WO2023062575A1 - Composés de sulfone de vinyle cyclique utilisés en tant qu'inhibiteurs de wrn - Google Patents

Composés de sulfone de vinyle cyclique utilisés en tant qu'inhibiteurs de wrn Download PDF

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WO2023062575A1
WO2023062575A1 PCT/IB2022/059817 IB2022059817W WO2023062575A1 WO 2023062575 A1 WO2023062575 A1 WO 2023062575A1 IB 2022059817 W IB2022059817 W IB 2022059817W WO 2023062575 A1 WO2023062575 A1 WO 2023062575A1
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alkyl
mmol
compound
pharmaceutically acceptable
acceptable salt
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Inventor
Ashley ADAMS
Joelle Lorraine Burgess
Michael J. BURY
Michael P. Demartino
Sarah E. Dowdell
Michal Pawel GLOGOWSKI
Nicole GODFREY
Todd L. Graybill
Sharada Manns
Dennis Murphy
Neysa Nevins
Lance Howard Ridgers
Barry George Shearer
Raynold SHENJE
Matthew Tallant
Maben YING
Valer JESO
James P. PHELAN
Brian T. Jones
Joshua P.G. TAYGERLY
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GlaxoSmithKline Intellectual Property No 4 Ltd
Ideaya Biosciences Inc
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GlaxoSmithKline Intellectual Property No 4 Ltd
Ideaya Biosciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • WRN inhibitors that inhibit Wemer Syndrome helicase enzyme (WRN) activity and in particular, inhibit the ATP dependent helicase domain activity and are therefore useful in treating cancers treatable by inhibition of WRN, including cancers characterized by microsatellite instability (MSI) and/or defective DNA mismatch repair system (dMMR).
  • MSI microsatellite instability
  • dMMR defective DNA mismatch repair system
  • pharmaceutical compositions comprising such compounds and methods making the same.
  • Cancer is a leading cause of death throughout the world.
  • a limitation of prevailing therapeutic approaches, e.g. chemotherapy is that their cytotoxic effects are not restricted to cancer cells and adverse side effects can occur within normal tissues. Consequently, novel strategies are needed to better target cancer cells.
  • Synthetic lethality arises when a combination of genetic deficiencies (e.g. gene mutations, silencing or global genomic lesions) and/or molecular perturbations (e.g. gene expression knockout/knockdown, pharmacological inhibition/activation) corresponding to two or more genes impaired cell wellbeing, whereas presence of single deficiency/perturbation does not (Dobzhansky, T., Genetics 1946; 31, 269-290, Huang et al., Nature Reviews Drug Discovery 2020; volume 19, pages 23-38)
  • genetic deficiencies e.g. gene mutations, silencing or global genomic lesions
  • molecular perturbations e.g. gene expression knockout/knockdown, pharmacological inhibition/activation
  • Microsatellite instability is a genomic lesion caused by defects in mismatch repair machinery (dMMR).
  • MSI status is present in colorectal cancer, endometrial cancer, gastric cancer and other cancer types. Mutation or silencing of MMR genes, including MLH1, MSH2, MSH6 and PMS2, abrogates cell’s ability to repair DNA mismatch mutations (Baudrin et al., Front. Oncol. 2018). As a consequence, tumor with MSI-H status carries higher mutation burden, disrupted microsatellite repeat sequences and extended TA dinucleotide repeat sequences across the genome (van Wietmarschen N. et al., Nature 2020; 586, pages 292-298).
  • MSI status can be assessed by molecular testing of certain microsatellites, next-generation sequencing of patient genome or by immunohistochemical evaluation of expression of certain MMR proteins. Tumors can be categorized into MSI high (MSI-H), MSI low (MSI-L) and MSS depending on the number of tested microsatellite showing instability. Based on a consensus NCI-Reference Panel (Bethesda, 1998), MSI can be assessed by molecular testing of five microsatellites - including two mononucleotides (BAT25 and BAT26) and three dinucleotides (D2S123, D5S346, D17S250).
  • Tumors are denoted as MSI-high (MSI-H) if two or more of the microsatellite markers show instability, MSI-low (MSI-L) if only one microsatellite marker shows instability, and MS-stable (MSS) if none of the five microsatellite markers show instability.
  • MSI-H MSI-high
  • MSI-L MSI-low
  • MSS MS-stable
  • tumors can be classified as a MSS neoplasms.
  • WRN WRN RecQ helicase
  • MSI-H microsatellite instability status
  • WRN contains an exonuclease domain and an ATP -dependent helicase domain. It is localized to the nucleus and unwinds double strand DNA, particularly secondary structures (fork DNA, holliday junction, G4-quadruaplex, DNA hairpin and cruciform etc.) during DNA replication, damage and repair processes.
  • Its helicase activity has been shown to be indispensable to the survival of MSI cell lines as helicase -deficient WRN mutant is insufficient to rescue impaired cell viability from WRN knockout or knockdown. The absence of either the WRN protein or inhibition of its helicase activity prevents normal DNA damage and repair processes, leading to increased DNA double-strand breaks (DSB) and subsequent growth arrest and cell death.
  • DSB DNA double-strand breaks
  • Covalent inhibitors represent a class of small molecules which form covalent bonds with their biological targets to inhibit activities of these targets in physiological or pathological conditions.
  • covalent inhibitors engage with nucleophilic residues (e.g. Cysteine, Serine, Threonine, Histidine, Arginine, Tyrosine) lining specific binding pockets on target proteins, in a nucleophilic addition or substitution reaction, with their reactive electrophilic warhead.
  • nucleophilic residues e.g. Cysteine, Serine, Threonine, Histidine, Arginine, Tyrosine
  • reactive warheads include epoxide, aziridine, ester, ketone, a, -unsaturated carbonyl, nitrile, etc.
  • Covalent inhibitors have been discovered as medicines for more than a century, starting with Aspirin being manufactured and marketed as painkillers and anti-inflammatory drug, although its mechanism of action was not revealed until 1970s to be an irreversible inhibitor of cyclooxygenase- 1 (COX- 1).
  • antibiotics Penicillin, proton pump inhibitor Omeprazole and Lansoprazole, anticoagulant Clopidogrel.
  • cyclic vinyl sulfone compounds that inhibit WRN activity and are therefore useful in treating cancer treatable by inhibition of WRN, including cancers characterized by high microsatellite instability (MSI-H) and/or defective DNA mismatch repair system (dMMR).
  • MSI-H microsatellite instability
  • dMMR defective DNA mismatch repair system
  • the cyclic vinyl sulfone compounds disclosed herein can inhibit, in particular, the ATP dependent helicase domain activity of WRN protein.
  • pharmaceutical compositions comprising such compounds, methods of using such compounds, and methods for making the same.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: ring A is aryl, heteroaryl, or (C3-Cn)cycloalkyl; each R 1 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, amino(Ci-C6)alkyl, (C3-Ce)cycloalkyl, hydroxyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-C6)alkylsulfanyl, amino, ((Ci-C6)alkyl)amino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, CN, COOH, CONH2, SF5, heterocycloalkyl, aryl, aryloxy,
  • R 3 is hydrogen or (Ci-Ce)alkyl; each R 4 is independently halogen, (Ci-Ce)alkyl, or halo(Ci-Ce)alkyl; each R la is independently halogen, CN, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, hydroxyl, or (Ci-Ce)alkoxy; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 1 or 2; and q is 0, 1, or 2; provided that the compound is not N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-6-(4- methoxyphenyl)-2 -oxo-1, 2-dihydropyridine-3-carboxamide.
  • a method of treating a cancer treatable by inhibition of WRN in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of treating a cancer characterized by MSI-H and/or dMMR in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer treatable by inhibition of WRN.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer characterized by high MSI and/or dMMR in a patient.
  • a method of treating a cancer in a patient comprising:
  • All the compounds and pharmaceutical compositions provided herein can be used in all the methods provided herein.
  • the compounds and pharmaceutical compositions provided herein can be used in all the methods for treatment and/or prevention of all diseases or disorders provided herein.
  • the compounds and pharmaceutical compositions provided herein are for use as a medicament.
  • WRN helicase inhibitor may present a novel therapy to tumor with mismatch repair deficiency (dMMR) and in particular those with high microsatellite instability (MSI-H).
  • covalent inhibitors are being developed more frequently for oncology indications, for example, EGFR inhibitor Afatinib, BTK inhibitor Ibrutinib and Acalabrutinib, and Kras G12C inhibitors sotorasib and adagrasib (Goebel L. et al., RSC Med. Chem. 2020, 11, 760).
  • these aforementioned irreversible kinase inhibitors and Kras G12C inhibitors are all Cysteine-reactive compounds, suggesting that targeting cysteine residue may be an effective strategy to develop covalent inhibitors for cancer targets.
  • the present application provides certain cyclic vinyl sulfone compounds as WRN covalent inhibitors that inhibit Werner Syndrome helicase enzyme (WRN) activity and in particular, inhibit the ATP dependent helicase domain activity and are therefore useful in treating cancers treatable by inhibition of WRN.
  • WRN Werner Syndrome helicase enzyme
  • any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkoxyalkyl means that an alkoxy group is attached to the parent molecule through an alkyl group.
  • alkyl represents a saturated, straight, or branched hydrocarbon moiety.
  • (Ci-Cejalkyl) refers to an alkyl moiety containing from 1 to 6 carbon atoms.
  • Exemplary alkyls include, but are not limited to methyl, ethyl, w-propyl. isopropyl, n- butyl, isobutyl, s-butyl. /-butyl, pentyl, and hexyl.
  • alkyl When the term “alkyl” is used in combination with other substituent groups, such as "halo(Ci-C6)alkyl” or “hydroxy(Ci-C6)alkyl”, the term “alkyl” is intended to encompass a divalent straight or branched-chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety.
  • halo(Ci-C6)alkyl is intended to mean a radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 6 carbon atoms, which is a straight or branched-chain carbon radical.
  • halo(Ci-C6)alkyl groups useful in the present disclosure include, but are not limited to, -CHF2 (difluoromethyl), -CF3 (trifluoromethyl), -CCh (trichloromethyl), 1,1 -difluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl.
  • hydroxy(Ci-C6)alkyl useful in the present disclosure include, but are not limited to, hydroxymethyl, hydroxyethyl, and hydroxyisopropyl.
  • Alkoxy refers to a group containing an alkyl radical, defined hereinabove, attached through an oxygen linking atom.
  • the term “(Ci-C4)alkoxy” refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
  • Exemplary “(Ci-C4)alkoxy” groups useful in the present disclosure include, but are not limited to, methoxy, ethoxy, w-propoxy. isopropoxy, w-butoxy. s-butoxy. isobutoxy, and /-butoxy.
