US20140275083A1 - 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh - Google Patents

3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh Download PDF

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US20140275083A1
US20140275083A1 US14/208,015 US201414208015A US2014275083A1 US 20140275083 A1 US20140275083 A1 US 20140275083A1 US 201414208015 A US201414208015 A US 201414208015A US 2014275083 A1 US2014275083 A1 US 2014275083A1
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oxazolidin
ethyl
pyrimidin
amino
hydroxyethyl
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Thomas Raymond Caferro
Zhuoliang Chen
Young Shin Cho
Abran Q. Costales
Julian Roy Levell
Gang Liu
James R. MANNING
Martin Sendzik
Cynthia Shafer
Michael David Shultz
James Sutton
Yaping Wang
Qian Zhao
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Novartis AG
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Novartis AG
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Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH INC.
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

  • the present invention is directed to novel 3-pyrimidinyl-4-yl-oxazolidin-2-one compounds, compositions containing these compounds, the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity and in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.
  • Isocitrate dehydrogenase is a key family of enzymes found in cellular metabolism. They are NADP + /NAD + and metal dependent oxidoreductases of the enzyme class EC 1.1.1.42.
  • the wild type proteins catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate generating carbon dioxide and NADPH/NADH in the process. They are also known to convert oxalosuccinate into alpha-ketoglutarate.
  • IDH1 cytosolic
  • IDH2 mitochondrial
  • glioma glioblastoma multiforme
  • paraganglioma supratentorial primordial neuroectodermal tumors
  • AML acute myeloid leukemia
  • prostate cancer thyroid cancer
  • colon cancer colon cancer
  • chondrosarcoma cholangiocarcinoma
  • peripheral T-cell lymphoma melanoma.
  • Mutant IDH2 is also associated with the rare neurometabolic disorder D-2-hydroxyglutaric aciduria type II (D-2-HGA type II). Germline mutations were found at R140 in IDH2 in 15 pateints having D-2-HGA type II. Patients having this disorder also have consistently increased levels of D-2-HG in their urine, plasma and cerebrospinal fluid. (See Kranendijk, M. et al., Science, 2010, 330, 336). Finally, patients with Ollier Disease and Mafucci Syndrome (two rare disorders that predispose to cartilaginous tumors) have been shown to be somatically mosaic for IDH1 and 2 mutations and exhibit high levels of D-2-HG. (See Amary et al., Nature Genetics, 2011 and Pansuriya et al., Nature Genetics, 2011).
  • this invention provides for a compound of formula (I)
  • R 1 , R 2a , R 2b and R 3 -R 7 are defined below.
  • this invention provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • this invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of a mutant IDH protein having a neomorphic activity such as reducing alpha-ketoglutarate to 2-hydroxyglutarate (2-HG neomorphic activity).
  • this invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of mutant IDH1 having a neomorphic activity, such as 2-HG neomorphic activity, and/or mutant IDH2 having a neomorphic activity, such as 2-HG neomorphic activity.
  • This invention further provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of IDH1 having a mutation at residue 97, 100 or 132, for example G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V; and/or an inhibitor of IDH2 having a mutation at residue 140 or 172, for example R172K, R172M, R172S, R172G, and R172W.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof as an inhibitor of IDH1 having a mutation at residue 97, 100 or 132, for example G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V; and/or an inhibitor of IDH2 having a mutation at residue 140 or 172, for example R172K, R172M, R172S, R172G, and R172W.
  • this invention provides for a method of treating a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of an effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the disease or disorder is a cell proliferation disorder, such as cancer.
  • the cancer is brain cancer, such as glioma, glioblastoma multiforme, paraganglioma, and supratentorial primordial neuroectodermal tumors (pNET); leukemia, such as acute myeloid leukemia (AML), myelodysplastic syndrome, and chronic myelogenous leukemia (CML); skin cancer, including melanoma; prostate cancer; thyroid cancer; colon cancer; lung cancer; sarcoma, including central chondrosarcoma, central and periosteal chondroma; and fibrosarcoma.
  • the disease or disorder is D-2-hydroxyglutaric aciduria.
  • the invention provides for a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with another therapeutic agent.
  • the present invention is directed to a compound of formula (I)
  • R 1 is hydrogen, methyl or ethyl
  • R 2a is hydrogen, methyl or C 1-3 haloalkyl
  • R 2b is OH, halo, C 1-6 alkoxy, C 1-3 haloalkyl, NH 2 , NH(CH 3 ) or N(CH 3 ) 2
  • R 3 and R 4 are each independently hydrogen, methyl or ethyl or R 3 and R 4 are joined together forming cyclopropyl, cyclobutyl or oxetanyl
  • R 5 and R 6 are each independently hydrogen, deuterium, halo, —C(O)OCH 3 , C 1-3 alkyl or C 1-3 haloalkyl;
  • each R is independently selected from the group consisting of H, C 1-3 alkyl and C 3-6 cycloalkyl.
  • Alkyl refers to a monovalent saturated hydrocarbon chain having the specified number of carbon atoms.
  • C 1-6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms.
  • Alkyl groups may be optionally substituted with one or more substituents as defined in formula (I).
  • Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
  • Alkoxy refers to any alkyl moiety attached through an oxygen bridge (i.e. a —O—C 1-3 alkyl group wherein C 1-3 alkyl is as defined herein). Examples of such groups include, but are not limited to, methoxy, ethoxy, and propoxy.
  • Aryl refers to a hydrocarbon ring system having an aromatic ring.
  • Aryl groups are monocyclic ring systems or bicyclic ring systems.
  • Monocyclic aryl ring refers to phenyl.
  • Bicyclic aryl rings refer to naphthyl and to rings wherein phenyl is fused to a C 5-7 cycloalkyl or C 5-7 cycloalkenyl ring as defined herein.
  • Aryl groups may be optionally substituted with one or more substituents as defined in formula (I).
  • Cycloalkyl refers to a saturated hydrocarbon ring system having the specified number of carbon atoms. Cycloalkyl groups are monocyclic or bicyclic ring systems. For example, C 3-6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 carbon atoms. Cycloalkyl groups may be optionally substituted with one or more substituents as defined in formula (I). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Cycloalkenyl refers to an unsaturated hydrocarbon ring system having the specified number of carbon atoms and having a carbon-carbon double bond within the ring.
  • C 5-7 cycloalkenyl refers to a cycloalkenyl group having from 5 to 7 carbon atoms.
  • cycloalkenyl groups have one carbon-carbon double bond within the ring.
  • cycloalkeneyl groups have more than one carbon-carbon double bond within the ring.
  • Cycloalkenyl rings are not aromatic. Cycloalkenyl groups may be optionally substituted with one or more substituents as defined in formula (I).
  • Halo refers to the halogen radicals fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to an alkyl group wherein at least one hydrogen atom attached to a carbon atom within the alkyl group is replaced with halo.
  • the number of halo substituents includes, but is not limited to, 1, 2, 3, 4, 5, or 6 substituents.
  • Haloalkyl includes, but is not limited to, monofluoromethyl, difluoroethyl, and trifluoromethyl.
  • Haloalkoxy refers to a haloalkyl moiety attached through an oxygen bridge (i.e. a —O—C 1-3 haloalkyl group wherein C 1-3 haloalkyl is as defined herein).
  • An example of a haloalkoxy group is trifluoromethoxy.
  • Heteroaryl refers to an aromatic ring system containing from 1 to 5 heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined in formula (I). Heteroaryl groups are monocyclic ring systems or are fused bicyclic ring systems. Monocyclic heteroaryl rings have from 5 to 6 ring atoms. Bicyclic heteroaryl rings have from 8 to 10 member atoms. Bicyclic heteroaryl rings include those ring systems wherein a heteroaryl ring is fused to a phenyl ring.
  • Heteroaryl includes, but is not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (including 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl), thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furanzanyl, thienyl, triazolyl, pyridinyl (including 2-, 3-, and 4-pyridinyl), pyrimidinyl, pyridazinyl, pyrazinyl, trazinyl, tetrazinyl, tetrzolyl, indonyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzimidazolyl, benzopyrany
  • Heteroatom refers to a nitrogen, oxygen, or sulfur atom.
  • Heterocyclic refers to a 3 to 11 membered saturated or unsaturated monocyclic or bicyclic ring containing from 1 to 4 heteroatoms. Heterocyclic ring systems are not aromatic. Heterocyclic groups containing more than one heteroatom may contain different heteroatoms. Heterocyclic includes ring systems wherein a sulfur atom is oxidized to form SO or SO 2 . Heterocyclic groups may be optionally substituted with one or more substituents as defined in formula (I). Heterocyclic groups are monocyclic, spiro, or fused or bridged bicyclic ring systems. Monocyclic heterocyclic rings have 3 to 7 ring atoms.
  • Examples of monocyclic heterocyclic groups include oxtanyl, tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, tetrahydro-thiopyran-1,1-dioxide, 1,4-diazepanyl, and the like.
  • Fused heterocyclic ring systems have from 8 to 11 ring atoms and include groups wherein a heterocyclic ring is fused to a phenyl ring, a heteroaryl ring or another heterocyclic ring.
  • fused heterocyclic rings include 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[1,3]dioxyl, octahydro-pyrrolo[1,2-a]pyrazinyl, octahydro-pyrido[1,2-a]pyrazinyl, octahydro-pyrrolo[3,4-c]pyrrolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazinyl and the like.
  • bridged heterocyclic groups examples include 3,8-diaza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[4.2.0]octanyl and the like.
  • spiro heterocyclic groups examples include 4,7-diaza-spiro[2.5]octanyl and the like.
  • 5-6 membered heterocylic refers to a heterocyclic group as defined above, having 5 or 6 ring atoms and containing from 1 to 4 heteroatoms.
  • Optionally substituted indicates that a group, such as an alkyl, cycloalkyl, heteroaryl, heterocyclic, phenyl, and benzyl may be unsubstitued or the group may be substituted with one or more substituents as defined in formula (I).
  • Oxo refers to a C ⁇ O group.
  • “Pharmaceutically acceptable” means a compound which is suitable for pharmaceutical use. Salts and solvates (e.g. hydrates and hydrates of salts) of compounds of the invention which are suitable for use in medicine are those where in the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.
  • “Substituted” in reference to a group such as alkyl, phenyl, benzyl, heteroaryl, and heterocyclic indicates that one or more hydrogen atoms attached to an atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation, for example, by hydrolysis, rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture).
  • a group may contain one or more substituents, one or more (as appropriate) atoms within the group may be substituted.
  • a single atom within the group may be substituted with more than one substituent as long as such substitution is accordance with the permitted valence of the atom.
  • Suitable substituents are defined for each substituted or optionally substituted group.
  • salts including pharmaceutically acceptable salts, of the compounds according to formula (I) may be prepared. These salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • Solvates, including pharmaceutically acceptable solvates, of the compounds of formula (I) may also be prepared.
  • “Solvate” refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • the compounds of formula (I), including salts and solvates thereof, may exist in crystalline forms, non-crystalline forms, or mixtures thereof.
  • the compound or salt or solvate thereof may also exhibit polymorphism, i.e. the capacity of occurring in different crystalline forms. These different crystalline forms are typically known as “polymorphs”. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, all of which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing a compound of formula (I).
  • the invention also includes various isomers of the compounds of formula (I).
  • “Isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereosiomers). With regard to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • any asymmetric atom (e.g., carbon or the like) of a compound of formula (I) can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)-configuration.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration.
  • Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)-form.
  • a compound of formula (I) can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • the invention includes unlabeled forms as well as isotopically labeled forms of compounds of formula (I).
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 F, 32 F, 35 S, 36 Cl, 125 I respectively.
  • the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • R 1 is hydrogen
  • R 2a is hydrogen or methyl.
  • R 2a is methyl.
  • R 2b is OH, fluoro, methoxy, t-butoxy, CHF 2 , CF 3 , NH 2 or NH(CH 3 ).
  • R 2b is OH, fluoro or NH 2 .
  • R 3 and R 4 are each hydrogen.
  • R 5 is hydrogen or halo.
  • R 5 is hydrogen, fluoro or chloro. More suitably R 5 is hydrogen or fluoro.
  • R 6 is hydrogen, halo, methyl, CH 2 F, CHF 2 , or CF 3 .
  • R 6 is hydrogen, fluoro, chloro, methyl, CH 2 F, CHF 2 , or CF 3 . More suitably R 6 is hydrogen or methyl.
  • R 5 is hydrogen and R 6 is hydrogen, halo, methyl, CH 2 F, CHF 2 , or CF 3 .
  • R 6 is hydrogen, fluoro, chloro, methyl, CH 2 F, CHF 2 , or CF 3 . More suitably R 6 is hydrogen or methyl.
  • R 6 is hydrogen and R 5 is hydrogen or halo.
  • R 5 is hydrogen, fluoro or chloro. More suitably R 5 is hydrogen or fluoro.
  • R 5 and R 5 are both hydrogen.
  • R 7 is
  • R 7 is
  • R 8 is hydrogen, fluoro, chloro or methyl and n is 1. In another embodiment each R 8 is independently fluoro or chloro and n is 2.
  • R 9 is hydrogen, halo, C 1-3 haloalkyl, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl.
  • R 9 is hydrogen, halo, CF 2 H, CF 3 , CF 2 CH 3 , C(CH 3 ) 2 F, C 1-6 alkyl optionally substituted with one substituent selected from the group consisting of: OH, phenyl and phenoxy, or C 3-6 cycloalkyl optionally substituted with one substituent selected from the group consisting of: cyano, C 1-3 alkyl, and C 1-3 alkoxy.
  • R 9 is hydrogen, halo, CF 2 H, CF 3 , CF 2 CH 3 , C(CH 3 ) 2 F, C 1-3 alkyl optionally substituted with one substituent selected from the group consisting of: OH, phenyl and phenoxy group, or cyclopropyl optionally substituted with one substituent selected from the group consisting of: cyano, C 1-3 alkyl, and C 1-3 alkoxy.
  • R 9 is phenyl or 2,3-dihydro-1H-indenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH 2 OH, C 1-4 alkyl, C 1-4 haloalkyl and C 1-3 haloalkoxy.
  • R 9 is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH 2 OH, C 1-4 alkyl, C 1-4 haloalkyl and C 1-3 haloalkoxy.
  • R 9 is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH 2 OH, C 1-4 alkyl, CF 2 H, CF 3 , C(CH 3 ) 2 CF 3 , OCF 3 , —OCH 2 CF 3 , and —OCHF 2 .
  • R 9 is phenyl substituted in the para position with chloro, fluoro, methyl, cyano, CF 3 or isopropyl.
  • R 9 is phenyl substituted in the para position with chloro, CF 3 or isopropyl.
  • R 9 is optionally substituted heteroaryl.
  • R 9 is optionally substituted pyrazolyl, pyridinyl, indolyl or isoquinolinyl.
  • R 9 is pyrazolyl or pyridinyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C 1-6 alkyl and C 1-6 haloalkyl, for example, fluoro, methyl and CF 3 or C(CH 3 ) 2 CF 3 .
  • R 9 is ⁇ OR 9a wherein R 9a is optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heterocyclic.
  • R 9a is tetrahydrofuranyl, CF 3 , CHF 2 , CHCF 3 , C 1-6 alkyl optionally substituted with one cyclopropyl, or phenyl optionally substituted with one halo.
  • R 9 is —SO 2 R 9a wherein R 9a is C 1-6 alkyl.
  • R 9 is —C(O)NHR 9a wherein R 9a is optionally substituted C 3-6 cycloalkyl.
  • R 9 is —C(O)NHR 9a wherein R 9a is cyclopentyl.
  • R 9 is CH 2 R 9b wherein R 9b is optionally substituted heterocyclic.
  • R 9b is optionally substituted 5 to 6 membered heterocyclic.
  • R 9b is piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted with one to four substituents each independently selected from the group consisting of: hydroxyl, halo, CH 2 OH, —NRR, cyano, C 1-3 alkyl, C 1-3 haloalkyl, and C 1-3 alkoxy.
  • R 9b is piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH 2 OH, fluoro, NH 2 , N(CH 3 ) 2 , NHCH 3 , methyl, and CF 3 .
  • each R is independently selected from the group consisting of: H, C 1-3 alkyl.
  • Another embodiment of the present invention is a compound according to formula (II).
  • Another embodiment of the present invention is a compound according to formula (III).
  • R 2b is OH, NH 2 or fluoro.
  • Another embodiment of the present invention is a compound according to formula (IV).
  • R 2b is OH or NH 2 .
  • R 2b is OH.
  • R 2b is NH 2 .
  • Another embodiment of the present invention is a compound according to formula (IV), wherein:
  • R 2b is OH
  • R 5 is hydrogen or fluoro
  • R 6 is hydrogen, chloro, methyl or CH 2 F
  • R 8 is hydrogen, methyl or fluoro; n is 1 or 2;
  • R 9 is methylcyclopropyl, isobutoxy, phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, C 1-4 alkyl, CF 2 H, and CF 3 , or pyridinyl optionally substituted with one or two substituents each independently selected from the group consisting of: methyl, CF 3 and C(CH 3 ) 2 CF 3 ;
  • R 5 is hydrogen and R 6 is chloro, methyl or CH 2 F or R 6 is hydrogen and R 5 is fluoro.
  • R 5 is hydrogen and R 6 are both hydrogen.
  • Another embodiment of the present invention is a compound according to formula (V).
  • Another embodiment of the present invention is a compound according to formula (V) wherein:
  • R 5 is hydrogen or fluoro
  • R 6 is hydrogen
  • R 8 is hydrogen or methyl; n is 1; and R 9 is phenyl optionally substituted with one chloro.
  • Preferred compounds of the invention include:
  • the compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.
  • the compounds of formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of formula (I).
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
  • R 2 is CH 2 R 2a R 2b
  • Non-commercial aminoacids can be prepared following the procedures of Scheme 1. Conversion of ketone 1 to the corresponding imidazolidine-2,4-dione 2 followed by hydrolysis provides aminoacid 3.
  • R 2 is CH 2 R 2a R 2b
  • aminoalcohol precursor of oxazolidinone
  • protected aminoacid 8 is converted into Weinreb amide 9 which is treated with different Grignard reagents sequentially to provide protected aminoalcohol 10. Either basic or acidic deprotection of 10 gives 11.
  • Insertion of CO unit into 7 or 11 to provide oxazolidinone 12 is accomplished with several reagents, including (but not limited to) triphosgene, Et 2 CO 3 or N-N′-darbonyldiimidazole, as shown in Scheme 2.
  • R 2 is CH 2 R 2a R 2b
  • Oxazolidinone 12 is coupled with dihalogen-pyrimidine 13 in the presence of NaH and the resulting 14 is treated with primary amine 15 under several different reaction conditions as shown in Scheme 3 to provide 16.
  • R 2 is CH 2 R 2a R 2b
  • intermediate 14 can be prepared by coupling the amino alcohol 11 and dihalogen-pyrimidine 13 in the presence of a base such as diisopropylethyl amine resulting in intermediate 17 which can be treated with triphosgene in the presence of a base such as 2,6-lutidine resulting in intermediate 14.
  • a base such as diisopropylethyl amine
  • R 2 is CH 2 R 2a R 2b
  • the compounds of the present invention are inhibitors of a mutant IDH protein having a neomorphic activity and are therefore useful in the treatment of diseases or disorders associated with such proteins including, but not limited to, cell proliferation disorders, such as cancer.
  • mutant IDH protein having a neomorphic activity examples include mutant IDH1 and mutant IDH2.
  • a neomorphic activity associated with mutant IDH1 and mutant IDH2 is the ability to produce 2-hydroxyglutarate (2-HG neomorphic activity), specifically R-2-HG (R-2-HG neomorphic activity).
  • Mutations in IDH1 associated with 2-HG neomorphic activity, specifically R-2-HG neomorphic activity include mutations at residues 97, 100, and 132, e.g. G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V.
  • Mutations in IDH2 associated with 2-HG neoactivity, specifically R-2-HG neomorphic activity, include mutations at residues 140 and 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.
  • Cell-proliferation disorders associated with a mutant IDH protein having a neomorphic activity include, but are not limited to, cancer.
  • cancers include Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral
  • the cancer associated with a mutant IDH protein having a neomorphic activity is brain cancer, such as astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma); oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma); oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma); ependymoma (e.g., myxopapillary
  • the cancer associated with a mutant IDH protein having a neomorphic acitvity is leukemia, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), MDS.MPN including chronic myelomonocytic leukemia, post MDS AML, post MPN AML, post MDS/MPN AML, del(5q)-associated high risk MDS or AML, blast-phase chronic myelogenous leukemia, angioimmunoblastic lymphoma and acute lymphoblastic leukemia.
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • CML chronic myelogenous leukemia
  • MPN myeloproliferative neoplasm
  • MDS.MPN including chronic myelomonocytic leukemia, post MDS AML, post
  • the cancer associated with a mutant IDH protein having a neomorphic activity is skin cancer, including melanoma.
  • the cancer associated with a mutant IDH protein having a neomorphic activity is prostate cancer, thyroid cancer, colon cancer, or lung cancer.
  • the cancer associated with a mutant IDH protein having a neomorphic activity is sarcoma, including central chondrosarcoma, central and periosteal chondroma, and fibrosarcoma.
  • the cancer associated with a mutant IDH protein having a neomorphic activity is cholangiocarcinoma.
  • Another disease or disorder associated with a mutant IDH protein having R-2-HG neomorphic activity is D-2-hydroxyglutaric aciduria.
  • Another disease or disorder associated with a mutant IDH protein having R-2-HG neomorphic activity is Diller disease and Mafucci syndrome.
  • neomorphic activity refers to a gain of novel activity of a protein that the wild-type protein does not have or does not exhibit to a significant degree.
  • a neomorphic activity associated with a mutant form of IDH1 and IDH2 is the ability to reduce alpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2-HG, specifically R-2-HG).
  • the wild type form of IDH1 and IDH2 does not have the ability to reduce alpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2-HG, specifically R-2-HG) or if it does have this ability, it does not produce significant (i.e. harmful or disease causing) amounts of 2-HG.
  • the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • the term “therapeutically effective amount” in reference to a compound of the invention means an amount of the compound sufficient to treat the subject's disease or condition, but low enough to avoid serious sides effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a therapeutically effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the subject being treated; the medical history of the subject being treated; the duration of the treatment; the nature of the concurrent therapy; the desired therapeutic effect; and like factors and can be routinely determined by the skilled artisan.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the compounds of the present invention may be administered by any suitable route including oral and parenteral administration.
  • Parenteral administration is typically by injection or infusion and includes intravenous, intramuscular, and subcontaneous injection or infusion.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution and half life which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the disease or condition being treated, the severity of the disease or condition, the age and physical condition of the subject being treated, the medical history of the subject being treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual subject's response to the dosing regimen or over time as the individual subject needs change. Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration, to a human weighing approximately 70 kg would range from about 5 mg to about 500 mg of a compound of formula (I).
  • One embodiment of the present invention provides for a method of treating a disease or disorder associated with a mutant form of IDH having a neomorphic activity comprising administration of a therapeutically effective amount of a compound of formula (I) to a subject in need of treatment thereof.
  • the disease or disorder associated with a mutant form of IDH having a neomorphic activity is a cell proliferation disorder.
  • the cell proliferation disorder is cancer.
  • the cancer is a cancer associated with mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity.
  • the neomorphic activity is R-2-HG neomorphic activity.
  • the cancer is associated with mutant IDH1 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V.
  • the cancer is associated with mutant IDH2 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 140 or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.
  • the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.
  • the cancer is glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
  • Another embodiment of the present invention provides for a method of treating a disease or disorder associated with a mutant form of IDH having R-2-HG neomorphic activity comprising administration of a therapeutically effective amount of a compound according to formula (I) to a subject in need thereof wherein the disease or disorder is D-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.
  • the therapy is a disease or disorder associated with a mutant form of IDH having a neomorphic activity.
  • the therapy is a cell proliferation disorder associated with a mutant form of IDH having a neomorphic activity.
  • the therapy is cancer.
  • the therapy is a cancer associated with a mutant IDH protein having a neomorphic activity, such as mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity.
  • the neomorphic activity is R-2-HG neomorphic activity.
  • the cancer is associated with mutant IDH1 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V.
  • the cancer is associated with mutant IDH2 having 2-HG or R-2-HG neomorphic activity having a mutation at residue at residues R140 or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.
  • the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.
  • the cancer is glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
  • Another embodiment of the present invention provides for the use of a compound of formula (I) in therapy wherein the therapy is D-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.
  • Another embodiment of the present invention provides for the use of a compound according to formula (I) in the manufacture of a medicament for the treatment of disease or disorder associated with a mutant form of IDH having a neomorphic activity.
  • the disease or disorder associated with a mutant form of IDH having a neomorphic activity is a cell proliferation disorder.
  • the cell proliferation disorder is cancer.
  • the cancer is a cancer associated with a mutant IDH protein having a neomorphic activity, such as mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity.
  • the neomorphic activity is R-2-HG neomorphic activity.
  • the cancer is associated with mutant IDH1 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V.
  • the cancer is associated with mutant IDH2 having 2-HG or R-2-HG neomorphic activity having a mutation at residue at residues 140 or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.
  • the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.
  • the cancer is glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
  • Another embodiment of the present invention provides for the use of a compound according to formula (I) in the manufacture of a medicament for the treatment of disease or disorder associated with a mutant form of IDH having R-2-HG neomorphic activity wherein the disease or disorder is D-2-hydroxyglutaric aciduria, Oilier Disease, or Mafucci Syndrome.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein a therapeutically effective amount of a compound of the invention can be extracted and then given to a subject, such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from about 5 mg to 500 mg of a compound of formula (I).
  • the term “pharmaceutically acceptable carrier or excipient” means a pharmaceutically acceptable material, composition or vehicle that, for example, are involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a subject and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must, of course, be of sufficiently high purity to render it pharmaceutically acceptable.
  • the compound of the invention and the pharmaceutically acceptable carrier or excipient(s) will typically be formulated into a dosage form adapted for administration to the subject by the desired route of administration.
  • dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; and (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution.
  • suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention, once administered to the subject, from one organ or portion of the body to another organ or another portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, lubricants, binders, disintegrants, fillers, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable carriers and excipients in appropriate amounts for the use in the invention.
  • resources available to the skilled artisan which describe pharmaceutically acceptable carriers and excipients and may be useful in selecting suitable pharmaceutically acceptable carriers and excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a therapeutically effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives, (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the composition can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
  • the compounds of the invention may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the invention is directed to a liquid oral dosage form.
  • Oral liquids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of the invention.
  • Syrups can be prepared by dissolving the compound of the invention in a suitably flavored aqueous solution; while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound of the invention in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or other natural sweeteners or saccharin or other artificial sweeteners and the like can also be added.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • the compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent(s).
  • the compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agent(s).
  • the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is the treatment of a disease or disorder associated with a mutant form of IDH.
  • Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
  • the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s).
  • the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I).
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the invention typically comprises directions for administration.
  • the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic agent may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
  • the invention provides the use of a compound of formula (I) for treating a disease or disorder associated with a mutant form of IDH, wherein the medicament is prepared for administration with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a disease or disorder associated with a mutant form of IDH, wherein the medicament is administered with a compound of formula (I).
  • the invention also provides a compound of formula (I) for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the compound of formula (I) is prepared for administration with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the other therapeutic agent is prepared for administration with a compound of formula (I).
  • the invention also provides a compound of formula (I) for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the compound of formula (I) is administered with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the other therapeutic agent is administered with a compound of formula (I).
  • the invention also provides the use of a compound of formula (I) for treating a disease or disorder associated with a mutant form of IDH, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a disease or disorder associated with a mutant form of IDH, wherein the patient has previously (e.g. within 24 hours) been treated with a compound of formula (I).
  • the other therapeutic agent is selected from: vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylating agents, anti-tumor antibiotics, anti-metabolites, retinoids, and other cytotoxic agents.
  • VEGF vascular endothelial growth factor
  • vascular endothelial growth factor (VEGF) receptor inhibitors include, but are not limited to, bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No.
  • topoisomerase II inhibitors include but are not limited to, etoposide (also known as VP-16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), and teniposide (also known as VM-26, sold under the tradename Vumon®).
  • etoposide also known as VP-16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®
  • teniposide also known as VM-26, sold under the tradename Vumon®
  • alkylating agents include but are not limited to, temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexylen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames
  • anti-tumor antibiotics include, but are not limited to, doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename Ienoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename EllenceTM), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), and mitomycin C (sold under the tradename Mutamycin®).
  • doxorubicin sold under the tradenames Adriamycin® and Rubex®
  • bleomycin sold under the
  • anti-metabolites include, but are not limited to, claribine (2-chlorodeoxyadenosine, sold under the tradename Ieustatin®), 5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCytTM), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, DroxiaTM and MylocelTM), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as
  • retinoids examples include, but are not limited to, alitretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), and bexarotene (sold under the tradename Targretin®).
  • Panretin® tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®)
  • Isotretinoin 13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan
  • cytotoxic agents include, but are not limited to, arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, and Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®).
  • Trisenox® arsenic trioxide
  • asparaginase also known as L-asparaginase, and Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®.
  • LCMS data (also reported herein as simply MS) were recorded using a Waters System (Acuity UPLC and a Micromass ZQ mass spectrometer; Column: Acuity HSS C18 1.8-micron, 2.1 ⁇ 50 mm; gradient: 5-95% acetonitrile in water with 0.05% TFA over a 1.8 min period; flow rate 1.2 mL/min; molecular weight range 200-1500; cone Voltage 20 V; column temperature 50° C.). All masses reported are those of the protonated parent ions unless recorded otherwise.
  • HRMS methods A, B, C and D are referred to throughout as HRMS (A), HRMS (B), HRMS (C) and HRMS (D) respectively.
  • Method A A solution of benzyl ((2R)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (134 mg, 0.45 mmol in 5 mL of THF) was pre-cooled to 0° C.) under nitrogen was treated with potassium tert-butoxide (153 mg, 1.4 mmol, 3.0 equiv), it was stirred at same temperature for 2 hours, 5 mL of water was added, it was extracted with EtOAc (2 ⁇ 20 mL), the combined organic layers were washed with water, brine, dried over Na 2 SO 4 , the solvent was removed to yield the desired product as a yellow oil, no further purification was required for next step.
  • potassium tert-butoxide 153 mg, 1.4 mmol, 3.0 equiv
  • reaction mixture was treated with aqueous saturated NH 4 Cl (200 mL), water (50 mL) and stirred vigorously at room temperature for 1 h. Separated the organics, extracted the aqueous with DCM (500 mL), combined the organics and washed them with 1N HCl (3 ⁇ 150 mL), and aqueous saturated NH4Cl, dried (MgSO4) and concentrated to dryness (careful not to leave under vacuum or heat excessively) to give a pale brown oil. TLC shows mostly product with some small by-product peaks at higher Rf and some baseline materials.
  • Method A A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (86 mg, 0.46 mmol) and 2,4-difluoropyrimidine (79 mg, 0.55 mmol, 1.2 equiv) in 3 ml of DMF was cooled to 0° C. under N2 before adding NaH (60%, 28 mg, 0.69 mmol, 1.5 equiv) slowly. The reaction mixture was stirred at 0° C. for 45 min., then gradually warmed to room temperature, and stirred at room temperature overnight. The reaction was quenched with 5 ml of water, and extracted with EtOAc (2 ⁇ 10 ml). The solvent was removed to yield the crude product.
  • Method B A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (5 g, 26.7 mmol) in DMF (50 mL) was cooled to ⁇ 5° C. under N2 atmosphere. Internal temperature was monitored and maintained at ca. ⁇ 5° C. during the portionwise addition of 60% NaH (1.602 g, 40.1 mmol) over 5 mins (no appreciable exotherm seen, but effervescence observed and cloudy suspension resulted). Added 2,4-difluoropyrimidine (2.507 mL, 29.4 mmol) dropwise whilst still maintaining the temperature at ca. ⁇ 5° C.
  • reaction mixture was stirred at this temperature for 15 mins before removing the cooling bath and allowing the reaction mixture to warm to room temperature (ca. 27° C. internal temp). Left stirring at room temperature for 2 h.
  • Workup [Safety Note: NaF salt present. Do not acidify workup] Quenched the reaction mixture with water (100 mL) which resulted in considerable effervescence although minimal increase in temperature.
  • reaction mixture was stirred at this temperature for 15 mins before removing the cooling bath and allowing the rm to warm to room temperature (ca. 27° C. internal temp). Left stirring at room temperature for 6 h. Sampled reaction mixture and quenched with water, extracted into EtOAc; TLC and LCMS show significant product but remaining oxazolidinone sm. Cooled reaction mixture to 0° C. and added an additional portion of trifluoropyrimidine (1.2 g, 8.95 mmol), warmed to room temperature and left stirring for 3 h at rt. Still faint residual sm seen by TLC of sample, but quenched reaction mixture at this point. Workup: [Safety Note: NaF salt present.
  • N-Methylmorpholine salt develops and was filtered from mixture.
  • Mother liquor was cooled to ⁇ 30° C. where upon sodium borohydride (1.22 g, 32.3 mmol) was added followed by the addition of water (25 mL) immediately afterwards.
  • Reaction mixture allowed to stir for 15 min at ⁇ 20° C. then gradually allowed to warm to room temperature.
  • Reaction mixture was stirred for 30 min at room temperature.
  • Reaction mixture was diluted with water, extracted with EtOAc.
  • Triphosgene 35 mg, 0.12 mmol, 0.4 equiv was added to a solution of (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol (86 mg, 0.30 mmol) in DCM (3 mL) at ⁇ 78° C., followed by the dropwise addition of 2,6-lutidine (0.14 mL, 1.2 mmol, 4 equiv). The solution was allowed to warm to room temperature and was then heated at 35° C. for 5 hours. The reaction was then cooled to room temperature and diluted with DCM (30 mL) and saturated aqueous sodium chloride (30 mL).
  • N,N-Diethylaminosulfur trifluoride (0.13 mL, 0.98 mmol, 1.5 equiv) was added to a solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one (215 mg, 0.652 mmol) in DCM at ⁇ 78° C. The reaction was stirred at ⁇ 78° C. for 1 hour, then warmed to room temperature and stirred for another hour. Additional N,N-Diethylaminosulfur trifluoride (0.26 mL, 2.0 mmol, 3 equiv) was added and the reaction stirred for another 1 hour.
  • Step 7 Preparation of (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)propanal
  • Step 8 Preparation of (S)-3-benzyl-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one
  • the mixture was diluted with ethylacetate (10 mL), stirred for 5 min and further slowly diluted with brine/water (1/1; 10 mL). The mixture was allowed to warm to 5° C. and poured into a mixture of brine/water (1/1; 20 mL) and ethylacetate (20 mL). The aqueous layer was separated and extracted with ethylacetate (25 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure.
  • the mixture was diluted with ethylacetate (10 mL), stirred for 5 min and further slowly diluted with brine/water (1/1; 10 mL). The mixture was allowed to warm to 5° C. and poured into a mixture of brine/water (1/1; 10 mL) and ethylacetate (10 mL). The aqueous layer was separated and extracted with ethylacetate (25 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure.
  • Step 1 A solution of 1-(5-fluoropyrimidin-2-yl)ethanone (700 mg, 5.0 mmol) and 4-fluorophenol (616 mg, 5.50 mmol) in 6 mL DMF was treated with potassium carbonate (829 mg 6.0 mmol) and heated to 50° C. for 3.5 h. The reaction mixture was poured into 20 mL water, and extracted with EtOAc (2 ⁇ 20 mL). Organics were washed with 20 mL each water, brine, and dried over Na 2 SO 4 . Mixture was filtered and concentrated on silica gel.
  • Step 2 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanone (290 mg, 1.25 mmol), NH4OAc (1.9 g, 24.6 mmol), and NaBH 3 CN (314 mg, 5.00 mmol) were taken up in 20 mL 200 proof EtOH, and heated at 130 C for 3 minutes in a microwave apparatus. The mixture was concentrated to remove the EtOH. Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added until aqueous pH was ⁇ 10. Separated layers, and extracted aqueous with EtOAc (25 ml). The combined organic layer was washed with 25 mL brine and dried with Na 2 SO 4 .
  • Step 1 In a well vented vial, 90% t-butyl nitrite (4.74 mL, 35.8 mmol) and CuCl (2.96 g, 29.9 mmol) were taken up in 30 mL ACN. Over 15 mins, 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine (6.0 g, 19.9 mmol) was added in portions. Gas evolved. The mixture was stirred 30 min at r.t., then warmed to 65 C for another 30 min. The reaction mixture was filtered through Celite. 200 mL Water was added to the filtrate. This was extracted with (2 ⁇ 150 mL) EtOAc.
  • Step 2 To a solution of 2-chloro-4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole (3.3 g, 10.3 mmol) and Pd(PPh3)2Cl2 (0.72 g, 1.03 mmol) in 50 mL dioxane under nitrogen, tributyl(1-ethoxyvinyl)stannane (3.82 ml, 11.32 mmol) was added. The mixture was heated to 100 C for 16 h. The reaction was cooled to r.t. and diluted with 25 mL EtOAc. 2M KF (15.4 ml) solution was added and stirred for 1 h.
  • Step 3 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanone ethanone (1.6 g, 4.87 mmol), NH4OAc (5.6 g, 73.1 mmol), and NaBH3CN (1.2 g, 19.5 mmol) were taken up in 40 mL 200 proof EtOH, and heated at 130 C for 10 minutes in a sealed tube. The mixture was concentrated to remove the EtOH. Crude was taken up in 50 ml water+50 mL EtOAc. 6N NaOH was added until aqueous pH was ⁇ 9. Separated layers, and extracted aqueous with EtOAc (50 ml).
  • 1,2-dibromoethane (0.11 ml, 1.22 mmol) and tetrabutylammonium bromide (19 mg, 0.06 mmol) were added and reaction mixture allowed to stir an additional 18 hours.
  • a third addition of 1,2-dibromoethane (0.11 ml, 1.22 mmol) was added and the reaction mixture heated to 50° C. for an additional 18 hours in a preheated aluminum tray.
  • the reaction mixture was quenched with a saturated solution of NH 4 Cl and the aqueous mixture extracted with EtOAc. Organics combined and washed twice with water, brine, dried (Na 2 SO 4 ), filtered and concentrated.
  • reaction mixture was added 1 ml of TFA to try to convert vinyl ether to the ketone which was unsuccessful. Resulting reaction mixture allowed to stir 5 min at room temperature. Reaction mixture was then quenched with a saturated solution of NaHCO 3 to pH 8. Aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na 2 SO 4 ), filtered and concentrated onto silica gel.
  • Step 1 preparation of tert-butyl 4-formyl-1H-imidazole-1-carboxylate
  • Step 2 preparation of (S,E)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)-1H-imidazole-1-carboxylate
  • Step 4 preparation of (S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethanamine hydrochloride
  • a vial containing di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine (55.8 mg, 0.116 mmol) and Pd 2 (dba) 3 (42 mg, 0.046 mmol) was evacuated under high vacuum for 1 minute and then recharged with argon. The process was repeated three more times and the toluene/dioxane solvent (10 mL) prepared as above was added followed by the palladium/ligand complex prepared as above was then added to the reaction vial containing the other starting materials. The reaction mixture was sealed and heated to 120° C. and stirred for 5 minutes. The reaction was cooled to room temperature.
  • Step 3 Preparation of ethyl 5-chloro-6-(1,1-difluoroethyl)nicotinate
  • Step 1 Preparation of ethyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate
  • Methylmagnesium bromide (3M in diethylether, 6.77 mL, 20.31 mmol) was added dropwise over ⁇ 15 min to a solution of 4-bromo-3-fluorobenzaldehyde (3.1 g, 15.27 mmol) in THF (50 mL) under argon at a temperature of ⁇ 60° C. to ⁇ 50° C. The ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred ⁇ 20 hr. The reaction mixture was slowly diluted/quenched with saturated aqueous ammonium chloride solution (20 mL) and further diluted with water (10 mL).
  • the reaction mixture was diluted further with water (50 mL) and extracted with diethylether (2 ⁇ 50 mL). The combined organic layers were washed with 1N aqueous sodium hydroxide solution (50 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure.
  • the crude material was purified by column chromatography [SiO 2 , 40 g, heptane/ethyl acetate] providing 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde (699 mg) as a dark yellow, volatile oil, which was contaminated with 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene.

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Abstract

The invention is directed to a formula (I):
Figure US20140275083A1-20140918-C00001
or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b and R3-R7 are herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.

Description

    FIELD OF THE INVENTION
  • The present invention is directed to novel 3-pyrimidinyl-4-yl-oxazolidin-2-one compounds, compositions containing these compounds, the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity and in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.
    • BACKGROUND OF THE INVENTION
  • Isocitrate dehydrogenase (IDH) is a key family of enzymes found in cellular metabolism. They are NADP+/NAD+ and metal dependent oxidoreductases of the enzyme class EC 1.1.1.42. The wild type proteins catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate generating carbon dioxide and NADPH/NADH in the process. They are also known to convert oxalosuccinate into alpha-ketoglutarate. Mutations in IDH1 (cytosolic) and IDH2 (mitochondrial) have been identified in multiple cancer types including, but not limited to, glioma, glioblastoma multiforme, paraganglioma, supratentorial primordial neuroectodermal tumors, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, and melanoma. (See L. Deng et al., Trends Mol. Med., 2010, 16, 387; T. Shibata et al., Am. J. Pathol., 2011, 178(3), 1395; Gaal et al., J. Clin. Endocrinol. Metab. 2010; Hayden et al., Cell Cycle, 2009; Balss et al., Acta Neuropathol., 2008). The mutations have been found at or near key residues in the active site: G97D, R100, R132, H133Q, and A134D for IDH1, and R140 and R172 for IDH2. (See L. Deng et al., Nature, 2009, 462, 739; L. Sellner et al., Eur. J. Haematol., 2011, 85, 457).
  • These mutant forms of IDH are shown to have a neomorphic activity (also known as a gain of function activity), reducing alpha-ketoglutarate to 2-hydroxyglutarate (2-HG). (See P. S. Ward et al., Cancer Cell, 2010, 17, 225) In general, production of 2-HG is enantiospecific, resulting in generation of the D-enantiomer (also known as R enantiomer or R-2-HG). Normal cells have low native levels of 2-HG, whereas cells harboring these mutations in IDH1 or IDH2 show significantly elevated levels of 2-HG. High levels of 2-HG have been detected in tumors harboring the mutations. For example, high levels of 2-HG have been detected in the plasma of patients with mutant IDH containing AML. (See S. Gross et al., J. Exp. Med., 2010, 207(2), 339). High levels of 2-HG are highly associated with tumorigenesis.
  • Mutant IDH2 is also associated with the rare neurometabolic disorder D-2-hydroxyglutaric aciduria type II (D-2-HGA type II). Germline mutations were found at R140 in IDH2 in 15 pateints having D-2-HGA type II. Patients having this disorder also have consistently increased levels of D-2-HG in their urine, plasma and cerebrospinal fluid. (See Kranendijk, M. et al., Science, 2010, 330, 336). Finally, patients with Ollier Disease and Mafucci Syndrome (two rare disorders that predispose to cartilaginous tumors) have been shown to be somatically mosaic for IDH1 and 2 mutations and exhibit high levels of D-2-HG. (See Amary et al., Nature Genetics, 2011 and Pansuriya et al., Nature Genetics, 2011).
  • Thus, there is a need for small molecule inhibitors of mutant IDH proteins having a neomorphic activity for the treatment of diseases and disorders associated with these proteins.
    • SUMMARY OF THE INVENTION
  • In one aspect, this invention provides for a compound of formula (I)
  • Figure US20140275083A1-20140918-C00002
  • or a pharmaceutically acceptable salt thereof wherein R1, R2a, R2b and R3-R7 are defined below.
  • In a second aspect, this invention provides for a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • In a third aspect, this invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of a mutant IDH protein having a neomorphic activity such as reducing alpha-ketoglutarate to 2-hydroxyglutarate (2-HG neomorphic activity). Suitably, this invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of mutant IDH1 having a neomorphic activity, such as 2-HG neomorphic activity, and/or mutant IDH2 having a neomorphic activity, such as 2-HG neomorphic activity. This invention further provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of IDH1 having a mutation at residue 97, 100 or 132, for example G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V; and/or an inhibitor of IDH2 having a mutation at residue 140 or 172, for example R172K, R172M, R172S, R172G, and R172W.
  • In a fourth aspect, this invention provides for a method of treating a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of an effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In one embodiment, the disease or disorder is a cell proliferation disorder, such as cancer. In another embodiment, the cancer is brain cancer, such as glioma, glioblastoma multiforme, paraganglioma, and supratentorial primordial neuroectodermal tumors (pNET); leukemia, such as acute myeloid leukemia (AML), myelodysplastic syndrome, and chronic myelogenous leukemia (CML); skin cancer, including melanoma; prostate cancer; thyroid cancer; colon cancer; lung cancer; sarcoma, including central chondrosarcoma, central and periosteal chondroma; and fibrosarcoma. In another embodiment the disease or disorder is D-2-hydroxyglutaric aciduria.
  • In a fifth aspect the invention provides for a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with another therapeutic agent.
  • These and other aspects of the present invention are described further in the following.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention is directed to a compound of formula (I)
  • Figure US20140275083A1-20140918-C00003
  • wherein:
    R1 is hydrogen, methyl or ethyl;
    R2a is hydrogen, methyl or C1-3 haloalkyl;
    R2b is OH, halo, C1-6 alkoxy, C1-3 haloalkyl, NH2, NH(CH3) or N(CH3)2;
    R3 and R4 are each independently hydrogen, methyl or ethyl or R3 and R4 are joined together forming cyclopropyl, cyclobutyl or oxetanyl;
    R5 and R6 are each independently hydrogen, deuterium, halo, —C(O)OCH3, C1-3 alkyl or C1-3 haloalkyl;
    • R7 is
  • Figure US20140275083A1-20140918-C00004
  • wherein:
      • ring A is a 6 membered heteroaryl ring having one to three nitrogen atoms;
      • ring B is a 5 membered heteroaryl ring having one to four heteroatoms each independently selected from the group consisting of N, O and S;
      • X is N or CH;
      • each R8 is independently hydrogen, halo, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy;
      • n is 1 or 2;
      • R9 is hydrogen, halo, C1-3 haloalkyl, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted 5 or 6 membered heterocyclic, optionally substituted heteroaryl, —OR9a, —SO2R9a, —C(O)NHR9a, CH2R9b or CHCH3R9b, provided that when X is N, R9 is hydrogen, C1-3 haloalkyl, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —SO2R9a or —C(O)NHR9a, wherein:
        • said C1-6 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: OH, phenyl and phenoxy, and
        • said C3-6 cycloalkyl, 5 or 6 membered heterocyclic, aryl and heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
      • R9a is optionally substituted C1-6 alkyl, C1-6 haloalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, or optionally substituted heterocyclic,
      • wherein:
        • said C1-6 alkyl is optionally substituted with one C3-6 cycloalkyl,
        • said C3-6 cycloalkyl and heterocyclic are each optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH2OH, —NRR, cyano, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy, and
        • said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
      • R9b is optionally substituted C3-6 cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclic,
        • said C3-6 cycloalkyl and heterocyclic are each optionally substituted with one to four substituents each independently selected from the group consisting of: hydroxyl, CH2OH, —NRR, —NRC(O)CH3, 4 to 6 membered heterocyclic, cyano, halo, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy, and
        • said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C1-6alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; and
  • each R is independently selected from the group consisting of H, C1-3 alkyl and C3-6 cycloalkyl.
  • “Alkyl” refers to a monovalent saturated hydrocarbon chain having the specified number of carbon atoms. For example, C1-6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted with one or more substituents as defined in formula (I). Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
  • “Alkoxy” refers to any alkyl moiety attached through an oxygen bridge (i.e. a —O—C1-3 alkyl group wherein C1-3 alkyl is as defined herein). Examples of such groups include, but are not limited to, methoxy, ethoxy, and propoxy.
  • “Aryl” refers to a hydrocarbon ring system having an aromatic ring. Aryl groups are monocyclic ring systems or bicyclic ring systems. Monocyclic aryl ring refers to phenyl. Bicyclic aryl rings refer to naphthyl and to rings wherein phenyl is fused to a C5-7 cycloalkyl or C5-7 cycloalkenyl ring as defined herein. Aryl groups may be optionally substituted with one or more substituents as defined in formula (I).
  • “Cycloalkyl” refers to a saturated hydrocarbon ring system having the specified number of carbon atoms. Cycloalkyl groups are monocyclic or bicyclic ring systems. For example, C3-6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 carbon atoms. Cycloalkyl groups may be optionally substituted with one or more substituents as defined in formula (I). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • “Cycloalkenyl” refers to an unsaturated hydrocarbon ring system having the specified number of carbon atoms and having a carbon-carbon double bond within the ring. For example, C5-7 cycloalkenyl refers to a cycloalkenyl group having from 5 to 7 carbon atoms. In certain embodiments, cycloalkenyl groups have one carbon-carbon double bond within the ring. In other embodiments, cycloalkeneyl groups have more than one carbon-carbon double bond within the ring. Cycloalkenyl rings are not aromatic. Cycloalkenyl groups may be optionally substituted with one or more substituents as defined in formula (I).
  • “Halo” refers to the halogen radicals fluoro, chloro, bromo, and iodo.
  • “Haloalkyl” refers to an alkyl group wherein at least one hydrogen atom attached to a carbon atom within the alkyl group is replaced with halo. The number of halo substituents includes, but is not limited to, 1, 2, 3, 4, 5, or 6 substituents. Haloalkyl includes, but is not limited to, monofluoromethyl, difluoroethyl, and trifluoromethyl.
  • “Haloalkoxy” refers to a haloalkyl moiety attached through an oxygen bridge (i.e. a —O—C1-3 haloalkyl group wherein C1-3 haloalkyl is as defined herein). An example of a haloalkoxy group is trifluoromethoxy.
  • “Heteroaryl” refers to an aromatic ring system containing from 1 to 5 heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined in formula (I). Heteroaryl groups are monocyclic ring systems or are fused bicyclic ring systems. Monocyclic heteroaryl rings have from 5 to 6 ring atoms. Bicyclic heteroaryl rings have from 8 to 10 member atoms. Bicyclic heteroaryl rings include those ring systems wherein a heteroaryl ring is fused to a phenyl ring. Heteroaryl includes, but is not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (including 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl), thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furanzanyl, thienyl, triazolyl, pyridinyl (including 2-, 3-, and 4-pyridinyl), pyrimidinyl, pyridazinyl, pyrazinyl, trazinyl, tetrazinyl, tetrzolyl, indonyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzimidazolyl, benzopyranyl, benzopyranyl, benzoxazolyl, benzoisoxazolyl, benzofuranyl, benzothiazolyl, benzothienyl, naphthyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, imidazo[2,1-b][1,3,4]thiadiazolyl and the like.
  • “Heteroatom” refers to a nitrogen, oxygen, or sulfur atom.
  • “Heterocyclic” refers to a 3 to 11 membered saturated or unsaturated monocyclic or bicyclic ring containing from 1 to 4 heteroatoms. Heterocyclic ring systems are not aromatic. Heterocyclic groups containing more than one heteroatom may contain different heteroatoms. Heterocyclic includes ring systems wherein a sulfur atom is oxidized to form SO or SO2. Heterocyclic groups may be optionally substituted with one or more substituents as defined in formula (I). Heterocyclic groups are monocyclic, spiro, or fused or bridged bicyclic ring systems. Monocyclic heterocyclic rings have 3 to 7 ring atoms. Examples of monocyclic heterocyclic groups include oxtanyl, tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, tetrahydro-thiopyran-1,1-dioxide, 1,4-diazepanyl, and the like. Fused heterocyclic ring systems have from 8 to 11 ring atoms and include groups wherein a heterocyclic ring is fused to a phenyl ring, a heteroaryl ring or another heterocyclic ring. Examples of fused heterocyclic rings include 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[1,3]dioxyl, octahydro-pyrrolo[1,2-a]pyrazinyl, octahydro-pyrido[1,2-a]pyrazinyl, octahydro-pyrrolo[3,4-c]pyrrolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazinyl and the like. Examples of bridged heterocyclic groups include 3,8-diaza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[4.2.0]octanyl and the like. Examples of spiro heterocyclic groups include 4,7-diaza-spiro[2.5]octanyl and the like.
  • “5-6 membered heterocylic” refers to a heterocyclic group as defined above, having 5 or 6 ring atoms and containing from 1 to 4 heteroatoms.
  • “Optionally substituted” indicates that a group, such as an alkyl, cycloalkyl, heteroaryl, heterocyclic, phenyl, and benzyl may be unsubstitued or the group may be substituted with one or more substituents as defined in formula (I).
  • “Oxo” refers to a C═O group.
  • “Pharmaceutically acceptable” means a compound which is suitable for pharmaceutical use. Salts and solvates (e.g. hydrates and hydrates of salts) of compounds of the invention which are suitable for use in medicine are those where in the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.
  • “Substituted” in reference to a group such as alkyl, phenyl, benzyl, heteroaryl, and heterocyclic, indicates that one or more hydrogen atoms attached to an atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation, for example, by hydrolysis, rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) atoms within the group may be substituted. In addition, a single atom within the group may be substituted with more than one substituent as long as such substitution is accordance with the permitted valence of the atom. Suitable substituents are defined for each substituted or optionally substituted group.
  • The skilled artisan will appreciate that salts, including pharmaceutically acceptable salts, of the compounds according to formula (I) may be prepared. These salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • Solvates, including pharmaceutically acceptable solvates, of the compounds of formula (I) may also be prepared. “Solvate” refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • The compounds of formula (I), including salts and solvates thereof, may exist in crystalline forms, non-crystalline forms, or mixtures thereof. The compound or salt or solvate thereof may also exhibit polymorphism, i.e. the capacity of occurring in different crystalline forms. These different crystalline forms are typically known as “polymorphs”. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, all of which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing a compound of formula (I).
  • The invention also includes various isomers of the compounds of formula (I). “Isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereosiomers). With regard to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • Any asymmetric atom (e.g., carbon or the like) of a compound of formula (I) can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)-form.
  • Accordingly, as used herein a compound of formula (I) can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • The invention includes unlabeled forms as well as isotopically labeled forms of compounds of formula (I). Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 31F, 32F, 35S, 36Cl, 125I respectively. The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3H and 14C, or those into which non-radioactive isotopes, such as 2H and 13C are present. Such isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
    • Representative Embodiments
  • Various embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide for further embodiments.
  • In one embodiment of the present invention R1 is hydrogen.
  • In another embodiment of the present invention R2a is hydrogen or methyl. Suitably R2a is methyl.
  • In another embodiment of the present invention R2b is OH, fluoro, methoxy, t-butoxy, CHF2, CF3, NH2 or NH(CH3). Suitably R2b is OH, fluoro or NH2.
  • In another embodiment of the present invention R3 and R4 are each hydrogen.
  • In another embodiment of the present invention R5 is hydrogen or halo. Suitably R5 is hydrogen, fluoro or chloro. More suitably R5 is hydrogen or fluoro.
  • In another embodiment of the present invention R6 is hydrogen, halo, methyl, CH2F, CHF2, or CF3. Suitably R6 is hydrogen, fluoro, chloro, methyl, CH2F, CHF2, or CF3. More suitably R6 is hydrogen or methyl.
  • In another embodiment of the present invention R5 is hydrogen and R6 is hydrogen, halo, methyl, CH2F, CHF2, or CF3. Suitably R6 is hydrogen, fluoro, chloro, methyl, CH2F, CHF2, or CF3. More suitably R6 is hydrogen or methyl.
  • In another embodiment of the present invention R6 is hydrogen and R5 is hydrogen or halo. Suitably R5 is hydrogen, fluoro or chloro. More suitably R5 is hydrogen or fluoro.
  • In another embodiment R5 and R5 are both hydrogen.
  • In another embodiment R7 is
  • Figure US20140275083A1-20140918-C00005
  • In another embodiment R7 is
  • Figure US20140275083A1-20140918-C00006
  • In another embodiment R8 is hydrogen, fluoro, chloro or methyl and n is 1. In another embodiment each R8 is independently fluoro or chloro and n is 2.
  • In another embodiment R9 is hydrogen, halo, C1-3 haloalkyl, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl. Suitably R9 is hydrogen, halo, CF2H, CF3, CF2CH3, C(CH3)2F, C1-6 alkyl optionally substituted with one substituent selected from the group consisting of: OH, phenyl and phenoxy, or C3-6 cycloalkyl optionally substituted with one substituent selected from the group consisting of: cyano, C1-3 alkyl, and C1-3 alkoxy. Suitably R9 is hydrogen, halo, CF2H, CF3, CF2CH3, C(CH3)2F, C1-3 alkyl optionally substituted with one substituent selected from the group consisting of: OH, phenyl and phenoxy group, or cyclopropyl optionally substituted with one substituent selected from the group consisting of: cyano, C1-3 alkyl, and C1-3 alkoxy.
  • In another embodiment R9 is phenyl or 2,3-dihydro-1H-indenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH2OH, C1-4 alkyl, C1-4 haloalkyl and C1-3 haloalkoxy.
  • In another embodiment R9 is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH2OH, C1-4 alkyl, C1-4 haloalkyl and C1-3 haloalkoxy. Suitably R9 is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH2OH, C1-4 alkyl, CF2H, CF3, C(CH3)2CF3, OCF3, —OCH2CF3, and —OCHF2. Suitably R9 is phenyl substituted in the para position with chloro, fluoro, methyl, cyano, CF3 or isopropyl. Suitably R9 is phenyl substituted in the para position with chloro, CF3 or isopropyl.
  • In another embodiment R9 is optionally substituted heteroaryl. Suitably R9 is optionally substituted pyrazolyl, pyridinyl, indolyl or isoquinolinyl. Suitably R9 is pyrazolyl or pyridinyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-6 alkyl and C1-6 haloalkyl, for example, fluoro, methyl and CF3 or C(CH3)2CF3.
  • In another embodiment R9 is −OR9a wherein R9a is optionally substituted C1-6 alkyl, C1-6 haloalkyl, optionally substituted phenyl, or optionally substituted 5 or 6 membered heterocyclic. Suitably R9a is tetrahydrofuranyl, CF3, CHF2, CHCF3, C1-6 alkyl optionally substituted with one cyclopropyl, or phenyl optionally substituted with one halo.
  • In another embodiment R9 is —SO2R9a wherein R9a is C1-6 alkyl.
  • In another embodiment R9 is —C(O)NHR9a wherein R9a is optionally substituted C3-6 cycloalkyl. Suitably R9 is —C(O)NHR9a wherein R9a is cyclopentyl.
  • In another embodiment R9 is CH2R9b wherein R9b is optionally substituted heterocyclic. Suitably R9b is optionally substituted 5 to 6 membered heterocyclic. Suitably R9b is piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted with one to four substituents each independently selected from the group consisting of: hydroxyl, halo, CH2OH, —NRR, cyano, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy. Suitably R9b is piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH2OH, fluoro, NH2, N(CH3)2, NHCH3, methyl, and CF3.
  • In another embodiment of the present invention each R is independently selected from the group consisting of: H, C1-3 alkyl.
  • Another embodiment of the present invention is a compound according to formula (II).
  • Figure US20140275083A1-20140918-C00007
  • Another embodiment of the present invention is a compound according to formula (III).
  • Figure US20140275083A1-20140918-C00008
  • wherein R2b is OH, NH2 or fluoro.
  • Another embodiment of the present invention is a compound according to formula (IV).
  • Figure US20140275083A1-20140918-C00009
  • wherein R2b is OH or NH2. Suitably R2b is OH. Suitably R2b is NH2.
  • Another embodiment of the present invention is a compound according to formula (IV), wherein:
  • R2b is OH;
  • R5 is hydrogen or fluoro;
  • R6 is hydrogen, chloro, methyl or CH2F;
  • R7 is
  • Figure US20140275083A1-20140918-C00010
  • R8 is hydrogen, methyl or fluoro;
    n is 1 or 2; and
  • R9 is methylcyclopropyl, isobutoxy, phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, C1-4 alkyl, CF2H, and CF3, or pyridinyl optionally substituted with one or two substituents each independently selected from the group consisting of: methyl, CF3 and C(CH3)2CF3; Suitably R5 is hydrogen and R6 is chloro, methyl or CH2F or R6 is hydrogen and R5 is fluoro. Suitably R5 is hydrogen and R6 are both hydrogen.
  • Another embodiment of the present invention is a compound according to formula (V).
  • Figure US20140275083A1-20140918-C00011
  • Another embodiment of the present invention is a compound according to formula (V) wherein:
  • R5 is hydrogen or fluoro;
    R6 is hydrogen;
  • Figure US20140275083A1-20140918-C00012
    • R7 is
  • R8 is hydrogen or methyl;
    n is 1; and
    R9 is phenyl optionally substituted with one chloro.
  • Preferred compounds of the invention include:
    • (R)-4-((R)-1-hydroxy(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-onethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chloro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-{2-[(S)-1-(5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
    • (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
    • (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
    • (R)-3-(5-fluoro-2-(((S)-1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (4R)-3-(5-fluoro-2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-(fluoromethyl)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-(4-(difluoromethyl)phenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(6-chloro-2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2,5-difluoro-4-(2-methylpyridin-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(6-chloro-2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one;
    • (S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-2-methyl-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
    • (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one; and
    • (S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one.
    General Synthetic Procedures
  • The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.
  • The compounds of formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of formula (I).
  • Those skilled in the art will recognize if a stereocenter exists in the compounds of formula (I). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).
  • The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
  • Figure US20140275083A1-20140918-C00013
  • wherein R2 is CH2R2aR2b
  • Non-commercial aminoacids can be prepared following the procedures of Scheme 1. Conversion of ketone 1 to the corresponding imidazolidine-2,4-dione 2 followed by hydrolysis provides aminoacid 3.
  • Figure US20140275083A1-20140918-C00014
  • wherein R2 is CH2R2aR2b
  • When aminoalcohol, precursor of oxazolidinone, is not commercially available, it can be prepared from aminoacid 3 following the procedures of Scheme 2. When R3=R4, protected aminoester 5 is treated with an appropriate Grignard reagent to give protected aminoalcohol 6 which goes through basic or acidic deprotection step. When R3=R4, protected aminoacid 8 is converted into Weinreb amide 9 which is treated with different Grignard reagents sequentially to provide protected aminoalcohol 10. Either basic or acidic deprotection of 10 gives 11. Insertion of CO unit into 7 or 11 to provide oxazolidinone 12 is accomplished with several reagents, including (but not limited to) triphosgene, Et2CO3 or N-N′-darbonyldiimidazole, as shown in Scheme 2.
  • Figure US20140275083A1-20140918-C00015
  • wherein R2 is CH2R2aR2b
  • Oxazolidinone 12 is coupled with dihalogen-pyrimidine 13 in the presence of NaH and the resulting 14 is treated with primary amine 15 under several different reaction conditions as shown in Scheme 3 to provide 16.
  • Figure US20140275083A1-20140918-C00016
  • wherein R2 is CH2R2aR2b
  • Alternately intermediate 14 can be prepared by coupling the amino alcohol 11 and dihalogen-pyrimidine 13 in the presence of a base such as diisopropylethyl amine resulting in intermediate 17 which can be treated with triphosgene in the presence of a base such as 2,6-lutidine resulting in intermediate 14.
  • Figure US20140275083A1-20140918-C00017
  • wherein R2 is CH2R2aR2b
  • Intermediate 14 can undergo modification of functional groups on R1, R2, R3 or R4 prior to transformation to compound 16 as described in Scheme 3.
    • Methods of Use
  • The compounds of the present invention are inhibitors of a mutant IDH protein having a neomorphic activity and are therefore useful in the treatment of diseases or disorders associated with such proteins including, but not limited to, cell proliferation disorders, such as cancer.
  • Examples of a mutant IDH protein having a neomorphic activity are mutant IDH1 and mutant IDH2. A neomorphic activity associated with mutant IDH1 and mutant IDH2 is the ability to produce 2-hydroxyglutarate (2-HG neomorphic activity), specifically R-2-HG (R-2-HG neomorphic activity). Mutations in IDH1 associated with 2-HG neomorphic activity, specifically R-2-HG neomorphic activity, include mutations at residues 97, 100, and 132, e.g. G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. Mutations in IDH2 associated with 2-HG neoactivity, specifically R-2-HG neomorphic activity, include mutations at residues 140 and 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.
  • Cell-proliferation disorders associated with a mutant IDH protein having a neomorphic activity include, but are not limited to, cancer. Examples of such cancers include Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primaiy; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; steosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T-Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor.
  • In another embodiment the cancer associated with a mutant IDH protein having a neomorphic activity is brain cancer, such as astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma); oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma); oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma); ependymoma (e.g., myxopapillary ependymoma, and anaplastic ependymoma); medulloblastoma; primitive neuroectodermal tumor, schwannoma, meningioma, meatypical meningioma, anaplastic meningioma; and pituitary adenoma. In another embodiment, the brain cancer is glioma, glioblastoma multiforme, paraganglioma, or suprantentorial primordial neuroectodermal tumors (sPNET).
  • In another embodiment the cancer associated with a mutant IDH protein having a neomorphic acitvity is leukemia, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), MDS.MPN including chronic myelomonocytic leukemia, post MDS AML, post MPN AML, post MDS/MPN AML, del(5q)-associated high risk MDS or AML, blast-phase chronic myelogenous leukemia, angioimmunoblastic lymphoma and acute lymphoblastic leukemia.
  • In another embodiment the cancer associated with a mutant IDH protein having a neomorphic activity is skin cancer, including melanoma.
  • In another embodiment the cancer associated with a mutant IDH protein having a neomorphic activity is prostate cancer, thyroid cancer, colon cancer, or lung cancer.
  • In another embodiment the cancer associated with a mutant IDH protein having a neomorphic activity is sarcoma, including central chondrosarcoma, central and periosteal chondroma, and fibrosarcoma.
  • In another embodiment the cancer associated with a mutant IDH protein having a neomorphic activity is cholangiocarcinoma.
  • Another disease or disorder associated with a mutant IDH protein having R-2-HG neomorphic activity is D-2-hydroxyglutaric aciduria.
  • Another disease or disorder associated with a mutant IDH protein having R-2-HG neomorphic activity is Diller disease and Mafucci syndrome.
  • As used herein the term “neomorphic activity” refers to a gain of novel activity of a protein that the wild-type protein does not have or does not exhibit to a significant degree. For example, a neomorphic activity associated with a mutant form of IDH1 and IDH2 is the ability to reduce alpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2-HG, specifically R-2-HG). The wild type form of IDH1 and IDH2 does not have the ability to reduce alpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2-HG, specifically R-2-HG) or if it does have this ability, it does not produce significant (i.e. harmful or disease causing) amounts of 2-HG.
  • As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • As used herein, the term “therapeutically effective amount” in reference to a compound of the invention means an amount of the compound sufficient to treat the subject's disease or condition, but low enough to avoid serious sides effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A therapeutically effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the subject being treated; the medical history of the subject being treated; the duration of the treatment; the nature of the concurrent therapy; the desired therapeutic effect; and like factors and can be routinely determined by the skilled artisan.
  • As used herein, the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • The compounds of the present invention may be administered by any suitable route including oral and parenteral administration. Parenteral administration is typically by injection or infusion and includes intravenous, intramuscular, and subcontaneous injection or infusion.
  • The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution and half life which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the disease or condition being treated, the severity of the disease or condition, the age and physical condition of the subject being treated, the medical history of the subject being treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual subject's response to the dosing regimen or over time as the individual subject needs change. Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration, to a human weighing approximately 70 kg would range from about 5 mg to about 500 mg of a compound of formula (I).
  • One embodiment of the present invention provides for a method of treating a disease or disorder associated with a mutant form of IDH having a neomorphic activity comprising administration of a therapeutically effective amount of a compound of formula (I) to a subject in need of treatment thereof. In one embodiment, the disease or disorder associated with a mutant form of IDH having a neomorphic activity is a cell proliferation disorder. In another embodiment, the cell proliferation disorder is cancer. In another embodiment, the cancer is a cancer associated with mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity. In another embodiment the neomorphic activity is R-2-HG neomorphic activity. In another embodiment the cancer is associated with mutant IDH1 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. In another embodiment the cancer is associated with mutant IDH2 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 140 or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W. In another embodiment the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma. In another embodiment the cancer is glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
  • Another embodiment of the present invention provides for a method of treating a disease or disorder associated with a mutant form of IDH having R-2-HG neomorphic activity comprising administration of a therapeutically effective amount of a compound according to formula (I) to a subject in need thereof wherein the disease or disorder is D-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.
  • Another embodiment of the present invention provides for the use of a compound of formula (I) in therapy. In a further embodiment the therapy is a disease or disorder associated with a mutant form of IDH having a neomorphic activity. In another embodiment the therapy is a cell proliferation disorder associated with a mutant form of IDH having a neomorphic activity. In another embodiment the therapy is cancer. In another embodiment the therapy is a cancer associated with a mutant IDH protein having a neomorphic activity, such as mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity. In another embodiment the neomorphic activity is R-2-HG neomorphic activity. In another embodiment the cancer is associated with mutant IDH1 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. In another embodiment the cancer is associated with mutant IDH2 having 2-HG or R-2-HG neomorphic activity having a mutation at residue at residues R140 or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W. In another embodiment the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma. In another embodiment the cancer is glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
  • Another embodiment of the present invention provides for the use of a compound of formula (I) in therapy wherein the therapy is D-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.
  • Another embodiment of the present invention provides for the use of a compound according to formula (I) in the manufacture of a medicament for the treatment of disease or disorder associated with a mutant form of IDH having a neomorphic activity. In one embodiment the disease or disorder associated with a mutant form of IDH having a neomorphic activity is a cell proliferation disorder. In another embodiment, the cell proliferation disorder is cancer. In another embodiment the cancer is a cancer associated with a mutant IDH protein having a neomorphic activity, such as mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity. In another embodiment the neomorphic activity is R-2-HG neomorphic activity. In another embodiment the cancer is associated with mutant IDH1 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. In another embodiment the cancer is associated with mutant IDH2 having 2-HG or R-2-HG neomorphic activity having a mutation at residue at residues 140 or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W. In another embodiment the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma. In another embodiment the cancer is glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
  • Another embodiment of the present invention provides for the use of a compound according to formula (I) in the manufacture of a medicament for the treatment of disease or disorder associated with a mutant form of IDH having R-2-HG neomorphic activity wherein the disease or disorder is D-2-hydroxyglutaric aciduria, Oilier Disease, or Mafucci Syndrome.
    • Compositions
  • In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.
  • The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a therapeutically effective amount of a compound of the invention can be extracted and then given to a subject, such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a therapeutically effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from about 5 mg to 500 mg of a compound of formula (I).
  • As used herein the term “pharmaceutically acceptable carrier or excipient” means a pharmaceutically acceptable material, composition or vehicle that, for example, are involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a subject and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must, of course, be of sufficiently high purity to render it pharmaceutically acceptable.
  • The compound of the invention and the pharmaceutically acceptable carrier or excipient(s) will typically be formulated into a dosage form adapted for administration to the subject by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; and (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution. Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention, once administered to the subject, from one organ or portion of the body to another organ or another portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, lubricants, binders, disintegrants, fillers, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable carriers and excipients in appropriate amounts for the use in the invention. In addition, there are a number of resources available to the skilled artisan, which describe pharmaceutically acceptable carriers and excipients and may be useful in selecting suitable pharmaceutically acceptable carriers and excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a therapeutically effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives, (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch) gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The composition can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
  • The compounds of the invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • In another aspect, the invention is directed to a liquid oral dosage form. Oral liquids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of the invention. Syrups can be prepared by dissolving the compound of the invention in a suitably flavored aqueous solution; while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound of the invention in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or other natural sweeteners or saccharin or other artificial sweeteners and the like can also be added.
  • In another aspect, the invention is directed to parenteral administration. Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
    • Combinations
  • The compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent(s). The compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agent(s).
  • In one embodiment, the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or disorder associated with a mutant form of IDH. Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
  • In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
  • In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I). In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.
  • In the combination therapies of the invention, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic agent may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
  • Accordingly, the invention provides the use of a compound of formula (I) for treating a disease or disorder associated with a mutant form of IDH, wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or disorder associated with a mutant form of IDH, wherein the medicament is administered with a compound of formula (I).
  • The invention also provides a compound of formula (I) for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the compound of formula (I) is prepared for administration with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the other therapeutic agent is prepared for administration with a compound of formula (I). The invention also provides a compound of formula (I) for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the compound of formula (I) is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the other therapeutic agent is administered with a compound of formula (I).
  • The invention also provides the use of a compound of formula (I) for treating a disease or disorder associated with a mutant form of IDH, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or disorder associated with a mutant form of IDH, wherein the patient has previously (e.g. within 24 hours) been treated with a compound of formula (I).
  • In one embodiment, the other therapeutic agent is selected from: vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylating agents, anti-tumor antibiotics, anti-metabolites, retinoids, and other cytotoxic agents.
  • Examples of vascular endothelial growth factor (VEGF) receptor inhibitors include, but are not limited to, bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No. WO 01/002369), Brivanib Alaninate ((S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)-2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No, WO 02/066470), pasireotide (also known as SOM230, and described in PCT Publication No, WO 02/010192), and sorafenib (sold under the tradename Nexavar®).
  • Examples of topoisomerase II inhibitors, include but are not limited to, etoposide (also known as VP-16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), and teniposide (also known as VM-26, sold under the tradename Vumon®).
  • Examples of alkylating agents, include but are not limited to, temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexylen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under the tradename Leukeran®), cyclophosphamide (sold under the tradenames Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC-Dome®), altretamine (also known as hexamethylmelamine (HMM) sold under the tradename Hexylen®), ifosfamide (sold under the tradename Ifex®), procarbazine (sold under the tradename Matulane®), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename Mustargen®), streptozocin (sold under the tradename Zanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSPA, and sold under the tradename Thioplex®.
  • Examples of anti-tumor antibiotics include, but are not limited to, doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename Ienoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename Ellence™), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), and mitomycin C (sold under the tradename Mutamycin®).
  • Examples of anti-metabolites include, but are not limited to, claribine (2-chlorodeoxyadenosine, sold under the tradename Ieustatin®), 5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCyt™), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, Droxia™ and Mylocel™), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename Leustatin™) methotrexate (also known as amethopterin, methotrexate sodim (MTX), sold under the tradenames Rheumatrex® and Trexall™), and pentostatin (sold under the tradename Nipent®).
  • Examples of retinoids include, but are not limited to, alitretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), and bexarotene (sold under the tradename Targretin®).
  • Examples of other cytotoxic agents include, but are not limited to, arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, and Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®).
    • INTERMEDIATES AND EXAMPLES
  • The following examples are intended to be illustrative only and not limiting in any way. Unless otherwise noted, the following Intermediates and Examples were purified vial silica gel column chromatograph using RediSep® Rf columns from Teledyne Isco, Inc. Abbreviations used are those conventional in the art or the following:
  • ACN acetonitrile
    BI NAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
    BSA bovine serum albumin
    • C Celsius
  • d doublet
    dd doublet of doublets
    DAST diethylaminosulfur trifluoride
    DEAD diethyl azodicarboxylate
    • DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide
  • DMSO dimethylsulfoxide
    DTT dithiothreitol
    EtOAc ethyl acetate
    EtOH ethanol
    g gram
    h hour(s)
    hr hour(s)
    HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
    HEPES 4-(2-hydroxyethyl)-1-piperazineethylanesulfonic acid
    HPLC high pressure liquid chromatography
    IPA isopropyl alcohol
    kg kilogram
    L liter
    LC liquid chromatography LCMS liquid chromatography and mass spectrometry
    MeOH methanol
    MS mass spectrometry
    m multiplet
    min minutes
    mL milliliter(s)
    μM micromolar
    m/z mass to charge ratio
    nm nanometer
    nM nanomolar
    N normal
    NADPH nicotinamide adenine dinucleotide phosphate
    • NMP N-methylpyrrolidone
  • NMR nuclear magnetic resonance
    PdCl2(dppf).CH2Cl2 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex
    psi pounds per square inch
    rac racemic
    Rt retention time
    s singlet
    sat. saturated
    SFC supercritical fluid chromatography
    t triplet
    tR rentention time
    TCEP tris(2-carboxyethyl)phosphine
    TEA triethylamine
    TFA trifluoroacetic acid
    THF tetrahydrofuran
    TLC thin layer chromatography
    • Instrumentation LCMS:
  • Unless otherwise noted, LCMS data (also reported herein as simply MS) were recorded using a Waters System (Acuity UPLC and a Micromass ZQ mass spectrometer; Column: Acuity HSS C18 1.8-micron, 2.1×50 mm; gradient: 5-95% acetonitrile in water with 0.05% TFA over a 1.8 min period; flow rate 1.2 mL/min; molecular weight range 200-1500; cone Voltage 20 V; column temperature 50° C.). All masses reported are those of the protonated parent ions unless recorded otherwise.
    • High Resolution Mass Spectrometry (HRMS):
  • HRMS Method A: ESI-MS data were recorded using a Synapt G2 HDMS (TOF mass spectrometer, Waters) with electrospray ionization source. The resolution of the MS system was approximately 15000. Leucine Enkephalin was used as lock mass (internal standards) infused from lockspary probe. The compound was infused into the mass spectrometer by UPLC (Acquity, Waters) from sample probe. The separation was performed on Acquity UPLC BEH C18 1×50 mm column at 0.2 mL/min flow rate with the gradient from 5% to 95% in 3 min. Solvent A was Water with 0.1% Formic Acid and solvent B was Acetonitrile with 0.1% Formic Acid. The mass accuracy of the system has been found to be <5 ppm with lock mass.
  • HRMS Method B: LC-MS/ESI-MS data were recorded on an Acquity G2 Xevo QT of −Rs(FWHM)>20000 Accuracy<5 ppm. The separation was performed on Acquity CSH 1.7 μm 2.1×50 mm-50° C. column Eluent A: Water+3.75 mM ammonium acetate. Eluent B: Acetonitrile. Gradient: from 2 to 98% B in 4.4 min-flow 1.0 mL/min.
  • HRMS Method C: Same as HRMS method B, except Gradient: from 40 to 98% B in 3.4 min-flow 1.0 mL/min.
  • HRMS Method D: LC-MS/ESI-MS data were recorded on an Acquity LCTp T of −Rs(FWHM)>12000<5 ppm. The separation was performed on Acquity BEHC18 1.7 μm 2.1×50 mm-50° C. column Eluent A: Water+0.1% Formic Acid+3.75 mM Am acetate. Eluent B: Acetonitrile+0.04% formic+3.75 mM Am Acetate+5% Water. Gradient: from 0.2 to 98% B in 4.4 min-flow 1.0 mL/min.
  • HRMS methods A, B, C and D are referred to throughout as HRMS (A), HRMS (B), HRMS (C) and HRMS (D) respectively.
    • Intermediates Intermediate 1: benzyl ((2R)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate
  • Figure US20140275083A1-20140918-C00018
  • A solution of (2S)-2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)butanoic acid (500 mg, 1.0 mmol) in 10 ml of THF and isobutyl chloroformate (167 mg, 1.2 mmol, 1.2 equiv) at −25° C. was added N-methylmorpholine (124 mg, 1.2 mmol, 1.2 equiv), the mixture was stirred at same temperature for 10 min and filtered. The filtrate was cooled to −20° C. and to it was added NaBH4, followed by 2 ml of water immediately afterwards. The reaction mixture was stirred at same temperature for 5 min. then graduately warm to room temperature for 25 min, poured it into water (10 ml) and extracted with EA (2×20 ml), the combines organic phases were washed with water, brine and dried over Na2SO4. The solvent was removed to yield the desired product as the clear oil. No further purification was required for next step. 1H NMR (400 MHz, CDCl3) δ 7.37-7.16 (m, 5H), 5.25 (d, J=8.0 Hz, 1H), 5.02 (s, 1H), 4.04 (ddd, J=12.0, 8.9, 2.8 Hz, 1H), 3.92-3.75 (m, 1H), 3.59 (dddd, J=32.3, 14.6, 8.2, 4.3 Hz, 2H), 1.10 (s, 9H), 1.09-1.06 (m, 3H).
    • Intermediate 2: (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00019
  • Method A: A solution of benzyl ((2R)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (134 mg, 0.45 mmol in 5 mL of THF) was pre-cooled to 0° C.) under nitrogen was treated with potassium tert-butoxide (153 mg, 1.4 mmol, 3.0 equiv), it was stirred at same temperature for 2 hours, 5 mL of water was added, it was extracted with EtOAc (2×20 mL), the combined organic layers were washed with water, brine, dried over Na2SO4, the solvent was removed to yield the desired product as a yellow oil, no further purification was required for next step. 1H NMR (400 MHz, CDCl3) δ 4.33 (t, J=8.7 Hz, 1H), 4.07 (dd, J=8.9, 5.5 Hz, 1H), 3.67-3.58 (m, 1H), 3.58-3.49 (m, 1H), 1.13 (s, 9H), 1.02 (d, J=6.0 Hz, 3H).
  • Method B: (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol hydrochloride (19.77 g, 100 mmol) was dissolved in DCM (200 mL) at 0° C., and added triethylamine (69.7 ml, 500 mmol). Solution was treated over 90 mins with a solution of triphosgene (12.76 g, 43.0 mmol) in DCM (100 mL) [keep the reaction mixture below 5° C.]. The reaction mixture was stirred at 0° C. for 30 mins before allowing to warm to room temperature and stirring overnight. The reaction mixture was treated with aqueous saturated NH4Cl (200 mL), water (50 mL) and stirred vigorously at room temperature for 1 h. Separated the organics, extracted the aqueous with DCM (500 mL), combined the organics and washed them with 1N HCl (3×150 mL), and aqueous saturated NH4Cl, dried (MgSO4) and concentrated to dryness (careful not to leave under vacuum or heat excessively) to give a pale brown oil. TLC shows mostly product with some small by-product peaks at higher Rf and some baseline materials. Subjected to flash column chromatography on silica with neat heptanes, 20% Et2O/heptanes, 50% Et2O/heptanes, neat Et2O, and 30% EtOAc/Et2O. TLC: neat ether, stain with cupric ammonium sulfate (heat hard for 1 minute to see the blue product stain); product Rf=0.34. Product off mostly with neat Et2O. One of the cleanest single fractions was concentrated to dryness to give 2.02 g of a very pale yellow/brown oil which crystallized upon standing. The remainder of the product fractions were combined and concentrated to dryness to give 15.2 g as a pale brown oil, which was seeded with crystals of the initial batch to give a pale brown crystalline solid. Overall yield ˜90%. 1H NMR (400 MHz, CDCl3) δ 5.28 (br s, 1H); 4.44 (t, 1H); 4.13-4.09 (m, 1H); 3.7-3.57 (m, 2H); 1.23 (s, 9H); 1.11 (d, 3H).
    • Intermediate 3: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00020
  • Method A: A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (86 mg, 0.46 mmol) and 2,4-difluoropyrimidine (79 mg, 0.55 mmol, 1.2 equiv) in 3 ml of DMF was cooled to 0° C. under N2 before adding NaH (60%, 28 mg, 0.69 mmol, 1.5 equiv) slowly. The reaction mixture was stirred at 0° C. for 45 min., then gradually warmed to room temperature, and stirred at room temperature overnight. The reaction was quenched with 5 ml of water, and extracted with EtOAc (2×10 ml). The solvent was removed to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 50%) provided the desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=5.8, 2.1 Hz, 1H), 8.14 (dd, J=5.8, 3.8 Hz, 1H), 4.85-4.63 (m, 2H), 4.56-4.30 (m, 2H), 1.26 (s, 9H), 1.05 (d, J=6.5 Hz, 3H).
  • Method B: A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (5 g, 26.7 mmol) in DMF (50 mL) was cooled to −5° C. under N2 atmosphere. Internal temperature was monitored and maintained at ca. −5° C. during the portionwise addition of 60% NaH (1.602 g, 40.1 mmol) over 5 mins (no appreciable exotherm seen, but effervescence observed and cloudy suspension resulted). Added 2,4-difluoropyrimidine (2.507 mL, 29.4 mmol) dropwise whilst still maintaining the temperature at ca. −5° C. After complete addition the reaction mixture was stirred at this temperature for 15 mins before removing the cooling bath and allowing the reaction mixture to warm to room temperature (ca. 27° C. internal temp). Left stirring at room temperature for 2 h. Workup: [Safety Note: NaF salt present. Do not acidify workup] Quenched the reaction mixture with water (100 mL) which resulted in considerable effervescence although minimal increase in temperature. Added EtOAc (75 mL) and separated, extracted the aqueous with EtOAc (2×75 mL), combined the organics, washed with water (100 mL), brine (50 mL), dried (MgSO4) and concentrated to dryness to give crude product as a pale yellow oil [8.33 g] which was purified by silica gel chromatography (initial ramp DCM/heptane 5 to 100%, then EtOAc/DCM 0% to 20%, product off with ˜5% EtOAc/DCM). Combined and concentrated the pure product fractions to dryness to give a white solid which was placed under high vacuum for 4 h. 1H NMR (400 MHz, CDCl3) δ 8.5 (dd, 1H), 8.15 (dd, 1H); 4.77-4.66 (m, 2H); 4.53-4.42 (m, 2H); 1.26 (s, 9H); 1.05 (d, 3H). MS m/z 284.1 (M+H)+.
  • Intermediate 4: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00021
  • A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (5 g, 26.7 mmol) in DMF (50 mL) was cooled to −5° C. under N2 atmosphere. Internal temperature was monitored and maintained at ca. −5° C. during the portionwise addition of 60% NaH (1.28 g, 32 mmol) over 5 mins (no appreciable exotherm seen, but effervescence observed and cloudy suspension resulted). Added 2,4,5-trifluoropyrimidine (3.76 g, 28 mmol) dropwise whilst still maintaining the temperature at ca. −5° C. After complete addition the reaction mixture was stirred at this temperature for 15 mins before removing the cooling bath and allowing the rm to warm to room temperature (ca. 27° C. internal temp). Left stirring at room temperature for 6 h. Sampled reaction mixture and quenched with water, extracted into EtOAc; TLC and LCMS show significant product but remaining oxazolidinone sm. Cooled reaction mixture to 0° C. and added an additional portion of trifluoropyrimidine (1.2 g, 8.95 mmol), warmed to room temperature and left stirring for 3 h at rt. Still faint residual sm seen by TLC of sample, but quenched reaction mixture at this point. Workup: [Safety Note: NaF salt present. Do not acidify workup] Quenched the reaction mixture with water (100 mL) which resulted in considerable effervescence. Added EtOAc (75 mL) and separated, extracted the aqueous with EtOAc (2×75 mL), combined the organics, washed with water (100 mL), brine (50 mL), dried (MgSO4) and concentrated to dryness to give crude product as a pale yellow oil. Crude was purified by silica gel chromatography (initial neat DCM, then ramp to 20% EtOAc/DCM). Pure product fractions were combined and concentrated to dryness to give a colourless oil which was placed under high vacuum. Upon standing the oil converted into a white solid. 1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J=3, 1 Hz, 1H); 4.73-4.68 (m, 1H); 4.62-4.52 (m, 2H); 4.34-4.28 (m, 1H); 1.20 (s, 9H); 1.11 (d, 3H). MS m/z 302.1 (M+H)+.
    • Intermediate 5: (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00022
  • A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (1.0 g, 3.35 mmol) in 20 ml of DCM was cooled in an ice bath, and treated with 8.16 mL of TFA. The mixture was stirred at same temperature for 4 hours, and allowed to warm to room temp and stir 16 h. The reaction was poured into 10 mL water. The DCM was removed in vacuo. The aqueous was basified by slow addition of saturated NaHCO3 solution, then extracted with (2×30 mL) EtOAc. The organics were washed with 30 mL brine, and dried over Na2SO4. Filtered and concentrated to give the desired alcohol, (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (0.56 g, 70% yield) as a white solid. HRMS (B) tR=0.80 min; MS m/z 228.4 (M+H)+.
    • Intermediate 6: (R)-methyl 3-(2-fluoropyrimidin-4-yl)-2-oxooxazolidine-4-carboxylate
  • Figure US20140275083A1-20140918-C00023
  • A solution of (R)-methyl 2-oxooxazolidine-4-carboxylate (200 mg, 1.4 mmol) and 2,4-fluoropyrimidine (176 mg, 1.5 mmol, 1.1 equiv) in DMF (3 mL) was treated with NaH (60%, 66.2 mg, 1.2 mmol, 1.2 equiv), then the resulting mixture was stirred at 0° C. for 45 minutes, then room temperature for 12 h. The reaction mixture was diluted with EtOAc (20 mL), washed with sat. NH4Cl (15 mL) and 4% aqueous NaCl (2×100 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10% to 50%) to provide
  • (R)-methyl 3-(2-fluoropyrimidin-4-yl)-2-oxooxazolidine-4-carboxylate (240 mg, white waxy solid) in 71% yield. 1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J=5.8, 2.0 Hz, 1H), 8.07 (dd, J=5.7, 3.7 Hz, 1H), 5.18 (dd, J=9.4, 3.7 Hz, 1H), 4.68 (t, J=9.4 Hz, 1H), 4.45 (dd, J=9.3, 3.7 Hz, 1H), 3.78 (s, 3H).
    • Intermediate 7: 2-amino-4,4,4-trifluoro-3-methylbutan-1-ol
  • Figure US20140275083A1-20140918-C00024
  • To a chilled (0° C.) solution of 2-amino-4,4,4-trifluoro-3-methylbutanoic acid (736 mg, 4.30 mmol) in THF (9 mL) was added aluminum (III) lithium hydride (2.26 mL, 9.03 mmol, 4M) dropwise. After addition complete, the reaction was allowed to stir at ambient temperature for 1 hour. Cool to 0° C. and quench w/sat. Na2SO4 soln, added EtOAc (50 mL), Na2SO4, filtered, conc. in vacuo afforded material that was a mixture of the title compound and the starting material acid in a 3:2 ratio which was used crude in the next step. 1H NMR (400 MHz, CDCl3) δ 3.71 (dd, J=10.7, 3.7 Hz, 1H), 3.57 (dd, J=10.4, 5.2 Hz, 1H), 3.45 (ddd, J=10.7, 8.0, 4.8 Hz, 2H), 3.28 (ddd, J=8.2, 5.3, 2.9 Hz, 1H), 3.06 (td, J=7.3, 3.6 Hz, 1H), 2.44-2.20 (m, 2H), 2.04-1.54 (m, 1H), 1.21-1.08 (m, 7H). 19F NMR (376 MHz, CDCl3) δ −68.33 (s), −70.12 (s).
    • Intermediate 8: 4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00025
  • To a solution of 2-amino-4,4,4-trifluoro-3-methylbutan-1-ol (580 mg, 3.69 mmol) in DCM (13 ml) was added triethylamine (1.132 ml, 8.12 mmol) and added dropwise a solution of triphosgene (329 mg, 1.107 mmol) in 1 mL in DCM (3 ml) over 10 min. The reaction mixture was washed with sat. NH4Cl solution (13 ml) dry, and concentrated in vacuo. Afforded 450 mg (lt yellow solid). Used crude in the next step. 1H NMR (400 MHz, CDCl3) δ 5.91 (d, J=13.3 Hz, 1H), 4.61-4.34 (m, 1H), 4.22-4.00 (m, 2H), 3.05 (q, J=7.3 Hz, 1H), 2.54-2.14 (m, 1H), 1.34 (t, J=7.3 Hz, 1H), 1.17 (d, J=7.1 Hz, 2H), 1.09 (d, J=7.1 Hz, 1H). MS 183.0507 m/z.
    • Intermediate 9: 3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00026
  • A solution of 4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (270 mg, 1.474 mmol) and 2,4-difluoropyrimidine (171 mg, 1.474 mmol, 1 eq) in DMF (4 mL) was treated with NaH (60%, 88 mg, 2.212 mmol, 1.5 eq), then the resulting mixture was stirred at 0° C. for 10 minutes, then room temperature for 1 h. The reaction mixture was quenched with sat. Na2SO4 (15 mL) diluted with EtOAc (20 mL), washed and 4% aqueous NaCl (3×20 mL), dried over Na2SO4, concentrated in vacuo. Flash column chromatography (silica, 120 g, 15 m) 5% EtOAc/DCM to provide 3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (100 mg, white solid). 1H NMR (400 MHz, CDCl3) δ 8.55 (dd, J=5.8, 2.1 Hz, 1H), 8.20 (dd, J=5.8, 3.7 Hz, 1H), 5.04-4.84 (m, 1H), 4.68 (dd, J=9.5, 2.6 Hz, 1H), 4.54 (t, J=9.2 Hz, 1H), 3.34 (ddddd, J=13.3, 9.3, 7.1, 3.9, 1.6 Hz, 1H), 1.29 (d, J=7.3 Hz, 3H). MS 279.0631 m/z.
    • Intermediate 10: (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00027
    • Step 1
  • To a round bottom flask was added NaH (0.54 g, 13.5 mmol, 57% despersion in mineral oil) to a solution of 2,4,6-trichloropyrimidine (1.22 ml, 10.6 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (1.8 g, 9.61 mmol) in DMF (32 mL) at 0° C. (ice bath) under a bubbler. The yellow suspension was then stirred at 0° C. for 15 min and then the ice bath was removed and reaction mixture allowed to stir 1 hr at room temperature. Reaction mixture was diluted with EtOAc and then carefully quenched with brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (2.1 g, 6.28 mmol, 65% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.04 (d, J=6.55 Hz, 3H) 1.26 (s, 9H) 4.38-4.48 (m, 2H) 4.64-4.75 (m, 2H) 8.22 (s, 1H). LCMS m/z 334.1 (M+H)+, Rt 1.10 min.
    • Step 2
  • To a round bottom flask containing (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (1 g, 2.99 mmol) was added DCM (7.5 mL) followed by the addition of TFA (7.5 mL). The resulting homogenous reaction mixture allowed to stir 1 hr at room temperature. The volatiles were then removed. Residue dissolved in DCM and neutralized with a saturated solution of NaHCO3. The phases were partioned, the aqueous phase extracted with DCM. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a white foam of (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (737 mg, 2.65 mmol, 89% yield). 1H NMR (400 MHz, CDCl3) δ 1.19 (d, J=6.46 Hz, 3H) 4.47 (dd, J=9.37, 8.53 Hz, 1H) 4.55 (quin, J=5.69 Hz, 1H) 4.63 (dd, J=9.49, 2.79 Hz, 1H) 4.89 (ddd, J=8.19, 4.96, 2.79 Hz, 1H) 8.24 (s, 1H). LCMS m/z 278.0 (M+H)+, Rt 0.66 min.
    • Step 3
  • To a round bottom flask was added (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (364 mg, 1.31 mmol) followed by the addition of DCM (10.8 mL). The reaction mixture was then cooled to 0° C. in a (ice/water bath) under nitrogen. To this cold solution was added tetrafluoroboric acid (0.20 mL, 1.31 mmol, 50% aqueous solution) followed by the addition of trimethylsilyldiazomethane (1.96 mL, 3.93 mmol, 2 M in hexanes) divided into 3 portions added 20 min apart. A second addition of trimethylsilyldiazomethane in hexanes (1.96 mL, 3.93 mmol, 2 M in hexanes) again divided into 3 portions added 20 min apart was added. Reaction mixture was quenched with water and diluted with DCM. Phases partioned and the aqueous phase extracted with DCM. Organic phases combined and washed with brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (119 mg, 0.41 mmol, 31% yield) as a colorless oil which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.09 (d, J=6.50 Hz, 3H) 3.44 (s, 3H) 4.09 (qd, J=6.46, 4.16 Hz, 1H) 4.38-4.49 (m, 1H) 4.60 (dd, J=9.49, 2.84 Hz, 1H) 4.99 (ddd, J=8.50, 3.95, 2.96 Hz, 1H) 8.23 (s, 1H). LCMS m/z 292.0 (M+H)+, Rt 0.86 min.
    • Intermediate 11: (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00028
    • Step 1
  • To a round bottom flask containing a stir bar and (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-methoxybutanoic acid (2.5 g, 10.7 mmol) in THF (80 mL) under nitrogen was cooled to −30° C. in a dry ice/acetone bath. To this cold solution was added isobutyl chloroformate (1.7 mL, 12.9 mmol) followed by the addition of N-methylmorpholine (1.4 mL, 12.9 mmol). Mixture was stirred for 15 min at −30° C. N-Methylmorpholine salt develops and was filtered from mixture.
  • Mother liquor was cooled to −30° C. where upon sodium borohydride (0.61 g, 16.1 mmol) was added followed by the addition of water (10 mL) immediately afterwards. Reaction mixture allowed to stir for 15 min at −20° C. then gradually allowed to warm to room temperature. Reaction mixture was stirred for 30 min at room temperature. Reaction mixture was then diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to afford tert-butyl ((2R,3R)-1-hydroxy-3-methoxybutan-2-yl)carbamate (2.0 g, 9.1 mmol, 85% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.18 (d, J=6.26 Hz, 3H) 1.45 (s, 9H) 3.33 (s, 3H) 3.55-3.84 (m, 4H). LCMS m/z 220.2 (M+H)+, Rt 0.57 min.
    • Step 2
  • To a round bottom flask containing tert-butyl ((2R,3R)-1-hydroxy-3-methoxybutan-2-yl) (2 g, 9.1 mmol) and stir bar was added DCM (5.0 mL) followed by the addition of TFA (5.0 mL). Resulting reaction mixture allowed to stir 30 min at room temperature. Volatiles were removed to afford (2R,3R)-2-amino-3-methoxybutan-1-ol (2.1 g, 9.0 mmol, 99% yield) as a TFA salt. Material was used in next step without further purification. LCMS m/z 120.0 (M+H)+, Rt 0.15 min.
    • Step 3
  • To a round bottom flask containing (2R,3R)-2-amino-3-methoxybutan-1-ol (2.1 g, 9.0 mmol) and a stir bar was added acetonitrile (100 mL) followed by the addition of 2,4-dichloropyrimidine (1.34 g, 9.0 mmol) and DIEA (4.7 mL, 27.0 mmol). Resulting reaction mixture allowed to stir 18 hr at room temperature. Volatiles were then removed. Residue was partitioned between EtOAc and water. Aqueous layer extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to afford (2R,3R)-2-((2-chloropyrimidin-4-yl)amino)-3-methoxybutan-1-ol (1.68 g, 3.63 mmol, 40% yield) which contains some unreacted 2,4-dichloropyrimidine. LCMS m/z 232.0 (M+H)+, Rt 0.38 min.
    • Step 4
  • To a round bottom flask containing (2R,3R)-2-((2-chloropyrimidin-4-yl)amino)-3-methoxybutan-1-ol (1.68 g, 3.63 mmol) and a stir bar under nitrogen was added DCM (18 mL). The resulting reaction mixture cooled to 0° C. in a brine/ice bath. To this cold solution was then added triphosgene (0.59 g, 1.99 mmol) followed by the addition of 2,6-dimethylpyridine (2 mL, 17.0 mmol). Resulting reaction mixture allowed to stir 30 min at 0° C. The reaction mixture was diluted with DCM and water and allowed to stir 1 hr at room temperature. The phases partitioned and the aqueous phase extracted with DCM. Organic phases were combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-3-(2-chloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (145 mg, 0.56 mmol, 15% yield) as a white crystalline. 1H NMR (400 MHz, CDCl3) δ 1.09 (d, J=6.26 Hz, 3H) 3.45 (s, 3H) 4.15 (qd, J=6.39, 4.30 Hz, 1H) 4.39-4.47 (m, 1H) 4.60 (dd, J=9.39, 2.74 Hz, 1H) 5.02 (dt, J=8.61, 3.52 Hz, 1H) 8.17 (d, J=5.87 Hz, 1H) 8.48 (d, J=5.87 Hz, 1H). LCMS m/z 258.1 (M+H)+, Rt 0.69 min.
    • Step 5
  • To a microwave vial with stir bar was added (R)-3-(2-chloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (145 mg, 0.56 mmol), potassium fluoride (327 mg, 5.63 mmol) and DMSO (4 mL). Vial capped and heated to 120° C. in a sand bath for 3 hr. Reaction mixture was then cooled to room temperature, diluted with water and aqueous mixture extracted with EtOAc. The Organic phases were combined and washed with water, brine, dried (Na2SO4), filtered and concentrated to afford a white crystalline of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (117 mg, 0.49 mmol, 86% yield). LCMS m/z 242.1 (M+H)+, Rt 0.63 min.
    • Intermediate 12: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00029
    • Step 1
  • To a round bottom flask containing a stir bar and (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butoxy)butanoic acid (8.55 g, 21.5 mmol) in THF (72 mL) under nitrogen was cooled to −30° C. in a dry ice/acetonitrile bath. To this cold solution was added isobutyl chloroformate (3.4 mL, 25.8 mmol) followed by the addition of N-methylmorpholine (2.8 mL, 25.8 mmol). Mixture was stirred for 15 min at −30° C. N-Methylmorpholine salt develops and was filtered from mixture. Mother liquor was cooled to −30° C. where upon sodium borohydride (1.22 g, 32.3 mmol) was added followed by the addition of water (25 mL) immediately afterwards. Reaction mixture allowed to stir for 15 min at −20° C. then gradually allowed to warm to room temperature. Reaction mixture was stirred for 30 min at room temperature. Reaction mixture was diluted with water, extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to afford (9H-fluoren-9-yl)methyl ((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (8.11 g, 21.15 mmol, 98% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.18 (s, 9H) 1.24 (d, J=5.87 Hz, 3H) 4.11-4.26 (m, 2H) 4.42 (d, J=7.04 Hz, 2H) 5.73 (d, J=7.43 Hz, 1H) 7.29-7.35 (m, 2H) 7.38-7.45 (m, 2H) 7.61 (t, J=6.06 Hz, 2H) 7.78 (d, J=7.43 Hz, 2H).). LCMS m/z 384.3 (M+H)+, Rt 0.96 min.
    • Step 2
  • To a round bottom flask with stir bar was added (9H-fluoren-9-yl)methyl ((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (4.7 g, 12.3 mmol) and acetonitrile (100 mL) followed by the addition of piperidine (1.8 mL, 18.4 mmol). The flask was capped and stirred for 18 hr at room temperature. The volatiles were then removed. A white solid develops which contains the amino alcohol product and the fmoc deprotection by products. Solids were redissolved in acetonitrile (50 ml) (some of the fmoc polymer is insoluble) and 2,4-dichloropyrimidine (5.48 g, 36.8 mmol) and DIEA (2.141 mL, 12.26 mmol) were added. Resulting reaction mixture allowed to stir 18 hr at room temperature. The volatiles were again removed. Reaction mixture was diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (2R,3S)-3-(tert-butoxy)-2-((2-chloropyrimidin-4-yl)amino)butan-1-ol (1.80 g, 6.58 mmol, 54% yield) as a colorless oil which crystallizes upon standing. LCMS m/z 274.1 (M+H)+, Rt 0.56 min.
    • Step 3
  • To a round bottom flask containing (2R,3S)-3-(tert-butoxy)-2-((2-chloropyrimidin-4-yl)amino)butan-1-ol (1.8 g, 6.58 mmol) and a stir bar under nitrogen was added DCM (66 ml). The resulting reaction mixture cooled to −70° C. in a dry ice/acetone bath. To this cold solution was added triphosgene (1.07 g, 3.62 mmol) followed by the addition of 2,6-dimethylpyridine (3.6 mL, 30.9 mmol). Resulting reaction mixture allowed to gradually warm to room temperature and stirred for 30 min at room temperature. Reaction mixture diluted with DCM and water and allowed to stir 1 hr at room temperature. The phases were then partioned and aqueous extracted with DCM. Organics phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (1.44 g, 4.80 mmol, 73% yield) as a white crystalline. LCMS m/z 300.1 (M+H)+, Rt 0.91 min.
    • Intermediate 13: (R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00030
  • A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.830 g, 4.43 mmol) and 2,4,6-trichloropyrimidine (0.894 g, 4.88 mmol, 1.10 equiv) in DMF (15 mL) was treated with NaH (60%, 0.248 g, 6.21 mmol, 1.40 equiv), then the resulting mixture (yellow) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and quenched with saturated aqueous NaCl (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (1.0 g, white solid) in 69% yield. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 4.70-4.66 (m, 2H), 4.45-4.40 (m, 2H), 1.26 (s, 9H), 1.04 (d, J=6.6 Hz, 3H); MS m/z 334.0 (M+H)+; Rt-1.10 min.
    • Intermediate 14: (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00031
  • A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.100 g, 0.534 mmol) and 4-chloro-6-(difluoromethyl)-2-(methylthio)pyrimidine (0.124 g, 0.587 mmol, 1.10 equiv) in DMF (2.7 mL) was treated with NaH (60%, 0.026 g, 0.64 mmol, 1.20 equiv), then the resulting mixture (yellow) was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (2×20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)oxazolidin-2-one (0.164 g, white solid) in 85% yield. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 6.45 (t, J=54 Hz, 1H), 4.80-4.72 (m, 1H), 4.66 (dd, J=9.4, 3.0 Hz, 1H), 4.49-4.34 (m, 2H), 2.58 (s, 3H), 1.25 (s, 9H), 1.02 (d, J=6.5 Hz, 3H); MS m/z 362.3 (M+H)+; Rt-1.09 min.
    • Intermediate 15: (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00032
  • A solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)oxazolidin-2-one (0.164 g, 0.454 mmol) in DCM (4.5 mL) was treated with m-CPBA (0.244 g, 1.09 mmol, 2.4 equiv) at 0° C. The mixture was allowed to warm to room temperature and stirred for 4 h. The reaction was carefully quenched with a 1:1 mixture of 1 M aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with DCM (3×20 mL) and the combined organic extracts were washed with saturated aqueous NaCl (20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20% to 40%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)oxazolidin-2-one as a white solid in 82% yield. MS m/z 338.1 (M+H-tert-butyl)+; Rt-0.87 min.
    • Intermediate 16: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00033
  • A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.070 g, 0.374 mmol) and 2,4-dichloro-6-(trifluoromethyl)pyrimidine (0.089 g, 0.411 mmol, 1.10 equiv) in DMF (1.3 mL) was treated with NaH (60%, 0.018 g, 0.45 mmol, 1.20 equiv), then the resulting mixture (yellow) was stirred at room temperature for 60 min. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (2×20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 15%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)oxazolidin-2-one (0.116 g, white solid) in 84% yield. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 4.76 (ddd, J=8.5, 4.2, 2.9 Hz, 1H), 4.70 (dd, J=9.5, 2.9 Hz, 1H), 4.50-4.42 (m, 2H), 1.26 (s, 9H), 1.04 (d, J=6.5 Hz, 3H). MS m/z 368.1 (M+H)+; Rt-1.10 min.
