WO2011158149A1 - 2-(3,5-disubstitutedphenyl)pyrimidin-4(3h)-one derivatives - Google Patents

2-(3,5-disubstitutedphenyl)pyrimidin-4(3h)-one derivatives Download PDF

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WO2011158149A1
WO2011158149A1 PCT/IB2011/052462 IB2011052462W WO2011158149A1 WO 2011158149 A1 WO2011158149 A1 WO 2011158149A1 IB 2011052462 W IB2011052462 W IB 2011052462W WO 2011158149 A1 WO2011158149 A1 WO 2011158149A1
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phenoxy
yloxy
oxo
phenyl
dihydropyrimidin
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PCT/IB2011/052462
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French (fr)
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Gary Erik Aspnes
Mary Theresa Didiuk
Angel Guzman-Perez
Robert John Maguire
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Pfizer Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to 2-(3,5-disubstitutedphenyl)pyrimidin- 4(3H)-one derivatives and the uses thereof as glucokinase activators.
  • Type I diabetes or insulin-dependent diabetes mellitus (IDDM)
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin dependent diabetes mellitus
  • GK glucokinase
  • G-6-P glucose-6-phosphate
  • Glucokinase is responsible for the conversion of glucose to glucose-6-phosphate (G-6-P), and it functions as a key regulator of glucose homeostasis.
  • GK regulates hepatic glucose utilization and output whereas in the pancreas it functions as a glucostat establishing the threshold for ⁇ -cell glucose- stimulated insulin secretion.
  • Glucokinase is also found in glucose sensing neurons of the ventromedial hypothalamus where it regulates the counter regulatory response (CRR) to hypoglycemia.
  • CTR counter regulatory response
  • glucokinase is reportedly expressed in the endocrine K and L cells where is may help regulate incretin release.
  • glucokinase would be an effective strategy for lowering blood glucose by up regulating hepatic glucose utilization, down regulating hepatic glucose output and normalizing glucose stimulated insulin secretion. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome,
  • hyperinsulinemia hypertension
  • obesity hyperinsulinemia
  • sulphonyl-ureas e.g., glipizide, glimepiride, glyburide
  • meglitinides e.g., nateglidine and repaglinide
  • B Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use.
  • C Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances.
  • D Thiazolidinediones (e.g.,
  • pioglitazone act on a specific receptor (peroxisome
  • proliferator-activated receptor-gamma in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia.
  • Insulin is used in more severe cases, either alone or in combination with the above agents.
  • an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are
  • the present invention provides compounds of Formula (I) that act as glucokinase mediators, in particular, glucokinase activators; therefore, may be used in the treatment of diseases mediated by such activation (e.g., diseases related to Type 2 diabetes, and diabetes-related and obesity- related co-morbidities).
  • diseases mediated by such activation e.g., diseases related to Type 2 diabetes, and diabetes-related and obesity- related co-morbidities.
  • R 1 is H, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, halo, C0 2 H, C0 2 (Ci-C 6 )alkyl or cyano; wherein said (C ⁇ i-C-6)alkyl and (Ci-Ce)alkoxy are optionally substituted with one to three halo or one (C-i-C 4 )alkoxy, hydroxy, C0 2 H or C0 2 (Ci-C 4 )alkyl; R 2 is OR 4 or C(0)NR 5 R 6 ;
  • R 3 is phenyl, 3 to 7 membered heterocyclyl or 5 to 6 membered heteroaryl; wherein said phenyl, 3 to 7 membered heterocyclyl or 5 to 6 membered heteroaryl are optionally substituted with one to three S(0) 2 R 7 , C(0)NR 8 R 9 , halo, (Ci-C 4 )alkyl, or (Ci-C 4 )alkoxy;
  • R 4 is (C-i-C6)alkyl, (C3-C7)cycloalkyl or 3 to 7 membered heterocyclyl;
  • R 5 and R 6 are each indepependently hydrogen, (Ci-C6)alkyl, (C3- C 7 )cycloalkyl or (Ci-C 6 )alkyl(C 3 -C 7 )cycloalkyl or R 5 and R 6 taken together with the nitrogen to which they are attached form an azetidine, pyrrolidine, morpholine or piperidine ring;
  • R 7 is (Ci-C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (Ci-C 6 )alkyl(C 3 -C 7 )cycloalkyl or NR 8 R 9 , wherein said (Ci-C6)alkyl, (C3-C7)cycloalkyl or (Ci-C6)alkyl(C3-C7)cycloalkyl is optionally substituted with one to three halo; and
  • R 8 and R 9 are each indepependently hydrogen, (Ci-C6)alkyl, (C3- C 7 )cycloalkyl or (Ci-C 6 )alkyl(C3-C 7 )cycloalkyl, each optionally substituted with one to three halo, or R 8 and R 9 taken together with the nitrogen to which they are attached form an azetidine, pyrrolidine, morpholine or piperidine ring.
  • Another embodiment of the present invention is the compound of the immediately preceding embodiment or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or methyl.
  • Another embodiment of the present invention is the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl or 5 to 6 membered heteroaryl; wherein said phenyl or 5 to 6 membered heteroaryl is substituted with S(0) 2 R 7 or C(0)NR 8 R 9 and is optionally substituted with halo or (C-i-C 4 )alkyl.
  • Yet another embodiment of the present invention is the immediately embodiment or a pharmaceutically acceptable salt thereof wherein R 3 is phenyl or a 5 to 6 membered heteroaryl selected from pyridinyl, pyrimidinyl or pyrazinyl; wherein said phenyl, pyridinyl, pyrimidinyl or pyrazinyl is substituted with S(0) 2 R 7 or C(0)NR 8 R 9 and is optionally substituted with fluoro or methyl.
  • Another embodiment of the present invention is the compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein R 2 is OR 4 ; and R 4 is isopropyl, 1-hydroxypropan-2-yl, 1-methoxypropan-2-yl, 1- hydroxybutan-2-yl, 3-hydroxybutan-2-yl, tetrahydrofuran-3-yl or 1-methyl-2- oxopyrrolidin-3-yl.
  • Another embodiment of the present invention is the compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein R 2 is C(O)NR 5 R 6 .
  • Another embodiment of the present invention is the compound of the immediately preceding embodiment or a pharmaceutically acceptable salt thereof wherein R 5 and R 6 are each methyl.
  • Another embodiment of the present invention is the compound of the immediately preceding
  • R 3 is phenyl or a 5 to 6 membered heteroaryl selected from pyridinyl, pyrimidinyl or pyrazinyl; wherein said phenyl, pyridinyl, pyrimidinyl or pyrazinyl is substituted with S(O) 2 R 7 or C(O)NR 8 R 9 and is optionally substituted with fluoro or methyl.
  • Still another embodiment of the present invention is the compound of the immediately preceding embodiment or a pharmaceutically acceptable salt thereof wherein R 7 is methyl, ethyl, isopropyl or NR 8 R 9 ; and R 8 and R 9 are independently hydrogen or methyl.
  • R 1 is hydrogen, methyl or ethyl
  • R 2 is OR 4
  • R 4 is isopropyl, 1-hydroxypropan- 2-yl, 1-methoxypropan-2-yl, 1-hydroxybutan-2-yl, 3-hydroxybutan-2-yl, tetrahydrofuran-3-yl or 1-methyl-2-oxopyrrolidin-3-yl
  • R 3 is phenyl or a 5 to 6 membered heteroaryl selected from pyridinyl, pyrimidinyl or pyrazinyl; wherein said phenyl, pyridinyl, pyrimidinyl or pyrazinyl is substituted with S(O) 2 R 7 or C(O)NR 8 R 9 and is optionally substituted with fluoro or methyl.
  • Another embodiment of the present invention is the compound of the immediately preceding embodiment or a pharmaceutically acceptable salt thereof wherein R 7 is methyl, ethyl, isopropyl or NR 8 R 9 ; and R 8 and R 9 are independently hydrogen or methyl.
  • Yet another embodiment of the present invention is the compound of the immediately preceding embodiment or a pharmaceutically acceptable salt thereof wherein R 4 is isopropyl or 1- hydroxypropan-2-yl.
  • Another embodiment of the present invention is a compound of Formula (I) selected from the group consisting of:
  • Another embodiment of the present invention is a compound of Formula (I) selected from the group consisting of:
  • compositions that comprises (1 ) a compound of the present invention, and (2) a pharmaceutically acceptable excipient, diluent, or carrier.
  • the composition comprises a therapeutically effective amount of a compound of the present invention.
  • the composition may also contain at least one additional pharmaceutical agent (described herein).
  • Preferred agents include anti-obesity agents and/or anti-diabetic agents (described herein below).
  • a mammal preferably a human
  • a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • glucokinase activators include Type II diabetes, hyperglycemia, metabolic syndrome, impaired glucose tolerance, glucosuria, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslididemia, hypertension, hyperinsulinemia, and insulin resistance syndrome.
  • Preferred diseases, disorders, or conditions include Type II diabetes, hyperglycemia, impaired glucose tolerance, obesity, and insulin resistance syndrome. More preferred are Type II diabetes, hyperglycemia, and obesity. Most preferred is Type II diabetes.
  • in yet another aspect of the present invention is a method of reducing the level of blood glucose in a mammal, preferably a human, which includes the step of administering to a mammal in need of such treatment a
  • Compounds of the present invention may be administered in combination with other pharmaceutical agents (in particular, anti-obesity and anti-diabetic agents described herein below).
  • the combination therapy may be administered as (a) a single pharmaceutical composition which comprises a compound of the present invention, at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) a second composition comprising at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier.
  • the pharmaceutical compositions may be administered
  • alkyl refers to a hydrocarbon radical of the general formula C n H 2n +i -
  • the alkane radical may be straight or branched.
  • (C-i-C6)alkyl refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, s-butyl, f-butyl, n-pentyl, 1-methylbutyl, 2- methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2- methylpentyl, and the like).
  • alkyl portion i.e., alkyl moiety
  • acyl e.g., alkanoyl
  • alkylamino dialkylamino
  • alkylsulfonyl alkylthio group
  • alkane radical or alkyl moiety may be
  • cycloalkyl refers to nonaromatic rings that are fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring. Unless specified otherwise, the carbocyclic ring is generally a 3- to 8- membered ring.
  • (C3-C7)cycloalkyl include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, norbornyl (bicyclo[2.2.1]heptyl) and the like.
  • heterocyclyl refers to the radical of nonaromatic rings that are fully hydrogenated and may exist as a single ring, bicyclic ring or a spiro ring.
  • the heterocyclic ring is a 4- to 7-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • Heterocyclyl groups include groups such as epoxy, aziridinyl, lactam rings, tetrahydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1 ,1-dioxide, and the like.
  • 5 to 6 membered heteroaryl means a radical of a 5 or 6 membered heteroaromatic ring.
  • the heteroaromatic ring can contain 1 to 4 heteroatoms selected from N, O and S.
  • 5 to 6 membered heteroaryl groups include pyrrolyl, furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.
  • Preferred 5 to 6 membered heteroaryl groups include pyridinyl, pyrimidinyl or pyrazinyl.
  • terapéuticaally effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • animal refers to humans (male or female), companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species.
  • companion animals e.g., dogs, cats and horses
  • food-source animals e.g., zoo animals, marine animals, birds and other similar animal species.
  • Edible animals refers to food-source animals such as cows, pigs, sheep and poultry.
  • substance or composition must be compatible chemically and/or
  • treating embrace both preventative, i.e., prophylactic, and palliative treatment.
  • modulated or “modulating”, or “modulate(s)", as used herein, unless otherwise indicated, refers to the activation of the activating the glucokinase enzyme with compounds of the present invention.
  • mediated refers to the treatment or prevention the particular disease, condition, or disorder, (ii) attenuation, amelioration, or elimination of one or more symptoms of the particular disease, condition, or disorder, or (iii) prevention or delay of the onset of one or more symptoms of the particular disease, condition, or disorder described herein, by activating the glucokinase enzyme via glucose binding enhancement, alleviating the inhibition of glucokinase regulatory protein, a key regulator of glucokinase activity in the liver, and/or by increasing the catalytic rate of the glucokinase enzyme (e.g., change Vmax).
  • Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wl) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic
  • reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates.
  • Examples section below For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, f-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethyleneoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxyl-protecting groups include for example, allyl, acetyl, silyl, benzyl, para-methoxybenzyl, trityl, and the like.
  • Preferred hydroxyl-protecting groups for certain of the reactions carried out include para-methoxy benzyl (PMB) or silyl groups such as ferf-butyl dimethylsilyl (TBDMS) or triisopropylsilyl (TIPS).
  • PMB para-methoxy benzyl
  • TDMS ferf-butyl dimethylsilyl
  • TIPS triisopropylsilyl
  • Scheme I outlines the general procedures one could use to provide compounds of the present invention having Formula (I).
  • An appropriately substituted benzonitrile derivative of general Formula (IV) is reacted with methyl chloroaluminum amide, CH3AICINH2, which is prepared in situ by reacting ammonium chloride and trimethyl aluminum in an appropriate solvent (see e.g. Levin, J. I.; Turos, E.; Weinreb, S.M.; Syn. Comm. 1982, 12(13), 989-993), to provide the appropriately substituted benzamidine derivative of general Formula (III).
  • ammonium chloride in an appropriate solvent such as toluene is first treated with a solution of trimethylaluminum chloride in toluene at a reduced temperature, typically around 0 °C, for a period of 15 minutes to 1 hour.
  • the benzonitrile derivative of general Formula (IV) is then added and the reaction is carried out at an elevated temperature, typically 100 °C to 110 °C, for a period of 4 to 48 hours to provide the benzamidine derivative of general Formula (III).
  • the benzamidine derivative of Formula (III) is then reacted with an appropriately substituted 1 ,3-dicarbonyl compound of general formula (II) in an appropriate solvent in the presence of a suitable base to provide the compound of Formula (I).
  • the 1 ,3-dicarbonyl compound (II) can be either an isolated appropriately substituted 3-oxopropanoate derivative or can be prepared in situ and used directly.
  • the group R as denoted in the 1 ,3-dicarbonyl compound of general formula (II) is typically a lower alkyl group such as methyl or ethyl.
  • the reaction is typically run in a suitable solvent such as ethanol and in the presence of a suitable base such as sodium ethoxide at an elevated temperature, typically at 65 °C to 85 °C for a period of 4 to 24 hours.
  • a suitable base such as sodium ethoxide
  • the reaction is typically quenched by addition of acid, such as hydrochloric acid, followed by extractive workup and chromatographic purification to provide the compound of Formula (I).
  • acid such as hydrochloric acid
  • extractive workup and chromatographic purification to provide the compound of Formula (I).
  • 1 ,3- dicarbonyl equivalent compounds can be used in place of the compound of Formula (II).
  • an appropriately substituted eneamine derivative such as a 3- (dimethylamino)acrylate derivative may be used in a similar manner.
  • Reaction Scheme II provides an alternate route to compounds of Formula (I) employing boronate intermediates.
  • the group R 2 represents either R 2 itself or a group which upon appropriate deprotection provides R 2 .
  • the protected phenol derivative of general Formula(X) can undergo borylation with bis pinacolato diboron in the presence of an appropriate catalyst such as (1 ,5-cyclooctadiene)(methoxy) iridium (I) dimer in the presence of 4,4'-di-tert-butyl-2,2'-bipyridine and an appropriate solvent such as methyl tert-butyl ether, tetrahydrofuran or dioxane, typically at an elevated temperature such as 80 °C to 110 °C thermally or under microwave irradiation for a period of 4 to 24 hours (see Hata, H; et al; Chemistry - An Asian Journal, 2007, 2(7), 849-859 or
  • the group Pg represents an appropriate protecting group such as para-methoxybenzyl
  • the group Lg represents an appropriate leaving group such as a halide, preferably chloride.
  • the borylated compound of Formula (IX) can then be reacted with an appropriately protected pyrimidine derivative of Formula (VIII) in an appropriate solvent such as aqueous acetonitrile in the presence of a catalyst such as 1 ,1'-bis(diphenylphosphino) ferrocene)-dichloropalladium (II) and a base such as sodium carbonate to provide the compound of general Formula (VII).
  • a catalyst such as 1 ,1'-bis(diphenylphosphino) ferrocene)-dichloropalladium (II) and a base such as sodium carbonate
  • the compound of Formula (VII) can then be deprotected with an appropriate deprotection reagent at the phenolic hydroxyl to provide the compound of Formula (VI).
  • an appropriate deprotection reagent at the phenolic hydroxyl to provide the compound of Formula (VI).
  • the hydroxyl protecting group is TBDMS
  • the compound of Formula (VI) can be deprotected upon treatment with a fluoride source such as tetrabutyl ammonium fluoride in an appropriate solvent such as tetrahydrofuran.
  • the compound of Formula (VI) can then be reacted with R 3 -Lg, where Lg represents an appropriate leaving group such as a halide to provide the compound of Formula (V).
  • reaction of compound (VI) with R 3 -Lg can be carried out in an appropriate solvent such as ⁇ , ⁇ -dimethylformamide in the presence of a base such as potassium carbonate at an elevated temperature, typically from 60 °C to 120 °C for 4 to 24 hours.
  • a method such as the Mitsunobu reaction can be used to install R 3 when R 3 is an alkyl group.
  • R 3 is an aryl group
  • other metal catalyzed coupling reactions can be used such as the Ullmann reaction or a palladium catalyzed coupling.
  • Reaction Scheme III provides another related route for the
  • the compound (IXa) can then be reacted with the compound of Formula (VIII) as described previously to provide the compound of Formula (Vila).
  • the phenolic hydroxyl groups in the compound of Formula (Vila) can then be deprotected using conditions appropriate for the the protecting group employed.
  • the compound of Formula (Vila) can then be reacted with R 3 -I_g to provide compound (Va) which can then be reacted with R 4 -I_g to provide the compound of formula (la).
  • Lg represents an appropriate leaving group.
  • R 3 -I_g and R 4 -Lg are typically run at an elevated temperature such as 60 °C to 120 °C in an appropriate solvent such as ⁇ , ⁇ -dimethylformamide in the presence of an appropriate base such as potassium carbonate.
  • an appropriate solvent such as ⁇ , ⁇ -dimethylformamide
  • an appropriate base such as potassium carbonate.
  • Other alternative methods for introduction of R 3 and R 4 can be employed as described for R 3 hereinabove.
  • Reaction Scheme IV provides an alternate synthetic route to compounds of Formula (la).
  • An appropriately substituted phenol of formula (XII) wherein Lg represents an appropriate leaving group such as a halide, preferably iodo is reacted with Pg-Lg wherein Pg represents an appropriate hydroxy protecting group such as triisopropylsilyl and Lg represents a leaving group such as a halide.
  • Pg represents an appropriate hydroxy protecting group such as triisopropylsilyl
  • Lg represents a leaving group such as a halide.
  • the resulting compound of Formula (XI) is then reacted with an appropriate alcohol R 3 OH to provide the compound of Formula (Xb) which can then undergoe borylation as previously described in Reaction Scheme II to provide the compound of Formula (IXb).
  • Reaction Scheme V provides the synthesis of compounds of Formula (lb) which are compounds of Formula (I) wherein the group R 2 is
  • 3-hydroxyphenyl benzoate is reacted with vinyl acetate in the presence of an appropriate catalyst such as di- -chlorobis(1 ,5- cyclooctadiene)diiridium(l) and an appropriate base such as sodium carbonate in an appropriate solvent such as toluene under an inert atmosphere.
  • the reaction is typically carried out at an elevated temperature such as 100 °C for a period of 4 to 24 hours.
  • the resulting 3-(vinyloxy) phenyl benzoate then undergoes cyclopropanation by reaction with chloroiodomethane in the presence of 1 M Diethylzinc solution in an appropriate solvent such as dichloroethane.
  • the reaction is typically started at 0 °C then allowed to gradually warm to room temperature to provide the cyclopropoxy derivative.
  • Saponification of the benzoate ester can be carried out upon treatment with a base such as sodium hydroxide in methanol.
  • Reaction Scheme VI provides the synthesis of compounds of Formula (lc) which are compounds of Formula (I) wherein the group R 2 is C(0)NR 5 R 6 .
  • the first step employs standard peptide coupling conditions using 3-hydroxy- 5-iodobenzoic acid and an appropriately substituted amine of formula
  • reaction can be run using peptide coupling reagents such as carbodiimide reagents such as EDCI in the presence of
  • hydroxybenzotriazole in an appropriate solvent such as DMF.
  • the reaction is typically carried out at 0°C to room temperature for a period of 1 to 24 hours.
  • the resulting amido substituted iodo-phenol can then be reacted with R 3 -I_g wherein Lg is an appropriate leaving group such as a halide.
  • the reaction is typically carried out in an appropriate solvent such as DMF in the presence of a base such as cesium carbonate at an elevated temperature such as 80 °C for 4 to 24 hours.
  • the resulting product can then undergoe borylation using Bis(pinacolato)diboron in the presence of potassium acetate and catalyst Pd(dppf)Cl2 in an appropriate solvent such as DMF.
  • the reaction can be initiated at reduced temperature such as 0°C then run at an elevated temperature such as 80°C for 4 to 24 hours to provide the borylated product. Further reaction as described previously for Reaction Schemes ll-IV provides the compound of Formula (lc).
  • the compounds of the present invention may be isolated and used perse, or when possible, in the form of its pharmaceutically acceptable salt.
  • salts refers to inorganic and organic salts of a compound of the present invention. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound with a suitable organic or inorganic acid or base and isolating the salt thus formed. Representative salts include the hydrobromide,
  • hydrochloride hydroiodide, sulfate, bisulfate, nitrate, acetate
  • laurylsulphonate salts and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, e.g., Berge, et al., J. Pharm. Sci.. 66, 1-19 (1977).
  • the compounds of the present invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. Unless specified otherwise, it is intended that all stereoisomeric forms of the compounds of the present invention as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of the present invention incorporates a double bond or a fused ring, both the cis- and trans- forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of a chiral HPLC column.
  • the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.
  • tautomer or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens.
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • the pyrimidonr ring of this invention may also exist in its hydroxy pyrimidine form. Both such forms are included in the compounds of Formula (I)-
  • Certain compounds of the present invention may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example, because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H,
  • Certain isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Positron emitting isotopes such as 15 0, 13 N, 11 C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate occupancy.
  • Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an
  • isotopically labeled reagent for a non-isotopically labeled reagent isotopically labeled reagent for a non-isotopically labeled reagent.
  • Polymorphs may be prepared by crystallization under various conditions, for example, using different solvents or different solvent mixtures for recrystallization;
  • crystallization at different temperatures and/or various modes of cooling, ranging from very fast to very slow cooling during crystallization.
  • Polymorphs may also be obtained by heating or melting the compound of the present invention followed by gradual or fast cooling.
  • the presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • Another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier.
  • the compounds of the present invention are useful for treating diseases, conditions and/or disorders modulated by the activation of the glucokinase enzyme; therefore, another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier.
  • compositions and processes used therein may also be used in the manufacture of a medicament for the therapeutic applications described herein.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)
  • a suitable solvent in the presence of one or more of the excipients described above.
  • the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
  • the pharmaceutical compositions also include solvates and hydrates of the compounds of Formula (I).
  • solvate refers to a molecular complex of a compound represented by Formula (I) (including
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, ethylene glycol, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • the solvates and/or hydrates preferably exist in crystalline form.
  • Other solvents may be used as intermediate solvates in the preparation of more desirable solvates, such as methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1 ,4-butyne-diol, and the like.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • the present invention further provides a method of treating diseases, conditions and/or disorders modulated by the activation of the glucokinase enzyme in an animal that includes administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier.
  • the method is particularly useful for treating diseases, conditions and/or disorders that benefit from the activation of glucokinase which include: eating disorders (e.g., binge eating disorder, anorexia, bulimia, weight loss or control and obesity), prevention of obesity and insulin resistance by glucokinase expression in skeletal muscle of transgenic mice (Otaegui, P.J., et.al., The FASEB Journal. 17; 2097-2099, (2003)); and Type II diabetes, insulin resistance syndrome, insulin
  • One aspect of the present invention is the treatment of obesity, and obesity-related disorders (e.g., overweight, weight gain, or weight
  • BMI body mass index
  • Overweight is typically defined as a BMI of 25-29.9 kg/m 2
  • obesity is typically defined as a BMI of 30 kg/m 2 .
  • Another aspect of the present invention is for the treatment or delaying the progression or onset of diabetes or diabetes-related disorders including Type 1 (insulin-dependent diabetes mellitus, also referred to as “IDDM”) and Type 2 (noninsulin-dependent diabetes mellitus, also referred to as “NIDDM”) diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, and diabetic complications (such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy, and retinopathy).
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM noninsulin-dependent diabetes mellitus
  • impaired glucose tolerance such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy, and retinopathy.
  • Metabolic syndrome includes diseases, conditions or disorders such as dyslipidemia, hypertension, insulin resistance, diabetes (e.g., Type 2 diabetes), weight gain, coronary artery disease and heart failure.
  • Metabolic Syndrome For more detailed information on Metabolic Syndrome, see, e.g., Zimmet, P.Z., et al., "The Metabolic Syndrome: Perhaps an Etiologic Mystery but Far From a Myth - Where Does the International Diabetes Federation Stand?,” Diabetes & Endocrinology, 7(2), (2005); and Alberti, K.G., et al., “The Metabolic Syndrome - A New Worldwide Definition,” Lancet, 366, 1059-62 (2005).
  • administration of the compounds of the present invention provides a statistically significant (p ⁇ 0.05) reduction in at least one
  • cardiovascular disease risk factor such as lowering of plasma leptin, C- reactive protein (CRP) and/or cholesterol, as compared to a vehicle control containing no drug.
  • CRP C- reactive protein
  • the administration of compounds of the present invention may also provide a statistically significant (p ⁇ 0.05) reduction in glucose serum levels.
  • the condition treated is impaired glucose tolerance, hyperglycemia, diabetic complications such as sugar cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic cardiomyopathy, anorexia nervosa, bulimia, cachexia, hyperuricemia, hyperinsulinemia, hypercholesterolemia,
  • hyperlipidemia hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis, vascular stenosis, solid tumors, skin cancer, melanoma, lymphoma, breast cancer, lung cancer, colorectal cancer, stomach cancer, esophageal cancer, pancreatic cancer, prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer and ovarian cancer.
  • the present invention also relates to therapeutic methods for treating the above described conditions in a mammal, including a human, wherein a compound of formula (I) of this invention is administered as part of an appropriate dosage regimen designed to obtain the benefits of the therapy.
  • a compound of formula (I) of this invention is administered as part of an appropriate dosage regimen designed to obtain the benefits of the therapy.
  • the appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the compound will depend upon the compound of formula (I) of this invention being used, the type of
  • compositions being used, the characteristics of the subject being treated and the severity of the conditions.
  • an effective dosage for the compounds of the present invention is in the range of 0.01 mg/kg/day to 30 mg/kg/day, preferably 0.01 mg/kg/day to 5 mg/kg/day of active compound in single or divided doses.
  • some variability in the general dosage range may be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular compound being administered and the like.
  • the determination of dosage ranges and optimal dosages for a particular patient is well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure. Practitioners will appreciate that "kg” refers to the weight of the patient measured in kilograms.
  • the compounds or compositions of this invention may be any organic compound or compositions of this invention.
  • Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • compositions of the present invention may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally and parenterally, (e.g.,
  • compositions of this invention may be administered intranasally, as a suppository, or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water.
  • the compounds of the present invention can be used in sustained release, controlled release, and delayed release formulations, which forms are also well known to one of ordinary skill in the art.
