((1 S,3S)-3-((6-bromo-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
  • Step C i-22c tert-Butyl ((1 S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
  • GM4B tert-butyl ((1 S,3S)-3-((6-bromo-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carba- mate compound i-22b (1.5 g, 4.2 mmol), potassium cyclopropyltrifluoroborate (2.48 g, 16.8 mmol), CS2CO3 (5.46 g, 16.8 mmol) and CataCXium A Pd G3 (CAS Reg. No. 1651823-59-4) (0.61 g, 0.84 mmol) were reacted in dioxane (70 mL) at 100 °C for 15 h.
  • GM5 (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (2.93 g, 18.6 mmol), 1-methyl-1 ,3-dihydro-2/7-imidazo[4,5-b]pyridin-2-one (CAS Reg. No.
  • Step A i-28a tert-Butyl ((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
  • GM4A tert-butyl ((1 S,3S)-3-((6-bromo-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carba- mate compound i-22b (300 mg, 0.84 mmol), 2,4,6-trimethyl-1 ,3,5,2,4,6-trioxatriborinane in THF (2.10 g, 8.37 mmol), K3PO4 (356 mg, 1.67 mmol) and 1 ,1’-bis(di-tert-butylphosphino)ferrocene palladium dichloride (CAS Reg. No.
  • Step B i-28b (I S.SSJ-A ⁇ -fe-Methyl-l ⁇ -triazin-S-yQcyclopentane-I.S-diamine x 2 TFA
  • Step A i-31 a tert-Butyl ((1 S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)carbamate
  • GM2 tert-butyl ((1 S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (420 mg, 2.10 mmol), 2-bromo-5-methylpyrazine (CAS Reg. No. 98006-90-7) (363 mg, 2.10 mmol), CS2CO3 (1.03 g, 3.15 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (62 mg, 0.07 mmol) were reacted in 1 ,4-dioxane (20 mL) at 100 °C for 15 h.
  • Step A i-35a tert-Butyl ((1 S,3S)-3-((3-cyano-2-oxo-2/-/-[1,3'-bipyridin]-6'- yl)amino)cyclopentyl)carbamate
  • Methyl hydrazinecarbimidothioate HI (CAS Reg. No. 35600-34-1) (9.87 g, 42.4 mmol) was added to a stirred solution of 1 ,1-dimethoxypropan-2-one (CAS Reg. No. 6342-56-9) (5.00 g, 42.3 mmol) in ethanol (250 mL) at rt and the resulting solution stirred at 80 °C for 16 h. The solvent was removed under reduced pressure and the obtained residue purified by flash chromatography on silica (gradient: 40 - 50% EtOAc in PE) to give the title compound (2.77 g, 46%) as a yellow solid.
  • GM32-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (150 mg, 0.67 mmol), 2- hydroxy-5-methylpyridine (CAS Reg. No. 1003-68-5) (367 mg, 3.36 mmol), CS2CO3 (658 mg, 2.02 mmol), Cu(l)l (128 mg, 0.67 mmol) and re/-(1R,2R)-/V 1 ,/ ⁇ / 2 -dimethylcyclohexane-1 ,2- diamine (96 mg, 0.67 mmol) were reacted in 1 ,4-dioxane (15 mL) at 100 °C for 15 h.
  • GM32-fluoro-5-iodopyridine (105 mg, 0.47 mmol), 2- hydroxy-3-methylpyridine (CAS Reg. No. 1003-56-1) (257 mg, 2.35 mmol), CS2CO3 (460 mg, 1.41 mmol), Cu(l)l (90 mg, 0.47 mmol) and re/-(1R,2R)-/V 1 ,/ ⁇ / 2 -dimethylcyclohexane-1 ,2-diamine (67 mg, 0.47 mmol) were reacted in 1 ,4-dioxane (10 mL) at 100 °C for 15 h.
  • Step A i-42a tert-Butyl ((1 S,3S)-3-((5-methoxy-2-oxo-2/-/-[1,3'-bipyridin]-6'- yl)amino)cyclopentyl)carbamate re/ ⁇ IR ⁇ -A/ ⁇ A ⁇ -Dimethylcyclohexane-l ⁇ -diamine (53 mg, 0.37 mmol) was added to fert-butyl ((1 S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1 a (300 mg, 0.74 mmol), 5-methoxypyridin-2-ol (233 mg, 1.86 mmol), CS2CO3 (727 mg, 2.23 mmol) and Cu(l)l (70.8 mg, 0.37 mmol) in 1 ,4-dioxane (15 mL) at 25 °C.
  • Step A i-44a tert-Butyl ((1 S,3S)-3-((5-chloro-2-oxo-2H-[1 ,3'-bipyridin]-6'- yl)amino)cyclopentyl)carbamate re/-(1F?,2F?)-/V 1 ,/ ⁇ / 2 -Dimethylcyclohexane-1 ,2-diamine (106 mg, 0.74 mmol) was added to tertbutyl ((1 S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (300 mg, 0.74 mmol), 5-chloropyridin-2(1/7)-one (193 mg, 1.49 mmol), Cu(l)l (142 mg, 0.74 mmol) and CS2CO3 (727 mg, 2.23 mmol) in 1 ,4-dioxane (25
  • Step B i-44b 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-5-chloro-2H-[1,3'-bipyridin]-2-one
  • Pd-PEPPSI-lpentCI 2-methylpyridine (CAS Reg. No. 1612891-29-8) (29 mg, 0.03 mmol) was added to methyl 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1/7-benzo[c(]imidazole-5- carboxylate compound i-48d (110 mg, 0.35 mmol), CS2CO3 (338 mg, 1.04 mmol) and (1 S,3S)- /V 1 -(6-cyclopropyl-1 ,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (76 mg, 0.35 mmol) in 1 ,4-dioxane (20 mL) at rt and the resulting mixture was stirred at 100 °C for 18 h under nitrogen.
  • Step B i-49b 6'-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1-(4- methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one
  • Pd-PEPPSI-lpentCI 2-methylpyridine (CAS Reg. No. 1612891-29-8) (21 mg, 0.03 mmol) was added to 6'-chloro-5-(1-(4-methoxybenzyl)-1/7-1 ,2,3-triazol-4-yl)-2/7-[1 ,3'-bipyridin]-2-one compound i-49a (200 mg, 0.51 mmol), (1 S,3S)-/V 1 -(6-cyclopropyl-1 ,2,4-triazin-3- yl)cyclopentane-1 ,3-diamine compound i-22d (167 mg, 0.76 mmol) and CS2CO3 (331 mg, 1.02 mmol) in 1 ,4-dioxane (10 mL) at rt and the resulting mixture was stirred at 100 °C for 15 h under nitrogen.
  • XPhos (0.431 g, 0.90 mmol), XPhos Pd G3 (CAS Reg. No. 1445085-55-1) (0.383 g, 0.45 mmol), 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1/7-pyrazole (CAS Reg. No. 110539-88-0 ) (2.13 g, 6.79 mmol), 5-iodopyridin-2-ol (CAS Reg. No.
  • Pd-PEPPSI-lpentCI 2-methylpyridine (CAS Reg. No. 1612891-29-8) (14 mg, 0.02 mmol) was added to 6'-chloro-5-(1-(4-methoxybenzyl)-1/7-pyrazol-4-yl)-2/7-[1 ,3'-bipyridin]-2-one compound i-50b (130 mg, 0.33 mmol), (1 S,3S)-/V 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1 ,3- diamine compound i-22d (109 mg, 0.50 mmol) and CS2CO3 (216 mg, 0.66 mmol) in 1 ,4- dioxane (10 mL) at rt and the resulting mixture was stirred at 100 °C for 15 h under nitrogen.
  • Step A i-51 a 5-Bromo-3-(6-fluoropyridin-3-yl)-1-methyl-1,3-dihydro-2H-benzo[cf]imidazol-2-one
  • Step B i-51 b 5-Bromo-3-(6-(((1 S,3S)-3-((6-cyclopropyl-1 ,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-benzo[cf]imidazol-2- one
  • Step A i-52a tert-Butyl ((1 S,3S)-3-((5-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate m-CPBA (733 mg, 3.40 mmol) was added portion-wise to a stirred solution of 5-methyl-3- (methylthio)-1 ,2,4-triazine (CAS Reg. No. 28735-24-2) (400 mg, 2.83 mmol) in DCM (8 mL) at rt and the resulting solution was stirred at this temperature for 2 h. The solvent was removed under reduced pressure to afford a pale-yellow solid which was dissolved in n-BuOH (8 mL).
  • Step A i-53a tert-Butyl ((1 S,3S)-3-((5,6-dimethyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
  • Step A i-54a tert-Butyl ((1 S,3S)-3-((2-oxo-3-(trifluoromethyl)-2H-[1,3 , -bipyridin]-6'- yl)amino)cyclopentyl)carbamate
  • TMEDA (0.942 mL, 6.24 mmol) was added to (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (983 mg, 6.24 mmol), pyrimidin-4(3H)-one (CAS Reg. No. 4562-27-0) (300 mg, 3.12 mmol) and Cu(OTf)2 (2.26 g, 6.24 mmol) in DCM (35 mL) at rt. Air was allowed to diffuse into the reaction mixture via a CaCh-tube on top of the flask. The resulting suspension was stirred at rt for 18 h.
  • Step C i-60c 3-(6-Chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5-carbonitrile
  • Step D i-60d 3-(6-Chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5-carbonitrile -60d
  • Step B i-61 b 3-Amino-4-((6-chloropyridin-3-yl)amino)benzonitrile
  • Step C i-61 c 1-(6-Chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5-carbonitrile
  • Step D i-61 d
  • 1-(6-Chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5-carbonitrile -61d CH3I 157 mg, 1.11 mmol
  • 2-Fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (300 mg, 1.35 mmol) was added to a mixture of pyridazin-3(2/7)-one (CAS Reg. No. 504-30-3) (259 mg, 2.69 mmol), Cu(l)l (128 mg, 0.67 mmol), CS2CO3 (1315 mg, 4.04 mmol) and re/-(1R,2R)-/V 1 ,/ ⁇ / 2 -dimethylcyclohexane-1 ,2- diamine (96 mg, 0.67 mmol) in 1 ,4-dioxane (20 mL) at rt and it was stirred at 100 °C for 15 h under nitrogen.
  • Step B i-63b 6'-Chloro-5-ethynyl-2H-[1,3'-bipyridin]-2-one
  • Step B i-67b 6'-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one
  • Step E i-81e 3-(6-Chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5- carbonitrile
  • Step B i-82b 5-Amino-6-((6-chloropyridin-3-yl)amino)nicotinonitrile
  • Step C i-82c 3-(6-Chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile
  • Step A i-85a tert-Butyl ((1 S,3S)-3-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1,2,4-triazin-3- yl)amino)cyclopentyl)carbamate
  • CS2CO3 (819 mg, 2.51 mmol) was added to a mixture of terf-butyl ((1 S,3S)-3-((6-bromo-1 ,2,4- triazin-3-yl)amino)cyclopentyl)carbamate compound i-22b (300 mg, 0.84 mmol), 1 - (tetra hydro- 2/7-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1/7-pyrazole (CAS Reg. No.
  • Step A i-86a tert-Butyl ((1 S,3S)-3-((6-(ethylthio)-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
  • Step A i-87a re/-tert-Butyl ((1 /?,3/?)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
  • Step B i-87b re/-(1R,3R)-/V 1 -(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 3HCI
  • Step A i-90a 6-Bromo-3-(methylthio)-1,2,4-triazine terf-Butyl nitrite (10.6 g, 103 mmol) was added dropwise to a mixture of 6-bromo-1 ,2,4-triazin-3- amine (CAS Reg. No. 58-4-028-01) (3.0 g, 17 mmol) and 1,2-dimethyldisulfane (16.2 g, 171 mmol) in MeCN (60 mL) at rt over a period of 10 minutes under air and the resulting solution was stirred at this temperature for 16 h. The solvent was removed under reduced pressure.
  • Step D i-90d 3-(Methylthio)-A/-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide
  • 6-carboxamide m-CPBA (1.05 g, 4.86 mmol) was added dropwise to 3-(methylthio)-/V-(oxetan-3-yl)-1,2,4- triazine-6-carboxamide compound i-90d (1.0 g, 4.42 mmol) in DCM (10 mL) at rt and the resulting solution was stirred at rt for 30 min.
  • CataCXium A Pd G3 (55 mg, 0.08 mmol) was added to a mixture of methyl 3-bromo-4-fluoro-2- methoxybenzoate (CAS Reg. No. 1935415-04-05) (200 mg, 0.76 mmol), 2-chloropyridine-5- boronic acid (CAS Reg. No. 444120-91-6) (179 mg, 1.14 mmol), K2CO3 (210 mg, 1.52 mmol) and water (2 mL) in 1 ,4-dioxane (8 mL) at rt under nitrogen and it was stirred at 80 °C for 8 h. The reaction mixture was poured into water (50 mL) and filtered through a Celite pad.
  • 3-Bromo-4-fluoro-2-methoxybenzamide compound i-92a (320 mg, 1.29 mmol) was added to a mixture of PdCh(dppf) DCM adduct (105 mg, 0.13 mmol), Na2COs (273 mg, 2.58 mmol) and 2- chloropyridine-5-boronic acid (CAS Reg. No. 444120-91-6) (305 mg, 1.94 mmol) in 1 ,4-dioxane (15 mL) and water (2.5 mL) at rt and it was stirred at 80 °C for 8 h. The reaction mixture was poured into water (50 mL) and filtered through Celite.
  • TFAA (0.13 mL, 0.93 mmol) was added to a mixture of TEA (0.258 mL, 1.85 mmol) and 3-(6- chloropyridin-3-yl)-4-fluoro-2-methoxybenzamide compound i-92b (130 mg, 0.46 mmol) in DCM (10 mL) at 0 °C.
  • DCM 10 mL
  • the reaction was allowed to reach rt and stirred at rt for 4 h.
  • the reaction mixture was poured into water (50 mL) and extracted with DCM (3 x 20 mL).
  • Step A i-104a tert-Butyl ((1S,3S)-3-((6-(1-ethoxyvinyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
  • Step B i-104b 1-(3-(((1S,3S)-3-Aminocyclopentyl)amino)-1,2,4-triazin-6-yl)ethan-1-one
  • RockPhos Pd G3 (CAS Reg. No. 2009020-38-4) (1.97 g, 2.35 mmol) was added to a mixture of 4-bromo-6-chloro-2-(4-methoxybenzyl)pyridazin-3(2/7)-one compound i-107a (7.75 g, 23.5 mmol), (E)-benzaldehyde oxime (3.70 g, 30.6 mmol) and CS2CO3 (15.6 g, 47.8 mmol) in DMF (40 mL) and water (10 mL) at 15 °C and it was stirred at 80 °C for 15 h. The reaction mixture was poured into sat.
  • 6-Chloro-4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one CS2CO3 (293 mg, 0.90 mmol) was added to a mixture of 6-chloro-4-hydroxy-2-(4- methoxybenzyl)pyridazin-3(2/-/)-one compound i-107b (200 mg, 0.75 mmol) and it was stirred at 20 °C for 1.5 h.
  • Sodium chlorodifluoroacetate (CAS Reg. No. 1895-39-2) (343 mg, 2.25 mmol) was added and the resulting mixture was stirred at 100 °C for 3.5 h. The reaction mixture was poured into sat.
  • the reaction was run in 10 parallel batches of identical size.
  • Step E i-109e rac-tert-Butyl (4-hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)carbamate
  • Step F i-109f rac-4-Amino-3-(((6-methyl-1,2,4-tnazin-3-yl)amino)methyl)butan-1-ol 109f
  • Step G i-109g rac-4-((5-lodopyridin-2-yl)amino)-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol
  • K3PO4 (60 mg, 0.28 mmol) was added to a mixture of (1 S,3S)-/V 1 -(6-cyclopropyl-1 ,2,4-triazin-3- yl)-/V 3 -(5-iodopyridin-2-yl)cyclopentane-1 ,3-diamine compound i-22e (40 mg, 0.09 mmol), pyridin-2(1/7)-one (CAS Reg. No.
  • EXAMPLE 52 e'- ⁇ lS.SSJ-S-Ge-Cyclopropyl-l ⁇ -triazin-S-yQaminoJcyclopentyQaminoJ-S-
  • GM4A (1 S,3S)-/V 1 -(6-cyclopropyl-1 ,2,4-triazin-3-yl)-/ ⁇ / 3 -(5-iodopyridin-2- yl)cyclopentane-1 ,3-diamine compound i-22e (95 mg, 0.22 mmol), (2,6-difluorophenyl)boronic acid (CAS Reg. No. 162101-25-9) (71 mg, 0.45 mmol), PdCI 2 (dppf) (CAS Reg.
  • GM2 CS2CO3 (238 mg, 0.73 mmol) was added to a mixture of (1 S,3S)-/V 1 -(6- cyclopropyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-22d (128 mg, 0.59 mmol), 3-(6-chloropyridin-3-yl)-1-methylimidazolidine-2, 4-dione compound i-7b (110 mg, 0.49 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (20.50 mg, 0.02 mmol) in 1 ,4-dioxane (3 mL) at 25 °C.
  • Example 58 The following Examples (58-66) where prepared in analogy to Example 57 starting from compound i-22d and the given electrophile intermediate, applying Buchwald-Hartwig amination (GM2). For the preparation of Example 58 DMF was used as solvent.
  • GM2 Buchwald-Hartwig amination
  • GM2 CS2CO3 (329 mg, 1.01 mmol) was added to a mixture of (1 S,3S)-/V 1 -(6- methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 2TFA compound i-28b (85 mg, 0.20 mmol), 6'-chloro-2/7-[1 ,3'-bipyridin]-2-one compound i-29a (62 mg, 0.30 mmol) and Pd-PEPPSI- IpentCI 2-methylpyridine (8.5 mg, 10 pmol) in dioxane (5 mL) at rt and the resulting suspension was stirred at 100 °C for 15 h under nitrogen.
  • ethyl 3-(((1S,3S)-3-((2-oxo-2/7-[1,3'-bipyridin]-6'-yl)amino)cyclo- pentyl)amino)-1,2,4-triazine-6-carboxylate compound 10 (33.3 mg, 0.08 mmol) was mixed with DMSO (0.5 mL), DIPEA (0.055 mL, 0.32 mmol) and 2-aminoacetamide HCI (CAS Reg. No. 1668-10-6) (17 mg, 0.16 mmol) and it was stirred at 70 °C overnight. The volatiles were removed and the residue redissolved in MeOH (1 mL).
  • Table 8 The following Examples (69-76) where prepared in analogy to Example 68 starting from compound 10 and the given amine, applying GM7.
  • GM1A the free base of (1 S,3S)-/V 1 -(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3- diamine 2TFA compound i-28b (60 mg, 0.31 mmol) was added to a mixture of 3-chloro-6'- fluoro-2/7-[1 ,3'-bipyridin]-2-one compound i-13a (139 mg, 0.62 mmol) and K2CO3 (129 mg, 0.93 mmol) in DMSO (5 mL). The resulting mixture was stirred at 120 °C for 15 h under a nitrogen atmosphere.

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Abstract

A compound with the Formula (I): A-B-C wherein A is of the formula (Ia) where X1 is N B is of formula (B-1) or (B-2) and C is selected from the group consisting of optionally substituted C6-10 carboaryl, C5-6 heteroaryl and C5-10 heterocyclyl and their use as PCSK9 inhibitors.

Description

PCSK9 Inhibitors and Methods of Use Thereof
The present disclosure relates to compounds which inhibit PCSK9 and their use in methods of treatment. The application claims the benefit of priority to US application No. 63/376,791, filed on 23rd September 2022, US application No. 63/483,797 filed on 8th February 2023, and US application No. 63/580,500 filed on 5 September 2023, which are incorporated herein by reference in their entirety.
Background
PCSK9, also referred to as “proprotein convertase subtilisin/kexin 9”, is a member of the secretory proprotein convertase family and plays an important role in cholesterol metabolism. PCSK9 increases the levels of circulating LDL cholesterol (LDL-C) via the enhanced degradation of the LDLRs independently of its catalytic activity. Secreted PCSK9 binds to the Epidermal Growth Factor domain A (EGFA) of the LDL receptor (LDLR) at the cell surface and the PCSK9/LDLR complex is internalized into endosomal/lysosomal compartments. The enhanced binding affinity of PCSK9 to the LDLR at the acidic pH of late endosomes/lysosomes reduces LDLR recycling and instead targets LDLR for lysosomal degradation. Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with low plasma LDL-C levels and a reduction in the incidence of adverse cardiovascular events.
For cardiovascular disease, few options exist for inhibiting PCSK9. Statins actually upregulate PCSK9 in HepG2 cells and in human primary hepatocytes through the increased expression of SREBP-2, a transcription factor that upregulates both the LDLR and PCSK9 genes. Since an elevated level of PCSK9 decreases the abundance of LDLR on the cell surface, increasing doses of statins have failed to achieve proportional LDL-C lowering effects.
Two monoclonal antibodies (mAbs) that bind selectively to extracellular PCSK9 and prevent its interaction with the LDLR, alirocumab and evolocumab, have recently received FDA approval for lowering LDL-C levels. In clinical trials, alirocumab showed an about 50% decrease in LDL levels compared to placebo (Elbitar 2016). Patients taking evolocumab showed an about 60- 75% decrease in LDL levels. The potency of these drugs demonstrates the potential for inhibitors of PCSK9 to be effective treatments for those with hypercholesterolemia and other cardiovascular diseases. However, both antibody drugs require intravenous administration and can cause allergic reactions or other deleterious immune responses in the body. Cardiovascular diseases often require management over a person’s lifetime, unlike an infection that could be episodic. Thus, ease of dosing and administration become important factors for patient compliance with maintenance drug treatments. There is a need for PCSK9 inhibitors with increased efficacy and greater ease of administration, which can be achieved with small molecule PCSK9 inhibitors. WO 2020/150473 A2 relates to heteroaryl compounds and pharmaceutical preparations thereof. It also relates to methods of treating or preventing cardiovascular diseases, and methods of treating sepsis or septic shock, using the described novel heterocyclic compounds. WO 2020/150474 A1 relates to an inhibitor pharmacophore of PCSK9 and heteroaryl compounds that bind the PCSK9 protein. Summary A first aspect provides a compound with the Formula (I): A-B-C (I) or a pharmaceutically acceptable salt and tautomeric forms or stereoisomers thereof, wherein A is of the following formula:
Figure imgf000004_0001
wherein the wavy line indicates the point of attachment to B; X1 is N; RA2 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) C1-6 alkoxy, optionally substituted by OH, C1-6 alkyl amido, or one or more halo groups; (vi) C1-6 acyl amido (wherein the acyl is optionally substituted by H or methyl); (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, OH, C2-3 alkynyl, C4-6 heterocyclyl, C1-3 alkyl wherein the C1-3 alkyl is optionally substituted with one or more halo or OH groups; (xiii) OH; and (xiv) C1-6 alkylamino; RA3 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon which is optionally substituted by OH, CN, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkyl acyl, C1-6 acyloxy, carboxy, C1-6 alkyl ester, C1-6 alkylamino, -C(=O)NH2, C1-6 alkyl amido, C1-6 alkyl acylamido, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl or one or more halo groups; (v) OH; (vi) C1-6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclyl or one or more halo groups; (vii) C1-6 acyloxy; (viii) C4 heterocycyl; (ix) NH2; (x) C1-6 alkylamino, optionally substituted by CN, OH, C4 heterocyclyl; (xi) C1-6 dialkylamino, optionally substituted by -NH2; (xii) C1-6 acylamido (where acyl substituent is H or Me); (xiii) carbaimidoyl or methyl-carbaimidoyl; (xiv) carboxyamino; (xv) C1-6 thioalkyl, optionally substituted by OH or NH2; (xvi) C1-6 alkyl sulfinyl; (xvii) C1-6 alkyl sulfonyl, optionally substituted by one or more halo groups; (xviii) C1-6 sulfonimodyl; (xix) C1-6 alkyl phosphinyl; (xx) carboxy; (xxi) C(=O)NH2; (xxii) C1-6 alkyl ester; (xxiii) C1-6 alkyl acyl, optionally substituted by one or more halo groups; (xxiv) C1-6 alkyl amido; or wherein RA3 and RA2 together with the carbon atoms to which they are bound form: (i) an optionally substituted C5-7 heterocycle ring; (ii) an optionally substituted C5-7 heteroaromatic ring; (iii) an optionally substituted C6 carboaromatic ring; (iv) an optionally substituted C5-7 carbocyclic ring wherein the optional substituents are selected from C1-6alkyl, halo, C1-6 alkoxy, NH2, C1-6alkylamino, OH, and CN; wherein B is of formula (B-1) or (B-2) (i)
Figure imgf000006_0001
wherein the wavy line indicates the point of attachment to A and C; RB1 is H, OH, =CHCH2-OH, O-C1-4 alkyl, C1-4 alkyl which C1-4 alkyl is optionally substituted by OH or OMe; (ii)
Figure imgf000006_0002
wherein the wavy line indicates the point of attachment to A and C; RB2 is C1-2 alkyl-OH, CH2CONHMe or C1-3 alkyl; wherein C is selected from the group consisting of C6-10 carboaryl, C5-6 heteroaryl and C5-10 heterocyclyl, which groups are optionally substituted by: (i) a group selected from C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl C4-10 heterocyclyl, or C5-10 bridged heterocyclyl, spiro C6-12heterocyclyl or a spiro C6-12 carbocyclyl, which are themselves optionally substituted by one or more of the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C1-6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1-6 alkoxy with optional substituents of one or more halo groups; f) C1-6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; h) C5-6 heteroaryl; i) C4-10 carbocyclyl with an optional methyl or =O substituent; j) C6-10 carboaryl with optional substituents of one or more halo groups; l) P(=O)Me2; m) carboxy or CH2-carboxy; n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; and/or (ii) one or more groups selected from carboxy, CN, halo, nitro, C1-6 alkyl, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkylacyl, C1-6 alkyl amido, di-C1-6 alkyl amido, C1-6 alkyl sulfonamido, and di-C1-6 alkyl sulfonamido. A second aspect provides a pharmaceutical composition comprising the compound of the first aspect and a pharmaceutically acceptable diluent, carrier or excipient. The third aspect provides the compound of the first aspect for use in a method of therapy. The third aspect also provides the use of a compound of the first aspect in the manufacture of a medicament for treating a cardiovascular disease. The third aspect also provides a compound of the first aspect for use in the treatment of a cardiovascular disease. The third aspect also provides a method of treating a cardiovascular disease comprising administering a therapeutically effective amount of a compound of the first aspect or a composition according to the second aspect to a patient in need thereof. The disclosure includes the combination of the aspects and features described except where such a combination is clearly impermissible or expressly avoided. Detailed Description Aspects and embodiments will now be discussed. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference. Compounds of Formula (I) and its use in the treatment of cardiovascular diseases are described herein. The compounds disclosed herein are PCSK9 inhibitors. The compounds may have higher inhibition of PCSK9, lower hERG activity, improved secondary pharmacology profile including GSK3β and/or other kinases, good stability, and/or improved activity in the treatment of cardiovascular diseases. The compounds may have an improved secondary pharmacology profile or an improved off-target profile. Definitions 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. The term “substituent” 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. A wide variety of 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. Unless otherwise stated, halo is selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), such as fluoro. Cyano (nitrile, carbonitrile): -CN. Hydroxy: -OH. Oxo: =O (oxygen double bonded to the rest of the molecule). 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. Thus, the term “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. The term “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. Examples of saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5) and hexyl (C6). Examples of saturated linear alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), n-butyl (C4), n-pentyl (amyl) (C5) and n-hexyl (C6). Examples of saturated branched alkyl groups include iso-propyl (C3), iso-butyl (C4), sec-butyl (C4), tert-butyl (C4), iso-pentyl (C5), and neo-pentyl (C5). C2-6 Alkenyl: The term “C2-6 alkenyl” as used herein, pertains to a hydrocarbon group having one or more carbon-carbon double bonds. Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, - CH=CH2), 1-propenyl (-CH=CH-CH3), 2-propenyl (allyl, -CH-CH=CH2), isopropenyl (1- methylvinyl, -C(CH3)=CH2), butenyl (C4), pentenyl (C5), and hexenyl (C6). 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. Examples of C16 alkoxy groups include, but are not limited to, OMe, OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (isopropoxy), O(nBu) (n-butoxy), O(sBu) (sec-butoxy), O(iBu) (isobutoxy), and O(tBu) (tert-butoxy). C1-6 acyloxy: The term C1-6 acyloxy (reverse ester) as used herein, pertains to an -OC(=O)R, wherein R is a C1-6 hydrocarbon group. Examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, or -OC(=O)C(CH3)3. Amino: -NR1R2, wherein R1 and R2 are independently amino substituents, for example, hydrogen, a C1-6 hydrocarbon group (also referred to as C1-6 alkylamino or C1-6 dialkylamino), or, in the case of a “cyclic” amino group, R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 6 ring atoms. Amino groups may be primary (-NH2), secondary (-NHR1), or tertiary (-NHR1R2), and in cationic form, may be quaternary (-+NR1R2R3). Examples of amino groups include, but are not limited to -NH2, -NHCH3, -NHC(CH3)2, -N(CH3)2, -N(CH2CH3)2, and -NHPh. Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino. C1-6 acylamido: Acylamido (acylamino): NR1C(=O)R2, wherein R1 is an amide substituent, for example, hydrogen or a C1-6 hydrocarbon group, and R2 is an acyl substituent, for example, a C1-6 hydrocarbon group. Examples of acylamide groups include, but are not limited to, NHC(=O)CH3 and NHC(=O)CH2CH3. In some embodiments R1 and R2 may together form a cyclic or bicyclic structure and form a cyclic acylamido groups. Examples of such groups include succinimidyl, maleimidyl, phthalimidyl, 2-oxo-3H-benzimidazol-1-yl, 3-methyl-2-oxo- benzimidazol-1-yl, 1-methyl-2-oxoimidazo[4,5-b]pyridin-3-yl, 2,5-dioxoimidazolidin-1-yl and 2,4- dioxoimidazolidin-1-yl:
Figure imgf000010_0001
succinimidyl maleimidyl phthalimidyl (2-oxo-3H-benzimidazol-1-yl)
Figure imgf000010_0002
(3-methyl-2-oxo-benzimidazol-1-yl) (1-methyl-2-oxo-imidazo[4,5-b]pyridin-3-yl)
Figure imgf000010_0003
(2,4-dioxoimidazolidin-1-yl) (2,5-dioxoimidazolidin-1-yl) Carbaimidoyl: -C(=NH)(NH2). Methyl-carbaimidoyl: -C(=N-CH3)NH2. Carboxyamino: -N(H)(C(=O)OH). C1-6 thioalkyl: The term C1-6 thioalkyl as used herein, pertains to an -SR, wherein R is a C1-6 hydrocarbon group. Examples of C1-6 alkylthio groups include, but are not limited to, -SCH3 and -SCH2CH3. C1-6 alkyl sulfinyl: The term C1-6 alkyl sulfinyl pertains to a sulfine (sulfinyl, sulfoxide) which has the structure -S(=O)R, wherein R is a C1-6 hydrocarbon group. Examples of C1-6 alkyl sulfinyl groups include, but are not limited to, -S(=O)CH3 and -S(=O)CH2CH3. C1-6 alkyl sulfonyl: The term C1-6 alkyl sulfonyl as used herein pertains to an -S(=O)2R, group wherein R is a C1-6 hydrocarbon group, including, for example, a fluorinated or perfluorinated C1-6 alkyl group. Examples of C1-6 alkyl sulfonyl groups include, but are not limited to, -S(=O)2CH3 (methanesulfonyl, mesyl), -S(=O)2CF3 (triflyl), -S(=O)2CH2CH3 (esyl), -S(=O)2C4F9 (nonaflyl) and -S(=O)2CH2CF3 (tresyl). C1-6 sulfonimodyl: The term C1-6 sulfonimodyl is also referred to as Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide) and has the structure -S(=O)2NR1R2, wherein R1 and R2 are independently amino substituents, as defined for amino groups. Examples of sulfonamido groups include, but are not limited to, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2N(CH3)2, -S(=O)2NH(CH2CH3) and -S(=O)2N(CH2CH3)2. C1-6 alkyl phosphinyl: The term C1-6 alkyl phosphinyl (phosphine oxide) has the structure - P(=O)R2, wherein each R is independently a C1-6 hydrocarbon group. Examples of C1-6 alkyl phosphinyl groups include, but are not limited to, P(=O)(CH3)2, P(=O)(CH2CH3)2 and P(=O)(tBu)2. Wherein each R group can be the same or different groups. Carboxy (carboxylic acid): -C(=O)OH. C1-6 alkyl ester: The term C1-6 alkyl ester (carboxylate, carboxylic acid ester, oxycarbonyl) has the structure -C(=O)OR, wherein R is a C1-6 hydrocarbon group. Examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3 and -C(=O)OC(CH3)3. C1-6 alkyl acyl: The term C1-6 alkyl acyl also known as Acyl (keto) has the structure -C(=O)R, wherein R is a C1-6 hydrocarbon group. Examples of C1-6 alkyl acyl groups include, but are not limited to, -C(=O)CH3 (acetyl), -C(=O)CH2CH3 (propionyl) or -C(=O)C(CH3)3 (t-butyryl). C1-6 alkyl amido: The term C1-6 alkyl amido (also referred to as carbamoyl, carbamyl, aminocarbonyl, carboxamide) has the structure C(=O)NR1R2, wherein R1 and R2 are independently amino substituents, as defined for amino groups for example, hydrogen, a C1-6 hydrocarbon group (also referred to as C16 alkylamido or C16 dialkylamido), or, in the case of a “cyclic” amido group, R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 6 ring atoms. Examples of amido groups include, but are not limited to, C(=O)NH2, C(=O)NHCH3, C(=O)N(CH3)2, C(=O)NHCH2CH3, and C(=O)N(CH2CH3)2, as well as amido groups in which R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl. C3-12 cycloalkyl: The term “C3-12 cycloalkyl” as used herein, pertains 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. Examples of 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), methylcyclopentene (C6), dimethylcyclopentene (C7) and methylcyclohexene (C7); and saturated polycyclic hydrocarbon compounds: norcarane (C7), norpinane (C7), norbornane (C7). C3-10 heterocyclyl: The term “C3-10 heterocyclyl” as used herein, pertains 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 heterocycloalkyl ring may be linked via either a carbon atom or a heteroatom. In this context the term ‘heteroatom’ means O, S, N, Si or B (Boron). In this context, the prefixes (e.g. C3-10 C3-7, C5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term “C5-6heterocyclyl”, 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., 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, 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: thiirane (C3), thietane (C4), thiolane (tetrahydrothiophene) (C5), thiane (tetrahydrothiopyran) (C6), thiepane (C7); O2: dioxolane (C5), dioxane (C6), and dioxepane (C7); O3: trioxane (C6); N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine (C6); N1O1: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), morpholine (C6), tetrahydrooxazine (C6), dihydrooxazine (C6), oxazine (C6); N1S1: thiazoline (C5), thiazolidine (C5), thiomorpholine (C6); N2O1: oxadiazine (C6); O1S1: oxathiole (C5) and oxathiane (thioxane) (C6); and, N1O1S1: oxathiazine (C6). Examples of bicyclic heterocyclyl groups include, but are not limited to those derived from:
Figure imgf000013_0001
C6-10 carboaryl: The term “C6-10 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. Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e. phenyl) (C6), naphthalene (C10) and azulene (C10). In this context, the prefixes (e.g. C5-7, C5-6, C5-10, etc.) denote the number of ring atoms, or range of number of ring atoms. For example, the term “C5-6 aryl” as used herein, pertains to an aryl group having 5 or 6 ring atoms. Examples of 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. In certain embodiments, each ring has from 5 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms. For the avoidance of doubt, 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. In this context the term ‘heteroatom’ means O, S, N, Si or B (Boron). Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: N1: pyrrole (azole) (C5), pyridine (azine) (C6); O1: furan (oxole) (C5); S1: thiophene (thiole) (C5); N1O1: oxazole (C5), isoxazole (C5), isoxazine (C6); N2O1: oxadiazole (furazan) (C5); N3O1: oxatriazole (C5); N1S1: thiazole (C5), isothiazole (C5); N2: imidazole (1,3-diazole) (C5), pyrazole (1,2-diazole) (C5), pyridazine (1,2-diazine) (C6), pyrimidine (1,3-diazine) (C6) (e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) (C6); N3: triazole (C5), triazine (C6); and, N4: tetrazole (C5). Examples of heteroaryl which comprise fused rings, include, but are not limited to Cg (with 2 fused rings) derived from:
Figure imgf000015_0001
Figure imgf000016_0001
Examples of heteroaryl which comprise fused rings, include, but are not limited to Cw (with 2 fused rings) derived from:
Figure imgf000016_0002
Figure imgf000017_0001
Spiro C6-i2 carbocyclyl: The term Spiro C6-i2carbocyclyl 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 Ce- i2carbocyclyl 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 Ce-12 heterocyclyl: The term Spiro C6-i2heterocyclyl 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 C6-i2heterocyclyl 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. In certain embodiments, each ring has from 9 to 11 ring atoms, of which from 1 to 2 are ring heteroatoms. For the avoidance of doubt, substituents on the heteroaryl ring may be linked via either a carbon atom or a heteroatom.
For the avoidance of doubt, where multiple substituents are independently selected from a given group, 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/Zurich: 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.
Therefore, in one embodiment there is provided 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. In one embodiment there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the pharmaceutically acceptable salt is a methanesulfonic acid salt. In one embodiment there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the pharmaceutically acceptable salt is a mono- methanesulfonic acid salt, i.e. the stoichiometry of the compound of the compound of Formula (I) to methanesulfonic acid is 1:1.
Other forms
Compounds and salts described in this specification may exist in solvated forms and unsolvated forms. For example, 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 kinase 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). In some embodiments, a single stereoisomer is obtained by isolating it from a mixture of isomers (e.g. a racemate) using, for example, chiral chromatographic separation. In other embodiments, 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.
According to one embodiment there is provided 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%. Conveniently, the single enantiomer is present in an enantiomeric excess (%ee) of > 99%.
According to another embodiment there is provided 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. Conveniently, the single enantiomer is present in an enantiomeric excess (%ee) of > 99%.
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 11C or 13C carbon isotope, or where one or more hydrogen atoms is a 2H or 3H 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. For example, tautomeric forms of some of the exemplified compounds where RA3 is OH can be shown as follows.
Figure imgf000020_0001
Compounds and salts described in this specification may be crystalline and may exhibit one or more crystalline forms. The compound of Formula (I) encompasses any crystalline or amorphous form of a compound of Formula (I), or mixture of such forms, which possesses PCSK9 inhibitory activity.
It is generally known that crystalline materials may be characterised using conventional techniques such as X-Ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis (TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of crystalline materials may be determined by Karl Fischer analysis.
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.
The term “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.
The term “treatment” is used synonymously with “therapy”. Similarly the term “treat” can be regarded as “applying therapy” where “therapy” is as defined herein. The term "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. For example, 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
The compounds of Formula (I), and pharmaceutically acceptable salts thereof, may be administered as pharmaceutical compositions, comprising one or more pharmaceutically acceptable excipients.
Therefore, in one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
The 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. As persons skilled in the art will appreciate, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.
The pharmaceutical compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing), or as a suppository for rectal dosing. The compositions may be obtained by conventional procedures well known in the art. Compositions intended for oral use may contain additional components, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
Suitable daily doses of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, in therapeutic treatment of humans are about 0.0001-100 mg/kg body weight. Pharmaceutical formulations as described herein may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.1 mg to 1000 mg. The daily dose will necessarily be varied depending upon the host treated, the particular route of administration, any therapies being co-administered, and the severity of the illness being treated. Accordingly, the practitioner who is treating any particular patient may determine the optimum dosage.
The pharmaceutical compositions described herein comprise compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and are therefore expected to be useful in therapy.
As such, in one embodiment there is provided 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.
In one embodiment there is provided 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. In one embodiment there is provided 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. In one embodiment there is provided 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.
Methods of Use The compounds described herein may be used in a method of therapy. Also provided is a method of treatment, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I. The term “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 timecourse of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the responsibility of general practitioners and other medical doctors.
A compound may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) for use in therapy. In one embodiment there is provided the use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) for the manufacture of a medicament. In another embodiment there is provided a method of treatment comprising administering to a subject the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I).
The compounds described herein are PCSK9 inhibitors. 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 LDLRs 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). 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. In certain embodiments, the method of inhibiting PCSK9 occurs in a subject in need thereof, thereby treating a disease or disorder mediated by PCSK9. Also, disclosed herein are methods of treating or preventing a disease or a disorder mediated by PCSK9 comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, disclosed herein are methods of treating a disease or a disorder mediated by PCSK9 comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, disclosed herein are methods of preventing a disease or a disorder mediated by PCSK9 comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The prevention of cardiovascular events through the inhibition of PCSK9 has been described, e.g., in Robinson 2015.
In some embodiments there is provided 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). In some embodiments there is provided 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. In some embodiments there is provided 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.
Exemplary cardiovascular diseases and conditions include, but are not limited to, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dimensia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure or congestive heart failure. In certain embodiments, exemplary cardiovascular diseases and conditions include, but are not limited to, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease. In certain embodiments, the disease is hypercholesterolemia, such as familial hypercholesterolemia or autosomal dominant hypercholesterolemia. In certain embodiments, the disease is hyperlipidemia. In certain embodiments, the disease is coronary artery disease.
In certain embodiments, the disclosed methods of treatment can decrease high levels of circulating serum cholesterol, such as LDL-C and VLDL-Cholesterol. In addition, the disclosed methods are useful for decreasing circulating serum triglycerides, circulating serum lipoprotein A, circulating serum LDL-C and atherogenic lipoproteins. In certain embodiments, 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.
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. In certain embodiments, conjointly administering one or more additional therapeutic agents with a compound described herein provides a synergistic effect. In certain embodiments, conjointly administering one or more additional therapeutic agents provides an additive effect.
In some embodiments in which a combination therapy is used, 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. In this context, 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. Typically, such 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. Such a combination may be used in combination with one or more further active ingredients.
In one aspect there is provided 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) 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) a citrate lyase inhibitor; and vi) anti-hypertensive drugs.
In a further aspect of the present specification there is provided 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) 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) citrate lyase inhibitor; vi) anti-hypertensive drugs.
In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from a statin, wherein the statin is selected from atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin or Simvastatin. In another aspect the statin is Rosuvastatin (Crestor).
In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from a cholesterol absorption inhibitor, wherein the cholesterol absorption inhibitor is selected from Ezetimibe (Ezetrol).
In another embodiment there is provided 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. In some aspects the SGLT2 inhibitor is selected from Dapagliflozin (Farxiga or Forxiga). In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from a P2Y12 inhibitor, wherein the P2Y12 inhibitor is selected from Ticagrelor and Clopidogrel (Plavix).
In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from a citrate lyase inhibitor, wherein the citrate lyase inhibitor is Bempedoic acid (Nexletol).
In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from Ezetimibe, Rosuvastatin, Dapagliflozin and Ticagrelor. In one embodiment there is one additional active ingredient. In another embodiment there are two additional active ingredients. In one embodiment the additional active ingredient is Ezetimibe, Rosuvastatin, Dapagliflozin or Ticagrelor. In another embodiment the additional two active ingredients are Ezetimibe and Rosuvastatin or Dapagliflozin and Rosuvastatin.
In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from antihypertensive drugs. In some aspects, 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. In another aspect there is provided the compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with: i) Valsartan; ii) Metoprolol; iii) Valsartan and HCTZ; iv) Olmesartan; v) Olmesartan and HCTZ; vi) Lisinopril; vii) Amlodipine; viii) Candesartan; ix) a calcium channel blocker; or x) HCTZ.
In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient for use in the simultaneous, separate or sequential treatment of a cardiovascular disease. In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cardiovascular disease, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one an additional active substance selected from Ezetimibe, Rosuvastatin, Dapagliflozin and Ticagrelor. In another embodiment there is provided a method of treating a cardiovascular disease in a subject, which comprises administering to said subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional active substance, wherein the at least one additional active substance is selected from Ezetimibe, Rosuvastatin, Dapagliflozin and Ticagrelor. Further Embodiments The following embodiments may apply to all aspects as described above or may relate to a single aspect. The embodiments may be combined together in any combination. X1 In some embodiments, X1 is N. RA2 In some embodiments RA2 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) C1-6 alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups; (vi) C1-6 acyl amido (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 C1-3alkyl amido, CN, OH, C2-3 alkynyl, C4-6 heterocyclyl, C1-3 alkyl which alkyl is optionally substituted with one or more halo or OH groups; (xiii) OH; and (xiv) C1-6 alkylamino. In some embodiments RA2 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) C1-6 alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups; (vi) C1-6 acyl amido (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) C5heteroaryl; (xii) C1-6 alkyl amido optionally substituted by C1-3alkyl amido, CN, C2-3 alkynyl, C4-6 heterocyclyl, C1-3 alkyl which alkyl is optionally substituted with one or more halo or OH groups; and (xiii) OH. In some embodiments RA2 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6acyl, C1-6alkoxy or one or more halo groups; (v) OH; (vi) C1-6 alkoxy, optionally substituted by OH, C1-6 alkyl amido, or one or more halo groups; (vii) C1-6 alkyl ester; (viii) C1-6 alkyl acyl; (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; and (x) C1-6 alkylamino In further embodiments RA2 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6acyl, C1-6alkoxy or one or more halo groups; (v) OH; (vi) C1-6 alkoxy, optionally substituted by OH, C1-6 alkyl amido, or one or more halo groups; (vii) C1-6 alkyl ester; (viii) C1-6 alkyl acyl; 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. In further embodiments RA2 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) 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 C1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups. In further embodiments RA2 is selected from the group consisting of: (i) H; (ii) halo; (iii) C1-6 alkyl ester; (iv) C1-6 hydrocarbon; (v) C1-6 alkyl amido optionally substituted by C1-3 alkyl amido, C2-3 alkynyl, C4-6 heterocyclyl, or C1- 3alkyl which alkyl is optionally substituted with one or more halo or OH groups; (vi) C1-6 thioalkyl; (vii)C1-6 alkyl acyl; (viii) C5 heteroaryl; or (ix) C1-6 alkylamino. When RA2 is halo, in some embodiments it is Br or Cl. In further embodiments it is Cl. In some embodiments RA2 is selected from CN, Cl, OMe, methyl, cyclopropyl, -OCHF2, -OCF3 and optionally substituted C1-6 alkylamido. In some embodiments RA2 is selected from C1-6alkyl ester, In some embodiments RA2 is CN. In some embodiments RA2 is H. In some embodiments RA2 is OH. In some embodiments RA2 is -C(=O)CH3. In some embodiments RA2 is -OCHF2. In some embodiments RA2 is cyclopropyl. In some embodiments RA2 is Cl. In some embodiments RA2 is methyl. In some embodiments RA2 is S-ethyl. In some embodiments RA2 is a pyrazole. In some embodiments RA2 is N(CH3)2. In some embodiments RA2 is C(=O)NH(CH2C(=O)NH2, C(=O)NHCH2C≡CH, C(=O)NH(oxetane), C(=O)NH(CH2CHF2), C(=O)NH(CH2CH3), C(=O)NH2, C(=O)NH(CH2), C(=O)N(CH3)2, C(=O)N(CH3)(CH2CH2OH), C(=O)N(CH3)(CH2C≡CH or C(=O)NH(CH2CH2OH). When RA2 is a C1-6 hydrocarbon it is an optionally substituted C1-6 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. When RA2 is optionally substituted C1-6 alkyl, in some embodiments 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. When RA2 is optionally substituted C1-6alkoxy, in some embodiments it is optionally substituted OMe or ethoxy. When RA2 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. In another embodiment where RA2 is optionally substituted C1-6alkoxy it is difluoromethoxy (OCHF2). When RA2 is C1-6 alkyl ester, in some embodiments it is -C(=O)OCH2CH3. When RA2 is C1-6 alkyl amido, in some embodiments the optional substituents are selected from one or more methyl groups, an oxetane ring, a C2alkylamido, ethyl which ethyl is optionally substituted by OH or one or more halo groups. In other embodiments when RA2 is C1-6 alkyl amido it is C(=O)NHCH2C(=O)NH2, C(=O)NHCH2CHCH, -C(=O)NH-oxetane, C(=O)NHCH2CHF2, C(=O)NHCH2CH2OH, C(=O)NHCH2CH3, C(=O)NH2, C(=O)NHCH3, C(=O)N(CH3)2. When RA2 is C1-6 alkyl amido, in some embodiments the optional substituent is OH. When RA2 is C1-6 alkylamino in some embodiments it is NHCH3, NHC(CH3)2, N(CH2CH3)2, or N(CH3)2. In some embodiments when RA2 is C1-6 alkylamino it is N(CH3)2. In other embodiments RA2 is selected from -OCHF2, Cl, -OMe, methyl, C(=O)CH3, CN, -CH2OH, H and cyclopropyl. In further embodiments RA2 is selected from methyl, -OCHF2, Cl, -CH2OH, H, CN, -C(=O)CH3 or -OMe. In further embodiments RA2 is selected from methyl, -OCHF2, Cl and cyclopropyl. In further embodiments RA2 is selected from H, -COOH, -CH2OH, methyl, CN, cyclopropyl, - C(=O)CH3, -OCHF2, Cl, -C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, - C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, - C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3. In some embodiments RA2 is selected from the group consisting of -CN, methyl, Cl, -C(=O)CH3, -C(=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -OCHF2, H, -OMe, and -OCF3. In some embodiments RA2 is selected from C(=O)OCH2CH3, cyclopropyl, methyl, C(=O)NH(CH2C(=O)NH2, C(=O)NHCH2C≡CH, C(=O)NH(oxetane), C(=O)NH(CH2CHF2), C(=O)NH(CH2CH3), C(=O)NH2, C(=O)NH(CH3), C(=O)N(CH3)2, H, C(=O)N(CH3)(CH2CH2OH), C(=O)N(CH3)(CH2C≡CH, Cl, N(CH3)2, pyrazole, S-ethyl, C(=O)CH3, or C(=O)NH(CH2CH2OH). In some embodiments RA2 is selected from CN, methyl, Cl, -C(=O)CH3, -C(C=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH-oxetane, - C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, - C(=O)N(CH3)2, -OCHF2, H, -OMe, -OCF3. These groups are as shown in the table below:
Figure imgf000033_0002
In some embodiments RA2 is selected from the following groups:
Figure imgf000033_0003
In some embodiments RA2 is selected from the following groups:
Figure imgf000033_0001
Figure imgf000034_0001
RA3 In some embodiments RA3 is selected from the group consisting of: ) H; i) halo; ii) CN; v) C1-6hydrocarbon optionally substituted by OH, CN, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkyl acyl, C1-6 acyloxy, carboxy, C1-6 alkyl ester, C1-6 alkylamino, -C(=O)NH2, C1-6 alkyl amido, C1-6 alkyl acylamido, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl or one or more halo groups; v) OH; vi) C1-6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclyl or one or more halo groups; vii) C1-6 acyloxy; viii) C4 heterocycyl; x) -NH2; x) C1-6 alkylamino, optionally substituted by CN, OH or C4heterocyclyl; xi) C1-6 dialkylamino, optionally substituted by -NH2; xii) C1-6 acylamido (where acyl substituent is H or Me); xiii) carbaimidoyl or methyl-carbaimidoyl; xiv) carboxyamino; xv) C1-6 thioalkyl, optionally substituted by OH or NH2; xvi) C1-6 alkyl sulfinyl; xvi) C1-6 alkyl sulfonyl, optionally substituted by one or more halo groups; xvii) C1-6 sulfonimodyl; xviii) C1-6 alkyl phosphinyl; xix) carboxy; xx) C(=O)NH2 xxi) C1-6 alkyl ester; (xxii) C1-6 alkyl acyl, optionally substituted by one or more halo groups; and (xxiii) C1-6 alkyl amido. In some embodiments RA3 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 alkyl acyl C1-6 acyloxy, carboxy, C1-6 alkylester, C1-6 alkylamino; -C(=O)NH2, C1-6 alkyl amido, C1-6 alkylacylamido, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl or one or more halo groups; (v) OH; and (vi) C1-6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclyl or one or more halo groups. In some embodiments RA3 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6hydrocarbon, optionally substituted by OH, CN, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkylacyl, C1-6 acyloxy, carboxy, C1-6 alkylester, C1-6 alkylamino; -C(=O)NH2, C1-6 alkyl amido, C1-6 alkylacylamido, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl or one or more halo groups; (v) OH; (vi) C1-6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclyl or one or more halo groups. Where RA3 is halo, in some embodiments it is Br or Cl. In some embodiments it is Cl. In further embodiments RA3 is Br. Where RA3 is a C1-6hydrocarbon it is an optionally substituted C1-6 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 RA3 is optionally substituted C1-6 alkyl, in some embodiments the optionally 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. In some embodiments RA3 is OH. When RA3 is optionally substituted C1-6alkoxy, in some embodiments it is optionally substituted OMe or ethoxy. In further embodiments it is OMe. When RA3 is optionally substituted C1-6alkoxy, 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. In some embodiments RA3 is selected from H, CF3, CN, C1-2alkyl, NH2 and halo. In other embodiments RA3 is selected from H, methyl, CN and Cl. In some embodiments RA3 is selected from H, OMe, CF3, CN, C1-2alkyl, NH2 and halo. In some embodiments RA3 is CN. In some embodiments RA3 is H. In some embodiments RA3 is methyl. In some embodiments RA3 is OMe. In some embodiments RA3 is selected from methyl, H and CN. In some embodiments RA3 is selected from H, methyl or OH. RA2 and RA3 When RA3 and RA2 together with the carbon atoms to which they are bound form an optionally substituted C6 carboaromatic ring or C5-7 heteroaromatic ring they form an optionally substituted benzene ring or an optionally substituted pyridine ring. When RA3 and RA2 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 methyl, ethyl, OMe, NH2, F, Cl and Br. In other embodiments the optional substituents are selected from methyl, NH2, Cl, F and OMe. In other embodiments the optional substituent is methyl. In one embodiment when RA2 and RA3 together with the carbon atoms to which they are bound form an optionally substituted C5-7 heteroaromatic ring, they form an optionally substituted pyridine. In some embodiments the optional substituent is NH2. In another embodiment RA2 and RA3 together with the carbon atoms to which they are bound form an unsubstituted pyridine. In another embodiment RA2 and RA3 together form an optionally substituted pyrazole, an optionally substituted pyrrole or an optionally substituted thiazole. In some embodiments the optional substituent is methyl. When RA3 and RA2 together with the carbon atoms to which they are bound form an optionally substituted C5-7 heteroaromatic ring, the optional substituents are selected from Ci-ealkyl, Ci-e 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.
When RA3 and RA2 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. In some embodiments 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. In some embodiments RA3 and RA2 together with the carbon atoms to which they are bound form an optionally substituted pyrrole or pyrazole.
When RA3 and RA2 together with the carbon atoms to which they are bound form an optionally substituted C5-7 heterocycle ring, the optional substituents are selected from NH2, Ci-ealkyl, Ci- ealkoxy and halo. In other embodiments the optional substituents are selected from methyl, ethyl, OMe, ethoxy, NH2, F, Cl and Br. In other embodiments the optional substituent is methyl.
In other embodiments RA2 and RA3 together with the carbon atoms to which they are bound form:
(i) optionally substituted Ce heteroaromatic ring; wherein the optional substituent is NH2;
(ii) optionally substituted Ce carboaromatic ring; wherein the optional substituent is F, OMe, Cl;
(iii) optionally substituted C5 heteroaromatic or C5 heterocycle ring wherein the optional substituent is methyl.
In some embodiments RA3 and RA2 together with the carbon atoms to which they are bound form an optionally substituted Ce carboaromatic ring or C5-7 heteroaromatic ring wherein the optional substituents are selected from Ci-ealkyl, and halo.
In some embodiments RA2 and RA3 together form an unsubstituted 2-pyrazole, a 2-pyrrole substituted by methyl, pyridine optionally substituted by NH2, or a phenyl optionally substituted by Cl, F or OMe.
In some embodiments RA2 and RA3 together form a ring selected from:
Figure imgf000038_0004
In some embodiments B is of formula (B-1):
Figure imgf000038_0001
wherein the wavy lines indicate the point of attachment to A and C; wherein RB1 is H, OH, -OMe, -O-Ethyl, -CH2OH, -CH2CH2OH or =CHCH2-OH.
In other embodiments RB1 is H, -CH2OH, -CH2CH2OH or =CHCH2-OH.
In other embodiments RB1 is -CH2OH, -CH2CH2OH or =CHCH2-OH.
In other embodiments RB1 is H.
In another embodiment B is of the formula (B-1 a):
Figure imgf000038_0002
(B-1a).
In further embodiments B is of the formula (B-1 b):
Figure imgf000038_0003
Therefore in some embodiments the compounds of Formula (I) is the S,S-enantiomer.