    • Intermediate 17: (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol
  • Figure US20140275083A1-20140918-C00034
  • A solution of (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol (267 mg, 1.35 mmol, 1.1 equiv), 2,4-dichloro-6-methylpyrimidine (200 mg, 1.23 mmol, 1.0 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.54 mL, 3.1 mmol, 2.5 equiv) in 1,4-dioxane (6 mL) was heated at 75° C. for 4 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane) provided (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol (86 mg, white solid) in 24% yield. 1H NMR (400 MHz, CDCl3) δ 6.17 (s, 1H), 4.02 (m, 2H), 3.79-3.64 (m, 2H), 2.30 (s, 3H), 1.22 (s, 9H), 1.18 (d, J=6.2 Hz, 3H); MS m/z 288.1 (M+H)+; Rt-0.59 min.
    • Intermediate 18: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00035
  • Triphosgene (35 mg, 0.12 mmol, 0.4 equiv) was added to a solution of (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol (86 mg, 0.30 mmol) in DCM (3 mL) at −78° C., followed by the dropwise addition of 2,6-lutidine (0.14 mL, 1.2 mmol, 4 equiv). The solution was allowed to warm to room temperature and was then heated at 35° C. for 5 hours. The reaction was then cooled to room temperature and diluted with DCM (30 mL) and saturated aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one (0.057 g, white solid) in 61% yield. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 4.73 (ddd, J=8.6, 4.1, 3.0 Hz, 1H), 4.65 (dd, J=9.4, 2.9 Hz, 1H), 4.48 (m, 1H), 4.41 (m, 1H), 2.52 (s, 3H), 1.26 (s, 9H), 1.03 (d, J=6.5 Hz, 3H); MS m/z 314.1 (M+H)+; Rt-1.02 min.
    • Intermediate 19: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoro-6-methylpyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00036
  • Potassium fluoride (0.063 g, 1.08 mmol, 10 equiv) was added to a solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one (34 mg, 0.108 mmol) in DMSO (1.1 mL). The suspension was heated at 120° C. for 3 hours and then cooled to room temperature. The reaction was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoro-6-methylpyrimidin-4-yl)oxazolidin-2-one, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=3.8 Hz, 1H), 4.71 (m, 1H), 4.65 (m, 1H), 4.46 (m, 1H), 4.41 (m, 1H), 2.53 (s, 3H), 1.25 (s, 9H), 1.03 (d, J=6.5 Hz, 3H); MS m/z 298.2 (M+H)+; Rt-0.96 min.
    • Intermediate 20: methyl 6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-2-chloropyrimidine-4-carboxylate
  • Figure US20140275083A1-20140918-C00037
  • Sodium hydride (60% dispersion in mineral oil, 23 mg, 0.58 mmol, 1.2 equiv) was added to a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (100 mg, 0.483 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (90 mg, 0.483 mmol, 1 equiv) in DMF (2.4 mL) at 0° C. The suspension was stirred at 0° C. for 1 hour, by which time it turned yellow. The reaction was quenched with dilute aqueous sodium chloride (20 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) separated the regioisomers and provided methyl 6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-2-chloropyrimidine-4-carboxylate (0.111 g, white solid) in 64% yield. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 4.76 (m, 1H), 4.69 (dd, J=9.4, 2.7 Hz, 1H), 4.52-4.41 (m, 2H), 4.02 (s, 3H), 1.26 (s, 9H), 1.05 (d, J=6.6 Hz, 3H). MS m/z 358.2 (M+H)+; Rt-1.00 min.
    • Intermediate 21: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00038
  • Sodium borohydride (60 mg, 1.59 mmol, 1.4 equiv) was added to a suspension of methyl 6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-2-chloropyrimidine-4-carboxylate (400 mg, 1.12 mmol) in methanol (11.2 mL) at 0° C. The ice bath was removed and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with saturated aqueous sodium chloride (30 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one (0.220 g, white solid) in 60% yield. 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 4.77-4.72 (m, 3H), 4.66 (dd, J=9.4, 2.9 Hz, 1H), 4.48 (m, 1H), 4.41 (m, 1H), 2.83 (m, 1H), 1.26 (s, 9H), 1.03 (d, J=6.6 Hz, 3H). MS m/z 330.1 (M+H)+; Rt-0.86 min.
    • Intermediate 22: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(fluoromethyl)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00039
  • N,N-Diethylaminosulfur trifluoride (0.13 mL, 0.98 mmol, 1.5 equiv) was added to a solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one (215 mg, 0.652 mmol) in DCM at −78° C. The reaction was stirred at −78° C. for 1 hour, then warmed to room temperature and stirred for another hour. Additional N,N-Diethylaminosulfur trifluoride (0.26 mL, 2.0 mmol, 3 equiv) was added and the reaction stirred for another 1 hour. The reaction was quenched with water (50 mL) and extracted with DCM (3×25 mL). The combined extracts were washed with saturated aqueous sodium chloride (30 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one (0.165 g, white solid) in 76% yield. 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 5.40 (d, J=44 Hz, 1H), 4.75 (ddd, J=8.6, 4.1, 3.0 Hz, 1H), 4.67 (dd, J=9.4, 2.9 Hz, 1H), 4.49 (m, 1H), 4.43 (m, 1H), 1.27 (s, 9H), 1.04 (d, J=6.5 Hz, 3H). MS m/z 332.1 (M+H)+; Rt-1.02 min.
    • Intermediate 23: (S)-4,6-difluoro-N-(1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine
  • Figure US20140275083A1-20140918-C00040
  • (S)-1-(1-(4-Fluorophenyl)-1H-pyrazol-4-yl)ethanamine (175 mg, 0.724 mmol) was added to a solution of 2,4,6-trifluoropyrimidine (146 mg, 1.09 mmol, 1.5 equiv) and N-ethyl-N-isopropylpropan-2-amine (0.32 mL, 1.8 mmol, 2.5 equiv) in 1,4-dioxane at room temperature. The mixture was stirred at room temperature for 1 hour and then the reaction was concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one (0.085 g) in 37% yield. 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.68 (s, 1H), 7.62 (dd, J=8.9, 4.6 Hz, 1H), 7.18-7.11, (m, 2H), 5.80 (t, J=1.2 Hz, 1H), 5.49 (m, 1H), 5.25 (m, 1H), 1.62 (d, J=6.8 Hz, 3H). MS m/z 320.1 (M+H)+; Rt-0.95 min.
  • The Intermediates in Table 1a were prepared by a method similar to the one described for the preparation of Intermediate 23.
  • TABLE 1a
    Figure US20140275083A1-20140918-C00041
         		Intermediate 24
    Figure US20140275083A1-20140918-C00042
         		Intermediate 25
  • TABLE 1b
    Chemical name, NMR chemical shifts and LCMS signal for each intermediate listed
    in Table 1a.
    1H NMR (400 MHz, CDCl3) δ
    Intermediate: Name ppm LCMS
    24: (S)-4,6-difluoro-N-(1-(1-(4-fluorophenyl)- 7.82 (s, 1H), 7.68 (s, 1H), MS m/z
    1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine 7.62 (dd, J = 8.9, 4.6 Hz, 1H), 320.1 (M + H)+;
    7.18-7.11, (m, 2H), 5.80 (t, J = 1.2 Hz, Rt-0.95 min
    1H), 5.49 (m, 1H), 5.25 (m,
    1H), 1.62 (d, J = 6.8 Hz, 3H).
    25: (S)—N-(1-(1-(4-chlorophenyl)-1H-pyrazol- MS m/z
    4-yl)ethyl)-4,6-difluoropyrimidin-2-amine 336.0 (M + H)+;
    Rt-1.04 min
    • Intermediate 26: (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00043
  • Imidazole (1.74 g, 25.6 mmol, 2.0 equiv) was added to a solution of (S)-4-(hydroxymethyl)oxazolidin-2-one (1.5 g, 12.8 mmol) and tert-butylchlorodiphenylsilane (3.95 mL, 15.4 mmol, 1.2 equiv) in DCM (43 mL) at room temperature. A white precipitate formed. The solution was stirred at room temperature for 16 hours and then diluted with water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20 to 65%) provided (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one (3.55 g, sticky colorless oil) in 78% yield. 1H NMR (400 MHz, CDCl3) δ 7.64 (m, 4H), 7.50-7.38 (m, 6H), 5.31 (m, 1H), 4.44 (t, J=8.7 Hz, 1H), 4.15 (m, 1H), 4.00 (m, 1H), 3.65 (d, J=5.5 Hz, 2H), 1.07 (s, 9H). MS m/z 356.1 (M+H)+; Rt-1.00 min.
    • Intermediate 27: (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00044
  • Sodium hydride (34 mg, 0.84 mmol, 1.5 equiv) was carefully added to a solution of (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one (200 mg, 0.563 mmol) in DMF (2.8 mL). The mixture was stirred at room temperature for 20 minutes and then 2,4-difluoropyrimidine (0.072 mL, 0.84 mmol, 1.5 equiv) was added (bubbling). The yellow suspension was stirred for 10 minutes and the reaction was then carefully quenched with saturated aqueous ammonium chloride (5 mL). Water (20 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 30%) provided (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (0.185 g, sticky colorless oil) in 73% yield. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=5.8, 2.2 Hz, 1H), 8.12 (dd, J=5.8, 3.4 Hz, 1H), 7.58 (m, 2H), 7.48-7.32 (m, 6H), 7.23 (m, 2H), 4.80 (m, 1H), 4.65 (dd, J=8.6, 3.0 Hz, 1H), 4.55 (m, 1H), 4.18 (dd, J=11.1, 3.5 Hz, 1H), 3.83 (dd, J=11.1, 2.1 Hz, 1H), 1.04 (s, 9H). MS m/z 452.3 (M+H)+; Rt-1.15 min.
    • Intermediate 28: (S)-3-(2-fluoropyrimidin-4-yl)-4-(hydroxymethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00045
  • A solution of tetrabutylammonium fluoride (1.0 M in THF, 0.44 mL, 0.44 mmol, 1.1 equiv) was added to a solution of (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (180 mg, 0.40 mmol) in THF (4 mL) at room temperature. The solution was stirred for 1 hour and then diluted with saturated aqueous sodium chloride (30 mL). The mixture was extracted with ethyl acetate (2×30 mL) and the combined extracts were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (S)-3-(2-fluoropyrimidin-4-yl)-4-(hydroxymethyl)oxazolidin-2-one (0.051 g, white solid) in 60% yield. 1H NMR (400 MHz, CDCl3) δ 8.51 (dd, J=5.8, 2.1 Hz, 1H), 8.19 (dd, J=5.8, 3.8 Hz, 1H), 4.86 (dq, J=8.1, 4.0 Hz, 1H), 4.55 (m, 2H), 4.09 (m, 1H), 3.96 (m, 1H), 2.18 (t, J=5.4 Hz, 1H). MS m/z 214.0 (M+H)+; Rt-0.37 min.
    • Intermediate 29: (R)-4-(fluoromethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00046
  • Perfluorobutanesulfonyl fluoride (0.18 mL, 0.98 mmol, 4 equiv) was added to a solution of (S)-3-(2-fluoropyrimidin-4-yl)-4-(hydroxymethyl)oxazolidin-2-one (52 mg, 0.24 mmol) in THF (1.2 mL) at room temperature. Triethylamine trihydrofluoride (0.16 mL, 0.98 mmol, 4 equiv) and triethylamine (0.41 mL, 3.0 mmol, 12 equiv) were then added and the solution was stirred at 40° C. for 18 hours. The reaction was then cooled to room temperature and diluted with water (25 mL). The mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (10 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-(fluoromethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (0.021 g, colorless oil) in 40% yield. 1H NMR (400 MHz, CDCl3) δ 8.53 (dd, J=5.7, 2.1 Hz, 1H), 8.18 (dd, J=5.7, 3.7 Hz, 1H), 5.08-4.93 (m, 2H), 4.91-4.72 (m, 1H), 4.66-4.55 (m, 2H). MS m/z 215.9 (M+H)+; Rt-0.57 min.
    • Intermediate 30: (R)-4-((R)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00047
    • Step 1
  • To a round bottom flask containing a stir bar and (2S,3S)-2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)butanoic acid DCHA (10 g, 20.4 mmol) in THF (160 mL) under nitrogen was cooled to −30° C. in a dry ice/acetone bath. To this cold white suspension was added isobutyl chloroformate (3.2 mL, 24.5 mmol) followed by the addition of N-methylmorpholine (2.7 mL, 24.5 mmol). Mixture was stirred for 20 min at −30° C. A N-Methylmorpholine salt develops and was filtered from mixture. Mother liquor was cooled to −30° C. where upon sodium borohydride (1.16 g, 30.6 mmol) was added followed by the addition of water (20 mL) immediately afterwards. Reaction mixture allowed to stir for 15 min at −20° C. then gradually allowed to warm to room temperature. The reaction mixture was stirred for 30 min at room temperature. The reaction mixture was then diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to afford benzyl ((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (5.27 g, 17.8 mmol, 88% yield) as a colorless oil. LCMS m/z 296.1 (M+H)+, Rt 0.84 min.
    • Step 2
  • To a round bottom flask containing benzyl ((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (5.27 g, 17.8 mmol) was added MeOH (100 mL). Solution was degassed with nitrogen for 15 min at which time palladium on carbon (0.95 g, 0.89 mmol) in MeOH (5 mL) was added. A hydrogen atmosphere was then inserted. Resulting reaction mixture allowed to stir 40 min at room temperature at atmospheric pressure when water (2 mL) was added and once again a hydrogen atmosphere was inserted at atmospheric pressure and the subsequent reaction mixture allowed to stir 18 hr at room temperature. The reaction mixture was filtered through a pad of celite and concentrated to a brown oil. Oil redissolved in toluene and concentrated to afford (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (2.5 g, 15.5 mmol, 87% yield) as a brown oil. LCMS m/z 162.1 (M+H)+, Rt 0.41 min (Mass ion only, no UV peak).
    • Step 3
  • To a round bottom flask containing (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (1.25 g, 7.75 mmol) and a stir bar was added acetonitrile (50 mL) followed by the addition of 2,4-difluoropyrimidine (0.99 g, 8.53 mmol) and DIEA (4.1 mL, 23.3 mmol). The resulting reaction mixture allowed to stir 1 hr at room temperature. The volatiles were then removed. Residue was partitioned between EtOAc and water. Aqueous layer extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a viscous yellow oil of (2R,3S)-3-(tert-butoxy)-2-((2-fluoropyrimidin-4-yl)amino)butan-1-ol (1.5 g, 5.83 mmol, 75% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.14 (s, 9H) 1.31 (d, J=6.26 Hz, 3H) 3.64 (d, J=12.91 Hz, 2H) 3.86 (br. s., 1H) 4.26 (d, J=10.17 Hz, 1H) 6.09 (br. s., 1H) 6.25 (br. s., 1H) 7.99 (br. s., 1H). LCMS m/z 258.2 (M+H)+, Rt 0.62 min
    • Step 4
  • To a round bottom flask containing (2R,3S)-3-(tert-butoxy)-2-((2-fluoropyrimidin-4-yl)amino)butan-1-ol (1.5 g, 5.83 mmol) and a stir bar under nitrogen was added DCM (58 mL). The resulting reaction mixture cooled to −70° C. in a dry ice/acetone bath. To this cold solution was added triphosgene (0.95 g, 3.21 mmol) followed by the addition of 2,6-dimethylpyridine (2.7 ml, 23.3 mmol). The resulting reaction mixture allowed to warm to room temperature and stirred for 1 hr.
  • The reaction mixture was then diluted with DCM and water and allowed to stir 1 hr at room temperature. The phases were then partioned and aqueous phase extracted with DCM. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (502 mg, 1.77 mmol, 30% yield) as a white crystalline. LCMS m/z 284.1 (M+H)+, Rt 0.89 min.
    • Step 5
  • To a round bottom flask containing (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (502 mg, 1.77 mmol) was added DCM (4 mL) and TFA (4 mL). Resulting reaction mixture stirred for 1 hr at room temperature. The volatiles were then removed and the residue neutralized with a saturated solution of NaHCO3. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a colorless residue of (R)-3-(2-fluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (382 mg, 1.68 mmol, 95% yield). LCMS m/z 228.1 (M+H)+, Rt 0.44 min.
    • Step 6
  • To a round bottom flask containing a solution of (R)-3-(2-fluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (348 mg, 1.53 mmol) in THF (5.1 mL) was added perfluorobutanesulfonyl fluoride (0.83 mL, 4.60 mmol) followed by the addition of triethylamine trihydrofluoride (0.75 mL, 4.60 mmol) and triethylamine (1.9 mL, 13.8 mmol). The resulting reaction mixture allowed to stir at room temperature for 6 hr. The reaction mixture was diluted with water and the aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided a viscous oil of (R)-4-((R)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (125 mg, 0.44 mmol, 28% yield) which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.34 (dd, J=24.26, 6.65 Hz, 3H) 4.45-4.55 (m, 1H) 4.61-4.68 (m, 1H) 5.11 (dt, J=7.63, 4.01 Hz, 1H) 5.30-5.52 (m, 1H) 8.13-8.17 (m, 1H) 8.52 (d, J=5.87 Hz, 1H). LCMS m/z 230.0 (M+H)+, Rt 0.66 min.
    • Intermediate 31: (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00048
    • Step 1
  • To a round bottom flask containing (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (1.25 g, 7.75 mmol) and a stir bar was added acetonitrile (50 mL) followed by the addition of 2,4,5-trifluoropyrimidine (1.04 g, 7.75 mmol) and DIEA (4.1 mL, 23.3 mmol). The resulting reaction mixture allowed to stir 1 hr at room temperature. The volatiles were then removed. Reaction mixture was then partitioned between EtOAc and water. Aqueous layer extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a viscous yellow oil of (2R,3S)-3-(tert-butoxy)-2-((2,5-difluoropyrimidin-4-yl)amino)butan-1-ol (1.56 g, 5.67 mmol, 73% yield). 1H NMR (400 MHz, CDCl3) δ 1.15 (s, 9H) 1.32 (d, J=6.26 Hz, 3H) 3.45 (br. s., 1H) 3.67 (d, J=11.35 Hz, 1H) 3.85-3.92 (m, 1H) 4.27 (d, J=11.74 Hz, 1H) 6.29 (d, J=5.48 Hz, 1H) 7.87 (d, J=2.35 Hz, 1H). LCMS m/z 276.4 (M+H)+, Rt 0.71 min.
    • Step 2
  • To a round bottom flask containing (2R,3S)-3-(tert-butoxy)-2-((2,5-difluoropyrimidin-4-yl)amino)butan-1-ol (1.56 g, 5.67 mmol) and a stir bar under nitrogen was added DCM (57 mL). The resulting reaction mixture cooled to −70° C. in a dry ice/acetone bath. To this cold solution was added triphosgene (0.93 g, 3.12 mmol) followed by the addition of 2,6-dimethylpyridine (2.64 ml, 22.7 mmol). The resulting reaction mixture allowed to warm to room temperature and stirred 90 hr at room temperature. The reaction mixture was then diluted with DCM and water and allowed to stir 1 hr at room temperature. The phases were then partioned and aqueous phase extracted with DCM. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (0.59 g, 1.96 mmol, 35% yield) as a white crystalline. 1H NMR (400 MHz, CDCl3) δ 1.03 (s, 9H) 1.16 (d, J=6.65 Hz, 3H) 4.15 (qd, J=6.39, 1.96 Hz, 1H) 4.43-4.52 (m, 1H) 4.59-4.72 (m, 2H) 8.43 (d, J=1.57 Hz, 1H). LCMS m/z 246.0 (-t-butyl fragment) (M+H)+, Rt 0.88 min.
    • Step 3
  • To a round bottom flask containing (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (590 mg, 1.96 mmol) was added DCM (4 mL) and TFA (4 mL). Resulting reaction mixture stirred for 1 hr at room temperature. The volatiles were then removed. Residue neutralized with a saturated solution of NaHCO3 and aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a colorless residue of (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (470 mg, 1.917 mmol, 98% yield). LCMS m/z 246.0 (M+H)+, Rt 0.41 min.
    • Step 4
  • To a round bottom flask containing a solution of (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (0.47 g, 1.917 mmol) in THF (6.4 mL) was added perfluorobutanesulfonyl fluoride (1.03 mL, 5.75 mmol) followed by the addition of triethylamine trihydrofluoride (0.94 mL, 5.75 mmol) and triethylamine (2.40 mL, 17.3 mmol) resulting reaction mixture allowed to stir at room temperature for 6 hr. The reaction mixture was diluted with water and the aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided a white crystalline of (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one (150 mg, 0.61 mmol, 32% yield). 1H NMR (400 MHz, CDCl3) δ 1.37 (dd, J=24.26, 6.26 Hz, 3H) 4.48 (dd, J=9.39, 4.70 Hz, 1H) 4.63 (t, J=8.80 Hz, 1H) 4.90-5.02 (m, 1H) 5.02-5.25 (m, 1H) 8.50 (s, 1H). LCMS m/z 248.0 (M+H)+, Rt 0.59 min.
    • Intermediate 32
  • Figure US20140275083A1-20140918-C00049
    • Step 1
  • To a round bottom flask containing (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (2.1 g, 7.41 mmol) was added DCM (18.5 mL) and TFA (18.5 mL). The resulting reaction mixture stirred for 1 hr at room temperature. The volatiles were then removed and the residue neutralized with a saturated solution of NaHCO3. The aqueous mixture was then extracted with EtOAc. The organic phases were combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a colorless residue of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (1.52 g, 6.69 mmol, 90% yield) which crystallizes upon standing. LCMS m/z 228.0 (M+H)+, Rt 0.44 min.
    • Step 2
  • To a round bottom flask containing a solution of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (1.52 g, 6.69 mmol) in THF (22 mL) was added perfluorobutanesulfonyl fluoride (3.6 mL, 20.1 mmol) followed by the addition of triethylamine trihydrofluoride (3.3 mL, 20.1 mmol) and triethylamine (8.4 mL, 60.2 mmol). The resulting reaction mixture allowed to stir at room temperature for 2 hr. The reaction mixture was then diluted with water and the aqueous mixture was extracted with EtOAc. The organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided a white crystalline of (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (207 mg, 0.90 mmol, 14% yield). 1H NMR (400 MHz, CDCl3) δ 1.44 (dd, J=23.48, 6.26 Hz, 3H) 4.47-4.57 (m, 1H) 4.66 (dd, J=8.80, 3.33 Hz, 1H) 4.71-4.86 (m, 1H) 5.22-5.45 (m, 1H) 8.21 (dd, J=5.48, 3.91 Hz, 1H) 8.52 (dd, J=5.48, 1.96 Hz, 1H). LCMS m/z 230.1 (M+H)+, Rt 0.63 min.
    • Intermediate 33: 4-(2-fluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00050
    • Step 1: Preparation of 2-amino-3-fluoro-3-methylbutan-1-ol
  • Figure US20140275083A1-20140918-C00051
  • To the solution of LiBH4 (2M in THF, 7.40 mL, 14.8 mmol) and trimethylchlorosilane (3.78 mL, 29.6 mmol) in THF (7 mL) was added 3-fluoro-D,L-valine (1 g, 7.40 mmol). The resulting mixture was stirred at room temperature for 24 hr. The reaction mixture was quenched with methanol and then concentrated under reduced pressure to give an oily product. The oily product was diluted with DCM and 10% aqueous sodium bicarbonate solution and then stirred at room temperature for ˜16 hr. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure providing 2-amino-3-fluoro-3-methylbutan-1-ol (350 mg) as a solid, which was used without further purification. MS m/z 121.9 (M+H)+; Rt-0.16 min.
    • Step 2: Preparation of 4-(2-fluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00052
  • To a solution of N,N′-carbonyldiimidazole (530 mg, 3.27 mmol in THF (5 mL) was added slowly a solution of 2-amino-3-fluoro-3-methylbutan-1-ol (360 mg, 2.97 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 18 hr, was diluted with DCM and stirred for additional 30 min. The separated organic layer was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane=0/100 to 80/20] to provide 4-(2-fluoropropan-2-yl)oxazolidin-2-one (150 mg) as a brown solid. MS m/z 148.0 (M+H)+; Rt-0.32 min. 1H NMR (400 Mhz, CDCl3) δ ppm 6.30 (br. s., 1H), 4.39-4.54 (m, 1H), 4.26 (dd, J=8.9, 5.1 Hz, 1H), 3.84-3.99 (m, 1H), 1.29-1.45 (m, 6H).
    • Intermediate 34: 3-(2-chloropyrimidin-4-yl)-4-(2-fluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00053
  • To the solution of 2,4-dichloropyrimidine (150 mg, 1.006 mmol) and 4-(2-fluoropropan-2-yl)oxazolidin-2-one (148 mg, 1.01 mmol) in DMF (4.5 mL), sodium hydride (60% wt. 89 mg, 2.21 mmol) was added to give a pale yellow mixture. The mixture was stirred at room temperature for 2 hr, diluted with EtOAc and stirred for additional 30 min. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane=0/100 to 80/20] providing 3-(2-chloropyrimidin-4-yl)-4-(2-fluoropropan-2-yl)oxazolidin-2-one (150 mg) as a brown solid. MS m/z 260.1 (M+H)+; Rt-0.72 min. 1H NMR (400 Mhz, CDCl3) δ ppm 8.51 (d, J=5.9 Hz, 1H), 8.17 (d, J=5.9 Hz, 1H), 5.14 (dd, J=17.4, 8.0 Hz, 1H), 4.66 (d, J=9.4 Hz, 1H), 4.43-4.52 (m, 1H), 1.42-1.52 (m, 3H), 1.30-1.40 (m, 3H).
    • Intermediate 35: (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00054
    • Step 1: Preparation of (S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate
  • Figure US20140275083A1-20140918-C00055
  • Reference: V. L. Truong, et al.; Synlett 2005, 8, 1279-1280.
  • To a solution of Boc-Asp(OBnzl)-OH (20 g, 61.9 mmol) in DME (60 mL) at −40° C. (dry ice/acetonitrile bath) was added N-methylmorpholine (7.07 mL, 64.3 mmol) over 5 min followed by isobutyl chloroformate (8.53 ml, 64.9 mmol) dropwise over 15 min, keeping the temperature below −10° C. The mixture was stirred for 30 min (−30° C. to −40° C.). The solids were quickly filtered off and rinsed with DME (60 mL). The clear filtrate was cooled to −35° C. and a solution of NaBH4 (2.93 g, 78 mmol) in 30 mL water was added dropwise maintaining a temperature between −30° C. and −15° C. [Caution: gas development]. Water (332 mL) was added dropwise over 30 min to the white suspension maintaining a temperature below −15° C. The thick white slurry was filtered, rinsed with water (300 mL). The filtered solid was dissolved in DCM (250 mL). The solution was dried over sodium sulfate, filtered off and concentrated under reduced pressure to provide (S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate (16.35 g) as a white solid. MS m/z 254.2 (M-tert-butyl)+; Rt-0.78 min. 1H NMR (400 Mhz, D3C(CO)CD3) δ ppm 7.45-7.28 (m, 4H), 5.92-5.80 (m, 1H), 5.11 (s, 2H), 4.07-3.91 (m, 1H), 3.67-3.48 (m, 2H), 2.82-2.77 (m, 1H), 2.74-2.68 (m, 1H), 2.61-2.52 (m, 1H), 1.39 (s, 9H).
    • Step 2: Preparation of (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate
  • Figure US20140275083A1-20140918-C00056
  • Reference: V. L. Truong, et al.; Synlett 2005, 8, 1279-1280.
  • To a solution of (S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate (16.3 g, 52.7 mmol) and pyridine (10.65 ml, 132 mmol) in DCE (157 mL) at 0° C. was added p-toluenesulfonic anhydride (17.10 g, 52.4 mmol) in two portions over 5 min. The mixture was stirred for a few minutes, then allowed to warm to room temperature and stirred for 1 hr. The mixture was heated for 6 hr at 92° C. and then allowed to cool to room temperature. The mixture was diluted with DCM (80 mL), washed with 1N aqueous HCl solution (2×200 mL), brine (200 mL), and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 220 g, EtOAc/heptane=5/95 to 75/25] to provide (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate (10.0 g) as a white solid. MS m/z 236.2 (M+H)+; Rt-0.59 min.
    • Step 3: Preparation of (R)-benzyl 2-((S)-2-oxooxazolidin-4-yl)propanoate
  • Figure US20140275083A1-20140918-C00057
  • To a solution of sodium bis(trimethylsilyl)amide (1 M in THF; 68.0 mL) under argon atmosphere was added THF (40.4 mL). The mixture was cooled to −78° C. and a solution of (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate (7.80 g, 33.2 mmol) in THF (85 mL) was added slowly over ˜15 min. The mixture was stirred for 1 hr at −78° C. and a solution of iodomethane (4.25 mL, 68.0 mmol) in THF (40.4 mL) was added slowly over ˜10 min. The reaction mixture was stirred for 1 hr at −78° C. and ˜1 hr at −40° C. The mixture was quenched with saturated aqueous ammonium chloride solution (˜100 mL) and allowed to warm to room temperature. The mixture was extracted with DCM (3×). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 220 g, EtOAc/heptane] to provide (R)-benzyl 2-((S)-2-oxooxazolidin-4-yl)propanoate (7.47 g) as a colorless oil. MS m/z 250.1 (M+H)+; Rt-0.65 min. 1H NMR (400 Mhz, DMSO-d6) δ ppm 7.85 (s, 1H), 7.44-7.28 (m, 5H), 5.10 (s, 2H), 4.36 (t, J=1.0 Hz, 1H), 4.11 (dd, J=5.4, 8.9 Hz, 1H), 4.06-3.98 (m, 1H), 2.69 (quin, J=6.9 Hz, 1H), 1.08 (d, J=7.1 Hz, 3H).
    • Step 4: Preparation of (R)-2-((S)-2-oxooxazolidin-4-yl)propanoic acid
  • Figure US20140275083A1-20140918-C00058
  • To a solution of (R)-benzyl 2-((S)-2-oxooxazolidin-4-yl)propanoate (1.99 g, 7.98 mmol) in THF (18.7 mL) was added Pd/C (10% wt., Degussa; 0.425 g). The mixture was stirred under hydrogen atmosphere (balloon) at room temperature for 4 hr. The mixture was filtered through a plug of celite and rinsed several times with THF. The filtrate was concentrated under reduced pressure providing (R)-2-((S)-2-oxooxazolidin-4-yl)propanoic acid (1.17 g) as a white solid, which was directly used without further purification. MS m/z 160.0 (M+H)+; Rt-0.26 min. 1H NMR (400 Mhz, CD3OD) δ ppm 4.53-4.47 (m, 1H), 4.26 (dd, J=5.7, 9.1 Hz, 1H), 4.13 (td, J=6.0, 8.8 Hz, 1H), 2.69-2.61 (m, 1H), 1.18 (d, J=7.2 Hz, 3H).
    • Step 5: Preparation of (R)-N-methoxy-N-methyl-2-((S)-2-oxooxazolidin-4-yl)propanamide
  • Figure US20140275083A1-20140918-C00059
  • To a mixture of (R)-2-((S)-2-oxooxazolidin-4-yl)propanoic acid (1.1 g, 6.91 mmol) in DCM (20 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.385 g, 10.37 mmol) at 0° C. The ice bath was removed and the mixture was stirred for 30 min at ambient temperature. A mixture of N,O-dimethylhydroxylamine (1.011 g, 10.37 mmol) and pyridine (1.677 mL, 20.74 mmol) in DCM (20 mL) was added and stirring was continued for ˜1 hr. The mixture was diluted with water (˜2 mL) and saturated sodium bicarbonate solution (˜2 mL) and stirred for ˜15 min. The mixture was diluted with dichloromethane (˜30 mL). The separated aqueous layer was extracted with DCM (1×), the organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure providing crude (R)-N-methoxy-N-methyl-2-((S)-2-oxooxazolidin-4-yl)propanamide (2.73 g) as an orange oil which was directly used without further purification. MS m/z 203.1 (M+H)+; Rt-0.36 min.
    • Step 6: Preparation of (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)-N-methoxy-N-methylpropanamide
  • Figure US20140275083A1-20140918-C00060
  • To a mixture of crude (R)-N-methoxy-N-methyl-2-((S)-2-oxooxazolidin-4-yl)propanamide (1.3 g, 6.43 mmol) and (bromomethyl)benzene (1.30 mL, 11.4 mmol) in THF (25 mL) was added slowly sodium hydride (60% wt.; 0.643 g) at 0° C. [Caution: gas development!]. The ice bath was removed and the mixture was stirred for ˜2 hr. The mixture were diluted carefully with water and ethyl acetate. The reaction was repeated on the same scale and the mixtures were combined. The aqueous layer was separated and extracted with ethyl acetate (1×). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 80 g, EtOAc/heptane=5/95 to 75/25] to provide (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)-N-methoxy-N-methylpropanamide (1.83 g) as a slightly yellow oil, which contained also N-methoxy-N-methylisobutyramide. MS m/z 293.7 (M+H)+; Rt-0.64 min.
    • Step 7: Preparation of (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)propanal
  • Figure US20140275083A1-20140918-C00061
  • To a solution of (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)-N-methoxy-N-methylpropanamide from Step 6 (1.5 g, 5.13 mmol) in THF (30 mL) was added dropwise DIBAL-H (1M solution in hexane; 11.29 mL) at −78° C. The mixture was stirred for 90 min at −78° C., diluted slowly with Rochelle's salt solution (1 M solution in water; ˜20 mL) and stirred vigorously for ˜15 min. The aqueous layer was separated and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated sodium bicarbonate solution and brine, filtered through a mixture of celite/silica gel. The filtrate was concentrated under reduced pressure providing crude (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)propanal (1.26 g) as a colorless oil, which was directly used without further purification. MS m/z 234.2 (M+H)+; Rt-0.60 min.
    • Step 8: Preparation of (S)-3-benzyl-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00062
  • To a solution of (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)propanal (1.26 g, 5.40 mmol) in DCM (13 mL) was added slowly DAST (2.85 mL, 21.6 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was carefully diluted with ice-water. The separated aqueous layer was extracted with DCM (3×). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2; 80 g, ethylacetate/heptane] providing (S)-3-benzyl-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (627 mg) as a slightly yellowish oil. MS m/z 255.7/257.3 (M+H)+; Rt-0.80 min. 1H NMR (400 Mhz, CD3OD) δ ppm 7.31-7.43 (m, 5H), 5.86 (dt, J=1.0 Hz, 1H), 4.70 (d, J=15.3 Hz, 1H), 4.32 (d, J=7.4 Hz, 2H), 4.23 (d, J=15.7 Hz, 1H), 4.06 (td, J=7.4, 2.7 Hz, 1H), 2.40-2.59 (m, 1H), 0.98 (d, J=7.0 Hz, 3H).
    • Step 9: Preparation of (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00063
  • To liquid ammonia at −50° C. under argon was slowly added a solution of (S)-3-benzyl-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (627 mg) (200 mg, 0.784 mmol) in diethylether (10 mL). Lithium (pellets; 54.4 mg, 7.84 mmol) were added in three portions. The reaction mixture became green then dark greenish blue over ˜10 min. The mixture was stirred for additional 15 min and then quenched slowly by the addition of saturated aqueous ammonium chloride solution (3 mL). The mixture was allowed to warm slowly to room temperature. The residue was diluted with diethylether (20 mL) and water (10 mL). The separated aqueous layer was extract with ether (2×25 mL) and DCM (3×20 mL). The DCM and ether layers were separately concentrated under reduced pressure. The residues were dissolved in DCM and combined. The organic layer was dried over magnesium sulfate, filtered off and concentrated under reduced pressure providing crude (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (114 mg) as a colorless solid, which was directly used without further purification. MS m/z 166.1 (M+H)+; Rt-0.37 min.
    • Intermediate 36: (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00064
  • To a solution of (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (223 mg, 1.35 mmol) and 2,4-difluoropyrimidine (157 mg, 1.35 mmol) in DMF (4.09 mL) was added sodium hydride (60% wt.; 70.2 mg) in three portions at <0° C. (sodium chloride/ice). After the first portion of sodium hydride the mixture was stirred for ˜5 min. The remaining two portions of sodium hydride were added over ˜5 min and stirring was continued for 30 min. The mixture was diluted with ethylacetate (10 mL), stirred for 5 min and further slowly diluted with brine/water (1/1; 10 mL). The mixture was allowed to warm to 5° C. and poured into a mixture of brine/water (1/1; 20 mL) and ethylacetate (20 mL). The aqueous layer was separated and extracted with ethylacetate (25 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane] to provide (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (207 mg) as a white solid.
  • MS m/z 262.1 (M+H)+; Rt-0.72 min. 1H NMR (400 Mhz, CD3OD) δ ppm 8.55 (dd, J=2.3, 5.8 Hz, 1H), 8.17 (dd, J=3.8, 5.8 Hz, 1H), 6.02 (q, J=1.0 Hz, 1H), 5.17 (td, J=3.1, 8.3 Hz, 1H), 4.62-4.52 (m, 2H), 3.11-2.88 (m, 1H), 1.05 (dd, J=0.7, 7.2 Hz, 3H).
    • Intermediate 37: (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00065
  • To a solution of (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (114 mg, 069 mmol) and 2,4-dichloro-5-fluoropyrimidine (115 mg, 0.690 mmol) in DMF (2.26 mL) was added sodium hydride (60% wt.; 35.9 mg) in three portions at <0° C. (sodium chloride/ice). After the first portion of sodium hydride the mixture was stirred for ˜5 min. The remaining two portions of sodium hydride were added over ˜5 min and stirring was continued for 30 min. The mixture was diluted with ethylacetate (10 mL), stirred for 5 min and further slowly diluted with brine/water (1/1; 10 mL). The mixture was allowed to warm to 5° C. and poured into a mixture of brine/water (1/1; 10 mL) and ethylacetate (10 mL). The aqueous layer was separated and extracted with ethylacetate (25 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane] to provide (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (134 mg) as a white solid. MS m/z 296.1 (M+H)+; Rt-0.75 min. 1H NMR (400 Mhz, CD3OD) δ ppm 8.69 (d, J=2.6 Hz, 1H), 5.99 (q, J=1.0 Hz, 1H), 5.17 (ddd, J=3.5, 7.4, 8.6 Hz, 1H), 4.69-4.50 (m, 2H), 2.88-2.70 (m, 1H), 1.04 (d, J=7.1 Hz, 3H).
    • Intermediate 38: 2-(1-azidoethyl)-5-(4-chlorophenyl)-4-methyloxazole
  • Figure US20140275083A1-20140918-C00066
  • Sodium azide (635 mg, 9.760 mmol) and a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctadecane was added to a solution of 2-(1-chloroethyl)-5-(4-chlorophenyl)-4-methyloxazole (250 mg, 0.976 mmol) in acetonitrile (10 ml) and refluxed at 80° C. for 3 hours. The reaction was concentrated in vacuo. Flash column chromatography (silica, 40 g) eluting with 0-5% EtOAc/DCM provided the title compound (254 mg, clear oil). HRMS (C) tR=1.52 min; MS m/z 262.0621
    • Intermediate 39: 1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethanamine
  • Figure US20140275083A1-20140918-C00067
  • SiliaBond®Diphenylphosphine (1500 mg, 1.19 mmol/g) was added to a solution of 2-(1-azidoethyl)-5-(4-chlorophenyl)-4-methyloxazole (366 mg, 1.393 mmol) in anhydrous methanol (15 ml) and shaken for 3 hours. The reaction was filtered and concentrated in vacuo. Flash column chromatography (silica, 40 g) eluting with 2-10% MeOH/DCM afforded 160 mg (white solid). HRMS (B) tR=1.73 min; MS m/z 236.0716
    • Intermediate 40: (2S)-N-(2-(4-chlorophenyl)-2-hydroxyethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide
  • Figure US20140275083A1-20140918-C00068
  • A solution of 2-amino-1-(4-chlorophenyl)ethanol (1000 mg, 5.83 mmol) and (S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (1280 mg, 5.83 mmol) in THF (20 ml) was added N,N′-methanediylidenedicyclohexanamine (1.1 eq, 1322 mg, 6.41 mmol) and allowed to stir at ambient temperature for 12 hours. Concentrate in vacuo, dilute w/EtOAc, filter washing w/EtOAc, wash w/water, brine, concentrate in vacuo. Used crude directly in the next step. 2 g of white solid. HRMS (B) tR=1.04 min; MS m/z 373.1
    • Intermediate 41: (S)-N-(2-(4-chlorophenyl)-2-oxoethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide
  • Figure US20140275083A1-20140918-C00069
  • 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (3.091 g, 7.29 mmol) was added to a solution of (2S)-N-(2-(4-chlorophenyl)-2-hydroxyethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide (2.173 g, 5.83 mmol) in dichloromethane (20 ml) and allowed to stir for 2 hours. Dilute w/dichloromethane (50 ml), wash w/a sol'n of sat. sodium bicarbonate and 10% Na2S2O3 solution, dry, concentrate in vacuo. 2.162 g (Used directly in the next step without further purification. HRMS (B) tR=1.24 min; MS m/z 371.2
    • Intermediate 42: (S)-2-(1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)isoindoline-1,3-dione
  • Figure US20140275083A1-20140918-C00070
  • Phosphoryl trichloride (1.m7 ml, 10.8 mmol) was added to a solution of (S)-N-(2-(4-chlorophenyl)-2-oxoethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide (2.162 g, 5.83 mmol) in toluene and heated at 110° C. for 15 hours. Dilute with dichloromethane (50 ml), wash with saturated sodium bicarbonate solution, water, brine, dried and concentrated in vacuo. Flash column chromatography (silica, 80 g) eluting with 0-50% EtOAc/DCM afforded the pure product 430 mg (yellow foam). HRMS (B) tR=1.42 min; MS m/z 353.1
    • Intermediate 43: (S)-2-(1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)isoindoline-1,3-dione
  • Figure US20140275083A1-20140918-C00071
  • To a stirred solution of (Z)-3-chloro-N′-hydroxybenzimidamide (500 mg, 2.93 mmol) and (S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (642 mg, 2.93 mmol) was added N,N′-methanediylidenedicyclohexanamine (1.1 eq, 665 mg, 3.22 mmol) and allowed to reflux at 100° C. for 12 hours. Concentrate in vacuo, dilute w/EtOAc, filter washing w/EtOAc, wash w/water, brine, concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-10% EtOAc/DCM afforded 300 mg. HRMS m/z 353.0567
    • Intermediate 44: (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine
  • Figure US20140275083A1-20140918-C00072
  • Hydrazine (0.55 ml, 6.09 mmol) was added to a solution of (S)-2-(1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)isoindoline-1,3-dione (430 mg, 1.219 mmol) in ethanol (15 ml) and heated at 80° C. for 13 hours. The reaction was concentrated in vacuo. Flash column chromatography (silica, 40 g) eluting with 2-10% MeOH/DCM afforded the desired product (200 mg, yellow oil). 1H NMR (400 MHz, CDCl3) δ 7.67-7.51 (m, 9H), 7.47-7.35 (m, 8H), 7.31-7.21 (m, 1H), 4.25 (q, J=6.8 Hz, 4H), 1.97-1.66 (m, 15H), 1.63-1.48 (m, 2H). HRMS (B) tR=1.49 min; MS m/z 222.0560
    • Intermediate 45: (Z)-3-chloro-N′-hydroxy-4-(trifluoromethoxy)benzimidamide
  • Figure US20140275083A1-20140918-C00073
  • To a solution of 3-chloror-4-(trifluoromethoxy)benzonitrile (1.0 g, 4.51 mmol) and hydroxylamine hydrochloride (1.5 eq, 0.47 g, 6.77 mmol) in ethanol (10 ml) was added N-ethyl-N-isopropylpropan-2-amine (1.6 eq, 1.26 ml, 7.22 mmol) and refluxed at 80° C. for 12 hours under N2. Allow to cool to rt. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), dry, concentrate in vacuo afforded (Z)-3-chloro-N′-hydroxy-4-(trifluoromethoxy)benzimidamide (0.71 g, 62.1%, white solid). Used crude in the next step. HRMS (B) m/z 254.0070
  • The intermediates in Table 2a were prepared using a method similar to that described for the preparation of Intermediate 45
  • TABLE 2a
    Figure US20140275083A1-20140918-C00074
         		Intermediate 46
    Figure US20140275083A1-20140918-C00075
         		Intermediate 47
    Figure US20140275083A1-20140918-C00076
         		Intermediate 48
    Figure US20140275083A1-20140918-C00077
         		Intermediate 49
    Figure US20140275083A1-20140918-C00078
         		Intermediate 50
    Figure US20140275083A1-20140918-C00079
         		Intermediate 51
    Figure US20140275083A1-20140918-C00080
         		Intermediate 52
    Figure US20140275083A1-20140918-C00081
         		Intermediate 53
    Figure US20140275083A1-20140918-C00082
         		Intermediate 54
    Figure US20140275083A1-20140918-C00083
         		Intermediate 55
    Figure US20140275083A1-20140918-C00084
         		Intermediate 56
    Figure US20140275083A1-20140918-C00085
         		Intermediate 57
    Figure US20140275083A1-20140918-C00086
         		Intermediate 58
    Figure US20140275083A1-20140918-C00087
         		Intermediate 59
    Figure US20140275083A1-20140918-C00088
         		Intermediate 60
    Figure US20140275083A1-20140918-C00089
         		Intermediate 61
    Figure US20140275083A1-20140918-C00090
         		Intermediate 62
    Figure US20140275083A1-20140918-C00091
         		Intermediate 63
    Figure US20140275083A1-20140918-C00092
         		Intermediate 64
  • TABLE 2b
    Chemical name and analytical data for each intermediate listed in Table 2a.
    Intermediate: Name Analytical data
    46: (Z)-4-bromo-N′-hydroxy-3- HRMS (B) tR = 1.24 min; MS m/z
    methoxybenzimidamide 243.9847.
    47: (Z)-4-chloro-N′-hydroxy-3- HRMS (B) tR = 1.35 min; MS m/z
    methylbenzimidamide 184.0403
    48: (Z)-N′-hydroxy-1,2-dimethyl-1H-indole-4- HRMS (B) tR = 1.13 min; MS m/z
    carboximidamide 203.1059
    49: (Z)-N′-hydroxy-2- HRMS (B) tR = 1.20 min; MS m/z
    (trifluoromethoxy)benzimidamide 220.0460
    50: (Z)-2,2-difluoro-N′-hydroxybenzo[d][1,3]dioxole- HRMS (B) tR = 1.33 min; MS m/z
    5-carboximidamide 216.0347
    51: (Z)-N′-hydroxy-3-(2,2,2- HRMS (B) tR = 1.46 min; MS m/z
    trifluoroethoxy)benzimidamide 234.061
    52: (Z)-4-chloro-N′-hydroxy-3-(trifluoromethoxy) HRMS (B) tR = 1.44 min; MS m/z
    benzimidamide 254.0070
    53: (Z)-N′-hydroxyisoquinoline-8-carboximidamide Anal. RP-HPLC tR = 0.93 min (Gradient:
    1 to 30% B in 3.2 min to 98% in 1.95 min.-
    flow 1 mL/min. Eluent A: Water + 3.75 mM
    H4Ac + 0.001% formic acid.
    Eluent B: ACN. Column: Acquity CSH
    1.7 μm 2.1 × 50 mm-50° C.) MS m/z
    187.0746
    54: (Z)-4-chloro-N′-hydroxy-2-(trifluoromethyl) HRMS (B) tR = 1.35 min; MS m/z
    benzimidamide 238.0121
    55: (Z)-N′-hydroxy-3- HRMS (B) tR = 1.36 min; MS m/z
    (trifluoromethyl)benzimidamide 204.0510
    56: (Z)-N′-hydroxy-4- HRMS (B) tR = 1.69 min; MS m/z
    (trifluoromethoxy)benzimidamide 220.0460
    57: (Z)-4-fluoro-N′-hydroxy-3-(trifluoromethoxy) HRMS (B) tR = 1.55 min; MS m/z
    benzimidamide 238.0365
    58: (Z)-3-(difluoromethoxy)-N′- HRMS (B) tR = 1.05 min; MS m/z
    hydroxybenzimidamide 202.0554
    59: (Z)-4-chloro-N′-hydroxy-3- HRMS (B) tR = 1.14 min; MS m/z
    methoxybenzimidamide 200.0352
    60: (Z)-4-chloro-N′-hydroxy-3-(trifluoromethyl) HRMS (B) tR = 1.19 min; MS m/z
    benzimidamide 239.3000 (M + H)
    61: (Z)-3-(tert-butyl)-N′-hydroxybenzimidamide HRMS (B) tR = 1.51 min; MS m/z
    193.1342 (M + H)
    62: (Z)-N′-hydroxy-1-methyl-1H-indole-6- HRMS (B) tR = 1.03 min; MS m/z
    carboximidamide 190.0883 (M + H)
    63: (Z)-N′-hydroxy-2,3-dihydro-1H-indene-5- HRMS (B) tR = 1.30 min; MS m/z
    carboximidamide 176.0950
    64: 4-chloro-N′-hydroxybenzimidamide MS m/z 171.0 (M + H)+; Rt-0.35 min.
    • Intermediate 65: (S)-tert-butyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate
  • Figure US20140275083A1-20140918-C00093
  • A solution of 4-chloro-N′-hydroxybenzimidamide (1.24 g, 7.27 mmol), (S)-2-(tert-butoxycarbonylamino)propanoic acid (1.38 g, 7.27 mmol, 1.0 equiv), and DCC (1.65 g, 8.00 mmol, 1.1 equiv) in 1,4-dioxane (73 mL) was heated at 100° C. for 18 hours. The reaction was then cooled to room temperature and concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane, 0 to 35%) provided (S)-tert-butyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate (1.13 g, white solid) in 48% yield. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 5.18 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.47 (s, 9H).
    • Intermediate 66: (S)-tert-butyl (1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate
  • Figure US20140275083A1-20140918-C00094
  • To a stirred solution of (Z)-3-chloro-N′-hydroxy-4-(trifluoromethoxy)benzimidamide (500 mg, 1.964 mmol) and (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (372 mg, 1.964 mmol) was added N,N′-methanediylidenedicyclohexanamine (1.1 eq, 446 mg, 2.160 mmol) and allowed to reflux at 100° C. for 12 hours. Concentrate in vacuo, dilute w/EtOAc, filter washing w/EtOAc, wash w/water, brine, concentrate in vacuo. Flash column chromatography (silica, 80 g) eluting w/0-5% EtOAc/DCM afforded 230 mg. HRMS m/z 407.0860
  • The intermediates in Table 3a were prepared using a method similar to that described for the preparation of Intermediate 66
  • TABLE 3a
    Figure US20140275083A1-20140918-C00095
         		Inter- me- diate 67
    Figure US20140275083A1-20140918-C00096
         		Inter- me- diate 68
    Figure US20140275083A1-20140918-C00097
         		Inter- me- diate 69
    Figure US20140275083A1-20140918-C00098
         		Inter- me- diate 70
    Figure US20140275083A1-20140918-C00099
         		Inter- me- diate 71
    Figure US20140275083A1-20140918-C00100
         		Inter- me- diate 72
    Figure US20140275083A1-20140918-C00101
         		Inter- me- diate 73
    Figure US20140275083A1-20140918-C00102
         		Inter- me- diate 74
    Figure US20140275083A1-20140918-C00103
         		Inter- me- diate 75
    Figure US20140275083A1-20140918-C00104
         		Inter- me- diate 76
    Figure US20140275083A1-20140918-C00105
         		Inter- me- diate 77
    Figure US20140275083A1-20140918-C00106
         		Inter- me- diate 78
    Figure US20140275083A1-20140918-C00107
         		Inter- me- diate 79
    Figure US20140275083A1-20140918-C00108
         		Inter- me- diate 80
    Figure US20140275083A1-20140918-C00109
         		Inter- me- diate 81
    Figure US20140275083A1-20140918-C00110
         		Inter- me- diate 82
    Figure US20140275083A1-20140918-C00111
         		Inter- me- diate 83
    Figure US20140275083A1-20140918-C00112
         		Inter- me- diate 84
    Figure US20140275083A1-20140918-C00113
         		Inter- me- diate 85
  • TABLE 3b
    Chemical name and analytical data for each intermediate listed in Table 3a.
    Intermediate: Name Analytical data
    67: (S)-tert-butyl (1-(3-(4-bromo-3-methoxyphenyl)-1,2,4- HRMS (C) tR = 1.20 min;
    oxadiazol-5-yl)ethyl)carbamate MS m/z 397.0637
    68: (S)-tert-butyl (1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5- HRMS (C) tR = 1.42 min;
    yl)ethyl)carbamate MS m/z 337.1193
    69: (S)-tert-butyl (1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol- HRMS (C) tR = 1.12 min;
    5-yl)ethyl)carbamate MS m/z 356.1848
    70: (S)-tert-butyl (1-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.12 min;
    5-yl)ethyl)carbamate MS m/z 373.1249
    71: (S)-tert-butyl(1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4- HRMS (C) tR = 1.41 min;
    oxadiazol-5-yl)ethyl)carbamate MS m/z 369.1136
    72: (S)-tert-butyl(1-(3-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4- HRMS (C) tR = 1.33 min;
    oxadiazol-5-yl)ethyl)carbamate MS m/z 387.1406
    73: (S)-tert-butyl (1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5- HRMS (C) tR = 0.71 min;
    yl)ethyl)carbamate MS m/z 340.1535
    74: (S)-tert-butyl(1-(3-(4-chloro-2-(trifluoromethyl)phenyl)-1,2,4- HRMS (C) tR = 1.35 min;
    oxadiazol-5-yl)ethyl)carbamate MS m/z 392.1055
    75: (S)-tert-butyl (1-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.41 min;
    5-yl)ethyl)carbamate MS m/z 357.1300
    76: (S)-tert-butyl(1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4- HRMS (C) tR = 1.42 min;
    oxadiazol-5-yl)ethyl)carbamate MS m/z 392.1302
    77: (S)-tert-butyl (1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.59 min;
    5-yl)ethyl)carbamate MS m/z 357.1300
    78: (S)-tert-butyl (1-(3-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.38 min;
    5-yl)ethyl)carbamate MS m/z 374.1378 (M + H)
    79: (S)-tert-butyl (1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.69 min;
    5-yl)ethyl)carbamate MS m/z 373.1249
    80: (S)-tert-butyl (1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.12 min;
    5-yl)ethyl)carbamate MS m/z 355.1344
    81: (S)-tert-butyl (1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol- HRMS (C) tR = 1.14 min;
    5-yl)ethyl)carbamate MS m/z 353.1142
    82: (S)-tert-butyl(1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4- HRMS (C) tR = 1.52 min;
    oxadiazol-5-yl)ethyl)carbamate MS m/z 391.0911
    83: (S)-tert-butyl (1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5- HRMS (C) tR = 1.03 min;
    yl)ethyl)carbamate MS m/z 342.1692
    84: (S)-tert-butyl (1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5- HRMS (C) tR = 1.62 min;
    yl)ethyl)carbamate MS m/z 345.2052
    85: (S)-tert-butyl (1-(3-(2,3-dihydro-1H-inden-5-yl)-1,2,4-oxadiazol- HRMS (C) tR = 1.50 min;
    5-yl)ethyl)carbamate MS m/z 329.1740
    • Intermediate 86: (S)-tert-butyl (1-(5-bromopyridin-2-yl)ethyl)carbamate
  • Figure US20140275083A1-20140918-C00114
  • To a solution of (S)-1-(5-bromopyridin-2-yl)ethanamine (300 mg, 1.49 mmol) in DCM (7.5 mL) was added di-tert-butyl dicarbonate (358 mg, 1.64 mmol) and triethylamine (0.31 mL, 2.24 mmol). The solution was stirred for 16 h at room temperature then washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 0 to 80%) provided a white solid (308 mg, 68.5% yield).
  • 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=2.2 Hz, 1H), 7.76 (dd, J=8.3, 2.4 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 5.57-5.42 (m, 1H), 4.86-4.73 (m, 1H), 1.43 (t, J=3.4 Hz, 12H); MS m/z 303.4 (M+H).
  • The intermediates in Table 4a were prepared using a method similar to that described for the preparation of Intermediate 86
  • TABLE 4a
    Figure US20140275083A1-20140918-C00115
         		Intermediate 87
    Figure US20140275083A1-20140918-C00116
         		Intermediate 88
    Figure US20140275083A1-20140918-C00117
         		Intermediate 89
    Figure US20140275083A1-20140918-C00118
         		Intermediate 90
    Figure US20140275083A1-20140918-C00119
         		Intermediate 91
  • TABLE 4b
    Chemical name and analytical data for each intermediate listed in Table 4a.
    Intermediate: Name Analytical data
    87: (S)-tert-butyl (1-(6-bromopyridin-3- 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 2.6 Hz,
    yl)ethyl)carbamate 1H), 7.49 (dd, J = 8.2, 2.5 Hz,
    1H), 7.44 (d, J = 8.3 Hz, 1H),
    4.88-4.69 (m, 2H), 1.45 (d, J = 7.1 Hz, 3H), 1.41 (s,
    9H); MS m/z 303.4 (M + H).
    88: (S)-tert-butyl (1-(5-bromo-4-methylpyridin-2- LCMS tR = 1.31 min; MS m/z 317.0
    yl)ethyl)carbamate (M + H)
    89: (S)-tert-butyl (1-(5-bromo-6-methylpyridin-2- LCMS tR = 1.35 min; MS m/z 317.1
    yl)ethyl)carbamate (M + H)
    90: (S)-tert-butyl (1-(5-bromo-3-fluoropyridin-2- LCMS tR = 1.31 min; MS m/z 319.0
    yl)ethyl)carbamate (M + H)
    91: (S)-tert-butyl (1-(5-bromo-3-methylpyridin-2- LCMS tR = 1.37 min; MS m/z 317.0
    yl)ethyl)carbamate (M + H)
    • Intermediate 92: (S)-tert-butyl (1-(5-(4-fluoro-3-methyl phenyl)pyridin-2-yl)ethyl)carbamate
  • Figure US20140275083A1-20140918-C00120
  • In a 5 mL microwave vial a solution of (S)-tert-butyl (1-(5-bromopyridin-2-yl)ethyl)carbamate (60 mg, 0.2 mmol), (4-fluoro-3-methylphenyl)boronic acid (37 mg, 0.24 mmol), Sodium bicarbonate (0.2 mL, 0.4 mmol, 2 M aqueous solution) in Dioxane (2 mL) was bubbled N2 for 3 min then Cl2Pd(dppf)CH2Cl2 (16 mg, 0.02 mmol) was added. The capped tube was heated to 100° C. for 16 h. After cooling the reaction mixture was diluted with EtOAc (10 mL) and washed with water (10 mL). After separation, the aqueous phase was extracted with EtOAc (3×10 mL). Combined organics were dried over Na2SO4, filtered and concentrated. The crude material was purified through silica gel column chromatography (EtOAc in Heptane 12 to 100%) to give a white solid (66 mg, 80% yield). LCMS tR=1.43 min; MS m/z 331.1 (M+H).
  • The intermediates in Table 5a were prepared using a method similar to that described for the preparation of Intermediate 92
  • TABLE 5a
    Figure US20140275083A1-20140918-C00121
         		Intermediate 93
    Figure US20140275083A1-20140918-C00122
         		Intermediate 94
    Figure US20140275083A1-20140918-C00123
         		Intermediate 95
    Figure US20140275083A1-20140918-C00124
         		Intermediate 96
    Figure US20140275083A1-20140918-C00125
         		Intermediate 97
    Figure US20140275083A1-20140918-C00126
         		Intermediate 98
    Figure US20140275083A1-20140918-C00127
         		Intermediate 99
    Figure US20140275083A1-20140918-C00128
         		Intermediate 100
    Figure US20140275083A1-20140918-C00129
         		Intermediate 101
    Figure US20140275083A1-20140918-C00130
         		Intermediate 102
    Figure US20140275083A1-20140918-C00131
         		Intermediate 103
    Figure US20140275083A1-20140918-C00132
         		Intermediate 104
    Figure US20140275083A1-20140918-C00133
         		Intermediate 105
  • TABLE 5b
    Chemical name and analytical data for each intermediate listed in Table 5a.
    Intermediate: Name Analytical data
    93: (S)-tert-butyl (1-(5-(3- LCMS tR = 1.69 min; MS m/z 365.5 (M − H).
    (trifluoromethyl)phenyl)pyridin-2-yl)ethyl)carbamate
    94: (S)-tert-butyl (1-(6-(4-fluoro-3- LCMS tR = 1.62 min; MS m/z 329.5 (M − H).
    methylphenyl)pyridin-3-yl)ethyl)carbamate
    95: (S)-tert-butyl (1-(6-(3- LCMS tR = 1.68 min; MS m/z 365.4 (M − H).
    (trifluoromethyl)phenyl)pyridin-3-yl)ethyl)carbamate
    96: (S)-tert-butyl (1-(2′-(trifluoromethyl)-[3,4′- 1H NMR (400 MHz, CDCl3) δ 8.83 (t, J = 3.9 Hz,
    bipyridin]-6-yl)ethyl)carbamate 2H), 7.92 (dd, J = 8.3, 2.5 Hz,
    1H), 7.87 (d, J = 1.7 Hz, 1H),
    7.73-7.66 (m, 1H), 7.42 (d, J = 8.1 Hz, 1H), 5.59 (d,
    J = 7.6 Hz, 1H), 4.93 (p, J = 6.9 Hz, 1H),
    1.50 (d, J = 7.0 Hz, 3H), 1.45 (s, 9H); MS
    m/z 368.2 (M + H).
    97: (S)-tert-butyl (1-(6′-(trifluoromethyl)-[2,3′- 1H NMR (400 MHz, CDCl3) δ 9.27 (d, J = 2.1 Hz,
    bipyridin]-5-yl)ethyl)carbamate 1H), 8.71 (s, 1H), 8.49 (dd, J = 8.3,
    2.1 Hz, 1H), 7.80-7.75 (m, 3H),
    4.90 (br s, 1H), 1.52 (d, J = 6.3 Hz, 3H),
    1.43 (s, 9H); MS m/z 368.2 (M + H).
    98: (S)-tert-butyl (1-(6′-(trifluoromethyl)-[3,3′- 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 2.1 Hz,
    bipyridin]-6-yl)ethyl)carbamate 1H), 8.79 (d, J = 2.3 Hz, 1H),
    8.04 (dd, J = 8.2, 2.3 Hz, 1H), 7.88 (dd, J = 8.1,
    2.4 Hz, 1H), 7.80 (d, J = 8.2 Hz,
    1H), 7.42 (d, J = 8.1 Hz, 1H), 5.60 (d, J = 7.8 Hz,
    1H), 4.93 (p, J = 6.9 Hz, 1H),
    1.50 (d, J = 6.8 Hz, 3H), 1.44 (s, 9H); MS
    m/z 368.2 (M + H).
    99: (S)-tert-butyl (1-(6-(trifluoromethyl)-[2,3′- 1H NMR (400 MHz, CDCl3) δ 9.15 (d, J = 2.3 Hz,
    bipyridin]-6′-yl)ethyl)carbamate 1H), 8.36 (dd, J = 7.8, 2.4 Hz,
    1H), 8.01-7.89 (m, 2H), 7.66 (dd, J = 7.5,
    1.1 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H),
    5.69 (d, J = 7.9 Hz, 1H), 4.92 (p, J = 6.9 Hz,
    1H), 1.49 (d, J = 6.8 Hz, 3H), 1.45 (s,
    9H); MS m/z 368.2 (M + H).
    100: (S)-tert-butyl (1-(4-methyl-2′-(trifluoromethyl)- 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 4.9 Hz,
    [3,4′-bipyridin]-6-yl)ethyl)carbamate 1H), 8.36 (s, 1H), 7.66 (s, 1H),
    7.51-7.42 (m, 1H), 7.21 (s, 1H), 5.60 (d,
    J = 7.7 Hz, 1H), 4.87 (p, J = 6.9 Hz, 1H),
    2.30 (s, 3H), 1.48 (d, J = 6.9 Hz, 3H),
    1.45 (s, 9H); MS m/z 326.4 (M + H − 56).
    101: (S)-tert-butyl (1-(2-methyl-2′-(trifluoromethyl)- 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 5.0 Hz,
    [3,4′-bipyridin]-6-yl)ethyl)carbamate 1H), 7.66 (s, 1H), 7.50 (d, J = 7.9 Hz,
    1H), 7.47 (dd, J = 4.9, 1.6 Hz, 1H),
    7.20 (d, J = 7.8 Hz, 1H), 5.75 (d, J = 7.5 Hz,
    1H), 4.86 (p, J = 6.9 Hz, 1H), 2.51 (s,
    3H), 1.48 (d, J = 6.9 Hz, 3H), 1.46 (s,
    9H); MS m/z 326.4 (M + H − 56).
    102: (S)-tert-butyl (1-(5-fluoro-2′-(trifluoromethyl)- 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 5.1 Hz,
    [3,4′-bipyridin]-6-yl)ethyl)carbamate 1H), 8.66 (s, 1H), 7.87-7.84 (m,
    1H), 7.70-7.67 (m, 1H), 7.65 (dd, J = 9.8,
    1.9 Hz, 1H), 5.76 (d, J = 7.7 Hz, 1H),
    5.31-5.23 (m, 1H), 1.47 (d, J = 6.8 Hz,
    3H), 1.45 (s, 9H); MS m/z 386.1 (M + H).
    103: (S)-tert-butyl (1-(5-methyl-2′-(trifluoromethyl)- 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 5.1 Hz,
    [3,4′-bipyridin]-6-yl)ethyl)carbamate 1H), 8.68 (d, J = 2.2 Hz, 1H),
    7.88-7.85 (m, 1H), 7.71 (d, J = 1.7 Hz,
    1H), 7.68 (dd, J = 5.0, 1.7 Hz, 1H),
    5.99 (d, J = 8.2 Hz, 1H), 5.13 (p, J = 6.7 Hz,
    1H), 2.48 (s, 3H), 1.45 (s, 9H), 1.42 (d, J = 6.6 Hz,
    3H); MS m/z 382.2 (M + H).
    104: 1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2- 1H NMR (400 MHz, CDCl3) δ 9.30 (d, J = 1.5 Hz,
    yl)ethanone 1H), 9.11 (d, J = 1.5 Hz, 1H),
    8.39 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H),
    7.78 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H),
    2.76 (s, 3H).); MS m/z 266.9 (M + H).
    105: 1-(5-(4-fluoro-3-methylphenyl)pyrazin-2- 1H NMR (400 MHz, CDCl3) δ 9.24 (d, J = 1.5 Hz,
    yl)ethanone 1H), 9.01 (d, J = 1.5 Hz, 1H),
    7.97 (dd, J = 7.3, 1.9 Hz, 1H), 7.89 (ddd,
    J = 7.6, 4.8, 2.3 Hz, 1H), 7.17 (t, J = 8.9 Hz,
    1H), 2.74 (s, 3H), 2.39 (d, J = 2.0 Hz,
    3H); MS m/z 230.9 (M + H).
  • The following intermediates were prepared using a method similar to that described for the preparation of Intermediate 92
    • Intermediate 106: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-MS)-1-(2′-(tert-butyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00134
  • LCMS tR=1.67 min; MS m/z 519.3 (M+H).
    • Intermediate 107: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2′-(1,1,1-trifluoro-2-methylpropan-2-yl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00135
  • 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=2.2 Hz, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.23 (d, J=5.6 Hz, 1H), 7.90 (dd, J=8.1, 2.3 Hz, 1H), 7.68 (s, 1H), 7.50 (d, J=5.8 Hz, 1H), 7.47-7.41 (m, 2H), 5.34 (p, J=6.9 Hz, 1H), 4.81-4.72 (m, 1H), 4.64 (dd, J=9.3, 2.9 Hz, 1H), 4.45 (p, J=6.3 Hz, 1H), 4.36 (t, J=9.0 Hz, 1H), 1.69 (s, 6H), 1.63 (d, J=6.9 Hz, 3H), 1.26 (s, 9H), 1.04 (d, J=6.4 Hz, 3H); MS m/z 573.3 (M+H).
    • Intermediate 108: (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid
  • Figure US20140275083A1-20140918-C00136
  • To a solution of (S)-4-(1-aminoethyl)-2-fluorobenzoic acid (5 g, 22.76 mmol) in water (66 mL) and THF (66 mL) was added di-tert-butyl dicarbonate (6.95 g, 31.9 mmol) and sodium carbonate (5.74 g, 68.3 mmol). The solution was stirred for 16 h at room temperature then THF was removed under reduced pressure. The aqueous solution was acidified with 1N HCl to pH 3-4 and extracted with EtOAc (3×60 mL). Combined organics were dried over Na2SO4, filtered and concentrated to give a white solid (1.94 g, 30.1% yield). The crude product was used to next step without further purification.
  • 1H NMR (400 MHz, MeOD) δ 7.89 (t, J=7.8 Hz, 1H), 7.20 (dd, J=8.2, 1.7 Hz, 1H), 7.13 (dd, J=12.0, 1.6 Hz, 1H), 4.70 (d, J=7.1 Hz, 1H), 1.47-1.35 (m, 12H); MS m/z 282.0 (M−H).
    • Intermediate 109: (S)-tert-butyl 1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate
  • Figure US20140275083A1-20140918-C00137
  • A solution of (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid (1.416 g, 5 mmol), N,O-dimethylhydroxylamine hydrochloride (732 mg, 7.5 mmol), HATU (2.85 g, 7.5 mmol) and DIPEA (3.49 mL, 20 mmol) in DMF (25 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with water. After separation, the aqueous phase was washed with EtOAc (2×75 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 12 to 100%) provided (S)-tert-butyl 1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate as a white solid (1.5 g, 92% yield).
  • 1H NMR (400 MHz, CDCl3) δ 7.40 (t, J=7.4 Hz, 1H), 7.13 (dd, J=7.8, 1.6 Hz, 1H), 7.04 (dd, J=10.7, 1.6 Hz, 1H), 4.80 (br s, 1H), 3.56 (s, 3H), 3.34 (s, 3H), 1.50-1.29 (m, 12H); MS m/z 327.1 (M+H).
    • Intermediate 110: (S)-tert-butyl 1-(3-fluoro-4-formyl phenyl)ethylcarbamate
  • Figure US20140275083A1-20140918-C00138
  • To a cooled (0° C.) Solution of (S)-tert-butyl 1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate (1.175 g, 3.6 mmol) in THF (36 mL) was added a solution of LAH in THF (1.0 M, 18 mL, 18 mmol) and the resulting mixture was stirred at 0° C. for 20 min. The reaction mixture was quenched by addition of a saturated Na2SO4 solution until gas evolution ceased. The reaction mixture was extracted with EtOAc (2×100 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 12 to 100%) provided (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate as a white solid (760 mg, 79% yield).
  • 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.87-7.80 (m, 1H), 7.20 (dd, J=8.2, 1.3 Hz, 1H), 7.11 (dd, J=11.5, 1.4 Hz, 1H), 4.80 (br s, 1H), 1.45 (br s, 12H); MS m/z 212.1 (M-56+H).
    • Intermediate 111: (S)-tert-butyl 1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylcarbamate
  • Figure US20140275083A1-20140918-C00139
  • A solution of (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate (267 mg, 1 mmol) and 1,2,2-trimethylpiperazine dihydrochloride (402 mg, 2 mmol) in THF (5 mL) was stirred at room temperature for 1 h and treated with sodium triacetoxyborohydride (848 mg, 4 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous solution of NaHCO3 (15 mL) and extracted with EtOAc (3×25 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (MeOH/CH2Cl2 0 to 10%) provided (S)-tert-butyl 1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylcarbamate as a white solid (186 mg, 49% yield).
  • 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J=7.7 Hz, 1H), 7.03 (dd, J=7.9, 1.9 Hz, 1H), 6.95 (dd, J=11.1, 1.8 Hz, 1H), 4.77 (s, 1H), 3.49 (s, 2H), 2.56 (br s, 4H), 2.24 (br s, 5H), 1.42 (br s, 12H), 1.04 (s, 6H); MS m/z 380.4 (M+H).
    • Intermediate 112: (S)-tert-butyl 1-(4-((4,4-difluoropiperidin-1-yl)methyl)-3-fluorophenyl)ethylcarbamate
  • Figure US20140275083A1-20140918-C00140
  • Following the procedure for intermediate 111: Title compound was prepared from (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate and 4,4-difluoropiperidine hydrochloride as a white solid. LCMS tR=1.63 min; MS m/z 371.5 (M−H).
    • Intermediate 113: 1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone
  • Figure US20140275083A1-20140918-C00141
  • A cloudy solution of 1-(5-bromopyrimidin-2-yl)ethanone (300 mg, 1.49 mmol), 3-(trifluoromethyl)phenylboronic acid (567 mg, 2.98 mmol), K3PO4 (950 mg, 4.48 mmol), DavePhos ligand [2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl] (59 mg, 0.15 mmol), and Pd(OAc)2 (17 mg, 0.075 mmol) in 6 mL toluene was heated at 100° C. for 1 h. The mixture was cooled to room temperature, and filtered through Celite. Filter cake was rinsed with 30 mL EtOAc. The filtrate was poured into 20 mL water. Layers were separated, and the aqueous was further extracted with EtOAc (20 mL). Combined organics were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated directly onto silica gel. Column chromatography (10-100% EtOAc/heptane) gave 0.26 g 1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone as tan solid. MS m/z 267.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 2H), 7.93-7.69 (m, 4H), 2.87 (s, 3H).
  • The intermediates in Table 6a were prepared using a method similar to that described for the preparation of Intermediate 113
  • TABLE 6a
    Figure US20140275083A1-20140918-C00142
         		Intermediate 114
    Figure US20140275083A1-20140918-C00143
         		Intermediate 115
    Figure US20140275083A1-20140918-C00144
         		Intermediate 116
    Figure US20140275083A1-20140918-C00145
         		Intermediate 117
    Figure US20140275083A1-20140918-C00146
         		Intermediate 118
    Figure US20140275083A1-20140918-C00147
         		Intermediate 119
    Figure US20140275083A1-20140918-C00148
         		Intermediate 120
    Figure US20140275083A1-20140918-C00149
         		Intermediate 121
    Figure US20140275083A1-20140918-C00150
         		Intermediate 122
    Figure US20140275083A1-20140918-C00151
         		Intermediate 123
    Figure US20140275083A1-20140918-C00152
         		Intermediate 124
  • TABLE 6b
    Chemical name and analytical data for each intermediate listed in Table 6a, using
    Anal. RP-HPLC Column = Inertsil C8 Column, 3.0 μm, 3.0 × 30 mm.
    Column Temperature = 50° C. Eluents = A: Water (5 mM Ammonium formate,
    2% ACN); B: ACN. Flow Rate = 2 mL/min. Gradient = 0 min 5% B; 5% to 95% B in
    1.70 min; 0.3 min 95% B; 2.1 min 1% B.)
    Intermediate: Name Analytical data
    114: 1-(5-(3,4-dichlorophenyl) pyrimidin-2- Anal. RP-HPLC tR = 1.17 min. MS m/z 266.9
    yl)ethanone. (M + H)+.
    115: 1-(5-(4-fluoro-3-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.26 min. MS m/z 285.2
    pyrimidin-2-yl)ethanone. (M + H)+.
    116: 1-(5-(4-chloro-3-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.33 min. MS m/z 301.3
    pyrimidin-2-yl)ethanone. (M + H)+.
    117:: 1-(5-(5-fluoro-2-methylphenyl) Anal. RP-HPLC tR = 1.16 min. MS m/z 231.2
    pyrimidin-2-yl)ethanone (M + H)+.
    118: 1-(5-(4-fluoro-3-methylphenyl) pyrimidin- 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 2H),
    2-yl)ethanone. 7.52-7.41 (m, 2H), 7.24-7.16 (m, 1H),
    2.85 (s, 3H), 2.41 (d, J = 2.0 Hz, 3H). Anal. RP-
    HPLC tR = 1.20 min. MS m/z 231.0 (M + H)+.
    119: 1-(5-(2,3-dichlorophenyl) pyrimidin-2- Anal. RP-HPLC tR = 1.15 min. MS m/z 267.9
    yl)ethanone (M + H)+.
    120: 1-(5-(4-fluoro-3-methylphenyl) pyridin-2- 1H NMR (400 MHz, CDCl3) δ 8.88 (dd, J = 2.3,
    yl)ethanone. 0.8 Hz, 1H), 8.13 (dd, J = 8.1, 0.8 Hz, 1H),
    7.98 (dd, J = 8.1, 2.3 Hz, 1H), 7.50-7.39 (m,
    2H), 7.21-7.12 (m, 1H), 2.78 (s, 3H),
    2.42-2.36 (m, 3H). Anal. RP-HPLC tR = 1.40 min.
    MS m/z 230.8 (M + H)+.
    121: 1-(5-(2-fluoro-3-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.19 min. MS m/z 285.0
    pyrimidin-2-yl)ethanone. (M + H)+.
    122: 1-(5-(4-chloro-3-methylphenyl) Anal. RP-HPLC tR = 1.30 min. MS m/z 247.2
    pyrimidin-2-yl)ethanone. (M + H)+.
    123: 1-(5-(3-chloro-5-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.27 min. MS m/z 301.0
    pyrimidin-2-yl)ethanone. (M + H)+.
    124: 1-(5-(4-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.22 min. MS m/z 266.8
    pyrimidin-2-yl)ethanone. (M + H)+.
    • Intermediate 125: (S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine
  • Figure US20140275083A1-20140918-C00153
  • 2,2,2-Trifluoroacetic acid (4 mL, 52 mmol) was added to a solution of (S)-tert-butyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate (0.613 g, 1.89 mmol) in DCM (10 mL) at room temperature. The solution was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with chloroform (3×30 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (500 mg, yellow oil). The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 4.37 (q, J=6.9 Hz, 1H), 1.62 (d, J=6.9 Hz, 3H). MS m/z 224.0 (M+H)+; Rt-0.56 min.
    • Intermediate 126: (S)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethanamine
  • Figure US20140275083A1-20140918-C00154
  • (S)-tert-butyl (1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate (2.0 g, 4.90 mmol) was treated with 90% TFA/water for 2 hours. Concentrate in vacuo and neutralized by passing through a column of MP-carbonate resin (6.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded 1.4 g waxy off-white solid. HRMS m/z 307.0335
    • Intermediate 127: (S)-1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine
  • Figure US20140275083A1-20140918-C00155
  • To a stirred solution of (S)-2-(1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)isoindoline-1,3-dione (100 mg, 0.283 mmol) in ethanol (5 ml) was added methylhydrazine (16 μL, 0.311 mmol). Stir for 13 hours at 80° C. Concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting with dichloromethane afforded 50 mg of desired product. HRMS m/z 224.4 (M+H)
  • The intermediates in Table 7a were prepared using a method similar to that described for the preparation of Intermediate 126 or Intermediate 127
  • TABLE 7a
    Figure US20140275083A1-20140918-C00156
         		Intermediate 128
    Figure US20140275083A1-20140918-C00157
         		Intermediate 129
    Figure US20140275083A1-20140918-C00158
         		Intermediate 130
    Figure US20140275083A1-20140918-C00159
         		Intermediate 131
    Figure US20140275083A1-20140918-C00160
         		Intermediate 132
    Figure US20140275083A1-20140918-C00161
         		Intermediate 133
    Figure US20140275083A1-20140918-C00162
         		Intermediate 134
    Figure US20140275083A1-20140918-C00163
         		Intermediate 135
    Figure US20140275083A1-20140918-C00164
         		Intermediate 136
    Figure US20140275083A1-20140918-C00165
         		Intermediate 137
    Figure US20140275083A1-20140918-C00166
         		Intermediate 138
    Figure US20140275083A1-20140918-C00167
         		Intermediate 139
    Figure US20140275083A1-20140918-C00168
         		Intermediate 140
    Figure US20140275083A1-20140918-C00169
         		Intermediate 141
    Figure US20140275083A1-20140918-C00170
         		Intermediate 142
    Figure US20140275083A1-20140918-C00171
         		Intermediate 143
    Figure US20140275083A1-20140918-C00172
         		Intermediate 144
    Figure US20140275083A1-20140918-C00173
         		Intermediate 145
    Figure US20140275083A1-20140918-C00174
         		Intermediate 146
    Figure US20140275083A1-20140918-C00175
         		Intermediate 147
    Figure US20140275083A1-20140918-C00176
         		Intermediate 148
  • TABLE 7b
    Chemical name and analytical data for each intermediate listed in Table 7a.
    Intermediate: Name Analytical data
    128: (S)-1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.88 min;
    yl)ethanamine m/z 297.0113
    129: (S)-1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 2.05 min;
    yl)ethanamine m/z 237.0669
    130: (S)-1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.38 min;
    yl)ethanamine m/z 256.1324
    131: (S)-1-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.92 min;
    yl)ethanamine m/z 273.0725
    132: (S)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol- HRMS (B) tR = 2.04 min;
    5-yl)ethanamine m/z 269.0612
    133: (S)-1-(3-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 2.02 min;
    yl)ethanamine m/z 287.0882
    134: (S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethanamine HRMS (B) tR = 0.68 min;
    m/z 240.1011
    135: (S)-1-(3-(4-chloro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol- HRMS (B) tR = 2.08 min;
    5-yl)ethanamine m/z 291.0386
    136: (S)-1-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 2.02 min;
    yl)ethanamine m/z 257.0776
    137: (S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 2.01 min;
    yl)ethanamine m/z 257.0776
    138: (S)-1-(3-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.20 min;
    yl)ethanamine m/z 274.0 (M + H)
    139: (S)-1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 2.09 min;
    yl)ethanamine m/z 273.0725
    140: (S)-1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol- HRMS (B) tR = 2.16 min;
    5-yl)ethanamine m/z 291.0631
    141: (S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethanamine HRMS (B) tR = 0.71 min;
    m/z 240.1011
    142: (S)-1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.67 min;
    yl)ethanamine m/z 242.1168
    143: (S)-1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.74 min;
    yl)ethanamine m/z 255.0819
    144: (S)-1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.82 min;
    yl)ethanamine m/z 253.0618
    145: (S)-1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol- HRMS (B) tR = 2.26 min;
    5-yl)ethanamine m/z 291.0386
    146: (S)-1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5- HRMS (B) tR = 1.67 min;
    yl)ethanamine m/z 242.1168
    147: (S)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethanamine HRMS (B) tR = 2.33 min;
    m/z 246.1552
    148: (S)-1-(3-(2,3-dihydro-1H-inden-5-yl)-1,2,4-oxadiazol-5- HRMS (B) tR = 2.02 min;
    yl)ethanamine m/z 229.1215
    • Intermediate 149: 1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanamine
  • Figure US20140275083A1-20140918-C00177
  • 1-(5-(3-(Trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone (260 mg, 0.977 mmol), NH4OAc (1.13 g, 14.6 mmol), and NaBH3CN (245 mg, 3.91 mmol) were taken up in 8 mL 200 proof EtOH, and heated at 120° C. for 5 minutes in a microwave apparatus. The mixture was concentrated to remove the EtOH. Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added until aqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc (25 ml). The combined organic layer was washed with 25 mL brine and dried with Na2SO4. Filtered and concentrated with reduced pressure to give 262 mg crude yellow oil, which was carried forward without further purification. Anal. RP-HPLC tR=0.90 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient ═O min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 268.1 (M+H)+.
  • The intermediates in Table 8a were prepared using a method similar to that described for the preparation of Intermediate 149
  • TABLE 8a
    Figure US20140275083A1-20140918-C00178
         		Intermediate 150
    Figure US20140275083A1-20140918-C00179
         		Intermediate 151
    Figure US20140275083A1-20140918-C00180
         		Intermediate 152
    Figure US20140275083A1-20140918-C00181
         		Intermediate 153
    Figure US20140275083A1-20140918-C00182
         		Intermediate 154
    Figure US20140275083A1-20140918-C00183
         		Intermediate 155
    Figure US20140275083A1-20140918-C00184
         		Intermediate 156
    Figure US20140275083A1-20140918-C00185
         		Intermediate 157
    Figure US20140275083A1-20140918-C00186
         		Intermediate 158
    Figure US20140275083A1-20140918-C00187
         		Intermediate 159
    Figure US20140275083A1-20140918-C00188
         		Intermediate 160
    Figure US20140275083A1-20140918-C00189
         		Intermediate 161
    Figure US20140275083A1-20140918-C00190
         		Intermediate 162
  • TABLE 8b
    Chemical name and analytical data for each intermediate listed in Table 8a.
    Intermediate: Name Analytical data
    150: 1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethanamine. Anal. RP-HPLC tR = 1.09 min; MS
    m/z 268.4 (M + H)+.
    151: 1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR = 1.04 min. MS
    yl)ethanamine. m/z 286.3 (M + H)+.
    152: 1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR = 1.06 min. MS
    yl)ethanamine. m/z 302.3 (M + H)+.
    153: 1-(5-(5-fluoro-2-methylphenyl)pyrimidin-2- Anal. RP-HPLC tR = 0.79 min. MS
    yl)ethanamine m/z 232.0 (M + H)+.
    154: 1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2- Anal. RP-HPLC tR = 0.81 min. MS
    yl)ethanamine m/z 231.9 (M + H)+.
    155: 1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethanamine Anal. RP-HPLC tR = 1.01 min. MS
    m/z 269.0 (M + H)+.
    156: 1-(5-(4-fluoro-3-methylphenyl)pyridin-2- Anal. RP-HPLC tR = 0.92 min. MS
    yl)ethanamine m/z 230.9 (M + H)+.
    157: 1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR = 0.96 min. MS
    yl)ethanamine. m/z 286.0 (M + H)+.
    158: 1-(5-(4-chloro-3-methylphenyl)pyrimidin-2- Anal. RP-HPLC tR = 0.97 min. MS
    yl)ethanamine. m/z 247.9 (M + H)+.
    159: 1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR = 1.06 min. MS
    yl)ethanamine. m/z 301.9 (M + H)+.
    160: 1-(5-(4-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR = 1.02 min. MS
    yl)ethanamine. m/z 268.2 (M + H)+.
    161: 1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2- LCMS tR = 1.04 min; MS m/z
    yl)ethanamine 267.9 (M + H)+.
    162: 1-(5-(4-fluoro-3-methylphenyl)pyrazin-2- LCMS tR = 0.91 min; MS m/z
    yl)ethanamine 231.9 (M + H)+.
    • Intermediate 163: 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanamine
  • Figure US20140275083A1-20140918-C00191
  • Step 1: A solution of 1-(5-fluoropyrimidin-2-yl)ethanone (700 mg, 5.0 mmol) and 4-fluorophenol (616 mg, 5.50 mmol) in 6 mL DMF was treated with potassium carbonate (829 mg 6.0 mmol) and heated to 50° C. for 3.5 h. The reaction mixture was poured into 20 mL water, and extracted with EtOAc (2×20 mL). Organics were washed with 20 mL each water, brine, and dried over Na2SO4. Mixture was filtered and concentrated on silica gel. Column chromatography (10-100% EtOAc/hept) gave 295 mg (25%) 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanone as a white solid used directly in the following step. MS m/z 233.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 2H), 7.23-7.07 (m, 4H), 2.78 (s, 3H).
  • Step 2: 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanone (290 mg, 1.25 mmol), NH4OAc (1.9 g, 24.6 mmol), and NaBH3CN (314 mg, 5.00 mmol) were taken up in 20 mL 200 proof EtOH, and heated at 130 C for 3 minutes in a microwave apparatus. The mixture was concentrated to remove the EtOH. Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added until aqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc (25 ml). The combined organic layer was washed with 25 mL brine and dried with Na2SO4. Filtered and concentrated with reduced pressure to give 275 mg crude tan oil, which was carried forward without further purification. Major product Anal. RP-HPLC tR=1.26 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 234.1 (M+H)+
    • Intermediate 164: 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanamine
  • Figure US20140275083A1-20140918-C00192
  • Step 1: In a well vented vial, 90% t-butyl nitrite (4.74 mL, 35.8 mmol) and CuCl (2.96 g, 29.9 mmol) were taken up in 30 mL ACN. Over 15 mins, 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine (6.0 g, 19.9 mmol) was added in portions. Gas evolved. The mixture was stirred 30 min at r.t., then warmed to 65 C for another 30 min. The reaction mixture was filtered through Celite. 200 mL Water was added to the filtrate. This was extracted with (2×150 mL) EtOAc. Organics were washed with 200 mL brine, and dried over Na2SO4. Filtered and concentrated on silica gel. Flash column chromatography (10-50% EA/hept) gave 3.35 g (52%) 2-chloro-4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole as a green oil. MS m/z 321.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.69 (dd, J=5.1, 0.8 Hz, 1H), 7.52 (dq, J=1.7, 0.8 Hz, 1H), 7.31-7.22 (m, 1H), 2.55 (s, 3H), 1.67 (s, 6H).
  • Step 2: To a solution of 2-chloro-4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole (3.3 g, 10.3 mmol) and Pd(PPh3)2Cl2 (0.72 g, 1.03 mmol) in 50 mL dioxane under nitrogen, tributyl(1-ethoxyvinyl)stannane (3.82 ml, 11.32 mmol) was added. The mixture was heated to 100 C for 16 h. The reaction was cooled to r.t. and diluted with 25 mL EtOAc. 2M KF (15.4 ml) solution was added and stirred for 1 h. Copious precipitate formed. The reaction was filtered through Celite and chased with EtOAc. The organic layer was rinsed with 60 mL water, and concentrated to give grey solid. Crude solid was dissolved in THF (50 mL) and 1N HCl (20.58 mL) was added. The reaction was stirred at r.t. for 2 h. The mixture was neutralized by addition of 1 N NaOH. THF was removed in vacuo. Extracted aqueous with 2×50 mL EtOAc. The organic layers were washed with 50 mL brine, and dried over Na2SO4. Filtered and concentrated on silica gel. Flash chromatography using 10-50% EtOAc in heptane gave 1.65 g (49%) 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanone as a yellow oil. MS m/z 329.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.72 (dd, J=5.2, 0.9 Hz, 1H), 7.60 (dq, J=1.8, 0.9 Hz, 1H), 7.34 (dd, J=5.1, 1.6 Hz, 1H), 2.74 (s, 3H), 2.63 (s, 3H), 1.69 (s, 6H).
  • Step 3: 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanone ethanone (1.6 g, 4.87 mmol), NH4OAc (5.6 g, 73.1 mmol), and NaBH3CN (1.2 g, 19.5 mmol) were taken up in 40 mL 200 proof EtOH, and heated at 130 C for 10 minutes in a sealed tube. The mixture was concentrated to remove the EtOH. Crude was taken up in 50 ml water+50 mL EtOAc. 6N NaOH was added until aqueous pH was −9. Separated layers, and extracted aqueous with EtOAc (50 ml). The combined organic layer was washed with 60 mL brine and dried with Na2SO4. Filtered and concentrated with reduced pressure to give 1.58 g crude tan oil. This material was taken up in 20 mL dioxane. 2.2 eq HCl (4N in dioxane) was added, and stirred 1 h. Yellow ppt was formed. The suspension was concentrated in vacuo to give 1.97 g 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanamine dihydrochloride salt as a yellow-green solid, which was carried forward without further purification. Major product Anal. RP-HPLC tR=1.23 min. MS m/z 330.1 (M+H)+.
    • Intermediate 165: 4-((S)-1-Amino-ethyl)piperidine-1-carboxylic acid benzyl ester
  • Figure US20140275083A1-20140918-C00193
  • Benzyl 4-((1S)-1-(1,1-dimethylethylsulfinamido)ethyl)piperidine-1-carboxylate (1.825 g, 4.98 mmole) was dissolved in dioxane (10 mL) and 4N HCl in dioxane (5 mL, 1.3 eq.) was added. The mixture was stirred for 3 hours at room temperature. The solvents were removed by rotary evaporation to give the title compound as a hydrochloride salt (1.3 g). 1H NMR (400 MHz, CD2Cl2) δ 8.46 (s, 2H), 7.44-7.27 (m, 5H), 5.11 (s, 2H), 4.26 (d, J=13.57 Hz, 2H), 3.24-3.12 (m, 1H), 2.86-2.61 (m, 2H), 1.99-1.86 (m, 3H), 1.38 (d, J=6.33 Hz, 3H), 1.34-1.23 (m, 2H). HRMS (C) tR=1.87 min; MS m/z 263.1760 (M+H)+
    • Intermediate 166: (S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethanamine
  • Figure US20140275083A1-20140918-C00194
  • To a solution of (S)-tert-butyl (1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)carbamate (66 mg, 0.47 mmol) in DCM (2 mL) was added TFA (2 mL, 26 mmol) slowly at −78° C. The reaction was stirred at room temperature for 1 h then concentrated and diluted with DCM (10 mL). The solution was stirred with 3 eq. of MP-carbonate resin (3.28 mmol/g, Biotage) for 1 hr at room temperature. The resin was removed by filtration and washed (2×5 mL) with DCM. The filtrate was concentrated and the crude residue was used to next step without further purification. LCMS tR=0.97 min; MS m/z 231.1 (M+H).
  • The intermediates in Table 9a were prepared using a method similar to that described for the preparation of Intermediate 166
  • TABLE 9a
    Figure US20140275083A1-20140918-C00195
         		Intermediate 167
    Figure US20140275083A1-20140918-C00196
         		Intermediate 168
    Figure US20140275083A1-20140918-C00197
         		Intermediate 169
    Figure US20140275083A1-20140918-C00198
         		Intermediate 170
    Figure US20140275083A1-20140918-C00199
         		Intermediate 171
    Figure US20140275083A1-20140918-C00200
         		Intermediate 172
    Figure US20140275083A1-20140918-C00201
         		Intermediate 173
    Figure US20140275083A1-20140918-C00202
         		Intermediate 174
    Figure US20140275083A1-20140918-C00203
         		Intermediate 175
    Figure US20140275083A1-20140918-C00204
         		Intermediate 176
    Figure US20140275083A1-20140918-C00205
         		Intermediate 177
    Figure US20140275083A1-20140918-C00206
         		Intermediate 178
    Figure US20140275083A1-20140918-C00207
         		Intermediate 179
  • TABLE 9b
    Chemical name and analytical data for each intermediate listed in Table 9a.
    Intermediate: Name Analytical data
    167: (S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethanamine LCMS tR = 1.12 min; MS
    m/z 267.7 (M + H).
    168: (S)-1-(6-(4-fluoro-3-methylphenyl)pyridin-3-yl)ethanamine LCMS tR = 1.05 min; MS
    m/z 231.4 (M + H).
    169: (S)-1-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)ethanamine LCMS tR = 1.14 min; MS
    m/z 267.4 (M + H).
    170: (S)-1-(2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine LCMS tR = 0.79 min; MS
    m/z 268.1 (M + H).
    171: (S)-1-(6′-(trifluoromethyl)-[2,3′-bipyridin]-5-yl)ethanamine LCMS tR = 0.81 min; MS
    m/z 268.1 (M + H).
    172: (S)-1-(6′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)ethanamine LCMS tR = 0.81 min; MS
    m/z 268.1 (M + H).
    173: (S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethanamine LCMS tR = 0.89 min; MS
    m/z 268.1 (M + H).
    174: (S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6- LCMS tR = 0.85 min; MS
    yl)ethanamine m/z 282.1 (M + H).
    175: (S)-1-(2-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6- LCMS tR = 0.86 min; MS
    yl)ethanamine m/z 282.1 (M + H).
    176: (S)-1-(5-fluoro-2′-(trifluoromethyl)-[3,4′-bipyridin]-6- LCMS tR = 0.88 min; MS
    yl)ethanamine m/z 286.1 (M + H).
    177: (S)-1-(5-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6- LCMS tR = 0.89 min; MS
    yl)ethanamine m/z 282.1 (M + H).
    178: (S)-1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1- LCMS tR = 0.29 min; MS
    yl)methyl)phenyl)ethanamine m/z 280.2 (M + H).
    179: (S)-1-(4-((4,4-difluoropiperidin-1-yl)methyl)-3- LCMS tR = 0.29 min; MS
    fluorophenyl)ethanamine m/z 273.2 (M + H).
    • Intermediate 180: (S)-tert-butyl (1-hydrazinyl-1-oxopropan-2-yl)carbamate
  • Figure US20140275083A1-20140918-C00208
  • A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)propanoate (1.00 g, 4.92 mmol) and hydrazine (0.23 mL, 1.5 equiv) in THF (8 mL) was heated in a sealed tube at 72° C. for 15 hours. Additional hydrazine (0.23 mL, 1.5 equiv) was added and heating was continued for another 21 hours. The reaction was then cooled to room temperature and concentrated in vacuo to give crude (S)-tert-butyl (1-hydrazinyl-1-oxopropan-2-yl)carbamate (1 g, white solid), which was used without purification. 1H NMR (400 MHz, CDCl3) δ 4.20 (m, 1H), 1.44 (s, 9H), 1.36 (d, J=7.1 Hz, 3H).
    • Intermediate 181: (S)-tert-butyl (1-(2-(4-chlorobenzoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate
  • Figure US20140275083A1-20140918-C00209
  • 4-Chlorobenzoyl chloride (0.63 mL, 4.92 mmol, 1.0 equiv) was added to a solution of (S)-tert-butyl (1-hydrazinyl-1-oxopropan-2-yl)carbamate (1.0 g, 4.92 mmol) in DCM (25 mL) at 0° C. A white precipitate formed. The mixture was stirred at 0° C. for 1 hour and the reaction mixture was then concentrated in vacuo to give crude (S)-tert-butyl (1-(2-(4-chlorobenzoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (1.55 g), which was used without purification. 1H NMR (400 MHz, CD3OD) δ 7.85 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 4.21 (q, J=7.0 Hz, 1H), 1.45 (s, 9H), 1.41 (d, J=7.2 Hz, 3H). MS m/z 342.1 (M+H)+; Rt-0.69 min.
  • Intermediate 182
    • (S)-tert-butyl (1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate
  • Figure US20140275083A1-20140918-C00210
  • A solution of (S)-tert-butyl (1-(2-(4-chlorobenzoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (1.0 g, 2.93 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (1.18 g, 2.93 mmol, 1.0 equiv) in THF (29 mL) was heated at reflux for 2 hours. The reaction wash then cooled to room temperature and filtered through a pad of celite, using THF to wash through. The filtrate was concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane, 0 to 30%) provided (S)-tert-butyl (1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate (0.600 g, light green solid) in 60% yield. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 5.23 (m, 1H), 1.72 (d, J=6.5 Hz, 3H), 1.48 (s, 9H). MS m/z 340.1 (M+H)+; Rt-0.99 min.
  • Intermediate 183
    • (S)-1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethanamine
  • Figure US20140275083A1-20140918-C00211
  • A solution of hydrogen chloride (4.0 M in 1,4-dioxane, 4 mL, 16 mmol, 9 equiv) was added to a solution of (S)-tert-butyl (1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate (600 mg, 1.77 mmol) in 1,4-dioxane (5 mL) at room temperature. The solution was stirred for 3 hours, by which time a white precipitate had formed. The reaction was concentrated in vacuo to give the hydrochloride salt of (S)-1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethanamine (480 mg, white solid) in 97% yield. The material was used without purification. 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 5.10 (q, J=6.9 Hz, 1H), 1.82 (d, J=6.9 Hz, 3H). MS m/z 240.0 (M+H)+; Rt-0.54 min.
    • Intermediate 184: (S)-tert-butyl but-3-yn-2-ylcarbamate
  • Figure US20140275083A1-20140918-C00212
  • A solution of (S)-tert-butyl (1-oxopropan-2-yl)carbamate (500 mg, 2.89 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (610 mg, 3.18 mmol, 1.1 equiv), and potassium carbonate (638 mg, 4.62 mmol, 1.6 equiv) in methanol (14.4 mL) was stirred at room temperature for 18 hours. The reaction was then diluted with ethyl acetate (30 mL) and saturated aqueous sodium chloride (40 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (20% EtOAc in Heptane) provided (S)-tert-butyl but-3-yn-2-ylcarbamate (0.258 g, white solid) in 53% yield. 1H NMR (400 MHz, CDCl3) δ 4.49 (m, 1H), 2.26 (d, J=2.2 Hz, 1H), 1.46 (s, 9H), 1.41 (d, J=6.8 Hz, 3H).
    • Intermediate 185: (S)-tert-butyl (1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)carbamate
  • Figure US20140275083A1-20140918-C00213
  • A solution of (S)-tert-butyl but-3-yn-2-ylcarbamate (250 mg, 1.48 mmol), 1-azido-4-chlorobenzene (227 mg, 1.48 mmol, 1.0 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.77 mL, 4.43 mmol, 3.0 equiv) in anhydrous acetonitrile (14.8 mL) was stirred at room temperature for 10 min. Copper(I) iodide (563 mg, 2.95 mmol, 2.0 equiv) was then added in portions. The mixture was stirred at room temperature for 30 min. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic extracts were washed with water (30 mL), saturated aqueous sodium chloride (30 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (S)-tert-butyl (1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)carbamate (0.428 g, white solid) in 90% yield. 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 5.02 (m, 1H), 1.63 (d, J=6.8 Hz, 3H), 1.46 (s, 9H). MS m/z 323.1 (M+H)+; Rt-0.92 min.
    • Intermediate 186: (S)-1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethanamine
  • Figure US20140275083A1-20140918-C00214
  • A solution of hydrogen chloride (4.0 M in 1,4-dioxane, 3.3 mL, 13.2 mmol, 10 equiv) was added to a solution of (S)-tert-butyl (1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)carbamate (425 mg, 1.32 mmol) in 1,4-dioxane (5 mL) at room temperature. The solution was stirred for 1 hour, by which time a white precipitate had formed. The reaction was concentrated in vacuo to give the hydrochloride salt of (S)-1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethanamine (338 mg, white solid) in 99% yield. The material was used without purification. 1H NMR (400 MHz, CD3OD) δ 8.68 (s, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.63 (d, J=9.0 Hz, 2H), 4.77 (q, J=6.9 Hz, 1H), 1.78 (d, J=6.9 Hz, 3H). MS m/z 223.1 (M+H)+; Rt-0.50 min.
    • Intermediate 187: 2-(6-methylpyridin-3-yl)thiazole-5-carbaldehyde
  • Figure US20140275083A1-20140918-C00215
  • A mixture of 2-bromothiazole-5-carbaldehyde (400 mg, 2.08 mmol), (6-methylpyridin-3-yl)boronic acid (428 mg, 3.12 mmol, 1.5 equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (170 mg, 0.21 mmol, 0.1 equiv) and 2.0 M aqueous sodium carbonate (5.2 mL, 10.4 mmol, 5 equiv) in 1,2-dimethoxyethane (6.9 mL) was heated in a microwave reactor at 110° C. for 20 minutes. The reaction was then diluted with ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (30 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc) provided 2-(6-methylpyridin-3-yl)thiazole-5-carbaldehyde (0.176 g, brown solid) in 41% yield. 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 9.15 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 8.19 (dd, J=8.1, 2.4 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 2.66 (s, 3H). MS m/z 205.0 (M+H)+; Rt-0.36 min.
  • The intermediates in Table 10a were prepared using a method similar to that described for the preparation of Intermediate 187
  • TABLE 10a
    Figure US20140275083A1-20140918-C00216
         		Intermediate 188
    Figure US20140275083A1-20140918-C00217
         		Intermediate 189
    Figure US20140275083A1-20140918-C00218
         		Intermediate 190
  • TABLE 10b
    Chemical name, NMR chemical shifts and LCMS signal for each intermediate
    listed in Table 10a.
    1H NMR (400 MHz, CDCl3) δ
    Intermediate: Name ppm LCMS
    188: 2-(6-methylpyridin-3-yl)thiazole-5- 10.08 (s, 1H), 9.15 (d, J = 2.0 Hz, MS m/z
    carbaldehyde 1H), 8.47 (s, 1H), 8.19 (dd, 205.0 (M + H)+;
    J = 8.1, 2.4 Hz, 1H), 7.31 (d, J = 8.3 Hz, Rt-0.36 min
    1H), 2.66 (s, 3H).
    189: 2-(6-(trifluoromethyl)pyridin-3- 10.13 (s, 1H), 9.37 (d, J = 1.6 Hz, MS m/z
    yl)thiazole-5-carbaldehyde 1H), 8.55 (s, 1H), 8.50 (dd, 259.0 (M + H)+;
    J = 8.2, 2.0 Hz, 1H), 7.85 (d, J = 8.2 Hz, Rt-0.74 min
    1H)
    190: 2-(2-(trifluoromethyl)pyridin-4- 10.14 (s, 1H), 8.91 (d, J = 5.0 Hz, MS m/z
    yl)thiazole-5-carbaldehyde 1H), 8.57 (d, J = 0.6 Hz, 259.0 (M + H)+;
    1H), 8.30 (s, 1H), 8.06 (d, J = 5.1 Hz, Rt-0.76 min
    1H)
    • Intermediate 191: 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole
  • Figure US20140275083A1-20140918-C00219
  • A solution of ethane-1,2-diol (0.081 mL, 1.45 mmol, 1.5 equiv), 1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (200 mg, 0.968 mmol), and camphorsulfonic acid (45 mg, 0.19 mmol, 0.2 equiv) in toluene (10 mL) was heated at reflux with a Dean-Stark apparatus for 1 hour. The reaction was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (30 mL) and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. Silica gel column chromatography (EtOAc with 7% methanol) provided 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole (0.100 g, tan solid) in 41% yield. 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.36 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 5.96 (s, 1H), 4.20 (m, 2H), 4.05 (m, 2H). MS m/z 251.0 (M+H)+; Rt-0.53 min.
    • Intermediate 192: 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole
  • Figure US20140275083A1-20140918-C00220
  • A solution of n-butyllithium (1.6 M in hexane, 0.37 mL, 0.60 mmol, 1.5 equiv) was added to a solution of N,N-diisopropylamine (0.085 mL, 0.60 mmol, 1.5 equiv) in THF (1.5 mL) at −78° C. The solution was stirred at −78° C. for 10 min and then a solution of 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole (100 mg, 0.40 mmol) in THF (1 mL) was added dropwise. The resulting solution was stirred at −78° C. for 30 min, and then iodomethane (0.042 mL, 0.68 mmol, 1.7 equiv) was added. The solution was allowed to warm to room temperature and then quenched with water (20 mL). The mixture was extracted with ethyl acetate (30 mL) and the organic extract was washed with saturated aqueous sodium chloride (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give crude 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole. The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.09 (s, 1H), 5.88 (s, 1H), 4.20 (m, 2H), 4.03 (m, 2H), 2.35 (s, 3H). MS m/z 265.0 (M+H)+; Rt-0.57 min.
    • Intermediate 193: 1-(4-chlorophenyl)-2-methyl-1H-imidazole-4-carbaldehyde
  • Figure US20140275083A1-20140918-C00221
  • A solution of 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole (1.05 g, 3.97 mmol) and camphorsulfonic acid (92 mg, 0.40 mmol, 0.1 equiv) in THF (26.5 mL) and water (13.3 mL) was heated at 60° C. for 1 hour. The reaction was then cooled to room temperature and quenched with saturated aqueous sodium bicarbonate (100 mL). The mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with saturated aqueous sodium chloride (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Silica gel column chromatography (EtOAc with 7% methanol) provided 1-(4-chlorophenyl)-2-methyl-1H-imidazole-4-carbaldehyde (0.600 g, tan solid) in 69% yield. 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.67 (s, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 2.40 (s, 3H). MS m/z 221.0 (M+H)+; Rt-0.47 min.