  • the compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases, conditions and/or disorders described herein. Therefore, methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided. Suitable
  • anti-obesity agents including appetite suppressants
  • anti-diabetic agents including appetite suppressants
  • anti-hyperglycemic agents including lipid lowering agents
  • lipid lowering agents including lipotyl-lowering agents
  • anti-hypertensive agents include anti-obesity agents (including appetite suppressants), anti-diabetic agents, anti-hyperglycemic agents, lipid lowering agents, and anti-hypertensive agents.
  • Suitable anti-diabetic agents include an acetyl-CoA carboxylase-2 (ACC-2) inhibitor, a diacylglycerol O-acyltransferase 1 (DGAT-1 ) inhibitor, a phosphodiesterase (PDE)-10 inhibitor, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an a-amylase inhibitor (e.g., tendamistat, trestatin and AL- 3688), an a-glucoside hydrolase inhibitor (e.g., acarbose), an a-glucosidase inhibitor (e.g., adiposine, camiglibose,
  • a PPAR ⁇ / ⁇ agonist e.g., CLX-0940, GW- 1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB- 219994
  • a biguanide e.g., metformin
  • GLP-11 glucagon-like peptide 1
  • PTP-1B protein tyrosine phosphatase-1 B
  • SIRT-1 inhibitor e.g., reservatrol
  • DPP- IV dipeptidyl peptidease IV
  • DPP- IV dipeptidyl peptidease IV
  • Suitable anti-obesity agents include 1 1 ⁇ -hydroxy steroid
  • dehydrogenase-1 ( ⁇ ⁇ -HSD type 1 ) inhibitors stearoyl-CoA desaturase-1 (SCD-1 ) inhibitor, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, ⁇ 3 adrenergic agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as
  • tetrahydrolipstatin i.e. orlistat
  • anorectic agents such as a bombesin agonist
  • neuropeptide-Y antagonists e.g., NPY Y5 antagonists
  • PYY3-36 including analogs thereof
  • thyromimetic agents dehydroepiandrosterone or an analog thereof, glucocorticoid agonists or antagonists, orexin
  • glucagon-like peptide-1 agonists such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH
  • ciliary neurotrophic factors such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH
  • human agouti-related protein (AGRP) inhibitors such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH
  • human agouti-related protein (AGRP) inhibitors such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH
  • human agouti-related protein (AGRP) inhibitors such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati,
  • Preferred anti-obesity agents for use in the combination aspects of the present invention include gut-selective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No.
  • gut-selective MTP inhibitors e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No.
  • CCKa agonists e.g., N-benzyl-2-[4-(1 H-indol-3-ylmethyl)-5- oxo-1 -phenyl-4,5-dihydro-2,3,6, 10b-tetraaza-benzo[e]azulen-6-yl]-N- isopropyl-acetamide described in PCT Publication No. WO 2005/1 16034 or US Publication No.
  • 5HT2c agonists e.g., lorcaserin
  • MCR4 agonist e.g., compounds described in US 6,818,658
  • lipase inhibitor e.g., Cetilistat
  • PYY3-36 as used herein "PYY 3- 3 6 " includes analogs, such as peglated PYY3-36 e.g., those described in US Publication 2006/0178501 ), opioid antagonists (e.g., naltrexone), oleoyl-estrone (CAS No.
  • compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
  • starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wl), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), Tyger Scientific (Princeton, NJ), and AstraZeneca Pharmaceuticals (London, England).
  • Chemical shifts are expressed in parts per million ( ⁇ ) relative to residual solvent as an internal reference.
  • the peak shapes are denoted as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quartet; m, multiplet; bs, broad singlet; 2s, two singlets.
  • Atmospheric pressure chemical ionization mass spectra were obtained on a FisonsTM Platform II Spectrometer (carrier gas: acetonitrile: available from Micromass Ltd, Manchester, UK).
  • Chemical ionization mass spectra were obtained on a Hewlett- PackardTM 5989 instrument (ammonia ionization, PBMS: available from Hewlett-Packard Company, Palo Alto, CA).
  • Electrospray ionization mass spectra were obtained on a WatersTM ZMD instrument (carrier gas: acetonitrile: available from Waters Corp., Milford, MA).
  • High resolution mass spectra (HRMS) were obtained on an AgilentTM Model 6210 using time of flight method.
  • the expected intensity ratio was observed (approximately 3:1 for 35 CI/ 37 CI-containing ions and 1 :1 for 79 Br/ 81 Br-containing ions) and the intensity of only the lower mass ion is given. In some cases only
  • the 5-bromo-pyrimidine-2-carbonyl chloride (55 g, 250 mmol) was dissolved in tetrahydrofuran (828 mL) and dimethylamine (2M solution in tetrahydrofuran) (373 mL, 745 mmol) was added portion-wise at room temperature. The reaction was stirred at room temperature under nitrogen for 16 hours, after which time, LCMS indicated completion. The mixture was diluted with ethyl acetate (500 mL) and washed with water (500 mL). The water layer was further extracted with dichloromethane (5x500 mL), all organics combined, and dried over magnesium sulfate.
  • the title compound was prepared by a method analogous to that described for 5-chloro-N,N-dimethylpyrazine-2-carboxamide, using azetidine
  • 3,5-difluoropicolinoyl chloride (11.2 g, 62.9 mmol) was suspended in dichloromethane (60mL) and cooled to 0°C.
  • Dimethylamine HCI salt (5.13g, 62.9mmol) was added.
  • a solution of triethylamine (27.2mL, 195mmol) in dichloromethane (20mL) was then added drop-wise over a period of 3.5 hours. Following the addition, the reaction was allowed to gradually warm to room temperature and stir for 15 hours. The reaction was diluted with saturated sodium bicarbonate and extracted four times with
  • Triisopropylchlorosilane (11.1 mL, 52.6 mmol) was added to a solution of (2R)-propane-1 ,2-diol (4000 mg, 52.6 mmol) and
  • the compound was prepared by a method analogous to that described for 1-fluoro-4-(isopropylsulfonyl)benzene as described in PCT International Patent Application Publication WO2007/31747.
  • the compound was prepared according to the procedure described in Tetrahedron Letters 2005, 3041 - 3044.
  • Step 1 A round bottom flask was charged with 3-iodophenol (10.0 g, 45.6 mmol), imidazole (4.65 g, 68.3 mmol), and anhydrous DMF (100 mL). The mixture was stirred under nitrogen at 0 °C until a homogeneous solution resulted. Triisopropylsilyl chloride (10.7 mL, 50.1 mmol) was added dropwise via syringe to the stirred solution under nitrogen at 0 °C. The ice- water bath was removed and the solution was stirred overnight under nitrogen at room temperature.
  • the reaction was poured into 500 mL water, and the aqueous was extracted with MTBE (methyl tert-butyl ether), 2 x 100 mL.
  • MTBE methyl tert-butyl ether
  • the combined extracts were washed with sodium bicarbonate solution (aq. sat.), brine, dried over sodium sulfate, filtered and concentrated to a crude oil used as is in the next step.
  • Step 2 A round bottom flask equipped with a condenser with an outlet to double manifold was charged with (3-iodophenoxy)triisopropylsilane (3.56 g, 9.84 mmol), cesium carbonate (4.81 g, 14.8 mmol), cuprous iodide (187 mg, 0.984 mmol), phenanthroline (354 mg, 1.97 mmol), then cyclobutanol (6.0 mL) as solvent and reactant. The mixture was heated to 120 °C overnight. The reaction was poured into water (150 mL) and extracted with about MTBE (100 mL). The biphasic mixture was filtered through celite to remove insolubles. The aqueous was extracted a second time with ethyl acetate. The combined extracts were washed with water once, brine once, dried over sodium sulfate, filtered and concentrated to an oil corresponding to 3-cyclobutoxyphenol.
  • Step 3 A round bottom flask was charged with the crude
  • Step 1 A sealed tube was charged with bispinacolatodiboron (1.30 g, 5.12 mmol), 4,4 , -di-tert-butyl-2,2'-bipyridine (229 mg, 0.853 mmol) and (1 ,5- cyclooctadiene) (methoxy)iridium(l) dimer (283 mg, 0.427 mmol) and the 3- cyclobutoxyphenoxy)triisopropylsilane (2.74 g, 8.53 mmol) in anhydrous 2- methyl tetrahydrofuran (4 ml_). The mixture was stirred under nitrogen at room temperature then the solution was diluted with heptanes (4 ml_) and the solution was heated under nitrogen to 115 °C over the week-end. The reaction was analysed by GC-MS. The starting material was now
  • Step 2 A round bottom flask was charged with (3-cyclobutoxy-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)triisopropylsilane (3.81 g, 8.53 mmol) in dioxane (30 ml_). Water (7 ml_) was added followed by sodium carbonate (2.71 g, 25.6 mmol), 2-chloro-4-(4-methoxybenzyloxy) pyrimidine (2.57 g, 10.2 mmol), and CI 2 Pd(dppf) (697 mg, 0.853 mmol). The mixture was heated to 105 °C under nitrogen with a reflux condenser overnight.
  • the reaction was partitioned between ethyl acetate and water.
  • the aqueous was acidified to pH 4 with HCI (aq. 1 N).
  • the aqueous was extracted a second time with ethyl acetate.
  • the combined extracts were washed with brine, dried over sodium sulfate, and concentrated to an oil.
  • the residue was purified by flash column chromatography (S1O2 (dry loading), 0%-40% ethyl acetate / heptane) to provide 2-(3-cyclobutoxy-5- (triisopropylsilyloxy)phenyl)-4-(4-methoxybenzyloxy)pyrimidine (1.16 g, 25.4%) as an oil.
  • Step 3 A round bottom flask was charged with 2-(3-cyclobutoxy-5- (triisopropylsilyloxy)phenyl)-4-(4-methoxybenzyloxy)pyrimidine (1.16 g, 2.17 mmol) and anhydrous THF (5 ml_). The solution was stirred under nitrogen at room temperature. 1 M Tetrabutylammonium fluoride (6.51 ml_, 6.51 mmol) was added via syringe, and the yellow solution was stirred under nitrogen at room temperature overnight. The reaction was diluted with ethyl acetate and sodium bicarbonate solution (sat.
  • the mixture was diluted with methanol and dichloromethane, stirred for a few minutes and filtered through a short pad of silica gel.
  • the silica gel pad was washed with methanol/dichloromethane.
  • the filtrate was concentrated, leading to the title compound 3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)benzamidine.
  • the crude compound was used without further purification.
  • Step 1 To a vial was added 3-hydroxy-5-isopropoxybenzonitrile (200 mg, 1.13 mmol), N,N-dimethylformamide (1.5 ml_), cesium carbonate (588 mg, 1.81 mmol) and 1-(methylsulfonyl)pyrrolidin-3-yl methanesulfonate (330 mg, 1.36 mmol) at room temperature. The reaction was heated at 100 °C for 2.5 h. The mixture was cooled to room temperature and diluted with ethyl acetate and water. The insoluble solid was filtered, collected and dried under vacuo. NMR showed it was the desired product. The organic layer was separated from the filtrate and washed with water three times, dried, filtered and concentrated.
  • Step 2 To a solution of ammonium chloride (187 mg, 3.50 mmol) in toluene (1 mL) was added a solution of trimethylaluminum (1.17 mL, 2 M in toluene, 2.33 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and the substrate 3-isopropoxy-5-(1-(methylsulfonyl)pyrrolidin-3- yloxy)benzonitrile (189 mg, 0.583 mmol) was added. The mixture was heated at 105°C over the weekend. LCMS of an aliquot indicated the desired product was generated cleanly.
  • Step 1 A round bottom flask was charged with the 3-hydroxyphenyl benzoate (3.03 g, 14.1 mmol), potassium carbonate (3.91 g, 28.3 mmol), dimethylacetamide (28 mL), the cyclopentyl iodide (1.96 mL, 17.0 mmol). The reaction was heated at 75 °C under nitrogen overnight. The reaction was poured into water (100 mL) and extracted with MTBE (2 X 75 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide 3-(cyclopentyloxy)phenyl benzoate (4.20g, 105%) as a colorless oil.
  • Step 2 A round bottom flask was charged with 3-(cyclopentyloxy) phenyl benzoate (4.00 g, 14.2 mmol) dissolved in methanol (100 ml_). To this, was added water (0.5 ml_) and solid KOH (1.87 g, 28.3 mmol). The solution was stirred under nitrogen overnight at room temperature. The reaction was concentrated to remove most of the methanol. The remaining liquid was diluted with some water and acidified to pH 3 with 1N HCI (aq.). The aqueous was extracted with MTBE (2 X 100 ml_).
  • Step 3 A round bottom flask was charged with the 3-(cyclopentyloxy) phenol (2.29 g, 12.8 mmol), DMF (30 ml_), imidazole (2.18 g, 32.1 mmol), and TIPS-CI (5.49 ml_, 25.7 mmol). The reaction was stirred under nitrogen over the weekend. The reaction was poured into water (250 ml_), and the aqueous was extracted with MTBE (2 X 100 ml_). The combined extracts were washed with 1 N sodium hydroxide (aq.), water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • 1 N sodium hydroxide aq.
  • the oil was dissolved in a minimum of 20% ethyl acetate / heptane and filtered through a pad of 250 g. of silica gel eluting with 20% ethyl acetate / heptane to provide (3-(cyclopentyloxy)phenoxy)triisopropylsilane (1.75 g, 40.8%) as a pale yellow oil.
  • Step 1 Sodium hydride (230 mg, 5.74 mmol, 60% dispersion) was added to a dried flask containing 3,5-dihydroxybenzonitrile (1 g, 7.40 mmol) and N,N-dimethylformamide (10 ml_) at 0 °C. The mixture was let warmed to room temperature and stirred for 5 minutes. 1-fluoro-4-(methylsulfonyl) benzene (900 mg, 5.17 mmol) was added and the reaction was heated at 65 °C over weekend. TLC and LCMS showed only a little product.
  • Step 2 To the solution of 3-hydroxy-5-(4-(methylsulfonyl)phenoxy) benzonitrile (150 mg, 0.518 mmol), (R)-1-methoxypropan-2-ol (93.4 mg, 1.04 mmol) and triphenylphosphine (408 mg, 1.55 mmol) in tetrahydrofuran (3 ml_) was added diisopropyl azodicarboxylate (0.205 ml_, 1.04 mmol). The mixture was stirred at room temperature overnight.
  • Tetrabutylammonium fluoride (10.5 mL, 1 M in THF, 10.5 mmol mmol) was added. The mixture was stirred at room temperature for 1 h. TLC indicated the starting material was consumed. The mixture was diluted with ethyl acetate and washed with ammonium chloride (saturated aqueous). The aqueous layer was back-extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated.
  • the title compound was prepared by a method analogous to that described for 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-((S)-1 -(tert- butyldimethylsilyloxy)propan-2-yloxy)phenol, using (R)-1 -(triisopropylsilyloxy) propan-2-ol. Purification by column chromatography didn't lead to the pure compound, which was used without further purification and characterization.
  • Step 1 A sealed tube is charged with fert-butyl(3-isopropoxy-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (3.00 g, 5.90 mmol), 2-chloro-4-(4-methoxybenzyloxy)pyrimidine (1.62 g, 6.48 mmol), Na 2 C0 3 (1.25 g, 11.8 mmol) and Pd(dppf)CI 2 (345 mg, 0.471 mmol) and purged with N 2 (g).
  • Step 2 The crude mixture was dissolved in THF (10mL) and TBAF solution (1 N / THF; 6.41 mL) was added and reaction stirred for 1.5 hours at room temperature.
  • the reaction mixture was diluted with NH 4 CI (sat.aq.) (20 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with brine (20 ml_), dried over Na 2 S0 4 filtered and concentrated under reduced pressure.
  • the flask containing the crude fert-butyl(3-isopropoxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane 1000 mg, 2.548 mmol
  • 4-(4-methoxybenzyloxy-2-chloro-5-methylpyrimidine 674 mg, 2.55 mmol, >95% purity
  • sodium carbonate 540 mg, 5.10 mmol
  • dichloro- ((bis-diphenylphosphino)ferrocenyl)palladium (II) 136 mg, 0.186 mmol
  • a microwave sealed tube was charged with bispinacolatodiboron (480 mg, 1.87 mmol), di- -methoxybis(1 ,5-cyclooctadiene)diiridium (I) (17.5 mg, 0.0265 mmol), 4,4'-di-tert-butyl-2,2 , -bipyridine (14.4 mg, 0.0535 mmol) and methylfertbutylether (1.5 ml_). The mixture was stirred for 10 minutes at room temperature or until a deep red solution is observed.
  • Step 1 A round bottom flask was charged with (S)-(3-sec-butoxy-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)(tert-butyl)
  • Step 2 The crude mixture was dissolved in THF (5ml) and then, TBAF 1 M / THF (3.4 ml_) was added in one portion. Reaction stirred for 1 hour at room temperature. NH 4 CI (sat.aq.) added and the reaction mixture was extracted with EtOAc (80 ml_ x 2). The combined organic layers were washed with brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • PEAK 2 R T : 4.73 min.
  • PEAK 2 will be named (+)-3-(4-(4-methoxybenzyloxy)-5- methylpyrimidin-2-yl)-5-(tetrahydrofuran-3-yloxy)phenol.
  • Step 1 (Vinylation): To a mixture of di- -chlorobis(1 ,5- cyclooctadiene)diiridium(l) (170 mg, 1 mol%) and sodium carbonate (1.48 g, 14.0 mmol) in toluene (23 mL), 3-hydroxyphenyl benzoate (5.00 g, 23.3 mmol) and vinyl acetate (4.31 mL, 46.7 mmol) were added, followed by stirring at 100 °C in an atmosphere of nitrogen gas overnight. Reaction cooled down to room temperature. The reaction mixture was concentrated under reduced pressure followed by adsorption over silica gel.
  • Step 2 (Cvclopropanation): 1 M Diethylzinc solution (16.6 mL, 16.6 mmol) was added to a mixture of 3-(vinyloxy)phenyl benzoate (2.00 g, 8.32 mmol), chloroiodomethane (2.42 mL, 33.3 mmol) and dichloroethane (28 mL) over 60 min. at 0 °C. Stirred overnight going slowly to room
  • Step 3 (Saponification): In a round bottom flask containing the 3- cyclopropoxyphenyl benzoate (1.48 g, 5.82 mmol), THF (12 mL) and methanol (12 mL) added. At room temperature, 1 N (aq.) sodium hydroxide (6.4 mL) is then added in one portion and the resulting mixture stirred for 1.5 hours. Reaction mixture acidified to pH ⁇ 1 with 1 N HCI (aq.). Extraction of the reaction mixture with dichloromethane (three times). Combined organic layers washed with brine, dried over sodium sulfate, filtered and
  • Step 4 (Phenol protection): In a round bottom flask at room
  • Step 1 A round bottom flask was charged with 3-hydroxybenzoic acid (2.00 g, 14.5 mmol), HATU (2-(1 H-7-Azabenzotriazol-1-yl)-1 , 1 ,3,3- tetramethyl uranium hexafluorophosphate methanaminium) (8.34 g, 21.7 mmol), diisopropylethyl amine (5.61 g, 43.4 mmol), methylamine (2M) / THF (21.7 ml_, 43.4 mmol) and N,N-dimethylformamide (48.3 ml_). The reaction mixture was stirred at room temperature for 3 hours. Ethyl Acetate added to the mixture (600 ml_) and washed with 1 N HCI/water (1 :1 ) (100 ml_).
  • Step 2 A round bottom flask was charged with the crude mixture from step 1 (2.39g, 14.5mmol; see above), imidazole (2.46 g, 36.2 mmol), tert- butyl dimethylsilyl chloride (TBDMS-CI, 4.36 g, 28.9 mmol) and
  • a microwave sealed tube was charged with bispinacolatodiboron (880 mg, 3.43 mmol), di- -methoxybis(1 ,5-cyclooctadiene)diiridium (I) (32.5 mg, 0.049 mmol), 4,4'-di-tert-butyl-2,2 , -bipyridine (26.3 mg, 0.098 mmol) and methyl fert-butyl ether (2.0 mL). The mixture was stirred for 10 minutes at room temperature or until a deep red solution is observed.
  • Precipitated white solid (triphenylphosphine oxide) was removed by vacuum filtration and rinsed with heptane. The filtrate was evaporated to give 14.6 g of an oil which was preadsorbed on to S1O2 gel. The residue was purified by flash column chromatography (S1O2, 10%-50% ethyl acetate / heptane) to provide (S)-3-(1-methoxy-1-oxopropan-2-yloxy)phenyl benzoate (6.81 g, 91%) as a thick colorless oil.
  • a microwave sealed tube was charged with bispinacolatodiboron (453mg, 1.76mmol di- -methoxybis(1 ,5-cyclooctadiene)diiridium (I) (16.6 mg, 0.025 mmol), 4,4'-di-tert-butyl-2,2 , -bipyridine (13.4 mg, 0.050 mmol) and methyl fert-butyl ether (1.5 ml_). The mixture was stirred for 10 minutes at room temperature or until a deep red solution is observed.
  • a microwave sealed tube was charged with bispinacolatodiboron (157 mg, 0.620 mmol) di- -methoxybis(1 ,5-cyclooctadiene)diiridium (I) (6.0 mg, 0.009 mmol), 4,4'-di-tert-butyl-2,2 , -bipyridine (4.80 mg, 0.018 mmol) and methyl f-butylether (0.5 mL). The mixture was stirred for 10 minutes at room temperature or until a deep red solution is observed.
  • the reaction mixture was poured into ammonium chloride solution (sat. aq.; 250 mL) and the aqueous was extracted with MTBE (2 x 100 mL). The aqueous layer was extracted a third time with 50 mL EtOAc. The combined extracts were washed with an equal volume of water, brine, dried over sodium sulfate, and concentrated to a dark colored oil. The residue was purified by flash column chromatography (Si0 2 , 0%-40% ethyl acetate / heptane) to provide 1 -isopropoxy-3-(4- (methylsulfonyl)phenoxy) benzene as a pale colored oil (2.78 g, 96%).
  • the regioisomers were purified by flash column chromatography (Si0 2 , isocratic 2:9:9, ethyl acetate:toluene:heptane) to provide 2-chloro-5-isopropyl-4-(4-methoxybenzyloxy)pyrimidine (933 mg, 61%).
  • a microwave tube was charged with bis(pinacolato)diboron (389 mg, 1.52 mmol), (1 ,5-cyclooctadiene)(methoxy)iridium(l) dimer (14.6 mg, 0.022 mmol), and 4 ,4'-d i-iert-buty I-2 ,2'-d i py ridy I (11.5 mg, 0.043 mmol).
  • the mixture was stirred for 10 minutes in methyl-ferf-butyl ether at room temperature until a deep red solution was observed.
  • Tetrabutyl ammonium fluoride (8.0 mL, 1 M in tetrahydrofuran, 8.0 mmol) was added to the solution of the crude 2-(3,5-bis(tert-butyldimethyl silyloxy)phenyl)-4-(4-methoxy benzyloxy)-5-methylpyrimidine (5.229 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 90 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous ammonium chloride solution. The aqueous layer was back- extracted twice with EtOAc (50 ml_).
  • a sealable tube was charged with 5-(4-(4-methoxybenzyloxy)-5- methylpyrimidin-2-yl)benzene-1 ,3-diol (350 mg, 1.03 mmol), potassium carbonate (286 mg, 2.07 mmol), (4-fluorophenyl)-methylsulfone (234 mg, 1.34 mmol) and dimethylformamide (5.2 ml_). Tube sealed and reaction heated at 120°C overnight. Reaction cooled down to room temperature. Ethyl Acetate was added and the mixture washed with HCI 1 N (aq.).
  • Example 1 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6-oxo- 1 ,6-dihvdropyrimidine-5-carbonitrile
  • Example 4 is representative of the general method of pyrimidinone preparation from amidines with 1 ,3-dicarbonyl equivalent prepared in situ.
  • sodium hydride 91.8 mg, 60% in oil, 2.29 mmol
  • ethyl butyrate 0.152 mL, 1.15 mmol
  • ethyl formate 0.092 mL, 1.15 mmol
  • the mixture was stirred at room temperature for 24 hours.
  • the solvent was evaporated under reduced pressure.
  • 3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)benzamidine 100 mg, 0.287 mmol
  • ethanol ethanol
  • the suspension was heated at 75 °C overnight. Water was added followed by 3-4 drops of 37% hydrochloric acid to adjust pH to about 2.
  • the mixture was extracted with EtOAc.
  • the organic layer was dried over sodium sulfate and
  • the title compound (56 mg, 45%) was prepared by a method analogous to that described for Example 4 using ethyl chloroacetate (0.183 ml_, 1.72 mmol) and ethyl formate (0.138 ml_, 1.72 mmol).
  • the title compound (42 mg, 17%) was prepared by a method analogous to that described for Example 4 using ethyl-2-methoxyacetate (0.269 mL, 2.29 mmol) and ethyl formate (0.184 mL, 2.29 mmol).
  • Example 8 Ethyl 2-(2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl) - 6-oxo- 1 , 6-d i h yd ro p yri m id i n-5-yl )acetate
  • the title compound (32 mg, 23%) was prepared by a method analogous to that described for Example 4 using diethyl succinate (0.385 ml_, 2.29 mmol) and ethyl formate (0.184 ml_, 2.29 mmol).
  • the title compound was prepared by a method analogous to that described for Example 14, using 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5- ((S)-1 -(triisopropylsilyloxy)propan-2-yloxy)phenol and 4-fluoro-A/,A/- dimethylbenzenesulfonamide.
  • reaction mixture transfered with ethyl acetate into a separately funnel containing an HCI solution (1 N, aq.) (10 mL) ca. pH 2-3 and extracted with ethyl acetate (3 X 20 mL). Combined organic layers were washed with water (1 X 10mL), brine (1 X 10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column
  • Example 22 3-fluoro-5-(3-isopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)-N,N-dimethylpicolinamide
  • Example 25 5-(3-isopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)- N.N-dimethylpyrazine-2-carboxamide
  • Example 26 4-(3-isopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)benzenesulfonamide
  • Example 27 4-(3-isopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)-N- methylbenzenesulfonamide
  • Example 28 4-(3-isopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)-
  • Example 32 4-(3-isopropoxy-5-(5-methyl-6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)-N-methylbenzenesulfonamide
  • Step 1 A sealed tube was charged with 3-hydroxy-5-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)-N,N-dimethylbenzamide (30 mg, 0.076 mmol), (4-fluorophenyl)-methylsulfone (19.9 mg, 0.114 mmol), potassium carbonate (21.0 mg, 0.152 mmol) and dimethylformamide (0.4 ml_). The tube was sealed and the reaction stirred at 120 °C overnight. EtOAc added to the reaction mixture and was washed once with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford the crude material. MS (M+1 ): 548.4.
  • Step 2 The crude material from Step 1 was dissolved in
  • Step 1 A sealed tube was charged with K 2 C0 3 (132 mg, 0.955 mmol),(4-fluorophenyl)-methylsulfone (99.8 mg, 0.573 mmol), (S)-3-(1-(fert- butyldimethylsilyloxy)propan-2-yloxy)-5-(4-(4-methoxybenzyloxy)-5- methylpyrimidin-2-yl)phenol (195 mg, 0.382 mmol) and DMF (1.9 mL). The reaction mixture was stirred at 120°C overnight. Reaction completed (TBS totally deprotects because of the fluoride ion formed during the process).
  • Step 2 A 20 dram vial was charged with (S)-2-(3-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)-5-(4-(methylsulfonyl)phenoxy) phenoxy)propan-1-ol (190 mg, 0.345 mmol) and dissolved in 0.5M
  • the title compound was prepared by a method analogous to that described for Example 40, using 3,5-difluoro-N,N-dimethylpicolinamide and (S)-3-(1 -(tert-butyldimethylsilyloxy) propan-2-yloxy)-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol.