In some embodiments B is of formula (B-2):
Figure imgf000039_0001
wherein the wavy line indicates the point of attachment to A and C; RB2 is C1-2 alkyl-OH, CH2CONHMe or C1-3 alkyl. In some of these embodiments, RB2 is C1-2 alkyl-OH, or C1-3 alkyl In some embodiments when B is of the formula (B-2) it is of the following formula (B-2a) wherein the wavy line indicates the point of attachment to A and C; and RB2 is C1-2alkyl-OH, CH2CONHMe or C1-2alkyl;
Figure imgf000039_0002
(B-2a). In some embodiments B is of the following formula:
Figure imgf000039_0003
. In further embodiments B is of the following formula:
Figure imgf000039_0004
. C C is selected from the group consisting of C6-10 carboaryl, C5-6 heteroaryl and C5-10 heterocyclyl, which groups are optionally substituted by: (i) C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl C4-10 heterocyclyl, or C5-10 bridged heterocyclyl, spiro C6-12heterocyclyl or a spiro C6-12carbocyclyl, which are themselves optionally substituted by one or more of the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C1-6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1-6 alkoxy with optional substituents of one or more halo groups; f) C1-6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; h) C5-6 heteroaryl; i) C4-10 carbocyclyl with an optional methyl or =O substituent; j) C6-10 carboaryl with optional substituents of one or more halo groups; l) P(=O)Me2; m) carboxy or CH2-carboxy; n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; (ii) one or more groups selected from carboxy, CN, halo, nitro, C1-6 alkyl, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkylacyl, C1-6 alkyl amido, di-C1-6 alkyl amido, C1-6 alkyl sulfonamido, and di-C1-6 alkyl sulfonamido. In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl, wherein the optional substituents are selected from C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl, C5- 10 heterocyclyl, C5-10 bridged heterocyclyl, spiro C6-12 heterocyclyl or a spiro C6-12 carbocyclyl, which are themselves optionally substituted by one or more of the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2 or OH; d) one or more C1-6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1-6 alkoxy with optional substituents of one or more halo groups; f) C1-6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; h) C5-6 heteroaryl; i) C4-10 carbocyclyl with an optional methyl or =O substituent; j) C6-10 carboaryl with optional substituents of one or more halo groups; l) P(=O)Me2; m) carboxy or CH2-carboxy; and/or n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl. When C is an optionally substituted C5-6 heteroaryl in some embodiments it is an optionally substituted C6heteroaryl. In other embodiments it is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl. In other embodiments it is an optionally substituted pyridinyl. When C is an optionally substituted C5-6 heteroaryl it can be optionally substituted by: (i) C6-10carboaryl, C4-10carbocyclyl, C5-10 heteroaryl, C5-10 heterocyclyl, or C5- 10bridged heterocyclyl, spiro C6-12heterocyclyl or a spiro C6-12carbocyclyl, which are themselves optionally substituted by one or more of the groups selected from: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) C1-6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1-6 alkoxy with optional substituents of one or more halo groups; f) C1-6alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; h) C5-6 heteroaryl; i) C4-10carbocyclyl with an optional methyl or =O substituent; j) C6-10carboaryl with optional substituents of one or more halo groups; l) P(=O)Me2; m) carboxy or CH2-carboxy; and/or n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; (ii) one or more groups selected from carboxy, CN, halo, nitro, C1-6 alkyl, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkylacyl, C1-6 alkyl amido, di-C1-6 alkyl amido, C1-6 alkyl sulfonamido and di-C1-6 alkyl sulfonamido. Where C is substituted by C6-10 carboaryl, C5-10 heteroaryl or C5-10 heterocyclyl, it may bear a number of substituent groups. The substituents are selected from: a) one or two =O groups; b) one or more halo groups, CN, NH2; c) one or more C1-6 alkyl including (CH3)2, C1-6 alkoxy, or C1-6alkylester, wherein each is optionally substituted by one or more halo groups; d) C5-6 heterocyclyl or C5-6heteroaryl with an optional methyl substituent; e) C6-10carboaryl optionally substituted by one or more halo atoms; f) P(=O)Me2; or g) carboxy or CH2-carboxy. In some embodiments one substituent of C is at the para position. In some embodiments when C is an optionally substituted C5-6heteroaryl, the optional substituents are selected from C1-6alkyl and halo. In further embodiments the optional substituent is methyl. In further embodiments C is substituted by methyl at the meta position. In other embodiments where C is substituted by an optionally substituted C6-10 carboaryl, C5-10 heteroaryl or C5-10 heterocyclyl, it may be substituted by an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted imidazolidinyl, an optionally substituted dihydroquinolinyl, an optionally substituted benzimidazolyl or an optionally substituted imidazopyridinyl. These group themselves may be optionally substituted by one or two =O groups, halo, CN, one or more C1-6 alkyl, C1-6 alkoxy, C1-6alkylester, C5-6 heterocyclyl (with an optional methyl substituent), phenyl substituted by F at the para position, carboxy, CH2-carboxy, tetrazolyl, pyrazolyl, triazolyl or P(=O)Me2. In other embodiments when C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl it may bear a number of substituent groups. The substituents are selected from an optionally substituted C5-10 heteroaryl and C5-10 heterocyclyl, which are themselves optionally substituted by one or two =O groups, one or more halo groups, CN, one or more C1-6 alkyl, C1-6 alkoxy, C1- 6alkylester, C5-6 heterocyclyl (with an optional methyl substituent), phenyl optionally substituted with one or two halo groups, carboxy, CH2-carboxy, tetrazolyl, pyrazolyl, triazolyl, a pyridine ring, NH2 or OH. In some embodiments the substituents are an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted imidazolidine, an optionally substituted dihydroquinoline, an optionally substituted benzimidazolyl or an optionally substituted imidazopyridinyl. In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl wherein the optional substituents are selected from: i) C6-10carboaryl, C5-10 heteroaryl C5-10 heterocyclyl, which are themselves optionally substituted by one or more of the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C1-6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1-6 alkoxy with optional substituents of one or more halo groups; f) C1-6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; h) C5-6 heteroaryl; i) C4-10 carbocyclyl with an optional methyl or =O substituent; j) C6-10 carboaryl with optional substituents of one or more halo groups; l) P(=O)Me2; m) carboxy, CH2-carboxy; and/or n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; ii) one or more groups selected from carboxy, CN, halo, nitro, C1-6 alkyl, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkylacyl, C1-6 alkyl amido, di-C1-6 alkyl amido, C1-6 alkyl sulfonamido and di-C1-6 alkyl sulfonamido. In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl wherein the optional substituents are selected from C6-10carboaryl, C5-10 heteroaryl C5-10 heterocyclyl, which are themselves optionally substituted by one or more groups selected from the following: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C1-6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1-6 alkoxy with optional substituents of one or more halo groups; f) C1-6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; h) C5-6 heteroaryl; i) C4-10carbocyclyl with an optional methyl or =O substituent; j) C6-10carboaryl with optional substituents of one or more halo groups; l) P(=O)Me2; m) carboxy, CH2-carboxy; and/or n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl. In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl, wherein the optional substituents are selected from C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl, C5- 10 heterocyclyl, C5-10 bridged heterocyclyl, spiro C6-12heterocyclyl or a spiro C6-12 carbocyclyl, which are themselves optionally substituted by one or more of the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2 or OH; d) one or more C1-6 alkyl groups including branched and cyclic and with a substituent selected from OH or one or more halo groups; e) C1-6 alkoxy with optional substituents of one or more halo groups; f) C1-6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; h) C5-6 heteroaryl; i) C4-10 carbocyclyl with an optional methyl or =O substituent; j) C6-10 carboaryl with optional substituents of one or more halo groups; l) P(=O)Me2; m) carboxy or CH2-carboxy; and/or n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl. In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl, wherein the optional substituents are selected from C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl, C5- 10 heterocyclyl, C5-10 bridged heterocyclyl, spiro C6-12heterocyclyl or a spiro C6-12 carbocyclyl, which are themselves optionally substituted by one or more of the following groups: a) one or more halo groups; b) CN, NH2 or OH; c) one or more C1-6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; d) C1-6 alkoxy with optional substituents of one or more halo groups; e) C1-6 alkylester; f) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; g) C5-6 heteroaryl; h) C4-10 carbocyclyl with an optional methyl or =O substituent; i) C6-10 carboaryl with optional substituents of one or more halo groups; j) P(=O)Me2; k) carboxy or CH2-carboxy; and/or l) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl. In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl, wherein the optional substituents are selected from C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl, C5- 10 heterocyclyl, C5-10 bridged heterocyclyl, spiro C6-12heterocyclyl or a spiro C6-12 carbocyclyl, which are themselves optionally substituted by one or two =O groups and substituted with one or more of the following groups: a) one or more halo groups; b) CN, NH2 or OH; c) one or more C1-6 alkyl groups including branched and cyclic and with a substituent selected from OH or one or more halo groups; d) C1-6 alkoxy with optional substituents of one or more halo groups; e) C1-6 alkylester; f) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; g) C5-6 heteroaryl; h) C4-10 carbocyclyl with an optional methyl or =O substituent; i) C6-10 carboaryl with optional substituents of one or more halo groups; j) P(=O)Me2; k) carboxy or CH2-carboxy; and/or l) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl. In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl wherein the optional substituents are selected from C6 heteroaryl or C6 heterocyclyl, which are themselves optionally substituted by one or more groups selected from the following: i) one or two =O groups; ii) methyl; iii) OMe; iv) Cl; v) CN; vi) CF3; vii) F; viii) pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl; ix) O-CF3; x) O-CHF2. In some embodiments C is a substituted pyridyl which is substituted by a C6 heterocyclyl or C6 heteroaryl, each of which contain either one or two N atoms and are substituted by =O and another group selected from methyl, Cl, OMe, CN, and OCHF2. In some embodiments C is a substituted pyridyl which is substituted by a pyridyl which is itself substituted by at least one =O group and another group selected from CF3, OCF3, Cl, CN, OMe, pyrazole optionally substituted by methyl, tetrazole, F, OCHF2 or triazole. In further embodiments C is an optionally substituted pyridinyl wherein the optional substituents are selected from phenyl and pyridyl which are themselves optionally substituted by methyl or CN. In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl wherein the optional substituents are selected from pyridine, pyridazine and pyrimidine which are themselves optionally substituted by one or more groups selected from the following: a) one or two =O groups; b) one or more halo groups; c) methyl; d) OMe; e) CN; or f) OCHF2. In some embodiments C is an optionally substituted pyridinyl wherein the optional substituent is phenyl or pyridyl which are themselves optionally substituted by one or more groups selected from the following: a) one or more OMe groups; b) one or more F groups; c) CN; d) tetrazole; or e) carboxy. In some embodiments C is an optionally substituted pyridinyl wherein the optional substituent is a C5 heteroaryl or C5 heterocyclyl which are themselves optionally substituted by one or more substituents selected from methyl and CN. In some embodiments C is an optionally substituted pyridinyl wherein the optional substituent is a pyrazole, triazole, imidazole or an oxazole which are themselves optionally substituted by one or more substituents selected from methyl and CN. In further embodiments the pyrazole, triazole, imidazole or oxazole are substituted by two methyl groups and optionally one CN group. In some embodiments C is an optionally substituted pyridinyl wherein the optional substituent is an unsubstituted C9 membered heterocyclyl containing 2 or 3 nitrogen atoms. In another embodiment C is of the formula (C-1):
Figure imgf000047_0001
(C-1) wherein D is C6-10 carboaryl, C5-10 heteroaryl or C5-10 heterocyclyl, which are themselves optionally substituted by =O, halo, CN, NH2, OH, one or more C1-6 alkyl groups, which alkyl is optionally substituted by halo, C1-6 alkoxy which is optionally substituted by halo, C1-6alkylester, C5-6 heterocyclyl (with an optional methyl substituent), carboxy, CH2-carboxy, P(=O)Me2, tetrazolyl, pyrazolyl or triazolyl. In some embodiments the optional substituents are selected from =O, CN, F, Cl, Br, CN, methyl, ethyl, OMe, ethoxy, O-CF3, OMe, CF3, P(=O)Me2 and C1-2 alkyl ester. When C is (C-1) in some embodiments D is an optionally substituted pyridin-2-one. In some embodiments the optional substituents are selected from OMe, Cl, F, methyl, trifluoromethyl, OCF3, -C(=O)OH (carboxy), CN, pyrazolyl, triazolyl, tetrazolyl, phenyl with an optional F substituent at the para position or piperazinyl with a methyl substituent. In some embodiments the pyridine-2-one is unsubstituted. In some embodiments the pyridin-2-one is pyridin-2(1H)- one. When C is (C-1), in some embodiments D is an optionally substituted 6 membered heteroaryl which contains one or two N atoms, one of which is bonded to (C-1), which is substituted by =O at the ortho position and the other optional substituents are selected from methyl, OMe, piperazine substituted by methyl, C(=O)OH (carboxy), Cl, phenyl substituted by fluoro, CN, CF3, F, pyrazolyl, triazolyl, tetrazolyl, or O-CF3. In some embodiments C is of the formula (C-1):
Figure imgf000047_0002
(C-1) wherein D is C6-10 carboaryl, C5-10 heteroaryl or C5-10 heterocyclyl, each of which are themselves optionally substituted by: i) one or two =O groups; ii) one or two C1-4 alkyl groups which can be branched; iii) OMe; iv) piperazinyl, optionally substituted by methyl; v) C(=O)OH (carboxy); vi) Cl; vii) F; viii) phenyl, optionally substituted by one or more fluoro; ix) CN; x) CF3; xi) O-CF3; xii) tetrazolyl, pyrazolyl, triazolyl each of which is optionally substituted by methyl; xiii) NH2; xiv) pyridinyl; xv) CH2OH; xvi) OH; xvii) P(=O)Me2; or xviii) OCHF2. In some embodiments C is of the formula (C-1):
Figure imgf000048_0001
(C-1) wherein D is C6-10 carboaryl, C5-10 heteroaryl or C5-10 heterocyclyl, each of which are themselves optionally substituted by: i) one or two =O groups; ii) one or two C1-4 alkyl groups which can be branched; i) OMe; ii) piperazinyl, optionally substituted by methyl; iii) C(=O)OH (carboxy); iv) Cl; v) F; vi) phenyl, optionally substituted by one or more fluoro; vii) CN; viii) CF3; ix) O-CF3; x) OMe; xi) tetrazolyl, pyrazolyl, triazolyl; xii) NH2; xiii) (CH3)2; xiv) pyridinyl; xv) CH2OH; xvi) OH; or xvii) P(=O)Me2. In some embodiments D is an optionally substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by =O at the ortho position, wherein the optional substituents are selected from: i) methyl; ii) OMe; iii) piperazinyl substituted by methyl; iv) C(=O)OH (carboxy); v) Cl; vi) phenyl substituted by fluoro; vii) CN; viii) CF3; ix) O-CF3; x) F; or xi) pyrazolyl, triazolyl or tetrazolyl. In some embodiments when C is (C-1), D is an optionally substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by =O at the ortho position wherein the optional substituents are selected from: i) methyl; ii) OMe; iii) piperazinyl substituted by methyl; iv) C(=O)OH (carboxy); v) Cl; vi) F; vii) phenyl substituted by fluoro; viii) CN; ix) CF3; x) O-CF3; xi) O-CHF2; xii) pyrazole, triazole, tetrazole each of which is optionally substituted by methyl. In some embodiments D is an optionally substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by =O at the ortho position, wherein the optional substituents are selected from: i) methyl; ii) OMe; iii) Cl; iv) F; v) CN; vi) CF3; vii) O-CF3; viii) O-CHF2; or ix) pyrazolyl, triazolyl or tetrazolyl each of which is optionally substituted by methyl. In some embodiments D is a substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by =O at the ortho position, wherein the substituents are selected from: i) OMe; ii) Cl; iii) F; iv) CN; v) CF3; vi) O-CF3; vii) O-CHF2; or viii) pyrazolyl, triazolyl or tetrazolyl each of which is optionally substituted by methyl. In some embodiments C is of the formula (C-1) wherein D is C6-10 carboaryl, C5-10 heteroaryl or C5-10 heterocyclyl, each of which are themselves optionally substituted by: i) one or two =O groups; ii) one or two C1-4 alkyl groups which can be branched and optionally substituted by one or more halo groups; iii) one or more OMe groups; iv) C(=O)OH (carboxy); v) halo; vi) CN; vii) C1-4 alkoxy optionally substituted by one or more halo groups; viii) tetrazolyl, pyrazolyl, triazolyl wherein each is optionally substituted by methyl; ix) P(=O)Me2. In some embodiments C is of the formula (C-1) and D is C6-10 carboaryl, C5-10 heteroaryl or C5-10 heterocyclyl, each of which are themselves optionally substituted by: one or two =O groups; methyl, CF3; OCF3; Cl, CN, OMe, pyrazole optionally substituted by methyl, tetrazole, F, OCHF2, triazole, C(=O)OH, P(=O)Me2. In some embodiments D is optionally substituted by 1, 2 or 3 substituents, In some embodiments D is optionally substituted by 1 substituent, In some embodiments D is optionally substituted by 2 or 3 substituents, In some embodiments when C is (C-1), D is an optionally substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by =O at the ortho position wherein the optional substituents are selected from: i) methyl; ii) OMe; iii) piperazinyl substituted by methyl; iv) C(=O)OH (carboxy); v) Cl; vi) F; vii) phenyl substituted by fluoro; viii) CN; ix) CF3; x) O-CF3; xi) pyrazole optionally substituted by methyl, triazole, tetrazole. In some embodiments C is of the formula (C-1) and D is an optionally substituted phenyl or piperidyl wherein there are one or two optional substituents selected from F, OMe and CN. In some embodiments C is of the formula (C-1) and D is an optionally substituted phenyl or pyridyl wherein there are one or two optional substituents selected from F, OMe and CN. In some embodiments D is an optionally substituted C5 heterocyclyl or C5 heteroaryl, wherein the optional substituents are selected from methyl and CN. In further embodiments D is an optionally substituted pyrazole, imidazole, triazole or oxazole wherein the optional substituents are selected from methyl and CN. In further embodiments D is a triazole substituted with two methyl groups. In further embodiments D is a pyrazole substituted by two methyl groups. In further embodiments D is an imidazole substituted by two methyl groups and CN. In further embodiments D is an oxazole substituted by two methyl groups. In some embodiments D is a C9 heterocyclyl or C9 heteroaryl comprising 2 or 3 nitrogen atoms. In further embodiments D is 1H-pyrazolo[3,4-b]pyridiyl, indazol-1-yl or indazol-2-yl. In some embodiments D is optionally substituted by 1, 2 or 3 substituents. In another embodiment D is of the formula (D-1):
Figure imgf000052_0001
wherein one or two of RD1, RD2, RD3 and RD4 are selected from a C1-6 alkyl optionally substituted by one or more halo groups; C1-6 alkoxy optionally substituted by one or more halo groups, C5-6 heterocyclyl or C5-6heteroaryl with an optional methyl substituent, carboxy, =O, halo, NH2, CN, or phenyl optionally substituted by one or more halo atoms; or wherein RD3 and RD4 form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(=O)Me2 and C(=O)OH; or wherein RD1, RD2, RD3 and RD4 are all H. In another embodiment one or two of RD1, RD2, RD3 and RD4 are selected from C1-6 alkyl optionally substituted by one or more halo groups, C1-6 alkoxy optionally substituted by one or more halo groups, C5-6 heterocyclyl or C5-6heteroaryl with an optional methyl substituent, carboxy halo, CN, or phenyl optionally substituted by one or more halo atoms, and the rest are H. In some embodiments D is of the formula (D-1) and one or two of RD1, RD2, RD3 and RD4 are selected from: i) methyl; ii) OMe; iii) piperazine substituted by methyl; iv) C(=O)OH (carboxy); v) Cl; vi) phenyl substituted by fluoro; vii) CN; viii) CF3; ix) F; x) pyrazolyl, triazolyl, tetrazolyl; xi) O-CF3 and the rest of RD1, RD2, RD3 and RD4 are H.
In some embodiments D is of the formula (D-1) and one or two of RD1, RD2, RD3 and RD4 are selected from: i) methyl; ii) OMe; iii) Cl; iv) CN; v) CF3; vi) F; vii) pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl; viii) O-CF3 ix) O-CHF2 and the rest of RD1, RD2, RD3 and RD4 are H.
In another embodiment one or two of RD1, RD2, RD3 and RD4 are selected from methyl, -OMe, halo, -C(=O)OH, CN, CF3, -OCF3, -OCHF2 and the rest of RD1, RD2, RD3 and RD4 are H.
In one embodiment all of RD1, RD2, RD3 and RD4 are H.
In another embodiment RD3 is selected from H, optionally substituted phenyl (wherein the optional substituent is halo), methyl, OMe, -C(=O)OH, -OCHF2, Cl, CN and piperazinyl optionally substituted by methyl wherein RD1, RD2 and RD4 are all H. In some embodiments RD3 is selected from H, CN, OMe, Cl, pyrazole optionally substituted by methyl, tetrazole, methyl, OCHF2, or triazole and wherein RD1, RD2 and RD4 are all H. In some embodiments RD3 is selected from H, CN, OMe, Cl, pyrazole, tetrazole, methyl, OCHF2, or triazole and wherein RD1, RD2 and RD4 are all H.
In some embodiments RD2 is selected from H, OMe, Cl and CN and wherein RD1, RD3 and RD4 are all H.
In other embodiments RD1 is selected from H, methyl, OMe, Cl, CF3, OCF3, OCHF2 and CN and RD2, RD3 and RD4 are all H. In some embodiments RD1 is selected from H, OMe, Cl, CF3, OCF3, OCHF2, CN, F, triazole and pyrazole optionally substituted by methyl, and RD2, RD3 and RD4 are all H.
In another embodiment RD3 and RD4 form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring wherein the optional substituents are selected from OH, CN, P(=O)Me2, methyl, OMe, halo and C(=O)OH.
In some embodiments RD3 and RD4 form an optionally substituted benzene ring or an optionally substituted pyridine ring.
In some embodiments RD3 and RD4 form an unsubstituted benzene ring or an unsubstituted pyridine ring.
In another embodiment D is of the formula (D-2):
Figure imgf000054_0001
(D-2)
Wherein XD is NRD5a or CRD5aRD5b;
RD5a is selected from H or methyl; either RD5b and RD6b are both H or together they are -CH2-;
RD6a is selected from H, =0, methyl, -CH2OH or -C(=O)OH, wherein when RD6a is =0, RD6b is absent;
RD7a is selected from H, =0, methyl, -CH2OH or -C(=O)OH; RD7b is H, wherein when RD7a is =0, RD7b is absent; or wherein RD6a and RD7a together form a benzene ring or a Ce heteroaromatic ring which is optionally substituted by CN, P(=0)Me2 or carboxy and RD6b and RD7b are absent.
In some embodiments C is of the formula (C-1) and D is of the formula (D-2) and XD is N and RD5a is methyl.
In some embodiments C is of the formula (C-1) and D is of the formula (D-2) and RD6a and RD6b both H and RD7a is selected from =0, -CH2OH or -C(=O)OH and RD7b is H or when RD7a is =0, RD7b is absent.
In some embodiments C is of the formula (C-1) and D is of the formula (D-2) and XD is N and RD5a is methyl wherein RD7a is selected from H and =0 and RD6a is H and =0, wherein when RD7a is =0, RD6a and RD6b are H and RD7b is absent and wherein RD6a is =0, RD7a and RD7b are H and RD6b is absent.
In some embodiments C is of the formula (C-1) and D is of the formula (D-2), RD7a is =0, and RD7b is absent, XD is C and RD5b and RD6b together are -CH2- and RD6a and RD5a are methyl.
In another embodiment RD6a and RD7a together form a benzene ring or a Ce heteroaromatic ring which is optionally substituted by CN, P(=0)Me2 or -C(=O)OH, and RD6b and RD7b are absent.
In some embodiments RD6a and RD7a together form a benzene ring or a pyridine ring which is optionally substituted by CN, P(=0)Me2, or C(=O)OH and RD6b and RD7b are absent.
In some embodiments RD6a and RD7a form an unsubstituted benzene ring and RD6b and RD7b are absent. In some embodiments RD6a and RD7a form an unsubstituted pyridine ring and RD6b and RD7b are absent.
In some embodiments XD is N and RD5a is H or methyl.
In some embodiments XD is C and RD5a is H or methyl and RD5b is H. In further embodiments both RD5a and RD5b are H.
In some embodiments RD7a is carboxy, -CH2OH or =0. In some embodiments RD7a is =0. RD7b is H, or when RD7a is =0, RD7b is absent. In some embodiments RD6a is H or =0. In some embodiments RD6a is =0 and RD6b is absent.
In some embodiments where RD7a is =0, RD6a and RD6b are H and RD7b is absent and where RD6a is =0, RD7a and RD7b are H and RD6a is absent.
In some embodiments XD is N and RD5a is H or methyl, RD6b is H and RD6a and RD7a together form a pyridine ring or a benzene ring which is optionally substituted by -C(=O)OH or CN or P(=0)Me2 and RD6b and RD7b are absent.
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
n some embodiments D is selected from the following table:
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
In some embodiments D is selected from the following table:
Figure imgf000061_0002
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0002
In another embodiment C has the formula (C-2):
Figure imgf000064_0001
(C-2) wherein one or two of RC7, RC8, RC9 and RC1° are selected from methyl, OMe, halo, C(=O)OH, piperazine optionally substituted by methyl, optionally substituted phenyl (wherein the optional substituent is methyl or halo), CN, CF3, -O-CF3, O-CHF2, tetrazolyl, pyrazolyl optionally substituted by methyl, or triazolyl and the rest of RC7, RC8, RC9 and RC1° are H; or RC9 and RC1° form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(=O)Me2 or - C(=O)OH; or wherein RC7, RC8, RC9 and Rc10 are all H.
In some embodiments one or two of RC7, RC8, RC9 and RC1° are selected from methyl, OMe, halo, C(=O)OH, piperazine optionally substituted by methyl, optionally substituted phenyl (wherein the optional substituent is methyl or halo), CN, CF3, -O-CF3, tetrazolyl, pyrazolyl, or triazolyl and the rest of RC7, RC8, RC9 and RC1° are H; or RC9 and RC1° form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(=O)Me2 or -C(=O)OH; or wherein RC7, RC8, RC9 and Rc10 are all H.
In one embodiment C has the formula (C-1) and all of RC7, RC8, RC9 and Rc10 are H.
In another embodiment one or two of RC7, RC8, RC9 and RC1° are selected from methyl, Cl, OMe, phenyl substituted with F at para position, -C(=O)OH, CN, OCF3, CF3, F, pyrazolyl, triazolyl, tetrazolyl, piperazinyl substituted by methyl and the rest of RC7, RC8, RC9 and RC1° are H. In another embodiment one or two of RC7, RC8, RC9 and RC1° are selected from methyl, OMe, Cl, CN, CF3, F; pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl; O- CF3, O-CHF2 and the rest of RD1, RD2, RD3 and RD4 are H.
In another embodiment one of RC7 and RC9 are independently selected from methyl, -OMe, Cl, - C(=O)OH, piperazinyl optionally substituted by methyl, optionally substituted phenyl (wherein the optional substituent is F), CN, CF3, -O-CF3, F, pyrazolyl, triazolyl or tetrazolyl and the other is H and Rc10 and RC8 are H. In another embodiment one of RC7 and RC9 are independently selected from methyl, -OMe, Cl, -C(=O)OH, CN, CF3, O-CHF2, -O-CF3, F, pyrazolyl, triazolyl or tetrazolyl and the other is H and Rc10 and RC8 are H.
In another embodiment RC9 is selected from H, optionally substituted phenyl (wherein the optional substituent is halo), methyl, OMe, C(=O)OH, Cl, CN, pyrazolyl, triazolyl, tetrazolyl, and piperazinyl optionally substituted with methyl and RC7, RC8 and RC1° are all H. In some embodiments RC9 is selected from H, CN, OMe, Cl, pyrazole optionally substituted by methyl, tetrazole, methyl, OCHF2, or triazole and RC7, RC8 and RC1° are all H.
In other embodiments RC7 is selected from H, methyl, OMe, Cl, F, CF3, -OCF3 and CN and RC8, RC9 and RC1° are all H. In some embodiments RC7 is selected from H, OMe, Cl, CF3, OCF3,
OCHF2, CN, F, triazole and pyrazole optionally substituted by methyl, and RC7, RC8 and RC1° are all H.
In some embodiments RC8 is selected from H, OMe, Cl and CN and wherein RC7, RC9 and RC1° are all H.
In another embodiment C is selected from the group consisting of the groups 1-48 listed in the following table:
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
In another embodiment C is selected from the group consisting of the 49-80 listed in the following table:
Figure imgf000068_0002
Figure imgf000069_0001
Figure imgf000070_0002
In another embodiment C is selected from the group consisting of the groups listed in the following table:
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0002
A-B-C
In other embodiments the compound of formula A-B-C is of the Formula (l-A):
Figure imgf000073_0001
wherein X1 is N.
In some embodiments RA2 is selected from the group consisting of:
(i) H;
(ii) halo;
(iii) Ci-6 alkyl ester;
(iv) Ci-6 hydrocarbon;
(v) Ci-6 alkyl amido optionally substituted by C1.3 alkyl amido, C^ alkynyl, C4-6 heterocyclyl, or C1.3 alkyl which alkyl is optionally substituted with one or more halo or OH groups;
(vi) C1.6 thioalkyl;
(vii)Ci-6 alkyl acyl;
(viii) C5 heteroaryl; or
(ix) alkylamino.
In some embodiments RA2 is selected from the group consisting of: Br, Cl, CN, H, -C(=O)CH3, C1.6 alkyl amido which alkyl amido is optionally substituted by Ci.salkyl amido, CN, C^ alkynyl, C4-6 heterocyclyl, C1.3 alkyl which alkyl is optionally substituted with one or more halo or OH groups, optionally substituted methoxy, methyl, ethyl or cyclopropyl wherein the optional substituents are selected from OH, CN, or one or more halo groups, an optionally substituted methoxy or ethoxy wherein the optional substituents are selected from alkyl amido or one or more halo groups. In further embodiments RA2 is selected from CN, methyl, Cl, -C(=O)CH3, - C(=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH- oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3, -C(=O)NH2, - C(=O)NHCH3, -C(=O)N(CH3)2, -OCHF2, H, -OMe, -OCF3. In some embodiments RA2 is selected from -C(=O)OCH2CH3, cyclopropyl, methyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CCH, - C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, C(=O)N(CH3)2, H, -C(=O)N(CH3)CH2CH2OH, -C(=O)N(CH3)CH2CCH, Cl, N(CH3)2, pyrazole, - SCH2CH3, -C(=O)CH3, and -C(=O)NHCH2CH2OH.
In some embodiments RA3 is selected from the group consisting of CN, Br, Cl, OH, H, CF3, Ci-2 alkyl, Ci.2alkoxy, NH2. In further embodiments RA3 is selected from H, methyl and CN. In some embodiments RA3 is selected from H, methyl or OH.
In other embodiments RA3 and RA2 together with the carbon atoms to which they are bound form an optionally substituted Ce carboaromatic ring or C5-7 heteroaromatic ring, the optional substituents are selected from NH2, C1-6 alkyl, Ci-e alkoxy and halo. In other embodiments the optional substituents are selected from NH2, methyl, ethyl, OMe, F, Cl and Br.
In some embodiments RA3 and RA2 together with the carbon atoms to which they are bound form an optionally substituted pyridine, an optionally substituted benzene, a pyrrole or a pyrazole. In some embodiments RA2 and RA3 together form an unsubstituted 2-pyrazole, a 2- pyrrole substituted by methyl, pyridine optionally substituted by NH2 or benzene optionally substituted by Cl, F or OMe.
In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl. In some embodiments the optional substituents are selected from:
(i) Ce-io carboaryl, C4-io carbocyclyl, C5-10 heteroaryl, C5-10 heterocyclyl, or C5-10 bridged heterocyclyl, spiro Ce-i 2 heterocyclyl or a spiro C6-i2 carbocyclyl, which are themselves optionally substituted by one or more of the groups selected from: a) one or two =0 groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more Ci-e alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1.6 alkoxy with optional substituents of one or more halo groups; f) C1.6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =0 substituent; h) C5-6 heteroaryl; i) C4-io carbocyclyl with an optional methyl or =0 substituent; j) Ce-io carboaryl with optional substituents of one or more halo groups; k) carboxy, CH2-carboxy; l) P(=0)Me2; (ii) one or more of the groups selected from carboxy, CN, halo, nitro, C1-6 alkyl, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkylacyl, C1-6 alkyl amido, di-C1-6 alkyl amido, C1-6 alkyl sulfonamido di-C1-6 alkyl sulfonamido. In other embodiments the compound of formula A-B-C is of the Formula (I-B):
Figure imgf000075_0001
wherein X1, RA2 and RA3 are as defined (I-A). In some embodiments Formula (I-B) can be Formula (I-Ba) or (I-Bb) as shown below:
Figure imgf000075_0002
In some embodiments D is C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl or C5-10 heterocyclyl which are themselves optionally substituted by one or more groups selected from the following: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C1-6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1-6 alkoxy with optional substituents of one or more halo groups; f) C1-6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; h) C5-6 heteroaryl; i) C4-10 carbocyclyl with an optional methyl or =O substituent; j) C6-10 carboaryl with optional substituents of one or more halo groups; l) carboxy, CH2-carboxy m) P(=O)Me2. In some embodiments D is an optionally substituted pyridine-2-one. In some embodiments the optional substituents are selected from OMe, Cl, F, pyrazole, triazole, tetrazole, methyl, trifluoromethyl (CF3), OCF3, carboxy (C(=O)OH), CN, phenyl with an optional F substituent at the para position or a piperazine with a methyl substituent. In some embodiments the pyridine- 2-one is unsubstituted. In some embodiments the pyridine-2-one is pyridin-2(1H)-one. In some embodiments D is an optionally substituted 6 membered heteroaryl which contains one or two N atoms, one of which is bonded to C, which is substituted by =O at the ortho position and the other optional substituents are selected from methyl, OMe, piperazinyl substituted by methyl, C(=O)OH (carboxy), Cl, F, pyrazolyl, triazolyl, tetrazolyl, phenyl substituted by fluoro, CN, CF3 or O-CF3. In some embodiments D is an optionally substituted 6 membered heteroaryl which contains one or two N atoms, one of which is bonded to C, which is substituted by =O at the ortho position and the other optional substituents are selected from methyl, OMe, piperazinyl substituted by methyl, C(=O)OH (carboxy), Cl, F, pyrazolyl optionally substituted with methyl, triazolyl, tetrazolyl, phenyl substituted by fluoro, CN, CF3, OCHF2 or O-CF3. In some embodiments D is an optionally substituted C5 heterocycle or C5 heteroaryl, wherein the optional substituents are selected from methyl and CN. In further embodiments D is an optionally substituted pyrazole, imidazole, triazole or oxazole wherein the optional substituents are selected from methyl. In further embodiments D is a triazole substituted with two methyl groups. In further embodiments D is a pyrazole substituted by two methyl groups. In further embodiments D is an imidazole substituted by two methyl groups and CN. In further embodiments D is an oxazole substituted by two methyl groups. In some embodiments D is a C9 heterocyclyl or C9 heteroaryl comprising 2 or 3 nitrogen atoms. In further embodiments D is 1H-pyrazolo[3,4-b]pyridiyl, indazol-1-yl or indazol-2-yl. In other embodiments the compound of formula A-B-C is of the Formula (l-C):
Figure imgf000077_0001
wherein X1, RA2 and RA3 are as defined (l-A).
In some embodiments one or two of RD1, RD2, RD3 and RD4 are selected from a Ci-e alkyl optionally substituted by one or more halo groups; Ci-e alkoxy optionally substituted by one or more halo groups, C5-6 heterocyclyl or C5-6 heteroaryl with an optional methyl substituent, carboxy, =0, halo, NH2, CN, or phenyl optionally substituted by one or more halo atoms; or wherein RD3 and RD4 form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring wherein the optional substituents are selected from OH, methyl, OMe, halo, C(=O)OH.
In another embodiment one or two of RD1, RD2, RD3 and RD4 are selected from methyl, OMe, halo, C(=O)OH, CN, CF3, OCF3, OCHF2, pyrazolyl, triazolyl, tetrazolyl and the rest are H. In another embodiment one or two of RD1, RD2, RD3 and RD4 are selected from methyl, OMe, halo, C(=O)OH, CN, CF3, OCF3, OCHF2, pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl and the rest are H.
In one embodiment all of RD1, RD2, RD3 and RD4 are H.
In some embodiments RD3 and RD4 form an unsubstituted benzene ring or an unsubstituted pyridine ring.
In other embodiments the compound of formula A-B-C is of Formula (l-D):
Figure imgf000078_0001
(I-D).
In some embodiments X1, RA2 and RA3 are as defined (l-A). In some embodiments XD is NRD5a or CRD5aRD5b;
RD5a is selected from H or methyl; either RD5b and RD6b are both H or together they are -CH2-;
RD6a is selected from H, =0, methyl, CH2OH or C(=O)OH;
RD7a is selected from H, =0, methyl, CH2OH or C(=O)OH; RD7b is H, wherein when RD7a is =0, RD7b is absent; or wherein RD6a and RD7a together form a benzene ring or a Ce heteroaromatic ring which is optionally substituted by CN, P(=0)Me2 or carboxy and RD6b and RD7b are absent.
In some embodiments RD6a and RD7a together form a benzene ring or a pyridine ring which is optionally substituted by CN, P(=0)Me2, or carboxy and RD6b and RD7a are absent.
In other embodiments the compound of formula A-B-C is of the Formula (l-E):
Figure imgf000078_0002
(I-E).
In some embodiments RA2 is selected from: (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) C1-6 alkoxy, optionally substituted by OH, C1-6 alkyl amido, or one or more halo groups; (vii) carboxy; (viii) C1-6alkyl 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 or OH groups. In some embodiments RA2 is selected from the group consisting of: (i) H; (ii) halo; (iii) C1-6 alkyl ester; (iv) C1-6 hydrocarbon; (v) C1-6 alkyl amido optionally substituted by C1-3 alkyl amido, C2-3 alkynyl, C4-6 heterocyclyl, or C1-3 alkyl which alkyl is optionally substituted with one or more halo or OH groups; (vi) C1-6 thioalkyl; (vii)C1-6 alkyl acyl; (viii) C5 heteroaryl; or (ix) alkylamino. In some embodiments RA2 is selected from CN, methyl, Cl, -C(=O)CH3, -C(=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH- oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3, -C(=O)NH2, - C(=O)NHCH3, -C(=O)N(CH3)2, -OCHF2, H, -OMe, -OCF3, or RA2 and RA3 together form an unsubstituted 2-pyrazole, a 2-pyrrole substituted by methyl, pyridine optionally substituted by NH2, or benzene optionally substituted by Cl, F or OMe. In some embodiments RA2 is selected from -C(=O)OCH2CH3, cyclopropyl, methyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, H, - C(=O)N(CH3)CH2CH2OH, -C(=O)N(CH3)CH2CCH, Cl, -N(CH3)2, pyrazole, -SCH2CH3, -C(=O)CH3, and -C(=O)NHCH2CH2OH. In some embodiments RA3 is selected from: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon optionally substituted by OH, CN, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkyl acyl C1-6 acyloxy, carboxy, C1-6 alkylester, C1-6 alkylamino; -C(=O)NH2, C1-6 alkyl amido, C1-6 alkylacylamido, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl or one or more halo groups; (v) OH; (vi) C1-6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclyl or one or more halo groups. In some embodiments RA3 is selected from: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon optionally substituted by OH, CN, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkyl acyl C1-6 acyloxy, carboxy, C1-6 alkylester, C1-6 alkylamino; -C(=O)NH2, C1-6 alkyl amido, C1-6 alkylacylamido, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl or one or more halo groups; (v) OH; (vi) C1-6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclyl or one or more halo groups. In some embodiments the compound is of the Formula (I-E) and RA3 is H, methyl or OH. In further embodiments the compound is of the Formula (I-E) and RA3 is H. In some embodiments the compound is of the Formula (I-E) and D is a C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl or C5-10 heterocyclyl, which are themselves optionally substituted by =O; halo; CN; NH2; OH; one or more C1-6 alkyl groups, which alkyl is optionally substituted by halo; C1-6 alkoxy which is optionally substituted by halo; C1-6alkylester; C5-6 heterocyclyl with an optional methyl substituent; carboxy; CH2-carboxy; tetrazolyl; pyrazolyl or triazolyl. In some embodiments the optional substituents are selected from =O, CN, F, Cl, Br, CN, methyl, ethyl, OMe, ethoxy, O-CF3, CF3, C1-2 alkyl ester. In some embodiments the compound is of the Formula (I-E) and D is a C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl or C5-10 heterocyclyl, which are themselves optionally substituted by =O; methyl; OMe; piperazinyl substituted by methyl; C(=O)OH (carboxy); Cl; F; phenyl substituted by fluoro; CN; CF3; OCHF2, O-CF3; pyrazole optionally substituted by methyl, triazole, tetrazole. In some embodiments the compound is of the Formula (I-E) and D is an optionally substituted pyridin-2-one. In some embodiments the optional substituents are selected from OMe, Cl, F, pyrazole, triazole, tetrazole, methyl, trifluoromethyl (CF3), OCF3, carboxy (C(=O)OH), CN, phenyl with an optional F substituent at the para position or a piperazinyl with a methyl substituent. In some embodiments the compound is of the Formula (I-E) and D is an optionally substituted pyridin-2-one or pyridin-2(1H)-one. In some embodiments the optional substituents are selected from OMe, Cl, F, pyrazole, triazole, tetrazole, methyl, trifluoromethyl (CF3), OCHF2, OCF3, carboxy (C(=O)OH), CN, phenyl with an optional F substituent at the para position or a piperazinyl with a methyl substituent. In some embodiments the pyridine-2-one is unsubstituted. In some embodiments the pyridine-2-one is pyridin-2(1H)-one. In some embodiments the compound is of the Formula (I-E) and D is an optionally substituted C5 heterocycle or C5 heteroaryl, wherein the optional substituents are selected from methyl and CN. In further embodiments D is an optionally substituted pyrazole, imidazole, triazole or oxazole wherein the optional substituents are selected from methyl. In further embodiments D is a triazole substituted with two methyl groups. In further embodiments D is a pyrazole substituted by two methyl groups. In further embodiments D is an imidazole substituted by two methyl groups and CN. In further embodiments D is an oxazole substituted by two methyl groups. In some embodiments D is a C9 heterocyclyl or C9 heteroaryl comprising 2 or 3 nitrogen atoms. In further embodiments D is 1H-pyrazolo[3,4-b]pyridiyl, indazol-1-yl or indazol-2-yl. In some embodiments D is optionally substituted by 1, 2 or 3 substituents. In another embodiment the compound is of Formula (I-Ea):
Figure imgf000081_0001
(I-Ea) wherein D and RA3 are a defined above for Formula (I-E). In another embodiment the compound is of Formula (I-Eb):
Figure imgf000082_0001
(I-Eb). Wherein D and RA3 are a defined above for Formula (I-E). In one embodiment the compound is of Formula (I) A-B-C (I) or a pharmaceutically acceptable salt, tautomeric forms or stereoisomers thereof, wherein A is of the following:
Figure imgf000082_0002
wherein the wavy line indicates the point of attachment to B; X1 is N; RA2 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) C1-6 alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups; (vi) C1-6 acyl amido (wherein the acyl is optionally substituted by H or methyl); (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 or C1-3 alkyl wherein the C1-3 alkyl is optionally substituted with one or more halo or OH groups; and (xiii) OH; RA3 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 alkyl acyl, C1-6 acyloxy, carboxy, C1-6 alkyl ester, C1-6 alkylamino, -C(=O)NH2, C1-6 alkyl amido, C1-6 alkyl acylamido, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl or one or more halo groups; (v) OH; (vi) C1-6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclyl or one or more halo groups; (vii) C1-6 acyloxy; (viii) C4 heterocycyl; (ix) -NH2; (x) C1-6 alkylamino, optionally substituted by CN, OH or C4 heterocyclyl; (xi) C1-6 dialkylamino, optionally substituted by -NH2; (xii) C1-6 acylamido (where acyl substituent is H or Me); (xiii) carbaimidoyl or methyl-carbaimidoyl; (xiv) carboxyamino; (xv) C1-6 thioalkyl, optionally substituted by OH or NH2; (xvi) C1-6 alkyl sulfinyl; (xvi) C1-6 alkyl sulfonyl, optionally substituted by one or more halo groups; (xvii) C1-6 sulfonimodyl; (xviii) C1-6 alkyl phosphinyl; (xix) carboxy; (xx) C(=O)NH2 (xxi) C1-6 alkyl ester; (xxii) C1-6 alkyl acyl, optionally substituted by one or more halo groups; and (xxiiv) C1-6 alkyl amido; or wherein RA3 and RA2 together with the carbon atoms to which they are bound form: (i) an optionally substituted C5-7 heterocycle ring; (ii) an optionally substituted C5-7 heteroaromatic ring; (iii) an optionally substituted C6 carboaromatic ring; (iv) an optionally substituted C5-7 carbocyclic ring wherein the optional substituents are selected from C1-6 alkyl, halo, C1-6 alkoxy, NH2, C1-6 alkylamino, OH, and CN; wherein B is of formula (B-1) or (B-2) i)
Figure imgf000084_0001
wherein the wavy line indicates the point of attachment to A and C; RB1 is H, OH, =CHCH2-OH, -O-C1-4 alkyl or C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted by OH or OMe; (ii)
Figure imgf000084_0002
wherein the wavy line indicates the point of attachment to A and C; RB2 is C1-2 alkyl-OH, CH2CONHMe or C1-3 alkyl; wherein C is selected from the group consisting of C6-10 carboaryl, C5-6 heteroaryl and C5-10 heterocyclyl, which groups are optionally substituted by: (i) C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl, C4-10 heterocyclyl, or C5-10 bridged heterocyclyl, spiro C6-12 heterocyclyl or a spiro C6-12 carbocyclyl, which are themselves optionally substituted by one or more of the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C1-6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1-6 alkoxy with optional substituents of one or more halo groups; f) C1-6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; h) C5-6 heteroaryl; i) C4-10 carbocyclyl with an optional methyl or =O substituent; j) C6-10 carboaryl with optional substituents of one or more halo groups; l) P(=O)Me2; m) carboxy or CH2-carboxy; and/or n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; (ii) one or more groups selected from carboxy, CN, halo, nitro, C1-6 alkyl, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkylacyl, C1-6 alkyl amido, di-C1-6 alkyl amido, C1-6 alkyl sulfonamido, and di-C1-6 alkyl sulfonamido. In some embodiments the compound is of Formula (I) A-B-C (I) or a pharmaceutically acceptable salt, tautomeric forms or stereoisomers thereof, wherein A is of the following:
Figure imgf000085_0001
wherein the wavy line indicates the point of attachment to B; RA2 is C1-6 alkylamino; X1, RA3, B and C are as defined above. In some embodiments the compound of Formula (I) is selected from the following in Table 1. Table 1.
Figure imgf000085_0002
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Further compounds are shown in Table 2:
Table 2.
Figure imgf000089_0002
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Further compounds are shown in Table 3:
Table 3.
Figure imgf000093_0002
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
In some embodiments the compound is selected from 50, 57, 129, 132 and 136. In some embodiments the compound is 132. General synthesis
The compounds according to general formula (l-B) can be prepared according to the following schemes 1 , 2, 3, 4 and 5. The schemes and procedures described below illustrate synthetic routes to the compounds of general formula (l-B) and are not intended to be limiting. It is clear that the order of transformations as exemplified in schemes 1, 2, 3, 4 and 5 can be modified in various ways. The order of transformations exemplified in these schemes is therefore not intended to be limiting.
Routes for the preparation of compounds of general formula (l-B) and corresponding intermediates are described in schemes 1 , 2, 3, 4 and 5.
Scheme 1.
Figure imgf000104_0001
Scheme 1: Routes for the preparation of compounds of general formula (l-B) in which X is a leaving group, PG is a protective group and D, X1, RA2 and RA3 have the meaning as given for general formula (l-B), supra. Monoarylated diamines of general formula (A3) can be obtained via nucleophilic aromatic substitution (SnAr) or palladium catalyzed Buchwald-Hartwig amination between monoprotected diamines (A1) or their corresponding salts and heteroaryls (A2a) with X being a leaving group like halogen or -S(O)Me as depicted in Scheme 1. For SNAr approaches with X being groups like for example fluorine or -S(O)Me, diamines (A1) may be reacted with (A2a) in the presence of inorganic bases like K2CO3 or Na2COs 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. In certain instances, it can be beneficial to apply microwave heating. For palladium catalyzed Buchwald-Hartwig aminations all methods that are known in the art may be applied. For example, diamines (A1) may be reacted with (A2a) in the presence of a palladium catalyst like Pd PEPPSI-IpentCl [CAS 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. Diamines of general formula (A1) and heteroaryls of general formula (A2a) are either commercially available or can be prepared according to procedures available from the public domain. For the synthesis of diamines (A1) see for example WO2004004726 and references therein. Arylated diamines of general formula (A6) can be obtained from (A3) via copper catalyzed Ullmann couplings with heterocycles (A4) or via palladium catalyzed Suzuki couplings with boronic acid derivatives (A5). For Ullmann couplings all methods that are known in the art may be applied. For example, (A3) may be reacted with (A4) 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. In some instances a ligand like N1,N2-dimethylcyclohexane- 1,2-diamine, TMEDA, N1,N2-dimethylethane-1,2-diamine or N,N-dimethylglycine might be added to the reaction mixture. For Suzuki couplings towards (A6) all methods that are known in the art may be applied. For example, (A3) may be reacted with boronic acid derivatives (A5) in the presence of a palladium catalyst like 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride [CAS 95408-45-0] or 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride [CAS 72287-26-4] and a base like Cs2CO3, K2CO3 or K3PO4 in polar solvents such as 1,4-dioxane, THF and water or mixtures thereof at temperatures between room temperature and 120 °C for 2-15 hours. Heterocycles of general formula (A4) and boronic acid derivatives of general formula (A5) are either commercially available or can be prepared according to procedures available from the public domain. Primary amines of general formula (A7) can be obtained from monoprotected diamines of general formula (A6) 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 Wuts 2014.
Final compounds of general formula (l-B) can be synthesized from primary amines of general formula (A7) via nucleophilic aromatic substitution (SNAr) or palladium catalyzed Buchwald- Hartwig amination. Primary amines of general formula (A7) can be reacted with heteroaryls of general formula (A8) with X being a leaving group like halogen such as chlorine or -S(O)Me applying procedures in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. Heteroaryls of general formula (A8) are either commercially available or can be prepared according to procedures available from the public domain.
An alternative route to compounds of general formula (l-B) starts with deprotection of diamines of general formula (A3) to give primary amines of general formula (A9) as depicted in Scheme 1. For deprotection the same procedures apply as described for the synthesis of (A 7) from (A6).
Primary amines of general formula (A9) in turn can be reacted with heteroaryls of general formula (A8) via nucleophilic aromatic substitution (SNA^ or palladium catalyzed Buchwald- Hartwig amination to give aryl iodides of general formula (A10) applying procedures in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.
Final compounds of general formula (l-B) can be synthesized from aryl iodides of general formula (10) via copper catalyzed Ullmann couplings with heterocycles H-D (A4) or via palladium catalyzed Suzuki couplings with boronic acid derivatives (A5) applying procedures in analogy to those described for the synthesis of compounds (A6) from (A3) in Scheme 1.
Yet another approach to compounds of general formula (l-B) starts from monoprotected diamines (1) or their corresponding salts and preassembled heteroaryls (A11a) with X being a leaving group like halogen or -S(O)Me via nucleophilic aromatic substitution (SNA^ or palladium catalyzed Buchwald-Hartwig amination to give arylated diamines of general formula (A6). The procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. Heteroaryls of general formula (A11a) are either commercially available or can be prepared according to procedures available from the public domain (for example via Chan-Lam coupling). Specific examples of (A11a) are described in the subsequent paragraphs.
An alternative route for the preparation of compounds of general formula (l-B) and intermediates of general formula (A10) is depicted in Scheme 2. Scheme 2
Figure imgf000107_0002
Figure imgf000107_0003
N
Method 6 Buchwald
Figure imgf000107_0001
coupling
Figure imgf000107_0004
Scheme 2: Routes for the preparation of compounds of general formula (l-B) and intermediates (A10) in which X is a leaving group, PG is a protective group and D, X1, RA2 and RA3 have the meaning as given for general formula (l-B), supra.
Monoarylated diamines of general formula (A12) can be obtained via nucleophilic aromatic substitution (SNA^ or palladium catalyzed Buchwald-Hartwig amination between monoprotected diamines (A1) or their corresponding salts and heteroaryls (A8) with X being a leaving group such as halogen or -S(O)Me. The procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.
Deprotection of diamines of general formula (A12) can give primary amines of general formula (A13). For deprotection the same procedures apply as described for the synthesis of (A7) from (A6) in Scheme 1.
Final compounds of general formula (l-B) in turn can be synthesized from primary amines (A13) or their corresponding salts and preassembled heteroaryls (A11a) with X being a leaving group like halogen or -S(O)Me via nucleophilic aromatic substitution (SNA^ or palladium catalyzed Buchwald-Hartwig amination. The procedures that can be applied are in analogy to those described for the synthesis of (A6) from (A1) and (A11a) in Scheme 1.
For the synthesis of intermediates of general formula (A10) primary amines (A13) or their corresponding salts may be reacted with heteroaryls (A2a) with X being a leaving group like halogen or -S(O)Me in a nucleophilic aromatic substitution (SNAr) or palladium catalyzed Buchwald-Hartwig amination. The procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.
Carboxylic acid derivatives of general formula (A21) may be synthesized according to the route depicted in Scheme 3. Nitro compounds of general formula (A15) can be obtained from reacting monoprotected diamines (A1) or their corresponding salts and nitroaryls (A14) with X being a leaving group like chlorine in a nucleophilic aromatic substitution (SNAr). The reaction can be carried out in the presence of inorganic bases like K2CO3 in polar solvents such as for example DMSO at temperatures between room temperature and the boiling point of the solvent for 2- 12 h. Nitroaryls of general formula (A14) are either commercially available or can be prepared according to procedures available from the public domain.
Anilines of general formula (A16) may be obtained from nitro compounds of general formula (A15) by reduction. For reduction all methods that are known in the art may be applied. For example, nitro compounds of general formula (A15) can be reacted in the presence of a metal catalyst like palladium on charcoal under an atmosphere of hydrogen gas (1-5 bar) in polar, protic solvents like methanol or ethanol at temperatures between 0 °C and the boiling point of the solvent for 15-24 h.
Scheme 3
Figure imgf000109_0001
Scheme 3: Routes for the preparation of compounds of general formula (A21) in which X is a leaving group, PG is a protective group, Aik is methyl or ethyl and X1, RA2 and RA3 have the meaning as given for general formula (l-B), supra.
Pyridones of general formula (A18) may be obtained from anilines (A16) by condensation with oxo-pyranes of general formula (A17) with Aik being methyl or ethyl in polar, protic solvents like ethanol at temperatures between room temperature and the boiling point of the solvent for 2- 12 h. Oxo-pyranes of general formula (A17) are either commercially available or can be prepared according to procedures available from the public domain.
Primary amines of general formula (A19) may be synthesized from (A18) via removal of the protective group. For deprotection the same procedures apply as described for the synthesis of (A 7) from (A6) in Scheme 1.
Carboxylic esters of general formula (A20) can be obtained from primary amines (A19) and heteroaryls (A8) via nucleophilic aromatic substitution (SNA^ or palladium catalyzed Buchwald- Hartwig amination applying procedures in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.
Carboxylic acid derivatives of general formula (A21) may be synthesized from carboxylic esters of general formula (A20) by ester hydrolysis. For saponification all methods that are known in the art may be applied. For example, esters (A20) may be reacted with bases like sodium hydroxide in polar, protic solvents like methanol, water or mixtures thereof at temperatures between 0 °C and the boiling point of the solvent for 0.5-2 h.
1,2,4-Triazines of general formula (A29) may be synthesized according to the routes depicted in Scheme 4. The methyl-thioether moiety of 3-(methylthio)-1 ,2,4-triazine (A22) [CAS 28735-21-9] might be activated for nucleophilic displacement by oxidation for which all methods that are known in the art may be applied. For example, (A22) can be reacted with mCPBA or Oxone® in inert solvents like dichloromethane at temperatures between 0 °C and the boiling point of the solvent for 0.5-2 h. The crude oxidation product may be directly converted to monoarylated diamines of general formula (A23) in a nucleophilic aromatic substitution (SNAr) by reacting it with primary amines of general formula (A1) in polar solvents such as for example nBuOH at temperatures between room temperature and the boiling point of the solvent for 2-18 hours.
Aryl bromides of general formula (A24) can be obtained from triazines of general formula (A23) by bromination. For bromination all methods that are known in the art may be applied. For example, triazines (A23) can be reacted with bromine or /V-bromosuccinimide (NBS) in solvents like methanol, water, DMF or mixtures thereof at temperatures between 0 °C and the boiling point of the solvent for 4-15 h.
3,6-Disubstituted triazines of general formula (A27) may be synthesized from aryl bromides (A24) via Suzuki coupling for which all methods that are known in the art may be applied. For example, (A24) may be reacted with potassium trifluoroborates (A25) or trioxatriborinanes (A26) in the presence of a palladium catalyst like CataCXium A Pd G3 [CAS 1651823-59-4] or 1,1'- bis(di-terf-butylphosphino)ferrocene palladium dichloride [CAS 95408-45-0] and a base like CS2CO3, K2CO3 or K3PO4 in polar solvents such as 1 ,4-dioxane, THF and water or mixtures thereof at temperatures between room temperature and 120 °C for 8-15 hours. Trifluoroborates of general formula (A25) or trioxatriborinanes (A26) are either commercially available or can be prepared according to procedures available from the public domain. Scheme 4
Figure imgf000111_0001
Scheme 4: Routes for the preparation of compounds of general formula (A29) in which X is a leaving group, PG is a protective group, Aik is methyl or ethyl, X2 and X3 are CH or N (provided that when X2 is N, X3 is CH and vice versa), RA2 is alkyl or cycloalkyl and D has the meaning as given for general formula (l-B), supra.