    • Intermediate 194: 1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carbaldehyde
  • Figure US20140275083A1-20140918-C00222
  • A mixture of 1H-pyrazole-3-carbaldehyde (0.700 g, 7.29 mmol), 5-bromo-2-(trifluoromethyl)pyridine (2.31 g, 10.2 mmol, 1.4 equiv), cesium carbonate (4.75 g, 14.6 mmol, 2.0 equiv), copper(I) iodide (0.069 g, 0.36 mmol, 0.05 equiv), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.23 mL, 1.46 mmol, 0.2 equiv) in DMF (9.5 mL) was heated in a sealed reaction vessel at 110° C. for 16 hours. The reaction was then cooled to room temperature and saturated aqueous ammonium chloride (100 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Silica gel column chromatography (EtOAc/heptane) provided 1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carbaldehyde (0.470 g, brown solid) in 27% yield. 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 9.18 (d, J=2.1 Hz, 1H), 8.34 (dd, J=8.7, 2.0 Hz, 1H), 8.12 (m, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.10 (d, J=1.8 Hz, 1H). MS m/z 241.9 (M+H)+; Rt-0.78 min.
    • Intermediate 195: (R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00223
  • A suspension of 5-(4-chlorophenyl)isoxazole-3-carbaldehyde (2.00 g, 9.63 mmol), (R)-2-methylpropane-2-sulfinamide (1.28 g, 10.6 mmol, 1.1 equiv) and anhydrous copper(II) sulfate (2.31 g, 14.5 mmol, 1.5 equiv) in 1,2-dichloroethane (19 mL) was heated at 55° C. for 2-18 hours. The reaction was then cooled to room temperature and filtered through a pad of celite, using 1,2-dichloroethane to wash through. The filtrate was concentrated in vacuo to give crude (R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide as a green solid, which was used without further purification. MS m/z 311.0 (M+H)+; Rt-1.11 min.
  • The intermediates in Table 11a were prepared using a method similar to that described for the preparation of Intermediate 195
  • TABLE 11a
    Figure US20140275083A1-20140918-C00224
         		Intermediate 196
    Figure US20140275083A1-20140918-C00225
         		Intermediate 197
    Figure US20140275083A1-20140918-C00226
         		Intermediate 198
    Figure US20140275083A1-20140918-C00227
         		Intermediate 199
    Figure US20140275083A1-20140918-C00228
         		Intermediate 200
    Figure US20140275083A1-20140918-C00229
         		Intermediate 201
    Figure US20140275083A1-20140918-C00230
         		Intermediate 202
    Figure US20140275083A1-20140918-C00231
         		Intermediate 203
    Figure US20140275083A1-20140918-C00232
         		Intermediate 204
    Figure US20140275083A1-20140918-C00233
         		Intermediate 205
    Figure US20140275083A1-20140918-C00234
         		Intermediate 206
    Figure US20140275083A1-20140918-C00235
         		Intermediate 207
    Figure US20140275083A1-20140918-C00236
         		Intermediate 208
    Figure US20140275083A1-20140918-C00237
         		Intermediate 209
    Figure US20140275083A1-20140918-C00238
         		Intermediate 210
    Figure US20140275083A1-20140918-C00239
         		Intermediate 211
    Figure US20140275083A1-20140918-C00240
         		Intermediate 212
    Figure US20140275083A1-20140918-C00241
         		Intermediate 213
    Figure US20140275083A1-20140918-C00242
         		Intermediate 214
  • TABLE 11b
    Chemical name and analytical data for each intermediate listed in Table 11a.
    Intermediate: Name Analytical data
    196: (R,E)-N-((5-(4-chlorophenyl)isoxazol-3- MS m/z 311.0 (M + H)+; Rt-1.11 min
    yl)methylene)-2-methylpropane-2-sulfinamide
    197: (R,E)-N-((2-(4-chlorophenyl)thiazol-5- MS m/z 327.1 (M + H)+; Rt-1.13 min
    yl)methylene)-2-methylpropane-2-sulfinamide
    198: (R,E)-2-methyl-N-((5-phenylthiophen-2- MS m/z 292.0 (M + H)+; Rt-1.05 min
    yl)methylene)propane-2-sulfinamide
    199: (R,E)-2-methyl-N-((5-phenylisoxazol-3- MS m/z 277.1 (M + H)+; Rt-1.02 min
    yl)methylene)propane-2-sulfinamide
    200: (R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-4- MS m/z 310.1 (M + H)+; Rt-1.00 min
    yl)methylene)-2-methylpropane-2-sulfinamide
    201: (R,E)-N-((5-(4-fluorophenyl)isoxazol-3- MS m/z 295.1 (M + H)+; Rt-1.00 min
    yl)methylene)-2-methylpropane-2-sulfinamide
    202: (R,E)-N-((1-(4-fluorophenyl)-1H-pyrazol-4- MS m/z 294.1 (M + H)+; Rt-0.90 min
    yl)methylene)-2-methylpropane-2-sulfinamide
    203: (R,E)-2-methyl-N-((5-(pyridin-2-yl)thiophen-2- MS m/z 293.1 (M + H)+; Rt-0.85 min
    yl)methylene)propane-2-sulfinamide
    204: (R,E)-2-methyl-N-((5- MS m/z 300.1 (M + H)+; Rt-0.43 min
    (morpholinomethyl)isoxazol-3-
    yl)methylene)propane-2-sulfinamide
    205: (R,E)-2-methyl-N-((2-morpholinothiazol-5- MS m/z 302.1 (M + H)+; Rt-0.69 min
    yl)methylene)propane-2-sulfinamide
    206: (R,E)-2-methyl-N-((2-(pyridin-2-yl)thiazol-5- MS m/z 294.2 (M + H)+; Rt-0.92 min
    yl)methylene)propane-2-sulfinamide
    207: (R,E)-2-methyl-N-((2-(pyridin-3-yl)thiazol-5- MS m/z 294.1 (M + H)+; Rt-0.63 min
    yl)methylene)propane-2-sulfinamide
    208: (R,E)-2-methyl-N-((2-(pyridin-4-yl)thiazol-5- MS m/z 294.1 (M + H)+; Rt-0.55 min
    yl)methylene)propane-2-sulfinamide
    209: (R,E)-N-((2-(4-(difluoromethyl)phenyl)thiazol- MS m/z 342.9 (M + H)+; Rt-0.86 min
    5-yl)methylene)-2-methylpropane-2-sulfinamide
    210: (R,E)-2-methyl-N-((2-(6-methylpyridin-3- MS m/z 308.1 (M + H)+; Rt-0.58 min
    yl)thiazol-5-yl)methylene)propane-2-sulfinamide
    211: (R,E)-2-methyl-N-((2-(6- MS m/z 362.1 (M + H)+; Rt-0.96 min
    (trifluoromethyl)pyridin-3-yl)thiazol-5-
    yl)methylene)propane-2-sulfinamide
    212: (R,E)-2-methyl-N-((2-(2- MS m/z 362.1 (M + H)+; Rt-0.97 min
    (trifluoromethyl)pyridin-4-yl)thiazol-5-
    yl)methylene)propane-2-sulfinamide
    213: (R,E)-2-methyl-N-((1-(6- MS m/z 345.0 (M + H)+; Rt-0.95 min
    (trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-
    yl)methylene)propane-2-sulfinamide
    214: (R,E)-N-((1-(4-chlorophenyl)-2-methyl-1H- MS m/z 324.0 (M + H)+; Rt-0.62 min
    imidazol-4-yl)methylene)-2-methylpropane-2-
    sulfinamide
    • Intermediate 215: (R)-N-((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00243
  • A solution of methylmagnesium bromide (3.0 M in diethyl ether, 12.8 mL, 38.4 mmol, 4 equiv) was added to a solution of (R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (2.98 g, 9.6 mmol) in DCM (96 mL) at 0° C. The solution became orange, then faded to yellow. The reaction was stirred at 0° C. for 30 min and then carefully quenched with saturated aqueous ammonium chloride (100 mL). The layers were separated and the aqueous layer was extracted with DCM (40 mL). The combined organic layers were washed with water (50 mL), saturated aqueous sodium chloride (50 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-N-((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.0 g, white solid) in 32% yield. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 6.50 (s, 1H), 4.75 (m, 1H), 3.47 (m, 1H), 1.70 (d, J=6.8 Hz, 3H), 1.25 (s, 9H). MS m/z 327.0 (M+H)+; Rt-0.94 min.
  • The intermediates in Table 12a were prepared using a method similar to that described for the preparation of Intermediate 215.
  • TABLE 12a
    Figure US20140275083A1-20140918-C00244
         		Intermediate 216
    Figure US20140275083A1-20140918-C00245
         		Intermediate 217
    Figure US20140275083A1-20140918-C00246
         		Intermediate 218
    Figure US20140275083A1-20140918-C00247
         		Intermediate 219
    Figure US20140275083A1-20140918-C00248
         		Intermediate 220
    Figure US20140275083A1-20140918-C00249
         		Intermediate 221
    Figure US20140275083A1-20140918-C00250
         		Intermediate 222
    Figure US20140275083A1-20140918-C00251
         		Intermediate 223
    Figure US20140275083A1-20140918-C00252
         		Intermediate 224
    Figure US20140275083A1-20140918-C00253
         		Intermediate 225
    Figure US20140275083A1-20140918-C00254
         		Intermediate 226
    Figure US20140275083A1-20140918-C00255
         		Intermediate 227
    Figure US20140275083A1-20140918-C00256
         		Intermediate 228
    Figure US20140275083A1-20140918-C00257
         		Intermediate 229
    Figure US20140275083A1-20140918-C00258
         		Intermediate 230
    Figure US20140275083A1-20140918-C00259
         		Intermediate 231
    Figure US20140275083A1-20140918-C00260
         		Intermediate 232
    Figure US20140275083A1-20140918-C00261
         		Intermediate 233
    Figure US20140275083A1-20140918-C00262
         		Intermediate 234
    Figure US20140275083A1-20140918-C00263
         		Intermediate 235
  • TABLE 12b
    Chemical name, NMR chemical shifts and LCMS signal for each intermediate
    listed in Table 12a.
    1H NMR (400 MHz, CDCl3) δ
    Intermediate: Name ppm LCMS
    216: (R)-N-((S)-1-(5-(4- 7.71 (d, J = 8.6 Hz, 2H), MS m/z
    chlorophenyl)isoxazol-3-yl)ethyl)-2- 7.45 (d, J = 8.6 Hz, 2H), 6.50 (s, 1H), 327.0 (M + H)+;
    methylpropane-2-sulfinamide 4.75 (m, 1H), 3.47 (m, 1H), Rt-0.94 min
    1.70 (d, J = 6.8 Hz, 3H), 1.25 (s, 9H).
    217: (R)-N-((S)-1-(2-(4-chlorophenyl)thiazol- CD3OD: 7.88 (d, J = 8.7 Hz, MS m/z
    5-yl)ethyl)-2-methylpropane-2-sulfinamide 2H), 7.73 (d, J = 1.0 Hz, 1H), 343.1 (M + H)+;
    7.47 (d, J = 8.7 Hz, 2H), Rt-0.97 min
    4.83 (m, 1H), 1.71 (d, J = 6.7 Hz,
    3H), 1.25 (s, 9H)
    218: (R)-2-methyl-N-((S)-1-(5- 7.58 (d, J = 7.4 Hz, 2H), MS m/z
    phenylthiophen-2-yl)ethyl)propane-2- 7.37 (m, 2H), 7.27 (m, 1H), 7.16 (d, J = 3.7 Hz, 308.1 (M + H)+;
    sulfinamide 1H), 6.95 (d, J = 3.7 Hz, Rt-0.95 min
    1H), 4.84 (m, 1H), 3.42 (m,
    1H), 1.70 (d, J = 6.6 Hz, 3H),
    1.26 (s, 9H)
    219: (R)-2-methyl-N-((S)-1-(5- MS m/z
    phenylisoxazol-3-yl)ethyl)propane-2- 293.2 (M + H)+;
    sulfinamide Rt-0.85 min
    220: (R)-N-((S)-1-(1-(4-chlorophenyl)-1H- 7.84 (s, 1H), 7.63 (s, 1H), MS m/z
    pyrazol-4-yl)ethyl)-2-methylpropane-2- 7.61 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7 Hz, 326.1 (M + H)+;
    sulfinamide 2H), 4.64 (m, 1H), Rt-0.89 min
    3.31 (m, 1H), 1.62 (d, J = 6.7 Hz,
    3H), 1.24 (s, 9H)
    221: (R)-N-((S)-1-(5-(4- 7.77 (dd, J = 8.9, 5.2 Hz, 2H), MS m/z
    fluorophenyl)isoxazol-3-yl)ethyl)-2- 7.16 (t, J = 8.7 Hz, 2H), 6.46 (s, 311.1 (M + H)+;
    methylpropane-2-sulfinamide 1H), 4.77 (m, 1H), 3.47 (d, J = 5.7 Hz, Rt-0.85 min
    1H), 1.70 (d, J = 6.8 Hz,
    3H), 1.25 (s, 9H)
    222: (R)-N-((S)-1-(1-(4-fluorophenyl)-1H- 7.80 (s, 1H), 7.63 (m, 3H), MS m/z
    pyrazol-4-yl)ethyl)-2-methylpropane-2- 7.14 (t, J = 8.5 Hz, 2H), 4.63 (m, 1H), 310.1 (M + H)+;
    sulfinamide 3.31 (d, J = 5.0 Hz, 1H), Rt-0.79 min
    1.62 (d, J = 6.7 Hz, 3H), 1.24 (s, 9H)
    223: (R)-2-methyl-N-((S)-1-(5-(pyridin-2- 8.53-8.59 (m, 1 H), MS m/z
    yl)thiophen-2-yl)ethyl)propane-2-sulfinamide 7.60-7.73 (m, 2 H), 7.43 (d, J = 3.7 Hz, 1 309.1 (M + H)+;
    H), 7.15 (ddd, J = 7.1, 5.0, 1.2 Hz, Rt-0.58 min
    1 H),
    6.99 (d, J = 3.8 Hz, 1 H), 4.84 (quin,
    J = 6.3 Hz, 1 H), 3.43 (d, J = 5.5 Hz,
    1 H), 1.70 (d, J = 6.6 Hz, 3
    H), 1.26 (s, 9 H)
    224: (R)-2-methyl-N-((S)-1-(5- MS m/z
    (morpholinomethyl)isoxazol-3- 316.1 (M + H)+;
    yl)ethyl)propane-2-sulfinamide Rt-0.38 min
    225: (R)-2-methyl-N-((S)-1-(2- 7.06 (s, 1H), 4.69 (quin, J = 6.1 Hz,
    morpholinothiazol-5-yl)ethyl)propane-2- 1H), 3.81 (m, 4H), 3.44 (m,
    sulfinamide 4H), 3.32 (d, J = 4.9 Hz, 1H),
    1.60 (d, J = 6.6 Hz, 3H),
    1.22 (s, 9H)
    226: (R)-2-methyl-N-((S)-1-(2-(pyridin-2- 8.60 (m, 1H), 8.15 (m, 1H), MS m/z
    yl)thiazol-5-yl)ethyl)propane-2-sulfinamide 7.80 (m, 2H), 7.33 (m, 1H), 4.93 (m, 310.0 (M + H)+;
    1H), 1.71 (d, J = 6.6 Hz, 3H), Rt-0.69 min
    1.25 (s, 9H)
    227: (R)-2-methyl-N-((S)-1-(2-(pyridin-3- 9.11 (m, 1H), 8.65 (m, 1H), MS m/z
    yl)thiazol-5-yl)ethyl)propane-2-sulfinamide 8.23 (m, 1H), 7.75 (m, 1H), 7.38 (m, 310.0 (M + H)+;
    1H), 4.90 (m, 1H), 3.50 (m, 1H), Rt-0.50 min
    1.71 (d, J = 6.6 Hz, 3H),
    1.24 (s, 9H)
    228: (R)-2-methyl-N-((S)-1-(2-(pyridin-4- 8.70 (m, 2H), 7.79 (m, 3H), MS m/z
    yl)thiazol-5-yl)ethyl)propane-2-sulfinamide 4.94 (m, 1H), 1.72 (d, J = 6.6 Hz, 3H) 310.2 (M + H)+;
    Rt-0.46 min
    229: (R)-N-((S)-1-(2-(4- 8.01 (d, J = 8.0 Hz, 2H), MS m/z
    (difluoromethyl)phenyl)thiazol-5-yl)ethyl)-2- 7.74 (s, 1H), 7.59 (d, J = 8.0 Hz, 2H), 359.1 (M + H)+;
    methylpropane-2-sulfinamide 6.69 (t, J = 56 Hz, 1H), 4.91 (m, Rt-0.89 min
    1H), 3.45 (d, J = 4.7 Hz, 1H),
    1.72 (d, J = 6.6 Hz, 3H),
    1.25 (s, 9H)
    230: (R)-2-methyl-N-((S)-1-(2-(6- 9.01 (d, J = 2.2 Hz, 1H), MS m/z
    methylpyridin-3-yl)thiazol-5- 8.10 (dd, J = 8.1, 2.3 Hz, 1H), 324.1 (M + H)+;
    yl)ethyl)propane-2-sulfinamide 7.73 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), Rt-0.49 min
    4.91 (m, 1H), 3.46 (d, J = 4.8 Hz,
    1H), 2.62 (s, 3H), 1.72 (d, J = 6.6 Hz,
    3H), 1.25 (s, 9H)
    231: (R)-2-methyl-N-((S)-1-(2-(6- 9.23 (s, 1H), 8.40 (d, J = 8.3 Hz, MS m/z
    (trifluoromethyl)pyridin-3-yl)thiazol-5- 1H), 7.82 (s, 1H), 7.78 (d, J = 8.3 Hz, 378.1 (M + H)+;
    yl)ethyl)propane-2-sulfinamide 1H), 4.95 (m, 1H), Rt-0.84 min
    3.49 (d, J = 4.1 Hz, 1H),
    1.74 (d, J = 6.6 Hz, 3H), 1.26 (s, 9H)
    232: (R)-2-methyl-N-((S)-1-(2-(2- 8.82 (d, J = 5.0 Hz, 1H), MS m/z
    (trifluoromethyl)pyridin-4-yl)thiazol-5- 8.19 (s, 1H), 7.97 (dd, J = 5.0, 1.6 Hz, 378.1 (M + H)+;
    yl)ethyl)propane-2-sulfinamide 1H), 7.85 (s, 1H), 4.95 (m, Rt-0.85 min
    1H), 3.49 (d, J = 4.5 Hz, 1H),
    1.74 (d, J = 6.6 Hz, 3H),
    1.26 (s, 9H)
    233: (R)-2-methyl-N-((R)-1-(5- MS m/z
    (morpholinomethyl)isoxazol-3- 316.2 (M + H)+;
    yl)ethyl)propane-2-sulfinamide Rt-0.43 min
    234: (R)-2-methyl-N-((S)-1-(1-(6- 9.06 (d, J = 2.3 Hz, 1H), MS m/z
    (trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3- 8.22 (dd, J = 8.6, 1.9 Hz, 1H), 361.1 (M + H)+;
    yl)ethyl)propane-2-sulfinamide 7.98 (dd, J = 2.6, 0.9 Hz, 1H), Rt-0.85 min
    7.78 (d, J = 8.6 Hz, 1H), 6.51 (dd, J = 2.5,
    0.9 Hz, 1H), 4.76 (m,
    1H), 3.48 (d, J = 4.1 Hz, 1H),
    1.68 (d, J = 6.8 Hz, 3H),
    1.24 (s, 9H)
    235: (R)-N-((S)-1-(1-(4-chlorophenyl)-2- 7.45 (d, J = 8.6 Hz, 2H), MS m/z
    methyl-1H-imidazol-4-yl)ethyl)-2- 7.24 (d, J = 8.6 Hz, 2H), 6.87 (s, 1H), 340.1 (M + H)+;
    methylpropane-2-sulfinamide 4.54 (m, 1H), 3.48 (d, J = 5.8 Hz, Rt-0.64 min
    1H), 2.33 (s, 3H), 1.65 (d, J = 6.8 Hz,
    3H), 1.22 (s, 9H)
    • Intermediate 236: (R)-N-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00264
    • Step 1
  • To an oven dried round bottom flask with stir bar was added 4-bromo-2-fluorobenzaldehyde (5 g, 24.6 mmol), (R)-2-methylpropane-2-sulfinamide (3.28 g, 27.1 mmol) and DCE (49 mL). To this mixture was then added copper (II) sulfate (5.90 g, 36.9 mmol). Reaction mixture was heated in a preheated oil bath to 55° C. for 18 hours. Reaction mixture was filtered through a pad celite, washing the solids with CH2Cl2. The filtrate was concentrated to afford a viscous yellow oil of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (7.73 g, 25.2 mmol, 103% yield). 1H NMR (400 MHz, CDCl3) δ 1.27 (s, 9H) 7.31-7.42 (m, 2H) 7.87 (t, J=7.87 Hz, 1H) 8.83 (s, 1H). LCMS m/z 307.9 (M+H)+, Rt 1.01 min.
    • Step 2
  • To a solution of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (7.73 g, 25.2 mmol) in CH2Cl2 (252 mL), cooled to 0° C. (water/ice bath) under nitrogen, was added 3M methyl magnesium bromide (33.7 mL, 101 mmol) in Et2O. Reaction mixture allowed to stir for 30 min at 0° C., then gradually allowed to warm to room temperature and stirred for 1 hour at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl. Aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided (R)-N-((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (4.93 g, 15.3 mmol, 60% yield) as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 1.20 (s, 9H) 1.56 (d, J=6.70 Hz, 3H) 3.34 (br. s., 1H) 4.77-4.87 (m, 1H) 7.19-7.31 (m, 3H). LCMS m/z 324.0 (M+H)+, Rt 0.90 min.
    • Step 3
  • To a microwave vial with stir bar was added (R)-N-((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-(1 g, 3.10 mmol), isopropenyl boronic acid pinacol ester (1.51 ml, 8.07 mmol), DME (8 ml), sodium carbonate (7.76 ml, 15.5 mmol) (2.0 M aq) and PdCl2(dppf). CH2Cl2 adduct (0.127 g, 0.155 mmol). Vessel was capped and heated by microwave irradiation for 20 min at 100° C. Reaction mixture was diluted with a saturated solution of NH4Cl. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 50 to 100%) provided (R)-N-((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (830 mg, 2.93 mmol, 94% yield) as a pale brown crystalline. 1H NMR (400 MHz, DMSO) δ 1.08-1.11 (m, 9H) 1.47 (d, J=6.80 Hz, 3H) 2.09 (d, J=0.54 Hz, 3H) 4.61-4.71 (m, 1H) 5.14 (t, J=1.32 Hz, 1H) 5.43 (d, J=5.58 Hz, 1H) 5.49 (s, 1H) 7.24-7.30 (m, 1H) 7.31-7.36 (m, 1H) 7.41-7.47 (m, 1H). LCMS m/z 284.0 (M+H)+, Rt 0.93 min.
    • Step 4
  • To a round bottom flask containing (R)-N-((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-(0.37 g, 1.31 mmol) in DCE (13 mL) at 0° C. was added under argon diethylzinc (1.0M in hexanes) (13.1 mL, 13.1 mmol) followed by the dropwise addition of chloroiodomethane (0.95 mL, 13.1 mmol). Reaction mixture allowed to warm to room temperature and stirred for 1 hour. Reaction mixture was cooled to 0° C. whereupon a second addition of diethylzinc (1.0M in hexanes) (13.1 mL, 13.1 mmol) took place followed by the addition of chloroiodomethane (0.95 mL, 13.1 mmol). Reaction mixture allowed to warm to room temperature and stirred 18 hours under argon. Reaction mixture was cooled to 0° C. in a ice bath and to the cold reaction mixture was slowly added a saturated solution of NH4Cl. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 20 to 100%) provided a white crystalline of (R)-N-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (89 mg, 0.299 mmol, 22.92% yield). 1H NMR (400 MHz, CDCl3) δ 0.75-0.79 (m, 2H) 0.85-0.90 (m, 2H) 1.20 (s, 9H) 1.55 (s, 3H) 1.57 (d, J=6.80 Hz, 1H) 3.34 (d, J=5.23 Hz, 1H) 4.75-4.85 (m, 1H) 6.90 (dd, J=12.30, 1.74 Hz, 1H) 6.97 (dd, J=8.05, 1.78 Hz, 1H) 7.22 (t, J=7.97 Hz, 1H). LCMS m/z 298.1 (M+H)+, Rt 1.01 min.
    • Intermediate 237: (R)-N-((S)-1-(4-(1-ethoxycyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00265
    • Step 1
  • To a microwave vial with stir bar was added (R)-N-((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.55 mmol) followed by the addition of tributyl(1-ethoxyvinyl)stannane (1.12 g, 3.10 mmol), triethylamine (0.65 ml, 4.65 mmol) and PdCl2(dppf). CH2Cl2 adduct (63 mg, 0.078 mmol). To the solids was added toluene (10 ml). Vial capped and heated in a preheated sand bath at 100° C. for 1 hour. Reaction mixture was loaded onto silica gel column. Silica gel column chromatography (MeOH/CH2Cl2 0 to 10% with 1% NH4OH buffer) provided (R)-N-((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (498 mg, 1.59 mmol, 102% yield) as a brown viscous oil which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.20 (s, 9H) 1.43 (t, J=6.97 Hz, 3H) 1.58 (d, J=6.75 Hz, 3H) 3.35 (d, J=4.74 Hz, 1H) 3.92 (q, J=6.96 Hz, 2H) 4.23 (d, J=2.79 Hz, 1H) 4.65 (d, J=2.79 Hz, 1H) 4.79-4.89 (m, 1H) 7.16-7.20 (m, 1H) 7.29-7.34 (m, 1H) 7.39 (dd, J=8.07, 1.66 Hz, 1H).
    • Step 2
  • To a round bottom flask containing (R)-N-((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.49 g, 1.56 mmol) and chloroiodomethane (1.14 mL, 15.6 mmol) in toluene (15 mL) at 0° C. under argon was added diethylzinc (1.0M in hexanes) (15.6 mL, 15.6 mmol). Reaction mixture allowed to warm to room temperature and stirred for 1 hour. Reaction mixture was cooled to 0° C. in an ice bath and to the cold reaction mixture was slowly added a saturated solution of NH4Cl. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (MeOH/CH2Cl2 0 to 10%) provided (R)-N-((S)-1-(4-(1-ethoxycyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (145 mg, 0.44 mmol, 28% yield) as a viscous brown oil. 1H NMR (300 MHz, CDCl3) δ 0.93-0.99 (m, 2H) 1.14-1.20 (m, 3H) 1.21 (s, 9H) 1.22-1.27 (m, 2H) 1.57-1.61 (m, 4H) 3.35 (d, J=4.98 Hz, 1H) 3.45 (q, J=7.07 Hz, 2H) 4.77-4.87 (m, 1H) 6.98 (dd, J=7.58, 1.43 Hz, 3H) 7.00-7.03 (m, 4H) 7.28-7.32 (m, 1H). LCMS m/z 328.1 (M+H)+, Rt 0.95 min.
    • Intermediate 238: (R)-N-((S)-1-(4-(1-cyanocyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00266
    • Step 1
  • To a microwave vial with a stir bar was added (R)-N-((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (300 mg, 0.93 mmol), 4-isoxazoleboronic acid pinacol ester (218 mg, 1.12 mmol), PdCl2(dppf).CH2Cl2 adduct (76 mg, 0.09 mmol), potassium fluoride (2.7 mL, 1.0 M in water, 2.79 mmol) and finally DMSO (9 mL). The reaction mixture was degassed with bubbling nitrogen (3 min) and the vial capped and heated in a preheated oil bath at 130° C. for 18 hours. The reaction mixture was diluted with a saturated solution of NH4Cl and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptanes 40 to 100%) provided (R)-N-((S)-1-(4-(cyanomethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (136 mg, 0.48 mmol, 52% yield) as a viscous brown oil. 1H NMR (400 MHz, CDCl3) δ 1.19 (s, 9H) 1.57 (d, J=6.80 Hz, 3H) 3.39 (d, J=4.35 Hz, 1H) 3.74 (s, 2H) 4.81-4.88 (m, 1H) 7.04 (d, J=10.66 Hz, 1H) 7.11 (d, J=7.97 Hz, 1H) 7.38 (t, J=7.73 Hz, 1H). LCMS m/z 283.0 (M+H)+, Rt 0.72 min.
    • Step 2
  • To a scintillation vial containing (R)-N-((S)-1-(4-(cyanomethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-(86 mg, 0.31 mmol) and a stir bar was added toluene (2 mL). To this mixture was then added tetrabutylammonium bromide (19 mg, 0.06 mmol) followed by the addition of NaOH (1.52 ml, 1.0 M (aq), 1.52 mmol) and 1,2-dibromoethane (0.11 ml, 1.22 mmol). Vial capped and reaction mixture was stirred vigorously at room temperature for 18 hours. Whereupon, 1,2-dibromoethane (0.11 ml, 1.22 mmol) and tetrabutylammonium bromide (19 mg, 0.06 mmol) were added and reaction mixture allowed to stir an additional 18 hours. A third addition of 1,2-dibromoethane (0.11 ml, 1.22 mmol) was added and the reaction mixture heated to 50° C. for an additional 18 hours in a preheated aluminum tray. The reaction mixture was quenched with a saturated solution of NH4Cl and the aqueous mixture extracted with EtOAc. Organics combined and washed twice with water, brine, dried (Na2SO4), filtered and concentrated. Crude material was passed through a small plug of silica gel using 10% MeOH:90% DCM to elute product. The solution was concentrated to afford a viscous orange oil of (R)-N-((S)-1-(4-(1-cyanocyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (23 mg, 0.08 mmol, 24% yield). 1H NMR (400 MHz, CDCl3) δ 1.20 (s, 9H) 1.38-1.44 (m, 2H) 1.56 (d, J=6.75 Hz, 3H) 1.73-1.79 (m, 2H) 3.37 (d, J=4.45 Hz, 1H) 4.78-4.88 (m, 1H) 6.94 (dd, J=11.35, 1.91 Hz, 1H) 7.09 (dd, J=8.07, 1.91 Hz, 1H) 7.34 (t, J=7.90 Hz, 1H). LCMS m/z 309.2 (M+H)+, Rt 0.83 min.
    • Intermediate 239: (R)-N-((S)-1-(2-fluoro-4-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00267
  • To a round bottom flask containing (R)-N-((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (204 mg, 0.72 mmol) and a stir bar was added MeOH (7.2 mL). To this solution was added palladium on carbon (77 mg, 10%, 0.07 mmol) in MeOH (1 mL). A hydrogen atmosphere was inserted and the resulting reaction mixture stirred at room temperature for 18 hours, at which time more palladium on carbon was added (300 mg) in MeOH (5 mL). A hydrogen atmosphere was inserted again and the reaction mixture allowed to stir an additional 18 hours at room temperature. The reaction mixture was filtered through a syringe filter and concentrated to afford a light brown viscous oil of (R)-N-((S)-1-(2-fluoro-4-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide (149 mg, 0.52 mmol, 73% yield) which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.20 (s, 9H) 1.24 (d, J=5.87 Hz, 6H) 1.58 (d, J=6.70 Hz, 3H) 2.89 (dt, J=13.79, 6.90 Hz, 1H) 3.35 (d, J=5.04 Hz, 1H) 4.76-4.85 (m, 1H) 6.90 (dd, J=12.03, 1.52 Hz, 1H) 6.98 (dd, J=7.90, 1.54 Hz, 1H) 7.24 (t, J=7.97 Hz, 1H). LCMS m/z 286.3 (M+H)+, Rt 1.01 min.
    • Intermediate 240: (R)-N-((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00268
  • To a two microwave vials with stir bars were added (R)-N-((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.5 g, 4.65 mmol), 1-methyl-4-1H-pyrazoleboronic acid pinacol ester (2.91 g, 13.9 mmol), DME (20 mL), sodium carbonate (11.6 mL, 23.3 mmol, 2.0 M aq) and PdCl2(dppf).CH2Cl2 adduct (190 mg, 0.23 mmol) divided between the two vials. The vials were capped and heated by microwave irradiation for 20 min at 100° C. respectively. The reaction mixtures combined, diluted with a saturated solution of NH4Cl and EtOAc. The phases were partitioned and the aqueous phase extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided a orange crystalline of (R)-N-((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.07 g, 3.31 mmol, 71% yield. 1H NMR (400 MHz, CDCL3) δ ppm 1.21 (s, 9H) 1.60 (d, J=6.80 Hz, 3H) 3.36 (d, J=4.25 Hz, 1H) 3.96 (s, 3H) 4.79-4.91 (m, 1H) 7.13 (dd, J=11.69, 1.61 Hz, 1H) 7.23 (dd, J=8.00, 1.64 Hz, 1H) 7.30-7.37 (m, 1H) 7.60 (s, 1H) 7.74 (s, 1H). LCMS m/z 324.0 (M+H)+, Rt 0.74 min.
  • The Intermediates in Table 13a were prepared by a method similar to the one described for the preparation of Intermediate 240.
  • TABLE 13a
    Figure US20140275083A1-20140918-C00269
         		Intermediate 241
    Figure US20140275083A1-20140918-C00270
         		Intermediate 242
  • TABLE 13b
    Chemical name, NMR chemical shifts and LCMS signal for each intermediate
    listed in Table 13.
    Intermediate: Name 1H NMR (400 MHz) δ ppm LCMS
    241: (R)-2-methyl-N-((S)-1-(4-(1- MS m/z 306.0
    methyl-1H-pyrazol-4- (M + H)+, Rt
    yl)phenyl)ethyl)propane-2- 0.71 min.
    sulfinamide
    242: (R)-N-((S)-1-(2-fluoro-4- (DMSO) 1.10 (s, 9 H) 1.47 (d, J = 6.75 Hz, 3 MS m/z 310.0
    (1H-pyrazol-4-yl)phenyl)ethyl)-2- H) 4.60-4.70 (m, 1 H) 5.41 (d, J = 5.48 Hz, (M + H)+, Rt
    methylpropane-2-sulfinamide 1 H) 7.38-7.44 (m, 3 H) 7.96 (br. s., 1 H) 0.67 min.
    8.23 (br. s., 1 H) 12.97 (br. s., 1 H)
    • Intermediate 243: (R)-N-((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00271
    • Step 1
  • To a oven dried round bottom flask with stir bar was added 2-fluoro-4-(trifluoromethyl)benzaldehyde (5 g, 26.0 mmol), (R)-2-methylpropane-2-sulfinamide (3.47 g, 28.6 mmol) and DCE (52 mL). To this mixture was then added copper (II) sulfate (6.23 g, 39.0 mmol). The reaction mixture was heated in a preheated oil bath at 55° C. for 18 hours. The reaction mixture was filtered through a pad celite, washing the solids with DCE. The filtrate was concentrated to afford a viscous green oil of (R,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methyl propane-2-sulfinamide (7.3 g, 24.7 mmol, 95% yield). Material was taken onto next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 9H) 7.44 (d, J=10.08 Hz, 1H) 7.51 (d, J=8.27 Hz, 1H) 8.13 (t, J=7.46 Hz, 1H) 8.92 (s, 1H). LCMS m/z 296.0 (M+H)+, Rt 1.02 min.
    • Step 2
  • To a solution of (R,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (7.3 g, 24.7 mmol) in CH2Cl2 (247 mL) cooled to 0° C. (water/ice bath) under nitrogen, was added 3M methyl magnesium bromide (33 mL, 99 mmol) in Et2O. Reaction mixture allowed to stir for 30 min at 0° C., then gradually allowed to warm to room temperature and stirred for 1 hour at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl. Aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided (R)-N-((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (4.68 g, 15.0 mmol, 61% yield) as a white crystalline solid. 1H NMR (400 MHz, CDCL3) δ 1.22 (s, 9H) 1.60 (d, J=6.80 Hz, 3H) 3.38 (d, J=4.01 Hz, 1H) 4.87-4.97 (m, 1H) 7.33 (d, J=10.32 Hz, 1H) 7.39-7.45 (m, 1H) 7.49-7.55 (m, 1H). LCMS m/z 312.0 (M+H)+, Rt 0.92 min.
    • Intermediate 244: (S)-tert-butyl 1-(3-chloro-4-(cyclopentylcarbamoyl)phenyl)ethyl carbamate
  • Figure US20140275083A1-20140918-C00272
    • Step 1
  • To a round bottom flask with stir bar was added 4-((S)-1-aminoethyl-2-chlorobenzoic acid HCl salt (1.05 g, 4.45 mmol) followed by the addition of THF (40 mL). To this solution was added DIEA (1.86 ml, 10.7 mmol). The reaction mixture becomes cloudy white followed by the addition of di-tert-butyl dicarbonate (1.07 g, 4.89 mmol). Resulting reaction mixture allowed to stir for 18 hours at room temperature. At which time the reaction mixture was then heated to 60° C. for 2 hours in a oil bath. Di-tert-butyl dicarbonate (1.07 g, 4.89 mmol) and NMP (20 ml) were then added and the resulting reaction mixture allowed to stir for 2 hours at 60° C. Volatiles were removed. The resulting oil was diluted with a saturated solution of NH4Cl and the aqueous mixture extracted with EtOAc. The organic phases combined, washed twice with water, brine, dried (Na2SO4), filtered and concentrated to a viscous yellow oil of (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-chlorobenzoic acid (2.32 g, 6.19 mmol, 139% yield) which contains some excess di-tert-butyl dicarbonate and NMP. LCMS m/z 284.9 (M+H)+ (carboxylic acid fragment+CH3CN adduct), Rt 0.75 min.
    • Step 2
  • To a round bottom flask with stir bar was added (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-chlorobenzoic acid (450 mg, 1.20 mmol), cyclopentylamine (355 μL, 3.60 mmol), EDC HCl (460 mg, 2.40 mmol), 1-hydroxy-7-aza-benzotriazole (229 mg, 1.68 mmol) and DMF (6 mL). To this mixture was then added DIEA (629 μL, 3.60 mmol). Reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phases were combined, washed with twice with water, brine, dried (Na2SO4), filtered and concentrated to a brown crystalline of (S)-tert-butyl 1-(3-chloro-4-(cyclopentylcarbamoyl)phenyl)ethylcarbamate (476 mg, 1.17 mmol, 97% yield). LCMS m/z 367.0 (M+H)+, Rt 0.90 min.
    • Intermediate 245: (R)-N-((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00273
    • Step 1
  • To a round bottom flask with stir bar was added 4-bromo-2,5-difluorobenzaldehyde (5.3 g, 24.0 mmol), (R)-2-methylpropane-2-sulfinamide (3.2 g, 26.4 mmol) and DCE (80 mL). To this mixture was then added copper (II) sulfate (5.74 g, 36.0 mmol). The reaction mixture was heated in a preheated oil bath at 60° C. for 18 hours. The reaction mixture was filtered through a pad celite, washing the solids with DCE. The filtrate was concentrated to afford a viscous green oil of (R,E)-N-(4-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (7.2 g, 22.2 mmol, 93% yield). Material was taken onto next step without further purification. LCMS m/z 326.0 (M+H)+, Rt 1.04 min.
    • Step 2
  • To a solution of (R,E)-N-(4-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (7.2 g, 22.2 mmol in CH2Cl2 (200 mL) cooled to 0° C. (water/ice bath) under nitrogen, was added 3M methyl magnesium bromide (29.6 mL, 89 mmol) in Et2O. Reaction mixture allowed to stir for 5 hours at 0° C. then quenched with the slow addition of a saturated solution of NH4Cl. Aqueous mixture adjusted to pH 8 with HCl (1 N) and extracted with DCM. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 30 to 100%) provided (R)-N-((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (6.86 g, 20.2 mmol, 91% yield) LCMS m/z 342.1 (M+H)+, Rt 0.96 min.
    • Step 3
  • To two microwave vials with stir bars were added (R)-N-((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.47 mmol), 1-Methyl-4-1H-pyrazoleboronic acid, pinacol ester (917 mg, 4.41 mmol), DME (6 ml), Na2CO3 (3.67 ml, 7.35 mmol) (2.0 M aq) and PdCl2(dppf).CH2Cl2 adduct (60.0 mg, 0.07 mmol) divided evenly between the two vessels. Vessels were capped and heated by microwave irradiation for 20 min at 100° C. Reaction mixtures were combined, diluted with a saturated solution of NH4Cl and EtOAc. Phases partitioned. Aqueous phase extracted with EtOAc and organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 60 to 100%) provided (R)-N-((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (370 mg, 1.08 mmol, 73.7% yield). 1H NMR (400 MHz, CDCL3) δ ppm 1.23 (s, 9H) 1.57-1.60 (m, 3H) 3.33 (d, J=4.06 Hz, 1H) 3.97 (s, 3H) 4.79-4.88 (m, 1H) 7.10 (dd, J=11.20, 6.06 Hz, 1H) 7.20 (dd, J=10.78, 6.19 Hz, 1H) 7.76 (d, J=2.20 Hz, 1H) 7.82 (s, 1H). LCMS m/z 342.1 (M+H)+, Rt 0.77 min.
    • Intermediate 246: (S)-N-((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00274
    • Step 1
  • To a mixture of 1H-imidazole-4-carbaldehyde (3.71 g, 38.6 mmol), 1-chloro-4-iodobenzene (13.81 g, 57.9 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.10 g, 7.72 mmol), copper(I) iodide (0.368 g, 1.93 mmol) and cesium carbonate (25.2 g, 77 mmol) was added DMF (50 mL). The reaction was sealed and heated to 110° C. for 18 hours. The reaction mixture was then cooled to room temperature and diluted with a saturated solution of NH4Cl. A brown solid develops. Solid was collected, washed with water and air dried. Solid material was then dissolved in 10% MeOH:90% DCM solution and dried (Na2SO4), filtered and concentrated to afford a dark brown solid 1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (8.55 g, 41.4 mmol, 107% yield). Material as used without further purification. LCMS m/z 207.1 (M+H)+, Rt 0.58 min.
    • Step 2
  • To a suspension of (S)-(−)tert-Butanesulfinamide (2.35 g, 19.4 mmol) and 1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (4 g, 19.4 mmol) in DCE (39 mL) was added CuSO4 (4.63 g, 29.0 mmol). The reaction mixture was heated at 60° C. for 18 hours in a oil bath. A dark brown suspension resulted. The reaction mixture was then cooled to room temperature, filtered through a pad of celite, rinsed with DCM. The solution was then concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (S,E)-N-((1-(4-chlorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.69 g, 5.45 mmol, 28.2% yield) as a light brown solid. LCMS m/z 310.0 (M+H)+, Rt 0.75 min.
    • Step 3
  • To a solution of (S,E)-N-((1-(4-chlorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.69 g, 5.45 mmol) in DCM (27 mL), cooled to −40° C. (acetone/dry ice) under N2, was added 3M MeMgBr (7.27 ml, 21.8 mmol) in diethyl ether. Reaction mixture allowed to stir for 1 hr at −40° C. Reaction mixture was quenched with the slow addition of a saturated solution of NH4Cl and diluted with EtOAc. Phases partitioned, aqueous phase extracted with EtOAc and the organic layers combined washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/MeOH:EtOAc 0 to 5%) provided (S)-N-((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (1.11 g, 3.41 mmol, 62% yield). 1H NMR (400 MHz, CDCL3) δ 1.25 (s, 9H) 1.58 (d, J=6.65 Hz, 3H) 3.80 (d, J=5.48 Hz, 1H) 4.59 (quin, J=6.36 Hz, 1H) 7.26 (s, 1H) 7.33 (d, J=8.61 Hz, 2H) 7.41-7.47 (m, 2H) 7.76 (d, J=1.17 Hz, 1H). LCMS m/z 326.1 (M+H)+, Rt 0.59 min.
    • Intermediate 247: (S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethanamine
  • Figure US20140275083A1-20140918-C00275
  • A solution of hydrochloric acid (4.0 M in 1,4-dioxane, 2.1 mL, 8.2 mmol, 2 equiv) was added to a solution of (R)-N-((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.34 g, 4.1 mmol) in 1,4-dioxane at room temperature. A precipitate formed. The suspension was stirred for 1 hour and then concentrated in vacuo to give the hydrochloride salt of (S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethanamine (1.1 g, light yellow solid), which was used without purification. 1H NMR (400 MHz, CD3OD) δ 7.87 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 6.98 (s, 1H), 4.72 (q, J=6.9 Hz, 1H), 1.72 (d, J=7.0 Hz, 3H). MS m/z 223.1 (M+H)+; Rt-0.59 min.
  • The intermediates in Table 14a were prepared using a method similar to that described for the preparation of Intermediate 247.
  • TABLE 14a
    Figure US20140275083A1-20140918-C00276
         		Intermediate 248
    Figure US20140275083A1-20140918-C00277
         		Intermediate 249
    Figure US20140275083A1-20140918-C00278
         		Intermediate 250
    Figure US20140275083A1-20140918-C00279
         		Intermediate 251
    Figure US20140275083A1-20140918-C00280
         		Intermediate 252
    Figure US20140275083A1-20140918-C00281
         		Intermediate 253
    Figure US20140275083A1-20140918-C00282
         		Intermediate 254
    Figure US20140275083A1-20140918-C00283
         		Intermediate 255
    Figure US20140275083A1-20140918-C00284
         		Intermediate 256
    Figure US20140275083A1-20140918-C00285
         		Intermediate 257
    Figure US20140275083A1-20140918-C00286
         		Intermediate 258
    Figure US20140275083A1-20140918-C00287
         		Intermediate 259
    Figure US20140275083A1-20140918-C00288
         		Intermediate 260
    Figure US20140275083A1-20140918-C00289
         		Intermediate 261
    Figure US20140275083A1-20140918-C00290
         		Intermediate 262
    Figure US20140275083A1-20140918-C00291
         		Intermediate 263
    Figure US20140275083A1-20140918-C00292
         		Intermediate 264
    Figure US20140275083A1-20140918-C00293
         		Intermediate 265
    Figure US20140275083A1-20140918-C00294
         		Intermediate 266
    Figure US20140275083A1-20140918-C00295
         		Intermediate 267
    Figure US20140275083A1-20140918-C00296
         		Intermediate 268
    Figure US20140275083A1-20140918-C00297
         		Intermediate 269
    Figure US20140275083A1-20140918-C00298
         		Intermediate 270
    Figure US20140275083A1-20140918-C00299
         		Intermediate 271
    Figure US20140275083A1-20140918-C00300
         		Intermediate 272
    Figure US20140275083A1-20140918-C00301
         		Intermediate 273
    Figure US20140275083A1-20140918-C00302
         		Intermediate 274
    Figure US20140275083A1-20140918-C00303
         		Intermediate 275
    Figure US20140275083A1-20140918-C00304
         		Intermediate 276
    Figure US20140275083A1-20140918-C00305
         		Intermediate 277
  • TABLE 14b
    Chemical name, NMR chemical shifts and LCMS signal for each intermediate
    listed in Table 14a.
    1H NMR (400 MHz, CD3OD) δ
    Intermediate: Name ppm LCMS
    248: (S)-1-(2-(4-chlorophenyl)thiazol-5- 7.97 (d, J = 8.7 Hz, 2H), MS m/z
    yl)ethanamine 7.94 (s, 1H), 7.52 (d, J = 8.7 Hz, 2H), 239.9 (M + H)+;
    4.95 (m, 1H), 1.78 (d, J = 6.8 Hz, Rt-0.59 min
    3H)
    249: (S)-1-(5-phenylthiophen-2- 7.29 (dd, J = 8.3, 1.2 Hz, 2H), MS m/z
    yl)ethanamine 7.05 (m, 2H), 6.99 (m, 2H), 187.1 (M − NH2)+;
    6.89 (dd, J = 3.8, 0.6 Hz, 1H), Rt-
    4.45 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H) 0.59 min
    250: (S)-1-(5-phenylisoxazol-3- 7.87 (m, 2H), 7.55 (m, 3H), MS m/z
    yl)ethanamine 6.95 (s, 1H), 4.72 (q, J = 6.9 Hz, 1H), 189.2 (M + H)+;
    1.73 (d, J = 6.9 Hz, 3H) Rt-0.50 min
    251: (S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4- 8.43 (s, 1H), 7.87 (s, 1H), MS m/z
    yl)ethanamine 7.78 (d, J = 9.0 Hz, 2H), 7.51 (d, J = 9.0 Hz, 223.1 (M + H)+;
    2H), 4.61 (q, J = 6.9 Hz, Rt-0.54 min
    1H), 1.72 (d, J = 6.9 Hz, 3H)
    252: (S)-1-(5-(4-fluorophenyl)isoxazol-3- 7.92 (dd, J = 9.0, 5.2 Hz, 2H), MS m/z
    yl)ethanamine 7.30 (t, J = 8.8 Hz, 2H), 6.92 (s, 207.1 (M + H)+;
    1H), 4.71 (q, 7.0 Hz, 1H), Rt-0.51 min
    1.72 (d, J = 7.0 Hz, 3H)
    253: (S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4- 8.39 (s, 1H), 7.86 (s, 1H), MS m/z
    yl)ethanamine 7.78 (dd, J = 9.2, 4.6 Hz, 2H), 207.1 (M + H)+;
    7.25 (dd, J = 9.1, 8.4 Hz, 2H), Rt-0.46 min
    4.60 (q, J = 6.9 Hz, 1H), 1.71 (d, J = 6.9 Hz,
    3H)
    254: (S)-1-(5-(pyridin-2-yl)thiophen-2- 8.73-8.78 (m, 1 H), 8.57 (td, MS m/z
    yl)ethanamine J = 8.0, 1.6 Hz, 1 H), 8.31 (d, 206.0 (M + H)+;
    J = 8.3 Hz, 1 H), 8.03 (d, J = 4.0 Hz, Rt-0.35 min
    1 H), 7.92 (ddd, J = 7.5, 6.0,
    1.1 Hz, 1 H), 7.50 (dd, J = 4.0,
    0.6 Hz, 1 H), 4.91-4.98 (m, 1
    H) 1.80 (d, J = 6.8 Hz, 3 H)
    255: (S)-1-(5-(morpholinomethyl)isoxazol-3- 6.97 (s, 1H), 4.72 (m, 3H), MS m/z
    yl)ethanamine 3.96 (m, 4H), 3.38 (m, 4H), 1.70 (d, J = 7.0 Hz, 212.1 (M + H)+;
    3H) Rt-0.14 min
    256: (S)-1-(2-morpholinothiazol-5- 7.56 (s, 1H), 4.78 (quin, J = 6.8 Hz, MS m/z
    yl)ethanamine 1H), 3.88 (m, 4H), 3.68 (m, 197.0 (M − NH2)+;
    4H), 1.71 (d, J = 6.9 Hz, 3H) Rt-
    0.26 min
    257: (S)-1-(2-(pyridin-2-yl)thiazol-5- 8.68 (m, 1H), 8.30 (m, 1H), MS m/z
    yl)ethanamine 8.17 (m, 1H), 8.09 (m, 1H), 7.66 (m, 189.0 (M − NH2)+;
    1H), 4.99 (q, J = 7.1 Hz, 1H), Rt-
    1.80 (d, J = 6.9 Hz, 3H) 0.39 min
    258: (S)-1-(2-(pyridin-3-yl)thiazol-5- 9.49 (d, J = 2.0 Hz, 1H), MS m/z
    yl)ethanamine 9.14 (m, 1H), 8.96 (m, 1H), 189.0 (M − NH2)+;
    8.23 (ddd, J = 8.3, 5.8, 0.7 Hz, 1H), Rt-
    8.17 (d, J = 0.7 Hz, 1H), 0.25 min
    5.04 (q, J = 6.9 Hz, 1H), 1.82 (d, J = 6.9 Hz,
    3H)
    259: (S)-1-(2-(pyridin-4-yl)thiazol-5- 8.97 (d, J = 6.9 Hz, 2H), MS m/z
    yl)ethanamine 8.62 (d, J = 6.9 Hz, 2H), 8.29 (d, J = 0.6 Hz, 189.0 (M − NH2)+;
    1H), 5.08 (q, J = 6.8 Hz, Rt-
    1H), 1.84 (d, J = 6.9 Hz, 3H) 0.24 min
    260: (S)-1-(2-(4- 8.09 (d, J = 7.7 Hz, 2H), MS m/z
    (difluoromethyl)phenyl)thiazol-5- 7.99 (s, 1H), 7.68 (d, J = 7.7 Hz, 2H), 256.0 (M + H)+;
    yl)ethanamine 6.84 (t, J = 56 Hz, 1H), 4.96 (m, Rt-0.56 min
    1H), 1.78 (d, J = 6.9 Hz, 3H)
    261: (S)-1-(2-(6-methylpyridin-3-yl)thiazol-5- 9.30 (d, J = 2.0 Hz, 1H), MS m/z
    yl)ethanamine 8.98 (dd, J = 8.5, 2.0 Hz, 1H), 220.1 (M + H)+;
    8.14 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H), Rt-0.27 min
    5.03 (q, J = 6.9 Hz, 1H),
    2.87 (s, 3H), 1.82 (d, J = 6.9 Hz, 3H)
    262: (S)-1-(2-(6-(trifluoromethyl)pyridin-3- 9.31 (d, J = 2.1 Hz, 1H), MS m/z
    yl)thiazol-5-yl)ethanamine 8.59 (dd, J = 8.2, 1.7 Hz, 1H), 274.0 (M + H)+;
    8.10 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), Rt-0.51 min
    5.01 (q, J = 6.8 Hz, 1H),
    1.81 (d, J = 6.8 Hz, 3H)
    263: (S)-1-(2-(2-(trifluoromethyl)pyridin-4- 8.87 (d, J = 5.1 Hz, 1H), MS m/z
    yl)thiazol-5-yl)ethanamine 8.34 (dd, J = 1.5, 0.7 Hz, 1H), 274.0 (M + H)+;
    8.17 (m, 1H), 5.02 (q, J = 6.9 Hz, Rt-0.51 min
    1H), 1.82 (d, J = 6.9 Hz, 3H)
    264: (R)-1-(5-(morpholinomethyl)isoxazol-3- 7.01 (s, 1H), 4.74 (m, 3H), MS m/z
    yl)ethanamine 4.00-3.86 (br m, 4H), 212.2 (M + H)+;
    3.45-3.37 (br m, 4H), 1.70 (d, J = 6.9 Hz, Rt-0.14 min
    3H)
    265: (S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)- 9.29 (d, J = 2.4 Hz, 1H), MS m/z
    1H-pyrazol-3-yl)ethanamine 8.56 (d, J = 2.6 Hz, 1H), 8.47 (dd, J = 8.6, 257.0 (M + H)+;
    2.5 Hz, 1H), 7.98 (d, J = 8.6 Hz, Rt-0.12 min
    1H), 6.73 (d, J = 2.6 Hz,
    1H), 4.68 (q, J = 7.0 Hz, 1H),
    1.72 (d, J = 6.9 Hz, 3H)
    266: (S)-1-(1-(4-chlorophenyl)-2-methyl-1H- 7.83 (d, J = 0.7 Hz, 1H), MS m/z
    imidazol-4-yl)ethanamine 7.72 (m, 2H), 7.63 (m, 2H), 4.75 (q, J = 7.0 Hz, 236.1 (M + H)+;
    1H), 2.63 (s, 3H), Rt-0.45 min
    1.79 (d, J = 7.0 Hz, 3H)
    267: (S)-1-(2-fluoro-4-(1- MS m/z
    methylcyclopropyl)phenyl)ethanamine 194.1 (M + H)+,
    Rt
    0.60 min.
    268: (S)-1-(4-(1-ethoxycyclopropyl)-2- (D2O) 0.98 (s, 1 H) MS m/z
    fluorophenyl)ethanamine 1.03-1.08 (m, 2 H) 1.14 (t, J = 7.09 Hz, 1 H) 224.1 (M + H)+,
    1.25-1.30 (m, 2 H) 1.64 (d, Rt
    J = 6.99 Hz, 3 H) 3.45-3.59 (m, 0.56 min.
    2 H) 7.16 (dd, J = 5.58, 1.47 Hz,
    1 H) 7.17-7.21 (m, 1 H)
    7.40-7.48 (m, 1 H)
    269: (S)-1-(4-(1-aminoethyl)-3- MS m/z
    fluorophenyl)cyclopropanecarbonitrile 205.1 (M + H)+,
    Rt
    0.44 min.
    270: (S)-1-(2-fluoro-4- MS m/z
    isopropylphenyl)ethanamine 182.1 (M + H)+,
    Rt
    0.59 min.
    271: (S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol- MS m/z
    4-yl)phenyl)ethanamine 220.1 (M + H)+,
    Rt
    0.43 min.
    272: (S)-1-(4-(1-methyl-1H-pyrazol-4- MS m/z
    yl)phenyl)ethanamine 185.1 (M + H)+,
    Rt
    0.41 min.
    273: (S)-1-(2-fluoro-4-(1H-pyrazol-4- (D2O) 1.66 (d, J = 6.99 Hz, 3 H) MS m/z
    yl)phenyl)ethanamine 4.76-4.82 (m, 1 H) 206.1 (M + H)+,
    7.39-7.52 (m, 3 H) 8.16 (s, 2 H) Rt
    0.37 min.
    274: (S)-1-(2-fluoro-4- (D2O) 1.67 (d, J = 6.94 Hz, 3 H) MS m/z
    (trifluoromethyl)phenyl)ethanamine 4.84 (q, J = 6.94 Hz, 1 H) 208.0 (M + H)+,
    7.54-7.70 (m, 3 H) Rt
    0.51 min.
    275: (S)-4-(1-aminoethyl)-2-chloro-N- MS m/z
    cyclopentylbenzamide 267.0 (M + H)+,
    Rt
    0.50 min.
    276: (S)-1-(2,5-difluoro-4-(1-methyl-1H- (D2O) 1.65 (d, J = 6.94 Hz, 3 H) MS m/z
    pyrazol-4-yl)phenyl)ethanamine 3.53 (q, J = 7.11 Hz, 1 H) 239.1 (M + H)+,
    3.91 (s, 3 H) 7.28 (dd, J = 11.10, 6.26 Hz, Rt
    1 H) 7.44 (dd, J = 11.18, 0.45 min.
    6.24 Hz, 1 H) 7.94 (s, 1 H)
    8.06 (d, J = 1.86 Hz, 1 H)
    277: (S)-1-(1-(4-chlorophenyl)-1H-imidazol- (D2O) 1.74 (d, J = 6.65 Hz, 3 H) MS m/z
    4-yl)ethanamine 4.76-4.85 (m, 1 H) 7.61 (q, 222.1 (M + H)+,
    J = 9.00 Hz, 4 H) 8.00 (s, 1 H) Rt
    9.04 (s, 1 H) 0.44 min.
    • Intermediate 278: (S)-1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethanamine
  • Figure US20140275083A1-20140918-C00306
    • Step 1
  • To a round bottom flask containing (R)-N-((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.02 g, 3.60 mmol) was added dioxane (7 mL). To this homogenous solution was then added HCl in Dioxane (1.80 mL, 7.20 mmol, 4 M). Resulting reaction mixture allowed to stir 10 min at room temperature. Volatiles removed. Et2O was added and mixture sonnicated briefly. Volatiles removed again. Et2O was added and the solid collected and washed with Et2O to afford a white HCl salt of (S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethanamine (742 mg, 3.44 mmol, 96% yield). 1H NMR (400 MHz, D2O) δ 1.65 (d, J=6.94 Hz, 3H) 2.12 (s, 3H) 5.23 (s, 1H) 5.50 (s, 1H) 7.37 (d, J=13.06 Hz, 1H) 7.43 (m, 2H). LCMS m/z 163.2 (deamino fragment) (M+H)+, Rt 0.56 min.
    • Step 2
  • To a RBF containing (S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethanamine (742 mg, 3.44 mmol) was added NMP (7 mL). To this solution was then added TEA (959 μl, 6.88 mmol) followed by the addition of Di-tert-butyl dicarbonate (976 mg, 4.47 mmol). Resulting reaction mixture allowed to stir 2 hr at room temperature. Reaction mixture was diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptanes 0 to 100%) provided (S)-tert-butyl (1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)carbamate (1.28 g, 4.58 mmol, 133% yield) as a white crystalline. 1H NMR (400 MHz, CDCl3) δ 1.40-1.48 (m, 12H) 2.12 (d, J=0.44 Hz, 3H) 4.98 (br. s., 2H) 5.10-5.12 (m, 1H) 5.37 (s, 1H) 7.11-7.16 (m, 1H) 7.19-7.24 (m, 2H). LCMS m/z 163.0 (deamino fragment) (M+H)+, Rt 1.13 min.
    • Step 3
  • To a round bottom flask containing (S)-tert-butyl (1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)carbamate (1.28 g, 4.58 mmol) was added DCM (23 mL). The homogenous solution was cooled to −70° C. in a acetone/dry ice bath. Ozone (g) was then gently bubbled through the solution for 25 min at which time the solution becomes pale blue in color. Dimethyl sulfide (1.02 mL, 13.8 mmol) was then added to the cold solution and mixture gradually allowed to warm to room temperature and stirred for 30 min. Reaction mixture was diluted with a water. Phases partitioned. Aqueous phase extracted with DCM. Organic phases combined, washed with brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided (S)-tert-butyl (1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (296 mg, 1.05 mmol, 23% yield) as a colorless oil that crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.38-1.49 (m, 12H) 2.59 (s, 3H) 5.01 (br. s., 1H) 7.40 (t, J=7.65 Hz, 1H) 7.62 (dd, J=11.20, 1.57 Hz, 1H) 7.71 (dd, J=7.95, 1.54 Hz, 1H). LCMS m/z 267.1 (carboxylic acid fragment+CH3CN) (M+H)+, Rt 0.89 min.
    • Step 4
  • To a solution of (S)-tert-butyl (1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (296 mg, 1.05 mmol) in DCM (5.2 mL), cooled to 0° C. (water/ice bath) under N2, was added 3M MeMgBr (1.4 mL, 4.21 mmol) in diethyl ether. Reaction mixture allowed to stir for 5 min at 0° C. Then gradually allowed to warm to room temperature and stirred for 30 min at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl and diluted with DCM. Phases partitioned, aqueous phase extracted with DCM and the organic layers combined washed with water, brine, dried (Na2SO4), filtered and concentrated to (S)-tert-butyl (1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (288 mg, 0.97 mmol, 92% yield) afford as a colorless oil which slowly crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.39-1.48 (m, 12H) 1.57 (s, 6H) 7.15-7.25 (m, 2H) 7.31-7.36 (m, 1H).
    • Step 5
  • To a RBF containing (S)-tert-butyl (1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (288 mg, 0.97 mmol) was added DCM (5 mL) the resulting colorless solution was cooled to −70° C. in a dry ice/acetone bath. To this cold solution under N2 was then added DAST (0.26 mL, 1.94 mmol) resulting reaction mixture allowed to stir 1 hr at −70° C. To the cold solution was added ice and resulting mixture allowed to warm to room temperature. Mixture diluted with DCM, phases partioned and the aqueous phase extracted with DCM. Organic layers combined, washed with brine, dried (Na2SO4), filtered and concentrated to onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 50%) provided (S)-tert-butyl (1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethyl)carbamate (126 mg, 0.42 mmol, 44% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.39-1.49 (m, 12H) 1.66 (d, J=21.52 Hz, 6H) 4.97 (br. s., 1H) 7.04-7.12 (m, 2H) 7.22-7.26 (m, 1H). LCMS m/z 285.1 (carboxylic acid fragment+CH3CN) (M+H)+, Rt 1.06 min.
    • Step 6
  • To a round bottom flask containing (S)-tert-butyl (1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethyl)carbamate (126 mg, 0.42 mmol) was added HCl in dioxane (2.1 mL, 8.42 mmol). Resulting reaction mixture allowed to stir 1 hr at room temperature. Volatiles were removed. Et2O was then added and the mixture sonnicated briefly. Volatiles were once again removed to a afford an HCl salt of (S)-1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethanamine (104 mg, 0.44 mmol, 105% yield) as a white solid. 1H NMR (400 MHz, D2O) δ 1.59-1.80 (m, 9H) 7.24-7.37 (m, 2H) 7.43-7.56 (m, 1H). LCMS m/z 200.1 (M+H)+, Rt 0.54 min.
    • Intermediate 279: (S)-2-(4-(1-aminoethyl)-3-fluorophenyl)propan-2-ol
  • Figure US20140275083A1-20140918-C00307
    • Step 1
  • To a microwave vial with stir bar was added (R)-N-((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1 g, 3.10 mmol) followed by the addition of tributyl(1-ethoxyvinyl)stannane (2.24 g, 6.21 mmol), TEA (1.3 mL, 9.31 mmol) and PdCl2(dppf).CH2Cl2 adduct (0.127 g, 0.155 mmol). To the solids was then added toluene (10 mL). Vial capped and heated by microwave irradiation at 100° C. for 30 min. To this reaction mixture was added 1 ml of TFA to try to convert vinyl ether to the ketone which was unsuccessful. Resulting reaction mixture allowed to stir 5 min at room temperature. Reaction mixture was then quenched with a saturated solution of NaHCO3 to pH 8. Aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided (R)-N-((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.60 g, 1.91 mmol, 62% yield) as a yellow viscous residue. 1H NMR (400 MHz, CDCl3) δ 1.20 (s, 9H) 1.43 (t, J=6.94 Hz, 3H) 1.56-1.63 (m, 5H) 3.36 (d, J=3.13 Hz, 1H) 3.92 (q, J=6.96 Hz, 2H) 4.23 (br. s., 1H) 4.65 (s, 1H) 4.79-4.91 (m, 1H) 7.30 (s, 2H) 7.40 (d, J=8.02 Hz, 1H).
    • Step 2
  • To a round bottom flask containing (R)-N-((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.91 mmol) was added MeOH (19 mL). To this homogenous solution was then added HCl (aq) (3.2 mL, 19.1 mmol, 3 M). Resulting reaction mixture was stirred at room temperature for 30 min. Volatiles were then removed. Residue triturated with Et2O to provide (S)-1-(4-(1-aminoethyl)-3-fluorophenyl)ethanone (0.43 g, 1.98 mmol, 103% yield) as a HCl salt. 1H NMR (400 MHz, D2O) δ 1.67 (d, J=6.99 Hz, 3H) 2.64 (s, 3H) 4.80-4.87 (m, 1H) 7.61 (t, J=7.73 Hz, 1H) 7.77 (dd, J=11.30, 1.66 Hz, 1H) 7.87 (dd, J=8.09, 1.64 Hz, 1H). LCMS m/z 182.0 (M+H)+, Rt 0.36 min.
    • Step 3
  • To a round bottom flask with stir bar was added (S)-1-(4-(1-aminoethyl)-3-fluorophenyl)ethanone (0.43 g, 1.98 mmol) followed by the addition of NMP (9.9 mL). To this solution was then added DIEA (0.83 mL, 4.74 mmol) and Di-tert-butyl dicarbonate (0.95 g, 4.35 mmol). The resulting reaction mixture allowed to stir 2 hr at room temperature. Reaction mixture was diluted with water, extracted with EtOAc. Organic phase washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (S)-tert-butyl 1-(4-acetyl-2-fluorophenyl)ethylcarbamate (369 mg, 1.31 mmol, 66.4% yield) as a colorless oil which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.38-1.49 (m, 12H) 2.59 (s, 3H) 5.01 (br. s., 1H) 7.40 (t, J=7.65 Hz, 1H) 7.62 (dd, J=11.20, 1.57 Hz, 1H) 7.71 (dd, J=7.95, 1.54 Hz, 1H). LCMS m/z 267.1 (carboxylic acid fragment+CH3CN) (M+H)+, Rt 0.89 min.
    • Step 4
  • To a solution of (S)-tert-butyl (1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (200 mg, 0.71 mmol) in DCM (7.1 mL), cooled to 0° C. (water/ice bath) under N2, was added 3M MeMgBr (10.95 mL, 2.84 mmol) in diethyl ether. Reaction mixture allowed to stir for 5 min at 0° C. Then gradually allowed to warm to room temperature and stirred for 30 min at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl and diluted with DCM. Phases partitioned, aqueous phase extracted with DCM and the organic layers combined washed with water, brine, dried (Na2SO4), filtered and concentrated to (S)-tert-butyl (1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (184 mg, 0.62 mmol, 87% yield) afford as a colorless oil which slowly crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.39-1.48 (m, 12H) 1.57 (s, 6H) 7.15-7.25 (m, 2H) 7.31-7.36 (m, 1H).
    • Step 5
  • To a round bottom flask containing (S)-tert-butyl (1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (184 mg, 0.62 mmol) and a stir bar was added dioxane (2 mL). To this reaction mixture was then added HCl in dioxane (0.93 ml, 3.71 mmol, 4.0M). Resulting reaction mixture allowed to stir at room temperature for 18 hr. Volatiles were then removed. Residue triturated with Et2O to afford (S)-2-(4-(1-aminoethyl)-3-fluorophenyl)propan-2-ol (142 mg, 0.61 mmol, 98% yield) as a HCl salt. 1H NMR (400 MHz, D2O) δ 1.53 (s, 6H) 1.64 (d, J=7.04 Hz, 3H) 3.73 (s, 1H) 7.28-7.37 (m, 2H) 7.42-7.48 (m, 1H). LCMS m/z 198.1 (M+H)+, Rt 0.37 min.
    • Intermediate 280: (R)-N-((S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00308
  • To a mixture of ethyl 2-oxocyclohexanecarboxylate (58.0 mg, 0.341 mmol), (R)-N-((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (580 mg, 1.705 mmol), Cs2CO3 (1555 mg, 4.77 mmol), copper(I) iodide (32.5 mg, 0.170 mmol) was added 2,2,2-trifluoroethanol (871 μl, 11.93 mmol). The reaction was sealed and heated at 78° C. for 24 hours. LCMS indicated complete conversion to product. The reaction mixture was then cooled to room temperature and diluted with EtOAc (20 mL). The mixture was filtered through a pad of celite and the pad was rinsed with EtOAc (20 mL). The organic was washed with water (2×15 mL), dried (Na2SO4) and concentrated. The residue was then filtered through a pad of silica gel (30 g) with EtOAc/heptane (1:3) to give crude (R)-N-((S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.601 g). LCMS (B) m/z 360.1 (M+H)+
    • Intermediate 281: (S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine
  • Figure US20140275083A1-20140918-C00309
  • To a solution of (R)-N-((S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.601 g, 1.672 mmol) in dioxane (10 ml) was added dropwise HCl (0.836 ml, 3.34 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS indicated complete conversion to product. The reaction mixture was concentrated and DCM (20 mL) and saturated NaHCO3 solution (10 mL) was added to the residue. The mixture was stirred for 10 minutes and phases were separated. Aqueous layer was then extracted with DCM (2×10 mL), and the combined organic was dried (Na2SO4) and concentrated to give crude product. LCMS (B) m/z 256.2 (M+H)+
  • The intermediates in Table 15a were prepared using a method similar to that described for the preparation of Intermediate 281.
  • TABLE 15a
    Figure US20140275083A1-20140918-C00310
         		Intermediate 282
    Figure US20140275083A1-20140918-C00311
         		Intermediate 283
    Figure US20140275083A1-20140918-C00312
         		Intermediate 284
  • TABLE 15b
    Chemical name and analytical data for each intermediate
    listed in Table 15a.
    Intermediate: Name Analytical data
    282: (S)-1-(4-bromo-2,5- LCMS m/z (M + H)+ 239.2,
    difluorophenyl)ethanamine RT 0.52 min.
    283: (S)-1-(2-fluoro-4-(2,2,2- LCMS m/z (M + H)+ 238.3,
    trifluoroethoxy)phenyl)ethanamine RT 0.57 min.
    284: (S)-1-(3-fluoro-4-(2,2,2- LCMS m/z (M + H)+ 238.3,
    trifluoroethoxy)phenyl)ethanamine RT 0.58 min.
    • Intermediate 285: (R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00313
  • To a mixture of 1H-pyrazole-3-carbaldehyde (1.52 g, 15.82 mmol), 1-chloro-4-iodobenzene (5.66 g, 23.73 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.450 g, 3.16 mmol), copper(I) iodide (0.151 g, 0.791 mmol) and K2CO3 (4.37 g, 31.6 mmol) was added toluene (20 mL). The reaction was sealed and heated to 110° C. for 18 hours. The reaction mixture was then cooled to room temperature and diluted with water (50 mL), and extracted with EtOAc (3×30 mL). The combined organic was then dried (Na2SO4) and concentrated to give crude 1-(4-chlorophenyl)-1H-pyrazole-3-carbaldehyde (1.86 g, 9.0 mmol), to which was added (R)-2-methylpropane-2-sulfinamide (1.20 g, 9.90 mmol), CuSO4 (2.155 g, 13.50 mmol) and DCE (30 ml). The reaction was sealed, heated at 60° C. for 18 hours. A dark green suspension resulted. The reaction mixture was then cooled to 20° C., filtered through a pad of celite, rinsed with DCM. The solution was then concentrated to give final crude product as a light green oil. The residue was purified via silica gel chromatography (EtOAc/Heptane). LCMS (B) m/z 310.3 (M+H)+
    • Intermediate 286: (R)-N-((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00314
  • To a solution of (R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (2.12 g, 6.84 mmol) in DCM (40 ml) at −40° C. was added methylmagnesium bromide (9.12 ml, 27.4 mmol). The reaction was stirred at −40° C. for 3 hours. The reaction mixture was then quenched with saturated NH4Cl solution (20 mL). The aqueous layer was adjusted to pH=8 with HCl (1M) and extracted with DCM (2×200 mL). The combined organic was dried (Na2SO4) and concentrated. The residue was then purified via silica gel chromatography (EtOAC/heptane) to give (R)-N-((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.11 g). LCMS (B) m/z 326.3 (M+H)+
    • Intermediate 287: (R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethanamine
  • Figure US20140275083A1-20140918-C00315
  • To a solution of (R)-N-((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.98 g, 3.01 mmol) in dioxane (10 ml) was added dropwise HCl (1.504 ml, 6.01 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS indicated complete conversion to product. The reaction mixture was concentrated and DCM (20 mL) and saturated NaHCO3 solution (10 mL) was added to the residue. The mixture was stirred for 10 minutes and phases were separated. Aqueous layer was then extracted with DCM (2×10 mL), and the combined organic was dried (Na2SO4) and concentrated to give product (0.556 g). LCMS (B) m/z 222.2 (M+H)+
    • Intermediate 288: (R)-N-((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00316
  • To a solution of (R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (2.12 g, 6.84 mmol) in DCM (40 ml) at −40° C. was added methylmagnesium bromide (9.12 ml, 27.4 mmol). The reaction was stirred at −40° C. for 3 hours. The reaction mixture was then quenched with saturated NH4Cl solution (20 mL). The aqueous layer was adjusted to pH=8 with HCl (1M) and extracted with DCM (2×200 mL). The combined organic was dried (Na2SO4) and concentrated. The residue was then purified via silica gel chromatography (EtOAC/heptane) to give (R)-N-((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.01 g). LCMS (B) m/z 326.3 (M+H)+
    • Intermediate 289: (S)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethanamine
  • Figure US20140275083A1-20140918-C00317
  • To a solution of (R)-N-((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.98 g, 3.01 mmol) in dioxane (10 ml) was added dropwise HCl (1.504 ml, 6.01 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS indicated complete conversion to product. The reaction mixture was concentrated and DCM (20 mL) and saturated NaHCO3 solution (10 mL) was added to the residue. The mixture was stirred for 10 minutes and phases were separated. Aqueous layer was then extracted with DCM (2×10 mL), and the combined organic was dried (Na2SO4) and concentrated to give crude product (0.501 g). LCMS (B) m/z 222.2 (M+H)+
  • The intermediates in Table 16a were prepared using a method similar to that described for the preparation of Intermediate 289
  • TABLE 16a
    Figure US20140275083A1-20140918-C00318
         		Intermediate 290
    Figure US20140275083A1-20140918-C00319
         		Intermediate 291
    Figure US20140275083A1-20140918-C00320
         		Intermediate 292
    Figure US20140275083A1-20140918-C00321
         		Intermediate 293
    Figure US20140275083A1-20140918-C00322
         		Intermediate 294
    Figure US20140275083A1-20140918-C00323
         		Intermediate 295
  • TABLE 16b
    Chemical name and analytical data for each intermediate listed in Table 16a.
    Intermediate: Name Analytical data
    290: (S)-1-(5-bromo-3-fluoropyridin-2- LCMS (B) m/z (M + H)+ 219.0, 221.0, RT
    yl)ethanamine 0.37 min.
    291: (R)-1-(5-bromo-3-fluoropyridin-2- LCMS (B) m/z (M + H)+ 219.0, 221.0, RT
    yl)ethanamine 0.38 min.
    292: (S)-1-(5-bromopyridin-2-yl)ethanamine LCMS (B) m/z (M + H)+ 201.0, 203.0, RT
    0.37 min.
    293: (R)-1-(5-bromopyridin-2-yl)ethanamine LCMS (B) m/z (M + H)+ 201.0, 203.0, RT
    0.40 min.
    294: (S)-1-(3,5-dichloropyridin-2-yl)ethanamine LCMS (B) m/z (M + H)+ 191.1, RT 0.45 min.
    295: (R)-1-(3,5-dichloropyridin-2-yl)ethanamine LCMS (B) m/z (M + H)+ 191.1, RT 0.44 min.
    • Intermediate 296: (R)-N-((S)-1-(2,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00324
  • To a solution of (R)-N-((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (230 mg, 0.676 mmol) in dioxane/H2O (5 mL/1 mL) was added sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxy-[1,1′-biphenyl]-3-sulfonate (34.7 mg, 0.068 mmol), (2-(trifluoromethyl)pyridin-4-yl)boronic acid (194 mg, 1.014 mmol), K2CO3 (234 mg, 1.690 mmol) followed by Pd2 dba3 (31.0 mg, 0.034 mmol). The reaction mixture was sealed and heated to 110° C. and stirred for 2 hours. LCMS show complete conversion. The reaction mixture was then cooled to room temperature and diluted with EtOAc (20 mL) and water (10 mL). The aqueous layer was then extracted with EtOAc (2×20 mL). The combined organic was then concentrated. The residue was purified by silica gel chromatography (50% heptane in EtOAc to 10% MeOH in EtOAc) to give product. (0.25 g). LCMS (B) m/z 407.6 (M+H)+
    • Intermediate 297: (S)-1-(2,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)ethanamine
  • Figure US20140275083A1-20140918-C00325
  • To a solution of (R)-N-((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.98 g, 3.01 mmol) in dioxane (10 ml) was added dropwise HCl (1.504 ml, 6.01 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS indicated complete conversion to product. The reaction mixture was concentrated and DCM (20 mL) and saturated NaHCO3 solution (10 mL) was added to the residue. The mixture was stirred for 10 minutes and phases were separated. Aqueous layer was then extracted with DCM (2×10 mL), and the combined organic was dried (Na2SO4) and concentrated to give crude product (0.501 g). LCMS (B) m/z 303.2 (M+H)+
  • The intermediates in Table 17a were prepared using a method similar to that described for the preparation of Intermediate 297
  • TABLE 17a
    Figure US20140275083A1-20140918-C00326
         		Intermediate 298
    Figure US20140275083A1-20140918-C00327
         		Intermediate 299
    Figure US20140275083A1-20140918-C00328
         		Intermediate 300
  • TABLE 17b
    Chemical name and analytical data for each intermediate
    listed in Table 17a.
    Intermediate: Name Analytical data
    298: (S)-1-(2,5-difluoro- LCMS (B) m/z (M + H)+ 249.2, RT 0.34 min.
    4-(2-methylpyridin-4-
    yl)phenyl)ethanamine
    299: (S)-1-(2,5-difluoro- LCMS (B) m/z (M + H)+ 249.1, RT 0.32 min.
    4-(6-methylpyridin-3-
    yl)phenyl)ethanamine
    300: (S)-1-(2,5- LCMS (B) m/z (M + H)+ 303.2, RT 0.64 min.
    difluoro-4-(6-
    (trifluoromethyl)pyridin-
    3-yl)phenyl)ethanamine
    • Intermediate 301: (R)-N-((S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00329
  • To a solution of di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine (80 mg, 0.166 mmol) in toluene/dioxane (8 mL/2 mL) was added Pd2 dba3 (60 mg, 0.066 mmol). The reaction mixture was sealed and heated to 120° C. and stirred for 5 minutes. The reaction was cooled to room temperature and 4-methyl-1H-imidazole (157 mg, 1.910 mmol), (R)-N-((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.470 mmol) and K3PO4 (624 mg, 2.94 mmol) was added to the reaction mixture. The reaction was sealed and heated to 120° C. for 2 hours. LCMS show complete conversion. The reaction mixture was then cooled to room temperature and diluted with EtOAc (20 mL) and water (10 mL). The aqueous layer was then extracted with EtOAc (2×20 mL). The combined organic was then concentrated. The residue was purified by silica gel chromatography (50% heptane in EtOAc to 10% MeOH in EtOAc) to give (S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethanamine (500 mg). LCMS (B) m/z 342.6 (M+H)+
    • Intermediate 302: (S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethanamine
  • Figure US20140275083A1-20140918-C00330
  • To a solution of (R)-N-((S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg) in MeOH (10 mL) was added dropwise HCl (732 μl, 2.93 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS indicated complete conversion to product. The reaction mixture was concentrated and DCM (20 mL) and saturated NaHCO3 solution (10 mL) was added to the residue. The mixture was stirred for 10 minutes and phases were separated. Aqueous layer was then extracted with DCM (2×10 mL), and the combined organic was dried (Na2SO4) and concentrated to give (S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethanamine (330 mg). LCMS (B) m/z 238.1 (M+H)+
    • Intermediate 303: (S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethanamine hydrochloride
  • Figure US20140275083A1-20140918-C00331
    • Step 1: preparation of tert-butyl 4-formyl-1H-imidazole-1-carboxylate
  • To di-tert-butyl dicarbonate (23.25 g, 107 mmol) and 1H-imidazole-4-carbaldehyde (9.75 g, 101 mmol) in THF (200 mL) was added DMAP (100 mg, 0.819 mmol). The reaction was stirred for two hours. The reaction mixture was then diluted with saturated NaHCO3 solution/EtOAc (100 mL/100 mL). The aqueous was then extracted with EtOAc (2×100 mL) and the combined organic was dried (Na2SO4) and concentrated to give crude product (19.9 g). LCMS (B) m/z 197.2 (M+H)+
    • Step 2: preparation of (S,E)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)-1H-imidazole-1-carboxylate
  • To CuSO4 (24.28 g, 152 mmol) and tert-butyl 4-formyl-1H-imidazole-1-carboxylate (19.9 g, 101 mmol) in DCE (100 mL) was added (S)-2-methylpropane-2-sulfinamide (13.52 g, 112 mmol). The reaction was heated to 65° C. for 18 hours. The reaction mixture was then cooled to room temperature and filtered through a pad of celite. The pad was rinsed with DCM (200 mL) and the filtrated was concentrated. The residue was then run through a pad of silica gel with heptane/EtOAc (3:1) as eluent. The filtrate was concentrated to give crude (S,E)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)-1H-imidazole-1-carboxylate (22 g). LCMS (B) m/z 300.2 (M+H)+
    • Step 3: preparation of (S,E)-N-((1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide
  • To (S,E)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)-1H-imidazole-1-carboxylate (18.61 g, 62.2 mmol) in DCM (250 mL) at −70° C. was added dropwise methylmagnesium bromide (83 mL, 249 mmol) in Et2O. The reaction was stirre at −70° C. for 4 hours. The reaction mixture was then warmed to −40° C. and stirred for one hour. The reaction was then quenched with cautious addition of HCl (1N). Cold bath was removed and while with stirring the aqueous layer was adjusted pH=8. The aqueous layer was separated and extracted with DCM (3×100 mL). The combined organic was dried (Na2SO4) and concentrated to give crude product as a mixture of tert-butyl 4-((S)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)-1H-imidazole-1-carboxylate and (S,E)-N-((1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide, to which was added DCM (300 mL) at 0° C. and formic acid (100 mL, 2651 mmol). The cold bath was then removed and he reaction was stirre for 2 hours. The reaction mixture was then concentrated under reduce pressure to remove DCM and formic acid. The residue was diluted with DCM (400 mL) and washed with saturated Na2CO3 aqueous solution (2×200 mL). The combined aqueous was extracted with DCM (2×200 mL). The combined organic was then dried (Na2SO4) and concentrated to give (S,E)-N-((1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (12.5 g). LCMS (B) m/z 216.1 (M+H)+
    • Step 4: preparation of (S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethanamine hydrochloride
  • To a 200 mL RBF was added toluene/dioxane (80 ml/20 mL). The flask was cooled to 0° C. and the mixture of solvents was evacuated under high vacuum for 2 minutes and then recharged with argon. The process was repeated three more times. This solvent was then used for the reaction.
  • A vial containing di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine (55.8 mg, 0.116 mmol) and Pd2(dba)3 (42 mg, 0.046 mmol) was evacuated under high vacuum for 1 minute and then recharged with argon. The process was repeated three more times and the toluene/dioxane solvent (10 mL) prepared as above was added followed by the palladium/ligand complex prepared as above was then added to the reaction vial containing the other starting materials. The reaction mixture was sealed and heated to 120° C. and stirred for 5 minutes. The reaction was cooled to room temperature.
  • A separate reaction vial was charged with (S,E)-N-((1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (500 mg, 2.322 mmol), 1-bromo-4-fluorobenzene (447 mg, 2.55 mmol) and K3PO4 (986 mg, 4.64 mmol). The vial was evacuated under high vacuum for 1 minute and then recharged with argon. The process was repeated three more times and the palladium/ligand complex prepared as above was then added to the reaction vial containing the other starting materials. The reaction was sealed and heated to 120° C. for 18 hours. LCMS show complete conversion. The reaction mixture was then cooled to room temperature and filtered through a pad of celite. The solid was rinsed with EtOAc (30 mL). The filtrate was then washed with water (2×20 mL). The aqueous layer was then extracted with EtOAc (20 mL). The combined organic was then concentrated. The residue was purified via silica gel chromatography (EtOAc/Heptane 70%-100% with 5% MeOH) to give (S)-N-((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide. LCMS (B) m/z 310.2 (M+H)+
  • To the above intermediate product was added MeOH (5 mL) and HCl (4M in dioxane, 1 mL). The reaction mixture was stirred for one hour and LCMS showed complete conversion, The mixture was then concentrated to give (S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethanamine hydrochloride (300 mg). LCMS (B) m/z 206.0 (M+H)+
    • Intermediate 304: 5-chloro-6-(1,1-difluoroethyl)nicotinaldehyde
  • Figure US20140275083A1-20140918-C00332
    • Step 1: Preparation of ethyl 5,6-dichloronicotinate
  • To a solution of 5,6-dichloronicotinic acid (20.01 g, 104 mmol) in EtOH (500 mL) at 20° C. was added chlorotrimethylsilane (132 mL, 1042 mmol). The reaction was stirred for 72 hours. The reaction mixture was then concentrated and diluted with EtOAc (500 mL), and washed with saturated NaHCO3 (2×100 mL) and brine (100 mL). The organic was then dried (Na2SO4) and concentrated under reduced pressure to give final crude product (21.25 g). LCMS m/z 220.1 (M+H)+, Rt 0.94 min.
    • Step 2: Preparation of ethyl 6-acetyl-5-chloronicotinate
  • To a suspension of ethyl 5,6-dichloronicotinate (5.26 g, 23.90 mmol) and tetraethylammonium-chloride (11.88 g, 71.7 mmol) in MeCN (50 mL) was added tributyl(1-ethoxyvinyl)stannane (9.50 g, 26.3 mmol) and PdCl2(PPh3)2 (0.671 g, 0.956 mmol). The reaction was sealed, heated at 80° C. for 5 hours. A dark color clear solution resulted. The reaction mixture was then cooled to 20° C., concentrated and diluted with EtOAc (200 mL), and washed with water (50 mL) and brine (50 mL). The organic was then dried (Na2SO4) and concentrated to give crude ethyl 5-chloro-6-(1-ethoxyvinyl)nicotinate. The residue was then dissolved in THF (100 mL) and HCl (20 mL, 3M in H2O) was added. The reaction mixture was stirred at 20° C. for 5 hours, and saturated NaHCO3 solution was added until pH=8. The mixture was then diluted with EtOAc (200 mL) and water (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organics was washed with brine (20 mL), dried (Na2SO4) and concentrated to afford the desired product (3.56 g). LCMS m/z 228.5 (M+H)+, Rt 0.83 min.
    • Step 3: Preparation of ethyl 5-chloro-6-(1,1-difluoroethyl)nicotinate
  • To a solution of ethyl 6-acetyl-5-chloronicotinate (3.01 g, 13.22 mmol) in CHCl3 (7 mL) was added DAST (5.20 mL, 39.7 mmol) and ethanol (0.061 g, 1.32 mmol). The reaction was sealed, heated at 60° C. for 24 hours. A dark color clear solution resulted. The reaction mixture was then cooled to 20° C., and added cautiously with cold concentrated NaHCO3 aqueous solution (50 mL). The aqueous layer was extracted with DCM (2×100 mL). The combined organic was then dried (Na2SO4) and concentrated. The residue was purified via silica gel flash chromatography (0-20 percent EtOAc-Hexanes) to afford the desired product as yellow oil (2.88 g). LCMS m/z 250.1 (M+H)+, Rt 0.99 min.
    • Step 4: Preparation of (5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)methanol
  • To a solution of ethyl 5-chloro-6-(1,1-difluoroethyl)nicotinate (2.68 g, 10.74 mmol) in Et2O (40 mL) was added LiBH4 (0.351 g, 16.10 mmol), followed by dropwise addition of methanol (0.653 mL, 16.10 mmol). The reaction was refluxed at 40° C. for one hour. The reaction mixture was then cooled to 0° C., and quenched with HCl (1M) until pH=2 for aqueous layer. The phases were separated and the aqueous layer was extracted with DCM (3×50 mL). The organic was then dried (Na2SO4) and concentrated under reduced pressure to give final crude product (2.12 g). LCMS m/z 208.0 (M+H)+, Rt 0.63 min.
    • Step 5: Preparation of 5-chloro-6-(1,1-difluoroethyl)nicotinaldehyde
  • To a solution of (5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)methanol (2.12 g, 10.21 mmol) in DCM (100 ml) was added PCC (3.30 g, 15.32 mmol). The reaction was stirred at 20° C. for 3 hours. A dark color suspension resulted. LCMS showed clean conversion to the product. The reaction mixture was then filtered through a pad of celite, and washed with DCM (200 mL). The filtrate was then concentrated to give crude product (1.78 g). LCMS m/z 224.0 (M+H2O+H)+, Rt 0.72 min.
    • Intermediate 305: 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinaldehyde
  • Figure US20140275083A1-20140918-C00333
    • Step 1: Preparation of ethyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate
  • To a solution of ethyl 5,6-dichloronicotinate (6.28 g, 28.5 mmol) and 2,2,2-trifluoroethanol (2.71 ml, 37.1 mmol) in THF (90 ml) at −73° C. was added NaHMDS (37.1 ml, 37.1 mmol). The reaction was stirred at −73° C. for 30 minutes, then at 0° C. for 5 hours. The reaction was quenched with 30 mL saturated NH4Cl solution. The reaction mixture was then poured into 50 mL brine and phases were separated. The aqueous layer was extracted with DCM (2×100 mL). The combined organics were dried (Na2SO4) and concentrated. Silica gel chromatography with 100% heptane to 30% EtOAc in heptane provided final product (7.51 g). LCMS m/z 284.1 (M+H)+, Rt 1.07 min.
    • Step 2: Preparation of (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol
  • To a solution of ethyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (7.51 g, 26.5 mmol) in Et2O (200 mL) was added LiBH4 (0.865 g, 39.7 mmol), followed by drop wise addition of methanol (1.611 ml, 39.7 mmol). The reaction was refluxed at 40° C. for one hour. The reaction mixture was then cooled to 0° C., and quenched with HCl (1M) until pH=2 for aqueous layer. The phases were separated and the aqueous layer was extracted with DCM (3×200 mL). The organic was then dried (Na2SO4) and concentrated under reduced pressure to give final crude product (6.31 g). LCMS m/z 242.1 (M+H)+, Rt 0.77 min.
    • Step 3: Preparation of 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinaldehyde
  • To a solution of (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (4.00 g, 16.56 mmol) in EtOAc (15 mL) was added manganese(IV) oxide (16.93 g, 166 mmol). The reaction was heated with microwave at 120° C. for 30 minutes. The mixture was then filtered through a pad of celite, and rinsed with EtOAc. The filtrated was concentrated to give crude product (3.38 g).
    • Intermediate 306: (S)-1-(2,3-difluorophenyl)ethanamine
  • Figure US20140275083A1-20140918-C00334
    • Step 1
  • To a oven dried round bottom flask with stir bar was added 2,3-difluorobenzaldehyde (0.5 g, 3.52 mmol), (R)-2-methylpropane-2-sulfinamide (0.469 g, 3.87 mmol) and DCE (7.04 mL). To this mixture was then added Copper (II) Sulfate (0.842 g, 5.28 mmol). Reaction mixture heated in a preheated oil bath to 55° C. for 24 hr. The reaction mixture was filtered through a celite pad washing solids with DCE. Combined filtrate was concentrated to afford a viscous yellow oil of (R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.8007 g, 3.26 mmol, 93% yield). MS m/z 246.1 (M+H)+; Rt-0.91 min.
    • Step 2
  • To a solution of (R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.800 g, 3.26 mmol) in DCM (32.6 mL), cooled to 0° C. (water/icebath) under N2, was added 3M MeMgBr (4.35 mL, 13.05 mmol) in diethyl ether. Reaction mixture allowed to stir for 30 min at 0° C. Then gradually allowed to warm to room temperature and stirred for 30 min at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl and diluted with EtOAc. Phases partitioned aqueous phase extracted with EtOAc and the organic layers combined washed with water, brine, dried with MgSO4, filtered and concentrated to afford (R)-N-((S)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.7868 g, 3.01 mmol, 92% yield) as yellow solid. MS m/z 262.0 (M+H)+; Rt-0.70 min.
    • Step 3
  • To a round bottom flask containing (R)-N-((S)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (786.8 mg, 3.01 mmol) was added Dioxane (10.000 mL). To this solution was added HCl in dioxane 4.0M (1.505 mL, 6.02 mmol) and the solution was allowed to stir 15 min at room temperature. The reaction mixture was concentrated, dissolved in Et2O 10 ml, and concentrated again. Et2O was again added and resulting mixture sonnicated and a solid material was filtered and dried to afford (S)-1-(2,3-difluorophenyl)ethanamine (0.4213 g, 2.176 mmol, 72.3% yield) as a white crystalline HCl salt. 1H NMR (400 MHz, <d2o>) d ppm 1.55 (d, J=6.99 Hz, 3H) 4.71 (q, J=6.96 Hz, 1H) 7.10-7.26 (m, 3H); MS m/z 158.0 (M+H)+; Rt-0.37 min.
  • The intermediates in Table A were prepared using a method similar to that described for the preparation of Intermediate 306
  • TABLE 18a
    Figure US20140275083A1-20140918-C00335
         		Intermediate 307
    Figure US20140275083A1-20140918-C00336
         		Intermediate 308
    Figure US20140275083A1-20140918-C00337
         		Intermediate 309
  • TABLE 18b
    Chemical name, NMR chemical shifts and LCMS signal for
    each compound listed in Table 18a.
    Intermediate: Name Analytical data
    307: (S)-1-(3,4- 1H NMR (400 MHz, <cd3od>) δ ppm
    difluorophenyl)ethanamine 1.61 (d, J = 6.90 Hz, 3 H) 4.47 (q, J = 6.90
    Hz, 1 H) 7.25-7.30 (m, 1 H)
    7.32-7.46 (m, 2 H)
    LCMS m/z 158.1.1 (M + H)+; Rt-0.39 min.
    308: (S)-1-(2,4- 1H NMR (400 MHz, <cd3od>) δ ppm
    difluorophenyl)ethanamine 1.65 (d, J = 1.00 Hz, 3 H) 4.71 (q, J = 6.91
    Hz, 1 H) 7.05-7.15 (m, 2 H)
    7.51-7.61 (m, 1 H)
    LCMS m/z 158.1.1 (M + H)+; Rt-0.37 min.
    • Intermediate 310: (S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethanamine
  • Figure US20140275083A1-20140918-C00338
    • Step 1: Preparation 1-(4-bromo-3-fluorophenyl)ethanol
  • Figure US20140275083A1-20140918-C00339
  • Methylmagnesium bromide (3M in diethylether, 6.77 mL, 20.31 mmol) was added dropwise over ˜15 min to a solution of 4-bromo-3-fluorobenzaldehyde (3.1 g, 15.27 mmol) in THF (50 mL) under argon at a temperature of −60° C. to −50° C. The ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred ˜20 hr. The reaction mixture was slowly diluted/quenched with saturated aqueous ammonium chloride solution (20 mL) and further diluted with water (10 mL). The separated aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide crude 1-(4-bromo-3-fluorophenyl)ethanol as a pale yellow oil, which was directly used without further purification.
  • LCMS m/z 201.0 (M−H2O)+, Rt 0.75 min.
    • Step 2: Preparation 1-(4-bromo-3-fluorophenyl)ethanone
  • Figure US20140275083A1-20140918-C00340
  • To a solution of crude 1-(4-bromo-3-fluorophenyl)ethanol oil (from Step 1) in DCM (100 mL) was added pyridinium dichromate (8.96 g, 23.82 mmol). The mixture was stirred overnight at room temperature. To the mixture was added celite, the reaction mixture was filtered through a celite pad and rinsed several times with DCM. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate] providing 1-(4-bromo-3-fluorophenyl)ethanone (3.08 g) as a white solid. 1H NMR (400 Mhz, CDCl3) δ ppm 7.72-7.58 (m, 3H), 2.59 (s, 3H).
    • Step 3: Preparation 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene
  • Figure US20140275083A1-20140918-C00341
  • To a solution of 1-(4-bromo-3-fluorophenyl)ethanone (3.08 g, 14.19 mmol) in chloroform (15 mL) was added DAST (5.62 mL, 42.6 mmol) and ethanol (0.083 mL, 1.42 mmol). The orange solution was heated at 60° C. for 24 hr in a sealed container. The reaction mixture was allowed to cool to ˜20° C. and to the mixture was added slowly saturated aqueous sodium bicarbonate solution (75 mL). Stirring was continued until off-gassed ceased (˜15 min). The separated aqueous layer was diluted with additional saturated aqueous sodium bicarbonate solution (25 mL) and carefully mixed. The basic aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, heptane/ethyl acetate] providing 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene (2.1 g) as a slightly cloudy colorless oil. 1H NMR (400 MHz, CD3OD) δ ppm 7.73 (dd, J=7.2, 8.1 Hz, 1H), 7.40 (dd, J=2.0, 9.4 Hz, 1H), 7.29 (m, J=1.0 Hz, 1H), 1.92 (t, J=18.4 Hz, 3H).
    • Step 4: Preparation 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde
  • Figure US20140275083A1-20140918-C00342
  • To a solution of 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene (2.1 g, 8.79 mmol) in THF (30.3 mL) was added n-butyllithium (1.6M in hexanes, 5.60 mL) over ˜20 min at −78° C. The mixture was stirred for 30 min at −78° C. and DMF (1.02 mL, 13.18 mmol) was added dropwise over ˜4 min. Stirring was continued for 1 hr, the mixture was diluted/quenched with 1N aqueous HCl/MeOH (2/1, 15 mL) and allowed to warm to room temperature. The reaction mixture was diluted further with water (50 mL) and extracted with diethylether (2×50 mL). The combined organic layers were washed with 1N aqueous sodium hydroxide solution (50 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate] providing 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde (699 mg) as a dark yellow, volatile oil, which was contaminated with 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene. 1H NMR (400 Mhz, CDCl3) δ ppm 10.40 (s, 1H), 7.95 (t, J=7.4 Hz, 1H), 7.39-7.47 (m, 2H), 7.35 (d, J=10.6 Hz, 1H), 1.94 (t, J=18.2 Hz, 4H) 7.73 (dd, J=7.2, 8.1 Hz, 1H).
    • Step 5: Preparation (R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00343
  • To a mixture of 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde (693 mg, from Step 4) and (R)-2-methylpropane-2-sulfinamide (513 mg, 4.24 mmol) in DCE (12.9 mL) was added copper(II) sulfate (882 mg, 5.52 mmol). The reaction mixture was placed in a pre-heated oil bath (55° C.) and heated for ˜2 d. The mixture was allowed to cool to room temperature, filtered through a pad of celite and rinsed with DCE. The combined filtrates were concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 24 g, heptane/ethyl acetate] providing (R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (497 mg) as a yellow oil. LCMS m/z 292.1 (M+H)+, Rt 0.97 min.
    • Step 6: Preparation N-((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Figure US20140275083A1-20140918-C00344
  • To a solution of (R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (497 mg, 1.706 mmol) in DCM (9.59 mL) was added methylmagnesium bromide (3M in diethylether; 1.20 mL) at 0° C. The reaction mixture was allowed to stir for 1 hr at 0° C., gradually allowed to warm to room temperature and stirred for 1 hr at room temperature. The mixture was cooled to 0° C., additional methylmagnesium bromide (3M in diethylether; 0.5 mL) was added and stirring was continued for 30 min at 0° C. The reaction mixture was carefully quenched with saturated aqueous ammonium chloride solution (6 mL) and diluted with water (20 mL). The separated aqueous phase was extracted with DCM (30 mL). The combined organic layers were washed with brine (50 mL), concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 24 g, heptane/ethyl acetate] providing N-((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (349 mg) as a white solid. LCMS m/z 308.2 (M+H)+, Rt 0.91 min.
    • Step 7: Preparation (5)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethanamine
  • Figure US20140275083A1-20140918-C00345
  • To N-((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (349 mg, 1.135 mmol) was added 4M HCl in dioxane (3.01 mL) to give a purple solution. To the mixture was added diethylether (20 mL) and the mixture was stirred for 15 min at ˜10° C. The mixture was concentrated under reduced pressure to ˜2 mL of volume and diethylether (20 mL) was added. The solids were filtered off, rinsed with diethylether (4×10 mL) and dried under reduced pressure providing (S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethanamine (244 mg) as an off-white solid (HCl salt). LCMS m/z 204.1 (M+H)+, Rt 0.42 min.
    • Intermediate 311: (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate
  • Figure US20140275083A1-20140918-C00346
  • A slurry of (S)-3-(1-aminoethyl)phenol (1.188 g, 6.84 mmol) and Boc2O (1.747 mL, 7.53 mmol) in DCM (17.10 mL) was stirred at room temperature under N2 while slowly adding DIEA (1.434 mL, 8.21 mmol). The initially insoluble starting materials slowly dissolve. The solution was stirred at room temperature for 16 hours and then concentrated. The oily residue was re-dissolved in EtOAc and washed with Na2CO3 saturated, followed by brine. The original aqueous layer was re-extracted with EtOAc, which was then washed with brine and combined with the previous EtOAc batch. The combined organics were dried over Na2SO4, filtered and concentrated to 2.4 g crude clear yellowish oil which was purified by silica gel column chromatography (EtOAc/Heptane 0 to 30%), yielding (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate as a clear colourless oil, which solidifies upon sitting (1.79 g, 7.55 mmol, 110% yield). 1H NMR (400 MHz, CDCl3) d 1.44 (br. s., 12H) 4.08-4.18 (m, 1H) 4.76 (br. s., 1H) 6.72 (dd, J=7.46, 1.83 Hz, 1H) 6.78 (br. s., 1H) 6.88 (br. s., 1H) 7.16-7.24 (m, 1H). LCMS m/z 223.0/182.0 (the parent not observed, just the Boc fragments) (M+H)+, Rt 0.71 min.
    • Intermediate 312: (S)-tert-butyl 1-(4-hydroxy-3-methylphenyl)ethylcarbamate
  • Figure US20140275083A1-20140918-C00347
  • Made as above Intermediate 195: (S)-tert-butyl 1-(4-hydroxy-3-methylphenyl)ethylcarbamate, clear colourless oil. (1.27 g, 5.05 mmol, 103% yield). 1H NMR (400 MHz, CDCl3) d 1.42 (s, 9H) 1.54 (s, 3H) 2.24 (s, 3H) 4.70 (br. s., 1H) 6.72 (d, J=8.22 Hz, 1H) 7.01 (d, J=9.00 Hz, 1H) 7.05 (s, 1H). LCMS m/z 252.2 (M+H)+, Rt 0.80 min.
    • Intermediate 313: (S)-1-(3-(cyclohexyloxy)phenyl)ethanamine hydrochloride
  • Figure US20140275083A1-20140918-C00348
    • Step 1
  • To a solution of (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate (100 mg, 0.421 mmol), cyclohexanol (0.180 ml, 1.686 mmol) and PPh3 (221 mg, 0.843 mmol) in THF (2 ml), was added DEAD (0.133 ml, 0.843 mmol) dropwise, under N2, at room temperature. The resulting yellow solution was stirred for 3 hours, at which point another batch of cyclohexanol (0.180 ml, 1.686 mmol), PPh3 (221 mg, 0.843 mmol), and 10 min later DEAD (0.133 ml, 0.843 mmol), was added at room temperature. The reaction mixture was stirred for 16 hours and then concentrated. The crude clear oil was re-dissolved in DMSO and purified by reverse phase HPLC. The combined product fractions were desalted by addition of equal amount of EtOAc and about 250 mg Na2CO3 in a separatory funnel. The phases were separated and the organic washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (S)-tert-butyl 1-(3-(cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232 mmol, 55.0% yield) as a clear colourless film. LCMS m/z 305.0/264.0 (the parent not observed, just the Boc fragments) (M+H)+, Rt 1.12 min.
    • Step 2
  • (S)-tert-butyl 1-(3-(cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232 mmol) was dissolved in 4M HCl in dioxane (1 ml, 4.00 mmol) and the resulting mixture was allowed to sit for 1 hour, then concentrated to yield (S)-1-(3-(cyclohexyloxy)phenyl)ethanamine as an HCl salt (yield assumed quantitative). LCMS m/z 220.1 (M+H)+, Rt 0.66 min.
  • The Intermediates in Table 19 were prepared using the method described for the preparation of Intermediate 313.
  • TABLE 19
    Intermediate: Name Structure LCMS
    314: (S)-1-(3-((S)-tetrahydrofuran-3- yloxy)phenyl)ethanamine
    Figure US20140275083A1-20140918-C00349
         		MS m/z 208.1 (M + H)+, Rt 0.41 min.
    315: (S)-1-(3- isobutoxyphenyl)ethanamine
    Figure US20140275083A1-20140918-C00350
         		MS m/z 194.1 (M + H)+, Rt 0.61 min.
    316: (S)-1-(4-isobutoxy-3- methylphenyl)ethanamine
    Figure US20140275083A1-20140918-C00351
         		MS m/z 191.1 (M + H)+, Rt 0.70 min.
    317: (S)-1-(2-fluoro-4- isobutoxyphenyl)ethanamine
    Figure US20140275083A1-20140918-C00352
         		MS m/z 195.2 (M + H)+, Rt 0.64 min.