  • alkoxy when used in combination with other substituent groups, such as "halo(Ci-C6)alkoxy", the term “alkoxy” is intended to encompass a divalent straight or branched-chain hydrocarbon radical, wherein the point of attachment is to the alkyl moiety through an oxygen linking atom.
  • halo(Ci-Ce)alkoxy refers to a straight- or branched-chain hydrocarbon radical, having at least 1 and up to 6 carbon atoms with one or more halogen atoms, which may be the same or different, attached to one or more carbon atoms, which radical is attached through an oxygen linking atom.
  • halo(Ci-Ce)alkoxy groups useful in the present disclosure include, but are not limited to, - OCHF2 (difluoromethoxy), -OCF3 (trifluoromethoxy), and -OCH(CF3)2 (hexafluoroisopropoxy) .
  • Alkylsulfanyl means a -SR radical where R is alkyl as defined above, e.g., methylsulfanyl, ethylsulfanyl, and the like.
  • (Ci-C6)alkylsulfanyl refers to a straight- or branched-chain hydrocarbon radical, having at least 1 and up to 6 carbon atoms, which radical is attached through S linking atom.
  • Amino means a -NH2.
  • Alkylamino means a -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.
  • ((Ci-C6)alkyl)amino- refers to a straight- or branched-chain hydrocarbon radical, having at least 1 and up to 6 carbon atoms, which radical is attached through an NH linking group.
  • Aminoalkyl means an alkyl radical, defined hereinabove, substituted with -NH2, e.g., aminomethyl, aminoethyl, and the like.
  • amino(Ci-C6)alkyl refers to a straight- or branched-chain hydrocarbon radical, having at least 1 and up to 6 carbon atoms, which radical is substituted with -NH2.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, e.g., phenyl or naphthyl.
  • cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring containing the specified number of carbon atoms which may be saturated or contains one double bond.
  • (C3-C6)cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having from three to six ring carbon atoms.
  • Exemplary “(C3-C6)cycloalkyl” groups useful in the present disclosure include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.
  • cycloalkyloxy refers to a group containing a cycloalkyl radical, defined hereinabove, attached through an oxygen linking atom.
  • exemplary “(C3-C6)cycloalkyloxy” groups useful in the present disclosure include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.
  • Halogen or “halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
  • hydroxy or “hydroxyl” means a -OH.
  • “Hydroxyalkyl” means an alkyl radical as defined above, substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy- ethyl, 2-hydroxypropyl, and 3 -hydroxypropyl.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more ring atoms are heteroatoms selected from N, O, and S, the remaining ring atoms being carbon.
  • Monocyclic heteroaryl moieties can have 5 or 6 ring atoms where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatoms selected from N, O, and S, the remaining ring atoms being carbon.
  • Bicyclic heteroaryl moieties can have 9 or 10 ring atoms where one or more, (in one embodiment, one, two, three, or four), ring atoms are heteroatoms selected from N, O, and S, the remaining ring atoms being carbon.
  • heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, p
  • Heterocycloalkyl means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, and S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being carbon. Additionally, one or two ring carbon atoms in the heterocycloalkyl ring can optionally be replaced by a -CO- group.
  • heterocycloalkyl includes, but is not limited to, azetidinyl, oxetanyl, pyrrolidine, piperidine, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazine, tetrahydro-pyranyl, thiomorpholino, and the like.
  • heterocycloalkyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • “Pharmaceutically acceptable salts” as used herein is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally- occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N’- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogen carbonic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogen sulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzene sulfonic, p-tolylsulfonic, citric, tartaric, methane sulfonic, and the like.
  • salts of amino acids such as arginate and the like
  • salts of organic acids like glucuronic or galactunoric acids and the like
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.
  • the compounds of Formula (I) or salts thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms).
  • the individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present disclosure.
  • the scope of the present disclosure includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Unless otherwise indicated, when a stereochemical depiction is shown, it is meant that the isomer with the depicted stereochemistry is present and substantially free of the other isomer(s). “Substantially free of’ another isomer indicates at least an 80/20 ratio of the two isomers, more preferably 90/10, or 95/5 or more.
  • a compound of Formula (I) or salts thereof may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present disclosure.
  • the compounds of Formula (I) are depicted as containing a pyridin-2-one moiety, the corresponding 2-hydroxypyridine tautomer is also included within the scope of the present disclosure.
  • the present disclosure includes all combinations and subsets of the particular groups defined hereinabove.
  • the compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds.
  • Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question that differ only in the presence of one or more isotopically enriched atoms.
  • Exemplary isotopes that can be incorporated into the compounds of the present disclosure, such as a compound of Formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • Isotopically labeled compounds e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • substituents such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon.
  • Positron emitting isotopes such as 15 O, 13 N, n C, and 15 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • “Pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • Disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • Patient is generally synonymous with the term “subject” and as used herein includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.
  • “In need of treatment” or “in need thereof’ as used herein refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s or caregiver's expertise.
  • administer refers to contact of, for example, a compound of Formula (I), or a pharmaceutical composition comprising same, to the subject, cell, tissue, organ, or biological fluid.
  • administration includes contact (e.g., in vitro or ex vivo) of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • “Therapeutically effective amount” as used herein means the amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease either alone or as part of a pharmaceutical composition and either in a single dose or as part of a series of doses, is sufficient to affect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.
  • the therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject’s condition, and the like.
  • measurement of the serum level of a compound of Formula (I) (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been used.
  • treatment refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, and slowing or eliminating the progression of the condition in a previously afflicted or diagnosed patient or subject.
  • “Inhibiting”, "reducing,” or any variation of these terms in relation ofWRN includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%,
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: ring A is aryl, heteroaryl, or (C3-Cn)cycloalkyl; each R 1 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, amino(Ci-C6)alkyl, (C3-Ce)cycloalkyl, hydroxyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-Ce)alkylsulfanyl, amino, ((Ci-C6)alkyl)amino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, CN, COOH, CONH2, SF5, heterocycloalkyl, aryl, aryloxy
  • R 3 is hydrogen or (Ci-Ce)alkyl; each R 4 is independently halogen, (Ci-Ce)alkyl, or halo(Ci-Ce)alkyl; each R la is independently halogen, CN, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, hydroxyl, or (Ci-Ce)alkoxy; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 1 or 2; and q is 0, 1, or 2; provided that the compound is not N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-6-(4- methoxyphenyl)-2 -oxo- l,2-dihydropyridine-3 -carboxamide (structure shown below).
  • a compound of Formula (I’ is aryl, 5- to 10-membered heteroaryl, or (C3-Ce)cycloalkyl; each R 1 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, amino(Ci-C6)alkyl, (C3-Ce)cycloalkyl, hydroxyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-Ce)alkylsulfanyl, amino, ((Ci-C6)alkyl)amino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, CN, COOH, CONH2, or 3- to 6-membered heterocycloalkyl;
  • R 3 is hydrogen or (Ci-Ce)alkyl; each R la is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxyl, or (Ci-Ce)alkoxy; m is 0, 1, 2, or 3; n is 0, 1, or 2; and p is 1 or 2; provided that the compound is not N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-6-(4- methoxyphenyl)-2 -oxo-1, 2-dihydropyridine-3-carboxamide.
  • ring A is aryl, heteroaryl, or (C3-Cn)cycloalkyl; each R 1 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, amino(Ci-C6)alkyl, (C3-Ce)cycloalkyl, hydroxyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-Ce)alkylsulfanyl, amino, ((Ci-C6)alkyl)amino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, CN, COOH, CONH2, SF5, heterocycloalkyl, aryl, aryl
  • R 3 is hydrogen or (Ci-Ce)alkyl; each R 4 is independently halogen, (Ci-Ce)alkyl, or halo(Ci-Ce)alkyl; each R la is independently halogen, CN, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, hydroxyl, or (Ci-Ce)alkoxy; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 1 or 2; and q is 0, 1, or 2; provided that when ring A is phenyl and m is 1, R 1 is not methoxy.
  • ring A is aryl, 5- to 10-membered heteroaryl, or (C3-Ce)cycloalkyl; each R 1 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, amino(Ci-C6)alkyl, (C3-Ce)cycloalkyl, hydroxyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-C6)alkylsulfanyl, amino, ((Ci-C6)alkyl)amino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, CN, COOH, CONH2, or 3- to 6-membered heterocycloalkyl;
  • R 3 is hydrogen or (Ci-Ce)alkyl; each R la is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxyl, or (Ci-Ce)alkoxy; m is 0, 1, 2, or 3; n is 0, 1, or 2; and p is 1 or 2; provided that when ring A is phenyl and m is 1, R 1 is not methoxy.
  • ring A is aryl, heteroaryl, or (C3-Cn)cycloalkyl; each R 1 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, amino(Ci-C6)alkyl, (C3-Ce)cycloalkyl, hydroxyl, halo(Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-C6)alkylsulfanyl, amino, ((Ci-C6)alkyl)amino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, CN, COOH, CONH2, SF5, heterocycloalkyl, aryl, aryloxy, (C3-Ce)cycloalkyl;
  • R 3 is hydrogen or (Ci-Ce)alkyl; each R 4 is independently halogen, (Ci-Ce)alkyl, or halo(Ci-Ce)alkyl; each R la is independently halogen, CN, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, hydroxyl, or (Ci-Ce)alkoxy; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 1 or 2; and q is 0, 1, or 2.
  • a compound according to Formula (F), or a pharmaceutically acceptable salt thereof wherein: ring A is aryl, 5- to 10-membered heteroaryl, or (C3-Ce)cycloalkyl; each R 1 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, amino(Ci-C6)alkyl, (C3-Ce)cycloalkyl, hydroxyl, halo(Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-C6)alkylsulfanyl, amino, ((Ci-C6)alkyl)amino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, CN, COOH, CONH2, or 3- to 6-membered heterocycloalkyl; or two adjacent R 1 groups taken together with
  • R 3 is hydrogen or (Ci-Ce)alkyl; each R la is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxyl, or (Ci-Ce)alkoxy; m is 0, 1, 2, or 3; n is 0, 1, or 2; and p is 1 or 2.
  • the present application provides a compound according to Formula (la), or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , R 2 , R 3 , m, n, and p are as defined herein.
  • the present application provides a compound according to Formula (lb), or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , R 2 , R 3 , m, n, and p are as defined herein.
  • the present application provides a compound according to Formula (I) as described herein, wherein ring A is aryl.
  • ring A is phenyl or naphthalenyl.
  • ring A is phenyl.
  • the present application provides a compound according to Formula (I) as described herein, wherein ring A is heteroaryl.
  • ring A is 5- to 10- membered heteroaryl.
  • ring A is 5-membered heteroaryl.
  • ring A is thiophenyl, thiazolyl, furanyl, or isoxazolyl.
  • ring A is thiophenyl.
  • ring A is thiazolyl.
  • ring A is furanyl.