Primary amines of general formula (A28) may be obtained from (A27) via removal of the protective group. For deprotection the same procedures apply as described for the synthesis of (A 7) from (A6) in Scheme 1 . Final compounds of general formula (A29) can be synthesized from primary amines (A28) or their corresponding salts and preassembled heteroaryls (A11) with X being a leaving group like halogen via nucleophilic aromatic substitution (SNA^ or palladium catalyzed Buchwald-Hartwig amination. The procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. Heteroaryls of general formula (A11) are either commercially available or can be prepared according to procedures available from the public domain. Specific examples of (A11) are described in the subsequent paragraphs.
In an alternative route to triazines of general formula (A29), primary amines (A28) or their corresponding salts may be first reacted with heteroaryls (A2) with X being a leaving group like halogen via nucleophilic aromatic substitution (SNAr) or palladium catalyzed Buchwald-Hartwig amination to give aryl iodides of general formula (A30). The procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. Heteroaryls of general formula (A2) are either commercially available or can be prepared according to procedures available from the public domain.
Final compounds of general formula (A29) can be synthesized from aryl iodides of general formula (A30) via copper catalyzed Ullmann couplings with heterocycles H-D (A4) or via palladium catalyzed Suzuki couplings with boronic acid derivatives (A5) applying procedures in analogy to those described for the synthesis of compounds (A6) from (A3) in Scheme 1.
In an alternative approach to 3,6-disubstituted triazines of general formula (A27), ketoacetals of general formula (A31) may be reacted with methyl hydrazinecarbimidothioate (A32) or its corresponding salts in polar solvents such as for example methanol at temperatures between room temperature and the boiling point of the solvent for 5-12 h to give triazine thioethers of general formula (A33) [for a similar approach to triazine thioethers see Duan 2012], Ketoacetals of general formula (A31) and methyl hydrazinecarbimidothioate (A32) are either commercially available or can be prepared according to procedures available from the public domain.
Triazine thioethers of general formula (A33) in turn could be transferred to 3,6-disubstituted triazines of general formula (A27) by a two-step approach including oxidation of (A33) followed by nucleophilic aromatic substitution (SNA^ with primary amines of general formula (A1) applying procedures in analogy to those described for the synthesis of compounds (A23) from (A22) in Scheme 4.
Carboxylic ester or amide derivatives of general formulae (A35) and (A37) may be synthesized according to the routes depicted in Scheme 5. Carboxylic esters of general formula (A35) may be obtained from primary amines (A7) [see Scheme 1] and triazines of general formula (A34) via nucleophilic aromatic substitution (SNA^ applying procedures in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. For example, (A 7) and (A34) can be reacted in the presence of an organic base like DIPEA in polar solvents such as NMP at temperatures between room temperature and the boiling point of the solvent for 0.5-2 h applying microwave heating. Triazines of general formula (A34) are either commercially available or can be prepared according to procedures available from the public domain.
Carboxamides of general formula (A37) can be obtained from carboxylic esters (A35) via direct amidation. For amidation reactions all methods that are known in the art may be applied. For example, esters (A35) can be reacted with amines (A36) in polar solvents such as methanol, ethanol or THF at temperatures between room temperature and the boiling point of the solvent for 1-5 hours. If an amine (A36) of limited nucleophilicity is used it is possible to increase the temperature and prolong the reaction time and/or to add Lewis acids like AIMes.
Scheme 5
Figure imgf000113_0001
Scheme 5: Routes for the preparation of compounds of general formulae (A35) and (A37) in which Aik is methyl or ethyl and D has the meaning as given for general formula (l-B), supra.
Alternatively, esters (A35) may first be hydrolyzed to carboxylic acids of general formula (A38). For saponification all methods that are known in the art may be applied. For example, esters (A35) may be reacted with bases like sodium hydroxide, lithium hydroxide or potassium hydroxide in polar, protic solvents like water or methanol or mixtures thereof at temperatures between 0 °C and the boiling point of the solvent for 0.5-24 hours. In certain cases it might be beneficial to add ethers like THF or 1,4-dioxane to the reaction mixture.
Carboxamides of general formula (A37) in turn can be obtained from carboxylic acids (A38) via amide coupling with appropriate amines (A36). For amide coupling all methods that are known from peptide chemistry in the art may be applied. For example, acids (A38) may be reacted with amines (A36) in polar, aprotic solvents like DMF, acetonitrile or NMP via an activated acid derivative. These activated derivatives can be obtained from acids (A38) with reagents such as HOBt, HOAt or /V-hydroxysuccinimide and a carbodiimide such as DCC or EDC or else with preformed reagents like HATLI, PyBOP or T3P®. In order to increase reactivity a suitable base such as DIPEA or triethylamine can be used. In certain cases, the activated acid derivative might be isolated prior to the reaction with the amine (A36). Amide formation might also be accomplished via the acid halide (which can be formed from a carboxylic acid by reaction with e.g. oxalyl chloride, thionyl chloride or sulfuryl chloride), mixed anhydride (which can be formed from a carboxylic acid by reaction with e.g. isobutylchloroformate), imidazolide (which can be formed from a carboxylic acid by reaction with e.g. GDI) or azide (which can be formed from a carboxylic acid by reaction with DPPA).
For the synthesis of final compounds of general formula (B-2) routes and methods comparable to the ones described in Schemes 1-5 may be applied. Without being intended to be limiting the routes to compounds of general formula (A43) in Schemes 6-7 are given for further illustration.
Diamines of general formula (A39) are either commercially available or can be prepared according to procedures available from the public domain.
Scheme 6
Figure imgf000114_0001
Scheme 6: Routes for the preparation of compounds of general formula (A43) in which X is a leaving group, PG is a protective group and D, X1, RA2, RA3 and RB2 have the meaning as given for general formulae (l-B) and (B-2), supra. Scheme 7
SNAr or
Figure imgf000115_0001
Method 6 Buchwald cou lin
Figure imgf000115_0002
Scheme 7: Routes for the preparation of compounds of general formula (A43) and intermediates (A45) in which X is a leaving group, PG is a protective group and D, X1, RA2, RA3 and RB2 have the meaning as given for general formulae (l-B) and (B-2), supra.
Further compounds with different formulae as described above can be prepared by similar methods.
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. Other abbreviations have their meanings customary perse to the skilled person.
Abbreviations Aq Aqueous
BINAP 2,2'-Bis(diphenylphosphaneyl)-1 , T-binaphthalene
Boc tert- Butoxycarbonyl
Brine Saturated aqueous sodium chloride solution nBuOH Butan-1-ol
CataCXium A Di(adamantan-1-yl)(butyl)phosphane (CAS Registry Number 321921-71-5)
CataCXium A Pd G3 Methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino- 1 , T- biphenyl-2-yl)palladium(ll) precatalyst generation 3
GDI 1 , 1 ’-Carbonyldiimidazole
CHAPS 3-[(3-Cholamidopropyl)dimethylammonio]-1 -propanesulfonate m-CPBA 3-Chlorobenzoperoxoic acid
DavePhos 2'-(Dicyclohexylphosphaneyl)-/\/,/\/-dimethyl-[1 , 1 '-bi pheny l]-2- amine (CAS Registry Number 213697-53-1) dba (all-trans)-Dibenzylideneacetone
DCC Dicyclohexylcarbodiimide
DCM Dichloromethane
DEA Diethylamine
DIPEA /V-ethyl-/V-isopropyl-propan-2-amine
DMA /V, /V- D i m ethyl aceta m i d e
DME Dimethoxyethane
DMF /V,/V-Dimethylformamide
DMSO Dimethyl sulfoxide
DPPA Diphenyl phosphorazidate dppf 1 , 1 ’-Bis(diphenylphosphino)ferrocene
EDC 2-(((Ethylimino)methylene)amino)-/\/,/\/-dimethylethan-1-amine hydrochloride
ESI Electrospray ionization
EtOAc Ethyl acetate
EtOH Ethanol
FA Formic acid
G3 Generation 3
Gmean Geometric mean
HATU (1-(Bis(dimethylamino)methylene]-1/7-1 ,2,3-triazolo[4,5- b]pyridinium-3-oxo hexafluorophosphate
HEPES (4-(2-Hydroxyethyl)-1 -piperazineethanesulfonic acid)
HOAt 3/7-[1,2,3]Triazolo[4,5-b]pyridin-3-ol HOBt 1H-Benzo[d][1,2,3]triazol-1-ol HPLC High performance liquid chromatography HRMS High resolution mass spectrometry i-PrOH Propan-2-ol IC50 Half maximal inhibitory concentration KD Dissociation constant MeCN Acetonitrile MeOH Methanol MS Mass spectrometry MTBD 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene MTBE Methyl tert-butyl ether MW Microwave NBS N-Bromosuccinimide NCS 1-Chloropyrrolidine-2,5-dione NIS 1-Iodopyrrolidine-2,5-dione NMP 1-Methylpyrrolidin-2-one NMR Nuclear magnetic resonance O.n Overnight Otf Trifluoromethanesulfonate Pd-118/PdCl2(dtbpf) [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium (0) Pd2(dba)3•CHCl3 Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct Pd(dppf)Cl2•DCM [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) CH2Cl2 (1:1) PdCl2(dppf) [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd-PEPPSI-IpentCl 2-methylpyridine (SP-4-1)-[1,3-Bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3- dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palla- dium (CAS Registry Number 1612891-29-8) PE Petroleum ether PG Protective group prep. Preparative PyBOP ((1H-Benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate qToF Quadrupole time-of-flight RockPhos Di-tert-butyl(2′,4′,6′-triisopropyl-3-methoxy-6-methyl-[1,1′- biphenyl]-2-yl)phosphine rt Room temperature sat. Saturated SFC Supercritical fluid chromatography SNAr Nucleophilic aromatic substitution T3P 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide TEA Triethylamine TFA Trifluoroacetic acid TFAA 2,2,2-Trifluoroacetic anhydride THF Tetrahydrofurane TLC Thin layer chromatography TMEDA N1,N1,N2,N2-Tetramethylethane-1,2-diamine tR Retention time UPLC Ultra high performance liquid chromatography XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, (9,9-dimethyl- 9H-xanthene-4,5-diyl)bis(diphenylphosphine) XPhos Dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane Units atm atmosphere C Celcius g gram h hour(s) Hz hertz L liter M mole per liter mg milligram MHz megahertz min minute(s) mL milliliter mm millimeter mM millimole per liter mol mole mmol millimole(s) nA nanoampere nL nanolitre µm micrometer µL microliter N equivalents per liter nm nanometer ppm parts per million Å Ångström The various embodiments described in this application are illustrated by the following examples which are not meant to limit the compound of Formula (I) in any way. The example testing experiments described herein serve to illustrate the present embodiments and is not limited to the examples given. EXPERIMENTAL SECTION – GENERAL PART General conditions (i) operations were carried out at room temperature (rt), i.e. in the range 17 to 28 °C and were needed under an atmosphere of an inert gas such as N2; (ii) where reactions refer to being degassed or purged, this can be performed for example by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (for example 5 to 10 min) or by repeatedly evacuating the vessel and backfill with appropriate inert atmosphere (for example nitrogen (g) or argon (g)); (iii) where reactions refer to the use of a microwave reactor, one of the following microwave reactors were used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator or CEM Explorer; (iv) in general, the course of reactions was followed by thin layer chromatography (TLC) and/or analytical high performance liquid chromatography (HPLC or UPLC) which was usually coupled to a mass spectrometer (LCMS); (v) to remove excess water, organic solutions were dried over anhydrous MgSO4 or Na2SO4, or by using ISOLUTE® Phase Separator, and work-up procedures were carried out using traditional phase separating techniques; (vi) evaporations were carried out either by rotary evaporation in vacuo or in a GenevacTM HT-4 / EZ-2 or Biotage® V10; (vii) unless otherwise stated, flash column chromatography was performed on normal phase silica, using either Merck Silica Gel (Art.9385) or pre-packed cartridges such as Biotage® SNAP cartridges (40-63 μm silica, 4–330 g), Biotage® Sfär Silica HC D cartridges (20 µm, 10–100 g), Interchim puriFlash™ cartridges (25 µm, 4–120 g), Interchim puriFlash™ cartridges (50 µm, 25–330 g), Grace™ GraceResolv™ Silica Flash Cartridges (4–120 g) or Agela Flash Colum Silica-CS cartridges (80–330 g), or on reverse phase silica using Agela Technologies C-18, spherical cartridges (20-35 pm, 100 A, 80-330 g), manually or automated using a Grace Reveleris® X2 Flash system or similar system;
(viii) preparative reversed phase HPLC and preparative reversed phase SFC were performed using standard HPLC and SFC instruments, respectively, equipped with either a MS and/or UV triggered fraction collecting instrument, using either isocratic or a gradient of the mobile phase as described in the experimental section; 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, extracted with DCM or EtOAc, and the organic phase was dried either over Na2SO4 or by using a phase-separator, and then concentrated at reduced pressure to give the purified compound;
(ix) chiral preparative chromatography was carried out using HPLC or SFC on a standard HPLC or SFC instrument, respectively, and using either isocratic or gradient run with mobile phase as described in the experimental section;
(x) preparative thin layer chromatography (TLC) was performed using TLC glass plates and applying a suitable solvent or mixture of solvents;
(xi) yields, where present, are not necessarily the maximum attainable, and some, 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 nuclear magnetic resonance (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 1H frequencies of 300, 400, 500 and 600 MHz, respectively. The experiments were typically recorded at 25 °C. Chemical shifts are given in ppm with the solvent as internal standard. Protons on heteroatoms such as NH and OH protons are only reported when detected in NMR and can therefore be missing. In certain instances, protons can be masked or partially masked by solvent peaks and will therefore either be missing and not reported or reported as multiplets overlapping with solvent. The following abbreviations have been used (and derivatives thereof, e.g. dd, doublet of doublets, etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet. 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 LIPLC, acquiring either positive and negative ion data, and generally, only ions relating to the parent structure are reported;
(xiv) intermediates were in certain cases not fully purified but their structures and purity were assessed by TLC, analytical HPLC/UPLC, and/or NMR analysis and/or mass spectrometry;
(xv) certain intermediates were isolated as TFA salts and can contain excess TFA. The excess can be calculated from the weight of the crude sample. Where stated the salts were treated according to literature-known processes to generate the corresponding free base prior to being used;
(xvi) unless stated otherwise compounds containing an asymmetric carbon and/or sulfur atom were not resolved;
(xvii) in general Examples and Intermediate compounds are named using ChemDraw Professional version 21.0.0.28 from PerkinElmer. ChemDraw Professional version 21.0.0.28 generates the names of chemical structures using the Cahn-lngold-Prelog (CIP) rules for stereochemistry and follows IIIPAC 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.
Where applicable ChemDraw is using labels in the graphical representation of stereocenters such and 'or' to describe the configuration of the stereochemical centers present in the structure. A number following the
Figure imgf000121_0001
and 'or1 flag is assigned to each stereocenter present.
In some cases, the purification methods as described above can provide those compounds of Formula (I) which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of Formula (I) which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of Formula (I) which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known in the art or be used as salt in subsequent biological assays. It is to be understood the specific form (e.g. salt, free base etc.) of a compound of Formula (I) as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
Purification Methods
HPLC Methods: PrepMethod A: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeOH in a H2O/NH4HCO3 (10 mM)/NH3 (0.1 %, aq) buffer system as mobile phase;
PrepMethod B: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NH3 (0.1 %, aq) buffer system as mobile phase;
PrepMethod C: The compound was purified by preparative HPLC on a Xbridge™ Shield RP18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.1 %, aq) buffer system as mobile phase;
PrepMethod D: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NHs (0.1 %, aq) buffer system as mobile phase;
PrepMethod E: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/FA (0.1 %) buffer system as mobile phase;
PrepMethod F: The compound was purified by preparative HPLC on a Xbridge™ C18 column (10 pm, 250x50 mm ID) using a gradient of MeCN in H2O/MeCN/NH3 (95/5/0.2) buffer system as mobile phase;
PrepMethod G: The compound was purified by preparative HPLC on a Kromasil C8 column (10 pm, 250x20 mm ID) using a gradient of MeCN in H2O/MeCN/FA (95/5/0.2) buffer system as mobile phase;
PrepMethod H: The compound was purified by preparative HPLC on a Xbridge™ C18 column (10 pm, 250x19 mm ID) using a gradient of MeCN in H2O/MeCN/NH3 (95/5/0.2) buffer system as mobile phase;
PrepMethod I: The compound was purified by preparative HPLC on a Xbridge™ C18 ODB column (5 pm, 150x19 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM, pH 9) buffer system as mobile phase;
PrepMethod J: The compound was purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/FA (0.1%) as mobile phase;
PrepMethod K: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
PrepMethod L: The compound was purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NHs (0.1 %, aq) buffer system as mobile phase; PrepMethod M: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NH3 (0.1%, aq) buffer system as mobile phase;
PrepMethod N: The compound was purified by preparative HPLC on a Xbridge™ OBD Phenyl column (5 pm, 150x19 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NHs (0.1 %, aq) buffer system as mobile phase;
PrepMethod O: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
PrepMethod P: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O as mobile phase;
PrepMethod Q: The compound was purified by preparative HPLC on a Xbridge™ Shield RP18 OBD column (5 pm, 250x19 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
PrepMethod R: The compound was purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/FA (10mM) as mobile phase;
PrepMethod S: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM) buffer system as mobile phase;
PrepMethod T: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 pm, 150x30 mm ID) using a gradient of 20 mM NaOH + 10% MeCN in a H2O/NH4HCO3 (10 mM)/NH3 (0.05%, aq) buffer system as mobile phase;
PrepMethod U: The compound was purified by preparative HPLC on a Xbridge™ OBD Phenyl column (5 pm, 250x19 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
PrepMethod V: The compound was purified by preparative HPLC on a Xbridge™ OBD Phenyl column (5 pm, 250x19 mm ID) using a gradient of MeCN in a H20/TFA (0.05%) buffer system as mobile phase;
PrepMethod X: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
PrepMethod Y: The compound was purified by preparative HPLC on a Xbridge™ Shield RP18 OBD column (5 pm, 100x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase; PrepMethod Z: The compound was purified by preparative HPLC on a Waters Xselect Peptide CSH C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in H2O/FA (0.1%) buffer system as mobile phase;
PrepMethod Z1 : The compound was purified by preparative HPLC on a Waters Xselect Peptide CSH C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NH3 (0.1 %, aq) buffer system as mobile phase;
PrepMethod Z2: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 pm, 150x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NH3 (0.05%, aq) buffer system as mobile phase;
PrepMethod Z3: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 pm, 100x30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 mM)/NHs (0.05%, aq) buffer system as mobile phase;
PrepMethod Z4: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 pm, 250x19 mm ID) using a gradient of MeCN in a H2O/TFA (0.005%) buffer system as mobile phase;
PrepMethod Z5: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 pm, 250x19 mm ID) using a gradient of MeOH in a H2O/NH4HCO3 (10 mM)/NH3 (0.05%, aq) buffer system as mobile phase;
PrepMethod Z6: The compound was purified by preparative HPLC on a Xbridge™ Shield RP18 OBD column (5 pm, 100x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.1 %, aq) buffer system as mobile phase;
PrepMethod Z7: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 pm, 100x50 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.1%, aq) buffer system as mobile phase;
PrepMethod Z8: The compound was purified by preparative HPLC on a Xbridge™ RP18 OBD column (5 pm, 100x30 mm ID) using a gradient of MeCN in H2O/NH4HCO3 (10 mM)/NHs (0.1%, aq) buffer system as mobile phase.
PrepMethod Z9: The compound was purified by preparative HPLC on a Xbridge™ C8 column (5 pm, 250x20 mm ID) using a gradient of MeCN in H2O/MeCN/NH3 (95/5/0.2) buffer system as mobile phase;
PrepMethod Z10: The compound was purified by preparative HPLC on a Xbridge™ C8 column (5 pm, 250x50 mm ID) using a gradient of MeCN in H2O/MeCN/NH3 (95/5/0.2) buffer system as mobile phase.
Preparative SFC Methods:
PrepMethod SFC-A: The compound was purified by preparative SFC on a Waters™ BEH (5 pm, 250x30 mm ID) using MeOH/H2O (NH3, 50 mM) (97/3) in CO2 as mobile phase; PrepMethod SFC-B: The compound was purified by preparative SFC on a Phenomenex Luna Hilic (3.5 pm, 100x3 mm ID) using MeOH/NHs 20 mM in CO2 as mobile phase;
PrepMethod SFC-C: The compound was purified by preparative SFC on a Waters™ Acquity UPC2 BEH (3.5 pm, 100x3 mm ID) using MeOH/H2O (NH3, 50 mM) (97/3) in CO2 as mobile phase;
PrepMethod SFC-D: The compound was purified by preparative SFC on a Waters™ BEH (5 pm, 250x30 mm ID) using MeOH/NHs (20 mM) in CO2 as mobile phase;
PrepMethod SFC-E: The compound was purified by preparative SFC on a Phenomenex Luna Hilic (5 pm, 250x30 mm ID) using MeOH/NHs 20 mM in CO2 as mobile phase.
Preparative HPLC Methods for Parallel Experiment Set-up:
PrepMethod Parallel A: The compound was purified by preparative HPLC on a Waters™ Xbridge™ C18 column (5 pm, 100x10 mm ID) using a gradient (2-94%) of MeCN in H2O/NH3 (pH 10) buffer system as mobile phase;
PrepMethod Parallel B: The compound was purified by preparative HPLC on a Waters™ Xselect™ CSH Fluoro Phenyl column (5 pm, 100x10 mm ID) using a gradient (2-94%) of MeCN in H2O/FA (pH 3) buffer system as mobile phase;
PrepMethod Parallel C: The compound was purified by preparative HPLC on a Waters™ Xbridge™ C18 OBD column (5 pm, 150x19 mm ID) using a gradient (5-95%) of MeCN in H2O/MeCN/NHs (95/5/0.2) (pH 10) buffer system as mobile phase;
PrepMethod Parallel D: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 pm, 150x19 mm ID) using a gradient (5-95%) of MeCN in a H2O/NH4HCO3 (10 mM) (pH 9) buffer system as mobile phase.
Synthesis Methods
General Method 1 (GM1): Nucleophilic Aromatic Substitution (SuAr)
Condition A (GM1A): Conventional heating
To a solution of the respective amine nucleophile or its salt (1 eq.) in DMSO (alternatively NMP or n-BuOH or 1,4-dioxane) is added base (1-7 eq.) and the respective heteroaryl electrophile (0.9-2 eq.) at rt and the resulting mixture stirred under heating (100-130 °C) until TLC and/or LCMS indicate complete consumption of the starting material (typically overnight). The reaction mixture is either concentrated under reduced pressure and the obtained crude material subjected to chromatography or prep. TLC and/or prep. HPLC to give the desired aniline product. In an alternative aqueous work-up, the reaction mixture is poured into sat. brine or water and extracted with EtOAc. The combined organic layers are washed with water or brine, dried over Na2SC>4, filtered and evaporated and the obtained crude material subjected to chromatography on silica to give the desired aniline product.
Condition B (GM1B): Microwave heating
To a mixture of the respective amine nucleophile or its salt (1 eq.) and the respective heteroaryl electrophile (1-1.5 eq.) in a microwave vial is added NMP and base (1-3 eq.), the vial capped and heated under microwave radiation until TLC and/or LCMS indicate consumption of the starting material (typically 0.5-2 h). The reaction mixture is concentrated under reduced pressure and the obtained crude material subjected to prep. HPLC to give the desired aniline product.
General Method 2 (GM2): Buchwald-Hartwiq Amination
A solution of the respective amine nucleophile or its salt (1 eq.) in 1 ,4-dioxane under nitrogen at rt is treated with the respective heteroaryl electrophile (0.5-4 eq.), CS2CO3 (1.2-5 eq.) and Pd PEPPSI-lpentCI [CAS 1612891-29-8] (3-7 mol%) and the reaction mixture stirred under heating (100 °C) until TLC and/or LCMS indicate complete consumption of the starting material (typically overnight). The reaction mixture is either filtered through a pad of Celite or silica, the filter cake washed with EtOAc and the combined filtrates concentrated under reduced pressure. The obtained crude material is either triturated with PE/EtOAc or subjected to prep. TLC and/or prep. HPLC to give the desired aniline product.
In an alternative aqueous work-up, the reaction mixture is concentrated under reduced pressure and the residue partitioned between EtOAc and water. The phases are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with water and/or brine, dried over Na2SO4, filtered and evaporated and the obtained crude material subjected to prep. TLC and/or prep. HPLC to give the desired aniline product.
General Method 3 (GM3): Ullmann Couplinq
A solution of the respective aryl halide (1 eq.) in 1 ,4-dioxane under nitrogen at rt is treated with the respective heteroatom nucleophile H-D (A4) (1-10 eq.), CS2CO3 (3-6 eq.), Cu(l)l (0.2-2 eq.) and re/-(1R,2/?)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine [CAS 67579-81-1] (0.2-2 eq.) and the reaction mixture stirred under heating (80-100 °C) until TLC and/or LCMS indicate complete consumption of the starting material (typically 15-18). The reaction mixture is diluted with EtOAc and washed sequentially with water and brine. Alternatively, the reaction mixture is diluted with water or brine and the aqueous layer extracted with EtOAc. The organic layer is dried over Na2SC>4, filtered and evaporated. The obtained crude material is either triturated with PE/EtOAc or subjected to prep. TLC and/or prep. HPLC to give the desired coupling product.
In an alternative non-aqueous work-up, the reaction mixture is filtered through a pad of Celite, the filter cake washed with DCM and the combined filtrates concentrated under reduced pressure. The obtained crude material is subjected to prep. TLC and/or prep. HPLC to give the desired coupling product.
General Method 4 (GM4): Suzuki Coupling
Condition A (GM4A): Coupling with boronic acid derivatives
A solution of the respective aryl halide (1 eq.) in a mixture of 1 ,4-dioxane and water under nitrogen at rt is treated with the respective boronic acid derivative (A5) (1.5-2 eq.) or (A26) (10 eq.), CS2CO3 (3 eq.) or K2CO3 (3 eq.) or K3PO4 (2-3 eq.) and 1 , 1 '-bis(di-fert- butylphosphino)ferrocene palladium dichloride [CAS 95408-45-0] (5-10 mol%) or 1 ,T- bis(diphenylphosphino)ferrocene palladium dichloride [CAS 72287-26-4] (10 mol%) and the reaction mixture stirred under heating (80-100 °C) until TLC and/or LCMS indicate complete consumption of the starting material (2-18). The reaction mixture is filtered through a pad of Celite, the filter cake washed with DCM and the combined filtrates concentrated under reduced pressure. The obtained crude material is subjected to prep. TLC and/or prep. HPLC to give the desired coupling product.
In an alternative aqueous work-up, the reaction mixture is diluted with water, the phases separated and the aqueous phase extracted with EtOAc. The combined organic layers are dried over Na2SC>4, filtered and evaporated and the obtained crude material subjected to prep. TLC and/or C18-flash chromatography or prep. HPLC to give the desired coupling product.
Condition B (GM4B): Coupling with trifluoroborates
A solution of the respective aryl halide (1 eq.) in 1 ,4-dioxane under nitrogen at rt is treated with the respective potassium trifluoroborate (A25) (4 eq.), CS2CO3 (4 eq.) and CataCXium A Pd G3 [CAS 1651823-59-4] (20 mol%) and the reaction mixture stirred under heating (100 °C) until TLC and/or LCMS indicate complete consumption of the starting material (typically 15). The reaction mixture is filtered through a pad of Celite, the filter cake washed with DCM and the combined filtrates concentrated under reduced pressure. The obtained crude material is subjected to prep. TLC and/or prep. HPLC to give the desired coupling product.
General Method 5
Figure imgf000127_0001
: Chan-Lam A mixture of the respective heteroatom nucleophile H-D (A4) (1 eq.) in 1 ,4-dioxane at rt is treated with the respective boronic acid (2-3 eq.), TMEDA (3 eq.) and Cu(0tf)2 (1.2-2 eq.) and the reaction mixture stirred under heating (100 °C) until TLC and/or LCMS indicate complete consumption of the starting material (typically 16). The reaction mixture is filtered through a pad of Celite, the filtrate concentrated under reduced pressure and the residue partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc, the combined organic layers washed with water, dried over Na2SO4, filtered and evaporated. The obtained crude material is subjected to C18-flash chromatography to give the desired coupling product.
General Method 6 (GM6): Boc Deprotection
Condition A (GM6A): Deprotection with HCI
A solution of the respective Boc protected amine (1 eq.) in MeOH at rt is treated with 4 M HCI in MeOH (13-77 eq.) and the reaction mixture stirred under heating (60-80 °C) until TLC and/or LCMS indicate complete consumption of the starting material (typically 2-3). The reaction mixture is concentrated under reduced pressure to give the desired amine as (an unspecified) HCI salt.
Condition B (GM6B): Deprotection with TFA
A solution of the respective Boc protected amine (1 eq.) in DCM at rt is treated with TFA (11- 190 eq.) and the reaction mixture stirred at rt until TLC and/or LCMS indicate complete consumption of the starting material (3-16). The reaction mixture is concentrated under reduced pressure to give the desired amine as (an unspecified) TFA salt.
General Method 7 (GM7): Amide Formation
In a microwave vial a solution of the respective ester (A35) in MeOH is treated with the respective amine or its salt (A36) (4-100 eq., neat or as a solution in THF) and where applicable additionally with DI PEA (4-8 eq.) at rt. The vial is capped, and the reaction mixture stirred at rt or heating (60-70 °C) until TLC and/or LCMS indicate complete consumption of the starting material (3). The reaction mixture is concentrated under reduced pressure and the obtained crude material subjected to preparative HPLC to give the desired amide.
General Method 8 (GM8): Methyl-thioether Oxidation
A solution of the methyl-thioether (1 eq.) in DCM is cooled to 0 °C and treated slowly with 3- chlorobenzoperoxoic acid (m-CPBA) [CAS 937-14-4] (0.9-1.2 eq.) and the resulting mixture stirred at rt until TLC and/or LCMS indicate complete consumption of the starting material (0.5- 2). The reaction mixture is directly used in the next step.
Alternatively, the reaction mixture is concentrated under reduced pressure and the obtained crude material is subjected to flash chromatography on silica to give the desired oxidation product.
Intermediates
Intermediate 1
6'-(((1 S,3S)-3-Aminocyclopentyl)amino)-2/-/-[1 ,3'-bipyridin]-2-one
Step A. i-1 a tert-Butyl ((1 S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate
Figure imgf000129_0001
According to GM1A 2-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (2.23 g, 9.99 mmol) was added to te/t-butyl ((1 S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (2.00 g, 9.99 mmol) and K2CO3 (2.76 g, 20 mmol) in DMSO (30 mL). The resulting solution was stirred at 125 °C for 18 h under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 x 75 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude material was purified by flash chromatography on silica (gradient: 0 - 50% EtOAc in PE) to give the title compound (2.70 g, 67%) as a pale yellow solid. MS (ESI): m/z [M+H]+ 403.9.
Step B. i-1 b tert-Butyl ((1 S,3S)-3-((2-oxo-2H-[1 ,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate
Figure imgf000129_0002
In a slight modification of GM3 re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine (CAS Reg. No. 67579-81-1) (0.212 g, 1.49 mmol) and Cu(l)l (0.283 g, 1.49 mmol) were added to te/t-butyl ((1 S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1 a (3.0 g, 7.44 mmol), K2CO3 (3.08 g, 22.3 mmol) and pyridin-2(1/7)-one (CAS Reg. No. 142-08-5) (1.42 g, 14.9 mmol) in 1 ,4-dioxane (20 mL). The resulting solution was stirred at 110 °C for 18 h under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (25 mL) and washed sequentially with water (3 x 25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude material was triturated with EtOAc: PE (5:1) to give a solid which was collected by filtration and dried under vacuum to give the title compound (2.70 g, 98%) as a yellow solid. MS (ESI): m/z [M+H]+ 371.2.
Step C. i-1 c
6'-(((1 S,3S)-3-Aminocyclopentyl)amino)-2/-/-[1 ,3'-bipyridin]-2-one
Figure imgf000130_0001
In a modification of GM6A HCI (2 M in diethyl ether, 27 mL, 54 mmol) was added slowly to tertbutyl ((1 S,3S)-3-((2-oxo-2/7-[1 ,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate compound i-1 b (1.0 g, 2.70 mmol) in DCM (10 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 3 h. This synthesis procedure was repeated for a second batch of terf-butyl ((1 S,3S)-3-((2-oxo-2/7- [1 ,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate compound i-1 b (1.7 g, 4.6 mmol). The two batches were combined and concentrated. The crude product was recrystallised with EtOAc:PE (5:1) to give a solid which was collected by filtration and dried under vacuum to give an unspecified HCI salt of the title compound (2.5 g, 100%) as a yellow solid. MS (ESI): m/z [M+H]+ 270.9.
Intermediate 3
6'-(((1S,3S)-3-Aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one x 2 HCI Step A. i-3a tert-Butyl ((1 S,3S)-3-((3-methoxy-2-oxo-2H-[1,3,-bipyridin]-6'- yl)amino)cyclopentyl)carbamate
Figure imgf000130_0002
According to GM3 terf-butyl ((1 S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1 a (500 mg, 1.24 mmol), 3-methoxypyridin-2(1/7)-one (CAS Reg. No. 20928-63-6) (776 mg, 6.20 mmol), re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine (176 mg, 1.24 mmol), CS2CO3 (2020 mg, 6.20 mmol) and Cu(l)l (236 mg, 1.24 mmol) were reacted in 1 ,4-dioxane (5 mL) at 100 °C for 15 h to give after aqueous work-up and preparative TLC (MeOH : DCM = 1 :20) the title compound (387 mg, 78 %) as a brown solid. MS (ESI): m/z [M+H]+ 401.3.
Step B. i-3b 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one x 2 HCI
Figure imgf000131_0001
According to GM6A3 tert-butyl ((1 S,3S)-3-((3-methoxy-2-oxo-2/7-[1 ,3'-bipyridin]-6'- yl)amino)cyclopentyl)carbamate compound i-3a (370 mg, 0.92 mmol) was reacted with 4 M HCI in MeOH (10 mL, 40 mmol) in MeOH (15 mL) at 60 °C for 2 h to give the crude title compound (340 mg, 99%) as a brown solid. MS (ESI): m/z [M+H]+ 301.1.
Intermediate 6 i-6a
1-(6-Chloropyridin-3-yl)-1,8-naphthyridin-2(1H)-one
Figure imgf000131_0002
According to GM5 (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (1.29 g, 8.21 mmol), 1 ,8-naphthyridin-2(1/7)-one (CAS Reg. No. 15936-09-1) (600 mg, 4.11 mmol), /V1,/V1,/V2,/V2-tetramethylethane-1 ,2-diamine (1431 mg, 12.32 mmol) and Cu(0tf)2 (1782 mg, 4.93 mmol) were reacted in 1 ,4-dioxane (10 mL) at 100 °C for 16 h to give upon purification by C18-flash chromatography (gradient: 5-43% MeCN in water + 0.1% NH3 (aq)) the title compound (252 mg, 23%) as a pale yellow solid. MS (ESI): m/z [M+H]+ 257.9.
Intermediate 7
3-(6-Chloropyridin-3-yl)-1-methylimidazolidine-2, 4-dione
Step A. i-7a
4-Nitrophenyl (6-chloropyridin-3-yl)carbamate
Figure imgf000132_0001
4-Nitrophenyl carbonochloridate (CAS Reg. No. 7693-46-1) (1.73 g, 8.56 mmol) was added to 6-chloropyridin-3-amine (CAS Reg. No. 5350-93-6) (1.0 g, 7.8 mmol) in MeCN (20 mL) at 20 °C and the resulting solution stirred at this temperature for 30 min. The reaction mixture was diluted with MeCN (200 mL), filtered through an organic phase filter and evaporated to give the crude title compound (2.18 g, 96%) as a purple solid. MS (ESI): m/z [M+H]+ 293.9.
Step B. i-7b
3-(6-Chloropyridin-3-yl)-1-methylimidazolidine-2, 4-dione
Figure imgf000132_0002
DI PEA (3.90 mL, 22.3 mmol) was added to methyl methylglycinate HCI (CAS Reg. No. 13515- 93-0) (1.04 g, 7.44 mmol) in MeCN (20 mL) at 20 °C. The resulting suspension was stirred at 20 °C for 15 min upon which 4-nitrophenyl (6-chloropyridin-3-yl)carbamate compound i-7a (2.18 g, 7.44 mmol) was added and stirring at 20 °C continued for 10 min. The mixture was concentrated under reduced pressure and the obtained crude material purified by flash chromatography on silica (gradient: 65-70% EtOAc in PE) to give the title compound (1.55 g, 92%) as a white solid. MS (ESI): m/z [M+H]+ 225.8.
Intermediate 8
6'-Chloro-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile
Step A. i-8a
Methyl 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate
Figure imgf000132_0003
6-Chloropyridin-3-amine (CAS Reg. No. 5350-93-6) (1.0 g, 7.8 mmol) was added to a solution of methyl 2-oxo-2/7-pyran-5-carboxylate (CAS Reg. No. 6018-41-3) (1.2 g, 7.8 mmol) in EtOH (20 mL) at 15 °C and it was stirred at 80 °C for 16 h. The reaction mixture was diluted with EtOH (20 mL), filtered through an organic phase filter and evaporated to give the crude title compound (1.53 g, 74%) as a purple solid. MS (ESI): m/z [M+H]+ 265.2.
Step B. i-8b
6'-Chloro-2-oxo-2H-[1 ,3'-bipyridine]-5-carboxylic acid
Figure imgf000133_0001
Methyl 6'-chloro-2-oxo-2/7-[1 ,3'-bipyridine]-5-carboxylate compound i-8a (300 mg, 1.13 mmol) was added to NaOH (91 mg, 2.3 mmol) in a mixture of THF (8 mL) and water (2 mL) at 20 °C and the resulting solution stirred at 20 °C for 15 h. The reaction mixture was concentrated und reduced pressure, the residue diluted with water (5 mL) and the pH adjusted to pH< 7 with 1 M HCI. The mixture was further diluted with water (100 mL) and extracted with EtOAc (3 x 75 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give crude title compound (230 mg, 81%) as a white solid. MS (ESI): m/z [M+H]+ 251.
Step C. i-8c 6'-Chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxamide
Figure imgf000133_0002
6'-Chloro-2-oxo-2/7-[1,3'-bipyridine]-5-carboxylic acid compound i-8b (160 mg, 0.64 mmol) was added to HATU (485 mg, 1.28 mmol), TEA (0.712 mL, 5.11 mmol) and NH4CI (137 mg,
2.55 mmol) in DMF (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 3 h, subsequently cooled to rt, quenched with sat brine (100 mL) and extracted with EtOAc (3 x 75 mL). The organic layer was dried over Na2SO4, filtered and evaporated and the obtained residue purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (130 mg, 82%) as a white solid. MS (ESI): m/z [M+H]+ 250.
Step D. i-8d
6'-Chloro-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile
Figure imgf000134_0001
6'-Chloro-2-oxo-2/7-[1,3'-bipyridine]-5-carboxamide compound i-8c (700 mg, 2.80 mmol) was added to a solution of pyridine (0.68 mL, 8.4 mmol) in DCM (10 mL). TFAA (1.19 mL, 8.41 mmol) was slowly added to the mixture at 0 °C and it was stirred at 20 °C for 1 h. The synthesis procedure was repeated with a second batch of 6'-chloro-2-oxo-2/7-[1 ,3'-bipyridine]-5- carboxamide compound i-8c (100 mg, 0.40 mmol). The two batches were combined, concentrated under reduced pressure and purified by preparative TLC (EtOAc:PE = 3:1) to give the title compound (540 mg, 72%) as a white solid. MS (ESI): m/z [M+H]+ 232.1.
Intermediate 9
3-(Trifluoromethoxy)pyridin-2-ol
Step A. i-9a
2-((4-Methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine
Figure imgf000134_0002
KotBu (682 mg, 6.07 mmol) was added to (4-methoxyphenyl)methanol (CAS Reg. No. 105-13- 5) (629 mg, 4.56 mmol) in 1 ,4-dioxane (2 mL) at 20 °C and it was stirred at 20 °C for 2 h. 2- Chloro-3-(trifluoromethoxy)pyridine (CAS Reg. No. 1206980-39-3) (600 mg, 3.04 mmol) was added to the reaction mixture and the resulting suspension was stirred at 100 °C for 15 h. The reaction mixture was poured into sat. brine (125 mL) and extracted with EtOAc (3 x 75 mL). The organic layer was dried over Na2SC>4, filtered and evaporated and the obtained residue was purified by preparative TLC (EtOAc:PE = 1 :5) to give the title compound (600 mg, 66%) as a pale yellow liquid. MS (ESI): m/z [M+H]+ 300.0.
Step B. i-9b 3-(Trifluoromethoxy)pyridin-2-ol
Figure imgf000134_0003
2-((4-Methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine compound i-9a (500 mg, 1.67 mmol) was added to TFA (10 mL) at 25 °C, it was warmed to 60 °C and the resulting solution stirred at this temperature for 15 h. The solvent was removed under reduced pressure and the obtained residue purified by preparative TLC (EtOAc:PE = 1:1) to give the title compound (150 mg, 50%) as a pale yellow solid. MS (ESI): m/z [M+H]+ 180.0. Intermediate 10 i-10a 6'-Chloro-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile
Figure imgf000135_0001
In a variation of GM5 pyridine (0.81 mL, 10 mmol) was added to a mixture of 2-oxo-1,2- dihydropyridine-3-carbonitrile (CAS Reg. No.20577-27-9) (600 mg, 5.00 mmol), (6- chloropyridin-3-yl)boronic acid (CAS Reg. No.444120-91-6) (1.57 g, 10 mmol), Cu(Oac)2 (1.82 g, 10 mmol) and 5Å molecular sieves (500 mg, dried 24 h at 200°C) in DCM (100 mL) and DMF (15 mL) at 25 °C. Air was allowed to diffuse into the reaction mixture via a CaCl2 tube. The resulting mixture was stirred at 25 °C for 15 h and subsequently filtered through Celite. The filter cake was washed with DCM (3 x 10 mL), the combined filtrates concentrated under reduced pressure and the residue partitioned between EtOAc (400 mL) and water (150 mL). The aqueous layer was extracted with EtOAc (5 x 200 mL), the combined organic layers were washed with sat. brine (5 x 100 mL), dried over Na2SO4, filtered and evaporated. The dry solid was triturated with DMF (3 x 5 mL), the solid filtered off and the filter cake washed with MTBE (3 x 5 mL). The solid was dried under vacuum to give the title compound (105 mg, 9%) as a grey solid. MS (ESI): m/z [M+H]+ 232.1. Intermediate 11 i-11a 2-(5-Bromopyrazin-2-yl)pyridazin-3(2H)-one
Figure imgf000135_0002
In a slight variation of GM32-bromo-5-iodopyrazine (CAS Reg. No.622392-04-5) (1.00 g, 3.51 mmol), pyridazin-3(2H)-one (CAS Reg. No.504-30-3) (0.337 g, 3.51 mmol), Cs2CO3 (2.287 g, 7.02 mmol), Cu(l)l (0.669 g, 3.51 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane- 1 ,2-diamine (0.499 g, 3.51 mmol) were reacted in 1 ,4-dioxane (25 mL) at 60 °C for 1 h to give upon non-aqueous work-up followed by preparative TLC (EtOAc: PE = 1 :1) the title compound (300 mg, 33%) as a white solid. The product contained the corresponding iodo compound as well. MS (ESI): m/z [M+H]+ 252.9.
Intermediate 12 i-12a
6'-Chloro-1-methyl-[3,3'-bipyridin]-2(1 /-/)-one
Figure imgf000136_0001
According to GM4A (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (301 mg, 1.91 mmol), 3-bromo-1-methylpyridin-2(1/7)-one (81971-38-2 ) (200 mg, 1.06 mmol), CS2CO3 (1.04 g, 3.19 mmol) and 1 ,1'-bis(di-terf-butylphosphino)ferrocene palladium dichloride (CAS Reg. No. 95408-45-0) (34.7 mg, 0.05 mmol) were reacted in a mixture of 1 ,4-dioxane (12 mL) and water (3 mL) at 80 °C for 15 h to give upon non-aqueous work-up followed by preparative TLC (100% EtOAc) the title compound (230 mg, 98%) as a light yellow solid. MS (ESI): m/z [M+H]+ 221.0.
Intermediate 13 i-13a
3-Chloro-6'-fluoro-2H-[1,3'-bipyridin]-2-one
Figure imgf000136_0002
In a slight variation of GM3 2-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (560 mg, 2.51 mmol), 3-chloropyridin-2(1/7)-one (CAS Reg. No. 13466-35-8) (651 mg, 5.02 mmol), potassium phosphate, tribasic (1.60 g, 7.53 mmol), Cu(l)l (478 mg, 2.51 mmol) and re/-(1R,2R)- /V^A^-dimethylcyclohexane-l ^-diamine (357 mg, 2.51 mmol) were reacted in 1 ,4-dioxane (60 mL) at 100 °C for 18 h. The reaction mixture was poured into sat. brine (350 mL) and filtered through Celite. The filtrate was extracted with EtOAc (3 x 250 mL), the organic layer dried over Na2SO4, filtered and evaporated. The crude material was purified by flash chromatography on silica (gradient: 0-30% EtOAc in PE) to give the title compound (258 mg, 45%) as a pale yellow solid. MS (ESI): m/z [M+H]+ 224.9.
Intermediate 14 i-14a
6'-Chloro-3-fluoro-[2,3'-bipyridine]-6-carbonitrile
Figure imgf000137_0001
According to GM4A, 1,1'-bis(di-terf-butylphosphino)ferrocene palladium dichloride (49 mg, 0.07 mmol) was added to 6-bromo-5-fluoropicolinonitrile (CAS Reg. No. 1416713-45-5) (300 mg, 1.49 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (352 mg, 2.24 mmol) and K3PO4 (950 mg, 4.48 mmol) in water (2 mL) and 1,4-dioxane (8 mL). The resulting solution was stirred at 100 °C for 2 h. Aqueous work-up and purification by preparative TLC (EtOAc:PE = 2:1) gave the title compound (214 mg, 61%) as a white solid; MS (ESI) m/z [M+H]+ = 234.0.
Intermediate 17
(1S,3S)-A/1-(5-Chloropyrazin-2-yl)-A/3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine Step A. i-17a
(1 S,3S)-/V1-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine x 3 HCI
Figure imgf000137_0002
i-17a
According to GM6A fert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1 a (Intermediate 1 , Step A) (1.29 g, 3.19 mmol) was reacted with HCI in MeOH (4 M, 10 mL, 40 mmol) in MeOH (20 mL) at 80 °C for 2 h to afford the title compound (1.27 g, 96 %) as a beige solid. MS (ESI): m/z [M+H]+ 303.90.
Step B. i-17b (1S,3S)-A/1-(5-Chloropyrazin-2-yl)-A/3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine
Figure imgf000138_0001
i-17b
According to GM1A (1 S,3S)-/V1-(5-iodopyridin-2-yl)cyclopentane-1 ,3-diamine compound i-17a (1.26 g, 3.05 mmol), 2,5-dichloropyrazine (CAS Reg. No. 19745-07-4) (0.910 g, 6.11 mmol) and Na2CC>3 (1.62 g, 15.3 mmol) were reacted in DMSO (25 mL) at 120 °C for 15 h. The mixture was filtered through a Celite pad and the filtrate purified by flash C18-flash chromatography (gradient : 10-61% MeCN in water, containing 0.1 % NH3, aq) to give the title compound (0.78 g, 61 %) as a beige solid. MS (ESI): m/z [M+H]+ 415.90.
Intermediate 21
1-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one
Step A. i-21 a
1-(6-Chloropyridin-3-yl)quinolin-2(1H)-one
Figure imgf000138_0002
According to GM5 quinolin-2(1/7)-one (CAS Reg. No. (59-31-4) (500 mg, 3.44 mmol), (6- chloropyridin-3-yl)boronic acid (CAS Reg. No. (444120-91-6) (1.63 g, 10.3 mmol), Cu(0tf)2 (2.49 g, 6.89 mmol) and N, N, N', N -tetramethylethylenediamine (1.20 g, 10.3 mmol) were reacted in 1 ,4-dioxane (20 mL) at 100 °C for 16 h to give upon purification by C18-flash chromatography (gradient: 5-46% MeCN in water, containing 0.1% NH3, aq) 1-(6-chloropyridin- 3-yl)quinolin-2(1/-/)-one (211 mg, 24 %) as a green solid. MS (ESI): m/z [M+H]+ 256.95.
Step B. i-21 b tert-Butyl ((1 S,3S)-3-((5-(2-oxoquinolin-1 (2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate
Figure imgf000138_0003
According to GM2 1-(6-chloropyridin-3-yl)quinolin-2(1/7)-one compound i-21 a (90 mg, 0.35 mmol), tert-butyl ((1 S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (211 mg, 1.05 mmol), CS2CO3 (571 mg, 1.75 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (29.5 mg, 0.04 mmol) were reacted in 1 ,4-dioxane (10 mL) at 100 °C for 15 h to give upon aqueous work-up and purification by preparative TLC (MeOH : DCM = 1 :40) tert-butyl ((1 S,3S)- 3-((5-(2-oxoquinolin-1 (2/-/)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate (122 mg, 83%) as a white solid. MS (ESI): m/z [M+H]+ 421.00.
Step C. i-21 c 1-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one
Figure imgf000139_0001
According to GM6A tert-butyl ((1 S,3S)-3-((5-(2-oxoquinolin-1(2/7)-yl)pyridin-2- yl)amino)cyclopentyl)carbamate compound i-21 b (110 mg, 0.26 mmol) was reacted with HCI in methanol (4 M, 5.0 mL, 20 mmol) in MeOH (10 mL) at 80 °C for 2 h to afford an unspecified HCI salt of 1-(6-(((1 S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1/7)-one (90 mg, 96%) as a brown gum. MS (ESI): m/z [M+H]+ 321.00.
Intermediate 22
(1 S,3S)-/V1-(6-Cyclopropyl-1,2,4-triazin-3-yl)-/V3-(5-iodopyridin-2-yl)cyclopentane-1,3- diamine
Step A. i-22a tert-Butyl ((1 S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
Figure imgf000139_0002
m-CPBA (5.60 g, 25.95 mmol) was added in small portions to a solution of 3-(methylthio)-1 ,2,4- triazine (CAS Reg. No. 28735-21-9) (3.0 g, 23.6 mmol) in DCM (80 mL) at 0 °C and the resulting suspension was stirred at 20 °C for 2 h. The solvent was removed under reduced pressure without heating, the residue dissolved in n-butanol (40 mL) and tert-butyl ((1 S,3S)-3- aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (5.20 g, 26.0 mmol) was added and the resulting solution was stirred at 120 °C for 18 h. The reaction mixture was poured into 1 M NaOH (250 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried (Na2SC>4), filtered and evaporated to afford the crude product as a brown solid which was purified by flash chromatography on silica (gradient: 5-60% EtOAc in PE) to give (3.7 g, 56%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 280.
Step B. i-22b tert-Butyl ((1 S,3S)-3-((6-bromo-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
Figure imgf000140_0001
A solution of Br2 in DCM (1 M, 15.9 mL, 15.9 mmol) was added dropwise to a solution of tertbutyl ((1 S,3S)-3-((1 ,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22a (3.7 g, 13.2 mmol) in a mixture of MeOH (60 mL) and water (30 mL) and the mixture was stirred at rt for 15 h. The solvent was removed under reduced pressure and the residue was poured into sat. Na2SOs(aq) (150 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford the crude product as brown solid which was purified by flash chromatography on silica (gradient: 5-30% EtOAc in PE) to give (3.5 g, 74%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 358.
Step C. i-22c tert-Butyl ((1 S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
Figure imgf000140_0002
According to GM4B tert-butyl ((1 S,3S)-3-((6-bromo-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carba- mate compound i-22b (1.5 g, 4.2 mmol), potassium cyclopropyltrifluoroborate (2.48 g, 16.8 mmol), CS2CO3 (5.46 g, 16.8 mmol) and CataCXium A Pd G3 (CAS Reg. No. 1651823-59-4) (0.61 g, 0.84 mmol) were reacted in dioxane (70 mL) at 100 °C for 15 h. Upon combination with a second batch (prepared in the same manner, 1.12 mmol scale) the material was purified by preparative TLC (EtOAc : PE = 1 :3) to afford (1.12 g, 66%) of the title compound as a pale yellow solid. MS (ESI): m/z [M+H]+ 320. Step D. i-22d (I S.SSJ-A^-fe-Cyclopropyl-l^^-triazin-S-yQcyclopentane-I.S-diamine x 4 TFA
Figure imgf000141_0001
According to GM6B terf-butyl ((1 S,3S)-3-((6-cyclopropyl-1 ,2,4-triazin-3- yl)amino)cyclopentyl)carbamate compound i-22c (500 mg, 1.57 mmol) was reacted with TFA (5.0 mL, 65 mmol) in DCM (20 mL) at rt for 15 h to give (940 mg, 89 %) of the title compound as a yellow gum (contains 4 mol eq of residual TFA). MS (ESI): m/z [M+H]+ 220.
Step E. i-22e
(1 S,3S)-/V1-(6-Cyclopropyl-1,2,4-triazin-3-yl)-/V3-(5-iodopyridin-2-yl)cyclopentane-1,3- diamine
Figure imgf000141_0002
According to GM1A (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine 4TFA compound i-22d (880 mg, 1.30 mmol), 2-fluoro-5-iodopyridine (436 mg, 1.95 mmol) and K2CO3 (900 mg, 6.51 mmol) were reacted in DMSO (10 mL) at 120 °C for 15 h to give upon aqueous work-up and purification by preparative TLC (EtOAc : PE = 3:1) the title compound (369 mg, 67%) as a pale yellow solid. MS (ESI): m/z [M+H]+ 423.
Intermediate 23 i-23a
1-(6-Chloropyridin-3-yl)-3-methylimidazolidine-2, 4-dione
Figure imgf000141_0003
Cui (0.230 g, 1.57 mmol) was added to a mixture of 2-chloro-5-iodopyridine (CAS Reg. No. 69045-79-0) (0.50 g, 2.09 mmol), 3-methylimidazolidine-2, 4-dione (CAS Reg. No. 6843-45-4) (0.48 g, 4.18 mmol), /V,/V-dimethylglycine hydrochloride (0.22 g, 1.57 mmol) and CS2CO3 (1.36 g, 4.18 mmol) in dioxane (20 mL) and the resulting suspension was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was poured into brine (125 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford the crude product as yellow gum which was purified by preparative TLC (EtOAc : PE = 1 :1) to give (0.25 g, 53%) of the title compound as a pale yellow oil which solidified on standing. MS (ESI): m/z [M+H]+ 226.
Intermediate 24 i-24a
3-(6-Chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
Figure imgf000142_0001
According to GM5 (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (2.93 g, 18.6 mmol), 1-methyl-1 ,3-dihydro-2/7-imidazo[4,5-b]pyridin-2-one (CAS Reg. No. 50339-06-5) (1.11 g, 7.44 mmol), Cu(0tf)2 (4.04 g, 11.2 mmol) and TMEDA (2.59 g, 22.3 mmol) were reacted in dioxane (100 mL) at 100 °C for 16 h to give upon work-up and purification by CIS- flash chromatography (gradient: 5-40% MeCN in water, containing 0.1% NH3, aq) (0.235 g, 12%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 261.
Intermediate 25 i-25a
6'-Chloro-3-methoxy-2H-[1,3'-bipyridin]-2-one
Figure imgf000142_0002
3-Methoxypyridin-2(1/7)-one (CAS Reg. No. 20928-63-6) (1.35 g, 10.8 mol) and 2-chloro-5- iodopyridine (CAS Reg. No. 69045-72-0) (1.03 g, 4.32 mmol) were added to dimethylglycine hydrochloride (301 mg, 2.16 mmol), Cui (411 mg, 2.16 mmol) and CS2CO3 (4.22 g, 13.0 mmol) in dioxane (20 mL) and the resulting solution was stirred at 100 °C for 15 h. The solvent was removed under reduced pressure and the crude product was purified by preparative TLC (PE : EtOAc = 1 :2) to afford (250 mg, 55%) of the title compound as a pale yellow solid. MS (ESI): m/z [M+H]+ 237. Intermediate 26 i-26a
6'-Chloro-5-methoxy-2H-[1,3'-bipyridin]-2-one
Figure imgf000143_0001
Cui (159 mg, 0.84 mmol) and /V,/V-dimethylglycine hydrochloride (117 mg, 0.84 mmol) were added to a mixture of 2-chloro-5-iodopyridine (400 mg, 1.67 mmol), 5-methoxypyridin-2(1/7)-one (CAS Reg. No. 61941-79-5) (523 mg, 4.18 mmol) and CS2CO3 (1.63 mg, 5.01 mmol) in dioxane (8 mL) and the resulting suspension was stirred at 100 °C for 15 h under nitrogen. The mixture was filtered through a Celite pad, the solvent removed under reduced pressure and the crude product purified by preparative TLC (EtOAc : PE = 3:1) to afford (179 mg, 45%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 237.