  • the final deprotection (PMB removal) was done with TFA in dichloromethane at room temperature.
  • the title compound was prepared by a method analogous to that described for Example 40, using 1-fluoro-4-(isopropylsulfonyl)benzene and (S)-3-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol.
  • the final deprotection was done with TFA in dichloromethane at room temperature. MS (M+1): 445.1.
  • the title compound was prepared by a method analogous to that described for Example 40, using 1-(cyclopropylsulfonyl)-4-fluorobenzene and (S)-3-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol.
  • the final deprotection was done with TFA in dichloromethane at room temperature. MS (M+1): 443.1.
  • the title compound was prepared by a method analogous to that described for Example 40, using tert-butyl 4-fluorophenylsulfonyl(methyl) carbamate and (S)-3-(1-(tert-butyldimethyl silyloxy)propan-2-yloxy)-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol.
  • the final deprotection was done with addition of TFA in the reaction mixture of step 1.
  • the title compound was prepared by a method analogous to that described for Example 40, using 4-fluoro-2-methyl-1-(methylsulfonyl) benzene and (S)-3-(1-(ferf-butyldimethylsilyloxy) propan-2-yloxy)-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol.
  • the final deprotection was done with addition of TFA in the reaction mixture of step 1.
  • Step 1 1-isopropoxy-3-(4-(methylsulfonyl)phenoxy)benzene (2.78 g,
  • Step 2 The crude 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy) phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane from step 1 (614 mg, 1.42 mmol) was charged into a round bottom flask. 2-chloro-5-isopropyl-4-(4- methoxy-benzyloxy)-pyrimidine (416 mg, 1.42 mmol), dichloro[1 ,2- bisdiphenylphosphino)ferrocene]palladium (II) (116 mg, 0.142 mmol) and sodium carbonate (452 mg, 4.26 mmol) were added.
  • a reflux condenser with outlet to a double manifold (nitrogen/vacuum) was attached and the apparatus was evacuated and filled with nitrogen 3 times.
  • Dioxane (5 ml_) and water (1 mL) were added and the mixture was refluxed under nitrogen for about 18 hours overnight.
  • Analysis by LCMS indicated that the reaction was complete.
  • the reaction was diluted with water, and the aqueous was extracted with EtOAc (2 x 75 mL). The combined extracts were washed with an equal volume of brine, dried over sodium sulfate and concentrated to an oily residue.
  • Step 3 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-5- isopropyl-4-(4-methoxybenzyloxy)pyrimidine (90 mg, 0.16 mmol) was charged into a round bottom flask and dissolved in dichloromethane (3 mL). Trifluoroacetic acid (60 ⁇ , 0.80 mmol) was added and the homogeneous solution was stirred overnight at room temperature. The reaction was diluted with MTBE (60 mL), transferred into a separatory funnel and washed with sodium bicarbonate solution (sat. aq.; 2 x 50mL).
  • LCMS indicated the methylation had proceeded about 65%, so an additional 5 mg of sodium hydride and another 5 ⁇ _ of methyl iodide were added and the mixture heated to 55°C for an hour, then cooled to room temperature and partitioned between saturated aqueous ammonium chloride solution and diethyl ether. The aqueous layer was extracted with a second portion of diethyl ether.
  • Example 60 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5-(tetrahvdro-2H- pyran-4-yloxy)phenyl)pyrimidin-4(3H)-one
  • silica gel was added to the reaction mixture and solvents are concentrated under reduced pressure.
  • the silica gel containing the crude material was loaded directly onto a silica gel column. This was flash chromatographed eluting with a 0-10% gradient of methanol in dichloromethane to afford 4-(4-methoxybenzyloxy)-5-methyl- 2-(3-(4-(methylsulfonyl)phenoxy)-5-(tetrahydro-2H-pyran-4- yloxy)phenyl)pyrimidine.
  • the final deprotection (PMB removal) was done with TFA in dichloromethane at room temperature until complete
  • Step 1 In an oven dried microwave tube, bispinacolatodiboron (175 mg, 0.683 mmol), 4,4'-di-tert-butyl-2,2 , -bipyridine (5.4 mg, 0.02 mmol) and (1 ,5-cyclooctadiene) (methoxy)iridium(l) dimer (6.6 mg, 0.01 mmol) dissolved in MTBE (0.5 ml_) and stirred ( ⁇ 10min.) until a deep red color is observed. 2-isopropoxy-6-(4-(methylsulfonyl)phenoxy)pyridine is then dissolved in MTBE (0.6 ml_) and transfered to the previous mixture in one portion.
  • Step 2 In a sealed tube, 2-isopropoxy-6-(4-(methylsulfonyl)phenoxy)- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (175 mg, 0.40 mmol), 2-chloro-5-ethyl-4-(4-methoxybenzyloxy)pyrimidine (135 mg, 0.48 mmol), Na2C0 3 (1.2 ml_; 1 M in water) and acetonitrile (2.0 ml_) was purged with nitrogen for 10 minutes. [1 ,1'-bis(diphenylphosphino)ferrocene]
  • Step 3 In a 20 dram vial, 5-ethyl-2-(2-isopropoxy-6-(4- (methylsulfonyl)phenoxy)pyridin-4-yl)-4-(4-methoxybenzyloxy)pyrimidine (35 mg) dissolved in dioxane (1.3 mL) and 4N HCI / dioxane (1 mL) added in one portion. 0.3 mL of methanol added to the mixture and reaction stirred at room temperature overnight. Reaction completed following LCMS. Volatiles are removed under reduced pressure.
  • Example 62 (S)-5-(3-(1-methoxypropan-2-yloxy)-5-(6-oxo-1 ,6- dihvdropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide
  • the title compound was prepared by a method analogous to that described for Example 37, using 1-(cyclopropylsulfonyl)-4-fluorobenzene. Purification by flash column chromatography (S1O2 , 0%-20% methanol / ethyl acetate) to provide 3-(4-(cyclopropylsulfonyl)phenoxy)-N,N-dimethyl-5- (5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl)benzamide (181 mg, 74%) as a white solid. MS (M+1): 454.1.
  • Example 68 (single enantiomer) 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)- 5-(tetrahvdrofuran-3-yloxy)phenyl)pyrimidin-4(3H)-one
  • Example 70 N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)-5-
  • Example 72 N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)-5-
  • Example 78 N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)-5-(pentan-
  • Example 80 5-(3-cvclopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)- N , N-d i methyl pyri m id i ne-2-carboxam ide
  • Example 85 Ethyl 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6- oxo-1 ,6-d i h yd ropyri m id i ne-5-carboxylate
  • Representative compounds of this invention were evaluated in biochemical assays (Assay 1 or Assay 2) to characterize their glucokinase activation properties.
  • the recombinant human glucokinase protein utilized in both assays was prepared and purified as described below.
  • Beta Cell Glucokinase His-Tag Growth and Induction Conditions
  • BL21 (DE3) cells (Invitrogen Corporation, Carlsbad, CA) containing pBCGK (C or N His) vector were grown at 37°C (in 2XYT) until the OD600 was between 0.6-1.0. Expression was induced by addition of
  • Beta Cell Glucokinase His-Tag Purification Conditions A Ni-NTA (Quigan, Germantown, MD) column (15-50 mL) was used for separation. Two buffers were prepared, 1 ) a lysis/nickel equilibration and wash buffer and 2) a nickel elution buffer.
  • the lysis/equilibration/wash buffer was prepared as such: 25 mM HEPES buffer at pH 7.5, 250 mM NaCI, 20 mM imidazole, and 14 mM ⁇ -mercaptoethanol as final concentrations.
  • the elution buffer was prepared as such: 25 mM HEPES at pH 7.5, 250 mM NaCI, 400 mM imidazole, and 14 mM ⁇ -mercaptoethanol as final concentrations.
  • the buffers were each filtered with a 0.22 ⁇ filter prior to use.
  • the cell pellet (1 L culture) was resuspended in 300 mL of the lysis/equilibration buffer.
  • the cells were then lysed (3 times) with a Microfluidics Model 1 10Y microfluidizer (Microfluidics Corporation, Newton, MA).
  • the slurry was centrifuged with a Beckman Coulter Model LE-80K ultracentrifuge (Beckman Coulter, Fullerton, CA) at 40,000 rpm for 45 minutes at 4°C.
  • the supernatant was transferred to a chilled flask. A volume of 20 ⁇ was saved for gel analysis.
  • a Pharmacia AKTA (GMI, Inc., Ramsey, MN) purification system was used for separation.
  • the prime lines were purged with lysis/equilibration buffer.
  • the Ni-NTA column was equilibrated with 200 mL of the lysis/equilibration buffer at a flow rate of 5 mL/minute. The supernantant was loaded over the column at 4 mlJminute and the flow-through was collected in a flask. The unbound proteins were washed with lysis/equilibration buffer at a flow rate of 5 mlJminute until the ultraviolet reaches baseline. The protein was then eluted from the column with the imidazole elution buffer via imidazole gradient 20 mM to 400 mM over 320 mL. The column was then stripped of any additional protein with 80 mL of the elution buffer.
  • the elution fractions were each 8 mL, for a total yield of 50 samples. Fractions were analyzed by sodium dodecyl sulfate polyacrylamide (SDS-PAGE) and the fractions containing protein of interest were pooled and concentrated to 10 mL using ultrafiltration cell with a 10,000 molecular weight cut-off (MWCO) Millipore membrane (Sigma-Aldrich, St. Louis, MO) under nitrogen gas (60 psi).
  • MWCO molecular weight cut-off Millipore membrane
  • Protein was further purified by size exclusion chromatography (SEC) using a Sedex 75 evaporative light scattering detector (320 ml_) (Amersham
  • Assay 1 Evaluating activator potency and maximum activation at 5 mM glucose
  • glucokinase (beta cell isoform) was His-tagged at the N- terminus and purified by a Ni column followed by size exclusion
  • Calbiochem (San Diego, CA) and other reagents were purchased from Sigma-Aldrich (St. Louis, MO).
  • the buffer conditions used in this assay were as follows: 50 mM HEPES, 5 mM glucose, 2.5 mM ATP, 3.5 mM MgCI 2 , 0.7 mM NADH, 2 mM dithiothreitol, 1 unit/mL pyruvate kinase/lactate dehydrogenase (PK/LDH), 0.2 mM phosphoenolpyruvate, and 25 mM KCI.
  • the buffer pH was 7.1.
  • the test compound in dimethylsulfoxide solution was added to the buffer and mixed by a plate shaker for 7.5 minutes. The final concentration of
  • dimethylsulfoxide introduced into the assay was 0.25%.
  • Glucokinase was added to the buffer mixture to initiate the reaction in the presence and absence of compound.
  • the reaction was monitored by absorbance at 340 nm due to the depletion of NADH.
  • the initial reaction velocity was measured by the slope of a linear time course of 0-300 seconds.
  • the percentage of maximum activation was calculated by the following equation:
  • Va/Vo 1 + (%max activation/100)/(1 + ECso/compound
  • Assay 2 Evaluating activator potency in a matrix assay at multiple glucose concentrations
  • the potency of a glucokinase activator and its modulation of the glucokinase enzyme's Km (for glucose) and Vmax can be characterized using a matrix assay wherein multiple combinations of activator and glucose concentrations are simultaneously evaluated.
  • Km for glucose
  • Vmax the potency of a glucokinase activator and its modulation of the glucokinase enzyme's Km (for glucose) and Vmax
  • the glucose titration is made at 2 times (2X) the final concentration.
  • the final glucose concentrations used are: 0 mM, 0.05 mM, 0.1 mM, 0.3 mM, 0.625 mM, 1.25 mM, 2.5 mM, 5 mM, 7.5 mm, 10 mM, 15 mM, 20 mM, 40 mM, 60 mM, 80 mM and 100 mm. Plates are stored at 4°C.
  • the glucokinase activator compounds of Formula (I) of the current invention are evaluated at 22 different compound concentrations.
  • the final compound concentrations that are employed are: 0.001 M, 0.0005 M, 0.00025 M, 0.000125 M,
  • the assay reagents and final concentrations of the reagents are as follows (reagent, final concentration): GK, 10 nM; Buffer, 1X; ddH 2 0; DTT, 2 mM; PEP, 0.8 mM; NADH, 0.7 mM; ATP, 2.5 mM; and PK/LDH, 8 U/mL.
  • the DTT is stored as a frozen 1 M stock.
  • PEP, NADH, and ATP are weighed out as powders.
  • the assay reagents are made up fresh daily, and in two separate components.
  • the enzyme mix and the substrate mix is outlined as follows.
  • the enzyme mix consists of GK, Buffer (5X), water and DTT.
  • the substrate mix consists of Buffer (5X), water, DTT, PEP, NADH, ATP and PK/LDH. Each mix is made up at 4 times the concentration of the final concentration used.
  • the assay volume is 40 ⁇ _ per well: 20 ⁇ _ from glucose, 10 ⁇ _ from enzyme, and 10 ⁇ _ from substrate.
  • the final assay plates have 1 ⁇ _ of compound solution or control in DMSO. When running multiple plates simultaneously on multiple readers, read triplicates on the same reader to decrease variability.
  • the procedure for carrying out the assay is as follows: Add 20 ⁇ _ of glucose to each well and centrifuge (1000 rpm, 10 seconds). Add 10 ⁇ _ of the enzyme mix. Shake plates on plate shaker (900 revolutions per minute) at room temperature (22°C) for 7 minutes to mix in the compound. Add 10 ⁇ _ of substrate mix. Shake briefly at room temperature to mix, about 10 seconds and centrifuge to remove bubbles.
  • the assay plates are read on a SpectraMax reader (Molecular Devices) using SoftMaxPro 4.8 software.
  • the reader should be configured to read absorbance at wavelength 340 nm, in kinetic mode, read every 30 seconds for 10 minutes. Automix and blanking are off and autocalibrate is set to once.
  • Biological Activity Table EC50 of representative examples determined by the method of Assay 1 or 2.

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Abstract

O N NH R3 R2 O R1 168 ABSTRACT The present invention provides a 2-(3,5-disubstitutedphenyl)pyrimidin- 4(3H)-one compound of Formula (I) 5 (I) or a pharmaceutically acceptable salt thereof wherein R 1, R2 and R3 are as defined herein. The compounds of Formula (I) have been found to act as glucokinase activators. Consequently, the compounds of Formula (I) and 10 the pharmaceutical compositions thereof are useful for the treatment of diseases, disorders, or conditions mediated by glucokinase.

Description

2-(3,5-DISUBSTITUTEDPHENYL)PYRIMIDIN-4(3H)-ONE DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to 2-(3,5-disubstitutedphenyl)pyrimidin- 4(3H)-one derivatives and the uses thereof as glucokinase activators.
BACKGROUND
Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood glucose levels. Two major forms of diabetes are recognized. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin. Type II diabetes, or non-insulin dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues and cells to respond appropriately to insulin. Aggressive control of NIDDM with medication is essential; otherwise it can progress into IDDM.
A promising area of diabetes research involves the use of small molecule allosteric activators of the glucokinase (GK) enzyme to lower blood glucose and normalize glucose stimulated insulin secretion Glucokinase is responsible for the conversion of glucose to glucose-6-phosphate (G-6-P), and it functions as a key regulator of glucose homeostasis. In the liver, GK regulates hepatic glucose utilization and output whereas in the pancreas it functions as a glucostat establishing the threshold for β-cell glucose- stimulated insulin secretion. Glucokinase is also found in glucose sensing neurons of the ventromedial hypothalamus where it regulates the counter regulatory response (CRR) to hypoglycemia. Finally, glucokinase is reportedly expressed in the endocrine K and L cells where is may help regulate incretin release.
Therapeutically, it is anticipated that activation of glucokinase would be an effective strategy for lowering blood glucose by up regulating hepatic glucose utilization, down regulating hepatic glucose output and normalizing glucose stimulated insulin secretion. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome,
hyperinsulinemia, hypertension, and obesity.
Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., "New drug targets for Type 2 diabetes and the metabolic syndrome" Nature 414; 821-827, (2001 )): (A) Insulin
secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g.,
pioglitazone, rosiglitazone) act on a specific receptor (peroxisome
proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents.
Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are
independent from the actions of insulin; (d) it would desirably be
metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.
Substituted acylaminoheteroaryls and several phenyl substited heteroaryls, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication No's. WO2006125958, WO2007028135, WO2007031739, WO2007/043638, WO2007/043638, WO2007061923 and WO2007/117995 and JP2007063225 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.
SUMMARY OF THE INVENTION
The present invention provides compounds of Formula (I) that act as glucokinase mediators, in particular, glucokinase activators; therefore, may be used in the treatment of diseases mediated by such activation (e.g., diseases related to Type 2 diabetes, and diabetes-related and obesity- related co-morbidities). A first aspect of the present invention are
compounds of Formula (I)
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein R1 is H, (Ci-C6)alkyl, (Ci-C6)alkoxy, halo, C02H, C02(Ci-C6)alkyl or cyano; wherein said (C~i-C-6)alkyl and (Ci-Ce)alkoxy are optionally substituted with one to three halo or one (C-i-C4)alkoxy, hydroxy, C02H or C02(Ci-C4)alkyl; R2 is OR4 or C(0)NR5R6;
R3 is phenyl, 3 to 7 membered heterocyclyl or 5 to 6 membered heteroaryl; wherein said phenyl, 3 to 7 membered heterocyclyl or 5 to 6 membered heteroaryl are optionally substituted with one to three S(0)2R7, C(0)NR8R9, halo, (Ci-C4)alkyl, or (Ci-C4)alkoxy;
R4 is (C-i-C6)alkyl, (C3-C7)cycloalkyl or 3 to 7 membered heterocyclyl;
wherein said (C~i-C-6)alkyl or (C3-C7)cycloalkyl is optionally substituted with one to two hydroxy, (C-i-C4)alkoxy or (C3-C7)cycloalkyl;
R5 and R6 are each indepependently hydrogen, (Ci-C6)alkyl, (C3- C7)cycloalkyl or (Ci-C6)alkyl(C3-C7)cycloalkyl or R5 and R6 taken together with the nitrogen to which they are attached form an azetidine, pyrrolidine, morpholine or piperidine ring;
R7 is (Ci-C6)alkyl, (C3-C7)cycloalkyl, (Ci-C6)alkyl(C3-C7)cycloalkyl or NR8R9, wherein said (Ci-C6)alkyl, (C3-C7)cycloalkyl or (Ci-C6)alkyl(C3-C7)cycloalkyl is optionally substituted with one to three halo; and
R8 and R9 are each indepependently hydrogen, (Ci-C6)alkyl, (C3- C7)cycloalkyl or (Ci-C6)alkyl(C3-C7)cycloalkyl, each optionally substituted with one to three halo, or R8 and R9 taken together with the nitrogen to which they are attached form an azetidine, pyrrolidine, morpholine or piperidine ring. Another embodiment of the present invention is the compound of the immediately preceding embodiment or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or methyl.
Another embodiment of the present invention is the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl or 5 to 6 membered heteroaryl; wherein said phenyl or 5 to 6 membered heteroaryl is substituted with S(0)2R7 or C(0)NR8R9 and is optionally substituted with halo or (C-i-C4)alkyl. Yet another embodiment of the present invention is the immediately embodiment or a pharmaceutically acceptable salt thereof wherein R3 is phenyl or a 5 to 6 membered heteroaryl selected from pyridinyl, pyrimidinyl or pyrazinyl; wherein said phenyl, pyridinyl, pyrimidinyl or pyrazinyl is substituted with S(0)2R7 or C(0)NR8R9 and is optionally substituted with fluoro or methyl.
Another embodiment of the present invention is the compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein R2 is OR4; and R4 is isopropyl, 1-hydroxypropan-2-yl, 1-methoxypropan-2-yl, 1- hydroxybutan-2-yl, 3-hydroxybutan-2-yl, tetrahydrofuran-3-yl or 1-methyl-2- oxopyrrolidin-3-yl.
Another embodiment of the present invention is the compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein R2 is C(O)NR5R6. Another embodiment of the present invention is the compound of the immediately preceding embodiment or a pharmaceutically acceptable salt thereof wherein R5 and R6 are each methyl. Another embodiment of the present invention is the compound of the immediately preceding
embodiment or a pharmaceutically acceptable salt thereof wherein R3 is phenyl or a 5 to 6 membered heteroaryl selected from pyridinyl, pyrimidinyl or pyrazinyl; wherein said phenyl, pyridinyl, pyrimidinyl or pyrazinyl is substituted with S(O)2R7 or C(O)NR8R9and is optionally substituted with fluoro or methyl. Still another embodiment of the present invention is the compound of the immediately preceding embodiment or a pharmaceutically acceptable salt thereof wherein R7 is methyl, ethyl, isopropyl or NR8R9; and R8 and R9 are independently hydrogen or methyl.
Another embodiment of the present invention is the compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or ethyl; R2 is OR4; and R4 is isopropyl, 1-hydroxypropan- 2-yl, 1-methoxypropan-2-yl, 1-hydroxybutan-2-yl, 3-hydroxybutan-2-yl, tetrahydrofuran-3-yl or 1-methyl-2-oxopyrrolidin-3-yl; and R3 is phenyl or a 5 to 6 membered heteroaryl selected from pyridinyl, pyrimidinyl or pyrazinyl; wherein said phenyl, pyridinyl, pyrimidinyl or pyrazinyl is substituted with S(O)2R7 or C(O)NR8R9 and is optionally substituted with fluoro or methyl. Another embodiment of the present invention is the compound of the immediately preceding embodiment or a pharmaceutically acceptable salt thereof wherein R7 is methyl, ethyl, isopropyl or NR8R9; and R8 and R9 are independently hydrogen or methyl. Yet another embodiment of the present invention is the compound of the immediately preceding embodiment or a pharmaceutically acceptable salt thereof wherein R4 is isopropyl or 1- hydroxypropan-2-yl.