    318: (S)-1-(4- (cyclopropylmethoxy)phenyl)ethanamine
    Figure US20140275083A1-20140918-C00353
         		MS m/z 175.1 (M + H)+, Rt 0.53 min.
    • Intermediate 319: (S)-1-(3-phenoxyphenyl)ethanamine
  • Figure US20140275083A1-20140918-C00354
  • Into a 20 ml microwave vial was weighted 1-(pyridin-2-yl)propan-2-one ligand (90 mg, 0.665 mmol), phenol (407 mg, 4.32 mmol), CuBr (47.7 mg, 0.332 mmol) and Cs2CO3 (2166 mg, 6.65 mmol). To the mixture was added DMSO (5 ml) and (S)-1-(3-bromophenyl)ethanamine (0.5 ml, 3.32 mmol). The tube was flushed with N2, capped, and the black mixture heated in the oil bath at 90° C. for 18 hours. The heterogenous mixture was diluted with EtOAc and filtered through a glass-fritted funnel, eluting with EtOAc and another 5 mls of DMSO. The volatiles were then removed in vacuo and the crude brown liquid was filtered through 1 um PTFE filter and purified by reverse phase HPLC. The combined product fractions were desalted by addition of equal amount of EtOAc and about 250 mg Na2CO3 in a separatory funnel. The phases were separated and the organic washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (S)-1-(3-phenoxyphenyl)ethanamine (361.5 mg, 1.678 mmol, 50.5% yield) as an amber oil. LCMS m/z 214.1 (M+H)+, Rt 0.61 min.
    • Intermediate 320: (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine
  • Figure US20140275083A1-20140918-C00355
    • Step 1
  • To a cloudy solution of 4-(trifluoromethoxy)benzaldehyde (5 g, 26.3 mmol) and (R)-2-methylpropane-2-sulfinamide (3.51 g, 28.9 mmol) in DCE (52 mL), under N2, was added copper (II) sulfate (6.30 g, 39.4 mmol), and the resulting mixture heated in a preheated oil bath at 55° C. for 22 hours. The reaction mixture was filtered through a pad of celite, eluting with DCM. The filtrate was concentrated to afford a viscous yellow oil of (R,E)-2-methyl-N-(4-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (7.9 g, 26.9 mmol, 102% yield). Material was taken onto next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (s, 9H) 7.32 (d, J=8.07 Hz, 2H) 7.91 (d, J=8.75 Hz, 2H) 8.59 (s, 1H). LCMS m/z 294.1 (M+H)+, Rt 1.01 min.
    • Step 2
  • To a solution of (R,E)-2-methyl-N-(4-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (7.7 g, 26.3 mmol) in CH2Cl2 (150 mL), cooled to 0° C. (water/ice bath), under nitrogen, was added 3M methyl magnesium bromide (35 mL, 105 mmol) in Et2O. The reaction mixture was stirred at 0° C. for 30 min, then allowed to warm up to room temperature and stirred additional 4 hrs. The reaction mixture was cooled again to 0° C. and quenched with the slow addition of a saturated NH4Cl solution. The by-phasic mixture was diluted with DCM and Water and the aqueous extracted with DCM two times. The organic phases were combined, washed with brine, dried (Na2SO4), filtered and concentrated to 11.5 g crude white solid. Silica gel column chromatography (EtOAc/Heptane 0 to 30%) afforded (R)-2-methyl-N-((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (5.08 g, 16.2 mmol, 62% yield) as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 1.21 (s, 9H) 1.53 (d, J=6.70 Hz, 3H) 3.31 (d, J=2.74 Hz, 1H) 4.59 (qd, J=6.67, 3.37 Hz, 1H) 7.18 (d, J=8.02 Hz, 2H) 7.36 (d, J=8.66 Hz, 2H). LCMS m/z 310.2 (M+H)+, Rt 0.90 min.
    • Step 3
  • (R)-2-methyl-N-((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (5.08 g, 16.4 mmol) was dissolved by swirling in 4M HCl in dioxane (16.4 ml, 65.6 mmol), at room temperature. The solution was allowed to sit for 1 hr with occasional swirling. To the clear solution was added 45 ml ether and the resulting cloudy solution sonicated for 1 min, upon which time the white solid product precipitates out. The solid was filtered through a Buchner funnel, washed 5 times with ˜20 ml ether and allowed to air dry. Obtained (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (3.2 g, 13.2 mmol, 80% yield), 1H NMR (400 MHz, CD3OD) δ 1.64 (d, J=6.90 Hz, 3H) 4.52 (q, J=6.88 Hz, 1H) 7.38 (d, J=8.02 Hz, 2H) 7.57 (d, J=8.71 Hz, 2H). LCMS m/z 206.1 (M+H)+, Rt 0.52 min.
  • The Intermediates in Table 20 were prepared using the method described for the preparation of Intermediate 320.
  • TABLE 20
    Intermediate: Name Structure 1H NMR (400 MHz, CD3OD), LCMS
    321: (S)-1-(2-fluoro-4- (trifluoromethoxy)phenyl) ethanamine
    Figure US20140275083A1-20140918-C00356
         		δ ppm 1.66 (d, J = 6.94 Hz, 3 H) 4.75 (q, J = 6.94 Hz, 1 H) 7.23-7.31 (m, 2 H) 7.60- 7.68 (m, 1 H). MS m/z 224.1 (M + H)+ Rt 0.54 min.
    322: (S)-1-(4- (difluoromethoxy)phenyl) ethanamine
    Figure US20140275083A1-20140918-C00357
         		δ ppm 1.63 (d, J = 6.90 Hz, 3 H) 4.48 (q, J = 6.88 Hz, 1 H) 6.63-7.10 (m, 1 H) 7.24 (d, J = 8.71 Hz, 2 H) 7.50 (d, J = 8.66 Hz, 2 H). MS m/z 171.1 (M + H)+, Rt 0.43 min.
    323: (S)-1-(3-fluoro-4- (trifluoromethoxy)phenyl) ethanamine
    Figure US20140275083A1-20140918-C00358
         		δ ppm 1.64 (d, J = 6.90 Hz, 3 H) 4.54 (q, J = 6.88 Hz, 1 H) 7.39 (dt, J = 8.52, 1.56 Hz, 1 H) 7.46-7.59 (m, 2 H). MS m/z 224.1 (M + H)+, Rt 0.55 min.
    324: (S)-1-(4- (difluoromethoxy)-3- fluorophenyl)ethanamine
    Figure US20140275083A1-20140918-C00359
         		δ ppm 1.62 (d, J = 6.90 Hz, 3 H) 4.49 (q, J = 6.83 Hz, 1 H) 6.67-7.10 (m, 1 H) 7.27- 7.33 (m, 1 H) 7.35-7.44 (m, 2 H). MS m/z 206.1 (M + H)+, Rt 0.46 min.
    325: (S)-1-(4- (difluoromethoxy)-2- fluorophenyl)ethanamine
    Figure US20140275083A1-20140918-C00360
         		δ ppm 1.65 (d, J = 6.94 Hz, 3 H) 4.71 (q, J = 6.94 Hz, 1 H) 6.71-6.97 (m, 1 H) 7.05- 7.14 (m, 2 H) 7.55 (t, J = 8.68 Hz, 1 H). MS m/z 206.1 (M + H)+, Rt 0.46 min.
    326: (S)-1-(3- (trifluoromethoxy)phenyl) ethanamine
    Figure US20140275083A1-20140918-C00361
         		δ ppm 1.63 (d, J = 6.90 Hz, 3 H) 4.53 (q, J = 6.86 Hz, 1 H) 7.35 (ddt, J = 8.21, 2.27, 1.09, 1.09 Hz, 1 H) 7.41 (s, 1 H) 7.47 (d, J = 7.82 Hz, 1 H) 7.54-7.61 (m, 1 H). MS m/z 206.1 (M + H)+, Rt 0.51 min.
    327: (S)-1-(3- (difluoromethoxy)phenyl) ethanamine
    Figure US20140275083A1-20140918-C00362
         		δ ppm 1.63 (d, J = 6.90 Hz, 3 H) 4.49 (q, J = 6.88 Hz, 1 H) 6.64-7.08 (m, 1 H) 7.21 (dd, J = 8.19, 1.83 Hz, 1 H) 7.26 (t, J = 2.03 Hz, 1 H) 7.33 (d, J = 7.78 Hz, 1 H) 7.45-7.53 (m, 1 H). MS m/z 188.1 (M + H)+, Rt 0.43 min.
    • Intermediate 328: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00363
  • To a Parshaker flask were added benzyl 4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-5-fluoropyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate (850 mg, 1.56 mmole) and 20% Pd(OH)2 in activated carbon (880 mg, 1.25 mmole), then was added MeOH (100 mL) under nitrogen gas. The reaction mixture was shaked under 50 psi hydrogen overnight. The reaction mixture was filtered through a celite. The celite cake was washed with MeOH and the filtrate was concentrate in vacuo. The resulting crude product was purified by flash column chromatography (basic alumina, 40 g) eluting w/0-20% MeOH/DCM to afford the title product as a white solid (230 mg). 1H NMR (400 MHz, CD2Cl2) δ 8.18 (d, J=2.87 Hz, 1H), 5.15 (br s, 1H), 4.71-4.63 (m, 1H), 4.56-4.47 (m, 1H), 4.47-4.34 (m, 2H), 4.25-4.14 (m, 1H), 3.96-3.82 (m, 1H), 3.16 (d, J=12.34 Hz, 2H), 2.67-2.54 (m, 2H), 1.85-1.66 (m, 2H), 1.64-1.52 (m, 1H), 1.40-1.26 (m, 2H), 1.20 (d, J=6.60 Hz, 3H), 1.18 (s, 9H), 1.10 (d, J=6.46 Hz, 3H). HRMS (C) tR=2.36 min; MS m/z 410.2571 (M+H)+
    • Intermediate 329: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00364
  • A cloudy solution of (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (32 mg, 0.078 mmol), 4-bromo-1-chloro-2-(trifluoromethyoxy)benzene (26 mg, 0.094 mmol), Pd(OAc)2 (2 mg, 8 umol), BINAP (5 mg, 8 umol), and Cs2CO3 (51 mg, 0.156 mmol) in 6 mL toluene was heated at 90° C. for 3 days. The mixture was cooled to room temperature, and filtered through Celite. The celite cake was rinsed with 5 mL EtOAc. The filtrate was poured into 5 mL water. Organic layer was separated, and the aqueous was further extracted with EtOAc (5 mL). The organic extracts were combined and concentrated by rotary evaporation. The crude was dissolved in a mixture of MeOH (1 mL) and DMSO (1 mL) and purified by reverse phase HPLC. Selected fractions were collected and concentrated by rotary evaporation to afford the title product as a colorless oil (34 mg). (400 MHz, CD2Cl2) δ 8.19 (d, J=2.95 Hz, 1H), 7.31 (d, J=8.85 Hz, 1H), 6.87-6.80 (m, 2H), 5.05 (br s, 1H), 4.73-4.63 (m, 1H), 4.56-4.44 (m, 2H), 4.25-4.13 (m, 1H), 4.01-3.88 (m, 1H), 3.79-3.69 (m, 2H), 2.82-2.69 (m, 2H), 2.00-1.79 (m, 2H), 1.68-1.56 (m, 1H), 1.54-1.36 (m, 2H), 1.23 (d, J=6.87 Hz, 3H), 1.15 (s, 9H), 1.09 (d, J=6.44 Hz, 3H), HRMS (C) tR=5.61 min; MS m/z 604.2328 (M+H)+
  • The intermediates in Table 21 were prepared with procedures similar to those used to prepare Intermediate 301
  • TABLE 21
    Intermediate: Name Structure LCMS
    330: (R)-N-((S)-1-(5-chloro-6- (1,1-difluoroethyl)pyridin-3- yl)ethyl)-2-methylpropane-2- sulfinamide
    Figure US20140275083A1-20140918-C00365
         		MS m/z 325.2 (M + H)+, Rt 0.85 min.
    331: (R)-N-((S)-1-(5-chloro-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)-2-methylpropane-2- sulfinamide
    Figure US20140275083A1-20140918-C00366
         		MS m/z 359.1 (M + H)+, Rt 0.95 min.
    332: (S)-1-(5-chloro-6-(1,1- difluoroethyl)pyridin-3- yl)ethanamine
    Figure US20140275083A1-20140918-C00367
         		MS m/z 221.1 (M + H)+, Rt 0.50 min.
    333: (S)-1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethanamine
    Figure US20140275083A1-20140918-C00368
         		MS m/z 255.1 (M + H)+, Rt 0.62 min.
  • The intermediates in Table 22 were prepared with procedures similar to those used to prepare Intermediate 302
  • TABLE 22
    Intermediate: Name Structure LCMS
    332: (S)-1-(5-chloro-6-(1,1- difluoroethyl)pyridin-3- yl)ethanamine
    Figure US20140275083A1-20140918-C00369
         		MS m/z 221.1 (M + H)+, Rt 0.50 min.
    333: (S)-1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethanamine
    Figure US20140275083A1-20140918-C00370
         		MS m/z 255.1 (M + H)+, Rt 0.62 min.
  • The intermediates in Table 23a were prepared using a method similar to that described for the preparation of Intermediate 306
  • TABLE 23a
    Figure US20140275083A1-20140918-C00371
         		Intermediate 334
    Figure US20140275083A1-20140918-C00372
         		Intermediate 335
    Figure US20140275083A1-20140918-C00373
         		Intermediate 336
    Figure US20140275083A1-20140918-C00374
         		Intermediate 337
    Figure US20140275083A1-20140918-C00375
         		Intermediate 338
    Figure US20140275083A1-20140918-C00376
         		Intermediate 339
    Figure US20140275083A1-20140918-C00377
         		Intermediate 340
    Figure US20140275083A1-20140918-C00378
         		Intermediate 341
  • TABLE 23b
    Chemical name and analytical data for each intermediate listed in Table 23a.
    Intermediate: Name Analytical data
    334: (S)-1-(4-bromo-2,5-difluorophenyl)ethanamine LCMS m/z (M + H)+ 236.0, RT 0.5 min.
    335: (S)-1-(4-bromo-2,3-difluorophenyl)ethanamine LCMS m/z (M + H)+ 238.1, RT 0.55 min.
    336: (S)-1-(4-bromo-2-fluorophenyl)ethanamine LCMS m/z (M + H)+ 218.0, 220.1, RT
    0.47 min.
    337: (S)-1-(4-chloro-2-fluorophenyl)ethanamine LCMS m/z (M + H)+ 174.2, RT 0.47 min.
    338: (S)-1-(4-bromo-3-fluorophenyl)ethanamine LCMS m/z (M + H)+ 218.1, 220.1, RT
    0.52 min.
    339: (S)-1-(3,4-dichlorophenyl)ethanamine LCMS m/z (M + H)+ 190.0, RT 0.57 min.
    340: (S)-1-(6-chloro-5-fluoropyridin-3- LCMS m/z (M + H)+ 175.2, RT 0.37 min.
    yl)ethanamine
    341: (S)-1-(5,6-dichloropyridin-3-yl)ethanamine LCMS m/z (M + H)+ 191.1, RT 0.42 min.
    • Intermediate 342: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00379
  • A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (112 mg, 0.40 mmol), (S)-1-phenylethanamine (58 mg, 0.48 mmol, 1.2 equiv), and DIPEA (153 mg, 1.2 mmol, 3.0 equiv) in DMSO (4.0 mL) was heated at 100° C. for 90 min. The reaction mixture was poured into 5 ml of water, extracted with EA (2×10 ml), the solvent was removed to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 50%) provided the pure product (142 mg, white solid) in a 93% yield. HRMS m/z 385.2231 (M+H)+, RT=3.35 min.
  • The Following Intermediates were prepared using a method similar to that described for the preparation of Intermediate 342 or Example 3
    • Intermediate 343: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2,3-dihydro-1H-inden-5-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00380
  • HRMS (B) tR=3.54 min; m/z 492.2485
    • Intermediate 344: (4R)-3-(2-((1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00381
  • HRMS (C) tR=1.76 min; MS m/z 561.43
    • Intermediate 345: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00382
  • HRMS (C) tR=1.94 min; m/z 480.2485
    • Intermediate 346: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00383
  • HRMS (C) tR=1.78 min; m/z 498.2391
    • Intermediate 347: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-phenethyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00384
  • HRMS (C) tR=1.71 min; m/z 480.2485
    • Intermediate 348: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00385
  • HRMS (B) tR=2.77 min; m/z 504.2337 (M+H)
    • Intermediate 349: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00386
  • HRMS (C) tR=1.96 min; m/z 554.1656
    • Intermediate 350: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00387
  • HRMS (B) tR=3.13 min; m/z 518.2089
    • Intermediate 351: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00388
  • HRMS (C) tR=1.97 min; m/z 536.1995
    • Intermediate 352: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00389
  • HRMS (C) tR=1.91 min; m/z 520.2046
    • Intermediate 353: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00390
  • HRMS (C) tR=1.87 min; m/z 520.2046
    • Intermediate 354: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00391
  • HRMS (C) tR=1.76 min; m/z 536.1995
    • Intermediate 355: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00392
  • HRMS (C) tR=1.76 min; m/z 550.2151
    • Intermediate 356: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00393
  • HRMS (B) tR=3.38 min; m/z 532.1882
    • Intermediate 357: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(3,4-dimethylphenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00394
  • HRMS (C) tR=1.63 min; m/z 480.2485
    • Intermediate 358: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00395
  • HRMS (B) tR=1.65 min; MS m/z 518.1 (M+H)
    • Intermediate 359: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00396
  • HRMS (B) tR=1.59 min; MS m/z 486.2
    • Intermediate 360: (4R)-3-(2-((1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00397
  • HRMS (C) tR=1.76 min; MS m/z 561.43
    • Intermediate 361: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00398
  • HRMS (C) tR=1.94 min; m/z 480.2485
    • Intermediate 362: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-((1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00399
  • HRMS (C) tR=1.96 min; m/z 512.2548
    • Intermediate 363: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00400
  • HRMS (C) tR=1.78 min; m/z 498.2391
    • Intermediate 364: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-phenethyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00401
  • HRMS (C) tR=1.71 min; m/z 480.2485
    • Intermediate 365: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00402
  • HRMS (B) tR=2.77 min; m/z 504.2337 (M+H)
    • Intermediate 366: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00403
  • HRMS (C) tR=1.96 min; m/z 554.1656
    • Intermediate 367: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00404
  • HRMS (B) tR=3.13 min; m/z 518.2089
    • Intermediate 368: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00405
  • HRMS (C) tR=1.97 min; m/z 536.1995
    • Intermediate 369: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00406
  • HRMS (C) tR=1.91 min; m/z 520.2046
    • Intermediate 370: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00407
  • HRMS (C) tR=1.87 min; m/z 520.2046
  • Intermediate 371
    • (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00408
  • HRMS (C) tR=1.76 min; m/z 536.1995
    • Intermediate 372: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00409
  • HRMS (C) tR=1.76 min; m/z 550.2151
  • Intermediate 373
    • (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00410
  • HRMS (B) tR=3.38 min; m/z 532.1882
    • Intermediate 374: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(3,4-dimethylphenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00411
  • HRMS (C) tR=1.63 min; m/z 480.2485
    • Intermediate 375: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00412
  • HRMS (B) tR=1.65 min; MS m/z 518.1 (M+H)
    • Intermediate 376: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00413
  • HRMS (B) tR=1.59 min; MS m/z 486.2
    • Intermediate 377: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-((1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00414
  • Anal. RP-HPLC tR=1.69 min; MS m/z 611.1 (M+H)+.
    • Intermediate 378: benzyl 4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-5-fluoropyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate
  • Figure US20140275083A1-20140918-C00415
  • 1H NMR (400 MHz, CD2Cl2) δ 8.18 (s, 1H), 7.41-7.30 (m, 5H), 5.15 (s, 2H), 5.03 (br s, 1H), 4.71-4.64 (m, 1H), 4.54-4.45 (m, 2H), 4.30-4.12 (m, 3H), 3.99-3.86 (m, 1H), 2.77 (br s, 2H), 1.87-1.57 (m, 3H), 1.36-1.24 (m, 2H), 1.20 (d, J=6.44 Hz, 3H), 1.16 (s, 9H), 1.09 (d, J=5.91 Hz, 3H). HRMS (C) tR=4.46 min; MS m/z 544.2964 (M+H)+
    • Intermediate 379: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00416
  • 1H NMR (400 MHz, CDCl3) δ 8.72 (d, J=2.3 Hz, 1H), 8.21 (d, J=5.7 Hz, 1H), 7.79 (dd, J=8.1, 2.4 Hz, 1H), 7.47 (d, J=5.8 Hz, 1H), 7.39-7.28 (m, 3H), 7.13-7.07 (m, 1H), 5.28 (p, J=6.9 Hz, 1H), 4.75 (dt, J=8.1, 3.5 Hz, 1H), 4.62 (dd, J=9.4, 3.1 Hz, 1H), 4.49-4.40 (m, 1H), 4.34 (t, J=9.0 Hz, 1H), 2.35 (d, J=1.9 Hz, 3H), 1.60 (d, J=6.7 Hz, 3H), 1.25 (s, 12H), 1.01 (d, J=6.5 Hz, 3H); MS m/z 492.6 (M−H).
    • Intermediate 380: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00417
  • LCMS tR=1.86 min; MS m/z 528.5 (M−H)+.
    • Intermediate 381: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6-(4-fluoro-3-methylphenyl)pyridin-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00418
  • LCMS tR=1.69 min; MS m/z 494.0 (M+H)+.
    • Intermediate 382: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00419
  • LCMS tR=1.74 min; MS m/z 530.0 (M+H)+.
    • Intermediate 383: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00420
  • 1H NMR (400 MHz, CDCl3) δ 8.86 (d, J=2.3 Hz, 1H), 8.83 (d, J=5.1 Hz, 1H), 8.20 (d, J=5.7 Hz, 1H), 7.93 (dd, J=8.1, 2.4 Hz, 1H), 7.87 (s, 1H), 7.69 (dd, J=5.2, 1.7 Hz, 1H), 7.48 (d, J=5.8 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 6.37-5.79 (m, 1H), 5.33 (p, J=6.9 Hz, 1H), 4.74 (ddd, J=8.2, 4.6, 3.0 Hz, 1H), 4.62 (dd, J=9.3, 3.0 Hz, 1H), 4.43 (qd, J=6.4, 4.2 Hz, 1H), 4.34 (t, J=9.0 Hz, 1H), 1.67 (br s, 1H), 1.62 (d, J=6.8 Hz, 3H), 1.26 (s, 9H), 1.02 (d, J=6.4 Hz, 3H); MS m/z 531.3 (M+H).
    • Intermediate 384: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6′-(trifluoromethyl)-[2,3′-bipyridin]-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00421
  • LCMS tR=1.51 min; MS m/z 531.1 (M+H).
    • Intermediate 385: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00422
  • LCMS tR=1.51 min; MS m/z 531.3 (M+H).
    • Intermediate 386: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00423
  • LCMS tR=1.59 min; MS m/z 531.2 (M+H).
    • Intermediate 387: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00424
  • LCMS tR=1.60 min; MS m/z 545.2 (M+H).
    • Intermediate 388: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00425
  • LCMS tR=1.65 min; MS m/z 545.2 (M+H).
    • Intermediate 389: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-fluoro-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00426
  • LCMS tR=1.65 min; MS m/z 549.2 (M+H).
    • Intermediate 390: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00427
  • LCMS tR=1.65 min; MS m/z 545.6 (M+H).
    • Intermediate 391: (R)-4-((S)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00428
  • LCMS tR=1.63 min; MS m/z 543.5 (M+H).
    • Intermediate 392: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00429
  • LCMS tR=0.94 min; MS m/z 486.0 (M−H).
    • Intermediate 393: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(4-((4,4-difluoropiperidin-1-yl)methyl)-3-fluorophenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00430
  • LCMS tR=1.81 min; MS m/z 534.5 (M−H).
    • Intermediate 394: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00431
  • LCMS tR=1.74 min; MS m/z 531.0 (M+H).
    • Intermediate 395: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00432
  • LCMS tR=1.71 min; MS m/z 495.0 (M+H).
    • Intermediate 396: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-(2,4-dichlorophenyl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00433
  • LCMS tR=1.84 min; MS m/z 536.0 (M+H).
    • Intermediate 397: (R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00434
  • LCMS tR=1.77 min; MS m/z 548.0 (M+H).
    • Intermediate 398: 4-(2-((S)-1-((4-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)thiazol-4-yl)benzonitrile
  • Figure US20140275083A1-20140918-C00435
  • LCMS tR=1.55 min; MS m/z 493.1 (M+H).
    • Intermediate 399: (R)-3-(2-(((S)-1-(5-bromopyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00436
  • 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J=2.2 Hz, 1H), 8.15 (d, J=6.0 Hz, 1H), 7.78 (dd, J=8.3, 2.3 Hz, 1H), 7.50 (d, J=5.9 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 5.22 (p, J=6.9 Hz, 1H), 4.72 (ddd, J=8.3, 4.7, 3.0 Hz, 1H), 4.62 (dd, J=9.3, 3.0 Hz, 1H), 4.41-4.31 (m, 2H), 1.56 (d, J=6.8 Hz, 3H), 1.21 (s, 9H), 1.00 (d, J=6.4 Hz, 3H). MS m/z 466.2 (M+H).
    • Intermediate 400: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-((1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00437
  • Anal. RP-HPLC tR=1.54, 1.56 min (Column=Acquity BEH C18 1.7 μm 2.1×50 mm. Column Temperature=50° C. Eluents=A: Water (3.75 mM Ammonium formate, 2% ACN); B: ACN (3.75 mM Ammonium formate, 5% Water). Flow Rate=1 mL/min. Gradient=2% to 98% B in 1.70 min.; MS m/z 549.3 (M+H)+.
    • Intermediate 401: (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00438
  • Anal. RP-HPLC tR=1.69 min; MS m/z 549.4 (M+H)+.
    • Intermediate 402: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-6-(difluoromethyl)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00439
  • A solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)oxazolidin-2-one (0.146 g, 0.371 mmol), (S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (91 mg, 0.41 mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.097 mL, 0.56 mmol, 1.5 equiv) in DMSO (2.0 mL) was heated at 85° C. for 18 h. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with DCM (20 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20% to 60%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-6-(difluoromethyl)pyrimidin-4-yl)oxazolidin-2-one as a yellow oily solid in 37% yield. MS m/z 537.2 (M+H)+; Rt-1.22 min.
    • Intermediate 403: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00440
  • A solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (70 mg, 0.209 mmol), (S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethanamine (60 mg, 0.23 mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.091 mL, 0.52 mmol, 2.5 equiv) in DMSO (1.0 mL) was heated at 85-110° C. for 3-5 h. The reaction was cooled to room temperature and diluted with ethyl acetate (30 mL) and dilute aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to give crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one, which was used without further purification. MS m/z 520.2 (M+H)+; Rt-1.31 min.
  • The intermediates in Table 24a were prepared using a method similar to that described for the preparation of Intermediate 403.
  • TABLE 24a
    Figure US20140275083A1-20140918-C00441
         		Intermediate 405
    Figure US20140275083A1-20140918-C00442
         		Intermediate 406
    Figure US20140275083A1-20140918-C00443
         		Intermediate 407
    Figure US20140275083A1-20140918-C00444
         		Intermediate 408
    Figure US20140275083A1-20140918-C00445
         		Intermediate 409
    Figure US20140275083A1-20140918-C00446
         		Intermediate 410
    Figure US20140275083A1-20140918-C00447
         		Intermediate 411
    Figure US20140275083A1-20140918-C00448
         		Intermediate 412
    Figure US20140275083A1-20140918-C00449
         		Intermediate 413
    Figure US20140275083A1-20140918-C00450
         		Intermediate 414
    Figure US20140275083A1-20140918-C00451
         		Intermediate 415
    Figure US20140275083A1-20140918-C00452
         		Intermediate 416
    Figure US20140275083A1-20140918-C00453
         		Intermediate 417
    Figure US20140275083A1-20140918-C00454
         		Intermediate 418
    Figure US20140275083A1-20140918-C00455
         		Intermediate 419
    Figure US20140275083A1-20140918-C00456
         		Intermediate 420
    Figure US20140275083A1-20140918-C00457
         		Intermediate 421
    Figure US20140275083A1-20140918-C00458
         		Intermediate 422
    Figure US20140275083A1-20140918-C00459
         		Intermediate 423
    Figure US20140275083A1-20140918-C00460
         		Intermediate 424
    Figure US20140275083A1-20140918-C00461
         		Intermediate 425
    Figure US20140275083A1-20140918-C00462
         		Intermediate 426
    Figure US20140275083A1-20140918-C00463
         		Intermediate 427
    Figure US20140275083A1-20140918-C00464
         		Intermediate 428
    Figure US20140275083A1-20140918-C00465
         		Intermediate 429
    Figure US20140275083A1-20140918-C00466
         		Intermediate 430
    Figure US20140275083A1-20140918-C00467
         		Intermediate 431
    Figure US20140275083A1-20140918-C00468
         		Intermediate 432
    Figure US20140275083A1-20140918-C00469
         		Intermediate 433
    Figure US20140275083A1-20140918-C00470
         		Intermediate 434
    Figure US20140275083A1-20140918-C00471
         		Intermediate 435
    Figure US20140275083A1-20140918-C00472
         		Intermediate 436
    Figure US20140275083A1-20140918-C00473
         		Intermediate 437
    Figure US20140275083A1-20140918-C00474
         		Intermediate 438
    Figure US20140275083A1-20140918-C00475
         		Intermediate 439
    Figure US20140275083A1-20140918-C00476
         		Intermediate 440
    Figure US20140275083A1-20140918-C00477
         		Intermediate 441
    Figure US20140275083A1-20140918-C00478
         		Intermediate 442
    Figure US20140275083A1-20140918-C00479
         		Intermediate 443
    Figure US20140275083A1-20140918-C00480
         		Intermediate 444
    Figure US20140275083A1-20140918-C00481
         		Intermediate 445
    Figure US20140275083A1-20140918-C00482
         		Intermediate 446
    Figure US20140275083A1-20140918-C00483
         		Intermediate 447
    Figure US20140275083A1-20140918-C00484
         		Intermediate 448
    Figure US20140275083A1-20140918-C00485
         		Intermediate 449
    Figure US20140275083A1-20140918-C00486
         		Intermediate 450
    Figure US20140275083A1-20140918-C00487
         		Intermediate 451
    Figure US20140275083A1-20140918-C00488
         		Intermediate 452
    Figure US20140275083A1-20140918-C00489
         		Intermediate 453
    Figure US20140275083A1-20140918-C00490
         		Intermediate 454
    Figure US20140275083A1-20140918-C00491
         		Intermediate 455
    Figure US20140275083A1-20140918-C00492
         		Intermediate 456
    Figure US20140275083A1-20140918-C00493
         		Intermediate 457
    Figure US20140275083A1-20140918-C00494
         		Intermediate 458
    Figure US20140275083A1-20140918-C00495
         		Intermediate 459
    Figure US20140275083A1-20140918-C00496
         		Intermediate 460
    Figure US20140275083A1-20140918-C00497
         		Intermediate 461
    Figure US20140275083A1-20140918-C00498
         		Intermediate 462
    Figure US20140275083A1-20140918-C00499
         		Intermediate 463
    Figure US20140275083A1-20140918-C00500
         		Intermediate 464
    Figure US20140275083A1-20140918-C00501
         		Intermediate 465
    Figure US20140275083A1-20140918-C00502
         		Intermediate 466
    Figure US20140275083A1-20140918-C00503
         		Intermediate 467
    Figure US20140275083A1-20140918-C00504
         		Intermediate 468
    Figure US20140275083A1-20140918-C00505
         		Intermediate 469
    Figure US20140275083A1-20140918-C00506
         		Intermediate 470
  • TABLE 24b
    Chemical name and analytical data for
    each intermediate listed in Table 24a.
    Intermediate: Name Analytical data
    405: (R)-4-((R)-1-tert-butoxyethyl)-3-(6-chloro-2- MS m/z 521.1
    ((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5- (M + H)+;
    yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.29 min
    406: (R)-4-((R)-1-tert-butoxyethyl)-3-(6-chloro-2- MS m/z 505.3
    ((S)-1-(2-fluoro-4- (M + H)+;
    (trifluoromethyl)phenyl)ethylamino)pyrimidin-4- Rt-1.29 min
    yl)oxazolidin-2-one
    407: (R)-4-((R)-1-tert-butoxyethyl)-3-(6-chloro-2- MS m/z 517.2
    ((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4- (M + H)+;
    yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2- Rt-1.13 min
    one
    408: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 535.2
    (((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4- (M + H)+;
    yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2- Rt-1.14 min
    one
    409: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 486.3
    (((S)-1-(5-phenylisoxazol-3- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.25 min
    410: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 537.2
    (((S)-1-(2-(4-chlorophenyl)thiazol-5- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.33 min
    411: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 520.2
    (4-chlorophenyl)thiazol-5-yl)ethyl)amino)-5- (M + H)+;
    fluoropyrimidin-4-yl)oxazolidin-2-one Rt-1.16 min
    412: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5- MS m/z 504.2
    (4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-5- (M + H)+;
    fluoropyrimidin-4-yl)oxazolidin-2-one Rt-1.16 min
    413: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 537.2
    (((S)-1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.28 min
    414: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 519.3
    (((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.30 min
    415: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 503.4
    (4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-5- (M + H)+;
    fluoropyrimidin-4-yl)oxazolidin-2-one Rt-1.11 min
    416: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5- MS m/z 518.2
    (4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6- (M + H)+;
    (fluoromethyl)pyrimidin-4-yl)oxazolidin-2-one Rt-1.18 min
    417: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 534.2
    (4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6- (M + H)+;
    (fluoromethyl)pyrimidin-4-yl)oxazolidin-2-one Rt-1.21 min
    418: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 502.2
    (4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin- (M + H)+;
    4-yl)oxazolidin-2-one Rt-0.99 min
    419: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 485.4
    (4-chlorophenyl)-1H-pyrazol-4- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.93 min
    420: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 520.2
    (((S)-1-(3-(4-chlorophenyl)isoxazol-5- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.30 min
    421: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3- MS m/z 504.3
    (4-chlorophenyl)isoxazol-5-yl)ethyl)amino)-5- (M + H)+;
    fluoropyrimidin-4-yl)oxazolidin-2-one Rt-1.13 min
    422: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 504.3
    (((S)-1-(5-(4-fluorophenyl)isoxazol-3- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.22 min
    423: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 509.4
    (((S)-1-(5-(morpholinomethyl)isoxazol-3- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.80 min
    424: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 509.4
    (((R)-1-(5-(morpholinomethyl)isoxazol-3- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.83 min
    425: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 499.3
    (4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6- (M + H)+;
    methylpyrimidin-4-yl)oxazolidin-2-one Rt-0.98 min
    426: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 503.2
    (((S)-1-(2-(pyridin-2-yl)thiazol-5- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.19 min
    427: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 503.3
    (((S)-1-(2-(pyridin-3-yl)thiazol-5- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.92 min
    428: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 503.3
    (((S)-1-(2-(pyridin-4-yl)thiazol-5- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.89 min
    429: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5- MS m/z 500.4
    (4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6- (M + H)+;
    methylpyrimidin-4-yl)oxazolidin-2-one Rt-1.02 min
    430: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 516.3
    (4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6- (M + H)+;
    methylpyrimidin-4-yl)oxazolidin-2-one Rt-1.04 min
    431: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 499.3
    (4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-6- (M + H)+;
    methylpyrimidin-4-yl)oxazolidin-2-one Rt-0.76 min
    432: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3- MS m/z 501.3
    (4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)- (M + H)+;
    6-methylpyrimidin-4-yl)oxazolidin-2-one Rt-1.04 min
    433: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 499.3
    (4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)amino)-6- (M + H)+;
    methylpyrimidin-4-yl)oxazolidin-2-one Rt-1.02 min
    434: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 500.2
    (4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)amino)- (M + H)+;
    6-methylpyrimidin-4-yl)oxazolidin-2-one Rt-0.88 min
    435: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 520.2
    (((S)-1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.14 min
    436: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 486.3
    (4-chlorophenyl)-1H-1,2,3-triazol-4- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.87 min
    437: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4- MS m/z 481.4
    (1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-6- (M + H)+;
    methylpyrimidin-4-yl)oxazolidin-2-one Rt-0.94 min
    438: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 533.4
    (2,5-difluoro-4-(2,2,2- (M + H)+;
    trifluoroethoxy)phenyl)ethyl)amino)-6- Rt-0.96 min
    methylpyrimidin-4-yl)oxazolidin-2-one
    439: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-methyl-2- MS m/z 497.3
    (((S)-1-(2-(6-methylpyridin-3-yl)thiazol-5- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.63 min
    440: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 537.3
    (6-(trifluoromethyl)pyridin-3-yl)thiazol-5- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.95 min
    441: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 537.3
    (2-(trifluoromethyl)pyridin-4-yl)thiazol-5- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.80 min
    442: methyl 6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2- MS m/z 560.3
    oxooxazolidin-3-yl)-2-(((S)-1-(2-(4- (M + H)+;
    chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidine-4- Rt-1.20 min
    carboxylate
    443: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 499.2
    (4-chlorophenyl)-2-methyl-1H-imidazol-4- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.77 min
    444: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 518.3
    (4-(difluoromethyl)phenyl)thiazol-5- (M + H)+;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.89 min
    445: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-(4- MS m/z 499.2
    chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-6- (M + H)+;
    (trifluoromethyl)pyrimidin-4-yl)oxazolidin-2-one Rt-1.27 min.
    446: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 471.3
    fluoro-4-(trifluoromethyl)phenyl)ethylamino) (M + H)+;
    pyrimidin-4-yl)oxazolidin-2-one Rt-1.01 min
    447: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(4-(1- MS m/z 487.3
    ethoxycyclopropyl)-2-fluorophenyl)ethylamino) (M + H)+;
    pyrimidin-4-yl)oxazolidin-2-one Rt-1.02 min
    448: 4-((S)-1-(4-((R)-4-((R)-1-tert-butoxyethyl)-2- MS m/z 530.3
    oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)-2- (M + H)+;
    chloro-N-cyclopentylbenzamide Rt-0.91 min
    449: 1-(4-((S)-1-(4-((R)-4-((R)-1-tert-butoxyethyl)-2- MS m/z 468.3
    oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)-3- (M + H)+;
    fluorophenyl)cyclopropanecarbonitrile Rt-0.91 min
    450: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 483.3
    fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl) (M + H)+;
    ethylamino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.86 min
    451:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(4-(1- MS m/z 465.3
    methyl-1H-pyrazol-4-yl)phenyl)ethylamino) (M + H)+;
    pyrimidin-4-yl)oxazolidin-2-one Rt-0.83 min
    452: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 469.3
    fluoro-4-(1H-pyrazol-4-yl)phenyl)ethylamino) (M + H)+;
    pyrimidin-4-yl)oxazolidin-2-one Rt-0.80 min
    453: (R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 489.3
    ((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl) (M + H)+;
    ethylamino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.15 min
    454: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 457.4
    fluoro-4-(1-methylcyclopropyl)phenyl) (M + H)+;
    ethylamino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.06 min
    455: (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 445.3
    fluoro-4-isopropylphenyl)ethylamino)pyrimidin-4- (M + H)+;
    yl)oxazolidin-2-one Rt-1.05 min
    456: (R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 501.3
    ((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4- (M + H)+;
    yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2- Rt-0.98 min
    one
    457: (R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 475.3
    ((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl) (M + H)+;
    ethylamino)pyrimidin-4-yl)oxazolidin-2-one Rt-1.20 min
    458: (R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 487.2
    ((S)-1-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl) (M + H)+;
    ethylamino)pyrimidin-4-yl)oxazolidin-2-one Rt-0.90 min
    459: (R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 463.3
    ((S)-1-(2-fluoro-4-isopropylphenyl)ethylamino) (M + H)+;
    pyrimidin-4-yl)oxazolidin-2-one Rt-1.20 min
    460: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2- MS m/z 461.3
    (((S)-1-(2-fluoro-4-(2-hydroxypropan-2- (M + H)+;
    yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2- Rt-1.14 min
    one
    461: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 519.3
    (2,5-difluoro-4-(1-methyl-1H-pyrazol-4- (M + H)+;
    yl)phenyl)ethyl)amino)-5-fluoropyrimidin-4- Rt-0.98 min
    yl)oxazolidin-2-one
    462: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 502.3
    (4-chlorophenyl)thiazol-5-yl)ethyl)amino) pyrimidin- (M + H)+;
    4-yl)oxazolidin-2-one Rt-0.95 min
    463: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 457.4
    (4-isobutoxyphenyl)ethyl)amino)pyrimidin-4- (M + H)+;
    yl)oxazolidin-2-one Rt 1.04 min
    464: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2- MS m/z 451.3
    (((S)-1-(2-fluoro-4- (M + H)+;
    methoxyphenyl)ethyl)amino)pyrimidin-4- Rt 1.03 min
    yl)oxazolidin-2-one
    465: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 421.2
    (2,3-difluorophenyl)ethyl)amino)pyrimidin-4- (M + H)+;
    yl)oxazolidin-2-one Rt = 0.91 min
    466: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 439.2
    (2,3-difluorophenyl)ethyl)amino)-5-fluoropyrimidin- (M + H)+;
    4-yl)oxazolidin-2-one Rt = 1.05 min;
    467: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 439.2
    (3,4-difluorophenyl)ethyl)amino)-5-fluoropyrimidin- (M + H)+;
    4-yl)oxazolidin-2-one Rt = 1.03 min;
    468: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 439.3
    (2,4-difluorophenyl)ethyl)amino)-5-fluoropyrimidin- (M + H)+;
    4-yl)oxazolidin-2-one Rt = 1.04 min;
    469: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 439.2
    (3,5-difluorophenyl)ethyl)amino)-5-fluoropyrimidin- (M + H)+;
    4-yl)oxazolidin-2-one Rt = 1.04 min;
    470: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-chloro-2- MS m/z 565.4
    (((S)-1-(5-(2-(trifluoromethyl)pyridin-4-yl)pyrimidin- (M + H)+;
    2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one Rt = 0.98 min;
    • Intermediate 473: (2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol
  • Figure US20140275083A1-20140918-C00507
  • A solution of (S)-4,6-difluoro-N-(1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine (80 mg, 0.25 mmol), (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol (55 mg, 0.28 mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.11 mL, 0.63 mmol, 2.5 equiv) in DMSO (1.3 mL) was heated at 85° C. for 16 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (30 mL) and dilute aqueous sodium chloride (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol (0.058 g, white solid) in 50% yield. 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.66 (s, 1H), 7.61 (m, 2H), 7.13 (t, J=8.6 Hz, 2H), 5.35 (s, 1H), 5.30-5.14 (m, 2H), 5.04 (m, 1H), 3.94 (m, 1H), 3.77-3.65 (m, 2H), 1.57 (d, J=6.9 Hz, 3H), 1.21 (s, 9H), 1.15 (d, J=6.0 Hz, 3H). MS m/z 461.3 (M+H)+; Rt-0.88 min.
    • Intermediate 474: (2R,3R)-3-(tert-butoxy)-2-((2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-fluoropyrimidin-4-yl)amino)butan-1-ol
  • Figure US20140275083A1-20140918-C00508
  • (2R,3R)-3-(tert-butoxy)-2-((2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-fluoropyrimidin-4-yl)amino)butan-1-ol was prepared using a method similar to that described for the preparation of Intermediate 473. 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (s, 1H), 7.67 (s, 1H), 7.60 (d, J=8.9 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 5.35 (s, 1H), 5.27 (m, 1H), 5.19 (m, 1H), 5.07 (m, 1H), 3.94 (m, 1H), 3.71 (m, 2H), 1.57 (d, J=6.8 Hz, 3H), 1.21 (s, 9H), 1.14 (d, J=5.9 Hz, 3H). MS m/z 477.3 (M+H)+; Rt-0.96 min
    • Intermediate 475: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00509
  • Triphosgene (18 mg, 0.062 mmol, 0.5 equiv) was added to a solution of (2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol (57 mg, 0.12 mmol) in DCM (1.2 mL) at −78° C., followed by the dropwise addition of 2,6-lutidine (0.058 mL, 0.49 mmol, 4 equiv). The solution was allowed to warm to room temperature and was then heated at 35° C. for 30 min. The reaction was then cooled to room temperature and diluted with DCM (30 mL) and saturated aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to give crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one, which was used without further purification. MS m/z 487.4 (M+H)+; Rt-1.12 min.
    • Intermediate 476: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00510
  • (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-fluoropyrimidin-4-yl)oxazolidin-2-one was prepared using a method similar to that described for the preparation of Intermediate 475. 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (s, 1H), 7.66 (s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 7.17 (s, 1H), 5.31 (m, 1H), 4.70 (m, 1H), 4.62 (dd, J=9.2, 3.0 Hz, 1H), 4.33 (m, 2H), 1.62 (d, J=6.8 Hz, 3H), 1.13 (br s, 9H), 1.02 (d, J=6.5 Hz, 3H). MS m/z 503.3 (M+H)+; Rt-1.21 min.
    • Intermediate 477
  • Figure US20140275083A1-20140918-C00511
  • To a microwave vial with a stir bar was added (R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (43.6 mg, 0.145 mmol) and (S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethanamine (25.1 mg, 0.121 mmol), followed by DMSO (605 uL) and DIEA (63.5 ul, 0.363 mmol). The vial was capped and the reaction mixture heated in a preheated oil bath at 110° C. for 21 hr. The mixture was diluted with water and extracted with EtOAc two times. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, concentrated and dried on house vacuum to afford crude (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one, as a brown solid film, (yield assumed quantitative). LCMS m/z 471.4 (M+H)+, Rt 0.85 min.
  • The compounds in Table 25 were prepared using methods similar to those described for the preparation of Intermediate 477.
  • TABLE 25
    Intermediate: Name Structure LCMS
    478: (R)-4-((R)-1-tert-butoxyethyl)-3-(2- ((S)-1-(3- isobutoxyphenyl)ethylamino)pyrimidin-4- yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00512
         		MS m/z 457.4 (M + H)+, Rt 1.04 min.
    479: (R)-4-((R)-1-tert-butoxyethyl)-3-(2- ((S)-1-(3- phenoxyphenyl)ethylamino)pyrimidin-4- yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00513
         		MS m/z 477.3 (M +H)+, Rt 1.00 min.
    480: (R)-4-((R)-1-tert-butoxyethyl)-3-(2- ((S)-1-(4- isopropoxyphenyl)ethylamino)pyrimidin- 4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00514
         		MS m/z 443.4 (M + H)+, Rt 0.94 min.
    481: (R)-4-((R)-1-tert-butoxyethyl)-3-(2- ((S)-1-(4-isobutoxy-3- methylphenyl)ethylamino)pyrimidin-4- yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00515
         		MS m/z 471.4 (M + H)+, Rt 1.09 min.
    482: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5- fluoro-2-(((S)-1-(4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00516
         		MS m/z 487.3 (M + H)+, Rt 1.18 min.
    483: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5- fluoro-2-(((S)-1-(2-fluoro-4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00517
         		MS m/z 505.4 (M + H)+, Rt 1.16 min.
    484: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4- (difluoromethoxy)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00518
         		MS m/z 469.3 (M + H)+, Rt 1.05 min.
    485: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5- fluoro-2-(((S)-1-(3-fluoro-4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00519
         		MS m/z 505.4 (M + H)+, Rt 1.14 min.
    486: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)-3- fluorophenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00520
         		MS m/z 487.3 (M + H)+, Rt 1.08 min.
    487: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)-2- fluorophenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00521
         		MS m/z 487.3 (M + H)+, Rt 1.04 min.
    488: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5- fluoro-2-(((S)-1-(3- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00522
         		MS m/z 487.3 (M + H)+, Rt 1.10 min.
    489: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(3- (difluoromethoxy)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00523
         		MS m/z 469.3 (M + H)+, Rt 1.03 min.
    • Intermediate 490
  • Figure US20140275083A1-20140918-C00524
  • To a microwave vial with a stir bar was added (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (75.0 mg, 0.224 mmol) and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (59.7 mg, 0.247 mmol), followed by DMSO (0.9 mL) and DIEA (118 ul, 0.673 mmol). The vial was capped and the reaction mixture heated in a preheated oil bath at 85° C. for 2 hr. The mixture was diluted with brine and extracted with EtOAc two times. The combined organic phases were dried over sodium sulfate, filtered, concentrated and dried on house vacuum to afford crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a brown solid film, (yield assumed quantitative). LCMS m/z 503.2 (M+H)+, Rt 1.24 min.
  • The compounds in Table 26 were prepared using methods similar to those described for the preparation of Intermediate 490
  • TABLE 26
    Intermediate: Name Structure LCMS
    491: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6- chloro-2-(((S)-1-(2-fluoro-4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00525
         		MS m/z 521.3 (M + H)+, Rt 1.33 min.
    492: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6- chloro-2-(((S)-1-(4- (difluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00526
         		MS m/z 485.2 (M + H)+, Rt 1.20 min.
    493: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6- chloro-2-(((S)-1-(3-fluoro-4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00527
         		MS m/z 521.3 (M + H)+, Rt 1.31 min.
    • Intermediate 494
  • Figure US20140275083A1-20140918-C00528
  • To a suspension of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (30.0 mg, 0.106 mmol) and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (38.4 mg, 0.159 mmol) in DMSO (0.53 mL), was added DIEA (64.7 ul, 0.371 mmol) in a microwave vial. The vial was capped and the reaction mixture heated in a preheated oil bath at 100° C. for 3 hr.
  • The mixture was diluted with dilute brine and extracted with EtOAc two times. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, concentrated and dried on house vacuum to afford crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a clear colorless oil which was used without further purification (yield assumed quantitative). LCMS m/z 469.3 (M+H)+, Rt 0.98 min.
  • The compounds in Table 27 were prepared using methods similar to those described for the preparation of Intermediate 494.
  • TABLE 27
    Intermediate: Name Structure LCMS
    495: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(3-fluoro-4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00529
         		MS m/z 487.3 (M + H)+, Rt 0.99 min.
    496: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(2-fluoro-4- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00530
         		MS m/z 487.3 (M + H)+, Rt 1.00 min.
    497: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)-3- fluorophenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00531
         		MS m/z 469.4 (M + H)+, Rt 0.91 min.
    498: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4- (cyclopropylmethoxy)phenyl)ethyl)amino)- pyrimidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00532
         		MS m/z 455.3 (M + H)+, Rt 0.96 min.
    499: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(2-fluoro-4- isobutoxyphenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00533
         		MS m/z 475.3 (M + H)+, Rt 1.07 min.
    500: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4- (difluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00534
         		MS m/z 451.3 (M + H)+, Rt 0.90 min.
    501: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)-2- fluorophenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00535
         		MS m/z 469.3 (M + H)+, Rt 0.90 min.
    502: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(3- (trifluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00536
         		MS m/z 469.3 (M + H)+, Rt 0.94 min.
    503: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(3- (difluoromethoxy)phenyl)ethyl)amino)pyr- imidin-4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00537
         		MS m/z 451.3 (M + H)+, Rt 0.87 min.
    • Intermediate 504: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00538
  • To a Parshaker flask were added benzyl 4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate (1 g, 1.90 mmole) and 20% Pd(OH)2 in activated carbon (1 g, 1.42 mmole), then was added MeOH (100 mL) under nitrogen gas. The reaction mixture was shaked under 50 spi hydrogen overnight. The reaction mixture was filtered through a celite. The celite cake was washed with MeOH and the filtrate was concentrate in vacuo to afford the title product as a white solid (630 mg). 1H NMR (400 MHz, CD2Cl2) δ 8.18-8.15 (m, 1H), 7.42-7.37 (m, 1H), 4.99 (br, s, 1H), 4.77-4.70 (m, 1H), 4.64-4.57 (m, 1H), 4.52-4.38 (m, 1H), 4.38-4.31 (m, 1H), 4.12-3.93 (m, 2H), 3.40-3.31 (m, 1H), 3.12-3.29 (m, 2H), 2.81-2.70 (m, 1H), 2.02-1.29 (m, 5H), 1.25 (s, 9H), 1.23-1.16 (m, 3H), 1.05-1.00 (m, 3H). HRMS (C) tR=2.65 min; MS m/z 392.2655 (M+H)+
    • Intermediate 505: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(2-(1,1,1-trifluoro-2-methyl propan-2-yl)pyridin-4-yl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00539
  • Intermediate 505 was prepared using a method similar to that described for the preparation of Intermediate 329. 1H NMR (400 MHz, CD2Cl2) δ 8.23-8.12 (m, 1H), 7.87 (d, J=7.45 Hz, 1H), 7.69 (d, J=6.22 Hz, 1H), 6.81-6.74 (m, 2H), 4.67 (m, 1H), 4.61-4.55 (m, 1H), 4.37-4.29 (m, 1H), 4.25-4.16 (m, 2H), 4.14-4.04 (m, 2H), 3.97-3.85 (m, 1H), 3.21-3.09 (m, 2H), 2.11-1.87 (m, 3H), 1.61 (s, 6H), 1.39-1.23 (m, 1H), 1.21 (d, J=7.45 Hz, 3H), 1.15-1.07 (m, 1H), 1.06 (s, 9H), 0.96 (d, J=6.62 Hz, 3H), HRMS (C) tR=4.80 min; MS m/z 579.3273 (M+H)+
    • Intermediate 506: (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoro methoxy)phenyl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00540
  • Intermediate 506 was prepared using a method similar to that described for the preparation of Intermediate 329. 1H NMR (400 MHz, CD2Cl2) δ 8.17 (br, s, 1H), 7.41 (d, J=6.14 Hz, 1H), 7.31 (d, J=7.98 Hz, 1H), 6.87-6.80 (m, 2H), 4.77-4.71 (m, 1H), 4.64-4.58 (m, 1H), 4.49-4.40 (m, 1H), 4.39-4.32 (m, 1H), 4.11-3.97 (m, 1H), 3.79-3.70 (m, 2H), 2.82-2.71 (m, 2H), 2.04-1.91 (m, 1H), 1.90-1.80 (m, 1H), 1.66-1.35 (m, 3H), 1.34-1.15 (m, 13H), 1.03 (d, J=7.36 Hz, 3H), HRMS (C) tR=5.68 min; MS m/z 586.2419 (M+H)+
    • Intermediate 507: benzyl 4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate
  • Figure US20140275083A1-20140918-C00541
  • Intermediate 507 was prepared using a method similar to that described for the preparation of Intermediate 342. 1H NMR (400 MHz, CD2Cl2) δ 8.16 (d, J=5.77 Hz, 1H), 7.41-7.31 (m, 6H), 5.15 (s, 2H), 4.76-4.71 (m, 1H), 4.64-4.58 (m, 1H), 4.48-4.41 (m, 1H), 4.38-4.31 (m, 1H), 4.30-4.18 (m, 2H), 4.09-3.96 (m, 1H), 2.77 (br s, 2H), 1.94-1.54 (m, 3H), 1.37-1.25 (m, 3H), 1.23 (s, 9H), 1.20 (d, J=6.53 Hz, 3H), 1.03 (d, J=5.91 Hz, 3H). HRMS (C) tR=4.64 min; MS m/z 526.3012 (M+H)+
  • The intermediates in Table 27b were prepared using methods similar to those described for the preparation of Intermediate 303.
  • TABLE 27b
    Intermediate: Name Structure LCMS
    508: (S)-1-(1-(3,4- difluorophenyl)-1H- imidazol-4-yl) ethanamine
    Figure US20140275083A1-20140918-C00542
         		LCMS(B) m/z (M + H)+ 224.1, RT 0.39 min.
    509: (S)-1-(1-(4- chloro-3- fluorophenyl)-1H- imidazol-4-yl) ethanamine
    Figure US20140275083A1-20140918-C00543
         		LCMS(B) m/z (M + H)+ 240.0, RT 0.48 min.
    510: (S)-1-(1-(3- chloro-4- fluorophenyl)-1H- imidazol-4-yl) ethanamine
    Figure US20140275083A1-20140918-C00544
         		LCMS(B) m/z (M + H)+ 240.1, RT 0.46 min.
    511: (S)-1-(1-(4- (difluoromethyl) phenyl)-1H- imidazol-4-yl) ethanamine
    Figure US20140275083A1-20140918-C00545
         		LCMS(B) m/z (M + H)+ 238.1, RT 0.41 min.
    512: (S)-1-(1-(4- (difluoromethyl)-3- fluorophenyl)-1H- imidazol-4-yl) ethanamine
    Figure US20140275083A1-20140918-C00546
         		LCMS(B) m/z (M + H)+ 256.0, RT 0.47 min.
    513: (S)-1-(1-(3,5- difluorophenyl)- 1H-imidazol-4-yl) ethanamine
    Figure US20140275083A1-20140918-C00547
         		LCMS(B) m/z (M + H)+ 224.1, RT 0.41 min.
    • EXAMPLES Example 1 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00548
  • To a solution of 1-(3-(4-chlorophenyl)isoxazol-5-yl)ethanamine (610 mg, 2.74 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (774 mg, 2.74 mmol) in DMSO (5 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 0.96 mL, 5.48 mmol) and heated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (50 ml), wash with water (50 ml), brine (50 ml), concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-25% EtOAc/DCM afforded 500 mg of white solid: 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J=5.8, 1.6 Hz, 1H), 7.80-7.65 (m, 2H), 7.58 (dd, J=5.8, 1.6 Hz, 1H), 7.49-7.37 (m, 2H), 6.48-6.35 (m, 1H), 5.66-5.44 (m, 1H), 4.71 (dddd, J=9.8, 8.5, 4.6, 3.0 Hz, 1H), 4.63 (ddd, J=9.4, 3.1, 2.1 Hz, 1H), 4.50-4.26 (m, 2H), 1.71 (s, 1H), 1.25 (s, 5H), 1.15 (s, 5H), 1.03 (dd, J=22.4, 6.4 Hz, 3H), 5.44-5.13 (m, 1H). HRMS (B) tR=3.36 min; m/z 485.1830
    • Example 2 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00549
  • To a solution of (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine 75 mg, 0.337 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (101 mg, 0.337 mmol) in DMSO (1 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 0.118 mL, 0.674 mmol) and heated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-10% EtOAc/DCM afforded 124 mg yellow foam: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=2.8 Hz, 1H), 7.61-7.49 (m, 2H), 7.45-7.36 (m, 2H), 7.28 (d, J=6.2 Hz, 1H), 5.65 (d, J=8.9 Hz, 1H), 5.43-5.27 (m, 1H), 4.69 (qd, J=5.6, 2.9 Hz, 1H), 4.62-4.35 (m, 2H), 4.23-4.01 (m, 1H), 1.68 (d, J=12.8 Hz, 2H), 1.26-1.16 (m, 2H), 1.12 (s, 8H), 1.05 (d, J=6.4 Hz, 3H). HRMS (C) tR=1.55 min; m/z 503.1736
    • Example 3
  • Figure US20140275083A1-20140918-C00550
  • To a solution of (S)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethanamine (150 mg, 0.488 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (138 mg, 0.488 mmol) in DMSO (1 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 170 uL, 0.975 mmol) and heated in a microwave at 115° C. for 2 hours. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-5% EtOAc/DCM afforded 140 mg. 1H NMR (400 MHz, CDCl3) δ 8.30-8.19 (m, 4H), 8.01 (dd, J=8.6, 2.1 Hz, 2H), 7.54 (d, J=5.7 Hz, 2H), 7.45 (dq, J=8.4, 1.5 Hz, 2H), 4.53 (dd, J=9.3, 2.4 Hz, 2H), 4.05 (p, J=6.1 Hz, 1H), 3.51 (s, 5H), 1.80 (s, 1H), 1.22 (t, J=6.5 Hz, 12H). Anal. RP-HPLC tR=2.73 min (Gradient: 2 to 98% B in 4.4 min-flow 1 mL/min. Eluent A: Water+3.75 mM NH4Ac+0.001% formic acid. Eluent B: ACN. Column: Acquity CSH 1.7 μm 2.1×50 mm−50° C.) HRMS m/z 514.1039
  • The Following Examples were prepared using a method similar to that described for the preparation of Intermediate 342 or Example 3
    • Example 4 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00551
  • 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J=5.6, 2.2 Hz, 3H), 7.96 (d, J=2.0 Hz, 3H), 7.84 (dd, J=8.3, 2.1 Hz, 3H), 7.59 (dd, J=5.8, 3.0 Hz, 3H), 7.46 (d, J=8.3 Hz, 3H), 5.71-5.42 (m, 3H), 5.32 (s, 1H), 4.75 (dtd, J=10.3, 5.2, 2.9 Hz, 3H), 1.67-1.60 (m, 3H), 4.64 (ddd, J=9.2, 6.2, 2.9 Hz, 3H), 4.49-4.31 (m, 6H), 4.14 (q, J=7.1 Hz, 1H), 2.46 (s, 9H), 2.07 (s, 1H), 1.77 (dd, J=6.8, 3.2 Hz, 9H), 1.27 (d, J=23.6 Hz, 29H), 1.05 (dd, J=11.3, 6.5 Hz, 9H). HRMS (C) tR=2.00 min; MS m/z 500.98
    • Example 5 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00552
  • 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J=5.8, 2.4 Hz, 3H), 8.02-7.83 (m, 6H), 7.59 (dd, J=5.8, 2.9 Hz, 3H), 7.12 (t, J=8.9 Hz, 3H), 5.72-5.47 (m, 5H), 5.32 (s, 1H), 4.75 (dtd, J=8.7, 4.8, 2.9 Hz, 3H), 4.64 (ddd, J=9.3, 6.2, 2.9 Hz, 3H), 4.49-4.28 (m, 6H), 3.52 (s, 2H), 2.36 (d, J=2.0 Hz, 9H), 1.78 (s, 2H), 1.65 (s, 3H), 1.30 (s, 22H), 1.24 (d, J=2.4 Hz, 6H), 1.05 (dd, J=11.3, 6.4 Hz, 10H). HRMS (C) tR=1.95 min; m/z 484.2234
    • Example 6 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00553
  • 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J=5.8, 1.7 Hz, 3H), 7.74-7.57 (m, 9H), 7.53-7.44 (m, 3H), 5.61 (qt, J=16.2, 9.7, 8.6 Hz, 7H), 5.32 (s, 1H), 4.75 (ddd, J=8.6, 4.6, 2.9 Hz, 3H), 4.64 (ddd, J=8.8, 5.8, 2.9 Hz, 3H), 4.50-4.30 (m, 6H), 4.14 (q, J=7.2 Hz, 2H), 4.01 (s, 9H), 2.07 (s, 2H), 1.85-1.73 (m, 9H), 1.62 (s, 2H), 1.36-1.18 (m, 30H), 1.05 (dd, J=10.8, 6.5 Hz, 9H). HRMS (C) tR=1.61 min; m/z 516.1888
    • Example 7 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00554
  • 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J=5.8, 3.2 Hz, 1H), 8.11-7.93 (m, 2H), 7.70-7.54 (m, 2H), 5.80-5.40 (m, 2H), 4.75 (dtd, J=8.6, 4.3, 2.2 Hz, 1H), 1.67-1.60 (m, 1H), 4.64 (ddd, J=9.4, 4.2, 2.9 Hz, 1H), 4.50-4.30 (m, 2H), 1.77 (dd, J=6.9, 3.4 Hz, 3H), 1.27 (d, J=21.9 Hz, 9H), 1.06 (dd, J=9.8, 6.5 Hz, 3H). HRMS (C) tR=2.05 min; m/z 570.1605
    • Example 8 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00555
  • 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=5.7 Hz, 3H), 8.10 (d, J=1.3 Hz, 3H), 7.84 (dd, J=8.3, 1.4 Hz, 3H), 7.71 (d, J=8.3 Hz, 3H), 7.64-7.55 (m, 3H), 7.20 (d, J=3.1 Hz, 3H), 6.55 (dd, J=3.1, 0.8 Hz, 3H), 5.64 (p, J=7.2 Hz, 5H), 5.32 (s, 1H), 1.69-1.61 (m, 4H), 4.77 (ddd, J=8.7, 4.7, 2.9 Hz, 3H), 4.65 (td, J=8.8, 8.4, 2.9 Hz, 3H), 4.52-4.27 (m, 6H), 3.90 (s, 9H), 3.51 (s, 2H), 1.89-1.75 (m, 9H), 1.28 (d, J=23.5 Hz, 27H), 1.06 (dd, J=10.9, 6.4 Hz, 10H). HRMS (C) tR=1.77 min; m/z 505.2437
    • Example 9 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00556
  • 1H NMR (400 MHz, CDCl3) δ 4.64 (ddd, J=9.9, 7.1, 2.9 Hz, 1H), 4.47-4.30 (m, 2H), 1.06 (dd, J=9.3, 6.4 Hz, 3H), 1.85-1.72 (m, 3H), 1.63 (s, 1H), 1.39 (s, 9H), 1.28 (d, J=21.1 Hz, 9H), 4.84-4.71 (m, 1H), 8.25 (d, J=5.7 Hz, 1H), 8.11 (q, J=2.0 Hz, 1H), 7.89 (dt, J=7.7, 1.4 Hz, 1H), 7.66-7.52 (m, 2H), 7.43 (t, J=7.8 Hz, 1H), 5.63 (p, J=7.3 Hz, 2H), 5.39-5.29 (m, OH). HRMS (C) tR=2.02 min; m/z 508.2798
    • Example 10 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00557
  • 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J=5.7, 2.9 Hz, 1H), 8.04 (dq, J=7.8, 1.3 Hz, 1H), 7.95 (dt, J=2.5, 1.2 Hz, 1H), 7.67-7.49 (m, 2H), 7.39 (ddt, J=8.2, 2.5, 1.2 Hz, 1H), 5.62 (h, J=6.7, 6.1 Hz, 2H), 4.75 (dtd, J=9.1, 4.7, 2.9 Hz, 1H), 4.64 (ddd, J=9.3, 4.9, 2.9 Hz, 1H), 4.49-4.26 (m, 2H), 1.78 (dd, J=6.8, 3.6 Hz, 3H), 1.61 (s, 1H), 1.27 (d, J=23.8 Hz, 9H), 1.06 (dd, J=10.0, 6.5 Hz, 3H). HRMS (C) tR=1.82 min; m/z 536.1995
    • Example 11 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00558
  • 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J=5.8, 3.3 Hz, 1H), 8.13-7.99 (m, 2H), 7.60 (dd, J=5.8, 2.0 Hz, 1H), 5.72-5.56 (m, 1H), 5.48 (s, 1H), 4.85-4.69 (m, 1H), 1.67-1.56 (m, 1H), 4.64 (ddd, J=9.5, 4.5, 2.9 Hz, 1H), 4.53-4.28 (m, 2H), 1.77 (dd, J=7.0, 3.4 Hz, 3H), 1.27 (d, J=22.0 Hz, 9H), 1.06 (dd, J=9.8, 6.4 Hz, 3H). HRMS (C) tR=1.87 min; m/z 554.1901
    • Example 12 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00559
  • 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J=5.9, 1.9 Hz, 1H), 8.09-7.92 (m, 2H), 7.59 (dd, J=5.7, 3.1 Hz, 1H), 7.43-7.32 (m, 2H), 5.60 (dt, J=15.5, 7.8 Hz, 2H), 4.75 (dtd, J=8.4, 5.0, 2.9 Hz, 1H), 4.64 (ddd, J=9.5, 7.1, 2.9 Hz, 1H), 4.49-4.27 (m, 2H), 2.99 (hept, J=6.9 Hz, 1H), 1.76 (dd, J=7.0, 2.8 Hz, 3H), 1.60 (dd, J=6.9, 2.8 Hz, 1H), 1.40-1.19 (m, 15H), 1.05 (dd, J=11.0, 6.5 Hz, 3H). HRMS (C) tR=2.23 min; m/z 494.2642
    • Example 13 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00560
  • 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=5.8 Hz, 1H), 7.91 (dd, J=7.5, 0.9 Hz, 1H), 7.60 (d, J=5.8 Hz, 1H), 7.44 (dt, J=8.2, 1.1 Hz, 1H), 7.33-7.20 (m, 1H), 6.99-6.89 (m, 1H), 5.66 (p, J=7.3 Hz, 1H), 4.77 (ddd, J=8.7, 4.7, 3.0 Hz, 1H), 1.66-1.60 (m, 1H), 4.66 (dd, J=9.5, 3.0 Hz, 1H), 4.53-4.44 (m, 1H), 4.38 (q, J=9.0, 8.3 Hz, 1H), 3.75 (s, 3H), 2.51 (d, J=0.9 Hz, 3H), 1.84-1.76 (m, 3H), 1.28 (d, J=26.5 Hz, 9H), 1.04 (d, J=6.5 Hz, 3H). HRMS (C) tR=1.65 min; MS m/z 519.60
    • Example 14 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00561
  • 135 mg orangish-red resin (solidified upon standing). 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=5.7 Hz, 1H), 7.62-7.46 (m, 3H), 7.45-7.36 (m, 2H), 4.85-4.69 (m, 1H), 4.64 (ddd, J=9.1, 5.6, 3.0 Hz, 1H), 4.44 (qd, J=6.4, 4.6 Hz, 1H), 4.34 (dt, J=15.4, 9.0 Hz, 1H), 2.40 (d, J=1.3 Hz, 3H), 1.79-1.60 (m, 3H), 1.34-1.18 (m, 11H), 1.04 (dd, J=14.8, 6.5 Hz, 3H). HRMS (C) tR=2.00 min; m/z 499.1986
    • Example 15 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00562
  • 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J=5.6, 2.2 Hz, 3H), 7.96 (d, J=2.0 Hz, 3H), 7.84 (dd, J=8.3, 2.1 Hz, 3H), 7.59 (dd, J=5.8, 3.0 Hz, 3H), 7.46 (d, J=8.3 Hz, 3H), 5.71-5.42 (m, 3H), 5.32 (s, 1H), 4.75 (dtd, J=10.3, 5.2, 2.9 Hz, 3H), 1.67-1.60 (m, 3H), 4.64 (ddd, J=9.2, 6.2, 2.9 Hz, 3H), 4.49-4.31 (m, 6H), 4.14 (q, J=7.1 Hz, 1H), 2.46 (s, 9H), 2.07 (s, 1H), 1.77 (dd, J=6.8, 3.2 Hz, 9H), 1.27 (d, J=23.6 Hz, 29H), 1.05 (dd, J=11.3, 6.5 Hz, 9H). HRMS (C) tR=2.00 min; MS m/z 500.98
    • Example 16 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00563
  • 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J=5.8, 2.4 Hz, 3H), 8.02-7.83 (m, 6H), 7.59 (dd, J=5.8, 2.9 Hz, 3H), 7.12 (t, J=8.9 Hz, 3H), 5.72-5.47 (m, 5H), 5.32 (s, 1H), 4.75 (dtd, J=8.7, 4.8, 2.9 Hz, 3H), 4.64 (ddd, J=9.3, 6.2, 2.9 Hz, 3H), 4.49-4.28 (m, 6H), 3.52 (s, 2H), 2.36 (d, J=2.0 Hz, 9H), 1.78 (s, 2H), 1.65 (s, 3H), 1.30 (s, 22H), 1.24 (d, J=2.4 Hz, 6H), 1.05 (dd, J=11.3, 6.4 Hz, 10H). HRMS (C) tR=1.95 min; m/z 484.2234
    • Example 17 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00564
  • 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J=5.8, 1.7 Hz, 3H), 7.74-7.57 (m, 9H), 7.53-7.44 (m, 3H), 5.61 (qt, J=16.2, 9.7, 8.6 Hz, 7H), 5.32 (s, 1H), 4.75 (ddd, J=8.6, 4.6, 2.9 Hz, 3H), 4.64 (ddd, J=8.8, 5.8, 2.9 Hz, 3H), 4.50-4.30 (m, 6H), 4.14 (q, J=7.2 Hz, 2H), 4.01 (s, 9H), 2.07 (s, 2H), 1.85-1.73 (m, 9H), 1.62 (s, 2H), 1.36-1.18 (m, 30H), 1.05 (dd, J=10.8, 6.5 Hz, 9H). HRMS (C) tR=1.61 min; m/z 516.1888
    • Example 18 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00565
  • 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J=5.8, 3.2 Hz, 1H), 8.11-7.93 (m, 2H), 7.70-7.54 (m, 2H), 5.80-5.40 (m, 2H), 4.75 (dtd, J=8.6, 4.3, 2.2 Hz, 1H), 1.67-1.60 (m, 1H), 4.64 (ddd, J=9.4, 4.2, 2.9 Hz, 1H), 4.50-4.30 (m, 2H), 1.77 (dd, J=6.9, 3.4 Hz, 3H), 1.27 (d, J=21.9 Hz, 9H), 1.06 (dd, J=9.8, 6.5 Hz, 3H). HRMS (C) tR=2.05 min; m/z 570.1605
    • Example 19 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00566
  • 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=5.7 Hz, 3H), 8.10 (d, J=1.3 Hz, 3H), 7.84 (dd, J=8.3, 1.4 Hz, 3H), 7.71 (d, J=8.3 Hz, 3H), 7.64-7.55 (m, 3H), 7.20 (d, J=3.1 Hz, 3H), 6.55 (dd, J=3.1, 0.8 Hz, 3H), 5.64 (p, J=7.2 Hz, 5H), 5.32 (s, 1H), 1.69-1.61 (m, 4H), 4.77 (ddd, J=8.7, 4.7, 2.9 Hz, 3H), 4.65 (td, J=8.8, 8.4, 2.9 Hz, 3H), 4.52-4.27 (m, 6H), 3.90 (s, 9H), 3.51 (s, 2H), 1.89-1.75 (m, 9H), 1.28 (d, J=23.5 Hz, 27H), 1.06 (dd, J=10.9, 6.4 Hz, 10H). HRMS (C) tR=1.77 min; m/z 505.2437
    • Example 20 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00567
  • 1H NMR (400 MHz, CDCl3) δ 4.64 (ddd, J=9.9, 7.1, 2.9 Hz, 1H), 4.47-4.30 (m, 2H), 1.06 (dd, J=9.3, 6.4 Hz, 3H), 1.85-1.72 (m, 3H), 1.63 (s, 1H), 1.39 (s, 9H), 1.28 (d, J=21.1 Hz, 9H), 4.84-4.71 (m, 1H), 8.25 (d, J=5.7 Hz, 1H), 8.11 (q, J=2.0 Hz, 1H), 7.89 (dt, J=7.7, 1.4 Hz, 1H), 7.66-7.52 (m, 2H), 7.43 (t, J=7.8 Hz, 1H), 5.63 (p, J=7.3 Hz, 2H), 5.39-5.29 (m, OH). HRMS (C) tR=2.02 min; m/z 508.2798
    • Example 21 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00568
  • 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J=5.7, 2.9 Hz, 1H), 8.04 (dq, J=7.8, 1.3 Hz, 1H), 7.95 (dt, J=2.5, 1.2 Hz, 1H), 7.67-7.49 (m, 2H), 7.39 (ddt, J=8.2, 2.5, 1.2 Hz, 1H), 5.62 (h, J=6.7, 6.1 Hz, 2H), 4.75 (dtd, J=9.1, 4.7, 2.9 Hz, 1H), 4.64 (ddd, J=9.3, 4.9, 2.9 Hz, 1H), 4.49-4.26 (m, 2H), 1.78 (dd, J=6.8, 3.6 Hz, 3H), 1.61 (s, 1H), 1.27 (d, J=23.8 Hz, 9H), 1.06 (dd, J=10.0, 6.5 Hz, 3H). HRMS (C) tR=1.82 min; m/z 536.1995
    • Example 22 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00569
  • 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J=5.8, 3.3 Hz, 1H), 8.13-7.99 (m, 2H), 7.60 (dd, J=5.8, 2.0 Hz, 1H), 5.72-5.56 (m, 1H), 5.48 (s, 1H), 4.85-4.69 (m, 1H), 1.67-1.56 (m, 1H), 4.64 (ddd, J=9.5, 4.5, 2.9 Hz, 1H), 4.53-4.28 (m, 2H), 1.77 (dd, J=7.0, 3.4 Hz, 3H), 1.27 (d, J=22.0 Hz, 9H), 1.06 (dd, J=9.8, 6.4 Hz, 3H). HRMS (C) tR=1.87 min; m/z 554.1901
    • Example 23 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00570
  • 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J=5.9, 1.9 Hz, 1H), 8.09-7.92 (m, 2H), 7.59 (dd, J=5.7, 3.1 Hz, 1H), 7.43-7.32 (m, 2H), 5.60 (dt, J=15.5, 7.8 Hz, 2H), 4.75 (dtd, J=8.4, 5.0, 2.9 Hz, 1H), 4.64 (ddd, J=9.5, 7.1, 2.9 Hz, 1H), 4.49-4.27 (m, 2H), 2.99 (hept, J=6.9 Hz, 1H), 1.76 (dd, J=7.0, 2.8 Hz, 3H), 1.60 (dd, J=6.9, 2.8 Hz, 1H), 1.40-1.19 (m, 15H), 1.05 (dd, J=11.0, 6.5 Hz, 3H). HRMS (C) tR=2.23 min; m/z 494.2642
    • Example 24 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00571
  • 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=5.8 Hz, 1H), 7.91 (dd, J=7.5, 0.9 Hz, 1H), 7.60 (d, J=5.8 Hz, 1H), 7.44 (dt, J=8.2, 1.1 Hz, 1H), 7.33-7.20 (m, 1H), 6.99-6.89 (m, 1H), 5.66 (p, J=7.3 Hz, 1H), 4.77 (ddd, J=8.7, 4.7, 3.0 Hz, 1H), 1.66-1.60 (m, 1H), 4.66 (dd, J=9.5, 3.0 Hz, 1H), 4.53-4.44 (m, 1H), 4.38 (q, J=9.0, 8.3 Hz, 1H), 3.75 (s, 3H), 2.51 (d, J=0.9 Hz, 3H), 1.84-1.76 (m, 3H), 1.28 (d, J=26.5 Hz, 9H), 1.04 (d, J=6.5 Hz, 3H). HRMS (C) tR=1.65 min; MS m/z 519.60
    • Example 25 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00572
  • 135 mg orange-red resin (solidified upon standing). 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=5.7 Hz, 1H), 7.62-7.46 (m, 3H), 7.45-7.36 (m, 2H), 4.85-4.69 (m, 1H), 4.64 (ddd, J=9.1, 5.6, 3.0 Hz, 1H), 4.44 (qd, J=6.4, 4.6 Hz, 1H), 4.34 (dt, J=15.4, 9.0 Hz, 1H), 2.40 (d, J=1.3 Hz, 3H), 1.79-1.60 (m, 3H), 1.34-1.18 (m, 11H), 1.04 (dd, J=14.8, 6.5 Hz, 3H). HRMS (C) tR=2.00 min; m/z 499.1986
    • Example 26 (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(4-(4-chlorophenyl)-5-methylthiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00573
  • 200 mg (white solid). 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J=2.9, 1.0 Hz, 1H), 7.68-7.52 (m, 2H), 7.47-7.35 (m, 2H), 5.99-5.65 (m, 1H), 5.49-5.20 (m, 1H), 4.67 (ddt, J=21.5, 8.9, 5.4 Hz, 1H), 4.58-4.40 (m, 2H), 4.22-4.05 (m, 1H), 2.53 (d, J=6.0 Hz, 3H), 1.74 (s, 1H), 1.16 (s, 5H), 1.13-1.05 (m, 6H), 1.01 (d, J=6.4 Hz, 3H). HRMS (B) tR=5.16 min; m/z 534.1744
    • Example 27 (4R)-3-(2-((1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00574
  • 210 mg (white solid). 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J=2.9, 1.9 Hz, 1H), 7.87-7.71 (m, 2H), 7.62-7.50 (m, 2H), 7.40 (d, J=8.7 Hz, 1H), 5.85 (d, J=15.8 Hz, 1H), 5.58-5.36 (m, 1H), 4.81-4.57 (m, 1H), 4.57-4.39 (m, 2H), 4.23-4.00 (m, 1H), 2.07 (s, 2H), 1.77 (s, 1H), 1.16 (s, 5H), 1.11 (d, J=6.4 Hz, 2H), 1.06 (s, 5H), 0.98 (d, J=6.4 Hz, 2H). HRMS (B) tR=5.15 min; m/z 566.1079 (M+H).
    • Example 28 (R)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00575
  • (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one (34 mg, 0.058 mmole) was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction solution was stirred for 2 hour at room temperature and was concentrated by rotary evaporation. The resulting residue was dissolved in DCM (2 mL) and water 2 mL) and the pH was adjusted to ˜9 with NH4OH. The DCM layer was separated and concentrated by rotary evaporation to afford 28 mg of the title product as a yellow oil (ratio of two peaks with same MS: 96/4% by LC-MS). (400 MHz, CD2Cl2) δ 8.22 (d, J=2.27 Hz, 1H), 7.31 (d, J=8.85 Hz, 1H), 6.88-6.79 (m, 2H), 5.12 (br s, 1H), 4.61-4.50 (m, 2H), 4.46-4.37 (m, 1H), 4.26-4.15 (m, 1H), 3.93 (br s, 1H), 3.77-3.68 (m, 2H), 3.20 (br s, 1H), 2.79-2.67 (m, 2H), 1.96-1.78 (m, 2H), 1.70-1.58 (m, 1H), 1.55-1.28 (m, 2H), 1.23 (d, J=6.63 Hz, 3H), 1.19 (d, J=7.19 Hz, 3H), HRMS (C) tR=4.47 min; MS m/z 548.1689 (M+H)+
    • Example 29 (R)-3-(5-fluoro-2-(((S)-1-(1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00576
  • A cloudy solution of (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (21 mg, 0.051 mmol), 4-bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine (14 mg, 0.051 mmol), Pd(OAc)2 (1 mg, 5 umol), BINAP (3 mg, 5 umol), and Cs2CO3 (25 mg, 0.077 mmol) in 6 mL toluene was heated at 90° C. overnight. The mixture was cooled to room temperature, and filtered through Celite. The celite cake was rinsed with 5 mL EtOAc. The filtrate was poured into 5 mL water. Organic layer was separated, and the aqueous was further extracted with EtOAc (5 mL). The organic extracts were combined and concentrated by rotary evaporation. The resulting crude was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction solution was stirred for 2 hour at room temperature and was concentrated by rotary evaporation. The resulting residue was dissolved in DCM (2 mL) and water (2 mL) and the pH was adjusted to ˜9 with NH4OH. The DCM layer was separated and concentrated by rotary evaporation. The crude was dissolved in a mixture of MeOH (1 mL) and DMSO (1 mL) and purified by reverse phase HPLC. Selected fractions were collected and concentrated by rotary evaporation to afford the title product as a colorless oil (5 mg) (ratio of two peaks with same MS: 93/7% by LC-MS). (400 MHz, CD2Cl2) δ 8.16-8.08 (m, 2H), 6.79-6.75 (m, 1H), 6.57-6.52 (m, 1H), 4.97-4.86 (m, 1H), 4.47-4.39 (m, 2H), 4.33-4.25 (m, 1H), 4.11-4.02 (m, 1H), 3.89-3.75 (m, 3H), 2.97 (br s, 1H), 2.80-2.67 (m, 2H), 1.84-1.67 (m, 2H), 1.67-1.55 (m, 1H), 1.48 (s, 6H), 1.38-1.15 (m, 2H), 1.11 (d, J=5.91 Hz, 3H), 1.07 (d, J=5.91 Hz, 3H), HRMS (C) tR=3.59 min; MS m/z 541.2557 (M+H)+
    • Examples 30, 31, 32, and 33 3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00577
  • To a solution of (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine 72 mg, 0.322 mmol) and 3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (90 mg, 0.322 mmol) in DMSO (1 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 0.113 mL, 0.645 mmol) and heated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), concentrate in vacuo. Flash column (silica, 40 g, 50μ) eluting w/0-5% EtOAc/DCM followed by Flash column (silica, 80 g, 15μ) eluting w/0-5% EtOAc/heptane separated 2 major peaks which were further separated via chiral SFC chromatography on an ID column (75 g/min, 120 bar, 21×250 mm) eluting 35% IPA/CO2 (v/v) to give: Example 30, Peak 1: 10 mg (white foam): 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=5.8 Hz, 1H), 8.09-7.95 (m, 2H), 7.58 (d, J=5.7 Hz, 1H), 7.54-7.41 (m, 2H), 5.83 (s, 1H), 5.28 (s, 1H), 4.72 (s, 1H), 4.54 (dd, J=9.6, 2.5 Hz, 1H), 4.37 (d, J=9.5 Hz, 1H), 3.44-3.15 (m, 1H), 1.78 (d, J=7.0 Hz, 3H), 1.63 (s, 1H), 1.32 (d, J=7.3 Hz, 3H), 1.23 (d, J=6.1 Hz, 3H). HRMS m/z 482.1081, RT=2.90 min. Chiral RT=2.15 min
  • Example 31, Peak 2: 38 mg (white foam): 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=5.7 Hz, 1H), 8.09-7.93 (m, 2H), 7.58 (d, J=5.7 Hz, 1H), 7.53-7.41 (m, 2H), 5.84 (s, 1H), 5.33 (s, 1H), 4.72 (s, 1H), 4.55 (dd, J=9.6, 2.4 Hz, 1H), 4.35 (t, J=8.8 Hz, 1H), 3.39-3.17 (m, 1H), 1.78 (d, J=7.0 Hz, 3H), 1.62 (d, J=6.9 Hz, 1H), 1.32 (d, J=7.3 Hz, 3H), 1.23 (d, J=6.2 Hz, 1H). HRMS m/z 482.1081, RT=2.89 min. Chiral RT=2.43 min
  • Example 32, Peak 3: 45 mg (white foam) 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=5.8 Hz, 1H), 8.09-7.91 (m, 2H), 7.59 (d, J=5.7 Hz, 1H), 7.52-7.38 (m, 2H), 6.22 (s, 1H), 5.38 (d, J=48.6 Hz, 1H), 4.86 (dd, J=8.2, 4.2 Hz, 1H), 1.83-1.75 (m, 3H), 4.56 (dd, J=9.3, 2.5 Hz, 1H), 4.43 (t, J=9.2 Hz, 1H), 3.50 (s, 1H), 2.97 (d, J=46.0 Hz, 1H), 1.23 (d, J=6.2 Hz, 1H), 1.12 (d, J=7.6 Hz, 3H). HRMS m/z 482.1081, RT=2.86 min. Chiral RT=2.55 min
  • Example 33, Peak 4: 12 mg (white foam) 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=5.8 Hz, 1H), 8.11-7.92 (m, 2H), 7.60 (d, J=5.6 Hz, 1H), 7.53-7.40 (m, 2H), 5.77 (s, 1H), 5.45 (s, 1H), 4.96-4.77 (m, 1H), 4.57 (dd, J=9.5, 2.4 Hz, 1H), 4.44 (t, J=9.1 Hz, 1H), 2.94 (s, 1H), 1.79 (d, J=7.1 Hz, 3H), 1.63 (d, J=7.1 Hz, 1H), 1.23 (d, J=6.1 Hz, 2H), 1.20-1.08 (m, 3H). HRMS m/z 482.1081, RT=2.86 min. Chiral RT=2.66 min
    • Example 34 3-(5-fluoro-2-(((S)-1-(3-fluoro-4-(hydroxymethyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00578
  • To a solution of (S)-(4-(1-aminoethyl)-2-fluorophenyl)methanol (62.6 mg, 0.37 mmol) and 3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (110 mg, 0.37 mmol) in DMSO (1 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 0.129 mL, 0.74 mmol) and heated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), concentrate in vacuo. Flash column (silica, 40 g, 50μ) eluting w/5-50% EtOAc/DCM afforded 155 mg (white foam):1H NMR (400 MHz, CDCl3) δ 8.22 (dd, J=6.6, 2.6 Hz, 1H), 7.40 (td, J=7.8, 5.2 Hz, 1H), 7.12 (ddd, J=7.8, 4.6, 1.6 Hz, 1H), 7.03 (ddd, J=10.9, 6.3, 1.7 Hz, 1H), 5.52 (d, J=22.7 Hz, 1H), 4.90 (p, J=7.0 Hz, 1H), 4.75 (d, J=9.6 Hz, 3H), 4.59 (dt, J=15.7, 9.1 Hz, 1H), 4.41 (ddd, J=12.4, 9.1, 6.2 Hz, 1H), 1.89 (d, J=18.6 Hz, 1H), 1.16 (d, J=7.2 Hz, 1H), 1.04-0.74 (m, 2H). HRMS m/z 446.1377, RT=2.03 min.
    • Example 35
  • Figure US20140275083A1-20140918-C00579
  • A solution of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (18.6 mg, 0.082 mmol) and 1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethanamine (22 mg, 0.082 mmol) in DMSO (2 mL) was heated at 100° C. for 2 h. The reaction mixture was poured into water (20 mL), and extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography ((25% MeOH in EtOAc)/Heptane 10 to 100%) provided (4R)-3-(2-(1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (12 mg, approx 1:1 mixture of diastereomers) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 4H), 8.15 (d, J=5.7 Hz, 2H), 7.51 (ddd, J=8.1, 2.8, 1.6 Hz, 2H), 7.40-7.11 (m, 6H), 6.07-5.96 (m, 2H), 5.32 (t, J=7.4 Hz, 1H), 5.09 (s, 1H), 4.81 (s, 1H), 4.68 (s, 1H), 4.43 (dd, J=7.3, 4.8 Hz, 2H), 4.33 (dd, J=9.4, 8.3 Hz, 1H), 4.18 (d, J=9.0 Hz, 2H), 3.62 (s, 1H), 3.23 (s, 1H), 1.62-1.58 (m, 6H), 1.07-0.97 (m, 3H), 0.87-0.77 (m, 3H). HRMS m/z 475.1039 and 475.1042 (M+H)+.
    • Example 36 (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00580
  • A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (68 mg, 0.18 mmol) in 3 ml of DCM was cooled to 0° C., treated with 1 ml of TFA, it was stirred at same temperature for 4 hours, the solvent was removed to yield the product as a TFA salt form, it was dissolved in 2 ml of MeOH, the TFA was removed by using a PL-HCO3 MP SPE (0.9 mmol) cartridge, the solvent was removed to yield the pure product (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a white solid (52 mg). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=5.8 Hz, 1H), 7.43 (d, J=5.8 Hz, 1H), 7.40-7.31 (m, 4H), 7.31-7.24 (m, 1H), 5.84 (s, 1H), 4.94 (s, 1H), 4.58 (q, J=4.9, 3.2 Hz, 1H), 4.40 (dd, J=9.3, 2.8 Hz, 1H), 4.31 (t, J=8.9 Hz, 1H), 1.56 (d, J=7.0 Hz, 3H), 0.98-0.74 (m, 3H).HRMS m/z 329.1619 (M+H)+, RT=2.23 min.
    • Example 37 and 38
  • Figure US20140275083A1-20140918-C00581
  • (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (97 mg, 0.17 mmol) was treated with 90% TFA/water for 2 hours. Concentrate in vacuo and neutralized by passing through a column of MP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded 58 mg of (R)-3-(2-(((R)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-(1-hydroxyethyl)oxazolidin-2-one as a waxy off-white foam. Separated the diastereomers via chiral SFC chromatography on an AD-H column (75 g/min, 120 bar, 21×250 mm) eluting 25% IPA/CO2 (v/v) to give (R)-3-(2-(((R)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Example 37 Peak 1: 23 mg (off-white foam). 1H NMR (400 MHz, CDCl3) δ 8.32-8.17 (m, 4H), 8.01 (dd, J=8.6, 2.1 Hz, 2H), 7.54 (d, J=5.7 Hz, 2H), 7.45 (dq, J=8.4, 1.5 Hz, 2H), 6.16 (s, 2H), 5.32 (s, 3H), 4.82-4.60 (m, 2H), 4.53 (dd, J=9.3, 2.4 Hz, 2H), 4.43 (s, 2H), 4.29 (q, J=8.9 Hz, 2H), 4.05 (p, J=6.1 Hz, 1H), 3.51 (s, 5H), 1.80 (s, 1H), 1.22 (t, J=6.5 Hz, 12H). HRMS (B) tR=2.75 min. MS m/z 514.0979 Chiral RT=2.10 min
  • Example 38 Peak 2: 58 mg (off-white foam). 1H NMR (400 MHz, CDCl3) δ 8.23 (dd, J=12.4, 3.9 Hz, 8H), 8.01 (dd, J=8.5, 2.1 Hz, 4H), 7.71-7.36 (m, 8H), 6.29 (s, 4H), 5.37 (d, J=37.2 Hz, 5H), 4.86 (ddd, J=7.7, 4.9, 2.4 Hz, 4H), 4.55 (dd, J=9.5, 2.6 Hz, 4H), 4.41 (t, J=8.9 Hz, 4H), 4.19-3.77 (m, 5H), 3.51 (s, 3H), 1.83 (s, 1H), 1.23 (d, J=6.1 Hz, 4H), 1.12-0.95 (m, 12H). HRMS (B) tR=2.73 min. MS m/z 514.0979 Chiral RT=3.70 min
  • The compounds in Table 28a were prepared using methods similar to those described for the preparation of Examples 35, 36, or 37/38.
  • TABLE 28a
    Figure US20140275083A1-20140918-C00582
         		39
    Figure US20140275083A1-20140918-C00583
         		40
    Figure US20140275083A1-20140918-C00584
         		41
    Figure US20140275083A1-20140918-C00585
         		42
    Figure US20140275083A1-20140918-C00586
         		43
    Figure US20140275083A1-20140918-C00587
         		44
    Figure US20140275083A1-20140918-C00588
         		45
    Figure US20140275083A1-20140918-C00589
         		46
    Figure US20140275083A1-20140918-C00590
         		47
    Figure US20140275083A1-20140918-C00591
         		48
    Figure US20140275083A1-20140918-C00592
         		49
    Figure US20140275083A1-20140918-C00593
         		50
    Figure US20140275083A1-20140918-C00594
         		51
    Figure US20140275083A1-20140918-C00595
         		52
    Figure US20140275083A1-20140918-C00596
         		53
    Figure US20140275083A1-20140918-C00597
         		54
    Figure US20140275083A1-20140918-C00598
         		55
    Figure US20140275083A1-20140918-C00599
         		56
    Figure US20140275083A1-20140918-C00600
         		57
    Figure US20140275083A1-20140918-C00601
         		58
    Figure US20140275083A1-20140918-C00602
         		59
    Figure US20140275083A1-20140918-C00603
         		60
    Figure US20140275083A1-20140918-C00604
         		61
    Figure US20140275083A1-20140918-C00605
         		62
    Figure US20140275083A1-20140918-C00606
         		63
    Figure US20140275083A1-20140918-C00607
         		64
    Figure US20140275083A1-20140918-C00608
         		65
    Figure US20140275083A1-20140918-C00609
         		66
    Figure US20140275083A1-20140918-C00610
         		67
    Figure US20140275083A1-20140918-C00611
         		68
    Figure US20140275083A1-20140918-C00612
         		69
    Figure US20140275083A1-20140918-C00613
         		70
    Figure US20140275083A1-20140918-C00614
         		71
    Figure US20140275083A1-20140918-C00615
         		72
    Figure US20140275083A1-20140918-C00616
         		73
    Figure US20140275083A1-20140918-C00617
         		74
    Figure US20140275083A1-20140918-C00618
         		75
    Figure US20140275083A1-20140918-C00619
         		76
    Figure US20140275083A1-20140918-C00620
         		77
    Figure US20140275083A1-20140918-C00621
         		78
    Figure US20140275083A1-20140918-C00622
         		79
  • TABLE 28b
    Chemical name, NMR chemical shifts and LCMS signal for each compound listed in Table 28a.
    Example: Name 1H NMR (400 MHz) δ ppm LCMS
    39: (4R)-3-(2-(1-(5-(5-fluoro-2- (CDCl3) δ 8.71 (d, J = 1.8 Hz, 4H), HRMS (B)
    methylphenyl)pyrimidin-2- 8.23 (dd, J = 5.8, 1.0 Hz, 2H), 7.44 m/z
    yl)ethylamino)pyrimidin-4-yl)-4-((R)-1- (dd, J = 12.1, 5.7 Hz, 2H), 7.35-7.26 439.1865
    hydroxyethyl)oxazolidin-2-one (m, 3H), 7.08 (tt, J = 8.4, 2.8 Hz, 2H), and
    6.95 (dt, J = 9.0, 2.7 Hz, 2H), 6.16 (t, 439.1865 (M +
    J = 8.5 Hz, 2H), 5.41 (p, J = 7.0 Hz, H)+
    1H), 5.20 (s, 1H), 4.91 (s, 1H), 4.78
    (s, 1H), 4.58-4.49 (m, 2H), 4.42 (dd,
    J = 9.4, 8.3 Hz, 2H), 4.29 (s, 2H), 3.84
    (s, 1H), 3.48 (br s, 1H), 2.27 (s, 6H),
    1.95 (br s, 2H), 1.71-1.67 (m, 3H),
    1.38-1.18 (m, 6H), 1.12 (br s, 3H)
    (approx 1:1 mixture of diastereomers)
    40: (4R)-4-((R)-1-hydroxyethyl)-3-(2- (CDCl3) δ 8.95 (s, 4H), 8.41 (d, J = HRMS (B)
    ((1-(5-(4- 5.8, 1H), 8.21 (d, J = 5.8 Hz, 1H), 7.92- m/z
    (trifluoromethyl)phenyl)pyrimidin-2- 7.66 (m, 7H), 7.48-7.44 (m, 3H), 475.1684 (M +
    yl)ethyl)amino)pyrimidin-4- 6.45-6.35 (m, 2H), 5.41 (p, J = 6.9 H)+
    yl)oxazolidin-2-one Hz, 1H), 5.22 (br s, 1H), 4.94-4.90
    (m, 2H), 4.78 (br s, 1H), 4.65-4.35
    (m, 4H), 4.30 (br s, 1H), 3.49 (br s,
    1H), 2.77 (br s, 1H), 1.70-1.66 (m,
    6H), 1.25-1.21 (m, 3H), 1.09 (br s,
    3H) (approx 1:1 mixture of
    diastereomers)
    41: (4R)-3-(2-(1-(5-(4-fluoro-3- (CDCl3) δ 8.85-8.75 (m, 4H), 8.16- HRMS (B)
    methylphenyl)pyrimidin-2- 8.08 (m,2H), 7.38-7.20 (m, 6H), m/z
    yl)ethylamino)pyrimidin-4-yl)-4-((R)-1- 7.09-7.05 (m, 2H), 6.08-6.04 (m, 439.1875 (M +
    hydroxyethyl)oxazolidin-2-one 2H), 5.34-5.25 (m, 1H), 5.14-5.10 H)+.
    (m, 1H), 4.86-4.78 (m, 1H), 4.57
    (dd, J = 9.5, 2.8 Hz, 1H), 4.49-4.28
    (m, 3H), 3.54 (br s, 1H), 2.29 (br s,
    6H), 1.58-1.53 (m, 6H), 1.19-1.12
    (m, 3H), 1.00 (br s, 3H) (approx 1:1
    mixture of diastereomers)
    42: (4R)-3-(2-((1-(5-(tert- (CDCl3) δ 8.74-8.72 (m, 4H), 8.20 (d, HRMS (B)
    butyl)pyrimidin-2- J = 5.8 Hz, 2H), 7.46-7.40 (m, 2H), m/z
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 6.19-6.15 (m, 2H), 5.37-5.29 (m, 387.2135 (M +
    hydroxyethyl)oxazolidin-2-one 1H), 5.30 (s, 1H), 4.98-4.86 (m, 1H), H)+
    4.82 (s, 1H), 4.61-4.50 (m, 3H), 4.47-
    4.37 (m, 2H), 4.32-4.21 (m, 2H),
    3.84 (s, 1H), 1.63-1.58 (m, 6H), 1.39-
    1.37 (m, 18H), 1.24-1.20 (m, 3H),
    1.14-1.00 (m, 3H) (approx 1:1
    mixture of diastereomers)
    43: (4R)-4-((R)-1-hydroxyethyl)-3-(2- (CDCl3) δ 8.94 (d, J = 4.4 Hz, 4H), HRMS (B)
    (1-(5-(3- 8.23 (dd, J = 5.8, 2.2 Hz, 2H), 7.86- m/z
    (trifluoromethyl)phenyl)pyrimidin-2- 7.63 (m, 8H), 7.44 (dd, J = 13.5, 5.7 475.1682
    yl)ethylamino)pyrimidin-4- Hz, 2H), 6.12 (dd, J = 15.1, 7.4 Hz, and
    yl)oxazolidin-2-one 2H), 5.41 (t, J = 7.4 Hz, 1H), 5.20 (br 475.1689 (M +
    s, 1H), 4.89 (d, J = 6.7 Hz, 1H), 4.80 H)+.
    (s, 1H), 4.58-4.48 (m, 2H), 4.43 (dd,
    J = 9.3, 8.2 Hz, 2H), 4.30 (br s, 1H),
    3.77 (br s, 1H), 3.36 (br s, 1H), 1.90
    (br s, 3H), 1.69 (d, J = 2.2 Hz, 3H),
    1.37-1.17 (m, 3H), 1.12 (br s, 3H)
    (approx 1:1 mixture of diastereomers)
    44: (R)-4-((R)-1-hydroxyethyl)-3-(2- (CDCl3) δ 8.21 (d, J = 5.9 Hz, 1H), HRMS (B)
    (((S)-1-(4-phenoxyphenyl)ethyl)amino) 7.45 (d, J = 5.7 Hz, 1H), 7.42-7.26 m/z
    pyrimidin-4-yl)oxazolidin-2-one (m, 4H), 7.13 (dd, J = 8.1, 6.7 Hz, 421.1875,
    1H), 7.07-6.88 (m, 4H), 5.66 (b, 1H), (M + H)+,
    4.97 (s, 1H), 4.67 (ddd, J = 8.2, 5.1, RT = 2.56
    2.5 Hz, 1H), 4.51-4.25 (m, 2H), 3.61 min.
    (b, 1H), 1.56 (d, J = 6.9 Hz, 3H), 0.95
    (d, J = 22.9 Hz, 3H).
    45: (4R)-3-(2-((1-(5-(4- HRMS (B)
    fluorophenoxy)pyrimidin-2- m/z
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 441.1676,
    hydroxyethyl)oxazolidin-2-one (M + H)+,
    RT = 2.13
    min.
    46: (4R)-3-(2-((1-(3-(4-chlorophenyl)- HRMS (B)
    1,2,4-oxadiazol-5- m/z
    yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- 431.1219,
    hydroxyethyl)oxazolidin-2-one. (M + H)+,
    RT = 2.16
    min.
    47: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 9.13 (d, HRMS m/z
    (((S)-1-(5-(3- J = 1.5 Hz, 1H), 8.73 (d, J = 1.4 Hz, 475.1686 (M +
    (trifluoromethyl)phenyl)pyrazin-2- 1H), 8.39 (s, 1H), 8.32 (d, J = 7.9 Hz, H)+.
    yl)ethyl)amino)pyrimidin-4- 1H), 8.16 (d, J = 5.9 Hz, 1H), 7.78 (d,
    yl)oxazolidin-2-one J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz,
    1H), 7.39 (d, J = 5.8 Hz, 1H), 5.28 (q,
    J = 7.0 Hz, 1H), 4.51 (dd, J = 9.2, 2.8
    Hz, 1H), 4.39 (t, J = 8.9 Hz, 1H), 3.81
    (br s, 0H), 1.65 (d, J = 7.1 Hz, 3H),
    0.80 (br s, 3H);
    48: (R)-3-(2-((S)-1-(3-fluoro-4-((3,3,4- 1H NMR (400 MHz, MeOD) δ 8.11 (d, HRMS m/z
    trimethylpiperazin-1- J = 5.8 Hz, 1H), 7.40-7.30 (m, 2H), 487.2808 (M +
    yl)methyl)phenyl)ethylamino)pyrimidin- 7.16 (dd, J = 8.0, 1.7 Hz, 1H), 7.07 H)+.
    4-yl)-4-((S)-1-hydroxyethyl)oxazolidin- (dd, J = 11.2, 1.7 Hz, 1H), 5.08 (q, J =
    2-one 7.0 Hz, 1H), 4.80 (br s, 1H), 4.52 (dd,
    J = 9.2, 2.8 Hz, 1H), 4.38 (t, J = 8.9
    Hz, 1H), 3.99 (br s, 1H), 3.48 (s, 2H),
    2.55 (t, J = 4.9 Hz, 2H), 2.48 (br s,
    2H), 2.20-2.18 (m, 5H), 1.50 (d, J =
    7.0 Hz, 3H), 1.04 (s, 6H), 0.78 (br s,
    3H);
    49: (R)-3-(2-((S)-1-(4-((4,4- 1H NMR (400 MHz, MeOD) δ 8.11 (d, HRMS m/z
    difluoropiperidin-1-yl)methyl)-3- J = 5.8 Hz, 1H), 7.38-7.30 (m, 2H), 480.2204 (M +
    fluorophenyl)ethylamino)pyrimidin-4- 7.18 (dd, J = 7.9, 1.7 Hz, 1H), 7.10 (d, H)+.