Intermediate 27 i-27a
6'-Chloro-3-methyl-2/-/-[1 ,3'-bipyridin]-2-one
Figure imgf000143_0002
In a slight variation of GM3 2-chloro-5-iodopyridine (600 mg, 2.51 mmol), 3-methylpyridin-2(1/7)- one (CAS Reg. No. 1003-56-1) (273 mg, 2.51 mmol), K3PO4 (1.60 g, 7.52 mmol), Cu(l)l (239 mg, 1.25 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine (178 mg, 1.25 mmol) were reacted in dioxane (20 mL) at 100 °C for 1 h to give upon aqueous work-up and purification by preparative TLC (DCM : MeOH = 20:1) the title compound (261 mg, 47%) as a brown solid. MS (ESI): m/z [M+H]+ 221.
Intermediate 28
(I S.SSJ-A^-fe-Methyl-l^^-triazin-S-yQcyclopentane-I.S-diamine x 2 TFA
Step A. i-28a tert-Butyl ((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
Figure imgf000144_0001
According to GM4A tert-butyl ((1 S,3S)-3-((6-bromo-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carba- mate compound i-22b (300 mg, 0.84 mmol), 2,4,6-trimethyl-1 ,3,5,2,4,6-trioxatriborinane in THF (2.10 g, 8.37 mmol), K3PO4 (356 mg, 1.67 mmol) and 1 ,1’-bis(di-tert-butylphosphino)ferrocene palladium dichloride (CAS Reg. No. 95408-45-0) (55 mg, 0.08 mmol) were reacted in a mixture of dioxane (4 mL) and water (1 mL) at 100 °C for 15 h to give upon aqueous work-up and purification by preparative TLC (MeOH : DCM = 1 :20) followed by C18-flash chromatography (gradient: 0-49% MeOH in water) the title compound (103 mg, 42%) as a brown solid. MS (ESI): m/z [M+H]+ 294.
Step B. i-28b (I S.SSJ-A^-fe-Methyl-l^^-triazin-S-yQcyclopentane-I.S-diamine x 2 TFA
Figure imgf000144_0002
According to GM6B tert-butyl ((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carba- mate compound i-28a (100 mg, 0.34 mmol) was reacted with TFA (5 mL) in DCM (5 mL) at rt for 15 h to afford (100 mg, 95%) of title compound as a white solid. MS (ESI): m/z [M+H]+ 194.
Intermediate 29 i-29a
6'-Chloro-2H-[1,3'-bipyridin]-2-one
Figure imgf000144_0003
According to GM3 2-chloro-5-iodopyridine (3.0 g, 12.5 mmol), pyridin-2(1/-/)-one (CAS Reg. No. 142-08-5) (3.57 g, 37.6 mmol), Cu(l)l (1.19 g, 6.26 mmol), Cs2CO3 (8.16 g, 25.1 mmol) and rel- (IR^R^/V^A^-dimethylcyclohexane-l ^-diamine (0.891 g, 6.26 mmol) were reacted in dioxane (80 mL) at 100 °C for 15 h to give upon aqueous work-up and trituration with PE:EtOAc (1 :1 , 30 mL) a solid which was collected by filtration and dried under vacuum to yield (0.60 g, 23%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 207. Intermediate 30 i-30a
3-(((1S,3S)-3-((2-Oxo-2H-[1,3'-bipyridin]-6,-yl)amino)cyclopentyl)amino)-1,2,4-triazine-6- carboxylic acid
Figure imgf000145_0001
Ethyl 3-(((1 S,3S)-3-((2-oxo-2/7-[1 ,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-1 ,2,4-triazine-6- carboxylate compound 10 (22 mg, 0.05 mmol), finely-ground NaOH (10 mg, 0.26 mmol) and water (0.5 mL) was added to a vial and the mixture was stirred at room temperature for 0.5 h. The compound was purified by preparative HPLC (PrepMethod G, gradient: 5-45%) to give (17 mg, 86%) of the title compound as an off-white solid. MS (ESI): m/z [M+H]+ 394.
Intermediate 31
(1 S,3S)-A/1-(5-Methylpyrazin-2-yl)cyclopentane-1,3-diamine
Step A. i-31 a tert-Butyl ((1 S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)carbamate
Figure imgf000145_0002
The reaction was run in 3 parallel batches.
According to GM2 tert-butyl ((1 S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44- 8) (420 mg, 2.10 mmol), 2-bromo-5-methylpyrazine (CAS Reg. No. 98006-90-7) (363 mg, 2.10 mmol), CS2CO3 (1.03 g, 3.15 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (62 mg, 0.07 mmol) were reacted in 1 ,4-dioxane (20 mL) at 100 °C for 15 h. Upon combination of batches, non-aqueous work-up and trituration (PE:EtOAc = 2:1 , 20 mL) a solid was collected by filtration which was dried under vacuum to yield the title compound (1.2 g, 63%) as a grey solid. MS (ESI): m/z [M+H]+ 293.3. 1H NMR (300MHz, CDCh) 6 ppm 1.46 (11 H, s), 1.93 (2H, td), 2.25 (2H, ddt), 2.39 (3H, d), 4.15 (1 H, d), 4.23 (1 H, p), 4.47 (1 H, d), 4.57 (1 H, s), 7.80 (1 H, d), 7.85 - 7.90 (1 H, m). Step B. i-31 b
(1 S,3S)-A/1 -(5-M ethyl pyrazin-2-yl)cyclopentane-1,3-diamine
Figure imgf000146_0001
According to GM6B tert-butyl ((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)carbamate compound i-31a (350 mg, 1.20 mmol) was reacted with TFA (2 mL, 26 mmol) in DCM (10 mL) at 20 °C for 15 h to afford an unspecified TFA salt of the title compound (704 mg, 91%) as a brown gum. MS (ESI): m/z [M+H]+ 193.0. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.44 - 1.64 (2H, m), 1.91 (2H, m), 2.06 - 2.19 (2H, m), 2.26 (3H, s), 3.60 - 3.73 (1 H, m), 4.21 - 4.32 (1H, m), 7.74 - 7.94 (5H, m).
Intermediate 35
Step A. i-35a tert-Butyl ((1 S,3S)-3-((3-cyano-2-oxo-2/-/-[1,3'-bipyridin]-6'- yl)amino)cyclopentyl)carbamate
Figure imgf000146_0002
In a slight variation of GM2 6'-chloro-2-oxo-2/7-[1,3'-bipyridine]-3-carbonitrile compound i-10a (560 mg, 1.89 mmol), fert-butyl ((1 S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400- 44-8) (1.13 g, 5.66 mmol), Cs2CO3 (1.84 g, 5.66 mmol) and Pd-PEPPSI-lpentCI 2- methylpyridine (79 mg, 0.09 mmol) were reacted in DMF (30 mL) at 100 °C for 15 h. The reaction mixture was filtered through a pad of Celite, the filter cake washed with DCM (3 x 10 mL) and the combined filtrates concentrated under reduced pressure. The obtained material was purified by C18-flash chromatography (gradient: 10-100% MeCN in water + 0.1% NH3 (aq), 910 mg material isolated) followed by preparative TLC (EtOAc:PE = 3:1) to give the title compound (174 mg, 23%) as a grey solid. MS (ESI): m/z [M+H]+ 396.20.
Step B. i-35b
6'-(((1 S,3S)-3-Aminocyclopentyl)amino)-2-oxo-2/-/-[1,3'-bipyridine]-3-carbonitrile x 4 HCI
Figure imgf000146_0003
According to GM6A fert-butyl ((1S,3S)-3-((3-cyano-2-oxo-2/7-[1,3'-bipyridin]-6'- yl)amino)cyclopentyl)carbamate compound i-35a (865 mg, 2.19 mmol) was reacted with HCI in methanol (4 M 8.0 mL, 32 mmol) in MeOH (20 mL) at 80 °C for 2 h to give the title compound (966 mg, 100%) as a brown gum. MS (ESI): m/z [M+H]+ 296.00.
Intermediate 36
Step A. i-36a
6-Methyl-3-(methylthio)-1,2,4-triazine
Figure imgf000147_0001
Methyl hydrazinecarbimidothioate HI (CAS Reg. No. 35600-34-1) (9.87 g, 42.4 mmol) was added to a stirred solution of 1 ,1-dimethoxypropan-2-one (CAS Reg. No. 6342-56-9) (5.00 g, 42.3 mmol) in ethanol (250 mL) at rt and the resulting solution stirred at 80 °C for 16 h. The solvent was removed under reduced pressure and the obtained residue purified by flash chromatography on silica (gradient: 40 - 50% EtOAc in PE) to give the title compound (2.77 g, 46%) as a yellow solid. MS (ESI): m/z [M+H]+ 141.9. 1H NMR (300 MHz, DMSO-cfe) 6 ppm 2.56 (3H, s), 2.59 (3H, s), 8.56 (1H, s).
Step B. i-36b
6-Methyl-3-(methylsulfinyl)-1,2,4-triazine
Figure imgf000147_0002
According to GM8 6-methyl-3-(methylthio)-1,2,4-triazine compound i-36a (1.99 g, 14.1 mmol) was treated with 3-chlorobenzoperoxoic acid (3.65 g, 16.9 mmol) in DCM (25 mL) at rt for 2 h to give upon purification by flash chromatography on silica (gradient: 10-20% MeOH in DCM) the title compound (1.36 g, 61%) as a yellow oil. MS (ESI): m/z [M+H]+ 157.8. 1H NMR (300 MHz, DMSO-cfe) 6 ppm 2.71 (3H, s), 2.96 (3H, s), 8.95 (1H, s).
Intermediate 37 i-37a
6 -Fluoro-5-methyl-2H-[1,3 -bipyndin]-2-one
Figure imgf000148_0001
According to GM32-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (150 mg, 0.67 mmol), 2- hydroxy-5-methylpyridine (CAS Reg. No. 1003-68-5) (367 mg, 3.36 mmol), CS2CO3 (658 mg, 2.02 mmol), Cu(l)l (128 mg, 0.67 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2- diamine (96 mg, 0.67 mmol) were reacted in 1 ,4-dioxane (15 mL) at 100 °C for 15 h. The reaction mixture was filtered through a pad of Celite, the filter cake washed with EtOAc (3 x 5 mL) and the combined filtrates diluted with water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (4 x 100 mL). The combined organic layers were were washed with water (2 x 50 mL), dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (EtOAc) to give the title compound (116 mg, 84%) as a white solid. MS (ESI): m/z [M+H]+ 204.9. 1H NMR (300 MHz, DMSO-cfe) 6 ppm 2.06 (3H, s), 6.47 (1 H, d), 7.36 (1 H, dd), 7.43 (1 H, dd), 7.53 - 7.54 (1 H, m), 8.12 (1 H, ddd), 8.33 (1 H, dd).
Intermediate 38 i-38a
6'-Fluoro-3-methyl-2/-/-[1 ,3'-bipyridin]-2-one
Figure imgf000148_0002
According to GM32-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (105 mg, 0.47 mmol), 2- hydroxy-3-methylpyridine (CAS Reg. No. 1003-56-1) (257 mg, 2.35 mmol), CS2CO3 (460 mg, 1.41 mmol), Cu(l)l (90 mg, 0.47 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine (67 mg, 0.47 mmol) were reacted in 1 ,4-dioxane (10 mL) at 100 °C for 15 h. The reaction mixture was filtered through a pad of Celite, the filter cake washed with EtOAc (3 x 5 mL) and the combined filtrates diluted with water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (4 x 75 mL). The combined organic layers were washed with water (2 x 50 mL), dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (EtOAc) to give the title compound (85 mg, 88%) as a white solid. MS (ESI): m/z [M+H]+ 205.0. 1H NMR (300 MHz, DMSO-cfe) 6 ppm 2.05 (3H, s), 6.29 (1 H, t), 7.36 (1 H, dd), 7.42 - 7.45 (1 H, m), 7.58 (1 H, dd), 8.13 (1 H, ddd), 8.32 - 8.34 (1 H, m). Intermediate 39 i-39a
(1 S,3S)-/V1-(5-lodopyridin-2-yl)-/V3-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1,3-diamine
Figure imgf000149_0001
According to GM1A 2-fluoro-5-iodopyridine (203 mg, 0.91 mmol) was added to a mixture of the 2HCI salt of (1 S,3S)-/V1-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-28b (220 mg, 0.83 mmol) and Na2COs (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). The organic layer was washed with saturated brine (4 x 125 mL), dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (EtOAc : PE = 1 :1) to give the title compound (140 mg, 43%) as a pale yellow solid. MS (ESI): m/z [M+H]+ 396.7. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.39 - 1.59 (2H, m), 1.79 - 1.95 (2H, m), 2.06 - 2.16 (2H, m), 2.37 (3H, s), 4.17 - 4.39 (2H, m), 6.37 (1 H, dd), 6.83 (1 H, d), 7.53 - 7.59 (2H, m), 8.10 (1 H, d), 8.16 (1 H, s).
Intermediate 42
Step A. i-42a tert-Butyl ((1 S,3S)-3-((5-methoxy-2-oxo-2/-/-[1,3'-bipyridin]-6'- yl)amino)cyclopentyl)carbamate
Figure imgf000149_0002
re/^IR^^-A/^A^-Dimethylcyclohexane-l ^-diamine (53 mg, 0.37 mmol) was added to fert-butyl ((1 S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1 a (300 mg, 0.74 mmol), 5-methoxypyridin-2-ol (233 mg, 1.86 mmol), CS2CO3 (727 mg, 2.23 mmol) and Cu(l)l (70.8 mg, 0.37 mmol) in 1 ,4-dioxane (15 mL) at 25 °C. The resulting suspension was stirred at 100 °C for 18 h under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with water (3 x 75 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (EtOAc) to give the title compound (263 mg, 88%) as a brown solid. MS (ESI) m/z [M+H]+ 401.0. Step B. i-42b 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-5-methoxy-2H-[1,3'-bipyridin]-2-one
Figure imgf000150_0001
TFA (5 ml, 64.90 mmol) was added to tert-butyl ((1 S,3S)-3-((5-methoxy-2-oxo-2/7-[1 ,3'- bipyridin]-6'-yl)amino)cyclopentyl)carbamate compound i-42a (400 mg, 1.00 mmol) in DCM (15 mL) at 25 °C. The resulting suspension was stirred at 25 °C for 18 h. The solvent was removed under reduced pressure to give the TFA salt of the crude title compound (1.1 g, 100%) as a black gum. MS (ESI) m/z [M+H]+ 301.0.
Intermediate 44
Step A. i-44a tert-Butyl ((1 S,3S)-3-((5-chloro-2-oxo-2H-[1 ,3'-bipyridin]-6'- yl)amino)cyclopentyl)carbamate
Figure imgf000150_0002
re/-(1F?,2F?)-/V1,/\/2-Dimethylcyclohexane-1 ,2-diamine (106 mg, 0.74 mmol) was added to tertbutyl ((1 S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (300 mg, 0.74 mmol), 5-chloropyridin-2(1/7)-one (193 mg, 1.49 mmol), Cu(l)l (142 mg, 0.74 mmol) and CS2CO3 (727 mg, 2.23 mmol) in 1 ,4-dioxane (25 mL) at 26 °C. The resulting solution was stirred at 100 °C for 18 h. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with water (3 x 25 mL) and sat brine (3 x 20 mL). The organic layer was dried over Na2SC>4, filtered and evaporated. The residue was purified by preparative TLC (EtOAc : PE = 2:1) to give the title compound (298 mg, 99%) as a green solid. MS (ESI) m/z [M+H]+ 405.0.
Step B. i-44b 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-5-chloro-2H-[1,3'-bipyridin]-2-one
Figure imgf000151_0001
TFA (5 mL, 64.90 mmol) was added to tert-butyl ((1 S,3S)-3-((5-chloro-2-oxo-2/7-[1 ,3'-bipyridin]- 6'-yl)amino)cyclopentyl)carbamate compound i-44a (220 mg, 0.54 mmol) in DCM (20 mL) at 25 °C. The resulting solution was stirred at 100 °C for 18 h. The solvent was removed under reduced pressure to give the TFA salt of the crude title compound (432 mg, 91%) as a brown gum. MS (ESI) m/z [M+H]+ 304.9.
Intermediate 47 i-47a
(1 S,3S)-/V1-(6-cyclopropy 1-1,2, 4-triazin-3-yl)-/V3-(5-iodopyri midi n-2-yl)cyclopentane-1,3- diamine
Figure imgf000151_0002
K2CO3 (126 mg, 0.91 mmol) was added to (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3- yl)cyclopentane-1 ,3-diamine compound i-22d (200mg, 0.91 mmol), 2-chloro-5-iodopyrimidine (CAS Reg. No. 32779-38-7) (329 mg, 1.37 mmol) in DMSO (5 mL) at rt and the resulting suspension was stirred at 120 °C for 15 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (2 x 25 mL) and brine (25 mL). The organic layer was dried (Na2SC>4), filtered and evaporated to afford crude product which was purified by flash CIS- flash chromatography (elution gradient: 0-60% MeCN in water) to afford (150 mg, 39%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 424.0.
Intermediate 48
Step A. i-48a
Methyl 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzoate
Figure imgf000152_0001
The reaction was run in 3 parallel batches (2 x 500 mg and 1 x 600 mg 6-chloropyridin-3- amine). Methyl 4-fluoro-3-nitrobenzoate (CAS Reg. No. 329-59-9) (929 mg, 4.67 mmol) was added to 6-chloropyridin-3-amine (CAS Reg. No. 5350-93-6) (500 mg, 3.89 mmol), XantPhos (338 mg, 0.58 mmol), Pd(OAc)2 (66 mg, 0.29 mmol) and K2CO3 (1.61 g, 11.7 mmol) in 1 ,4- dioxane (25 mL) at rt and the resulting mixture was stirred at 80 °C for 18 h under nitrogen. The three reaction mixtures were combined, taken up with EtOAc (200 mL), loaded onto silica gel and subjected to flash chromatography on silica (gradient: 10-20% EtOAc in n-heptane) to afford (851 mg, 71 % combined yield) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 307.9.
Step B. i-48b
Methyl 3-amino-4-((6-chloropyridin-3-yl)amino)benzoate
Figure imgf000152_0002
Methyl 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzoate compound i-48a (420 mg, 1.37 mmol) was added to zinc (535 mg, 8.19 mmol) and NH4CI (730 mg, 13.65 mmol) in EtOAc (10 mL) and EtOH (10 mL) at rt and the resulting mixture was stirred at 60 °C for 18 h. The reaction mixture was filtered through celite.The celite was washed with EtOAc (3 x 25 mL). The filtrate was concentrated under reduced pressure to afford (761 mg) of the crude title compound (containing salts) as a light pink solid which was used in the next step without further purification. MS (ESI): m/z [M+H]+ 277.9.
Step C. i-48c
Methyl 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5-carboxylate
Figure imgf000153_0001
Methyl 3-amino-4-((6-chloropyridin-3-yl)amino)benzoate compound i-48b (300mg, 1.08 mmol) was added to GDI (771 mg, 4.75 mmol) in DMF (20 mL) at rt and the resulting solution was stirred at 80 °C for 18 h. The reaction mixture was concentrated, diluted with EtOAc (200 mL) and washed sequentially with brine (3 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude solid was triturated with MeCN to give a solid which was collected by filtration and dried under vacuum to give (226 mg, 69%) of the title compound as a pink solid. MS (ESI): m/z [M+H]+ 303.8.
Step D. i-48d
Methyl 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5- carboxylate
Figure imgf000153_0002
i-48d
CH3I (246 mg, 1.73 mmol) was added to methyl 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1/7- benzo[d]imidazole-5-carboxylate compound i-48c (351 mg, 1.16 mmol) and Na2COs (367 mg, 3.47 mmol) in DMF (20 mL) at rt and the resulting mixture was stirred at 100 °C for 18 h. The reaction mixture was concentrated, diluted with EtOAc (250 mL) and washed sequentially with brine (3 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford (92 mg, 25%) of the crude product as a pale yellow solid which was used in the next step without further purification. MS (ESI): m/z [M+H]+ 317.9.
Step E. i-48e
Methyl 1-(6-(((1 S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-
3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[q]imidazole-5-carboxylate
Figure imgf000154_0001
Pd-PEPPSI-lpentCI 2-methylpyridine (CAS Reg. No. 1612891-29-8) (29 mg, 0.03 mmol) was added to methyl 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1/7-benzo[c(]imidazole-5- carboxylate compound i-48d (110 mg, 0.35 mmol), CS2CO3 (338 mg, 1.04 mmol) and (1 S,3S)- /V1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (76 mg, 0.35 mmol) in 1 ,4-dioxane (20 mL) at rt and the resulting mixture was stirred at 100 °C for 18 h under nitrogen. The reaction mixture was concentrated, diluted with EtOAc (200 mL) and washed sequentially with brine (3 x 75 mL). The organic layer was dried over Na2SO4, filtered and evaporated and the obtained residue purified by preparative TLC (EtOAc : PE = 1:1) to afford (90 mg, 52%) of the title compound as a pale yellow solid. MS (ESI): m/z [M+H]+ 510.1.
Intermediate 49
Step A. i-49a
6'-Chloro-5-(1-(4-methoxybenzyl)-1 H-1,2,3-triazol-4-yl)-2H-[1 ,3'-bipyridin]-2-one
Figure imgf000154_0002
Cu(l)l (103 mg, 1.04 mmol) was added to 6'-chloro-5-ethynyl-2/7-[1 ,3'-bipyridin]-2-one compound i-63b (240 mg, 1.04 mmol) and 1-(azidomethyl)-4-methoxybenzene (255 mg, 1.56 mmol) in 1,4-dioxane (10 mL) at rt and the resulting suspension was stirred at 100 °C for 16 h under nitrogen. The mixture was filtered through a Celite pad and the filter cake washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure and the residue purified by preparative TLC (MeOH : DCM = 1: 20) to afford (410 mg, 100%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 394.0.
Step B. i-49b 6'-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1-(4- methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one
Figure imgf000155_0001
Pd-PEPPSI-lpentCI 2-methylpyridine (CAS Reg. No. 1612891-29-8) (21 mg, 0.03 mmol) was added to 6'-chloro-5-(1-(4-methoxybenzyl)-1/7-1 ,2,3-triazol-4-yl)-2/7-[1 ,3'-bipyridin]-2-one compound i-49a (200 mg, 0.51 mmol), (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3- yl)cyclopentane-1 ,3-diamine compound i-22d (167 mg, 0.76 mmol) and CS2CO3 (331 mg, 1.02 mmol) in 1 ,4-dioxane (10 mL) at rt and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with water (50 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered and evaporated and the obtained residue purified by preparative TLC (MeOH : DCM = 1 : 10) to afford (166 mg, 57%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 577.2.
Step C. i-49c
5-(1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)-6'-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one
Figure imgf000155_0002
Prepared in a similar way as described for compound i-49b from 6'-chloro-5-(1-(4- methoxybenzyl)-1/7-1 ,2,3-triazol-4-yl)-2/7-[1 ,3'-bipyridin]-2-one compound i-49a (109 mg, 0.28 mmol), the 4xTFA salt of (1 S,3S)-/V1-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-28b (340 mg, 0.55 mmol), CS2CO3 (451 mg, 1.38 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (23 mg, 0.03 mmol) in 1 ,4-dioxane (5 mL) and purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 : 20) to give the title compound (22 mg, 14%) as a brown solid. MS (ESI): m/z [M+H]+ 551.0. Intermediate 50
Step A. i-50a
5-(1 -(4-Methoxybenzyl)-1 H-pyrazol-4-yl)pyridin-2-ol
Figure imgf000156_0001
XPhos (0.431 g, 0.90 mmol), XPhos Pd G3 (CAS Reg. No. 1445085-55-1) (0.383 g, 0.45 mmol), 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1/7-pyrazole (CAS Reg. No. 110539-88-0 ) (2.13 g, 6.79 mmol), 5-iodopyridin-2-ol (CAS Reg. No. 13472-79- 2) (1.0 g, 4.5 mmol) and CS2CO3 (4.42 g, 13.6 mmol) in dioxane (10 mL) and water (2 mL) were stirred under an atmosphere of nitrogen at 80 °C for 15 h. The mixture was filtered through a Celite pad. The filter cake was washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure to give the crude product which was purified by flash C18-flash chromatography (elution gradient: 0-50% MeCN in water) to afford (160 mg, 13%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 282.0.
Step B. i-50b
6'-Chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one
Figure imgf000156_0002
Cu(l)l (102 mg, 0.53 mmol) was added to 5-(1-(4-methoxybenzyl)-1/7-pyrazol-4-yl)pyridin-2-ol compound i-50a (150 mg, 0.53 mmol), 2-chloro-5-iodopyridine (CAS Reg. No. 69045-79-0 ) (128 mg, 0.53 mmol), re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine (114 mg, 0.80 mmol) and CS2CC>3 (347 mg, 1.07 mmol) in 1 ,4-dioxane (10 mL) at rt and the resulting suspension was stirred at 60 °C for 5 h under nitrogen. The mixture was filtered through a Celite pad. The filter cake was washed with EtOAc (20 mL) and the filtrate concentrated under reduced pressure. The obtained residue was first purified by preparative TLC (MeOH : DCM = 1 : 10) and then by flash C18-flash chromatography (elution gradient: 0-30% MeCN in water) to afford (150 mg, 72%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 393.0. Step C. i-50c
6'-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1-(4- methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one
Figure imgf000157_0001
Pd-PEPPSI-lpentCI 2-methylpyridine (CAS Reg. No. 1612891-29-8) (14 mg, 0.02 mmol) was added to 6'-chloro-5-(1-(4-methoxybenzyl)-1/7-pyrazol-4-yl)-2/7-[1 ,3'-bipyridin]-2-one compound i-50b (130 mg, 0.33 mmol), (1 S,3S)-/V1-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1 ,3- diamine compound i-22d (109 mg, 0.50 mmol) and CS2CO3 (216 mg, 0.66 mmol) in 1 ,4- dioxane (10 mL) at rt and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with water (50 mL) and brine (25 mL). The organic layer was dried (Na2SC>4), filtered and evaporated to give the crude product which was purified by preparative TLC (MeOH: DCM = 1: 10) to afford (117 mg, 61%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 576.3.
Step D. i-50d
5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-6'-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one
Figure imgf000157_0002
Prepared in a similar way as described for compound i-50c from 6'-chloro-5-(1-(4- methoxybenzyl)-1/7-pyrazol-4-yl)-2/7-[1,3'-bipyridin]-2-one compound i-50b and (1S,3S)-/V1-(6- methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-28b and purified by preparative TLC (MeOH : DCM = 1: 15), to give the title compound (82 mg, 73%) as a yellow solid. MS (ESI): m/z [M+H]+ 550.0. Step E. i-50e
5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-6'-(((1S,3S)-3-((5-methylpyrazin-2- yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one
Figure imgf000158_0001
Prepared in a similar way as described for compound i-50c from 6'-chloro-5-(1-(4- methoxybenzyl)-1/7-pyrazol-4-yl)-2/7-[1 ,3'-bipyridin]-2-one compound i-50b and (1 S,3S)-/V1-(5- methylpyrazin-2-yl)cyclopentane-1 ,3-diamine compound i-31 b and purified by preparative TLC (MeOH : DCM = 1 : 15) to give the title compound (150 mg, 43%) as a yellow solid. MS (ESI): m/z [M+H]+ 549.0.
Intermediate 51
Step A. i-51 a 5-Bromo-3-(6-fluoropyridin-3-yl)-1-methyl-1,3-dihydro-2H-benzo[cf]imidazol-2-one
Figure imgf000158_0002
TMEDA (1.33 mL, 8.81 mmol) was added to 5-bromo-1-methyl-1 ,3-dihydro-2/7- benzo[d]imidazol-2-one (CAS Reg. No. 84712-08-3 ) (1.0 g, 4.4 mmol), (6-fluoropyridin-3- yl)boronic acid (CAS Reg. No. 351019-18-6 ) (1.55 g, 11.0 mmol) and Cu(OTf)2 (3.19 g, 8.81 mmol) in DCM (30 mL) at rt. Air was allowed to diffuse into the reaction mixture via a CaCh-tube on top of the flask and the resulting mixture was stirred at rt for 15 h. The reaction mixture was diluted with water (150 mL) and extracted with DCM (4 x 300 mL). The combined organic layers were washed with water (2 x 200 mL), dried (Na2SC>4), filtered and evaporated. The obtained material was purified by purified by flash chromatography on silica (gradient: 0- 60% EtOAc in n-heptane) to afford (0.38 g, 27%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 321.8/323.8 (Br isotope pattern).
Step B. i-51 b 5-Bromo-3-(6-(((1 S,3S)-3-((6-cyclopropyl-1 ,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-benzo[cf]imidazol-2- one
Figure imgf000159_0001
K2CO3 (219 mg, 1.59 mmol) was added to 5-bromo-3-(6-fluoropyridin-3-yl)-1-methyl-1 ,3- dihydro-2/7-benzo[c(]imidazol-2-one compound i-51 a (358 mg, 1.11 mmol) and (1 S,3S)-/V1-(6- cyclopropyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-22d (116 mg, 0.53 mmol) in DMSO (5 mL) at rt and the resulting mixture was stirred at 120 °C for 15 h. The mixture was filtered through a Celite pad and the filter cake washed with DCM (4 x 5 mL). The filtrate was concentrated under reduced pressure and purified by flash C18-flash chromatography (elution gradient: 0-100% MeOH in water) to afford (95 mg, 34%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 521/523 (Br isotope pattern).
Intermediate 52
Step A. i-52a tert-Butyl ((1 S,3S)-3-((5-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
Figure imgf000159_0002
m-CPBA (733 mg, 3.40 mmol) was added portion-wise to a stirred solution of 5-methyl-3- (methylthio)-1 ,2,4-triazine (CAS Reg. No. 28735-24-2) (400 mg, 2.83 mmol) in DCM (8 mL) at rt and the resulting solution was stirred at this temperature for 2 h. The solvent was removed under reduced pressure to afford a pale-yellow solid which was dissolved in n-BuOH (8 mL). tert-Butyl ((1 S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (567 mg, 2.83 mmol) was added and the resulting solution was stirred at 120 °C for 15 h. The reaction mixture was quenched with 1 M NaOH (aq) (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SC>4), filtered and evaporated and the residue purified by preparative TLC (EtOAc : PE = 3: 1) to afford (220 mg, 26%) of the title compound as an orange solid. MS (ESI): m/z [M+H]+ 294.2. Step B i-52b
(I S.SSJ-A^-fS-Methyl-l^^-triazin-S-yQcyclopentane-I.S-diamine
Figure imgf000160_0001
terf-Butyl ((1 S,3S)-3-((5-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i- 52a (210 mg, 0.72 mmol) was treated with DCM (6 mL) and TFA (2 mL) and the resulting mixture stirred at rt for 3 h. The reaction mixture was quenched with sat. NaHCCh (100 mL) and extracted with (7 M NH3 in MeOH: DCM = 1 : 20) (3 x 75 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to afford (120 mg, 87%) of the title compound as an orange solid which was used without further purification. MS (ESI): m/z [M+H]+ 194.1.
Intermediate 53
Step A. i-53a tert-Butyl ((1 S,3S)-3-((5,6-dimethyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
Figure imgf000160_0002
5,6-Dimethyl-3-(methylthio)-1 ,2,4-triazine (CAS Reg. No. 7275-70-9) (400 mg, 2.58 mmol) was added portion-wise to a stirred solution of 3-chlorobenzoperoxoic acid (667 mg, 3.09 mmol) in DCM (10 mL) at rt and the resulting solution was stirred at this temperature for 2 h. The solvent was removed under reduced pressure to afford a pale-yellow solid which was dissolved in n- BuOH (10 mL). terf-Butyl ((1 S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (567 mg, 2.83 mmol) was added and the resulting solution was stirred at 120 °C for 15 h. The reaction mixture was quenched with 1 M NaOH aq (100 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were dried (Na2SC>4), filtered and evaporated and the obtained material purified by preparative TLC (EtOAc : PE = 2: 1) to afford (115 mg, 14%) of the title compound as an orange solid. MS (ESI): m/z [M+H]+ 308.2.
Step B. i-53b
(I S.SSJ-A^-fS.e-Dimethyl-l^^-triazin-S-yQcyclopentane-I.S-diamine x 3 TFA
Figure imgf000161_0001
tert-Butyl ((1 S,3S)-3-((5,6-dimethyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i- 53a (100 mg, 0.33 mmol) was treated with TFA (2 mL) and DCM (6 mL) .The resulting mixture was stirred at rt for 3 h and the organic solvents were removed by evaporation to afford (112 mg, 63%) of the crude title compound as a brown oil which was used in the next step without further purification. MS (ESI): m/z [M+H]+ 208.0.
Intermediate 54
Step A. i-54a tert-Butyl ((1 S,3S)-3-((2-oxo-3-(trifluoromethyl)-2H-[1,3,-bipyridin]-6'- yl)amino)cyclopentyl)carbamate
Figure imgf000161_0002
3-(Trifluoromethyl)pyridin-2(1/7)-one (CAS Reg. No. 22245-83-6) (324 mg, 1.98 mmol) was added to tert-butyl ((1 S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (400 mg, 0.99 mmol), Cu(l)l (94 mg, 0.50 mmol), CS2CO3 (970 mg, 2.98 mmol) and re/-(1R,2R)- /V^A^-dimethylcyclohexane-l ^-diamine (70 mg, 0.50 mmol) in 1 ,4-dioxane (20 mL) at rt and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was poured into water (150 mL), extracted with EtOAc (5 x 100 mL) and the combined organic layers were dried (Na2SC>4), filtered and evaporated to afford crude product. The residue was first purified by preparative TLC (MeOH : EtOAc = 1 : 1) and then by flash C18-flash chromatography (gradient: 0-100% MeCN in water) to afford (235 mg, 54%) of the title compound as a pale yellow solid. MS (ESI): m/z [M+H]+ 439.2.
Step B. i-54b
6'-(((1 S,3S)-3-Aminocyclopentyl)amino)-3-(trifluoromethyl)-2/-/-[1,3'-bipyridin]-2-one
Figure imgf000161_0003
terf-Butyl ((1 S,3S)-3-((2-oxo-3-(trifluoromethyl)-2/7-[1 ,3'-bipyridin]-6'-yl)amino)cyclopentyl)car- bamate compound i-54a (220 mg, 0.50 mmol) was added to a mixture of 4M HCI in MeOH (2 mL, 8 mmol) and MeOH (8 mL) at rt and the resulting mixture was stirred at 60 °C for 2 h. The solvent was removed under reduced pressure and the material purified by flash C18-flash chromatography (gradient: 0-100% MeCN in water) to give (148 mg, 87%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 339.0.
Intermediate 57 i-57a
3-(5-Bromopyrazin-2-yl)-1-methylpyridin-2(1H)-one
Figure imgf000162_0001
2-Bromo-5-iodopyrazine (CAS Reg. No. 622392-04-5) (1.68 g, 5.88 mmol) was added to (1- methyl-2-oxo-1 ,2-dihydropyridin-3-yl)boronic acid (CAS Reg. No. 1454558-46-3) (300 mg, 1.96 mmol), KOAc (578 mg, 5.88 mmol) and PdCh(dppf) x DCM (160 mg, 0.20 mmol) in 1,4- dioxane (16 mL) and water (4 mL) at rt and the resulting mixture was stirred at 100 °C for 2 h under nitrogen. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (4 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated and the obtained material was purified by flash chromatography on silica (gradient: 0-100% EtOAc in n-heptane) to afford (360 mg, 69%) of the title compound as a brown solid. MS (ESI): m/z [M+H]+ 265.8/267.8.
Intermediate 58 i-58a
3-(6-Chloropyridin-3-yl)pyrimidin-4(3H)-one
Figure imgf000162_0002
TMEDA (0.942 mL, 6.24 mmol) was added to (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (983 mg, 6.24 mmol), pyrimidin-4(3H)-one (CAS Reg. No. 4562-27-0) (300 mg, 3.12 mmol) and Cu(OTf)2 (2.26 g, 6.24 mmol) in DCM (35 mL) at rt. Air was allowed to diffuse into the reaction mixture via a CaCh-tube on top of the flask. The resulting suspension was stirred at rt for 18 h. The reaction mixture was diluted with DCM (150 mL), and washed sequentially with water (2 x 50 mL). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by preparative TLC (EtOAc : PE = 2: 1) to afford (243 mg, 37%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 207.9.
Intermediate 59 i-59a
3-(2-Chloropyrimidin-5-yl)-1-methylpyridin-2(1H)-one
Figure imgf000163_0001
3-Bromo-1-methylpyridin-2(1/7)-one (CAS Reg. No. 81971-38-2) (300 mg, 1.60 mmol) was added to (2-chloropyrimidin-5-yl)boronic acid (CAS Reg. No. 1003845-06-4) (505 mg,
3.19 mmol), K2CO3 (662 mg, 4.79 mmol) and Pd-118/PdCl2(dtbpf) (104 mg, 0.16 mmol) in 1 ,4- dioxane (8 mL) and water (2 mL) at rt and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was poured into water (150 mL) and the aqueous layer was extracted with EtOAc (5 x 150 mL).The combined organic layers were dried (Na2SO4), filtered and evaporated and the residue was purified by preparative TLC (MeOH : DCM = 1 : 20) to afford (105 mg, 30%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 221.9.
Intermediate 60
Step A. i-60a
3-((6-Chloropyridin-3-yl)amino)-4-nitrobenzonitrile
Figure imgf000163_0002
K2CO3 (6.45 g, 46.7 mmol) was added to 3-fluoro-4-nitrobenzonitrile (CAS Reg. No 218632-01- 0) (3.10 g, 18.7 mmol), 6-chloropyridin-3-amine (CAS Reg. No. 5350-93-6) (2.0 g, 15.6 mmol) and Pd(OAc)2 (0.262 g, 1.17 mmol) and XantPhos (1.35 g, 2.33 mmol) in MeCN (40 mL) at rt and the resulting mixture was stirred at 80 °C for 15 h under nitrogen. The reaction mixture was filtered through celite and the filter cake washed with DCM (3 x 50 mL). The combined filtrates were concentrated under reduced pressure and taken up with EtOAc (250 mL). The organic layer was washed sequentially with sat. NaHCCh (3 x 250 mL), dried (Na2SO4), filtered and evaporated. The obtained residue was purified by preparative TLC (DCM) to afford (0.63 g, 15%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 275.1.
Step B. i-60b
4-Amino-3-((6-chloropyridin-3-yl)amino)benzonitrile
Figure imgf000164_0001
Zinc (971 mg, 14.9 mmol) was added to 3-((6-chloropyridin-3-yl)amino)-4-nitrobenzonitrile compound i-60a (510 mg, 1.86 mmol) and NH4CI (795 mg, 14.8 mmol) in EtOH (15 mL) at rt and the resulting mixture was stirred at 60 °C for 5 h. The reaction mixture was filtered through celite and the filter cake washed with EtOH (3 x 50 mL). The combined filtrates were concentrated under reduced pressure to afford (363 mg, 80%) of the title compound as a brown solid which was used in the next step directly without further purification. MS (ESI): m/z [M+H]+ 245.1.
Step C. i-60c 3-(6-Chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5-carbonitrile
Figure imgf000164_0002
GDI (795 mg, 4.90 mmol) was added to 4-amino-3-((6-chloropyridin-3-yl)amino)benzonitrile compound i-60b (300 mg, 1.23 mmol) in DMF (2 mL) at rt and the resulting mixture was stirred at 80 °C for 24 h. The solid was filtered off to afford the crude product which was triturated with MeCN and dried under vacuum to give (242 mg, 73%) of the title compound as a pink solid. MS (ESI): m/z [M+H]+ 271.0.
Step D. i-60d 3-(6-Chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5-carbonitrile
Figure imgf000165_0001
-60d
CS2CO3 (542 mg, 1.66 mmol) was added to a mixture of 3-(6-chloropyridin-3-yl)-2-oxo-2,3- dihydro-1/7-benzo[d]imidazole-5-carbonitrile compound i-60c (150 mg, 0.55 mmol) and CH3I (118 mg, 0.83 mmol) in DMF (5 mL) at rt and it was stirred at 100 °C for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with brine (3 x 50 mL). The organic layer was dried (Na2SO4), filtered and evaporated and the obtained material was triturated with MeCN. The formed solid was collected by filtration and dried under vacuum to give (110 mg, 70%) of the title compound as a pink solid. MS (ESI): m/z [M+H]+ 285.1.
Intermediate 61
Step A. i-61 a
4-((6-Chloropyridin-3-yl)amino)-3-nitrobenzonitrile
Figure imgf000165_0002
Pd(OAc)2 (0.262 g, 1.17 mmol) was added to a mixture of K2CO3 (6.45 g, 46.7 mmol), 4-fluoro- 3-nitrobenzonitrile (CAS Reg. No. 1009-35-4) (2.84 g, 17.1 mmol), 6-chloropyridin-3-amine CAS Reg. No. 5350-93-6 (2.0 g, 15.6 mmol) and XantPhos (1.35 g, 2.33 mmol) in MeCN (40 mL) at rt and it was stirred at 80 °C for 15 h under nitrogen. The reaction mixture was filtered through Celite and the filter cake washed with DCM (3 x 200 mL). The combined filtrates were concentrated under reduced pressure and taken up with EtOAc (300 mL). The organic layer was washed sequentially with sat. NaHCOs (3 x 400 mL), dried over (Na2SO4), filtered and evaporated. The obtained material was purified by preparative TLC (DCM) to afford (0.70 g, 16%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 275.0
Step B. i-61 b 3-Amino-4-((6-chloropyridin-3-yl)amino)benzonitrile
Figure imgf000166_0001
Zinc (1.33 g, 20.4 mmol) was added to NH4CI (1.09 g, 20.4 mmol), 4-((6-chloropyridin-3- yl)amino)-3-nitrobenzonitrile compound i-61 a (0.70 g, 2.54 mmol) in EtOH (15 mL) at rt and the resulting mixture was stirred at 60 °C for 5 h. The reaction mixture was filtered through Celite and the filter cake washed with EtOH (3 x 50 mL). The combined filtrates were concentrated under reduced pressure to afford (0.51 g, 81%) of the title compound as a brown solid which was used in the next step without further purification. MS (ESI): m/z [M+H]+ 245.1.
Step C. i-61 c 1-(6-Chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5-carbonitrile
Figure imgf000166_0002
GDI (1.19 g, 7.36 mmol) was added to 3-amino-4-((6-chloropyridin-3-yl)amino)benzonitrile compound i-61 b (450 mg, 1.84 mmol) in DMF (10 mL) at rt and the resulting mixture was stirred at 80 °C for 24 h. The solid was filtered off to afford the crude product which was triturated with MeCN and dried under vacuum to give (342 mg, 69%) of the title compound as a pink solid. MS (ESI): m/z [M+H]+ 270.9.
Step D. i-61 d 1-(6-Chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5-carbonitrile
Figure imgf000166_0003
-61d CH3I (157 mg, 1.11 mmol) was added to a mixture of 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro- 1H-benzo[d]imidazole-5-carbonitrile compound i-61 c (200 mg, 0.74 mmol) and CS2CO3 (722 mg, 2.22 mmol) in DMF (8 mL) at rt and it was stirred at 100 °C for 15 h. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with brine (3 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford (119 mg, 57%) of the title compound as a yellow solid which was used in the next step without further purification. MS (ESI): m/z [M+H]+ 285.0.
Intermediate 62 i-62a
2-(6-Fluoropyridin-3-yl)pyridazin-3(2H)-one
Figure imgf000167_0001
2-Fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (300 mg, 1.35 mmol) was added to a mixture of pyridazin-3(2/7)-one (CAS Reg. No. 504-30-3) (259 mg, 2.69 mmol), Cu(l)l (128 mg, 0.67 mmol), CS2CO3 (1315 mg, 4.04 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2- diamine (96 mg, 0.67 mmol) in 1 ,4-dioxane (20 mL) at rt and it was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was diluted with water (50 mL) and the aqueous layer extracted with EtOAc (8 x 30 mL). The combined organic layers were dried (Na2SC>4), filtered and evaporated and the residue purified by preparative TLC (EtOAc) to afford (242 mg, 94%) of the title compound as a brown solid. MS (ESI): m/z [M+H]+ 191.9.
Intermediate 63
Step A. i-63a
5-((tert-Butyldimethylsilyl)ethynyl)-6'-chloro-2H-[1,3'-bipyridin]-2-one
Figure imgf000167_0002
CS2CC>3 (2.23 g, 6.86 mmol) was added to 5-((tert-butyldimethylsilyl)ethynyl)pyridin-2(1/7)-one (CAS Reg. No. 2448766-74-1 ) (800 mg, 3.43 mmol), 2-chloro-5-iodopyridine (CAS Reg. No. 69045-79-0 ) (821 mg, 3.43 mmol), Cu(l)l (653 mg, 3.43 mmol) and re/-(1R,2R)-/V1,/V2- dimethylcyclohexane-1 ,2-diamine (731 mg, 5.14 mmol) in 1 ,4-dioxane (20 mL) at rt and the resulting suspension was stirred at 60 °C for 5 h under nitrogen. The mixture was combined with a second batch made in the same way and filtered through a Celite pad. The filter cake was washed with EtOAc (100 mL) and the combined filtrates were concentrated under reduced pressure. The crude product was purified by flash chromatography on silica (gradient: 0-50% EtOAc in n-heptane) to afford (590 mg, 25%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 345.0.
Step B. i-63b 6'-Chloro-5-ethynyl-2H-[1,3'-bipyridin]-2-one
Figure imgf000168_0001
A solution of TBAF in THF (1 M, 8.55 mL, 8.55 mmol) was added to 5-((tert- butyldimethylsilyl)ethynyl)-6'-chloro-2/7-[1 ,3'-bipyridin]-2-one compound i-63a (590 mg, 1.71 mmol) in THF (15 mL) at rt and the resulting solution was stirred at for 2 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (EtOAc : PE = 2: 1) followed by flash C18-flash chromatography (elution gradient: 0-30% MeCN in water) to afford (290 mg, 74%) of the title compound as a beige solid. MS (ESI): m/z [M+H]+ 231.0.
Intermediate 67
Step A. i-67a
5-(1 -Methyl-1 H-pyrazol-4-yl)pyridin-2-ol
Figure imgf000168_0002
A mixture of 5-iodo-2(1H)-pyridinone (CAS Reg. No. 13472-79-2) (500 mg, 2.26 mmol), 1- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS Reg. No. 761446-44- 0) (565 mg, 2.71 mmol) and XPhos (CAS Reg. No. 564483-18-7) (108 mg, 0.23 mmol) in 1,4- dioxane (10 mL) and water (1 mL) was treated with XPhos Pd G3 (CAS Reg. No. 1445085-55- 1) (192 mg, 0.23 mmol) under nitrogen and stirred at 100 °C for 18 h. The reaction mixture was cooled to rt and filtered through a pad of Celite. The filter cake was washed with EtOAc (100 mL) and the combined filtrates concentrated under reduced pressure. The obtained material was purified by flash chromatography on silica (gradient: 10-20% MeOH in DCM) to afford the title compound (250 mg, 63%) as a green solid. MS (ESI): m/z [M+H]+ 175.9.
Step B. i-67b 6'-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one
Figure imgf000169_0001
According to GM3 5-(1-methyl-1/7-pyrazol-4-yl)pyridin-2-ol compound i-67a (250 mg, 1.43 mmol), 2-chloro-5-iodopyridine (342 mg, 1.43 mmol), rel-(/\ R^^-A/^A^-dimethylcyclo- hexane-1,2-diamine (203 mg, 1.43 mmol), CS2CO3 (1.4 g, 4.3 mmol) and Cu(l)l (272 mg, 1.43 mmol) were reacted in 1,4-dioxane (8 mL) at 100 °C for 18 h to give upon non-aqueous work-up (EtOAc) and flash chromatography on silica (gradient: 0-10% MeOH in DCM) the title compound (250 mg, 61%) as a green solid, m/z [M+H]+ 287.1/289 (Cl isotope pattern).
Intermediate 68a i-68a
6'-(((1 S,3S)-3-((6-Methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(2-(tetrahydro-2H- pyran-2-yl)-2H-1,2,3-triazol-4-yl)-2H-[1,3,-bipyridin]-2-one
Figure imgf000169_0002
3-Chloro-6'-(((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2/7-[1 ,3'- bipyridin]-2-one Example 129 (280 mg, 0.70 mmol) was added to a mixture of 1-(tetrahydro-2H- pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazole (CAS Reg. No. 2710298-24-9) (393 mg, 1.41 mmol), Cs2CO3 (688 mg, 2.11 mmol), XPhos (CAS Reg. No. 564483-18-7) (34 mg, 0.07 mmol) and XPhos Pd G3 (CAS Reg. No. 1445085-55-1) (59 mg, 0.07 mmol) in 1,4-dioxane (16 mL) and water (4 mL) under nitrogen. The resulting reaction mixture was stirred at 100 °C for 15 h and subsequently poured into saturated brine (150 mL). It was extracted with EtOAc (4 x 150 mL) and the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude material was purified by preparative TLC (7 M NH3 in MeOH:DCM = 1 :20) to give the title compound (335 mg, 93%) as a pale yellow solid. MS (ESI): m/z [M+H]+ 515.1.
Intermediate 76 i-76a
(6-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid
Figure imgf000170_0001
terf-Butyl ((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i- 28a (1.32 g, 4.50 mmol) was dissolved in DCM (15 mL) and TFA (5 mL). After stirring for 1 h toluene was added, and the resulting mixture was concentrated. The residue was dissolved in DMSO (10 mL) and treated with 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (CAS Reg. No. 444120-95-0) (1.81 g, 8.11 mmol) and K2CO3 (2.25 g, 16.3 mmol), and the resulting mixture was stirred at 80 °C for 20 h. The mixture was cooled to rt, solids were filtered off and the filtrate purified by preparative HPLC (PrepMethod G, gradient 0-50%) to afford (1.07 g, 66%) of the title compound as a red solid MS (ESI) m/z [M+H]+ 315.
Intermediate 77
Step. A i-77a
(1 S,3S)-/V1-(5-(2,4-Dimethyl-1/-/-imidazol-1-yl)pyridin-2-yl)-/V3-(6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine
Figure imgf000170_0002
A mixture of (6-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)boronic acid compound i-76a (0.126 g, 0.40 mmol), 2,4-dimethyl-1/7-imidazole (CAS Reg. No. 930-62-1), CU(OAC)2 (0.175 g, 0.96 mmol) and pyridine (0.178 mL, 2.21 mmol) in DCM (4 mL) and DMF (0.8 mL) was stirred at rt for 24 h. Solids were filtered off and washed with MeOH. The combined filtrates were concentrated and purified by preparative HPLC (PrepMethod F, gradient 20-60%) to afford (52 mg, 36%) of the title compound as a beige solid. MS (ESI) m/z [M+H]+ 365. Step. B i-77b
(1S,3S)-A/1-(5-(5-lodo-2,4-dimethyl-1H-imidazol-1-yl)pyridin-2-yl)-A/3-(6-methyl-1,2,4-triazin-
3-yl)cyclopentane-1,3-diamine
Figure imgf000171_0001
A mixture of compound i-77a (0.051 g, 0.14 mmol) and NIS (0.063 g, 0.28 mmol) in MeCN (2 mL) was stirred at rt for 2 h. The mixture was concentrated, the residue dissolved in DCM and washed with water. The organic layer was concentrated and purified by preparative HPLC (PrepMethod H, gradient 20-60%) to afford (55 mg, 80%) of the title compound as a beige solid. MS (ESI) m/z [M+H]+ 491.
Intermediate 80 i-80a
6-Methyl-3-(methylsulfinyl)-1,2,4-triazin-5(4H)-one
Figure imgf000171_0002
According to GM8 6-methyl-3-(methylthio)-1,2,4-triazin-5(4/7)-one (CAS Reg. No. 1566-32-1) (300 mg, 1.91 mmol) was treated portionwise with 3-chlorobenzoperoxoic acid (494 mg, 2.29 mmol) in DCM (25 mL) at rt for 2 h to give upon purification by preparatvie TLC
(DCM : MeOH = 10:1) the title compound (200 mg, 61%) as a white solid. MS (ESI): m/z [M+H]+ 174. 1H NMR (400 MHz, DMSO-cfe) 6 ppm 2.15 (3H, s), 2.71 (3H, s).
Intermediate 81
Step A. i-81 a
A/-(6-Chloropyridin-3-yl)-6-methyl-3-nitropyridin-2-amine
Figure imgf000171_0003
XantPhos (CAS Reg. No. 161265-03-8) (34 mg, 0.06 mmol) was added to a mixture of 2-chloro- 6-methyl-3-nitropyridine (CAS Reg. No. 56057-19-3) (1.00 g, 8.69 mmol), 6-chloropyridin-3- amine (CAS Reg. No. 5350-93-6) (1.12 g, 7.8 mmol), Na2COs (1.84 g, 17.4 mmol) and
Pd(OAc)2 (13 mg, 0.06 mmol) in THF (15 mL) at rt under nitrogen and it was stirred at 80 °C for 15 h. The reaction mixture was concentrated under reduced pressure and taken up with EtOAc (250 mL). The organic layer was washed with sat. brine (4 x 125 mL), dried over Na2SC>4, filtered and evaporated. The crude material was purified by flash chromatography on silica (gradient: 0-10% EtOAc in PE) to give the title compound (1.43 g, 93%) as a yellow solid. MS (ESI): m/z [M+H]+ 265.0/267 (Cl isotope pattern).
Step B. i-81 b
A/2-(6-chloropyridin-3-yl)-6-methylpyridine-2,3-diamine
Figure imgf000172_0001
/V-(6-Chloropyridin-3-yl)-6-methyl-3-nitropyridin-2-amine compound i-81 a (1.4 g, 5.3 mmol) was added to a mixture of zinc (2.08 g, 31.7 mmol) and NH4CI (2.83 g, 52.9 mmol) in a mixture of EtOH (8 mL) and EtOAc (8 mL) at rt and it was stirred at 60 °C for 15 h. The reaction mixture was filtered through a pad of Celite, the filtrate concentrated under reduced pressure and the crude material purified by preparative TLC (EtOAc) to give the title compound (1.2 g, 97%) as a yellow solid. MS (ESI): m/z [M+H]+ 235.0/237 (Cl isotope pattern).
Step C. i-81 c 3-(6-Chloropyridin-3-yl)-5-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
Figure imgf000172_0002
/V2-(6-chloropyridin-3-yl)-6-methylpyridine-2,3-diamine compound i-81 b (65 mg, 0.28 mmol) in
DMF (5 mL) was treated with GDI (CAS Reg. No. 530-62-1) (225 mg, 1.38 mmol) at rt under nitrogen and it was stirred at 80 °C for 2 h. The reaction mixture was diluted with EtOAc
(100 mL) and washed with water (3 x 50 mL). The organic layer was dried over Na2SO4, filtered and evaporated and the crude material purified by preparative HPLC to give the title compound (42 mg, 58%) as a pale-yellow powder. MS (ESI): m/z [M+H]+ 260.9/263 (Cl isotope pattern). Step D. i-81 d 3-(6-Chloropyridin-3-yl)-1,5-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
Figure imgf000173_0001
In a vial a mixture of 3-(6-chloropyridin-3-yl)-5-methyl-1 ,3-dihydro-2/7-imidazo[4,5-b]pyridin-2- one compound i-81c (340 mg, 1.30 mmol) and K2CO3 (541 mg, 3.01 mmol) in DMF (25 mL) was treated with iodomethane (1.85 g, 13.0 mmol) at rt under nitrogen and it was stirred at 80 °C for 1 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (3 x 50 mL). The organic layer was dried over Na2SO4, filtered and evaporated and the crude material purified by flash chromatography on silica (gradient: 0-50% EtOAc in PE) to give the title compound (305 mg, 85%) as a pink film. MS (ESI): m/z [M+H]+ 275.0/277 (Cl isotope pattern).
Step E. i-81e 3-(6-Chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5- carbonitrile
Figure imgf000173_0002
The reaction was run in 3 parallel batches (2 x starting from 100 mg and 1 x starting from 150 mg of compound i-81 d). In a vial a mixture of 3-(6-chloropyridin-3-yl)-1 ,5-dimethyl-1,3- dihydro-2/7-imidazo[4,5-b]pyridin-2-one compound i-81d (150 mg, 0.55 mmol), 2- hydroxyisoindoline-1 , 3-dione (CAS Reg. No. 524-38-9) (45 mg, 0.27 mmol) and tert-butyl nitrite (CAS Reg. No. 540-80-7) (169 mg, 1.64 mmol) in MeCN (4 mL) was treated with Pd(OAc)2 (12 mg, 0.05 mmol) at rt under nitrogen and it was stirred at 80 °C for 24 h. The reaction mixtures of the three parallel batches were combined, poured into water (200 mL) and the mixture extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated and the crude material purified by preparative TLC (EtOAc:PE = 1:3) to give the title compound (180 mg, 44% average yield) as a brown solid. MS (ESI): m/z [M+H]+ 286.2/288 (Cl isotope pattern). Intermediate 82
Step A. i-82a
6-((6-Chloropyridin-3-yl)amino)-5-nitronicotinonitrile
Figure imgf000174_0001
Na2CC>3 (1.73 g, 16.3 mmol) was added to a mixture of 6-chloro-5-nitronicotinonitrile (CAS Reg. No. 160906-98-9) (1.00 g, 5.45 mmol), 6-chloropyridin-3-amine (CAS Reg. No. 5350-93-6) (1.40 g, 10.9 mmol), XantPhos (CAS Reg. No. 161265-03-8) (315 mg, 0.54 mmol) and Pd(OAc)2 (61 mg, 0.27 mmol) in 1 ,4-dioxane (15 mL) at rt under nitrogen and it was stirred at 80 °C for 3 h. The reaction mixture was filtered through a filter membrane, concentrated under reduced pressure and the crude material was purified by preparative TLC (EtOAc : PE = 1 :1) to give the title compound (1.28 g, 85%) as a yellow solid. MS (ESI): m/z [M+H]+ 275.8/278 (Cl isotope pattern).