Another embodiment of the present invention is a compound of Formula (I) selected from the group consisting of:
2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6-oxo-1 ,6- dihydropyrimidine-5-carbonitrile; 2-(3-isopropoxy-5-(4- (methylsulfonyl)phenoxy)phenyl)-5-methylpyrimidin-4(3H)-one; 2-(3- isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)pyrimidin-4(3H)-one; 5- ethyl-2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)pyrimidin-4(3H)- one; 5-chloro-2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)
phenyl)pyrimidin-4(3H)-one; 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy) phenyl)-5-methoxypyrimidin-4(3H)-one; 2-(3-isopropoxy-5-(4- (methylsulfonyl)phenoxy)phenyl)-5-(methoxymethyl)pyrimidin-4(3H)-one; Ethyl 2-(2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl) -6-oxo-1 ,6- dihydropyrimidin-5-yl)acetate; 2-(2-(3-isopropoxy-5-(4-(methylsulfonyl) phenoxy)phenyl)-6-oxo-1 ,6-dihydropyrimidin-5-yl)acetic acid; 2-(3- isopropoxy-5-(1-(methylsulfonyl)pyrrolidin-3-yloxy)phenyl)-5-methylpyrimidin- 4(3H)-one; 2-(3-isopropoxy-5-(1-(methylsulfonyl)pyrrolidin-3-yloxy)phenyl) pyrimidin-4(3H)-one; (S)-2-(3-(1 -methoxypropan-2-yloxy)-5-(4- (methylsulfonyl)phenoxy)phenyl)-5-methylpyrimidin-4(3H)-one; 5-ethyl-2-{3- [(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl} pyrimidin-4(3H)-one; (S)-5-(3-(1 -hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide; (S)-2- (3-(1-hydroxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy)
phenyl)pyrimidin-4(3H)-one; (S)-2-(3-(4-(ethylsulfonyl)phenoxy)-5-(1- hydroxypropan-2-yloxy)phenyl)pyrimidin-4(3H)-one; (S)-4-(3-(1 - hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylbenzenesulfonamide; N,N-dimethyl-5-(3-(1-methyl-2-oxopyrrolidin-3- yloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)pyrazine-2-carboxamide; 5-(3-isopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrimidine-2-carboxamide; 2-(3-(2-(azetidine-1-carbonyl)pyrimidin-5- yloxy)-5-isopropoxyphenyl)pyrimidin-4(3H)-one; 2-(3-isopropoxy-5-(2- (pyrrolidine-1-carbonyl)pyrimidin-5-yloxy)phenyl)pyrimidin-4(3H)-one; 3- fluoro-5-(3-isopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpicolinamide; 2-(3-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)- 5-isopropoxyphenyl) pyrimidin-4(3H)-one; 2-(3-(5-(azetidine-1- carbonyl)pyrazin-2-yloxy)-5-isopropoxyphenyl)pyrimidin-4(3H)-one; 5-(3- isopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrazine-2-carboxamide; 4-(3-isopropoxy-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)benzene sulfonamide; 4-(3-isopropoxy-5-(6- oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N-methylbenzenesulfonamide; 4-(3- isopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,2- dimethylbenzenesulfonamide; 5-(3-sec-butoxy-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide; 5-(3- isopropoxy-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl) phenoxy)-N,N- dimethylpyrimidine-2-carboxamide; 3-fluoro-5-(3-isopropoxy-5-(5-methyl-6- oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpicolinamide; 4-(3- isopropoxy-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N- methylbenzenesulfonamide; (S)-5-(3-sec-butoxy-5-(5-methyl-6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide; (S)-5- (3-sec-butoxy-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrimidine-2-carboxamide; (S)-5-(3-sec-butoxy-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide; (S)-5- (3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrimidine-2-carboxamide; N,N-dimethyl-3-(5-methyl-6-oxo-1 ,6- dihydropyrimidin-2-yl)-5-(4-(methylsulfonyl)phenoxy)benzamide; 3-(4- (ethylsulfonyl)phenoxy)-N,N-dimethyl-5-(5-methyl-6-oxo-1 ,6- dihydropyrimidin-2-yl)benzamide; 3-(4-(isopropylsulfonyl)phenoxy)-N, Nidi methyl-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl)benzamide; (S)-2-(3-(1 - hydroxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy)phenyl)-5- methylpyrimidin-4(3H)-one; (S)-2-(3-(4-(ethylsulfonyl)phenoxy)-5-(1- hydroxypropan-2-yloxy)phenyl)-5-methylpyrimidin-4(3H)-one; (S)-2-(3-(4- (cyclopropylsulfonyl)phenoxy)-5-(1-hydroxypropan-2-yloxy)phenyl)-5- methylpyrimidin-4(3H)-one; (S)-4-(3-(1-hydroxypropan-2-yloxy)-5-(5-methyl- 6-0X0-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylbenzenesulfonamide; (S)-3-fluoro-5-(3-(1-hydroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpicolinamide; (S)-5-(3-(1- hydroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide; (S)-5-(3-(1 - hydroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide; (S)-4-(3-(1 - hydroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N-methylbenzenesulfonamide; (S)-3-fluoro-5-(3-(1 - hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpicolinamide; (S)-2-(3-(1 -hydroxypropan-2-yloxy)-5-(4- (isopropylsulfonyl)phenoxy)phenyl) pyrimidin-4(3H)-one; (S)-2-(3-(4- (cyclopropylsulfonyl)phenoxy)-5-(1-hydroxypropan-2-yloxy)phenyl)pyrimidin- 4(3H)-one; (S)-4-(3-(1-hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N-methylbenzenesulfonamide; (S)-2-(3-(1- hydroxypropan-2-yloxy)-5-(3-methyl-4-(methylsulfonyl)phenoxy)
phenyl)pyrimidin-4(3H)-one; (S)-5-(3-(1-hydroxypropan-2-yloxy)-5-(6-oxo- 1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide;
2- (3-(1-hydroxybutan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy)phenyl) pyrimidin-4(3H)-one; 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)- 5-isopropylpyrimidin-4(3H)-one; 2-(3-(4-(ethylsulfonyl)phenoxy)-5-((2S,3R)-
3- hydroxybutan-2-yloxy)phenyl)pyrimidin-4(3H)-one; 5-methyl-2-{3-[4- (methylsulfonyl)phenoxy]-5-(tetrahydrofuran-3-yloxy)phenyl}pyrimidin-4(3H)- one; 5-methyl-2-(3-(1-methyl-2-oxopyrrolidin-3-yloxy)-5-(4-(methylsulfonyl) phenoxy)phenyl)pyrimidin-4(3H)-one; (S)-2-(3-(1-methoxypropan-2-yloxy)-5- (4-(methylsulfonyl)phenoxy)phenyl) pyrimidin-4(3H)-one; 5-methyl-2-(3-(4- (methylsulfonyl)phenoxy)-5-(tetrahydro-2H-pyran-4-yloxy)phenyl)pyrimidin- 4(3H)-one; 5-ethyl-2-(2-isopropoxy-6-(4-(methylsulfonyl)phenoxy)pyridin-4- yl)pyrimidin-4(3H)-one; (S)-5-(3-(1 -methoxypropan-2-yloxy)-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide; 3-(4- (cyclopropylsulfonyl)phenoxy)-N,N-dimethyl-5-(5-methyl-6-oxo-1 ,6- dihydropyrimidin-2-yl)benzamide; 5-(3-cyclobutoxy-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide; 5-(3- cyclobutoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrazine-2-carboxamide; 5-(3-(cyclopentyloxy)-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide; 5-(3- (cyclopentyloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrazine-2-carboxamide; (single enantiomer) 5-methyl-2-(3-(4- (methylsulfonyl)phenoxy)-5-(tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4(3H)- one; (single enantiomer) 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5- (tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4(3H)-one; N,N-dimethyl-5-(3-(6- oxo-1 ,6-dihydropyrimidin-2-yl)-5-(tetrahydrofuran-3-yloxy)phenoxy) pyrimidine-2-carboxamide; 2-(3-(4-(methylsulfonyl)phenoxy)-5- (tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4(3H)-one; N,N-dimethyl-5-(3-(6- oxo-1 ,6-dihydropyrimidin-2-yl)-5-(tetrahydrofuran-3-yloxy)phenoxy)pyrazine- 2-carboxam ide ; (R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-d i hyd ropy ri m idi n-2- yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide; (R)-5-(3-sec-butoxy-5- (6-0X0-1 ,6-d i hyd ropy ri m idi n-2-y I )phenoxy )-N , N-d i methyl py razi ne-2- carboxamide; (R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-3-fluoro-N,N-dimethylpicolinamide; (S)-5-(3-(1-methoxypropan- 2-yloxy)-5-(6-oxo-1 ,6-dihydro pyrimidin-2-yl)phenoxy)-N,N- dimethylpyrimidine-2-carboxamide; (S)-2-(3-(4-(ethylsulfonyl)phenoxy)-5-(1- methoxypropan-2-yloxy)phenyl)pyrimidin-4(3H)-one; N,N-dimethyl-5-(3-(6- oxo-1 ,6-dihydropyrimidin-2-yl)-5-(pentan-3-yloxy)phenoxy)pyrazine-2- carboxamide; N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihydropyrimidin-2-yl)-5-(pentan- 3- yloxy)phenoxy)pyrimidine-2-carboxamide; 5-(3-cyclopropoxy-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide; 5-(3- cyclopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrazine-2-carboxamide; 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)- 5-(pyrrolidine-1 -carbonyl) phenyl)pyrimidin-4(3H)-one; 5-(hydroxymethyl)-2- (3-isopropoxy-5-(4-(methylsulfonyl)phenoxy) phenyl)pyrimidin-4(3H)-one; 5- methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5-(tetrahydro-2H-pyran-3- yloxy)phenyl)pyrimidin-4(3H)-one; and Ethyl 2-(3-isopropoxy-5-(4- (methylsulfonyl)phenoxy)phenyl)-6-oxo-1 ,6-dihydropyrimidine-5-carboxylate; or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention is a compound of Formula (I) selected from the group consisting of:
2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-5-methylpyrimidin- 4(3H)-one; (S)-2-(3-(1-methoxypropan-2-yloxy)-5-(4-(methylsulfonyl) phenoxy)phenyl)-5-methylpyrimidin-4(3H)-one; (S)-2-(3-(4- (ethylsulfonyl)phenoxy)-5-(1-hydroxypropan-2-yloxy)phenyl) pyrimidin-4(3H)- one; (S)-4-(3-(1 -hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N,N-dimethylbenzenesulfonamide; 5-(3-sec-butoxy-5-(6-oxo- 1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide;
4- (3-isopropoxy-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N- methylbenzenesulfonamide; 3-(4-(ethylsulfonyl)phenoxy)-N,N-dimethyl-5-(5- methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl)benzamide; 3-(4-(isopropylsulfonyl) phenoxy )-N , N-d i methy l-5-(5-methy l-6-oxo- 1 ,6-d i hydropy ri m id i n-2- yl)benzamide; (S)-2-(3-(1-hydroxypropan-2-yloxy)-5-(4-(methylsulfonyl) phenoxy) phenyl)pyrimidin-4(3H)-one; (S)-4-(3-(1 -hydroxypropan-2-yloxy)-5- (5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N-methylbenzene sulfonamide; (S)-3-fluoro-5-(3-(1 -hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpicolinamide; (S)-2-(3-(1- hydroxypropan-2-yloxy)-5-(4-(isopropylsulfonyl)phenoxy)phenyl) pyrimidin- 4(3H)-one; (S)-2-(3-(4-(cyclopropylsulfonyl)phenoxy)-5-(1-hydroxypropan-2- yloxy)phenyl)pyrimidin-4(3H)-one; 2-(3-(4-(ethylsulfonyl)phenoxy)-5- ((2S,3R)-3-hydroxybutan-2-yloxy)phenyl)pyrimidin-4(3H)-one; (S)-2-(3-(1- methoxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy) phenyl) pyrimidin- 4(3H)-one; 3-(4-(cyclopropylsulfonyl)phenoxy)-N,N-dimethyl-5-(5-methyl-6- oxo-1 ,6-dihydropyrimidin-2-yl)benzamide; (R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide; (R)- 5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrazine-2-carboxamide; (R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-3-fluoro-N,N-dimethylpicolinamide; (S)-2-(3- (4-(ethylsulfonyl)phenoxy)-5-(1-methoxypropan-2-yloxy)phenyl)pyrimidin- 4(3H)-one; N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihydropyrimidin-2-yl)-5-(pentan-3- yloxy)phenoxy)pyrazine-2-carboxamide; and N,N-dimethyl-5-(3-(6-oxo-1 ,6- dihydropyrimidin-2-yl)-5-(pentan-3-yloxy)phenoxy)pyrimidine-2-carboxamide; or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention is a pharmaceutical composition that comprises (1 ) a compound of the present invention, and (2) a pharmaceutically acceptable excipient, diluent, or carrier. Preferably, the composition comprises a therapeutically effective amount of a compound of the present invention. The composition may also contain at least one additional pharmaceutical agent (described herein). Preferred agents include anti-obesity agents and/or anti-diabetic agents (described herein below).
In yet another aspect of the present invention is a method for treating a disease, condition, or disorder mediated by glucokinase, in particular, activation of said enzyme, in a mammal that includes the step of
administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present invention, or a pharmaceutical composition thereof.
Diseases, disorders, or conditions mediated by glucokinase activators include Type II diabetes, hyperglycemia, metabolic syndrome, impaired glucose tolerance, glucosuria, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslididemia, hypertension, hyperinsulinemia, and insulin resistance syndrome. Preferred diseases, disorders, or conditions include Type II diabetes, hyperglycemia, impaired glucose tolerance, obesity, and insulin resistance syndrome. More preferred are Type II diabetes, hyperglycemia, and obesity. Most preferred is Type II diabetes.
In yet another aspect of the present invention is a method of reducing the level of blood glucose in a mammal, preferably a human, which includes the step of administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of the present invention, or a pharmaceutical composition thereof.
Compounds of the present invention may be administered in combination with other pharmaceutical agents (in particular, anti-obesity and anti-diabetic agents described herein below). The combination therapy may be administered as (a) a single pharmaceutical composition which comprises a compound of the present invention, at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) a second composition comprising at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier. The pharmaceutical compositions may be administered
simultaneously or sequentially and in any order.
Definitions
As used herein, the term "alkyl" refers to a hydrocarbon radical of the general formula CnH2n+i - The alkane radical may be straight or branched. For example, the term "(C-i-C6)alkyl" refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, s-butyl, f-butyl, n-pentyl, 1-methylbutyl, 2- methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2- methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy, acyl (e.g., alkanoyl), alkylamino, dialkylamino, alkylsulfonyl, and alkylthio group have the same definition as above. When indicated as being "optionally substituted", the alkane radical or alkyl moiety may be
unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls).
The term "cycloalkyl" refers to nonaromatic rings that are fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring. Unless specified otherwise, the carbocyclic ring is generally a 3- to 8- membered ring. For example, (C3-C7)cycloalkyl include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, norbornyl (bicyclo[2.2.1]heptyl) and the like.
The term "3 to 7 membered heterocyclyl" refers to the radical of nonaromatic rings that are fully hydrogenated and may exist as a single ring, bicyclic ring or a spiro ring. The heterocyclic ring is a 4- to 7-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Heterocyclyl groups include groups such as epoxy, aziridinyl, lactam rings, tetrahydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1 ,1-dioxide, and the like.
The phrase "5 to 6 membered heteroaryl" means a radical of a 5 or 6 membered heteroaromatic ring. The heteroaromatic ring can contain 1 to 4 heteroatoms selected from N, O and S. 5 to 6 membered heteroaryl groups include pyrrolyl, furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl and the like. Preferred 5 to 6 membered heteroaryl groups include pyridinyl, pyrimidinyl or pyrazinyl.
The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
The term "animal" refers to humans (male or female), companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species. "Edible animals" refers to food-source animals such as cows, pigs, sheep and poultry.
The phrase "pharmaceutically acceptable" indicates that the
substance or composition must be compatible chemically and/or
toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
The terms "treating", "treat", or "treatment" embrace both preventative, i.e., prophylactic, and palliative treatment.
The terms "modulated" or "modulating", or "modulate(s)", as used herein, unless otherwise indicated, refers to the activation of the activating the glucokinase enzyme with compounds of the present invention.
The terms "mediated" or "mediating" or "mediate(s)", as used herein, unless otherwise indicated, refers to the treatment or prevention the particular disease, condition, or disorder, (ii) attenuation, amelioration, or elimination of one or more symptoms of the particular disease, condition, or disorder, or (iii) prevention or delay of the onset of one or more symptoms of the particular disease, condition, or disorder described herein, by activating the glucokinase enzyme via glucose binding enhancement, alleviating the inhibition of glucokinase regulatory protein, a key regulator of glucokinase activity in the liver, and/or by increasing the catalytic rate of the glucokinase enzyme (e.g., change Vmax).
The term "compounds of the present invention" (unless specifically identified otherwise) refer to compounds of Formula (I) and any
pharmaceutically acceptable salts of the compounds, as well as, all stereoisomers (including diastereoisomers and enantiomers), tautomers, conformational isomers, and isotopically labeled compounds. Hydrates and solvates of the compounds of the present invention are considered compositions of the present invention, wherein the compound is in
association with water or solvent, respectively.
DETAILED DESCRIPTION
Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wl) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic
Synthesis, v. 1 -19, Wiley, New York (1967-1999 ed.), or Beilsteins
Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).
For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to
synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the
compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, f-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxyl-protecting groups (O-Pg) include for example, allyl, acetyl, silyl, benzyl, para-methoxybenzyl, trityl, and the like. Preferred hydroxyl-protecting groups for certain of the reactions carried out include para-methoxy benzyl (PMB) or silyl groups such as ferf-butyl dimethylsilyl (TBDMS) or triisopropylsilyl (TIPS). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
Scheme I outlines the general procedures one could use to provide compounds of the present invention having Formula (I). An appropriately substituted benzonitrile derivative of general Formula (IV) is reacted with methyl chloroaluminum amide, CH3AICINH2, which is prepared in situ by reacting ammonium chloride and trimethyl aluminum in an appropriate solvent (see e.g. Levin, J. I.; Turos, E.; Weinreb, S.M.; Syn. Comm. 1982, 12(13), 989-993), to provide the appropriately substituted benzamidine derivative of general Formula (III). Typically, ammonium chloride in an appropriate solvent such as toluene is first treated with a solution of trimethylaluminum chloride in toluene at a reduced temperature, typically around 0 °C, for a period of 15 minutes to 1 hour. The benzonitrile derivative of general Formula (IV) is then added and the reaction is carried out at an elevated temperature, typically 100 °C to 110 °C, for a period of 4 to 48 hours to provide the benzamidine derivative of general Formula (III). The benzamidine derivative of Formula (III) is then reacted with an appropriately substituted 1 ,3-dicarbonyl compound of general formula (II) in an appropriate solvent in the presence of a suitable base to provide the compound of Formula (I). The 1 ,3-dicarbonyl compound (II) can be either an isolated appropriately substituted 3-oxopropanoate derivative or can be prepared in situ and used directly. The group R as denoted in the 1 ,3-dicarbonyl compound of general formula (II) is typically a lower alkyl group such as methyl or ethyl.
Reaction Scheme I
Figure imgf000019_0001
The reaction is typically run in a suitable solvent such as ethanol and in the presence of a suitable base such as sodium ethoxide at an elevated temperature, typically at 65 °C to 85 °C for a period of 4 to 24 hours. The reaction is typically quenched by addition of acid, such as hydrochloric acid, followed by extractive workup and chromatographic purification to provide the compound of Formula (I). It is to be appreciated that other 1 ,3- dicarbonyl equivalent compounds can be used in place of the compound of Formula (II). For example, instead of compounds of Formula (II) an appropriately substituted eneamine derivative, such as a 3- (dimethylamino)acrylate derivative may be used in a similar manner.
Reaction Scheme II provides an alternate route to compounds of Formula (I) employing boronate intermediates. In Reaction Scheme II the group R2 represents either R2 itself or a group which upon appropriate deprotection provides R2. The protected phenol derivative of general Formula(X) can undergo borylation with bis pinacolato diboron in the presence of an appropriate catalyst such as (1 ,5-cyclooctadiene)(methoxy) iridium (I) dimer in the presence of 4,4'-di-tert-butyl-2,2'-bipyridine and an appropriate solvent such as methyl tert-butyl ether, tetrahydrofuran or dioxane, typically at an elevated temperature such as 80 °C to 110 °C thermally or under microwave irradiation for a period of 4 to 24 hours (see Hata, H; et al; Chemistry - An Asian Journal, 2007, 2(7), 849-859 or
Mkhalid, I.; Barnard, J.H.; Marder, T.B.; Murphy, J.M.; Hartwig, J.F. Chem. Rev., 2010, 110(2), 890-931 ) to provide the borylated compound of Formula (IX). In the compound of Formula (VIII) the group Pg represents an appropriate protecting group such as para-methoxybenzyl, and the group Lg represents an appropriate leaving group such as a halide, preferably chloride. The borylated compound of Formula (IX) can then be reacted with an appropriately protected pyrimidine derivative of Formula (VIII) in an appropriate solvent such as aqueous acetonitrile in the presence of a catalyst such as 1 ,1'-bis(diphenylphosphino) ferrocene)-dichloropalladium (II) and a base such as sodium carbonate to provide the compound of general Formula (VII).
The compound of Formula (VII) can then be deprotected with an appropriate deprotection reagent at the phenolic hydroxyl to provide the compound of Formula (VI). For example, when the hydroxyl protecting group is TBDMS the compound of Formula (VI) can be deprotected upon treatment with a fluoride source such as tetrabutyl ammonium fluoride in an appropriate solvent such as tetrahydrofuran. The compound of Formula (VI) can then be reacted with R3-Lg, where Lg represents an appropriate leaving group such as a halide to provide the compound of Formula (V). For example, the reaction of compound (VI) with R3-Lg can be carried out in an appropriate solvent such as Ν,Ν-dimethylformamide in the presence of a base such as potassium carbonate at an elevated temperature, typically from 60 °C to 120 °C for 4 to 24 hours. Alternatively a method such as the Mitsunobu reaction can be used to install R3 when R3 is an alkyl group. When R3 is an aryl group other metal catalyzed coupling reactions can be used such as the Ullmann reaction or a palladium catalyzed coupling. Reaction Scheme
Figure imgf000021_0001
Reaction Scheme III provides another related route for the
preparation of compounds within Formula I. The bis protected resorcinol of Formula (Xa) wherein Pg is an appropriate phenolic hydroxyl protecting group such as TBDMS is reacted with bis-pinacolato diboron in the presence of an appropriate catalyst such as (1 ,5-cyclooctadiene)(methoxy) iridium (I) dimer in the presence of 4,4'-di-tert-butyl-2,2'-bipyridine and an appropriate solvent such as methyl tert-butyl ether or dioxane, typically at an elevated temperature such as 80 °C to 110 °C under microwave irradiation or thermally for a period of 4 to 24 hours to provide the borylated compound (IXa). The compound (IXa) can then be reacted with the compound of Formula (VIII) as described previously to provide the compound of Formula (Vila). The phenolic hydroxyl groups in the compound of Formula (Vila) can then be deprotected using conditions appropriate for the the protecting group employed. The compound of Formula (Vila) can then be reacted with R3-I_g to provide compound (Va) which can then be reacted with R4-I_g to provide the compound of formula (la). In each case Lg represents an appropriate leaving group. The reactions with R3-I_g and R4-Lg are typically run at an elevated temperature such as 60 °C to 120 °C in an appropriate solvent such as Ν,Ν-dimethylformamide in the presence of an appropriate base such as potassium carbonate. Other alternative methods for introduction of R3 and R4 can be employed as described for R3 hereinabove.
Reaction Scheme III
Figure imgf000022_0001
(Via) (Va) (la)
In either Scheme II or Scheme III the protecting group on the pyrimidone needs to be removed. This can be accomplished by various methods. For example, in the case of the para-methoxybenzyl protecting group, it can be deprotected under acidic conditions, such as trifluoroacetic acid or hydrogen chloride in a suitable solvent such as dioxane. Reaction Scheme IV
Figure imgf000023_0001
Reaction Scheme IV provides an alternate synthetic route to compounds of Formula (la). An appropriately substituted phenol of formula (XII) wherein Lg represents an appropriate leaving group such as a halide, preferably iodo, is reacted with Pg-Lg wherein Pg represents an appropriate hydroxy protecting group such as triisopropylsilyl and Lg represents a leaving group such as a halide. The resulting compound of Formula (XI) is then reacted with an appropriate alcohol R3OH to provide the compound of Formula (Xb) which can then undergoe borylation as previously described in Reaction Scheme II to provide the compound of Formula (IXb). Reaction of the compound of Formula (IXb) with the protected pyrimidinone of Formula (VIII) as previously described provides compound (Vlb) which is then deprotected to provide compound (Va). The compound (Va) is the reacted with R4-Lg wherein Lg is an appropriate leaving group followed by deprotection of the pyrimidinone moiety as previously described to provide the compound of Formula (la).
Reaction Scheme V provides the synthesis of compounds of Formula (lb) which are compounds of Formula (I) wherein the group R2 is
cyclopropoxy. 3-hydroxyphenyl benzoate is reacted with vinyl acetate in the presence of an appropriate catalyst such as di- -chlorobis(1 ,5- cyclooctadiene)diiridium(l) and an appropriate base such as sodium carbonate in an appropriate solvent such as toluene under an inert atmosphere. The reaction is typically carried out at an elevated temperature such as 100 °C for a period of 4 to 24 hours. The resulting 3-(vinyloxy) phenyl benzoate then undergoes cyclopropanation by reaction with chloroiodomethane in the presence of 1 M Diethylzinc solution in an appropriate solvent such as dichloroethane. The reaction is typically started at 0 °C then allowed to gradually warm to room temperature to provide the cyclopropoxy derivative. Saponification of the benzoate ester can be carried out upon treatment with a base such as sodium hydroxide in methanol.
Protection of the phenolic hydroxy followed by borylation and further reaction as previously described above provides the compounds of Formula (lb).
Reaction Scheme V
Figure imgf000024_0001
Reaction Scheme VI provides the synthesis of compounds of Formula (lc) which are compounds of Formula (I) wherein the group R2 is C(0)NR5R6. The first step employs standard peptide coupling conditions using 3-hydroxy- 5-iodobenzoic acid and an appropriately substituted amine of formula
NR5R6. The reaction can be run using peptide coupling reagents such as carbodiimide reagents such as EDCI in the presence of
hydroxybenzotriazole (HOBT) in an appropriate solvent such as DMF. The reaction is typically carried out at 0°C to room temperature for a period of 1 to 24 hours. The resulting amido substituted iodo-phenol can then be reacted with R3-I_g wherein Lg is an appropriate leaving group such as a halide. The reaction is typically carried out in an appropriate solvent such as DMF in the presence of a base such as cesium carbonate at an elevated temperature such as 80 °C for 4 to 24 hours. The resulting product can then undergoe borylation using Bis(pinacolato)diboron in the presence of potassium acetate and catalyst Pd(dppf)Cl2 in an appropriate solvent such as DMF. The reaction can be initiated at reduced temperature such as 0°C then run at an elevated temperature such as 80°C for 4 to 24 hours to provide the borylated product. Further reaction as described previously for Reaction Schemes ll-IV provides the compound of Formula (lc).
Reaction Scheme VI
Figure imgf000025_0001
The compounds of the present invention may be isolated and used perse, or when possible, in the form of its pharmaceutically acceptable salt. The term "salts" refers to inorganic and organic salts of a compound of the present invention. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound with a suitable organic or inorganic acid or base and isolating the salt thus formed. Representative salts include the hydrobromide,
hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate,
trifluoroacetate, oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate, malate, borate, benzoate, lactate, phosphate, hexafluorophosphate, benzene sulfonate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and
laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, e.g., Berge, et al., J. Pharm. Sci.. 66, 1-19 (1977).
The compounds of the present invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. Unless specified otherwise, it is intended that all stereoisomeric forms of the compounds of the present invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of the present invention incorporates a double bond or a fused ring, both the cis- and trans- forms, as well as mixtures, are embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by
converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the
diastereoisomers and converting (e.g., hydrolyzing) the individual
diastereoisomers to the corresponding pure enantiomers. Also, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column. Alternatively, the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.
It is also possible that the intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons. For example, the pyrimidonr ring of this invention may also exist in its hydroxy pyrimidine form. Both such forms are included in the compounds of Formula (I)-
Certain compounds of the present invention may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example, because of steric hindrance or ring strain, may permit separation of different conformers.
The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H,
11 Cj 13Cj 14Cj 13N j 15N j 15Q 17^ 18Q 31 p 32ρ_ 35^ 18ρ_ 123, 125, 36^ respectively.
Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 150, 13N, 11C, and 18F are useful for positron emission tomography (PET) studies to examine substrate occupancy.
Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an
isotopically labeled reagent for a non-isotopically labeled reagent.
Certain compounds of the present invention may exist in more than one crystal form (generally referred to as "polymorphs"). Polymorphs may be prepared by crystallization under various conditions, for example, using different solvents or different solvent mixtures for recrystallization;
crystallization at different temperatures; and/or various modes of cooling, ranging from very fast to very slow cooling during crystallization.
Polymorphs may also be obtained by heating or melting the compound of the present invention followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
Compounds of the present invention are useful for treating diseases, conditions and/or disorders modulated by the activation of the glucokinase enzyme; therefore, another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier. The compounds of the present invention
(including the compositions and processes used therein) may also be used in the manufacture of a medicament for the therapeutic applications described herein.
A typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents
recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product. The pharmaceutical compositions also include solvates and hydrates of the compounds of Formula (I). The term "solvate" refers to a molecular complex of a compound represented by Formula (I) (including
pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, ethylene glycol, and the like, The term "hydrate" refers to the complex where the solvent molecule is water. The solvates and/or hydrates preferably exist in crystalline form. Other solvents may be used as intermediate solvates in the preparation of more desirable solvates, such as methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1 ,4-butyne-diol, and the like.
The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
The present invention further provides a method of treating diseases, conditions and/or disorders modulated by the activation of the glucokinase enzyme in an animal that includes administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier. The method is particularly useful for treating diseases, conditions and/or disorders that benefit from the activation of glucokinase which include: eating disorders (e.g., binge eating disorder, anorexia, bulimia, weight loss or control and obesity), prevention of obesity and insulin resistance by glucokinase expression in skeletal muscle of transgenic mice (Otaegui, P.J., et.al., The FASEB Journal. 17; 2097-2099, (2003)); and Type II diabetes, insulin resistance syndrome, insulin
resistance, and hyperglycemia (Poitout, V., et.al., "An integrated view of β- cell dysfunction in type-ll diabetes", Annul. Rev. Medicine, 47; 69-83, (1996)).
One aspect of the present invention is the treatment of obesity, and obesity-related disorders (e.g., overweight, weight gain, or weight
maintenance).
Obesity and overweight are generally defined by body mass index (BMI), which is correlated with total body fat and estimates the relative risk of disease. BMI is calculated by weight in kilograms divided by height in meters squared (kg/m2). Overweight is typically defined as a BMI of 25-29.9 kg/m2, and obesity is typically defined as a BMI of 30 kg/m2. See, e.g., National Heart, Lung, and Blood Institute, Clinical Guidelines on the
Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, DC: U.S. Department of Health and Human Services, NIH publication no. 98-4083 (1998).
Another aspect of the present invention is for the treatment or delaying the progression or onset of diabetes or diabetes-related disorders including Type 1 (insulin-dependent diabetes mellitus, also referred to as "IDDM") and Type 2 (noninsulin-dependent diabetes mellitus, also referred to as "NIDDM") diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, and diabetic complications (such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy, and retinopathy).
Yet another aspect of the present invention is the treatment of diabetes- or obesity-related co-morbidities, such as metabolic syndrome. Metabolic syndrome includes diseases, conditions or disorders such as dyslipidemia, hypertension, insulin resistance, diabetes (e.g., Type 2 diabetes), weight gain, coronary artery disease and heart failure. For more detailed information on Metabolic Syndrome, see, e.g., Zimmet, P.Z., et al., "The Metabolic Syndrome: Perhaps an Etiologic Mystery but Far From a Myth - Where Does the International Diabetes Federation Stand?," Diabetes & Endocrinology, 7(2), (2005); and Alberti, K.G., et al., "The Metabolic Syndrome - A New Worldwide Definition," Lancet, 366, 1059-62 (2005). Preferably, administration of the compounds of the present invention provides a statistically significant (p<0.05) reduction in at least one
cardiovascular disease risk factor, such as lowering of plasma leptin, C- reactive protein (CRP) and/or cholesterol, as compared to a vehicle control containing no drug. The administration of compounds of the present invention may also provide a statistically significant (p<0.05) reduction in glucose serum levels.
In yet another aspect of the present invention, the condition treated is impaired glucose tolerance, hyperglycemia, diabetic complications such as sugar cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic cardiomyopathy, anorexia nervosa, bulimia, cachexia, hyperuricemia, hyperinsulinemia, hypercholesterolemia,
hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis, vascular stenosis, solid tumors, skin cancer, melanoma, lymphoma, breast cancer, lung cancer, colorectal cancer, stomach cancer, esophageal cancer, pancreatic cancer, prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer and ovarian cancer.
The present invention also relates to therapeutic methods for treating the above described conditions in a mammal, including a human, wherein a compound of formula (I) of this invention is administered as part of an appropriate dosage regimen designed to obtain the benefits of the therapy. The appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the compound will depend upon the compound of formula (I) of this invention being used, the type of
pharmaceutical compositions being used, the characteristics of the subject being treated and the severity of the conditions.