  • ring A is 6-membered heteroaryl.
  • ring A is pyridyl or pyrazinyl.
  • ring A is pyridyl.
  • ring A is 9-membered heteroaryl. In one embodiment, ring A is benzothiophenyl or benzofuranyl. In another embodiment, ring A is 10-membered heteroaryl.
  • the present application provides a compound according to Formula (I) as described herein, wherein ring A is (C3-Cn)cycloalkyl. In one embodiment, ring A is (C3-Ce)cycloalkyl. In one embodiment, ring A is (C5-Ce)cycloalkyl. In one embodiment, ring A is cyclohexyl. In one embodiment, ring A is cyclopentyl. In one embodiment, ring A is cyclohexenyl.
  • ring A is selected from the group consisting of phenyl, naphthalenyl, thiophenyl, pyridyl, pyrazinyl, benzothiophenyl, benzofuranyl, furanyl, 1,3 -thiazolyl, isoxazolyl, cyclohexyl, cyclopentyl, and cyclohexenyl.
  • ring A is not substituted, i.e., m is 0. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3.
  • ring A is substituted, and each R 1 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, amino(Ci-C6)alkyl, (C3-Ce)cycloalkyl, hydroxyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-Ce)alkylsulfanyl, amino, ((Ci-C6)alkyl)amino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, CN, COOH, CONH2, SF5, heterocycloalkyl, aryl, aryloxy, (C3-Ce)cycloalkyl-(Ci-C4)alkyl-O-, aryl-(Ci-C4)alkyl-
  • each R 1 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, amino(Ci-C6)alkyl, (C3-Ce)cycloalkyl, hydroxyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-Ce)alkylsulfanyl, amino, ((Ci-C6)alkyl)amino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, CN, COOH, CONH2, or 3- to 6-membered heterocycloalkyl.
  • each R 1 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (Ci-Ce)alkylsulfanyl, or (C3-C6)cycloalkyl. In one embodiment, each R 1 is independently halogen. In one embodiment, each R 1 is independently chloro or fluoro. In one embodiment, each R 1 is independently (Ci-Ce)alkyl or halo(Ci-Ce)alkyl. In one embodiment, each R 1 is independently (Ci-Ce)alkyl. In one embodiment, each R 1 is independently halo(Ci-Ce)alkyl. In one embodiment, each R 1 is independently methyl or ethyl. In one embodiment, each R 1 is methyl. In one embodiment, each R 1 is ethyl. In one embodiment, each R 1 is independently trifluoromethyl or perfluoroethyl. In one embodiment, each R 1 is trifluoromethyl.
  • each R la is independently halogen, CN, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, hydroxyl, or (Ci-Ce)alkoxy.
  • each R la is independently halogen.
  • each R la is independently (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, or (Ci-Ce)alkoxy.
  • ring A is aryl fused with a 5- or 6-membered non-aromatic ring. In one embodiment, ring A is phenyl fused with a 5- or 6-membered non-aromatic ring. In one embodiment, ring A is
  • n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In some embodiments, each R 2 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, or CN. In one embodiment, each R 2 is independently chloro or fluoro. In one embodiment, each R 2 is independently (Ci-Ce)alkyl or halo(Ci-Ce)alkyl. In one embodiment, R 2 is trifluoromethyl. In one embodiment, R 2 is CN. In one embodiment, R 2 is hydroxyl.
  • R 3 is hydrogen. In one embodiment, R 3 is (Ci-Ce)alkyl. In one embodiment, R 3 is (Ci-C2)alkyl. In one embodiment, R 3 is methyl.
  • each R 4 is independently halogen, (Ci-Ce)alkyl, or halo(Ci-Ce)alkyl. In one embodiment, each R 4 is halogen. In one embodiment, each R 4 is (Ci-Ce)alkyl. In one embodiment, R 4 is F. In one embodiment, R 4 is methyl.
  • p is 1. In one embodiment, p is 2.
  • q is 0. In one embodiment, q is 1. In one embodiment, q is 2.
  • the present application provides a compound according to Formula (Ic), or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , R 2 , m, and n are as defined herein.
  • the present application provides a compound according to Formula (Id), or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , R 2 , m, and n are as defined herein. In one embodiment, the present application provides a compound according to Formula (le), or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , R 2 , m, and n are as defined herein.
  • the present application provides a compound according to Formula (If), or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , R 2 , m, and n are as defined herein. In one embodiment, the present application provides a compound according to Formula (Ig), or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , and m are as defined herein.
  • ring A is phenyl. In one embodiment, ring A is thiophenyl. In one embodiment, ring A is (C3-Ce)cycloalkyl.
  • the present application provides a compound according to Formula (Ih), or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , and m are as defined herein.
  • ring A is phenyl.
  • ring A is thiophenyl.
  • ring A is (C3-Ce)cycloalkyl.
  • the present application provides a compound according to Formula (li), or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , and m are as defined herein.
  • ring A is phenyl.
  • ring A is thiophenyl.
  • ring A is (C3-Ce)cycloalkyl.
  • the present disclosure provides a compound selected from the group of Examples 1-70. In some embodiments, the present disclosure provides a compound selected from the group of Examples 1-173. It is understood that the embodiments set forth above include all combination of embodiments and subembodiments listed therein.
  • the compounds of this disclosure may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working examples. A skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. In all of the schemes described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M.
  • compositions suitable for administration to a subject may be in the form of compositions suitable for administration to a subject.
  • compositions are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable or physiologically acceptable excipients.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount.
  • the pharmaceutical compositions may be used in the methods disclosed herein; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic methods and uses described herein.
  • compositions can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein. Furthermore, the pharmaceutical compositions may be used in combination with other therapeutically active agents or compounds as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs.
  • Pharmaceutical compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets, capsules and the like contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets, capsules, and the like.
  • excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action.
  • a time-delay material such as glyceryl monostearate or glyceryl di-stearate may be employed.
  • the tablets may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release.
  • Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene -vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide and glycolide copolymers, polylactide and glycolide copolymers, or ethylene vinyl acetate copolymers in order to control delivery of an administered composition.
  • a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene -vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide and glycolide copolymers, polylactide and glycolide copolymers, or ethylene vinyl acetate copolymers in order to control delivery of an administered composition.
  • the oral agent can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, by the use of hydroxymethyl cellulose or gelatin-microcapsules or poly (methyl methacrylate) microcapsules, respectively, or in a colloid drug delivery system.
  • Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, microbeads, and lipid-based systems, including oil- in-water emulsions, micelles, mixed micelles, and liposomes. Methods for the preparation of the above-mentioned formulations are known in the art.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture thereof.
  • excipients can be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, (hydroxypropyl)methyl cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example a naturally-occurring phosphatide (e.g., lecithin), or condensation products of an alkylene oxide with fatty acids (e.g., poly-oxyethylene stearate), or condensation products of ethylene with long chain aliphatic alcohols (e.g., for heptdecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, ka
  • the pharmaceutical compositions may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • compositions typically comprise a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fdlers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants.
  • antioxidants e.g., ascorbic acid and sodium bisulfate
  • preservatives e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate
  • emulsifying agents suspending agents, dispersing agents, solvent
  • a suitable vehicle may be physiological saline solution or citrate buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration.
  • Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
  • Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof.
  • the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof.
  • Acceptable buffering agents include, for example, a Tris buffer, N-(2-Hydroxyethyl)piperazine-N'-(2 -ethane sulfonic acid) (HEPES), 2-(N-Morpholino)ethanesulfonic acid (MES), 2-(N-Morpholino)ethanesulfonic acid sodium salt (MES), 3 -(N-Morpholino)propane sulfonic acid (MOPS), and N- tris[Hydroxymethyl]methyl-3 -aminopropanesulfonic acid (TAPS).
  • HEPES 2-(N-Morpholino)ethanesulfonic acid
  • MES 2-(N-Morpholino)ethanesulfonic acid sodium salt
  • MOPS 3 -(N-Morpholino)propane sulfonic acid
  • TAPS N- tris[Hydroxymethyl]methyl-3
  • a pharmaceutical composition After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form.
  • the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas a multi-use container (e.g., a multi-use vial) is provided in other embodiments.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • the suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents mentioned herein.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
  • Acceptable diluents, solvents and dispersion media include water, Ringer's solution, isotonic sodium chloride solution, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid, find use in the preparation of injectables. Prolonged absorption of particular injectable formulations can be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin).
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof may also be administered in the form of suppositories for rectal administration or sprays for nasal or inhalation use.
  • the suppositories can be prepared by mixing the drug with a suitable nonirritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable nonirritating excipient include, but are not limited to, cocoa butter and polyethylene glycols.
  • Compounds of Formula (I), or a pharmaceutically acceptable salt thereof and compositions containing the same may be administered in any appropriate manner.
  • Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracistemal, intraarticular, intraperitoneal, intracerebral (intraparenchymal) and intracerebro ventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal and inhalation.
  • Depot injections which are generally administered subcutaneously or intramuscularly, may also be utilized to administer the compounds of Formula (I), or a pharmaceutically acceptable salt thereof over a defined period of time.
  • Particular embodiments of the present disclosure contemplate oral administration.
  • a method for decreasing proliferation in a proliferative cell having a microsatellite instability comprising decreasing the helicase activity of Werner syndrome ATP-dependent helicase (WRN) in the proliferative cell.
  • decreasing the helicase activity of Wemer syndrome ATP-dependent helicase (WRN) in the proliferative cell is achieved by administering a compound of Formula of (I) (or any embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof.
  • the proliferative cell is characterized as having MSI low (MSI-L).
  • the proliferative cell is characterized as having high MSI (MSI-H), used interchangeably with MSI-high.
  • MSI-L or MSI- H can be characterized as MSI, including MSI-L or MSI- H, or as MSS (MS-stable), according to the method known in the art (see, for example, Dudley, Jonathan C., et al., Clinical Cancer Research, 22(4): 813-820, 2016.).
  • MSI-H is used to classify tumors as having a high frequency of MSI.
  • a tumor can be classified as MSI, including MSI-low or MSI-high, using polymerase chain reaction (PCR) and/or immunohistochemistry (IHC) assays.
  • PCR polymerase chain reaction
  • IHC immunohistochemistry
  • a tumor is classified as MSI-H by PCR if (i) there is a shift (usually downward) in the size of at least two microsatellite loci from a reference panel of five microsatellite loci in tumor relative to normal, where the reference panel can be the “Bethesda Panel,” also referred to herein as the “NCI-Reference Panel (Bethesda, 1998)”, which includes two mononucleotide loci (BAT-25 and BAT-26) and three dinucleotide loci (D2S123, D5S346, and D17S250), or alternatively, the reference panel can be Promega Corporation’s MSI Analysis System, which includes five mononucleotide loci (BAT-25, BAT-26, NR-21, NR-24, and MONO-27); or (ii) there is a shift in the size of 30% or more microsatellite loci from a reference panel of more than five microsatellite loci in tumor relative to
  • the MSI-H phenotype is associated with germline defects in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, and is the primary phenotype observed in tumors from patients with HNPCC/Lynch syndrome.