Step B. i-82b 5-Amino-6-((6-chloropyridin-3-yl)amino)nicotinonitrile
Figure imgf000174_0002
6-((6-Chloropyridin-3-yl)amino)-5-nitronicotinonitrile compound i-82a (1.28 g, 4.64 mmol) was added to a mixture of zinc (1.52 g, 23.2 mmol) and acetic acid (2.79 g, 46.4 mmol) in EtOH (15 mL) at rt and it was stirred at 60 °C for 2 h. The reaction mixture was filtered through a filter membrane, the filtrate concentrated under reduced pressure and the crude material purified by preparative TLC (EtOAc : PE = 1 :1) to give the title compound (1.26 g, 100%) as a yellow solid. MS (ESI): m/z [M+H]+ 246.0/248 (Cl isotope pattern).
Step C. i-82c 3-(6-Chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile
Figure imgf000175_0001
5-Amino-6-((6-chloropyridin-3-yl)amino)nicotinonitrile compound i-82b (1.26 g, 5.13 mmol) in DMF (15 mL) was treated with CDI (CAS Reg. No. 530-62-1) (4.16 g, 25.6 mmol) at rt under nitrogen and it was stirred at 80 °C for 2 h. The reaction mixture was poured into water (100 mL) and the mixture extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated and the crude material purified by preparative TLC
(DCM : MeOH = 10:1) to give the title compound (590 mg, 38%) as a yellow oil. MS (ESI): m/z [M+H]+ 271.9/274 (Cl isotope pattern).
Step D. i-82d
3-(6-Chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6- carbonitrile
Figure imgf000175_0002
82d
In a vial a mixture of 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1/7-imidazo[4,5-b]pyridine-6- carbonitrile compound i-82c (580 mg, 2.13 mmol) and K2CO3 (885 mg, 6.40 mmol) in DMF (2 mL) was treated with iodomethane (3.03 g, 21.4 mmol) at rt under nitrogen and it was stirred at 60 °C for 1 h. The reaction mixture was poured into water (100 mL) and the mixture extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated and the crude material purified by preparative TLC (DCM : PE = 10:1) to give the title compound (401 mg, 66%) as a brown oil. MS (ESI): m/z [M+H]+ 285.9/288 (Cl isotope pattern).
Intermediate 83
Step A. i-83a
(IS.SSJ-A^-n^^-Triazin-S-yQcyclopentane-I.S-diamine
Figure imgf000176_0001
HCI (4 M in MeOH, 4 mL, 16 mmol) was added slowly to fert-butyl ((1S,3S)-3-((1,2,4-triazin-3- yl)amino)cyclopentyl)carbamate compound i-22a (200 mg, 0.72 mmol) in MeOH (10 mL) at 20 °C and the resulting solution was stirred at 60 °C for 1 h. The solvent was removed under reduced pressure to give an unspecified HCI salt of the crude title compound (265 mg, 100 %) as a brown gum that was directly used in the next step. MS (ESI): m/z [M+H]+ 179.8.
Step B. i-83b
6'-(((1 S,3S)-3-((1 ,2,4-Triazin-3-yl)amino)cyclopentyl)amino)-2/-/-[1,3'-bipyridin]-2-one
Figure imgf000176_0002
(1 S,3S)-/V1-(1,2,4-Triazin-3-yl)cyclopentane-1,3-diamine compound i-83a (255 mg, 0.69 mmol) was added to 6'-fluoro-2/7-[1,3'-bipyridin]-2-one compound i-100a (197 mg, 1.04 mmol) and K2CO3 (477 mg, 3.45 mmol) in DMSO (5 mL) at 25 °C. The resulting mixture was stirred at 120 °C for 15 h under a nitrogen atmosphere. The crude product was purified by C18 flash chromatography (gradient: 40-55% MeCN in water) to give the title compound (175 mg, 72%) as a brown gum. MS (ESI): m/z [M+H]+ 349.9.
Intermediate 84
Step A. i-84a
(IS.SSJ-A^-fe-Bromo-l^^-triazin-S-yQcyclopentane-I.S-diamine
Figure imgf000176_0003
TFA (2.2 mL, 29 mmol) was added to terf-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3- yl)amino)cyclopentyl)carbamate compound i-22b (1.2 g, 3.4 mmol) in DCM (20 mL) at 30 °C and the resulting mixture stirred at this temperature for 5 h. The reaction mixture was concentrated, diluted with MeOH : DCM = 1:10 (300 mL) and washed sequentially with sat. NaHCCh (3 x 125 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give the crude title compound (0.563 g, 65%) as a black gum that was directly used in the next step. MS (ESI): m/z [M+H]+ 259.8.
Step B. i-84b
6'-(((1 S,3S)-3-((6-Bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2/-/-[1,3'-bipyridin]-2- one
Figure imgf000177_0001
(1 S,3S)-/V1-(6-bromo-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-84a (530 mg, 2.05 mmol) was added to 6'-fluoro-2/7-[1 ,3'-bipyridin]-2-one compound i-100a (781 mg, 4.11 mmol) and Na2COs (653 mg, 6.16 mmol) in DMSO (20 mL) at 30 °C and the resulting mixture was stirred at 120 °C for 15 h. The reaction mixture was concentrated, diluted with EtOAc (250 mL) and washed sequentially with sat. brine (3 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated and the obtained residue was purified by preparative TLC (EtOAc) to give the title compound (117 mg, 13%) as a yellow solid. MS (ESI): m/z [M+H]+ 427.8.
Intermediate 85
Step A. i-85a tert-Butyl ((1 S,3S)-3-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1,2,4-triazin-3- yl)amino)cyclopentyl)carbamate
Figure imgf000177_0002
CS2CO3 (819 mg, 2.51 mmol) was added to a mixture of terf-butyl ((1 S,3S)-3-((6-bromo-1 ,2,4- triazin-3-yl)amino)cyclopentyl)carbamate compound i-22b (300 mg, 0.84 mmol), 1 - (tetra hydro- 2/7-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1/7-pyrazole (CAS Reg. No. 903550-26-5) (466 mg, 1.67 mmol) and PdCh(dtbpf) (55 mg, 0.08 mmol) in 1 ,4-dioxane (5 mL) at 20 °C and the resulting suspension was stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated and the residue was purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :20) to give the title compound (273 mg, 76%) as a brown solid. MS (ESI): m/z [M+H]+ 430.1.
Step B. i-85b
(I S.SSJ-A^-fS-flW-Pyrazol-S-yQ-l^^-triazin-S-yQcyclopentane-I.S-diamine
Figure imgf000178_0001
terf-Butyl ((1 S,3S)-3-((6-(1-(tetrahydro-2/7-pyran-2-yl)-1/7-pyrazol-5-yl)-1 ,2,4-triazin-3- yl)amino)cyclopentyl)carbamate compound i-85a (263 mg, 0.61 mmol) was added to TFA (2 mL) and DCM (2 mL) at 20 °C and the resulting solution stirred at 60 °C for 2 h. The solvent was removed under reduced pressure and the residue purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :20) to give the title compound (431 mg, 100%) as a brown gum. MS (ESI): m/z [M+H]+ 245.9.
Intermediate 86
Step A. i-86a tert-Butyl ((1 S,3S)-3-((6-(ethylthio)-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
Figure imgf000178_0002
Sodium ethanethiolate (141 mg, 1.67 mmol) was added to fert-butyl ((1 S,3S)-3-((6-bromo-1 ,2,4- triazin-3-yl)amino)cyclopentyl)carbamate compound i-22b (200 mg, 0.56 mmol) in EtOH (5 mL) at 20 °C and the resulting solution was stirred at 60 °C for 16 h. The solvent was removed under reduced pressure and the residue purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :20) to give the title compound (84 mg, 44%) as an orange solid. MS (ESI): m/z [M+H]+ 339.9.
Step B. i-86b
(1 S,3S)-/V1-(6-(Ethylthio)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine x 3.3TFA
Figure imgf000178_0003
TFA (2 mL, 26 mmol) was added to terf-butyl ((1 S,3S)-3-((6-(ethylthio)-1,2,4-triazin-3- yl)amino)cyclopentyl)carbamate compound i-86a (73.8 mg, 0.22 mmol) in DCM (2 mL) at 20 °C and the resulting solution was stirred at this temperature for 16 h. The solvent was removed under reduced pressure to give the title compound (133 mg, 99%) as a brown gum. The compound was used directly in the next step. MS (ESI): m/z [M+H]+ 239.9.
Intermediate 87
Step A. i-87a re/-tert-Butyl ((1 /?,3/?)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
AND Enantiomer
Figure imgf000179_0001
i-87a
DIPEA (0.94 mL, 5.4 mmol) and re/-tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate (CAS Reg. No. 947732-58-3) (0.446 g, 2.23 mmol) were added to a solution of crude 6-methyl-3- (methylsulfinyl)-1,2,4-triazine compound i-36b (0.283 g, 1.8 mmol) in MeCN (6 mL) and the resulting mixture was stirred at 50 °C for 5 days. The reaction solution was cooled to rt, concentrated under reduced pressure and the residue was dissolved in DCM and washed with 1 M NaOH (aq). The phases were separated and the aqueous phase was re-extracted with DCM (3x). The organic phases were combined, passed through a phase separator and concentrated. The obtained brown solid was further purified by flash chromatography on silica (gradient: 0-100 % EtOAc : MeOH = 95:5 in n-heptane) to give the title compound (0.280 g, 53%) as an yellow solid. MS (ESI): m/z [M+H]+ 294.1.
Step B. i-87b re/-(1R,3R)-/V1-(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 3HCI
AND Enantiomer
Figure imgf000179_0002
A solution of rel- tert- butyl ((1R,3R)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-87a (280 mg, 0.95 mmol) in dioxane (4 mL) was treated with HCI (4 M in dioxane, 5 mL, 20 mmol) at rt and the formed slurry was stirred at rt for 20 h. The mixture was concentrated to dryness to give the crude title compound (312 mg) as a light-yellow solid. MS (ESI): m/z [M+H]+ 194.1. Intermediate 90
Step A. i-90a 6-Bromo-3-(methylthio)-1,2,4-triazine
Figure imgf000180_0001
terf-Butyl nitrite (10.6 g, 103 mmol) was added dropwise to a mixture of 6-bromo-1 ,2,4-triazin-3- amine (CAS Reg. No. 58-4-028-01) (3.0 g, 17 mmol) and 1,2-dimethyldisulfane (16.2 g, 171 mmol) in MeCN (60 mL) at rt over a period of 10 minutes under air and the resulting solution was stirred at this temperature for 16 h. The solvent was removed under reduced pressure. The crude product was combined with three other equal batches prepared in the same way and purified by flash chromatography on silica (gradient: 0-20% EtOAc in n-heptane) to afford (8.60 g, 60%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 205.8/207.8 (Br isotope pattern).
Step B. i-90b
Ethyl 3-(methylthio)-1 ,2,4-triazine-6-carboxylate
Figure imgf000180_0002
Pd(OAc)2 (0.142 g, 0.63 mmol) and XantPhos (0.584 g, 1.01 mmol) were added to a mixture of 6-bromo-3-(methylthio)-1,2,4-triazine compound i-90a (2.6g, 12.6 mmol) and TEA (5.3 mL, 38 mmol) in EtOH (26 mL) at rt under air. The resulting suspension was put under an atmosphere of carbon monoxide (20 atm) and stirred at 85 °C for 16 h. The mixture was combined with three other equal batches prepared in the same way and filtered through a Celite pad. The filter cake was washed with EtOAc (100 mL) and the combined filtrates were concentrated under reduced pressure. The obtained material was purified by flash chromatography on silica (gradient: 0- 20% EtOAc in n-heptane) to afford (6.10 g, 73%) of the title compound as a yellow oil. MS (ESI): m/z [M+H]+ 200.
Step C. i-90c
3-(Methylthio)-1,2,4-triazine-6-carboxylic acid
Figure imgf000181_0001
NaOH (1 M aq) (18 mL, 18 mmol) was added dropwise to ethyl 3-(methylthio)-1,2,4-triazine-6- carboxylate compound i-90b (3.0 g, 15 mmol) in THF (20 mL) and water (10 mL) at 0 °C and the resulting solution was stirred at rt for 1 h. The reaction mixture was diluted with water/ice (150 mL), the aqueous layer was adjusted to pH 2 with 2 M HCI (aq) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to afford (2.5 g, 97%) of the title compound as a brown gum which was used without further purification. MS (ESI): m/z [M+H]+ 172.
Step D. i-90d 3-(Methylthio)-A/-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide
Figure imgf000181_0002
T3P in EtOAc (50% w/w) (18.6 g, 29.2 mmol) was added to a mixture of crude 3-(methylthio)- 1,2,4-triazine-6-carboxylic acid compound i-90c (2.5 g, 14.6 mmol), oxetan-3-amine (2.14 g, 29.2 mmol) and DI PEA (7.65 mL, 43.8 mmol) in EtOAc (75 mL) at rt and the resulting solution was stirred at 60 °C for 15 h. The reaction mixture was poured into sat. NaHCOs (aq) (150 mL) and extracted with EtOAc (3 x 125 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to afford yellow gum. Theis material was triturated with EtOAc : PE = 1: 3 (10 mL) to afford (1.0 g, 30%) of the title compound as a pale yellow solid. MS (ESI): m/z [M+H]+ 227.1.
Step E. i-90e
3-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-/V-(oxetan-3-yl)-1,2,4-triazine-
6-carboxamide
Figure imgf000181_0003
m-CPBA (1.05 g, 4.86 mmol) was added dropwise to 3-(methylthio)-/V-(oxetan-3-yl)-1,2,4- triazine-6-carboxamide compound i-90d (1.0 g, 4.42 mmol) in DCM (10 mL) at rt and the resulting solution was stirred at rt for 30 min. (1S,3S)-/V1-(5-lodopyridin-2-yl)cyclopentane-1,3- diamine x 2HCI compound i-17a (1.08 g, 2.87 mmol) and TEA (3.1 mL, 22 mmol) were added to the reaction mixture and it was stirred at rt for another 8 h. The reaction mixture was poured into 1 M NaOH aq (150 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried (Na2SC>4), filtered and evaporated to afford yellow oil which solidified on standing. This material was purified by preparative TLC (7 M NH3 in MeOH : DCM = 1: 20) to afford (0.50 g, 23%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 481.7.
Intermediate 91
Step A. i-91 a
Methyl 3-(6-chloropyridin-3-yl)-4-fluoro-2-methoxybenzoate
Figure imgf000182_0001
CataCXium A Pd G3 (55 mg, 0.08 mmol) was added to a mixture of methyl 3-bromo-4-fluoro-2- methoxybenzoate (CAS Reg. No. 1935415-04-05) (200 mg, 0.76 mmol), 2-chloropyridine-5- boronic acid (CAS Reg. No. 444120-91-6) (179 mg, 1.14 mmol), K2CO3 (210 mg, 1.52 mmol) and water (2 mL) in 1 ,4-dioxane (8 mL) at rt under nitrogen and it was stirred at 80 °C for 8 h. The reaction mixture was poured into water (50 mL) and filtered through a Celite pad. The filtrate was extracted with EtOAc (3 x 25 mL) and the combined organic layers were dried over Na2SC>4, filtered and evaporated. The obtained material was purified by preparative TLC (PE : EtOAc = 3: 1) to afford (160 mg, 71%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 296.0.
Step B. i-91 b
Methyl 3-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-
3-yl)-4-fluoro-2-methoxybenzoate
Figure imgf000182_0002
(1 S,3S)-/V -(6-Cyclopropyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-22d (133 mg, 0.61 mmol) was added to a mixture of methyl 3-(6-chloropyridin-3-yl)-4-fluoro-2- methoxybenzoate compound i-91 a (150 mg, 0.51 mmol), Pd-PEPPSI-IPentCI 2-methylpyridine (43 mg, 0.05 mmol) and CS2CO3 (496 mg, 1.52 mmol) in 1 ,4-dioxane (10 mL) at rt under nitrogen and it was stirred at 100 °C for 8 h. The reaction mixture was poured into water (20 mL) and filtered through a Celite pad. The filtrate was extracted with EtOAc (3 x 10 mL) and the combined organic layers were dried (Na2SO4), filtered and evaporated. The obtained material was purified by preparative TLC (EtOAc : PE = 1 : 1) to afford (90 mg, 37%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 479.2.
Intermediate 92
Step A. i-92a
3-Bromo-4-fluoro-2-methoxybenzamide
Figure imgf000183_0001
Sodium methoxide (30% w/w in MeOH, 458 mg, 2.54 mmol) was added dropwise to 3-bromo- 2,4-difluorobenzamide (CAS Reg. No. 1518200-63-9) (500 mg, 2.12 mmol) in DMSO (30 mL) at rt and the resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with sat. NH4CI aq (3 x 50 mL), dried (Na2SC>4), filtered and evaporated and the residue was purified by preparative TLC (DCM : MeOH = 30: 1) to afford (400 mg, 76%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 249.8.
Step B. i-92b
3-(6-Chloropyridin-3-yl)-4-fluoro-2-methoxybenzamide
Figure imgf000183_0002
3-Bromo-4-fluoro-2-methoxybenzamide compound i-92a (320 mg, 1.29 mmol) was added to a mixture of PdCh(dppf) DCM adduct (105 mg, 0.13 mmol), Na2COs (273 mg, 2.58 mmol) and 2- chloropyridine-5-boronic acid (CAS Reg. No. 444120-91-6) (305 mg, 1.94 mmol) in 1 ,4-dioxane (15 mL) and water (2.5 mL) at rt and it was stirred at 80 °C for 8 h. The reaction mixture was poured into water (50 mL) and filtered through Celite. The filtrate was extracted with EtOAc (3x) and the combined organic layers were dried (Na2SO4), filtered and evaporated. The obtained material was purified by preparative TLC (EtOAc : PE = 1 : 2) to afford (130 mg, 36%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 281.
Step C. i-92c
3-(6-Chloropyridin-3-yl)-4-fluoro-2-methoxybenzonitrile
Figure imgf000184_0001
TFAA (0.13 mL, 0.93 mmol) was added to a mixture of TEA (0.258 mL, 1.85 mmol) and 3-(6- chloropyridin-3-yl)-4-fluoro-2-methoxybenzamide compound i-92b (130 mg, 0.46 mmol) in DCM (10 mL) at 0 °C. The reaction was allowed to reach rt and stirred at rt for 4 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated and the obtained material was purified by preparative TLC (PE : EtOAc = 3: 1) to afford (100 mg, 82%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]+ 263.
Intermediate 100 i-100a
6'-Fluoro-2H-[1,3'-bipyridin]-2-one
Figure imgf000184_0002
re/-(1R,2R)-/V1,/\/2-Dimethylcyclohexane-1 ,2-diamine (1.50 g, 10.5 mmol) was added to a mixture of pyridin-2(1/7)-one (CAS Reg. No. 142-08-5) (5.0 g, 52.6 mmol), 2-fluoro-5- iodopyridine (CAS Reg. No. 171197-80-1) (17.6 g, 78.9 mmol), Cu(l)l (4.01 g, 21.0 mmol) and K2CO3 (14.53 g, 105.2 mmol) in 1 ,4-dioxane (50 mL) and it was stirred at 90 °C for 18 h under a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica (gradient: 0-50% EtOAc in PE) to give the title compound (11.6 g, 116%) as a brown solid. MS (ESI): m/z [M+H]+ 191.1. 1H NMR (300 MHz, DMSO-ds) 6 ppm 6.36 (1 H, dt), 6.52 (1 H, d), 7.36 (1 H, dd), 7.54 (1 H, ddd), 7.73 (1 H, dd), 8.14 (1 H, ddd), 8.35 (1 H, dd). Intermediate 104
Step A. i-104a tert-Butyl ((1S,3S)-3-((6-(1-ethoxyvinyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate
Figure imgf000185_0001
Bis(triphenylphosphine)palladium (II) dichloride (CAS Reg. No. 13965-03-2) (59 mg, 0.08 mmol) was added to a mixture of terf-butyl ((1 S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclo- pentyl)carbamate compound i-22b (300 mg, 0.84 mmol), tributyl(1-ethoxyvinyl)tin (CAS Reg. No. 97674) (605 mg, 1.67 mmol) and lithium chloride (177 mg, 4.19 mmol) in 1,4-dioxane (20 mL) at 20 °C under a nitrogen atmosphere and it was stirred at 100 °C for 6 h. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica (gradient: 2-25% EtOAc in PE) to give the title compound along with tin impurities (500 mg) as a yellow solid. MS (ESI): m/z [M+H]+ 350.1.
Step B. i-104b 1-(3-(((1S,3S)-3-Aminocyclopentyl)amino)-1,2,4-triazin-6-yl)ethan-1-one
Figure imgf000185_0002
4 M HCI in dioxane (4.0 mL, 16 mmol) was added to fert-butyl ((1S,3S)-3-((6-(1-ethoxyvinyl)- 1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-104a (250 mg, 1.05 mmol) in EtOAc (3 mL) at 20 °C and the resulting suspension was stirred at 20 °C for 18 h. The solvent was removed under reduced pressure to give an unspecified HCI salt of the title compound (200 mg) as a yellow gum which was used without further purification. MS (ESI) m/z [M+H]+ 222.
Intermediate 107
Step A. i-107a
4-Bromo-6-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one
Figure imgf000186_0001
1-(Chloromethyl)-4-methoxybenzene (7.48 g, 47.8 mmol) was added to a mixture of 4-bromo-6- chloro-3(2/7)-pyridazinone (CAS Reg. No. 933041-13-5) (5.0 g, 24 mmol) and CS2CO3 (15.6 g, 47.8 mmol) in MeCN (80 mL) at 15 °C and it was stirred at 60 °C for 3 h. The mixture was filtered through a pad of Celite, the filter cake washed with DCM (3 x 20 mL) and the combined filtrates were concentrated under reduced pressure. The obtained material was triturated with EtOAc : PE = 1 :5 (25 mL), the formed solid collected by filtration and dried under vacuum to give the title compound (7.8 g, 98%) as a yellow solid. MS (ESI): m/z [M+H]+ 329/331 (Br/CI isotope pattern).
Step B. i-107b
6-Chloro-4-hydroxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one
Figure imgf000186_0002
RockPhos Pd G3 (CAS Reg. No. 2009020-38-4) (1.97 g, 2.35 mmol) was added to a mixture of 4-bromo-6-chloro-2-(4-methoxybenzyl)pyridazin-3(2/7)-one compound i-107a (7.75 g, 23.5 mmol), (E)-benzaldehyde oxime (3.70 g, 30.6 mmol) and CS2CO3 (15.6 g, 47.8 mmol) in DMF (40 mL) and water (10 mL) at 15 °C and it was stirred at 80 °C for 15 h. The reaction mixture was poured into sat. brine (100 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with sat. brine (3 x 100 mL), dried over Na2SO4, filtered and evaporated and the residue was purified by flash chromatography on silica (gradient: 0-100% EtOAc in PE) to give the title compound (4.0 g, 64%) as a tan solid. MS (ESI): m/z [M+H]+ 267/269 (Cl isotope pattern).
Step C. i-107c
6-Chloro-4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one
Figure imgf000186_0003
CS2CO3 (293 mg, 0.90 mmol) was added to a mixture of 6-chloro-4-hydroxy-2-(4- methoxybenzyl)pyridazin-3(2/-/)-one compound i-107b (200 mg, 0.75 mmol) and it was stirred at 20 °C for 1.5 h. Sodium chlorodifluoroacetate (CAS Reg. No. 1895-39-2) (343 mg, 2.25 mmol) was added and the resulting mixture was stirred at 100 °C for 3.5 h. The reaction mixture was poured into sat. brine (50 mL) and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with sat. brine (3 x 50 mL), dried over Na2SC>4, filtered and evaporated and the residue was purified by reparative TLC (EtOAc: PE = 1 :3) to give the title compound (175 mg, 74%) as a yellow gum. MS (ESI): m/z [M+H]+ 317/319 (Cl isotope pattern).
Step D. i-107d
4-(Difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one
Figure imgf000187_0001
107d
Pd-C (11 mg, 0.11 mmol) was added to a mixture of 6-chloro-4-(difluoromethoxy)-2-(4- methoxybenzyl)pyridazin-3(2/-/)-one compound i-107c (680 mg, 2.15 mmol) in MeOH (30 mL) at 20 °C and the resulting suspension was stirred at this temperature for 2 h under a hydrogen atmosphere. The reaction mixture was concentrated under reduced pressure to afford the title compound (576 mg, 95%) as a white solid which was directly used in the next step without further purification. MS (ESI): m/z [M+H]+ 283.0.
Step E. i-107e 4-(Difluoromethoxy)pyridazin-3(2H)-one
Figure imgf000187_0002
TFA (20 mL) was added to 4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2/7)-one compound i-107d (546 mg, 1.93 mmol) at 20 °C and the mixture was stirred at 80 °C for 15 h. The reaction mixture was concentrated under reduced pressure to give an unspecified TFA salt of the title compound (483 mg, 90%) as a black gum which was used without further purification. MS (ESI): m/z [M+H]+ 162.9.
Intermediate 108
Step A. i-108a
2-Bromo-1-(6-fluoropyridin-3-yl)propan-1-one
Figure imgf000188_0001
A solution of 1-(6-fluoropyridin-3-yl)propan-1-one (CAS Reg. No. 949154-27-2) (201 mg,
1.31 mmol) in HOAc (2 mL) was treated with HBr (CAS Reg. No. 10035-10-6) (33wt% in HOAc, 238 pL, 1.31 mmol) and bromine (67 pL, 1.3 mmol) and the mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude title compound (410 mg) which was used in the next step without further purification.
Step B. i-108b
4-(6-Fluoropyridin-3-yl)-2,5-dimethyloxazole
Figure imgf000188_0002
A mixture of crude 2-bromo-1-(6-fluoropyridin-3-yl)propan-1-one compound i-108a (270 mg, 1.2 mmol) in xylenes (4 mL) was treated with acetamide (593 mg, 11.6 mmol) and stirred at 135 °C for 20 h. The reaction mixture was concentrated under reduced pressure and the obtained residue purified by preparative HPLC (PrepMethod Z9, gradient: 20-60%) to give the title compound (83 mg, 37%) as a brown solid. MS (ESI): m/z [M+H]+ 193.0. 1H NMR (500 MHz, CDCh) 6 ppm 2.44 (3H, s), 2.47 (3H, s), 6.96 (1H, dd), 8.04 (1 H, dt), 8.42 (1 H, d).
Intermediate 109
Step A. i-109a
2-(2-(Benzyloxy)ethyl)malonamide
Figure imgf000188_0003
The reaction was run in 10 parallel batches of identical size.
Diethyl 2-(2-(benzyloxy)ethyl)malonate (CAS Reg. No. 41478-45-9) (2.0 g, 6.8 mmol) was treated with NH3 (7 M in MeOH, 25 mL, 140 mmol) at rt and the mixture was stirred at 60 °C for 16 h. The 10 reaction mixtures were combined and concentrated under reduced pressure. The obtained material was triturated with EtOAc (50 mL), the solid isolated by filtration and dried under reduced pressure to give the title compound (14.7 g, 92%) as a white solid. MS (ESI): m/z [M+H]+ 237.3.
Step B. i-109b
Di-tert-butyl (2-(2-(benzyloxy)ethyl)propane-1,3-diyl)dicarbamate
Figure imgf000189_0001
A solution of 2-(2-(benzyloxy)ethyl)malonamide compound i-109a (13.5 g, 57.1 mmol) in THF (250 mL) was treated with BH3xSMe2 (10 M in SMe2, 45.7 mL, 457 mmol) at 20 °C and the reaction mixture stirred at 60 °C for 16 h. The mixture was quenched with MeOH (400 mL) and concentrated under reduced pressure to give a pale-yellow gum. This material was dissolved in 1,4-dioxane (250 mL) at 20 °C and treated with Na2COs (18.2 g, 171 mmol) in water (250 mL) followed by BOC2O (39.8 mL, 171 mmol) and the resulting suspension stirred at 20 °C for 15 h. The reaction mixture was poured into sat. brine (500 mL) and the aqueous layer was extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated and the obtained material purified by flash chromatography on silica (gradient: 2- 20% EtOAc in PE) to give the title compound (9.0 g, 39%) as a colourless gum. MS (ESI): m/z [M+H]+ 409.3.
Step C. i-109c
Di-tert-butyl (2-(2-hydroxyethyl)propane-1 ,3-diyl)dicarbamate
Figure imgf000189_0002
Pd(OH)2-C (15%, 928 mg, 0.99 mmol) was added to a mixture of di-tert-butyl (2-(2- (benzyloxy)ethyl)propane-1,3-diyl)dicarbamate compound i-109b (9.0 g, 22 mmol) and TFA (3.0 mL, 39 mmol) in MeOH (50 mL) at 20 °C. The resulting suspension was evacuated and backfilled with hydrogen gas 3 times and stirred at 20 °C for 16 h under a hydrogen atmosphere. The mixture was concentrated under reduced pressure to afford the title compound (7.0 g, quant.) as a colourless gum which was directly used in the next step without further purification. MS (ESI): m/z [M+H]+ 319.2.
Step D. i-109d rac-tert-Butyl (2-(aminomethyl)-4-hydroxybutyl)carbamate
Figure imgf000190_0001
109d
A solution of crude di-tert-butyl (2-(2-hydroxyethyl)propane-1,3-diyl)dicarbamate compound i- 109c (7.0 g, 22 mmol) in MeOH (20 mL) was treated with HCI in MeOH (4 M, 20 mL, 80 mmol) at 20 °C and the reaction mixture was stirred at 60 °C for 5 h. The mixture was concentrated under reduced pressure and the obtained material was triturated with EtOAc (20 mL). The formed solid (fully deprotected title compound) was filtered off and the filtrate concentrated under reduced pressure to give an unspecified HCI salt of the title compound (1.4 g, purity 70%) as a pale-yellow gum which was directly used in the next step without further purification. MS (ESI): m/z [M+H]+ 219.2.
Step E. i-109e rac-tert-Butyl (4-hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)carbamate
Figure imgf000190_0002
A suspension of crude rac-tert-butyl (2-(aminomethyl)-4-hydroxybutyl)carbamate compound i- 109d (1.4 g) and K2CO3 (1.55 g, 11.2 mmol) in /-PrOH (40 mL) was treated with 6-methyl-3- (methylsulfinyl)-1,2,4-triazine compound i-36b (0.283 g, 1.8 mmol) at 20 °C and the reaction mixture was stirred at 100 °C for 15 h. The mixture was cooled to rt and concentrated under reduced pressure and the obtained material was purified by flash chromatography on silica (gradient: 0-5% 7 M NH3 in MeOH : DCM) to give the title compound (700 mg, 10% over three steps) as a pale-yellow gum. MS (ESI): m/z [M+H]+ 312.
Step F. i-109f rac-4-Amino-3-(((6-methyl-1,2,4-tnazin-3-yl)amino)methyl)butan-1-ol
Figure imgf000191_0001
109f
A solution of rac- tert- butyl (4-hydroxy-2-(((6-methyl-1 ,2,4-triazin-3-yl)amino)methyl)butyl)carba- mate compound i-109e (700 mg, 2.25 mmol) in MeOH (15 mL) was treated with HCI in MeOH (4 M, 3.0 mL, 12 mmol) at 20 °C and the reaction mixture was stirred at 60 °C for 15 h. The mixture was concentrated under reduced pressure to give an unspecified HCI salt of the title compound (530 mg) as a yellow gum which was directly used in the next step without further purification. MS (ESI): m/z [M+H]+ 212.1.
Step G. i-109g rac-4-((5-lodopyridin-2-yl)amino)-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol
Figure imgf000191_0002
According to GM1A 2-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (499 mg, 2.24 mmol) was added to crude rac-4-amino-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol compound i-109f (530 mg, 1.86 mmol) and K2CO3 (515 mg, 3.73 mmol) in DMSO (10 mL) at 20 °C. The resulting mixture was stirred at 120 °C for 15h, cooled to rt and poured into sat. brine (250 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layers were dried over Na2SC>4, filtered and evaporated to afford a brown gum. The obtained material was purified by preparative TLC (7 M NH3 in MeOH : DCM = 1:20) to give the title compound (230 mg, 25% over two steps) as a yellow gum. MS (ESI): m/z [M+H]+ 415.1. 1H NMR (300 MHz, DMSO-cfe) 6 ppm 1.49 (2H, q), 1.99 (1 H, quint), 2.38 (3H, s), 3.23 - 3.39 (4H, m), 3.49 (2H, t), 5.75 (1H, s), 6.41 (1H, d), 6.78 (1H, brs), 7.44 (1 H, brs), 7.56 (1 H, dd), 8.06 (1 H, d), 8.14 (1 H, s).
Examples
EXAMPLE 10
Ethyl 3-(((1 S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6,-yl)amino)cyclopentyl)amino)-1,2,4- triazine-6-carboxylate - compound 10
Figure imgf000192_0001
According to GM1 B 6'-(((1 S,3S)-3-aminocyclopentyl)amino)-2/7-[1 ,3'-bipyridin]-2-one compound i-1 c (226 mg, 0.84 mmol), ethyl 3-bromo-1 ,2,4-triazine-6-carboxylate (CAS Reg. No. 2091717-09-6) (194 mg, 0.84 mmol) and DI PEA (0.437 mL, 2.51 mmol) were reacted in NMP (2 mL) under microwave irradiation at 100 °C for 1 h to give upon purification by preparative HPLC (PrepMethod F, gradient: 15-55%) the title compound (182 mg, 52%) as a yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C21H24N7O3: 422.1936, found: 422.1924. 1H NMR (500 MHz, DMSO-cfe, mixture of two rotamers ca 1.4/1) 5 ppm 1.32 (3H, t), 1.5-1.58 (1 H, m), 1.58-1.67 (1 H, m), 1.87-2.04 (2H, m), 2.11-2.24 (2H, m), 4.29-4.44 (4H, m), 6.27 (1 H, td), 6.44 (1 H, dt), 6.53 (1 H, d), 6.94-7.02 (1 H, m), 7.40 (1 H, dd), 7.44-7.51 (1 H, m), 7.57-7.63 (1 H, m), 7.93 (1 H, d), 8.58 (d, minor rotamer), 8.63-8.71 (1 H, m), 9.09 (1 H, d, major rotamer).
EXAMPLE 50
6'-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 50
Figure imgf000192_0002
K3PO4 (60 mg, 0.28 mmol) was added to a mixture of (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3- yl)-/V3-(5-iodopyridin-2-yl)cyclopentane-1 ,3-diamine compound i-22e (40 mg, 0.09 mmol), pyridin-2(1/7)-one (CAS Reg. No. 142-08-5) (27 mg, 0.28 mmol), Cu(l)l (9.0 mg, 0.05 mmol) and /V^A^-dimethylethane-l ^-diamine (4.2 mg, 0.05 mmol) in dioxane (2 mL) and the resulting suspension was heated at 100 °C for 16 h under nitrogen. The solvent was removed under reduced pressure and the residue was poured into water (50 mL), extracted with EtOAc (2 x 100 mL), dried (Na2SO4), filtered and evaporated to afford a crude product which was purified by preparative TLC (MeOH:DCM = 1 :40) followed by preparative HPLC (PrepMethod A, gradient: 33-58%) to give (12.4 mg, 34 %) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C21H24N7O: 390.2036, found: 390.2042. 1H NMR (300 MHz, DMSO-d6) 5 ppm 0.82 - 1.01 (4H, m), 1.42 - 1 .63 (2H, m,), 1 .90 (2H, m), 1.99 - 2.22 (3H, m), 4.21 - 4.42 (2H, m), 6.25 (1 H, td), 6.43 (1 H, ddd), 6.51 (1 H, dd), 6.91 (1 H, d), 7.38 (1 H, dd), 7.42 - 7.63 (3H, m), 7.91 (1 H, d), 8.17 (1 H, s).
EXAMPLE 51
6'-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-
(trifluoromethyl)-2H-[1,3'-bipyridin]-2-one - compound 51
Figure imgf000193_0001
According to GM3 (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)-/\/3-(5-iodopyridin-2- yl)cyclopentane-1 ,3-diamine compound i-22e (90 mg, 0.21 mmol), 3-(trifluoromethyl)pyridin- 2(1/7)-one (CAS Reg. No. 22245-83-6) (695 mg, 4.26 mmol), Cs2CO3 (417 mg, 1.28 mmol), Cu(l)l (162 mg, 0.85 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine (121 mg, 0.85 mmol) were reacted in 1 ,4-dioxane (10 mL) at 100 °C for 15 h to give upon aqueous workup and purification by preparative TLC (7 M NH3 in MeOH:DCM = 1 :20) followed by preparative HPLC (PrepMethod B, 34-54%) the title compound (33 mg, 33%) as a pale yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C22H23F3N7O: 458.1910, found: 458.1928. 1H NMR (300 MHz, DMSO-ds) 6 ppm 0.87 - 1 .00 (4H, m), 1.45 - 1.65 (2H, m), 1.85 - 2.24 (5H, m), 4.29 - 4.42 (2H, m), 6.43 (1 H, t), 6.55 (1 H, d), 7.03 (1 H, d), 7.46 (1 H, dd), 7.55 (1 H, br d), 7.97 - 8.04 (3H, m), 8.19 (1 H, s).
EXAMPLE 52 e'-^lS.SSJ-S-Ge-Cyclopropyl-l^^-triazin-S-yQaminoJcyclopentyQaminoJ-S-
(trifluoromethoxy)-2H-[1,3'-bipyridin]-2-one - compound 52
Figure imgf000193_0002
Prepared in analogy to Example 51 from (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)-/\/3-(5- iodopyridin-2-yl)cyclopentane-1 ,3-diamine compound i-22e (90 mg, 0.21 mmol) and 3- (trifluoromethoxy)pyridin-2-ol compound i-9b (382 mg, 2.13 mmol) and purified by preparative TLC (7 M NH3 in MeOH:DCM = 1 :20) followed by preparative HPLC (PrepMethod B, gradient: 38-58%) to give a white solid (20 mg, 19%). HRMS (ESI) m/z [M+H]+ calcd for C22H23F3N7O2: 474.1860, found: 474.1816. 1H NMR (300 MHz, DMSO-d6) 5 ppm 0.87 - 1.00 (4H, m), 1.45 - 1.61 (2H, m), 1.88 - 2.21 (5H, m), 4.28 - 4.39 (2H, m), 6.33 (1 H, t), 6.55 (1 H, d), 7.02 (1 H, d), 7.45 (1 H, dd), 7.50 - 7.60 (1 H, m), 7.69 - 7.74 (2H, m), 7.98 (1 H, d), 8.19 (1 H, s).
EXAMPLE 53
(1 S,3S)-A/1-(6-Cyclopropyl-1,2,4-triazin-3-yl)-A/3-(5-(2,6-difluorophenyl)pyridin-2- yl)cyclopentane-1,3-diamine - compound 53
Figure imgf000194_0001
According to GM4A (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)-/\/3-(5-iodopyridin-2- yl)cyclopentane-1 ,3-diamine compound i-22e (95 mg, 0.22 mmol), (2,6-difluorophenyl)boronic acid (CAS Reg. No. 162101-25-9) (71 mg, 0.45 mmol), PdCI2(dppf) (CAS Reg. No 72287-26-4) (16 mg, 0.02 mmol) and K2CO3 (93 mg, 0.67 mmol) were reacted in a mixture of 1 ,4-dioxane (8 mL) and water (2 mL) at 100 °C for 15 h. Aqueous work-up of the reaction mixture and purification by preparative TLC (EtOAc:PE = 1 :1) followed by preparative HPLC (PrepMethod D, gradient: 44-59%) gave the title compound (18 mg, 19%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C22H23F2N6: 409.1946, found: 409.1960. 1H NMR (300 MHz, DMSO-d6) 5 ppm 0.94 (m, 4H), 1 .45 - 1.66 (m, 2H), 1.92 (m, 2H), 1.99 - 2.24 (m, 3H), 4.37 (d, 2H), 6.53 - 6.61 (m, 1 H), 6.93 (d, 1 H), 7.12 - 7.24 (m, 2H), 7.34 - 7.49 (m, 2H), 7.55 (s, 1 H), 8.04 (d, 1 H), 8.19 (s, 1 H).
EXAMPLE 54
(1 S,3S)-A/1-(6-Cyclopropyl-1,2,4-triazin-3-yl)-A/3-(5-(2-fluoro-6-methoxyphenyl)pyridin-2- yl)cyclopentane-1,3-diamine - compound 54
Figure imgf000194_0002
Prepared in analogy to Example 53 from (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)-/\/3-(5- iodopyridin-2-yl)cyclopentane-1 ,3-diamine compound i-22e (95 mg, 0.22 mmol) and (2-fluoro- 6-methoxyphenyl)boronic acid (CAS Reg. No. 78495-63-3) (76 mg, 0.45 mmol) applying 1,1'- bis(di-terf-butylphosphino)ferrocene palladium dichloride (CAS Reg. No. 95408-45-0) (15 mg, 0.02 mmol) and purified by preparative TLC (EtOAc:PE = 2:1) followed by preparative HPLC (PrepMethod C, gradient: 40-65%) to give a white solid (46 mg, 48%). HRMS (ESI) m/z [M+H]+ calcd for C23H26FN6O: 421.2146, found: 421.2166. 1H NMR (300 MHz, DMSO-d6) 5 ppm 0.7- 1.08 (4H, m), 1.42-1.77 (2H, m), 1.81-1.99 (2H, m), 1.99-2.32 (3H, m), 3.75 (3H, s), 4.19-4.57 (2H, m), 6.51 (1 H, d), 6.73 (1 H, d), 6.8-7.07 (2H, m), 7.2-7.45 (2H, m), 7.55 (1 H, d), 7.83-8.03 (1 H, m), 8.19 (1 H, s).
EXAMPLE 55
3-Chloro-6'-(((1 S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-
[1,3'-bipyridin]-2-one - compound 55
Figure imgf000195_0001
According to GM1A (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine 4TFA compound i-22d (80 mg, 0.36 mmol), 3-chloro-6'-fluoro-2/7-[1 ,3'-bipyridin]-2-one compound i- 13a (164 mg, 0.73 mmol) and K2CO3 (151 mg, 1.09 mmol) were reacted in DMSO (15 mL) at 120 °C for 15 h to give upon non-aqueous work-up and purification by preparative TLC (EtOAc:PE = 2:1) followed by preparative HPLC (PrepMethod D, gradient: 24-44%) the title compound (45 mg, 29%) as a pale yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C21 H23CIN7O: 424.1648, found: 424.1650. 1H NMR (300 MHz, DMSO-d6) 6 ppm 0.87 - 1.00 (4H, m), 1.42 - 1.66 (2H, m), 1.87 - 2.21 (5H, m), 4.28 - 4.39 (2H, m), 6.31 (1 H, t), 6.54 (1 H, d), 7.01 (1 H, d), 7.44 (1 H, dd), 7.50 - 7.61 (1 H, m), 7.67 (1 H, dd), 7.82 (1 H, dd), 7.96 (1 H, d), 8.19 (1 H, s).
EXAMPLE 56
Example
6'-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'- bipyridine]-5-carbonitrile - compound 56
Figure imgf000196_0001
According to GM2 (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine 4TFA compound i-22d (292 mg, 0.43 mmol), 6'-chloro-2-oxo-2/7-[1 ,3'-bipyridine]-5-carbonitrile compound i-8d (100 mg, 0.43 mmol), CS2CO3 (563 mg, 1.73 mmol) and Pd-PEPPSI-lpentCI 2- methylpyridine (18 mg, 0.02 mmol) were reacted in 1 ,4-dioxane (12 mL) at 100 °C for 15 h to give upon non-aqueous work-up and purification by preparative HPLC (PrepMethod D, gradient: 23-43%) the title compound (71 mg, 39%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C22H23N8O: 415.1990, found: 415.1970. 1H NMR (300 MHz, DMSO-d6) 5 ppm 0.77-1.04 (4H, m), 1.38-1.68 (2H, m), 1.8-1.97 (2H, m), 1.97-2.23 (3H, m), 4.2-4.45 (2H, m), 6.53 (2H, t), 7.02 (1 H, d), 7.42 (1 H, dd), 7.53 (1 H, d), 7.72 (1 H, dd), 7.97 (1 H, d), 8.17 (1 H, s), 8.55 (1 H, d).
EXAMPLE 57
3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1- methylimidazolidine-2, 4-dione - compound 57
Figure imgf000196_0002
According to GM2 CS2CO3 (238 mg, 0.73 mmol) was added to a mixture of (1 S,3S)-/V1-(6- cyclopropyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-22d (128 mg, 0.59 mmol), 3-(6-chloropyridin-3-yl)-1-methylimidazolidine-2, 4-dione compound i-7b (110 mg, 0.49 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (20.50 mg, 0.02 mmol) in 1 ,4-dioxane (3 mL) at 25 °C. The resulting suspension was stirred at 100 °C for 16 h under a nitrogen atmosphere. The solvent was removed under reduced pressure, the residue taken up with water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated and the obtained residue was purified by preparative TLC (7 M NH3 in MeOH:DCM = 1 :20) followed by preparative HPLC (PrepMethod D, gradient: 20-35%) to give the title compound (10 mg, 5%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C20H25N8O2: 409.2094, found: 409.2104. 1H NMR (300 MHz, DMSO-cfe) 6 0.93 (m, 4H), 1.44 - 1.63 (m, 2H), 1.92 (m, 2H), 2.01 - 2.08 (m, 1 H), 2.08 - 2.20 (m, 2H), 2.91 (s, 3H), 4.08 (s, 2H), 4.32 (m, 2H),
6.52 (m, 1 H), 6.89 (d, 1 H), 7.27 (m, 1H), 7.55 (d, 1H), 7.80 - 7.88 (m, 1H), 8.18 (s, 1 H).
Table 7: The following Examples (58-66) where prepared in analogy to Example 57 starting from compound i-22d and the given electrophile intermediate, applying Buchwald-Hartwig amination (GM2). For the preparation of Example 58 DMF was used as solvent.
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
EXAMPLE 67
6'-(((1 S,3S)-3-((6-Methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1 ,3'-bipyridin]-2- one - compound 67
Figure imgf000201_0001
According to GM2 CS2CO3 (329 mg, 1.01 mmol) was added to a mixture of (1 S,3S)-/V1-(6- methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 2TFA compound i-28b (85 mg, 0.20 mmol), 6'-chloro-2/7-[1 ,3'-bipyridin]-2-one compound i-29a (62 mg, 0.30 mmol) and Pd-PEPPSI- IpentCI 2-methylpyridine (8.5 mg, 10 pmol) in dioxane (5 mL) at rt and the resulting suspension was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was diluted with EtOAc (200 mL) and washed sequentially with saturated brine (2 x 15 mL) and water (2 x 15 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product which was purified by preparative TLC (MeOH : DCM = 1:25) followed by preparative HPLC (PrepMethod C, gradient: 10-30%) to give (35 mg, 48 %) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H22N7O: 364.1880, found: 364.1866. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.44 - 1.66 (2H, m), 1.85 - 2.00 (2H, m), 2.06 - 2.24 (2H, m), 2.39 (3H, s), 4.25 - 4.45 (2H, m), 6.27 (1 H, td), 6.44 (1 H, ddd), 6.53 (1 H, dd), 6.94 (1 H, d), 7.37 - 7.65 (4H, m), 7.90 - 7.96 (1 H, m), 8.17 (1 H, s).
EXAMPLE 68
A/-(2-Amino-2-oxoethyl)-3-(((1S,3S)-3-((2-oxo-2H-[1,3,-bipyridin]-6'- yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxamide - compound 68
Figure imgf000201_0002
According to GM7, ethyl 3-(((1S,3S)-3-((2-oxo-2/7-[1,3'-bipyridin]-6'-yl)amino)cyclo- pentyl)amino)-1,2,4-triazine-6-carboxylate compound 10 (33.3 mg, 0.08 mmol) was mixed with DMSO (0.5 mL), DIPEA (0.055 mL, 0.32 mmol) and 2-aminoacetamide HCI (CAS Reg. No. 1668-10-6) (17 mg, 0.16 mmol) and it was stirred at 70 °C overnight. The volatiles were removed and the residue redissolved in MeOH (1 mL). Another amount of DIPEA (55 pL, 0.32 mmol) and 2-aminoacetamide HCI (17 mg, 0.16 mmol) was added and the reaction mixture stirred at 70 °C for one week. Purification by preparative SFC (PrepMethod SFC-A) gave the title compound (1.8 mg, 5%). HRMS (ESI) m/z [M+H]+ calcd for C21H24N9O3: 450.1996, found: 450.1984. 1H NMR (600 MHz, DMSO-d6) 5 ppm 1.51-1.66 (2H, m), 1.88-2.01 (2H, m), 2.1- 2.22 (2H, m), 3.85 (2H, d), 6.27-6.31 (1H, m), 6.44 (1H, d), 6.53 (1H, d), 6.94 (1H, s), 7.08 (1H, s), 7.39 (1H, dd), 7.43 (1H, s), 7.48 (1H, ddd), 7.58 (1H, d), 7.90 (1H, d), 8.66 (1H, s), 8.80 (1H, s).
Table 8: The following Examples (69-76) where prepared in analogy to Example 68 starting from compound 10 and the given amine, applying GM7.
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0002
EXAMPLE 129
3-Chloro-6'-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 129
Figure imgf000206_0001
According to GM1A the free base of (1 S,3S)-/V1-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3- diamine 2TFA compound i-28b (60 mg, 0.31 mmol) was added to a mixture of 3-chloro-6'- fluoro-2/7-[1 ,3'-bipyridin]-2-one compound i-13a (139 mg, 0.62 mmol) and K2CO3 (129 mg, 0.93 mmol) in DMSO (5 mL). The resulting mixture was stirred at 120 °C for 15 h under a nitrogen atmosphere. The reaction mixture was diluted with saturated brine (100 mL) and extracted with EtOAc (5 x 75 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (MeOH : DCM = 1 :10) followed by preparative HPLC (PrepMethod D, gradient: 18-32%) to give (15 mg, 12%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H21CIN7O: 398.1490, found: 398.1468. 1H NMR (300 MHz, MeOH-cL) 5 ppm 1.58-1.70 (2H, m), 1.98-2.09 (2H, m), 2.22-2.35 (2H, m), 2.44 (3H, s), 4.33-4.49 (2H, m), 6.24 (1 H, dd), 6.62 (1 H, d), 7.46 (1 H, dd), 7.59 (1 H, dd), 7.81 (1 H, dd), 7.97 (1 H, dd), 8.20 (1 H, s). EXAMPLE 132
3-Methoxy-6'-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2/-/-[1,3'- bipyridin]-2-one - compound 132
Figure imgf000207_0001
In a slight variation of GM1 A the free base of 6'-(((1 S,3S)-3-aminocyclopentyl)amino)-3- methoxy-2/7-[1 ,3'-bipyridin]-2-one 2HCI compound i-3b (160 mg, 0.53 mmol) was added to a solution of 6-methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (167 mg, 1.07 mmol) in 1,4-dioxane (20 mL) at rt and the resulting mixture stirred at 100 °C for 15 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (4 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (EtOAc : MeOH = 2:1) followed by preparative HPLC (PrepMethod K, gradient: 21-31%) to give (32 mg, 15%) of the title compound as a white solid. MS (ESI): m/z [M+H]+ 394.15. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.46-1.59 (2H, m), 1.83-1.98 (2H, m), 2.07-2.20 (2H, m), 2.37 (3H, s), 3.71 (3H, s), 4.28-4.39 (2H, m), 6.18 (1 H, t), 6.52 (1 H, d), 6.85 (1 H, dd), 6.93 (1H, d), 7.15 (1 H, dd), 7.36 (1H, dd), 7.56 (1 H, br s), 7.90 (1H, d), 8.16 (1H, s).
EXAMPLE 128
6'-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'- bipyridine]-5-carbonitrile - compound 128
Figure imgf000207_0002
In a slight variation of GM2 6'-chloro-2-oxo-2/7-[1,3'-bipyridine]-5-carbonitrile compound i-8d (70 mg, 0.30 mmol) was added to a mixture of (1S,3S)-/V1-(6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine 3TFA compound i-28b (162 mg, 0.30 mmol), K2CO3 (125 mg, 0.91 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (13 mg, 20 pmol) in dioxane (10 mL) at rt and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was filtered through a pad of Celite, the filter cake washed with EtOAc (3 x 20 mL) and the combined filtrates concentrated under reduced pressure. The obtained material was purified by preparative TLC (MeOH : DCM = 1:10) followed by preparative HPLC (PrepMethod E, gradient: 8-28%) to give (30 mg, 26%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C2OH2I N80: 389.1832, found: 389.1800. 1H NMR (300 MHz, MeOH-cL) 5 ppm 1.56 - 1.72 (2H, m), 1.96 - 2.11 (2H, m), 2.21 - 2.34 (2H, m), 2.44 (3H, s), 4.33 - 4.48 (2H, m), 6.62 (2H, t), 7.45 (1 H, dd), 7.69 (1 H, dd), 7.98 (1 H, d), 8.20 (1H, s), 8.36 (1H, dd).
EXAMPLE 130
5-Methyl-6'-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 130
Figure imgf000208_0001
According to GM1A 6'-fluoro-5-methyl-2/7-[1 ,3'-bipyridin]-2-one compound i-37a (100 mg, 0.49 mmol) was added to a mixture of the 2HCI salt of (1 S,3S)-/V1-(6-methyl-1 ,2,4-triazin-3- yl)cyclopentane-1,3-diamine compound i-28b (391 mg, 1.47 mmol) and Na2COs (415 mg, 3.92 mmol) in DMSO (5 mL). The resulting mixture was stirred at 120 °C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the obtained material was purified by C18-flash chromatography (gradient: MeCN in water) followed by preparative HPLC (PrepMethod D, gradient: 17-34%) to give (50 mg, 27%) of the title compound as a pale yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C20H24N7O: 378.2036, found: 378.2034. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.44 - 1.63 (2H, m), 1.84 - 1.99 (2H, m), 2.03 (3H, s), 2.10 - 2.19 (2H, m), 2.38 (3H, s), 4.29 - 4.40 (2H, m), 6.39 (1 H, d), 6.52 (1H, d), 6.91 (1H, d), 7.33 - 7.40 (3H, m), 7.56 (1H, brd), 7.91 (1H, d), 8.17 (1 H, s).
EXAMPLE 131
3-Methyl-6'-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 131
Figure imgf000208_0002
According to GM1A 6'-fluoro-3-methyl-2/7-[1 ,3'-bipyridin]-2-one compound i-38a (80 mg, 0.39 mmol) was added to a mixture of the 2HCI salt of (1 S,3S)-/V1-(6-methyl-1 ,2,4-triazin-3- yl)cyclopentane-1 ,3-diamine compound i-28b (209 mg, 0.78 mmol) and Na2COs (332 mg, 3.13 mmol) in DMSO (4 mL). The resulting mixture was stirred at 120 °C for 20 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the obtained material was purified by C18-flash chromatography (gradient: MeCN in water) followed by preparative HPLC (PrepMethod D, gradient: 18-34%) to give (30 mg, 20%) of the title compound as a pale yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C20H24N7O: 378.2036, found: 378.2056. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.46 - 1.62 (2H, m), 1.86 - 1.97 (2H, m), 2.02 (3H, s), 2.07 - 2.19 (2H, m), 2.38 (3H, s), 4.27 - 4.40 (2H, m), 6.19 (1 H, t), 6.53 (1 H, d), 6.92 (1 H, d), 7.34 - 7.40 (2H, m), 7.44 - 7.47 (1 H, m), 7.56 (1 H, brs), 7.91 (1 H, d), 8.17 (1 H, s).
EXAMPLE 136
6'-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'- bipyridine]-3-carbonitrile - compound 136
Figure imgf000209_0001
In a slight variation of GM1 A the free base of 6'-(((1 S,3S)-3-aminocyclopentyl)amino)-2-oxo-2/7- [1 ,3'-bipyridine]-3-carbonitrile 4HCI compound i-35b (110 mg, 0.37 mmol) was added to a solution of 6-methyl-3-(methylsulfinyl)-1 ,2,4-triazine compound i-36b (117 mg, 0.74 mmol) in 1 ,4-dioxane (3 mL) at rt and the resulting mixture stirred at 100 °C for 15 h. The reaction mixture was concentrated under reduced pressure and the obtained material was purified by preparative TLC (MeOH : DCM = 1 :25) followed by preparative HPLC (PrepMethod D, gradient: 10-35%) to give (11 mg, 8%) of the title compound as a yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C2OH2I N80: 389.1832, found: 389.1842. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.45 - 1.60 (2H, m), 1.89 - 1.97 (2H, m), 2.10 - 2.19 (2H, m), 2.38 (3H, s), 4.27 - 4.42 (2H, m), 6.46 (1 H, t), 6.54 (1 H, d), 7.06 (1 H, d), 7.45 (1 H, dd), 7.57 (1 H, brs), 7.98 (1 H, d), 8.05 (1 H, dd), 8.17 (1 H, s) 8.22 (1 H, dd).