In general, an effective dosage for the compounds of the present invention is in the range of 0.01 mg/kg/day to 30 mg/kg/day, preferably 0.01 mg/kg/day to 5 mg/kg/day of active compound in single or divided doses. However, some variability in the general dosage range may be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular compound being administered and the like. The determination of dosage ranges and optimal dosages for a particular patient is well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure. Practitioners will appreciate that "kg" refers to the weight of the patient measured in kilograms.
The compounds or compositions of this invention may be
administered in single (e.g., once daily) or multiple doses or via constant infusion. The compounds of this invention may also be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
The compounds or compositions of the present invention may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally and parenterally, (e.g.,
intravenously, subcutaneously or intramedullary). Further, the
pharmaceutical compositions of this invention may be administered intranasally, as a suppository, or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water.
It is also noted that the compounds of the present invention can be used in sustained release, controlled release, and delayed release formulations, which forms are also well known to one of ordinary skill in the art.
The compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases, conditions and/or disorders described herein. Therefore, methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided. Suitable
pharmaceutical agents that may be used in combination with the compounds of the present invention include anti-obesity agents (including appetite suppressants), anti-diabetic agents, anti-hyperglycemic agents, lipid lowering agents, and anti-hypertensive agents.
Suitable anti-diabetic agents include an acetyl-CoA carboxylase-2 (ACC-2) inhibitor, a diacylglycerol O-acyltransferase 1 (DGAT-1 ) inhibitor, a phosphodiesterase (PDE)-10 inhibitor, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an a-amylase inhibitor (e.g., tendamistat, trestatin and AL- 3688), an a-glucoside hydrolase inhibitor (e.g., acarbose), an a-glucosidase inhibitor (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), a PPARy agonist (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone,
rosiglitazone and troglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW- 1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB- 219994), a biguanide (e.g., metformin), a glucagon-like peptide 1 (GLP-1) agonist (e.g., exendin-3 and exendin-4), a protein tyrosine phosphatase-1 B (PTP-1B) inhibitor (e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S., et al., Drug Discovery Today, 12(9/10), 373-381 (2007)), SIRT-1 inhibitor (e.g., reservatrol), a dipeptidyl peptidease IV (DPP- IV) inhibitor (e.g., sitagliptin, vildagliptin, alogliptin and saxagliptin), an insulin secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, insulin, an insulin mimetic, a glycogen phosphorylase inhibitor, and a VPAC2 receptor agonist. Preferred antidiabetic agents are metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin and saxagliptin).
Suitable anti-obesity agents include 1 1β-hydroxy steroid
dehydrogenase-1 (Ι ΐβ-HSD type 1 ) inhibitors, stearoyl-CoA desaturase-1 (SCD-1 ) inhibitor, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, β3 adrenergic agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as
tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y antagonists (e.g., NPY Y5 antagonists), PYY3-36 (including analogs thereof), thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid agonists or antagonists, orexin
antagonists, glucagon-like peptide-1 agonists, ciliary neurotrophic factors (such as Axokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) inhibitors, ghrelin antagonists, histamine 3 antagonists or inverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTP inhibitors, such as dirlotapide), opioid antagonist, orexin antagonist, and the like.
Preferred anti-obesity agents for use in the combination aspects of the present invention include gut-selective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No.
913541^17-6), CCKa agonists (e.g., N-benzyl-2-[4-(1 H-indol-3-ylmethyl)-5- oxo-1 -phenyl-4,5-dihydro-2,3,6, 10b-tetraaza-benzo[e]azulen-6-yl]-N- isopropyl-acetamide described in PCT Publication No. WO 2005/1 16034 or US Publication No. 2005-0267100 A1 ), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g., compounds described in US 6,818,658), lipase inhibitor (e.g., Cetilistat), PYY3-36 (as used herein "PYY3-36" includes analogs, such as peglated PYY3-36 e.g., those described in US Publication 2006/0178501 ), opioid antagonists (e.g., naltrexone), oleoyl-estrone (CAS No. 180003-17-2), obinepitide (TM30338), pramlintide (Symlin®), tesofensine (NS2330), leptin, liraglutide, bromocriptine, orlistat, exenatide (Byetta®), AOD-9604 (CAS No. 221231-10-3) and sibutramine. Preferably, compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
All of the above recited U.S. patents and publications are incorporated herein by reference.
Embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.
EXAMPLES
Unless specified otherwise, starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wl), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), Tyger Scientific (Princeton, NJ), and AstraZeneca Pharmaceuticals (London, England).
General Experimental Procedures
NMR spectra were recorded on a Varian Unity™ 400 (available from Varian Inc., Palo Alto, CA) at room temperature at 400 MHz for proton.
Chemical shifts are expressed in parts per million (δ) relative to residual solvent as an internal reference. The peak shapes are denoted as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quartet; m, multiplet; bs, broad singlet; 2s, two singlets. Atmospheric pressure chemical ionization mass spectra (APCI) were obtained on a Fisons™ Platform II Spectrometer (carrier gas: acetonitrile: available from Micromass Ltd, Manchester, UK). Chemical ionization mass spectra (CI) were obtained on a Hewlett- Packard™ 5989 instrument (ammonia ionization, PBMS: available from Hewlett-Packard Company, Palo Alto, CA). Electrospray ionization mass spectra (ES) were obtained on a Waters™ ZMD instrument (carrier gas: acetonitrile: available from Waters Corp., Milford, MA). High resolution mass spectra (HRMS) were obtained on an Agilent™ Model 6210 using time of flight method. Where the intensity of chlorine or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3:1 for 35CI/37CI-containing ions and 1 :1 for 79Br/81Br-containing ions) and the intensity of only the lower mass ion is given. In some cases only
representative 1H NMR peaks are given. Optical rotations were determined on a PerkinElmer™ 241 polarimeter (available from PerkinElmer Inc., Wellesley, MA) using the sodium D line (λ = 589 nm) at the indicated temperature and are reported as follows [a]Dtemp, concentration (c = g/100 ml), and solvent.
Column chromatography was performed with either Baker™ silica gel (40 μιτη; J.T. Baker, Phillipsburg, NJ) or Silica Gel 50 (EM Sciences™, Gibbstown, NJ) in glass columns or in Flash 40 Biotage™ columns (ISC, Inc., Shelton, CT) or Biotage™ SNAP cartridge KPsil or Redisep Rf silica (from Teledyne™ Isco™) under low nitrogen pressure.
Preparation of Starting Materials and Intermediates
The following starting materials are commercially available from the corresponding sources: 4-fluoro-N-methylbenzenesulfonamide and 4-fluoro- Ν,Ν-dimethylbenzene sulfonamide from Combi-Blocks Inc. (San Diego, CA); 4-fluoro-2-methyl-1-(methylsulfonyl)benzene from Matrix Scientific
(Columbia, SC); and 3,5-dihydroxybenzonitrile from Alfa Aesar (Ward Hill, MA).
Preparation of 1-(cvclopropylsulfonyl)-4-fluorobenzene:
Figure imgf000037_0001
The title compound was prepared according to a previously reported procedure (WO2005121110, page 173). 1H NMR (400 MHz, CDCI3) δ ppm 1.05 (m, 2 H), 1.35 (m, 2 H), 2.45 (m, 1 H), 7.20 (t, 2 H), 7.9 (m, 2 H).
Preparation of 5-bromo-N,N-dimethylpyrimidine-2-carboxamide:
H
Figure imgf000038_0001
Oxalyl chloride (47.4 g, 369 mmol) was added to a suspension of 5- bromo-pyrimidine-2-carboxylic acid (50 g, 250 mmol) in dichloromethane (821 mL) at room temperature followed by 1-2 drops of N,N- dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours when LCMS in methanol indicated the presence of the methyl ester and some acid. More N,N-dimethylformamide (0.2 mL) was added to the reaction mixture. The acid dissolved after 30 minutes, at which time LCMS showed the corresponding methyl ester and no starting material peak was observed. The reaction was concentrated and dried in vacuo to afford the crude 5-bromo-pyrimidine-2-carbonyl chloride (55 g, 100%).
The 5-bromo-pyrimidine-2-carbonyl chloride (55 g, 250 mmol) was dissolved in tetrahydrofuran (828 mL) and dimethylamine (2M solution in tetrahydrofuran) (373 mL, 745 mmol) was added portion-wise at room temperature. The reaction was stirred at room temperature under nitrogen for 16 hours, after which time, LCMS indicated completion. The mixture was diluted with ethyl acetate (500 mL) and washed with water (500 mL). The water layer was further extracted with dichloromethane (5x500 mL), all organics combined, and dried over magnesium sulfate. The filtrate was concentrated and then suspended in methyl-f-butylether (650 mL). The solution was then heated to reflux. The hot solution was allowed to cool overnight to afford pink crystals. The crystals were filtered and washed with cold methyl-f-butylether (100 mL). The solid was dried in a vacuum oven at 55°C for 12 hours to afford the title compound 5-bromo-N,N-dimethyl pyrimidine-2-carboxamide (44 g, 77%) as a pink solid. 1H NMR (400 MHz, CDCI3) δ ppm 2.94 (s, 3 H) 3.13 (s, 3 H) 8.85 (s, 2 H).
Preparation of 5-chloro-N,N-dimethylpyrazine-2-carboxamide:
H
Figure imgf000039_0001
5-chloropyrazine-2-carbonyl chloride (2.13g, 12.05 mmol) and dimethylamine HCI salt (1.06 g, 12.7 mmol) were suspended in
dichloromethane (50 mL) with stirring. Triethylamine (5.04mL, 36.2 mmol) in dichloromethane (25 mL) was added dropwise at 0°C to the reaction mixture. The combined solution was warmed up to ambient temperature and stirred for 4 hours. The reaction was diluted with dichloromethane, washed with 1 N HCI, water, and brine. The organics were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column
chromatography eluting with a gradient of 30 - 80% ethyl acetate in heptane to provide desired 5-chloro-N,N-dimethylpyrazine-2-carboxamide (2.24 g, 85%). 1H NMR (400 MHz, CDCI3) δ ppm 3.12 (s, 3 H), 3.15 (s, 3 H), 8.53 (d, J=1.37 Hz, 1 H), 8.74 (d, J=1.37 Hz, 1 H).
Figure imgf000039_0002
The title compound was prepared by a method analogous to that described for 5-chloro-N,N-dimethylpyrazine-2-carboxamide, using azetidine
hydrochloride in place of dimethylamine hydrochloride. 1H NMR (400 MHz, CDCI3) δ ppm 2.33 - 2.42 (m, 2 H), 4.23 - 4.29 (m, 2 H), 4.63 - 4.69 (m, 2 H), 8.51 (d, J=1.37 Hz, 1 H), 9.08 (d, J=1.37 Hz, 1 H).
Preparation of 3,5-difluoro-N,N-dimethylpicolinamide:
Figure imgf000040_0001
3,5-difluoropyridine-2-carboxylic acid (20.0 g, 125.7 mmol) was dissolved in dichloromethane (190 mL). Thionyl chloride (46 mL, 630 mmol) was added, followed by 5 drops of anhydrous Ν,Ν-dimethylformamide. The reaction was heated to reflux and stirred for 18 hours. After cooling to room temperature, the reaction was concentrated and azeotroped with
dichloromethane to give the desired 3,5-difluoropicolinoyl chloride (22.3g, 100%).
3,5-difluoropicolinoyl chloride (11.2 g, 62.9 mmol) was suspended in dichloromethane (60mL) and cooled to 0°C. Dimethylamine HCI salt (5.13g, 62.9mmol) was added. A solution of triethylamine (27.2mL, 195mmol) in dichloromethane (20mL) was then added drop-wise over a period of 3.5 hours. Following the addition, the reaction was allowed to gradually warm to room temperature and stir for 15 hours. The reaction was diluted with saturated sodium bicarbonate and extracted four times with
dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by column chromatography (30 - 100% ethyl acetate in heptane) gave the title compound 3,5-difluoro- N,N-dimethylpicolinamide (10.5 g, 89%) as an off-white oil. 1H NMR (400
MHz, CDCI3) δ ppm 2.92 (s, 3 H), 3.14 (s, 3 H), 7.26 - 7.30 (m, 1 H), 8.34 (s,
1 H).
Figure imgf000040_0002
The title compound was prepared by a method analogous to that described for 3,5-difluoro-N,N-dimethylpicolinamide, using azetidine hydrochloride in place of dimethylamine hydrochloride. 1H NMR (400 MHz, CDCI3) δ ppm 2.28 - 2.39 (m, 2 H), 4.24 (t, J=7.71 Hz, 2 H), 4.32 (t, J=7.71 Hz, 2 H), 7.26 - 7.31 (m, 1 H), 8.31 (s, 1 H). MS (M+1): 199.0.
Figure imgf000041_0001
Triisopropylchlorosilane (11.1 mL, 52.6 mmol) was added to a solution of (2R)-propane-1 ,2-diol (4000 mg, 52.6 mmol) and
diisopropylethylamine (12.8 mL, 73.6 mmol) in dichloromethane (90 mL). The mixture was stirred at room temperature overnight. TLC indicated and LCMS of an aliquot indicated substantial amount of the starting material was not consumed. 2 equivalents of imidazole followed by N,N- dimethylformamide (10 mL) were added. The mixture was stirred for another day. TLC and LCMS of an aliquot indicated the desired product was produced. The mixture was quenched with 1 N hydrochloric acid (50 mL) and extracted with diethyl ether (200 mL x 2). The organic layers were combined, washed with brine and concentrated. Purification by column chromatography eluting with 0 - 30% ethyl acetate in hexane gave the title compound (R)-1-(triisopropylsilyloxy)propan-2-ol (10.3 g, 84.3%) as a colorless liquid. 1H NMR (400 MHz, CDCI3) δ ppm 3.85 (m, 1 H), 3.69 (dd, J = 9.6, 3.4 Hz, 1 H), 3.44 (dd, J = 9.6, 7.9 Hz, 1 H), 2.57 (d, J = 3.0 Hz, 1 H), 1.12 (d, J = 6.2 Hz, 3 H), 1.06-1.04 (m, 21 H). MS (M+1): 233.5.
Preparation of (R)-1-(tert-butyldimethylsilyloxy)propan-2-ol
Figure imgf000041_0002
The title compound was prepared by an analogous method as described for (R)-1-(triisopropylsilyloxy)propan-2-ol using tert-butyl chlorodimethylsilane. 1H NMR (400 MHz, CDCI3) δ ppm 0.05 (s, 6 H), 0.88 - 0.90 (m, 9 H), 1.10 (d, J=6.25 Hz, 3 H), 2.43 (d, J=3.12 Hz, 1 H), 3.32 (dd, J=9.76, 7.81 Hz, 1 H), 3.57 (dd, J=9.86, 3.42 Hz, 1 H), 3.75 - 3.84 (m, 1 H). Preparation of 1-(ethylsulfonyl)- -fluorobenzene
Figure imgf000042_0001
The compound was prepared by a method analogous to that described for 1-fluoro-4-(isopropylsulfonyl)benzene as described in PCT International Patent Application Publication WO2007/31747.
Preparation of 1-fluoro-4-(isopropylsulfonyl)benzene
Figure imgf000042_0002
A mixture of the thiophenol (1.0 g, 7.8 mmol), isopropyl iodide (1.17 ml_, 11.7 mmol) and potassium carbonate (1.62 g, 11.7 mmol) in DMF (10 ml_) was stirred at 60 °C overnight. The reaction was filtered. The filtrate was partitioned between water and ether. The aqueous was extracted with ether. Combined organic layers were washed with water, brine, dried
(Na2S04) and concentrated in vacuo to give a colorless oil (2 g). NMR showed a lot of DMF present. This material was dissolved in ether and washed with water and brine, dried (Na2S04) and concentrated in vacuo to give a colorless oil (1.34 g, 100%). 1H NMR (400 MHz, CDCI3) δ ppm 7.36 - 7.42 (m, 2 H), 6.95 - 7.02 (m, 2 H), 3.19 - 3.30 (m, 1 H), 1.25 (d, 6 H).
To a solution of the sulfide (1.34 g, 7.87 mmol) in methylene chloride (25 ml_) at 0 °C was added mCPBA (4.17 g, 70%, 16.9 mmol) portion-wise. The mixture as stirred at room temperature overnight. The reaction was diluted with methylene chloride and washed with sat aqueous NaHC03
(4x15 ml_), brine, dried (Na2S04) and concentrated in vacuo. The residue was purified over 40 g redisep silica cartridge (eluted with 0-25% ethyl acetate in heptane) to give a white solid (2 g). This material was dissolved in ethyl acetate and washed with saturated Na2C03 (6 x 10 ml_) and brine, dried (Na2S04) and concentrated in vacuo to give a white solid (1.38 g, 87%). 1H NMR (400 MHz, CDCI3) δ ppm 7.86-7.92 (m, 2 H), 7.20-7.27 (m, 2 H), 3.11-3.23 (m, 1 H), 1.29 (d, 6 H). MS (M+1 ) 203.3. retention time 1.7 min (std).
Preparation of tert-butyl 4-fluorophenylsulfonyl(methyl)carbamate
Figure imgf000043_0001
A mixture of 4-fluoro-A/-methylbenzenesulfonamide (2 g, 10 mmol), (Boc)20 (3.46 g, 15.9 mmol), dimethylaminopyridine (0.646 g, 5.28 mmol) in acetonitrile (50 mL) was stirred at room temperature for 12 hours. The mixture was concentrated in vacuum and the residue was purified by Combiflash (petroleum ether/ethyl acetate, from 0% to 10%) to give the product (3 g, yield: 100%) as a white solid. 1H NMR (400 MHz, CDCI3) δ ppm 7.95 (m, 2 H), 7.22 (m, 2 H), 3.37 (s, 3 H), 1.39 (s, 9 H).
Preparation of tert-butyl 4-fluo -2-methylphenylsulfonyl(methyl)carbamate
Figure imgf000043_0002
The compound was prepared by a method analogous to that described for tert-butyl 4-fluorophenylsulfonyl(methyl)carbamate. 1H NMR (400 MHz, CDCI3) δ ppm 1.26 (s, 9 H), 2.49 (s, 3 H), 3.34 (s, 3 H), 6.95 - 7.03 (m, 2 H), 8.07 (dd, J=8.50, 5.76 Hz, 1 H).
Preparation of azetidin-1-yl(5-bromopyrimidin-2-yl)methanone:
Figure imgf000043_0003
To a suspension of 5-bromopyrimidine-2-carboxylic acid in methylene chloride (15 mL with 1 mL of THF added), oxalyl chloride was added at room temperature followed by a few drops of DMF. The mixture was stirred at room temperature for 1 hour. Additional oxalyl chloride (0.3 mL) was added and the mixture was stirred at room temperature for another 1.5 hours.
Reaction appears completed by LCMS. Reaction mixture was concentrated to dryness under reduced pressure.
To a solution of the resulting acid chloride (328 mg, 1.48 mmol) in methylene chloride (3 mL) at room temperature was added triethylamine (0.825 mL, 5.92 mmol) followed by azetidine hydrochloride (208 mg, 2.22 mmol). The mixture was stirred at room temperature over the weekend. The reaction mixture was partitioned between water and ethyl acetate.
Combined organic layers were washed with brine, filtered and concentrated in vacuo. The residue was purified over 12 g redisep silica cartridge (eluted with 20-100% ethyl acetate in heptane) to give a white solid (157.5 mg, 44%). 1H NMR (400 MHz, CDCI3) δ ppm 2.28 - 2.45 (m, 2 H), 4.21 - 4.35 (m, 2 H), 4.59 (dd, J=8.10, 7.32 Hz, 2 H), 8.89 (s, 2 H). MS (M+1 ): 242.2.
Preparation of (5-bromopyrimidin-2-yl)(pyrrolidin-1 -vQmethanone
Figure imgf000044_0001
The compound was prepared by a method analogous to that described for azetidin-1-yl(5-bromopyrimidin-2-yl)methanone. 1H NMR (400 MHz, CDCI3) δ ppm 1.81 - 2.02 (m, 4 H), 3.51 (t, J=6.35 Hz, 2 H), 3.68 (t, J=6.55 Hz, 2 H), 8.86 (s, 2 H). MS (M+1 ): 256.3.
Preparation of 3-bromo-1-methylpyrrolidin-2-one
Figure imgf000044_0002
The compound was prepared according to the procedure described in Tetrahedron Letters 2005, 3041 - 3044.
Preparation 1-(methylsulfonyl)pyrrolidin-3-yl methanesulfonate
Figure imgf000045_0001
The compound was prepared according to the procedure described in US Patent 5,770,611.
Preparation of 2-chloro-5-ethyl-4-(4-methoxybenzyloxy)pyrimidine
Figure imgf000045_0002
In a round bottom flask, (4-methoxyphenyl)methanol (859 mg) and lithium f-butoxide (453 mg) are stirred in THF (5.65 ml_) at 70 °C for 15 minutes and then cooled to room temperature. In a separate flask, 2,4- dichloro-5-ethylpyrimidine (1.00 g) is dissolved in DMF (10 ml_) and this solution is than transferred dropwise (over 30 minutes) to the previous mixture at 0 °C and then let warmed to room temperature. After 3 hours, the reaction proved to be completed by GC-MS with an isomers ratio of ~ 18 / 1. Reaction mixture diluted with ethyl acetate and washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford the crude. The residue was purified by flash column chromatography (S1O2, 5%-30% ethyl acetate / heptane) to provide 2-chloro-5-ethyl-4-(4- methoxybenzyloxy)pyrimidine (787 mg, 50%) as a colorless oil (Isomers ratio after purification ~ 32 / 1 ). MS (M+1 ): 279.0. 1H NMR (400 MHz, CDCI3) δ ppm 1.16 (m, J=7.43, 7.43 Hz, 3 H), 2.52 (q, J=7.62 Hz, 2 H), 3.81 (s, 3 H), 5.37 (s, 2 H), 6.85 - 6.95 (m, 2 H), 7.34 - 7.43 (m, 2 H), 8.10 (s, 1 H).
Preparation of 2-fluoro-6-(4-(methylthio)phenoxy)pyridine
Figure imgf000045_0003
In a sealed tube are combined 4-(methylthio)phenol (609 mg), 2,6- difluoropyridine (500 mg) and potassium carbonate (1.20 g) in DMF (11 mL) at 90 °C for 5 hours. Reaction proved to be completed by LC-MS and cooled down to room temperature. Reaction mixture diluted with EtOAc and washed with water three times, with brine one time, dried over sodium sulfate, filtered and concentrated to afford the crude material. The residue was purified by flash column chromatography (Si02, 0%-10% ethyl acetate / heptane) to provide 2-fluoro-6-(4-(methylthio)phenoxy)pyridine (929 mg, 91%) as a colorless oil. MS (M+1 ): 236.3. 1H NMR (500 MHz, CDCI3) δ ppm 2.51 (s, 3 H), 6.62 (dd, J=7.81 , 2.68 Hz, 1 H), 6.74 (dd, J=7.93, 1.59 Hz, 1 H), 7.08 - 7.12 (m, 2 H), 7.30 - 7.34 (m, 2 H), 7.76 (q, J=8.05 Hz, 1 H).
Figure imgf000046_0001
In a round bottom flask, sodium hydride dispersion 60% (204 mg) added to a solution of isopropanol (0.39 mL) in THF (17 mL). Stirred at room temperature for 30 minutes. 2-fluoro-6-(4-(methylthio)phenoxy)pyridine (800 mg) was then added in one portion (in 7 mL of THF). The flask was sealed and reaction heated at 120 °C overnight after which time the reaction proved to be completed by LC-MS. Reaction mixture diluted with EtOAc, and washed with water once, with brine once, dried over sodium sulfate, filtered and concentrated to afford the crude material. The residue was purified by flash column chromatography (Si02 (dry loading), 0%-30% ethyl acetate / heptane) to provide 2-isopropoxy-6-(4-(methylthio)phenoxy)pyridine (818 mg, 87%) as a light yellow oil. MS (M+1 ): 276.1. 1H NMR (400 MHz, CDCI3) δ ppm 1.24 (d, J=6.05 Hz, 6 H), 2.49 (s, 3 H), 5.03 (spt, J=6.19 Hz, 1 H), 6.29 (d, J=7.80 Hz, 1 H), 6.37 (d, J=8.00 Hz, 1 H), 7.04 - 7.09 (m, 2 H), 7.26 - 7.30 (m, 2 H), 7.51 (t, J=7.90 Hz, 1 H).
Preparation of 2-isopropoxy-6-(4-(methylsulfonyl)phenoxy)pyridine
Figure imgf000047_0001
In a round bottom flask, 2-isopropoxy-6-(4- (methylthio)phenoxy)pyridine (815 mg) dissolved in EtOAc (7.4 mL), methanol (7.6 mL) and water (5.0 mL) at room temperature. Oxone (3.91 g) was added portion-wise and the resulting mixture stirred at room
temperature for 6 hours. Reaction proved to be completed by TLC. The reaction mixture diluted with EtOAc, washed with water two times, with brine once, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2 (dry loading), 40%-60% ethyl acetate / heptane) to provide 2-isopropoxy-6- (4-(methylsulfonyl)phenoxy)pyridine (790 mg, 87%) as a colorless oil. MS (M+1): 308.1. 1H NMR (400 MHz, CDCI3) δ ppm 1.20 (d, 6 H), 3.05 (s, 3 H), 4.92 (spt, J=6.24 Hz, 1 H), 6.42 - 6.47 (m, 2 H), 7.22 - 7.29 (m, 2 H), 7.58 (t, J=7.90 Hz, 1 H), 7.89 - 7.95 (m, 2 H).
Figure imgf000047_0002
Step 1 : A round bottom flask was charged with 3-iodophenol (10.0 g, 45.6 mmol), imidazole (4.65 g, 68.3 mmol), and anhydrous DMF (100 mL). The mixture was stirred under nitrogen at 0 °C until a homogeneous solution resulted. Triisopropylsilyl chloride (10.7 mL, 50.1 mmol) was added dropwise via syringe to the stirred solution under nitrogen at 0 °C. The ice- water bath was removed and the solution was stirred overnight under nitrogen at room temperature. The reaction was poured into 500 mL water, and the aqueous was extracted with MTBE (methyl tert-butyl ether), 2 x 100 mL. The combined extracts were washed with sodium bicarbonate solution (aq. sat.), brine, dried over sodium sulfate, filtered and concentrated to a crude oil used as is in the next step. Step 2: A round bottom flask equipped with a condenser with an outlet to double manifold was charged with (3-iodophenoxy)triisopropylsilane (3.56 g, 9.84 mmol), cesium carbonate (4.81 g, 14.8 mmol), cuprous iodide (187 mg, 0.984 mmol), phenanthroline (354 mg, 1.97 mmol), then cyclobutanol (6.0 mL) as solvent and reactant. The mixture was heated to 120 °C overnight. The reaction was poured into water (150 mL) and extracted with about MTBE (100 mL). The biphasic mixture was filtered through celite to remove insolubles. The aqueous was extracted a second time with ethyl acetate. The combined extracts were washed with water once, brine once, dried over sodium sulfate, filtered and concentrated to an oil corresponding to 3-cyclobutoxyphenol.
Step 3: A round bottom flask was charged with the crude
cyclobutoxyphenol (1.61 g, 9.83 mmol), DMF (N,N-dimethylformamide) (30 mL), imidazole (2.01 g, 29.5 mmol), and TIPS-CI (triisopropylchloride) (5.26 mL, 24.6 mmol). The reaction was stirred under nitrogen over the weekend. The reaction was poured into water (250 mL) and the aqueous was extracted with MTBE (2 times 100 mL). The combined extracts were washed with sodium hydroxide (1N, aq.), water, brine, dried over sodium sulfate, filtered and concentrated to an oil. The oil was analysed by TLC, which showed the desired product nearly at the solvent front. No
unprotected phenol was observed. The oil was dissolved in a minimum amount of 20% ethyl acetate-heptane and filtered through a pad of 200 g. of silica gel eluting with 20% ethyl acetate-heptane. The fractions for desired product were combined and concentrated to provide (3-cyclobutoxy phenoxy)triisopropylsilane (2.74g, 86.8%) as a pale colored oil. Used as is in the next step.