  • a tumor is classified as MSI-H in IHC test if it shows a loss of protein expression for at least 1 of the above 4 mismatch repair genes.
  • Cells can be similarly classified as MSI-H using the tests described herein for tumors.
  • a tumor or cell is classified as MSI-H using PCR to amplify the five microsatellite loci of the “Bethesda Panel” (BAT-25, BAT-26, D2S123, D5S346, and D17S250) from both tumor tissue or cells and normal tissue or cells, wherein the tumor or cell is classified as MSI-H if there is a shift in the size of at least two of the microsatellite loci from the tumor tissue or cells relative to the normal tissue or cells. In some embodiments, the shift in size of the microsatellite loci is a downward shift.
  • a tumor or cell is classified as MSI-H using PCR to amplify the five microsatellite loci of Promega Corporation’s MSI Analysis System (BAT-25, BAT-26, NR- 21, NR-24, and MONO-27) from both tumor tissue or cells and normal tissue or cells, wherein the tumor or cell is classified as MSI-H if there is a shift in the size of at least two of the microsatellite loci from the tumor tissue or cells relative to the normal tissue or cells. In some embodiments, the shift in size of the microsatellite loci is a downward shift.
  • a tumor is classified as MSI-H using IHC to determine the expression level of the MMR proteins MLH1, MSH2, MSH6, and/or PMS2 in both tumor tissue and normal tissue, wherein the tumor is classified as MSI-H if there is a loss of protein expression for at least one of the MMR proteins in the tumor tissue relative to the normal tissue.
  • the loss of protein expression is a decrease of at least 20% (such as a decrease of 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more).
  • a tumor is classified as MSI-L by PCR if (i) there is a shift in the size of one microsatellite locus from a reference panel of five microsatellite loci in tumor relative to normal, where the reference panel can be the “Bethesda Panel” or Promega Corporation’s MSI Analysis System; or (ii) there is a shift in the size of less than 30% microsatellite loci from a reference panel of more than five microsatellite loci in tumor relative to normal.
  • MSI- L tumors are thought to represent a distinct mutator phenotype with potentially different molecular etiology than MSI-H tumors (Thibodeau, 1998; Wu et al., 1999, Am J Hum Genetics 65: 1291-1298). Cells can be similarly classified as MSI-L using the tests described herein for tumors.
  • Cancers classified as MSI-H include, but not limited to, uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adenoid cystic carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, and endocervical adenocarcinoma.
  • the present disclosure provides a method for treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein: ring A is aryl, heteroaryl, or (C3-Cn)cycloalkyl; each R 1 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, amino(Ci-C6)alkyl, (C3-Ce)cycloalkyl, hydroxyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-C6)alkylsulfanyl, amino, ((Ci-C6)alkyl)amino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-,
  • R 3 is hydrogen or (Ci-Ce)alkyl; each R 4 is independently halogen, (Ci-Ce)alkyl, or halo(Ci-Ce)alkyl; each R la is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxyl, or (Ci-Ce)alkoxy; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 1 or 2; and q is 0, 1, or 2.
  • the present disclosure provides a method for treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (F) or a pharmaceutically acceptable salt thereof: wherein: ring A is aryl, 5- to 10-membered heteroaryl, or (C3-Ce)cycloalkyl; each R 1 is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, amino(Ci-C6)alkyl, (C3-Ce)cycloalkyl, hydroxyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, (C3-Ce)cycloalkoxy, (Ci-C6)alkylsulfanyl, amino, ((Ci-C6)alkyl)amino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)
  • R 3 is hydrogen or (Ci-Ce)alkyl; each R la is independently halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, hydroxyl, or (Ci-Ce)alkoxy; m is 0, 1, 2, or 3; n is 0, 1, or 2; and p is 1 or 2.
  • the present disclosure provides use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of comprising the compound, in the manufacture of a medicament for treating cancer.
  • the cancer is treatable by inhibition of WRN.
  • the cancer is characterized by MSI-H and/or dMMR.
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of comprising the compound, for use a method of treatment.
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of comprising the compound, for use_in treating cancer.
  • the cancer is treatable by inhibition of WRN.
  • the cancer is characterized by MSI-H and/or dMMR.
  • the present disclosure contemplates the use of compounds of Formula (I), or a pharmaceutically acceptable salt thereof in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation).
  • active therapeutic agents e.g., chemotherapeutic agents
  • prophylactic or therapeutic modalities e.g., radiation
  • the various active agents frequently have different, complementary mechanisms of action.
  • Such combination therapy may be especially advantageous by allowing a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse effects associated with one or more of the agents.
  • such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.
  • “combination” is meant to include therapies that can be administered separately, for example, formulated separately for separate administration (e.g., as may be provided in a kit), and therapies that can be administered together in a single formulation (i.e., a “co-formulation”).
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof are administered or applied sequentially, e.g., where one agent is administered prior to one or more other agents.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof are administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a coformulation). Regardless of whether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for purposes of the present disclosure.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof may be used in combination with at least one other (active) agent in any manner appropriate under the circumstances.
  • treatment with the at least one active agent and at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof is maintained over a period of time.
  • treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), while treatment with the compound of Formula (I), or a pharmaceutically acceptable salt thereof is maintained at a constant dosing regimen.
  • treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), while treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof is reduced (e.g., lower dose, less frequent dosing or shorter treatment regimen).
  • treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), and treatment with the compound of Formula (I), or a pharmaceutically acceptable salt thereof is increased (e.g., higher dose, more frequent dosing or longer treatment regimen).
  • treatment with the at least one active agent is maintained and treatment with the compound of Formula (I), or a pharmaceutically acceptable salt thereof is reduced or discontinued (e.g., lower dose, less frequent dosing or shorter treatment regimen).
  • treatment with the at least one active agent and treatment with the compound of Formula (I), or a pharmaceutically acceptable salt thereof are reduced or discontinued (e.g., lower dose, less frequent dosing or shorter treatment regimen).
  • the present disclosure provides methods for treating cancer with a compound of Formula (I), or a pharmaceutically acceptable salt thereof and at least one additional therapeutic or diagnostic agent.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof provided herein may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof.
  • the dosing regimen may also take into consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered. Effective dosage amounts and dosage regimens can readily be determined from, for example, safety and dose-escalation trials, in vivo studies (e.g., animal models), and other methods known to the skilled artisan.
  • dosing parameters dictate that the dosage amount be less than an amount that could be irreversibly toxic to the subject (the maximum tolerated dose (MTD)) and not less than an amount required to produce a measurable effect on the subject.
  • MTD maximum tolerated dose
  • Such amounts are determined by, for example, the pharmacokinetic and pharmacodynamic parameters associated with ADME, taking into consideration the route of administration and other factors.
  • An effective dose is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it.
  • the “median effective dose” or EDso of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population to which it is administered.
  • the ED50 is commonly used as a measure of reasonable expectance of an agent’s effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors.
  • the effective amount is more than the calculated EDso, in other situations the effective amount is less than the calculated ED50, and in still other situations the effective amount is the same as the calculated ED50.
  • an effective dose of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as provided herein may be an amount that, when administered in one or more doses to a subject, produces a desired result relative to a healthy subject.
  • an effective dose may be one that improves a diagnostic parameter, measure, marker and the like of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as the diagnostic parameter, measure, marker and the like exhibited by a normal subject.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof disclosed herein may be administered (e.g., orally) at dosage levels of about 0.01 mg/kg to about 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • compositions can be provided in the form of tablets, capsules and the like containing from 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient.
  • the dosage of the compound of Formula (I), or a pharmaceutically acceptable salt thereof is contained in a “unit dosage form”.
  • unit dosage form refers to physically discrete units, each unit containing a predetermined amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, either alone or in combination with one or more additional agents, sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the particular agent and the effect to be achieved.
  • HPLC / MS was performed using mass directed auto purification (MDAP) chromatography.
  • HPLC column commonly used was Acquity UPLC CSH C18 column (30 mm x 2. 1 mm i.d. 1.7 pm packing diameter) at 45 °C.
  • the naming programs used are ACDLABs 11.0 Namebatch, ACD IUPAC, or ChemDraw.
  • Step 1 methyl 6-(3,4-dimethylphenyl)-2 -methoxynicotinate methyl 6-bromo-2 -methoxynicotinate (250 mg, 1.0 mmol), (3,4-dimethylphenyl)boronic acid (150 mg, 1.0 mmol), K2CO3 (280 mg, 2.0 mmol) and APhos Pd G3 (65 mg, 0.10 mmol) were placed into a flask vial equipped with a magnetic stir bar and dissolved in THF (4 mL) and H2O (1 mL). The reaction was heated to 80°C and stirred for 17 h then cooled and poured into brine and extracted twice with EtOAc.
  • Step 1 2-chloro-6-phenyl-4-(trifluoromethyl)nicotinic acid
  • Step 1 methyl 6-(cyclohex-l-en-l-yl)-2 -methoxynicotinate
  • Step 3 6-cyclohexyl-2-oxo-l,2-dihydropyridine-3 -carboxylic acid
  • the following compounds were synthesized in an analogous manner to the preparation described above.
  • the palladium catalyst used for the cross-coupling
  • HC1 concentration used for the hydrolysis
  • Step 1 methyl 2-oxo-6-phenyl-l,2-dihydropyridine-3-carboxylate
  • 2-oxo-6-phenyl-l,2-dihydropyridine-3-carboxylic acid 180 mg, 0.81 mmol was dissolved in DMF (4.5 mL) and NaH (60 wt% in mineral oil) (65 mg, 1.6 mmol) was added. The reaction was stirred at r.t for 15 min and then iodomethane (0.051 mL, 0.81 mmol) was added dropwise. After 1 h, additional iodomethane (0.051 mL, 0.81 mmol) was added and continued stirring at r.t for another 1.5 h. The reaction was diluted with H2O and extracted with EtOAc.
  • Step 2 l-methyl-2-oxo-6-phenyl-l,2-dihydropyridine-3-carboxylic acid methyl l-methyl-2-oxo-6-phenyl-l,2-dihydropyridine-3 -carboxylate (85 mg, 0.35 mmol) and LiOH (34 mg, 1.4 mmol) were combined in methanol (2 mb) and stirred at r.t. for 2 h.