EXAMPLE 138
6'-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(trifluoromethoxy)-
2H-[1,3'-bipyridin]-2-one - compound 138
Figure imgf000210_0001
According to GM3 (1 S,3S)-/V1-(5-iodopyridin-2-yl)-/\/3-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane- 1,3-diamine compound i-39a (130 mg, 0.33 mmol), the 5HCI salt of 3-(trifluoromethoxy)pyridin- 2-ol compound i-9b (142 mg, 0.39 mmol), CS2CO3 (534 mg, 1.64 mmol), Cu(l)l (75 mg, 0.85 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1,2-diamine (56 mg, 0.39 mmol) were reacted in 1 ,4-dioxane (20 mL) at 100 °C for 15 h. The reaction mixture was concentrated under reduced pressure and the obtained material was taken up with EtOAc (250 mL). The organic layer was washed with saturated brine (5 x 75 mL), dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (EtOAc) followed by preparative HPLC (PrepMethod C, 18-45%) the title compound (27 mg, 18%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C20H21 F3N7O2: 448.1704, found: 448.1676. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.44 - 1.63 (2H, m), 1.84 - 1.99 (2H, m), 2.07 - 2.23 (2H, m), 2.38 (3H, s), 4.28 - 4.43 (2H, m), 6.32 (1H, t), 6.54 (1 H, d), 7.03 (1H, d), 7.44 (1 H, dd), 7.58 (1 H, brd), 7.69 - 7.73 (2H, m), 7.97 (1 H, d), 8.17 (1H, s).
EXAMPLE 112
5-Chloro-6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H- [1 ,3'-bipyridin]-2-one - compound 112
Figure imgf000210_0002
(7R,2R)-/V7,/\/2-Dimethylcyclohexane-1,2-diamine (182 mg, 1.28 mmol) was added to (1 S,3S)- /\/1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)-/\/3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine compound i-22e (180 mg, 0.43 mmol), 5-chloropyridin-2(1/7)-one (CAS Reg. No. 4214-79-3) (828 mg, 6.39 mmol), Cu(l)l (244 mg, 1.28 mmol) and CS2CO3 (694 mg, 2.13 mmol) in 1,4-dioxane (25 mL) at rt and the resulting suspension was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was diluted with EtOAc (150 mL) and washed sequentially with water (3 x 75 mL) and brine (3 x 50 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford the crude product. The residue was first purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 : 20) and then by preparative HPLC (PrepMethod D, gradient 25-45%) to afford (40 mg, 22%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C21 H23CIN7O: 424.1648, found: 424.1610. 1H NMR (300 MHz, DMSO-d6) 5 ppm 0.82-1.01 (4H, m), 1.42-1.62 (2H, m), 1.79-2.2 (5H, m), 4.27-4.38 (2H, m), 6.49 (2H, t), 6.96 (1 H, d), 7.34-7.63 (3H, m), 7.91 (2H, dd), 8.17 (1 H, s).
EXAMPLE 113
3-(5-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyrazin-2-yl)-1- methylpyridin-2(1H)-one - compound 113
Figure imgf000211_0001
Pd-PEPPSI-lpentCI 2-methylpyridine (24 mg, 0.03 mmol) was added to 3-(5-bromopyrazin-2-yl)- 1-methylpyridin-2(1/-/)-one compound i-57a (150 mg, 0.56 mmol), (1 S,3S)-/V1-(6-cyclopropyl- 1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (148 mg, 0.68 mmol) and CS2CO3 (1.47 g, 4.51 mmol) in 1 ,4-dioxane (5 mL) at rt and the resulting solution was stirred at 100 °C for 18 h under nitrogen. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with water (3 x 25 mL) and brine (3 x 20 mL). The organic layer was dried (Na2SC>4), filtered and evaporated to afford crude product. The residue was first purified by preparative TLC (7 M NH3 in MeOH : DCM = 1: 20) and then by preparative HPLC (PrepMethod D, gradient 19-39%) to afford (15 mg, 7%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C2I H25N8O: 405.2146, found: 405.2166. 1H NMR (300 MHz, DMSO-ds) 6 ppm 0.84 - 1.03 (4H, m), 1.44 - 1.68 (2H, m), 1.85 - 2.22 (5H, m), 3.52 (3H, s), 4.26 - 4.47 (2H, m), 6.35 (1H, t), 7.29 (1 H, d), 7.55 (1 H, d), 7.72 (1H, dd), 7.96 (1H, d), 8.08 - 8.25 (2H, m), 9.16 (1 H, d).
EXAMPLE 114
3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)pyrimidin-4(3H)-one - compound 114
Figure imgf000211_0002
(1 S,3S)-/V1-(6-Cyclopropyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-22d
(137 mg, 0.63 mmol) was added to 3-(6-chloropyridin-3-yl)pyrimidin-4(3/7)-one compound i-
58a (100 mg, 0.48 mmol), Pd-PEPPSI-lpentCI 2-methylpyridine (20 mg, 0.02 mmol) and CS2CO3 (785 mg, 2.41 mmol) in 1 ,4-dioxane (5 mL) at rt and the resulting suspension was stirred at 100 °C for 18 h under nitrogen. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with water (3x 25 mL) and brine (2x20 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The residue was first purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 : 20) and then by preparative HPLC (PrepMethod C, gradient 17-37%) to afford (56 mg, 30%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 ppm 0.75 - 1.06 (4H, m), 1.30 - 1.73 (2H, m), 1.80 - 1.96 (2H, m), 1.97 - 2.05 (1 H, m), 2.07 - 2.23 (2H, m), 4.32 (2H, m), 6.46 (1 H,d), 6.53 (1 H, d), 7.03 (1 H, d), 7.43 (1 H, dd), 7.48 - 7.65 (1 H, m), 7.89 - 8.00 (2H, m), 8.17 - 8.21 (1 H, m), 8.41 (1 H, s).
EXAMPLE 115
3-(2-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyrimidin-5- yl)-1-methylpyridin-2(1H)-one - compound 115
Figure imgf000212_0001
3-(2-Chloropyrimidin-5-yl)-1-methylpyridin-2(1/-/)-one compound i-59a (90 mg, 0.41 mmol) was added to (1S,3S)-N1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i- 22d (134 mg, 0.61 mmol), Cs2CC>3 (397 mg, 1.22 mmol) Pd-PEPPSI-lpentCI 2-methylpyridine (17 mg, 0.02 mmol) in 1 ,4-dioxane (10 mL) at rt and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was poured into water (150 mL) and the aqueous layer was extracted with EtOAc (4 x 150 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to afford the crude product. The residue was first purified by preparative TLC (MeOH : DCM = 1 : 20) and then by preparative HPLC (PrepMethod A, gradient 35-50%) to afford (54 mg, 33%) of the title compound as a pale yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C2I H25N8O: 405.2146, found: 405.2142. 1H NMR (300 MHz, DMSO-ds) 6 ppm 0.84 - 1.00 (4H, m), 1.45 - 1.62 (2H, m), 1.90 - 2.16 (2H, m), 1.97 - 2.20 (3H, m), 3.48 (3H, s), 4.31 - 4.45 (2H, m), 6.28 (1 H, t), 7.39 (1 H, d), 7.52 (1 H, d), 7.64 (2H, dd), 8.16 (1 H, s), 8.62 (2H, s).
EXAMPLE 116
3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1- methyl-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5-carbonitrile - compound 116
Figure imgf000213_0001
3-(6-Chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1/7-benzo[c(]imidazole-5-carbonitrile compound i-60d (150 mg, 0.53 mmol) was added to (1 S,3S)-/V1-(6-cyclopropyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine compound i-22d (139 mg, 0.63 mmol), CS2CO3 (515 mg, 1.58 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (22 mg, 0.03 mmol) in 1,4-dioxane (10 mL) at rt and the resulting suspension was stirred at 100 °C for 18 under nitrogen. The reaction mixture was filtered through Celite. The filter cake was washed with DCM (2 x 5mL) and the combined filtrates were concentrated under reduced pressure to afford the crude product. The residue was first purified by preparative TLC (EtOAc : PE = 1: 1) and the by preparative HPLC (PrepMethod D, gradient 30-50%) to afford (48 mg, 20%) of the title compound as a grey solid. HRMS (ESI) m/z [M+H]+ calcd for C25H26N9O: 468.2254, found: 468.2266. 1H NMR (300 MHz, DMSO-ds) 6 ppm 0.82 - 1.05 (4H, m), 1.45 - 1.68 (2H, m), 1.84 - 2.01 (2H, m), 2.01 - 2.09 (1 H, m), 2.11-2,2 (2H, m), 3.44 (3H, s), 4.28 - 4.45 (2H, m), 6.62 (1 H, d), 7.04 (1 H, d), 7.31 (1H, d), 7.42 (1 H, d), 7.39 - 7.52 (1 H, m), 7.57 (1 H, d), 7.57 - 7.65 (1H, m), 8.07 (1 H, d), 8.19 (1 H, s).
EXAMPLE 117
1-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[oQimidazole-5-carbonitrile - compound 117
Figure imgf000213_0002
1-(6-Chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1/7-benzo[d]imidazole-5-carbonitrile compound i-61d (100 mg, 0.35 mmol) was added to (1 S,3S)-/V1-(6-cyclopropyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine compound i-22d (92 mg, 0.42 mmol), CS2CO3 (343 mg, 1.05 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (15 mg, 0.02 mmol) in 1,4-dioxane (10 mL) at rt and the resulting suspension was stirred at 100 °C for 18 h under nitrogen. The reaction mixture was filtered through Celite. The filter cake was washed with DCM (2 x 5 mL) and the combined filtrates were concentrated under reduced pressure to afford the crude product. The residue was first purified by preparative TLC (EtOAc : PE = 1: 1) and then by preparative HPLC (PrepMethod C, gradient 28-52%) to afford (30 mg, 18%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C25H26N9O: 468.2254, found: 468.2208. 1H NMR (300 MHz, DMSO-d6) 5 ppm 0.91 (2H, m), 0.96 (2H, m), 1.45 - 1.68 (2H, m), 1.90-2.25 (5H, m), 3.42 (3H, s), 4.36 (2H, dt), 6.62 (1 H, d), 7.00 - 7.08 (2H, m), 7.45 - 7.51 (2H, m), 7.55 (1 H, s), 7.79 (1 H, d), 8.06 (1H, d), 8.19 (1H, s).
EXAMPLE 118
2-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)pyridazin-3(2H)-one - compound 118
Figure imgf000214_0001
2-(6-Fluoropyridin-3-yl)pyridazin-3(2/7)-one compound i-62a (200 mg, 1.05 mmol) was added to (1 S,3S)-/V1-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-22d (344 mg, 1.57 mmol) and K2CO3 (578 mg, 4.18 mmol) in DMSO (5 mL) at rt and the resulting mixture was stirred at 120 °C for 15 h. The reaction mixture was poured into brine (150 mL), extracted with EtOAc (4 x 100 mL). The organic layers were combined and washed with saturated brine (3 x 100 mL), dried (Na2SO4), filtered and evaporated to afford crude product. The residue was first purified by preparative TLC (MeOH : DCM = 1 : 20) and then by preparative HPLC (PrepMethod C, gradient 17-37%) to afford (70 mg, 17%) of the title compound as a pale-yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C20H23N8O: 391.1990, found: 391.1984. 1H NMR (300 MHz, DMSO-d6) 5 ppm 0.84 - 0.98 (4H, m), 1.53 (2H, m), 1.80 - 1.97 (2H, m), 2.01 - 2.22 (3H, m), 4.27 - 4.40 (2H, m), 6.51 (1 H, d), 6.91 - 7.04 (2H, m), 7.40 - 7.59 (3H, m), 8.00 (1 H, dd), 8.09 (1H, d), 8.17 (1 H, s).
EXAMPLE 119
2-(2-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyrimidin-5- yl)pyridazin-3(2H)-one - compound 119
Figure imgf000215_0001
Cu(l)l (63 mg, 0.33 mmol) was added to (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)-/\/3-(5- iodopyrimidin-2-yl)cyclopentane-1 ,3-diamine compound i-47a (140 mg, 0.33 mmol), pyridazin- 3(2/-/)-one (CAS Reg. No. 504-30-3) (33 mg, 0.35 mmol), CS2CO3 (216 mg, 0.66 mmol) and rel- (IR^R^/V^A^-dimethylcyclohexane-l ^-diamine (71 mg, 0.50 mmol) in 1 ,4-dioxane (10 mL) at rt under nitrogen. The resulting suspension was stirred at 80 °C for 16 h and subsequently filtered through a Celite pad. The filter cake was washed with EtOAc (20 mL) and the combined filtrates were concentrated under reduced pressure. The residue was first purified by preparative TLC (MeOH : DCM = 1 : 10) and then by preparative HPLC (PrepMethod M, gradient 23-43%) to afford (80 mg, 62%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H22N9O: 392.1942, found: 392.1930. 1 H NMR (400 MHz, DMSO-d6) 5 ppm 0.86 - 1.03 (4H, m), 1.50 - 1.63 (2H, m), 1.94 (2H, t), 2.01 - 2.09 (1 H, m), 2.09 - 2.19 (2H, m), 4.30-4.45 (2H, m), 7.07 (1 H, dd), 7.49 (2H, dd), 7.70 (1 H, d), 8.06 (1 H, dd), 8.18 (1 H, s), 8.47 (2H, s).
EXAMPLE 120
2'-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-6H-[1,5'- bipyrimidin]-6-one - compound 120
Figure imgf000215_0002
re/-(1R,2R)-/V1,/\/2-Dimethylcyclohexane-1 ,2-diamine (118 mg, 0.83 mmol) was added to (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)-/\/3-(5-iodopyrimidin-2-yl)cyclopentane-1 ,3-diamine compound i-47a (70 mg, 0.17 mmol), pyrimidin-4(3/7)-one (CAS Reg. No. 4562-27-0) (79 mg, 0.83 mmol), Cu(l)l (157 mg, 0.83 mmol) and CS2CO3 (108 mg, 0.33 mmol) in 1 ,4-dioxane (10 mL) at rt and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (4 x 100 mL). The organic layers were combined, washed with water (2 x 50 mL), dried (Na2SC>4), filtered and evaporated to afford crude product. The residue was first purified by preparative TLC (EtOAc) and then by preparative HPLC (PrepMethod D, gradient 15-30%) to afford (4 mg, 6%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H22N9O: 392.1942, found: 392.1912. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.85-1 (4H, m), 1.47-1.63 (2H, m), 1.86-2.19 (5H, m), 4.24-4.46 (2H, m), 6.51 (1 H, d), 7.54 (1 H, s), 7.77 (1 H, d), 7.98 (1 H, d), 8.19 (1 H, s), 8.37 (2H, s), 8.46 (1 H, s).
EXAMPLE 121
1-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[oQimidazole-5-carboxylic acid - compound 121
Figure imgf000216_0001
Methyl 1-(6-(((1 S,3S)-3-((6-cyclopropyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)- 3-methyl-2-oxo-2,3-dihydro-1/7-benzo[c(]imidazole-5-carboxylate compound i-48e (75 mg, 0.15 mmol) was added to a mixture of NaOH (10 mg, 0.25 mmol) in MeOH (9 mL) and water (3 mL) rt and the resulting mixture was stirred at 30 °C for 18 h. The solvent was removed under reduced pressure and the residue first purified by preparative TLC (EtOAc) and then by preparative HPLC (PrepMethod N, gradient 6-23%) to afford (6 mg, 8%) of the title compound as a pale-yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C25H27N8O3: 487.2200, found: 487.2182. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.81-1.03 (4H, m), 1.49-1.65 (2H, m), 1.84- 2.22 (5H, m), 3.43 (4H, s), 4.31-4.44 (2H, m), 6.62 (1 H, d), 6.92 (1 H, d), 7.02 (1 H, d), 7.48 (1 H, dd), 7.57 (1 H, d), 7.67-7.78 (2H, m), 8.06 (1 H, d), 8.19 (1 H, s).
EXAMPLE 122
6'-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1H-1,2,3- triazol-4-yl)-2H-[1,3’-bipyridin]-2-one - compound 122
Figure imgf000216_0002
6'-(((1 S,3S)-3-((6-Cyclopropyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1-(4- methoxybenzyl)-1/7-1 ,2,3-triazol-4-yl)-2/7-[1 ,3'-bipyridin]-2-one compound i-49b (140 mg, 0.24 mmol) was dissolved in TFA (5 mL) at rt and the resulting solution was stirred at 80 °C for 2 h. Excess TFA was removed under reduced pressure and the residue adjusted to pH 8 with sat. Na2COs(aq). The reaction mixture was extracted with DCM (100 mL) and the organic layer washed sequentially with water (2 x 25 mL) and brine (25 mL). The organic layer was dried (Na2SC>4), filtered and evaporated and the residue was first purified by preparative TLC (DCM : MeOH = 15: 1) and then by preparative HPLC (PrepMethod K, gradient 15-28%) to afford (27 mg, 24%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C23H25N10O: 457.2208, found: 457.2168. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.88 - 0.99 (4H, m), 1.55 (2H, ddt), 1.88 - 1.99 (2H, m), 2.02 - 2.21 (3H, m), 4.30 - 4.40 (2H, m), 6.56 (1 H, br d), 6.60 (1 H, d), 6.99 (1 H, d), 7.48 (1 H, dd), 7.56 (1 H, br s), 7.99 (1 H, dd), 8.02 (1 H, d), 8.17 (1 H, d), 8.19 (1 H, s), 8.24 (1 H, s), 15.04 (1 H,s).
EXAMPLE 123
6'-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1H-pyrazol-4- yl)-2H-[1,3'-bipyridin]-2-one - compound 123
Figure imgf000217_0001
6'-(((1 S,3S)-3-((6-Cyclopropyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1-(4- methoxybenzyl)-1/7-pyrazol-4-yl)-2/7-[1 ,3'-bipyridin]-2-one compound i-50c (110 mg, 0.19 mmol) was dissolved in TFA (5 mL) at rt and the resulting solution was stirred at 80 °C for 5 h. Excess TFA was removed under reduced pressure and the residue adjusted to pH 8 with sat. Na2COs(aq). The reaction mixture was extracted with DCM (100 mL) and the organic layer washed sequentially with water (2 x 25 mL) and brine (25 mL). The organic layer was dried (Na2SC>4), filtered and evaporated and the residue was first purified by preparative TLC (DCM : MeOH = 15: 1) and then by preparative HPLC (PrepMethod C, gradient 18-38%) to afford (20 mg, 23%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C24H26N9O: 456.2254, found: 456.2242. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.87 - 1.02 (4H, m), 1.48 - 1.63 (2H, m), 1.88 - 1.98 (2H,m), 2.02 - 2.21 (3H, m), 4.18 - 4.44 (2H, m), 6.51 (1 H, d), 6.55 (1 H, d) , 6.96 (1 H, d), 7.45 (1 H,dd), 7.57 (1 H, s), 7.82 (1 H,dd), 7.95 (3H, d), 8.08 (1 H, s), 8.19 (1 H, s), 12.84 (1 H, s). EXAMPLE 124
6'-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1H-tetrazol-5- yl)-2H-[1,3'-bipyridin]-2-one - compound 124
Figure imgf000218_0001
DMF (1.5 mL) was added to a vial charged with 6'-(((1 S,3S)-3-((6-cyclopropyl-1 ,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2-oxo-2/7-[1 ,3'-bipyridine]-5-carbonitrile Example 56 (29 mg, 0.07 mmol), sodium azide (13.7 mg, 0.21 mmol) and triethylamine hydrochloride (29 mg, 0.21 mmol) and the mixture was heated to 110 °C for 16 h. The reaction mixture was combined with a second batch made in the same way (0.02 mmol scale), evaporated and the residue purified by preparative SFC (PrepMethod SFC-D) to afford (18 mg, 42%) of the title compound. HRMS (ESI) m/z [M+H]+ calcd for C22H24N11O: 458.2160, found: 458.2192. 1H NMR (600 MHz, DMSO-ds) 6 ppm 0.83-0.91 (2H, m), 0.91-1 (2H, m), 1.43-1.65 (2H, m), 1.9-1.97 (3H, m), 2.13-2.2 (2H, m), 4.28-4.4 (2H, m), 6.57 (1 H, d), 6.65 (1 H, d), 6.94 (1 H, s, NH), 7.38 (1 H, s, NH), 7.47 (1 H, dd), 7.99-8.06 (2H, m), 8.13 (1 H, s), 8.29 (1 H, s).
EXAMPLE 125
3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5-
(dimethylphosphoryl)-1-methyl-1,3-dihydro-2H-benzo[cf]imidazol-2-one - compound 125
Figure imgf000218_0002
Dimethylphosphine oxide (15.9 mg, 0.20 mmol) was added to 5-bromo-3-(6-(((1 S,3S)-3-((6- cyclopropyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methyl-1 ,3-dihydro-2/7- benzo[d]imidazol-2-one compound i-51 b (70 mg, 0.10 mmol), XantPhos Pd G3 (CAS: 1445085-97-1) (4.85 mg, 5.10 pmol), XantPhos (5.9 mg, 10.2 pmol) and K2CO3 (28 mg, 0.20 mmol) in 1 ,4-dioxane (5 mL) at rt and the resulting suspension was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (4 x 50 mL). The organic layers were combined and washed with water (2 x 20 mL), dried (Na2SO4), filtered and evaporated to afford crude product. The residue was first purified by preparative TLC (MeOH : DCM = 1 : 20) and then by preparative HPLC (PrepMethod C, gradient 15-33%) to afford (2 mg, 4%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C26H32N8O2P: 519.2380, found: 519.2386. 1H NMR (300 MHz, Methanol-d4) 5 ppm 0.93 - 1.08 (4H, m), 1.59 - 1.71 (2H, m), 1.73 (3H, s), 1.77 (3H, s), 1.96 - 2.14 (3H, m), 2.22 - 2.37 (2H, m), 3.53 (3H, s), 4.37 - 4.50 (2H, m), 6.69 (1 H, d), 7.31 - 7.43 (2H, m), 7.51 (1 H, m), 7.50 - 7.66 (1 H, m), 8.07 (1 H, d), 8.17 (1 H, s).
EXAMPLE 126
6'-(((1S,3S)-3-((5-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2- one - compound 126
Figure imgf000219_0001
(1 S,3S)-/V1-(5-Methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-52b (80 mg, 0.41 mmol) was added to Pd-PEPPSI-lpentCI 2-methylpyridine (17.41 mg, 0.02 mmol), 6'- chloro-2/7-[1 ,3'-bipyridin]-2-one compound i-29a (128 mg, 0.62 mmol) and CS2CO3 (405 mg, 1.24 mmol) in 1 ,4-dioxane (8 mL). The resulting mixture was stirred at 100 °C for 15 h under a nitrogen atmosphere. The reaction mixture was filtered through Celite and the filter cake washed with EtOAc (3 x 20 mL). The combined filtrates were concentrated under reduced pressure and the crude product purified by preparative TLC (MeOH : DCM = 1 :10) and then by preparative HPLC (PrepMethod E, gradient: 2-19%) to give the title compound (35 mg, 23%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H22N7O: 364.1880, found: 364.1848. 1H NMR (300 MHz, MeOH-d4) 6 ppm 1.58 - 1.74 (2H, m), 2.00 - 2.12 (2H, m), 2.22 - 2.35 (2H, m), 2.38 (3H, s), 4.30 - 4.59 (2H, m), 6.44 - 6.53 (1 H, m), 6.59 - 6.68 (2H, m), 7.47 (1 H, dd), 7.57 - 7.69 (2H, m), 7.96 (1 H, d), 8.42 (1 H, s).
EXAMPLE 127
6'-(((1S,3S)-3-((5,6-Dimethyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 127
Figure imgf000220_0001
(1 S,3S)-/V1-(5,6-Dimethyl-1 ,2,4-triazin-3-yl)cyclopentane-1,3-diamine 3TFA compound i-53b (100 mg, 0.18 mmol) was added to Pd-PEPPSI-lpentCI 2-methylpyridine (7.66 mg, 9.10 pmol), CS2CO3 (178 mg, 0.55 mmol) and 6'-chloro-2/7-[1,3'-bipyridin]-2-one compound i-29a (37.6 mg, 0.18 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at 100 °C for 15 h under a nitrogen atmosphere. The reaction mixture was filtered through Celite and the filter cake washed with EtOAc (3 x 20 mL). The combined filtrates were concentrated under reduced pressure and the residue purified by preparative TLC (MeOH : DCM = 1:10) followed by preparative HPLC (PrepMethod E, gradient: 3-14%) to give the title compound (8.4 mg, 12%) as a grey solid. HRMS (ESI) m/z [M+H]+ calcd for C20H24N7O: 378.2036, found: 378.2048. 1H NMR (300 MHz, MeOH-d4) 6 ppm 1.6-1.7 (2H, m), 2.03-2.12 (2H, m), 2.24-2.35 (2H, m), 2.43 (6H, d), 4.29-4.5 (2H, m), 6.47 (1H, t), 6.59-6.72 (2H, m), 7.51 (1 H, dd), 7.57-7.65 (2H, m), 7.96 (1 H, s).
EXAMPLE 133
5-Methoxy-6'-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 133
Figure imgf000220_0002
6'-((( 1 S,3S)-3-Aminocyclopentyl)amino)-5-methoxy-2/7-[1 ,3'-bipyridin]-2-one compound i-42b (100 mg, 0.33 mmol) was added to 6-methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (105 mg, 0.67 mmol) in 1,4-dioxane (6 mL) and /-PrOH (2 mL) at 30 °C. The resulting solution was stirred at 100 °C for 18 h. The solvent was removed under reduced pressure and the residue purified by preparative TLC (EtOAc : MeOH = 3:1) and then by preparative HPLC (PrepMethod K, gradient: 16-34%) to give the title compound (46 mg, 35%) as a pale-yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C20H24N7O2: 394.1986, found: 394.1990. 1H NMR (300 MHz, DMSO-ds) 6 ppm 1.44 - 1.65 (2H, m), 1.82 - 2.04 (2H, m), 2.07 - 2.24 (2H, m), 2.39 (3H, s), 3.65 (3H, s), 4.21 - 4.49 (2H, m), 6.43 (1H, d), 6.54 (1 H, d), 6.93 (1 H, d), 7.19 (1H, d), 7.36 (1 H, dd), 7.42 (1H, dd), 7.59 (1 H, br s), 7.97 (1 H, d), 8.18 (1H, s). EXAMPLE 134
5-Chloro-6'-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 134
Figure imgf000221_0001
6-Methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (155 mg, 0.98 mmol) was added to 6'-((( 1 S,3S)-3-aminocyclopentyl)amino)-5-chloro-2/7-[1 ,3'-bipyridin]-2-one compound i-44b (150 mg, 0.49 mmol) in 1,4-dioxane (6 mL) and /-PrOH (2 mL) at 25 °C. The resulting solution was stirred at 100 °C for 18 h. The solvent was removed under reduced pressure and the residue purified by preparative TLC (EtOAc : MeOH = 3:1) and then by preparative HPLC (PrepMethod D, gradient: 15-45%) to give the title compound (24 mg, 12%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H21CIN7O: 398.1490, found: 398.1494. 1H NMR (300 MHz, DMSO-ds) 6 ppm 1.42-1.68 (2H, m), 1.84-2.01 (2H, m), 2.06-2.23 (2H, m), 2.38 (3H, s), 4.23- 4.49 (2H, m), 6.50 (2H, t), 6.99 (1H, d), 7.41 (1 H, dd), 7.5-7.65 (2H, m), 7.93 (2H, dd), 8.18 (1H, s).
EXAMPLE 135
6'-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(trifluoromethyl)-
2H-[1,3'-bipyridin]-2-one - compound 135
Figure imgf000221_0002
6-Methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (130 mg, 0.83 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-(trifluoromethyl)-2/7-[1,3'-bipyridin]-2-one compound i-54b (140 mg, 0.41 mmol) in 1 ,4-dioxane (15 mL) at 30 °C. The resulting mixture was stirred at 100 °C for 15 h. The solvent was removed under reduced pressure and the residue purified by preparative TLC (MeOH : EtOAc = 1 :1) and then by preparative HPLC (PrepMethod L, gradient: 23-43%) to give the title compound (15 mg, 8%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C20H21 F3N7O: 432.1754, found: 432.1724. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.46 - 1.64 (2H, m), 1.85 - 2.00 (2H, m), 2.08 - 2.20 (2H, m), 2.39 (3H, s), 4.22 - 4.47 (2H, m), 6.43 (1 H, t), 6.55 (1 H, d), 7.04 (1 H, d), 7.46 (1H, dd), 7.58 (1 H, brs), 7.92 - 8.06 (3H, m), 8.18 (1 H, s). EXAMPLE 137
3-Fluoro-6'-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 137
Figure imgf000222_0001
re/-(1R,2R)-/V1,/\/2-Dimethylcyclohexane-1 ,2-diamine (25.1 mg, 0.18 mmol) was added to (1 S,3S)-/V1-(5-iodopyridin-2-yl)-/\/3-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-39a (70 mg, 0.18 mmol), 3-fluoropyridin-2-ol (CAS Reg. No. 1547-29-1) (100 mg, 0.88 mmol), Cu(l)l (33.6 mg, 0.18 mmol) and CS2CO3 (173 mg, 0.53 mmol) in 1 ,4-dioxane (2 mL) at 20 °C. The resulting suspension was stirred at 100 °C for 15 h under a nitrogen atmosphere. The reaction mixture was evaporated, the residue taken up with EtOAc (100 mL) and washed sequentially with sat. brine (3 x 100 mL). The organic layer was dried over Na2SC>4, filtered and evaporated and the crude product was purified by flash chromatography on a C18 column (gradient: 40-50% water in MeCN) to give the title compound (28.2 mg, 42%) as a yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C19H21 FN7O: 382.1786, found: 382.1756. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.45-1.64 (2H, m), 1.82-2.03 (2H, m), 2.05-2.23 (2H, m),
2.39 (3H, s), 4.2-4.45 (2H, m), 6.19-6.31 (1 H, m), 6.55 (1 H, d), 7.02 (1 H, d), 7.41-7.54 (2H, m),
7.58 (1 H, brs), 7.87-8.02 (1 H, m), 8.18 (1 H, s), 12.13 (1 H, brs).
EXAMPLE 151
A/-(2-Hydroxyethyl)-A/-methyl-3-(((1 S,3S)-3-((2-oxo-2H-[1,3,-bipyridin]-6'- yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxamide - compound 151
Figure imgf000222_0002
HATU (43 mg, 0.11 mmol) was added to a solution of the crude lithium salt of 3-(((1 S,3S)-3-((2- oxo-2/7-[1 ,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-1 ,2,4-triazine-6-carboxylic acid compound i-30a (30 mg, 0.075 mmol), 2-(methylamino)ethan-1-ol (9.0 pl, 0.11 mmol) and DIPEA (0.039 mL, 0.23 mmol) in DMF (0.75 mL) at rt and the reaction was stirred at rt for 1.5 h. The mixture was diluted with DMSO (ca 1 mL) and purified by preparative SFC (PrepMethod SFC-A) to give (11 mg, 31%) of the title compound. MS (ESI): m/z [M+H]+ 451.2. 1H NMR (600 MHz, DMSO-ds, mixture of rotamers ca 2/1) 5 ppm 1.46-1.69 (2H, m), 1.86-2.02 (2H, m), 2.1-2.24 (2H, m), 3.01 and 3.16 (3H, s, N-Me two rotamers), 4.34 (1H, q), 6.28 (1 H, td), 6.44 (1 H, dt), 6.49-6.61 (1 H, m), 6.95 (1 H, d, NH), 7.34-7.43 (1H, m), 7.48 (1 H, ddd), 7.58 (1 H, ddd), 7.91 (1 H, d), 8.9 and 8.45 (1H, two singlets, rotamers). (Some protons are hidden in the solvent/water peaks).
EXAMPLE 152
A/-Methyl-3-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6,-yl)amino)cyclopentyl)amino)-A/-(prop- 2-yn-1-yl)-1,2,4-triazine-6-carboxamide - compound 152
Figure imgf000223_0001
HATLI (43 mg, 0.11 mmol) was added to a solution of the crude lithium salt 3-(((1 S,3S)-3-((2- oxo-2/7-[1 ,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-1 ,2,4-triazine-6-carboxylic acid compound i-30a (30 mg, 0.075 mmol), /V-methylprop-2-yn-1 -amine (9.5 pL, 0.11 mmol) and DI PEA (39 pL, 0.23 mmol) in DMF (0.75 mL) and the reaction was stirred at rt for 1.5 h. The mixture was diluted with DMSO (ca 1 mL) and purified by preparative SFC (PrepMethod SFC-A) to give (11 mg, 34%) of the title compound. MS (ESI): m/z [M+H]+ 445.2. 1H NMR (600 MHz, DMSO-ds, mixture of two rotamers ca 1.4/1) 5 ppm 5 1.47-1.58 (1 H, m), 1.58-1.67 (1 H, m), 1.9-2.03 (2H, m), 2.13-2.22 (2H, m), 3.04 and 3.17 (3H, s, rotamers), 3.23 and 3.27 (1 H, s, rotamers), 4.26-4.39 (1H, m), 4.31 and 4.45 (2H, s, rotamers), 6.28 (1 H, td), 6.44 (1H, dt), 6.54 (1 H, d), 6.96 (1H, brs, NH), 7.39 (1H, dd), 7.48 (1H, ddd), 7.55-7.62 (1 H, m), 7.85-7.96 (1H, m), 8.48 (1H, s). (not all signals seen due to broadening/rotamers).
EXAMPLE 153
S-MlS.SSJ-S-GS-Methoxy^-oxo^H-n.S'-bipyridinJ-e'-yQaminoJcyclopentyQaminoJ-A/-
(oxetan-3-yl)-1,2,4-triazine-6-carboxamide - compound 153
Figure imgf000224_0001
re/-(1R,2R)-/V1,/\/2-Dimethylcyclohexane-1 ,2-diamine (32 mg, 0.23 mmol) was added to 3- (((1 S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-/\/-(oxetan-3-yl)-1 ,2,4-triazine-6- carboxamide compound i-90e (110 mg, 0.23 mmol), 3-methoxypyridin-2(1/7)-one (CAS Reg. No. 20928-63-6) (57 mg, 0.46 mmol), CS2CO3 (74 mg, 0.23 mmol) and Cu(l)l (44 mg, 0.23 mmol) in 1 ,4-dioxane (15 mL) at rt and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was poured into water (125 mL) and extracted with EtOAc (4 x 100 mL). The organic layer was dried (Na2SC>4), filtered and evaporated and the residue was first purified by preparative TLC (7 M NH3 in MeOH: DCM = 1 : 15) followed by preparative HPLC (PrepMethod K, gradient: 53-68%) to afford (51 mg, 47%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C23H27N8O4: 479.2150, found: 479.2168 . 1H NMR (300 MHz, DMSO-ds) 6 ppm 1.43 - 1.73 (2 H, m), 1.82 - 2.27 (4 H, m), 3.71 (3H, s), 4.22 - 4.48 (2H, m), 4.63 - 4.78 (4H, m), 5.06 (1 H, sxt), 6.21 (1 H, t), 6.52 (1H, d), 6.78 - 7.01 (2H, m), 7.10 - 7.23 (1 H, m), 7.39 (1 H, dd), 7.90 (1H, d), 8.35-8.95 (2H, s, rotamers), 9.52 (1H, d).
EXAMPLE 154
S-MlS.SSJ-S-GS-Methoxy^-oxo^H-n.S'-bipyridinJ-e'-yQaminoJcyclopentyQaminoJ-A/- (oxetan-3-yl)-1,2,4-triazine-6-carboxamide - compound 154
Figure imgf000224_0002
Prepared in a similar way as described for Example 153 starting from 3-(((1S,3S)-3-((5- iodopyridin-2-yl)amino)cyclopentyl)amino)-/\/-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide compound i-90e (110 mg, 0.23 mmol) and 5-methoxypyridin-2(1/7)-one (CAS Reg. No 61941- 79-5) (57 mg, 0.46 mmol). PrepMethod O, gradient: 7-28%. Yield 13 mg (12%). White solid. HRMS (ESI) m/z [M+H]+ calcd for C23H27N8O4: 479.2150, found: 479.2176. 1H NMR (300 MHz, DMSCM 6 ppm 1.43 - 1.71 (2H, m), 2.00 (2H, s), 2.10 - 2.33 (2H, m), 3.65 (3H, s), 4.28 - 4.64 (2H, m), 4.65-4.80 (4H, m), 4.9-5.1 (1 H, m), 6.43 (1 H, d), 6.54 (1 H, d), 6.93 (1 H, d), 7.19 (1 H, d), 7.36 (1 H, dd), 7.43 (1 H, dd), 7.98 (1 H, d), 8.35-8.95 (2H, s, rotamers), 9.52 (1 H, d).
EXAMPLE 155
S-MlS.SSJ-S-GS-Methyl^-oxo^H-n.S'-bipyridinJ-e'-yQaminoJcyclopentyQaminoJ-A/-
(oxetan-3-yl)-1,2,4-triazine-6-carboxamide - compound 155
Figure imgf000225_0001
Prepared in a similar way as described for Example 153 starting from 3-(((1 S,3S)-3-((5- iodopyridin-2-yl)amino)cyclopentyl)amino)-/\/-(oxetan-3-yl)-1 ,2,4-triazine-6-carboxamide compound i-90e (120 mg, 0.25 mmol) and 3-methylpyridin-2(1/7)-one (54 mg, 0.50 mmol) (CAS Reg. No 1003-56-1). PrepMethod M, gradient: 16-34%. Yield 30 mg (26%). HRMS (ESI) m/z [M+H]+ calcd for C23H27N8O3: 463.2200, found: 463.2202. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.45-1.75 (2H, m), 2.03 (5H, s), 2.1-2.3 (2H, m), 4.37.3-4.5 (2H, m), 4.65-4.8 (4H, m), 4.98- 5.12 (1 H, m), 6.20 (1 H, t), 6.54 (1 H, d), 6.96 (1 H, d), 7.32 - 7.51 (3H, m), 7.93 (1 H, d), 8.35- 8.95 (2H, s, rotamers), 9.54 (1 H, d).
EXAMPLE 156
S-MlS.SSJ-S-GS-Methyl^-oxo^H-n.S'-bipyridinJ-e'-yQaminoJcyclopentyQaminoJ-A/-
(oxetan-3-yl)-1,2,4-triazine-6-carboxamide - compound 156
Figure imgf000225_0002
Prepared in a similar way as described for Example 153 starting from 3-(((1 S,3S)-3-((5- iodopyridin-2-yl)amino)cyclopentyl)amino)-/\/-(oxetan-3-yl)-1 ,2,4-triazine-6-carboxamide compound i-90e (150 mg, 0.31 mmol) and 5-methylpyridin-2(1/7)-one (CAS Reg. No 1003-68- 5) (41 mg, 0.37 mmol). PrepMethod P, gradient: 5-26%. Yield 27 mg (19%). White solid. HRMS (ESI) m/z [M+H]+ calcd for C23H27N8O3: 463.2200, found: 463.2208. 1H NMR (300 MHz, DMSO- d6) 6 ppm 1.5-1.7 (2H, m), 1.85 - 2.00 (2H, m), 2.04 (3H, d), 2.15 - 2.22 (2H, m), 4.26 - 4.56 (2H, m), 4.65-4.8 (4H, m), 5.0-5.1 (1 H, m), 6.39 (1 H, d), 6.53 (1 H, d), 6.94 (1 H, d), 7.27 - 7.48 (3H, m), 7.92 (1 H, d), 8.35-8.95 (2H, s, rotamers), 9.54 (1 H, d).
EXAMPLE 157
3-(((1S,3S)-3-((3-Chloro-2-oxo-2H-[1,3'-bipyridin]-6,-yl)amino)cyclopentyl)amino)-A/-
(oxetan-3-yl)-1,2,4-triazine-6-carboxamide - compound 157
Figure imgf000226_0001
Prepared in a similar way as described for Example 153 starting from 3-(((1 S,3S)-3-((5- iodopyridin-2-yl)amino)cyclopentyl)amino)-/\/-(oxetan-3-yl)-1 ,2,4-triazine-6-carboxamide compound i-90e (120 mg, 0.25 mmol) and 3-chloropyridin-2(1/-/)-one (CAS Reg. No 13466-35- 8) (65 mg, 0.50 mmol). PrepMethod P, gradient: 5-28%. Yield 70 mg (58%). Yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C22H24CIN8O3: 483.1654, found: 483.1646. 1H NMR (300 MHz, DMSO-ds) 6 ppm 1.45-1.75 (2H, m), 1.88 - 2.02 (2H, m), 2.1-2.3 (2H, m), 4.29 - 4.57 (2H, m), 4.67 - 4.75 (4H, m), 4.95- 5.15 (1 H, m), 6.31 (1 H, t), 6.55 (1 H, d), 7.03 (1 H, d), 7.45 (1 H, dd), 7.66 (1 H, dd), 7.82 (1 H, dd), 7.97 (1 H, d), 8.35-8.95 (2H, s, rotamers), 9.54 (1 H, d).
EXAMPLE 158
3-(((1S,3S)-3-((5-Chloro-2-oxo-2H-[1,3'-bipyridin]-6,-yl)amino)cyclopentyl)amino)-A/-
(oxetan-3-yl)-1,2,4-triazine-6-carboxamide - compound 158
Figure imgf000226_0002
Prepared in a similar way as described for Example 153 starting from 3-(((1 S,3S)-3-((5- iodopyridin-2-yl)amino)cyclopentyl)amino)-/\/-(oxetan-3-yl)-1 ,2,4-triazine-6-carboxamide compound i-90e (150 mg, 0.31 mmol) and 5-chloropyridin-2(1/-/)-one (CAS Reg. No 4214-79- 3) (81 mg, 0.62 mmol). PrepMethod D, gradient: 26-38%. Yield 27 mg (18%). White solid. HRMS (ESI) m/z [M+H]+ calcd for C22H24CIN8O3: 483.1654, found: 483.1670. 1H NMR
(300 MHz, DMSO-ds) 6 ppm 1.50-1.70 (2H, m), 1.90-2.05 (2H, m), 2.07 - 2.38 (2H, m), 4.22 - 4.55 (2H, m), 4.64-4.76 (4H, m), 5.05 (1 H, sxt), 6.46-6.56 (2H, m), 7.00 (1 H, d), 7.42 (1 H, dd),
7.55 (1 H, dd), 7.93 (2H, d), 8.35-8.95 (2H, s, rotamers), 9.54 (1 H, d).
EXAMPLE 159
S-MlS.SSJ-S-GS-Cyano^-oxo^H-n.S'-bipyridinJ-e'-yQaminoJcyclopentyQaminoJ-A/-
(oxetan-3-yl)-1,2,4-triazine-6-carboxamide - compound 159
Figure imgf000227_0001
m-CPBA (330 mg, 1.63 mmol) was added to a stirred solution of 3-(methylthio)-/V-(oxetan-3-yl)- 1,2,4-triazine-6-carboxamide compound i-90d (184 mg, 0.81 mmol) in DCM (10 mL) which was cooled to 0 °C in an ice bath. The temperature was increased to room temperature and the resulting solution was stirred for 3 h. 6'-(((1 S,3S)-3-Aminocyclopentyl)amino)-2-oxo-2/7-[1 ,3'- bipyridine]-3-carbonitrile compound i-35b (120 mg, 0.41 mmol) and TEA (0.227 mL, 1.63 mmol) were added and the resulting solution was stirred at rt for an additional 15 h. The reaction mixture was diluted with sat. NaHCCh (aq, 50 mL) and extracted with EtOAc (4 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated and the residue purified by preparative TLC (EtOAc) followed by preparative HPLC (PrepMethod D, gradient: 14-25%) to afford (15 mg, 8%) of the title compound as a yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C23H24N9O3: 474.1996, found: 474.2026. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.48-1.73 (2H, m), 1.9-2.1 (2H, s), 2.14 - 2.24 (2H, m), 4.27 - 4.80 (6H, m), 5.04 (1H, sxt), 6.47 (1 H, t), 6.56 (1 H, d), 7.09 (1 H, d), 7.47 (1 H, dd), 7.95 - 8.10 (2H, m), 8.23 (1 H,dd), 8.35- 8.95 (2H, s, rotamers), 9.53 (1H, d).
EXAMPLE 160
A/-(Oxetan-3-yl)-3-(((1S,3S)-3-((2-oxo-3-(trifluoromethoxy)-2H-[1,3,-bipyridin]-6'- yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxamide - compound 160
Figure imgf000227_0002
Prepared in a similar way as described for Example 153 starting from 3-(((1 S,3S)-3-((5- iodopyridin-2-yl)amino)cyclopentyl)amino)-/\/-(oxetan-3-yl)-1 ,2,4-triazine-6-carboxamide compound i-90e (80 mg, 0.17 mmol) and 3-(trifluoromethoxy)pyridin-2(1/7)-one (CAS Reg. No 1361696-33-4) (36 mg, 0.20 mmol). PrepMethod R, gradient: 10-27%. Yield 17 mg (19%). Yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C23H24F3N8O4: 533.1868, found: 533.1912.
1H NMR (300 MHz, DMSO-d6) 5 ppm 1.45 -1.75 (2H, m), 1.9 - 2.1 (2H, m), 2.12 - 2.22 (2H, m), 4.35 (2H, d), 4.6 - 4.8 (4H, m), 5.02 (1 H, sxt), 6.32 (1 H, t), 6.54 (1 H, d), 7.03 (1 H, d), 7.44 (1 H, dd), 7.65-7.8 (2H, m), 7.97 (1 H, d), 8.35-8.95 (2H, s, rotamers), 9.52 (1 H, d).
EXAMPLE 161
A/-(Oxetan-3-yl)-3-(((1 S,3S)-3-((2-oxo-3-(trifluoromethyl)-2H-[1,3,-bipyridin]-6'- yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxamide - compound 161
Figure imgf000228_0001
Prepared in a similar way as described for Example 153 starting from 3-(((1 S,3S)-3-((5- iodopyridin-2-yl)amino)cyclopentyl)amino)-/\/-(oxetan-3-yl)-1 ,2,4-triazine-6-carboxamide compound i-90e (110 mg, 0.23 mmol) and 3-(trifluoromethyl)pyridin-2(1/7)-one (CAS Reg. No 22245-83-6) (75 mg, 0.46 mmol). PrepMethod D, gradient: 20-40%. Yield 51 mg (43%). Paleyellow solid. HRMS (ESI) m/z [M+H]+ calcd for C23H24F3N8O3: 517.1918, found: 517.1958. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.47 - 1.75 (2H, m), 1.9 - 2.1 (2H, d), 2.11 - 2.27 (2H, m), 4.29 - 4.61 (2H, m), 4.64 - 4.77 (4H, m), 4.98 - 5.12 (1 H, m), 6.43 (1 H, t), 6.56 (1 H, d), 7.06 (1 H, d), 7.47 (1 H, dd), 7.95 - 8.07 (3H, m), 8.34 - 8.97 (2H, s, rotamers), 9.54 (1 H, d).
EXAMPLE 165
6'-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-
(difluoromethoxy)-2H-[1,3'-bipyridin]-2-one - compound 165
Figure imgf000228_0002
Prepared in a similar way as described in Example 153 starting from (1 S,3S)-/V1-(6-cyclopropyl- 1 ,2,4-triazin-3-yl)-/V3-(5-iodopyridin-2-yl)cyclopentane-1 ,3-diamine compound i-22e (85 mg, 0.20 mmol) and 3-(difluoromethoxy)pyridin-2(1/7)-one (CAS Reg. No. 1241752-48-6) (130 mg, 0.81 mmol). PrepMethod D, gradient: 29-40%. Yield 28 mg (31%). Pale-yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C22H24F2N7O2: 456.1954, found: 456.1932. 1H NMR (300 MHz, DMSO-ds) 6 ppm 0.86 - 1.01 (4H, m), 1.43 - 1.72 (2H, m), 1.88 - 1.98 (2H, m), 2.01 - 2.18 (3H, m), 4.25 - 4.46 (2H, m), 6.30 (1 H, t), 6.55 (1 H, d), 7.00 (1 H, brd), 7.16 (1 H, t, OCHF2), 7.38 - 7.49 (2H, m), 7.59 (2H, brd), 7.97 (1 H, d), 8.19 (1 H, s).
EXAMPLE 166
6'-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-
(difluoromethoxy)-2H-[1,3'-bipyridin]-2-one - compound 166
Figure imgf000229_0001
Prepared in a similar way as described in Example 153 from (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4- triazin-3-yl)-/V3-(5-iodopyridin-2-yl)cyclopentane-1 ,3-diamine compound i-22e (70 mg, 0.17 mmol) and 5-(difluoromethoxy)pyridin-2(1/7)-one (CAS Reg. No. 130318-75-1) (53 mg, 0.33 mmol). PrepMethod O, gradient: 21-51 %. Yield 21 mg (28%). White solid. HRMS (ESI) m/z [M+H]+ calcd for C22H24F2N7O2: 456.1954, found: 456.1960 1H NMR (300 MHz, DMSO-d6) 5 ppm 0.61 - 1.11 (4 H, m), 1.4 - 1.7 (2 H, m), 1.8-1.98 (2 H, m), 1.98 - 2.27 (3 H, m), 4.25 - 4.45 (2 H, m), 6.52 (2 H, brt), 6.69 - 7.31 (2 H, m), 7.03 (1 H, t, OCHF2), 7.31 - 7.65 (2 H, m), 7.76 (1 H, s), 7.96 (1 H, s), 8.19 (1 H, s).
EXAMPLE 167
3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4- fluoro-2-methoxybenzoic acid - compound 167
Figure imgf000229_0002
NaOH (20 mg, 0.50 mmol) was added to methyl 3-(6-(((1 S,3S)-3-((6-cyclopropyl-1 ,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-fluoro-2-methoxybenzoate compound i-91 b (80 mg, 0.17 mmol) in water (1 mL) and THF (4 mL) at rt and the resulting mixture was stirred at rt for 4 h. The reaction mixture was adjusted to pH = 6 with 0.1 M HCI (aq). The solvent and water was removed under reduced pressure and the crude was purified by preparative HPLC (PrepMethod O, gradient: 17-30%) to afford (69 mg, 89%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C24H26FN6O3: 465.2044, found: 465.2052. 1H NMR (300 MHz, DMSO-ds) 6 ppm 0.86-1.03 (4H, m), 1.37-1.67 (2H, m), 1.81-1.99 (2H, m), 1.99- 2.21 (3H, m), 3.80 (3H, s), 4.06-4.48 (2H, m), 6.52 (1 H, d), 6.74 (1 H, d), 6.99 (1 H, d), 7.33 (1 H, d), 7.45-7.61 (1 H, m), 7.82 (1 H, t), 7.91 (1 H, s), 8.19 (1 H, s).
EXAMPLE 168
3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4- fluoro-2-methoxybenzonitrile - compound 168
Figure imgf000230_0001
3-(6-Chloropyridin-3-yl)-4-fluoro-2-methoxybenzonitrile compound i-92c (40 mg, 0.15 mmol) was added to (1 S,3S)-/V1-(6-cyclopropyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-22d (40 mg, 0.18 mmol), Pd-PEPPSI-IPentCI 2-methylpyridine (12.8 mg, 0.02 mmol) and CS2CO3 (99 mg, 0.30 mmol) in 1 ,4-dioxane (2 mL) at rt under nitrogen and the resulting solution was stirred at 100 °C for 8 h. The reaction mixture was poured into water (20 mL), filtered through a Celite pad and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over (Na2SO4), filtered and evaporated and the residue purified by preparative HPLC (PrepMethod T, gradient: 42-55%) to afford (24 mg, 36%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C24H25FN7O: 446.2098, found: 446.2134. 1H NMR (300 MHz, DMSO-ds) 6 ppm 0.83 - 1.01 (3H, m), 1.45 -1.65 (2 H, m), 1.84 - 2.21 (4H, m), 3.66 (3H, s), 4.30 - 4.44 (2H, m), 6.57 (1 H, d), 6.95 (1 H, d), 7.29 (1 H, t), 7.41 - 7.47 (1 H, m), 7.54 (1 H, d), 7.85 (1 H, dd), 8.02 (1 H, br s), 8.19 (1 H, s).
EXAMPLE 169
(1 S,3S)-A/1-(6-Cyclopropyl-1,2,4-triazin-3-yl)-A/3-(5-(6-fluoro-2-methoxy-3-(1H-tetrazol-5- yl)phenyl)pyridin-2-yl)cyclopentane-1,3-diamine - compound 169
Figure imgf000231_0001
(nBu)2Sn(OAc)2 (118 mg, 0.34 mmol) was added to 3-(6-(((1 S,3S)-3-((6-cyclopropyl-1 ,2,4- triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-fluoro-2-methoxybenzonitrile Example 168 (50.0 mg, 0.11 mmol) and trimethylsilyl azide (65 mg, 0.56 mmol) in toluene (5 mL) at 0 °C under nitrogen and the resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue purified by preparative HPLC (PrepMethod II, gradient: 20-34%) to afford (5 mg, 9%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C24H26FN10O: 489.2270, found: 489.2288. 1H NMR (300 MHz, DMSO-d6) 5 ppm 0.84-1.04 (4H, m), 1.43-1.65 (2H, m), 1.84-1.99 (2H, m), 1.99-2.22 (3H, m), 3.35 (3H, s), 4.26-4.43 (2H, m), 6.58 (1 H, d), 7.23 (1 H, t), 7.48 (1 H, d), 7.87 (1 H, dd), 8.04 (1 H, s), 8.18 (1 H, s).
EXAMPLE 173 re/-3-Methyl-6'-(((1/?,3/?)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 173
Figure imgf000231_0002
re/-(1R,3R)-/V1-(6-Methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine 3HCI compound i-87b (0.312 g, 1.03 mmol), 6'-fluoro-3-methyl-2/7-[1 ,3'-bipyridin]-2-one compound i-38a (0.211 g, 1.03 mmol) and K2CO3 (0.570 g, 4.12 mmol) was added to a vial. The vial was capped and the reaction was stirred at 100 °C for 48 h. The mixture was cooled to rt, EtOAc and brine were added and the phases were separated. The aqueous phase was extracted once more with EtOAc. The organic phases were combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and the residue purified by preparative HPLC (PrepMethod F, gradient: 10-70%). The collected compound was concentrated and freeze dried overnight. The obtained solid was dissolved in DCM and washed with a small amount of water. The phases were separated and the organic phase was evaporated. The residue was dissolved in MeCN/water (1 :1) and freeze dried overnight to give the title compound (0.190 g, 48%) as a yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C20H24N7O: 378.2036, found: 378.2038. 1H NMR (500 MHz, MeOH-d4) 6 1.55-1.74 (2H, m), 1.96-2.11 (2H, m), 2.11-2.19 (3H, m), 2.22-2.37 (2H, m), 2.44 (3H, s), 4.31-4.53 (2H, m), 6.37 (1 H, t), 6.62 (1 H, dd), 7.41-7.45 (2H, m), 7.45- 7.49 (1 H, m), 7.93 (1 H, dd), 8.19 (1 H, s).
EXAMPLE 180
4-Methoxy-6'-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 180
Figure imgf000232_0001
CS2CO3 (247 mg, 0.76 mmol) was added to (1S,3S)-/V1-(5-iodopyridin-2-yl)-/\/3-(6-methyl-1 ,2,4- triazin-3-yl)cyclopentane-1 ,3-diamine compound i-39a (100 mg, 0.25 mmol), 4-methoxypyridin- 2(1/7)-one (CAS Reg. No. 92545-13-8) (158 mg, 1.26 mmol), (1 /?,2/?)-/V1.A/2- dimethylcyclohexane-1 ,2-diamine (36 mg, 0.25 mmol) and Cu(l)l (48 mg, 0.25 mmol) in 1 ,4- dioxane (5 mL) at rt and the resulting mixture was stirred at 100 °C for 16 h under nitrogen. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (4 x 100 mL), the combined organic layers were dried (Na2SC>4), filtered and evaporated to afford the crude product. The residue was first purified by preparative TLC (MeOH : DCM = 1 : 30) and then by preparative HPLC (PrepMethod O, gradient: 10-39%) to afford (28 mg, 28%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C20H24N7O2: 394.1986, found: 394.1980. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.45 - 1.65 (2H, m), 1.85 - 2.0 (2H, m), 2.1 - 2.25 (2H, m), 2.39 (3H, s), 3.77 (3H, s), 4.25 - 4.45 (2H, m), 5.85 (1 H, d), 6.00 (1 H, dd), 6.52 (1 H, d), 6.90 (1 H, d), 7.35 (1 H, dd), 7.51 (1 H, d), 7.56 (1 H, s), 7.88 (1 H, d), 8.18 (1 H, s).
EXAMPLE 182
4-Chloro-6'-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 182
Figure imgf000232_0002
Prepared in a similar way as described for Example 180 using (1S,3S)-/V1-(5-iodopyridin-2-yl)- /V3-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-39a (80 mg, 0.20 mmol) and 4-chloropyridin-2(1/-/)-one (CAS Reg. No 40673-25-4) (131 mg, 1.01 mmol) and purified by preparative HPLC (PrepMethod T, gradient: 25-45%). Yield 37 mg (46%). White solid. HRMS (ESI) m/z [M+H]+ calcd for CI9H2ICIN7O: 398.1490, found: 398.1474. 1H NMR (300 MHz, DMSO-ds) 6 ppm 1.49 - 1.61 (2H, m), 1.85 - 2.0 (2H, m), 2.12 - 2.21 (2H, m), 2.39 (3H, s), 4.30 - 4.42 (2H, m), 6.41 (1 H, dd), 6.53 (1 H, d), 6.62 (1 H, d), 6.99 (1 H, d), 7.40 (1 H, dd), 7.56 (1 H, s), 7.72 (1 H, d), 7.93 (1 H, d), 8.18 (1 H, s).