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2- J = 11.3 Hz, 1H), 5.08 (q, J = 6.9 Hz,
    one 1H), 4.80 (br s, 1H), 4.52 (dd, J = 9.1,
    2.8 Hz, 1H), 4.38 (t, J = 8.9 Hz, 1H),
    4.01 (br s, 1H), 3.60 (s, 2H), 2.60-
    2.58 (m, 4H), 2.05-1.89 (m, 4H),
    1.50 (d, J = 7.0 Hz, 3H), 0.77 (br s,
    3H)
    50: (R)-3-(2-(((S)-1-(5-(4-fluoro-3- 1H NMR (400 MHz, MeOD) δ 8.70 (d, HRMS m/z
    methylphenyl)pyridin-2- J = 2.5 Hz, 1H), 8.14 (s, 1H), 7.97 (dd, 438.1927 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- J = 8.2, 2.3 Hz, 1H), 7.55-7.43 (m, H)+.
    hydroxyethyl)oxazolidin-2-one 3H), 7.36 (d, J = 5.8 Hz, 1H), 7.13
    (dd, J = 9.5, 8.5 Hz, 1H), 5.16 (q, J =
    7.0 Hz, 1H), 4.78 (br s, 1H), 4.51 (dd,
    J = 9.3, 2.7 Hz, 1H), 4.37 (t, J = 8.9
    Hz, 1H), 3.67 (br s, 1H), 2.33 (d, J =
    1.9 Hz, 3H), 1.59 (d, J = 7.1 Hz, 3H),
    0.68 (br s, 3H);
    51: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 8.79 (d, HRMS m/z
    (((S)-1-(5-(3- J = 2.5 Hz, 1H), 8.14 (s, 1H), 8.06 (dd, 474.1739 (M +
    (trifluoromethyl)phenyl)pyridin-2- J = 8.3, 2.4 Hz, 1H), 7.95-7.89 (m, H)+.
    yl)ethyl)amino)pyrimidin-4- 2H), 7.74-7.64 (m, 2H), 7.55 (d, J =
    yl)oxazolidin-2-one 8.2 Hz, 1H), 7.36 (d, J = 5.7 Hz, 1H),
    5.18 (q, J = 7.0 Hz, 1H), 4.79 (s, 1H),
    4.51 (dd, J = 9.1, 2.7 Hz, 1H), 4.37 (t,
    J = 8.9 Hz, 1H), 3.63 (br s, 1H), 1.60
    (d, J = 7.0 Hz, 3H), 0.68 (br s, 3H);
    52: (R)-3-(2-(((S)-1-(6-(4-fluoro-3- 1H NMR (400 MHz, MeOD) δ 8.60 (d, HRMS m/z
    methylphenyl)pyridin-3- J = 2.2 Hz, 1H), 8.13 (d, J = 6.0 Hz, 438.1985 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 7.88 (dd, J = 8.3, 2.3 Hz, 1H), H)+.
    hydroxyethyl)oxazolidin-2-one 7.84-7.69 (m, 3H), 7.35 (d, J = 5.8
    Hz, 1H), 7.12 (t, J = 9.0 Hz, 1H), 5.17
    (q, J = 7.0 Hz, 1H), 4.83 (br s, 1H),
    4.52 (dd, J = 9.3, 2.7 Hz, 1H), 4.39 (t,
    J = 8.9 Hz, 1H), 3.87 (br s, 1H), 2.33
    (d, J = 1.9 Hz, 3H), 1.59 (d, J = 7.0
    Hz, 3H), 0.76 (br s, 3H);
    53: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 8.68 (d, HRMS m/z
    (((S)-1-(6-(3- J = 2.1 Hz, 1H), 8.27 (s, 1H), 8.19 (d, 474.1816 (M +
    (trifluoromethyl)phenyl)pyridin-3- J = 7.7 Hz, 1H), 8.14 (d, J = 5.8 Hz, H)+.
    yl)ethyl)amino)pyrimidin-4- 1H), 7.98-7.85 (m, 2H), 7.76-7.62
    yl)oxazolidin-2-one (m, 2H), 7.35 (d, J = 5.8 Hz, 1H), 5.19
    (q, J = 7.0 Hz, 1H), 4.83 (s, 1H), 4.52
    (dd, J = 9.1, 2.7 Hz, 1H), 4.39 (t, J =
    8.9 Hz, 1H), 3.84 (br s, 1H), 1.60 (d, J =
    7.1 Hz, 3H), 0.75 (br s, 3H);
    54: (R)-3-(2-(((S)-1-(5-(4-fluoro-3- 1H NMR (400 MHz, MeOD) δ 9.00 (d, HRMS m/z
    methylphenyl)pyrazin-2- J = 1.5 Hz, 1H), 8.65 (d, J = 1.5 Hz, 439.1872 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 8.15 (d, J = 5.9 Hz, 1H), 7.94 H)+.
    hydroxyethyl)oxazolidin-2-one (ddd, J = 7.3, 2.3, 0.9 Hz, 1H), 7.87
    (ddd, J = 7.7, 4.9, 2.4 Hz, 1H), 7.38
    (d, J = 5.8 Hz, 1H), 7.16 (dd, J = 9.5,
    8.6 Hz, 1H), 5.25 (q, J = 7.0 Hz, 1H),
    4.82 (br s, 1H), 4.51 (dd, J = 9.3, 2.8
    Hz, 1H), 4.38 (t, J = 8.9 Hz, 1H), 3.84
    (br s, 1H), 2.35 (d, J = 1.8 Hz, 3H),
    1.63 (d, J = 7.1 Hz, 3H), 0.80 (br s,
    3H);
    55: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 8.95 (d, HRMS m/z
    (((S)-1-(2′-(trifluoromethyl)-[3,4′- J = 2.3 Hz, 1H), 8.79 (d, J = 5.1 Hz, 475.1685 (M +
    bipyridin]-6-yl)ethyl)amino)pyrimidin-4- 1H), 8.22 (dd, J = 8.3, 2.4 Hz, 1H), H)+.
    yl)oxazolidin-2-one 8.19-8.11 (m, 2H), 7.99 (dd, J = 5.1,
    1.7 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H),
    7.37 (d, J = 5.8 Hz, 1H), 5.19 (q, J =
    7.0 Hz, 1H), 4.78 (s, 1H), 4.55-4.45
    (m, 1H), 4.37 (t, J = 8.9 Hz, 1H), 3.73-
    3.44 (m, 1H), 1.60 (d, J = 7.0 Hz,
    3H), 0.69 (br s, 3H);
    56: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 9.30 (d, HRMS m/z
    (((S)-1-(6′-(trifluoromethyl)-[2,3′- J = 2.0 Hz, 1H), 8.75 (s, 1H), 8.60 (dd, 475.1689 (M +
    bipyridin]-5-yl)ethyl)amino)pyrimidin-4- J = 8.2, 2.1 Hz, 1H), 8.14 (d, J = 5.8 H)+.
    yl)oxazolidin-2-one Hz, 5H), 7.98 (t, J = 1.4 Hz, 2H), 7.93
    (d, J = 8.4 Hz, 1H), 7.36 (d, J = 5.8
    Hz, 1H), 5.20 (q, J = 7.0 Hz, 1H), 4.83
    (br s, 1H), 4.52 (dd, J = 9.2, 2.7 Hz,
    1H), 4.39 (t, J = 8.9 Hz, 1H), 3.80 (br
    s, 1H), 1.61 (d, J = 7.0 Hz, 3H), 0.75
    (br s, 3H);
    57: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 9.03 (d, HRMS m/z
    (((S)-1-(6′-(trifluoromethyl)-[3,3′- J = 2.2 Hz, 1H), 8.88 (d, J = 1.8 Hz, 475.1689 (M +
    bipyridin]-6-yl)ethyl)amino)pyrimidin-4- 1H), 8.34 (dd, J = 8.3, 2.2 Hz, 1H), H)+.
    yl)oxazolidin-2-one 8.15 (dd, J = 8.1, 2.5 Hz, 2H), 7.93 (d,
    J = 8.4 Hz, 1H), 7.63-7.58 (m, 1H),
    7.37 (d, J = 5.8 Hz, 1H), 5.19 (q, J =
    7.1 Hz, 1H), 4.79 (br s, 1H), 4.51 (dd,
    J = 9.1, 2.7 Hz, 1H), 4.38 (t, J = 8.9
    Hz, 1H), 3.71-3.47 (m, 1H), 1.61 (d,
    J = 7.1 Hz, 3H), 0.70 (br s, 3H);
    58: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 9.24- HRMS m/z
    (((S)-1-(6-(trifluoromethyl)-[2,3′- 9.19 (m, 1H), 8.47 (dd, J = 8.3, 2.3 475.1721 (M +
    bipyridin]-6′-yl)ethyl)amino)pyrimidin- Hz, 1H), 8.24-8.07 (m, 3H), 7.79 (dd, H)+.
    4-yl)oxazolidin-2-one J = 7.7, 0.9 Hz, 1H), 7.60 (d, J = 8.2
    Hz, 2H), 7.39 (d, J = 5.9 Hz, 1H), 5.21
    (q, J = 7.0 Hz, 1H), 4.80 (br s, 1H),
    4.58-4.44 (m, 1H), 4.38 (t, J = 8.8
    Hz, 1H), 3.69 (br s, 1H), 1.61 (d, J =
    7.1 Hz, 3H), 0.69 (br s, 3H);
    59: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 8.81 (d, HRMS m/z
    (((S)-1-(4-methyl-2′-(trifluoromethyl)- J = 5.0 Hz, 1H), 8.38 (s, 1H), 8.15 (d, 489.1881 (M +
    [3,4′-bipyridin]-6- J = 5.1 Hz, 1H), 7.90 (s, 1H), 7.72 (dd, H)+.
    yl)ethyl)amino)pyrimidin-4- J = 5.0, 1.6 Hz, 1H), 7.45 (s, 1H), 7.37
    yl)oxazolidin-2-one (d, J = 5.8 Hz, 1H), 5.14 (q, J = 7.0
    Hz, 1H), 4.79 (br s, 1H), 4.52 (dd, J =
    9.3, 2.7 Hz, 1H), 4.38 (t, J = 8.9 Hz,
    1H), 3.65 (br s, 1H), 2.32 (s, 3H), 1.58
    (d, J = 7.1 Hz, 3H), 0.77 (br s, 3H);
    60: (R)-3-(2-(((S)-1-(5-fluoro-2′- 1H NMR (400 MHz, MeOD) δ 8.82- HRMS m/z
    (trifluoromethyl)-[3,4′-bipyridin]-6- 8.80 (m,2H), 8.19 (d, J = 1.5 Hz, 1H), 493.1575 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 8.14 (d, J = 5.8 Hz, 1H), 8.10 (dd, J = H)+.
    hydroxyethyl)oxazolidin-2-one 10.8, 1.9 Hz, 1H), 8.00 (dd, J = 5.2,
    1.7 Hz, 1H), 7.38 (d, J = 5.8 Hz, 1H),
    5.54 (q, J = 6.9 Hz, 1H), 4.64 (s, 1H),
    4.55 (dd, J = 9.3, 2.7 Hz, 1H), 4.41 (t,
    J = 8.8 Hz, 1H), 3.93 (br s, 1H), 1.60
    (d, J = 6.9 Hz, 3H) 0.87 (br s, 3H);
    61: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 8.79 (s, HRMS m/z
    (((S)-1-(5-methyl-2′-(trifluoromethyl)- 1H), 8.78 (d, J = 4.6 Hz, 1H), 8.15 (s, 489.1829 (M +
    [3,4′-bipyridin]-6- 1H), 8.14 (d, J = 6.3 Hz, 1H), 8.05 (s, H)+.
    yl)ethyl)amino)pyrimidin-4- 1H), 7.98 (d, J = 5.0 Hz, 1H), 7.37 (d,
    yl)oxazolidin-2-one J = 5.8 Hz, 0H), 5.49-5.38 (m, 1H),
    4.90-4.84 (m, 1H), 4.55 (dd, J = 9.2,
    2.6 Hz, 1H), 4.41 (t, J = 8.8 Hz, 1H),
    3.96 (br s, 1H), 2.57 (s, 3H), 1.53 (d, J =
    6.7 Hz, 3H), 0.87 (br s, 3H);
    62: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 8.79 (d, HRMS m/z
    (((S)-1-(2-methyl-2′-(trifluoromethyl)- J = 5.0 Hz, 1H), 8.15 (d, J = 5.9 Hz, 489.1840
    [3,4′-bipyridin]-6- 1H), 7.88 (s, 1H), 7.74-7.65 (m, 2H), (M + H)+.
    yl)ethyl)amino)pyrimidin-4- 7.39 (d, J = 8.0 Hz, 1H), 7.37 (d, J =
    yl)oxazolidin-2-one 5.8 Hz, 1H), 5.14 (t, J = 7.1 Hz, 1H),
    4.79 (br s, 1H), 4.52 (dd, J = 9.3, 2.7
    Hz, 1H), 4.38 (t,J = 8.9 Hz, 1H), 3.61
    (br s, 1H), 2.53 (s, 3H), 1.59 (d, J =
    7.0 Hz, 3H), 0.76 (br s, 3H);
    63: (R)-3-(2-(((S)-1-(2′-(tert-butyl)- 1H NMR (400 MHz, MeOD) δ 8.85 (d, HRMS m/z
    [3,4′-bipyridin]-6- J = 1.8 Hz, 1H), 8.56 (dd, J = 5.3, 0.8 463.2439 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- Hz, 1H), 8.16-8.08 (m, 1H), 7.73 (d, H)+.
    hydroxyethyl)oxazolidin-2-one J = 0.7 Hz, 1H), 7.58 (d, J = 8.2 Hz,
    1H), 7.54 (dd, J = 5.2, 1.7 Hz, 1H),
    7.36 (d, J = 5.8 Hz, 1H), 5.18 (q, J =
    7.0 Hz, 1H), 4.78 (br s, 1H), 4.56-
    4.46 (m, 1H), 4.37 (t, J = 8.8 Hz, 1H),
    3.59 (br s, 1H), 1.60 (d, J = 7.1 Hz,
    3H), 1.42 (s, 9H), 0.67 (br s, 3H);
    64: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 8.84 (d, HRMS m/z
    (((S)-1-(2′-(1,1,1-trifluoro-2- J = 2.2 Hz, 1H), 8.64 (d, J = 5.1 Hz, 517.2167 (M +
    methylpropan-2-yl)-[3,4′-bipyridin]-6- 1H), 8.16-8.03 (m, 2H), 7.86 (s, 1H), H)+.
    yl)ethyl)amino)pyrimidin-4- 7.64 (dd, J = 5.1, 1.6 Hz, 1H), 7.58 (d,
    yl)oxazolidin-2-one J = 8.2 Hz, 1H), 7.35 (d, J = 5.8 Hz,
    1H), 5.18 (q, J = 7.0 Hz, 1H), 4.78 (br
    s, 1H), 4.50 (dd, J = 9.3, 2.7 Hz, 1H),
    4.37 (t, J = 8.8 Hz, 1H), 3.57 (br s,
    1H), 1.68 (s, 6H), 1.60 (d, J = 7.1 Hz,
    3H), 0.67 (br s, 3H);
    65: 4-(2-((S)-1-((4-((R)-4-((R)-1- 1H NMR (400 MHz, MeOD) δ 8.19 (d, HRMS m/z
    hydroxyethyl)-2-oxooxazolidin-3- J = 5.8 Hz, 1H), 8.15-8.09 (m, 2H), 437.1375 (M +
    yl)pyrimidin-2-yl)amino)ethyl)thiazol-4- 7.90 (s, 1H), 7.80-7.74 (m, 2H), 7.43 H)+.
    yl)benzonitrile (d, J = 5.8 Hz, 1H), 5.51 (q, J = 7.5
    Hz, 1H), 4.82 (br s, 1H), 4.49 (dd, J =
    9.0, 3.1 Hz, 1H), 4.38 (t, J = 8.9 Hz,
    1H), 4.10 (br s, 1H), 1.73 (d, J = 7.1
    Hz, 3H), 0.78 (br s, 3H);
    66: (R)-3-(2-(((S)-1-(5-(4- 1H NMR (400 MHz, MeOD) δ 8.16 (d, HRMS m/z
    chlorophenyl)isoxazol-3- J = 5.8 Hz, 1H), 7.82-7.76 (m, 2H), 430.1260 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 7.53-7.47 (m, 2H), 7.40 (d, J = 5.8 H)+.
    hydroxyethyl)oxazolidin-2-one Hz, 1H), 6.78 (s, 1H), 5.34 (q, J = 7.1
    Hz, 1H), 4.87 (ddd, J = 8.4, 4.2, 2.7
    Hz, 1H), 4.54 (dd, J = 9.2, 2.7 Hz,
    1H), 4.41 (t, J = 8.9 Hz, 1H), 4.31 (br
    s, 1H), 1.63 (d, J = 7.0 Hz, 3H), 0.93
    (br s, 3H);
    67: (R)-3-(2-(((R)-1-(4-(2,4- 1H NMR (400 MHz, MeOD) δ 8.18 (d, HRMS m/z
    dichlorophenyl)thiazol-2- J = 5.8 Hz, 1H), 7.86 (d, J = 8.4 Hz, 480.0639 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 7.78 (s, 1H), 7.58 (d, J = 2.2 Hz, H)+.
    hydroxyethyl)oxazolidin-2-one 1H), 7.44-7.39 (m, 2H), 5.43 (q, J =
    7.0 Hz, 1H), 4.64 (br s, 1H), 4.56-
    4.49 (m, 2H), 4.30 (br s, 1H), 1.71 (d,
    J = 7.0 Hz, 3H), 1.06 (d, J = 6.5 Hz,
    3H);
    68: (R)-3-(2-(((S)-1-(4-(2,4- 1H NMR (400 MHz, MeOD) δ 8.19 (d, HRMS m/z
    dichlorophenyl)thiazol-2- J = 5.8 Hz, 1H), 7.91 (d, J = 8.5 Hz, 480.0637 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 7.81 (s, 1H), 7.58 (d, J = 2.1 Hz, H)+.
    hydroxyethyl)oxazolidin-2-one 1H), 7.46-7.39 (m, 2H), 5.50 (q, J =
    7.0 Hz, 1H), 4.82 (br s, 1H), 4.51 (dd,
    J = 9.0, 2.7 Hz, 1H), 4.38 (t, J = 8.9
    Hz, 1H), 4.04 (br s, 1H), 1.72 (d, J =
    7.0 Hz, 3H), 0.82 (br s, 3H);
    69: (R)-3-(2-(((R)-1-(4-(4- 1H NMR (400 MHz, MeOD) δ 8.17 (d, HRMS m/z
    bromophenyl)thiazol-2- J = 5.8 Hz, 1H), 7.86-7.81 (m, 2H), 490.0533 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 7.69 (s, 1H), 7.59-7.54 (m, 2H), 7.42 H)+.
    hydroxyethyl)oxazolidin-2-one (d, J = 5.8 Hz, 1H), 5.44 (q, J = 7.0
    Hz, 1H), 4.69 (br s, 1H), 4.52 (ddt, J =
    19.3, 9.1, 4.6 Hz, 2H), 4.26 (br s, 1H),
    1.71 (d, J = 7.0 Hz, 3H), 1.08 (d, J =
    6.5 Hz, 3H);
    70: (R)-3-(2-(((S)-1-(4-(4- 1H NMR (400 MHz, MeOD) δ 8.21 (d, HRMS m/z
    bromophenyl)thiazol-2- J = 5.8 Hz, 1H), 7.89-7.84 (m, 2H), 490.0533 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 7.71 (s, 1H), 7.61-7.56 (m, 2H), 7.44 H)+.
    hydroxyethyl)oxazolidin-2-one (d, J = 5.8 Hz, 1H), 5.52 (t, J = 3.5 Hz,
    1H), 4.84 (br s, 1H), 4.52 (dd, J = 9.4,
    2.8 Hz, 1H), 4.40 (t, J = 8.9 Hz, 1H),
    4.13 (br s, 1H), 1.74 (d, J = 7.0 Hz,
    3H), 0.81 (br s, 3H);
    71: 4-(2-((R)-1-((4-((R)-4-((R)-1- 1H NMR (400 MHz, MeOD) δ 8.17 (d, HRMS m/z
    hydroxyethyl)-2-oxooxazolidin-3- J = 5.8 Hz, 1H), 8.14-8.09 (m, 2H), 437.1382 (M +
    yl)pyrimidin-2-yl)amino)ethyl)thiazol-4- 7.91 (s, 1H), 7.80-7.74 (m, 2H), 7.42 H)+.
    yl)benzonitrile (d, J = 5.8 Hz, 1H), 5.46 (q, J = 7.0
    Hz, 1H), 4.70 (br s, 1H), 4.59-4.45
    (m, 2H), 4.27 (br s, 1H), 1.73 (d, J =
    7.0 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H);
    72: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 8.12 (d, HRMS m/z
    ((S)-1-(4-((4-methylpiperazin-1- J = 5.8 Hz, 1H), 7.41-7.22 (m, 5H), 441.2593 (M +
    yl)methyl)phenyl)ethylamino)pyrimidin- 5.09 (q, J = 7.0 Hz, 1H), 4.53 (dd, J = H)+.
    4-yl)oxazolidin-2-one 9.3, 2.8 Hz, 1H), 4.39 (t, J = 8.9 Hz,
    1H), 3.99 (s, 1H), 3.52 (d, J = 1.5 Hz,
    2H), 2.56 (bs, 8H), 2.28 (s, 3H), 1.52
    (d, J = 7.0 Hz, 3H), 0.78 (s,3H).
    73: (4R)-3-(2-((1-(3-fluoro-4-(4- 1H NMR (400 MHz, MeOD) δ 8.14 (t, HRMS m/z
    methyl-1H-pyrazol-1- J = 5.7 Hz, 1H), 7.86-7.77 (m, 1H), 427.1870 (M +
    yl)phenyl)ethyl)amino)pyrimidin-4-yl)- 7.64 (td, J = 8.3, 2.2 Hz, 1H), 7.56 (d, H)+.
    4-((R)-1-hydroxyethyl)oxazolidin-2-one J = 3.0 Hz, 1H), 7.42-7.28 (m, 3H),
    5.20-4.99 (m, 1H), 4.75-4.47 (m,
    2H), 4.37 (dt,J = 17.1, 8.9 Hz, 1H),
    2.17 (s, 3H), 1.56 (d,J = 7.1 Hz, 3H),
    1.10 (d, J = 6.5 Hz, 1.5H), 0.82 (br s,
    1.5H).
    74: (4R)-3-(2-((1-(5-(3,4- 1H NMR (400 MHz, MeOD) δ 8.27 (d, HRMS m/z
    dichlorophenyl)-1H-imidazol-2- J = 3.1 Hz, 1H), 7.63 (d, J = 5.0 Hz, 481.0930 (M +
    yl)ethyl)amino)-5-fluoropyrimidin-4-yl)- 1H), 7.50 (dd,J = 8.4, 1.6 Hz, 1H), H)+.
    4-((R)-1-hydroxyethyl)oxazolidin-2-one 7.41 (s, 1H), 5.14 (q, J = 7.0 Hz, 1H),
    4.72 (td, J = 7.1, 5.1 Hz, 1H), 4.56-
    4.42 (m, 2H), 4.16 (qd, J = 6.4, 5.1
    Hz, 1H), 1.63 (dd, J = 10.1, 7.1 Hz,
    3H), 1.11 (d, J = 6.5 Hz, 3H).
    75: (4R)-3-(2-((1-(5-(3,4- 1H NMR (400 MHz, MeOD) δ 8.19 (d, HRMS m/z
    dichlorophenyl)-1H-imidazol-2- J = 5.8 Hz, 1H), 7.91 (s, 1H), 7.63 (s, 463.1018 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.41 (d, H)+
    hydroxyethyl)oxazolidin-2-one J = 5.8 Hz, 1H), 5.27-5.12 (m, 1H),
    4.67 (s, 1H), 4.62-4.47 (m, 2H), 4.26
    (s, 1H), 1.65 (d, J = 7.1 Hz, 3H), 1.08
    (d, J = 6.5 Hz, 3H).
    76: (R)-3-(2-(((S)-1-(5-((4,4- 1H NMR (400 MHz, MeOD) δ 8.47 (d, HRMS m/z
    difluoropiperidin-1-yl)methyl)pyridin-2- J = 2.0 Hz, 1H), 8.15 (d, J = 5.9 Hz, 463.2250 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 7.78 (dd, J = 8.0, 2.2 Hz, 1H), H)+.
    hydroxyethyl)oxazolidin-2-one 7.45 (d, J = 8.1 Hz, 1H), 7.37 (d, J =
    5.7 Hz, 1H), 5.26-5.08 (m, 1H),
    4.81 (d, J = 6.4 Hz, 1H), 4.53 (dd, J =
    9.1, 2.7 Hz, 1H), 4.39 (t, J = 8.9 Hz,
    1H), 3.95-3.64 (m, 1H), 3.61 (s, 2H),
    2.59 (t, J = 5.6 Hz, 4H), 1.99 (tt, J =
    13.7, 5.6 Hz, 4H), 1.56 (d, J = 7.0 Hz,
    3H), 0.77 (s, 3H).
    77: (R)-3-(2-(((S)-1-(6-((4,4- 1H NMR (400 MHz, MeOD) δ 8.52 (d, HRMS m/z
    difluoropiperidin-1-yl)methyl)pyridin-3- J = 2.3 Hz, 1H), 8.14 (d, J = 5.9 Hz, 463.2267 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 7.85 (dd, J = 8.1, 2.3 Hz, 1H), H)+.
    hydroxyethyl)oxazolidin-2-one 7.51 (d, J = 8.0 Hz, 1H), 7.36 (d, J =
    5.8 Hz, 1H), 5.16 (q, J = 7.1 Hz, 1H),
    4.83 (d, J = 4.5 Hz, 1H), 4.54 (dd, J =
    9.3, 2.7 Hz, 1H), 4.40 (t, J = 8.9 Hz,
    1H), 4.16-3.76 (br s, 1H), 3.69 (s, 2H),
    2.61 (t, J = 5.7 Hz, 4H), 1.99 (tt, J =
    13.5, 5.6 Hz, 4H), 1.57 (d, J = 7.0 Hz,
    3H), 0.83 (s, 3H).
    78: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 9.13 (d, HRMS m/z
    (((R)-1-(5-(3- J = 1.5 Hz, 1H), 8.79 (d, J = 1.5 Hz, 475.1685 (M +
    (trifluoromethyl)phenyl)pyrazin-2- 1H), 8.40 (s, 1H), 8.33 (d, J = 7.8 Hz, H)+.
    yl)ethyl)amino)pyrimidin-4- 1H), 8.15 (d, J = 5.8 Hz, 1H), 7.78 (d,
    yl)oxazolidin-2-one J = 7.9 Hz, 1H), 7.72 (t, J = 7.8 Hz,
    1H), 7.38 (d, J = 5.8 Hz, 1H), 5.25 (q,
    J = 7.0 Hz, 1H), 4.59-4.51 (m, 2H),
    4.33 (br s, 1H), 1.64 (d, J = 7.0 Hz,
    3H), 1.09 (d, J = 6.5 Hz, 3H);
    79: (R)-3-(2-(((R)-1-(5-(4-fluoro-3- 1H NMR (400 MHz, MeOD) δ 8.99 (d, HRMS m/z
    methylphenyl)pyrazin-2- J = 1.5 Hz, 1H), 8.70 (d, J = 1.6 Hz, 439.1869 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 8.14 (d, J = 5.8 Hz, 1H), 7.99- H)+.
    hydroxyethyl)oxazolidin-2-one 7.92 (m, 1H), 7.88 (ddd, J = 8.4, 4.9,
    2.4 Hz, 1H), 7.37 (d, J = 5.8 Hz, 1H),
    7.16 (dd, J = 9.5, 8.6 Hz, 1H), 5.22 (q,
    J = 7.0 Hz, 1H), 4.64 (br s, 1H), 4.60-
    4.51 (m, 2H), 4.32 (t, J = 8.7 Hz, 1H),
    2.35 (d, J = 2.0 Hz, 3H), 1.62 (d, J =
    7.0 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H);
  • The compounds in Table 29a were prepared using methods similar to those described for the preparation of Examples 35, 36, or 37/38.
  • TABLE 29a
    Figure US20140275083A1-20140918-C00623
         		80 and 81
    Figure US20140275083A1-20140918-C00624
         		82 and 83
    Figure US20140275083A1-20140918-C00625
         		84 and 85
    Figure US20140275083A1-20140918-C00626
         		86 and 87
    Figure US20140275083A1-20140918-C00627
         		88 and 89
    Figure US20140275083A1-20140918-C00628
         		90 and 91
    Figure US20140275083A1-20140918-C00629
         		92 and 93
    Figure US20140275083A1-20140918-C00630
         		94 and 95
    Figure US20140275083A1-20140918-C00631
         		96 and 97
    Figure US20140275083A1-20140918-C00632
         		98 and 99
    Figure US20140275083A1-20140918-C00633
         		100 and 101
    Figure US20140275083A1-20140918-C00634
         		102 and 103
    Figure US20140275083A1-20140918-C00635
         		104 and 105
    Figure US20140275083A1-20140918-C00636
         		106 and 107
    Figure US20140275083A1-20140918-C00637
         		108 and 109
    Figure US20140275083A1-20140918-C00638
         		110 and 111
    Figure US20140275083A1-20140918-C00639
         		112 and 113
    Figure US20140275083A1-20140918-C00640
         		114 and 115
    Figure US20140275083A1-20140918-C00641
         		116 and 117
    Figure US20140275083A1-20140918-C00642
         		118 and 119
    Figure US20140275083A1-20140918-C00643
         		120 and 121
    Figure US20140275083A1-20140918-C00644
         		122 and 123
    Figure US20140275083A1-20140918-C00645
         		124 and 125
    Figure US20140275083A1-20140918-C00646
         		126 and 127
    Figure US20140275083A1-20140918-C00647
         		128 and 129
    Figure US20140275083A1-20140918-C00648
         		130 and 131
    Figure US20140275083A1-20140918-C00649
         		132 and 133
    Figure US20140275083A1-20140918-C00650
         		134 and 135
    Figure US20140275083A1-20140918-C00651
         		136 and 137
    Figure US20140275083A1-20140918-C00652
         		138 and 139
    Figure US20140275083A1-20140918-C00653
         		140 and 141
    Figure US20140275083A1-20140918-C00654
         		142 and 143
    Figure US20140275083A1-20140918-C00655
         		144 and 145
    Figure US20140275083A1-20140918-C00656
         		146 and 147
    Figure US20140275083A1-20140918-C00657
         		148 and 149
    Figure US20140275083A1-20140918-C00658
         		150 and 151
    Figure US20140275083A1-20140918-C00659
         		152 and 153
    Figure US20140275083A1-20140918-C00660
         		154 and 155
    Figure US20140275083A1-20140918-C00661
         		156 and 157
    Figure US20140275083A1-20140918-C00662
         		158 and 159
    Figure US20140275083A1-20140918-C00663
         		160 and 161
    Figure US20140275083A1-20140918-C00664
         		162 and 163
    Figure US20140275083A1-20140918-C00665
         		164 and 165
    Figure US20140275083A1-20140918-C00666
         		166 and 167
    Figure US20140275083A1-20140918-C00667
         		168 and 169
    Figure US20140275083A1-20140918-C00668
         		170 and 171
    Figure US20140275083A1-20140918-C00669
         		172 and 173
    Figure US20140275083A1-20140918-C00670
         		174 and 175
    Figure US20140275083A1-20140918-C00671
         		176 and 177
    Figure US20140275083A1-20140918-C00672
         		178 and 179
    Figure US20140275083A1-20140918-C00673
         		180 and 181
    Figure US20140275083A1-20140918-C00674
         		182 and 183
    Figure US20140275083A1-20140918-C00675
         		184 and 185
    Figure US20140275083A1-20140918-C00676
         		186 and 187
    Figure US20140275083A1-20140918-C00677
         		188 and 189
    Figure US20140275083A1-20140918-C00678
         		190 and 191
    Figure US20140275083A1-20140918-C00679
         		192 and 193
    Figure US20140275083A1-20140918-C00680
         		194 and 195
    Figure US20140275083A1-20140918-C00681
         		196 and 197
    Figure US20140275083A1-20140918-C00682
         		198 and 199
    Figure US20140275083A1-20140918-C00683
         		200 and 201
  • TABLE 29b
    Chemical name, NMR chemical shifts, chiral separation
    conditions and LCMS signal for compounds listed in Table 29a.
    Chiral separation conditions, peak identification and
    Example: Name analytical data
    80 and 81: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-((1-(5-(4-fluoro-3- chromatography (Column AD-H 20 × 250 mm 35% IPA 10 mM
    (trifluoromethyl)phenyl)pyrimidin- NH4OH in CO2, flow 75 g/min, 232 nm UV collection) to
    2-yl)ethyl)amino)pyrimidin-4-yl)- give (R)-3-(2-(((S)-1-(5-(4-fluoro-3-
    4-((R)-1-hydroxyethyl)oxazolidin- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
    2-one 4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-
    (((R)-1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one.
    80: First eluted product (40 mg) 1H NMR (400 MHz, CDCl3)
    δ 8.90 (s, 2H), 8.22 (d, J = 5.76 Hz, 1H), 7.83-7.70 (m,
    2H), 7.49-7.35 (m, 2H), 6.12 (d, J = 8.09 Hz, 1H), 5.40 (p,
    J = 7.25 Hz, 1H), 4.89 (s, 1H), 4.51 (dd, J = 2.70, 9.45 Hz,
    1H), 4.42 (dd, J = 8.23, 9.37 Hz, 1H), 3.30 (s, 1H), 1.68 (d,
    J = 7.25 Hz, 3H), 1.12 (br s, 3H). HRMS(B) m/z 493.1599
    (M + H)+.
    81: Second eluted product (45 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.91 (s, 2H), 8.22 (d, J = 5.7 Hz, 1H), 7.84-7.71
    (m, 2H), 7.40 (dd, J = 11.6, 7.2 Hz, 2H), 6.14 (d, J = 6.8 Hz,
    1H), 5.21 (s, 1H), 4.79 (s, 1H), 4.58-4.48 (m, 1H), 4.30 (s,
    1H), 3.81 (s, 1H), 1.66 (m, 3H), 1.24 (m, 3H). HRMS(B) m/z
    493.1600 (M + H)+.
    82 and 83: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-((1-(5-(4-chloro-3- chromatography (Column AD-H 20 × 250 mm 30% IPA 10 mM
    (trifluoromethyl)phenyl)pyrimidin- NH4OH in CO2, flow 75 g/min, 232 nm UV collection) to
    2-yl)ethyl)amino)pyrimidin-4-yl)- give (R)-3-(2-(((S)-1-(5-(4-chloro-3-
    4-((R)-1-hydroxyethyl)oxazolidin- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
    2-one 4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-
    (((R)-1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one.
    82: First eluted product (13 mg) 1H NMR (400 MHz, CDCl3)
    δ 8.91 (s, 2H), 8.22 (d, J = 5.8 Hz, 1H), 7.90-7.85 (m, 1H),
    7.68 (d, J = 1.8 Hz, 2H), 7.45 (d, J = 5.7 Hz, 1H), 6.08 (d, J =
    8.2 Hz, 1H), 5.40 (q, J = 7.5 Hz, 1H), 4.89 (s, 1H), 4.51
    (dd, J = 9.4, 2.7 Hz, 1H), 4.42 (dd, J = 9.4, 8.3 Hz, 1H),
    4.09 (s, 1H), 3.29 (s, 1H), 1.68 (d, J = 7.5 Hz, 3H), 1.12 (br
    s, 3H). HRMS(B) m/z 509.1306 (M + H)+.
    83: Second eluted product (12 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.93 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H), 7.88 (d, J =
    1.7 Hz, 1H), 7.69 (d, J = 1.4 Hz, 2H), 7.42 (d, J = 5.7 Hz,
    1H), 6.09 (d, J = 6.8 Hz, 1H), 5.21 (s, 1H), 4.78 (s, 1H),
    4.53 (d, J = 8.9 Hz, 1H), 4.31 (s, 1H), 3.70 (s, 1H), 1.66 (m,
    3H), 1.24 (m, 3H). HRMS(B) m/z 509.1312 (M + H)+.
    84 and 85: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-((1-(5-(3,4- chromatography (Column C6 AD-H 20 × 250 mm 35% IPA 5
    dichlorophenyl)pyrimidin-2- mM NH4OH in CO2, flow 80 mL/min, 232 nm UV collection)
    yl)ethyl)amino)pyrimidin-4-yl)-4- to give (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-
    ((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(5-(3,4-
    dichlorophenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-
    ((R)-1-hydroxyethyl)oxazolidin-2-one.
    84: First eluted product (28 mg) 1H NMR (400 MHz, CDCl3)
    δ 8.89 (s, 2H), 8.22 (d, J = 5.7 Hz, 1H), 7.70-7.58 (m, 2H),
    7.49-7.37 (m, 2H), 6.03 (d, J = 7.5 Hz, 1H), 5.39 (t, J =
    7.4 Hz, 1H), 4.89 (s, 1H), 4.55-4.47 (m, 1H), 4.42 (dd, J =
    9.4, 8.3 Hz, 1H), 3.25 (s, 1H), 1.67 (dd, J = 7.0, 4.3 Hz,
    3H), 1.12 (br s, 3H). HRMS(B) m/z 475.1026 (M + H)+.
    85: Second eluted product (22 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.90 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H), 7.71-7.57
    (m, 2H), 7.46-7.38 (m, 2H), 6.01 (s, 1H), 5.18 (s, 1H),
    4.78 (s, 1H), 4.53 (d, J = 9.0 Hz, 1H), 4.31 (s, 2H), 3.64 (s,
    1H), 1.66 (d, J = 6.9 Hz, 3H), 1.26-1.21 (m, 3H).
    HRMS(B) m/z 475.1032 (M + H)+.
    86 and 87: (R)-4-((R)-1- Chiral separation was achieved by chiral SFC column
    hydroxyethyl)-3-(2-((1-(5-(3- chromatography (Column AD-H 20 × 250 mm 35% IPA 10 mM
    (trifluoromethyl)phenyl)pyrimidin- NH4OH in CO2, flow 75 g/min, 232 nm UV collection) to
    2-yl)ethyl)amino)pyrimidin-4- give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-
    yl)oxazolidin-2-one (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
    4-yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-
    (((R)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one.
    86:: First eluted product (80 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.94 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H), 7.85-7.63
    (m, 4H), 7.46 (d, J = 5.7 Hz, 1H), 6.11 (d, J = 8.2 Hz, 1H),
    5.41 (p, J = 7.2 Hz, 1H), 4.90 (s, 1H), 4.52 (dd, J = 9.5, 2.6
    Hz, 1H), 4.43 (dd, J = 9.4, 8.3 Hz, 1H), 3.34 (s, 1H), 1.67
    (d, J = 7.2 Hz, 3H), 1.12 br(s, 3H). HRMS(B) m/z 475.1681
    (M + H)+.
    87: Second eluted product (67 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.95 (s, 2H), 8.20 (d, J = 5.9 Hz, 1H), 7.86-7.64
    (m, 4H), 7.46 (d, J = 5.9 Hz, 1H), 6.48 (br s, 1H), 5.20 (br s,
    1H), 4.79 (br s, 1H), 4.55 (d, J = 8.6 Hz, 1H), 4.34-4.30 (m,
    2H), 3.65 (br s, 1H), 1.67 (d, J = 7.2 Hz, 3H), 1.25 (d, J =
    6.5 Hz, 3H). HRMS(B) m/z 475.1677 (M + H)+.
    88 and 89: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-((1-(5-(4-chloro-3- chromatography (Column C6 AD-H 20 × 250 mm 35% IPA 5
    methylphenyl)pyrimidin-2- mM NH4OH in CO2, flow 80 mL/min, 232 nm UV collection)
    yl)ethyl)amino)pyrimidin-4-yl)-4- to give (R)-3-(2-(((S)-1-(5-(4-chloro-3-
    ((R)-1-hydroxyethyl)oxazolidin-2- methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-
    one ((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-
    (5-(4-chloro-3-methylphenyl)pyrimidin-2-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one.
    88: First eluted product (16 mg) 1H NMR (400 MHz, CDCl3)
    δ 8.79 (s, 2H), 8.13 (d, J = 5.7, 1H), 7.44-7.17 (m, 4H),
    6.07-5.96 (m, 1H), 5.29 (t, J = 7.7 Hz, 1H), 5.12 (s, 1H),
    4.81 (d, J = 7.3 Hz, 1H), 4.55 (s, 1H), 4.43 (dd, J = 9.4, 2.6
    Hz, 1H), 3.38 (s, 1H), 2.39 (s, 3H), 1.57 (d, J = 7.7 Hz, 3H),
    1.02 (br s, 3H). HRMS(B) m/z 455.1575 (M + H)+.
    89: Second eluted product (9 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.80 (s, 2H), 8.13 (d, J = 5.7 Hz, 1H), 7.41 (d, J =
    8.3 Hz, 1H), 7.37-7.23 (m, 3H), 5.97 (br s, 1H), 5.08 (br s,
    1H), 4.71 (br s, 1H), 4.45 (d, J = 9.0 Hz, 1H), 4.40-4.18
    (m, 2H), 3.86 (br s, 1H), 2.39 (s, 3H), 1.57 (d, J = 7.7 Hz,
    3H), 1.16-1.13 (m, 3H). HRMS(B) m/z 455.1578 (M + H)+.
    90 and 91: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-((1-(5-(3-chloro-5- chromatography (Column Coated 1 P9: AD-H 4.6 × 100 mm
    (trifluoromethyl)phenyl)pyrimidin- 5-55% IPA 5 mM NH3 in CO2, flow 5 mL/min, 177 nm UV
    2-yl)ethyl)amino)pyrimidin-4-yl)- collection) to give (R)-3-(2-(((S)-1-(5-(3-chloro-5-
    4-((R)-1-hydroxyethyl)oxazolidin- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
    2-one 4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-
    (((R)-1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one.
    90: First eluted product (4 mg) 1H NMR (400 MHz, CDCl3)
    δ 8.83 (s, 2H), 8.14 (d, J = 5.8 Hz, 1H), 7.69-7.57 (m, 3H),
    7.37 (d, J = 5.8 Hz, 1H), 5.99 (d, J = 7.7 Hz, 1H), 5.32 (p, J =
    7.1 Hz, 1H), 4.81 (d, J = 7.5 Hz, 1H), 4.42 (dd, J = 9.4,
    2.4 Hz, 1H), 4.33 (dd, J = 9.4, 8.3 Hz, 1H), 3.18 (br s, 1H),
    1.57 (d, J = 9.5 Hz, 3H), 1.03 (br s, 3H). HRMS(B) m/z
    509.1299 (M + H)+.
    91: Second eluted product (4 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.83 (s, 2H), 8.13 (d, J = 5.7 Hz, 1H), 7.69-7.58
    (m, 3H), 7.34 (d, J = 5.7 Hz, 1H), 5.97 (d, J = 7.5 Hz, 1H),
    5.35-5.31 (m, 1H), 5.13 (br s, 1H), 4.45 (d, J = 9.0 Hz, 1H),
    4.35-4.24 (m, 1H), 4.22 (s, 1H), 3.62 (br s, 1H), 1.57 (d, J =
    7.0 Hz, 3H), 1.19-1.16 (m, 3H). HRMS(B) m/z 509.1298
    (M + H)+.
    92 and 93: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-((1-(3-(4-chlorophenyl)- chromatography IA, 5 UM, 20 × 250 MM column, 74 ml/min,
    1,2,4-oxadiazol-5- 60 bar, eluting 25% IPA with 5 mM NH4OH/CO2 (v/v) to
    yl)ethyl)amino)pyrimidin-4-yl)-4- give (R)-3-(2-(((R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-
    ((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
    92: First eluted product (12.4 mg). HRMS(B) m/z 431.1225
    (M + H)+. RT = 2.39 min.
    93: Second eluted product (14.3 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.25 (d, J = 6.0 Hz, 1H), 8.10-7.94 (m, 2H), 7.57
    (d, J = 5.7 Hz, 1H), 7.53-7.43 (m, 2H), 5.96 (b, 1H), 5.38
    (s, 1H), 4.84 (ddd, J = 8.3, 4.5, 2.5 Hz, 1H), 4.54 (dd, J =
    9.4, 2.5 Hz, 1H), 4.40 (dd, J = 9.4, 8.3 Hz, 1H), 4.18-3.59
    (b, 1H), 1.79 (d, J = 7.1 Hz, 3H), 1.01 (b, 3H). HRMS(B)
    m/z 431.1219 (M + H)+, RT = 2.40 min.
    94 and 95: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-((1-(5-(4-fluorophenyl)- chromatography ID-H, 5 UM, 20 × 250 MM column, 80
    1,3,4-oxadiazol-2- ml/min, 99 bar, eluting 30% IPA with 5 mM NH4OH/CO2
    yl)ethyl)amino)pyrimidin-4-yl)-4- (v/v) to give (R)-3-(2-(((R)-1-(5-(4-fluorophenyl)-1,3,4-
    ((R)-1-hydroxyethyl)oxazolidin-2- oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-
    fluorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
    94: First eluted product (30.1 mg). HRMS (B) m/z 415.1519
    (M + H)+. RT = 1.80 min.
    95: Second eluted product (32.3 mg). HRMS(B) m/z
    415.1521 (M + H)+, RT = 1.79 min.
    96 and 97: Chiral separation was achieved by chiral SFC column
    (R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography IA, 5 UM, 20 × 250 MM column, 80 ml/min,
    ((1-(3-(2-phenoxyethyl)-1,2,4- 99 bar, eluting 20% IPA with 5 mM NH4OH/CO2 (v/v) to
    oxadiazol-5- give(R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(2-
    yl)ethyl)amino)pyrimidin-4- phenoxyethyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-
    yl)oxazolidin-2-one yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-
    (((S)-1-(3-(2-phenoxyethyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one.
    96: First eluted product (19.2 mg). HRMS(B) m/z 441.1867
    (M + H)+. RT = 1.90 min.
    97: Second eluted product (31.2 mg). HRMS(B) m/z
    441.1864 (M + H)+, RT = 1.94 min.
    98 and 99: Chiral separation was achieved by chiral SFC column
    (R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography IA, 5 UM, 20 × 250 MM column, 80 ml/min,
    ((1-(5-(p-tolyl)-1,3,4-oxadiazol-2- 100 bar, eluting 15% IPA with 0.5% NH4OH/CO2 (v/v) to
    yl)ethyl)amino)pyrimidin-4- give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(5-(p-tolyl)-
    yl)oxazolidin-2-one. 1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-
    2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(p-
    tolyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-
    yl)oxazolidin-2-one.
    98: First eluted product (48 mg). HRMS(B) m/z 411.1768 (M +
    H)+. RT = 1.82 min.
    99: Second eluted product (50 mg). HRMS(B) m/z
    411.1768 (M + H)+, RT = 1.82 min.
    100 and 101: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-((1-(3-(4-fluorophenyl)- chromatography IA, 5 UM, 20 × 250 MM column, 80 ml/min,
    1,2,4-oxadiazol-5- 100 bar, eluting 15% IPA with 0.5% NH4OH/CO2 (v/v) to
    yl)ethyl)amino)pyrimidin-4-yl)-4- give (R)-3-(2-(((R)-1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-
    ((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
    100: First eluted product (40 mg). HRMS(B) m/z 415.1516
    (M + H)+. RT = 1.96 min.
    101: Second eluted product (13 mg). HRMS(B) m/z
    415.1518 (M + H)+. RT = 1.97 min.
    102 and 103: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-((1-(5-(2-fluorophenyl)- chromatography IA, 5 UM, 20 × 250 MM column, 74 ml/min,
    1,3,4-oxadiazol-2- 99 bar, eluting 35% IPA with 5 mM NH4OH/CO2 (v/v) to
    yl)ethyl)amino)pyrimidin-4-yl)-4- give (R)-3-(2-(((R)-1-(5-(2-fluorophenyl)-1,3,4-oxadiazol-2-
    ((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one. hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(2-
    fluorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
    102: First eluted product (44 mg). HRMS(B) m/z 415.1514
    (M + H)+. RT = 1.58 min.
    103: Second eluted product (51 mg). HRMS(B) m/z
    415.1510 (M + H)+. RT = 1.58 min.
    104 and 105: Chiral separation was achieved by chiral SFC column
    (R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography IA, 5 UM, 20 × 250 MM column, 74 ml/min,
    ((1-(5-(m-tolyl)-1,3,4-oxadiazol- 99 bar, eluting 35% IPA with 5 mM NH4OH/CO2 (v/v) to
    2-yl)ethyl)amino)pyrimidin-4- give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(5-(m-tolyl)-
    yl)oxazolidin-2-one 1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-
    2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(m-
    tolyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-
    yl)oxazolidin-2-one.
    104: First eluted product (42 mg). HRMS(B) m/z 411.1762
    (M + H)+. RT = 1.78 min.
    105: Second eluted product (51 mg). HRMS(B) m/z
    411.1762 (M + H)+. RT = 1.82 min.
    106 and 107: Chiral separation was achieved by chiral SFC column
    (R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography IA, 5 UM, 20 × 250 MM column, 74 ml/min,
    ((1-(5-(o-tolyl)-1,3,4-oxadiazol-2- 99 bar, eluting 35% IPA with 5 mM NH4OH/CO2 (v/v) to
    yl)ethyl)amino)pyrimidin-4- give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(5-(o-tolyl)-
    yl)oxazolidin-2-one 1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-
    2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(o-
    tolyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-
    yl)oxazolidin-2-one.
    106: First eluted product (44 mg). HRMS(B) m/z 411.1766
    (M + H)+. RT = 1.80 min.
    107: Second eluted product (42 mg). HRMS(B) m/z
    411.1764 (M + H)+. RT = 1.80 min.
    108 and 109: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-((1-(4-(4-chlorophenyl)- chromatography ID, 5 UM, 20 × 250 MM column, 89 ml/min,
    5-methylthiazol-2- 99 bar, eluting 22% MeOH/CO2 (v/v) to give (R)-3-(2-(((R)-
    yl)ethyl)amino)pyrimidin-4-yl)-4- 1-(4-(4-chlorophenyl)-5-methylthiazol-2-
    ((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(4-(4-
    chlorophenyl)-5-methylthiazol-2-yl)ethyl)amino)pyrimidin-4-
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
    108: First eluted product (44 mg). HRMS(B) m/z 411.1766
    (M + H)+. RT = 1.80 min.
    109: Second eluted product (34 mg). HRMS(B) m/z
    460.1198 (M + H)+. RT = 2.41 min.
    110 and 111: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-{1-[5-(3-fluoro-phenyl)- chromatography IA, 5 UM, 20 × 250 MM column, 80 ml/min,
    [1,3,4]oxadiazol-2-yl]- eluting 20% IPA with 5 mM NH4OH/CO2 (v/v) to give (R)-3-
    ethylamino}-pyrimidin-4-yl)-4- (2-{(R)-1-[5-(3-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-
    ((R)-1-hydroxy-ethyl)-oxazolidin- ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-
    2-one. oxazolidin-2-one and (R)-3-(2-{(S)-1-[5-(3-fluoro-phenyl)-
    [1,3,4]oxadiazol-2-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-
    hydroxy-ethyl)-oxazolidin-2-one.
    110: First eluted product (34.1 mg). HRMS(B) m/z
    415.1510 (M + H)+. RT = 1.70 min.
    111: Second eluted product (41.9 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.23 (s, 1H), 7.82 (dt, J = 7.7, 1.2 Hz, 1H), 7.72
    (ddd, J = 9.1, 2.6, 1.6 Hz, 1H), 7.64-7.42 (m, 2H), 7.35-
    7.17 (m, 1H), 6.21 (s, 1H), 5.57-5.35 (m, 1H), 4.93 (dt, J =
    6.7, 2.9 Hz, 1H), 4.61 (dd, J = 9.5, 2.4 Hz, 2H), 4.42 (dd, J =
    9.3, 8.3 Hz, 2H), 3.98 (s, 1H), 1.08 (d, J = 6.4 Hz, 3H),
    0.92-0.77 (m, 3H). HRMS(B) m/z 415.1515 (M + H)+,
    RT = 1.70 min.
    112 and 113: Chiral separation was achieved by chiral SFC column
    (R)-4-((R)-1-Hydroxy-ethyl)-3-{2- chromatography AD-H 20 × 250 mm, 20% MeOH in CO2,
    [1-(5-pyridin-3-yl- 80 g/min, UV220 nm to give (R)-4-((R)-1-Hydroxy-ethyl)-3-
    [1,3,4]oxadiazol-2-yl)- {2-[(R)-1-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-ethylamino]-
    ethylamino]-pyrimidin-4-yl}- pyrimidin-4-yl}-oxazolidin-2-one and (R)-4-((R)-1-Hydroxy-
    oxazolidin-2-one ethyl)-3-{2-[(S)-1-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-
    ethylamino]-pyrimidin-4-yl}-oxazolidin-2-one.
    112: First eluted product (39.9 mg). HRMS(B) m/z
    398.1566 (M + H)+. RT = 1.18 min.
    113: Second eluted product (40.2 mg). 1H NMR (400 MHz,
    CDCl3) δ 9.26 (s, 1H), 8.80 (s, 1H), 8.33 (d, J = 7.9 Hz, 1H),
    8.23 (s, 1H), 7.54 (d, J = 5.3 Hz, 1H), 7.48 (dd, J = 8.2, 4.6
    Hz, 1H), 6.17 (s, 1H), 5.46 (s, 1H), 4.99-4.84 (m, 1H),
    4.60 (dd, J = 9.3, 2.3 Hz, 2H), 4.42 (dd, J = 9.3, 8.3 Hz,
    2H), 4.01 (s, 1H), 1.09 (d, J = 6.5 Hz, 3H), 0.91-0.81 (m,
    3H). HRMS(B) m/z 398.1660, (M + H)+. RT = 1.17 min.
    114 and 115: Chiral separation was achieved by chiral SFC column
    (R)-3-{2-[1-(5-Benzyl- chromatography AD-H 21 × 250 mm, 25% MeOH in CO2,
    [1,2,4]oxadiazol-3-yl)- 75 g/min, UV224 nm to give (R)-3-{2-[(R)-1-(5-Benzyl-
    ethylamino]-pyrimidin-4-yl}-4- [1,2,4]oxadiazol-3-yl)-ethylamino]-pyrimidin-4-yl}-4-((R)-1-
    ((R)-1-hydroxy-ethyl)-oxazolidin- hydroxy-ethyl)-oxazolidin-2-one and (R)-3-{2-[(S)-1-(5-
    2-one Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-pyrimidin-4-yl}-4-
    ((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
    114: First eluted product (48.9 mg). HRMS(B) m/z
    411.1855 (M + H)+. RT = 1.85 min.
    115: Second eluted product (52.2 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.13 (d, J = 5.7 Hz, 1H), 7.38 (d, J = 5.8 Hz, 1H),
    7.31-7.13 (m, 5H), 6.09 (s, 1H), 5.21 (dq, J = 14.4, 7.1
    Hz, 1H), 4.90-4.69 (m, 1H), 4.42 (dd, J = 9.4, 2.5 Hz, 1H),
    4.33-4.20 (m, 1H), 4.12 (s, 2H), 3.99 (d, J = 24.4 Hz, 1H),
    1.54 (d, J = 7.1 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H). HRMS(B)
    m/z 411.1864, (M + H)+. RT = 1.86 min.
    116 and 117: Chiral separation was achieved by chiral SFC column
    (R)-3-{2-[1-(5-Benzyl- chromatography AD-H 21 × 250 mm, 25% MeOH in CO2,
    [1,2,4]oxadiazol-3-yl)- 75 g/min, UV231 nm to give (R)-3-{2-[(R)-1-(5-Benzyl-
    ethylamino]-5-fluoro-pyrimidin-4- [1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-
    yl}-4-((R)-1-hydroxy-ethyl)- ((R)-1-hydroxy-ethyl)-oxazolidin-2-one and (R)-3-{2-[(S)-1-
    oxazolidin-2-one (5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-
    pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
    116: First eluted product (29.4 mg). HRMS(B) m/z 429.1667
    (M + H)+. RT = 1.84 min.
    117: Second eluted product (52.2 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.14 (d, J = 2.8 Hz, 1H), 7.38-7.13 (m, 5H), 5.64
    (d, J = 8.3 Hz, 1H), 5.25-5.08 (m, 1H), 4.66 (s, 1H), 4.44
    (t, J = 9.0 Hz, 1H), 4.28 (dd, J = 9.1, 5.8 Hz, 1H), 4.12 (s,
    2H), 3.84 (s, 1H), 1.58-1.50 (m, 3H), 0.99 (d, J = 6.4 Hz,
    3H). HRMS(B) m/z 429.1671, (M + H)+. RT = 1.84 min.
    118 and 119: Chiral separation was achieved by chiral SFC column
    (R)-3-{2-[1-(5-Benzyl- chromatography AD-H 21 × 250 mm, 25% IPA in CO2,
    [1,2,4]oxadiazol-3-yl)- 75 g/min, UV240 nm to give (R)-3-{2-[(R)-1-(5-Benzyl-
    ethylamino]-5-fluoro-pyrimidin-4- [1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-
    yl}-4-((R)-1-hydroxy-ethyl)- ((R)-1-hydroxy-ethyl)-oxazolidin-2-one and (R)-3-{2-[(S)-1-
    oxazolidin-2-one (5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-
    pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
    118: First eluted product (34.3 mg). HRMS(B) m/z
    477.0856 (M + H)+. RT = 2.31 min.
    119: Second eluted product (33.5 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.25 (d, J = 5.8 Hz, 1H), 8.04-7.81 (m, 2H), 7.76-
    7.58 (m, 2H), 7.55 (d, J = 5.8 Hz, 1H), 5.38 (s, 1H), 4.84
    (ddd, J = 8.3, 4.5, 2.5 Hz, 1H), 4.54 (dd, J = 9.4, 2.5 Hz,
    1H), 4.39 (dd, J = 9.4, 8.3 Hz, 1H), 3.92 (s, 1H), 1.78 (d, J =
    7.1 Hz, 3H), 1.01 (d, J = 7.2 Hz, 3H). HRMS(B) m/z
    477.0856 (M + H)+. RT = 2.32 min.
    120 and 121: Chiral separation was achieved by chiral SFC column
    (R)-3-{2-[1-(5-Benzyl- chromatography OJ-H 21 × 250 mm, 15% MeOH in CO2,
    [1,2,4]oxadiazol-3-yl)- 80 g/min, UV233 nm to give and (R)-3-{2-[(S)-1-(5-Benzyl-
    ethylamino]-5-fluoro-pyrimidin-4- [1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-
    yl}-4-((R)-1-hydroxy-ethyl)- ((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
    oxazolidin-2-one 120: First eluted product (40.1 mg). HRMS(B) m/z
    429.1785 (M + H)+. RT = 2.23 min.
    121: Second eluted product (42.9 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.25 (d, J = 5.8 Hz, 1H), 7.87-7.63 (m, 2H), 7.55
    (d, J = 5.8 Hz, 1H), 7.39-7.13 (m, 1H), 6.13 (s, 1H), 5.34
    (d, J = 20.8 Hz, 1H), 4.84 (ddd, J = 8.3, 4.5, 2.5 Hz, 1H),
    4.54 (dd, J = 9.4, 2.5 Hz, 1H), 4.39 (t, J = 8.9 Hz, 1H), 3.86
    (d, J = 36.7 Hz, 1H), 2.34 (d, J = 1.9 Hz, 3H), 1.77 (d, J =
    7.1 Hz, 3H), 1.01 (d, J = 6.8 Hz, 4H). HRMS(B) m/z
    429.1783 (M + H)+. RT = 2.24 min.
    122 and 123: Chiral separation was achieved by chiral SFC column
    (R)-3-(5-Fluoro-2-{1-[3-(3-fluoro- chromatography OJ-H 21 × 250 mm, 15% MeOH in CO2,
    4-methyl-phenyl)- 80 g/min, UV233 nm to give (R)-3-(5-Fluoro-2-{(R)-1-[3-(3-
    [1,2,4]oxadiazol-5-yl]- fluoro-4-methyl-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-
    ethylamino}-pyrimidin-4-yl)-4- pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one and
    ((R)-1-hydroxy-ethyl)-oxazolidin- (R)-3-{2-[(S)-1-(5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-
    2-one 5-fluoro-pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-
    one.
    122: First eluted product (58.7 mg). HRMS(B) m/z 447.1573
    (M + H)+. RT = 2.22 min.
    123: Second eluted product (36.4 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.17 (d, J = 2.7 Hz, 1H), 7.63 (dddd, J = 17.6, 9.8,
    8.0, 1.7 Hz, 2H), 7.32-7.14 (m, 1H), 5.96-5.72 (m, 1H),
    5.22 (q, J = 6.9, 5.9 Hz, 1H), 4.69-4.57 (m, 1H), 4.45 (t, J =
    9.0 Hz, 1H), 4.35 (dd, J = 9.2, 5.6 Hz, 1H), 4.14-3.96
    (m, 1H), 2.25 (d, J = 1.9 Hz, 3H), 1.67 (dd, J = 11.7, 7.0 Hz,
    3H), 0.95 (t, J = 7.8 Hz, 3H). HRMS(B) m/z 447.1573 (M +
    H)+. RT = 2.22 min.
    124 and 125: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-{1-[3-(3,4-Difluoro- chromatography AD-H 21 × 250 mm, 25% IPA in CO2,
    phenyl)-[1,2,4]oxadiazol-5-yl]- 75 g/min, UV226 nm to give (R)-3-(2-{(R)-1-[3-(3,4-Difluoro-
    ethylamino}-pyrimidin-4-yl)-4- phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-
    ((R)-1-hydroxy-ethyl)-oxazolidin- ((R)-1-hydroxy-ethyl)-oxazolidin-2-one and (R)-3-(2-{(S)-1-
    2-one [3-(3,4-Difluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-
    pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
    124: First eluted product (43.2 mg). HRMS(B) m/z
    443.1112 (M + H)+. RT = 2.09 min.
    125: Second eluted product (40.7 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.16 (d, J = 5.8 Hz, 1H), 7.93-7.67 (m, 2H), 7.47
    (d, J = 5.7 Hz, 1H), 7.30-7.10 (m, 1H), 6.07 (s, 1H), 5.30
    (s, 1H), 4.76 (ddd, J = 8.3, 4.6, 2.5 Hz, 1H), 4.45 (dd, J =
    9.4, 2.5 Hz, 1H), 4.31 (dd, J = 9.4, 8.4 Hz, 1H), 4.02-3.52
    (m, 1H), 1.69 (d, J = 7.1 Hz, 3H), 1.07-0.88 (m, 3H).
    HRMS(B)m/z 433.1109, (M + H)+. RT = 2.18 min.
    126 and 127: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-{1-[3-(3,4-Dichloro- chromatography IA. 21 × 250 mm, 30% (70%
    phenyl)-isoxazol-5-yl]- MeOH: 30% DCM) in CO2, 70 g/min, UV239 nm to give (R)-3-
    ethylamino}-pyrimidin-4-yl)-4- (2-{(R)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-
    ((R)-1-hydroxy-ethyl)-oxazolidin- ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-
    2-one oxazolidin-2-one and (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-
    phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-
    hydroxy-ethyl)-oxazolidin-2-one.
    126: First eluted product (37.4 mg). HRMS(B) m/z
    464.0869 (M + H)+. RT = 2.63 min.
    127: Second eluted product (27.3 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.15 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.53 (dd, J =
    8.3, 2.0 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 6.37 (s, 1H),
    5.70 (s, 1H), 5.11 (s, 1H), 4.77 (ddd, J = 7.4, 4.6, 2.6 Hz,
    1H), 4.46 (dd, J = 9.4, 2.5 Hz, 1H), 4.31 (dd, J = 9.4, 8.4
    Hz, 1H), 1.61 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 7.5 Hz, 3H).
    HRMS(B) m/z 464.0855, (M + H)+. RT = 2.56 min.
    128 and 129: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-{1-[3-(2,4-Dichloro- chromatography OJ-H. 21 × 250 mm, 15% MeOH in CO2,
    phenyl)-isoxazol-5-yl]- 75 g/min, UV231 nm to give (R)-3-(2-{(R)-1-[3-(2,4-Dichloro-
    ethylamino}-pyrimidin-4-yl)-4- phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-
    ((R)-1-hydroxy-ethyl)-oxazolidin- hydroxy-ethyl)-oxazolidin-2-one and (R)-3-(2-{(S)-1-[3-(2,4-
    2-one Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-
    4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
    128: First eluted product (72.9 mg). HRMS(B) m/z
    464.0869 (M + H)+. RT = 2.54 min.
    129: Second eluted product (36.5 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.39-8.11 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.56-
    7.47 (m, 2H), 7.42-7.28 (m, 1H), 6.60 (s, 1H), 5.80 (s,
    1H), 5.27 (d, J = 37.0 Hz, 1H), 4.72-4.45 (m, 3H), 4.31 (t,
    J = 8.7 Hz, 1H), 1.71 (d, J = 6.9 Hz, 3H), 1.19 (d, J = 6.4
    Hz, 3H). HRMS(B) m/z 464.0876, (M + H)+. RT = 2.55 min.
    130 and 131: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-{1-[3-(3,4-Difluoro- chromatography ID 21 × 250 mm, 30% iIPA in CO2,
    phenyl)-[1,2,4]oxadiazol-5-yl]- 75 g/min, UV233 nm to give and (R)-3-(2-{(S)-1-[3-(3,4-
    ethylamino}-5-fluoro-pyrimidin-4- Difluorophenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-5-fluoro-
    yl)-4-((R)-1-hydroxy-ethyl)- pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
    oxazolidin-2-one 130: First eluted product (63.9 mg). HRMS(B) m/z
    451.1324 (M + H)+. RT = 2.20 min.
    131: Second eluted product (58.1 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.25 (d, J = 2.8 Hz, 1H), 7.97-7.72 (m, 2H), 7.27
    (dt, J = 9.9, 8.4 Hz, 1H), 6.09 (s, 1H), 5.47-5.16 (m, 1H),
    4.84-4.64 (m, 1H), 4.54 (t, J = 9.0 Hz, 1H), 4.43 (dd, J =
    9.1, 5.4 Hz, 1H), 3.87 (s, 1H), 1.76 (d, J = 7.1 Hz, 3H), 1.04
    (d, J = 6.5 Hz, 3H). HRMS(B) m/z 451.1324 (M + H)+.
    RT = 2.20 min.
    132 and 133: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-{1-[3-(3,4-Dichloro- chromatography IC. 21 × 250 mm, 40% MeOH in CO2,
    phenyl)-isoxazol-5-yl]- 80 g/min, UV239 nm to give (R)-3-(2-{(R)-1-[3-(3,4-Dichloro-
    ethylamino}-5-fluoro-pyrimidin-4- phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-
    yl)-4-((R)-1-hydroxy-ethyl)- 4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one and (R)-3-(2-{(S)-
    oxazolidin-2-one 1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-
    fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-
    one.
    132: First eluted product (107 mg). HRMS(B) m/z 482.0781
    (M + H)+. RT = 2.63 min.
    133: Second eluted product (61.1 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.22 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 1.9 Hz, 1H),
    7.61 (dd, J = 8.3, 2.0 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 6.45
    (s, 1H), 5.72 (d, J = 7.6 Hz, 1H), 5.25 (t, J = 7.1 Hz, 1H),
    4.66-4.42 (m, 2H), 4.26 (t, J = 6.2 Hz, 1H), 1.68 (d, J =
    6.9 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H). HRMS(B) m/z
    482.0777 (M + H)+. RT = 2.63 min.
    134 and 135: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-{1-[3-(2,4-Dichloro- chromatography AD-H, 21 × 250 mm, 35% IPA in CO2,
    phenyl)-isoxazol-5-yl]- 75 g/min, UV237 nm to give (R)-3-(2-{(R)-1-[3-(2,4-Dichloro-
    ethylamino}-5-fluoro-pyrimidin-4- phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-
    yl)-4-((R)-1-hydroxy-ethyl)- 4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one and (R)-3-(2-{(S)-
    oxazolidin-2-one 1-[3-(2,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-
    fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-
    one.
    134: First eluted product (53.4 mg). HRMS(B) m/z
    482.0778 (M + H)+. RT = 2.54 min.
    135: Second eluted product (107 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.21 (d, J = 2.8 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H),
    7.50 (d, J = 2.0 Hz, 1H), 7.42-7.22 (m, 1H), 6.60 (s, 1H),
    5.88 (s, 1H), 5.24 (t, J = 6.7 Hz, 1H), 4.98-4.71 (m, 1H),
    4.63-4.40 (m, 2H), 3.83 (s, 1H), 1.70 (d, J = 7.1 Hz, 3H),
    1.05 (d, J = 6.4 Hz, 3H). HRMS(B) m/z 482.0774 (M + H)+.
    RT = 2.53 min.
    136 and 137: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-{1-[4-(3-Chloro-4-fluoro- chromatography OD-H, 21 × 250 mm, 30% IPA in CO2,
    phenyl)-thiazol-2-yl]-ethylamino}- 75 g/min, UV220 nm to give (R)-3-(2-{(R)-1-[4-(3-Chloro-4-
    pyrimidin-4-yl)-4-((R)-1-hydroxy- fluoro-phenyl)-thiazol-2-yl]-ethylamino}-pyrimidin-4-yl)-4-
    ethyl)-oxazolidin-2-one ((R)-1-hydroxy-ethyl)-oxazolidin-2-one and (R)-3-(2-{(S)-1-
    [4-(3-Chloro-4-fluoro-phenyl)-thiazol-2-yl]-ethylamino}-
    pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one.
    136: First eluted product (76.9 mg). HRMS(B) m/z
    464.0930 (M + H)+. RT = 2.50 min.
    137: Second eluted product (88.6 mg). 1H NMR (400 MHz,
    CDCl3) δ 8.22 (d, J = 6.0 Hz, 1H), 7.95 (dd, J = 7.0, 2.2 Hz,
    1H), 7.72 (ddd, J = 8.6, 4.5, 2.2 Hz, 1H), 7.50 (d, J = 5.7
    Hz, 1H), 7.34 (s, 1H), 7.18 (t, J = 8.6 Hz, 1H), 5.61-5.35
    (m, 1H), 4.75 (ddd, J = 8.1, 4.4, 2.4 Hz, 1H), 4.45 (dd, J =
    9.3, 2.7 Hz, 1H), 4.34 (t, J = 8.9 Hz, 1H), 3.87 (s, 1H), 1.73
    (d, J = 6.9 Hz, 3H), 0.90 (q, J = 6.9, 6.3 Hz, 3H). HRMS(B)
    m/z 464.0940 (M + H)+. RT = 2.49 min.
    138 and 139: Chiral separation was achieved by chiral SFC column
    (R)-3-(5-fluoro-2-((1-(5-(3- chromatography (Column AD-H 20 × 250 mm 45% IPA 10 mM
    (trifluoromethyl)phenyl)pyrimidin- NH4OH in CO2, flow 75 g/min, 238 nm UV collection) to
    2-yl)ethyl)amino)pyrimidin-4-yl)- give (R)-3-(5-fluoro-2-(((S)-1-(5-(3-
    4-((R)-1-hydroxyethyl)oxazolidin- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
    2-one 4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(5-
    fluoro-2-(((R)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one.
    138: First eluted product (6 mg) 1H NMR (400 MHz, CDCl3)
    δ 8.84 (s, 2H), 8.15 (d, J = 2.8 Hz, 1H), 7.76-7.55 (m, 3H),
    6.17 (br s, 1H), 5.24 (t, J = 7.1 Hz, 1H), 4.56 (d, J = 7.4 Hz,
    1H), 4.47 (t, J = 8.8 Hz, 1H), 4.33 (dd, J = 9.0, 5.1 Hz, 1H),
    4.00 (br s, 1H), 1.59 (d, J = 6.9 Hz, 3H), 1.06 (br d, J = 5.7
    Hz, 3H). HRMS(B) m/z 493.1587 (M + H)+.
    139: Second eluted product (10 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.86 (s, 2H), 8.14 (d, J = 2.9 Hz, 1H), 7.77-7.55
    (m, 4H), 6.32 (br s, 1H), 5.18 (br s, 1H), 4.49-4.29 (m,
    3H), 3.96 (p, J = 6.1 Hz, 1H), 2.69 (br s, 1H), 1.58 (d, J =
    7.0 Hz, 3H), 1.15 (d, J = 5.9 Hz, 3H). HRMS(B) m/z
    493.1591 (M + H)+.
    140 and 141: Chiral separation was achieved by chiral SFC column
    (4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column OD 20 × 250 mm 25% MeOH in
    ((1-(2-phenylthiazol-5- CO2, flow 75 g/min, 238 nm UV collection) to give(R)-4-
    yl)ethyl)amino)pyrimidin-4- ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(2-phenylthiazol-5-
    yl)oxazolidin-2-one yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
    ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(2-phenylthiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
    140: First eluted product (48 mg) 1H NMR (400 MHz,
    CDCl3) δ 10.83 (s, 1H), 8.13-7.69 (m, 5H), 7.47 (d, J = 4.6
    Hz, 4H), 5.31-5.14 (m, 1H), 4.82 (d, J = 7.7 Hz, 1H), 4.66
    (dd, J = 9.6, 2.2 Hz, 1H), 4.46 (dd, J = 9.6, 8.0 Hz, 1H),
    3.38 (d, J = 9.6 Hz, 1H), 1.84 (d, J = 6.8 Hz, 3H), 1.55-
    1.09 (m, 1H), 1.03-0.71 (m, 4H). HRMS(B) m/z 411.1365.
    Chiral RT = 2.90 min
    141: Second eluted product (46 mg) 1H NMR (400 MHz,
    CDCl3) δ 11.03 (s, 1H), 8.11-7.64 (m, 5H), 7.49 (d, J = 4.9
    Hz, 3H), 5.52-5.10 (m, 1H), 4.70 (dd, J = 23.0, 8.0 Hz,
    2H), 4.42 (t, J = 8.6 Hz, 2H), 1.86 (d, J = 6.8 Hz, 3H), 1.53-
    1.08 (m, 4H), 0.99-0.61 (m, 1H). HRMS(B) m/z
    411.1365. Chiral RT = 4.00 min
    142 and 143: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(3-(3- chromatography (Column AD 20 × 250 mm 20% MeOH in
    chlorophenyl)-1,2,4-oxadiazol-5- CO2, flow 90 g/min, 238 nm UV collection) to give (R)-3-(2-
    yl)ethyl)amino)pyrimidin-4-yl)-4- (((R)-1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-
    ((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(3-
    chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
    142: First eluted product (15.5 mg): 1H NMR (400 MHz,
    CDCl3) δ 8.16 (d, J = 5.8 Hz, 4H), 7.79 (dd, J = 7.6, 1.8 Hz,
    4H), 7.56-7.26 (m, 15H), 5.83 (s, 4H), 5.17 (s, 4H), 4.57
    (q, J = 6.1 Hz, 4H), 4.39 (dd, J = 9.3, 2.5 Hz, 4H), 4.29-
    4.04 (m, 9H), 3.96 (p, J = 6.2 Hz, 1H), 2.96 (s, 4H), 1.88-
    1.56 (m, 5H), 1.49-1.01 (m, 28H), 0.93-0.59 (m, 4H).
    HRMS(B) m/z 430.1156. Chiral RT = 3.40 min
    143: Second eluted product (10 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.25 (d, J = 5.8 Hz, 3H), 7.91 (dd, J = 7.7, 1.8 Hz,
    3H), 7.62-7.52 (m, 6H), 7.43 (dtd, J = 25.2, 7.5, 1.6 Hz,
    6H), 6.30 (s, 3H), 5.40 (s, 3H), 4.87 (ddd, J = 8.3, 4.3, 2.3
    Hz, 3H), 4.55 (dd, J = 9.5, 2.5 Hz, 3H), 4.39 (t, J = 8.9 Hz,
    3H), 4.10-3.75 (m, 4H), 3.50 (s, 3H), 3.18-2.93 (m, 3H),
    1.72 (d, J = 6.8 Hz, 0H), 1.39-1.16 (m, 5H), 1.10-0.93
    (m, 9H), 0.93-0.76 (m,2H). HRMS(B) m/z 430.1156.
    Chiral RT = 4.80 min
    144 and 145: Chiral separation was achieved by chiral SFC column
    (4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column ID 21 × 250 mm 25% MeOH in
    ((1-(3-(4-isopropylphenyl)-1,2,4- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-4-
    oxadiazol-5- ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(4-isopropylphenyl)-
    yl)ethyl)amino)pyrimidin-4- 1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-
    yl)oxazolidin-2-one 2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-
    isopropylphenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
    144: First eluted product (36 mg): (CDCl3) δ 8.24 (d, J =
    5.7 Hz, 1H), 8.06-7.88 (m, 2H), 7.50 (d, J = 5.8 Hz, 1H),
    7.41-7.32 (m, 2H), 6.05 (s, 1H), 5.22 (s, 1H), 4.71 (s, 1H),
    4.49 (dd, J = 9.3, 2.5 Hz, 1H), 4.43-4.14 (m, 2H), 4.12-
    3.99 (m, 0H), 3.51 (s, 1H), 3.37 (s, 1H), 2.98 (hept, J = 6.9
    Hz, 1H), 2.04-1.73 (m, 1H), 1.44-1.17 (m, 11H).
    HRMS(B) m/z 438.2016. Chiral RT = 3.20 min
    145: Second eluted product (36 mg): CDCl3) δ 8.25 (d, J =
    5.7 Hz, 1H), 8.05-7.91 (m, 2H), 7.54 (d, J = 5.7 Hz, 1H),
    7.42-7.31 (m, 2H), 6.23 (s, 1H), 5.33 (d, J = 10.8 Hz, 1H),
    4.85 (ddd, J = 8.5, 4.5, 2.3 Hz, 1H), 4.56 (dd, J = 9.4, 2.5
    Hz, 1H), 1.84-1.73 (m, 3H), 4.39 (t, J = 8.9 Hz, 1H), 3.86
    (s,1H), 3.51 (s, 1H), 3.15 (s,1H), 2.97 (hept, J = 7.0 Hz,
    1H), 1.94 (d, J = 7.1 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H), 0.99
    (d, J = 6.9 Hz, 3H). HRMS(B) m/z 438.2016. Chiral RT =
    4.60 min
    146 and 147: Chiral separation was achieved by chiral SFC column
    (4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250 mm 25% MeOH in
    ((1-(3-(2- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-4-
    (trifluoromethoxy)phenyl)-1,2,4- ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(2-
    oxadiazol-5- (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4- yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
    yl)oxazolidin-2-one ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(2-
    (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
    146: First eluted product (8.3 mg): (CDCl3) δ 8.25 (d, J =
    5.9 Hz, 1H), 8.07 (dd, J = 7.8, 1.8 Hz, 1H), 7.69-7.39 (m,
    4H), 5.73 (s, 1H), 5.26 (s, 1H), 4.78-4.57 (m, 1H), 4.48
    (dd, J = 9.3, 2.3 Hz, 1H), 4.39-4.00 (m, 2H), 3.52 (s, 1H),
    2.93 (s, 1H), 1.80 (d, J = 7.1 Hz, 3H), 1.62 (s, 3H), 1.21 (dd,
    J = 18.6, 6.3 Hz, 5H). HRMS(B) m/z 480.1369. Chiral RT =
    2.10 min
    147: Second eluted product (38.5 mg): (CDCl3) δ 8.25 (d, J =
    5.8 Hz, 1H), 8.10 (dd, J = 8.0, 1.7 Hz, 1H), 7.67-7.52
    (m, 2H), 7.51-7.40 (m, 2H), 5.88 (s, 1H), 5.39 (s, 1H),
    4.86 (ddd, J = 8.5, 4.6, 2.5 Hz, 1H), 1.75-1.64 (m, 1H),
    4.55 (dd, J = 9.4, 2.5 Hz, 1H), 4.39 (t, J = 8.9 Hz, 1H), 4.14-
    3.58 (m, 1H), 2.86 (s, 1H), 1.80 (d, J = 7.1 Hz, 3H), 1.23
    (d, J = 6.1 Hz, 1H), 1.00 (s, 3H). HRMS(B) m/z 480.1369.
    Chiral RT = 2.55 min
    148 and 149: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(3-(4-fluoro-3- chromatography (Column AD-H 21 × 250 mm 15% MeOH in
    methylphenyl)-1,2,4-oxadiazol-5- CO2, flow 80 g/min, 238 nm UV collection) to give(R)-3-(2-
    yl)ethyl)amino)pyrimidin-4-yl)-4- (((R)-1-(3-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-5-
    ((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    fluoro-3-methylphenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    148: First eluted product (13 mg): (CDCl3) δ 8.25 (d, J =
    5.8 Hz, 1H), 8.03-7.80 (m, 2H), 7.52 (d, J = 5.7 Hz, 1H),
    7.13 (t, J = 8.9 Hz, 1H), 5.85 (s, 1H), 5.23 (s, 1H), 4.69 (d, J =
    8.4 Hz, 1H), 4.50 (dd, J = 9.5, 2.5 Hz, 1H), 4.41-4.04
    (m, 2H), 3.51 (s, 2H), 3.11 (s, 1H), 2.36 (d, J = 2.0 Hz, 3H),
    1.78 (d, J = 7.1 Hz, 3H), 1.21 (d, J = 6.4 Hz, 4H). HRMS(B)
    m/z 428.1608 Chiral RT = 4.25 min
    149: Second eluted product (49 mg): (CDCl3) δ 8.25 (d, J =
    5.7 Hz, 1H), 8.01-7.80 (m, 2H), 7.56 (d, J = 5.7 Hz, 1H),
    7.12 (t, J = 8.9 Hz, 1H), 5.76 (s, 1H), 5.46-5.12 (m, 1H),
    4.85 (ddd, J = 8.4, 4.6, 2.4 Hz, 1H), 4.55 (dd, J = 9.5, 2.5
    Hz, 1H), 4.40 (t, J = 8.9 Hz, 1H), 2.89 (s, 1H), 2.35 (d, J =
    2.0 Hz, 3H), 1.79 (d,J = 7.1 Hz, 3H), 1.43-1.13 (m, 2H),
    1.16-0.74 (m, 3H). HRMS(B) m/z 428.1608 Chiral RT =
    6.15 min
    150 and 151: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(3-(4-ethylphenyl)- chromatography (Column ID 21 × 250 mm 40% MeOH +
    1,2,4-oxadiazol-5- 10 mM NH4OH in CO2, flow 75 g/min, 238 nm UV
    yl)ethyl)amino)-5- collection) to give (R)-3-(2-(((R)-1-(3-(4-ethylphenyl)-1,2,4-
    fluoropyrimidin-4-yl)-4-((R)-1- oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-5-
    fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
    150: First eluted product (106 mg): (CDCl3) δ 8.24 (d, J =
    2.9 Hz, 1H), 7.99-7.87 (m, 2H), 7.38-7.22 (m, 2H), 5.96
    (d, J = 7.1 Hz, 1H), 5.31 (d, J = 9.1 Hz, 1H), 4.56-4.25 (m,
    4H), 3.49 (s, 4H), 3.30 (d, J = 13.4 Hz, 1H), 2.72 (q, J = 7.6
    Hz, 2H), 1.68 (s, 0H), 1.66-1.38 (m, 2H), 1.35-1.08 (m,
    7H). HRMS(B) m/z 442.1765 Chiral RT = 2.80 min
    151: Second eluted product (10.6 mg): (CDCl3) δ 8.27 (d, J =
    2.7 Hz, 2H), 8.05-7.87 (m, 4H), 7.39-7.23 (m, 4H),
    5.77 (d, J = 6.7 Hz, 2H), 5.30-5.17 (m, 2H), 4.73 (dt, J =
    10.7, 5.1 Hz, 2H), 4.54 (t, J = 9.1 Hz, 2H), 1.85-1.73 (m,
    6H), 4.44 (dd, J = 9.2, 5.6 Hz, 2H), 3.86-3.59 (m, 2H),
    3.51 (s, 2H), 2.72 (q, J = 7.6 Hz, 6H), 1.37-1.19 (m, 8H),
    1.01 (d, J = 6.9 Hz, 8H), 0.92-0.69 (m, 1H). HRMS(B) m/z
    442.1765 Chiral RT = 4.05 min
    152 and 153: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(5-(3,4- chromatography (Column IC 4.6 × 100 mm 5-55% IPA + 20
    dimethylphenyl)-1,3,4-oxadiazol- mM NH4OH/in CO2, flow 75 g/min, 238 nm UV collection)
    2-yl)ethyl)amino)pyrimidin-4-yl)- to give(R)-3-(2-(((S)-1-(5-(3,4-dimethylphenyl)-1,3,4-
    4-((R)-1-hydroxyethyl)oxazolidin- oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(5-(3,4-
    dimethylphenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-
    4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
    152: First eluted product (25 mg): (CDCl3) δ 8.22 (d, J =
    5.8 Hz, 1H), 7.84-7.79 (m, 1H), 7.75 (dd, J = 8.0, 1.8 Hz,
    1H), 7.48 (d, J = 5.7 Hz, 1H), 7.34-7.20 (m, 1H), 5.90 (d, J =
    4.6 Hz, 1H), 5.18 (s, 1H), 4.93-4.74 (m, 1H), 1.85-1.71
    (m, 3H), 4.61 (dd, J = 9.3, 2.2 Hz, 1H), 4.50-4.38 (m, 1H),
    4.33 (t, J = 8.8 Hz, 1H), 4.21 (s, 1H), 4.11-4.00 (m, 0H),
    2.34 (s, 6H), 1.22 (dd, J = 10.3, 6.3 Hz, 5H). HRMS(B) m/z
    425.1982. Chiral RT = 1.75 min
    153: Second eluted product (25 mg): (CDCl3) δ 8.23 (d, J =
    5.7 Hz, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.75 (dd, J = 7.8, 1.9
    Hz, 1H), 7.53 (d, J = 5.7 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H),
    5.67 (d, J = 6.0 Hz, 1H), 5.48-5.30 (m, 1H), 5.02-4.91
    (m, 1H), 4.62 (dd, J = 9.5, 2.3 Hz, 1H), 4.42 (dd, J = 9.4,
    8.3 Hz, 1H), 3.88 (s, 2H), 2.34 (s, 6H), 1.79 (d, J = 7.2 Hz,
    3H), 1.63 (s, 1H), 1.33-1.16 (m, 1H), 1.06 (d, J = 6.4 Hz,
    3H). HRMS(B) m/z 425.1981. Chiral RT = 2.15 min
    154 and 155: Chiral separation was achieved by chiral SFC column
    (4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column OJ-H 21 × 250 mm 20% MeOH + 5
    ((1-(3-(isoquinolin-8-yl)-1,2,4- mM NH4OH/CO2/in CO2, flow 75 g/min, 238 nm UV
    oxadiazol-5- collection) to give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-
    yl)ethyl)amino)pyrimidin-4- (isoquinolin-8-yl)-1,2,4-oxadiazol-5-
    yl)oxazolidin-2-one yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
    ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(isoquinolin-8-yl)-1,2,4-
    oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
    154: First eluted product (10 mg): (CDCl3) δ 8.47-8.11
    (m, 4H), 7.99 (d, J = 8.1 Hz, 2H), 7.83 (t, J = 7.9 Hz, 3H),
    7.57 (s, 4H), 5.94 (s, 2H), 5.47 (s, 2H), 4.95-4.65 (m, 2H),
    4.42 (d, J = 88.6 Hz, 6H), 3.52 (s, 5H), 2.09-1.51 (m, 1H),
    1.47-0.99 (m, 7H), 0.96-0.68 (m, 1H). HRMS(B) m/z
    447.1655. Chiral RT = 2.55 min
    155: Second eluted product (28.7 mg): (CDCl3) δ 10.26 (s,
    2H), 8.63 (s, 2H), 8.28 (d, J = 7.3 Hz, 4H), 7.97 (d, J = 8.2
    Hz, 2H), 7.77 (t, J = 7.8 Hz, 3H), 7.58 (d, J = 5.3 Hz, 2H),
    6.08 (s, 2H), 5.62 (p, J = 7.1 Hz, 2H), 5.11-4.84 (m, 2H),
    4.61 (dd, J = 8.8, 2.7 Hz, 2H), 4.41 (t, J = 8.9 Hz, 2H), 4.30
    (s, 2H), 3.89 (s, 2H), 3.63-3.43 (m, 8H), 1.73 (d, J = 33.4
    Hz, 0H), 1.32 (q, J = 5.2 Hz, 3H), 1.04 (d, J = 7.1 Hz, 6H).
    HRMS(B) m/z 447.1655. Chiral RT = 2.90 min
    156 and 157: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(3-(4-chloro-2- chromatography (Column IC 4.6 × 100 mm 5-55% IPA + 20
    (trifluoromethyl)phenyl)-1,2,4- mM NH4OH in CO2, flow 75 g/min, 238 nm UV collection)
    oxadiazol-5- to give(R)-3-(2-(((R)-1-(3-(4-chloro-2-
    yl)ethyl)amino)pyrimidin-4-yl)-4- (trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
    ((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    chloro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    156: First eluted product (50 mg): (CDCl3) δ 8.16 (d, J =
    5.9 Hz, 1H), 7.81-7.64 (m, 1H), 7.57 (dd, J = 8.3, 2.1 Hz,
    1H), 7.48 (d, J = 5.8 Hz, 1H), 6.50 (s, 1H), 5.35 (s, 1H),
    4.78 (ddd, J = 7.4, 4.6, 2.4 Hz, 1H), 4.45 (dd, J = 9.3, 2.5
    Hz, 1H), 4.31 (dd, J = 9.4, 8.3 Hz, 1H), 3.92 (d, J = 48.4 Hz,
    1H), 3.41 (s, 1H), 3.18-2.11 (m, 1H), 1.70 (d, J = 7.1 Hz,
    3H), 1.30-1.08 (m, 1H), 0.93 (d, J = 7.6 Hz, 3H).
    HRMS(B) m/z 498.1030. Chiral RT = 2.03 min
    157: Second eluted product (15 mg): (CDCl3) δ 8.15 (d, J =
    6.2 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 8.3 Hz,
    1H), 7.59 (dd, J = 8.4, 2.1 Hz, 1H), 7.47 (d, J = 5.6 Hz, 1H),
    5.96 (s, 1H), 5.17 (s, 1H), 4.73-4.47 (m, 1H), 4.40 (dd, J =
    9.2, 2.4 Hz, 1H), 4.21 (d, J = 37.9 Hz, 1H), 3.42 (s, 3H),
    1.60 (s, 3H), 1.33-0.99 (m, 1H), 0.92-0.64 (m, 1H).
    HRMS(B) m/z 498.1030. Chiral RT = 2.18 min
    158 and 159: Chiral separation was achieved by chiral SFC column
    (4R)-3-(5-fluoro-2-((1-(3-(4- chromatography (Column ID 21 × 250 mm 40% MeOH +
    isopropylphenyl)-1,2,4- 10 mM NH4OH in CO2, flow 75 g/min, 238 nm UV
    oxadiazol-5- collection) to give (R)-3-(5-fluoro-2-(((R)-1-(3-(4-
    yl)ethyl)amino)pyrimidin-4-yl)-4- isopropylphenyl)-1,2,4-oxadiazol-5-
    ((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one hydroxyethyl)oxazolidin-2-one and (R)-3-(5-fluoro-2-(((S)-1-
    (3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    158: First eluted product (51 mg): (CDCl3) δ 8.17 (d, J =
    2.7 Hz, 1H), 7.92-7.83 (m, 2H), 7.30-7.21 (m, 2H), 5.83
    (d, J = 6.5 Hz, 1H), 5.21 (dd, J = 13.8, 6.9 Hz, 1H), 4.77-
    4.57 (m, 1H), 4.46 (t, J = 9.1 Hz, 1H), 4.36 (dd, J = 9.2, 5.6
    Hz, 1H), 3.96 (p, J = 6.1 Hz, 1H), 3.63 (s, 1H), 2.88 (hept, J =
    7.0 Hz, 1H), 1.76-1.60 (m, 3H), 1.19 (d, J = 7.0 Hz,
    7H), 1.14 (d, J = 6.1 Hz, 4H), 0.93 (d, J = 7.0 Hz, 3H).
    HRMS(B) m/z 456.1921 Chiral RT = 2.60 min
    159: Second eluted product (54 mg): (CDCl3) δ 8.24 (d, J =
    3.0 Hz, 1H), 8.02-7.89 (m, 2H), 7.39-7.30 (m, 2H), 5.98
    (d, J = 7.2 Hz, 1H), 5.31 (d, J = 8.6 Hz, 1H), 4.52-4.27 (m,
    4H), 1.83-1.67 (m, 3H), 3.49 (s, 1H), 2.97 (hept, J = 6.9
    Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H), 1.21 (dd, J = 11.1, 6.2 Hz,
    5H). HRMS(B) m/z 456.1921. Chiral RT = 3.70 min
    160 and 161: Chiral separation was achieved by chiral SFC column
    (4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250 mm 25% IPA in
    ((1-(3-(3-(trifluoromethyl)phenyl)- CO2, flow 75 g/min, 238 nm UV collection) to give(R)-4-
    1,2,4-oxadiazol-5- ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(3-
    yl)ethyl)amino)pyrimidin-4- (trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
    yl)oxazolidin-2-one yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
    ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(3-
    (trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
    160: First eluted product (15 mg): (CDCl3) δ 8.27 (d, J =
    2.0 Hz, 1H), 8.16 (t, J = 7.3 Hz, 2H), 7.71 (d, J = 7.9 Hz,
    1H), 7.56 (t, J = 7.8 Hz, 1H), 1.74-1.56 (m, 3H), 7.50-
    7.37 (m, 1H), 6.06 (s, 1H), 5.26 (d, J = 47.9 Hz, 1H), 4.59
    (d, J = 9.5 Hz, 1H), 4.52-4.23 (m,2H), 1.14 (dd, J = 6.3,
    4.8 Hz, 5H), 1.03-0.88 (m, 2H), 0.88-0.71 (m, 0H), 4.85-
    4.72 (m, 0H), 4.16 (s, 1H), 3.97 (p, J = 6.1 Hz, 0H), 2.88
    (s, 1H), 2.34-1.77 (m, 1H). HRMS(B) m/z 464.1420.
    Chiral RT = 2.10 min
    161: Second eluted product (38.5 mg): (CDCl3) δ 8.36 (d, J =
    1.8 Hz, 1H), 8.31-8.19 (m, 2H), 7.87-7.76 (m, 1H),
    7.64 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 5.7 Hz, 1H), 6.04 (s,
    1H), 5.42 (s, 1H), 4.87 (ddd, J = 8.4, 4.7, 2.5 Hz, 1H), 4.55
    (dd, J = 9.5, 2.5 Hz, 1H), 4.41 (dd, J = 9.5, 8.3 Hz, 1H),
    4.11-3.72 (m, 1H), 2.83 (s, 1H), 2.13-1.57 (m, 1H), 1.23
    (d, J = 6.1 Hz, 2H), 1.05 (d, J = 9.5 Hz, 3H). HRMS(B) m/z
    464.1420 Chiral RT = 2.55 min
    162 and 163: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(3-(4-fluoro-3- chromatography (Column AD-H 21 × 250 mm 10% MeOH in
    (trifluoromethoxy)phenyl)-1,2,4- CO2, flow 80 g/min, 238 nm UV collection) to give (R)-3-(2-
    oxadiazol-5- (((R)-1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-
    yl)ethyl)amino)pyrimidin-4-yl)-4- oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    ((R)-1-hydroxyethyl)oxazolidin-2- hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    one fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    162: First eluted product (13 mg): CDCl3) δ 8.24 (d, J = 5.9
    Hz, 1H), 8.04 (ddt, J = 13.4, 6.5, 1.9 Hz, 2H), 7.55 (d, J =
    5.7 Hz, 1H), 7.35 (t, J = 9.0 Hz, 1H), 6.08 (s, 1H), 5.27 (s,
    1H), 4.78-4.58 (m, 1H), 4.52 (dd, J = 9.3, 2.5 Hz, 1H),
    4.44 (d, J = 15.7 Hz, 1H), 4.25 (d, J = 11.2 Hz, 1H), 3.51 (s,
    2H), 2.97 (s, 1H), 1.98-1.67 (m, 0H), 1.22 (d, J = 6.5 Hz,
    4H). HRMS(B) m/z 498.1275 Chiral RT = 3.60 min
    163: Second eluted product (40 mg): (CDCl3) δ 8.25 (d, J =
    6.2 Hz, 1H), 8.13-7.98 (m, 2H), 7.57 (d, J = 5.6 Hz, 1H),
    7.35 (dd, J = 9.4, 8.6 Hz, 1H), 5.77 (s, 1H), 5.40 (s, 1H),
    4.85 (ddd, J = 8.2, 4.7, 2.5 Hz, 1H), 4.54 (dd, J = 9.4, 2.5
    Hz, 1H), 4.41 (dd, J = 9.4, 8.3 Hz, 1H), 3.87 (t, J = 65.5 Hz,
    1H), 3.52 (s, 1H), 2.76 (s, 1H), 1.79 (d, J = 7.1 Hz, 3H),
    1.34-1.25 (m, 1H), 1.05 (s, 3H).). HRMS(B) m/z 498.1275
    Chiral RT = 4.80 min
    164 and 165: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(3-(3- chromatography (Column AD-H 21 × 250 mm 35% IPA in
    (difluoromethoxy)phenyl)-1,2,4- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-3-(2-
    oxadiazol-5- (((R)-1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    ((R)-1-hydroxyethyl)oxazolidin-2- hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(3-
    one (difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    164: First eluted product (18 mg): (CDCl3) δ 8.25 (d, J =
    5.8 Hz, 1H), 7.92 (dt, J = 7.7, 1.4 Hz, 1H), 7.83 (t, J = 2.0
    Hz, 1H), 7.62-7.43 (m, 2H), 7.36-7.24 (m, 1H), 6.61 (t, J =
    73.3 Hz, 1H), 6.25 (d, J = 59.0 Hz, 1H), 5.36 (d, J = 30.2
    Hz, 1H), 4.86 (ddd, J = 8.5, 4.8, 2.5 Hz, 1H), 4.55 (dd, J =
    9.3, 2.5 Hz, 1H), 4.40 (t, J = 8.9 Hz, 1H), 3.51 (s, 2H), 1.83
    (s, 1H), 1.34-1.16 (m, 1H), 1.02 (s, 3H). HRMS(B) m/z
    462.1463 Chiral RT = 1.65 min
    165: Second eluted product (63 mg): (CDCl3) δ 8.25 (d, J =
    5.8 Hz, 1H), 7.92 (dt, J = 7.7, 1.4 Hz, 1H), 7.83 (t, J = 2.0
    Hz, 1H), 7.62-7.43 (m, 2H), 7.36-7.24 (m, 1H), 6.61 (t, J =
    73.3 Hz, 1H), 6.25 (d, J = 59.0 Hz, 1H), 5.36 (d, J = 30.2
    Hz, 1H), 4.86 (ddd, J = 8.5, 4.8, 2.5 Hz, 1H), 4.55 (dd, J =
    9.3, 2.5 Hz, 1H), 4.40 (t, J = 8.9 Hz, 1H), 3.51 (s, 2H), 1.83
    (s, 1H), 1.34-1.16 (m, 1H), 1.02 (s, 3H). HRMS(B) m/z
    462.1463 Chiral RT = 2.10 min
    166 and 167: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(3-(4-chloro-3- chromatography (Column AD-H 21 × 250 mm 30% MeOH in
    methoxyphenyl)-1,2,4-oxadiazol- CO2, flow 80 g/min, 238 nm UV collection) to give (R)-3-(2-
    5-yl)ethyl)amino)pyrimidin-4-yl)- (((R)-1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5-
    4-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    166: First eluted product (10 mg): (CDCl3) δ 8.38-8.18
    (m, 1H), 7.61 (hept, J = 2.3, 1.9 Hz, 2H), 7.57-7.45 (m,
    2H), 5.89 (s, 1H), 5.33 (s, 2H), 4.70 (s, 1H), 4.50 (dd, J =
    9.4, 2.4 Hz, 1H), 4.00 (s, 2H), 3.07 (s, 1H), 1.75 (s, 2H),
    1.34-1.11 (m, 6H). HRMS(B) m/z 461.1464. RT = 2.24
    min. Chiral RT = 2.85 min
    167: Second eluted product (120 mg): (CDCl3) δ 8.25 (d, J =
    5.8 Hz, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 5.7 Hz,
    1H), 7.52-7.46 (m, 1H), 5.74 (s, 1H), 5.35 (d, J = 20.7 Hz,
    1H), 4.85 (ddd, J = 8.3, 4.7, 2.4 Hz, 1H), 4.54 (dd, J = 9.5,
    2.5 Hz, 1H), 4.40 (dd, J = 9.4, 8.3 Hz, 1H), 4.01 (s, 3H),
    3.52 (s, 3H), 2.85 (s, 1H), 1.88-1.76 (m, 2H), 1.67 (s, 1H),
    1.23 (d, J = 6.1 Hz, 1H), 1.03 (s, 3H). HRMS(B) m/z
    461.1464. RT = 2.23 min. Chiral RT = 3.55 min
    168 and 169: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(3-(2,2- chromatography (Column AD-H 21 × 250 mm 35% IPA in
    difluorobenzo[d][1,3]dioxol-5-yl)- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-3-(2-
    1,2,4-oxadiazol-5- (((R)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-
    yl)ethyl)amino)pyrimidin-4-yl)-4- oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    ((R)-1-hydroxyethyl)oxazolidin-2- hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(2,2-
    one difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    168: First eluted product (14 mg): (CDCl3) δ 8.23 (d, J =
    6.2 Hz, 1H), 7.86 (dd, J = 8.2, 1.8 Hz, 1H), 7.78 (d, J = 1.7
    Hz, 1H), 7.55 (d, J = 5.7 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H),
    6.46 (s, 1H), 5.29 (d, J = 27.6 Hz, 1H), 4.90-4.58 (m, 1H),
    4.52 (dd, J = 9.4, 2.5 Hz, 1H), 4.46-4.17 (m, 2H), 3.51 (s,
    1H), 2.93 (s, 2H), 1.22 (dd, J = 8.8, 6.2 Hz, 4H). HRMS(B)
    m/z 476.1256. RT = 2.42 min. Chiral RT = 1.65 min
    169: Second eluted product (62 mg): (CDCl3) δ 8.15 (d, J =
    5.8 Hz, 1H), 7.79 (dd, J = 8.3, 1.7 Hz, 1H), 7.69 (d, J = 1.7
    Hz, 1H), 7.47 (d, J = 5.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H),
    6.38 (s, 1H), 5.26 (d, J = 24.5 Hz, 1H), 4.76 (ddd, J = 8.5,
    4.6, 2.4 Hz, 1H), 4.46 (dd, J = 9.3, 2.5 Hz, 1H), 4.32 (t, J =
    8.9 Hz, 1H), 4.06-3.60 (m, 1H), 3.42 (s, 2H), 1.86 (d, J =
    7.1 Hz, 3H), 1.14 (d, J = 6.1 Hz, 1H), 1.04-0.72 (m, 3H).
    HRMS(B) m/z 476.1256. RT = 2.43 min. Chiral RT = 1.95
    min
    170 and 171: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(3-(4-chloro-3- chromatography (Column AD-H 21 × 250 mm 20% MeOH in
    (trifluoromethyl)phenyl)-1,2,4- CO2, flow 80 g/min, 238 nm UV collection) to give (R)-3-(2-
    oxadiazol-5- (((R)-1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4-
    yl)ethyl)amino)pyrimidin-4-yl)-4- oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    ((R)-1-hydroxyethyl)oxazolidin-2- hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    one chloro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    170: First eluted product (23 mg): (CDCl3) δ 8.42 (d, J =
    2.0 Hz, 1H), 8.25 (d, J = 5.9 Hz, 1H), 8.18 (dd, J = 8.4, 2.1
    Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 5.7 Hz, 1H),
    5.81 (s, 1H), 5.33 (s, 2H), 4.66 (s, 1H), 4.52 (dd, J = 9.3,
    2.5 Hz, 1H), 4.46-4.14 (m, 2H), 2.84 (s, 1H), 1.79 (d, J =
    7.0 Hz, 3H), 1.23 (d, J = 6.5 Hz, 4H). HRMS(B) m/z
    498.1030. RT = 2.57 min. Chiral RT = 2.70 min
    171: Second eluted product (83 mg): (CDCl3) δ 8.42 (d, J =
    2.0 Hz, 1H), 8.31-8.12 (m, 2H), 7.62 (dd, J = 26.0, 7.1 Hz,
    2H), 1.92-1.70 (m, 3H), 6.31 (s, 1H), 5.32 (s, 2H), 4.86
    (ddd, J = 8.3, 4.8, 2.4 Hz, 1H), 4.54 (dd, J = 9.3, 2.5 Hz,
    1H), 4.42 (dd, J = 9.4, 8.3 Hz, 1H), 4.13-3.77 (m, 1H),
    2.71 (s, 2H), 1.44-0.84 (m, 4H). HRMS(B) m/z 498.1030.
    RT = 2.57 min. Chiral RT = 3.60 min
    172 and 173: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(3-(4-ethylphenyl)- chromatography (Column IA 21 × 250 mm 40% IPA + 10 mM
    1,2,4-oxadiazol-5- NH4OH in CO2, flow 75 g/min, 238 nm UV collection) to
    yl)ethyl)amino)pyrimidin-4-yl)-4- give (R)-3-(2-(((R)-1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-
    ((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
    172: First eluted product (73 mg): (CDCl3) δ 8.24 (d, J =
    5.8 Hz, 1H), 8.05-7.87 (m, 2H), 7.50 (d, J = 5.8 Hz, 1H),
    7.41-7.30 (m, 2H), 5.98 (s, 1H), 1.57-1.47 (m, 0H), 5.22
    (s, 1H), 4.71 (s, 1H), 4.13-4.00 (m, 0H), 4.48 (dd, J = 9.5,
    2.4 Hz, 1H), 4.33 (s, 1H), 4.18 (s, 1H), 3.51 (d, J = 5.3 Hz,
    0H), 3.30 (s, 1H), 2.73 (q, J = 7.6 Hz, 2H), 1.78 (d, J = 7.1
    Hz, 3H), 1.39-1.08 (m, 7H). HRMS(B) m/z 424.1859. RT =
    2.39 min. Chiral RT = 2.15 min
    173: Second eluted product (17 mg): (CDCl3) δ 8.25 (d, J =
    5.8 Hz, 2H), 8.04-7.89 (m, 4H), 7.54 (d, J = 5.8 Hz, 2H),
    7.39-7.29 (m, 4H), 5.97 (s, 2H), 5.53-5.22 (m, 2H), 4.85
    (ddd, J = 8.2, 4.4, 2.4 Hz, 2H), 4.55 (dd, J = 9.3, 2.5 Hz,
    2H), 4.39 (dd, J = 9.4, 8.3 Hz, 2H), 4.12-3.97 (m, 0H),
    3.76 (d, J = 62.5 Hz, 2H), 3.51 (s, 2H), 3.03 (s, 2H), 2.72 (q,
    J = 7.6 Hz, 4H), 1.98-1.71 (m, 1H), 1.45-1.13 (m, 10H),
    1.12-0.80 (m, 7H). HRMS(B) m/z 424.1859. RT = 2.40
    min. Chiral RT = 3.25 min
    174 and 175: Chiral separation was achieved by chiral SFC column
    (4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250 mm 25% IPA in
    ((1-(3-(4-(trifluoromethyl)phenyl)- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-4-
    1,2,4-oxadiazol-5- ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(4-
    yl)ethyl)amino)pyrimidin-4- (trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
    yl)oxazolidin-2-one yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
    ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-
    (trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
    174: First eluted product (55 mg): (CDCl3) δ 8.30-8.14
    (m, 3H), 7.76 (dd, J = 8.7, 2.5 Hz, 2H), 7.55 (dd, J = 12.4,
    5.8 Hz, 1H), 6.61 (s, 1H), 5.32 (s, 1H), 4.77-4.62 (m, 1H),
    4.62-4.46 (m, 1H), 4.40 (t, J = 8.8 Hz, 1H), 4.24 (t, J = 9.0
    Hz, 1H), 3.51 (s, 1H), 1.81 (s, 2H), 1.22 (dd, J = 9.6, 6.3
    Hz, 4H). HRMS(B) m/z 464.1420. RT = 2.43 min. Chiral RT =
    2.55 min
    175: Second eluted product (51 mg): (CDCl3) δ 8.22 (dd, J =
    21.0, 7.0 Hz, 3H), 7.75 (d, J = 8.1 Hz, 2H), 7.56 (d, J =
    5.8 Hz, 1H), 6.47 (s, 1H), 5.37 (d, J = 39.2 Hz, 1H), 4.86
    (ddd, J = 8.7, 4.7, 2.5 Hz, 1H), 4.55 (dd, J = 9.3, 2.5 Hz,
    1H), 4.40 (t, J = 8.9 Hz, 1H), 4.19-3.70 (m, 1H), 3.50 (s,
    1H), 2.01-1.70 (m, 0H), 1.23 (d, J = 6.1 Hz, 1H), 1.01 (s,
    3H). HRMS(B) m/z 464.1420. RT = 2.44 min. Chiral RT =
    3.25 min
    176 and 177: Chiral separation was achieved by chiral SFC column
    (4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250 mm 15% IPA in
    ((1-(3-phenethyl-1,2,4-oxadiazol- CO2, flow 80 g/min, 238 nm UV collection) to give (R)-4-
    5-yl)ethyl)amino)pyrimidin-4- ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-phenethyl-1,2,4-
    yl)oxazolidin-2-one oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
    and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-phenethyl-
    1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-
    2-one
    176: First eluted product (17 mg): (CDCl3) δ 8.25 (d, J =
    6.2 Hz, 1H), 7.54 (d, J = 5.5 Hz, 1H), 7.36-7.07 (m, 5H),
    5.83 (s, 1H), 5.10 (s, 1H), 4.67 (d, J = 7.6 Hz, 1H), 4.57-
    4.41 (m, 1H), 4.10 (d,J = 38.8 Hz, 2H), 3.36-3.14 (m,
    1H), 3.07 (d, J = 2.1 Hz, 4H), 1.94-1.67 (m, 1H), 1.28 (d, J =
    3.8 Hz, 1H), 1.18 (d, J = 6.5 Hz, 3H). HRMS(B) m/z
    424.1859. RT = 2.24 min. Chiral RT = 4.50 min
    177: Second eluted product (19 mg): (CDCl3) δ 8.25 (d, J =
    5.9 Hz, 1H), 7.56 (d, J = 5.7 Hz, 1H), 7.38-7.08 (m, 5H),
    6.03 (s, 1H), 5.31 (d, J = 11.3 Hz, 1H), 4.84 (ddd, J = 8.3,
    4.5, 2.3 Hz, 1H), 4.56 (dd, J = 9.3, 2.5 Hz, 1H), 4.40 (dd, J =
    9.3, 8.3 Hz, 1H), 3.91-3.62 (m, 1H), 3.51 (s, 2H), 3.36-
    3.10 (m, 1H), 3.06 (s, 4H), 1.72 (d, J = 7.0 Hz, 3H), 1.59-
    1.35 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H).). HRMS(B) m/z
    424.1859. RT = 2.30 min. Chiral RT = 5.90 min
    178 and 179: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(3-(4-chloro-3- chromatography (Column AD-H 21 × 250 mm 20% IPA in
    (trifluoromethoxy)phenyl)-1,2,4- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-3-(2-
    oxadiazol-5-yl)ethyl)amino)-5- (((R)-1-(3-(4-chloro-3-(trifluoromethoxy)phenyl)-1,2,4-
    fluoropyrimidin-4-yl)-4-((R)-1- oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    chloro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    178: First eluted product (49 mg): (CDCl3) δ 8.26 (d, J = 2.8
    Hz, 1H), 8.05 (p, J = 1.4 Hz, 1H), 8.03-7.92 (m, 1H), 7.62
    (d, J = 8.4 Hz, 1H), 5.73 (d, J = 7.6 Hz, 1H), 5.44-5.25 (m,
    1H), 4.60-4.40 (m, 3H), 4.32 (p, J = 5.7, 5.3 Hz, 1H), 2.81-
    1.89 (m, 2H), 1.80 (s, 3H), 1.22 (d, J = 6.3 Hz, 3H).).