Preparation of 3-cvclobutoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl) phenol
Figure imgf000049_0001
Step 1 : A sealed tube was charged with bispinacolatodiboron (1.30 g, 5.12 mmol), 4,4,-di-tert-butyl-2,2'-bipyridine (229 mg, 0.853 mmol) and (1 ,5- cyclooctadiene) (methoxy)iridium(l) dimer (283 mg, 0.427 mmol) and the 3- cyclobutoxyphenoxy)triisopropylsilane (2.74 g, 8.53 mmol) in anhydrous 2- methyl tetrahydrofuran (4 ml_). The mixture was stirred under nitrogen at room temperature then the solution was diluted with heptanes (4 ml_) and the solution was heated under nitrogen to 115 °C over the week-end. The reaction was analysed by GC-MS. The starting material was now
consumed. The reaction was filtered through 90 g. of silica gel and the filtrate was concentrated to provide (3-cyclobutoxy-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenoxy)triisopropylsilane (5.15 g, 135%). Use as a crude oil.
Step 2: A round bottom flask was charged with (3-cyclobutoxy-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)triisopropylsilane (3.81 g, 8.53 mmol) in dioxane (30 ml_). Water (7 ml_) was added followed by sodium carbonate (2.71 g, 25.6 mmol), 2-chloro-4-(4-methoxybenzyloxy) pyrimidine (2.57 g, 10.2 mmol), and CI2Pd(dppf) (697 mg, 0.853 mmol). The mixture was heated to 105 °C under nitrogen with a reflux condenser overnight. The reaction was partitioned between ethyl acetate and water. The aqueous was acidified to pH 4 with HCI (aq. 1 N). The aqueous was extracted a second time with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated to an oil. The residue was purified by flash column chromatography (S1O2 (dry loading), 0%-40% ethyl acetate / heptane) to provide 2-(3-cyclobutoxy-5- (triisopropylsilyloxy)phenyl)-4-(4-methoxybenzyloxy)pyrimidine (1.16 g, 25.4%) as an oil. MS (M+1 ): 535.4.
Step 3: A round bottom flask was charged with 2-(3-cyclobutoxy-5- (triisopropylsilyloxy)phenyl)-4-(4-methoxybenzyloxy)pyrimidine (1.16 g, 2.17 mmol) and anhydrous THF (5 ml_). The solution was stirred under nitrogen at room temperature. 1 M Tetrabutylammonium fluoride (6.51 ml_, 6.51 mmol) was added via syringe, and the yellow solution was stirred under nitrogen at room temperature overnight. The reaction was diluted with ethyl acetate and sodium bicarbonate solution (sat. aq.) the phases separated, and the aqueous was extracted a second time with ethyl acetate. The combined organics extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to provide 3-cyclobutoxy-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol (974 mg, 118%) as a crude solid. MS (M+1 ): 379.2.
Preparation of 3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)benzonitrile
Figure imgf000050_0001
A solution of 3,5-dihydroxybenzonitrile (6000 mg, 44.40 mmol) in N,N- dimethylformamide (30 ml_) was cooled in an ice-water bath while stirring magnetically under nitrogen. Added sodium hydride (60 % dispersion, 1950 mg, 48.8 mmol) slowly and stirred ~5 minutes at rt. (4-fluorophenyl)- methylsulfone (8510 mg, 48.8 mmol) was added and the mixture was heated at 65 °C over the weekend (2.5 days). The reaction was cooled to room temperature followed by the addition of potassium carbonate (12.3 g, 88.8 mmol) and 2-iodopropane (8.88 ml_, 88.8 mmol). The reaction mixture was stirred at 65 °C for 4 h. The solution was quenched with water (10 ml_) and 1 N hydrochloric acid. The residue was extracted with ethyl acetate (50 ml_ x 3). The combined organic layers were washed with brine (5 ml), dried with sodium sulfate and concentrated. Purification by column chromatography eluting with 0 - 30% ethyl acetate in hexane gave the title compound 3- isopropoxy-5-(4-(methylsulfonyl)phenoxy)benzonitrile (4100 mg, 27.9%) as a white solid. 1H NMR (400 MHz, CDCI3) δ ppm 7.94 (d, J = 9.0 Hz, 2 H), 7.13
(d, J = 9.0 Hz, 2 H), 6.95 (m, 1 H), 6.86 (m, 1 H), 6.77 (m, 1 H), 4.53 (heptet,
J = 6.0 Hz, 1 H), 3.06 (s, 3 H), 1.34 (d, J = 6.0 Hz, 6 H).
Preparation of 3-isopropo -5-(4-(methylsulfonyl)phenoxy)benzamidine
Figure imgf000051_0001
To a solution of ammonium chloride (2580 mg, 0.376 mmol) in toluene (15 ml_) was added a solution of trimethylaluminum (24.1 ml_, 2 M in toluene, 48.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and 3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)benzonitrile (4000 mg, 12.07 mmol) was added. The mixture was heated at 110 °C for 36 h. LCMS of an aliquot indicated the desired product was generated cleanly. The mixture was diluted with methanol and dichloromethane, stirred for a few minutes and filtered through a short pad of silica gel. The silica gel pad was washed with methanol/dichloromethane. The filtrate was concentrated, leading to the title compound 3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)benzamidine. The crude compound was used without further purification. 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J = 9.0 Hz, 2 H), 7.24 (d, J = 9.0 Hz, 2 H), 7.18 (m, 1 H), 7.05 (m, 1 H), 6.98 (m, 1 H), 4.69 (heptet, J = 6.0 Hz, 1 H), 3.11 (s, 3 H), 1.33 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 349.0.
Preparation of 3-hvdroxy-5-isopropoxybenzonitrile
Figure imgf000052_0001
A mixture of the 3,5-dihydroxybenzonitrile (150 mg, 1.11 mmol), 2- iodopropane (208 mg, 1.22 mmol) and potassium carbonate (169 mg, 1.22 mmol) in N,N-dimethylformamide (2 ml_) was stirred at 65 °C for 5 h and at room temperature for 2 days. LCMS showed starting material, mono- isopropylation and bis-isopropylation products. Water was added and the mixture was acidified to PH~5. The mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column
chromatography eluting with 5 - 100% ethyl acetate in hexane gave the title compound 3-hydroxy-5-isopropoxybenzonitrile (66.5 mg, 33.8%) as a white solid. 1H NMR (400 MHz, CDCI3) δ ppm 6.69 - 6.72 (m, 2 H), 6.64 (s, 1 H), 6.61 (m, 1 H), 4.53 (heptet, J = 6.0 Hz, 1 H), 1.31 (d, J = 6.0 Hz, 6 H). MS (M-1 ): 176.0.
Preparation of 3-isopropoxy-5-(1 -(methylsulfonyl)pyrrolidin-3-yloxy) benzamidine
Figure imgf000052_0002
Step 1 : To a vial was added 3-hydroxy-5-isopropoxybenzonitrile (200 mg, 1.13 mmol), N,N-dimethylformamide (1.5 ml_), cesium carbonate (588 mg, 1.81 mmol) and 1-(methylsulfonyl)pyrrolidin-3-yl methanesulfonate (330 mg, 1.36 mmol) at room temperature. The reaction was heated at 100 °C for 2.5 h. The mixture was cooled to room temperature and diluted with ethyl acetate and water. The insoluble solid was filtered, collected and dried under vacuo. NMR showed it was the desired product. The organic layer was separated from the filtrate and washed with water three times, dried, filtered and concentrated. Purification by column chromatography eluting with 20 - 80% ethyl acetate in hexane gave the title compound 3- isopropoxy-5-(1-(methylsulfonyl)pyrrolidin-3-yloxy)benzonitrile (total: 282 mg, 77%) as a white solid.
Step 2: To a solution of ammonium chloride (187 mg, 3.50 mmol) in toluene (1 mL) was added a solution of trimethylaluminum (1.17 mL, 2 M in toluene, 2.33 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and the substrate 3-isopropoxy-5-(1-(methylsulfonyl)pyrrolidin-3- yloxy)benzonitrile (189 mg, 0.583 mmol) was added. The mixture was heated at 105°C over the weekend. LCMS of an aliquot indicated the desired product was generated cleanly. The mixture was diluted with methanol, stirred for a few minutes and filtered through a short pad of silica gel. Washed with methanol. The filtrate was concentrated, leading to the title compound 3-isopropoxy-5-(1 -(methylsulfonyl)pyrrolidin-3-yloxy) benzamidine (302 mg) as a white solid. The crude compound was used without further purification. MS (M+1 ): 342.5.
Figure imgf000053_0001
Step 1 : A round bottom flask was charged with the 3-hydroxyphenyl benzoate (3.03 g, 14.1 mmol), potassium carbonate (3.91 g, 28.3 mmol), dimethylacetamide (28 mL), the cyclopentyl iodide (1.96 mL, 17.0 mmol). The reaction was heated at 75 °C under nitrogen overnight. The reaction was poured into water (100 mL) and extracted with MTBE (2 X 75 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide 3-(cyclopentyloxy)phenyl benzoate (4.20g, 105%) as a colorless oil. Use in the next step without any further purification. Step 2: A round bottom flask was charged with 3-(cyclopentyloxy) phenyl benzoate (4.00 g, 14.2 mmol) dissolved in methanol (100 ml_). To this, was added water (0.5 ml_) and solid KOH (1.87 g, 28.3 mmol). The solution was stirred under nitrogen overnight at room temperature. The reaction was concentrated to remove most of the methanol. The remaining liquid was diluted with some water and acidified to pH 3 with 1N HCI (aq.). The aqueous was extracted with MTBE (2 X 100 ml_). The combined extracts were washed with 15% sodium carbonate solution (aq.), brine, dried over sodium sulfate, filtered and concentrated to provide 3-(cyclopentyloxy) phenol (2.29 g, 90.6%) as an oil. Use in the next step without any further purification. MS (M-1): 177.1.
Step 3: A round bottom flask was charged with the 3-(cyclopentyloxy) phenol (2.29 g, 12.8 mmol), DMF (30 ml_), imidazole (2.18 g, 32.1 mmol), and TIPS-CI (5.49 ml_, 25.7 mmol). The reaction was stirred under nitrogen over the weekend. The reaction was poured into water (250 ml_), and the aqueous was extracted with MTBE (2 X 100 ml_). The combined extracts were washed with 1 N sodium hydroxide (aq.), water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The oil was dissolved in a minimum of 20% ethyl acetate / heptane and filtered through a pad of 250 g. of silica gel eluting with 20% ethyl acetate / heptane to provide (3-(cyclopentyloxy)phenoxy)triisopropylsilane (1.75 g, 40.8%) as a pale yellow oil.
Preparation of (3-(cvclopentyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenoxy)triisopropylsilane
Figure imgf000054_0001
The title compound (3-(cyclopentyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)triisopropylsilane was prepared by a method analogous to that described for tert-butyl(3-isopropoxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane using (3- (cyclopentyloxy)phenoxy)triisopropylsilane. MS (M): 460.
Preparation of 3-(cvclopentyloxy)-5-(4-(4-methoxybenzyloxy)pyrimidin-2- yl)phenol
Figure imgf000055_0001
The title compound 3-(cyclopentyloxy)-5-(4-(4-methoxybenzyloxy) pyrimidin-2-yl)phenol was prepared by a method analogous to that described for 3-isopropoxy-5-(4-(4-methoxybenzyloxy) pyrimidin-2-yl)phenol using 2- chloro-4-(4-methoxybenzyloxy)pyrimidine. 1H NMR (400 MHz, CDCI3) δ ppm 1.31 (s, 1 H), 1.61 - 1.69 (m, 2 H), 1.76 - 1.87 (m, 2 H), 1.88 - 1.99 (m, 4 H), 3.83 (s, 3 H), 4.83 - 4.89 (m, 1 H), 5.49 (s, 2 H), 6.55 (t, J=2.34 Hz, 1 H), 6.64 (d, J=5.66 Hz, 1 H), 6.90 - 6.96 (m, 2 H), 7.40 - 7.46 (m, 2 H), 7.52 (dd, J=2.34, 1.37 Hz, 1 H), 7.60 (dd, J=2.34, 1.37 Hz, 1 H), 8.49 (d, J=5.66 Hz, 1 H). MS (M+1 ): 393.3.
Preparation of (S)-3-(1 -methoxypropan-2-yloxy)-5-(4-(methylsulfonyl) phenoxy)benzonitrile:
Figure imgf000055_0002
Step 1 : Sodium hydride (230 mg, 5.74 mmol, 60% dispersion) was added to a dried flask containing 3,5-dihydroxybenzonitrile (1 g, 7.40 mmol) and N,N-dimethylformamide (10 ml_) at 0 °C. The mixture was let warmed to room temperature and stirred for 5 minutes. 1-fluoro-4-(methylsulfonyl) benzene (900 mg, 5.17 mmol) was added and the reaction was heated at 65 °C over weekend. TLC and LCMS showed only a little product. Another 100 mg of sodium hydride and 200 mg of 1-fluoro-4-(methylsulfonyl)benzene were added and the reaction was heated at 75 °C for 18 h and 150 °C for 18 hours. LCMS showed the desired mono-arylation and bis-arylation products were generated. N,N-dimethylformamide was removed. Ethyl acetate and ammonium chloride (saturated aqueous) were added. The organic layer was separated and washed by water twice followed by brine wash. The organic layer was dried, filtered and concentrated. Purification by column chromatography eluting with 20 - 60% EtOAc in hexane gave the title compound 3-hydroxy-5-(4-(methylsulfonyl)phenoxy)benzonitrile (780 mg, 36.4%) as a white solid. MS (M-1 ): 288.2.
Step 2: To the solution of 3-hydroxy-5-(4-(methylsulfonyl)phenoxy) benzonitrile (150 mg, 0.518 mmol), (R)-1-methoxypropan-2-ol (93.4 mg, 1.04 mmol) and triphenylphosphine (408 mg, 1.55 mmol) in tetrahydrofuran (3 ml_) was added diisopropyl azodicarboxylate (0.205 ml_, 1.04 mmol). The mixture was stirred at room temperature overnight. Purification by column chromatography eluting with 0 - 30% ethyl acetate in hexane gave the title compound (S)-3-(1-methoxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy) benzonitrile (170 mg, 90.8%) as an oil. 1H NMR (400 MHz, CDCI3) δ ppm 7.92 (d, J = 8.9 Hz, 2 H), 7.11 (d, J = 8.9 Hz, 2 H), 7.01 (m, 1 H), 6.86 (m, 1 H), 6.83 (m, 1 H), 4.53 (m, 1 H), 3.54 (dd, J = 10.4, 6.2 Hz, 1 H), 3.48 (dd, J = 10.4, 3.8 Hz, 1 H), 3.35 (s, 3 H), 3.04 (s, 3 H), 1.28 (d, J = 6.4 Hz, 3 H). MS (M+1 ): 362.1.
Preparation of (S)-3-(1 -methoxypropan-2-yloxy)-5-(4-(methylsulfonyl) phenoxy)benzamidine
Figure imgf000057_0001
The title compound was prepared by a method analogous to that described for 3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)benzamidine. MS (M+1 ): 379.5. The crude was used without further purification.
Preparation of (S)-3-(1-(benzyloxy)propan-2-yloxy)-5-(4-(methylsulfonyl) phenoxy)benzonitrile
Figure imgf000057_0002
To a solution of 3-hydroxy-5-(4-(methylsulfonyl)phenoxy)benzonitrile (380 mg, 1.31 mmol), (f?)-1-(benzyloxy)propan-2-ol (436 mg, 2.63 mmol) and triphenylphosphine (1030 mg, 3.94 mmol) in tetrahydrofuran (4 mL) was added diisopropyl azodicarboxylate (0.521 mL, 2.63 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water, dried over sodium sulfate and concentrated. The crude was purified by CombiFlash (40 g silica gel, ethyl acetate/heptane: 0-80%), leading to the desired product. 1H NMR (400 MHz, CDCI3) δ ppm 1.31 (d, J=6.25 Hz, 3 H), 3.05 (s, 3 H), 3.54-3.57 (dd, J=10.4, 3.9 Hz, 1 H), 3.59-3.63 (dd, J = 10.4, 6.25 Hz, 1 H), 4.54 (s, 2 H), 4.55 (m, 1 H), 6.86 (m, 2 H), 7.02 (dd, J=2.25, 1.27 Hz, 1 H), 7.06 - 7.15 (m, 2 H), 7.20 - 7.39 (m, 5 H), 7.81 - 7.98 (m, 2 H). MS (M+1 ): 438.2.
Preparation of (S)-3-(1-(benzyloxy)propan-2-yloxy)-5-(4-(methylsulfonyl) phenoxy)benzamidine
Figure imgf000058_0001
To a solution of ammonium chloride (284 mg, 5.31 mmol) in toluene (1.3 ml_) was added a solution of trimethylaluminum (1.77 ml_, 2 M in toluene, 3.54 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and (S)-3-(1-(benzyloxy)propan-2yloxy)-5-(4-(methylsulfonyl)phenoxy) benzonitrile (387 mg, 0.885 mmol) in toluene (3 ml_) was added. The mixture was heated at 110 °C overnight. LCMS of an aliquot indicated desired product was generated cleanly. The mixture was diluted with methanol, stirred for a few minutes and filtered through a short pad of silica gel (washed with methanol). The filtrate was concentrated. The crude was used as is. MS (M+1 ): 455.5.
Preparation of (S)-2-(3-(1-(benzyloxy)propan-2-yloxy)-5-(4-(methylsulfonyl)
Figure imgf000058_0002
The title compound (48 mg, 37%) was prepared by a method analogous to that previously described using (S)-3-(1-(benzyloxy)propan-2- yloxy)-5-(4-(methylsulfonyl)phenoxy)benzamidine. MS (M+1): 535.5.
Figure imgf000058_0003
A suspension of (4-methoxyphenyl)methanol (9720 mg, 70.4 mmol) and sodium fert-butoxide (3560 mg, 37.04 mmol) in tetrahydrofuran (60 mL) was refluxed for 1 h. The suspension was cooled to 0 °C and was added dropwise to the solution of 2,4-bischloropyrimidine (5010 mg, 33.63 mmol) in N,N-dimethylformamide (25 mL) at -70 °C. The mixture was gradually warmed up to room temperature over 2 h and quenched with 1 N
hydrochloric acid. The mixture was extracted with diethyl ether (100 mL x 4). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography eluting with 0 - 25% ethyl acetate in hexane gave the title compound 4-(4- methoxybenzyloxy)-2-chloropyrimidine (early fractions were collected as a single regioisomer, 1700 mg, 18.3%) as a white solid. 1H NMR (400 MHz, CDCI3) δ ppm 8.28 (d, J = 5.8 Hz, 1 H), 7.39 (d, J = 8.6 Hz, 2 H), 6.92 (d, J = 8.6 Hz, 2 H), 6.66 (d, J = 5.8 Hz, 1 H), 5.35 (s, 2 H), 3.81 (s, 3 H). MS (M+1 ): 251.3.
Figure imgf000059_0001
The flask containing the crude 3,5-bis(fert-butyldimethylsilyloxy) phenylboronic acid (2000 mg, 5.229 mmol), 4-(4-methoxybenzyloxy)-2- chloropyrimidine (1310 mg, 5.23 mmol, >95% purity), sodium carbonate (1110 mg, 10.5 mmol) and dichloro-((bis-diphenylphosphino)ferrocenyl) palladium (II) (280 mg, 0.382 mmol) was evacuated and refilled with nitrogen three times. Dimethoxyethane (12 mL) and water (4 mL) were added. The mixture was heated at 70 °C overnight. LCMS of an aliquot indicated the desired product and the mono-desilylation product were generated. The mixture was diluted with water and ammonium chloride (saturated aqueous). The mixture was extracted with (50 mL x 4). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated.
The crude residue was dissolved in tetrahydrofuran (10 mL).
Tetrabutylammonium fluoride (10.5 mL, 1 M in THF, 10.5 mmol mmol) was added. The mixture was stirred at room temperature for 1 h. TLC indicated the starting material was consumed. The mixture was diluted with ethyl acetate and washed with ammonium chloride (saturated aqueous). The aqueous layer was back-extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated. Purification by column chromatography eluting with 0 - 100% ethyl acetate in hexane gave the title compound 5-(4-(4- methoxybenzyloxy)pyrimidin-2- yl)benzene-1 ,3-diol (1 100 mg, 64.9% over two steps) as a white solid. 1 H NMR (400 MHz, CD3OD) δ ppm 8.45 (d, J = 5.8 Hz, 1 H), 7.41 (d, J = 8.6 Hz, 2 H), 7.36 (d, J = 2.4 Hz, 2 H), 6.92 (d, J = 8.6 Hz, 2 H), 6.71 (d, J = 5.8 Hz, 1 H), 6.40 (t, J = 2.4 Hz, 1 H), 5.49 (s, 2 H), 3.77 (s, 3 H). MS (M+1 ): 325.4.
Preparation of 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-((S)-1 -(tert-
Figure imgf000060_0001
To a solution of the 5-(4-(4-methoxybenzyloxy)pyrimidin-2- yl)benzene-1 ,3-diol (300 mg, 0.925 mmol), (f?)-1 -(fert-butyldimethylsilyloxy) propan-2-ol (176 mg, 0.925 mmol) and triphenylphosphine (485 mg, 1 .85 mmol) in tetrahydrofuran (3 mL) was added diisopropyl azodicarboxylate (0.3 mL, 1 .15 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water, dried over sodium sulfate and concentrated. Purification by column chromatography eluting with 0 - 80% ethyl acetate in hexane gave the title compound 3-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)-5-((S)-1 -(fe/if-butyldimethylsilyloxy)propan- 2-yloxy)phenol (152 mg, 33.1%) as an oil. 1H NMR (400 MHz, CDCI3) δ ppm 8.47 (d, J = 5.8 Hz, 1 H), 7.60 (m, 1 H), 7.51 (m, 1 H), 7.41 (d, J = 8.6 Hz, 2 H), 6.91 (d, J = 8.6 Hz, 2 H), 6.63 (d, J = 5. 8 Hz, 1 H), 6.56 (m, 1 H), 5.68 (s, 1 H), 5.46 (dd, J = 12.2, 12.2 Hz, 2 H), 4.54 (m, 1 H), 3.84 (dd, J = 10.4, 5.6 Hz, 1 H), 3.80 (s, 3 H), 3.68 (dd, J = 10.4, 5.2 Hz, 1 H), 1.32 (d, J = 6.0 Hz, 3 H), 0.87 (s, 6 H), 0.07 (s, 3 H), 0.04 (s, 3 H).
Preparation of 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-((S)-1 -
Figure imgf000061_0001
The title compound was prepared by a method analogous to that described for 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-((S)-1 -(tert- butyldimethylsilyloxy)propan-2-yloxy)phenol, using (R)-1 -(triisopropylsilyloxy) propan-2-ol. Purification by column chromatography didn't lead to the pure compound, which was used without further purification and characterization.
Figure imgf000061_0002
To a stirred solution of resorcinol (5.00 g, 45.4 mmol) in DMF (45 ml_) at room temperature was added potassium carbonate (12.6 g, 90.8 mmol) followed by the addition of 2-iodopropane (5.90 ml_, 59.0 mmol) in one portion. The resulting mixture was stirred at room temperature overnight. The next morning, the reaction was stopped and diluted with HCI solution (aq. 1 N, 200ml_) and ethyl acetate (500ml_). The organic layer was extracted and washed with water (3 x 300ml_), brine (100ml_), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (S1O2, 0%-20% ethyl acetate / heptane) to provide 3-isopropoxyphenol (2.9 g, 42%) as an orange oil. 1H NMR (400 MHz, CDCI3) δ 1.32 (d, 6 H), 4.50 (spt, J = 6.06 Hz, 1 H), 4.74 (s, 1 H), 6.35 - 6.43 (m, 2 H), 6.47 (dd, J = 8.11 , 1.66 Hz, 1 H), 7.04 - 7.14 (m, 1 H).
Figure imgf000062_0001
In a round bottom flask was dissolved in dichloromethane (27 ml_), 3- isopropoxyphenol (2.90 g, 19.1 mmol), imidazole (1.95 g, 28.6 mmol) and fert-butylchlorodimethylsilane (3.45 g, 22.9 mmol). The reaction mixture was stirred at room temperature for 1 hour, after which time, no more starting material remain by TLC (Stain over KMn04 solution). The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (S1O2, 0%-20% ethyl acetate / heptane) to provide fert-butyl(3-isopropoxyphenoxy)dimethylsilane (4.56 g, 90%) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ 0.17 - 0.21 (m, 6 H), 0.96 - 0.99 (m, 9 H), 1.31 (d, J = 6.06 Hz, 6 H), 4.49 (spt, J = 6.06 Hz, 1 H), 6.36 - 6.39 (m, 1 H), 6.39 - 6.43 (m, 1 H), 6.49 (dd, J = 8.21 , 2.35 Hz, 1 H), 7.08 (t, J = 8.11 Hz, 1 H).
Preparation of tert-butyl(3-isopropoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-
Figure imgf000062_0002
In an oven dried microwave tube, bispinacolatodiboron (3.07 g, 12.0 mmol), 4,4'-di-tert-butyl-2,2,-bipyridine (91.8 mg, 0.342 mmol) and (1 ,5- cyclooctadiene) (methoxy)iridium(l) dimer (113 mg, 0.171 mmol) dissolved in MTBE (1.3 mL) and stirred (~10min.) until a deep red color is observed, tert- butyl(3-isopropoxyphenoxy)dimethylsilane is then dissolved in MTBE (1.5 mL) and transfered to the previous mixture in one portion. The tube was sealed and heated in the microwave at 100 °C for 10 hours. Reaction mixture filtered through a short pad of silica gel (100 mL of 30% ethyl acetate / heptane solution). Organics concentrated to provide ferf-butyl(3- isopropoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy) dimethylsilane as a orange oil (1.21 g, 91%) containing 18% of ferf-butyl(3- isopropoxyphenoxy)dimethylsilane. 1H NMR (400 MHz, CDCI3) δ 0.17 - 0.20 (m, 6 H), 0.94 - 0.98 (m, 9 H), 1.28 - 1.33 (m, 18 H), 4.54 (spt, J = 6.06 Hz, 1 H), 6.46 (t, J = 2.35 Hz, 1 H), 6.83 - 6.86 (m, 1 H), 6.94 (d, J = 1.95 Hz, 1 H).
Figure imgf000063_0001
Step 1 : A sealed tube is charged with fert-butyl(3-isopropoxy-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (3.00 g, 5.90 mmol), 2-chloro-4-(4-methoxybenzyloxy)pyrimidine (1.62 g, 6.48 mmol), Na2C03 (1.25 g, 11.8 mmol) and Pd(dppf)CI2 (345 mg, 0.471 mmol) and purged with N2 (g). DME (dimethoxyethane) / H20 (3 / 1 ) (18 mL) was added to the mixture and the tube was sealed and heated in an oil bath at 70 °C overnight under magnetic stirring. The reaction mixture was diluted with H20 (10 mL) and NH4CI (sat. aq.) (30 mL) to ca. pH 7. The mixture was extracted with ethyl acetate (3 X 100mL). The combined organic layers were washed with NH4CI (aq sat.) (50 mL), brine (50 mL), dried over Na2S04, filtered and concentrated under reduced pressure.