EXAMPLE 183
6'-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'- bipyridine]-4-carbonitrile - compound 183
Figure imgf000233_0001
Prepared in a similar way as described for Example 180 using (1S,3S)-/V1-(5-iodopyridin-2-yl)- /V3-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-39a (100 mg, 0.25 mmol) and 2-oxo-1 ,2-dihydropyridine-4-carbonitrile (CAS Reg. No 94805-51-3) (152 mg, 1.26 mmol) and purified by preparative HPLC (PrepMethod T, gradient: 25-45%). Yield 28 mg (29%).
Yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C2oH2iN80: 389.1832, found: 389.1820. 1H NMR (300 MHz, DMSO-ds) 6 ppm 1.49 - 1.61 (2 H, m), 1.85 - 2.05 (2H, m), 2.11 - 2.23 (2H, m), 2.39 (3H, s), 4.25-4.45 (2H, m), 6.59 (1 H, d), 6.59 (1 H, dd), 7.04 (1 H, d), 7.11 (1 H, d), 7.43 (1 H, dd), 7.56 (1 H, brs), 7.88 (1 H, d), 7.95 (1 H, d), 8.18 (1 H, s).
EXAMPLE 185
5-(Difluoromethoxy)-6'-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-
2H-[1,3'-bipyridin]-2-one - compound 185
Figure imgf000233_0002
Prepared in a similar way as described for Example 180 using (1S,3S)-/V1-(5-iodopyridin-2-yl)- /V3-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-39a (150 mg, 0.38 mmol) and 5-(difluoromethoxy)pyridin-2(1/7)-one (CAS Reg. No 130318-75-1) (183 mg, 1.14 mmol) and purified by preparative HPLC (PrepMethod M, gradient: 25-40%). Yield 79 mg (49%). White solid. HRMS (ESI) m/z [M+H]+ calcd for C20H22F2N7O2: 430.1798, found: 430.1772. 1H NMR (300 MHz, DMSO-ds) 6 ppm 1.43 - 1.68 (2H, m), 1.85 - 2.0 (2H, m), 2.07 - 2.24 (2H, m), 2.39 (3H, s), 4.24 - 4.46 (2H, m), 6.47 - 6.54 (2H, m), 6.96 (1 H, d), 7.02 (1 H, t, OCHF2) 7.42 (1 H , dd), 7.5 - 7.6 (2H, m), 7.75 (1 H, d), 7.96 (1 H, d), 8.18 (1 H, s).
EXAMPLE 187
3-(Difluoromethoxy)-6'-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-
2H-[1,3'-bipyridin]-2-one - compound 187
Figure imgf000234_0001
Prepared in a similar way as described for Example 180 (1 S,3S)-A/1-(5-iodopyridin-2-yl)-A/3-(6- methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-39a (100 mg, 0.25 mmol) and 3-(difluoromethoxy)pyridin-2(1/7)-one (CAS Reg. No 1241752-48-6) (81 mg, 0.50 mmol) and purified by preparative HPLC (PrepMethod O, gradient: 20-40%). Yield 45 mg (41%). White solid. HRMS (ESI) m/z [M+H]+ calcd for C20H22F2N7O2: 430.1798, found: 430.1832. 1H NMR (300 MHz, DMSO-ds) 6 ppm 1.43-1.66 (2H, m), 1.86-2.02 (2H, m), 2.1-2.25 (2H, m), 2.39 (3H, s), 4.26-4.45 (2H, m), 6.30 (1 H, t), 6.55 (1 H, d), 7.01 (1 H, d), 7.16 (1 H, t, CHF2), 7.37-7.49 (2H, m), 7.52-7.63 (2H, m), 7.97 (1 H, d), 8.18 (1 H, s).
EXAMPLE 197
1-(6-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,8- naphthyridin-2(1H)-one - compound 197
Figure imgf000234_0002
(1 S,3S)-/V1-(6-Methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine 4.5HCI compound i-28b (250 mg, 0.70 mmol) was added to 1-(6-chloropyridin-3-yl)-1 ,8-naphthyridin-2(1/7)-one compound i-6a (150 mg, 0.58 mmol), Pd-PEPPSI-lpentCI 2-methylpyridine (24.5 mg, 0.03 mmol) and K2CO3 (241 mg, 1.75 mmol) in 1 ,4-dioxane (10 mL) at 15 °C. The resulting mixture was stirred at 100 °C for 15 h under a nitrogen atmosphere. The reaction mixture was poured into sat. brine (100 mL) and extracted with EtOAc (4 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated and the residue purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :15) followed by preparative HPLC (PrepMethod D, gradient: 15-31%) to give the title compound (90 mg, 37%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C22H23N8O: 415.1990, found: 415.2008. 1H NMR (300 MHz, DMSO-d6) 1.49 - 1.66 (2H, m), 1.88 - 2.03 (2H, m), 2.08 - 2.28 (2H, m), 2.39 (3H, s), 4.29 - 4.46 (2H, m), 6.59 (1 H, d), 6.76 (1 H, d), 6.84 (1 H, d), 7.20 - 7.35 (2H, m), 7.57 (1 H, d), 7.79 (1 H, d), 8.04 (1 H, d), 8.15 - 8.24 (2H, m), 8.44 (1 H, dd).
EXAMPLE 198
6'-((( 1 S,3S)-3-((6-Methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(1 -methyl-1 H- pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one - compound 198
Figure imgf000235_0001
3-Chloro-6'-(((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2/7-[1 ,3'- bipyridin]-2-one Example 129 (100 mg, 0.25 mmol) was added to (1 -methyl-1 /-/-pyrazol-4- yl)boronic acid (CAS Reg. No. 847818-55-7) (63 mg, 0.50 mmol), CS2CO3 (246 mg, 0.75 mmol), XPhos Pd G3 (21 mg, 0.03 mmol) and XPhos (12 mg, 0.03 mmol) in 1 ,4-dioxane (12 mL) and water (3 mL) at rt and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was poured into sat. brine (125 mL) and extracted with EtOAc (4 x 100 mL), the combined organic layers were dried (Na2SC>4), filtered and evaporated to afford the crude product. The crude was first purified by preparative TLC (MeOH : EtOAc = 1 : 40) followed by preparative HPLC (PrepMethod Z1 , gradient: 15-29%) to afford (50 mg, 45%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C23H26N9O: 444.2254, found: 444.2264. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.45 - 1.65 (2H, m), 1.84 - 2.04 (2H, m), 2.1 - 2.25 (2H, m), 2.39 (3H, s), 3.85 (3H, s), 4.25 - 4.45 (2H, m), 6.36 (1 H, t), 6.55 (1 H, d), 6.95 (1 H, d), 7.45 (1 H, dd), 7.5 - 7.65 (2H, m), 7.85 (1 H, dd), 7.97 (1 H, d), 8.01 (1 H, s), 8.18 (1 H, s), 8.31 (1 H, s).
EXAMPLE 199
6'-((( 1 S,3S)-3-((6-Methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(1 H-pyrazol-4-yl)-
2H-[1,3'-bipyridin]-2-one - compound 199
Figure imgf000236_0001
3-Chloro-6'-(((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2/7-[1 ,3'- bipyridin]-2-one Example 129 (150 mg, 0.38 mmol) was added to (1-(terf-butoxycarbonyl)-1/7- pyrazol-4-yl)boronic acid (CAS Reg. No. 1188405-87-9) (160 mg, 0.75 mmol), XPhos (18 mg, 0.04 mmol), CS2CO3 (369 mg, 1.13 mmol) and XPhos Pd 3G (32 mg, 0.04 mmol) in 1 ,4-dioxane (8 mL) and water (2 mL) at rt and the resulting solution was stirred at 100 °C for 18 h under nitrogen. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with water (3 x 75 mL) and sat. brine (3 x 25 mL). The organic layer was dried (Na2SC>4), filtered and evaporated to afford crude product. The crude was first purified by preparative TLC (MeOH (7 M NH3) : DCM = 1 : 20) followed by preparative HPLC (PrepMethod X, gradient: 8-38%) to afford (47 mg, 29%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C22H24N9O: 430.2098, found: 430.2120. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.38 - 1.67 (2H, m), 1.79 - 2.03 (2H, m), 2.17 (2 H, m), 2.39 (3H, s), 4.25 - 4.45 (2H, m), 6.36 (1 H, t), 6.56 (1 H, d), 6.95 (1 H, d), 7.45 (1 H, dd), 7.5 - 7.65 (2H, m), 7.85 - 7.92 (1 H, m), 7.96 (1 H, d), 8.08 (1 H, s), 8.18 (1 H, s), 8.34 (1 H, s), 12.86 (1 H, s).
EXAMPLE 200
6'-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(1H-1,2,3-triazol-4- yl)-2H-[1,3'-bipyridin]-2-one - compound 200
Figure imgf000236_0002
4-Methylbenzenesulfonic acid (44 mg, 0.25 mmol) was added to 6'-(((1 S,3S)-3-((6-methyl-1 ,2,4- triazin-3-yl)amino)cyclopentyl)amino)-3-(2-(tetrahydro-2/7-pyran-2-yl)-2/7-1 ,2,3-triazol-4-yl)-2/7- [1 ,3'-bipyridin]-2-one compound i-68a (130 mg, 0.25 mmol) in EtOH (8 mL) and water (0.1 mL) at rt and the resulting solution was stirred at 60 °C for 8 h. The reaction mixture was diluted with EtOAc (125 mL) and washed sequentially with sat. aq NaHCOs (3 x 75 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford the crude product. The crude product was purified by preparative HPLC (PrepMethod Z2, gradient: 9-30%) to afford (39 mg, 36%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C21H23N10O: 431.2050, found: 431.2040. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.47 - 1.65 (2H, m), 1.87 - 2.02 (2H, m), 2.08 - 2.25 (2H, m), 2.39 (3H, s), 4.29 - 4.45 (2H, m), 6.48 (1 H, t), 6.57 (1 H, d), 6.98 (1 H, brd), 7.48 (1 H, dd), 7.53 - 7.61 (1 H, m), 7.72 (1 H, brd), 8.00 (1 H, d), 8.18 (1H, s), 8.28 (1 H, brs), 8.38 (1 H, brs), 15.17 (1 H, brs)
EXAMPLE 201
6'-((( 1 S,3S)-3-((6-Methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1 -methyl-1 H- pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one - compound 201
Figure imgf000237_0001
A mixture of 6'-chloro-5-(1-methyl-1/7-pyrazol-4-yl)-2/7-[1 ,3'-bipyridin]-2-one compound i-67b (90 mg, 0.31 mmol), (1 S,3S)-/V1-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine x 2HCI compound i-28b (125 mg, 0.47 mmol), CS2CO3 (511 mg, 1.57 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (13 mg, 0.02 mmol) in DMF (4 mL) was stirred under an atmosphere of nitrogen at 100 °C for 18 h. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with sat. brine (4 x 35 mL). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was first purified by preparative TLC (MeOH : EtOAc = 1: 5) followed by preparative HPLC (PrepMethod D, gradient: 12-29%) to afford (8 mg, 6%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C23H26N9O: 444.2254, found: 444.2288. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.46 - 1.66 (2H, m), 1.85 - 2.0 (2H, m), 2.09 - 2.28 (2H, m), 2.39 (3H, s), 3.82 (3H, s), 4.25 - 4.45 (2H, m), 66.49 - 6.56 (2H, m), 6.95 (1 H, d), 7.45 (1 H, dd), 7.51 - 7.63 (1H, m), 7.7 - 7.8 (2H, m), 7.88 (1 H, d), 7.98 (1H, d), 8.03 (1H, s), 8.18 (1 H, s).
EXAMPLE 202
6'-((( 1 S,3S)-3-((6-Methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1 H-pyrazol-4-yl)-
2H-[1,3'-bipyridin]-2-one - compound 202
Figure imgf000238_0001
5-(1-(4-Methoxybenzyl)-1/7-pyrazol-4-yl)-6'-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2/7-[1,3'-bipyridin]-2-one compound i-50d (74 mg, 0.13 mmol) in TFA (7 mL) was stirred at 80 °C for 5 h. The reaction mixture was evaporated to afford crude product which was purified by preparative HPLC (PrepMethod Z3, gradient: 34-64%) to afford the title compound (17 mg, 30%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C22H24N9O: 430.2098, found: 430.2098. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.45 - 1.66 ( H, m), 1.88 - 2.01 (2H, m), 2.12 - 2.23 (2H, m), 2.39 (3 H, s), 4.3 -4.45 (2H, m), 6.49 - 6.57 (2H, m), 6.95 (1 H, d), 7.45 (1H, m), 7.57 (1H, d), 7.81 (1 H, dd), 7.86 (1 H, s), 7.91 (1 H, d), 7.99 (1 H, d), 8.10 (1 H, s), 8.18 (1H, s), 12.86 (1 H, s).
EXAMPLE 208
6'-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1H-1,2,3-triazol-4- yl)-2H-[1,3'-bipyridin]-2-one - compound 208
Figure imgf000238_0002
5-(1-(4-Methoxybenzyl)-1/7-1,2,3-triazol-4-yl)-6'-(((1S,3S)-3-((6-methyl-1 ,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2/7-[1,3'-bipyridin]-2-one compound i-49c (20 mg, 0.04 mmol) was added into TFA (2.5 mL) at rt and the resulting suspension was stirred at 80 °C for 2 h under nitrogen. The solvent was removed under reduced pressure to afford crude product which was purified by preparative HPLC (PrepMethod O, gradient: 2-27%) to afford (0.64 mg, 4%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C21H23N10O: 431.2050, found: 431.2050. 1H NMR (300 MHz, Methanol-d4) 5 1.55-1.81 (2H, m), 1.88-2.14 (2H, m), 2.21-2.34 (2H, m), 2.47 (3H, s), 4.28-4.52 (2H, m), 6.57-6.75 (2H, m), 7.53 (1H, dd), 7.99 (1H, s), 8.05 (1 H, d), 8.07-8.12 (2H, m), 8.22 (1 H, s). EXAMPLE 210
1-Methyl-3-(6-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5-carbonitrile - compound 210
Figure imgf000239_0001
In a slight variation of GM2 Pd-PEPPSI-lpentCI 2-methylpyridine (19 mg, 0.02 mmol) was added to a mixture of /V1-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine 2HCI compound i-28b (120 mg, 0.45 mmol), 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1/7- benzo[d]imidazole-5-carbonitrile compound i-60d (141 mg, 0.50 mmol) and CS2CO3 (441 mg, 1.35 mmol) in DMF (15 mL) at rt and the resulting mixture was stirred at 90 °C for 18 h under nitrogen. The reaction mixture was concentrated under reduced pressure and taken up with EtOAc (200 mL). The organic layer was washed with sat. brine (5 x 75 mL), dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (EtOAc) followed by preparative HPLC (PrepMethod O, gradient: 30-47%) to give (48 mg, 24%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C23H24N9O: 442.2098, found: 442.2132. 1H NMR (300 MHz, DMSO-cfe) 6 ppm 1.50 - 1.61 (2H, m), 1.87 - 2.02 (2H, m), 2.11 - 2.24 (2H, m), 2.38 (3H, s), 3.43 (3H, s), 4.30 - 4.43 (2H, m), 6.62 (1 H, d), 7.03 (1 H, d), 7.30 (1 H, d), 7.42 (1 H, d), 7.47 (1 H, dd), 7.53 - 7.62 (2H, m), 8.07 (1 H, d), 8.17 (1 H, s).
EXAMPLE 211
3-Methyl-1 -(6-((( 1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)-2-oxo-2,3-dihydro-1H-benzo[cf]imidazole-5-carbonitrile - compound 211
Figure imgf000239_0002
In analogy to Example 210 /V1-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine 2HCI compound i-28b (100 mg, 0.38 mmol), 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1/7- benzo[d]imidazole-5-carbonitrile compound i-61d (118 mg, 0.41 mmol), Pd-PEPPSI-lpentCI 2- methylpyridine (16 mg, 0.02 mmol) and CS2CO3 (367 mg, 1.13 mmol) were reacted in 1 ,4- dioxane (15 mL) at 100 °C for 18 h under nitrogen. Upon aqueous work-up (EtOAc) and preparative TLC (EtOAc) the title compound (38 mg, 23%) was obtained. HRMS (ESI) m/z [M+H]+ calcd for C23H24N9O: 442.2098, found: 442.2122. 1H NMR (300 MHz, DMSO-cfe) 6 ppm 1.49 - 1.62 (2H, m), 1.89 - 1.99 (2H, m), 2.12 - 2.21 (2H, m), 2.38 (3H, s), 3.42 (3H, s), 4.32 - 4.42 (2H, m), 6.63 (1 H, d), 7.01 - 7.08 (2H, m), 7.45 - 7.58 (3H, m), 7.78 (1 H, d), 8.06 (1 H, d), 8.18 (1 H, s).
EXAMPLE 212
1-Methyl-3-(6-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one - compound 212
Figure imgf000240_0001
In analogy to Example 210 /V1-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine 4.5HCI compound i-28b (247 mg, 0.69 mmol), 3-(6-chloropyridin-3-yl)-1-methyl-1 ,3-dihydro-2/7- imidazo[4,5-b]pyridin-2-one compound i-24a (150 mg, 0.58 mmol), Pd-PEPPSI-lpentCI 2- methylpyridine (24 mg, 0.03 mmol) and K2CO3 (239 mg, 1.73 mmol) were reacted in 1 ,4- dioxane (15 mL) at 100 °C for 15 h under nitrogen. Upon aqueous work-up (EtOAc), preparative TLC (7 M NH3 in MeOH:DCM = 1 :25) followed by preparative HPLC (PrepMethod D, gradient: 15-35%) the title compound (40 mg, 17%) was obtained as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C21H24N9O: 418.2098, found: 418.2132. 1H NMR (300 MHz, DMSO-cfe) 6 ppm 1.46 - 1.64 (2H, m) 1.86 - 2.02 (2H, m), 2.07 - 2.27 (2H, m), 2.38 (3H, s), 3.40 (3H, s), 4.32 - 4.42 (2H, m), 6.59 (1 H, d), 6.92 (1 H, d), 7.13 (1 H, dd), 7.48 - 7.57 (3H, m), 7.93 (1 H, d), 8.10 (1 H, d), 8.17 (1 H, s).
EXAMPLE 213
1-Methyl-3-(6-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carbonitrile - compound 213
Figure imgf000241_0001
In analogy to Example 210 /V1-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-28b (135 mg, 0.70 mmol), 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1/7-imidazo[4,5- b]pyridine-5-carbonitrile compound i-81e (100 mg, 0.35 mmol), Pd-PEPPSI-lpentCI 2- methylpyridine (29 mg, 0.04 mmol) and CS2CO3 (342 mg, 1.05 mmol) were reacted in DMF (15 mL) at 100 °C for 15 h under nitrogen. Upon Celite filtration, aqueous work-up (EtOAc), preparative TLC (EtOAc: PE = 3:1) followed by preparative HPLC (PrepMethod Z5, gradient: 42- 88%) the title compound (6 mg, 4%) was obtained as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C22H23N10O: 443.2050, found: 443.2076. 1H NMR (300 MHz, DMSO-cfe) 6 ppm 1.49 - 1.64 (2H, m), 1.87 - 2.02 (2H, m), 2.13 - 2.21 (2H, m), 2.38 (3H, s), 3.44 (3H, s), 4.30 - 4.44 (2H, m), 6.61 (1 H, d), 7.01 (1 H, d), 7.49 (1 H, dd), 7.55 - 7.57 (1 H, m), 7.73 (1 H, d), 7.81 (1 H, d), 8.08 (1 H, d), 8.17 (1 H, s).
EXAMPLE 214
1-Methyl-3-(6-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile - compound 214
Figure imgf000241_0002
In analogy to Example 210 /V1-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-28b (135 mg, 0.70 mmol), 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1/7-imidazo[4,5- b]pyridine-6-carbonitrile compound i-82d (100 mg, 0.35 mmol), Pd-PEPPSI-lpentCI 2- methylpyridine (29 mg, 0.04 mmol) and CS2CO3 (342 mg, 1.05 mmol) were reacted in DMF (10 mL) at 100 °C for 16 h under nitrogen. Upon aqueous work-up (EtOAc), preparative TLC (EtOAc: PE = 1 :1) followed by preparative HPLC (PrepMethod O, gradient: 22-40%) the title compound (27 mg, 17%) was obtained as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C22H23N10O: 443.2050, found: 443.2056. 1H NMR (300 MHz, DMSO-cfe) 6 ppm 1.45 - 1.64 (2H, m), 1.85 - 2.01 (2H, m), 2.12 - 2.20 (2H, m), 2.38 (3H, s), 3.42 (3H, s), 4.29 - 4.43 (2H, m), 6.59 (1 H, d), 7.01 (1 H, d), 7.49 (1 H, dd), 7.57 (1 H, brs), 8.07 - 8.09 (2H, m), 8.17 (1 H, s), 8.42 (1 H, d).
EXAMPLE 220
4-Methoxy-2-(6-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-
3-yl)pyridazin-3(2H)-one - compound 220
Figure imgf000242_0001
re/-(1R,2R)-/V1,/\/2-Dimethylcyclohexane-1 ,2-diamine (64.6 mg, 0.45 mmol) was added to (1 S,3S)-/V1-(5-iodopyridin-2-yl)-/\/3-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-39a (180 mg, 0.45 mmol), 4-methoxypyridazin-3(2/7)-one (CAS Reg. No. 38732- 07-9) (115 mg, 0.91 mmol), Cu(l)l (87 mg, 0.45 mmol) and K2CO3 (188 mg, 1.36 mmol) in DMF (10 mL) at 20 °C. The resulting mixture was stirred at 100 °C for 15 h under a nitrogen atmosphere. The reaction mixture was poured into sat. brine (100 mL) and extracted with EtOAc (5 x 125 mL). The combined organic layers were washed with sat. brine (4 x 100 mL), dried over Na2SC>4, filtered and evaporated. The residue was purified by preparative TLC (MeOH : DCM = 1 :15) followed by preparative HPLC (PrepMethod O, gradient: 5-35%) to give the title compound (95 mg, 53%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H23N8O2: 395.1938, found: 395.1936. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.4-1.68 (2H, m), 1.82-2.03 (2H, m), 2.1-2.25 (2H, m), 2.39 (3H, s), 3.85 (3H, s), 4.23-4.49 (2H, m), 6.53 (1 H, d), 6.81 (1 H, d), 6.93 (1 H, d), 7.43-7.63 (2H, m), 7.90 (1 H, d), 8.08 (1 H, d), 8.17 (1 H, s).
EXAMPLE 221
4-Chloro-2-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)pyridazin-3(2H)-one - compound 221
Figure imgf000242_0002
re/-(1R,2R)-/V1,/\/2-Dimethylcyclohexane-1 ,2-diamine (71.8 mg, 0.50 mmol) was added to
(1 S,3S)-/V1-(5-iodopyridin-2-yl)-/\/3-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-39a (200 mg, 0.50 mmol), 4-chloropyridazin-3(2/7)-one (CAS Reg. No. 1677-79-8) (132 mg, 1.01 mmol), Cu(l)l (96 mg, 0.50 mmol) and K2CO3 (209 mg, 1.51 mmol) in DMF (15 mL) at 25 °C. The resulting solution was stirred at 100 °C for 18 h under a nitrogen atmosphere. The reaction mixture was concentrated, diluted with EtOAc (250 mL) and washed sequentially with sat. brine (3 x 75 mL). The organic layer was dried over Na2SO4, filtered and evaporated and the residue was purified by preparative TLC (MeOH : DCM = 1:15) followed by preparative HPLC (PrepMethod C, gradient: 18-33%) to give the title compound (55.4 mg, 27%) as a yellow solid. HRMS (ESI) m/z [M+H]+ calcd for Ci8H2oCIN80: 399.1442, found: 399.1428.
1H NMR (300 MHz, DMSO-d6) 5 ppm 1.44-1.66 (2H, m), 1.83-2.03 (2H, m), 2.08-2.25 (2H, m), 2.39 (3H, s), 4.25-4.47 (2H, m), 6.54 (1H, d), 7.02 (1 H, d), 7.48-7.61 (2H, m), 7.84 (1 H, d), 8.00 (1 H, d), 8.12 (1H, d), 8.18 (1 H, s).
EXAMPLE 222
6-Chloro-2-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)pyridazin-3(2H)-one - compound 222
Figure imgf000243_0001
re/-(1R,2R)-/V1,/\/2-Dimethylcyclohexane-1 ,2-diamine (71.8 mg, 0.50 mmol) was added to (1 S,3S)-/V1-(5-iodopyridin-2-yl)-/\/3-(6-methyl-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-39a (200 mg, 0.50 mmol), 6-chloropyridazin-3(2/7)-one (CAS Reg. No. 19064-67- 6) (132 mg, 1.01 mmol), Cu(l)l (96 mg, 0.50 mmol) and K2CO3 (209 mg, 1.51 mmol) in DMF (15 mL) at 25 °C. The resulting solution was stirred at 100 °C for 18 h under a nitrogen atmosphere. The reaction mixture was concentrated, diluted with EtOAc (250 mL) and washed sequentially with sat. brine (3 x 75 mL). The organic layer was dried over Na2SO4, filtered and evaporated and the residue was purified by preparative TLC (MeOH : DCM = 1:20) followed by preparative HPLC (PrepMethod D, gradient: 20-30%) to give the title compound (38 mg, 19%) as a yellow solid. HRMS (ESI) m/z [M+H]+ calcd for Ci8H2oCIN80: 399.1442, found: 399.1464. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.40 - 1.65 (2 H, m), 1.82 - 1.99 (2 H, m), 2.05 - 2.22 (2 H, m), 2.39 (3 H, s), 4.25 - 4.45 (2 H, m), 6.53 (1 H, d), 7.03 (1 H, d), 7.13 (1 H, d), 7.45- 7.72 (3 H, m), 8.11 (1 H, d), 8.18 (1 H, s).
EXAMPLE 247
2-(6-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)benzonitrile - compound 247
Figure imgf000244_0001
A mixture of (6-(((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)boronic acid compound i-76a (0.099 g, 0.32 mmol), 2-bromobenzonitrile (CAS Reg. No. 2042-37-7) (0.132 g, 0.72 mmol), Pd-118 (0.021 g, 0.03 mmol) and K2CO3 1.8 M (700 pL, 1.26 mmol) in 1 ,4-dioxane (3 mL) was stirred a 90 °C for 2 h. Solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and purified by preparative HPLC (PrepMethod F, gradient 30-70%) to afford (67 mg, 57%) of the title compound as a beige solid. HRMS (ESI) m/z [M+H]+ calcd for C21H22N7: 372.1932, found: 372.1938; 1H NMR (500 MHz, MeOH-d4) 6 ppm 1.57-1.72 (2H, m), 1.97-2.12 (2H, m), 2.23- 2.35 (2H, m), 2.43 (3H, s), 4.33-4.49 (2H, m), 6.63 (1 H, d), 7.45 (1 H, td), 7.5-7.55 (1 H, m), 7.62-7.72 (2H, m), 7.78 (1 H, dd), 8.16 (1 H, d), 8.18 (1 H, s).
EXAMPLE 248
(I S.SSJ-A^-fe-Methyl-l^^-triazin-S-yQ-A^-fS-methyl-^.S'-bipyridinJ-e'-yQcyclopentane-I.S- diamine - compound 248
Figure imgf000244_0002
A mixture of (6-(((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)boronic acid compound i-76a (0.104 g, 0.33 mmol), 2-bromo-3-methylpyridine (CAS Reg. No. 3430-17-9) (74 pL, 0.66 mmol), Pd-118 (22 mg, 0.03 mmol) and aq K2CO3 (1.8 M, 736 pL, 1.32 mmol) in 1 ,4-dioxane (3 mL) was stirred at 90 °C for 2 h. Solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and purified by preparative HPLC (PrepMethod F, gradient 20-60%) to afford (58 mg, 49%) of the title compound as a beige solid. HRMS (ESI) m/z [M+H]+ calcd for C20H24N7: 362.2088, found: 362.2074. 1H NMR (500 MHz, MeOH-d4) 6 ppm 1.58-1.73 (2H, m), 1.97-2.13 (2H, m), 2.24- 2.36 (2H, m), 2.38 (3H, s), 2.44 (s, 3H), 4.33-4.5 (2H, m), 6.63 (1 H, d), 7.27 (1 H, dd), 7.60 (1 H, dd), 7.73 (1 H, dd), 8.11 (1 H, s), 8.19 (1 H, s), 8.38 (1 H, d). EXAMPLE 249
(1 S,3S)-/V1-(5-(3,5-Dimethyl-1 H-pyrazol-1-yl)pyridin-2-yl)-/V3-(6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine - compound 249
Figure imgf000245_0001
A mixture of 6-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)boronic acid compound i-76a (0.122 g, 0.39 mmol), 3,5-dimethyl-1/7-pyrazole (CAS Reg. No. 67-51-6) (0.149 g, 1.55 mmol), diacetoxycopper (0.169 g, 0.93 mmol) and pyridine (0.17 mL, 2.1 mmol) in DCM (4 mL) and DMF (0.8 mL) was stirred at rt for 20 h. Solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and purified by preparative HPLC (PrepMethod F, gradient 20-60%) to yield a pale-blue solid. DCM and water were added to the solid. Phases were separated on a phase separator and the organic layer concentrated to afford (73 mg, 52%) of the title compound as an off-white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H25N8: 365.2196, found: 365.2186; 1H NMR (500 MHz, MeOH-d4) 6 ppm 1.56-1.71 (2H, m), 1.96-2.11 (2H, m), 2.19 (3H, s), 2.22 (3H, s), 2.24-2.33 (2H, m), 2.44 (3H, s), 4.36 (1H, p), 4.44 (1 H, p), 6.02 (1H, s), 6.61 (1H, d), 7.42 (1H, dd), 7.96 (1 H, d), 8.19 (1 H, s).
EXAMPLE 250
2,4-Dimethyl-1-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)-1H-imidazole-5-carbonitrile - compound 250
Figure imgf000245_0002
A mixture of (1S,3S)-/V1-(5-(5-iodo-2,4-dimethyl-1/7-imidazol-1-yl)pyridin-2-yl)-/\/3-(6-methyl- 1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-77b (40 mg, 0.08 mmol), cyanocopper (29 mg, 0.33 mmol) and Pd(OAc)2 (7.33 mg, 0.03 mmol) in NMP (1 mL) was stirred at 120 °C for 5 h. The mixture was concentrated, the residue dissolved in DCM and washed with water. The organic layer was concentrated under reduced pressure and purified by preparative HPLC (PrepMethod F, gradient 10-50%) to afford (3 mg, 9%) of the title compound as a beige solid. HRMS (ESI) m/z [M+H]+ calcd for C20H24N9: 390.2150, found: 390.2166. 1H NMR (500 MHz, MeOH-d4) 6 1.6-1.72 (2H, m), 2-2.12 (2H, m), 2.25-2.34 (5H, m), 2.34 (3H, s), 2.45 (3H, s), 4.36-4.5 (2H, m), 6.65 (1 H, dd), 7.44 (1 H, dd), 8.01 (1 H, d), 8.20 (1 H, s).
EXAMPLE 254
6'-(((1 S,3S)-3-((6-Methyl-5-oxo-4,5-dihydro-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2/-/- [1,3'-bipyridin]-2-one - compound 254
Figure imgf000246_0001
According to GM1A 6'-(((1 S,3S)-3-aminocyclopentyl)amino)-2/7-[1 ,3'-bipyridin]-2-one HCI compound i-1 c (283 mg, 0.92 mmol), 6-methyl-3-(methylsulfinyl)-1 ,2,4-triazin-5(4/7)-one compound i-80a (160 mg, 0.92 mmol) and DIPEA (484 pL, 2.77 mmol) were reacted in 1 ,4- dioxane (10 mL) at 100 °C for 15 h. The reaction mixture was diluted with sat. brine (100 ml) and extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative HPLC (PrepMethod E, gradient: 2-28%) to give the title compound (42 mg, 12%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H22N7O2: 380.1830, found: 380.1846. 1H NMR (300 MHz, MeOH-d4) 6 ppm 1.54 - 1.66 (2H, m), 2.00 (2H, t), 2.14 (3H, s), 2.21 - 2.32 (2H, m), 4.30 - 4.40 (2H, m), 6.47 (1 H, dt), 6.60 - 6.64 (2H, m), 7.45 (1 H, dd), 7.57 - 7.64 (2H, m), 7.95 (1 H, brd).
EXAMPLE 255
6'-(((1S,3S)-3-((6-Chloro-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2- one - compound 255
Figure imgf000246_0002
/V-chlorosuccinimide (NCS) (19 mg, 0.14 mmol) was added to a mixture of 6'-(((1 S,3S)-3- ((1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2/7-[1 ,3'-bipyridin]-2-one compound i-83b (50 mg, 0.14 mmol) in MeCN (2 mL) at 25 °C and it was stirred for 17 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :20) followed by preparative HPLC (PrepMethod O, gradient: 12- 42%) to give the title compound (5.7 mg, 10%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C18H19CIN7O: 384.1334, found: 384.1310. 1H NMR (300 MHz, MeOH-d4) 6 ppm 1.62 - 1.76 (2H, m), 2.10 (2H, t), 2.26 - 2.38 (2H, m), 4.45 - 4.54 (1 H, m), 4.58 - 4.67 (1 H, m), 6.47 (1 H, dt), 6.60 - 6.64 (1 H, m), 7.58 - 7.64 (2H, m), 7.69 (1 H, d), 8.00 (1 H, d), 8.25 (1 H, d), 8.46 (1 H, d).
EXAMPLE 256
6'-(((1S,3S)-3-((6-(Dimethylamino)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 256
Figure imgf000247_0001
According to GM2 CS2CO3 (183 mg, 0.56 mmol) was added to a mixture of 6'-(((1 S,3S)-3-((6- bromo-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2/7-[1 ,3'-bipyridin]-2-one compound i-84b (80 mg, 0.19 mmol), dimethylamine in THF (2 M, 0.28 mL, 0.56 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (16 mg, 2 pmol) in dioxane (5 mL) at rt and the resulting suspension was stirred at 100 °C for 16 h under nitrogen. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to afford crude product which was purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :25) followed by preparative HPLC (PrepMethod C, gradient: 15-33%) to give (17 mg, 23 %) of the title compound as a yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C20H25N8O: 393.2146, found: 393.2140. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.43 - 1.61 (2H, m), 1.82 - 1.97 (2H, m), 2.07 - 2.18 (2H, m), 2.96 (6H, s), 4.23 - 4.34 (2H, m), 6.27 (1 H, dt), 6.44 (1 H, d), 6.53 (1 H, d), 6.77 (1 H, d), 6.92 (1 H, d), 7.39 (1 H, dd), 7.47 (1 H, ddd), 7.61 (1 H, dd), 7.92 (1 H, d), 8.23 (1 H, s).
EXAMPLE 257
6,-(((1S,3S)-3-((6-(1H-Pyrazol-5-yl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 257
Figure imgf000247_0002
According to GM1A (1 S,3S)-/V1-(6-(1/7-pyrazol-5-yl)-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-85b 4TFA (370 mg, 0.53 mmol), 6'-fluoro-2/7-[1 ,3'-bipyridin]-2-one (CAS Reg. No. 2062643-92-7) compound i-100a (150 mg, 0.79 mmol) and K2CO3 (365 mg, 2.64 mmol) were reacted in DMSO (5 mL) at 100 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with sat. brine (3 x 50 mL), dried (Na2SC>4), filtered and evaporated to afford crude product which was purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :30) followed by preparative HPLC (PrepMethod D, gradient: 7-37%) the title compound (3.0 mg, 1.4%) as a pale yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C21 H22CIN9O: 416.1942, found: 416.1940. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.50 - 1.68 (2H, m), 1.92 - 2.05 (2H, m), 2.13 - 2.24 (2H, m), 4.30 - 4.51 (2H, m), 6.27 (1 H, dt), 6.44 (1 H, d), 6.54 (1 H, d), 6.81 (1 H, d), 6.96 (1 H, d), 7.40 (1 H, dd), 7.47 (1 H, ddd), 7.61 (1 H, dd), 7.85 - 7.93 (3H, m), 8.75 (1 H, s), 13.10 (1 H, brs).
EXAMPLE 258
6'-(((1S,3S)-3-((6-(Ethylthio)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- bipyridin]-2-one - compound 258
Figure imgf000248_0001
According to GM1A (1 S,3S)-/V1-(6-(ethylthio)-1 ,2,4-triazin-3-yl)cyclopentane-1 ,3-diamine compound i-86b 3.3TFA (123 mg, 0.20 mmol), 6'-fluoro-2/7-[1 ,3'-bipyridin]-2-one (CAS Reg. No. 2062643-92-7) compound i-100a (57 mg, 0.30 mmol) and Na2COs (106 mg, 1.00 mmol) were reacted in DMSO (5 mL) at 120 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with sat. brine (3 x 50 mL), dried (Na2SO4), filtered and evaporated to afford crude product which was purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :20) followed by preparative HPLC (PrepMethod T, gradient: 25-43%) to give the title compound (3.0 mg, 1.4%) as a pale-yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C20H24N7OS: 410.1758, found: 410.1750. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.26 (3H, t), 1.48 - 1.64 (2H, m), 1.88 - 1.99 (2H, m), 2.11 - 2.20 (2H, m), 3.10 (2H, q), 4.30 - 4.40 (2H, m), 6.27 (1 H, t), 6.44 (1 H, d), 6.53 (1 H, d), 6.94 (1 H, d), 7.40 (1 H, dd), 7.47 (1 H, ddd), 7.60 (1 H, dd), 7.77 (1 H, brs), 7.92 (1 H, d), 8.28 (1 H, s). EXAMPLE 260
6'-(((1 S,3S)-3-((6-Acetyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2/-/-[1,3'-bipyridin]-2- one - compound 260
Figure imgf000249_0001
In a slight variation of GM2 Pd-PEPPSI-lpentCI 2-methylpyridine (17 mg, 0.02 mmol) was added to a mixture of 1-(3-(((1 S,3S)-3-aminocyclopentyl)amino)-1 ,2,4-triazin-6-yl)ethan-1-one compound i-104b (180 mg, 0.81 mmol), 6'-chloro-2/7-[1 ,3'-bipyridin]-2-one compound i-29a (84 mg, 0.41 mmol) and CS2CO3 (398 mg, 1 .22 mmol) in DMF (10 mL) at 25 °C and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was concentrated under reduced pressure and taken up with EtOAc (200 mL). The organic layer was washed with sat. brine (3 x 50 mL), dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (DCM:MeOH = 15:1) followed by preparative HPLC (PrepMethod O, gradient: 15-36%) to give (17 mg, 5.4%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C20H22N7O2: 392.1830, found: 392.1850. 1H NMR (500 MHz, DMSO-cfe, 2 rotamers) 5 ppm 1.53-1.69 (2H, m), 1.89-2.04 (2H, m), 2.13-2.26 (2H, m), 2.60 (3H, s), 4.33-4.45 (1.5H, m), 4.66 (0.5H, q), 6.27 (1 H, dt), 6.44 (1 H, d), 6.54 (1 H, dd), 6.97 (1 H, dd), 7.41 (1 H, dd), 7.47 (1 H, ddd), 7.60 (1 H, d), 7.93 (1 H, d), 8.62 (0.5H, d), 8.66 (1 H, d), 9.10 (0.5H, d).
EXAMPLE 277
2-(6-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-oxo-
2,3-dihydropyridazine-4-carbonitrile - compound 277
Figure imgf000249_0002
A mixture of 4-chloro-2-(6-(((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)py- ridin-3-yl)pyridazin-3(2/-/)-one compound 221 (75 mg, 0.19 mmol), XPhos Pd G3 (CAS Reg. No. 1445085-55-1) (48 mg, 0.06 mmol), XPhos (27 mg, 0.06 mmol) and zinc cyanide (44 mg, 0.38 mmol) in DMF (10 mL) was sealed in a microwave tube under a nitrogen atmosphere and the resulting mixture was stirred at 140 °C for 1 h under microwave irradiation. The reaction mixture was quenched with sat. brine (150 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated and the residue was purified by preparative TLC (MeOH : DCM = 1 :10) followed by preparative HPLC PrepMethod O, gradient: 18-37%) to give the title compound (50 mg, 68%) as an orange solid. HRMS (ESI) m/z [M+H]+ calcd for C19H20N9O: 390.1786, found: 390.1802. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.44 - 1.63 (2H, m), 1.84 - 2.00 (2H, m), 2.07 - 2.23 (2H, m), 2.38 (3H, s), 4.29 - 4.43 (2H, m), 6.55 (1 H, d), 7.08 (1 H, d), 7.52 - 7.56 (2H, m), 8.14 (1 H, d), 8.17 (1 H, s), 8.19 (1 H, d), 8.22 (1 H, d).
EXAMPLE 281
4-(Difluoromethoxy)-2-(6-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one - compound 281
Figure imgf000250_0001
In a slight variation of GM3 (1 S,3S)-/V1-(5-iodopyridin-2-yl)-/\/3-(6-methyl-1 ,2,4-triazin-3- yl)cyclopentane-1 ,3-diamine compound i-39a (150 mg, 0.38 mmol), 4-(difluoromethoxy)pyrida- zin-3(2/-/)-one compound i-107e (184 mg, 1.14 mmol), K2CO3 (157 mg, 1.14 mmol), Cu(l)l (72 mg, 0.38 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine (56 mg, 0.39 mmol) were reacted in DMF (10 mL) at 100 °C for 18 h. The reaction mixture was diluted with EtOAc (150 mL) and the organic layer was washed sequentially with water (3 x 75 mL) and sat. brine (3 x 50 mL), dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :15) followed by preparative HPLC (PrepMethod D, gradient: 10-40%) to give the title compound (76 mg, 47%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H21F2N8O2: 431.1750, found: 431.1742. 1H NMR (300 MHz, DMSO-ds) 6 ppm 1.44 - 1.63 (2H, m), 1.84 - 2.00 (2H, m), 2.07 - 2.23 (2H, m), 2.38 (3H, s), 4.28 - 4.43 (2H, m), 6.54 (1 H, d), 7.00 (1 H, d), 7.24 (1 H, d), 7.46 (1 H, t), 7.52 (1 H, dd), 7.57 (1 H, brs), 8.02 (1 H, d), 8.11 (1 H, d), 8.17 (1 H, s). 19F NMR (282 MHz, DMSO-d6) 5 ppm -84.49 (2F, s).
EXAMPLE 304
(1 S,3S)-Af-(3-Methoxy-[2,3'-bipyridin]-6,-yl)-/V3-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-
1,3-diamine - compound 304
Figure imgf000251_0001
According to GM4A (6-(((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin- 3-yl)boronic acid compound i-76a (50 mg, 0.16 mmol), 2-bromo-3-methoxypyridine (CAS Reg. No. 24100-18-3) (60 mg, 0.32 mmol), aq. K2CO3 (1.8 M, 354 pL, 0.64 mmol) and 1 , 1 '-bis(di-tert- butylphosphino)ferrocene palladium dichloride (CAS Reg. No. 95408-45-0) (10 mg, 0.02 mmol) were reacted in 1 ,4-dioxane (1.5 mL) at 90 °C for 2 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by multiple preparative HPLC runs (PrepMethod Z10, gradient: 30-70% followed by PrepMethod G, gradient: 0-50% followed by PrepMethod Z9, gradient: 30-70%) to give the title compound (27 mg, 45%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C20H24N7O: 378.2036, found: 378.2044. 1H NMR (500 MHz, MeOH-d4) 6 ppm 1.57-1.72 (2H, m), 1.98-2.13 (2H, m), 2.24-2.35 (2H, m), 2.44 (3H, s), 3.90 (3H, s), 4.37 (1 H, p), 4.45 (1 H, p), 6.59 (1 H, d), 7.29 (1 H, dd), 7.50 (1 H, dd), 7.92 (1H, dd), 8.14 (1 H, dd), 8.19 (1 H, s), 8.49 (1 H, s).
EXAMPLE 305
(1 S,3S)-Af-(6-Methoxy-[2,3'-bipyridin]-6,-yl)-/V3-(6-methyl-1,2,4-triazin-3-yl)cyclopentane- 1,3-diamine - compound 305
Figure imgf000251_0002
According to GM4A (6-(((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin- 3-yl)boronic acid compound i-76a (50 mg, 0.16 mmol), 2-bromo-6-methoxypyridine (CAS Reg. No. 40473-07-2) (39 pL, 0.32 mmol), aq. K2CO3 (1.8 M, 354 pL, 0.64 mmol) and 1,1'-bis(di-tert- butylphosphino)ferrocene palladium dichloride (CAS Reg. No. 95408-45-0) (10 mg, 0.02 mmol) were reacted in 1 ,4-dioxane (1.5 mL) at 90 °C for 2 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z10, gradient: 30-70%) to give the title compound (18 mg, 30%) as an off-white solid. HRMS (ESI) m/z [M+H]+ calcd for C20H24N7O: 378.2036, found: 378.2030. 1H NMR (500 MHz, MeOH-d4) 6 ppm 1.57-1.73 (2H, m), 1.97-2.12 (2H, m), 2.23-2.35 (2H, m), 2.44 (3H, s), 3.97 (3H, s), 4.37 (1 H, p), 4.44 (1 H, p), 6.60 (2H, ddd), 7.27 (1 H, dd), 7.63 (1 H, dd), 8.09 (1 H, dd), 8.19 (1 H, s), 8.67 (1 H, d). EXAMPLE 306
(1 S,3S)-A/f-(5-(2-Methoxyphenyl)pyridin-2-yl)-A/3-(6-methyl-1,2,4-triazin-3-yl)cyclopentane- 1,3-diamine - compound 306
Figure imgf000252_0001
According to GM4A (6-(((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin- 3-yl)boronic acid compound i-76a (50 mg, 0.16 mmol), 1-bromo-2-methoxybenzene (CAS Reg. No. 578-57-4) (40 pL, 0.32 mmol), aq. K2CO3 (1.8 M, 354 pL, 0.64 mmol) and 1 , T-bis(di-tert- butylphosphino)ferrocene palladium dichloride (10 mg, 0.02 mmol) were reacted in 1 ,4-dioxane (1 .5 mL) at 90 °C for 2 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z10, gradient: 30-70%) to give the title compound (30 mg, 50%) as an off-white solid. HRMS (ESI) m/z [M+H]+ calcd for C2I H25N6O: 377.2084, found: 377.2086. 1H NMR (500 MHz, MeOH-d4) 6 ppm 1.56-1.72 (2H, m), 1.96-2.12 (2H, m), 2.23-2.35 (2H, m), 2.44 (3H, s), 3.80 (3H, s), 4.32 (1 H, p), 4.44 (1 H, p), 6.56 (1 H, dd), 6.98 (1 H, td), 7.03 (1 H, dd), 7.23 (1 H, dd), 7.27 (1 H, ddd), 7.60 (1 H, dd), 8.06 (1 H, d), 8.18 (1 H, s).
EXAMPLE 307
(1 S,3S)-Af-(5-(2,6-Dimethoxyphenyl)pyridin-2-yl)-/V3-(6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine - compound 307
Figure imgf000252_0002
According to GM4A (6-(((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin- 3-yl)boronic acid compound i-76a (50 mg, 0.16 mmol), 2-bromo-1 ,3-dimethoxybenzene (CAS Reg. No. 16932-45-9) (69 mg, 0.32 mmol), aq. K2CO3 (1.8 M, 354 pL, 0.64 mmol) and 1,1'- bis(di-terf-butylphosphino)ferrocene palladium dichloride (10 mg, 0.02 mmol) were reacted in 1 ,4-dioxane (1.5 mL) at 90 °C for 2 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z10, gradient: 30-70%) to give the title compound (45 mg, 70%) as an off-white solid. HRMS (ESI) m/z [M+H]+ calcd for C22H27N6O2: 407.2190, found: 407.2200. 1H NMR (500 MHz, MeOH-d4) 6 ppm 1.56-1.71 (2H, m), 1.96-2.12 (2H, m), 2.22-2.34 (2H, m), 2.43 (3H, s), 3.71 (6H, s), 4.30 (1 H, p), 4.44 (1 H, p), 6.54 (1 H, d), 6.69 (2H, d), 7.24 (1 H, t), 7.35 (1 H, dd), 7.79-7.86 (1 H, m), 8.18 (1 H, s).
EXAMPLE 308
(1 S,3S)-Af-(5-(2-Fluoro-6-methoxyphenyl)pyridin-2-yl)-/V3-(6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine - compound 308
Figure imgf000253_0001
According to GM4A (6-(((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin- 3-yl)boronic acid compound i-76a (50 mg, 0.16 mmol), 2-bromo-1-fluoro-3-methoxybenzene (CAS Reg. No. 446-59-3) (65 mg, 0.32 mmol), aq. K2CO3 (1.8 M, 354 pL, 0.64 mmol) and 1,1'- bis(di-terf-butylphosphino)ferrocene palladium dichloride (10 mg, 0.02 mmol) were reacted in 1 ,4-dioxane (1.5 mL) at 90 °C for 2 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z10, gradient: 30-70%) to give the title compound (39 mg, 62%) as an off-white solid. HRMS (ESI) m/z [M+H]+ calcd for C2I H24FN6O: 395.1990, found: 395.1964. 1H NMR (500 MHz, MeOH-d4) 6 ppm 1.56-1.72 (2H, m), 1.97-2.12 (2H, m), 2.23-2.35 (2H, m), 2.44 (3H, s), 3.78 (3H, s), 4.33 (1 H, p), 4.44 (1 H, p), 6.57 (1 H, dd), 6.77 (1 H, ddd), 6.87 (1 H, dt), 7.27 (1 H, td), 7.44 (1 H, ddd), 7.92 (1 H, s), 8.18 (1 H, s).
EXAMPLE 309
(1 S,3S)-Af-([2,3'-Bipyridin]-6,-yl)-/V3-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine
- compound 309
Figure imgf000253_0002
According to GM4A (6-(((1 S,3S)-3-((6-methyl-1 ,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin- 3-yl)boronic acid compound i-76a (50 mg, 0.16 mmol), 2-bromopyridine (CAS Reg. No. 109- 04-6) (30 pL, 0.32 mmol), aq. K2CO3 (1.8 M, 354 pL, 0.64 mmol) and 1 ,1 '-bis(di-tert- butylphosphino)ferrocene palladium dichloride (10 mg, 0.02 mmol) were reacted in 1 ,4-dioxane (1 .5 mL) at 90 °C for 2 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z10, gradient: 10-60%) to give the title compound (3 mg, 5%) as an off-white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H22N7: 348.1932, found: 348.1904.
EXAMPLE 310
(1S,3S)-Af-(5-(1H-Pyrazolo[3,4-b]pyridin-1-yl)pyridin-2-yl)-/V3-(6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine - compound 310
Figure imgf000254_0001
A mixture of 6-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)boronic acid compound i-76a (96 mg, 0.31 mmol), 1/7-pyrazolo[3,4-b]pyridine (CAS Reg. No. 271-73-8) (0.109 g, 0.92 mmol), diacetoxycopper (0.133 g, 0.73 mmol) and pyridine (0.14 mL, 1.7 mmol) in DCM (3 mL) and DMF (0.6 mL) was stirred at rt for 20 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z9, gradient: 0-60%) to give the title compound (8 mg, 7%) as an off-white solid. HRMS (ESI) m/z [M+H]+ calcd for C20H22N9: 388.1992, found: 388.2024. 1H NMR (500 MHz, MeOH-d4) 6 ppm 1.59-1.73 (2H, m), 2-2.16 (2H, m), 2.31 (2H, ddt), 2.44 (3H, s), 4.39 (1 H, p), 4.46 (1 H, p), 6.70 (1H, d), 7.29 (1H, dd), 8.01 (1 H, dd), 8.20 (1 H, s), 8.26 (1H, s), 8.29 (1 H, dd), 8.57 (1 H, dd), 8.59 (1 H, d).
EXAMPLE 311
(1S,3S)-Af-(5-(1H-lndazol-1-yl)pyridin-2-yl)-/V3-(6-methyl-1,2,4-triazin-3-yl)cyclopentane- 1,3-diamine - compound 311
Figure imgf000254_0002
A mixture of 6-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)boronic acid compound i-76a (100 mg, 0.32 mmol), indazole (CAS Reg. No. 271-44-3) (0.113 g, 0.95 mmol), diacetoxycopper (0.156 g, 0.86 mmol) and pyridine (0.15 mL, 1.9 mmol) in DCM (3 mL) and DMF (0.6 mL) was stirred at rt for 20 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z9, gradient: 30-70%) to give the title compound (7 mg, 6%) as solid along with its 2-regiosiomer (see compound 312). HRMS (ESI) m/z [M+H]+ calcd for C2I H23N8: 387.2040, found: 387.2030. 1H NMR (500 MHz, MeOH-d4) 6 ppm 1.59-1.73 (2H, m), 2-2.14 (2H, m), 2.24-2.37 (2H, m), 2.44 (3H, s), 4.40 (1 H, p), 4.46 (1 H, p), 6.71 (1H, d), 7.23 (1 H, ddd), 7.45 (1 H, ddd), 7.54 (1H, dd), 7.67 (1H, dd), 7.83 (1 H, dt), 8.14-8.26 (3H, m).
EXAMPLE 312
(1S,3S)-Af-(5-(2H-lndazol-2-yl)pyridin-2-yl)-/V3-(6-methyl-1,2,4-triazin-3-yl)cyclopentane- 1,3-diamine - compound 312
Figure imgf000255_0001
Isolated from the above reaction mixture: yield 2 mg, 1.6%. MS (ESI) m/z [M+H]+ 387.4.
1H NMR (500 MHz, MeOH-d4) 5 ppm 1.59-1.74 (2H, m), 1.99-2.13 (2H, m), 2.24-2.37 (2H, m), 2.45 (3H, s), 4.37-4.5 (2H, m), 6.69 (1 H, d), 7.11 (1H, ddd), 7.33 (1H, ddd), 7.66 (1 H, dd), 7.75 (1 H, dt), 7.93 (1 H, dd), 8.20 (1 H, s), 8.50 (1 H, d), 8.59 (1H, d).
EXAMPLE 313
(1S,3S)-Af-(5-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridin-2-yl)-/V3-(6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine - compound 313
Figure imgf000255_0002
A mixture of 6-(((1 S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)boronic acid compound i-76a (100 mg, 0.32 mmol), 3,5-dimethyl-4/7-1 ,2,4-triazole (0.093 g, 0.95 mmol) (CAS Reg. No. 7343-34-2) (93 mg, 0.95 mmol), diacetoxycopper (0.139 g, 0.76 mmol) and pyridine (0.15 mL, 1.9 mmol) in DCM (3 mL) and DMF (0.6 mL) was stirred at rt for 20 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z9, gradient: 20-60%) to give the title compound (31 mg, 27%) as solid. HRMS (ESI) m/z [M+H]+ calcd for CI8H24N9: 366.2150, found: 366.2160. 1H NMR (500 MHz, MeOH-d4) 5 ppm 1.57-1.72 (2H, m), 1.98-2.11 (2H, m), 2.22-2.32 (2H, m), 2.33 (3H, s), 2.39 (3H, s), 2.44 (3H, s), 4.34-4.49 (2H, m), 6.62 (1 H, dd), 7.48 (1 H, dd), 8.02-8.07 (1 H, m), 8.19 (1 H, s).
EXAMPLE 314
(1 S,3S)-Af-(5-(2,5-Dimethyloxazol-4-yl)pyridin-2-yl)-/V3-(6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine - compound 314
Figure imgf000256_0001
According to GM1A 4-(6-fluoropyridin-3-yl)-2,5-dimethyloxazole compound i-108b (83 mg, 0.43 mmol) was added to a mixture of the 3 TFA salt of (1 S,3S)-/V1-(6-methyl-1 ,2 ,4-triazin-3- yl)cyclopentane-1 ,3-diamine compound i-28b (393 mg, 0.73 mmol) and K2CO3 (537 mg, 3.89 mmol) in DMSO (3 mL). The resulting mixture was stirred at 80 °C for 1 week under a nitrogen atmosphere. The solids were filtered off and the filtrate was purified by preparative HPLC (PrepMethod Z9, gradient: 20-60%) to give the title compound (55 mg, 35%) as brown solid. HRMS (ESI) m/z [M+H]+ calcd for C19H24N7O: 366.2036, found: 366.2032. 1H NMR (500 MHz, MeOH-d4) 6 ppm 1.55-1.71 (2H, m), 1.96-2.11 (2H, m), 2.22-2.33 (2H, m), 2.42 (6H, s), 2.43 (3H, s), 4.33 (1 H, p), 4.43 (1 H, p), 6.59 (1 H, d), 7.62 (1 H, dd), 8.15 (1 H, d), 8.18 (1 H, s).
EXAMPLE 315 rac-6'-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)-3-methyl-2H- [1,3'-bipyridin]-2-one - compound 315
Figure imgf000256_0002
According to GM3 rac-4-((5-iodopyridin-2-yl)amino)-3-(((6-methyl-1 ,2,4-triazin-3-yl)amino)me- thyl)butan-1-ol compound i-109g (90 mg, 0.22 mmol), 3-methylpyridin-2(1/7)-one (CAS Reg. No. 1003-56-1) (24 mg, 0.22 mmol), CS2CO3 (142 mg, 0.43 mmol), Cu(l)l (21 mg, 0.11 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine (15 mg, 0.11 mmol) were reacted in 1 ,4-dioxane (15 mL) at 80 °C for 18 h under nitrogen. The reaction mixture was diluted with EtOAc (150 mL) and the organic layer was washed sequentially with water (3 x 75 mL) and sat. brine (3 x 50 mL), dried over Na2SC>4, filtered and evaporated and the crude material was purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :15) followed by preparative HPLC (PrepMethod X, gradient: 8-38%) to give the title compound (46 mg, 54%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C20H26N7O2: 396.2142, found: 396.2158. 1H NMR (400 MHz, DMSO-ds) 6 ppm 1.52 (2H, q), 2.02-2.06 (4H, m), 2.37 (3H, s), 3.32-3.38 (4H, m, partly covered by water peak), 3.52 (2H, q), 4.47 (1 H, t), 6.19 (1 H, t), 6.55 (1 H, d), 6.86 (1 H, brt), 7.35-7.40 (2H, m), 7.44-7.50 (2H, m), 7.89 (1 H, d), 8.16 (1 H, s).