    HRMS(B) m/z 533.1171. RT = 2.64 min. Chiral RT = 3.05
    min
    179: Second eluted product (81 mg): (CDCl3) δ 8.27 (d, J =
    2.7 Hz, 1H), 8.04 (p, J = 1.4 Hz, 1H), 7.97 (dd, J = 8.4, 1.9
    Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 5.68 (t, J = 4.0 Hz, 1H),
    5.33 (s, 1H), 4.68 (dt, J = 10.9, 4.6 Hz, 1H), 4.56 (t, J = 9.0
    Hz, 1H), 4.44 (dd, J = 9.2, 5.3 Hz, 1H), 3.85 (s, 1H), 1.95
    (d, J = 7.0 Hz, 2H), 1.84-1.73 (m, 3H), 1.36-1.19 (m,
    1H), 1.08 (s, 3H). HRMS(B) m/z 533.1173. RT = 2.64 min.
    Chiral RT = 3.75 min
    180 and 181: Chiral separation was achieved by chiral SFC column
    (4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250 mm 25% IPA in
    ((1-(3-(4- CO2, flow 80 g/min, 238 nm UV collection) to (R)-4-((R)-1-
    (trifluoromethoxy)phenyl)-1,2,4- hydroxyethyl)-3-(2-(((R)-1-(3-(4-(trifluoromethoxy)phenyl)-
    oxadiazol-5- 1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-
    yl)ethyl)amino)pyrimidin-4- 2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-
    yl)oxazolidin-2-one (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
    180: First eluted product (19 mg): (CDCl3) δ 8.24 (d, J =
    5.8 Hz, 1H), 8.16-8.06 (m, 2H), 7.53 (d, J = 5.8 Hz, 1H),
    7.34 (d, J = 8.3 Hz, 2H), 6.24 (s, 1H), 5.29 (d, J = 24.7 Hz,
    1H), 4.81-4.61 (m, 1H), 1.85-1.74 (m, 3H), 4.51 (dd, J =
    9.4, 2.4 Hz, 1H), 4.46-4.32 (m, 1H), 4.31-4.13 (m, 1H),
    3.51 (s, 1H), 3.25 (d, J = 66.2 Hz, 1H), 1.22 (dd, J = 8.9, 6.3
    Hz, 4H). HRMS(B) m/z 480.1369. RT = 2.50 min. Chiral
    RT = 2.20 min
    181: Second eluted product (44 mg): (CDCl3) δ 8.25 (d, J =
    5.8 Hz, 1H), 8.17-8.05 (m, 2H), 7.55 (d, J = 5.7 Hz, 1H),
    7.33 (d, J = 8.3 Hz, 2H), 6.41 (s, 1H), 5.35 (d, J = 27.1 Hz,
    1H), 4.96-4.77 (m, 1H), 4.55 (dd, J = 9.3, 2.5 Hz, 1H),
    4.40 (t, J = 8.9 Hz, 1H), 4.16-3.55 (m, 1H), 3.03 (s, 1H),
    1.78 (d, J = 7.1 Hz, 3H), 1.23 (d, J = 6.1 Hz, 1H), 1.01 (s,
    3H). HRMS(B) m/z 480.1369. RT = 2.51 min. Chiral RT =
    2.45 min
    182 and 183: Chiral separation was achieved by chiral SFC column
    (4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250 mm 30% IPA in
    ((1-(3-(3-(2,2,2- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-4-
    trifluoroethoxy)phenyl)-1,2,4- ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(3-(2,2,2-
    oxadiazol-5- trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4- yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
    yl)oxazolidin-2-one ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(3-(2,2,2-
    trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
    182: First eluted product (13.8 mg): (CDCl3) δ 8.14 (d, J =
    5.9 Hz, 1H), 7.67 (t, J = 6.8 Hz, 1H), 7.60-7.52 (m, 1H),
    7.46 (dd, J = 14.2, 5.8 Hz, 1H), 7.37 (td, J = 8.0, 2.8 Hz,
    1H), 7.05 (dd, J = 8.2, 2.7 Hz, 1H), 4.71-4.51 (m, 1H),
    4.51-4.23 (m, 4H), 4.23-4.04 (m, 1H), 3.97 (hept, J = 6.1
    Hz, 1H), 1.64 (d, J = 1.5 Hz, 3H), 1.13 (dd, J = 10.4, 6.3 Hz,
    6H). HRMS(B) m/z 494.1526. RT = 2.38 min. Chiral RT =
    1.95 min
    183: Second eluted product (65 mg): (CDCl3) δ 8.25 (d, J =
    5.8 Hz, 1H), 7.77 (dt, J = 7.7, 1.2 Hz, 1H), 7.63 (dd, J = 2.7,
    1.4 Hz, 1H), 7.56 (d, J = 5.7 Hz, 1H), 7.45 (t, J = 8.0 Hz,
    1H), 7.14 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 6.06 (s, 1H), 5.35
    (d, J = 24.3 Hz, 1H), 4.85 (ddd, J = 8.3, 4.5, 2.5 Hz, 1H),
    4.55 (dd, J = 9.3, 2.5 Hz, 1H), 4.51-4.34 (m, 4H), 4.05
    (hept, J = 6.1 Hz, 1H), 3.89 (s, 1H), 2.96 (s, 1H), 1.84-
    1.75 (m, 3H), 1.23 (d, J = 6.2 Hz, 6H), 1.02 (s, 3H).
    HRMS(B) m/z 494.1526. RT = 2.39 min. Chiral RT = 2.45
    min
    184 and 185: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(5-(4- chromatography (Column AD-H 21 × 250 mm 20% MeOH in
    chlorophenyl)-4-methyloxazol-2- CO2, flow 80 g/min, 238 nm UV collection) to give (R)-3-(2-
    yl)ethyl)amino)pyrimidin-4-yl)-4- (((R)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-
    ((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-
    chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
    184: First eluted product (48 mg): (CDCl3) δ 8.21 (d, J =
    5.7 Hz, 1H), 7.58-7.35 (m, 5H), 5.94 (s, 1H), 4.62 (dd, J =
    9.2, 2.5 Hz, 1H), 4.55-4.42 (m, 1H), 1.74-1.65 (m, 3H),
    4.32 (t, J = 8.9 Hz, 1H), 3.51 (s, 2H), 2.38 (s, 3H), 2.27-
    1.93 (m, 1H), 1.22 (d, J = 6.6 Hz, 3H). HRMS(B) m/z
    443.1360. RT = 2.51 min. Chiral RT = 2.90 min
    185: Second eluted product (31 mg): (CDCl3) δ 7.61-7.47
    (m, 3H), 7.45-7.35 (m, 2H), 5.84 (s, 1H), 5.31 (d, J = 10.0
    Hz, 1H), 4.94 (s, 1H), 4.58 (d, J = 9.8 Hz, 2H), 1.78-1.66
    (m, 3H), 4.44 (t, J = 8.8 Hz, 1H), 4.22 (s, 1H), 3.52 (s, 2H),
    2.38 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H). HRMS(B) m/z
    443.1360. RT = 2.52 min. Chiral RT = 4.00 min
    186 and 187: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(5-(4- chromatography (Column AD-H 21 × 250 mm 30% IPA in
    chlorophenyl)-4-methyloxazol-2- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-3-(2-
    yl)ethyl)amino)-5- (((R)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-
    fluoropyrimidin-4-yl)-4-((R)-1- yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-
    chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-
    fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
    186: First eluted product (114 mg): (MeOD) δ 8.14 (dd, J =
    111.8, 3.1 Hz, 1H), 7.64-7.53 (m, 2H), 7.53-7.42 (m,
    2H), 5.35-5.18 (m, 1H), 5.18-5.05 (m, 1H), 4.80-4.70
    (m, 1H), 4.55-4.45 (m, 2H), 4.17 (td, J = 6.7, 3.9 Hz, 1H),
    4.07 (dt, J = 8.9, 5.4 Hz, 1H), 2.38 (d, J = 1.9 Hz, 3H), 1.67
    (dd, J = 7.1, 5.4 Hz, 3H), 1.14 (dd, J = 27.1, 6.3 Hz, 3H).
    HRMS(B) m/z 461.1266. RT = 2.29 min. Chiral RT = 3.60
    min
    187: Second eluted product (14 mg): (MeOD) δ 8.14 (dd, J =
    115.3, 3.2 Hz, 1H), 7.59 (ddt, J = 6.7, 4.3, 2.1 Hz, 2H),
    7.53-7.42 (m, 2H), 5.14 (dq, J = 30.9, 6.9 Hz, 1H), 4.71
    (dt, J = 9.6, 4.6 Hz, 1H), 4.39 (q, J = 7.4, 5.0 Hz, 1H), 3.98
    (ddt, J = 28.7, 12.3, 5.6 Hz, 2H), 2.37 (d, J = 2.3 Hz, 3H),
    1.67 (dd, J = 7.1, 4.0 Hz, 3H), 1.32 (d, J = 6.5 Hz, 2H), 1.17
    (d, J = 6.1 Hz, 2H), 1.08-0.76 (m, 2H). HRMS(B) m/z
    461.1266. RT = 2.37 min. Chiral RT = 6.05 min
    188 and 189: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(4-(4- chromatography (Column ID 21 × 250 mm 25% MeOH 10
    chlorophenyl)-5-methylthiazol-2- mM NH4OH in CO2, flow 75 g/min, 230 nm UV collection)
    yl)ethyl)amino)-5- to give (R)-3-(2-(((R)-1-(4-(4-chlorophenyl)-5-methylthiazol-
    fluoropyrimidin-4-yl)-4-((R)-1- 2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(4-(4-
    chlorophenyl)-5-methylthiazol-2-yl)ethyl)amino)-5-
    fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
    188: First eluted product (61.8 mg): 1H NMR (400 MHz,
    CDCl3) δ 8.24 (d, J = 3.2 Hz, 1H), 7.64-7.53 (m, 2H), 7.49-
    7.38 (m, 2H), 5.75 (d, J = 6.1 Hz, 1H), 5.22 (s, 1H), 4.54-
    4.24 (m, 4H), 3.49 (s, 2H), 2.52 (s, 3H), 1.17 (d, J = 6.4 Hz,
    3H). HRMS(E) m/z 478.1114 (M + H). RT = 5.98 min. Chiral
    RT = 3.90 min.
    189: Second eluted product (82 mg): 1H NMR (400 MHz,
    CDCl3) δ 8.32-7.93 (m, 1H), 7.68-7.52 (m, 2H), 7.43
    (dd, J = 8.6, 2.5 Hz, 2H), 5.75 (d, J = 6.8 Hz, 1H), 5.35-
    5.21 (m, 1H), 4.58 (dt, J = 8.6, 5.3 Hz, 1H), 1.77-1.64 (m,
    3H), 4.53-4.43 (m, 1H), 4.38 (dd, J = 9.0, 5.0 Hz, 1H),
    3.96 (d, J = 11.1 Hz, 1H), 3.50 (s, 2H), 2.52 (d, J = 6.1 Hz,
    3H), 1.04 (d, J = 49.6 Hz, 3H). HRMS(B) m/z 477.1038. RT =
    2.48 min. Chiral RT = 5.80 min.
    190 and 191: Chiral separation was achieved by chiral SFC column
    (4R)-3-(2-((1-(4-(4- chromatography (Column ID 21 × 250 mm 30% MeOH 10
    bromophenyl)thiazol-2- mM NH4OH in CO2, flow 75 g/min, 230 nm UV collection)
    yl)ethyl)amino)-5- to give (R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-
    fluoropyrimidin-4-yl)-4-((R)-1- yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(4-(4-
    bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
    190: First eluted product (63.7 mg): 1H NMR (400 MHz,
    CDCl3) δ 8.26 (d, J = 3.0 Hz, 1H), 7.86-7.71 (m, 2H), 7.62-
    7.50 (m, 2H), 7.41 (s, 1H), 5.80 (d, J = 6.7 Hz, 1H), 1.83-
    1.68 (m, 3H), 5.33 (t, J = 5.2 Hz, 1H), 4.38 (t, J = 13.2 Hz,
    4H), 3.51 (s, 1H), 1.20 (d, J = 6.2 Hz, 3H). HRMS(E) m/z
    510.0447 (M + H). RT = 5.95 min. Chiral RT = 3.30 min.
    191: Second eluted product (77.1): 1H NMR (400 MHz,
    CDCl3) δ 8.13 (dd, J = 109.6, 2.8 Hz, 1H), 7.78 (dd, J = 8.6,
    2.1 Hz, 2H), 7.57 (dd, J = 8.8, 2.3 Hz, 2H), 7.40 (s, 1H),
    5.78 (d, J = 6.5 Hz, 1H), 1.82-1.67 (m, 3H), 5.46-5.24
    (m, 1H), 4.64-4.26 (m, 2H), 4.05-3.74 (m, 1H), 3.51 (s,
    1H), 0.96 (s, 3H). HRMS(E) m/z 510.0445 (M + H). RT =
    5.91 min. Chiral RT = 5.40 min.
    192 and 193: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-((1-(5-(3,4- chromatography (Column IC 21 × 250 mm, 45% MeOH in
    dichlorophenyl)pyrimidin-2- CO2, flow 75 g/min, 220 nm UV collection) to give (R)-3-(2-
    yl)ethyl)amino)-5- (((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-
    fluoropyrimidin-4-yl)-4-((R)-1- fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
    hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-
    yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one.
    192: First eluted product (49 mg 1H NMR (400 MHz,
    CDCl3) δ 8.88 (s, 2H), 8.24 (d, J = 2.8 Hz, 1H), 7.76-7.51
    (m, 2H), 7.48-7.35 (m, 1H), 6.17 (d, J = 7.9 Hz, 1H), 5.30
    (tt, J = 12.5, 5.8 Hz, 1H), 4.69-4.47 (m, 2H), 4.41 (dd, J =
    8.9, 5.1 Hz, 1H), 4.09 (br s, 1H), 1.69-1.65 (m, 3H), 1.15
    (d, J = 6.2 Hz, 3H). HRMS(B) m/z 493.0948 (M + H)+.
    193: Second eluted product (40 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.89 (d, J = 1.6 Hz, 2H), 8.25 (d, J = 2.9 Hz, 1H),
    7.76-7.53 (m, 2H), 7.43 (ddd, J = 8.3, 3.9, 2.2 Hz, 1H),
    6.24 (d, J = 7.5 Hz, 1H), 5.26 (br s, 1H), 4.60-4.36 (m,
    4H), 1.64 (d, J = 4.8 Hz, 2H), 1.29-1.25 (m, 3H). HRMS(B)
    m/z 493.0949 (M + H)+.
    194 and 195: Chiral separation was achieved by chiral SFC column
    (R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column IA 21 × 250 mm, 35% IPA 10 mM
    ((1-(5-(3-methyl-4- NH4OH in CO2, flow 75 g/min, 235 nm UV collection) to
    (trifluoromethyl)phenyl)pyrimidin- give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-methyl-4-
    2-yl)ethyl)amino)pyrimidin-4- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
    yl)oxazolidin-2-one 4-yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-
    (((R)-1-(5-(3-methyl-4-(trifluoromethyl)phenyl)pyrimidin-2-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one.
    194: First eluted product (15 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.95 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H), 7.77 (d, J =
    8.5 Hz, 1H), 7.54-7.42 (m, 4H), 6.07 (d, J = 8.2 Hz, 1H),
    5.45-5.36 (m, 1H), 4.89 (s, 1H), 4.52 (dd, J = 9.5, 2.6 Hz,
    1H), 4.42 (dd, J = 9.4, 8.3 Hz, 1H), 3.36 (br s, 1H), 2.60
    (dq, J = 3.7, 1.7 Hz, 3H), 1.71-1.60 (m, 3H), 1.11 (br s,
    3H). HRMS(D) m/z 489.1850 (M + H)+.
    195: Second eluted product (11 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.94 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H), 7.81-7.74
    (m, 1H), 7.49 (d, J = 6.9 Hz, 1H), 7.42 (d, J = 5.7 Hz, 1H),
    6.02 (br s, 1H), 5.18 (br s, 1H), 4.80 (br s, 1H), 4.53 (d, J =
    8.8 Hz, 1H), 4.30 (br s, 2H), 3.71 (br s, 1H), 2.60 (q, J = 1.8
    Hz, 3H), 1.69-1.65 (m, 3H), 1.25-1.19 (m, 3H). HRMS(D)
    m/z 489.1862 (M + H)+.
    196 and 197: Chiral separation was achieved by chiral SFC column
    (R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column IC 21 × 250 mm, 30% IPA 10 mM
    ((1-(4-methyl-5-(2-(1,1,1- NH4OH in CO2, flow 75 g/min, 227 nm UV collection) to
    trifluoro-2-methylpropan-2- give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-5-(2-
    yl)pyridin-4-yl)thiazol-2- (1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-
    yl)ethyl)amino)pyrimidin-4- yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
    yl)oxazolidin-2-one ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(4-methyl-5-(2-(1,1,1-
    trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one.
    198: First eluted product (50 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.65 (dd, J = 5.1, 0.8 Hz, 1H), 8.26 (d, J = 5.8 Hz,
    1H), 7.59-7.49 (m, 2H), 7.24 (dd, J = 5.2, 1.6 Hz, 1H),
    5.63 (d, J = 6.4 Hz, 1H), 5.38 (s, 1H), 4.80 (ddd, J = 8.3,
    4.5, 2.5 Hz, 1H), 4.51 (dd, J = 9.4, 2.5 Hz, 1H), 4.40 (dd, J =
    9.4, 8.3 Hz, 1H), 3.93 (br s, 1H), 2.79 (br s, 1H), 2.54 (s,
    3H), 1.73 (d, J = 7.0 Hz, 3H), 1.67 (s, 6H), 1.05 (d, J = 6.9
    Hz, 3H). HRMS(D) m/z 537.1898 (M + H)+.
    199: Second eluted product (50 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.65 (dd, J = 5.2, 0.8 Hz, 1H), 8.25 (d, J = 5.8 Hz,
    1H), 7.59-7.46 (m, 2H), 7.26 (dd, J = 5.1, 1.6 Hz, 1H),
    5.69 (s, 1H), 5.13 (br s, 1H), 4.82 (br s, 1H), 4.58 (d, J = 6.7
    Hz, 1H), 4.31 (t, J = 8.4 Hz, 2H), 4.15 (br s, 1H), 2.53 (s,
    3H), 1.76-1.65 (m, 9H), 1.25-1.18 (m, 3H). HRMS(D)
    m/z 537.1900(M + H)+.
    198 and 199: Chiral separation was achieved by chiral SFC column
    (4R)-3-(5-fluoro-2-((1-(4-methyl- chromatography (Column ID 21 × 250 mm, 25% IPA 10 mM
    5-(2-(1,1,1-trifluoro-2- NH4OH in CO2, flow 75 g/min, 230 nm UV collection) to
    methylpropan-2-yl)pyridin-4- give
    yl)thiazol-2- (4R)-3-(5-fluoro-2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-
    yl)ethyl)amino)pyrimidin-4-yl)-4- methylpropan-2-yl)pyridin-4-yl)thiazol-2-
    ((R)-1-hydroxyethyl)oxazolidin-2- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    one hydroxyethyl)oxazolidin-2-one and (4R)-3-(5-fluoro-2-(((R)-
    1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-
    yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-
    ((R)-1-hydroxyethyl)oxazolidin-2-one.
    200: First eluted product (7 mg) 1H NMR (400 MHz, CDCl3)
    δ 8.55 (td, J = 5.4, 0.8 Hz, 1H), 8.17 (dd, J = 4.5, 2.8 Hz,
    1H), 7.46-7.40 (m, 1H), 7.16 (ddd, J = 8.1, 5.1, 1.6 Hz,
    1H), 5.56 (dd, J = 14.8, 6.8 Hz, 1H), 5.20-5.13 (m, 1H),
    4.49-4.37 (m, 2H), 4.30 (d, J = 6.8 Hz, 1H), 3.32 (d, J =
    3.7 Hz, 1H), 2.46 (s, 3H), 1.67-1.50 (m, 9H), 1.18-1.12
    (m, 3H). HRMS(D) m/z 555.1821 (M + H)+.
    201: Second eluted product (33 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.60-8.52 (m, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.42
    (dt, J = 1.7, 0.8 Hz, 1H), 7.21-7.12 (m, 1H), 5.56 (d, J =
    6.9 Hz, 1H), 5.24 (p, J = 7.0 Hz, 1H), 4.55 (dt, J = 8.6, 5.5
    Hz, 1H), 4.45 (t, J = 8.8 Hz, 1H), 4.31 (dd, J = 9.0, 5.2 Hz,
    1H), 3.95 (td, J = 13.7, 13.0, 6.9 Hz, 1H), 2.45 (s, 3H), 1.64
    (d, J = 6.9 Hz, 3H), 1.57 (s, 6H), 1.00 (d, J = 6.0 Hz,
    3H). HRMS(D) m/z 555.1839 (M + H)+.
    200 and 201: Chiral separation was achieved by chiral SFC column
    (R)-3-(2-((1-(5-(2-fluoro-3- chromatography (Column IA 21 × 250 mm, 25% MeOH
    (trifluoromethyl)phenyl)pyrimidin- 10 mM NH4OH in CO2, flow 75 g/min, 232 nm UV
    2-yl)ethyl)amino)pyrimidin-4-yl)- collection) to give (R)-3-(2-(((S)-1-(5-(2-fluoro-3-
    4-((R)-1-hydroxyethyl)oxazolidin- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-
    2-one 4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-
    (((R)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one.
    192: First eluted product (35 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.85-8.79 (m, 2H), 8.12 (dd, J = 6.1, 4.0 Hz,
    1H), 7.70-7.52 (m, 2H), 7.41-7.30 (m, 2H), 6.14 (s, 1H),
    5.36-5.27 (m, 1H), 4.85-4.76 (m, 1H), 4.43 (dd, J = 9.4,
    2.6 Hz, 1H), 4.38-4.24 (m, 1H), 4.13-3.93 (m, 1H), 3.15
    (br s, 1H), 1.60 (d, J = 7.0 Hz, 3H), 1.02 (br s,
    3H). HRMS(D) m/z 493.1605 (M + H)+.
    193: Second eluted product (36 mg) 1H NMR (400 MHz,
    CDCl3) δ 8.83 (d, J = 1.4 Hz, 2H), 8.12 (d, J = 5.8 Hz, 1H),
    7.71-7.53 (m, 2H), 7.42-7.31 (m, 2H), 6.19 (br s, 1H),
    5.08 (br s, 1H), 4.68 (br s, 1H), 4.46 (d, J = 8.3 Hz, 1H),
    4.21 (br s, 2H), 3.50 (br s, 1H), 1.60 (d, J = 7.0 Hz, 3H),
    1.19-1.12 (m, 3H). HRMS(D) m/z 493.1630 (M + H)+.
    • Examples 202 and 203 (4R)-3-(2-((1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00684
  • (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one (124 mg, 0.246 mmol) was treated with 90% TFA/water for 2 hours. Concentrated in vacuo and neutralized by passing through a column of MP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded the diastereomeric mixture. Chiral SFC chromatography on an ID column (75 g/min, 120 bar, 21×250 mm) eluting 45% IPA/CO2 (v/v) to give (R)-3-(2-(((R)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
  • 202: Peak 1: 15 mg (pale orange foam): (CDCl3) δ 8.22 (d, J=3.2 Hz, 1H), 7.63-7.50 (m, 2H), 7.45-7.38 (m, 2H), 7.28 (s, 1H), 5.65 (d, J=7.0 Hz, 1H), 5.16 (s, 1H), 4.80-4.25 (m, 3H), 3.51 (s, 1H), 1.71 (d, J=7.0 Hz, 3H), 1.38-1.15 (m, 4H). HRMS (B) m/z 447.1110. RT=2.20 min.
  • 203: Peak 2: 87 mg (pale orange foam): (CDCl3) δ 8.24 (d, J=2.9 Hz, 1H), 7.59-7.49 (m, 2H), 7.46-7.37 (m, 2H), 7.24-7.18 (m, 1H), 5.66 (d, J=8.1 Hz, 1H), 5.32 (dd, J=8.3, 6.6 Hz, 1H), 4.79 (s, 1H), 4.56 (t, J=8.9 Hz, 1H), 4.39 (dd, J=9.1, 5.7 Hz, 1H), 4.04 (td, J=11.0, 9.7, 4.8 Hz, 1H), 3.51 (s, 1H), 1.70 (s, 1H), 1.23 (d, J=6.2 Hz, 2H), 1.16 (d, J=6.4 Hz, 3H). HRMS (B) m/z 447.1110. RT=2.20 min.
    • Examples 204 and 205 (4R)-3-(2-((1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00685
  • (4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (3.50 g, 2.88 mmol) was treated with 90% TFA/water for 2 hours. Concentrated in vacuo and neutralized by passing through a column of MP-carbonate resin (6.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded the diastereomeric mixture. Chiral SFC chromatography on an OJ-H column (75 g/min, 120 bar, 21×250 mm) eluting 30% IPA+10 mM NH4OH/CO2 (v/v) to give (R)-3-(2-(((S)-1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
  • 204: Peak 1: 1.40 g (white powder crystals): 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=5.8 Hz, 1H), 7.76-7.63 (m, 2H), 7.54 (d, J=5.7 Hz, 1H), 7.50-7.37 (m, 2H), 6.46 (s, 1H), 5.90-5.55 (m, 1H), 5.27-5.04 (m, 1H), 4.93-4.79 (m, 1H), 4.56 (dd, J=9.3, 2.5 Hz, 1H), 4.40 (dd, J=9.4, 8.4 Hz, 1H), 3.51 (s, 2H), 3.25 (d, J=68.4 Hz, 1H), 1.98-1.55 (m, 2H), 0.91 (s, 3H). HRMS (B) m/z 429.1204. RT=2.45 min.
  • 205: Peak 2: 1.35 g (off-white foam): 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=6.0 Hz, 1H), 7.79-7.64 (m, 2H), 7.54 (d, J=5.8 Hz, 1H), 7.49-7.37 (m, 2H), 6.47 (s, 1H), 5.77 (s, 1H), 1.80-1.61 (m, 4H), 5.16 (s, 1H), 4.71-4.45 (m, 2H), 4.46-4.22 (m, 2H), 3.51 (s, 2H), 2.87 (s, 1H), 1.20 (d, J=6.5 Hz, 4H). HRMS (B) m/z 429.1204. RT=2.45 min.
    • Example 206 (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00686
  • (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (360 mg, 0.741 mg) was treated with 90% TFA/water for 2 hours. Concentrated in vacuo and neutralized by passing through a column of MP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded the desired product (120 mg, pale yellow foam). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=6.0 Hz, 1H), 7.64-7.49 (m, 3H), 7.49-7.35 (m, 2H), 7.29 (s, 1H), 5.33 (dd, J=9.4, 5.1 Hz, 1H), 5.04-4.81 (m, 1H), 1.80-1.69 (m, 3H), 4.71-4.53 (m, 1H), 4.45 (dd, J=9.4, 8.1 Hz, 1H), 4.28-3.97 (m, 1H), 3.51 (s, 3H), 1.14 (d, J=6.4 Hz, 3H). HRMS (B) m/z 429.1204. RT=2.22 min.
    • Example 207 (R)-3-(6-chloro-2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00687
  • Trifluoroacetic acid (2 mL) was added to a solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(6-chloro-2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (25.0 mg, 0.039 mmol), in DCM (2 mL) and the solution was stirred at room temperature for 1 h. The reaction mixture was then concentrated and purification by reverse phase HPLC provided the trifluoroacetate salt of (R)-3-(6-chloro-2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (10.0 mg, white solid) in 44% yield. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J=8.4 Hz, 2H), 7.63 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 5.30 (br m, 1H), 4.80-4.77 (m, 1H), 4.55-4.52 (m, 1H), 4.41-4.36 (m, 1H), 3.77-3.62 (br m, 1H), 1.78 (d, J=7.1 Hz, 3H), 0.95 (br m, 3H); HRMS m/z 465.0847 (M+H)+; Rt-2.25 min.
  • The compounds in Table 30a were prepared using methods similar to those described for the preparation of Examples 35, 36, 37/38, or 207.
  • TABLE 30a
    Figure US20140275083A1-20140918-C00688
         		208
    Figure US20140275083A1-20140918-C00689
         		209
    Figure US20140275083A1-20140918-C00690
         		210
    Figure US20140275083A1-20140918-C00691
         		211
    Figure US20140275083A1-20140918-C00692
         		212
    Figure US20140275083A1-20140918-C00693
         		213
    Figure US20140275083A1-20140918-C00694
         		214
    Figure US20140275083A1-20140918-C00695
         		215
    Figure US20140275083A1-20140918-C00696
         		216
    Figure US20140275083A1-20140918-C00697
         		217
    Figure US20140275083A1-20140918-C00698
         		218
    Figure US20140275083A1-20140918-C00699
         		219
    Figure US20140275083A1-20140918-C00700
         		220
    Figure US20140275083A1-20140918-C00701
         		221
    Figure US20140275083A1-20140918-C00702
         		222
    Figure US20140275083A1-20140918-C00703
         		223
    Figure US20140275083A1-20140918-C00704
         		224
    Figure US20140275083A1-20140918-C00705
         		225
    Figure US20140275083A1-20140918-C00706
         		226
    Figure US20140275083A1-20140918-C00707
         		227
    Figure US20140275083A1-20140918-C00708
         		228
    Figure US20140275083A1-20140918-C00709
         		229
    Figure US20140275083A1-20140918-C00710
         		230
    Figure US20140275083A1-20140918-C00711
         		231
    Figure US20140275083A1-20140918-C00712
         		232
    Figure US20140275083A1-20140918-C00713
         		233
    Figure US20140275083A1-20140918-C00714
         		234
    Figure US20140275083A1-20140918-C00715
         		235
    Figure US20140275083A1-20140918-C00716
         		236
    Figure US20140275083A1-20140918-C00717
         		237
    Figure US20140275083A1-20140918-C00718
         		238
    Figure US20140275083A1-20140918-C00719
         		239
    Figure US20140275083A1-20140918-C00720
         		240
    Figure US20140275083A1-20140918-C00721
         		241
    Figure US20140275083A1-20140918-C00722
         		242
    Figure US20140275083A1-20140918-C00723
         		243
    Figure US20140275083A1-20140918-C00724
         		244
    Figure US20140275083A1-20140918-C00725
         		245
    Figure US20140275083A1-20140918-C00726
         		246
    Figure US20140275083A1-20140918-C00727
         		247
    Figure US20140275083A1-20140918-C00728
         		248
    Figure US20140275083A1-20140918-C00729
         		249
    Figure US20140275083A1-20140918-C00730
         		250
    Figure US20140275083A1-20140918-C00731
         		251
    Figure US20140275083A1-20140918-C00732
         		252
    Figure US20140275083A1-20140918-C00733
         		253
    Figure US20140275083A1-20140918-C00734
         		254
    Figure US20140275083A1-20140918-C00735
         		255
    Figure US20140275083A1-20140918-C00736
         		256
    Figure US20140275083A1-20140918-C00737
         		257
    Figure US20140275083A1-20140918-C00738
         		258
    Figure US20140275083A1-20140918-C00739
         		259
    Figure US20140275083A1-20140918-C00740
         		260
    Figure US20140275083A1-20140918-C00741
         		261
    Figure US20140275083A1-20140918-C00742
         		262
    Figure US20140275083A1-20140918-C00743
         		263
    Figure US20140275083A1-20140918-C00744
         		264
    Figure US20140275083A1-20140918-C00745
         		265
    Figure US20140275083A1-20140918-C00746
         		266
    Figure US20140275083A1-20140918-C00747
         		267
    Figure US20140275083A1-20140918-C00748
         		268
    Figure US20140275083A1-20140918-C00749
         		269
    Figure US20140275083A1-20140918-C00750
         		270
    Figure US20140275083A1-20140918-C00751
         		271
    Figure US20140275083A1-20140918-C00752
         		272
    Figure US20140275083A1-20140918-C00753
         		273
    Figure US20140275083A1-20140918-C00754
         		274
    Figure US20140275083A1-20140918-C00755
         		275
    Figure US20140275083A1-20140918-C00756
         		276
    Figure US20140275083A1-20140918-C00757
         		277
    Figure US20140275083A1-20140918-C00758
         		278
    Figure US20140275083A1-20140918-C00759
         		279
    Figure US20140275083A1-20140918-C00760
         		280
    Figure US20140275083A1-20140918-C00761
         		281
    Figure US20140275083A1-20140918-C00762
         		282
    Figure US20140275083A1-20140918-C00763
         		283
    Figure US20140275083A1-20140918-C00764
         		284
    Figure US20140275083A1-20140918-C00765
         		285
    Figure US20140275083A1-20140918-C00766
         		286
    Figure US20140275083A1-20140918-C00767
         		287
    Figure US20140275083A1-20140918-C00768
         		288
    Figure US20140275083A1-20140918-C00769
         		289
    Figure US20140275083A1-20140918-C00770
         		290
    Figure US20140275083A1-20140918-C00771
         		291
    Figure US20140275083A1-20140918-C00772
         		292
    Figure US20140275083A1-20140918-C00773
         		293
    Figure US20140275083A1-20140918-C00774
         		294
    Figure US20140275083A1-20140918-C00775
         		295
    Figure US20140275083A1-20140918-C00776
         		296
    Figure US20140275083A1-20140918-C00777
         		297
    Figure US20140275083A1-20140918-C00778
         		298
    Figure US20140275083A1-20140918-C00779
         		299
    Figure US20140275083A1-20140918-C00780
         		300
    Figure US20140275083A1-20140918-C00781
         		301
    Figure US20140275083A1-20140918-C00782
         		302
    Figure US20140275083A1-20140918-C00783
         		303
    Figure US20140275083A1-20140918-C00784
         		304
    Figure US20140275083A1-20140918-C00785
         		305
    Figure US20140275083A1-20140918-C00786
         		306
    Figure US20140275083A1-20140918-C00787
         		307
    Figure US20140275083A1-20140918-C00788
         		308
    Figure US20140275083A1-20140918-C00789
         		309
    Figure US20140275083A1-20140918-C00790
         		310
    Figure US20140275083A1-20140918-C00791
         		311
    Figure US20140275083A1-20140918-C00792
         		312
    Figure US20140275083A1-20140918-C00793
         		313
    Figure US20140275083A1-20140918-C00794
         		314
    Figure US20140275083A1-20140918-C00795
         		315
    Figure US20140275083A1-20140918-C00796
         		316
    Figure US20140275083A1-20140918-C00797
         		317
    Figure US20140275083A1-20140918-C00798
         		318
    Figure US20140275083A1-20140918-C00799
         		319
    Figure US20140275083A1-20140918-C00800
         		320
    Figure US20140275083A1-20140918-C00801
         		321
    Figure US20140275083A1-20140918-C00802
         		322
    Figure US20140275083A1-20140918-C00803
         		323
    Figure US20140275083A1-20140918-C00804
         		324
    Figure US20140275083A1-20140918-C00805
         		325
    Figure US20140275083A1-20140918-C00806
         		326
    Figure US20140275083A1-20140918-C00807
         		327
    Figure US20140275083A1-20140918-C00808
         		328
    Figure US20140275083A1-20140918-C00809
         		329
    Figure US20140275083A1-20140918-C00810
         		330
    Figure US20140275083A1-20140918-C00811
         		331
    Figure US20140275083A1-20140918-C00812
         		332
    Figure US20140275083A1-20140918-C00813
         		333
    Figure US20140275083A1-20140918-C00814
  • TABLE 30b
    Chemical name, NMR chemical shifts and LCMS signal for each compound listed in Table 30a.
    Example: Name 1H NMR (400 MHz, CDCl3) δ ppm LCMS
    208: (R)-3-(6-chloro-2- 7.59 (s, 1H), 7.52-7.48 (m, 1H), HRMS
    ((S)-1-(2-fluoro-4- 7.44-7.42 (m, 1H), 7.37 (d, J = 9.7 Hz, 1H), m/z
    (trifluoromethyl)phenyl)ethylamino)pyrimidin- 5.31 (br m, 1H), 4.68-4.66 (m, 1H), 449.1009
    4-yl)-4- 4.49-4.46 (m, 1H), 4.38-4.34 (m, 1H), 3.43 (br (M + H)+;
    ((R)-1- m, 1H), 1.59 (d, J = 7.0 Hz, 3H), 0.83 (br Rt-2.39 min
    hydroxyethyl)oxazolidin-2- m, 3H)
    one
    209: (R)-3-(6-chloro-2- 7.77 (s, 1H), 7.61 (s, 1H), 7.55 (s, 1H), HRMS
    ((S)-1-(2-fluoro-4-(1- 7.36-7.30 (m, 1H), 7.25-7.21 (m, 1H), m/z
    methyl-1H-pyrazol-4- 7.17 (dd, J = 11.4, 1.5 Hz, 1H), 5.26 (br m, 461.1505
    yl)phenyl)ethylamino)pyrimidin- 1H), 4.70 (ddd, J = 8.1, 5.2, 2.5 Hz, 1H), (M + H)+;
    4-yl)-4-((R)-1- 4.45 (dd, J = 9.4, 2.5 Hz, 1H), Rt-2.00
    hydroxyethyl)oxazolidin-2- 4.39-4.31 (m, 1H), 3.98 (s, 3H), 3.67-3.55 (m, 1H),
    one 1.57 (d, J = 6.9 Hz, 3H), 0.82 (br m, 3H)
    210: (R)-3-(2-((S)-1-(3-(4- 8.00 (d, J = 8.6 Hz, 2H), 7.91 (s, 1H), HRMS
    chlorophenyl)-1,2,4- 7.48 (d, J = 8.6 Hz, 2H), 6.45 (t, J = 56 Hz, 1H), m/z
    oxadiazol-5- 4.84 (m, 1H), 4.83 (dt, J = 5.3, 2.5 Hz, 1H), 481.1206
    yl)ethylamino)-6- 4.57 (d, J = 9.0 Hz, 1H), 4.46-4.37 (m, (M + H)+;
    (difluoromethyl)pyrimidin- 1H), 3.69 (m, 1H), 1.83 (d, J = 7.0 Hz, 3H), Rt-2.32
    4-yl)-4-((R)-1- 0.96 (br m, 3H)
    hydroxyethyl)oxazolidin-2-
    one
    211: (R)-3-(2-((S)-1-(3-(4- 8.00 (d, J = 8.6 Hz, 2H), 7.93 (s, 1H), HRMS
    chlorophenyl)-1,2,4- 7.48 (d, J = 8.6 Hz, 2H), 5.31 (br. s., 1H), m/z
    oxadiazol-5- 4.90-4.80 (m, 1H), 4.57 (dd, J = 9.6, 1.8 Hz, 499.1106
    yl)ethylamino)-6- 1H), 4.48-4.35 (m, 1H), 3.74 (br m, 1H), (M + H)+;
    (trifluoromethyl)pyrimidin- 1.81 (d, J = 7.1 Hz, 3H), 1.25-0.84 (br m, Rt-2.50
    4-yl)-4-((R)-1- 3H)
    hydroxyethyl)oxazolidin-2-
    one
    212: (R)-3-(6-chloro-2- 7.90 (s, 1H), 7.80 (s, 1H), 7.59 (br s, 1H), HRMS
    (((S)-1-(2,5-difluoro-4-(1- 7.25-7.21 (m, 1H), 7.12 (dd, J = 11.0, 6.3 Hz, m/z
    methyl-1H-pyrazol-4- 1H), 5.25 (br m, 1H), 4.72 (m, 1H), 479.1415
    yl)phenyl)ethyl)amino)pyrimidin- 4.49 (d, J = 9.4 Hz, 1H), 4.43-4.33 (m, (M + H)+;
    4-yl)-4-((R)-1- 1H), 4.02 (s, 3H), 3.72 (br m, 1H), 1.58 (d, Rt-2.04
    hydroxyethyl)oxazolidin-2- J = 7.0 Hz, 3H), 0.88 (br s, 3H)
    one
    213: (R)-3-(6-chloro-2- 7.70 (d, J = 8.6 Hz, 2H), 7.60 (s, 1H), HRMS
    (((S)-1-(5-(4- 7.46 (d, J = 8.6 Hz, 2H), 6.54 (s, 1H), 5.23 (m, m/z
    chlorophenyl)isoxazol-3- 1H), 4.87 (m, 1H), 4.58 (d, J = 9.5 Hz, 1H), 464.0894
    yl)ethyl)amino)pyrimidin-4- 4.47-4.39 (m, 1H), 3.89 (m, 1H), 1.67 (d, (M + H)+;
    yl)-4-((R)-1- J = 7.1 Hz, 3H), 1.05 (d, J = 5.7 Hz, 3H) Rt-2.38
    hydroxyethyl)oxazolidin-2-
    one
    214: (R)-3-(6-chloro-2- 7.78-7.73 (m, 2H), 7.59 (s, 1H), HRMS
    (((S)-1-(5-phenylisoxazol- 7.50-7.44 (m, 3H), 6.54 (s, 1H), 5.23 (m, 1H), m/z
    3-yl)ethyl)amino)pyrimidin- 4.87 (m, 1H), 4.58 (d, J = 9.5 Hz, 1H), 430.1278
    4-yl)-4-((R)-1- 4.42 (d, J = 9.3, 8.4 Hz, 1H), 3.89 (m, 1H), (M + H)+;
    hydroxyethyl)oxazolidin-2- 1.67 (d, J = 7.1 Hz, 3H), 1.05 (d, J = 5.7 Hz, 3H) Rt-2.19
    one
    215: (R)-3-(6-fluoro-2- 7.80 (s, 1H), 7.73 (s, 1H), 7.63-7.55 (m, HRMS
    (((S)-1-(1-(4-fluorophenyl)- 2H), 7.19-7.10 (m, 3H), 5.04 (m, 1H), m/z
    1H-pyrazol-4- 4.72 (m, 1H), 4.47 (m, 1H), 4.43-4.34 (m, 431.1644
    yl)ethyl)amino)pyrimidin-4- 1H), 3.73 (m, 1H), 1.62 (d, J = 6.9 Hz, 3H), (M + H)+;
    yl)-4-((R)-1- 0.97 (br m, 3H) Rt-2.06
    hydroxyethyl)oxazolidin-2-
    one
    216: (R)-3-(6-chloro-2- 7.95 (s, 1H), 7.80 (d, J = 8.7 Hz, 2H), HRMS
    (((S)-1-(2-(4- 7.65 (s, 1H), 7.48 (d, J = 8.7 Hz, 2H), 5.35 (m, m/z
    chlorophenyl)thiazol-5- 1H), 4.80 (m, 1H), 4.59 (d, J = 8.5 Hz, 1H), 480.0666
    yl)ethyl)amino)pyrimidin-4- 4.40 (m, 1H), 3.72 (m, 1H), 1.74 (d, J = 6.9 Hz, (M + H)+;
    yl)-4-((R)-1- 3H), 0.97 (br s, 3H) Rt-2.46
    hydroxyethyl)oxazolidin-2-
    one
    217: (R)-3-(2-(((S)-1-(2-(4- 8.14 (d, J = 3.4 Hz, 1H), 7.93 (s, 1H), HRMS
    chlorophenyl)thiazol-5- 7.79 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, m/z
    yl)ethyl)amino)-5- 2H), 5.33 (m, 1H), 4.71 (m, 1H), 4.58 (t, J = 9.0 Hz, 464.0964
    fluoropyrimidin-4-yl)-4- 1H), 4.48 (dd, J = 9.3, 5.3 Hz, (M + H)+;
    ((R)-1- 1H), 3.72 (m, 1H), 1.79 (d, J = 7.0 Hz, 3H), Rt-2.08
    hydroxyethyl)oxazolidin-2- 1.02 (d, J = 6.2 Hz, 3H)
    one
    218: (R)-3-(2-(((S)-1-(5-(4- 8.07 (d, J = 3.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, HRMS
    chlorophenyl)isoxazol-3- 2H), 7.46 (d, J = 8.8 Hz, 2H), 6.62 (s, m/z
    yl)ethyl)amino)-5- 1H), 5.31 (m, 1H), 4.95 (m, 1H), 4.62 (t, J = 9.0 Hz, 448.1186
    fluoropyrimidin-4-yl)-4- 1H), 4.43 (dd, J = 9.3, 5.4 Hz, (M + H)+;
    ((R)-1- 1H), 3.98-3.88 (m, 1H), 1.73 (d, J = 7.1 Hz, Rt-2.03
    hydroxyethyl)oxazolidin-2- 3H), 1.18 (d, J = 6.5 Hz, 3H)
    one
    219: (R)-3-(6-chloro-2- 7.85 (d, J = 8.4 Hz, 2H), 7.65 (s, 1H), HRMS
    (((S)-1-(5-(4- 7.48 (d, J = 8.4 Hz, 2H), 5.44 (m, 1H), 4.86 (m, m/z
    chlorophenyl)-1,3,4- 1H), 4.59 (d, J = 9.5 Hz, 1H), 4.40 (t, J = 8.9 Hz, 481.0618
    thiadiazol-2- 1H), 3.33 (m, 1H), 1.80 (d, J = 7.0 Hz, (M + H)+;
    yl)ethyl)amino)pyrimidin-4- 3H), 0.91 (br s, 3H) Rt-2.25
    yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-
    one
    220: (R)-3-(6-chloro-2- 7.86 (s, 1H), 7.79 (s, 1H), 7.60 (s, 1H), HRMS
    (((S)-1-(1-(4- 7.56 (d, J = 9.0 Hz, 2H), 7.44 (d, J = 9.0 Hz, m/z
    chlorophenyl)-1H-pyrazol- 2H), 5.03 (m, 1H), 4.76 (m, 1H), 463.1055
    4-yl)ethyl)amino)pyrimidin- 4.51 (m, 1H), 4.45-4.33 (m, 1H), 3.75 (m, 1H), (M + H)+;
    4-yl)-4-((R)-1- 1.63 (d, J = 6.9 Hz, 3H), 0.96 (br m, 3H) Rt-2.31
    hydroxyethyl)oxazolidin-2-
    one
    221: (R)-3-(2-(((S)-1-(1-(4- 8.24 (d, J = 2.7 Hz, 1H), 7.85 (s, 1H), HRMS
    chlorophenyl)-1H-pyrazol- 7.70 (s, 1H), 7.59 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 8.9 Hz, m/z
    4-yl)ethyl)amino)-5- 2H), 5.34 (m, 1H), 5.04 (m, 1H), 447.1350
    fluoropyrimidin-4-yl)-4- 4.57-4.48 (m, 2H), 4.43-4.34 (m, 1H), (M + H)+;
    ((R)-1- 3.84 (m, 1H), 1.61 (d, J = 6.9 Hz, 3H), Rt-1.98
    hydroxyethyl)oxazolidin-2- 1.08 (d, J = 6.2 Hz, 3H)
    one
    222: (R)-3-(2-(((S)-1-(5-(4- 7.82 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H), HRMS
    chlorophenyl)isoxazol-3- 7.46 (d, J = 8.5 Hz, 2H), 6.65 (s, 1H), 5.46 (s, m/z
    yl)ethyl)amino)-6- 1H), 5.36-5.29 (m, 2H), 4.96 (m, 1H), 462.1347
    (fluoromethyl)pyrimidin-4- 4.62 (d, J = 9.0 Hz, 1H), 4.53-4.45 (m, (M + H)+;
    yl)-4-((R)-1- 1H), 3.99 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H), Rt-2.22
    hydroxyethyl)oxazolidin-2- 1.13 (d, J = 6.6 Hz, 3H)
    one
    223: (R)-3-(2-(((S)-1-(2-(4- 7.88 (s, 1H), 7.87 (s, 1H), 7.80 (d, J = 8.6 Hz, HRMS
    chlorophenyl)thiazol-5- 2H), 7.46 (d, J = 8.6 Hz, 2H), 5.47 (s, m/z
    yl)ethyl)amino)-6- 1H), 5.38-5.30 (m, 2H), 4.86 (ddd, J = 8.1, 478.1116
    (fluoromethyl)pyrimidin-4- 4.3, 2.2 Hz, 1H), 4.69-4.62 (m, 1H), (M + H)+;
    yl)-4-((R)-1- 4.45 (dd, J = 9.5, 8.2 Hz, 1H), 3.61 (m, Rt-2.28
    hydroxyethyl)oxazolidin-2- 1H), 1.80 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 6.4 Hz,
    one 3H)
    224: (R)-3-(2-(((S)-1-(2-(4- 7.99 (d, J = 7.1 Hz, 1H), 7.93 (s, 1H), HRMS
    chlorophenyl)thiazol-5- 7.85-7.78 (m, 3H), 7.47 (d, J = 8.7 Hz, 2H), m/z
    yl)ethyl)amino)pyrimidin-4- 5.43-5.34 (m, 1H), 4.89 (ddd, J = 8.1, 446.1065
    yl)-4-((R)-1- 4.1, 2.2 Hz, 1H), 4.69 (dd, J = 9.4, 8.2 Hz, (M + H)+;
    hydroxyethyl)oxazolidin-2- 1H), 3.69 (dd, J = 6.3, 4.4 Hz, 1H), 1.83 (d, Rt-1.90
    one J = 7.0 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H)
    225: (R)-3-(2-(((S)-1-(1-(4- 10.64 (d, J = 5.9 Hz, 1H), 7.98 (s, 1H), HRMS
    chlorophenyl)-1H-pyrazol- 7.95 (d, J = 7.1 Hz, 1H), 7.78-7.74 (m, m/z
    4-yl)ethyl)amino)pyrimidin- 2H), 7.59 (d, J = 9.0 Hz, 2H), 7.43 (d, J = 9.0 Hz, 429.1441
    4-yl)-4-((R)-1- 2H), 5.06 (quin, J = 6.7 Hz, 1H), (M + H)+;
    hydroxyethyl)oxazolidin-2- 4.84 (ddd, J = 8.2, 4.4, 2.3 Hz, 1H), Rt-1.62
    one 4.62 (dd, J = 9.6 2.3 Hz, 1H), 4.45 (dd, J = 9.5,
    8.2 Hz, 1H), 3.80-3.69 (m, 1H), 1.70 (d, J = 7.0 Hz,
    3H), 0.96 (d, J = 6.5 Hz, 3H)
    226: (R)-3-(6-chloro-2- 7.70 (d, J = 8.6 Hz, 2H), 7.65 (s, 1H), HRMS
    (((S)-1-(3-(4- 7.45 (d, J = 8.6 Hz, 2H), 6.50 (s, 1H), 5.09 (m, m/z
    chlorophenyl)isoxazol-5- 1H), 4.87 (m, 1H), 4.59 (d, J = 9.1 Hz, 1H), 464.0898
    yl)ethyl)amino)pyrimidin-4- 4.46-4.37 (m, 1H), 3.49 (m, 1H), 1.72 (d, (M + H)+;
    yl)-4-((R)-1- J = 7.1 Hz, 3H), 0.89 (br s, 3H) Rt-2.37
    hydroxyethyl)oxazolidin-2-
    one
    227: (R)-3-(2-(((S)-1-(3-(4- 8.13 (d, J = 3.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, HRMS
    chlorophenyl)isoxazol-5- 2H), 7.44 (d, J = 8.5 Hz, 2H), 6.52 (s, m/z
    yl)ethyl)amino)-5- 1H), 5.17 (m, 1H), 4.94 (m, 1H), 448.1190
    fluoropyrimidin-4-yl)-4- 4.64-4.57 (m, 1H), 4.52 (dd, J = 9.4, 5.4 Hz, (M + H)+;
    ((R)-1- 1H), 3.66 (m, 1H), 1.76 (d, J = 7.1 Hz, 3H), Rt-2.07
    hydroxyethyl)oxazolidin-2- 1.04 (d, J = 6.4 Hz, 3H)
    one
    228: (R)-3-(2-(((S)-1-(1-(4- 7.84 (br s, 1H), 7.76 (s, 1H), 7.57 (d, J = 8.9 Hz, HRMS
    chlorophenyl)-1H-pyrazol- 2H), 7.44 (d, J = 9.0 Hz, 2H), m/z
    4-yl)ethyl)amino)-6- 7.13 (s, 1H), 5.05 (m, 1H), 4.72 (m, 1H), 447.1347
    fluoropyrimidin-4-yl)-4- 4.47 (m, 1H), 4.43-4.35 (m, 1H), 1.62 (d, J = 6.9 Hz, (M + H)+;
    ((R)-1- 3H), 0.96 (br m, 3H) Rt-2.23
    hydroxyethyl)oxazolidin-2-
    one
    229: (R)-3-(6-chloro-2- 7.82-7.69 (m, 2H), 7.62 (s, 1H), 7.17 (t, J = 8.6 Hz, HRMS
    (((S)-1-(5-(4- 2H), 6.51 (s, 1H), 5.23 (d, J = 5.8 Hz, m/z
    fluorophenyl)isoxazol-3- 1H), 4.89 (m, 1H), 4.59 (m, 1H), 448.1192
    yl)ethyl)amino)pyrimidin-4- 4.47-4.40 (m, 1H), 3.91 (m, 1H), 1.68 (d, J = 7.1 Hz, (M + H)+;
    yl)-4-((R)-1- 3H), 1.07 (d, J = 6.3 Hz, 3H) Rt-2.23
    hydroxyethyl)oxazolidin-2-
    one
    230: (R)-3-(6-chloro-2- 7.59 (s, 1H), 6.57 (s, 1H), 5.23 (m, 1H), HRMS
    (((S)-1-(5- 4.82 (m, 1H), 4.56 (m, 1H), 4.43-4.34 (m, m/z
    (morpholinomethyl)isoxazol- 2H), 4.20 (m, 1H), 3.97 (m, 4H), 3.24 (m, 453.1662
    3- 4H), 1.61 (d, J = 7.2 Hz, 3H), 1.04 (br s, (M + H)+;
    yl)ethyl)amino)pyrimidin-4- 3H) Rt-1.26
    yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-
    one
    231: (R)-3-(6-chloro-2- 7.55 (s, 1H), 6.55 (s, 1H), 5.87 (m, 1H), HRMS
    (((R)-1-(5- 5.05 (m, 1H), 4.65 (m, 1H), 4.56 (m, 1H), m/z
    (morpholinomethyl)isoxazol- 4.34-4.31 (m, 2H), 4.20 (m, 1H), 453.1651
    3- 3.97-3.95 (m, 4H), 3.18 (m, 4H), 1.62 (d, J = 7.0 Hz, (M + H)+;
    yl)ethyl)amino)pyrimidin-4- 3H), 1.18 (d, J = 6.5 Hz, 3H) Rt-1.27
    yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-
    one
    232: (R)-3-(2-(((S)-1-(1-(4- 10.78 (d, J = 5.8 Hz, 1H), 7.98 (s, 1H), HRMS
    chlorophenyl)-1H-pyrazol- 7.73 (s, 1H), 7.59 (d, J = 8.7 Hz, 2H), m/z
    4-yl)ethyl)amino)-6- 7.56 (s, 1H), 7.43 (d, J = 8.7 Hz, 2H), 5.00 (m, 443.1596
    methylpyrimidin-4-yl)-4- 1H), 4.89-4.74 (m, 1H), 4.60 (dd, J = 9.6, (M + H)+;
    ((R)-1- 2.2 Hz, 1H), 4.52-4.35 (m, 1H), 3.69 (dd, Rt-1.62
    hydroxyethyl)oxazolidin-2- J = 6.5, 4.6 Hz, 1H), 2.52 (s, 3H), 1.69 (d,
    one J = 7.0 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H)
    233: (R)-3-(6-chloro-2- 8.63 (m, 1H), 8.14 (s, 1H), 7.95-7.89 (m, HRMS
    (((S)-1-(2-(pyridin-2- 2H), 7.61 (s, 1H), 7.42 (m, 1H), 5.28 (m, m/z
    yl)thiazol-5- 1H), 4.52 (m, 1H), 4.47-4.35 (m, 3H), 447.1011
    yl)ethyl)amino)pyrimidin-4- 1.77 (m, 3H), 0.96 (br s, 3H) (M + H)+;
    yl)-4-((R)-1- Rt-1.99
    hydroxyethyl)oxazolidin-2-
    one
    234: (R)-3-(6-chloro-2- 9.30 (m, 1H), 8.70 (m, 1H), 8.54 (m, 1H), HRMS
    (((S)-1-(2-(pyridin-3- 7.88 (s, 1H), 7.69 (m, 1H), 7.61 (s, 1H), m/z
    yl)thiazol-5- 5.30 (m, 1H), 4.52 (m, 1H), 4.42-4.36 (m, 447.1011
    yl)ethyl)amino)pyrimidin-4- 3H), 1.76 (d, J = 6.9 Hz, 3H), 1.03 (br s, (M + H)+;
    yl)-4-((R)-1- 3H) Rt-1.72
    hydroxyethyl)oxazolidin-2-
    one
    235: (R)-3-(6-chloro-2- 8.83 (m, 2H), 8.12 (m, 2H), 7.98 (s, 1H), HRMS
    (((S)-1-(2-(pyridin-4- 7.63 (s, 1H), 5.40 (m, 1H), 4.73 (m, 1H), m/z
    yl)thiazol-5- 4.52 (m, 1H), 4.39 (m, 1H), 1.77 (m, 3H), 447.1006
    yl)ethyl)amino)pyrimidin-4- 1.00 (br s, 3H) (M + H)+;
    yl)-4-((R)-1- Rt-1.52
    hydroxyethyl)oxazolidin-2-
    one
    236: (R)-3-(2-(((S)-1-(5-(4- 11.03 (d, J = 6.8 Hz, 1H), 7.71 (d, J = 8.7 Hz, HRMS
    chlorophenyl)isoxazol-3- 2H), 7.56 (s, 1H), 7.46 (d, J = 8.7 Hz, m/z
    yl)ethyl)amino)-6- 2H), 6.70 (s, 1H), 5.32 (quin, J = 7.1 Hz, 444.1443
    methylpyrimidin-4-yl)-4- 1H), 4.95 (ddd, J = 7.9, 4.4, 1.9 Hz, 1H), (M + H)+;
    ((R)-1- 4.62 (dd, J = 9.5, 1.9 Hz, 1H), Rt-1.81
    hydroxyethyl)oxazolidin-2- 4.53-4.43 (m, 1H), 4.06-3.94 (m, 1H), 2.51 (s, 3H),
    one 1.74 (d, J = 7.2 Hz, 3H), 1.13 (d, J = 6.6 Hz,
    3H)
    237: (R)-3-(2-(((S)-1-(2-(4- 11.12 (d, J = 5.4 Hz, 1H), 7.88 (s, 1H), HRMS
    chlorophenyl)thiazol-5- 7.81 (d, J = 8.7 Hz, 2H), 7.62 (s, 1H), m/z
    yl)ethyl)amino)-6- 7.45 (d, J = 8.7 Hz, 2H), 5.37-5.27 (m, 1H), 460.1213
    methylpyrimidin-4-yl)-4- 4.84 (ddd, J = 8.2, 4.2, 2.2 Hz, 1H), (M + H)+;
    ((R)-1- 4.65 (dd, J = 9.6, 2.2 Hz, 1H), 4.44 (dd, J = 9.4, Rt-1.88
    hydroxyethyl)oxazolidin-2- 8.3 Hz, 1H), 3.61-3.52 (m, 1H), 2.52 (s,
    one 3H), 1.81 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 6.5 Hz,
    3H)
    238: (R)-3-(2-(((S)-1-(1-(4- 11.13 (d, J = 8.3 Hz, 1H), 8.43 (s, 1H), HRMS
    chlorophenyl)-1H- 7.91 (s, 1H), 7.67 (s, 1H), 7.60 (d, J = 8.8 Hz, m/z
    imidazol-4-yl)ethyl)amino)- 2H), 7.46 (d, J = 8.8 Hz, 2H), 443.1599
    6-methylpyrimidin-4-yl)-4- 5.97 (quin, J = 7.0 Hz, 1H), 4.98 (ddd, J = 8.1, (M + H)+;
    ((R)-1- 4.4, 2.4 Hz, 1H), 4.77 (dd, J = 9.6, 2.3 Hz, Rt-1.35
    hydroxyethyl)oxazolidin-2- 1H), 4.53-4.46 (m, 1H), 4.44-4.36 (m,
    one 1H), 2.55 (s, 3H), 1.70 (d, J = 6.8 Hz, 3H),
    1.06 (d, J = 6.6 Hz, 3H)
    239: (R)-3-(2-(((S)-1-(3-(4- 11.42 (d, J = 5.0 Hz, 1H), 8.00 (d, J = 8.6 Hz, HRMS
    chlorophenyl)-1,2,4- 2H), 7.64 (s, 1H), 7.48 (d, J = 8.6 Hz, m/z
    oxadiazol-5- 2H), 5.30-5.20 (m, 1H), 4.77 (ddd, J = 7.9, 445.1393
    yl)ethyl)amino)-6- 4.5, 2.0 Hz, 1H), 4.57 (dd, J = 9.5, 1.9 Hz, (M + H)+;
    methylpyrimidin-4-yl)-4- 1H), 4.40 (dd, J = 9.4, 8.2 Hz, 1H), Rt-1.96
    ((R)-1- 3.65-3.55 (m, 1H), 2.56 (s, 3H), 1.90 (d, J = 7.2 Hz,
    hydroxyethyl)oxazolidin-2- 3H), 0.92 (d, J = 6.5 Hz, 3H)
    one
    240: (R)-3-(2-(((S)-1-(1-(4- 10.80 (d, J = 7.3 Hz, 1H), 7.79 (d, J = 2.5 Hz, HRMS
    chlorophenyl)-1H-pyrazol- 1H), 7.54-7.48 (m, 3H), m/z
    3-yl)ethyl)amino)-6- 7.46-7.41 (m, 2H), 6.58 (d, J = 2.5 Hz, 1H), 443.1601
    methylpyrimidin-4-yl)-4- 5.40-5.30 (m, 1H), 4.85 (ddd, J = 7.7, 5.1, 2.3 Hz, (M + H)+;
    ((R)-1- 1H), 4.50-4.38 (m, 2H), Rt-1.66
    hydroxyethyl)oxazolidin-2- 4.02-3.93 (m, 1H), 2.50 (s, 3H), 1.71 (d, J = 7.1 Hz,
    one 3H), 0.94 (d, J = 6.5 Hz, 3H)
    241: (R)-3-(2-(((S)-1-(1-(4- 11.00 (m, 1H), 8.15 (s, 1H), 7.69 (d, J = 8.5 Hz, HRMS
    chlorophenyl)-1H-1,2,3- 2H), 7.53 (s, 1H), 7.51 (d, J = 8.5 Hz, m/z
    triazol-4-yl)ethyl)amino)-6- 2H), 5.51 (m, 1H), 4.70 (m, 1H), 444.1548
    methylpyrimidin-4-yl)-4- 4.58 (m, 1H), 4.51 (m, 1H), 3.96 (m, 1H), (M + H)+;
    ((R)-1- 2.50 (s, 3H), 1.78 (d, J = 6.5 Hz, 3H), 1.17 (d, J = 6.5 Hz, Rt-1.54
    hydroxyethyl)oxazolidin-2- 3H)
    one
    242: (R)-3-(6-chloro-2- 7.97 (s, 1H), 7.69 (m, 2H), 7.60 (s, 1H), HRMS
    (((S)-1-(1-(4- 7.52 (d, J = 8.9 Hz, 2H), 5.41 (m, 1H), m/z
    chlorophenyl)-1H-1,2,3- 4.97 (m, 1H), 4.54 (m, 1H), 4.43 (m, 1H), 464.1003
    triazol-4- 3.77 (m, 1H), 1.71 (d, J = 7.0 Hz, 3H), 1.05 (br (M + H)+;
    yl)ethyl)amino)pyrimidin-4- s, 3H) Rt-2.15
    yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-
    one
    243: (R)-3-(2-(((S)-1-(1-(4- 10.91 (d, J = 7.3 Hz, 1H), 8.15 (s, 1H), HRMS
    chlorophenyl)-1H-1,2,3- 7.89 (d, J = 7.0 Hz, 1H), 7.75 (d, J = 7.0 Hz, m/z
    triazol-4- 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 430.1398
    yl)ethyl)amino)pyrimidin-4- 2H), 5.53 (quin, J = 6.9 Hz, 1H), (M + H)+;
    yl)-4-((R)-1- 5.04 (m, 1H), 4.60-4.50 (m, 2H), 3.99 (m, Rt-1.56
    hydroxyethyl)oxazolidin-2- 1H), 1.79 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 6.5 Hz,
    one 3H)
    244: (R)-3-(2-(((S)-1-(4- 11.05 (d, J = 5.9 Hz, 1H), 7.56 (s, 1H), HRMS
    (1,1-difluoroethyl)-2- 7.52 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 8.7 Hz, m/z
    fluorophenyl)ethyl)amino)- 1H), 7.24 (s, 1H), 5.37 (quin, J = 6.7 Hz, 425.1803
    6-methylpyrimidin-4-yl)-4- 1H), 4.75 (m, 1H), 4.56 (dd, J = 9.6, 2.3 Hz, (M + H)+;
    ((R)-1- 1H), 4.40 (m, 1H), 3.47 (m, 1H), Rt-1.68
    hydroxyethyl)oxazolidin-2- 2.53 (s, 3H), 1.92 (t, J = 18.2, Hz, 3H), 1.66 (d,
    one J = 7.0 Hz, 3H), 0.84 (d, J = 6.5 Hz, 3H)
    245: (R)-3-(2-(((S)-1-(2,5- 11.1 (d, J = 6.6 Hz, 1H), 7.58 (s, 1H), HRMS
    difluoro-4-(2,2,2- 7.25 (m, 1H), 6.83 (dd, J = 10.5, 6.6 Hz, 1H), m/z
    trifluoroethoxy)phenyl)ethyl)amino)- 5.33 (quin, J = 6.9 Hz, 1H), 4.83 (ddd, J = 8.1, 477.1574
    6- 4.7, 2.3 Hz, 1H), 4.59 (dd, J = 9.6, 2.3 Hz, (M + H)+;
    methylpyrimidin-4-yl)-4- 1H), 4.48-4.37 (m, 3H), 3.83 (m, 1H), Rt-1.78
    ((R)-1- 2.53 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H),
    hydroxyethyl)oxazolidin-2- 0.96 (d, J = 6.5 Hz, 3H)
    one
    246: (R)-4-((R)-1- 11.16 (d, J = 6.9 Hz, 1H), 9.54 (d, J = 1.9 Hz, HRMS
    hydroxyethyl)-3-(6-methyl- 1H), 8.76 (dd, J = 8.3, 2.1 Hz, 1H), m/z
    2-(((S)-1-(2-(6- 8.00 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 441.1710
    methylpyridin-3-yl)thiazol- 7.63 (s, 1H), 5.43 (quin, J = 6.9 Hz, 1H), (M + H)+;
    5-yl)ethyl)amino)pyrimidin- 5.06 (ddd, J = 7.9, 4.2, 1.8 Hz, 1H), 4.74 (dd, J = 9.6, Rt-1.16
    4-yl)oxazolidin-2-one 1.9 Hz, 1H), 4.14 (m, 1H), 2.86 (s,
    3H), 2.52 (s, 3H), 1.87 (d, J = 7.1 Hz, 3H),
    1.13 (d, J = 6.4 Hz, 3H)
    247: (R)-4-((R)-1- 11.05 (br s, 1H), 9.21 (s, 1H), 8.34 (d, J = 8.8 Hz, HRMS
    hydroxyethyl)-3-(2-(((S)-1- 1H), 7.97 (d, J = 7.0 Hz, 1H), m/z
    (2-(6- 7.92 (s, 1H), 7.82 (d, J = 7.0 Hz, 1H), 7.79 (d, J = 8.3 Hz, 481.1272
    (trifluoromethyl)pyridin-3- 1H), 5.35 (m, 1H), 4.85 (m, 1H), (M + H)+;
    yl)thiazol-5- 4.64 (m, 1H), 4.46 (m, 1H), 3.58 (m, 1H), Rt-1.77
    yl)ethyl)amino)pyrimidin-4- 1.85 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.4 Hz,
    yl)oxazolidin-2-one 3H)
    248: (R)-4-((R)-1- 11.05 (br s, 1H), 8.84 (d, J = 5.1 Hz, 1H), HRMS
    hydroxyethyl)-3-(2-(((S)-1- 8.15 (s, 1H), 7.99 (d, J = 7.1 Hz, 1H), m/z
    (2-(2- 7.95 (s, 1H), 7.92 (dd, J = 5.1, 1.3 Hz, 1H), 481.1268
    (trifluoromethyl)pyridin-4- 7.83 (d, J = 7.0 Hz, 1H), 5.36 (m, 1H), 4.85 (m, (M + H)+;
    yl)thiazol-5- 1H), 4.65 (dd, J = 9.7, 2.0 Hz, 1H), Rt-1.72
    yl)ethyl)amino)pyrimidin-4- 4.46 (m, 1H), 3.62 (m, 1H), 1.85 (d, J = 6.9 Hz,
    yl)oxazolidin-2-one 3H), 0.97 (d, J = 6.5 Hz, 3H)
    249: methyl 2-(((S)-1-(2- 8.27 (s, 1H), 7.96 (s, 1H), 7.80 (d, J = 8.6 Hz, HRMS
    (4-chlorophenyl)thiazol-5- 2H), 7.47 (d, J = 8.6 Hz, 2H), 5.41 (m, m/z
    yl)ethyl)amino)-6-((R)-4- 1H), 4.66 (m, 1H), 4.45 (m, 1H), 4.01 (s, 504.1111
    ((R)-1-hydroxyethyl)-2- 3H), 3.75 (m, 1H), 1.78 (d, J = 6.9 Hz, 3H), (M + H)+;
    oxooxazolidin-3- 0.98 (d, J = 6.1 Hz, 3H) Rt-2.17
    yl)pyrimidine-4-
    carboxylate
    250: (R)-3-(2-(((S)-1-(1-(4- 11.00 (d, J = 8.5 Hz, 1H), 7.95 (m, 1H), LCMS m/z
    chlorophenyl)-2-methyl- 7.87 (m, 1H), 7.61 (m, 2H), 7.43 (d, J = 1.8 Hz, 443.2 (M + H)+;
    1H-imidazol-4- 1H), 7.35 (m, 2H), 5.95 (m, 1H), Rt-
    yl)ethyl)amino)pyrimidin-4- 5.02 (m, 1H), 4.80 (dd, J = 9.6, 2.4 Hz, 1H), 0.60
    yl)-4-((R)-1- 4.50 (m, 1H), 4.40 (m, 1H), 2.60 (m, 3H),
    hydroxyethyl)oxazolidin-2- 1.70 (m, 3H), 1.07 (m, 3H)
    one
    251: (R)-3-(2-(((S)-1-(2-(4- 10.92 (br s, 1H), 7.95 (m, 3H), 7.84 (s, 1H), LCMS m/z
    (difluoromethyl)phenyl)thiazol- 7.80 (d, J = 7.0 Hz, 1H), 7.60 (d, J = 8.2 Hz, 462.2 (M + H)+;
    5- 2H), 6.69 (t, J = 56 Hz, 1H), 5.27 (m, Rt-
    yl)ethyl)amino)pyrimidin-4- 1H), 4.81 (ddd, J = 8.2, 4.3, 2.1 Hz, 1H), 0.70
    yl)-4-((R)-1- 4.64 (dd, J = 9.6, 2.1 Hz, 1H), 4.45 (m,
    hydroxyethyl)oxazolidin-2- 1H), 3.39 (br m, 1H), 1.84 (d, J = 7.0 Hz,
    one 3H), 0.89 (d, J = 6.5 Hz, 3H)
    252: (R)-3-(2-((S)-1-(2- (CD3OD) 0.77 (br. s., 3 H) 1.64 (d, J = 6.99 Hz, HRMS (B)
    fluoro-4-(trifluoromethyl)phenyl)ethylamino) 3 H) 4.40-4.47 (m, 1 H) 4.57 (dd, m/z
    pyrimidin-4-yl)-4-((R)-1- J = 9.22, 2.52 Hz, 1 H) 5.43-5.51 (m, 1 H) 415.1402
    hydroxyethyl)oxazolidin-2- 7.50 (d, J = 9.15 Hz, 2 H) 7.62 (t, J = 7.73 Hz, (M + H)+;
    one 1 H) 7.67 (d, J = 6.85 Hz, 1 H) 8.15 (d, Rt-2.18 min
    J = 6.80 Hz, 1 H)
    253: (R)-3-(2-((S)-1-(4-(1- (CD3OD) 0.80 (br. s., 3 H) 0.95-1.00 (m, 2 HRMS (B)
    ethoxycyclopropyl)-2- H) 1.15 (t, J = 7.07 Hz, 3 H) 1.19-1.23 (m, m/z
    fluorophenyl) 2 H) 1.61 (d, J = 6.99 Hz, 3 H) 3.44 (qd, 431.2090
    ethylamino)pyrimidin-4-yl)- J = 7.05, 1.34 Hz, 2 H) 4.41-4.49 (m, 1 H) (M + H)+;
    4-((R)-1-hydroxyethyl) 4.59 (dd, J = 9.19, 2.49 Hz, 1 H) 5.40 (br. s., Rt-1.72 min
    oxazolidin-2-one 1 H) 7.06 (d, J = 2.15 Hz, 1 H) 7.09 (s, 1 H)
    7.36 (t, J = 7.92 Hz, 1 H) 7.66 (d, J = 6.85 Hz,
    1 H) 8.12 (d, J = 7.14 Hz, 1 H)
    254: 2-chloro-N- (CD3OD) 0.86 (br. s., 3 H) 1.57 (d, J = 6.99 Hz, HRMS (B)
    cyclopentyl-4-((S)-1-(4- 3 H) 1.59-1.69 (m, 3 H) 1.74 (d, m/z
    ((R)-4-((R)-1- J = 4.99 Hz, 2 H) 1.95-2.06 (m, 2 H) 474.1908
    hydroxyethyl)-2- 2.66 (s, 1 H) 4.29 (d, J = 6.46 Hz, 1 H) (M + H)+;
    oxooxazolidin-3- 4.38-4.46 (m, 1 H) 4.57 (dd, J = 9.24, 2.54 Hz, 1 Rt-1.58 min
    yl)pyrimidin-2- H) 5.13 (br. s., 1 H) 7.39 (s, 2 H) 7.47 (s, 1
    ylamino)ethyl)benzamide H) 7.61 (d, J = 6.21 Hz, 1 H) 8.13 (br. s., 1
    H) 8.40 (br. s., 1 H)
    255: 1-(3-fluoro-4-((S)-1- (CD3OD) 0.80 (br. s., 3 H) 1.47-1.51 (m, 2 HRMS (B)
    (4-((R)-4-((R)-1- H) 1.60 (d, J = 6.94 Hz, 3 H) 1.72-1.76 (m, m/z
    hydroxyethyl)-2- 2 H) 4.41-4.47 (m, 1 H) 4.58 (dd, J = 9.22, 412.1785
    oxooxazolidin-3- 2.57 Hz, 1 H) 5.39 (br. s., 1 H) 7.12 (dd, (M + H)+;
    yl)pyrimidin-2- J = 11.64, 1.91 Hz, 1 H) 7.18 (dd, J = 8.09, Rt-1.51 min
    ylamino)ethyl)phenyl)cyclopropanecarbonitrile 1.79 Hz, 1 H) 7.41 (t, J = 8.05 Hz, 1 H)
    7.64 (d, J = 6.65 Hz, 1 H) 8.13 (d, J = 6.80 Hz, 1
    H)
    256: (R)-3-(2-((S)-1-(2- (CD3OD) 0.82 (br. s., 3 H) 1.64 (d, J = 6.94 Hz, HRMS (B)
    fluoro-4-(1-methyl-1H- 3 H) 3.92 (s, 3 H) 4.07 (d, J = 16.09 Hz, m/z
    pyrazol-4-yl)phenyl) 1 H) 4.43-4.50 (m, 1 H) 4.60 (dd, J = 9.22, 427.1890
    ethylamino)pyrimidin-4-yl)- 2.47 Hz, 1 H) 4.91 (ddd, J = 8.20, 3.97, 2.45 Hz, (M + H)+;
    4-((R)-1-hydroxyethyl) 2 H) 5.45 (br. s., 1 H) 7.31-7.44 (m, 3 Rt-1.37 min
    oxazolidin-2-one H) 7.73 (d, J = 7.09 Hz, 1 H) 7.82 (d, J = 0.68 Hz,
    1 H) 7.98 (s, 1 H) 8.13 (d, J = 7.04 Hz, 1
    H)
    257: (R)-4-((R)-1- (CD3OD) 0.80 (br. s., 3 H) 1.62 (d, J = 6.94 Hz, HRMS (B)
    hydroxyethyl)-3-(2-((S)-1- 3 H) 3.92 (s, 3 H) 3.99 (br. s., 1 H) m/z
    (4-(1-methyl-1H-pyrazol-4- 4.42-4.50 (m, 1 H) 4.60 (dd, J = 9.24, 2.45 Hz, 409.1982
    yl)phenyl)ethylamino) 1 H) 5.21 (br. s., 1 H) 7.38 (d, J = 8.17 Hz, (M + H)+;
    pyrimidin-4-yl)oxazolidin- 2 H) 7.53-7.59 (m, 2 H) 7.73 (d, Rt-1.27 min
    2-one J = 7.14 Hz, 1 H) 7.79 (d, J = 0.68 Hz, 1 H)
    7.93 (s, 1 H) 8.12 (d, J = 6.11 Hz, 1 H)
    258: (R)-3-(2-((S)-1-(2- (CD3OD) 0.83 (br. s., 3 H) 1.65 (d, J = 6.99 Hz, HRMS (B)
    fluoro-4-(1H-pyrazol-4- 3 H) 4.07 (br. s., 1 H) 4.43-4.52 (m, 1 m/z
    yl)phenyl)ethylamino) H) 4.61 (dd, J = 9.24, 2.45 Hz, 1 H) 413.1732
    pyrimidin-4-yl)-4-((R)-1- 4.90-4.94 (m, 2 H) 5.45 (br. s., 1 H) (M + H)+;
    hydroxyethyl)oxazolidin-2- 7.36-7.42 (m, 3 H) 7.73 (d, J = 7.04 Hz, 1 H) 7.98 (s, 2 Rt-1.26 min
    one H) 8.13 (d, J = 6.90 Hz, 1 H)
    259: (R)-3-(5-fluoro-2-((S)- (CD3OD) 0.75 (br. s., 3 H) 1.54 (d, J = 7.04 Hz, HRMS (B)
    1-(2-fluoro-4- 3 H) 3.85 (br. s., 1 H) 4.42-4.55 (m, 2 m/z
    (trifluoromethyl)phenyl)ethylamino)pyrimidin- H) 5.27 (q, J = 6.99 Hz, 1 H) 433.1299
    4-yl)-4- 7.42 (d, J = 8.90 Hz, 2 H) 7.58 (t, J = 7.92 Hz, 1 H) (M + H)+;
    ((R)-1-hydroxyethyl) 8.21 (d, J = 2.74 Hz, 1 H) Rt-2.03 min
    oxazolidin-2-one
    260: (R)-3-(2-((S)-1-(2- (CD3OD) 0.73-0.87 (m, 7 H) 1.39 (s, 3 H) HRMS (B)
    fluoro-4-(1- 1.60 (d, J = 6.94 Hz, 3 H) 3.99 (br. s., 1 H) m/z
    methylcyclopropyl)phenyl) 4.40-4.49 (m, 1 H) 4.59 (dd, J = 9.19, 2.54 Hz, 401.1992
    ethylamino)pyrimidin-4-yl)- 1 H) 5.39 (br. s., 1 H) 7.01 (dd, (M + H)+;
    4-((R)-1-hydroxyethyl) J = 12.40, 1.74 Hz, 1 H) 7.05 (dd, J = 8.00, Rt-1.87 min
    oxazolidin-2-one 1.79 Hz, 1 H) 7.29 (t, J = 8.09 Hz, 1 H)
    7.69 (d, J = 6.99 Hz, 1 H) 8.12 (d, J = 6.94 Hz, 1
    H)
    261: (R)-3-(2-((S)-1-(2- (CD3OD) 8.12 (d, J = 6.7 Hz, 1 H), 7.69 (d, HRMS (B)
    fluoro-4- J = 7.0 Hz, 1 H), 7.31 (t, J = 8.0 Hz, 1 H), m/z
    isopropylphenyl)ethylamino)pyrimidin- 6.98-7.09 (m, 2 H), 5.42 (d, J = 12.9 Hz, 1 389.1987
    4-yl)-4-((R)-1- H), 4.59 (dd, J = 9.2, 2.5 Hz, 1 H), (M + H)+;
    hydroxyethyloxazolidin-2- 4.40-4.49 (m, 1 H), 2.91 (spt, J = 6.8 Hz, 1 H), Rt-1.83 min
    one 1.61 (d, J = 6.7 Hz, 3 H), 1.23 (d, J = 7.0 Hz,
    6 H), 0.80 (br. s., 3 H)
    262: (R)-3-(5-fluoro-2-((S)- (CD3OD) 0.75 (br. s., 3 H) 1.53 (d, J = 6.94 Hz, HRMS (B)
    1-(2-fluoro-4-(1-methyl- 3 H) 3.91 (s, 3 H) 4.42-4.56 (m, 2 H) m/z
    1H-pyrazol-4- 4.65 (br. s., 1 H) 5.22 (m, J = 7.04 Hz, 1 H) 445.1800
    yl)phenyl)ethylamino)pyrimidin- 7.22-7.31 (m, 2 H) 7.31-7.40 (m, 1 H) (M + H)+;
    4-yl)-4-((R)-1- 7.79 (s, 1 H) 7.94 (s, 1 H) 8.21 (br. s., 1 H) Rt-1.64 min
    hydroxyethyl)oxazolidin-2-
    one
    263: (R)-3-(5-fluoro-2-((S)- (CD3OD) 0.52-0.78 (m, 5 H) 0.82 (br. s., 2 HRMS (B)
    1-(2-fluoro-4-(1- H) 1.36 (s, 3 H) 1.49 (d, J = 6.99 Hz, 3 H) m/z
    methylcyclopropyl)phenyl) 3.86 (br. s., 1 H) 4.42-4.56 (m, 2 H) 419.1895
    ethylamino)pyrimidin-4-yl)- 4.62 (br. s., 1 H) 5.18 (m, J = 6.31 Hz, 1 H) (M + H)+;
    4-((R)-1-hydroxyethyl) 6.90-7.00 (m, 2 H) 7.24 (t, J = 8.17 Hz, 1 H) Rt-2.21 min
    oxazolidin-2-one 8.20 (d, J = 2.93 Hz, 1 H)
    264: (R)-3-(5-fluoro-2-((S)- (CD3OD) 0.76 (br. s., 3 H) 1.53 (d, J = 6.90 Hz, HRMS (B)
    1-(2-fluoro-4-(1H-pyrazol- 3 H) 3.91 (br. s., 1 H) 4.42-4.57 (m, 2 m/z
    4-yl)phenyl) H) 4.66 (br. s., 1 H) 5.23 (d, J = 6.41 Hz, 1 431.1640
    ethylamino)pyrimidin-4-yl)- H) 7.28-7.40 (m, 3 H) 7.97 (s, 2 H) (M + H)+;
    4-((R)-1-hydroxyethyl) 8.21 (br. s., 1 H) Rt-1.55 min
    oxazolidin-2-one
    265: (R)-3-(5-fluoro-2-((S)- (CD3OD) 0.71 (br. s., 3 H) 1.21 (d, J = 6.94 Hz, HRMS (B)
    1-(2-fluoro-4- 6 H) 1.50 (d, J = 6.99 Hz, 3 H) 2.87 (dt, m/z
    isopropylphenyl)ethylamino)pyrimidin- J = 13.72, 6.83 Hz, 1 H) 3.89 (br.s., 1 H) 407.1890
    4-yl)-4-((R)-1- 4.43-4.56 (m, 2 H) 4.63 (br. s., 1 H) (M + H)+;
    hydroxyethyl) oxazolidin- 5.20 (q, J = 6.52 Hz, 1 H) 6.90-7.00 (m, 2 H) Rt-2.18 min
    2-one 7.26 (t, J = 7.90 Hz, 1 H) 8.21 (d, J = 2.84 Hz,
    1 H)
    266: (R)-3-(5-fluoro-2-((S)- (CD3OD) 0.73 (br. s., 3 H) 1.47-1.52 (m, 9 HRMS (B)
    1-(2-fluoro-4-(2- H) 4.43-4.55 (m, 3 H) 4.59-4.67 (m, 1 H) m/z
    hydroxypropan-2- 5.15-5.27 (m, 1 H) 423.1838
    yl)phenyl)ethylamino)pyrimidin- 7.15-7.23 (m, 2 H) 7.30 (t, J = 8.09 Hz, 1 H) (M + H)+;
    4-yl)-4-((R)-1- 8.20 (d, J = 3.08 Hz, 1 H) Rt-1.59 min
    hydroxyethyl)oxazolidin-2-
    one
    267: (R)-3-(2-(((S)-1-(2,5- (CD3OD) 0.79 (br. s., 3 H) 1.52 (d, J = 6.99 Hz, HRMS (B)
    difluoro-4-(1-methyl-1H- 3 H) 3.92 (s, 3 H) 4.43-4.56 (m, 2 H) m/z
    pyrazol-4- 4.64 (d, J = 3.42 Hz, 1 H) 5.21 (q, J = 6.83 Hz, 463.1708
    yl)phenyl)ethyl)amino)-5- 1 H) 7.14 (dd, J = 11.40, 6.31 Hz, 1 H) (M + H)+;
    fluoropyrimidin-4-yl)-4- 7.39 (dd, J = 10.93, 6.14 Hz, 1 H) 7.86 (d, Rt-1.72 min
    ((R)-1-hydroxyethyl) J = 0.59 Hz, 1 H) 8.00 (d, J = 1.86 Hz, 1 H)
    oxazolidin-2-one 8.23 (d, J = 3.03 Hz, 1 H)
    268: (R)-3-(2-(((S)-1-(2-(4- (CD3CN) 0.98 (d, J = 6.65 Hz, 3 H) 1.72 (d, HRMS (B)
    chlorophenyl) thiazol-5- J = 7.04 Hz, 3 H) 4.00 (br. s., 1 H) m/z
    yl)ethyl)amino) pyrimidin- 4.26-4.42 (m, 1 H) 4.51 (dd, J = 8.80, 2.93 Hz, 1 446.1060
    4-yl)-4-((S)-1- H) 4.62 (dd, J = 7.24, 1.37 Hz, 1 H) (M + H)+;
    hydroxyethyl)oxazolidin-2- 5.49 (quin, J = 6.85 Hz, 1 H) 7.49 (d, J = 8.61 Hz, Rt-1.81 min
    one 2 H) 7.66-7.78 (m, 2 H) 7.91 (d, J = 8.61 Hz,
    2 H) 8.05 (d, J = 7.04 Hz, 1 H)
    10.52 (br. s., 1 H)
    269: (R)-3-(6-chloro-2- (CDCl3) 0.80 (br. s., 3 H) 1.26 (s, 3 H) HRMS (B)
    (((S)-1-(2-fluoro-4-(2- 1.63-1.73 (m, 9 H) 4.28-4.36 (m, 1 H) m/z
    fluoropropan-2- 4.44 (dd, J = 9.39, 2.54 Hz, 1 H) 4.64 (br. s., 1 H) 441.1501
    yl)phenyl)ethyl)amino)pyrimidin- 5.21 (br. s., 1 H) 7.07-7.18 (m, 2 H) (M + H)+;
    4-yl)-4-((R)-1- 7.28-7.33 (m, 1 H) 7.51 (s, 1 H) Rt-2.35 min
    hydroxyethyl)oxazolidin-2-
    one
    270: (R)-3-(5-chloro-2- (CD3OD) δ HRMS (B)
    (((S)-1-(1-(4- 8.20 (s, 1 H), 8.03 (d, J = 1.2 Hz, 1 H), m/z
    chlorophenyl)-1H- 7.30-7.52 (m, 6 H), 5.06 (d, J = 6.7 Hz, 1 H), 399.1029
    imidazol-4- 4.67 (dt, J = 8.6, 6.1 Hz, 1 H), 4.45 (t, J = 8.8 Hz, (M + H)+
    yl)ethyl)amino)pyrimidin-4- 1 H), 4.31 (dd, J = 9.0, 6.3 Hz, 1 H), RT = 1.95 min.
    yl)-4-((R)-1- 3.81 (br. s., 1 H), 1.49 (d, J = 6.7 Hz, 3 H),
    hydroxyethyl)oxazolidin-2- 0.91 (br. s., 3 H)
    one
    271: (R)-3-(2-((S)-1-(2,5- (CD3OD) 8.14 (br. s., 1 H), 7.64 (d, J = 6.7 Hz, HRMS (B)
    difluoro-4- 1 H), 7.07 (dd, J = 10.2, 6.3 Hz, 2 H), m/z
    isopropylphenyl)ethylamino)pyrimidin- 5.37 (d, J = 5.1 Hz, 1 H), 4.85 (s, 1H), 407.1895,
    4-yl)-4-((R)-1- 4.57 (dd, J = 9.4, 2.3 Hz, 1 H), 4.38-4.49 (m, 1 (M + H)+,
    hydroxyethyl)oxazolidin-2- H), 3.96 (br. s., 1 H), 3.11-3.25 (m, 1 H), RT = 1.95 min.
    one 1.57 (d, J = 7.0 Hz, 3 H), 1.23 (dd, J = 7.0,
    2.0 Hz, 6 H), 0.80 (br. s., 3 H)
    272: (R)-3-(2-(((S)-1-(4- (CD3OD) 8.14 (d, J = 5.9 Hz, 1 H), 7.51 (d, HRMS (B)
    bromo-2,5- J = 6.3 Hz, 1 H), 7.44 (dd, J = 9.4, 5.5 Hz, 1 m/z
    difluorophenyl)ethyl)amino)pyrimidin- H), 7.24 (dd, J = 9.0, 6.3 Hz, 1 H), 5.33 (q, 443.0527,
    4-yl)-4-((R)-1- J = 6.7 Hz, 1 H), 4.85 (s, 8 H), 4.54 (dd, (M + H)+,
    hydroxyethyl)oxazolidin-2- J = 9.2, 2.5 Hz, 2 H), 4.34-4.47 (m, 1 H), RT = 1.74 min.
    one 1.54 (d, J = 6.7 Hz, 3 H), 0.83 (br. s., 3 H)
    273: (R)-3-(2-((S)-1-(5- (CD3OD) 8.55 (d, J = 1.2 Hz, 1 H), 8.16 (d, HRMS (B)
    chloro-6-(1,1- J = 5.9 Hz, 1 H), 7.99 (s, 1 H), 7.64 (d, m/z
    difluoroethyl)pyridin-3- J = 5.9 Hz, 1 H), 5.27 (br. s., 1 H), 4.85 (s, 2 428.1299,
    yl)ethylamino)pyrimidin-4- H), 4.56 (dd, J = 9.0, 2.3 Hz, 1 H), (M + H)+,
    yl)-4-((R)-1- 4.39-4.47 (m, 1 H), 2.04 (t, J = 19.0 Hz, 3 H), RT = 1.65 min.
    hydroxyethyl)oxazolidin-2- 1.63 (d, J = 7.0 Hz, 3 H), 0.82 (br. s., 3 H)
    one
    274: (R)-3-(2-((S)-1-(5- (CD3OD) 8.15 (d, J = 2.0 Hz, 2 H), 7.92 (d, HRMS (B)
    chloro-6-(2,2,2- J = 2.3 Hz, 1 H), 7.71 (d, J = 7.0 Hz, 1 H), m/z
    trifluoroethoxy)pyridin-3- 5.25 (br. s., 1 H), 4.89-4.99 (m, 3H), 462.1149,
    yl)ethylamino)pyrimidin-4- 4.59 (dd, J = 9.4, 2.3 Hz, 1 H), 4.41-4.50 (m, 1 (M + H)+,
    yl)-4-((R)-1- H), 4.00 (br. s., 1 H), 1.62 (d, J = 7.0 Hz, 6 RT = 1.87 min.
    hydroxyethyl)oxazolidin-2- H)
    one
    275: (R)-3-(2-((S)-1-(4- (CD3OD) 8.16 (br. s., 1 H), 7.71 (d, J = 6.7 Hz, HRMS (B)
    bromo-2,3- 1 H), 7.36-7.48 (m, 1 H), m/z
    difluorophenyl)ethylamino) 7.09-7.22 (m, 1 H), 5.42 (br. s., 1 H), 4.87 (s, 1 H), 443.0532,
    pyrimidin-4-yl)-4-((R)-1- 4.57 (dd, J = 9.0, 2.3 Hz, 1 H), (M + H)+,
    hydroxyethyl)oxazolidin-2- 4.39-4.50 (m, 1 H), 3.82 (br. s., 1 H), 1.62 (d, J = 7.0 Hz, RT = 1.81 min.
    one 6 H)
    276: (R)-3-(2-(((S)-1-(4- (CD3OD) 8.22 (d, J = 2.3 Hz, 1 H), 7.41 (dd, HRMS (B)
    bromo-2,5- J = 9.0, 5.5 Hz, 1 H), 7.21 (dd, J = 9.2, 6.5 Hz, m/z
    difluorophenyl)ethyl)amino)- 1 H), 5.13-5.23 (m, 1 H), 461.0432,
    5-fluoropyrimidin-4-yl)-4- 4.86 (s, 1 H), 4.38-4.55 (m, 2 H), (M + H)+,
    ((R)-1- 3.99-4.16 (m, 1 H), 1.49 (d, J = 7.0 Hz, 6 H) RT = 2.01 min.
    hydroxyethyl)oxazolidin-2-
    one
    277: (R)-3-(2-(((S)-1-(4- (CD3OD) 8.20 (d, J = 2.3 Hz, 1 H), HRMS (B)
    bromo-2- 7.18-7.38 (m, 3 H), 5.18 (q, J = 7.0 Hz, 1 H), m/z
    fluorophenyl)ethyl)amino)- 4.61 (t, J = 9.0 Hz, 1 H), 4.42-4.55 (m, 2 H), 443.0534,
    5-fluoropyrimidin-4-yl)-4- 3.89 (br. s., 1 H), 1.49 (d, J = 7.0 Hz, 6 H) (M + H)+,
    ((R)-1- RT = 1.99 min.
    hydroxyethyl)oxazolidin-2-
    one
    278: (R)-3-(2-(((S)-1-(4- (CD3OD) 8.21 (d, J = 2.7 Hz, 1 H), 7.36 (t, HRMS (B)
    chloro-2- J = 8.4 Hz, 1 H), 7.05-7.21 (m, 2 H), m/z
    fluorophenyl)ethyl)amino)- 5.20 (q, J = 7.0 Hz, 1 H), 4.62 (d, J = 8.6 Hz, 1 H), 399.1029,
    5-fluoropyrimidin-4-yl)-4- 4.42-4.56 (m, 2 H), 3.90 (br. s., 1 H), (M + H)+,
    ((R)-1- 1.50 (d, J = 7.0 Hz, 6 H) RT = 1.95 min.
    hydroxyethyl)oxazolidin-2-
    one
    279: (R)-3-(2-((S)-1-(5- (CD3OD) 8.45 (s, 1 H), 8.21 (d, J = 2.7 Hz, HRMS (B)
    bromo-3-fluoropyridin-2- 1 H), 7.86 (dd, J = 9.4, 2.0 Hz, 1 H), 5.35 (q, m/z
    yl)ethylamino)-5- J = 6.7 Hz, 1 H), 4.67-4.77 (m, 1H), 444.0483,
    fluoropyrimidin-4-yl)-4- 4.43-4.58 (m, 2 H), 4.08-4.20 (m, 1 H), 1.51 (d, (M + H)+,
    ((R)-1- J = 6.7 Hz, 3 H), 1.09 (d, J = 6.7 Hz, 3 H) RT = 1.75 min.
    hydroxyethyl)oxazolidin-2-
    one
    280: (R)-3-(2-((R)-1-(5- (CD3OD) 8.44 (s, 1 H), 8.22 (d, J = 2.7 Hz, HRMS (B)
    bromo-3-fluoropyridin-2- 1 H), 7.86 (dd, J = 9.4, 1.6 Hz, 1 H), m/z
    yl)ethylamino)-5- 5.30-5.38 (m, 1 H), 4.61-4.71 (m, 1H), 444.0478,
    fluoropyrimidin-4-yl)-4- 4.50-4.58 (m, 1 H), 4.43-4.49 (m, 1 H), (M + H)+,
    ((R)-1- 3.92 (br. s., 1 H), 1.52 (d, J = 7.0 Hz, 6 H) RT = 1.75 min.
    hydroxyethyl)oxazolidin-2-
    one
    281: (R)-3-(2-((S)-1-(3-(4- (CD3OD) 8.27 (br. s., 1 H), 8.01 (dd, HRMS (B)
    chlorophenyl)-1,2,4- J = 8.6, 2.3 Hz, 2 H), 7.47-7.56 (m, 2 H), m/z
    oxadiazol-5- 5.30-5.43 (m, 1 H), 4.68 (d, J = 13.7 Hz, 1 449.1140,
    yl)ethylamino)-5- H), 4.40-4.57 (m, 2 H), 4.00 (br. s., 1 H), (M + H)+,
    fluoropyrimidin-4-yl)-4- 1.72 (d, J = 7.0 Hz, 6 H) RT = 2.04 min.
    ((R)-1-
    hydroxyethyl)oxazolidin-2-
    one
    282: (R)-3-(2-((S)-1-(5- (CD3OD) 8.65 (d, J = 2.0 Hz, 1 H), 8.22 (d, HRMS (B)
    bromopyridin-2- J = 2.3 Hz, 1 H), 8.07 (dd, J = 8.6, 2.3 Hz, 1 m/z
    yl)ethylamino)-5- H), 7.51 (d, J = 8.2 Hz, 1 H), 5.00-5.08 (m, 426.0574,
    fluoropyrimidin-4-yl)-4- 1 H), 4.61 (br. s., 1 H), 4.42-4.55 (m, 2 (M + H)+,
    ((R)-1- H), 4.06-4.17 (m, 1 H), 1.55 (d, J = 7.0 Hz, RT = 1.61 min.
    hydroxyethyl)oxazolidin-2- 3 H), 1.08 (d, J = 6.7 Hz, 3 H)
    one
    283: (R)-3-(2-(((S)-1-(4- (CD3OD) 8.21 (d, J = 2.7 Hz, 1 H), 7.52 (t, HRMS (B)
    bromo-3- J = 7.6 Hz, 1 H), 7.21 (dd, J = 9.8, 2.0 Hz, 1 m/z
    fluorophenyl)ethyl)amino)- H), 7.12 (dd, J = 8.2, 2.0 Hz, 1 H), 443.0526,
    5-fluoropyrimidin-4-yl)-4- 4.88-4.97 (m, 1 H), 4.59 (d, J = 8.2 Hz, 1 H), (M + H)+,
    ((R)-1- 4.42-4.55 (m, 2 H), 3.88 (br. s., 1 H), 1.49 (d, RT = 1.96 min.
    hydroxyethyl)oxazolidin-2- J = 7.0 Hz, 3 H), 0.80 (br. s., 3 H)
    one
    284: (R)-3-(2-(((S)-1-(5- (CD3OD) 8.51 (s, 1H), 8.24 (s, 1H), 7.76 (s, HRMS (B)
    chloro-6-(1,1- 1H), 5.13 (m, 1 H), 4.91 (m, 1H), m/z
    difluoroethyl)pyridin-3- 4.42-4.55 (m, 2H), 4.41 (br. s., 1 H), 2.12 (t, 446.1208,
    yl)ethyl)amino)-5- J = 7.0 Hz, 3H), 1.22 (m, 6H) (M + H)+,
    fluoropyrimidin-4-yl)-4- RT = 1.85 min.
    ((R)-1-
    hydroxyethyl)oxazolidin-2-
    one
    285: (R)-3-(2-(((S)-1-(5- (CD3OD) 8.22 (d, J = 2.7 Hz, 1 H), 8.11 (d, HRMS (B)
    chloro-6-(2,2,2- J = 2.0 Hz, 1 H), 7.84 (d, J = 2.0 Hz, 1 H), m/z
    trifluoroethoxy)pyridin-3- 4.89-5.02 (m, 3 H), 4.62 (d, J = 3.5 Hz, 1 480.1065,
    yl)ethyl)amino)-5- H), 4.42-4.57 (m, 2 H), 3.90 (br. s., 1 H), (M + H)+,
    fluoropyrimidin-4-yl)-4- 1.52 (d, J = 7.0 Hz, 3 H), 0.85 (br. s., 3 H) RT = 2.10 min.