Step 2: The crude mixture was dissolved in THF (10mL) and TBAF solution (1 N / THF; 6.41 mL) was added and reaction stirred for 1.5 hours at room temperature. The reaction mixture was diluted with NH4CI (sat.aq.) (20 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with brine (20 ml_), dried over Na2S04 filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Si02, 10%-60% ethyl acetate / heptane) to provide 3-isopropoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)phenol as a white solid (790 mg, 37%). 1H NMR (400 MHz, CDCI3) δ 1.36 (d, J = 6.06 Hz, 6 H), 3.81 (s, 3 H), 4.63 (spt, J = 6.25 Hz, 1 H), 5.10 (s, 1 H), 5.46 (s, 2 H), 6.53 (t, J = 2.35 Hz, 1 H), 6.63 (d, J = 5.86 Hz, 1 H), 6.87 - 6.94 (m, 2 H), 7.37 - 7.44 (m, 2 H), 7.51 (dd, J = 2.35, 1.37 Hz, 1 H), 7.60 (dd, J = 2.35, 1.37 Hz, 1 H), 8.47 (d, J = 5.86 Hz, 1 H); MS (M+1 ): 367.5.
Figure imgf000064_0001
A mixture of 5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)benzene-1 ,3- diol (200 mg, 0.617 mmol), 2-iodobutane (71.2 μΙ_, 0.648 mmol) and potassium carbonate (85.3 mg, 0.617 mmol) in N,N-dimethylformamide (1 ml_) was stirred at 65 °C overnight. The mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid, dried over sodium sulfate and concentrated. Purification by column chromatography eluting with 0 - 30% ethyl acetate in hexane gave the title compound 3-(4-(4-methoxybenzyloxy) pyrimidin-2-yl)-5-sec-butoxyphenol (30 mg, 13%) as a white solid. 1H NMR (400 MHz, DMSO-de) δ ppm 9.57 (s, 1 H), 8.56 (d, J = 5.6 Hz, 1 H), 7.44- 7.42 (d, J = 8.6 Hz, 2 H), 7.43 (m, 1 H), 7.37 (m, 1 H), 6.93 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 5.6 Hz, 1 H), 6.44 (m, 1 H), 5.44 (s, 2 H), 4.36 (m, 1 H), 3.72 (s, 3 H), 1.67-1.57 (m, 2 H), 1.23 (d, J = 6.0 Hz, 3 H), 0.93 (t, J = 7.4 Hz, 3 H).MS (M+1 ): 451.5.
Preparation of 4-(4-methoxybenzyloxy-2-ch loro-5-meth yl pyri m id i ne
Figure imgf000065_0001
(4-methoxyphenyl)methanol (9400 mg, 68.0 mmol) and 2,4-dichloro- 5-methylpyrimidine (9810 mg, 60.2 mmol) were dissolved in toluene (200 ml_) and cooled to -25 °C. Powdered Potassium hydroxide (5350 mg, 95.4 mmol) was added with stirring and stirred at this temperature for 2.5 hrs. Reaction appears nearly complete by TLC and LC/MS. Diluted to 500 ml_ with ethyl acetate and washed with water (2 x 500 ml) and brine (100 ml_). The organic layer was dried over magnesium sulfate, filtered and
concentrated to an oil. Oil partially crystallized on standing over weekend. Dissolved in dichloromethane and filtered through a plug of silica gel (85g), eluting with 100% dichloromethane until a significant amount of (4- methoxyphenyl)methanol was evident by TLC (100% dichloromethane, potassium permanganate stain). Filtrate was concentrated under reduced pressure. NMR of the oil obtained suggests ca 8% wrong regioisomer and 20% unreacted staring material still present with very little detectable (4- methoxyphenyl)methanol. Oil began to solidify on standing, dissolved in hot heptane/dichloromethane then cooled to RT and seeded with a small amount of reserved solid from above. Resulting crystals were collected by filtration and washed with 2 x 5% dichloromethane/heptane and 2 x heptane. Dried under air stream to give the title compound 4-(4-methoxybenzyloxy-2- chloro-5-methylpyrimidine (5.85 g, 37%, single regioisomer) as a white solid. 1H NMR (400 MHz, CDCI3) δ ppm 8.10 (s, 1 H), 7.39 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 5.37 (s, 2 H), 3.81 (s, 3 H), 2.09 (s, 3 H). MS (M+1 ): 416.4.
Preparation of 3-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2-yl)-5- isopropoxyphenol
Figure imgf000066_0001
The flask containing the crude fert-butyl(3-isopropoxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (1000 mg, 2.548 mmol), 4-(4-methoxybenzyloxy-2-chloro-5-methylpyrimidine (674 mg, 2.55 mmol, >95% purity), sodium carbonate (540 mg, 5.10 mmol) and dichloro- ((bis-diphenylphosphino)ferrocenyl)palladium (II) (136 mg, 0.186 mmol) was evacuated and refilled with N2 three times. 1 ,2-Dimethoxyethane (7 mL) and water (2.3 mL) were added. The mixture was heated at 70 °C for 5 h and 65 °C overnight. The mixture was diluted with water and ammonium chloride (saturated aqueous). The mixture was extracted with ethyl acetate (50 mL x 4). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude was dissolved in tetrahydrofuran (10 mL) and tetrabutylammonium fluoride (3.82 mL, 1 M in tetrahydrofuran, 3.82 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate and washed with ammonium chloride (saturated aqueous). The aqueous layer was back-extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated. Purification by column chromatography eluting with 0 - 100% ethyl acetate in hexane gave the title compound 3-(4- (4-methoxybenzyloxy)-5-methylpyrimidin-2-yl)-5-isopropoxyphenol (470 mg, 48.5% over 2 steps) as a white solid. 1H NMR (400 MHz, CDCI3) δ ppm 8.29 (s, 1 H), 7.55 (m, 1 H), 7.49 (m, 1 H), 7.42 (d, J = 8.8 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 6.51 (m, 1 H), 5.48 (s, 2 H), 4.65 (heptet, J = 6.0 Hz, 1 H), 3.80 (s, 3 H), 2.15 (s, 3 H), 1.36 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 381.5.
Preparation of (S)-3-sec-butoxyphenyl benzoate
Figure imgf000067_0001
Triphenylphosphine (3.67g, 14.0mmol) and
diisopropylazodicarboxylate, DIAD (2.41 mL, 12.1 mmol) stirred in 50 ml_ of THF for 15 minutes until the ylid formed crashed out of the solution. (R)- butan-2-ol (1.12ml_, 12.1 mmol) followed by 3-hydroxyphenyl benzoate (2.00g, 9.34mmol) are then added in one portion to the previously formed suspension. The heterogeneous mixture become a clear solution. The reaction was stirred at room temperature for 4 hours. Reaction on going but not completed. The mixture was heated at 50 °C overnight. THF removed under reduced pressure. The residue was purified by flash column chromatography (S1O2, 0%-20% ethyl acetate / heptane) to provide (S)-3- sec-butoxyphenyl benzoate (2.25 g, 89%) as a yellow oil containing a certain amount of triphenylphosphine. Use without further purification. MS (M+1 ): 271.4.
Figure imgf000067_0002
(S)-3-sec-butoxyphenyl benzoate (2.25g, 8.32mmol) dissolved in THF (21 mL) and methanol (15ml_) and then, at room temperature, sodium hydroxide (1 M aq., 8.32ml_) added dropwise. Stirred for 30 minutes at room temperature. Reaction mixture acidified to pH 2 with HCI (1 N, aq.) and organics removed under reduced pressure. Ethyl Acetate added to the flask and extracted 1x with water, 1x with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a colorless oil (1.03g, 74%). 1H NMR (400 MHz, CDCI3) δ ppm 0.95 (m, J=7.43, 7.43 Hz, 3 H), 1.27 (d, J=6.06 Hz, 3 H), 1.54 - 1.66 (m, 1 H), 1.66 - 1.79 (m, 1 H), 4.24 (sxt, J=6.06 Hz, 1 H), 4.64 (br. s., 1 H), 6.34 - 6.39 (m, 2 H), 6.43 - 6.49 (m, 1 H), 7.06 - 7.12 (m, 1 H). MS (M+1 ): 167.2.
Preparation of (S)-(3-sec-butoxyphenoxy)(tert-butyl)dimethylsilane
Figure imgf000068_0001
In a round bottom flask, (S)-3-sec-butoxyphenol (1.02 g, 6.13 mmol), fert-butylchlorodimethylsilane (1.39 g, 9.20 mmol) and imidazole (836 mg, 12.3 mmol) stirred in dichloromethane at room temperature overnight.
Dichloromethane added and the reaction mixture was washed with water 2 times, brine 1 time, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude material. The residue was purified by flash column chromatography (S1O2, 0%-30% EtOAc / heptane) to provide (S)-(3-sec-butoxyphenoxy)(tert-butyl)dimethylsilane (1.52 g, 88%) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ ppm 0.16 - 0.20 (m, 6 H), 0.92 - 0.98 (m, 12 H), 1.27 (d, J=6.06 Hz, 3 H), 1.54 - 1.65 (m, 1 H), 1.65 - 1.78 (m, 1 H), 4.23 (sxt, J=6.06 Hz, 1 H), 6.36 - 6.42 (m, 2 H), 6.46 - 6.51 (m, 1 H), 7.07 (t, J=8.01 Hz, 1 H). MS (M+1): 281.5.
Preparation of (S)-(3-sec-butoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-
Figure imgf000068_0002
A microwave sealed tube was charged with bispinacolatodiboron (480 mg, 1.87 mmol), di- -methoxybis(1 ,5-cyclooctadiene)diiridium (I) (17.5 mg, 0.0265 mmol), 4,4'-di-tert-butyl-2,2,-bipyridine (14.4 mg, 0.0535 mmol) and methylfertbutylether (1.5 ml_). The mixture was stirred for 10 minutes at room temperature or until a deep red solution is observed. (S)-(3-sec- butoxyphenoxy)(tert-butyl)dimethylsilane (750 mg, 2.67 mmol) was then added to the previously formed solution (in 1.2 ml_ of methyl fert-butyl ether) of and the reaction stirred for 6 hours at 100 °C in the microwave. Reaction mixture filtered through a pad of silica gel (30% ethyl acetate/heptane).
Concentration of the organics give (S)-(3-sec-butoxy-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenoxy)(tert-butyl)dimethylsilane (1.03g, 47.5%) as an orange oil. The purity is 75% and the only contaminant observed is the remaining (S)-(3-sec-butoxyphenoxy) (tert-butyl)dimethylsilane. The material was used without further purification. 1H NMR (400 MHz, CDCI3) δ ppm 0.16 - 0.20 (m, 6 H), 0.95 - 0.97 (m, 9 H), 1.23 - 1.28 (m, 6 H), 1.31 (s, 12 H), 1.55 - 1.76 (m, 2 H), 4.25 - 4.34 (m, 1 H), 6.47 (t, J=2.35 Hz, 1 H), 6.81 - 6.85 (m, 1 H), 6.93 (d, J=1.76 Hz, 1 H).
Preparation of (S)-3-seobutoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2- vQphenol
Figure imgf000069_0001
Step 1 : A round bottom flask was charged with (S)-(3-sec-butoxy-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)(tert-butyl)
dimethylsilane (1.00 g, 1.80 mmol), 2-chloro-4-(4-methoxybenzyloxy) pyrimidine (555 mg, 1.20 mmol), sodium carbonate (391 mg, 3.69 mmol) and [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (135 mg, 0.184 mmol). The flask was purged with nitrogen. DME / H20 (2 / 1 ) (6 ml_) were added and the reaction mixture was heated at 70°C overnight. Ammonium chloride (sat.aq.) added and the mixture was extracted with ethyl acetate (80 ml_ x 2). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure.
Step 2: The crude mixture was dissolved in THF (5ml) and then, TBAF 1 M / THF (3.4 ml_) was added in one portion. Reaction stirred for 1 hour at room temperature. NH4CI (sat.aq.) added and the reaction mixture was extracted with EtOAc (80 ml_ x 2). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (S1O2, 20%-60% ethyl acetate / heptane) to provide (S)-3- sec-butoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)phenol (327 mg, 47%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (t, 3 H), 1.26 (d, J=6.05 Hz, 3 H), 1.53 - 1.73 (m, 2 H), 3.74 - 3.76 (m, 3 H), 4.32 - 4.42 (m, 1 H), 5.47 (s, 2 H), 6.46 (t, J=2.34 Hz, 1 H), 6.85 (d, J=5.66 Hz, 1 H), 6.92 - 6.96 (m, 2 H), 7.40 (dd, J=2.34, 1.37 Hz, 1 H), 7.43 - 7.49 (m, 3 H), 8.58 (d, J=5.66 Hz, 1 H), 9.59 (s, 1 H). MS (M+1 ): 381.5.
Preparation of (S)-3-sec-butoxy-5-(4-(4-methoxybenzyloxy)-5- methylpyrimidin-2-yl)phen
Figure imgf000070_0001
The title compound ((S)-3-sec-butoxy-5-(4-(4-methoxybenzyloxy)-5- methylpyrimidin-2-yl)phenol) was prepared by a method analogous to that described for (S)-3-sec-butoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2- yl)phenol using 2-chloro-4-(4-methoxybenzyloxy)-5-methylpyrimidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (t, 3 H), 1.25 (d, J=6.06 Hz, 3 H), 1.53 - 1.74 (m, 2 H), 2.12 (s, 3 H), 3.75 (s, 3 H), 4.31 - 4.42 (m, 1 H), 5.50 (s, 2 H), 6.43 (t, J=2.25 Hz, 1 H), 6.92 - 6.98 (m, 2 H), 7.35 - 7.39 (m, 1 H), 7.41 - 7.44 (m, 1 H), 7.44 - 7.49 (m, 2 H), 8.43 (d, J=0.78 Hz, 1 H), 9.55 (s, 1 H). MS (M+1 ): 395.5.
Preparation of (±)-3-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2-yl)-5- (tetrahvdrofuran-3-yloxy)phenol
Figure imgf000070_0002
The title compound (±)-3-(4-(4-methoxybenzyloxy)-5-methylpyrimidin- 2-yl)-5-(tetrahydrofuran-3-yloxy)phenol was prepared by a method
analogous to that described for (S)-3-sec-butoxy-5-(4-(4-methoxybenzyloxy) pyrimidin-2-yl)phenol using (±)-tetrahydrofuran-3-ol for the first step involving a mitsunobu reaction. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 - 2.00 (m, 1 H), 2.09 (s, 3 H), 2.13 - 2.25 (m, 1 H), 3.71 (s, 3 H), 3.72 - 3.90 (m, 4 H), 4.97 - 5.03 (m, 1 H), 5.47 (s, 2 H), 6.40 (t, J=2.24 Hz, 1 H), 6.89 - 6.94 (m, 2 H), 7.32 (dd, J=2.34, 1.37 Hz, 1 H), 7.41 - 7.45 (m, 3 H), 8.40 (d, J=0.98 Hz, 1 H), 9.60 (s, 1 H). MS (M+1 ): 409.0.
Both enantiomers were isolated by preparative SFC using column Chiralpak IC (21 X 250 mm), 65 /35 (C02 / Ethanol), 65 ml_ / min. to provide both enantioenriched compounds. PEAK 1 : RT: 4.33 min. (> 99.5%ee), [O]D = - 8.6 (c = 0.5, DMSO), from here, PEAK 1 will be named (-)-3-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)-5-(tetrahydrofuran-3- yloxy)phenol. PEAK 2: RT: 4.73 min. (98.1%ee), [a]D = + 9.6 (c = 0.5, DMSO), from here, PEAK 2 will be named (+)-3-(4-(4-methoxybenzyloxy)-5- methylpyrimidin-2-yl)-5-(tetrahydrofuran-3-yloxy)phenol.
Preparation of (±)-3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-
(tetrahydrofuran-3-yloxy)phenol
Figure imgf000071_0001
The title compound (±)-3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5- (tetrahydrofuran-3-yloxy)phenol was prepared by a method analogous to that described for (S)-3-sec-butoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2- yl)phenol using (±)-tetrahydrofuran-3-ol for the first step involving a Mitsunobu reaction and 2-chloro-4-(4-methoxybenzyloxy)pyrimidine for the step involving a Suzuki cross-coupling. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92 - 2.01 (m, 1 H), 2.14 - 2.25 (m, 1 H), 3.72 (s, 3 H), 3.72 - 3.90 (m, 4 H), 4.99 - 5.05 (m, 1 H), 5.44 (s, 2 H), 6.43 (t, J=2.35 Hz, 1 H), 6.83 (d, J=5.67 Hz, 1 H), 6.88 - 6.94 (m, 2 H), 7.35 (dd, J=2.35, 1.37 Hz, 1 H), 7.40 - 7.45 (m, 2 H), 7.46 (dd, J=2.15, 1.37 Hz, 1 H), 8.55 (d, J=5.67 Hz, 1 H), 9.65 (s, 1 H). MS (M+1 ): 395.0.
Preparation of 3-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2-yl)-5- (tetrahvdro-2H-pyran-3-yloxy)phenol
Figure imgf000072_0001
The title compound 3-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2- yl)-5-(tetrahydro-2H-pyran-3-yloxy)phenol was prepared by a method analogous to that described for (S)-3-sec-butoxy-5-(4-(4-methoxybenzyloxy) pyrimidin-2-yl)phenol using tetrahydro-2H-pyran-3-ol for the first step involving a Mitsunobu reaction and 2-chloro-4-(4-methoxybenzyloxy)-5- methylpyrimidine for the step involving a Suzuki cross-coupling. 1H NMR (400 MHz, CDCI3) δ ppm 1.63 (m, J=12.95, 8.60, 4.27, 4.27 Hz, 1 H), 1.73 - 1.96 (m, 2 H), 2.01 - 2.15 (m, 1 H), 2.17 (s, 3 H), 3.57 - 3.67 (m, 2 H), 3.72 - 3.78 (m, 1 H), 3.82 (s, 3 H), 3.92 - 4.01 (m, 1 H), 4.35 - 4.44 (m, 1 H), 5.48 (s, 2 H), 6.58 (t, J=2.35 Hz, 1 H), 6.91 - 6.95 (m, 2 H), 7.40 - 7.45 (m, 2 H), 7.54 (dd, J=2.35, 1.37 Hz, 1 H), 7.56 - 7.59 (m, 1 H), 8.29 (s, 1 H). MS (M+1 ): 423.2.
Preparation of (R)-3-sec-butoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2- yl)phenol
Figure imgf000073_0001
The title compound (R)-3-sec-butoxy-5-(4-(4-methoxybenzyloxy) pyrimidin-2-yl)phenol was prepared by a method analogous to that described for (S)-3-sec-butoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)phenol using (S)-butan-2-ol for the first step involving a Mitsunobu reaction and 2-chloro- 4-(4-methoxybenzyloxy)pyrimidine for the step involving a Suzuki cross- coupling.1H NMR (400 MHz, CDCI3) δ ppm 0.98 (t, J=7.52 Hz, 3 H), 1.31 (d, J=6.06 Hz, 3 H), 1.59 - 1.69 (m, 1 H), 1.70 - 1.82 (m, 1 H), 3.78 - 3.81 (m, 3 H), 4.38 (q, J=6.06 Hz, 1 H), 5.48 (s, 2 H), 6.57 (t, J=2.25 Hz, 1 H), 6.66 (d, J=5.86 Hz, 1 H), 6.88 - 6.93 (m, 2 H), 7.38 - 7.43 (m, 2 H), 7.53 - 7.59 (m, 2 H), 8.48 (d, J=5.86 Hz, 1 H). MS (M+1 ): 380.9.
Preparation of (S)-3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-(1 - methoxypropan-2-yloxy)phenol
Figure imgf000073_0002
The title compound (S)-3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5- (1-methoxypropan-2-yloxy)phenol was prepared by a method analogous to that described for (S)-3-sec-butoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2- yl)phenol using (R)-1-methoxypropan-2-ol for the first step involving a mitsunobu reaction and 2-chloro-4-(4-methoxybenzyloxy)pyrimidine for the step involving a Suzuki cross-coupling. 1H NMR (400 MHz, CDCI3) δ ppm 1.34 (d, 3 H), 3.41 (s, 3 H), 3.51 (dd, J=10.24, 4.39 Hz, 1 H), 3.57 - 3.65 (m, 1 H), 3.80 (s, 3 H), 4.58 - 4.70 (m, 1 H), 5.29 (br. s., 1 H), 5.45 (s, 2 H), 6.57 (t, J=2.34 Hz, 1 H), 6.62 (d, J=5.66 Hz, 1 H), 6.86 - 6.94 (m, 2 H), 7.37 - 7.43 (m, 2 H), 7.53 (dd, J=2.34, 1.37 Hz, 1 H), 7.61 - 7.64 (m, 1 H), 8.46 (d, J=5.66 Hz, 1 H). MS (M+1 ): 397.0.
Preparation of 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-(pentan-3- yloxy)phenol
Figure imgf000074_0001
The title compound 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5- (pentan-3-yloxy)phenol was prepared by a method analogous to that described for (S)-3-sec-butoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2- yl)phenol using pentan-3-ol for the first step involving a Mitsunobu reaction and 2-chloro-4-(4-methoxybenzyloxy)pyrimidine for the step involving a Suzuki cross-coupling. 1H NMR (400 MHz, CDCI3) δ ppm 0.98 (t, J=7.41 Hz, 6 H), 1.64 - 1.80 (m, 4 H), 3.82 (s, 3 H), 4.17 - 4.25 (m, 1 H), 5.47 (s, 2 H), 6.58 (t, J=2.24 Hz, 1 H), 6.64 (d, J=5.85 Hz, 1 H), 6.92 (d, J=8.58 Hz, 2 H), 7.42 (d, J=8.58 Hz, 2 H), 7.53 - 7.57 (m, 1 H), 7.61 (s, 1 H), 8.49 (d, J=5.66 Hz, 1 H). MS (M+1): 445.2.
Preparation of 3-cvclopropoxyphenol
Figure imgf000074_0002
Step 1 (Vinylation): To a mixture of di- -chlorobis(1 ,5- cyclooctadiene)diiridium(l) (170 mg, 1 mol%) and sodium carbonate (1.48 g, 14.0 mmol) in toluene (23 mL), 3-hydroxyphenyl benzoate (5.00 g, 23.3 mmol) and vinyl acetate (4.31 mL, 46.7 mmol) were added, followed by stirring at 100 °C in an atmosphere of nitrogen gas overnight. Reaction cooled down to room temperature. The reaction mixture was concentrated under reduced pressure followed by adsorption over silica gel. The residue was purified by flash column chromatography (S1O2 , 0%-12% ethyl acetate / heptane) to provide 3-(vinyloxy)phenyl benzoate (5.23 g, 93%) as a yellow oil. 1H NMR (400 MHz, CDCI3) δ ppm 4.51 (dd, J=6.06, 1.76 Hz, 1 H), 4.85 (dd, J=13.68, 1.76 Hz, 1 H), 6.67 (dd, J=13.68, 6.06 Hz, 1 H), 6.91 - 7.00 (m, 3 H), 7.36 - 7.41 (m, 1 H), 7.50 - 7.56 (m, 2 H), 7.63 - 7.69 (m, 1 H), 8.19 - 8.25 (m, 2 H). MS (M-1 ): 239.1.
Step 2 (Cvclopropanation): 1 M Diethylzinc solution (16.6 mL, 16.6 mmol) was added to a mixture of 3-(vinyloxy)phenyl benzoate (2.00 g, 8.32 mmol), chloroiodomethane (2.42 mL, 33.3 mmol) and dichloroethane (28 mL) over 60 min. at 0 °C. Stirred overnight going slowly to room
temperature and stirred for 2 hours. NH4CI (aq. sat) and ethyl acetate were added to the reaction mixture. Mixture was extracted twice with ethyl acetate. Combined organic layers washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude mixture. The residue was purified by flash column chromatography (S1O2 (dry loading), 0%-15% ethyl acetate / heptane) to provide 3-cyclopropoxyphenyl benzoate (1.48 g, 70%) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ ppm 0.76 - 0.83 (m, 4 H), 3.71 - 3.79 (m, 1 H), 6.81 - 6.87 (m, 1 H), 6.93 - 6.99 (m, 2 H), 7.30 - 7.37 (m, 1 H), 7.49 - 7.57 (m, 2 H), 7.62 - 7.68 (m, 1 H), 8.19 - 8.25 (m, 2 H). MS (M+1): 255.0.
Step 3 (Saponification): In a round bottom flask containing the 3- cyclopropoxyphenyl benzoate (1.48 g, 5.82 mmol), THF (12 mL) and methanol (12 mL) added. At room temperature, 1 N (aq.) sodium hydroxide (6.4 mL) is then added in one portion and the resulting mixture stirred for 1.5 hours. Reaction mixture acidified to pH~1 with 1 N HCI (aq.). Extraction of the reaction mixture with dichloromethane (three times). Combined organic layers washed with brine, dried over sodium sulfate, filtered and
concentrated to afford the crude oil. The residue was purified by flash column chromatography (S1O2, 0%-5% methanol / dichloromethane) to provide 3-cyclopropoxyphenol (830 mg, 95%) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ ppm 0.77 (d, J=4.49 Hz, 4 H), 3.68 - 3.74 (m, 1 H), 4.81 (s, 1 H), 6.42 - 6.46 (m, 1 H), 6.58 (t, J=2.35 Hz, 1 H), 6.62 - 6.67 (m, 1 H), 7.14 (t, J=8.11 Hz, 1 H). MS (M+1): 151.1.
Step 4 (Phenol protection): In a round bottom flask at room
temperature, 3-cyclopropoxyphenol (900 mg, 5.99 mmol), tert- butyldimethylsilyl chloride (1.04 g, 6.89 mmol), imidazole (530 mg, 7.79 mmol) and dichloromethane (8.6 ml_) stirred together overnight. Reaction diluted with dichloromethane (50 ml_) and washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford the desired crude material. The residue was purified by flash column
chromatography (S1O2, 100% dichloromethane) to provide tert-butyl(3- cyclopropoxyphenoxy)dimethylsilane (1.42 g, 90%) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ ppm 0.19 - 0.23 (m, 6 H), 0.75 - 0.79 (m, 4 H), 0.97 - 1.01 (m, 9 H), 3.67 - 3.74 (m, 1 H), 6.44 - 6.49 (m, 1 H), 6.56 (t, J=2.25 Hz, 1 H), 6.65 - 6.70 (m, 1 H), 7.12 (t, J=8.11 Hz, 1 H). MS (M+1 ): 265.1.
Preparation of 3-cvclopropoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2- vQphenol
Figure imgf000076_0001
The title compound 3-cyclopropoxy-5-(4-(4-methoxybenzyloxy) pyrimidin-2-yl)phenol was prepared by a method analogous to that described for (S)-3-sec-butoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)phenol using tert-butyl(3-cyclopropoxyphenoxy)dimethylsilane for the borylation step involving a Ir (I) catalyzed CH insertion reaction and 2-chloro-4-(4- methoxybenzyloxy)pyrimidine for the step involving a Suzuki cross-coupling. 1H NMR (400 MHz, CDCI3) δ ppm 0.72 - 0.83 (m, 4 H), 3.76 - 3.84 (m, 4 H), 5.45 (s, 2 H), 6.64 (d, J=5.86 Hz, 1 H), 6.72 (t, J=2.25 Hz, 1 H), 6.87 - 6.94 (m, 2 H), 7.38 - 7.44 (m, 2 H), 7.56 - 7.59 (m, 1 H), 7.71 - 7.76 (m, 1 H), 8.47 (d, J=5.86 Hz, 1 H). MS (M+1 ): 365.2.