EXAMPLE 316 rac-6'-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)-5-methyl-2H- [1,3'-bipyridin]-2-one - compound 316
Figure imgf000257_0001
According to GM3 rac-4-((5-iodopyridin-2-yl)amino)-3-(((6-methyl-1 ,2,4-triazin-3-yl)amino)me- thyl)butan-1-ol compound i-109g (100 mg, 0.24 mmol), 5-methylpyridin-2(1/7)-one (CAS Reg. No 1003-68-5) (53 mg, 0.48 mmol), CS2CO3 (157 mg, 0.48 mmol), Cu(l)l (23 mg, 0.12 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine (17 mg, 0.12 mmol) were reacted in 1 ,4-dioxane (15 mL) at 80 °C for 15 h under nitrogen. The reaction mixture was filtered through a filter membrane and the obtained residue purified by preparative TLC (DCM : MeOH = 10:1) followed by preparative HPLC (PrepMethod D, gradient: 10-28%) to give the title compound (35 mg, 37%) as a yellow solid. HRMS (ESI) m/z [M+H]+ calcd for C20H26N7O2: 396.2142, found: 396.2128. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.53 (2H, q), 2.03-2.06 (4H, m), 2.38 (3H, s), 3.30-3.39 (4H, m, partly covered by water peak), 3.53 (2H, q), 4.45 (1 H, t), 6.39 (1 H, d), 6.56 (1 H, d), 6.83 (1 H, t), 7.33-7.40 (3H, m), 7.48 (1 H, brs), 7.89 (1 H, d), 8.16 (1 H, s).
EXAMPLE 317 rac-6'-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)-5-methoxy-
2H-[1,3'-bipyridin]-2-one - compound 317
Figure imgf000258_0001
According to GM3 rac-4-((5-iodopyridin-2-yl)amino)-3-(((6-methyl-1 ,2,4-triazin-3-yl)amino)me- thyl)butan-1-ol compound i-109g (90 mg, 0.22 mmol), 5-methoxypyridin-2(1/7)-one (CAS Reg. No. 61941-79-5) (54 mg, 0.43 mmol), Cs2CO3 (142 mg, 0.43 mmol), Cu(l)l (21 mg, 0.11 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine (15 mg, 0.11 mmol) were reacted in 1 ,4-dioxane (15 mL) at 80 °C for 18 h under nitrogen. The reaction mixture was diluted with EtOAc (150 mL) and the organic layer was washed sequentially with water (3 x 75 mL) and sat. brine (3 x 50 mL), dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :15, 96 mg isolated) followed by preparative HPLC (PrepMethod X, gradient: 8-38%) to give the title compound (43 mg, 48%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C2oH26N703: 412.2092, found: 412.2090.
1H NMR (400 MHz, DMSO-d6) 5 ppm 1.52 (2H, q), 2.03 (1 H, qn), 2.33 (3H, s), 3.31-3.38 (4H, m, partly covered by water peak), 3.52 (2H, q), 3.64 (3H, s), 4.47 (1 H, t), 6.42 (1 H, d), 6.56 (1 H, d), 6.86 (1 H, t), 7.18 (1 H, d), 7.35 (1 H, dd), 7.42 (1 H, dd), 7.50 (1 H, brs), 7.95 (1 H, d), 8.16 (1 H, s).
EXAMPLE 318 rac-1-(6-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)pyridin-3- yl)quinolin-2(1H)-one - compound 318
Figure imgf000258_0002
According to GM2 the crude HCI salt of rac-4-amino-3-(((6-methyl-1 ,2,4-triazin-3- yl)amino)methyl)butan-1-ol compound i-109f (150 mg, 0.53 mmol), 1-(6-chloropyridin-3- yl)quinolin-2(1/-/)-one compound i-21 a (203 mg, 0.79 mmol), CS2CO3 (516 mg, 1.58 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (22 mg, 0.03 mmol) were reacted in 1 ,4-dioxane (10 mL) at 100 °C for 18 h under nitrogen. The reaction mixture was concentrated under reduced pressure and taken up with EtOAc (150 mL). The organic layer was washed with sat. brine (3 x 50 mL), dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (MeOH : DCM = 1 :20) followed by preparative HPLC (PrepMethod O, gradient: 19-34%) to give the title compound (37 mg, 16%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C23H26N7O2: 432.2142, found: 432.2148. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.56 (2H, q), 2.04-2.13 (1 H, m), 2.37 (3H, s), 3.32-3.42 (4H, m, partly covered by water peak), 3.55 (2H, q), 4.49 (1 H, t), 6.64-6.74 (3H, m), 6.93 (1 H, brt), 7.23 (1 H, t), 7.30 (1 H, dd), 7.45 (1 H, t), 7.52 (1 H, brs), 7.75 (1 H, d), 7.82 (1 H, t), 8.01 (1 H, d), 8.16 (1 H, s).
EXAMPLE 319 rac-3-(6-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)pyridin-3- yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one - compound 319
Figure imgf000259_0001
According to GM2 the crude HCI salt of rac-4-amino-3-(((6-methyl-1 ,2,4-triazin-3- yl)amino)methyl)butan-1-ol compound i-109f (153 mg, 0.54 mmol), 3-(6-chloropyridin-3-yl)-1- methyl-1 ,3-dihydro-2/7-imidazo[4,5-b]pyridin-2-one compound i-24a (140 mg, 0.54 mmol), CS2CO3 (875 mg, 2.69 mmol) and Pd-PEPPSI-lpentCI 2-methylpyridine (36 mg, 0.04 mmol) were reacted in 1 ,4-dioxane (20 mL) at 100 °C for 18 h under nitrogen and subsequently filtered through Celite. The filter cake was washed with DCM (2 x 10 mL), the combined filtrates concentrated under reduced pressure and the residue was purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :15) followed by preparative HPLC (PrepMethod O, gradient: 13-28%) to give the title compound (30 mg, 13%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C21H26N9O2: 436.2204, found: 436.2220. 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.53 (2H, q), 2.01-2.09 (1 H, m), 2.37 (3H, s), 3.30-3.40 (7H, m, partly covered by water peak), 3.53 (2H, q), 4.48 (1 H, t), 6.62 (1 H, d), 6.86 (1 H, t), 7.14 (1 H, dd), 7.49-7.58 (3H, m), 7.94 (1 H, dd), 8.08 (1 H, d), 8.16 (1 H, s).
EXAMPLE 320 rac-1-(6-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)pyridin-3- yl)-1,8-naphthyridin-2(1H)-one - compound 320
Figure imgf000260_0001
According to GM3 the crude HCI salt of rac-4-amino-3-(((6-methyl-1 ,2,4-triazin-3- yl)amino)methyl)butan-1-ol compound i-109f (248 mg, 0.87 mmol), 1-(6-chloropyridin-3-yl)-1 ,8- naphthyridin-2(1/-/)-one compound i-6a (150 mg, 0.58 mmol), CS2CO3 (569 mg, 1.75 mmol), Cu(l)l (111 mg, 0.58 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine (83 mg, 0.58 mmol) were reacted in 1 ,4-dioxane (10 mL) at 80 °C for 15 h under nitrogen. The reaction mixture was poured into water (125 mL) and the aqueous layer was extracted with EtOAc (4 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (7 M NH3 in MeOH : DCM = 1 :15) followed by preparative HPLC (PrepMethod O, gradient: 13-25%) to give the title compound (48 mg, 19%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C22H25N8O2: 433.2094, found: 433.2126. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.55 (2H, q), 2.02-2.11 (1 H, m), 2.38 (3H, s), 3.33-3.41 (4H, m, partly covered by water peak), 3.55 (2H, q), 4.49 (1 H, t), 6.61 (1 H, d), 6.75 (1 H, d), 6.78 (1 H, t), 7.25 (1 H, dd), 7.29 (1 H, dd), 7.54 (1 H, brs), 7.78 (1 H, d), 8.03 (1 H, d), 8.16 (1 H, s), 8.20 (1 H, dd), 8.44 (1 H, dd).
EXAMPLE 321 rac-1-(6-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)pyridin-3- yl)-3-methyl-1,3-dihydro-2H-benzo[cf]imidazol-2-one - compound 321
Figure imgf000260_0002
According to GM3 rac-4-((5-iodopyridin-2-yl)amino)-3-(((6-methyl-1 ,2,4-triazin-3-yl)amino)me- thyl)butan-1-ol compound i-109g (60 mg, 0.14 mmol), 1-methyl-1 ,3-dihydro-2/7-benzo[c(]imida- zol-2-one (CAS Reg. No. 1849-01-0) (43 mg, 0.29 mmol), CS2CO3 (142 mg, 0.43 mmol), Cu(l)l (28 mg, 0.14 mmol) and re/-(1R,2R)-/V1,/\/2-dimethylcyclohexane-1 ,2-diamine (21 mg, 0.14 mmol) were reacted in 1 ,4-dioxane (10 mL) at 80 °C for 15 h under nitrogen. The reaction mixture was concentrated under reduced pressure and taken up with EtOAc (200 mL). The organic layer was washed with sat. brine (3 x 50 mL), dried over Na2SO4, filtered and evaporated and the crude material was purified by preparative TLC (MeOH : DCM = 1 :15) followed by flash C18-flash chromatography (gradient: 0-40% MeCN in water) to give the title compound (20 mg, 32%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C22H27N8O2: 435.2252, found: 435.2282. 1H NMR (300 MHz, MeOH-cL) 5 ppm 1.67 (2H, q), 2.10-2.19 (1 H, m), 2.43 (3H, s), 3.37-3.58 (7H, m), 3.74 (2H, t), 6.71 (1 H, dd), 6.94 (1 H, d), 7.07-7.22 (3H, m), 7.48 (1 H, dd), 8.08 (1 H, dd), 8.19 (1 H, s).
Assays and methods used
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 IC50 of inhibitors of the interaction between the human PCSK9 and Alexa647 labelled small molecule, fluorescent probe displacement was monitored by homogenous TR- FRET technology. Upon binding of a terbium (Tb) cryptate conjugated anti-His mouse antibody (mAb Anti-6His Tb cryptate Gold, Cisbio) to PCSK9-TEV-His6, the displacement of the probe from PCSK9 was assessed by reduction of the proximity and FRET signal between the Tb cryptate that serves as a FRET -donor and the Alexa647 probe that serves as acceptor.
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 NaCI, 0.005 (v/v) % Tween 20). 6 pL were subsequently added to an assayready plate containing 0.06 pL of controls and test compound 10 dose-response serial dilutions starting at a concentration of 10 mM (with 100 pM 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.
Assay 2 - Biophysical human PCSK9 Assay
This assay measures binding of compounds to PCSK9 by SPR (“surface plasmon resonance”, a biophysical method). The 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 NaCI, 0.05% (v/v) Tween 20 pH 7.4.
For the surface tethering of PCSK9, biotinylated human PCSK9 (31-692)-Avi-His6 at a concentration of 0.5mg/mL was used. Prior to the surface tethering, the surface was exposed to a solution of 50mM NaOH, 500mM NaCI via 3 consecutive injections of this solution with a contact time of 60 s and a flowrate of 10 pL min-1 to remove non-conjugated streptavidin. The PCSK9 protein was diluted to a concentration of 20 pg/mL using running buffer and injected with a contact time of 180-300 s and a flowrate of 10 pL 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 (Rll). Remaining biotin binding sites were blocked via 2 consecutive injections of a 10 pM D-biotin solution in running buffer with a contact time of 60 s and a flowrate of 10 pL 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 pL 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 Rlls. Kinetic- and affinity data on active compounds are only provided for those compounds where the binding signal at the highest compound concentration (10mM) is > 50% of the theoretical maximum binding signal for a 1 :1 binding interaction (Rmax, typically between 15-20 RUs) in order to enable a proper fitting of the data.
Assay 3 - PCSK9 LDL-C uptake assay
This assay measures for PCSK9 antagonist activity based on a test compound’s capacity to restore LDL-C-uptake in HepG2 cells. The assay is based on exogenous PCSK9 and LDL-C complexed with a pH-sensitive dye. Outside the cells, at neutral pH, the pHrodo Red-LDL is dimly fluorescent but upon LDLR mediated endocytosis it fluoresces brightly. PCSK9 traffics the LDLR to intracellular degradation and reduces uptake of LDL-C. Inhibition of PCSK9 reduces LDLR degradation and the increased LDL-C uptake is quantified by fluorescence microscopy.
Preparation of assay reagents
Cell medium: MEM supplemented with 10% FBS, 1x NEAA and Sodium Pyruvate Assay medium: OptiMem supplemented with penicillin/streptomycin Cells: HepG2 (ATCC #HB-8065)
PCSK9: Sequence: MGTVSSRRSW WPLPLLLLLL LLLGPAGARA QEDEDGDYEE LVLALRSEED GLAEAPEHGT TATFHRCAKD PWRLPGTYVV VLKEETHLSQ SERTARRLQA QAARRGYLTK ILHVFHGLLP GFLVKMSGDL LELALKLPHV DYIEEDSSVF AQSIPWNLER ITPPRYRADE YQPPDGGSLV EVYLLDTSIQ SDHREIEGRV MVTDFENVPE EDGTRFHRQA SKCDSHGTHL AGVVSGRDAG VAKGASMRSL RVLNCQGKGT VSGTLIGLEF IRKSQLVQPV GPLVVLLPLA GGYSRVLNAA CQRLARAGW LVTAAGNFRD DACLYSPASA PEVITVGATN AQDQPVTLGT LGTNFGRCVD LFAPGEDIIG ASSDCSTCFV SQSGTSQAAA HVAGIAAMML SAEPELTLAE LRQRLIHFSA KDVINEAWFP EDQRVLTPNL VAALPPSTHG AGWQLFCRTV WSAHSGPTRM ATAIARCAPD EELLSCSSFS RSGKRRGERM EAQGGKLVCR
AHNAFGGEGV YAIARCCLLP QANCSVHTAP PAEASMGTRV HCHQQGHVLT
GCSSHWEVED LGTHKPPVLR PRGQPNQCVG HREASIHASC CHAPGLECKV KEHGIPAPQE QVTVACEEGW TLTGCSALPG TSHVLGAYAV DNTCVVRSRD VSTTGSTSEE AVTAVAICCR SRHLAQASQE LQENLYFQGH HHHHH
Step by step protocol for running the assay:
Day 1
1. Cryopreserved HepG2 cells were thawed in assay medium and centrifuged for 5 min at 250 g. Supernatant was discarded and the cell pellet resuspended in cell medium and counted with a Nucleocounter. Cells were again centrifuged 5min at 250 g and the pellet was resuspended to 500000 cells/mL in assay medium. 2. 20 pL of above cell mix was dispensed into black pclear TC treated 384 well plates with Multidrop Combi and left at room temperature for 20 minutes.
3. Plates were incubated at 37 °C, 5% CO2for 24 h Day 2
1. Test compounds were prepared in concentration response in DMSO with a half-log dilution factor in DMSO in Echo 384 LDV plates starting at 10 mM.
2. 30 nL of above test compounds were dispensed with Echo 655 to cells for a top concentration of 10 pM
3. 10 pL PCSK9 in assay medium was dispensed to cells with Multidrop Combi for 125 nM final concentration in the wells.
4. Plates were incubated at 37 °C, 5% CO2for 24 h
Day 3
1. 10 pL pHrodo Red-LDL in assay medium was dispensed to cells with Multidrop Combi for 6 pg/mL
2. Plates were incubated at 37 °C, 5% CO2 and imaged with the Incucyte S3 after 4 h and 24 h
Image data was processed using Incucyte 2021, a software to identify cells and red fluorescent intensity. Screener was used to further process data. Data was normalized as %effect of the signal between median values of the on-plate controls of DMSO and 100 nM Evolocumab according to the formula %effect=-100*(x - DMSO)/(Evolocumab - DMSO) where x equals the measured signal. Concentration response data of the normalized values were fitted using a four-parameter logistic fit.
Assay 4 - In vivo assessment of compound effects on plasma LDL-C levels
A liver-specific human PCSK9 knock-in mouse model (hPCSK9-KI) was generated by expressing human PCSK9 under the control of a mouse albumin promoter/enhancer in C57BL/6N mice as previously described in Carreras 2019. For all in vivo studies, heterozygous male hPCSK9-KI mice and their wildtype littermates were housed individually, and heterozygous female hPCSK9-KI mice were house in groups of 4-6 mice per cage. All animals had free access to enrichment and were housed in a temperature-controlled room (22 °C) with a 12: 12-h light/dark cycle. They were fed a chow diet and water ad libitum.
For in vivo assessment of test compound activity, mice were randomised into experimental groups of for example 8 mice per group. Mice were ~ 12 weeks of age at the time of study start. On day -1, blood samples were drawn from the tail vein and baseline levels of plasma LDL-C were assessed using an enzymatic method. Baseline plasma levels of human PCSK9 were assessed by ELISA. Starting on day 0, test compounds were dosed by oral gavage at for example15 mg/kg BID for up to 21 days. Blood samples were drawn from the tail vein and plasma levels of LDL-C and human PCSK9 were assessed using the afore mentioned methods.
Assay 5 - hERG assay (human Ether-a-go-go-Related Gene)
This assay (human Ether-a-go-go-Related Gene) measures activity of the compounds at the potassium ion channel hERG (human Ether-a-go-go-Related Gene).
Experiments were performed on the SyncroPatch 384PE high throughput patch clamp platform at room temperature and medium resistance chips with 4 patch holes per site. Chinese hamster ovary K1 (CHO) cell lines over-expressing the ion channel of choice (hERG) were used in assay-ready format and kept in liquid nitrogen or were used from live culture. Cells were either thawed and diluted in HBSS or were detached from flasks and resuspended in HBSS. HBSS comprised 140 mM NaCI, 4mM KCI, 10mM HEPES and 5mM Glucose (pH7.4). The internal patch clamp solution was KF 120 mM, KCI 20 mM, HEPES 10 mM, EGTA 10 mM, and 25 pM Escin (pH 7.2). After the sealing process was complete, the external solution was exchanged for external patch clamp solution comprising NaCI 80 mM, KCI 4 mM, HEPES 10 mM, CaCl2 2 mM, MgCh 1 mM, glucose 5 mM, and NMDG 60 mM (pH 7.4). All solutions were stored at room temperature, except Escin, which was stored at 4 °C. All test compounds were dispensed in greiner-bio 384 well plates and tested in a 6 point cumulative assay (final DMSO concentration 0.33%). Only wells that passed previously agreed acceptance criteria for this platform were used in this analysis (30 MegaOhm seal resistance, Z prime >0.4 and current size >0.2 nA).
High concentration hERG
Experiments were performed on the QPatchll high throughput patch clamp platform at room temperature using single holes QChips. Chinese hamster ovary K1 (CHO) cell lines overexpressing 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 6 - GSK3p Assay (ThermoFisher assay)
This assay measures the activity of the compounds at GSK3p (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 pM.
Assay Protocol
Bar-coded Corning, low volume NBS, black 384-well plate
1. 2.5 pL - 4X Test Compound or 100 nL 100X plus 2.4 pL kinase buffer
2. 5 pL - 2X Peptide/Kinase Mixture
3. 2.5 pL - 4X ATP Solution
4. 30-second plate shake
5. 60-minute Kinase Reaction incubation at room temperature
6. 5 pL - Development Reagent Solution
7. 30-second plate shake
8. 60-minute Development Reaction incubation at room temperature
9. Read on fluorescence plate reader and analyse the data
In step 2, the 2X GSK3P (GSK3 beta) I 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 MgCh, 1 mM EGTA (egtazic acid). The final 10 pL Kinase Reaction consists of 0.22 - 0.92 ng GSK3P (GSK3 beta) and 2 pM Ser/Thr 09 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCI2, 1 mM EGTA.
In step 3 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 MgCI2, 1 mM EGTA).
In 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).
Graphing Software
SelectScreen® Kinase Profiling Service uses XLfit from I DBS. 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.
Table 10 - Activity results in Assays 1, 2, 5 and 6 for compounds 1-80
Figure imgf000267_0001
Figure imgf000268_0001
Table 11 - Activity results in Assays 1, 2, 5 and 6 for compounds 112-138
Figure imgf000268_0002
Figure imgf000269_0001
Table 12 - Activity results in Assay 3
Figure imgf000269_0002
Figure imgf000270_0001
Table 13 - Activity results in Assays 1, 2, 3, 5 and 6 for compounds 151-314
Figure imgf000271_0001
Figure imgf000272_0001
The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the disclosure in diverse forms thereof.
While the disclosure has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the disclosure.
For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.
Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise” and “include”, and variations such as “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means for example +/- 10%.
References
A number of publications are cited above in order to more fully describe and disclose the compound of formula (I) and the state of the art to which it pertains. Full citations for these references are provided below. The entirety of each of these references is incorporated herein.
Figure imgf000273_0001
Figure imgf000274_0001
For standard molecular biology techniques, see Sambrook, J., Russel, D.W. Molecular Cloning, A Laboratory Manual. 3 ed. 2001, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press.
Numbered statements 1. A compound of Formula (I) A-B-C (I) or a pharmaceutically acceptable salt, tautomeric forms or stereoisomers thereof, wherein A is of the following:
Figure imgf000275_0001
wherein the wavy line indicates the point of attachment to B; X1 is N; RA2 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) C1-6 alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups; (vi) C1-6 acyl amido (wherein the acyl is optionally substituted by H or methyl); (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, OH, C2-3 alkynyl, C4-6 heterocyclyl or C1-3 alkyl wherein the C1-3 alkyl is optionally substituted with one or more halo or OH groups; and (xiii) OH; and (xiv) C1-6 alkylamino; RA3 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6hydrocarbon optionally substituted by OH, CN, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkyl acyl, C1-6 acyloxy, carboxy, C1-6 alkyl ester, C1-6 alkylamino, -C(=O)NH2, C1-6 alkyl amido, C1-6 alkyl acylamido, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl or one or more halo groups; (v) OH; (vi) C1-6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclyl or one or more halo groups; (vii) C1-6 acyloxy; (viii) C4 heterocycyl; (ix) -NH2; (x) C1-6 alkylamino, optionally substituted by CN, OH or C4 heterocyclyl; (xi) C1-6 dialkylamino, optionally substituted by -NH2; (xii) C1-6 acylamido (where acyl substituent is H or Me); (xiii) carbaimidoyl or methyl-carbaimidoyl; (xiv) carboxyamino; (xv) C1-6 thioalkyl, optionally substituted by OH or NH2; (xvi) C1-6 alkyl sulfinyl; (xvii) C1-6 alkyl sulfonyl, optionally substituted by one or more halo groups; (xviii) C1-6 sulfonimodyl; (xix) C1-6 alkyl phosphinyl; (xx) carboxy; (xxi) C(=O)NH2 (xxii) C1-6 alkyl ester; (xxiii) C1-6 alkyl acyl, optionally substituted by one or more halo groups; (xxiv) C1-6 alkyl amido; or wherein RA3 and RA2 together with the carbon atoms to which they are bound form: (i) an optionally substituted C5-7 heterocycle ring; (ii) an optionally substituted C5-7 heteroaromatic ring; (iii) an optionally substituted C6 carboaromatic ring; (iv) an optionally substituted C5-7 carbocyclic ring wherein the optional substituents are selected from C1-6 alkyl, halo, C1-6 alkoxy, NH2, C1-6 alkylamino, OH, and CN; wherein B is of formula (B-1) or (B-2) i)
Figure imgf000276_0001
wherein the wavy line indicates the point of attachment to A and C; RB1 is H, OH, =CHCH2-OH, -O-C1-4 alkyl or C1-4 alkyl, wherein the C1-4alkyl is optionally substituted by OH or OMe; (ii)
Figure imgf000277_0001
wherein the wavy line indicates the point of attachment to A and C; RB2 is C1-2 alkyl-OH, CH2CONHMe or C1-3 alkyl; wherein C is selected from the group consisting of C6-10 carboaryl, C5-6 heteroaryl and C5-10 heterocyclyl, which groups are optionally substituted by: (i) C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl C4-10 heterocyclyl, or C5-10 bridged heterocyclyl, spiro C6-12heterocyclyl or a spiro C6-12carbocyclyl, which are themselves optionally substituted by one or more of the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C1-6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1-6 alkoxy with optional substituents of one or more halo groups; f) C1-6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; h) C5-6 heteroaryl; i) C4-10 carbocyclyl with an optional methyl or =O substituent; j) C6-10 carboaryl with optional substituents of one or more halo groups; l) P(=O)Me2; m) carboxy or CH2-carboxy; n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; (ii) one or more groups selected from carboxy, CN, halo, nitro, C1-6 alkyl, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkylacyl, C1-6 alkyl amido, di-C1-6 alkyl amido, C1-6 alkyl sulfonamido, and di-C1-6 alkyl sulfonamido. 2. The compound of statement 1 or a pharmaceutically acceptable salt thereof, wherein RA2 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) C1-6 alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups; (vi) C1-6 acyl amido (wherein the acyl is optionally substituted by H or methyl); (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 or C1-3 alkyl wherein the C1-3 alkyl is optionally substituted with one or more halo or OH groups; and (xiii) OH. 3. The compound of statement 1 or a pharmaceutically acceptable salt thereof, wherein RA2 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6acyl, C1-6alkoxy or one or more halo groups; (v) OH; (vi) C1-6 alkoxy, optionally substituted by OH, C1-6 alkyl amido, or one or more halo groups; (vii) C1-6 alkyl ester; (viii) C1-6 alkyl acyl; (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; and (x) C1-6 alkylamino. 4. The compound of any one of statements 1 -3 or a pharmaceutically acceptable salt thereof, wherein RA2 is selected from the group consisting of: (i) H; (ii) halo; (iii) CN; (iv) C1-6 hydrocarbon, optionally substituted by OH, CN, C1-6acyl, C1-6alkoxy or one or more halo groups; (v) OH; (vi) C1-6 alkoxy, optionally substituted by OH, C1-6 alkyl amido, or one or more halo groups; (vii) C1-6 alkyl ester; (viii) C1-6 alkyl acyl; 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. 5. The compound of any of statements 1, 3, or 4 or a pharmaceutically acceptable salt thereof, wherein RA2 is selected from the group consisting of: (i) H; (ii) halo; (iii) C1-6 alkyl ester; (iv) C1-6 hydrocarbon; (v) C1-6 alkyl amido optionally substituted by C1-3 alkyl amido, C2-3 alkynyl, C4-6 heterocyclyl, or C1-3 alkyl which alkyl is optionally substituted with one or more halo or OH groups; (vi) C1-6 thioalkyl; (vii)C1-6 alkyl acyl; (viii) C5 heteroaryl; or (ix) C1-6 alkylamino. 6. The compound of any one of statements 1 to 5 or a pharmaceutically acceptable salt thereof, wherein RA2 is selected from the group consisting of -CN, methyl, Cl, -C(=O)CH3, -C(=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -OCHF2, H, -OMe, and -OCF3. 7. The compound of any one of statement 1 to 6 or a pharmaceutically acceptable salt thereof, wherein RA2 is selected from the group consisting of -C(=O)OCH2CH3, cyclopropyl, methyl, H, Cl,- C(=O)CH3, S-ethyl, pyrazole, -N(CH3)2, - C(=O)NH(CH2C(=O)NH2, -C(=O)NHCH2C≡CH, - C(=O)NH(oxetane), -C(=O)NH(CH2CHF2), -C(=O)NH(CH2CH3), -C(=O)NH2, - C(=O)NH(CH3), -C(=O)N(CH3)2, -C(=O)N(CH3)(CH2CH2OH), -C(=O)N(CH3)(CH2C≡CH or -C(=O)NH(CH2CH2OH). 8. The compound of any one of statements 1 to 7 or a pharmaceutically acceptable salt thereof, wherein RA2 is selected from the group consisting of -OCHF2, methyl, and cyclopropyl. 9. The compound of any one of statements 1 to 8 or a pharmaceutically acceptable salt thereof, wherein RA3 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 alkyl acyl C1-6 acyloxy, carboxy, C1-6 alkylester, C1-6 alkylamino; -C(=O)NH2, C1-6 alkyl amido, C1-6 alkylacylamido, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl or one or more halo groups; (v) OH; and (vi) C1-6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclyl or one or more halo groups. 10. The compound of any one of statements1 to 9 or a pharmaceutically acceptable salt thereof, wherein RA3 is selected from the group consisting of H, CF3, CN, C1-2 alkyl, NH2 and halo. 11. The compound of any one of statements 1 to 10 or a pharmaceutically acceptable salt thereof, wherein RA3 is selected from the group consisting of H, CN and methyl. 12. The compound of any one of statements 1 to 9 or a pharmaceutically acceptable salt thereof, wherein RA3 is selected from the group consisting of H, methyl and OH. 13. The compound of statement 1 or a pharmaceutically acceptable salt thereof, wherein RA3 and RA2 together with the carbon atoms to which they are bound form an optionally substituted C6 carboaromatic ring or C5 heteroaromatic ring, wherein the optional substituents are selected from methyl, NH2, Cl, F and OMe. 14. The compound of statement13 or a pharmaceutically acceptable salt thereof, wherein RA2 and RA3 together with the carbon atoms to which they are bound form: (i) an optionally substituted C6 heteroaryl ring; wherein the optional substituent is NH2 (ii) an optionally substituted C6 carboaryl ring, wherein the optional substituent is f, OMe, Cl; or (iii) an optionally substituted C5 heteroaryl or C5 heterocyclic ring wherein the optional substituents are methyl. 15. The compound of statement 13 or a pharmaceutically acceptable salt thereof, wherein RA3 and RA2 together with the carbon atoms to which they are bound form: an unsubstituted 2- pyrazole; a 2-pyrrole substituted by methyl; a pyridine optionally substituted by NH2; or a phenyl optionally substituted by Cl, F or OMe.
16. The compound of any one of statements 1 to 15 or a pharmaceutically acceptable salt thereof, wherein B is of formula (B-1)
Figure imgf000281_0001
wherein the wavy line indicates the point of attachment to A and C; wherein RB1 is selected from the group consisting of H, OH, OMe, -O-Ethyl, -CH2OH, -CH2CH2OH and =CHCH2-OH.
17. The compound of statement 16 or a pharmaceutically acceptable salt thereof, wherein RB1 is selected from the group consisting of -CH2OH, -CH2CH2OH and =CHCH2-OH.
18. The compound of any one of statements 1 to 16 or a pharmaceutically acceptable salt thereof, wherein B is of the following formula (B-1a):
Figure imgf000281_0002
(B-1 a).
19. The compound of any one of statements 1 to 16 or claim 18 or a pharmaceutically acceptable salt thereof, wherein B is of the following formula (B-1 b):
Figure imgf000281_0003
(B-1 b).
20. The compound of any one of statements 1 to 15 or a pharmaceutically acceptable salt thereof, wherein B is of the following formula:
Figure imgf000282_0001
21. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted C5-6 heteroaryl. 22. The compound of any one of statements 1 to 21 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl, wherein the optional substituents are selected from C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl, C5-10 heterocyclyl, C5-10 bridged heterocyclyl, spiro C6-12 heterocyclyl or a spiro C6-12 carbocyclyl, which are themselves optionally substituted by one or more of the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2 or OH; d) one or more C1-6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1-6 alkoxy with optional substituents of one or more halo groups; f) C1-6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; h) C5-6 heteroaryl; i) C4-10 carbocyclyl with an optional methyl or =O substituent; j) C6-10 carboaryl with optional substituents of one or more halo groups; l) P(=O)Me2; m) carboxy or CH2-carboxy; and/or n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl. 23. The compound of any one of statements 1 to 22 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl wherein the optional substituents are selected from C6 heteroaryl or C6 heterocyclyl, which are themselves optionally substituted by one or more groups selected from the following: i) one or two =O groups; ii) methyl; iii) OMe; iv) Cl; v) CN; vi) CF3; vii) F; viii) pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl; ix) O-CF3; x) O-CHF2.
24. The compound of any one of statements 1 to 22 or a pharmaceutically acceptable salt thereof, wherein C is substituted by Ce-w carboaryl, C5-10 heteroaryl, or C5-10 heterocyclyl, which are themselves optionally substituted by: a) one or two =0 groups; b) one or more halo groups, CN or NH2; c) one or more Ci-e alkyl groups, Ci-e alkoxy, or Ci-ealkylester, wherein each group is optionally substituted by one or more halo groups; d) C5-6 heterocyclyl or C5-6 heteroaryl with an optional methyl substituent; e) Ce-w carboaryl optionally substituted by one or more halo atoms; f) carboxy or CH2-carboxy; or g) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1 ,2,4-oxadiazol-3-yl.
25. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is a Ce-w carboaryl, C5-6 heteroaryl and C5-10 heterocyclyl, wherein each group is substituted by methyl.
26. The compound of statement 25 or a pharmaceutically acceptable salt thereof, wherein the methyl group on C is at the para position.
27. The compound of any one of statements 1 to 24 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted pyridinyl wherein the optional substituent is phenyl or pyridyl which are themselves optionally substituted by one or more groups selected from the following: a) one or more OMe groups; b) one or more F groups; c) CN; d) tetrazole; or e) carboxy. 28. The compound of any one of statements 1 to 22 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted pyridinyl wherein the optional substituent is a Cs heteroaryl or Cs heterocyclyl which are themselves optionally substituted by one or more substituents selected from methyl and CN.
29. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is of the formula (C-1):
Figure imgf000284_0001
(C-1) wherein D is Ce-w carboaryl, C5-10 heteroaryl or C5-10 heterocyclyl, each which are themselves optionally substituted by: i) one or two =0 groups; ii) one or two C1.4 alkyl groups which can be branched; iii) OMe; iv) piperazinyl, optionally substituted by methyl; v) C(=O)OH (carboxy); vi) Cl; vii) F; viii) phenyl, optionally substituted by one or more fluoro; ix) CN; x) CF3; xi) O-CF3; xii) tetrazolyl, pyrazolyl, triazolyl each of which is optionally substituted by methyl; xiii) NH2; xiv) pyridinyl; xv) CH2OH; xvi)0H; xvii) P(=O)Me2; or xviii) OCHF2.
30. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is of the formula (C-1):
Figure imgf000285_0001
(C-1) wherein D is Ce-w carboaryl, C5-10 heteroaryl or C5-10 heterocyclyl, each which are themselves optionally substituted by: i) one or two =0 groups; ii) one or two C1.4 alkyl groups which can be branched; iii) OMe; iv) piperazinyl, optionally substituted by methyl; v) C(=O)OH (carboxy); vi) Cl; vii) F; viii) phenyl, optionally substituted by one or more fluoro; ix) CN; x) CF3; xi) O-CF3; xii) tetrazolyl, pyrazolyl, triazolyl; xiii) NH2; xiv)(CH3)2; xv) pyridinyl; xvi)CH2OH; xvii) OH; xviii) P(=0)Me2.
31 . The compound of statements 29 or 30 or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by =0 at the ortho position, wherein the optional substituents are selected from: i) methyl; ii) OMe; iii) piperazinyl substituted by methyl; iv) C(=O)OH (carboxy); v) Cl; vi) phenyl substituted by fluoro; vii) CN; viii) CF3; ix) O-CF3; x) F; or xi) pyrazolyl, triazolyl or tetrazolyl each of which is optionally substituted by methyl.
32 The compound of statements 29 or 30 or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by =0 at the ortho position, wherein the optional substituents are selected from: i) methyl; ii) OMe; iii) Cl; iv) F; v) CN; vi) CF3; vii) O-CF3; viii) O-CHF2; or ix) pyrazolyl, triazolyl or tetrazolyl each of which is optionally substituted by methyl.
33. The compound of any one of statements 29 to 32 or a pharmaceutically acceptable salt thereof, wherein D is of the formula (D-1):
Figure imgf000286_0001
wherein one or two of RD1, RD2, RD3 and RD4 are selected from i) C1.6 alkyl, optionally substituted by one or more halo groups; ii) C1.6 alkoxy, optionally substituted by one or more halo groups; iii) C5-6 heterocyclyl or C5-6 heteroaryl with an optional methyl substituent; iv) carboxy or CH2-carboxy; v) =0, halo, NH2 or CN; vi) phenyl, optionally substituted by one or more halo atoms; and the rest are H; or wherein RD3 and RD4 form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo and C(=O)OH; or wherein RD1, RD2, RD3 and RD4 are all H.
34. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein one or two of RD1, RD2, RD3 and RD4 are selected from: i) methyl; ii) OMe; iii) piperazinyl substituted by methyl; iv) C(=O)OH (carboxy); v) Cl; vi) phenyl substituted by fluoro; vii) ON; viii) CF3; ix) O-CF3 x) F; xi) pyrazolyl, triazolyl or tetrazolyl; and the rest of RD1, RD2, RD3 and RD4 are H.
35. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein one or two of RD1, RD2, RD3 and RD4 are selected from: i) methyl; ii) OMe; iii) Cl; iv) CN; v) CF3; vi) F; vii) pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl; viii) O-CF3 ix) O-CHF2 and the rest of RD1, RD2, RD3 and RD4 are H.
36. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein RD1, RD2, RD3 and RD4 are H. 37. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein RD3 is selected from the group consisting of: H; optionally substituted phenyl, wherein the optional substituent is halo, methyl, OMe, C(=O)OH, Cl, CN; or piperazinyl optionally substituted by methyl; or pyrazolyl, triazolyl, or tetrazolyl, and wherein RD1, RD2 and RD4 are all H.
38. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein RD3 is selected from H, CN, OMe, Cl, pyrazole optionally substituted by methyl, tetrazole, methyl, OCHF2, or triazole and wherein RD1, RD2 and RD4 are all H.
39. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein RD1 is selected from H, methyl, OMe, Cl, F, CF3, OCF3, and CN, and wherein RD2, RD3 and RD4 are all H.
40. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein RD1 is selected from H, OMe, Cl, CF3, OCF3, OCHF2, CN, F, pyrazole optionally substituted by methyl and triazole and RD2, RD3 and RD4 are all H.
41 . The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein RD3 and RD4form an unsubstituted benzene ring or an unsubstituted pyridine ring.
42. The compound of statements 29 or 30 or a pharmaceutically acceptable salt thereof, wherein C is of the formula (C-1) and D is an optionally substituted phenyl or piperidyl, wherein there are one or two optional substituents selected from F, OMe and CN.
43. The compound of statements 29 or 30 or a pharmaceutically acceptable salt thereof, wherein D is of the formula (D-2):
Figure imgf000288_0001
wherein XD is NRD5a or CRD5aRD5b;
RD5a is selected from H or methyl; either RD5b and RD6b are both H or together they are -CH2-;
RD6a is selected from H, =0, methyl, -CH2OH or -C(=O)OH, wherein when RD6a is =0, RD6b is absent;
RD7a is selected from H, =0, methyl, -CH2OH or -C(=O)OH;
RD7b is H, wherein when RD7a is =0, RD7b is absent; or wherein RD6a and RD7a together form a benzene ring or a Ce heteroaromatic ring which is optionally substituted by CN, P(=0)Me2 or carboxy and RD6b and RD7b are absent.
44. The compound of statement 43 or a pharmaceutically acceptable salt thereof, wherein: a) when RD6a and RD6b are H, RD7a is selected from =0, carboxy or CH2OH and RD7b is H or when RD7a is =0, RD7b is absent; b) when RD7a is H, RD7b is H, RD6a is =0 and RD6b is absent.
45. The compound of statement 43 or a pharmaceutically acceptable salt thereof, wherein RD6a and RD7a together form a benzene ring or a Ce heteroaromatic ring which is optionally substituted by CN, C(=O)OH or P(=0)Me2 and RD6b and RD7b are absent.
46. The compound of statement 43 or a pharmaceutically acceptable salt thereof, wherein RD6a and RD7a form an unsubstituted benzene ring or an unsubstituted pyridine ring and RD6b and RD7b are absent.
47. The compound of statements 29 or 30 or a pharmaceutically acceptable salt thereof, wherein D is selected from the following groups:
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
48. The compound of statements 29 or 30 or a pharmaceutically acceptable salt thereof, wherein D is selected from the following groups:
Figure imgf000292_0002
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0002
49. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is of the formula (C-2):
Figure imgf000295_0001
wherein one of RC7, RC8, RC9 and RC1° are selected from the group consisting of: methyl; OMe; piperazinyl optionally substituted by methyl; C(=O)OH (carboxy); Cl; F; pyrazolyl optionally substituted by methyl; triazolyl; tetrazole; optionally substituted phenyl (wherein the optional substituent is methyl or halo); CN; CF3; O-CHF2, O-CF3; and the rest of RC7, RC8, RC9 and RC1° are H; or
RC9 and RC1° form a benzene or 6 membered heteroaromatic ring, and RC7 and RC8 are both H; or wherein RC7, RC8, RC9 and Rc10 are all H.
50. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is of the formula (C-2):
Figure imgf000296_0001
wherein one of RC7, RC8, RC9 and RC1° are selected from the group consisting of: methyl; OMe; piperazinyl optionally substituted by methyl; C(=O)OH (carboxy); Cl; F; pyrazolyl; triazolyl; tetrazole; optionally substituted phenyl (wherein the optional substituent is methyl or halo); CN;
CF3; O-CF3; and the rest of RC7, RC8, RC9 and RC1° are H; or
RC9 and RC1° form a benzene or 6 membered heteroaromatic ring, and RC7 and RC8 are both H; or wherein RC7, RC8, RC9 and Rc10 are all H.
51 . The compound of statements 49 or 50 or a pharmaceutically acceptable salt thereof, wherein: a) all of RC7, RC8, RC9 and Rc10 are H; or b) RC9 is selected from H, optionally substituted phenyl (wherein the optional substituent is F), methyl, OMe, C(=O)OH, Cl, F, pyrazolyl, triazolyl, tetrazolyl, CN and piperazinyl optionally substituted by methyl, and RC7, RC8 and RC1° are all H; or c) RC7 is selected from H, methyl, OMe, O-CF3, CF3, Cl, F and CN and RC8, RC9 and RC1° are all H.
52. The compound of statement 51 or a pharmaceutically acceptable salt thereof, wherein: a) all of RC7, RC8, RC9 and Rc10 are H; or b) RC9 is selected from H, CN, OMe, Cl, pyrazole optionally substituted by methyl, tetrazole, methyl, OCHF2, or triazole and RC7, RC8 and RC1° are all H; or c) RC7 is selected from H, OMe, Cl, CF3, OCF3, OCHF2, CN, F, triazole or pyrazole optionally substituted by methyl, and RC7, RC8 and RC1° are all H.
53. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is selected from the group consisting of:
Figure imgf000297_0001
Figure imgf000298_0001
54. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is selected from the group consisting of:
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0002
55. The compound of any of the preceding statements or a pharmaceutically acceptable salt thereof, wherein A-B-C is of the formula (l-A), (l-B), (l-Ba), (l-Bb), (l-C), (l-D), (l-E), (l-Ea) or (I- Eb):
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
wherein
Figure imgf000303_0002
are as defined in any of the preceding claims.
56. The compound of Table 1 , Table 2 or Table 3 or a pharmaceutically acceptable salt thereof. 57. The compound of any one of statements 1 to 56 or a pharmaceutically acceptable salt thereof, for use in therapy.
58. A pharmaceutical composition comprising the compound of any one of statements 1 to
56 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient. 59. The compound of any one of statements 1 to 56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52 for use in the treatment of a cardiovascular disease.
60. The compound for use according to statement 59 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 citrate lyase inhibitor; and vi) anti-hypertensive drugs.
61. The compound use according to statement 59 or 60 when the cardiovascular disease is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dimensia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease heart failure or congestive heart failure.
62. Use of a compound of any one of statementsi to 56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52 in a method of medical treatment.
63. A method of medical treatment comprising administering to the patient the pharmaceutical composition of statement 58.
64. Use of a compound of any one of statements 1 to 56 in the manufacture of a medicament for use in therapy.
65. A method of treating PCSK9-mediated disease or disorder in a patient 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 1 to 56 or the pharmaceutical composition according to statement 58.
66. The method according to statement 65, wherein the disease or disorder is a cardiovascular disease or disorder. 67. The method according to statement 66, wherein the cardiovascular disease or disorder is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dimensia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease heart failure or congestive heart failure.

Claims

Claims 1. A compound of Formula (I) A-B-C (I) or a pharmaceutically acceptable salt, tautomeric forms or stereoisomers thereof, wherein A is of the following:
Figure imgf000306_0001
wherein the wavy line indicates the point of attachment to B; X1 is N; RA2 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) C1-6 alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups; (vi) C1-6 acyl amido (wherein the acyl is optionally substituted by H or methyl); (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, OH, C2-3 alkynyl, C4-6 heterocyclyl or C1-3 alkyl wherein the C1-3 alkyl is optionally substituted with one or more halo or OH groups; and (xiii) OH; and (xiv) C1-6 alkylamino; RA3 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 alkyl acyl, C1-6 acyloxy, carboxy, C1-6 alkyl ester, C1-6 alkylamino, -C(=O)NH2, C1-6 alkyl amido, C1-6 alkyl acylamido, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl or one or more halo groups; (v) OH; (vi) C1-6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclyl or one or more halo groups; (vii) C1-6 acyloxy; (viii) C4 heterocycyl; (ix) -NH2; (x) C1-6 alkylamino, optionally substituted by CN, OH or C4 heterocyclyl; (xi) C1-6 dialkylamino, optionally substituted by -NH2; (xii) C1-6 acylamido (where acyl substituent is H or Me); (xiii) carbaimidoyl or methyl-carbaimidoyl; (xiv) carboxyamino; (xv) C1-6 thioalkyl, optionally substituted by OH or -NH2; (xvi) C1-6 alkyl sulfinyl; (xvi) C1-6 alkyl sulfonyl, optionally substituted by one or more halo groups; (xvii) C1-6 sulfonimodyl; (xviii) C1-6 alkyl phosphinyl; (xix) carboxy; (xx) -C(=O)NH2 (xxi) C1-6 alkyl ester; (xxii) C1-6 alkyl acyl, optionally substituted by one or more halo groups; (xxiii) C1-6 alkyl amido; or wherein RA3 and RA2 together with the carbon atoms to which they are bound form: (i) an optionally substituted C5-7 heterocycle ring; (ii) an optionally substituted C5-7 heteroaromatic ring; (iii) an optionally substituted C6 carboaromatic ring; (iv) an optionally substituted C5-7 carbocyclic ring wherein the optional substituents are selected from C1-6 alkyl, halo, C1-6 alkoxy, -NH2, C1-6 alkylamino, OH, and CN; wherein B is of formula (B-1) or (B-2) i)
Figure imgf000307_0001
wherein the wavy line indicates the point of attachment to A and C; RB1 is H, OH, =CHCH2-OH, -O-C1-4 alkyl or C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted by OH or OMe; (ii)
Figure imgf000308_0001
wherein the wavy line indicates the point of attachment to A and C; RB2 is C1-2 alkyl-OH, CH2C(=O)NHMe or C1-3 alkyl; wherein C is selected from the group consisting of C6-10 carboaryl, C5-6 heteroaryl and C5-10 heterocyclyl, which groups are optionally substituted by: (i) C6-10 carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl, C4-10 heterocyclyl, or C5-10 bridged heterocyclyl, spiro C6-12 heterocyclyl or a spiro C6-12 carbocyclyl, which are themselves optionally substituted by one or more of the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C1-6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1-6 alkoxy with optional substituents of one or more halo groups; f) C1-6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =O substituent; h) C5-6 heteroaryl; i) C4-10 carbocyclyl with an optional methyl or =O substituent; j) C6-10 carboaryl with optional substituents of one or more halo groups; l) P(=O)Me2; m) carboxy or CH2-carboxy; n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; (ii) one or more groups selected from carboxy, CN, halo, nitro, C1-6 alkyl, C1-6 thioalkyl, C1-6 alkoxy, C1-6 alkylacyl, C1-6 alkyl amido, di-C1-6 alkyl amido, C1-6 alkyl sulfonamido, and di-C1-6 alkyl sulfonamido.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein RA2 is selected from the group consisting of: (i) H; (ii) halo;
(iii) Ci-6 alkyl ester;
(iv) Ci-6 hydrocarbon;
(v) Ci-6 alkyl amido optionally substituted by C1.3 alkyl amido, C2-3 alkynyl, C4-6 heterocyclyl, or C1.3 alkyl which alkyl is optionally substituted with one or more halo or OH groups;
(vi) C1.6 thioalkyl;
(vii)Ci-6 alkyl acyl;
(viii) C5 heteroaryl; or
(ix) C1.6 alkylamino.
3. The compound of either of claims 1 or 2 or a pharmaceutically acceptable salt thereof, wherein RA2 is selected from the group consisting of -C(=O)OCH2CH3, cyclopropyl, methyl, H, Cl, -C(=O)CH3, -S-ethyl, pyrazole, -
N(CH3)2, -C(=O)NH(CH2C(=O)NH2, -C(=O)NHCH2C=CH, -C(=O)NH(oxetane), -C(=O)NH(CH2C HF2), -C(=O)NH(CH2CH3), -C(=O)NH2I -C(=O)NH(CH3), -C(=O)N(CH3)2, -
C(=O)N(CH3)(CH2CH2OH), -C(=O)N(CH3)(CH2CECH) or -C(=O)NH(CH2CH2OH).
4. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein RA3 is selected from the group consisting of:
(i) H;
(ii) halo;
(iii) CN;
(iv) C1.6 hydrocarbon, optionally substituted by OH, CN, Ci-e thioalkyl, Ci-e alkoxy, Ci-e alkyl acyl C1.6 acyloxy, carboxy, Ci-e alkylester, Ci-e alkylamino; -C(=O)NH2, Ci-e alkyl amido, Ci-e alkylacylamido, Ci-e alkyl sulfinyl, Ci-e alkyl sulfonyl or one or more halo groups;
(v) OH;
(vi) C1.6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclyl or one or more halo groups.
5. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein RA3 is selected from the group consisting of H, methyl and OH.
6. The compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein B is of the following formula: a)
Figure imgf000310_0001
7. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl, wherein the optional substituents are selected from Ce-w carboaryl, C4-10 carbocyclyl, C5-10 heteroaryl, C5-10 heterocyclyl, C5-10 bridged heterocyclyl, spiro Ce-12 heterocyclyl or a spiro Ce-12 carbocyclyl, which are themselves optionally substituted by one or more of the following groups: a) one or two =0 groups; b) one or more halo groups; c) CN, NH2 or OH; d) one or more C1.6 alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups; e) C1.6 alkoxy with optional substituents of one or more halo groups; f) C1.6 alkylester; g) C5-6 heterocyclyl with an optional methyl, OH or =0 substituent; h) C5-6 heteroaryl; i) C4-10 carbocyclyl with an optional methyl or =0 substituent; j) Ce-w carboaryl with optional substituents of one or more halo groups; l) P(=0)Me2; m) carboxy or CH2-carboxy; and/or n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.
8. The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein C is: a) an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl wherein the optional substituents are selected from Ce heteroaryl or Ce heterocyclyl, which are themselves optionally substituted by one or more groups selected from the following: i) one or two =0 groups; ii) methyl; iii) OMe; iv) Cl; v) CN; vi) CF3; vii) F; viii) pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl; ix) O-CF3; x) O-CHF2; or b) an optionally substituted pyridinyl wherein the optional substituent is phenyl or pyridyl which are themselves optionally substituted by one or more groups selected from the following: f) one or more OMe groups; g) one or more F groups; h) CN; i) tetrazole; or j) carboxy; or c) an optionally substituted pyridinyl wherein the optional substituent is a C5 heteroaryl or C5 heterocyclyl which are themselves optionally substituted by one or more substituents selected from methyl and CN.
9. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof,
Figure imgf000311_0001
(C-1) wherein D is Ce-w carboaryl, C5-10 heteroaryl or C5-10 heterocyclyl, each which are themselves optionally substituted by: i) one or two =0 groups; ii) one or two C1.4 alkyl groups which can be branched; iii) OMe; iv) piperazinyl, optionally substituted by methyl; v) C(=O)OH (carboxy); vi) Cl; vii) F; viii) phenyl, optionally substituted by one or more fluoro; ix) CN; x) CF3; xi) O-CF3; xii) tetrazolyl, pyrazolyl, triazolyl each of which is optionally substituted by methyl; xiii) NH2; xiv) pyridinyl; xv) CH2OH; xvi)OH; xvii) P(=O)Me2; or xviii) OCHF2.
10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein D is of the formula (D-1):
Figure imgf000312_0001
wherein one or two of RD1, RD2, RD3 and RD4 are selected from i) C1.6 alkyl, optionally substituted by one or more halo groups; ii) C1.6 alkoxy, optionally substituted by one or more halo groups; iii) C5-6 heterocyclyl or C5-6 heteroaryl with an optional methyl substituent; iv) carboxy or CH2-carboxy; v) =0, halo, NH2 or CN; vi) phenyl, optionally substituted by one or more halo atoms; and the rest are H; or wherein RD3 and RD4 form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo and C(=O)OH; or wherein RD1, RD2, RD3 and RD4 are all H.
11 . The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein: a) one or two of RD1, RD2, RD3 and RD4 are selected from: i) methyl; ii) OMe; iii) Cl; iv) CN; v) CF3; vi) F; vii) pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl; viii) O-CF3 ix) O-CHF2 and the rest of RD1, RD2, RD3 and RD4 are H; b) RD1, RD2, RD3 and RD4 are all H; c) RD3 is selected from H, CN, OMe, Cl, pyrazole optionally substituted by methyl, tetrazole, methyl, OCHF2, or triazole and wherein RD1, RD2 and RD4 are all H; d) RD1 is selected from H, OMe, Cl, CF3, OCF3, OCHF2, CN, F, pyrazole optionally substituted by methyl or triazole and RD2, RD3 and RD4 are all H; or e) RD3 and RD4form an unsubstituted benzene ring or an unsubstituted pyridine ring.
12. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein D is of the formula (D-2):
Figure imgf000313_0001
(D-2) wherein XD is NRD5a or CRD5aRD5b;
RD5a is selected from H or methyl; either RD5b and RD6b are both H or together they are -CH2-;
RD6a is selected from H, =0, methyl, -CH2OH or -C(=O)OH, wherein when RD6a is =0, RD6b is absent;
RD7a is selected from H, =0, methyl, -CH2OH or -C(=O)OH;
RD7b is H, wherein when RD7a is =0, RD7b is absent; or wherein RD6a and RD7a together form a benzene ring or a Ce heteroaromatic ring which is optionally substituted by CN, P(=0)Me2 or carboxy and RD6b and RD7b are absent.
13. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000314_0001
Figure imgf000315_0001
Figure imgf000316_0002
14. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein C is of the formula (C-2):
Figure imgf000316_0001
wherein one of RC7, RC8, RC9 and RC1° are selected from the group consisting of: methyl; OMe; piperazinyl optionally substituted by methyl; C(=O)OH (carboxy); Cl; F; pyrazolyl optionally substituted by methyl; triazolyl; tetrazole; optionally substituted phenyl (wherein the optional substituent is methyl or halo); CN; CF3; O-CHF2, O-CF3; and the rest of RC7, RC8, RC9 and RC1° are H; or
RC9 and RC1° form a benzene or 6 membered heteroaromatic ring, and RC7 and RC8 are both H; or wherein RC7, RC8, RC9 and Rc10 are all H.
15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein: a) all of RC7, RC8, RC9 and Rc10 are H; or b) RC9 is selected from H, CN, OMe, Cl, pyrazole optionally substituted by methyl, tetrazole, methyl, OCHF2, or triazole and RC7, RC8 and RC1° are all H; or c) RC7 is selected from H, OMe, Cl, CF3, OCF3, OCHF2, CN, F, triazole or pyrazole optionally substituted by methyl, and RC7, RC8 and RC1° are all H.
16. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein C is selected from the group consisting of:
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0002
17. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein A-B-C is of the formula (l-A), (l-B), (l-Ba), (l-Bb), (l-C), (l-D), (l-E), (l-Ea) or (I- Eb):
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
D
(l-Eb). wherein X1, RA2, RA3, C, D, RD1, RD2, RD3, RD4, RD1a, RD2a, RD3a, RD4a, XD, RD6a, RD6b and RD7a are as defined in any of the preceding claims.
18. The compound of Table 1 , Table 2 or Table 3 or a pharmaceutically acceptable salt thereof.
19. The compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, for use in therapy.
20. A pharmaceutical composition comprising the compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.
21 . The compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20 for use in the treatment of a cardiovascular disease optionally wherein the cardiovascular disease is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dimensia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease heart failure or congestive heart failure..
22. The compound or a pharmaceutically acceptable salt thereof, for use according to claim 21 wherein the compound is administered simultaneously, separately or sequentially in combination with an additional active ingredient selected from the group consisting of: vii) a statin; viii) a cholesterol absorption inhibitor; ix) a SGLT2 inhibitor; x) a P2Y12 inhibitor; xi) a citrate lyase inhibitor; and xii) anti-hypertensive drugs.
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