  • 6-(3,5-difluorophenyl)-2-hydroxynicotinic acid 100 mg, 0.40 mmol
  • pyridine 0.80 ml
  • Perfluorophenyl 2,2,2-trifluoroacetate 0. 14 ml, 0.80 mmol
  • Step 3 (R)-6-bromo-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2 -methoxynicotinamide
  • Step 4 (R)-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-hydroxy-6-iodonicotinamide
  • Step 1 methyl 5-bromo-2-methoxy-6-phenylnicotinate
  • Step 4 (R)-5-cyano-N-(l, l-dioxido-2,3-dihydrothiophen-3-yl)-2-methoxy-6- phenylnicotinamide
  • Step 2 methyl 2-methoxy-6-phenyl-5-(trifluoromethyl)nicotinate
  • Step 3 2-oxo-6-phenyl-5 -(trifluoromethyl)- l,2-dihydropyridine-3 -carboxylic acid
  • Step 1 methyl 5-bromo-2-methoxy-6-phenylnicotinate
  • Step 2 methyl 2-methoxy-5-methyl-6-phenylnicotinate
  • Step 1 methyl 2-chloro-5-fluoro-6-phenylnicotinate methyl 2-chloro-5-fluoro-6-phenylnicotinate was obtained from Suzuki coupling conditions similar to those already above using methyl 2,6-dichloro-5-fluoronicotinate and phenylboronic acid.
  • ES-LCMS m/z 266.0 [M+H] + .
  • 5-fluoro-2-oxo-6-phenyl-l,2-dihydropyridine-3-carboxylic acid was obtained from hydrolysis of 5-fluoro-2-methoxy-6-phenylnicotinate using HC1 under similar conditions to those already described above.
  • 'H NMR (400 MHz, DMSO-de) 5 8.34 (br d, J 9.5 Hz, 1H), 7.82 - 7.73 (m, 2H), 7.63 - 7.54 (m, 3H).
  • ES-LCMS m/z iM [M+H] + .
  • Step 2 methyl 2-methoxy-6-phenyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)nicotinate
  • 5-methoxy-2-oxo-6-phenyl-l,2-dihydropyridine-3-carboxylic acid was obtained from hydrolysis of 2,5-dimethoxy-6-phenylnicotinate using HC1 under similar conditions to those already described above.
  • ES-LCMS m/z 246.2 [M+H] + .
  • Step 1 methyl 5-chloro-2-methoxy-6-phenylnicotinate methyl 5-chloro-2-methoxy-6-phenylnicotinate was obtained from methyl 2-methoxy-6- phenylnicotinate using NCS under similar conditions to those already described above.
  • ES-LCMS m/z 278.0 [M+H] + .
  • 5-chloro-2-methoxy-6-phenylnicotinic acid was obtained from hydrolysis of methyl 5-chloro- 2-methoxy-6-phenylnicotinate using Li OH under conditions similar to those already described above.
  • ES-LCMS m/z 264.0 [M+H] + .
  • Step 3 (R)-5-chloro-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-methoxy-6- phenylnicotinamide
  • Step 2 perfluorophenyl 5 -chloro-6-cyclohexyl -2 -oxo- l,2-dihydropyridine-3 -carboxylate perfluorophenyl 5-chloro-6-cyclohexyl-2-oxo- l,2-dihydropyridine-3-carboxylate was obtained from 5 -chloro-6-cyclohexyl -2 -oxo- l,2-dihydropyridine-3 -carboxylic acid and perfluorophenyl 2,2,2-trifluoroacetate in accordance with a procedure already described above.
  • Step 1 methyl 5-((tert-butoxycarbonyl)amino)-2-methoxy-6-phenylnicotinate
  • the reaction mixture was then stirred at 90°C for 12 h.
  • the mixture was concentrated in vacuo and taken up in 50 mL water and 50 mL ethyl acetate. Layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with saturated sodium chloride (50 mL) and water (50 mL), dried over sodium sulphate, and concentrated in vacuo to give crude mixture.
  • Step 2 5-((tert-butoxycarbonyl)amino)-2-methoxy-6-phenylnicotinic acid
  • Step 3 perfluorophenyl 5-((tert-butoxycarbonyl)amino)-2-methoxy-6-phenylnicotinate perfluorophenyl 5-((tert-butoxycarbonyl)amino)-2-methoxy-6-phenylnicotinate was obtained from 5-((tert-butoxycarbonyl)amino)-2-methoxy-6-phenylnicotinic acid and perfluorophenyl 2,2,2-trifluoroacetate in accordance with a procedure already described above.
  • ES-LCMS m/z 511.0 [M+H] + .
  • Step 4 tert-butyl (R)-(5-((l,l-dioxido-2,3-dihydrothiophen-3-yl)carbamoyl)-6-methoxy-2- phenylpyridin-3 -yl)carbamate
  • tert-butyl (R)-(5-((l,l-dioxido-2,3-dihydrothiophen-3-yl)carbamoyl)-6-methoxy-2- phenylpyridin-3-yl)carbamate was obtained from perfluorophenyl 5 -((tert- butoxycarbonyl)amino)-2-methoxy-6-phenylmcotinate using general amidation method B conditions.
  • Step 1 methyl 2-methoxy-6-phenyl-5-vinylnicotinate
  • Step 2 methyl 5-formyl-2-methoxy-6-phenylnicotinate
  • Step 4 (R)-N-(l, l-dioxido-2,3-dihydrothiophen-3-yl)-5-formyl-2-oxo-6-phenyl-l,2- dihydropyridine-3-carboxamide
  • R N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-5-formyl-2-oxo-6-phenyl-l,2- dihydropyridine-3 -carboxamide was obtained from 5-formyl-2-oxo-6-phenyl-l,2- dihydropyridine -3 -carboxylic acid using general amidation method C conditions.
  • Step 1 methyl 4-chloro-6-phenylnicotinate methyl 4-chloro-6-phenylnicotinate was obtained from Suzuki coupling conditions similar to those already above using methyl 4,6-dichloronicotinate and phenylboronic acid. 'H NMR (400 MHz, DMSO-de) 5 9.05 (s, 1H), 8.27 (s, 1H), 8.24 - 8.17 (m, 2H), 7.58 - 7.45 (m, 3H), 3.91 (s, 3H). ES-LCMS m/z 248.0 [M+H] + .
  • Step 3 methyl 4-acetoxy-2-oxo-6-phenyl-l,2-dihydropyridine-3-carboxylate
  • Step 4 4-hydroxy-2-oxo-6-phenyl-l,2-dihydropyridine-3 -carboxylic acid
  • Step 1 methyl 2,4-dichloro-6-phenylnicotinate
  • Step 4 (R)-N-(l, l-dioxido-2,3-dihydrothiophen-3-yl)-2,4-dimethoxy-6-phenylnicotinamide M 11r .C « °°
  • Step 1 2-methoxy-6-(l-methyl-lH-pyrazol-5-yl)nicotinic acid, formic acid salt
  • 2-methoxy-6-(l-methyl-lH-pyrazol-5-yl)nicotinic acid, formic acid salt was obtained via a Suzuki cross-coupling procedure similar to ones described previously using methyl 6-bromo- 2 -methoxynicotinate and 1 -methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1H- pyrazole.
  • 6-(l-methyl-lH-pyrazol-5-yl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid was obtained from 2-methoxy-6-(l-methyl-lH-pyrazol-5-yl)nicotinic acid using TMS-I using a procedure similar to ones described previously.
  • ES-LCMS m/z 220.0 [M+H] + .
  • Step 1 methyl 2-methoxy-6-(4-methylcyclohex-l-en-l-yl)nicotinate methyl 2-methoxy-6-(4-methylcyclohex-l-en-l-yl)nicotinate was obtained via a Suzuki crosscoupling procedure similar to ones described previously using methyl 6-chloro-2- methoxynicotinate and 4,4,5 ,5 -tetramethyl -2-(4-methylcyclohex- 1 -en- 1 -yl)- 1 ,3,2- dioxaborolane.
  • 2-methoxy-6-(4-methylcyclohex-l-en-l-yl)nicotinic acid was obtained via a Li OH hydrolysis procedure similar to ones described previously using methyl 2-methoxy-6-(4-methylcyclohex- l-en-l-yl)nicotinate.
  • Step 3 N-((R)- 1 , 1 -dioxido-2,3-dihydrothiophen-3-yl)-2-methoxy-6-(4-methylcyclohex- 1 -en- 1 -yl)nicotinamide
  • N-((R)- 1 , 1 -dioxido-2,3 -dihydrothiophen-3 -yl)-2-methoxy-6-(4-methylcyclohex- 1 -en- 1 - yl)nicotinamide was obtained via aHATU amide coupling procedure similar to ones described previously using 2-methoxy-6-(4-methylcyclohex-l-en-l-yl)nicotinic acid.
  • Step 1 4-azido-5-(methoxycarbonyl)-2 -phenylpyridine 1 -oxide
  • Step 2 methyl 4-azido-2-chloro-6-phenylnicotinate methyl 4-azido-2-chloro-6-phenylnicotinate was obtained via an oxalyl chloride procedure similar to ones described previously using 4-azido-5-(methoxycarbonyl)-2-phenylpyridine 1- oxide.
  • Tf NMR 400 MHz, DMSO-de
  • ES-LCMS m/z 289.0 [M+H] + .
  • Step 3 methyl 4-azido-2-methoxy-6-phenylmcotinate methyl 4-azido-2-methoxy-6-phenylnicotinate was obtained via NaOMe alkoxylation procedure similar to ones described previously using methyl 4-azido-2-chloro-6- phenylnicotinate. The desire product was contaminated with unreacted methyl 4-azido-2- chloro-6-phenylnicotinate and used in the next step as is. NMR was a complex mixture of desired product and impurities.
  • Step 4 4-azido-2-methoxy-6-phenylnicotinic acid
  • Step 5 (R)-4-azido-N-( 1 , 1 -dioxido-2,3-dihydrothiophen-3-yl)-2-methoxy-6- phenylnicotinamide
  • Step 6 (R)-4-amino-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-methoxy-6- phenylnicotinamide
  • Step 2 methyl 6-chloro-5 -hydroxy-2 -methoxynicotinate
  • Step 3 methyl 5 -hydroxy-2 -methoxy-6-(4-(trifluoromethyl)phenyl)nicotinate
  • Step 4 5 -hydroxy-2 -methoxy-6-(4-(trifluoromethyl)phenyl)nicotinic acid
  • Step 5 (R)-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-5-hydroxy-2-methoxy-6-(4-
  • Step 1 methyl 6-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-2 -methoxynicotinate and methyl 6-(5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-2 -methoxynicotinate
  • the fdtrate was concentrated and purified by normal phase chromatography (EtOAc / Hexanes, 0-100 % gradient, 30 min run). The fractions containing desired product were combined and concentrated to afford a mixture of methyl 6-(5,6-dihydro-4H- cyclopenta[b]thiophen-2-yl)-2 -methoxynicotinate (major product) and methyl 6-(5,6-dihydro- 4H-cyclopenta[b]thiophen-3-yl)-2-methoxynicotinate (minor product) (100 mg, 0.26 mmol, 8.5 % yield) as a pale yellow solid.