    ((R)-1-
    hydroxyethyl)oxazolidin-2-
    one
    286: (R)-3-(2-(((S)-1-(2,4- (CD3OD) 8.21 (d, J = 2.3 Hz, 1 H), HRMS (B)
    dichlorophenyl)ethyl)amino)- 7.36-7.46 (m, 2 H), 7.24 (dd, J = 8.2, 2.0 Hz, 1 m/z
    5-fluoropyrimidin-4-yl)- H), 5.25 (q, J = 6.7 Hz, 1 H), 4.59 (br.s., 1 415.0741,
    4-((R)-1- H), 4.40-4.54 (m, 2 H), 3.81 (br. s., 1 H), (M + H)+,
    hydroxyethyl)oxazolidin-2- 1.47 (d, J = 7.0 Hz, 6 H) RT = 2.07 min.
    one
    287: (R)-3-(2-(((S)-1-(6- (CD3OD) 8.40 (d, J = 2.3 Hz, 1 H), 8.12 (br. HRMS (B)
    bromopyridin-3- s., 1 H), 7.75 (dd, J = 8.4, 2.5 Hz, 1 H), m/z
    yl)ethyl)amino)-5- 7.59 (d, J = 8.2 Hz, 1 H), 5.17 (br. s., 1 H), 426.0570,
    fluoropyrimidin-4-yl)-4- 5.05 (q, J = 7.0 Hz, 1 H), 4.43 (t, J = 8.6 Hz, 1 H), (M + H)+,
    ((R)-1- 4.00-4.14 (m, 2 H), 1.59 (d, J = 7.0 Hz, 3 RT = 1.51 min.
    hydroxyethyl)oxazolidin-2- H), 1.40 (d, J = 6.7 Hz, 3 H)
    one
    288: (R)-3-(2-(((S)-1-(4- (CD3OD) 8.21 (d, J = 3.1 Hz, 1 H), 7.38 (t, HRMS (B)
    chloro-3- J = 8.0 Hz, 1 H), 7.12-7.28 (m, 2 H), m/z
    fluorophenyl)ethyl)amino)- 4.88-5.00 (m, 1 H), 4.59 (br. s., 1 H), 399.1031,
    5-fluoropyrimidin-4-yl)-4- 4.42-4.55 (m, 2 H), 3.89 (br. s., 1 H), 1.49 (d, J = 7.0 Hz, (M + H)+,
    ((R)-1- 3 H), 0.81 (br. s., 3 H) RT = 1.91 min.
    hydroxyethyl)oxazolidin-2-
    one
    289: (R)-3-(2-(((R)-1-(5- (CD3OD) 8.57 (d, J = 2.3 Hz, 1 H), HRMS (B)
    bromopyridin-2- 7.88-7.97 (m, 2 H), 7.37 (d, J = 8.6 Hz, 1 H), m/z
    yl)ethyl)amino)-5- 5.09 (br. s., 1 H), 4.94 (d, J = 7.0 Hz, 1H), 4.38 (t, 426.0574,
    fluoropyrimidin-4-yl)-4- J = 8.8 Hz, 1 H), 3.93-4.12 (m, 2 H), (M + H)+,
    ((R)-1- 1.51 (d, J = 7.0 Hz, 3 H), 1.31 (d, J = 6.3 Hz, 3 H) RT = 1.55 min.
    hydroxyethyl)oxazolidin-2-
    one
    290: (R)-3-(2-(((S)-1-(3,4- (CD3OD) 8.20 (d, J = 2.7 Hz, 1 H), 7.51 (d, HRMS (B)
    dichlorophenyl)ethyl)amino)- J = 2.0 Hz, 1 H), 7.43 (d, J = 8.2 Hz, 1 H), m/z
    5-fluoropyrimidin-4-yl)- 7.29 (dd, J = 8.4, 1.8 Hz, 1 H), 415.0738,
    4-((R)-1- 4.87-4.97 (m, 1 H), 4.59 (br. s., 1 H), 4.40-4.55 (m, (M + H)+,
    hydroxyethyl)oxazolidin-2- 2 H), 3.89 (br. s., 1 H), 1.49 (d, J = 7.0 Hz, 6 RT = 2.02 min.
    one H)
    291: (R)-3-(2-(((S)-1-(6- (CDCl3) 8.25 (s, 1H), 8.22 (m, 1H), HRMS (B)
    chloro-5-fluoropyridin-3- 7.51 (m, 1H), 5.51 (s, 1H), 4.91 (m, 1 H), m/z
    yl)ethyl)amino)-5- 4.51 (m, 2H), 4.41 (m, 1 H), 3.62 (m, 1H), 400.0981,
    fluoropyrimidin-4-yl)-4- 1.45 (d, J = 7.0 Hz, 3 H), 1.01 (br. s., 3H) (M + H)+,
    ((R)-1- RT = 1.61 min.
    hydroxyethyl)oxazolidin-2-
    one
    292: (R)-3-(2-(((S)-1-(5,6- (CDCl3) 8.37 (s, 1H), 8.15 (m, 1H), HRMS (B)
    dichloropyridin-3- 7.76 (m, 1H), 5.68 (s, 1H), 4.94 (m, 1 H), m/z
    yl)ethyl)amino)-5- 4.51 (m, 2H), 4.45 (m, 1 H), 3.68 (m, 1H), 416.0690,
    fluoropyrimidin-4-yl)-4- 1.58 (d, J = 7.0 Hz, 3 H), 1.01 (br. s., 3H) (M + H)+,
    ((R)-1- RT = 1.73 min.
    hydroxyethyl)oxazolidin-2-
    one
    293: (R)-3-(2-(((R)-1-(3,5- (cdcl3) 8.43 (d, J = 2.0 Hz, 1 H), 8.23 (d, HRMS (B)
    dichloropyridin-2- J = 2.3 Hz, 1 H), 7.72 (d, J = 2.0 Hz, 1 H), m/z
    yl)ethyl)amino)-5- 6.29 (d, J = 7.8 Hz, 1 H), 5.50 (br. s., 1 H), 416.0685,
    fluoropyrimidin-4-yl)-4- 4.48-4.59 (m, 2 H), 4.37-4.47 (m, 1 H), (M + H)+,
    ((R)-1- 4.24 (br. s., 1 H), 1.48 (d, J = 6.7 Hz, 3 H), RT = 1.83 min.
    hydroxyethyl)oxazolidin-2- 1.22 (d, J = 6.7 Hz, 3 H)
    one
    294: (R)-3-(2-(((S)-1-(3,5- (CDCl3) 8.42 (d, J = 2.0 Hz, 1 H), 8.22 (d, HRMS (B)
    dichloropyridin-2- J = 2.7 Hz, 1 H), 7.72 (d, J = 2.0 Hz, 1 H), m/z
    yl)ethyl)amino)-5- 6.22 (d, J = 8.2 Hz, 1 H), 5.51 (br. s.,1 H), 416.0687,
    fluoropyrimidin-4-yl)-4- 4.47-4.67 (m, 2 H), 4.34-4.45 (m, 1 H), (M + H)+,
    ((R)-1- 1.49 (d, J = 7.0 Hz, 3 H), 1.14 (br. s., 3 H) RT = 1.82 min.
    hydroxyethyl)oxazolidin-2-
    one
    295: (R)-3-(6-chloro-2- (CDCl3) 8.43 (d, J = 2.0 Hz, 1 H), 7.73 (d, HRMS (B)
    (((S)-1-(3,5- J = 2.0 Hz, 1 H), 7.50 (s, 1 H), 6.39 (d, m/z
    dichloropyridin-2- J = 7.4 Hz, 1 H), 5.52 (br. s., 1 H), 432.0391,
    yl)ethyl)amino)pyrimidin-4- 4.72-4.93 (m, 1 H), 4.32-4.62 (m, 2 H), (M + H)+,
    yl)-4-((R)-1- 4.13 (br. s., 1 H), 1.50 (d, J = 6.7 Hz, 3 H), RT = 2.27 min.
    hydroxyethyl)oxazolidin-2- 1.07 (br. s., 3 H)
    one
    296: (R)-3-(6-chloro-2- (CDCl3) 8.13 (br. s., 1 H), 7.49 (s, 1 H), HRMS (B)
    (((S)-1-(3-fluoro-5-(2,2,2- 7.07 (dd, J = 10.8, 2.2 Hz, 1 H), 6.17 (br. s., m/z
    trifluoroethoxy)pyridin-2- 1 H), 5.40 (br. s., 1 H), 4.70-5.04 (m, 1 H), 480.1066,
    yl)ethyl)amino)pyrimidin-4- 4.52 (br. s., 1 H), 4.41 (q, J = 7.8 Hz, 3 H), (M + H)+,
    yl)-4-((R)-1- 4.18 (br. s., 1 H), 1.53 (br. s., 3 H), RT = 2.21 min.
    hydroxyethyl)oxazolidin-2- 1.01-1.18 (m, 3 H)
    one
    297: (R)-3-(2-(((R)-1-(1-(4- (CDCl3) 8.19 (d, J = 2.7 Hz, 1 H), 7.81 (d, HRMS (B)
    chlorophenyl)-1H-pyrazol- J = 2.3 Hz, 1 H), 7.59 (d, J = 9.0 Hz, 2 H), m/z
    3-yl)ethyl)amino)-5- 7.41 (d, J = 9.0 Hz, 2 H), 6.39 (d, J = 2.3 Hz, 1 447.1348,
    fluoropyrimidin-4-yl)-4- H), 5.12 (br. s., 1 H), 4.25-4.58 (m, 4 H), (M + H)+,
    ((R)-1- 3.03 (br. s., 1 H), 1.61 (d, J = 7.0 Hz, 3 H), RT = 2.00 min.
    hydroxyethyl)oxazolidin-2- 1.20 (d, J = 6.3 Hz, 3 H)
    one
    298: (R)-3-(2-(((S)-1-(1-(4- (CDCl3) 8.19 (d, J = 2.0 Hz, 1 H), 7.80 (d, HRMS (B)
    chlorophenyl)-1H-pyrazol- J = 2.0 Hz, 1 H), 7.58 (d, J = 9.0 Hz, 2 H), m/z
    3-yl)ethyl)amino)-5- 7.41 (d, J = 9.0 Hz, 2 H), 6.39 (d, J = 2.3 Hz, 1 447.1345,
    fluoropyrimidin-4-yl)-4- H), 5.18 (br. s., 1 H), 4.60 (t, J = 5.5 Hz, 1 (M + H)+,
    ((R)-1- H), 4.51 (t, J = 8.6 Hz, 1 H), 4.34 (dd, J = 8.8, RT = 1.98 min.
    hydroxyethyl)oxazolidin-2- 5.3 Hz, 1 H), 4.00 (br. s., 1 H), 1.62 (d,
    one J = 7.0 Hz, 3 H), 1.03 (br. s., 3 H)
    299: (R)-3-(2-(((R)-1-(1-(4- (CDCl3) 8.20 (d, J = 2.7 Hz, 1 H), 7.76 (s, 1 HRMS (B)
    chlorophenyl)-1H- H), 7.45 (d, J = 8.6 Hz, 2 H), 7.31 (d, J = 8.6 Hz, m/z
    imidazol-4-yl)ethyl)amino)- 2 H), 7.14 (s, 1 H), 5.61 (d, J = 7.4 Hz, 1 447.1346,
    5-fluoropyrimidin-4-yl)-4- H), 5.07 (d, J = 5.9 Hz, 1 H), 4.32-4.57 (m, (M + H)+,
    ((R)-1- 4 H), 1.59 (d, J = 6.7 Hz, 3 H), 1.21 (d, RT = 1.32 min.
    hydroxyethyl)oxazolidin-2- J = 6.3 Hz, 3 H)
    one
    300: (R)-3-(2-(((S)-1-(1-(4- (CDCl3) 8.19 (d, J = 2.7 Hz, 1 H), 7.71 (s, 1 HRMS (B)
    chlorophenyl)-1H- H), 7.45 (d, J = 8.6 Hz, 2 H), 7.30 (d, J = 8.6 Hz, m/z
    imidazol-4-yl)ethyl)amino)- 2 H), 7.12 (s, 1 H), 5.42 (d, J = 7.8 Hz, 1 447.1350,
    5-fluoropyrimidin-4-yl)-4- H), 5.20 (quin, J = 7.1 Hz, 1 H), 4.74 (br. s., (M + H)+,
    ((R)-1- 1 H), 4.54 (t, J = 8.8 Hz, 1 H), 4.29 (dd, RT = 1.34 min.
    hydroxyethyl)oxazolidin-2- J = 8.6, 5.9 Hz, 1 H), 3.99 (br. s., 1 H),
    one 1.62 (d, J = 7.0 Hz, 3 H), 1.15 (d, J = 6.3 Hz, 3 H)
    301: (R)-3-(2-(((S)-1-(2,5- (CDCl3) 8.20 (d, J = 2.7 Hz, 1 H), 7.09 (dd, HRMS (B)
    difluoro-4-(2,2,2- J = 11.3, 7.0 Hz, 1 H), 6.79 (dd, J = 10.4, 6.8 Hz, m/z
    trifluoroethoxy)phenyl)ethyl)amino)- 1 H), 5.52 (br. s., 1 H), 5.11 (quin, 481.1315,
    5- J = 6.7 Hz, 1 H), 4.45-4.59 (m, 2 H), (M + H)+,
    fluoropyrimidin-4-yl)-4- 4.31-4.44 (m, 3 H), 3.87 (br. s., 1 H), 1.53 (d, RT = 2.04 min.
    ((R)-1- J = 7.0 Hz, 3 H), 1.03 (d, J = 4.3 Hz, 3 H)
    hydroxyethyl)oxazolidin-2-
    one
    302: (R)-3-(5-fluoro-2- (CDCl3) 8.19 (d, J = 2.3 Hz, 1 H), HRMS (B)
    (((S)-1-(2-fluoro-4-(2,2,2- 6.62-6.75 (m, 3 H), 5.48 (br. s., 1 H), 5.14 (t, m/z
    trifluoroethoxy)phenyl)ethyl)amino)pyrimidin- J = 6.8 Hz, 1 H), 4.43-4.54 (m, 2 H), 463.1403,
    4-yl)-4- 4.24-4.40 (m, 3 H), 3.82 (br. s., 1 H), 1.53 (d, (M + H)+,
    ((R)-1- J = 6.7 Hz, 3 H), 0.99 (br. s., 3 H) RT = 2.03 min.
    hydroxyethyl)oxazolidin-2-
    one
    303: (R)-3-(5-fluoro-2- (CDCl3) 8.20 (d, J = 2.3 Hz, 1 H), 7.12 (dd, HRMS (B)
    (((S)-1-(3-fluoro-4-(2,2,2- J = 11.7, 2.0 Hz, 1 H), 7.04-7.09 (m, 1 H), m/z
    trifluoroethoxy)phenyl)ethyl)amino)pyrimidin- 6.93-7.03 (m, 1 H), 5.44 (br. s., 1 H), 463.1403,
    4-yl)-4- 4.86 (d, J = 6.3 Hz, 1 H), 4.45-4.55 (m, 1 H), (M + H)+,
    ((R)-1- 4.27-4.45 (m, 3 H), 3.76 (br. s., 1 H), RT = 1.99 min.
    hydroxyethyl)oxazolidin-2- 1.51 (d, J = 7.0 Hz, 3 H), 1.01 (br. s., 3 H)
    one
    304: (R)-3-(5-fluoro-2- (CDCl3) 8.22 (d, J = 2.7 Hz, 1 H), 7.77 (d, HRMS (B)
    (((S)-1-(1-(4-fluorophenyl)- J = 2.3 Hz, 1 H), 7.54-7.67 (m, 2 H), m/z
    1H-pyrazol-3- 7.14 (t, J = 8.4 Hz, 2 H), 6.36 (d, J = 2.3 Hz, 1 H), 431.1643,
    yl)ethyl)amino)pyrimidin-4- 5.66 (d, J = 7.8 Hz, 1 H), 5.10-5.25 (m, 1 (M + H)+,
    yl)-4-((R)-1- H), 4.55-4.64 (m, 1 H), 4.47-4.54 (m, 1 RT = 1.80 min.
    hydroxyethyl)oxazolidin-2- H), 4.34 (dd, J = 8.6, 5.1 Hz, 1 H), 4.02 (br.
    one s., 1 H), 1.61 (d, J = 7.0 Hz, 6 H)
    305: (R)-3-(5-fluoro-2- (CDCl3) 8.30 (d, J = 2.7 Hz, 1 H), 8.20 (d, HRMS (B)
    (((S)-1-(5-(2,2,2- J = 2.7 Hz, 1 H), 7.23-7.37 (m, 2 H), m/z
    trifluoroethoxy)pyridin-2- 5.96-6.10 (m, 1 H), 4.97-5.14 (m, 1H), 446.1449,
    yl)ethyl)amino)pyrimidin-4- 4.44-4.57 (m, 2 H), 4.28-4.44 (m, 3 H), (M + H)+,
    yl)-4-((R)-1- 3.96 (br. s., 1 H), 1.54 (d, J = 6.7 Hz, 6 H) RT = 1.58 min.
    hydroxyethyl)oxazolidin-2-
    one
    306: (R)-3-(5-fluoro-2- (CDCl3) 8.28 (d, J = 2.3 Hz, 1 H), 8.20 (d, HRMS (B)
    (((R)-1-(5-(2,2,2- J = 3.1 Hz, 1 H), 7.21-7.36 (m, 2 H), m/z
    trifluoroethoxy)pyridin-2- 6.02 (d, J = 6.7 Hz, 1 H), 5.00 (br. s., 1H), 446.1447,
    yl)ethyl)amino)pyrimidin-4- 4.25-4.57 (m, 5 H), 1.52 (d, J = 6.7 Hz, 3 H), (M + H)+,
    yl)-4-((R)-1- 1.20 (d, J = 6.3 Hz, 3 H) RT = 1.59 min.
    hydroxyethyl)oxazolidin-2-
    one
    307: (R)-3-(2-(((S)-1-(1-(4- (CD3OD) 9.02 (br. s., 1 H), 8.20 (d, J = 6.7 Hz, HRMS (B)
    chlorophenyl)-1H- 1 H), 7.89 (s, 1 H), 7.64-7.72 (m, 3 m/z
    imidazol-4- H), 7.56-7.64 (m, 2 H), 5.37 (d, J = 6.3 Hz, 429.1438,
    yl)ethyl)amino)pyrimidin-4- 1 H), 4.75-5.01 (m, 2 H), 4.56 (dd, J = 9.4, (M + H)+,
    yl)-4-((R)-1- 2.3 Hz, 1 H), 4.40-4.50 (m, 1 H), 1.72 (d, RT = 1.30 min.
    hydroxyethyl)oxazolidin-2- J = 7.0 Hz, 3 H), 1.02 (d, J = 6.3 Hz, 3 H)
    one
    308: (R)-3-(2-(((S)-1-(1-(4- (CD3OD) 8.19 (d, J = 2.3 Hz, 1 H), 8.15 (d, HRMS (B)
    chlorophenyl)-1H-pyrazol- J = 7.0 Hz, 1 H), 7.74 (dd, J = 7.8, 6.7 Hz, 3 m/z
    3-yl)ethyl)amino)pyrimidin- H), 7.45 (d, J = 9.0 Hz, 2 H), 6.53 (d, J = 2.3 Hz, 429.1441,
    4-yl)-4-((R)-1- 1 H), 5.46 (br. s., 1 H), 4.81-4.97 (m, (M + H)+,
    hydroxyethyl)oxazolidin-2- 2 H), 4.60 (dd, J = 9.4, 2.3 Hz, 1 H), RT = 1.65 min.
    one 4.42-4.53 (m, 1 H), 4.32 (br. s., 1 H), 1.69 (d,
    J = 7.0 Hz, 3H), 0.91 (br. s., 3 H)
    309: (R)-3-(6-chloro-2- (CD3OD) 9.34 (s, 1 H), 7.95 (s, 1 H), HRMS (B)
    (((S)-1-(1-(4- 7.67-7.75 (m, 2 H), 7.60-7.67 (m, 2 H), m/z
    chlorophenyl)-1H- 7.44 (s, 1 H), 5.34 (br. s., 1 H), 4.75-4.88 (m, 2 463.1056,
    imidazol-4- H), 4.52 (d, J = 9.8 Hz, 1 H), 4.36-4.45 (m, (M + H)+,
    yl)ethyl)amino)pyrimidin-4- 1 H), 1.68 (d, J = 7.0 Hz, 3 H), 0.99 (br. s., 3 RT = 1.68 min.
    yl)-4-((R)-1- H)
    hydroxyethyl)oxazolidin-2-
    one
    310: (R)-3-(6-chloro-2- (cd3od) 8.04 (d, J = 2.3 Hz, 1 H), 7.71 (dd, HRMS (B)
    (((S)-1-(1-(4-fluorophenyl)- J = 9.0, 4.7 Hz, 2 H), 7.35 (s, 1 H), 7.19 (t, m/z
    1H-pyrazol-3- J = 8.8 Hz, 2 H), 6.43 (d, J = 2.7 Hz, 1 H), 447.1346,
    yl)ethyl)amino)pyrimidin-4- 5.29 (q, J = 7.0 Hz, 1 H), 4.79-4.87 (m, 2 (M + H)+,
    yl)-4-((R)-1- H), 4.52 (dd, J = 9.2, 2.5 Hz, 1 H), RT = 2.18 min.
    hydroxyethyl)oxazolidin-2- 4.35-4.44 (m, 1 H), 1.59 (d, J = 7.0 Hz, 3 H),
    one 0.85 (br. s., 3 H)
    311: (R)-3-(2-(((S)-1-(2,4- (CD3OD) 8.15 (d, J = 6.7 Hz, 1 H), 7.70 (d, HRMS (B)
    dichlorophenyl)ethyl)amino)pyrimidin- J = 7.0 Hz, 1 H), 7.51 (d, J = 2.0 Hz, 1 H), m/z
    4-yl)-4-((R)-1- 7.46 (d, J = 8.6 Hz, 1 H), 7.34 (dd, J = 8.6, 2.0 Hz, 397.0834,
    hydroxyethyl)oxazolidin-2- 1 H), 5.47 (d, J = 5.1 Hz, 1 H), 4.57 (dd, (M + H)+,
    one J = 9.0, 2.3 Hz, 2 H), 4.33-4.50 (m, 2 H), RT = 1.77 min.
    3.80 (br. s., 2 H), 1.58 (d, J = 7.0 Hz, 6 H)
    312: (R)-3-(2-(((S)-1-(3,4- (CD3OD) 8.13 (d, J = 6.7 Hz, 1 H), 7.70 (d, HRMS (B)
    dichlorophenyl)ethyl)amino)pyrimidin- J = 7.0 Hz, 1 H), 7.57 (d, J = 2.0 Hz, 1 H), m/z
    4-yl)-4-((R)-1- 7.51 (d, J = 8.2 Hz, 1 H), 7.33 (dd, J = 8.4, 2.2 Hz, 397.0831,
    hydroxyethyl)oxazolidin-2- 1 H), 5.19 (br. s., 1 H), 4.75-5.00 (m, (M + H)+,
    one 2 H), 4.58 (dd, J = 9.4, 2.3 Hz, 1 H), RT = 1.72 min.
    4.34-4.51 (m, 1 H), 3.92 (br. s., 1 H), 1.59 (d,
    J = 6.7 Hz,
    6 H)
    313: (R)-3-(6-chloro-2- (CDCl3) 7.80 (d, J = 2.3 Hz, 1 H), 7.56 (d, HRMS (B)
    (((S)-1-(1-(4- J = 8.6 Hz, 2 H), 7.51 (s, 1 H), 7.42 (d, m/z
    chlorophenyl)-1H-pyrazol- J = 8.6 Hz, 3 H), 6.39 (d, J = 2.3 Hz, 1H), 463.1056,
    3-yl)ethyl)amino)pyrimidin- 6.08 (br. s., 1 H), 5.22 (br. s., 1 H), (M + H)+,
    4-yl)-4-((R)-1- 4.76 (ddd, J = 7.9, 5.0, 2.3 Hz, 1 H), RT = 2.34 min.
    hydroxyethyl)oxazolidin-2- 4.40-4.49 (m, 1 H), 4.31-4.39 (m, 1 H), 3.99 (br. s.,
    one 1 H), 1.61 (dd, J = 7.0 Hz, 6 H)
    314: (R)-3-(2-(((S)-1-(2,5- (CDCl3) 10.88 (br. s., 1 H), 7.93 (d, J = 7.0 Hz, HRMS (B)
    difluoro-4-(2,2,2- 1 H), 7.75 (d, J = 7.0 Hz, 1 H), m/z
    trifluoroethoxy)phenyl)ethyl)amino)pyrimidin- 7.20-7.30 (m, 1 H), 6.83 (dd, J = 10.6, 6.7 Hz, 1 463.1410,
    4-yl)-4- H), 5.34 (t, J = 6.8 Hz, 1 H), 4.85 (ddd, (M + H)+,
    ((R)-1- J = 7.4, 4.7, 2.0 Hz, 1 H), 4.61 (dd, J = 9.4, RT = 1.79 min.
    hydroxyethyl)oxazolidin-2- 2.0 Hz, 1 H), 4.34-4.52 (m, 3 H),
    one 3.78-3.96 (m, 1 H), 1.61 (d, J = 7.0 Hz, 3 H),
    0.96 (d, J = 6.3 Hz, 3 H)
    315: (R)-3-(2-(((S)-1-(2- (CDCl3) 10.61 (d, J = 4.7 Hz, 1 H), 7.98 (d, HRMS (B)
    fluoro-4-(2,2,2- J = 5.5 Hz, 1 H), 7.75 (d, J = 5.9 Hz, 1 H), m/z
    trifluoroethoxy)phenyl)ethyl)amino)pyrimidin- 7.41 (t, J = 8.8 Hz, 1 H), 6.64-6.85 (m, 2 H), 445.1492,
    4-yl)-4- 5.39 (t, J = 6.5 Hz, 1 H), 4.85 (ddd, J = 7.6, (M + H)+,
    ((R)-1- 4.9, 2.0 Hz, 1 H), 4.60 (dd, J = 9.8, 2.0 Hz, 1 RT = 1.74 min.
    hydroxyethyl)oxazolidin-2- H), 4.40-4.50 (m, 1 H), 4.35 (q, J = 8.2 Hz,
    one 2 H), 3.79-3.96 (m, 1 H), 1.61 (d, J = 7.0 Hz,
    3 H), 0.94 (d, J = 6.3 Hz, 3 H)
    316: (R)-3-(2-(((S)-1-(3- (cdcl3) 10.84 (d, J = 3.9 Hz, 1 H), 7.92 (d, HRMS (B)
    fluoro-4-(2,2,2- J = 7.0 Hz, 1 H), 7.73 (d, J = 7.0 Hz, 1 H), m/z
    trifluoroethoxy)phenyl)ethyl)amino)pyrimidin- 7.09-7.20 (m, 2 H), 6.97-7.10 (m, 1 H), 445.1491,
    4-yl)-4- 4.93 (t, J = 6.7 Hz, 1 H), 4.78 (td, J = 5.1, 2.3 Hz, (M + H)+,
    ((R)-1- 1 H), 4.56 (dd, J = 9.4, 2.0 Hz, 1 H), RT = 1.69 min.
    hydroxyethyl)oxazolidin-2- 4.35-4.47 (m, 3 H), 3.64-3.75 (m, 1 H),
    one 1.62 (d, J = 7.0 Hz, 3 H), 0.94 (d, J = 6.3 Hz, 3
    H)
    317: (R)-3-(2-(((S)-1-(5- (CDCl3) 11.02 (d, J = 6.7 Hz, 1 H), 8.59 (d, HRMS (B)
    bromopyridin-2- J = 1.6 Hz, 1 H), 8.03 (dd, J = 8.4, 1.8 Hz, 1 m/z
    yl)ethyl)amino)pyrimidin-4- H), 7.94 (d, J = 6.7 Hz, 1 H), 7.76 (d, J = 6.7 Hz, 408.0668,
    yl)-4-((R)-1- 1 H), 7.58 (d, J = 8.6 Hz, 1 H), 5.40 (t, (M + H)+,
    hydroxyethyl)oxazolidin-2- J = 7.0 Hz, 1 H), 4.83-4.95 (m, 1 H), RT = 1.29 min.
    one 4.62 (dd, J = 9.4, 1.6 Hz, 1 H), 4.40-4.51 (m, 1
    H), 3.70-3.84 (m, 1 H), 1.70 (d, J = 7.0 Hz,
    3 H), 1.02 (d, J = 6.3 Hz, 3 H)
    318: (R)-3-(2-(((R)-1-(5- (CDCl3) 10.97 (d, J = 4.3 Hz, 1 H), 8.62 (d, HRMS (B)
    bromopyridin-2- J = 1.6 Hz, 1 H), 8.09 (dd, J = 8.2, 1.6 Hz, 1 m/z
    yl)ethyl)amino)pyrimidin-4- H), 7.99 (d, J = 6.7 Hz, 1 H), 7.77 (d, J = 6.7 Hz, 408.0670,
    yl)-4-((R)-1- 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 5.37 (t, (M + H)+,
    hydroxyethyl)oxazolidin-2- J = 6.5 Hz, 1 H), 4.59-4.74 (m, 2 H), RT = 1.33 min.
    one 4.29-4.46 (m, 2 H), 1.70 (d, J = 6.7 Hz, 3 H),
    1.17 (d, J = 6.3 Hz, 3 H)
    319: (R)-3-(2-(((S)-1-(4,5- (CD3OD) 8.15 (d, J = 7.0 Hz, 1 H), 7.70 (d, HRMS (B)
    dichloro-2- J = 6.3 Hz, 1 H), 7.58 (d, J = 7.0 Hz, 1 H), m/z
    fluorophenyl)ethyl)amino) 7.41 (d, J = 9.8 Hz, 1 H), 5.42 (d, J = 3.5 Hz, 1 415.0733,
    pyrimidin-4-yl)-4-((R)-1- H), 4.87 (d, J = 5.5 Hz, 2 H), 4.58 (dd, (M + H)+,
    hydroxyethyl)oxazolidin-2- J = 9.0, 2.3 Hz, 1 H), 4.38-4.50 (m, 1 H), RT = 1.84 min.
    one 3.91 (br. s., 1 H), 1.60 (d, J = 7.0 Hz, 3 H),
    0.84 (br. s., 3H)
    320: (R)-3-(2-(((S)-1-(2,5- (CD3OD) 9.26 (s, 1 H), 8.19 (d, J = 7.0 Hz, HRMS (B)
    difluoro-4-(4-methyl-1H- 1 H), 7.77 (d, J = 6.7 Hz, 1 H), m/z
    imidazol-1- 7.54-7.71 m, 3 H), 5.51 (d, J = 5.9 Hz, 1 H), 445.1794,
    yl)phenyl)ethyl)amino)pyrimidin- 4.81-4.90 (m, 1 H), 4.58 (dd, J = 9.2, 2.2 Hz, 1 (M + H)+,
    4-yl)-4-((R)-1- H), 4.41-4.51 (m, 1 H), 3.75 (br. s., 1 H), RT = 1.02 min.
    hydroxyethyl)oxazolidin-2- 2.44 (s, 3 H), 1.66 (d, J = 6.7 Hz, 3 H),
    one 0.87 (br. s., 3 H)
    321: (R)-3-(5-chloro-2- (CD3OD) 8.20 (s, 1 H), 7.43 (d, J = 7.0 Hz, HRMS (B)
    (((S)-1-(4,5-dichloro-2- 1 H), 7.26 (d, J = 9.4 Hz, 1 H), 5.11 (br. s., 1 m/z
    fluorophenyl)ethyl)amino) H), 4.68-4.90 (m, 1 H), 4.43 (t, J = 8.2 Hz, 1 449.0347,
    pyrimidin-4-yl)-4-((R)-1- H), 4.25-4.37 (m, 1 H), 3.44-3.86 (m, 1 (M + H)+,
    hydroxyethyl)oxazolidin-2- H), 1.42 (d, J = 7.0 Hz, 3 H), 0.73 (br. s., 3 RT = 2.14 min.
    one H)
    322: (R)-3-(2-(((S)-1-(2,5- (CD3OD) 8.74 (d, J = 6.3 Hz, 1 H), HRMS (B)
    difluoro-4-(2- 8.11-8.22 (m, 2 H), 8.07 (d, J = 6.3 Hz, 1 H), m/z
    methylpyridin-4- 7.59-7.77 (m, 2 H), 7.40-7.53 (m, 1H), 456.1840,
    yl)phenyl)ethyl)amino)pyrimidin- 5.48 (d, J = 5.5 Hz, 1 H), 4.77-5.01 (m, 2 H), (M + H)+,
    4-yl)-4-((R)-1- 4.57 (dd, J = 9.0, 2.3 Hz, 1 H), RT = 1.10 min.
    hydroxyethyl)oxazolidin-2- 4.38-4.51 (m, 1 H), 2.83 (s, 3 H), 1.66 (d, J = 7.0 Hz, 2
    one H), 0.82 (br.s., 3 H)
    323: (R)-3-(2-(((S)-1-(2,5- (CD3OD) 8.91 (s, 1 H), 8.60 (d, J = 8.2 Hz, HRMS (B)
    difluoro-4-(6- 1 H), 8.18 (d, J = 6.3 Hz, 1 H), 7.95 (d, m/z
    methylpyridin-3- J = 8.2 Hz, 1 H), 7.73 (d, J = 6.3 Hz, 1H), 456.1847,
    yl)phenyl)ethyl)amino)pyrimidin- 7.54 (dd, J = 10.2, 6.7 Hz, 1 H), 7.42 (dd, (M + H)+,
    4-yl)-4-((R)-1- J = 10.8, 6.1 Hz, 1 H), 5.49 (d, J = 4.7 Hz, 1 RT = 1.18 min.
    hydroxyethyl)oxazolidin-2- H), 4.88 (s, 1 H), 4.58 (dd, J = 9.2, 2.2 Hz, 1
    one H), 4.39-4.51 (m, 1 H), 3.83 (br. s., 1 H),
    2.82 (s, 3 H), 1.66 (d, J = 7.0 Hz, 3 H),
    0.83 (br. s., 3 H)
    324: (R)-3-(2-(((S)-1-(2,5- (CD3OD) 8.80 (d, J = 5.1 Hz, 1 H), 8.18 (d, HRMS (B)
    difluoro-4-(2- J = 6.7 Hz, 1 H), 7.97-8.07 (m, 1 H), m/z
    (trifluoromethyl)pyridin-4- 7.77-7.90 (m, 2 H), 7.54 (dd, J = 10.6, 6.3 Hz, 1 510.1560,
    yl)phenyl)ethyl)amino)pyrimidin- H), 7.40 (dd, J = 11.0, 6.3 Hz, 1 H), 5.49 (br. (M + H)+,
    4-yl)-4-((R)-1- s., 1 H), 4.79-5.02 (m, 1 H), RT = 1.94 min.
    hydroxyethyl)oxazolidin-2- 4.53-4.68 (m, 1 H), 4.39-4.52 (m, 1 H), 3.80 (br. s.,
    one 1 H), 1.61-1.73 (m, 6 H)
    325: (R)-3-(2-(((S)-1-(2,5- (CD3OD) 8.90 (s, 1 H), 8.12-8.29 (m, 2 HRMS (B)
    difluoro-4-(6- H), 7.92 (d, J = 8.2 Hz, 1 H), 7.75 (d, J = 6.7 Hz, m/z
    (trifluoromethyl)pyridin-3- 1 H), 7.43-7.55 (m, 1 H), 7.37 (dd, 510.1565,
    yl)phenyl)ethyl)amino)pyrimidin- J = 10.8, 6.1 Hz, 1 H), 5.47 (br. s., 1 H), (M + H)+,
    4-yl)-4-((R)-1- 4.81-4.97 (m, 1 H), 4.58 (dd, J = 9.0, 2.3 Hz, RT = 1.98 min.
    hydroxyethyl)oxazolidin-2- 1 H), 4.39-4.51 (m, 1 H), 3.82 (br. s.,
    one 1 H), 1.66 (d,
    J = 7.0 Hz, 3 H), 0.82 (br. s., 3 H)
    326: (R)-4-((R)-1- HRMS (B)
    hydroxyethyl)-3-(2-(((S)-1- m/z
    (4- 401.2188
    isobutoxyphenyl)ethyl)amino)pyrimidin- (M + H)+;
    4- Rt 1.80 min
    yl)oxazolidin-2-one
    327: (R)-3-(5-fluoro-2- (CD3OD) 8.22 (d, J = 3.13 Hz, 1H), HRMS (B)
    (((S)-1-(2-fluoro-4- 7.14-7.41 (m, 1H), 6.55-6.79 (m, 2H), 5.19 (q, m/z
    methoxyphenyl)- J = 7.04 Hz, 1H), 4.68 (d, J = 3.91 Hz, 1 H), 395.1525
    ethyl)amino)pyrimidin-4- 4.43-4.60 (m, 2H), 3.92 (d, J = 17.22 Hz, (M + H)+;
    yl)-4-((R)-1-hydroxy- 1H), 3.78 (s, 3H), 1.50 (d, J = 6.65 Hz, 3H) Rt 1.78 min
    ethyl)oxazolidin-2-one
    328: (R)-3-(2-(((S)-1-(2,3- 1H NMR (400 MHz, <cd3od>) 0.83 (br. s., HRMS (B)
    difluorophenyl)ethyl)amino)pyrimidin- 3 H) 1.60 (d, J = 6.65 Hz, 3 H) m/z
    4-yl)-4-((R)-1- 4.40-4.45 (m, 1 H) 4.56 (d, J = 7.43 Hz, 1 H) 4.85 (m, 365.1414,
    hydroxyethyl)oxazolidin-2- 2H) 5.39-5.47 (m, 1 H) 7.11-7.21 (m, 3 (M + H)+,
    one H) 7.61-7.68 (m, 1 H) 8.12 (d, J = 6.65 Hz, RT = 1.49 min.
    1 H)
    329: (R)-3-(2-(((S)-1-(2,3- 1H NMR (400 MHz, <cd3od>) 0.81 (br. s., HRMS (B)
    difluorophenyl)ethyl)amino)- 3 H) 1.52 (d, J = 7.04 Hz, 3 H) m/z
    5-fluoropyrimidin-4-yl)-4- 3.81-3.96 (m, 1 H) 4.44-4.56 (m, 2 H) 383.1327,
    ((R)-1- 4.57-4.68 (m, 1 H) 5.21-5.32 (m, 1 H) (M + H)+,
    hydroxyethyl)oxazolidin-2- 7.01-7.22 (m, 3H) 8.21 (d, J = 3.08 Hz, 1 H) RT = 1.81 min.
    one
    330: (R)-3-(2-(((S)-1-(3,4- 1H NMR (400 MHz, <cd3od>) 0.83 (br. s., HRMS (B)
    difluorophenyl)ethyl)amino)- 3 H) 1.48 (d, J = 7.04 Hz, 3 H) m/z
    5-fluoropyrimidin-4-yl)-4- 3.81-3.97 (m, 1 H) 4.39-4.57 (m, 2 H) 383.1328,
    ((R)-1- 4.59-4.68 (m, 1 H) (M + H)+,
    hydroxyethyl)oxazolidin-2- 4.89-5.01 (m, 2 H) 7.11-7.32 (m, 3 H) 8.21 (d, RT = 1.81 min.
    one J = 3.13 Hz, 1 H)
    331: (R)-3-(2-(((S)-1-(2,4- 1H NMR (400 MHz, <cd3od>) 0.73 (br. s., HRMS (B)
    difluorophenyl)ethyl)amino)- 3 H) 1.41 (d, J = 6.99 Hz, 3 H) 3.81 (br. s., 1 m/z
    5-fluoropyrimidin-4-yl)-4- H) 4.32-4.47 (m, 2 H) 4.54 (d, J = 3.03 Hz, 383.1323,
    ((R)-1- 1 H) (M + H)+,
    hydroxyethyl)oxazolidin-2- 5.11 (d, J = 6.94 Hz, 1 H) 6.73-6.89 (m, 2 H) RT = 1.80 min.
    one 7.29 (td, J = 8.57, 6.53 Hz, 1 H) 8.11 (d,
    J = 2.98 Hz, 1 H)
    332: (R)-3-(2-(((S)-1-(3,5- HRMS (B)
    difluorophenyl)ethyl)amino)- m/z
    5-fluoropyrimidin-4-yl)-4- 383.1328,
    ((R)-1- (M + H)+,
    hydroxyethyl)oxazolidin-2- RT = 1.81 min.
    one
    333: (R)-3-(5-chloro-2- 1H NMR (400 MHz, <cd3od>) LCMS
    (((S)-1-(5-(2- 1.26-1.39 (m, 3 H) 1.61 (d, J = 7.04 Hz, 3 H) m/z 509.2,
    (trifluoromethyl)pyridin-4- 4.74-4.79 (m, 3 H) 4.96 (br. s., 1 H) 5.13 (d, (M + H)+,
    yl)pyrimidin-2- J = 7.04 Hz, 1 H) 7.69 (d, J = 7.83 Hz, 1 H) RT = 0.69 min.
    yl)ethyl)amino)pyrimidin-4- 7.99 (d, J = 4.30 Hz, 1 H) 8.17 (s, 1 H)
    yl)-4-((R)-1- 8.29 (d, J = 8.22 Hz, 1 H) 8.80 (d, J = 5.09 Hz, 1
    hydroxyethyl)oxazolidin-2- H) 8.96 (s, 1 H)
    one
    • Example 334 (R)-3-(5-fluoro-2-(((S)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00815
  • To (R)-3-(2-(((S)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (20 mg, 0.042 mmol) in MeOH (10 mL) was added Pd(OH)2 (10 mg, 0.014 mmol). The reaction was purged with N2 and H2 three times each. A hydrogen balloon was applied to the reaction. The reaction mixture was stirred for one hour and concentrated. The residue was applied directly to HPLC separation to give product (15 mg). 1HNMR (CD3OD) δ ppm 8.21 (d, J=3.1 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.12-7.28 (m, 2H), 4.88-5.00 (m, 1H), 4.59 (br. s., 1H),4.42-4.55 (m, 2H), 3.89 (br. s., 1H), 1.49 (d, J=7.0 Hz, 3H), 0.81 (br. s., 3H). HRMS (B) m/z 446.1448 (M+H)+, RT=1.90 min.
    • Example 335 (R)-3-(2-((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethylamino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00816
  • A mixture of (R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloro-5-fluoropyrimidin-4-yl)oxazolidin-2-one (40 mg, 0.126 mmol), (S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanamine (36.9 mg, 0.164 mmol) and Huenig's base (0.11 mL, 0.629 mmol) in DMSO (0.25 mL) under argon atmosphere was heated at ˜120° C. for ˜16 hr in a sealed vial. The mixture was allowed to cool to room temperature and diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×), the combined organic layers were washed with brine and dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was dissolved in DCM (0.8 mL) and cooled to 0° C. To the mixture was added trifluoroacetic acid (0.3 mL), the ice-bath was removed and the mixture was stirred for ˜1 hr at room temperature. The mixture was diluted with methanol (2 mL) and concentrated under reduced pressure. The residue was dissolved in DMSO/water (˜9/1), filtered through a syringe filter, and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (R)-3-(2-((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethylamino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one as its trifluoroacetic acid salt (19 mg) as a white solid.
  • 1H NMR (400 Mhz, CD3OD) δ ppm 9.77 (d, J=2.7 Hz, 1H), 9.06 (t, J=7.8 Hz, 1H), 8.80-8.87 (m, 2H), 8.12-8.44 (m, 1H), 6.82 (q, J=6.7 Hz, 1H), 6.12-6.21 (m, 1H), 5.99-6.11 (m, 2H), 5.30-5.52 (m, 1H), 3.09 (d, J=7.0 Hz, 3H), 2.14-2.51 (m, 3H). HRMS m/z 415.1390 (M+H)+; Rt-1.84 min.
  • The following Example was prepared using a method similar to that described for the preparation of Example 335
    • Example 336 (R)-3-(2-(((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00817
  • 1H NMR (400 Mhz, CCl3D) δ ppm 8.19 (d, J=2.7 Hz, 1H), 7.33-7.44 (m, 1H), 7.18-7.30 (m, 2H), 5.49 (m, J=5.9 Hz, 1H), 5.19 (m, J=6.7, 6.7 Hz, 1H), 4.41-4.52 (m, 2H), 4.34 (m, J=7.2, 3.7 Hz, 1H), 1.90 (t, J=18.2 Hz, 3H), 1.51-1.60 (m, 3H), 0.80-1.00 (m, 3H). HRMS m/z 429.1553 (M+H)+; Rt-1.98 min.
    • Example 337 (R)-3-(6-chloro-2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00818
  • A mixture of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (55 mg, 0.165 mmol), (S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride (35 mg, 0.155 mmol) and Huenig's base (0.072 mL, 0.411 mmol) in DMSO (0.6 mL) under argon atmosphere was heated at ˜85° C. for ˜3 hr in a sealed vial. The mixture was allowed to cool to room temperature and diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×), the combined organic layers were washed with brine and dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was dissolved in DCM (0.8 mL) and cooled to 0° C. To the mixture was added trifluoroacetic acid (0.4 mL), the ice-bath was removed and the mixture was stirred for ˜1 hr at room temperature. The mixture was diluted with methanol (2 mL) and concentrated under reduced pressure. The residue was dissolved in DMSO/water (˜9/1), filtered through a syringe filter, and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (R)-3-(6-chloro-2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one as its trifluoroacetic acid salt (8.2 mg) as a white solid.
  • 1H NMR (400 Mhz, CD3OD) δ ppm 7.50 (m, J=7.60, 7.6 Hz, 1H), 7.25-7.38 (m, 3H), 6.76 (t, J=1.0 Hz, 1H), 5.31-5.43 (m, 1H), 4.72-4.81 (m, 1H), 4.52 (m, J=7.0 Hz, 1H), 4.34-4.44 (m, 1H), 1.55 (d, J=7.0 Hz, 3H), 0.54-0.75 (m, CH3). HRMS m/z 431.1097 (M+H)+; Rt-2.21 min.
  • The following Example was prepared using a method similar to that described for the preparation of Example 337
    • Example 338 (R)-3-(6-chloro-2-(((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00819
  • 1H NMR (400 Mhz, CD3OD) δ ppm 7.45 (m, J=7.6, 7.6 Hz, 1H), 7.21-7.36 (m, 3H), 5.34 (m, J=7.0 Hz, 1H), 4.71-4.79 (m, 1H), 4.45-4.55 (m, 1H), 4.32-4.41 (m, 1H), 1.89 (t, J=18.2 Hz, 3H), 1.52 (d, J=7.0 Hz, 3H), 0.55-0.71 (m, CH3). HRMS m/z 445.1257 (M+H)+; Rt-2.32 min.
    • Example 339 (R)-3-(6-chloro-2-(((S)-1-(5-phenylthiophen-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00820
  • A solution of (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (0.040 g, 0.144 mmol), (S)-1-(5-(pyridin-2-yl)thiophen-2-yl)ethanamine hydrochloride (0.083 g, 0.346 mmol, 2.4 equiv) and N-ethyl-N-isopropylpropan-2-amine (0.075 mL, 0.432 mmol, 3.0 equiv) in DMSO (0.72 mL) was heated at 100° C. for 1 h. Purification by reverse phase HPLC separated the regioisomeric products and provided the trifluoroacetate salt of (R)-3-(6-chloro-2-(((S)-1-(5-phenylthiophen-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (7.0 mg, white solid) in 8% yield. 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.56-7.52 (m, 2H), 7.40-7.34 (m, 2H), 7.29 (d, J=7.4 Hz, 1H), 7.15 (d, J=3.6 hz, 1H), 6.93 (br s, 1H), 5.21 (m, 1H), 4.78-4.68 (m, 1H), 4.50-4.31 (m, 2H), 3.85 (m, 1H), 1.69 (d, J=6.9 Hz, 3H), 0.93 (br s, 3H); HRMS m/z 445.1109 (M+H)+; Rt-2.49 min.
  • The following Example was prepared using a method similar to that described for the preparation of Example 339
    • Example 340 (R)-3-(6-chloro-2-(((S)-1-(5-(pyridin-2-yl)thiophen-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00821
  • 1H NMR (400 MHz, CDCl3) δ ppm 8.84 (d, J=5.0 Hz, 1H), 8.05 (t, J=7.8 Hz, 1H), 7.77-7.70 (m, 2H), 7.60 (s, 1H), 7.47 (t, J=6.5 Hz, 1H), 7.13 (d, J=3.9 Hz, 1H), 5.19 (m, 1H), 4.87 (m, 1H), 4.62 (m, 1H), 4.37 (t, J=9.0 Hz, 1H), 3.61 (m, 1H), 1.70 (d, J=7.0 Hz, 3H), 0.89 (br s, 3H). HRMS m/z 446.1054 (M+H)+; Rt-2.04
    • Example 341 1:1 TFA:DCM
  • Figure US20140275083A1-20140918-C00822
  • A solution of (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (56.5 mg, 0.12 mmol) in DCM (0.6 ml) was treated with TFA (0.6 ml) at room temperature. The resulting solution was let sit for 2 hours, then concentrated. The crude material was purified by reverse phase HPLC. Product fractions were combined and lyophilized to afford (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (15.2 mg, 0.036 mmol, 30% yield) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 0.65 (br. s., 3H) 1.41 (d, J=6.99 Hz, 3H) 1.84-1.94 (m, 1H) 2.10-2.22 (m, 1H) 3.67-3.89 (m, 4H) 4.33-4.47 (m, 2H) 4.70-4.77 (m, 1H) 4.96 (dd, J=6.06, 4.60 Hz, 1H) 5.01-5.11 (m, 1H) 6.73 (dd, J=8.07, 2.05 Hz, 1H) 6.89-6.97 (m, 2H) 7.19 (t, J=7.85 Hz, 1H) 7.24 (d, J=6.06 Hz, 1H) 8.14 (br. s., 1H). LCMS m/z 415.3 (M+H)+, Rt 0.55 min. HRMS (A) m/z 415.1981 (M+H)+, Rt 1.33 min.
  • The compounds in Table 31a were prepared using methods similar to those described for the preparation of Example 341.
  • TABLE 31a
    Figure US20140275083A1-20140918-C00823
         		342
    Figure US20140275083A1-20140918-C00824
         		343
    Figure US20140275083A1-20140918-C00825
         		344
    Figure US20140275083A1-20140918-C00826
         		345
    Figure US20140275083A1-20140918-C00827
         		346
    Figure US20140275083A1-20140918-C00828
         		347
    Figure US20140275083A1-20140918-C00829
         		348
    Figure US20140275083A1-20140918-C00830
         		349
    Figure US20140275083A1-20140918-C00831
         		350
    Figure US20140275083A1-20140918-C00832
         		351
    Figure US20140275083A1-20140918-C00833
         		352
    Figure US20140275083A1-20140918-C00834
         		353
    Figure US20140275083A1-20140918-C00835
         		354
    Figure US20140275083A1-20140918-C00836
         		355
  • TABLE 31b
    Chemical name, NMR chemical shifts and LCMS signal for each compound listed
    in Table 31a.
    Example: Name 1H NMR (400 MHz) d ppm LCMS
    342: (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3- (DMSO-d6) δ 0.93 (s, 3 H) HRMS m/z
    isobutoxyphenyl)ethylamino)pyrimidin-4- 0.95 (s, 3 H) 1.41 (d, J = 6.99 Hz, 401.2189
    yl)oxazolidin-2-one 3 H) 1.96 (dquin, J = 13.30, (M + H)+;
    6.64, 6.64, 6.64, 6.64 Hz, 1 H) Rt-1.86 min
    3.55-3.89 (m, 4 H)
    4.34-4.41 (m, 1 H) 4.42-4.48 (m, 1 H)
    4.71-4.78 (m, 1 H) 5.06 (br.
    s., 1 H) 6.73 (dd, J = 8.14,
    1.93 Hz, 1 H) 6.87-6.99 (m, 2 H)
    7.17 (t, J = 7.87 Hz, 1 H)
    7.23 (d, J = 6.02 Hz, 1 H) 8.13 (br.
    s., 1 H)
    343: (R)-3-(6-chloro-2-(((S)-1-(4- (DMSO-d6) δ 0.55 (d, J = 6.31 Hz, HRMS m/z
    (isobutylsulfonyl)phenyl)ethyl)amino)pyrimidin- 3 H) 0.94 (dd, J = 6.70, 1.91 Hz, 483.1472
    4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 6 H) 1.43 (d, J = 6.85 Hz, 3 (M + H)+;
    H) 1.97 (dt, J = 13.11, 6.70 Hz, Rt-2.10 min
    1 H) 3.14 (d, J = 6.36 Hz, 2 H)
    4.31-4.49 (m, 3 H) 4.71 (br.
    s., 1 H) 5.09 (t, J = 7.19 Hz, 1
    H) 7.17 (s, 1 H) 7.61 (d,
    J = 8.22 Hz, 2 H) 7.83 (d,
    J = 8.31 Hz, 2 H) 8.49 (d,
    J = 7.78 Hz, 1 H)
    344: (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4- (DMSO-d6) δ 0.59 (br. s., 3 H) HRMS m/z
    (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin- 1.44 (d, J = 6.99 Hz, 3 H) 413.1435
    4-yl)oxazolidin-2-one 3.83 (br. s., 1 H) 4.34-4.41 (m, 1 (M + H)+;
    H) 4.41-4.47 (m, 1 H) Rt-1.72 min
    4.70-4.76 (m, 2 H) 5.09 (quin,
    J = 7.24 Hz, 1 H) 7.24 (d,
    J = 6.02 Hz, 1 H) 7.28 (d,
    J = 7.97 Hz, 2 H) 7.49 (d,
    J = 8.61 Hz, 2 H) 8.16 (br. s., 1
    H) 8.24 (br. s., 1 H)
    345: (R)-3-(2-(((S)-1-(3-fluoro-4- (DMSO-d6) δ 0.57 (br. s., 3 H) HRMS m/z
    (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin- 1.43 (d, J = 7.04 Hz, 3 H) 431.1345
    4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 4.31-4.47 (m, 3 H) 4.71 (br. s., 1 H) (M + H)+;
    5.08 (t, J = 7.16 Hz, 1 H) Rt-1.83 min
    7.23 (d, J = 5.87 Hz, 1 H) 7.29 (d,
    J = 8.66 Hz, 1 H)
    7.42-7.52 (m, 2 H) 8.09 (br. s., 1 H)
    8.16 (br. s., 1 H)
    346: (R)-3-(2-(((S)-1-(2-fluoro-4- (DMSO-d6) δ 0.37-0.66 (m, 3 HRMS m/z
    (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin- H) 1.43 (d, J = 7.04 Hz, 3 H) 431.1341
    4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 4.32-4.46 (m, 2 H) 4.71 (br. (M + H)+;
    s., 1 H) 5.26 (br. s., 1 H) Rt-1.85 min
    7.18 (d, J = 8.51 Hz, 1 H) 7.22 (d,
    J = 5.82 Hz, 1 H) 7.29 (d,
    J = 10.86 Hz, 1 H) 7.49 (t,
    J = 8.49 Hz, 1 H) 8.03 (br. s., 1
    H) 8.16 (br. s., 1 H)
    347: (R)-3-(2-(((S)-1-(4-(difluoromethoxy)-3- (DMSO-d6) δ 0.64 (br. s., 3 H) HRMS m/z
    fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)- 1.42 (d, J = 6.99 Hz, 3 H) 413.1436
    1-hydroxyethyl)oxazolidin-2-one 4.34-4.47 (m, 3 H) 4.67-4.78 (m, 1 (M + H)+;
    H) 5.06 (quin, J = 7.27 Hz, 1 H) Rt-1.60 min
    6.93-7.18 (m, 1 H)
    7.19-7.32 (m, 3 H) 7.38 (d, J = 11.84 Hz,
    1 H) 8.03-8.11 (m, 1 H)
    8.15 (br. s., 1 H)
    348: (R)-3-(2-(((S)-1-(4-(difluoromethoxy)-3- (DMSO-d6) δ 0.60 (br. s., 3 H) HRMS m/z
    fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4- 1.41 (d, J = 7.04 Hz, 3 H) 431.1333
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 4.35-4.43 (m, 1 H) 4.45-4.57 (m, 2 (M + H)+;
    H) 4.89 (br. s., 1 H) Rt-1.89 min
    6.91-7.17 (m, 1 H) 7.17-7.31 (m, 2 H)
    7.31-7.41 (m, 1 H)
    7.82-8.03 (m, 1 H) 8.34 (br. s., 1 H)
    349: (R)-3-(2-(((S)-1-(4- (DMSO-d6) δ 0.61 (br. s., 3 H) HRMS m/z
    (difluoromethoxy)phenyl)ethyl)amino)pyrimidin- 1.37 (d, J = 7.04 Hz, 3 H) 395.1523
    4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 4.29-4.42 (m, 3 H) 4.65-4.73 (m, 1 (M + H)+;
    H) 5.01 (quin, J = 7.20 Hz, 1 H) Rt-1.49 min
    7.04 (d, J = 8.51 Hz, 2 H)
    7.09 (s, 1 H) 7.17 (d, J = 5.92 Hz, 1
    H) 7.37 (d, J = 8.51 Hz, 2 H)
    8.08 (br. s., 1 H)
    350: (R)-3-(2-(((S)-1-(4-(difluoromethoxy)-2- (DMSO-d6) δ 0.61 (br. s., 3 H) HRMS m/z
    fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)- 0.93 (br. s., 1 H) 1.44 (d, 413.1431
    1-hydroxyethyl)oxazolidin-2-one J = 6.94 Hz, 3 H) 3.76 (br. s., 1 (M + H)+;
    H) 4.34-4.47 (m, 2 H) 4.73 (d, Rt-1.60 min
    J = 3.57 Hz, 1 H) 5.26 (quin,
    J = 6.90 Hz, 1 H) 6.98 (dd,
    J = 8.46, 2.20 Hz, 1 H) 7.06 (dd,
    J = 11.20, 2.30 Hz, 1 H) 7.26 (d,
    J = 5.77 Hz, 1 H) 7.43 (t, J = 8.66 Hz,
    1 H) 8.17 (br. s., 1 H)
    351: (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3- (DMSO-d6) δ 0.60 (br. s., 3 H) HRMS m/z
    (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin- 1.44 (d, J = 7.04 Hz, 3 H) 413.1432
    4-yl)oxazolidin-2-one 3.87 (br. s., 1 H) 4.34-4.47 (m, 2 (M + H)+;
    H) 4.71-4.76 (m, 2 H) Rt-1.73 min
    5.14 (quin, J = 7.23 Hz, 1 H)
    7.13-7.21 (m, 1 H) 7.25 (d, J = 5.97 Hz,
    1 H) 7.34 (s, 1 H)
    7.38-7.46 (m, 2 H) 8.16 (br. s., 1 H)
    352: (R)-3-(2-(((S)-1-(3- (DMSO-d6) δ 0.63 (br. s., 3 H) HRMS m/z
    (difluoromethoxy)phenyl)ethyl)amino)pyrimidin- 1.43 (d, J = 7.04 Hz, 3 H) 395.1534
    4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 3.85 (br. s., 4 H) 4.35-4.47 (m, 2 (M + H)+;
    H) 4.71-4.76 (m, 1 H) Rt-1.52 min
    5.09 (quin, J = 7.30 Hz, 1 H)
    6.96-7.02 (m, 1 H) 7.17 (d, J = 7.48 Hz,
    1 H) 7.21-7.27 (m, 2 H)
    7.31-7.37 (m, 1 H) 8.15 (br.
    s., 1 H)
    353: (R)-3-(2-(((S)-1-(4-(difluoromethoxy)-2- (DMSO-d6) δ 0.33-1.02 (m, 3 HRMS m/z
    fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4- H) 1.40 (d, J = 6.99 Hz, 3 H) 431.1334
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 4.32-4.55 (m, 3 H) 5.13 (br. (M + H)+;
    s., 1 H) 6.96 (dd, J = 8.53, 2.37 Hz, Rt-1.92 min
    1 H) 7.04 (dd, J = 11.10,
    2.40 Hz, 1 H) 7.17-7.38 (m, 1
    H) 7.41 (t, J = 8.58 Hz, 1 H)
    7.97 (br. s., 1 H) 8.34 (br. s., 1
    H)
    354: (R)-3-(5-fluoro-2-(((S)-1-(3- (DMSO-d6) δ 0.15-0.91 (m, 3 HRMS m/z
    (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin- H) 1.41 (d, J = 7.04 Hz, 3 H) 431.1337
    4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 4.27-4.56 (m, 3 H) 4.94 (br. (M + H)+;
    s., 2 H) 7.15 (d, J = 7.34 Hz, 1 Rt-2.04 min
    H) 7.30 (s, 1 H) 7.34-7.45 (m,
    2 H) 7.97 (br. s., 1 H) 8.33 (br.
    s., 1 H)
    355: (R)-3-(2-(((S)-1-(3- (DMSO-d6) δ 0.58 (br. s., 3 H) HRMS m/z
    (difluoromethoxy)phenyl)ethyl)amino)-5- 1.41 (d, J = 7.04 Hz, 3 H) 413.1435
    fluoropyrimidin-4-yl)-4-((R)-1- 3.89 (br. s., 2 H) 4.33-4.57 (m, 3 (M + H)+;
    hydroxyethyl)oxazolidin-2-one H) 4.90 (br. s., 1 H) Rt-1.83 min
    6.93-7.00 (m, 1 H) 7.11-7.18 (m, 1 H)
    7.21 (d, J = 7.78 Hz, 1 H)
    7.32 (t, J = 8.00 Hz, 1 H) 7.93 (br. s.,
    1 H) 8.32 (br. s., 1 H)
    • Example 356 1:3 TFA:DCM
  • Figure US20140275083A1-20140918-C00837
  • A solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (70.1 mg, 0.147 mmol) in DCM (1.1 ml) was treated with TFA (368 ul) at room temperature. The resulting solution was let sit for 30 min, then concentrated. The crude material was purified by reverse phase HPLC. Product fractions were combined and lyophilized to afford (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (41.3 mg, 0.097 mmol, 66% yield) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 0.64 (br. s., 3H) 1.42 (d, J=6.90 Hz, 3H) 3.70 (br. s., 1H) 4.32-4.48 (m, 3H) 4.67-4.75 (m, 1H) 5.08 (br. s., 1H) 6.78 (d, J=7.87 Hz, 1H) 6.91 (d, J=7.87 Hz, 2H) 7.00-7.18 (m, 3H) 7.22-7.37 (m, 4H) 8.14 (br. s., 1H). LCMS m/z 421.3 (M+H)+, Rt 0.72 min. HRMS (A) m/z 421.1873 (M+H)+, Rt 1.84 min.
  • The compounds in Table 32a were prepared using methods similar to those described for the preparation of Example 356
  • TABLE 32a
    Figure US20140275083A1-20140918-C00838
         		357
    Figure US20140275083A1-20140918-C00839
         		358
    Figure US20140275083A1-20140918-C00840
         		359
    Figure US20140275083A1-20140918-C00841
         		360
    Figure US20140275083A1-20140918-C00842
         		361
    Figure US20140275083A1-20140918-C00843
         		362
    Figure US20140275083A1-20140918-C00844
         		363
    Figure US20140275083A1-20140918-C00845
         		364
    Figure US20140275083A1-20140918-C00846
         		365
    Figure US20140275083A1-20140918-C00847
         		366
    Figure US20140275083A1-20140918-C00848
         		367
    Figure US20140275083A1-20140918-C00849
         		368
    Figure US20140275083A1-20140918-C00850
         		369
    Figure US20140275083A1-20140918-C00851
         		370
    Figure US20140275083A1-20140918-C00852
         		371
    Figure US20140275083A1-20140918-C00853
         		372
  • TABLE 32b
    Chemical name, NMR chemical shifts and LCMS signal for each compound listed
    in Table 32a.
    Example: Name 1H NMR (400 MHz) δ ppm LCMS
    357: (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(4- (DMSO-d6) δ 0.69 (br. s., 3 HRMS m/z
    isopropoxyphenyl)ethylamino)pyrimidin-4- H) 1.20 (d, J = 6.02 Hz, 6 H) 387.2032
    yl)oxazolidin-2-one 1.39 (d, J = 6.90 Hz, 3 H) (M + H)+;
    4.33-4.46 (m, 2 H) Rt-1.54 min
    4.51 (dt, J = 11.93, 5.87 Hz, 1 H)
    4.74 (br. s., 1 H)
    4.94-5.05 (m, 1 H) 6.80 (d,
    J = 8.41 Hz, 2 H)
    7.17-7.29 (m, 3 H) 8.12 (d, J = 5.67 Hz,
    1 H)
    358: (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(4- The NMR not taken (not HRMS m/z
    isobutoxy-3-methylphenyl)ethylamino)pyrimidin-4- enough material made). 415.2340
    yl)oxazolidin-2-one (M + H)+;
    Rt-1.98 min
    359: (R)-3-(6-chloro-2-(((S)-1-(4- (DMSO-d6) δ 0.56 (d, HRMS m/z
    (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- J = 6.11 Hz, 3 H) 477.1054
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 0.78-1.00 (m, 1 H) 1.41 (d, J = 6.85 Hz, (M + H)+;
    3 H) 3.78 (br. s., 1 H) Rt-2.39 min
    4.66-4.74 (m, 1 H)
    4.97-5.10 (m, 1 H) 7.16 (s, 1 H)
    7.28 (d, J = 8.22 Hz, 2 H)
    7.47 (d, J = 8.66 Hz, 2 H)
    8.40 (d, J = 7.63 Hz, 1 H)
    360: (R)-3-(5-fluoro-2-(((S)-1-(4- (DMSO-d6) δ 0.49 (br. s., 3 HRMS m/z
    (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- H) 1.43 (d, J = 7.04 Hz, 3 H) 431.1345
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 4.39 (dd, J = 8.31, 4.30 Hz, (M + H)+;
    1 H) 4.46-4.60 (m, 2 H) Rt-2.05 min
    4.92 (br. s., 2 H)
    7.23-7.31 (m, 2 H) 7.47 (d,
    J = 8.61 Hz, 2 H) 7.98 (br.
    s., 1 H) 8.34 (d, J = 2.20 Hz,
    1 H)
    361: (R)-3-(6-chloro-2-(((S)-1-(2-fluoro-4- (DMSO-d6) δ 0.50 (d, HRMS m/z
    (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- J = 6.02 Hz, 3 H) 0.93 (dd, 465.0958
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one J = 12.30, 6.33 Hz, 1 H) (M + H)+;
    1.42 (d, J = 6.99 Hz, 3 H) Rt-2.45 min
    4.25-4.57 (m, 3 H) 4.66 (br. s., 1
    H) 5.14-5.27 (m, 1 H)
    7.13-7.25 (m, 2 H) 7.29 (d,
    J = 10.07 Hz, 1 H)
    7.40-7.59 (m, 1 H)
    8.36-8.49 (m, 1 H)
    362: (R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4- (DMSO-d6) δ 0.48 (br. s., 3 HRMS m/z
    (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- H) 0.91-1.34 (m, 1 H) 449.1243
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 1.45 (d, J = 7.04 Hz, 3 H) (M + H)+;
    4.34-4.59 (m, 3 H) 5.16 (br. s., 1 Rt-2.09 min
    H) 7.20 (d, J = 8.51 Hz, 1 H)
    7.32 (d, J = 10.51 Hz, 1 H)
    7.52 (t, J = 8.56 Hz, 1 H)
    8.06 (br. s., 1 H) 8.37 (br.
    s., 1 H)
    363: (R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4- (DMSO-d6) δ HRMS m/z
    isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)- 0.40-0.82 (m, 3 H) 0.95 (d, J = 6.65 Hz, 437.2005
    1-hydroxyethyl)oxazolidin-2-one 6 H) 1.40 (d, J = 6.99 Hz, (M + H)+;
    3 H) 1.98 (dquin, Rt-2.28 min
    J = 13.29, 6.64, 6.64, 6.64,
    6.64 Hz, 1 H) 3.71 (d,
    J = 6.50 Hz, 2 H)
    4.38-4.70 (m, 4 H) 5.12 (br. s., 1 H)
    6.65-6.78 (m, 2 H) 7.29 (t,
    J = 9.00 Hz, 1 H) 7.89 (br.
    s., 1 H) 8.35 (br. s., 1 H)
    364: (R)-3-(2-(((S)-1-(4- (DMSO-d6) δ 0.62 (br. s., 3 HRMS m/z
    (difluoromethoxy)phenyl)ethyl)amino)-5- H) 1.42 (d, J = 6.99 Hz, 3 H) 413.1433
    fluoropyrimidin-4-yl)-4-((R)-1- 4.35-4.44 (m, 1 H) (M + H)+;
    hydroxyethyl)oxazolidin-2-one 4.47-4.54 (m, 1 H) 4.56 (br. s., 1 Rt-1.83 min
    H) 4.91 (br. s., 1 H) 7.10 (d,
    J = 8.51 Hz, 2 H)
    6.95-7.35 (m, 1 H) 7.41 (d, J = 8.61 Hz,
    2 H) 7.94 (br. s., 1 H)
    8.34 (d, J = 2.64 Hz, 1 H)
    365: (R)-3-(5-fluoro-2-(((S)-1-(3-fluoro-4- (DMSO-d6) δ HRMS m/z
    (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- 0.26-1.06 (m, 3 H) 1.44 (d, J = 6.99 Hz, 449.1244
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 3 H) 4.35-4.61 (m, 2 (M + H)+;
    H) 5.21 (br. s., 3 H) Rt-2.09 min
    7.25-7.38 (m, 1 H)
    7.42-7.55 (m, 2 H) 8.00 (br. s., 1 H)
    8.37 (br. s., 1 H)
    366: (R)-3-(6-chloro-2-(((S)-1-(4- (DMSO-d6) δ 0.65 (d, HRMS m/z
    (difluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- J = 6.06 Hz, 3 H) 429.1139
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 0.87-1.02 (m, 1 H) 1.42 (d, J = 6.70 Hz, (M + H)+;
    3 H) 4.36-4.54 (m, 2 Rt-2.20 min
    H) 4.69-4.79 (m, 1 H)
    4.99-5.11 (m, 1 H)
    6.96-7.39 (m, 1 H) 7.12 (d, J = 8.51 Hz,
    2 H) 7.17 (d, J = 7.24 Hz,
    1 H) 7.43 (d, J = 8.51 Hz,
    2 H) 8.39 (d, J = 8.02 Hz,
    1 H)
    367: (R)-3-(6-chloro-2-(((S)-1-(3-fluoro-4- (DMSO-d6) δ 0.57 (d, HRMS m/z
    (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- J = 6.21 Hz, 3 H) 1.43 (d, 465.0959
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one J = 6.75 Hz, 3 H) (M + H)+;
    4.31-4.55 (m, 3 H) 4.71 (br. s., 1 H) Rt-2.43 min
    4.99-5.13 (m, 1 H)
    7.20 (s, 1 H) 7.30 (d, J = 8.56 Hz,
    1 H) 7.40-7.58 (m, 2 H)
    8.41 (d, J = 7.19 Hz, 1 H)
    368: (R)-3-(5-fluoro-2-(((S)-1-(4- (DMSO-d6) δ 0.48 (br. s., 3 HRMS m/z
    (isobutylsulfonyl)phenyl)ethyl)amino)pyrimidin-4- H) 0.96 (dd, J = 6.70, 1.12 Hz, 467.1758
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 6 H) 1.46 (d, J = 7.04 Hz, (M + H)+;
    3 H) 2.00 (dquin, Rt-1.78 min
    J = 13.27, 6.60, 6.60, 6.60,
    6.60 Hz, 1 H) 3.15 (d,
    J = 6.46 Hz, 2 H)
    4.34-4.61 (m, 4 H) 4.98 (br. s., 1 H)
    7.62 (d, J = 8.31 Hz, 2 H)
    7.83 (d, J = 8.31 Hz, 2 H)
    8.07 (br. s., 1 H) 8.35 (br.
    s., 1 H)
    369: (R)-3-(5-fluoro-2-(((S)-1-(4- (DMSO-d6) δ 0.45 (br. s., 3 HRMS m/z
    (isopropylsulfonyl)phenyl)ethyl)amino)pyrimidin-4- H) 1.11 (d, J = 6.80 Hz, 6 H) 453.1604
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 1.43 (d, J = 7.04 Hz, 3 H) (M + H)+;
    3.33 (dt, J = 13.58, 6.78 Hz, Rt-1.57 min
    1 H) 4.37 (dd, J = 8.05, 4.13 Hz,
    1 H) 4.43-4.58 (m, 2
    H) 4.97 (br. s., 1 H) 7.61 (d,
    J = 8.36 Hz, 2 H) 7.76 (d,
    J = 8.36 Hz, 2 H) 8.06 (br.
    s., 1 H) 8.33 (br. s., 1 H)
    370: (R)-3-(6-chloro-2-(((S)-1-(4- (DMSO-d6) δ 0.53 (d, HRMS m/z
    (isopropylsulfonyl)phenyl)ethyl)amino)pyrimidin-4- J = 6.21 Hz, 3 H) 1.11 (dd, 469.1314
    yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one J = 6.77, 3.74 Hz, 6 H) (M + H)+;
    1.43 (d, J = 6.75 Hz, 3 H) Rt-1.92 min
    3.34 (dt, J = 13.17, 6.50 Hz, 1 H)
    3.68 (br. s., 1 H) 4.38 (dd,
    J = 16.43, 7.97 Hz, 2 H)
    4.64-4.76 (m, 1 H)
    4.98-5.17 (m, 1 H) 7.18 (s, 1 H)
    7.62 (d, J = 8.31 Hz, 2 H) 7.78 (d,
    J = 8.27 Hz, 2 H) 8.50 (d,
    J = 7.34 Hz, 1 H)
    371: (R)-3-(2-(((S)-1-(4- (DMSO-d6) δ HRMS m/z
    (cyclopropylmethoxy)phenyl)ethyl)amino)pyrimidin- 0.24-0.35 (m, 2 H) 0.54 (dd, J = 8.09, 399.2034
    4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 1.74 Hz, 2 H) 0.74 (br. s., 3 (M + H)+;
    H) 1.12-1.24 (m, 1 H) Rt-1.59 min
    1.42 (d, J = 6.99 Hz, 3 H) 3.76 (d,
    J = 6.99 Hz, 2 H)
    4.36-4.50 (m, 3 H) 4.78 (d, J = 2.89 Hz,
    1 H) 4.98-5.10 (m, 1
    H) 6.84 (d, J = 8.61 Hz, 2 H)
    7.18-7.36 (m, 3 H)
    8.15 (d, J = 5.62 Hz, 1 H)
    372: (R)-3-(2-(((S)-1-(2-fluoro-4- (DMSO-d6) δ HRMS m/z
    isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)- 0.51-0.82 (m, 3 H) 0.94 (d, J = 6.70 Hz, 419.2102
    1-hydroxyethyl)oxazolidin-2-one 6 H) 1.42 (d, J = 6.85 Hz, (M + H)+;
    3 H) 1.97 (dquin, Rt-1.95 min
    J = 13.32, 6.70, 6.70, 6.70,
    6.70 Hz, 1 H) 3.70 (d,
    J = 6.55 Hz, 2 H)
    4.35-4.48 (m, 2 H) 4.71-4.79 (m, 1
    H) 5.24 (quin, J = 7.10 Hz, 1
    H) 6.65-6.79 (m, 2 H)
    7.19-7.34 (m, 2 H) 8.15 (br. s.,
    1 H)
    • Example 373 (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00854
  • To a microwave vial with stir bar was added (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (28 mg, 0.12 mmol) and DMSO (1 mL). To this reaction mixture was added (S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethanamine (48 mg, 0.17 mmol) and DIEA (61 ul, 0.35 mmol). Vial was capped and the reaction mixture was heated in a preheated sand bath at 80° C. for 18 hr. Reaction mixture was purified by reverse phase HPLC. Product fractions combined, frozen and lyopholyzed to afford a TFA salt of (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (28 mg, 0.04 mmol, 38% yield). 1H NMR (400 MHz, CDCl3) δ 1.01 (d, J=6.65 Hz, 3H) 1.82 (d, J=7.04 Hz, 3H) 3.24 (s, 3H) 3.72-3.86 (m, 1H) 4.36-4.47 (m, 1H) 4.60 (dd, J=9.39, 2.35 Hz, 1H) 4.92-5.01 (m, 1H) 5.48 (t, J=7.04 Hz, 1H) 7.43 (d, J=8.61 Hz, 2H) 7.72 (s, 1H) 7.77-7.85 (m, 4H) 8.02 (d, J=7.04 Hz, 1H) 10.95 (d, J=6.65 Hz, 1H).). LCMS m/z 460.2 (M+H)+, Rt 0.82 min. HRMS (B) m/z 460.1213 (M+H)+, Rt 2.28 min.
  • The compounds in Table 33a were prepared using methods similar to those described for the preparation of Example 373.
  • TABLE 33a
    Figure US20140275083A1-20140918-C00855
         		374
    Figure US20140275083A1-20140918-C00856
         		375
    Figure US20140275083A1-20140918-C00857
         		376
    Figure US20140275083A1-20140918-C00858
         		377
    Figure US20140275083A1-20140918-C00859
         		378
    Figure US20140275083A1-20140918-C00860
         		379
  • TABLE 33b
    Chemical name, NMR chemical shifts and LCMS signal for each compound listed
    in Table 33a.
    Example: Name 1H NMR (400 MHz, CDCl3) δ ppm HRMS
    374: (R)-3-(6-chloro-2- 0.89 (br. s., 3 H) 1.56 (br. s., 3 H) 3.20 (br. HRMS (B)
    (((S)-1-(2,5-difluoro-4-(1- s., 3 H) 3.96 (s, 3 H) 4.28-4.37 (m, 1 H) m/z
    methyl-1H-pyrazol-4- 4.50 (dd, J = 9.39, 2.89 Hz, 1 H) 4.88 (ddd, 493.1567
    yl)phenyl)ethyl) J = 8.50, 4.32, 2.98 Hz, 1 H) 5.30 (quin, (M + H)+;
    amino)pyrimidin-4-yl)-4- J = 6.97 Hz, 1 H) 5.50 (br. s., 1 H) 7.07 (dd, Rt-2.35 min
    ((R)-1-methoxyethyl) J = 10.91, 6.36 Hz, 1 H) 7.21 (dd, J = 10.88,
    oxazolidin-2-one 6.04 Hz, 1 H) 7.55 (s, 1 H) 7.76 (d, J = 2.45 Hz,
    1 H) 7.79 (s, 1 H)
    375: (R)-3-(6-chloro-2- 0.69-0.95 (m, 3 H) 1.57-1.61 (m, 3 H) HRMS (B)
    (((S)-1-(2-fluoro-4- 3.16 (br. s., 3 H) 4.26-4.37 (m, 1 H) m/z
    (trifluoromethyl) 4.49 (dd, J = 9.39, 2.74 Hz, 1 H) 4.78-4.90 (m, 1 463.1170
    phenyl)ethyl)amino)pyrimidin- H) 5.37 (quin, J = 6.93 Hz, 1 H) 5.51 (br. s., (M + H)+;
    4-yl)-4-((R)-1- 1 H) 7.33 (d, J = 9.44 Hz, 1 H) Rt-2.74 min
    methoxyethyl)oxazolidin- 7.38-7.43 (m, 1 H) 7.44-7.51 (m, 1 H) 7.56 (s, 1 H)
    2-one
    376: (R)-3-(6-chloro-2- 1.01 (d, J = 4.21 Hz, 3 H) 1.72-1.77 (m, 3 HRMS (B)
    (((S)-1-(2-(4- H) 3.21 (br. s., 3 H) 4.31-4.42 (m, 1 H) m/z
    chlorophenyl)thiazol-5- 4.53 (dd, J = 9.46, 2.76 Hz, 1 H) 4.89 (ddd, 494.0823
    yl)ethyl)amino)pyrimidin-4- J = 8.36, 4.21, 2.79 Hz, 1 H) 5.46 (br. s., 1 (M + H)+;
    yl)-4-((R)-1- H) 7.42-7.48 (m, 2 H) 7.65 (s, 1 H) Rt-2.80 min
    methoxyethyl)oxazolidin- 7.80 (d, J = 8.56 Hz, 3 H)
    2-one
    377: (R)-3-(2-(((S)-1-(5- 1.00 (d, J = 6.26 Hz, 3 H) 1.74 (d, J = 7.04 Hz, HRMS (B)
    (4-chlorophenyl) isoxazol- 3 H) 3.46 (s, 3 H) 4.03-4.19 (m, 1 H) m/z
    3-yl)ethyl)amino) 4.43 (t, J = 8.80 Hz, 1 H) 4.65 (dd, J = 9.59, 444.1433
    pyrimidin-4-yl)-4-((R)-1- 2.54 Hz, 1 H) 5.03 (ddd, J = 7.92, 4.60, 2.74 Hz, (M + H)+;
    methoxyethyl)oxazolidin- 1 H) 5.44 (quin, J = 7.14 Hz, 1 H) Rt-2.21 min
    2-one 6.69 (s, 1 H) 7.45 (d, J = 8.61 Hz, 2 H) 7.71 (d,
    J = 8.61 Hz, 2 H) 7.80 (d, J = 7.04 Hz, 1 H)
    7.94 (d, J = 7.04 Hz, 1 H) 10.98 (d, J = 7.43 Hz,
    1 H)
    378: (R)-3-(2-(((S)-1-(1- 1.04 (d, J = 5.87 Hz, 3 H) 1.75 (d, J = 6.26 Hz, HRMS (B)
    (4-chlorophenyl)-1H- 3 H) 3.31 (s, 3 H) 3.95 (br. s., 1 H) m/z
    imidazol-4-yl)ethyl) 4.46 (t, J = 8.61 Hz, 1 H) 4.60 (dd, J = 9.39, 443.1598
    amino)pyrimidin-4-yl)-4- 2.35 Hz, 1 H) 5.07 (d, J = 3.13 Hz, 1 H) (M + H)+;
    ((R)-1-methoxyethyl) 5.57 (br. s., 1 H) 7.44 (d, J = 8.61 Hz, 2 H) Rt-1.57 min
    oxazolidin-2-one 7.57 (d, J = 8.22 Hz, 2 H) 7.61 (br. s., 1 H)
    7.85 (d, J = 7.04 Hz, 1 H) 7.96 (d, J = 6.65 Hz, 1
    H) 8.53 (br. s., 1 H) 10.90 (d, J = 6.65 Hz, 1
    H)
    379: (R)-3-(2-(((S)-1-(2,5- 0.97 (d, J = 6.65 Hz, 3 H) 1.67 (d, J = 7.04 Hz, HRMS (B)
    difluoro-4-(6- 3 H) 2.88 (s, 3 H) 3.30 (s, 3 H) m/z
    methylpyridin-3- 3.67-3.89 (m, 1 H) 4.37-4.49 (m, 1 H) 4.61 (dd, 470.2007
    yl)phenyl)ethyl)amino)pyrimidin- J = 9.39, 2.35 Hz, 1 H) 4.94-5.07 (m, 1 H) (M + H)+;
    4-yl)-4-((R)-1- 5.62 (quin, J = 6.95 Hz, 1 H) 7.22-7.26 (m, Rt-1.53 min
    methoxyethyl)oxazolidin- 1 H) 7.48 (dd, J = 10.37, 6.06 Hz, 1 H)
    2-one 7.66 (d, J = 8.22 Hz, 1 H) 7.82 (d, J = 7.04 Hz, 1
    H) 7.97 (d, J = 7.04 Hz, 1 H) 8.34 (d, J = 8.22 Hz,
    1 H) 9.00 (s, 1 H) 11.04 (d, J = 7.83 Hz,
    1 H)
    • Example 380 (S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00861
    • Step 1
  • To a microwave vial with stir bar was added (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (147 mg, 0.49 mmol) and DMSO (4 mL). To this reaction mixture was added (S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethanamine HCl (148 mg, 0.54 mmol) and DIEA (0.26 mL, 1.47 mmol). Vial capped and the reaction mixture was heated in a preheated sand bath at 110° C. for 42 hr. The reaction mixture was diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (82 mg, 0.16 mmol, 33% yield). 1H NMR (400 MHz, CDCl3) δ 0.82 (br. s., 9H) 0.90-0.98 (m, 3H) 1.71 (d, J=6.90 Hz, 3H) 4.13 (q, J=7.16 Hz, 1H) 4.21-4.32 (m, 1H) 4.42-4.51 (m, 1H) 4.56 (dd, J=8.31, 2.79 Hz, 1H) 5.39 (br. s., 1H) 7.34-7.45 (m, 2H) 7.57 (d, J=5.77 Hz, 1H) 7.64 (s, 1H) 7.76-7.86 (m, 2H) 8.22 (d, J=5.82 Hz, 1H). LCMS m/z 502.3 (M+H)+, Rt 0.92 min.
    • Step 2
  • To a round bottom flask containing a stir bar and (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (82 mg, 0.16 mmol) was added DCM (1 mL) followed by the addition of TFA (1 mL). Resulting reaction mixture allowed to stir 30 min at RT. The volatiles were then removed and the residue neutralized by the addition of a saturated solution of NaHCO3. The aqueous mixture was then extracted with DCM. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a brown foam of (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (61 mg, 0.14 mmol, 84% yield) which was used without further purification. LCMS m/z 446.2 (M+H)+, Rt 0.71 min.
    • Step 3
  • To a round bottom flask with stir bar was added (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (19 mg, 0.04 mmol) followed by the addition of DCM (1 mL) under nitrogen. Mixture was cooled to 0° C. in a ice/water bath. To this cold solution was added DIEA (0.03 mL, 0.17 mmol) followed by the addition of methanesulfonyl chloride (10 μL, 0.13 mmol). Reaction mixture stirred for 1 hr at 0° C. The reaction mixture was then quenched with water and diluted with DCM. Phases partitioned and the aqueous phase extracted with DCM. Organic layers combined and washed with brine, dried (Na2SO4), filtered and concentrated to afford a orange residue of (S)-1-((R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-2-oxooxazolidin-4-yl)ethyl methanesulfonate (21 mg, 0.04 mmol, 94% yield). LCMS m/z 524.2 (M+H)+, Rt 0.75 min.
    • Step 4
  • To a microwave vial containing (S)-1-((R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-2-oxooxazolidin-4-yl)ethyl methanesulfonate (21 mg, 0.04 mmol) in DMF (1 mL) was added sodium azide (13 mg, 0.20 mmol). Resulting reaction mixture heated to 50° C. for 1 hr in a sand bath then to 80° C. for 42 hr. Reaction mixture was diluted with water and extracted with EtOAc. Organic phases combined, washed with brine, dried (Na2SO4), filtered and concentrated to a yellow residue of (S)-4-((R)-1-azidoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (14 mg, 0.030 mmol, 74.2% yield). LCMS m/z 471.2 (M+H)+, Rt 0.92 min.
    • Step 5
  • To a round bottom flask containing (S)-4-((R)-1-azidoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (14 mg, 0.03 mmol) and stir bar was added THF (1 mL) and trimethylphosphine (0.06 mL, 0.06 mmol, 1.0 M in THF). The resulting reaction mixture allowed to stir 2 hr at RT. A second addition of trimethylphosphine (0.06 mL, 0.06 mmol) occurred and the mixture allowed to stir 1.5 hr at RT. Reaction was quenched by the addition of a saturated solution of NH4Cl and EtOAc. The phases were partitioned and aqueous phase extracted with EtOAc. Organic phases combined and washed with brine, dried (Na2SO4), filtered and concentrated to a yellow residue. Residue dissolved in DMSO and purified by reverse phase HPLC. Product fractions combined, frozen and lyopholyzed to afford (S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (2.6 mg, 4.60 μmol, 15% yield) as a TFA salt. 1H NMR (400 MHz, CD3CN) δ 1.26-1.44 (m, 3H) 1.68 (d, J=6.65 Hz, 3H) 3.83 (quin, J=6.26 Hz, 1H) 4.43-4.53 (m, 1H) 7.46 (d, J=8.61 Hz, 2H) 7.76 (s, 1H) 7.89 (d, J=8.61 Hz, 2H) 8.20 (br. s., 1H). LCMS m/z 445.2 (M+H)+, Rt 0.65 min. HRMS (B) m/z 445.1211 (M+H)+, Rt 1.58 min.
  • The compounds in Table 34a were prepared using methods similar to those described for the preparation of Example 380
  • TABLE 34a
    Figure US20140275083A1-20140918-C00862
         		381
    Figure US20140275083A1-20140918-C00863
         		382
    Figure US20140275083A1-20140918-C00864
         		383
  • TABLE 34b
    Chemical name, NMR chemical shifts and LCMS
    signal for each compound listed in Table 34a.
    Example: Name 1H NMR (400 MHz) δ ppm HRMS
    381: (S)-4-((R)-1- (DMSO) 1.03-1.32 (m, 3 H) 1.55 (d, HRMS (B)
    aminoethyl)-3-(2-(((S)-1- J = 6.65 Hz, 3 H) 3.86 (br. s., 1 H) 4.51 (d, m/z
    (1-(4-chlorophenyl)-1H- J = 7.04 Hz, 1 H) 5.23 (br. s., 1 H) 7.28 (d, 428.1598
    imidazol-4-yl)ethyl) J = 5.87 Hz, 1 H) 7.60-7.68 (m, 2 H) 7.73 (M + H)+;
    amino)pyrimidin-4- (d, J = 8.61 Hz, 2 H) 7.83 (br. s., 1 H) 8.25 Rt-1.12
    yl)oxazolidin-2-one (d, J = 5.87 Hz, 1 H) min
    382: (S)-4-((R)-1- (DMSO) 1.09 (br. s., 3 H) 1.56 (d, J = 7.04 HRMS (B)
    aminoethyl)-3-(2-(((S)-1- Hz, 3 H) 4.45-4.54 (m, 1 H) 5.37 (br. s., 1 m/z
    (5-(4-chlorophenyl) H) 7.00 (s, 1 H) 7.26 (d, J = 5.87 Hz, 1 H) 429.1438
    isoxazol-3-yl)ethyl)amino) 7.60 (d, J = 8.61 Hz, 2 H) 7.87 (d, J = 8.61 (M + H)+;
    pyrimidin-4-yl)oxazolidin- Hz, 2 H) 8.07 (br. s., 1 H) 8.24 (d, J = 5.87 Rt-1.49
    2-one Hz, 1 H) min
    383: (S)-4-((R)-1- (CDCl3) 1.24 (br. s., 1 H) 1.53 (d, J = 5.87 HRMS (B)
    aminoethyl)-3-(2-(((S)-1- Hz, 3 H) 2.64 (br. s., 3 H) 3.31 (br. s., 3 H) m/z
    (2,5-difluoro-4-(6- 4.42 (br. s., 1 H) 7.23-7.26 (m, 3 H) 7.40 455.2005
    methylpyridin-3- (br. s., 1 H) 7.95-8.12 (m, 2 H) 8.67 (br. (M + H)+;
    yl)phenyl)ethyl)amino)pyrimidin- s., 1 H) Rt-1.06
    4-yl)oxazolidin-2- min
    one
    • Example 384 (S)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(methylamino)ethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00865
  • To a microwave vial containing (S)-1-((R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-2-oxooxazolidin-4-yl)ethyl methanesulfonate (20 mg, 0.04 mmol) in DMF (1 mL) was added methyl amine (30 mg, 0.38 mmol, 40% wt in H2O). Resulting reaction mixture allowed to stir at 80° C. for 18 hr whereupon a second addition of methylamine (0.1 mL, 40% wt in H2O) occurred. The reaction mixture was stirred at 80° C. for 18 hr. The reaction mixture was then diluted with water and extracted with EtOAc. Organic phases combined and washed with brine, dried (Na2SO4),filtered and concentrated. Residue dissolved in DMSO and purified by reverse phase HPLC. Product fractions combined, frozen and lyopholyzed to afford a TFA salt of (S)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(methylamino)ethyl)oxazolidin-2-one (3.4 mg, 5.87 μmol, 15% yield). 1H NMR (400 MHz, CDCl3) δ 1.47 (d, J=5.87 Hz, 3H) 1.78 (d, J=7.04 Hz, 3H) 2.70 (s, 3H) 4.02 (br. s., 1H) 4.14 (br. s., 2H) 5.33 (br. s., 1H) 5.73 (d, J=6.26 Hz, 1H) 6.23 (d, J=5.48 Hz, 1H) 7.41 (d, J=8.61 Hz, 2H) 7.78 (s, 1H) 7.83 (d, J=8.22 Hz, 2H) 8.05 (d, J=5.48 Hz, 1H). LCMS m/z 459.2 (M+H)+, Rt 0.73 min. HRMS (B) m/z 459.1373 (M+H)+, Rt 1.68 min.
    • Example 385 (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00866
  • To a microwave vial with stir bar was added (R)-4-((R)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (20 mg, 0.09 mmol) and DMSO (1 mL). To this reaction mixture was added (S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethanamine (34 mg, 0.13 mmol) and DIEA (46 uL, 0.26 mmol). Vial was then capped and heated in a preheated sand bath at 80° C. for 2 hr. Reaction mixture was then purified by reverse phase HPLC. Product fractions combined, frozen and lyopholyzed to afford a TFA salt of (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one (4.2 mg, 7.63 μmol, 8.74% yield). 1H NMR (400 MHz, CDCl3) δ 1.21 (dd, J=24.26, 6.26 Hz, 3H) 1.74 (d, J=6.65 Hz, 3H) 4.52-4.58 (m, 2H) 4.79-5.06 (m, 1H) 5.29 (br. s., 1H) 5.65 (t, J=6.85 Hz, 1H) 7.41 (d, J=8.61 Hz, 2H) 7.52 (s, 1H) 7.57 (d, J=9.00 Hz, 2H) 7.82 (d, J=6.65 Hz, 1H) 7.98 (d, J=7.04 Hz, 1H) 8.48 (s, 1H) 10.97 (d, J=6.65 Hz, 1H).). LCMS m/z 431.1 (M+H)+, Rt 0.61 min. HRMS (B) m/z 431.1392 (M+H)+, Rt 1.54 min.
  • The compounds in Table 35a were prepared using methods similar to those described for the preparation of Example 385.
  • TABLE 35a
    Figure US20140275083A1-20140918-C00867
         		386
    Figure US20140275083A1-20140918-C00868
         		387
    Figure US20140275083A1-20140918-C00869
         		388
    Figure US20140275083A1-20140918-C00870
         		389
    Figure US20140275083A1-20140918-C00871
         		390
    Figure US20140275083A1-20140918-C00872
         		391
    Figure US20140275083A1-20140918-C00873
         		392
    Figure US20140275083A1-20140918-C00874
         		393
    Figure US20140275083A1-20140918-C00875
         		394
    Figure US20140275083A1-20140918-C00876
         		395
    Figure US20140275083A1-20140918-C00877
         		396
    Figure US20140275083A1-20140918-C00878
         		397
    Figure US20140275083A1-20140918-C00879
         		398
    Figure US20140275083A1-20140918-C00880
         		399
    Figure US20140275083A1-20140918-C00881
         		400
    Figure US20140275083A1-20140918-C00882
         		401
    Figure US20140275083A1-20140918-C00883
         		402
  • TABLE 35b
    Chemical name, NMR chemical shifts and LCMS
    signal for each compound listed in Table 35a.
    Example: Name 1H NMR (400 MHz, CDCl3) δ ppm HRMS
    386: (R)-3-(2-(((S)-1-(5- 10.84 (d, J = 6.7 Hz, 1 H), 8.02 (d, J = 7.0 Hz, HRMS (B)
    (4-chlorophenyl) isoxazol- 1 H), 7.79 (d, J = 7.0 Hz, 1 H), 7.71 (d, m/z
    3-yl)ethyl)amino) J = 8.6 Hz, 2 H), 7.46 (d, J = 8.2 Hz, 2 H), 432.1242
    pyrimidin-4-yl)-4-((R)-1- 6.63 (s, 1 H), 5.33 (quin, J = 6.9 Hz, 1 H), (M + H)+;
    fluoroethyl)oxazolidin-2- 4.95-5.21 (m, 2 H), 4.58-4.71 (m, 1 H), Rt-2.18
    one 4.43-4.56 (m, 1 H), 1.75 (d, J = 7.0 Hz, 3 min
    H), 1.17 (dd, J = 23.9, 5.9 Hz, 3 H)
    387: (R)-3-(2-(((S)-1-(2- 1.18 (dd, J = 24.26, 6.65 Hz, 3 H) 1.82 (d, HRMS (B)
    (4-chlorophenyl) thiazol-5- J = 7.04 Hz, 3 H) 4.44-4.55 (m, 1 H) 4.57- m/z
    yl)ethyl)amino) pyrimidin- 4.66 (m, 1 H) 4.69-4.94 (m, 1 H) 5.00- 448.1014
    4-yl)-4-((R)-1- 5.13 (m, 1 H) 5.40 (quin, J = 6.65 Hz, 1 H) (M + H)+;
    fluoroethyl)oxazolidin-2- 7.43 (d, J = 8.22 Hz, 2 H) 7.75 (s, 1 H) 7.77- Rt-2.27
    one 7.88 (m, 3 H) 8.04 (d, J = 6.65 Hz, 1 H) min
    11.00 (d, J = 5.48 Hz, 1 H)
    388: (R)-3-(2-(((S)-1-(1- 1.36 (dd, J = 23.87, 6.26 Hz, 3 H) 1.71 (d, HRMS (B)
    (4-chlorophenyl)-1H- J = 6.26 Hz, 3 H) 4.46-4.58 (m, 1 H) 4.59- m/z
    imidazol-4-yl)ethyl) 4.69 (m, 1 H) 4.86-5.12 (m, 2 H) 5.59 (br. 431.1400
    amino)pyrimidin-4-yl)-4- s., 1 H) 7.42 (d, J = 8.61 Hz, 2 H) 7.57 (d, (M + H)+;
    ((S)-1-fluoroethyl) J = 9.00 Hz, 3 H) 7.90 (d, J = 6.65 Hz, 1 H) Rt-1.55
    oxazolidin-2-one 7.99 (d, J = 7.04 Hz, 1 H) 8.41 (br. s., 1 H) min
    11.02 (d, J = 7.04 Hz, 1 H)
    389: (R)-3-(2-(((S)-1-(2- 1.26 (dd, J = 21.91, 6.65 Hz, 3 H) 1.81 (d, HRMS (B)
    (4-chlorophenyl) thiazol-5- J = 7.04 Hz, 3 H) 4.43-4.55 (m, 1 H) 4.57- m/z
    yl)ethyl)amino) pyrimidin- 4.65 (m, 1 H) 4.65-4.93 (m, 2 H) 5.33 448.1007
    4-yl)-4-((S)-1- (quin, J = 6.65 Hz, 1 H) 7.45 (d, J = 8.22 Hz, (M + H)+;
    fluoroethyl)oxazolidin-2- 2 H) 7.71 (s, 1 H) 7.81 (d, J = 8.61 Hz, 2 H) Rt-2.22
    one 7.91 (d, J = 7.04 Hz, 1 H) 8.08 (d, J = 7.04 min
    Hz, 1 H) 10.94 (d, J = 5.87 Hz, 1 H)
    390: (R)-3-(2-(((S)-1-(5- 1.48 (dd, J = 23.48, 6.26 Hz, 3 H) 1.73 (d, HRMS (B)
    (4-chlorophenyl) isoxazol- J = 7.04 Hz, 3 H) 4.41-4.56 (m, 1 H) 4.67 m/z
    3-yl)ethyl)amino) (dd, J = 9.20, 2.54 Hz, 1 H) 4.74-5.05 (m, 2 432.1233
    pyrimidin-4-yl)-4-((S)-1- H) 5.22 (t, J = 6.65 Hz, 1 H) 6.62 (s, 1 H) (M + H)+;
    fluoroethyl)oxazolidin-2- 7.46 (d, J = 8.22 Hz, 2 H) 7.70 (d, J = 8.22 Rt-2.16
    one Hz, 2 H) 7.86 (d, J = 7.04 Hz, 1 H) 7.99 (d, min
    J = 7.04 Hz, 1 H) 10.88 (d, J = 6.26 Hz, 1 H)
    391: (R)-3-(2-(((S)-1-(3- 1.11 (dd, J = 24.26, 7.04 Hz, 3 H) 1.90 (d, HRMS (B)
    (4-chlorophenyl)-1,2,4- J = 7.04 Hz, 3 H) 4.40-4.48 (m, 1 H) 4.50- m/z
    oxadiazol-5- 4.57 (m, 1 H) 4.66-4.89 (m, 1 H) 4.93- 433.1190
    yl)ethyl)amino)pyrimidin-4- 5.02 (m, 1 H) 5.30-5.41 (m, 1 H) 7.47 (d, (M + H)+;
    yl)-4-((R)-1-fluoroethyl) J = 8.61 Hz, 2 H) 7.84 (d, J = 7.04 Hz, 1 H) Rt-2.30
    oxazolidin-2-one 8.00 (d, J = 8.61 Hz, 2 H) 8.10 (d, J = 6.65 min
    Hz, 1 H) 11.06 (d, J = 4.30 Hz, 1 H)
    392: (R)-4-((R)-1- 1.20 (dd, J = 23.87, 6.26 Hz, 3 H) 1.84 (d, HRMS (B)
    fluoroethyl)-3-(2-(((S)-1- J = 7.04 Hz, 3 H) 4.46-4.55 (m, 1 H) 4.57- m/z
    (2-(2-(trifluoromethyl) 4.65 (m, 1 H) 4.68-4.93 (m, 1 H) 5.07 (d, 483.1232
    pyridin-4-yl)thiazol-5- J = 5.87 Hz, 1 H) 5.46 (t, J = 6.85 Hz, 1 H) (M + H)+;
    yl)ethyl)amino)pyrimidin-4- 7.80 (d, J = 7.04 Hz, 1 H) 7.86 (s, 1 H) 7.94 Rt-2.06
    yl)oxazolidin-2-one (d, J = 5.09 Hz, 1 H) 8.04 (d, J = 7.04 Hz, 1 min
    H) 8.17 (s, 1 H) 8.83 (d, J = 5.09 Hz, 1 H)
    11.14 (br. s., 1 H)
    393: (R)-4-((R)-1- 1.20 (dd, J = 23.87, 6.26 Hz, 3 H) 1.84 (d, HRMS (B)
    fluoroethyl)-3-(2-(((S)-1- J = 7.04 Hz, 3 H) 4.44-4.56 (m, 1 H) 4.57- m/z
    (2-(6-(trifluoromethyl) 4.65 (m, 1 H) 4.68-4.94 (m, 1 H) 5.07 (d, 483.1233
    pyridin-3-yl)thiazol-5- J = 5.48 Hz, 1 H) 5.45 (t, J = 6.65 Hz, 1 H) (M + H)+;
    yl)ethyl)amino)pyrimidin-4- 7.72-7.88 (m, 3 H) 8.03 (d, J = 7.04 Hz, 1 Rt-2.07
    yl)oxazolidin-2-one H) 8.36 (d, J = 7.83 Hz, 1 H) 9.21 (s, 1 H) min
    11.12 (br. s., 1 H)
    394: (R)-3-(2-(((S)-1-(1- 1.21 (dd, J = 23.48, 6.65 Hz, 3 H) 1.69 (d, HRMS (B)
    (4-chlorophenyl)-1H- J = 6.65 Hz, 3 H) 4.48-4.56 (m, 1 H) 4.59- m/z
    pyrazol-4-yl)ethyl)amino) 4.64 (m, 1 H) 4.87-5.25 (m, 3 H) 7.43 (d, 431.1407
    pyrimidin-4-yl)-4-((R)-1- J = 8.61 Hz, 2 H) 7.62 (d, J = 8.61 Hz, 2 H) (M + H)+;
    fluoroethyl)oxazolidin-2- 7.67 (s, 1 H) 7.74 (d, J = 6.65 Hz, 1 H) 7.95- Rt-1.95
    one 8.02 (m, 2 H) 10.74 (d, J = 5.48 Hz, 1 H) min
    395: (R)-3-(2-(((S)-1-(2- 1.17 (dd, J = 23.48, 4.70 Hz, 3 H) 1.76 (d, HRMS (B)
    (4-chlorophenyl) thiazol-5- J = 6.65 Hz, 3 H) 4.39 (dd, J = 9.39, 4.30 Hz, m/z
    yl)ethyl)amino)-5- 1 H) 4.60 (t, J = 9.00 Hz, 1 H) 4.68-4.90 466.0916
    fluoropyrimidin-4-yl)-4- (m, 2 H) 5.32 (d, J = 5.09 Hz, 1 H) 7.44 (d, (M + H)+;
    ((R)-1-fluoroethyl) J = 8.61 Hz, 2 H) 7.79 (d, J = 8.61 Hz, 2 H) Rt-2.32
    oxazolidin-2-one 7.85 (s, 1 H) 8.19 (d, J = 3.13 Hz, 1 H) min
    396: (R)-3-(2-(((S)-1-(1- 1.28 (dd, J = 23.09, 6.65 Hz, 3 H) 1.68 (d, HRMS (B)
    (4-chlorophenyl)-1H- J = 6.65 Hz, 3 H) 4.44-4.55 (m, 1 H) 4.57- m/z
    pyrazol-4-yl)ethyl)amino) 4.65 (m, 1 H) 4.67-4.78 (m, 1 H) 4.81- 431.1407
    pyrimidin-4-yl)-4-((S)-1- 5.04 (m, 1 H) 5.09 (t, J = 6.65 Hz, 1 H) 7.43 (M + H)+;
    fluoroethyl)oxazolidin-2- (d, J = 8.61 Hz, 2 H) 7.56-7.67 (m, 3 H) Rt-1.88
    one 7.84 (d, J = 6.65 Hz, 1 H) 7.93 (s, 1 H) 8.00 min
    (d, J = 7.04 Hz, 1 H) 10.73 (d, J = 5.87 Hz, 1
    H)
    397: (R)-3-(2-(((S)-1-(1- 1.24 (dd, J = 23.87, 5.87 Hz, 3 H) 1.68 (d, HRMS (B)
    (4-chlorophenyl)-1H- J = 6.65 Hz, 3 H) 4.39 (dd, J = 9.39, 3.91 Hz, m/z
    pyrazol-4-yl)ethyl)amino)- 1 H) 4.62 (t, J = 9.00 Hz, 1 H) 4.76-4.99 449.1303
    5-fluoropyrimidin-4-yl)-4- (m, 2 H) 5.14 (q, J = 7.04 Hz, 1 H) 7.43 (d, (M + H)+;
    ((R)-1-fluoroethyl) J = 8.61 Hz, 2 H) 7.57 (d, J = 8.61 Hz, 2 H) Rt-2.20
    oxazolidin-2-one 7.76 (s, 1 H) 7.96 (s, 1 H) 8.15 (d, J = 3.91 min
    Hz, 1H)
    398: (R)-3-(2-(((S)-1-(5- 1.15 (dd, J = 24.26, 6.26 Hz, 3 H) 1.72 (d, HRMS (B)
    (4-chlorophenyl) isoxazol- J = 7.04 Hz, 3 H) 4.42 (dd, J = 9.39, 4.30 Hz, m/z
    3-yl)ethyl)amino)-5- 1 H) 4.62 (t, J = 9.00 Hz, 1 H) 4.73-5.07 450.1145
    fluoropyrimidin-4-yl)-4- (m, 2 H) 5.17-5.23 (m, 1 H) 6.54 (s, 1 H) (M + H)+;
    ((R)-1-fluoroethyl) 7.45 (d, J = 8.61 Hz, 2 H) 7.68 (d, J = 8.22 Rt-2.26
    oxazolidin-2-one Hz, 2 H) 8.15 (d, J = 3.52 Hz, 1 H) min
    399: (R)-3-(2-(((S)-1-(1- 1.29 (dd, J = 23.87, 5.09 Hz, 3 H) 1.75 (d, HRMS (B)
    (4-chlorophenyl)-1H- J = 6.65 Hz, 3 H) 4.38 (d, J = 6.26 Hz, 1 H) m/z
    imidazol-4-yl)ethyl) 4.58 (t, J = 8.80 Hz, 1 H) 4.93 (br. s., 1 H) 449.1313
    amino)-5-fluoropyrimidin- 5.32 (br. s., 1 H) 7.42 (d, J = 7.83 Hz, 3 H) (M + H)+;
    4-yl)-4-((R)-1-fluoroethyl) 7.56 (d, J = 7.83 Hz, 2 H) 8.19 (br. s., 1 H) Rt-1.52
    oxazolidin-2-one 8.62 (br. s., 1 H) min
    400: (R)-3-(2-(((S)-1-(1- 1.33-1.53 (m, 3 H) 1.71 (br. s., 3 H) 2.60 HRMS (B)
    (4-chlorophenyl)-2-methyl- (s, 3 H) 4.54 (br. s., 1 H) 4.62 (d, J = 7.04 m/z
    1H-imidazol-4- Hz, 1 H) 4.94-5.20 (m, 1 H) 5.69 (br. s., 1 445.1556
    yl)ethyl)amino)pyrimidin-4- H) 7.30 (d, J = 8.22 Hz, 2 H) 7.59 (d, J = 8.61 (M + H)+;
    yl)-4-((S)-1-fluoroethyl) Hz, 2 H) 7.82-8.02 (m, 1 H) Rt-1.42
    oxazolidin-2-one min
    401: (R)-4-((S)-1- 1.36 (dd, J = 24.26, 5.87 Hz, 3 H) 1.72 (d, HRMS (B)
    fluoroethyl)-3-(2-(((S)-1- J = 5.87 Hz, 3 H) 4.44-4.58 (m, 1 H) 4.63 m/z
    (1-(4-fluorophenyl)-1H- (dd, J = 9.19, 2.93 Hz, 1 H) 4.87-5.18 (m, 2 415.1695
    imidazol-4-yl)ethyl) H) 5.54 (br. s., 1 H) 7.39-7.58 (m, 3 H) (M + H)+;
    amino)pyrimidin-4- 7.87 (d, J = 6.65 Hz, 1 H) 7.97 (d, J = 5.87 Rt-1.34
    yl)oxazolidin-2-one Hz, 1 H) 8.26 (br. s., 1 H) 10.95 (br. s., 1 min
    H)
    402: (R)-3-(2-(((S)-1-(2,5- 1.32 (dd, J = 23.09, 6.26 Hz, 3 H) 1.66 (d, HRMS (B)
    difluoro-4-(4-methyl-1H- J = 7.04 Hz, 3 H) 2.45 (s, 3 H) 4.45-4.56 m/z
    imidazol-1- (m, 1 H) 4.63 (dd, J = 9.00, 2.74 Hz, 1 H) 447.1761
    yl)phenyl)ethyl)amino)pyrimidin- 4.70-4.97 (m, 2 H) 5.48 (quin, J = 6.95 Hz, (M + H)+;
    4-yl)-4-((S)-1- 1 H) 7.11 (s, 1 H) 7.56 (dd, J = 10.17, 6.65 Rt-1.20
    fluoroethyl)oxazolidin-2- Hz, 1 H) 7.86 (d, J = 7.04 Hz, 1 H) 8.00 (d, min
    one J = 7.04 Hz, 1 H) 8.59 (s, 1 H) 11.07 (br. s.,
    1 H)
    • Example 403 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00884
  • A solution of (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (10 mg, 0.044 mmol), (S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)ethanamine (19 mg, 0.065 mmol, 1.5 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.031 mL, 0.175 mmol, 4 equiv) in DMSO (0.5 mL) was heated at 90° C. for 3 hours. The reaction was then cooled to room temperature. Purification by reverse phase HPLC provided the trifluoroacetate salt of (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (14 mg, white solid) in 55% yield. 1H NMR (400 MHz, CDCl3) δ 10.83 (d, J=7.1 Hz, 1H), 9.06 (d, J=2.3 Hz, 1H), 8.15 (dd, J=8.5, 2.4 Hz, 1H), 7.93-8.04 (m, 2H), 7.81 (dd, J=7.7, 6.3 Hz, 2H), 6.61 (d, J=2.6 Hz, 1H), 5.28 (quin, J=7.1 Hz, 1H), 4.96-5.17 (m, 1H), 4.68-4.81 (m, 1H), 4.62 (dd, J=9.1, 3.2 Hz, 1H), 4.45-4.54 (m, 1H), 1.72 (d, J=7.1 Hz, 3H), 1.14-1.29 (m, 3H); HRMS m/z 466.1625 (M+H)+; Rt-1.83 min.