  • Step 2 6-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-2-methoxynicotinic acid and 6-(5,6- dihydro-4H-cyclopenta[b]thiophen-3-yl)-2 -methoxynicotinic acid
  • 4H-cyclopenta[b]thiophen-3-yl)-2 -methoxynicotinic acid were obtained via a LiOH hydrolysis procedure similar to ones described previous using the mixture of isomers methyl 6-(5,6- dihydro-4H-cyclopenta[b]thiophen-2-yl)-2-methoxynicotinate and methyl 6-(5,6-dihydro-4H- cyclopenta[b]thiophen-3-yl)-2 -methoxynicotinate.
  • ES-LCMS m/z 276.0 [M+H] + two isomer peaks, —5.5:1 mixture).
  • Step 3 (R)-6-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-N-(l,l-dioxido-2,3- dihydrothiophen-3-yl)-2 -methoxynicotinamide and (R)-6-(5,6-dihydro-4H- cyclopenta[b]thiophen-3-yl)-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2- methoxynicotinamide
  • the mixture was quenched with saturated sodium thiosulfate solution (10 mL) and was stirred at room temperature over 16 h.
  • the mixture was combined with additional water and DCM and filtered. The layers were separated, the aqueous layer was extracted with DCM (3 x 10 mL), the combined organic phase passed through a hydrophobic frit and concentrated to afford the crude product mixture.
  • the crude product mixture was purified via normal phase chromatography (15% EtOAc / heptane, isocratic) to afford methyl 6-(l -hydroxy cyclohexyl)-2 -methoxynicotinate (260 mg, 0.85 mmol, 65 % yield) as a thick, transparent, oil.
  • Step 2 6-(l -hydroxy cyclohexyl)-2-methoxynicotinic acid
  • 6-(l-hydroxycyclohexyl)-2-methoxynicotinic acid was obtained via a Li OH hydrolysis procedure similar to ones described previously using methyl 6-(l -hydroxy cyclohexyl)-2- methoxynicotinate.
  • Step 1 6-bromo-5 -hydroxy-2 -methoxynicotinate
  • 6-bromo-5-hydroxy-2-methoxynicotinate was obtained from an NBS bromination via a procedure similar to ones described previously using methyl 5-hydroxy-2-methoxynicotinate.
  • 'H NMR 400 MHz, DMSO-de
  • ES- LCMS m/z 262.1 [M+H] + .
  • Step 2 methyl 6-bromo-2-methoxy-5-(methoxymethoxy)nicotinate
  • the resulting biphasic system was extracted with diethyl ether (3 x 50 mL) and the combined organic portions were combined with hexane (100 mL). The resulting mixture was washed with water (3 x 50 mL), washed once with brine, dried over MgSO-i. fdtered, and concentrated to afford methyl 6- bromo-2-methoxy-5-(methoxymethoxy)nicotinate (2.2 g, 7.1 mmol, 98 % yield) as an off- white solid.
  • Step 3 6-bromo-2-methoxy-5 -(methoxymethoxy )nicotinic acid
  • 6-bromo-2-methoxy-5-(methoxymethoxy)nicotinic acid was obtained via a Li OH hydrolysis procedure similar to ones described previously using methyl 6-bromo-2-methoxy-5- (methoxymethoxy)nicotinate.
  • 'H NMR 400 MHz, DMSO-de) 5 13.24 (br s, 1H), 7.94 (s, 1H), 5.27 (s, 2H), 3.87 (s, 3H), 3.42 (s, 3H).
  • ES-LCMS m/z 292.0 [M+H] + .
  • Step 4 (R)-6-bromo-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-methoxy-5-
  • (methoxymethoxy)nicotinamide was obtained from a perfluorophenyl 2,2,2-trifluoroacetate coupling protocol similar to ones already described herein using 6-bromo-2-methoxy-5- (methoxymethoxy)nicotinic acid.
  • Step 1 methyl 6-(l-fluorocyclohexyl)-2 -methoxynicotinate
  • methyl 6-(cyclohex-l-en-l-yl)-2 -methoxynicotinate 1.0 g, 4.1 mmol
  • trifluorotoluene 6.4 mL
  • l,l,2,2-tetramethyl-l,2-ethanediamino-N,N'-bis(3,5-di- tert-butylsalicylidene)-cobalt(II) 0.074 g, 0.12 mmol
  • l-fluoro-2,4,6-trimethylpyridin-l- ium tetrafluoroborate 1.8 g, 8.1 mmol
  • Step 2 6-(l-fluorocyclohexyl)-2 -methoxynicotinic acid
  • 6-(l-fluorocyclohexyl)-2 -methoxynicotinic acid was obtained via a Li OH hydrolysis procedure similar to ones described previously using methyl 6-(l-fluorocyclohexyl)-2- methoxynicotinate.
  • the desired compound contained -20% (by weight) of the cyclohexyl byproduct (carried over from previous step).
  • ES- LCMS m/z 254.1 [M+H] + .
  • Step 3 (R)-N-( 1 , 1 -dioxido-2,3-dihydrothiophen-3-yl)-6-( 1 -fluorocyclohexyl)-2- methoxynicotinamide
  • Step 1 methyl 6-(2-hydroxyphenyl)-2 -methoxynicotinate methyl 6-(2-hydroxyphenyl)-2-methoxynicotinate was obtained via a Suzuki coupling protocol similar to ones already described herein using 6-chloro-2-methoxynicotinate and (2- hydroxyphenyl)boronic acid.
  • Step 2 methyl 2-methoxy-6-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)nicotinate
  • the mixture was then heated to 60 °C for another 40 h.
  • the mixture was then diluted with diethyl ether and water.
  • the phases were separated, and the aqueous phase was extracted three times with diethyl ether.
  • the combined organic portions were dried over MgSC>4, fdtered, and concentrated to afford the crude product mixture.
  • the crude product mixture was purified via normal phase chromatography (20-30% EtOAc / heptane) to afford methyl 2-methoxy-6-(2- ((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)nicotinate (110 mg, 0.28 mmol, 45 % yield) as a semi-solid.
  • Step 3 2-methoxy-6-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)nicotinic acid methoxy-6-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)nicotinic acid was obtained via a LiOH hydrolysis protocol similar to ones already described herein using methyl 2-methoxy-6- (2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)nicotinate.
  • Step 1 methyl 6-(2-(cyclohexylmethoxy)phenyl)-2 -methoxynicotinate methyl 6-(2-(cyclohexylmethoxy)phenyl)-2-methoxynicotinate was obtained via a Mitsunobu protocol similar to ones already described herein using methyl 6-(2-hydroxyphenyl)-2- methoxynicotinate.
  • Step 2 6-(2-(cyclohexylmethoxy)phenyl)-2 -methoxynicotinic acid
  • 6-(2-(cyclohexylmethoxy)phenyl)-2-methoxynicotinic acid was obtained via a LiOH hydrolysis procedure similar to ones described previously using methyl 6-(2- (cyclohexylmethoxy)phenyl)-2-methoxynicotinate.
  • the rection mixture was diluted by ice cold water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic phase was washed with water (10 mL), saturated brine (5 mL) dried over sodium sulphate and evaporated in vacuo to give the crude product of 4 g as a brown oil.
  • the crude mixture was purified via reverse phase chromatography (MeCN / H2O, 0.1% formic acid modifier, 0%- 100% gradient, 60 min run) to afford 2-chloro-6-(l-methylcyclohexyl)nicotinonitrile (380 mg, 1.5 mmol, 20 % yield) as light brown solid.
  • Aqueous layer was injected directly to be purified via reverse phase chromatography (MeCN / H2O, 0.1% formic acid modifier, 0%-100% gradient, 60 min run) to afford 2-chloro-6-(l-methylcyclohexyl)nicotinic acid (200 mg, 0.78 mmol, 51 % yield) as a light brown solid.
  • Step 4 (R)-N-( 1 , 1 -dioxido-2,3-dihydrothiophen-3-yl)-2-methoxy-6-( 1 - methylcyclohexyl)nicotinamide
  • Step 1 tert-butyl (l-(6-chloro-5-cyanopyridin-2-yl)cyclohexyl)carbamate tert-butyl (l-(6-chloro-5-cyanopyridin-2-yl)cyclohexyl)carbamate was obtained via a photo- Minisci reaction via procedure similar to one already described herein using 2- chloronicotinonitrile and l-((tert-butoxycarbonyl)amino)cyclohexane-l -carboxylic acid.
  • Step 2 6-(l-((tert-butoxycarbonyl)amino)cyclohexyl)-2-ethoxynicotinic acid
  • 6-(l-((tert-butoxycarbonyl)amino)cyclohexyl)-2-ethoxynicotinic acid was obtained via a hydrolysis and SNAr using a procedure similar to one already described herein using tert-butyl (l-(6-chloro-5-cyanopyridin-2-yl)cyclohexyl)carbamate and NaOH in EtOH.
  • Step 3 tert-butyl (R)-(l-(5-((l,l-dioxido-2,3-dihydrothiophen-3-yl)carbamoyl)-6- ethoxypyridin-2-yl)cyclohexyl)carbamate tert-butyl (R) - ( 1 -(5 -(( 1 , 1 -dioxido-2,3 -dihydrothiophen-3 -yl)carbamoyl)-6-ethoxypyridin-2- yl)cyclohexyl)carbamate was obtained from a HATU coupling protocol similar to ones already described herein using 6-(l-((tert-butoxycarbonyl)amino)cyclohexyl)-2 -ethoxynicotinic acid.
  • N-hydroxyphthalimide In a 40 mL vial, N-hydroxyphthalimide (4.5 g, 28 mmol) was suspended in DCM to produce a total volume of 40 mL (a suspension resulted).
  • Stock solution of DCC In a 40 mL vial, DCC (5.7 g, 28 mmol) was dissolved in DCM to produce total of 40 mL.
  • Stock solution of DMAP In a 40 mL vial, DMAP (310 mg, 2.5 mmol) was dissolved in 40 mL of DCM.
  • Step 2 (R)-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-methoxy-6-(4-
  • the vial was purged with dry nitrogen gas (3x) and then degassed DMA (6.6 mL) was added.
  • the reaction mixture was irradiated over 16 h using the Penn PHD reactor (395 nm wavelength, 100% intensity, 800 rpm stirring).
  • the mixture was combined with EtOAc and water and transferred to a separatory funnel.
  • the phases were separated, and the aqueous phase was extracted with EtOAc (3x).
  • the combined organic portions were diluted with hexane (30 mL) and the new organic phase was washed with water (3x), once with brine, and then concentrated to afford the crude product mixture.
  • 6-(2,2-difluorocyclohexyl)-N-((R)-l,l-dioxido-2,3-dihydrothiophen-3-yl)-2- methoxynicotinamide was obtained via photoredox catalysis according to a procedure similar to one already described using l,3-dioxoisoindolin-2-yl 2,2-difluorocyclohexane-l- carboxylate and (R)-6-bromo-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2- methoxynicotinamide.
  • 6-(2,2-difluorocyclohexyl)-N-((R)-l,l-dioxido-2,3-dihydrothiophen-3-yl)-2- methoxynicotinamide was obtained via photoredox catalysis according to a procedure similar to one already described using l,3-dioxoisoindolin-2-yl (ls,3R,5S)-3,5-dimethylcyclohexane- 1 -carboxylate and (R)-6-bromo-N-( 1 , 1 -dioxido-2,3 -dihydrothiophen-3 -yl)-2- methoxynicotinamide.
  • Step 1 (2-bromobenzyl)triphenylphosphonium bromide
  • Step 2 (E)-l-bromo-2-styrylbenzene and (Z)-l-bromo-2-styrylbenzene
  • Step 3 methyl 2-methoxy-6-(2-phenethylphenyl)nicotinate
  • Step 1 tert-butyl (R)-4-(2,2-difluorovinyl)-2,2-dimethyloxazolidine-3-carboxylate
  • Step 3 benzyl (R)-(4,4-difluoro-l-hydroxybut-3-en-2-yl)carbamate
  • Step 4 (R)-S-(2-(((benzyloxy)carbonyl)amino)-4,4-difluorobut-3-en-l-yl) benzothioate
  • Step 5 benzyl (R)-(5-fluoro-2,3-dihydrothiophen-3-yl)carbamate
  • the flask was positioned into a heating block set to 65 °C (internal temperature of the reaction mixture likely lower), the heating was turned on, and the reaction mixture was stirred at 1700 rpm for 3 h. After this period, the mixture was allowed to cool down to rt, THF was removed in vacuo, the evaporation residue suspended in 50 mL DCM, filtered, the filtrate concentrated in vacuo, and subjected to normal phase chromatography (0-100 % EtOAc / heptane) to yield benzyl (R)-(5-fluoro-2,3- dihydrothiophen-3-yl)carbamate (1.3 g, 5.1 mmol, 65 % yield) as a white solid.
  • Step 6 benzyl (R)-(5-fluoro-l,l-dioxido-2,3-dihydrothiophen-3-yl)carbamate
  • Step 7 (R)-3-amino-5-fhioro-2,3-dihydrothiophene 1,1 -dioxide hydrobromide
  • Step 1 tert-butyl (R)-4-ethynyl -2, 2-dimethyloxazolidine-3 -carboxylate
  • Step 2 tert-butyl (R)-2,2-dimethyl-4-(prop-l-yn-l-yl)oxazolidine-3-carboxylate
  • Step 3 benzyl (R)-(l-hydroxypent-3-yn-2-yl)carbamate, hydrochloride
  • Step 4 (R)-S-(2-(((benzyloxy)carbonyl)amino)pent-3-yn-l-yl) benzothioate
  • Step 5 benzyl (R)-(5-methyl-2,3-dihydrothiophen-3-yl)carbamate
  • Step 6 benzyl (R)-(5-methyl-l,l-dioxido-2,3-dihydrothiophen-3-yl)carbamate
  • Step 1 methyl 6-(2-hydroxycyclohexyl)-2 -methoxynicotinate
  • the reaction mixture was quenched with water (20 mL) and EtOAc (30 mL) was added. The mixture was then separated two and the organic layer was washed with sat. sodium thiosulfate (2 x 30 mL) and sat. NaCl (8 mL), dried over with Na2SC>4, and concentrated under vacuo to afford the crude product.
  • the crude product was purified via normal phase chromatography (0-100% EtOAc / petroleum ether over 30 min) to afford methyl 6-(2 -hydroxy cyclohexyl)-2 -methoxynicotinate (140 mg, 0.50 mmol, 8.2 % yield) as a yellow gum.
  • 6-(2-hydroxycyclohexyl)-2-methoxynicotinic acid was obtained via a LiOH hydrolysis procedure similar to ones described previously using methyl 6-(2-hydroxycyclohexyl)-2- methoxynicotinate.
  • N-((R)-l,l-dioxido-2,3-dihydrothiophen-3-yl)-6-(2-hydroxycyclohexyl)-2- methoxynicotinamide was obtained from a HATU coupling protocol similar to ones already described herein using 6-(2-hydroxycyclohexyl)-2 -methoxynicotinic acid.
  • Amidation method B syntheses (using isolated perfluorophenyl esters)
  • Phenylboronic acid (0.036 g, 0.30 mmol), (R)-N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-6- iodo-2 -oxo- l,2-dihydropyridine-3 -carboxamide (0.075 g, 0.20 mmol), and P(t-Bn)?
  • Pd G4 (0.020 g, 0.020 mmol) were dissolved in 1,4-dioxane (1.6 mb) under N2.
  • 2 M aqueous CS2CO3 (0.40 mb, 0.79 mmol
  • a solution containing of APhos Pd G3 (0.0039 g, 6.1 pmol) and (R)-6-bromo-N-(l,l-dioxido- 2,3-dihydrothiophen-3-yl)-2-methoxy-5- (methoxymethoxy)nicotinamide (0.050 g, 120 pmol) was prepared in 0.75 mL of 1,4-dioxane under dry nitrogen gas. This solution was added to a glass vial containing a magnetic stirrer and 4-methoxyphenyl boronic acid (0.028 g, 180 pmol).
  • CS2CO3 (0.10 g, 153 pL, 2 M, 310 pmol) was added and the vial was capped and stirred over 16 h at 50 °C.
  • the mixtures were diluted with an equal volume of DCM and passed through a phase separator. The resulting mixtures were concentrated, and the resulting residue re-dissolved in acetonitrile (490 pL).
  • TMS-I (0.17 g, 860 pmol) was added. The resulting mixture was heated at 50 °C for 5 min and then quenched with 50 uL of water followed by dissolution in 100 uL of DMSO.
  • TMS-I was typically used as the deprotecting agent as described below, but other agents are also applicable e.g. BBrs, BCE, HC1, and in situ preparation of TMS-I from TMS-C1 and Nal. An example procedure is shown below.
  • Functional WRN unwinding activity can be measured using a Anorogenic plate based 384 well assay configured to measure the separation of labeled double stranded DNA substrate.
  • Compounds were dosed out in neat DMSO with a 1:3 serial dilution scheme. 100 nF of compound was stamped into Greiner low volume black assay plates (Greiner Cat#784076) using the Echo Acoustic Dispenser to generate assay ready plates. All solutions were prepared in assay buffer (25 mM TRIS (pH8.0), 5 mM NaCl, 2 mM MgCh, 1 mM DTT, 0.05% BSA) for this 10 pb low volume reaction.
  • assay buffer 25 mM TRIS (pH8.0), 5 mM NaCl, 2 mM MgCh, 1 mM DTT, 0.05% BSA
  • a 2X WRN Enzyme cocktail was made containing 200 pM of recombinant full-length WRN protein (1- 1432).
  • a 2X Substrate cocktail was made to consist of both 200 pM ATP (any ultrapure ATP sample) and 12 nM of the Auorescent quenched labeled double stranded DNA oligomer (IDT Custom synthesis; 5'-5IABkFQ (SEQ ID NO. 1)/GCA CTG GCC GTC GTT TTA CGG TCG TGA CT-3' (SEQ ID NO. 2): 5'-TTT TTT ACT TAA CGA CGG CCA GTG C (SEQ ID NO. 3)/36-TAMTSP/-3' (SEQ ID NO.
  • Fluorescent intensity was measured using excitation and emission wavelengths of 525 nm and 598 nm, respectively.
  • High florescent intensity (DMSO with buffer) represents full inhibition of unwinding activity and low florescent intensity (DMSO with enzyme) represents no inhibition of unwinding activity.
  • the potency of the compounds was determined using a four-parameter inhibition model to generate pICso, Hill Slope, maximum inhibition.
  • Reversibility of inhibition by certain compounds in the present disclosure was determined utilizing reagents and equipment from the functional WRN unwinding, Anorogenic assay described in Example A, specifically using the assay buffer, recombinant full-length WRN protein, ATP, and Auorescent quenched labeled double stranded DNA oligomer (DNA). Reversibility of inhibition was determined by 128-fold dilution enzyme and inhibitor from a pre-incubation reaction into assay buffer containing the DNA and ATP substrates. Reversible inhibition is inferred by a regain of enzymatic activity over a monitored reaction time course; irreversible inhibition is inferred by a failure to regain enzymatic activity.
  • the compounds were serially diluted 1:2 in neat DMSO and 100 nL dispensed into Greiner low volume black assay plates for the pre-incubation reaction. Ten nanoliters of WRN enzyme was added to the compounds and allowed to react at RT for 30 min. Assay buffer was added to a single row to serve as the no-enzyme control. After incubation 0.85 pL of enzyme/inhibitor solution was transferred with mixing to 108 pL of substrate cocktail in a NUNC black 384, 120 pL volume plate (Cat#262260) containing 100 pM ATP and 60 nM DNA. Fluorescent intensity was measured using excitation and emission wavelengths of 525 nm and 598 nm, respectively over 500 minutes.
  • the compounds showed dose-dependent inhibition relative to the no-inhibitor control reactions and several concentrations showed complete inhibition. No regain of activity was seen in the 500 minute time courses for any of the compounds, and it was therefore concluded that these compounds are irreversible inhibitors of the WRN enzyme.

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Abstract

L'invention concerne certains dérivés succinamido de Formule (I) : (I) qui inhibent l'enzyme hélicase ATP-dépendante du syndrome de Wemer (WRN), en particulier inhibent l'activité du domaine hélicase WRN et sont utiles dans le traitement de cancers pouvant être traités par inhibition de WRN, y compris des cancers caractérisés par une instabilité des microsatellites (MSI) et/ou un système de réparation des mésappariements ADN défectueux (dMMR). L'invention concerne également des compositions pharmaceutiques comprenant de tels composés, des procédés d'utilisation de tels composés, et des procédés de fabrication de ceux-ci.