  • The compounds in Table 36a were prepared using methods similar to those described for the preparation of Example 403.
  • TABLE 36a
    Figure US20140275083A1-20140918-C00885
         		404
    Figure US20140275083A1-20140918-C00886
         		405
    Figure US20140275083A1-20140918-C00887
         		406
  • TABLE 36b
    Chemical name, NMR chemical shifts and LCMS
    signal for each compound listed in Table 36a.
    Example: Name 1H NMR (400 MHz, CDCl3) δ ppm LCMS
    404: (R)-3-(2-(((S)-1-(1-(4- 8.22 (d, J = 5.5 Hz, 1H), 7.77 (s, 1H), 7.45 LCMS m/z
    chlorophenyl)-1H- (m, 3H), 7.30 (d, J = 8.7 Hz, 2H), 7.11 (s, 417.1 (M +
    imidazol-4- 1H), 5.14 (m, 1H), 4.93 (m, 1H), 4.48 (m, H)+; Rt-0.59
    yl)ethyl)amino)pyrimidin-4- 4H), 1.63 (d, J = 6.8 Hz, 3H) min.
    yl)-4-
    (fluoromethyl)oxazolidin-
    2-one
    405: (R)-3-(2-(((S)-1-(5-(4- 8.25 (m, 1H), 7.68 (m, 2H), 7.53 (m, 1H), LCMS m/z
    chlorophenyl)isoxazol-3- 7.44 (m, 2H), 6.48 (s, 1H), 5.47 (m, 1H), 418.2 (M +
    yl)ethyl)amino)pyrimidin-4- 4.95 (m, 1H), 4.50 (m, 4H), 1.66 (d, J = 6.8 H)+; Rt-0.82
    yl)-4- Hz, 3H) min.
    (fluoromethyl)oxazolidin-
    2-one
    406: (R)-3-(2-(((S)-1-(1-(4- 7.96 (m, 1H), 7.82 (m, 1H), 7.60 (d, J = 8.4 LCMS m/z
    chlorophenyl)-2-methyl- Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.22 (s, 445.2 (M +
    1H-imidazol-4- 1H), 5.73 (m, 1H), 5.42 (m, 1H), 5.05- H)+; Rt-0.67
    yl)ethyl)amino)pyrimidin-4- 4.90 (m, 1H), 4.54 (m, 2H), 2.60 (s, 3H), min.
    yl)-4-((R)-1- 1.72 (d, J = 6.7 Hz, 3H), 1.34-1.20 (m,
    fluoroethyl)oxazolidin-2- 3H)
    one
    • Example 407 (R)-4-((S)-1-hydroxyethyl)-3-(2-MS)-1-(1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)pipendin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00888
  • Example 407 was prepared using a method similar to that described for the preparation of Example 28. Product was purified by reverse phase HPLC. 1H NMR (400 MHz, CD2Cl2) δ 8.23 (d, J=4.18 Hz, 1H), 8.19 (d, J=4.88 Hz, 1H), 7.37 (d, J=4.88 Hz, 1H), 6.68 (br, s, 1H), 6.68-6.63 (m, 1H), 5.03 (br, s, 1H), 4.80 (br, s, 1H), 4.50-4.36 (m, 3H), 4.09-3.91 (m, 3H), 2.90-2.79 (m, 2H), 1.99-1.79 (m, 2H), 1.78-1.65 (m, 2H), 1.59 (s, 6H), 1.52-1.32 (m, 2H), 1.23 (d, J=6.97 Hz, 3H), 1.18 (d, J=6.27 Hz, 3H), HRMS (C) tR=3.62 min; MS m/z 523.2649 (M+H)+
    • Example 408 (R)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00889
  • Example 408 was prepared using a method similar to that described for the preparation of Example 28. TFA salt form of product was converted to free base form by using a PL-HCO3 MP SPE cartrage, eluting with MeOH. 1H NMR (400 MHz, CD2Cl2) δ 8.07 (d, J=5.33 Hz, 1H), 7.25 (d, J=4.33 Hz, 1H), 7.19 (d, J=9.48 Hz, 1H), 6.76-6.68 (m, 2H), 4.98 (br, s, 1H), 4.69 (br, s, 1H), 4.39-4.25 (m, 3H), 3.90 (br, s, 1H), 3.65-3.56 (m, 2H), 2.68-2.56 (m, 2H), 1.86-1.15 (m, 6H), 1.12 (d, J=6.52 Hz, 3H), 1.07 (d, J=4.74 Hz, 3H), HRMS (C) tR=4.44 min; MS m/z 530.1782 (M+H)+
    • Example 409 (S)-3-(2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00890
  • A mixture of (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (40 mg, 0.135 mmol), (S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride (61.1 mg, 0.271 mmol), Huenig's base (0.095 mL, 0.541 mmol) in DMSO (0.7 mL) under argon atmosphere was heated at 107° C. for ˜16 hr. The mixture was diluted with DMSO and water, filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (S)-3-(2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one as its trifluoroacetic acid salt (35.4 mg).
  • 1H NMR (400 Mhz, CD3OD) δ ppm 8.26 (br. s., 1H), 7.42-7.54 (m, 1H), 7.23-7.33 (m, 2H), 6.55-6.91 (m, 1H), 5.26 (q, J=6.9 Hz, 1H), 4.52 (t, J=9.0 Hz, 1H), 4.36-4.45 (m, 1H), 1.53 (d, J=7.0 Hz, 4H), 0.78 (br. s., 3H). HRMS m/z 449.1412 (M+H)+; Rt-2.27 min.
    • Examples 410 and 411 (S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one/(S)-3-(2-(((R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00891
  • A mixture of (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (40 mg, 0.153 mmol), (S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine/(R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (mixture of diastereomers ˜3/1, 37.7 mg, 0.168 mmol) and Huenig's base (0.059 mL, 0.337 mmol) in DMSO (0.7 mmol) under argon atmosphere was heated/radiated in the microwave at 140° C. for 15 min. The mixture was diluted with DMSO and water, filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (31.8 mg; first eluted product) and (S)-3-(2-(((R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (11.5 mg; second eluted product) as their trifluoroacetic acid salts.
  • 410: First eluted product: 1H NMR (500 Mhz, CD3OD) δ ppm 8.22 (s, 1H), 8.03-7.93 (m, 2H), 7.54-7.46 (m, 3H), 5.84 (m, 1H), 5.49 (q, J=7.2 Hz, 1H), 5.13 (dt, J=8.4, 3.1 Hz, 1H), 4.60-4.21 (m, 2H), 2.74 (m, 1H), 1.75 (d, J=7.2 Hz, 3H), 0.90 (br. s, 3H). HRMS m/z 465.1260 (M+H)+; Rt-2.41 min.
  • 411: Second eluted product: 1H NMR (500 Mhz, CD3OD) δ ppm 8.19 (dd, J=7.5, 6.0 Hz, 1H), 8.10-7.91 (m, 2H), 7.55-7.50 (m, 2H), 7.47 (d, J=5.8 Hz, 1H), 6.08 (td, J=55.6, 3.5 Hz, 1H), 5.40 (t, J=7.1 Hz, 1H), 4.59-4.42 (m, 1H), 4.39 (s, 1H), 3.03 (s, 1H), 1.72 (d, J=7.2 Hz, 3H), 1.03 (d, J=7.2 Hz, 3H). HRMS m/z 465.1250 (M+H)+; Rt-2.42 min.
  • The following Examples were prepared using a method similar to that described for the preparation of Examples 410/411
    • Example 412 (S)-3-(2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00892
  • 1H NMR (400 Mhz, CD3OD) δ ppm 8.19 (d, J=6.7 Hz, 1H), 7.70 (d, J=6.7 Hz, 1H), 7.47-7.56 (m, 1H), 7.28-7.40 (m, 2H), 6.60-6.95 (m, 1H), 5.57-5.95 (m, 1H), 5.47 (m, J=5.1 Hz, 1H), 5.12 (dt, J=7.8, 3.13 Hz, 1H), 4.46-4.60 (m, 2H), 1.63 (d, J=7.0 Hz, 3H), 0.77-0.95 (m, 3H). HRMS m/z 431.1506 (M+H)+; Rt-2.09 min.
    • Example 413 and 414 (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one/(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((R)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00893
  • A mixture of (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one 30 mg, 0.115 mmol), 1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethanamine (53.1 mg, 0.230 mmol), Huenig's Base 0.05 mL, 0.287 mmol) in DMSO (0.7 mL) under argon atmosphere was heated at 120° C. for ˜16 hr. Additional amine (2 eq) was added and heating was continued for 3 hrs. More amine (2 eq) was added and heating was continued for 3 hr. The mixture was diluted with DMSO and water, filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one/(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((R)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as their trifluoroacetic acid salts as off-white solids.
  • 413: First eluted product (2.8 mg): 1H NMR (500 Mhz, CD3OD) δ ppm 8.98 (s, 2H), 8.16 (s, 1H), 7.59 (dd, J=7.3, 2.3 Hz, 1H), 7.56-7.45 (m, 2H), 7.18 (t, J=9.0 Hz, 1H), 6.40-5.96 (m, 1H), 5.25 (q, J=6.9 Hz, 1H), 4.52 (dd, J=9.4, 2.8 Hz, 1H), 4.42 (t, J=8.4 Hz, 1H), 3.08 (s, 1H), 2.34 (d, J=2.0 Hz, 3H), 1.62 (d, J=7.0 Hz, 3H), 1.05 (d, J=7.2 Hz, 3H). HRMS m/z 473.1916 (M+H)+; Rt-2.12 min.
  • 414: Second eluted product (2.9 mg): 1H NMR (500 Mhz, CD3OD) δ ppm 8.96 (s, 2H), 8.16 (s, 1H), 7.57 (dd, J=7.5, 2.4 Hz, 1H), 7.53-7.43 (m, 2H), 7.17 (t, J=9.0 Hz, 1H), 5.92 (t, J=56.9 Hz, 1H), 5.30 (q, J=7.0 Hz, 1H), 5.13 (dt, J=6.9, 3.3 Hz, 1H), 4.57-4.40 (m, 2H), 2.53 (s, 1H), 2.34 (d, J=2.0 Hz, 3H), 1.64 (d, J=7.0 Hz, 3H), 0.87 (s, 3H). HRMS m/z 473.1919 (M+H)+; Rt-2.17 min.
  • The compounds in Table 37a were prepared using methods similar to those described for the preparation of Examples 35, 36, or 37/38.
  • TABLE 37a
    Figure US20140275083A1-20140918-C00894
         		415
    Figure US20140275083A1-20140918-C00895
         		416
    Figure US20140275083A1-20140918-C00896
         		417
    Figure US20140275083A1-20140918-C00897
         		418
    Figure US20140275083A1-20140918-C00898
         		419
    Figure US20140275083A1-20140918-C00899
         		420
    Figure US20140275083A1-20140918-C00900
         		421
    Figure US20140275083A1-20140918-C00901
         		422 and 423
  • TABLE 37b
    Chemical name, NMR chemical shifts, chiral separation
    conditions and LCMS signal for compounds listed in Table 37a.
    Chiral separation conditions, peak identification and
    Example: Name analytical data
    415: (R)-4-((R)-1-hydroxyethyl)- Chiral separation was achieved by chiral SFC column
    3-(2-(((S)-1-(3-(1-methyl-1H- chromatography (Column OD-H 21 × 250 mm 30% MeOH +
    indol-6-yl)-1,2,4-oxadiazol-5- 20 mM NH4OH in CO2, flow 80 g/min, 238 nm UV
    yl)ethyl)amino)pyrimidin-4- collection) to give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-
    yl)oxazolidin-2-one (1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
    ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(1-methyl-1H-indol-6-
    yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-
    yl)oxazolidin-2-one
    415: Peak 2: (11 mg): (CDCl3) δ 8.25 (d, J = 5.7 Hz, 1H),
    8.08 (d, J = 1.1 Hz, 1H), 7.80 (dd, J = 8.3, 1.4 Hz, 1H), 7.70
    (d, J = 8.3 Hz, 1H), 7.54 (d, J = 5.7 Hz, 1H), 7.19 (d, J = 3.1
    Hz, 1H), 6.54 (dd, J = 3.0, 0.9 Hz, 1H), 5.96 (s, 1H), 5.35 (s,
    1H), 4.96-4.81 (m, 1H), 4.55 (dd, J = 9.5, 2.5 Hz, 1H),
    4.38 (dd, J = 9.3, 8.4 Hz, 1H), 3.88 (s, 4H), 3.19 (s, 1H),
    2.63 (s, 8H), 1.80 (d, J = 6.7 Hz, 1H), 0.96 (d, J = 6.4 Hz,
    3H). HRMS(B) m/z 449.1812RT = 2.18 min.
    416: (R)-4-((R)-1-hydroxyethyl)- Chiral separation was achieved by chiral SFC column
    3-(2-(((S)-1-(3-(3- chromatography (Column IA-H 21 × 250 mm 15% MeOH in
    (trifluoromethoxy)phenyl)-1,2,4- CO2, flow 80 g/min, 238 nm UV collection) to give (R)-4-
    oxadiazol-5- ((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(3-
    yl)ethyl)amino)pyrimidin-4- (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
    yl)oxazolidin-2-one yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-
    ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(3-
    (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
    416: Peak 2 (62 mg): (CDCl3) δ 8.25 (d, J = 5.8 Hz, 1H),
    8.02 (dt, J = 7.7, 1.3 Hz, 1H), 7.95 (dt, J = 2.3, 1.3 Hz, 1H),
    7.67-7.46 (m, 2H), 7.40 (ddt, J = 8.3, 2.5, 1.1 Hz, 1H),
    5.90 (s, 1H), 5.40 (s, 1H), 4.86 (ddd, J = 8.4, 4.7, 2.5 Hz,
    1H), 4.55 (dd, J = 9.5, 2.5 Hz, 1H), 4.41 (t, J = 8.9 Hz, 1H),
    3.90 (s, 1H), 3.52 (s, 1H), 2.77 (s, 1H), 1.86-1.77 (m, 3H),
    1.34-1.19 (m, 1H), 1.03 (s, 3H). HRMS(B) m/z 480.1369.
    RT = 2.67 min. Chiral RT = 4.80 min
    417: (R)-3-(2-(((S)-1-(3-(1,2- Chiral separation was achieved by chiral SFC column
    dimethyl-1H-indol-4-yl)-1,2,4- chromatography (Column IA 21 × 250 mm 40% MeOH in
    oxadiazol-5- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-3-(2-
    yl)ethyl)amino)pyrimidin-4-yl)-4- (((R)-1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-
    ((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(1,2-
    dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one.
    417: Peak 2 (120 mg): (CDCl3) δ 8.16 (d, J = 6.2 Hz, 1H),
    7.89 (dd, J = 7.5, 0.9 Hz, 1H), 7.63 (d, J = 6.2 Hz, 1H), 7.45
    (dt, J = 8.1, 1.0 Hz, 1H), 7.34-7.21 (m, 1H), 6.95-6.85
    (m, 1H), 5.47-5.19 (m, 1H), 1.91-1.79 (m, 3H), 4.81
    (ddd, J = 8.3, 4.3, 2.4 Hz, 1H), 4.52 (dd, J = 9.5, 2.4 Hz,
    1H), 4.35 (dd, J = 9.5, 8.3 Hz, 1H), 3.75 (s, 4H), 3.52 (s,
    2H), 2.51 (d, J = 1.0 Hz, 3H), 0.86 (d, J = 5.5 Hz, 3H).
    HRMS(B) m/z 463.1968. RT = 2.23 min. Chiral RT = 3.35
    min
    418: (R)-3-(2-(((S)-1-(3-(4- Chiral separation was achieved by chiral SFC column
    chloro-3- chromatography (Column AD-H 21 × 250 mm 15% MeOH +
    (trifluoromethoxy)phenyl)-1,2,4- 10 mM NH4OH in CO2, flow 75 g/min, 238 nm UV
    oxadiazol-5- collection) to give (R)-3-(2-(((R)-1-(3-(4-chloro-3-
    yl)ethyl)amino)pyrimidin-4-yl)-4- (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
    ((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    chloro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    418: Peak 2 (120 mg): CDCl3) δ 8.25 (d, J = 5.8 Hz, 1H),
    8.05 (p, J = 1.4 Hz, 1H), 7.98 (dd, J = 8.4, 1.9 Hz, 1H), 7.70-
    7.49 (m, 2H), 5.74 (s, 1H), 5.51-5.35 (m, 1H), 4.85 (ddd,
    J = 8.3, 4.8, 2.5 Hz, 1H), 4.54 (dd, J = 9.3, 2.5 Hz, 1H), 4.41
    (dd, J = 9.4, 8.3 Hz, 1H), 2.72 (s, 1H), 1.79 (d, J = 7.1 Hz,
    3H), 1.63 (d, J = 7.1 Hz, 2H), 1.05 (s, 3H). HRMS(B) m/z
    515.1243. Chiral RT = 4.20 min
    419: (R)-3-(2-(((S)-1-(3-(4- Chiral separation was achieved by chiral SFC column
    chloro-3-methylphenyl)-1,2,4- chromatography (Column IA 21 × 250 mm 30% MeOH in
    oxadiazol-5- CO2, flow 75 g/min, 238 nm UV collection) to give (R)-3-(2-
    yl)ethyl)amino)pyrimidin-4-yl)-4- (((R)-1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5-
    ((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    chloro-3-methylphenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    419: Peak 2 (92 mg) (CDCl3) δ 8.20 (d, J = 6.0 Hz, 1H),
    7.95 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 8.3, 2.2 Hz, 1H), 7.61
    (d, J = 6.0 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 5.33 (d, J = 7.1
    Hz, 1H), 4.84 (ddd, J = 8.4, 4.7, 2.4 Hz, 1H), 1.89-1.74
    (m, 3H), 4.56 (dd, J = 9.4, 2.5 Hz, 1H), 4.41 (dd, J = 9.4, 8.3
    Hz, 1H), 3.74 (d, J = 41.0 Hz, 1H), 3.52 (s, 1H), 2.46 (s,
    3H), 1.12-0.85 (m, 3H). HRMS(B) m/z 411.1365. Chiral
    RT = 2.85 min
    420: (R)-3-(2-(((S)-1-(3-(4- Chiral separation was achieved by chiral SFC column
    bromo-3-methoxyphenyl)-1,2,4- chromatography (Column IA 21 × 250 mm 30% MeOH in
    oxadiazol-5- CO2, flow 90 g/min, 238 nm UV collection) to give (R)-3-(2-
    yl)ethyl)amino)pyrimidin-4-yl)-4- (((R)-1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5-
    ((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-
    bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    420: Peak 2 (96 mg) (CDCl3) δ 8.22 (d, J = 6.0 Hz, 1H),
    7.67 (d, J = 8.1 Hz, 1H), 7.63-7.52 (m, 3H), 5.37 (s, 1H),
    4.84 (ddd, J = 8.3, 4.7, 2.4 Hz, 1H), 1.91-1.72 (m, 3H),
    4.55 (dd, J = 9.5, 2.5 Hz, 1H), 4.41 (t, J = 8.9 Hz, 1H), 4.00
    (s, 3H), 3.52 (s, 1H), 1.02 (s, 3H). HRMS(B) m/z 504.0757.
    Chiral RT = 3.50 min
    421: (R)-3-(2-(((S)-1-(3-(3-(tert- Chiral separation was achieved by chiral SFC column
    butyl)phenyl)-1,2,4-oxadiazol-5- chromatography (Column IA-H 21 × 250 mm 15% MeOH in
    yl)ethyl)amino)pyrimidin-4-yl)-4- CO2, flow 80 g/min, 238 nm UV collection) to give (R)-3-(2-
    ((R)-1-hydroxyethyl)oxazolidin- (((R)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-
    2-one yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(3-
    (tert-butyl)phenyl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    421: Peak 2 (62 mg): (CDCl3) δ 8.25 (d, J = 5.7 Hz, 1H),
    8.08 (t, J = 1.8 Hz, 1H), 7.87 (dt, J = 7.6, 1.4 Hz, 1H), 7.66-
    7.51 (m, 1H), 7.43 (t, J = 7.8 Hz, 1H), 5.92-5.68 (m, 1H),
    5.35 (d, J = 9.3 Hz, 1H), 4.86 (ddd, J = 8.4, 4.4, 2.4 Hz,
    1H), 1.74-1.64 (m, 1H), 4.55 (dd, J = 9.5, 2.5 Hz, 1H),
    4.39 (dd, J = 9.4, 8.3 Hz, 1H), 3.51 (d, J = 5.3 Hz, 3H), 3.00
    (d, J = 4.9 Hz, 1H), 1.79 (d, J = 7.2 Hz, 3H), 1.38 (s, 9H),
    1.08 (q, J = 5.5 Hz, 1H), 1.00 (s, 3H). HRMS(B) m/z
    452.2172. RT = 2.88 min. Chiral RT = 5.20 min
    422 and 423: (R)-3-(2-(((R)-1- Chiral separation was achieved by chiral SFC column
    (3-(2,3-dihydro-1H-inden-5-yl)- chromatography (Column ID 21 × 250 mm 40% IPA + 10 mM
    1,2,4-oxadiazol-5- NH4OH in CO2, flow 75 g/min, 222 nm UV collection) to
    yl)ethyl)amino)pyrimidin-4-yl)-4- give (R)-3-(2-(((R)-1-(3-(2,3-dihydro-1H-inden-5-yl)-1,2,4-
    ((R)-1-hydroxyethyl)oxazolidin- oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(2,3-
    dihydro-1H-inden-5-yl)-1,2,4-oxadiazol-5-
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-
    hydroxyethyl)oxazolidin-2-one
    422: First eluted product (15 mg): 1H NMR (400 MHz,
    CDCl3) δ 8.24 (d, J = 5.8 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H),
    7.81 (dd, J = 7.8, 1.7 Hz, 1H), 7.50 (d, J = 5.7 Hz, 1H), 7.34
    (d, J = 7.8 Hz, 1H), 5.81 (s, 1H), 5.27 (d, J = 43.6 Hz, 1H),
    4.70 (d, J = 7.9 Hz, 1H), 4.49 (dd, J = 9.3, 2.4 Hz, 1H), 4.42-
    4.09 (m, 2H), 3.51 (d, J = 3.1 Hz, 3H), 3.23 (s, 1H), 2.98
    (t, J = 7.4 Hz, 4H), 2.14 (p, J = 7.5 Hz, 2H), 1.78 (d, J = 7.0
    Hz, 3H), 1.75-1.62 (m, 0H), 1.21 (dd, J = 14.9, 6.3 Hz,
    4H), 1.14 (d, J = 5.5 Hz, 1H). HRMS(D) m/z 437.1944
    (M + H). RT = 3.57 min. Chiral RT = 2.35 min.
    423: Second eluted product (63 mg): 1H NMR (400 MHz,
    CDCl3) δ 8.25 (d, J = 5.7 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H),
    7.83 (dd, J = 7.8, 1.6 Hz, 1H), 7.54 (d, J = 5.7 Hz, 1H), 7.33
    (d, J = 7.8 Hz, 1H), 5.79 (s, 1H), 5.32 (s, 1H), 4.85 (ddd, J =
    8.4, 4.5, 2.5 Hz, 1H), 4.55 (dd, J = 9.5, 2.5 Hz, 1H), 4.39 (t,
    J = 8.9 Hz, 1H), 3.75 (d, J = 49.5 Hz, 1H), 3.51 (s, 1H), 2.97
    (t, J = 7.4 Hz, 5H), 2.13 (p, J = 7.5 Hz, 2H), 1.78 (d, J = 7.2
    Hz, 3H), 1.63 (s, 1H), 1.23 (d, J = 6.1 Hz, 1H), 0.98 (d, J =
    7.1 Hz, 4H). HRMS(D) m/z 437.1942 (M + H). RT = 3.58 min.
    Chiral RT = 3.50 min.
    • Example 424 and 425 (4R)-3-(2-((1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00902
  • A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (150 mg, 0.529 mmol), 1-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamine (118 mg, 0.529 mmol, 1.0 equiv), and DIEA (0.185 mL, 1.059 mmol, 2.0 equiv) in DMSO (2 mL) was heated at 110° C. for 120 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (10 mL), 4% brine (10 mL), concentrated in vacuo. The crude material, (R)-5-((R)-1-tert-Butoxy-ethyl)-1-(2-{1-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-pyrimidin-4-yl)-imidazolidin-2-one, was carried to the next step without further purification.
  • (R)-5-((R)-1-tert-Butoxy-ethyl)-1-(2-{1-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-pyrimidin-4-yl)-imidazolidin-2-one (200 mg, 0.411 mmol) was treated with 10:1 TFA/water (10 ml) for 2 hours. The reaction was conc. in vacuo and neutralized by passing through a column of MP-carbonate eluting with MeOH/DCM/MeOH and Flash column (silica, 15μ, 40 g) eluting w/5-60% EtOAc/heptane over 2.5 hours to give (R)-3-(2-(((R)-1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
  • 424: first eluted product (45 mg, 50.8%). HRMS m/z 430.1156.
  • 425: Second eluted product (46 mg, 52.0%). 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.09 (dq, J=8.4, 2.0, 1.6 Hz, 3H), 7.64 (d, J=6.4 Hz, 1H), 7.58-7.48 (m, 2H), 5.48-5.27 (m, 1H), 4.94 (t, J=6.6 Hz, 1H), 4.63-4.40 (m, 2H), 1.13 (d, J=6.5 Hz, 3H), 0.89 (d, J=7.1 Hz, 0H), 1.83-1.72 (m, 3H).HRMS m/z 430.1156.
    • Example 426 (S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00903
  • A mixture of (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (23.35 mg, 0.089 mmol), (S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethanamine hydrochloride (30 mg, 0.116 mmol) and Huenig's base (0.047 mL, 0.268 mmol) in DMSO (0.6 mL) under argon atmosphere was heated at 80° C. for ˜16 hr. The mixture was diluted with DMSO and water, filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one as its trifluoroacetic acid salt (30.2 mg) as a white solid.
  • 1H NMR (400 Mhz, CD3OD) δ ppm 9.07 (br. s., 1H), 8.24 (d, J=6.3 Hz, 1H), 7.85 (s, 1H), 7.53-7.72 (m, 5H), 5.64-6.06 (m, 1H), 5.36 (q, J=6.9 Hz, 1H), 5.07-5.23 (m, 1H), 4.41-4.62 (m, 2H), 2.62-2.90 (m, 1H), 1.71 (d, J=6.7 Hz, 3H), 0.97 (d, J=7.0 Hz, 3H);
  • LCMS m/z 463.2 (M+H)+, Rt 0.64 min.
  • The following Example was prepared using a method similar to that described for the preparation of Example 415
    • Example 427 (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
  • Figure US20140275083A1-20140918-C00904
  • 1H NMR (400 Mhz, CD3OD) δ ppm 9.13 (s, 1H), 8.25 (d, J=6.7 Hz, 1H), 7.86 (s, 1H), 7.61-7.73 (m, 3H), 7.36 (m, J=8.6, 8.6 Hz, 2H), 5.69-6.06 (m, 1H), 5.37 (q, J=6.7 Hz, 1H), 5.10-5.18 (m, 1H), 4.46-4.59 (m, 2H), 2.67-2.82 (m, 1H), 1.72 (d, J=7.0 Hz, 3H), 0.98 (d, J=7.4 Hz, 3H)
  • LCMS m/z 447.2 (M+H)+, Rt 0.57 min.
  • The Examples in Table 38a were prepared using methods similar to those described for the preparation of Examples 385 and 403.
  • TABLE 38a
    Figure US20140275083A1-20140918-C00905
         		428
    Figure US20140275083A1-20140918-C00906
         		429
    Figure US20140275083A1-20140918-C00907
         		430
    Figure US20140275083A1-20140918-C00908
         		431
    Figure US20140275083A1-20140918-C00909
         		432
    Figure US20140275083A1-20140918-C00910
         		433
    Figure US20140275083A1-20140918-C00911
         		434
    Figure US20140275083A1-20140918-C00912
         		435
    Figure US20140275083A1-20140918-C00913
         		436
    Figure US20140275083A1-20140918-C00914
         		437
    Figure US20140275083A1-20140918-C00915
         		438
    Figure US20140275083A1-20140918-C00916
         		439
    Figure US20140275083A1-20140918-C00917
         		440
    Figure US20140275083A1-20140918-C00918
         		441
    Figure US20140275083A1-20140918-C00919
         		442
    Figure US20140275083A1-20140918-C00920
         		443
    Figure US20140275083A1-20140918-C00921
         		444
    Figure US20140275083A1-20140918-C00922
         		445
    Figure US20140275083A1-20140918-C00923
         		446
    Figure US20140275083A1-20140918-C00924
         		447
    Figure US20140275083A1-20140918-C00925
         		448
    Figure US20140275083A1-20140918-C00926
         		449
    Figure US20140275083A1-20140918-C00927
         		450
    Figure US20140275083A1-20140918-C00928
         		451
    Figure US20140275083A1-20140918-C00929
         		452
    Figure US20140275083A1-20140918-C00930
         		453
    Figure US20140275083A1-20140918-C00931
         		454
    Figure US20140275083A1-20140918-C00932
         		455
    Figure US20140275083A1-20140918-C00933
         		456
    Figure US20140275083A1-20140918-C00934
         		457
    Figure US20140275083A1-20140918-C00935
         		458
    Figure US20140275083A1-20140918-C00936
         		459
    Figure US20140275083A1-20140918-C00937
         		460
    Figure US20140275083A1-20140918-C00938
         		461
    Figure US20140275083A1-20140918-C00939
         		462
    Figure US20140275083A1-20140918-C00940
         		463
    Figure US20140275083A1-20140918-C00941
         		464
    Figure US20140275083A1-20140918-C00942
         		465
  • TABLE 38b
    Chemical name, NMR chemical shifts, chiral separation
    conditions and LCMS signal for compounds listed in Table 38a.
    Example: Name 1H NMR (400 MHz) δ ppm LCMS
    428: (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1- (CDCl3) 11.13 (d, J = 5.9 Hz, 1 H), LCMS (B)
    (2-(2-(trifluoromethyl)pyridin-4-yl)thiazol-5- 8.84 (d, J = 5.0 Hz, 1 H), 8.17 (s, 1 m/z 483.1;
    yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2- H), 8.06 (d, J = 7.0 Hz, 1 H), 7.89- Rt = 0.79
    one 7.96 (m, 2 H), 7.80 (s, 1 H), 5.34- min.
    5.44 (m, 1 H), 4.81-4.90 (m, 1 H),
    4.66-4.78 (m, 2 H), 4.59-4.65
    (m, 1 H), 4.47-4.55 (m, 1 H), 1.83
    (d, J = 7.0 Hz, 3 H), 1.21-1.32 (m,
    3 H)
    429: (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)- (CDCl3) 8.22 (d, J = 2.9 Hz, 1 H), LCMS (B)
    1H-imidazol-4-yl)ethyl)amino)-5- 7.75 (d, J = 1.2 Hz, 1 H), 7.44 (d, m/z 435.1;
    fluoropyrimidin-4-yl)-4- J = 8.9 Hz, 2 H), 7.30 (d, J = 8.9 Hz, Rt = 0.62
    (fluoromethyl)oxazolidin-2-one 2 H), 7.11 (s, 1H), 5.57 (d, J = 7.7 min.
    Hz, 1 H), 5.02-5.14 (m, 1 H), 4.75-
    4.89 (m, 1 H), 4.56-4.64 (m, 2
    H), 4.43-4.53 (m, 2 H), 1.61 (d,
    J = 6.8 Hz, 3 H)
    430: (R)-3-(5-fluoro-2-(((S)-1-(1-(4- (CDCl3) 8.62 (d, J = 3.9 Hz, 1 H), LCMS (B)
    fluorophenyl)-1H-imidazol-4- 8.14-8.21 (m, 1 H), 7.48 (dd, m/z 419.2;
    yl)ethyl)amino)pyrimidin-4-yl)-4- J = 8.9, 4.4 Hz, 3 H), 7.24-7.34 (m, Rt = 0.57
    (fluoromethyl)oxazolidin-2-one 2 H), 5.38 (br. s., 1 min.
    H), 4.88-5.03 (m, 1 H), 4.42-
    4.73 (m, 4 H), 1.75 (t, J = 6.3 Hz, 3
    H)
    431: (R)-3-(2-(((S)-1-(1-(3,4- (CDCl3) 8.63 (br. s., 1 H), 8.17 (d, LCMS (B)
    difluorophenyl)-1H-imidazol-4- J = 3.3 Hz, 1 H), 7.36-7.52 (m, 4 m/z 437.2;
    yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- H), 5.36 (br. s., 1 H), 4.94 (d, Rt = 0.59
    (fluoromethyl)oxazolidin-2-one J = 18.7 Hz, 1 H), min.
    4.43-4.74 (m, 4 H), 1.74 (d, J = 7.1
    Hz, 3 H)
    432: (R)-3-(2-(((S)-1-(1-(4-chloro-3- (CDCl3) 8.57 (s, 1 H), 8.18 (d, LCMS (B)
    fluorophenyl)-1H-imidazol-4- J = 1.9 Hz, 1 H), 7.63 (t, J = 7.6 Hz, 1 m/z 453.1;
    yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- H), 7.48 (br. s., 1 H), 7.35 (d, J = 8.5 Rt = 0.64
    (fluoromethyl)oxazolidin-2-one Hz, 1 H), 7.24-7.29 (m, 1 H), 5.33 min.
    (d, J = 5.3 Hz, 1 H), 4.84-4.98 (m,
    1 H), 4.54-4.74 (m, 3 H), 4.48 (t,
    J = 7.5 Hz, 1 H), 1.73 (d, J = 6.5 Hz,
    3 H)
    433: (R)-3-(2-(((S)-1-(1-(3-chloro-4- (CDCl3) 8.56 (s, 1 H), 8.18 (d, LCMS (B)
    fluorophenyl)-1H-imidazol-4- J = 1.9 Hz, 1H), 7.57-7.63 (m, 1 m/z 453.1;
    yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- H), 7.33-7.48 (m, 3 H), 5.34 (br. Rt = 0.64
    (fluoromethyl)oxazolidin-2-one s., 1 H), 4.85-5.00 (m, 1 H), 4.41- min.
    4.75 (m, 4 H), 1.73 (d, J = 7.0 Hz, 3
    H)
    434: (R)-3-(2-(((S)-1-(1-(4- (CDCl3) 8.67 (s, 1 H), 8.17 (d, LCMS (B)
    (difluoromethyl)phenyl)-1H-imidazol-4- J = 3.3 Hz, 1 H), 7.76 (d, J = 8.3 Hz, m/z 451.2;
    yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- 2 H), 7.60 (d, J = 8.4 Hz, 2 H), 7.51- Rt = 0.61
    (fluoromethyl)oxazolidin-2-one 7.57 (m, 1H), min.
    6.58-6.90 (m, 1 H), 5.38 (d, J = 6.5
    Hz, 1 H), 4.86-5.01 (m, 1 H), 4.41-
    4.75 (m, 4 H), 1.75 (d, J = 7.1 Hz,
    3 H)
    435: (R)-3-(2-(((S)-1-(1-(4- (CDCl3) 8.60 (d, J = 1.1 Hz, 1 H), LCMS (B)
    (difluoromethyl)-3-fluorophenyl)-1H- 8.17 (d, J = 3.3 Hz, 1 H), 7.84 (t, m/z 469.2;
    imidazol-4-yl)ethyl)amino)-5- J = 7.8 Hz, 1 H), 7.53 (d, J = 4.0 Hz, Rt = 0.63
    fluoropyrimidin-4-yl)-4- 1 H), 7.41 (d, min.
    (fluoromethyl)oxazolidin-2-one J = 8.3 Hz, 1 H), 7.35 (d, J = 9.7 Hz,
    1 H), 6.78-7.10 (m, 1 H), 5.33 (d,
    J = 6.4 Hz, 1 H), 4.85-4.99 (m, 1
    H), 4.42-4.73 (m, 4 H), 1.73 (d,
    J = 7.1 Hz, 3 H)
    436: (R)-3-(2-(((S)-1-(1-(3,5- (CDCl3) 8.63 (s, 1 H), 8.16 (dd, LCMS (B)
    difluorophenyl)-1H-imidazol-4- J = 3.3, 2.0 Hz, 1 H), 7.51 (br. s., 1 m/z 437.1;
    yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- H), 7.09 (d, J = 6.6 Hz, 2 H), 6.97- Rt = 0.59
    (fluoromethyl)oxazolidin-2-one 7.05 (m, 1 H), 5.35 (d, J = 6.4 Hz, 1 min.
    H), 4.40-4.93 (m, 5 H), 1.73 (d,
    J = 7.0 Hz, 3 H)
    437: (R)-3-(2-(((S)-1-(5-(4- (CDCl3) 8.13 (d, J = 3.9 Hz, 1 H), LCMS (B)
    chlorophenyl)isoxazol-3-yl)ethyl)amino)-5- 7.69 (d, J = 8.4 Hz, 2 H), 7.46 (d, m/z 436.1;
    fluoropyrimidin-4-yl)-4- J = 8.4 Hz, 2 H), 6.57 (s, 1 H), 5.18 Rt = 0.91
    (fluoromethyl)oxazolidin-2-one (d, J = 7.1 Hz, 1 H), 4.93-5.08 (m, min.
    1 H), 4.64-4.72 (m, 1 H), 4.55
    (dd, J = 8.7, 7.2 Hz, 1 H), 4.27-
    4.52 (m, 2 H), 1.71 (d, J = 7.1 Hz, 3
    H)
    438: (R)-3-(2-(((S)-1-(2-(4- (CDCl3) 8.18 (d, J = 3.5 Hz, 1 H), LCMS (B)
    chlorophenyl)thiazol-5-yl)ethyl)amino)-5- 7.89 (s, 1 H), 7.75-7.80 (m, 2 H), m/z 452.1;
    fluoropyrimidin-4-yl)-4- 7.44-7.50 (m, 2 H), 5.28 (d, J = 6.6 Rt = 0.93
    (fluoromethyl)oxazolidin-2-one Hz, 1 H), 4.80-4.93 (m, 1 H), 4.68 min.
    (t, J = 8.9 Hz, 1 H), 4.42-4.49 (m, 1
    H), 4.16-4.41 (m, 2 H), 1.77 (d,
    J = 7.0 Hz, 3 H)
    439: (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)- (CDCl3) 8.13 (d, J = 3.1 Hz, 1 H), LCMS (B)
    2-methyl-1H-imidazol-4-yl)ethyl)amino)-5- 7.58-7.63 (m, 2 H), 7.31-7.37 m/z 449.2;
    fluoropyrimidin-4-yl)-4- (m, 2 H), 7.14-7.18 (m, 1 H), 5.41 Rt = 0.65
    (fluoromethyl)oxazolidin-2-one (br. s., 1 H), 4.77-4.96 (m, 1 H), min.
    4.46-4.72 (m, 4 H), 2.60 (s, 3 H),
    1.70 (d, J = 6.9 Hz, 3 H)
    440: (R)-3-(5-fluoro-2-(((S)-1-(2-(2- (CDCl3) 8.85 (d, J = 5.1 Hz, 1 H), LCMS (B)
    (trifluoromethyl)pyridin-4-yl)thiazol-5- 8.20 (d, J = 3.5 Hz, 1 H), 8.16 (s, 1 m/z 487.1;
    yl)ethyl)amino)pyrimidin-4-yl)-4- H), 7.92-7.96 (m, 1 H), 7.90 (s, 1 Rt = 0.86
    (fluoromethyl)oxazolidin-2-one H), 5.36 (d, min.
    J = 7.0 Hz, 1 H), 4.78-4.91 (m, 1
    H), 4.24-4.72 (m, 4 H), 1.79 (d,
    J = 6.9 Hz, 3 H)
    441: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(2- (CDCl3) 8.88 (d, J = 6.0 Hz, 1 H), LCMS (B)
    methylpyridin-4-yl)phenyl)ethyl)amino)-5- 8.19 (d, J = 3.0 Hz, 1 H), 7.76 (d, m/z 462.2;
    fluoropyrimidin-4-yl)-4- J = 6.2 Hz, 1 H), 7.72 (s, 1 H), 7.21- Rt = 0.60
    (fluoromethyl)oxazolidin-2-one 7.33 (m, 2 H), 5.19-5.30 (m, 1 min.
    H), 4.78 (br. s., 1 H), 4.64 (t, J = 8.8
    Hz, 1 H), 4.41-4.49 (m, 1 H), 4.09-
    4.37 (m, 2 H), 2.90 (s, 3 H), 1.63
    (d, J = 6.9 Hz, 3 H)
    442: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(6- (CDCl3) 9.01 (s, 1 H), 8.33 (d, LCMS (B)
    methylpyridin-3-yl)phenyl)ethyl)amino)-5- J = 8.2 Hz, 1 H), 8.17 (d, J = 3.2 Hz, m/z 462.1;
    fluoropyrimidin-4-yl)-4- 1 H), 7.67 (d, J = 8.3 Hz, 1 H), 7.21- Rt = 0.61
    (fluoromethyl)oxazolidin-2-one 7.29 (m, 2 H), 5.18-5.29 (m, 1 min.
    H), 4.06-4.83 (m, 5 H), 2.89 (s, 3
    H), 1.62 (d, J = 7.0 Hz, 3 H)
    443: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(6- (CDCl3) 8.89 (s, 1 H), 8.15 (dd, LCMS (B)
    (trifluoromethyl)pyridin-3- J = 3.7, 1.2 Hz, 1 H), 8.06 (d, J = 8.2 m/z 516.1;
    yl)phenyl)ethyl)amino)-5-fluoropyrimidin-4- Hz, 1 H), 7.82 (d, J = 8.2 Hz, 1 H), Rt = 0.97
    yl)-4-(fluoromethyl)oxazolidin-2-one 7.17-7.30 (m, 2 H), 5.28 (d, J = 5.7 min.
    Hz, 1 H), 4.77-4.90 (m, 1 H), 4.67
    (t, J = 8.8 Hz, 1 H), 4.49 (t, J = 7.8
    Hz, 1 H), 4.07-4.29 (m, 2 H), 1.66
    (d, J = 6.7 Hz, 3 H)
    444: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(2- (CDCl3) 8.85 (d, J = 5.0 Hz, 1 H), LCMS (B)
    (trifluoromethyl)pyridin-4- 8.15 (dd, J = 3.4, 2.4 Hz, 1 H), 7.84 m/z 516.0;
    yl)phenyl)ethyl)amino)-5-fluoropyrimidin-4- (s, 1 H), 7.67 (d, J = 4.9 Hz, 1 H), Rt = 0.96
    yl)-4-(fluoromethyl)oxazolidin-2-one 7.21-7.33 (m, 2 H), 5.28 (br. s., 1 min.
    H), 4.81 (d, J = 14.6 Hz, 1 H), 4.67
    (t, J = 8.8 Hz, 1 H), 4.45-4.53 (m, 1
    H), 4.07-4.33 (m, 2 H), 1.63-
    1.68 (m, 3 H)
    445: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(4- (CDCl3) 8.82 (s, 1 H), 8.18 (d, LCMS (B)
    methyl-1H-imidazol-1- J = 3.1 Hz, 1 H), 7.39 (dd, J = 10.3, m/z 451.1;
    yl)phenyl)ethyl)amino)-5-fluoropyrimidin-4- 6.0 Hz, 1 H), 7.27-7.30 (m, 1 H), Rt = 0.58
    yl)-4-(fluoromethyl)oxazolidin-2-one 7.11 (s, 1 H), 5.19-5.28 (m, 1 H), min.
    4.74 (br. s., 1 H), 4.64 (t, J = 8.6 Hz,
    1 H), 4.39-4.47 (m, 1 H), 4.13-
    4.32 (m, 2 H), 2.49 (s, 3 H), 1.63
    (d, J = 7.0 Hz, 3 H)
    446: (R)-3-(2-(((S)-1-(1-(4- (CDCl3) 8.72 (s, 1 H), 8.18 (d, LCMS m/z
    (difluoromethyl)-3-fluorophenyl)-1H- J = 3.1 Hz, 1 H), 7.79-7.91 (m, 1 483.0 (M +
    imidazol-4-yl)ethyl)amino)-5- H), 7.61 (br. s., 1 H), 7.33-7.48 H)+, Rt 0.68
    fluoropyrimidin-4-yl)-4-((S)-1- (m, 2 H), 6.94 (t, J = 54.0 Hz, 1 H), min; HPLC
    fluoroethyl)oxazolidin-2-one 5.34 (d, J = 6.7 Hz, 1 H), 4.71-5.05 2.801 min.
    (m, 2 H), 4.55-4.65 (m, 1 H), 4.50
    (dd, J = 8.4, 6.5 Hz, 1 H), 1.74 (d,
    J = 7.0 Hz, 3 H), 1.33 (dd, J = 23.5,
    6.7 Hz, 3 H)
    447: (R)-3-(2-(((S)-1-(1-(4- (CDCl3) 8.81 (s, 1 H), 8.18 (d, LCMS m/z
    (difluoromethyl)phenyl)-1H-imidazol-4- J = 3.1 Hz, 1 H), 7.76 (d, J = 8.2 Hz, 465.0 (M +
    yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- 2 H), 7.62 (d, J = 8.2 Hz, 2 H), 6.74 H)+, Rt 0.65
    ((S)-1-fluoroethyl)oxazolidin-2-one (t, J = 56.0 Hz, 1 H), 5.38 (q, J = 6.7 min; HPLC
    Hz, 1 H), 4.73-5.06 (m, 2 H), 4.59 2.624 min.
    (t, J = 8.8 Hz, 1 H), 4.45-4.53 (m, 1
    H), 1.76 (d, J = 7.0 Hz, 3 H), 1.34
    (dd, J = 23.5, 6.3 Hz, 3 H).
    448: (R)-3-(2-(((S)-1-(1-(4-chloro-3- (CDCl3) 8.73 (s, 1 H), 8.18 (d, LCMS m/z
    fluorophenyl)-1H-imidazol-4- J = 3.1 Hz, 1 H), 7.64 (t, J = 8.0 Hz, 1 467.0 (M +
    yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- H), 7.57 (br. s., 1 H), 7.29-7.44 H)+, Rt 0.69
    ((S)-1-fluoroethyl)oxazolidin-2-one (m, 2 H), 5.34 (d, J = 6.7 Hz, 1 H), min; HPLC
    4.73-4.87 (m, 1 H), 4.59 (t, J = 8.8 2.847 min.
    Hz, 1 H), 4.45-4.53 (m, 1 H), 1.74
    (d, J = 7.0 Hz, 3 H), 1.33 (dd,
    J = 23.1, 6.3 Hz, 3 H)
    449: (R)-3-(2-(((S)-1-(1-(3,5- (CDCl3) 8.58 (s, 1 H), 8.18 (d, LCMS m/z
    difluorophenyl)-1H-imidazol-4- J = 2.7 Hz, 1 H), 7.53 (br. s., 1 H), 451.1 (M +
    yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- 7.09 (d, J = 5.1 Hz, 2 H), 7.00 (t, H)+, Rt 0.64
    ((S)-1-fluoroethyl)oxazolidin-2-one J = 8.4 Hz, 1 H), 5.29-5.36 (m, 1 min; HPLC
    H), 5.00 (br. s., 1 H), 4.87 (br. s., 1 2.132 min.
    H), 4.70-4.83 (m, 1 H), 4.54-
    4.64 (m, 1 H), 4.46-4.53 (m, 1 H),
    1.73 (d, J = 7.0 Hz, 3 H), 1.33 (dd,
    J = 23.1, 6.3 Hz, 3H).
    450: (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)- (CDCl3) 8.64 (s, 1 H), 8.18 (d, LCMS m/z
    1H-imidazol-4-yl)ethyl)amino)-5- J = 3.1 Hz, 1 H), 7.57 (d, J = 8.6 Hz, 449.0 (M +
    fluoropyrimidin-4-yl)-4-((S)-1- 2 H), 7.51 (br. s., 1 H), 7.44 (d, H)+, Rt 0.67
    fluoroethyl)oxazolidin-2-one J = 8.6 Hz, 2 H), 5.35 (d, J = 6.7 Hz, min; HPLC
    1 H), 5.01 (br. s., 1 H), 4.89 (br. s., 2.354 min.
    1 H), 4.71-4.86 (m, 1 H), 4.54-
    4.64 (m, 1 H), 4.44-4.53 (m, 1 H),
    1.74 (d, J = 7.0 Hz, 3 H), 1.33 (dd,
    J = 23.5, 6.7 Hz, 3 H).
    451: (R)-3-(5-fluoro-2-(((S)-1-(1-(4- (CDCl3) 8.61 (s, 1 H), 8.18 (d, LCMS m/z
    fluorophenyl)-1H-imidazol-4- J = 2.7 Hz, 1 H), 7.48 (dd, J = 8.4, 433.1 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- 4.1 Hz, 3 H), 7.28-7.34 (m, 2 H), H)+, Rt 0.61
    fluoroethyl)oxazolidin-2-one 5.35 (d, J = 6.7 Hz, 1 H), 4.70-4.85 min; HPLC
    (m, 1 H), 4.54-4.62 (m, 1 H), 4.45- 1.997 min.
    4.53 (m, 1 H), 1.75 (d, J = 7.0 Hz,
    3 H), 1.33 (dd, J = 23.1, 6.3 Hz, 3
    H).
    452: (R)-3-(2-(((S)-1-(5-(4- (CDCl3) 8.11 (d, J = 3.5 Hz, 1 H), LCMS m/z
    chlorophenyl)isoxazol-3-yl)ethyl)amino)-5- 7.69 (d, J = 8.6 Hz, 2 H), 7.46 (d, 450.0 (M +
    fluoropyrimidin-4-yl)-4-((S)-1- J = 8.6 Hz, 2 H), 6.54 (s, 1 H), 5.17 H)+, Rt 0.96
    fluoroethyl)oxazolidin-2-one (d, J = 5.1 Hz, 1 min; HPLC
    H), 4.69-4.92 (m, 2 H), 4.51- 4.131 min.
    4.65 (m, 2 H), 1.70 (d, J = 7.0 Hz, 3
    H), 1.30 (dd, J = 23.1, 6.3 Hz, 3 H).
    453: (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)- (CDCl3) 8.14 (d, J = 3.5 Hz, 1 H), LCMS m/z
    1H-pyrazol-4-yl)ethyl)amino)-5- 7.94 (s, 1 H), 7.68 (s, 1 H), 7.59 (d, 449.0 (M +
    fluoropyrimidin-4-yl)-4-((S)-1- J = 8.6 Hz, 2 H), 7.43 (d, J = 8.6 Hz, H)+, Rt 0.92
    fluoroethyl)oxazolidin-2-one 2 H), 5.08 (q, J = 6.7 Hz, 1 H), 4.65- min; HPLC
    4.87 (m, 2 H), 4.59 (t, J = 8.8 Hz, 1 3.864 min.
    H), 4.47-4.55 (m, 1 H), 1.66 (d,
    J = 7.0 Hz, 3 H), 1.22 (dd, J = 23.5,
    6.7 Hz, 3 H).
    454: (R)-3-(2-(((S)-1-(1-(3,5- (CDCl3) 10.92 (d, J = 6.7 Hz, 1 H), LCMS m/z
    difluorophenyl)-1H-imidazol-4- 8.30 (br. s., 1 H), 7.99 (d, J = 6.7 433.2 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- Hz, 1 H), 7.88 (d, J = 7.0 Hz, 1 H), H)+, Rt 0.59
    fluoroethyl)oxazolidin-2-one 7.57 (br. s., 1 H), 6.92-7.11 (m, 3 min; HPLC
    H), 5.48 (d, J = 6.3 Hz, 1 H), 4.84- 1.946 min.
    5.14 (m, 2 H), 4.59-4.70 (m, 1 H),
    4.48-4.57 (m, 1 H), 1.69 (d, J = 6.7
    Hz, 3 H), 1.34 (dd, J = 23.5, 5.9 Hz,
    3 H).
    455: (R)-3-(2-(((S)-1-(1-(4- (CDCl3) 10.91 (d, J = 7.0 Hz, 1 H), LCMS m/z
    (difluoromethyl)-3-fluorophenyl)-1H- 8.24 (br. s., 1 H), 7.98 (d, J = 6.7 465.2 (M +
    imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)- Hz, 1 H), 7.88 (d, J = 7.0 Hz, 1 H), H)+, Rt 0.63
    4-((S)-1-fluoroethyl)oxazolidin-2-one 7.82 (t, J = 7.4 Hz, 1 H), 7.58 (br. s., min; HPLC
    1 H), 7.30-7.43 (m, 2 H), 6.94 (dt, 2.191 min.
    J = 55.6, 1.0 Hz, 1 H), 5.44 (br. s., 1
    H), 4.80-5.22 (m, 2 H), 4.64 (d,
    J = 9.0 Hz, 1 H), 4.54 (t, J = 8.8 Hz, 1
    H), 1.71 (d, J = 6.3 Hz, 3 H), 1.36
    (dd, J = 23.5, 6.3 Hz, 3 H).
    456: (R)-3-(2-(((S)-1-(1-(4- (CDCl3) 11.00 (d, J = 7.0 Hz, 1 H), LCMS m/z
    (difluoromethyl)phenyl)-1H-imidazol-4- 8.46 (s, 1 H), 7.99 (d, J = 7.0 Hz, 1 447.3 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- H), 7.90 (d, J = 7.0 Hz, 1 H), 7.75 H)+, Rt 0.58
    fluoroethyl)oxazolidin-2-one (d, J = 8.2 Hz, 2 H), 7.66 (s, 1 H), min; HPLC
    7.59 (d, J = 8.2 Hz, 2 H), 6.74 (t, 1.898 min.
    J = 55.6 Hz, 1 H), 5.58 (t, J = 6.8 Hz,
    1 H), 4.91-5.14 (m, 2 H), 4.60-
    4.68 (m, 1 H), 4.49-4.59 (m, 1 H),
    1.72 (d, J = 6.7 Hz, 3 H), 1.36 (dd,
    J = 23.5, 6.3 Hz, 3 H).
    457: (R)-3-(2-(((S)-1-(1-(3-chloro-4- (CDCl3) 10.97 (d, J = 7.4 Hz, 1 H), LCMS m/z
    fluorophenyl)-1H-imidazol-4- 8.33 (s, 1 H), 7.99 (d, J = 6.7 Hz, 1 449.1 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- H), 7.90 (d, J = 7.0 Hz, 1 H), 7.50- H)+, Rt 0.63
    fluoroethyl)oxazolidin-2-one 7.65 (m, 2 H), 7.37 (d, J = 5.9 Hz, 2 min; HPLC
    H), 5.53 (t, J = 6.7 Hz, 1 H), 4.87- 2.193 min.
    5.19 (m, 2H), 4.60-4.70 (m, 1 H),
    4.44-4.59 (m, 1 H), 1.71 (d, J = 6.7
    Hz, 3 H), 1.36 (dd, J = 23.5, 5.9 Hz,
    3 H).
    458: (R)-3-(2-(((S)-1-(1-(4-chloro-3- (CDCl3) 10.94 (d, J = 7.0 Hz, 1 H), LCMS m/z
    fluorophenyl)-1H-imidazol-4- 8.27 (s, 1 H), 7.98 (d, J = 7.0 Hz, 1 449.2 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- H), 7.88 (d, J = 6.7 Hz, 1 H), 7.62 (t, H)+, Rt 0.64
    fluoroethyl)oxazolidin-2-one J = 8.0 Hz, 1 H), 7.55 (s, 1 H), 7.31 min; HPLC
    (dd, J = 9.0, 2.3 Hz, 1 H), 7.23 (br. 2.279 min.
    s., 1 H), 5.48 (t, J = 6.8 Hz, 1 H),
    4.83-5.19 (m, 2 H), 4.60-4.69
    (m, 1 H), 4.46-4.58 (m, 1 H), 1.70
    (d, J = 6.7 Hz, 3 H), 1.35 (dd,
    J = 23.5, 6.3 Hz, 3 H).
    459: (R)-3-(2-(((S)-1-(1-(3,4- (CDCl3) 10.96 (d, J = 7.0 Hz, 1 H), LCMS m/z
    difluorophenyl)-1H-imidazol-4- 8.27 (s, 1 H), 7.98 (d, J = 7.0 Hz, 1 433.2 (M +
    yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- H), 7.89 (d, J = 7.0 Hz, 1 H), 7.53 H)+, Rt 0.59
    fluoroethyl)oxazolidin-2-one (s, 1 H), 7.31-7.45 (m, 2 H), 5.51 min; HPLC
    (t, J = 6.7 Hz, 1 H), 4.84-5.19 (m, 2 1.870 min.
    H), 4.60-4.72 (m, 1 H), 4.43-
    4.58 (m, 1 H), 1.70 (d, J = 6.7 Hz, 3
    H), 1.36 (dd, J = 23.5, 6.3 Hz, 3 H).
    460: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(1- (CDCl3) 10.96 (d, J = 6.7 Hz, 1 H), LCMS m/z
    methyl-1H-pyrazol-4- 7.99 (d, J = 7.0 Hz, 1 H), 7.71-7.89 447.3 (M +
    yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4- (m, 3 H), 7.20 (ddd, J = 14.6, 10.7, H)+, Rt 0.68
    ((S)-1-fluoroethyl)oxazolidin-2-one 6.1 Hz, 2 H), 5.33 (quin, J = 6.7 Hz, min; HPLC
    1 H), 4.64-4.77 (m, 2 H), 4.52- 2.612 min.
    4.64 (m, 2 H), 4.45-4.51 (m, 1 H),
    3.99 (s, 3 H), 1.64 (d, J = 7.0 Hz, 3
    H), 1.23 (dd, J = 23.5, 6.7 Hz, 3 H).
    461: (R)-3-(5-fluoro-2-(((S)-1-(1-(4- (CD3OD) 9.32 (s, 1 H), 8.33 (d, LCMS (B)
    fluorophenyl)-1H-imidazol-4- J = 2.7 Hz, 1 H), 7.94 (s, 1 H), 7.72 m/z 433.1;
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- (dd, J = 9.0, 4.3 Hz, 2 H), 7.37 (t, Rt = 0.60
    fluoroethyl)oxazolidin-2-one J = 8.4 Hz, 2 H), 5.21 (q, J = 6.4 Hz, min.
    1 H), 4.78-4.95 (m, 2 H), 4.63 (t,
    J = 9.2 Hz, 1 H), 4.41 (dd, J = 9.2,
    4.5 Hz, 1 H), 1.70 (d, J = 7.0 Hz, 3
    H), 1.12-1.29 (m, 3 H)
    462: (R)-3-(5-fluoro-2-(((S)-1-(5-fluoro-2′- (CD3OD) 8.74-8.84 (m, 2 H), LCMS (B)
    (trifluoromethyl)-[3,4′-bipyridin]-6- 8.24 (br. s., 1 H), 8.14 (s, 1 H), m/z 513.2;
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 8.09 (dd, J = 10.8, 1.4 Hz, 1 H), Rt = 0.87
    fluoroethyl)oxazolidin-2-one 7.97 (d, J = 4.7 Hz, 1 H), 5.41 (d, min
    J = 6.3 Hz, 1 H), 4.75-4.94 (m, 2
    H), 4.60 (t, J = 9.2 Hz, 1 H), 4.41
    (dd, J = 9.2, 4.9 Hz, 1 H), 1.59 (d,
    J = 7.0 Hz, 3 H), 1.04 (br. s., 3 H)
    463: (R)-3-(2-(((S)-1-(5-fluoro-2′- (CD3OD) 8.87 (s, 1 H), 8.82 (d, LCMS (B)
    (trifluoromethyl)-[3,4′-bipyridin]-6- J = 5.1 Hz, 1 H), 8.15-8.27 (m, 3 m/z 495.2;
    yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- H), 8.00 (d, J = 4.7 Hz, 1 H), 7.81 Rt = 0.75
    fluoroethyl)oxazolidin-2-one (d, J = 6.7 Hz, 1 H), 5.63 (d, J = 5.5 min
    Hz, 1 H), 4.75-5.02 (m, 2 H), 4.64
    (dd, J = 9.0, 2.7 Hz, 1 H), 4.48-
    4.58 (m, 1 H), 1.68 (d, J = 7.0 Hz, 3
    H), 1.21-1.46 (m, 3 H)
    464: (R)-3-(2-(((S)-1-(5-fluoro-2′- (CD3OD) 8.76-8.88 (m, 2 H), LCMS (B)
    (trifluoromethyl)-[3,4′-bipyridin]-6- 8.11-8.25 (m, 3 H), 7.99 (d, J = 5.1 m/z 495.2;
    yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- Hz, 1 H), 7.67 (d, J = 4.7 Hz, 1 H), Rt = 0.75
    fluoroethyl)oxazolidin-2-one 5.57 (d, J = 6.7 Hz, 1 H), 5.10 (br. s., min
    1 H), 4.76-4.96 (m, 2 H), 4.47-
    4.62 (m, 2 H), 1.67 (d, J = 6.7 Hz, 3
    H), 0.92-1.21 (m, 3 H)
    465: (R)-3-(5-fluoro-2-(((S)-1-(5-fluoro-2′- (CD3OD) 8.73-8.86 (m, 2 H), LCMS (B)
    (trifluoromethyl)-[3,4′-bipyridin]-6- 8.24 (br. s., 1 H), 8.16 (s, 1 H), m/z 513.2;
    yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- 8.11 (d, J = 11.0 Hz, 1 H), 7.98 (d, Rt = 0.95
    fluoroethyl)oxazolidin-2-one J = 5.1 Hz, 1 H), 5.43(d, J = 6.7 Hz, 1 min
    H), 4.85 (s, 2 H), 4.61 (t, J = 9.0 Hz,
    1 H), 4.42-4.52 (m, 1 H), 1.58 (d,
    J = 7.0 Hz, 3 H), 1.17 (d, J = 19.2 Hz,
    3 H)
  • The compounds listed in Table 39 are made using methods similar to those described for Examples 1-465 and as outlined in the general synthetic procedures.
  • TABLE 39
    The compounds in Table 39 are prepared following chemistry similar to that
    described for Examples 1-465 or as outlined in the Schemes given above.
    Example Name
    Figure US20140275083A1-20140918-C00943
         		(R)-4-(fluoromethyl)-3-(2- (((S)-1-(1-(4- fluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00944
         		(R)-3-(2-(((S)-1-(1-(3- chloro-4-fluorophenyl)- 1H-imidazol-4- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- (fluoromethyl)oxazolidin- 2-one
    Figure US20140275083A1-20140918-C00945
         		(R)-3-(2-(((S)-1-(1-(4- chloro-3-fluorophenyl)- 1H-imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
    Figure US20140275083A1-20140918-C00946
         		(R)-3-(2-(((S)-1-(1-(3,4- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
    Figure US20140275083A1-20140918-C00947
         		(R)-3-(2-(((S)-1-(1-(4- (difluoromethyl)-3- fluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
    Figure US20140275083A1-20140918-C00948
         		(R)-3-(2-(((S)-1-(1-(4- chloro-2,5- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
    Figure US20140275083A1-20140918-C00949
         		(R)-3-(2-(((S)-1-(1-(4- chloro-2,5- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- (fluoromethyl)oxazolidin- 2-one
    Figure US20140275083A1-20140918-C00950
         		(R)-3-(2-(((S)-1-(1-(4- chloro-2,5- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00951
         		(R)-3-(2-(((S)-1-(1-(4- chloro-2,5- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00952
         		(R)-3-(2-(((S)-1-(1-(4- chloro-2-fluorophenyl)- 1H-imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
    Figure US20140275083A1-20140918-C00953
         		(R)-3-(2-(((S)-1-(1-(4- chloro-2-fluorophenyl)- 1H-imidazol-4- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- (fluoromethyl)oxazolidin- 2-one
    Figure US20140275083A1-20140918-C00954
         		(R)-3-(2-(((S)-1-(1-(2,4- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
    Figure US20140275083A1-20140918-C00955
         		(R)-3-(2-(((S)-1-(1-(2,4- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one
    Figure US20140275083A1-20140918-C00956
         		(R)-3-(2-(((S)-1-(1-(4- chloro-2-fluorophenyl)- 1H-imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00957
         		(R)-3-(2-(((S)-1-(1-(4- chloro-2-fluorophenyl) 1H-imidazol-4- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4 ((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00958
         		(R)-3-(2-(((S)-1-(1-(2,4- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00959
         		(R)-3-(2-(((S)-1-(1-(2,4- difluorophenyl)-1H- imidazol-4- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00960
         		(R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(2′- (trifluoromethyl)-[3,4′- bipyridin]-6- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00961
         		(R)-3-(5-fluoro-2-(((S)-1- (2′-(trifluoromethyl)-[3,4′- bipyridin]-6- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00962
         		(R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(5-(2- (trifluoromethyl)pyridin-4- yl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00963
         		(R)-3-(5-fluoro-2-(((S)-1- (5-(2- (trifluoromethyl)pyridin-4- yl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00964
         		(R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(5-(3- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00965
         		(R)-3-(5-fluoro-2-(((S)-1- (5-(3- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00966
         		(R)-3-(5-fluoro-2-(((S)-1- (5-(2-fluoro-3- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00967
         		(R)-3-(2-(((S)-1-(5-(2- fluoro-3- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00968
         		(R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(5-(3- (trifluoromethyl)phenyl) pyridin-2- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
    Error! Not a valid embedded object. (R)-3-(5-fluoro-2-(((S)-1- (5-(3- (trifluoromethyl)phenyl) pyridin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00969
         		(R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(5-(4- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00970
         		(R)-3-(5-fluoro-2-(((S)-1- (5-(4- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00971
         		(R)-3-(2-(((S)-1-(5-(4- chloro-3- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00972
         		(R)-3-(2-(((S)-1-(5-(4- fluoro-3- methylphenyl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00973
         		(R)-3-(2-(((S)-1-(5-(4- chloro-3- (trifluoromethyl)phenyl) pyrimidin-2-yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00974
         		(R)-3-(5-fluoro-2-(((S)-1- (5-(4-fluoro-3- (trifluoromethyl)phenyl) pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00975
         		(R)-3-(2-(((S)-1-(5-(4- fluoro-3- methylphenyl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00976
         		(R)-3-(5-fluoro-2-(((S)-1- (5-(4-fluoro-3- methylphenyl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00977
         		(R)-3-(2-(((S)-1-(5-(4- chloro-3-fluorophenyl)-4- methylpyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00978
         		(R)-3-(2-(((S)-1-(5-(4- chloro-3-fluorophenyl)-4- methylpyrimidin-2- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00979
         		(R)-3-(2-(((S)-1-(5-(3- chlorophenyl)-4- methylpyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00980
         		(R)-3-(2-(((S)-1-(5-(3- chlorophenyl)-4- methylpyrimidin-2- yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00981
         		(R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(4-methyl-2′- (trifluoromethyl)-[3,4′- bipyridin]-6- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one
    Figure US20140275083A1-20140918-C00982
         		(R)-3-(5-fluoro-2-(((S)-1- (4-methyl-2′- (trifluoromethyl)-[3,4′- bipyridin]-6- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00983
         		(R)-3-(2-(((S)-1-(2,5- difluoro-4-(4-methyl-1H- imidazol-1- yl)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00984
         		(R)-3-(2-(((S)-1-(2,5- difluoro-4-(1-methyl-1H- pyrazol-4- yl)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00985
         		(R)-3-(2-(((S)-1-(2,5- difluoro-4-(2- methylpyridin-4- yl)phenyl)ethyl)amino) pyrimidin-4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00986
         		(R)-3-(2-(((S)-1-(2,5- difluoro-4-(2- methylpyridin-4- yl)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4 - ((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00987
         		(R)-3-(2-(((S)-1-(2,5- difluoro-4-(2- (trifluoromethyl)pyridin-4- yl)phenyl)ethyl)amino) pyrimidin-4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one
    Figure US20140275083A1-20140918-C00988
         		(R)-3-(2-(((S)-1-(2,5- difluoro-4-(2- (trifluoromethyl)pyridin-4- yl)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1- fluoroethyl)oxazolidin-2- one
    • Biological Data Mutant IDH1 Biochemical Assay: LC-MS Detection of 2-HG.
  • Mutant IDH1 R132H catalytic activity was monitored using the quantitative liquid chromatography/mass spectrometry (LC-MS) detection of 2-HG, a product of the NADPH-dependent alpha-KG reduction reaction.
  • More specifically, the biochemical reactions were performed at room temperature in 384-well Greiner flat-bottom plates (Costar, Cat. No. 781201) using a final reaction volume of 30 μL and the following assay buffer conditions: 50 mM HEPES pH 7.4, 10 mM MgCl2, 50 mM KCl, 1 mM DTT, 0.02% BSA, 5 uM NADPH and 100 uM alpha-KG.
  • The final reaction mixture contained 3.3% DMSO and inhibitors with concentrations ranging 0.02-50 μM. The IDH1 enzyme was used at a final concentration of 0.25 nM. Following 45 minutes incubation, the reaction mixtures were quenched by the addition of 10 μL of 16% formic acid containing 800 nM of 5-carbon labeled 13C-2-HG). The protein was then precipitated by the addition of 2.5 volumes of acetonitrile followed by centrifugation (3000×g, 20 minutes). The concentration of 2-HG in the resulting supernatants was measured by LC-MS (see below).
  • LC-MS method. Reaction mixture supernatants were submitted to chromatographic separation on a BiobasicAX column (2.1 mm×20 mm, 5 μm particle, Thermo Scientific Inc.). The chromatographic mobile phases were A) 25 mM ammonium biocarbonate and B) acetonitrile (0.1% ammonium hydroxide). Nicotinamide was eluted at 1 ml/min using a 85-5% B gradient over 0.9 minutes (Agilent 1200SL LC system, Thermofisher LX-4 autosampler) and analyzed by multiple reaction monitoring (MRM) on a API4000 QTrap mass spectrometer (ABSciex, Framingham, Mass.) in the positive electrospray ionization (ESI+) mode. The mass transition for 2-HG and 13C-2-HG were 147→129 and 152→134, respectively. The relative responses (2-HG/13C-2-HG) were measured at varied inhibitor concentrations and used to calculate inhibitory IC50 values (normalized IC50 regression curves).
    • R132 Protein Expression and Purification.
  • IDH1 R132H was cloned into the pET47b vector using the restriction sites Xmal/XhoI which yields an in frame, N-terminal His6 site cleavable with Prescission protease. This plasmid was transformed into Rosetta™ 2(DE3) (Novagen) cells. In shake flasks, 8 L of cells were grown in Terrific Broth (Teknova) (plus kanamycin 50 μg/mL and chloramphenicol 34 μg/mL) at 37° C. to an OD600 of 0.8 and protein expression was induced by addition of IPTG to a concentration of 0.20 mM. The cells were subsequently grown for 18 hours at 18° C.
    • His6-IDH1 (R132H) Uncut Protein
  • (SEQ ID NO: 1)
    MAHHHHHHSAALEVLFQGPGMSKKISGGSVVEMQGDEMTRIIWELIKEKL
    IFPYVELDLHSYDLGIENRDATNDQVTKDAAEAIKKHNVGVKCATITPDE
    KRVEEFKLKQMWKSPNGTIRNILGGTVFREAIICKNIPRLVSGWVKPIII
    GHHAYGDQYRATDFVVPGPGKVEITYTPSDGTQKVTYLVHNFEEGGGVAM
    GMYNQDKSIEDFAHSSFQMALSKGWPLYLSTKNTILKKYDGRFKDIFQEI
    YDKQYKSQFEAQKIWYEHRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDS
    VAQGYGSLGMMTSVLVCPDGKTVEAEAAHGTVTRHYRMYQKGQETSTNPI
    ASIFAWTRGLAHRAKLDNNKELAFFANALEEVSIETIEAGFMTKDLAACI
    KGLPNVQRSDYLNTFEFMDKLGENLKIKLAQAKL (stop)
    • IDH1 (R132H) Prescission Cut Protein (N-Term gpg is Cloning Artifact)
  • (SEQ ID NO: 2)
    GPGMSKKISGGSVVEMQGDEMTRIIWELIKEKLIFPYVELDLHSYDLGIE
    NRDATNDQVTKDAAEAIKKHNVGVKCATITPDEKRVEEFKLKQMWKSPNG
    TIRNILGGTVFREAIICKNIPRLVSGWVKPIIIGHHAYGDQYRATDFVVP
    GPGKVEITYTPSDGTQKVTYLVHNFEEGGGVAMGMYNQDKSIEDFAHSSF
    QMALSKGWPLYLSTKNTILKKYDGRFKDIFQEIYDKQYKSQFEAQKIWYE
    HRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDSVAQGYGSLGMMTSVLVC
    PDGKTVEAEAAHGTVTRHYRMYQKGQETSTNPIASIFAWTRGLAHRAKLD
    NNKELAFFANALEEVSIETIEAGFMTKDLAACIKGLPNVQRSDYLNTFEF
    MDKLGENLKIKLAQAKL (stop)
    • Purification
  • The cells were homogenized in Lysis Buffer with protease inhibitors (cOmplete EDTA-free protease inhibitor tablets (Roche), 1 tablet per 50 mL of buffer), DNAse, and to 200 μM PMSF and lysed in a Microfluidizer. After lysis, Triton X-100 was added to 0.1% and stirred at 4° C. for 30 minutes.
  • The cleared lysate was loaded onto 2×5 mL HisTrap FF crude columns (GE), washed extensively with Lysis Buffer until the A280 stabilized and eluted with Ni Elution Buffer. Peak eluted fractions were concentrated to 30 mL, EDTA was added to 1 mM and GST-Prescission protease was added to 3 U/100 μg of protein. The sample was dialyzed against 2 L Dialysis Buffer I (MWCO 50 kDa) for 6 hours at 4° C. then dialyzed against 2 L of Dialysis Buffer II for at least 6 more hours. GST-Prescission cleaved sample was rocked with Glutathione Agarose Beads, spun down and then the supernatant was loaded through a 5 mL HisTrap HP column and the flow through was collected.
  • Flow through was then diluted with ice cold 20 mM Tris pH 7.4 and 1 mM TCEP until the conductivity dropped to less than 5 mS/cm (a roughly three fold dilution). This sample was then flowed through a HiTrap Q column and the flow through was concentrated to 10 mL and loaded onto an equilibrated 26/60 Superdex 200 column using SEC Buffer as the mobile phase. Peak fractions were collected, concentrated and aliquoted.
  • Lysis Buffer:
  • 50 mM Tris pH=7.4, 500 mM NaCl, 20 mM Imidazole, and 1 mM TCEP
  • Ni Elution Buffer:
  • 50 mM Tris pH=7.4, 150 mM NaCl, 200 mM Imidazole, and 1 mM TCEP
  • Dialysis Buffer I:
  • 20 mM Tris pH=7.4, 150 mM NaCl, 1 mM TCEP, and 50 mM Imidazole
  • Dialysis Buffer II:
  • 20 mM Tris pH=7.4, 150 mM NaCl, and 1 mM TCEP
    • SEC Buffer:
  • 20 mM Tris pH=7.4, 150 mM NaCl, and 1 mM TCEP
  • The results of the mutant IDH1 biochemical assay (mIDH R132H) are given in Table 40. Some of the examples were run in the assay multiple times and therefore the IC50 values are expressed as a range of activity.
    • Fluorescence Biochemical Assay
  • The IDH1 (R132H) mutant catalyzes the reduced form of NADP+ (NADPH) and α-ketoglutarate (α-KG) to form nicotinamide adenine dinucleotide phosphate (NADP+) and R (−)-2-hydroxyglutarate (2HG). The reaction can be monitored kinetically by following the oxidation of NADPH to NADP+ which is measured using fluorescence, excitation at 355 nm and emission at 530 nm. Reactions were monitored using the Perkin-Elmer Envision, Model 2101. More specifically, the biochemical reactions were performed at room temperature in 384-well Greiner flat-bottom plates (Cat. No. 781076) using a final reaction volume of 20 μL and the following assay buffer conditions: 50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM DTT, 0.02% BSA, 0.02% Tween-20, 10 μM NADPH and 100 μM α-KG. The final reaction mixture contained 2.5% DMSO and test compounds with concentrations ranging 0.0000008-25 μM. The IDH1 (R132H) enzyme was used at a final concentration of 10 nM. Curve fitting for dose response 1050 determinations was done in the Helios module of the software package DAVID. The 4-parameter logistic model was used: y=min+((max−min)/1+(×/IC50)slope).
  • The results of the fluorescence biochemical assay (mIDH R132H) are given in Table 40. Some of the examples were run in the assay multiple times and therefore the IC50 values are expressed as a range of activity.
  • TABLE 40
    Results of the LC-MS and fluorescence biochemical assays.
    LC-MS Fluorescence
    Example biochemical biochemical
    Number assay IC50 (μM) assay IC50 (μM)
    1 — 1.410
    2 — 0.406 to 0.412
    3 — —
    4 2.010 1.420
    5 3.684 17.800 
    6 1.185 1.270
    7 1.609 to 4.527 2.950
    8 0.314 to 2.79  2.040
    9 3.019 2.200
    10 1.710 11.700 
    11 2.453 3.050
    12 0.892 3.270
    13 >5    2.190
    14 0.813 0.405
    15 — —
    16 — —
    17 — —
    18 — —
    19 — —
    20 — —
    21 — —
    22 — —
    23 — —
    24 — —
    25 — —
    26 — 3.350
    27 — 2.800
    28 0.005 —
    29 0.027 —
    30 0.472 1.090
    31 0.757 0.627
    32 0.010 0.016
    33 2.085 3.660
    34 0.590 0.889 to 0.893
    35 0.055 0.033
    36 3.497 1.410
    37 3.745 2.690
    38 0.056 0.055
    39 0.211 0.202
    40 0.370 0.175
    41 0.179 0.253
    42 1.557 >25    
    43 0.045 —
    44 0.033 to 0.034 0.029
    45 1.237 1.000
    46 1.930 2.530
    47 0.036 0.033
    48 0.775 0.463
    49 0.094 —
    50 0.043 0.037
    51 0.016 0.013
    52 0.194 0.131 to 0.289
    53 0.059 0.042 to 0.051
    54 0.119 0.116
    55 0.323 0.267 to 0.291
    56 1.549 2.920
    57 1.131 1.270
    58 0.029 0.027
    59 0.033 0.079 to 0.085
    60 0.201 1.100
    61 0.156 0.313
    62 0.087  0.53 to 0.599
    63 0.005 <0.0159
    64 0.008 <0.0159
    65 0.582 0.797
    66 0.066 0.061 to 0.082
    67 1.437 1.010
    68 0.112 0.050
    69 >5    0.639
    70 0.080 0.073
    71 >5    >25    
    72  12.152 —
    73 0.571 0.181
    74 >5    —
    75 — —
    76 0.546 to 0.568 —
    77 0.911 —
    78 2.560 1.630
    79 >5    5.310
    80 0.031 0.037
    81 1.089 —
    82 0.022 0.019
    83 0.489 0.662 to 0.683
    84 0.013 0.012 to 0.083
    85 0.524 1.930
    86 0.019 0.032 to 0.049
    87 >5    6.690
    88 0.034 0.048 to 0.058
    89 1.776 1.360
    90 0.013 0.034
    91 — 0.274
    92 2.301 to 3.074 2.74 to 8.91
    93 0.029 to 0.134 0.043 to 0.383
    94 25.642  14.900 
    95 1.113 1.530
    96 >50     —
    97 0.984 0.972
    98 0.487 0.351
    99 3.057 9.790
    100 18.066  —
    101 0.572 —
    102 >50     —
    103 6.354 —
    104 >50     >25    
    105 1.720 2.430
    106 32.926  >25    
    107 1.416 1.220
    108 5.902 11.700 
    109 0.136 to 0.167 0.0486 to 0.193 
    110 23.402  >25    
    111 3.511 2.780
    112 >50     >25    
    113 42.325  >25    
    114 >50     >25    
    115 3.760 7.890
    116 >50     >25    
    117 2.010 1.410
    118 1.539 3.560
    119 0.029 to 0.042 0.045
    120 2.668 —
    121 0.045 to 0.081 0.182
    122 0.268 0.370
    123 0.024 to 0.029 0.017 to 0.044
    124 18.8   >25    
    125 0.158 0.206
    126 0.216 0.274
    127 0.025 to 0.033 0.032
    128 0.071 0.050
    129 2.814 1.800
    130 2.999 1.510
    131 0.153 to 0.171 0.056
    132 1.421 0.956
    133 0.004 to 0.008 0.007
    134 2.360 1.460
    135 0.016 0.011
    136 >5    11.300 
    137 0.294 1.190
    138 0.024 0.012
    139 0.146 0.260
    140 4.032 10.600 
    141 0.116 0.660
    142 3.977 >25    
    143 0.572 0.756
    144 1.685 1.670
    145 0.036 0.020
    146 >5    —
    147 0.368 —
    148 >5    9.590
    149 0.168 to 0.216 0.194
    150 >5    —
    151 0.012 0.043 to 0.044
    152 >5    5.990
    153 0.288 0.329
    154 3.839 1.790
    155 0.857 0.756
    156 1.145 2.700
    157 0.032 0.033
    158 4.374 —
    159 0.006 <0.0159
    160 1.115 1.230
    161 0.305 0.158
    162 >5    3.620
    163 0.152 0.079
    164 >5    4.680
    165 0.304 0.152
    166 0.243 0.871
    167 0.067 to 0.076 0.131
    168 >5    3.200
    169 0.044 to 0.086 0.038
    170 1.884 3.690
    171 0.031 to 0.052 0.056
    172 3.407 —
    173 0.040 0.051 to 0.078
    174 0.238 0.230
    175 0.049 0.298 to 0.538
    176 4.591 12.400 
    177 1.587 1.230
    178 0.077 0.364
    179 0.005 to 0.006 0.007
    180 2.728 >25    
    181 0.122 0.138
    182 1.378 1.920
    183 0.243 0.128
    184 0.757 0.502
    185 0.021 0.023
    186 2.583 2.32 to 2.58
    187 0.010 0.022
    188 — 8.380
    189 0.156 0.064
    190 0.014 0.037
    191 — >50    
    192 0.010 —
    193 0.358 —
    194 — 0.051
    195 — 2.930
    196 0.005 <0.0159
    197 — 2.010
    198 — 0.020
    199 — 1.200
    200 0.005 0.043
    201 — 0.344
    202 1.093 1.680
    203 0.008 0.016
    204 0.02 to 0.05 0.026 to 0.059
    205 2.052 2.700
    206 0.022  0.03 to 0.051
    207   <0.0228624 0.011
    208 — 0.101
    209 0.164 0.087
    210 0.374 0.153
    211 2.628 0.496
    212 0.057 0.035
    213 0.018 0.011 to 0.019
    214 0.107 0.046
    215 0.106 to 0.138 0.055
    216 0.011 0.004
    217 0.019 to 0.025 0.012 to 0.033
    218 0.018 to 0.044 0.019
    219 0.015 0.014
    220 0.017 0.014
    221 0.046 0.061
    222 0.053 0.047
    223 0.014 0.023 to 0.046
    224 <0.022 to 0.027  <0.016 to 0.029 
    225 0.038 to 0.063 0.028 to 0.042
    226 — 0.009
    227  0.22 to 0.023 0.015
    228 0.014 to 0.045 0.018 to 0.019
    229 0.081 0.054
    230 — >25    
    231 — >25    
    232 0.026 0.024
    233 — 0.377
    234 — 0.213
    235 — 0.964
    236 0.023 0.024 to 0.042
    237 0.013  0.02 to 0.025
    238 0.012 0.017 to 0.024
    239 0.020 0.049 to 0.058
    240 0.067 0.142
    241 0.157 0.114
    242 0.053 0.042
    243 0.172 0.141
    244 — 0.300
    245 — 0.115
    246 — 0.273
    247 — 0.079
    248 — 0.172
    249 — 0.635
    250 — 0.025 to 0.047
    251 — 0.020
    252 0.353 to 0.482 0.309
    253 0.121 0.109
    254 — 0.234
    255 — 0.450
    256 0.489 0.570
    257 — 1.200
    258 0.435 0.737
    259 0.103 0.049 to 0.105
    260 0.039 0.040
    261 0.089 0.064
    262 0.167 0.088
    263 — 0.014
    264 0.249 0.152
    265 0.036 —
    266 — 0.453
    267 0.095 0.048
    268 — 0.338
    269 — 0.251
    270 0.163 0.174
    271 — 0.339
    272 — 0.117
    273 0.585 —
    274 0.265 —
    275 0.311 —
    276 0.051 —
    277 0.086 —
    278 0.119 0.301
    279 — 12.700 
    280 — 3.640
    281 0.064 0.026
    282 4.270
    283 0.248 0.068
    284 — 0.266
    285 0.146 0.053
    286 0.145 0.036
    287 46.301  2.250
    288 0.178 0.055
    289 — 2.110
    290 0.053 0.034
    291 — >25    
    292 — 1.850
    293 — >7.91 
    294 0.563 0.466
    295 — >25    
    296 0.277 0.251
    297 — 2.960
    298 0.038 0.020
    299 — 0.457
    300 0.017 0.010
    301 0.033 0.021
    302 — 0.045
    303 0.097 0.009
    304 — 0.304
    305 0.772 to 1.781 0.968
    306 — 2.570
    307 0.038 0.029 to 0.049
    308 0.073 0.049 to 0.097
    309 0.004 to 0.005 0.003
    310 0.128 0.072
    311 0.445 0.518
    312 0.144 0.066
    313 0.019 0.020
    314 0.157 to 0.182 0.106 to 0.121
    315  0.35 to 0.463 0.161 to 0.514
    316 0.261 0.123 to 0.29 
    317 — 3.7 to 5.63
    318 — >25    
    319 0.086 0.035
    320 0.381 0.426
    321 0.087 0.013
    322 0.042 0.055 to 0.088
    323 0.072 0.071 to 0.122
    324 — 0.030
    325 0.181 0.041
    326 — 0.063
    327 0.562 0.236
    328 — 1.800
    329 0.435 0.863
    330 0.850 0.268
    331 0.780 0.190
    332 0.704 1.020
    333 0.640 0.944
    334 0.943 0.341
    335 0.166 to 0.167 0.257
    336 0.048 to 0.049 0.027
    337 0.119 0.313
    338 0.093 0.091
    339 0.024 to 0.027 0.017
    340 0.120 0.061
    341 — 7.050
    342 4.001 0.465
    343 0.225 0.073
    344 0.300 0.190
    345 0.378 0.201
    346 0.290 0.189
    347 0.564 0.395
    348 0.128 0.177
    349 — 0.681
    350 — 0.413
    351 — 0.168
    352 — 0.770
    353 0.117 0.103
    354 0.286 0.051
    355 0.381 0.152
    356 0.132 0.120
    357 0.439 0.358
    358 — 0.123
    359 0.193 0.171
    360 0.119 0.056
    361 0.170 0.107
    362 0.142 0.072
    363 0.009 0.007
    364 0.286 to 0.472 0.124
    365 0.137 0.033
    366 0.345 0.151
    367 0.209 0.127
    368 0.127 0.091
    369 1.277 0.397
    370 1.303 0.441
    371 0.110 0.125
    372 0.029 0.014 to 0.044
    373 — 0.051
    374 0.021 0.032
    375 0.241 0.093
    376 0.027 0.023
    377 — 0.052
    378 — 0.025 to 0.028
    379 — 0.053
    380 0.050 0.036 to 0.055
    381 0.059 0.139
    382 0.098 0.219
    383 — 0.164
    384 — 10.5 to >25 
    385 — <0.016 to 0.027 
    386 — 0.059
    387 — 0.032 to 0.036
    388 0.006 <0.0159
    389 — 0.020
    390 0.022 0.022 to 0.037
    391 — 0.038 to 0.067
    392 — 0.101 to 0.142
    393 — 0.057 to 0.081
    394 — 0.037 to 0.046
    395 — 0.034 to 0.045
    396 — 0.024 to 0.041
    397 — 0.064 to 0.067
    398 — 0.038 to 0.04 
    399 — 0.018
    400 — 0.018 to 0.033
    401 — 0.023 to 0.03 
    402 — 0.044 to 0.05 
    403 — 0.137
    404 — 0.021 to 0.025
    405 — 0.027 to 0.037
    406 — 0.028 to 0.03 
    407 0.071 —
    408 0.043 —
    409 0.501 to 0.515 0.209
    410 0.034 0.020
    411 1.601 0.756
    412 0.223 to 0.347 0.108
    413 — 0.023
    414 — 2.210
    415 0.204 0.483 to 0.859
    416 0.110 0.097
    417 0.078 to 0.147 0.207
    418 0.016 to 0.075 0.015 to 0.044
    419 0.039 to 0.06  0.096
    420 0.047 to 0.078 0.089
    421 0.021 0.023
    422 — 1.76 to 2.03
    423 — 0.036 to 0.042
    424 6.429 7.710
    425 0.202 to 0.214 0.303
    426 — <0.0159
    427 — 0.039 to 0.55 
    428 —  0.0678
    429 — <0.016 
    430 — 0.050
    431 — 0.047
    432 — 0.016
    433 — 0.032
    434 — 0.017
    435 — 0.017
    436 — 0.06 
    437 — 0.036
    438 — 0.045
    439 — 0.392
    440 — 0.172
    441 — <0.016 
    442 — 0.038
    443 — 0.029
    444 — <0.016 
    445 — 0.112
    446 —  0.0268
    447 — 0.028
    448 — <0.016 
    449 —  0.0297
    450 — <0.016 
    451 —  0.0435
    452 —  0.0293
    453 —  0.0357
    454 —  0.0234
    455 — <0.016 
    456 — <0.016 
    457 — 0.017
    458 — <0.016 
    459 —  0.0246
    460 — 0.024 to 0.043
    461 — 0.045 to 0.064
    462 —  0.0738
    463 —  0.0395
    464 —  0.0937
    465 —  0.0681
    • ENUMERATED EMBODIMENTS Embodiment 1
  • A compound according to formula (I)
  • Figure US20140275083A1-20140918-C00989
  • wherein:
    R1 is hydrogen, methyl or ethyl;
    R2a is hydrogen, methyl or C1-3 haloalkyl;
    R2b is OH, halo, C1-6 alkoxy, C1-3 haloalkyl, NH2, NH(CH3) or N(CH3)2;
    R3 and R4 are each independently hydrogen, methyl or ethyl or R3 and R4 are joined together forming cyclopropyl, cyclobutyl or oxetanyl;
    R5 and R6 are each independently hydrogen, deuterium, halo, —C(O)OCH3, C1-3 alkyl or C1-3 haloalkyl;
    • R7 is
  • Figure US20140275083A1-20140918-C00990
  • wherein:
      • ring A is a 6 membered heteroaryl ring having one to three nitrogen atoms;
      • ring B is a 5 membered heteroaryl ring having one to four heteroatoms each independently selected from the group consisting of N, O and S;
      • X is N or CH;
      • each R8 is independently hydrogen, halo, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy;
      • n is 1 or 2;
      • R9 is hydrogen, halo, C1-3 haloalkyl, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted 5 or 6 membered heterocyclic, optionally substituted heteroaryl, —OR9a, —SO2R9a, —C(O)NHR9a, CH2R9b or CHCH3R9b, provided that when X is N, R9 is hydrogen, C1-3 haloalkyl, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —SO2R9a or —C(O)NHR9a,
      • wherein:
        • said C1-6 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: OH, phenyl and phenoxy, and
        • said C3-6 cycloalkyl, 5 or 6 membered heterocyclic, aryl and heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
      • R9a is optionally substituted C1-6 alkyl, C1-6 haloalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, or optionally substituted heterocyclic,
      • wherein:
        • said C1-6 alkyl is optionally substituted with one C3-6 cycloalkyl,
        • said C3-6 cycloalkyl and heterocyclic are each optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH2OH, —NRR, cyano, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy, and
        • Said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
      • R9b is optionally substituted C3-6 cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclic,
        • said C3-6 cycloalkyl and heterocyclic are each optionally substituted with one to four substituents each independently selected from the group consisting of: hydroxyl, CH2OH, —NRR, —NRC(O)CH3, 4 to 6 membered heterocyclic, cyano, halo, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy, and
        • said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; and
      • each R is independently selected from the group consisting of H, C1-3 alkyl and C3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.
    Embodiment 2
  • The compound according to embodiment 1 wherein R3 and R4 are both hydrogen; or a pharmaceutically acceptable salt thereof.
    • Embodiment 3
  • The compound according to embodiment 1 or 2 wherein R1 is hydrogen; or a pharmaceutically acceptable salt thereof.
    • Embodiment 4
  • The compound according to any one of embodiments 1-3 according to formula (II):
  • Figure US20140275083A1-20140918-C00991
  • or a pharmaceutically acceptable salt thereof.
    • Embodiment 5
  • The compound according to any one of embodiments 1-4 wherein:
      • R5 is hydrogen or halo; and
      • R6 is hydrogen, halo, methyl, CH2F, CHF2, or CF3; or a pharmaceutically acceptable salt thereof.
    Embodiment 6
  • The compound according to embodiment 5 wherein R5 is hydrogen; or a pharmaceutically acceptable salt thereof.
    • Embodiment 7
  • The compound according embodiment 5 wherein R6 is hydrogen; or a pharmaceutically acceptable salt thereof.
    • Embodiment 8
  • The compound according to embodiment 5 wherein R5 and R6 are both hydrogen; or a pharmaceutically acceptable salt thereof.
    • Embodiment 9
  • The compound according to any one of embodiments 1-8 wherein R2a is methyl; or a pharmaceutically acceptable salt thereof.
    • Embodiment 10
  • The compound according to any one of embodiments 1-9 wherein R2b is OH, fluoro, methoxy, t-butoxy, CHF2, CF3, NH2 or NH(CH3); or a pharmaceutically acceptable salt thereof.
    • Embodiment 11
  • The compound according to any one of embodiments 1-10 having the following formula:
  • Figure US20140275083A1-20140918-C00992
  • wherein R2b is OH, NH2 or fluoro; or a pharmaceutically acceptable salt thereof.
    • Embodiment 12
  • The compound according to any one of embodiments 1-11 according to formula (IV):
  • Figure US20140275083A1-20140918-C00993
  • wherein R2b is OH or NH2; or a pharmaceutically acceptable salt thereof.
    • Embodiment 13
  • The compound according to embodiment 12 wherein R2b is OH; or a pharmaceutically acceptable salt thereof.
    • Embodiment 14
  • The compound according to embodiment 12 wherein R2b is NH2; or a pharmaceutically acceptable salt thereof.
    • Embodiment 15
  • The compound according to any one of embodiments 1-11 according to formula (V):
  • Figure US20140275083A1-20140918-C00994
  • or a pharmaceutically acceptable salt thereof.
    • Embodiment 16
  • The compound according to embodiment 15 wherein R2a is methyl; or a pharmaceutically acceptable salt thereof.
    • Embodiment 17
  • The compound according to any one of embodiments 1-16 wherein R7 is:
  • Figure US20140275083A1-20140918-C00995
    Figure US20140275083A1-20140918-C00996
  • or a pharmaceutically acceptable salt thereof.
    • Embodiment 18
  • The compound according to any one of embodiments 1-17 wherein R9 is hydrogen, halo, C1-3 haloalkyl, optionally substituted C1-6 alkyl or optionally substituted C3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.
    • Embodiment 19
  • The compound according to any one of embodiments 1-17 wherein R9 is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH2OH, C1-4 alkyl, C1-4 haloalkyl and C1-3 haloalkoxy; or a pharmaceutically acceptable salt thereof.
    • Embodiment 20
  • The compound according to any one of embodiments 1-17 wherein R9 is pyrazolyl, pyridinyl, indolyl or isoquinolinyl each of which is optionally substituted; or a pharmaceutically acceptable salt thereof.
    • Embodiment 21
  • The compound according to any one of embodiments 1-17 wherein R9 is CH2R9b wherein R9b is piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, halo, CH2OH, —NRR, cyano, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy.
    • Embodiment 22
  • The compound according to embodiment 1 according to formula (IV)
  • Figure US20140275083A1-20140918-C00997
  • wherein:
  • R2b is OH;
  • R5 is hydrogen or fluoro;
  • R6 is hydrogen, chloro, methyl or CH2F;
  • R7 is
  • Figure US20140275083A1-20140918-C00998
  • R8 is hydrogen, methyl or fluoro;
    n is 1 or 2; and
  • R9 is methylcyclopropyl, isobutoxy, phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, C1-4 alkyl, CF2H and CF3 or pyridinyl optionally substituted with one or two substituents each independently selected from the group consisting of: methyl, CF3 and C(CH3)2CF3; or a pharmaceutically acceptable salt thereof.
    • Embodiment 23
  • The compound according to embodiment 22 wherein:
  • R5 is hydrogen and R6 is chloro, methyl or CH2F or
    R6 is hydrogen and R5 is fluoro; or a pharmaceutically acceptable salt thereof.
    • Embodiment 24
  • The compound according to embodiment 22 wherein R5 and R6 are both hydrogen; or a pharmaceutically acceptable salt thereof.
    • Embodiment 25
  • The compound according to embodiment 1 according to formula (V)
  • Figure US20140275083A1-20140918-C00999
  • wherein:
    R2b is fluoro;
    R5 is hydrogen or fluoro;
    R6 is hydrogen;
    • R7 is
  • Figure US20140275083A1-20140918-C01000
  • R8 is hydrogen or methyl;
    n is 1; and
    R9 is phenyl optionally substituted with one chloro; or a pharmaceutically acceptable salt thereof.
    • Embodiment 26
  • The compound according to embodiment 1 selected from the group consisting of:
    • (R)-4-((R)-1-hydroxy(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-onethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chloro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (4R)-3-(5-fluoro-2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and
    • (R)-3-(2-(((S)-1-(2,5-difluoro-4-(2-methylpyridin-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.
    Embodiment 27
  • The compound according to embodiment 1 selected from the group consisting of:
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-{2-[(S)-1-(5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
    • (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
    • (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
    • (R)-3-(5-fluoro-2-(((S)-1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-(fluoromethyl)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-(4-(difluoromethyl)phenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(6-chloro-2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and
    • (R)-3-(2-(((S)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.
    Embodiment 28
  • The compound according to embodiment 1 selected from the group consisting of:
    • (R)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
    • (R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and
    • (R)-3-(2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.
    Embodiment 29
  • The compound according to embodiment 1 selected from the group consisting of:
    • (R)-3-(6-chloro-2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one; and
    • (S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.
    Embodiment 29
  • The compound according to embodiment 1 selected from the group consisting of:
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-2-methyl-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
    • (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
    • (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one; and
    • (S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.
    Embodiment 30
  • A pharmaceutical composition comprising a compound according to any one of embodiments 1-29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
    • Embodiment 31
  • A method for the treatment of a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of a therapeutically effective amount of a compound according to any one of embodiments 1-29, or a pharmaceutically acceptable salt thereof, to subject in need of thereof.
    • Embodiment 32
  • A method for the treatment of a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of a therapeutically effective amount of a compound according to any one of embodiments 1-29, or a pharmaceutically acceptable salt thereof, and another therapeutic agent to subject in need of thereof.

Claims (33)

What is claimed is:
1. A compound according to formula (I)
Figure US20140275083A1-20140918-C01001
wherein:
R1 is hydrogen, methyl or ethyl;
R2a is hydrogen, methyl or C1-3 haloalkyl;
R2b is OH, halo, C1-6 alkoxy, C1-3 haloalkyl, NH2, NH(CH3) or N(CH3)2;
R3 and R4 are each independently hydrogen, methyl or ethyl or R3 and R4 are joined together forming cyclopropyl, cyclobutyl or oxetanyl;
R5 and R6 are each independently hydrogen, deuterium, halo, —C(O)OCH3, C1-3 alkyl or C1-3 haloalkyl;
R7 is
Figure US20140275083A1-20140918-C01002
wherein:
ring A is a 6 membered heteroaryl ring having one to three nitrogen atoms;
ring B is a 5 membered heteroaryl ring having one to four heteroatoms each independently selected from the group consisting of N, O and S;
X is N or CH;
each R8 is independently hydrogen, halo, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy;
n is 1 or 2;
R9 is hydrogen, halo, C1-3 haloalkyl, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted 5 or 6 membered heterocyclic, optionally substituted heteroaryl, —OR9a, —SO2R9a, —C(O)NHR9a, CH2R9b or CHCH3R9b, provided that when X is N, R9 is hydrogen, C1-3 haloalkyl, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —SO2R9a or —C(O)NHR9a, wherein:
said C1-6 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: OH, phenyl and phenoxy, and
Said C3-6 cycloalkyl, 5 or 6 membered heterocyclic, aryl and heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
R9a is optionally substituted C1-6 alkyl, C1-6 haloalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, or optionally substituted heterocyclic,
wherein:
said C1-6 alkyl is optionally substituted with one C3-6 cycloalkyl,
Said C3-6 cycloalkyl and heterocyclic are each optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH2OH, —NRR, cyano, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy, and
Said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
R9b is optionally substituted C3-6 cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclic,
said C3-6 cycloalkyl and heterocyclic are each optionally substituted with one to four substituents each independently selected from the group consisting of: hydroxyl, CH2OH, —NRR, —NRC(O)CH3, 4 to 6 membered heterocyclic, cyano, halo, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy, and
Said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C1-6 alkyl, Cl—6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; and
each R is independently selected from the group consisting of H, C1-3 alkyl and C3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein R3 and R4 are both hydrogen; or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 wherein R1 is hydrogen; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 according to formula (II):
Figure US20140275083A1-20140918-C01003
or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 wherein:
R5 is hydrogen or halo; and
R6 is hydrogen, halo, methyl, CH2F, CHF2, or CF3; or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5 wherein R5 is hydrogen; or a pharmaceutically acceptable salt thereof.
7. The compound according claim 5 wherein R6 is hydrogen; or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 5 wherein R5 and R6 are both hydrogen; or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 wherein R2a is methyl; or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 wherein R2b is OH, fluoro, methoxy, t-butoxy, CHF2, CF3, NH2 or NH(CH3); or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 having the following formula:
Figure US20140275083A1-20140918-C01004
wherein R2b is OH, NH2 or fluoro; or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1 according to formula (IV):
Figure US20140275083A1-20140918-C01005
wherein R2b is OH or NH2; or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 12 wherein R2b is OH; or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 12 wherein R2b is NH2; or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1 according to formula (V):
Figure US20140275083A1-20140918-C01006
or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 15 wherein R2a is methyl; or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 1 wherein R7 is:
Figure US20140275083A1-20140918-C01007
Figure US20140275083A1-20140918-C01008
or a pharmaceutically acceptable salt thereof.
18. The compound according to claim 1 wherein R9 is hydrogen, halo, C1-3 haloalkyl, optionally substituted C1-6 alkyl or optionally substituted C3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.
19. The compound according to claim 1 wherein R9 is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH2OH, C1-4 alkyl, C1-4 haloalkyl and C1-3 haloalkoxy; or a pharmaceutically acceptable salt thereof.
20. The compound according to claim 1 wherein R9 is pyrazolyl, pyridinyl, indolyl or isoquinolinyl each of which is optionally substituted; or a pharmaceutically acceptable salt thereof.
21. The compound according to claim 1 wherein R9 is CH2R9b wherein R9b is piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, halo, CH2OH, —NRR, cyano, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy.
22. The compound according to claim 1 according to formula (IV)
Figure US20140275083A1-20140918-C01009
wherein:
R2b is OH;
R5 is hydrogen or fluoro;
R6 is hydrogen, chloro, methyl or CH2F;
R7 is
Figure US20140275083A1-20140918-C01010
R8 is hydrogen, methyl or fluoro;
n is 1 or 2; and
R9 is methylcyclopropyl, isobutoxy, phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, C1-4 alkyl, CF2H and CF3 or pyridinyl optionally substituted with one or two substituents each independently selected from the group consisting of: methyl, CF3 and C(CH3)2CF3; or a pharmaceutically acceptable salt thereof.
23. The compound according to claim 22 wherein:
R5 is hydrogen and R6 is chloro, methyl or CH2F or
R6 is hydrogen and R5 is fluoro; or a pharmaceutically acceptable salt thereof.
24. The compound according to claim 22 wherein R5 and R6 are both hydrogen; or a pharmaceutically acceptable salt thereof.
25. The compound according to claim 1 according to formula (V)
Figure US20140275083A1-20140918-C01011
wherein:
R2b is fluoro;
R5 is hydrogen or fluoro;
R6 is hydrogen;
R7 is
Figure US20140275083A1-20140918-C01012
R8 is hydrogen or methyl;
n is 1; and
R9 is phenyl optionally substituted with one chloro; or a pharmaceutically acceptable salt thereof.
26. The compound according to claim 1 selected from the group consisting of:
(R)-4-((R)-1-hydroxy(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-onethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(4-chloro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
(R)-3-(5-fluoro-2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and
(R)-3-(2-(((S)-1-(2,5-difluoro-4-(2-methylpyridin-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.
27. The compound according to claim 1 selected from the group consisting of:
(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-{2-[(S)-1-(5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
(R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
(R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;
(R)-3-(5-fluoro-2-(((S)-1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-(fluoromethyl)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(2-(4-(difluoromethyl)phenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(6-chloro-2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and
(R)-3-(2-(((S)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.
28. The compound according to claim 1 selected from the group consisting of:
(R)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;
(R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and
(R)-3-(2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.
29. The compound according to claim 1 selected from the group consisting of:
(R)-3-(6-chloro-2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one; and
(S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.
30. The compound according to claim 1 selected from the group consisting of:
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-2-methyl-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one; and
(S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof.
31. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
32. A method for the treatment of a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to subject in need of thereof.
33. A method for the treatment of a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and another therapeutic agent to subject in need of thereof.
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