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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024010782A1 (fr) * 2022-07-06 2024-01-11 Vividion Therapeutics, Inc. Compositions pharmaceutiques comprenant des inhibiteurs de l'hélicase wrn
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WO2025054488A1 (fr) * 2023-09-08 2025-03-13 Moma Therapeutics, Inc. Dérivés tricycliques et utilisations associées
WO2025067429A1 (fr) * 2023-09-28 2025-04-03 InventisBio Co., Ltd. Composés, leurs procédés de préparation et leurs utilisations
WO2024215923A3 (fr) * 2023-04-11 2025-04-03 Nimbus Wadjet, Inc. Inhibiteurs de wrn à base de sulfone vinylique cyclique
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WO2025114480A1 (fr) 2023-11-28 2025-06-05 Forx Therapeutics Ag Composés inhibiteurs de wrn
WO2025130971A1 (fr) * 2023-12-21 2025-06-26 勤浩医药（苏州）有限公司 Composé cyclique fusionné, composition pharmaceutique le contenant et son utilisation
WO2025133395A1 (fr) 2023-12-22 2025-06-26 Forx Therapeutics Ag Composés inhibiteurs bicycliques (hétéro)arylène wrn
WO2025149544A1 (fr) * 2024-01-11 2025-07-17 F. Hoffmann-La Roche Ag Procédé de préparation de n-[(1s,2e)-1-cyclopropyl-3-(méthanesulfonyl)prop-2-en-1-yl]-2-(1,1-difluoroéthyl)-4-phénoxypyrimidine-5-carboxamide
WO2025149547A1 (fr) * 2024-01-11 2025-07-17 F. Hoffmann-La Roche Ag Nouvelles formes solides de n-[(1s,2e)-1-cyclopropyl-3-(méthanesulfonyl)prop-2-en-1-yl]-2-(1,1-difluoroéthyl)-4-phénoxypyrimidine-5-carboxamide
WO2025190405A1 (fr) * 2024-03-15 2025-09-18 南京再明医药有限公司 Composé inhibiteur de wrn contenant de l'azote et son utilisation
WO2025191176A1 (fr) 2024-03-14 2025-09-18 Forx Therapeutics Ag Composés inhibiteurs de wrn
WO2025223559A1 (fr) * 2024-04-26 2025-10-30 上海济煜医药科技有限公司 Composés amides aromatiques utilisés en tant qu'inhibiteurs de l'hélicase wrn, leur procédé de préparation et leur utilisation
WO2025247373A1 (fr) * 2024-05-31 2025-12-04 Laekna Pharmaceutical Ningbo Co., Ltd. Composés cycliques fusionnés et leur utilisation en tant qu'inhibiteurs de l'hélicase wrn
WO2025261486A1 (fr) * 2024-06-22 2025-12-26 InventisBio Co., Ltd. Composés, leurs procédés de préparation et leurs utilisations
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WO2026003380A1 (fr) 2024-06-28 2026-01-02 Forx Therapeutics Ag Composés inhibiteurs de wrn
WO2026006803A1 (fr) * 2024-06-28 2026-01-02 Amgen Inc. Composés à noyau à 5 chaînons utilisés en tant que modulateurs de l'hélicase d'adn recq du syndrome de werner et leurs utilisations
WO2026006805A1 (fr) * 2024-06-28 2026-01-02 Amgen Inc. Composés à noyau à 6 chaînons utilisés comme modulateurs de l'hélicase à adn recq du syndrome de werner et leurs utilisations
WO2026046368A1 (fr) * 2024-08-30 2026-03-05 广州科恩泰生物医药科技有限公司 Composé contenant de l'azote pour inhiber l'hélicase wrn, composition pharmaceutique le contenant et utilisation associée

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019236448A1 (fr) * 2018-06-04 2019-12-12 The Broad Institute, Inc. Traitement thérapeutique de cancers à instabilité de microsatellites
WO2019241802A2 (fr) * 2018-06-15 2019-12-19 Ideaya Biosciences, Inc. Procédés d'inhibition de cellules prolifératives
EP3848365A1 (fr) * 2018-09-03 2021-07-14 Tyligand Bioscience (Shanghai) Limited Inhibiteur de trk utilisés en tant que médicament anticancéreux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019236448A1 (fr) * 2018-06-04 2019-12-12 The Broad Institute, Inc. Traitement thérapeutique de cancers à instabilité de microsatellites
WO2019241802A2 (fr) * 2018-06-15 2019-12-19 Ideaya Biosciences, Inc. Procédés d'inhibition de cellules prolifératives
EP3848365A1 (fr) * 2018-09-03 2021-07-14 Tyligand Bioscience (Shanghai) Limited Inhibiteur de trk utilisés en tant que médicament anticancéreux

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
AGGARWAL M. ET AL: "Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 108, no. 4, 10 January 2011 (2011-01-10), pages 1525 - 1530, XP055795378, ISSN: 0027-8424, Retrieved from the Internet <URL:https://www.pnas.org/content/pnas/108/4/1525.full.pdf> DOI: 10.1073/pnas.1006423108 *
AGGARWAL MONIKA ET AL: "Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 108, no. 4, 10 January 2011 (2011-01-10), pages 1525 - 1530, XP093012713, ISSN: 0027-8424, DOI: 10.1073/pnas.1006423108 *
BAUDRIN ET AL., FRONT. ONCOL., 2018
BERGE, S.M. ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
DOBZHANSKY, T., GENETICS, vol. 31, 1946, pages 269 - 290
DUDLEY, JONATHAN C. ET AL., CLINICAL CANCER RESEARCH, vol. 22, no. 4, 2016, pages 813 - 820
GOEBEL L. ET AL., RSC MED. CHEM., vol. 11, 2020, pages 760
HUANG ET AL., NATURE REVIEWS DRUG DISCOVERY, vol. 19, 2020, pages 23 - 38
JOSHUA A. SOMMERS ET AL: "A high-throughput screen to identify novel small molecule inhibitors of the Werner Syndrome Helicase-Nuclease (WRN)", PLOS ONE, vol. 14, no. 1, 9 January 2019 (2019-01-09), pages e0210525, XP055724955, DOI: 10.1371/journal.pone.0210525 *
JOURNAL OF BIOLOGICAL CHEMISTRY
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
KORENAGA, T.KOSAKI T.FUKUMURA, R.EMA T.SAKAI, T., ORG. LETT., vol. 7, 2005, pages 4915
STN REGISTRY ET AL: "N-(2,3-dihydro-1,1-dioxido-3-thienyl)-1,2-dihydro-6-(4-methoxyphenyl)-2-oxo-3-pyridinecarboxamide", 12 March 2014 (2014-03-12), pages 1 - 1, XP093012912, Retrieved from the Internet <URL:ww.stn.org> [retrieved on 20230111] *
T.W. GREENP.G.M. WUTS: "Protecting Groups in Organic Synthesis", 1991, JOHN WILEY & SONS
VAN WIETMARSCHEN N. ET AL., NATURE, vol. 586, 2020, pages 292 - 298
WU ET AL., AM J HUM GENETICS, vol. 65, 1999, pages 1291 - 1298

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US12187685B2 (en) 2022-07-06 2025-01-07 Vividion Therapeutics, Inc. Pharmaceutical compositions comprising WRN helicase inhibitors
WO2024028169A1 (fr) * 2022-08-01 2024-02-08 Nerviano Medical Sciences S.R.L. Nouveaux composés thiophénoliques à substitution spécifique
WO2024105610A1 (fr) 2022-11-18 2024-05-23 Novartis Ag Combinaisons pharmaceutiques et leurs utilisations
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WO2024246863A1 (fr) * 2023-06-01 2024-12-05 Glaxosmithkline Intellectual Property (No.4) Limited Composés chimiques et leurs utilisations
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WO2025073792A1 (fr) 2023-10-02 2025-04-10 Forx Therapeutics Ag Composés inhibiteurs de wrn
WO2025104043A1 (fr) * 2023-11-13 2025-05-22 Breakpoint Therapeutics Gmbh Nouveaux composés, compositions et leurs utilisations thérapeutiques
WO2025114480A1 (fr) 2023-11-28 2025-06-05 Forx Therapeutics Ag Composés inhibiteurs de wrn
WO2025130971A1 (fr) * 2023-12-21 2025-06-26 勤浩医药（苏州）有限公司 Composé cyclique fusionné, composition pharmaceutique le contenant et son utilisation
WO2025133395A1 (fr) 2023-12-22 2025-06-26 Forx Therapeutics Ag Composés inhibiteurs bicycliques (hétéro)arylène wrn
WO2025149544A1 (fr) * 2024-01-11 2025-07-17 F. Hoffmann-La Roche Ag Procédé de préparation de n-[(1s,2e)-1-cyclopropyl-3-(méthanesulfonyl)prop-2-en-1-yl]-2-(1,1-difluoroéthyl)-4-phénoxypyrimidine-5-carboxamide
WO2025149547A1 (fr) * 2024-01-11 2025-07-17 F. Hoffmann-La Roche Ag Nouvelles formes solides de n-[(1s,2e)-1-cyclopropyl-3-(méthanesulfonyl)prop-2-en-1-yl]-2-(1,1-difluoroéthyl)-4-phénoxypyrimidine-5-carboxamide
WO2025191176A1 (fr) 2024-03-14 2025-09-18 Forx Therapeutics Ag Composés inhibiteurs de wrn
WO2025190405A1 (fr) * 2024-03-15 2025-09-18 南京再明医药有限公司 Composé inhibiteur de wrn contenant de l'azote et son utilisation
WO2025223559A1 (fr) * 2024-04-26 2025-10-30 上海济煜医药科技有限公司 Composés amides aromatiques utilisés en tant qu'inhibiteurs de l'hélicase wrn, leur procédé de préparation et leur utilisation
WO2025247373A1 (fr) * 2024-05-31 2025-12-04 Laekna Pharmaceutical Ningbo Co., Ltd. Composés cycliques fusionnés et leur utilisation en tant qu'inhibiteurs de l'hélicase wrn
WO2025261470A1 (fr) * 2024-06-21 2025-12-26 南京再明医药有限公司 Composé sulfonyle et son utilisation
WO2025261486A1 (fr) * 2024-06-22 2025-12-26 InventisBio Co., Ltd. Composés, leurs procédés de préparation et leurs utilisations
WO2026002176A1 (fr) * 2024-06-28 2026-01-02 武汉人福创新药物研发中心有限公司 Composé contenant un cycle aromatique utilisé en tant qu'inhibiteur de wrn et son utilisation
WO2026003380A1 (fr) 2024-06-28 2026-01-02 Forx Therapeutics Ag Composés inhibiteurs de wrn
WO2026006803A1 (fr) * 2024-06-28 2026-01-02 Amgen Inc. Composés à noyau à 5 chaînons utilisés en tant que modulateurs de l'hélicase d'adn recq du syndrome de werner et leurs utilisations
WO2026006805A1 (fr) * 2024-06-28 2026-01-02 Amgen Inc. Composés à noyau à 6 chaînons utilisés comme modulateurs de l'hélicase à adn recq du syndrome de werner et leurs utilisations
WO2026046368A1 (fr) * 2024-08-30 2026-03-05 广州科恩泰生物医药科技有限公司 Composé contenant de l'azote pour inhiber l'hélicase wrn, composition pharmaceutique le contenant et utilisation associée

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