:
Figure imgf000077_0001
Step 1 : A round bottom flask was charged with 3-hydroxybenzoic acid (2.00 g, 14.5 mmol), HATU (2-(1 H-7-Azabenzotriazol-1-yl)-1 , 1 ,3,3- tetramethyl uranium hexafluorophosphate methanaminium) (8.34 g, 21.7 mmol), diisopropylethyl amine (5.61 g, 43.4 mmol), methylamine (2M) / THF (21.7 ml_, 43.4 mmol) and N,N-dimethylformamide (48.3 ml_). The reaction mixture was stirred at room temperature for 3 hours. Ethyl Acetate added to the mixture (600 ml_) and washed with 1 N HCI/water (1 :1 ) (100 ml_).
Washed 2 times with water, 1 time with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude material. Used as is in the next step, m/z (M+H)+ = 166.2
Step 2: A round bottom flask was charged with the crude mixture from step 1 (2.39g, 14.5mmol; see above), imidazole (2.46 g, 36.2 mmol), tert- butyl dimethylsilyl chloride (TBDMS-CI, 4.36 g, 28.9 mmol) and
dichloromethane (36.2 ml_). The reaction mixture was stirred at room temperature overnight. Dichloromethane added and organic layer washed with water 2 times, brine 1 time, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude material. The residue was purified by flash column chromatography (S1O2, 20%-70% ethyl acetate / heptane) to provide 3-(tert-butyldimethylsilyloxy)-N,N- dimethylbenzamide (1.37 g, 34%). 1H NMR (400 MHz, CDCI3) δ ppm 0.14 - 0.22 (m, 6 H), 0.94 - 0.99 (m, 9 H), 2.84 - 3.17 (m, 6 H), 6.82 - 6.88 (m, 2 H), 6.97 (d, J=7.62 Hz, 1 H), 7.20 - 7.26 (m, 1 H). MS (M+1): 280.5.
Preparation of 3-(tert-butyldimethylsilyloxy)-N,N-dimethyl-5-(4,4.5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide
Figure imgf000078_0001
A microwave sealed tube was charged with bispinacolatodiboron (880 mg, 3.43 mmol), di- -methoxybis(1 ,5-cyclooctadiene)diiridium (I) (32.5 mg, 0.049 mmol), 4,4'-di-tert-butyl-2,2,-bipyridine (26.3 mg, 0.098 mmol) and methyl fert-butyl ether (2.0 mL). The mixture was stirred for 10 minutes at room temperature or until a deep red solution is observed. 3-(tert- butyldimethylsilyloxy)-N,N-dimethylbenzamide (1.37 g, 4.90 mmol) was then added to the previously formed solution (in 3.0 mL of methyl fert-butyl ether) and the reaction stirred for 10 hours at 100°C in the microwave. Reaction mixture filtered through a pad of silica gel (30% ethyl acetate/heptane).
Concentration of the organics give the title compound as an orange oil.
Crude mixture filtered through silica gel (30% ethyl acetate/heptane) a second time to removed more of the orange color. Isolated yield: 1.16 g (58%) (Around 94% pure according to 1H NMR) of an orange solid. MS (M+1 ): 406.6.
Preparation of 3-hvdroxy-5-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2-yl)- N.N-dimethylbenzamide
Figure imgf000079_0001
The flask containing 3-(tert-butyldimethylsilyloxy)-N,N-dimethyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide (500mg, 1.10mmol), 2-chloro-4-(4-methoxybenzyloxy)-5-methylpyrimidine (360mg, 1.36mmol), Na2C03 (3.4mL; 1 M in water) and acetonitrile (4.5mL) was purged with nitrogen for 10 minutes. [1 ,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium (II) (57.8mg, 0.07mmol) was added in one portion and the mixture heated for 30 minutes in the microwave at 140°C. Following by LCMS, the reaction was completed. Only unprotected product observed (minus TBDMS protection). Ammonium choride solution (sat.aq.) added and the mixture was extracted with EtOAc (100 ml_ x 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column
chromatography (SiO2, 40%-100% ethyl acetate / heptane) to provide 3- hyd roxy-5-(4-(4-methoxy benzy loxy )-5-methy I py ri m id i n-2-y I )-N , N- dimethylbenzamide (228mg, 51%) as an orange solid. 1H NMR (400 MHz, DMSO-de) δ ppm 2.13 (s, 3 H), 2.88 - 3.05 (m, 6 H), 3.32 (s, 3 H), 5.51 (s, 2 H), 6.86 (dd, J=2.44, 1.47 Hz, 1 H), 6.91 - 6.98 (m, 2 H), 7.40 - 7.51 (m, 2 H), 7.79 (t, J=1.47 Hz, 1 H), 7.87 (dd, J=2.44, 1.47 Hz, 1 H), 8.41 - 8.51 (m, 1 H), 9.89 (s, 1 H). MS (M+1 ): 394.3.
Preparation of (S)-3-(1-methoxy-1-oxopropan-2-yloxy)phenyl benzoate:
Figure imgf000079_0002
A round bottom flask was charged with triphenylphosphine (10.5g, 40.0mmol), DIAD (diisopropyl azodicarboxylate) (6.4ml_, 32.5mmol) and THF (65 ml_). Reaction mixture stirred for 15 minutes at room temperature to form the ylid. (R)-methyl 2-hydroxypropanoate (3.12ml_, 32.5mmol) followed by the 3-hydroxyphenyl benzoate (5.36 g, 25.0 mmol) are then added in one portion to the previously formed solution. The reaction mixture was stirred at room temperature overnight. Solvent was evaporated to give 26g of a crude oil. The residue was triturated with ethyl acetate / heptane. Precipitated white solid (triphenylphosphine oxide) was removed by vacuum filtration and rinsed with heptane. The filtrate was evaporated to give 14.6 g of an oil which was preadsorbed on to S1O2 gel. The residue was purified by flash column chromatography (S1O2, 10%-50% ethyl acetate / heptane) to provide (S)-3-(1-methoxy-1-oxopropan-2-yloxy)phenyl benzoate (6.81 g, 91%) as a thick colorless oil. 1H NMR (400 MHz, CDCI3) δ ppm 1.62 (d, J=6.83 Hz, 3 H), 3.76 (s, 3 H), 4.77 (q, 1 H), 6.73 - 6.81 (m, 2 H), 6.82 - 6.87 (m, 1 H), 7.30 (t, J=8.19 Hz, 1 H), 7.50 (t, 2 H), 7.62 (tt, 1 H), 8.18 (dd, J=8.29, 1.27 Hz, 2 H). MS (M+1): 301.4.
:
Figure imgf000080_0001
To a stirred solution of LiAIH4 (83ml_, 1 M in THF, 83mmol) cooled in a cold water bath was added a solution of (S)-3-(1-methoxy-1-oxopropan-2- yloxy)phenyl benzoate (6200 mg, 20.64 mmol) in THF (100 ml_) dropwise at such a rate so as to maintain the internal temperature below 20°C. The bath was removed and the resulting solution was stirred at room temperature overnight. The reaction flask was cooled to ~0°C and added ~20 ml_ water dropwise. THF gently ref I uxed. After the addition was complete and the reaction did not react to water further the mixture was stirred for 1 hour. Sodium hydroxide (1 N, aq.; 20ml_) was added and resulting mixture stirred for 1 h. at room temperature. Dark grey suspension became a white suspension. Gelatinous solids were removed by filtration and rinsed with THF (500ml_). Filtrates and rinses were combined and concentrated on the rotovap to give 4.76 g of a yellow oil, but water was visible as droplets. To the crude oil was added ammonium chloride solution (aq. sat.) and ethyl acetate (100ml_). The extracted organic layer was dried over MgS04, filtered and evaporated to give 3.77g of an oil. The residue was purified by flash column chromatography (S1O2, 25%-100% ethyl acetate / heptane) to provide (S)-3-(1-hydroxypropan-2-yloxy)phenol (1.34g, 38%) as a clear colorless oil. 1H NMR (400 MHz, CDCI3) δ ppm 1.22 - 1.27 (m, 3 H), 3.64 - 3.77 (m, 2 H), 4.45 (td, J=6.40, 3.62 Hz, 1 H), 6.40 - 6.45 (m, 2 H), 6.47 - 6.51 (m, 1 H), 7.11 (t, J=8.50 Hz, 1 H). MS (M+1 ): 169.1.
Preparation of (S)-tert-butyl(2-(3-(tert-butyldimethylsilyloxy) phenoxy) propoxy)dimethylsilane
Figure imgf000081_0001
A round bottom flask was charged with (S)-3-(1-hydroxypropan-2- yloxy)phenol (3.3 g, 19.6 mmol), imidazole (4.01g, 58.9 mmol) and dichloromethane (49 ml_) and cooled to 0°C. Tert-butyldimethylsilyl chloride (7.39g, 49.0mmol) added in one portion and the reaction mixture stirred for 15 minutes, allowed to warmed at room temperature and stirred for another 30 minutes. Reaction followed by TLC using cerium ammonium molybdate solution to stain the TLC plate. The residue was purified by flash column chromatography (S1O2, 5%-60% ethyl acetate / heptane) to provide (S)-tert- butyl(2-(3-(tert-butyldimethylsilyloxy)phenoxy)propoxy)dimethylsilane (2.24g, 29%) as an orange oil. 1H NMR (400 MHz, CDCI3) δ ppm 0.04 - 0.07 (m, 6 H), 0.17 - 0.20 (m, 6 H), 0.87 - 0.90 (m, 9 H), 0.96 - 0.98 (m, 9 H), 1.28 (d, J=6.25 Hz, 3 H), 3.61 (dd, J=10.46, 5.57 Hz, 1 H), 3.79 (dd, J=10.55, 5.47 Hz, 1 H), 4.36 (q, J=6.06 Hz, 1 H), 6.39 - 6.43 (m, 2 H), 6.49 - 6.53 (m, 1 H), 7.05 - 7.10 (m, 1 H).
Preparation of (S)-tert-butyl(2-(3-(tert-butyldimethylsilyloxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)propoxy)dimethylsilane
Figure imgf000082_0001
A microwave sealed tube was charged with bispinacolatodiboron (453mg, 1.76mmol di- -methoxybis(1 ,5-cyclooctadiene)diiridium (I) (16.6 mg, 0.025 mmol), 4,4'-di-tert-butyl-2,2,-bipyridine (13.4 mg, 0.050 mmol) and methyl fert-butyl ether (1.5 ml_). The mixture was stirred for 10 minutes at room temperature or until a deep red solution is observed. (S)-tert-butyl(2- (3-(tert-butyldimethylsilyloxy)phenoxy)propoxy)dimethylsilane (1.00 g, 2.52 mmol) was then added to the previously formed solution (in 1 ml_ of methylfertbutylether) and the reaction was stirred for 10 hours at 100°C in the microwave. Reaction mixture filtered through a pad of silica gel (30% ethyl acetate/heptane). Concentration of the organics give (S)-tert-butyl(2- (3-(tert-butyldimethylsilyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)propoxy)dimethylsilane (1.32g, 100%; 80% pure according to 1H NMR) as a light yellow oil. 1H NMR (400 MHz, CDCI3) δ ppm 0.04 - 0.07 (m, 6 H), 0.17 - 0.19 (m, 6 H), 0.87 - 0.89 (m, 9 H), 0.95 - 0.98 (m, 9 H), 1.27 (d, J=6.06 Hz, 3 H), 1.31 (s, 12 H), 3.58 (dd, J=10.36, 5.67 Hz, 1 H), 3.78 (dd, J=10.36, 5.47 Hz, 1 H), 4.38 - 4.47 (m, 1 H), 6.49 (t, J=2.35 Hz, 1 H), 6.85 (d, J=1.76 Hz, 1 H), 6.96 (d, J=2.35 Hz, 1 H).
Preparation of (S)-3-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-5-(4-(4-
Figure imgf000082_0002
A microwave sealed tube was charged with (S)-fert-butyl(2-(3-(tert- butyldimethylsilyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)propoxy)dimethylsilane (400 mg, 0.460 mmol), 2-chloro-4-(4- methoxybenzyloxy)-5-methylpyrimidine (146 mg, 0.552 mmol), Na2C03
(1.4mL; 1 M in water) and acetonitrile (2.3 ml_) was purged with nitrogen for 10 minutes. [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (16.8mg, 0.023mmol) was added in one portion and the mixture heated for 30 minutes in the microwave at 140 °C. Following by LCMS, the reaction was completed. Almost only mono-deprotected product observed (minus the TBS on the phenol moiety). Reaction mixture diluted with ethyl acetate and washed with water/citric acid 1N (2/1 ) (aqueous ca. pH 3). Aqueous layer extracted with ethyl acetate a second time. Organic layers washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude brown oil. The residue was purified by flash column chromatography (S1O2, 10%-40% ethyl acetate / heptane) to provide (S)-3-(1-(tert-butyl dimethyl silyloxy)propan-2-yloxy)-5-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2- yl)phenol (198mg, 84%) as a white solid. 1H NMR (500 MHz, CDCI3) δ ppm 0.08 (d, J=12.93 Hz, 6 H), 0.89 - 0.91 (m, 9 H), 1.34 (d, J=6.10 Hz, 3 H), 2.19 (s, 3 H), 3.68 (dd, J=10.61 , 5.49 Hz, 1 H), 3.81 - 3.87 (m, 4 H), 4.49 - 4.60 (m, 1 H), 5.46 - 5.59 (m, 2 H), 6.58 (t, J=2.20 Hz, 1 H), 6.89 - 6.97 (m, 2 H), 7.44 (d, J=8.54 Hz, 2 H), 7.52 - 7.63 (m, 2 H), 8.32 (s, 1 H). MS (M+1 ): 511.5.
Preparation of (S)-3-(1 -hvdroxypropan-2-yloxy)-5-(4-(4-methoxybenzyloxy)- 5-methylpyrimidin- -yl)phenol
Figure imgf000083_0001
The title compound (S)-3-(1-hydroxypropan-2-yloxy)-5-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)phenol was prepared by a method analogous to that described for (S)-3-(1-(fert-butyldimethyl silyloxy)propan-2-yloxy)-5-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2- yl)phenol except: the crude (S)-3-(1-(fert-butyldimethylsilyloxy)propan-2- yloxy)-5-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2-yl)phenol (theoretical 0.5mmol) was taken up in THF (2ml_) to which was added TBAF (1 M in THF; 0.75ml_). The resulting mixture was stirred at room temperature overnight. Reaction quenched with ammonium chloride solution (aq. sat.) and extracted 2 times with ethyl acetate. Combined organics were washed with brine, dried over Na2S04, filtered and evaporated to give a crude dark oil. The residue was purified by flash column chromatography (Si02, 0%-80% ethyl acetate / heptane) to provide (S)-3-(1-hydroxypropan-2-yloxy)-5-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)phenol (70mg, 35%) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.29 (d, J=6.25 Hz, 3 H), 2.18 (d, J=0.78 Hz, 3 H), 3.67 (dd, J=10.75, 5.08 Hz, 2 H), 3.77 (s, 3 H), 4.46 - 4.55 (m, 1 H), 5.55 (s, 2 H), 6.57 (t, J=2.25 Hz, 1 H), 6.90 (d, J=8.79 Hz, 2 H), 7.37 (t, J=2.54 Hz, 2 H), 7.42 (d, J=8.79 Hz, 2 H), 8.28 (d, J=0.78 Hz, 1 H). MS (M+1 ): 397.0.
Preparation of (S)-3-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-5-(4-(4-
Figure imgf000084_0001
(S)-3-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol was prepared by a method analogous to that described for (S)-3-(1-(tert-butyldimethylsilyloxy)propan-2- yloxy)-5-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2-yl)phenol, using 2- chloro-4-(4-methoxybenzyloxy)pyrimidine. 1H NMR (400 MHz, CDCI3) δ ppm 0.05 (d, 6 H), 0.87 (s, 9 H), 1.31 (d, J=6.25 Hz, 3 H), 3.66 (dd, J=10.55, 5.28 Hz, 1 H), 3.79 - 3.84 (m, 4 H), 4.47 - 4.56 (m, 1 H), 5.47 (d, J=4.10 Hz, 2 H), 6.59 (t, J=2.25 Hz, 1 H), 6.65 (d, J=5.86 Hz, 1 H), 6.88 - 6.93 (m, 2 H), 7.40 (d, J=8.60 Hz, 2 H), 7.55 - 7.60 (m, 2 H), 8.47 (d, J=5.86 Hz, 1 H). MS (M+1 ): 497.3. Preparation of 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-(4-
Figure imgf000085_0001
In a sealed tube, (4-fluorophenyl)-methylsulfone (80,1 mg,
0.460mmol),5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)benzene-1 ,3-diol (125mg, 0.385mmol), potassium carbonate (79.5mg, 0.575mmol) stirred in DMF (2.6ml_) at 120°C overnight. Mixture of non-reacted starting material, desired product and bis-addition products are observed by LCMS. Reaction cooled down to room temperature and dissolved back in ethyl acetate, washed 2 times with NH4CI (sat. aq.) / water (1/1 ), brine, dried over sodium sulfate, filtered and concentrated to provide a crude oil. The residue was purified by flash column chromatography (S1O2, 100% ethyl acetate) to provide 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-(4- (methylsulfonyl)phenoxy)phenol (210mg, 114%; contaminated with bis- addition product) as a colorless oil. MS (M+1 ): 479.2.
Preparation of 1-(tert-butyldimethylsilyloxy)butan-2-ol
Figure imgf000085_0002
A round bottom flask was charged with t-butyldimethylsilyl chloride (418mg, 2.77mmol), imidazole (227mg, 3.33mmol) and dissolved in dichloromethane (20ml_). The reaction mixture was cooled to -40°C and a solution of 1 ,2-butanediol (250 mg in 10 ml_ of dichloromethane) was added dropwise to the previously formed solution. The reaction was stirred 30 minutes at that temperature before warming it up to room temperature and stirred for an additional 3 hours. The reaction mixture was filtered to removed imidazole hydrochloride that had formed. The residue was purified by flash column chromatography (S1O2 (dry loaded), 5-20% ethyl acetate / heptane) to provide 1-(tert-butyldimethylsilyloxy)butan-2-ol (450mg, 80%) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ ppm 0.03 - 0.09 (m, 6 H), 0.88 - 0.90 (m, 9 H), 0.95 (t, J=7.52 Hz, 3 H), 1.37 - 1.49 (m, 2 H), 2.39 (br. s., 1 H), 3.39 (dd, J=9.67, 7.33 Hz, 1 H), 3.55 (m, J=9.65, 6.67, 3.37, 3.37 Hz, 1 H), 3.62 (dd, J=9.77, 3.32 Hz, 1 H).
Figure imgf000086_0001
A round bottom flask was charged with 1 ,3-benzenediol (2.0g, 18mmol), t-butyldimethylsilyl chloride (8.21 g, 54.5 mmol), imidazole (3.71 g, 54.5 mmol) and was dissolved in dichloromethane (36 mL). The reaction mixture was stirred at room temperature overnight. A solid formed
(imidazole-HCI) which was filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure to give a crude oil. The residue was purified by flash column chromatography (S1O2 (dry loaded), 0-10% ethyl acetate / heptane) to provide 1 ,3-bis(tert-butyldimethylsilyloxy)benzene (4.04g, 66%) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ ppm 0.17 - 0.21 (m, 12 H), 0.96 - 1.00 (m, 18 H), 6.35 (t, J=2.25 Hz, 1 H), 6.45 (d, J=2.35 Hz, 1 H), 6.47 (d, J=2.35 Hz, 1 H), 7.06 (t, J=8.11 Hz, 1 H).
Preparation of (5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3-
Figure imgf000086_0002
A microwave sealed tube was charged with bispinacolatodiboron (157 mg, 0.620 mmol) di- -methoxybis(1 ,5-cyclooctadiene)diiridium (I) (6.0 mg, 0.009 mmol), 4,4'-di-tert-butyl-2,2,-bipyridine (4.80 mg, 0.018 mmol) and methyl f-butylether (0.5 mL). The mixture was stirred for 10 minutes at room temperature or until a deep red solution is observed. (5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 ,3-phenylene)bis(oxy)bis(tert-butyldimethylsilane (300mg, 0.886mmol) was then added to the previously formed solution (in 0.5ml_ of methylfertbutylether) and the reaction was stirred for 16 hours at 100°C in the microwave. Reaction mixture filtered through a pad of silica gel (20% EtOAc/Heptane). Concentration of the organics give (S)-tert-butyl(2- (3-(tert-butyldimethylsilyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)propoxy)dimethylsilane (401 mg, 97%; 89% pure according to 1H NMR; contain unreacted starting material) as a white solid. 1H NMR (400 MHz, CDCI3) 5 ppm 0.16 - 0.20 (m, 12 H) 0.95 - 0.99 (m, 18 H) 1.32 (s, 12 H) 6.42 (t, J=2.35 Hz, 1 H) 6.89 (d, J=2.35 Hz, 2 H).
Preparation of 1 -isopropoxy-3-(4-(methylsulfonyl)phenoxy)benzene
Figure imgf000087_0001
3-isopropoxyphenol (1.43 g, 9.42 mmol) was charged into a round bottom flask. 4-bromophenylmethylsulfone (2.22 g, 9.42 mmol), cuprous iodide (359 mg, 1.88 mmol) and cesium carbonate (6.14 g, 18.8 mmol) were added along with DMAC (N,N-dimethylacetamide) (30 mL). The mixture was stirred under nitrogen at room temperature and 2,2,6,6-tetramethyl-3,5- heptanedione (0.78 mL, 3.77 mmol) was added. The mixture was heated under nitrogen at 85 °C for about 20 hours. Analysis by LCMS and TLC showed the reaction to be complete. The reaction mixture was poured into ammonium chloride solution (sat. aq.; 250 mL) and the aqueous was extracted with MTBE (2 x 100 mL). The aqueous layer was extracted a third time with 50 mL EtOAc. The combined extracts were washed with an equal volume of water, brine, dried over sodium sulfate, and concentrated to a dark colored oil. The residue was purified by flash column chromatography (Si02, 0%-40% ethyl acetate / heptane) to provide 1 -isopropoxy-3-(4- (methylsulfonyl)phenoxy) benzene as a pale colored oil (2.78 g, 96%). 1H NMR (400 MHz, CDCI3) δ ppm 1.33 (d, J=6.05 Hz, 6 H), 3.04 (s, 3 H), 4.46 - 4.56 (m, 1 H), 6.56 - 6.64 (m, 2 H), 6.74 (ddd, J=8.39, 2.34, 0.78 Hz, 1 H), 7.07 - 7.10 (m, 2 H), 7.27 (t, J=8.10 Hz, 1 H), 7.85 - 7.89 (m, 2 H).
Preparation of 2,4-dichloro-5-isopropylpyrimidine
Figure imgf000088_0001
5-isopropylpyrimidine-2,4(1 H,3H)-dione (4.90 g, 31.8 mmol) was suspended in POCI3 (20ml_, 210mmol) and H3P04 (0.21 mL, 3.6 mmol) was added, followed by DIPEA (diisopropylethylamine) (6.1 mL, 35 mmol) dropwise. The reaction mixture was slowly heated to 100°C and stirred overnight. The next morning the reaction proved to be finished by TLC and was cooled to room temperature and added dropwise to a vigorously stirred mixture of heptane / warm water while keeping the internal temperature below 50°C. After the addition was completed the resulting mixture stirred for another hour. Layers were eparated and aqueous layer extracted again with heptane. Combined org. layers washed with brine, dried (Na2S04), filtered and concentrated in vacuo to an oil (5.7 g, 94%). 1H NMR (400 MHz, CDCI3) δ ppm 1.32 (d, J=7.05 Hz, 6 H), 3.17 - 3.36 (m, 1 H), 8.46 (s, 1 H).
Figure imgf000088_0002
2,4-dichloro-5-isopropylpyrimidine (1 ,00 g, 5.23 mmol) was charged in a round bottom flask with anhydrous toluene (25 mL) and 4-Methoxybenzyl alcohol (0.72 mL, 5.76 mmol) was added. The mixture was stirred under nitrogen at room temperature until a homogeneous solution resulted then it was cooled to -30°C. To this stirred solution was added powdered
potassium hydroxide (518 mg, 7.85 mmol) and the mixture was stirred at - 30°C allowing for slow equilibration to room temperature overnight. At this time the reaction was judged complete by GCMS and TLC. A mixture of desired regioisomer: undesired regioisomer (4:1 ratio) was observed. The reaction was diluted with water ( about 50 ml_) and ethyl acetate (50 ml_). The aqueous was extracted a second time with ethyl acetate (25 ml_). The combined extracts were washed with brine, dried over sodium sulfate and concentrated to an oil. The regioisomers were purified by flash column chromatography (Si02, isocratic 2:9:9, ethyl acetate:toluene:heptane) to provide 2-chloro-5-isopropyl-4-(4-methoxybenzyloxy)pyrimidine (933 mg, 61%). 1H NMR (400 MHz, CDCI3) δ ppm 1.20 (d, J=6.63 Hz, 6 H), 2.77 - 3.24 (m, 1 H), 3.80 (s, 3 H), 5.38 (s, 2 H), 6.74 - 6.98 (m, 2 H), 7.29 - 7.50 (m, 2 H), 8.13 (s, 1 H).
Preparation of 3-((2S,3 -3-hvdroxybutan-2-yloxy)phenyl benzoate
Figure imgf000089_0001
To a solution of resorcinol monobenzoate (2.20 g, 10 mmol) and meso-2,2-dioxo-4,5-dimethyl-1 ,3,2-dioxathiolane (1.52 g, 10 mmol;
prepared as described in JACS, 1950, 72, 5497) in N,N-dimethylformamide (40 ml_) was added potassium carbonate (1.65 g, 12 mmol). The resulting mixture was stirred at 90°C overnight. Solvent was evaporated under reduced pressure. The residue was taken up and stirred in a mixture of 25 ml_ each diethyl ether and 4 M sulfuric acid for 3 days. The layers were allowed to separate. The aqueous layer was extracted with a second portion of diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to afford 2.89 g of crude product as a reddish oil. This material was flash chromatographed eluting with a 0-50% gradient of ethyl acetate in heptane to afford the title compound (1.43 g, 50%) as a clear colorless oil. 1H NMR (400 MHz, CDCI3) δ ppm 1.21 - 1.28 (m, 6 H), 1.82 (br. s., 1 H), 3.79 - 3.88 (m, 1 H), 4.11 - 4.19 (m, 1 H), 6.78 - 6.86 (m, 3 H), 7.30 (t, 1 H), 7.47 - 7.53 (m, 2 H), 7.62 (t, 1 H), 8.19 (dd, J=8.40, 1.37 Hz, 2 H). MS (M+1 ): 287.4.
Figure imgf000090_0001
To a stirred solution of 3-((2S,3R)-3-hydroxybutan-2-yloxy)phenyl benzoate (1400 mg, 4.89 mmol) in tetrahydrofuran (12.5 mL) was added a solution of lithium hydroxide monohydrate (205 mg, 4.89 mmol) in water (12.5 mL). The resulting mixture was stirred at room temperature for 4 hours. An additional 45 mg of lithium hydroxide monohydrate was added and continued to stir the mixture at room temperature overnight. The reaction mixture was acidified with 1 N hydrochloric acid and extracted 3 times with 50 mL ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to afford 1.26 g of crude product as a dark yellow oil which was flash
chromatographed eluting using a 25-100% gradient of ethyl acetate in heptane to afford the title compound (519 mg, 58.2%). 1H NMR (400 MHz, CDCI3) δ ppm 1.21 - 1.28 (m, 6 H), 3.83 (t, J=6.54 Hz, 1 H), 4.06 - 4.16 (m, 1 H), 6.40 - 6.46 (m, 2 H), 6.46 - 6.52 (m, 1 H), 7.07 - 7.14 (m, 1 H). MS (M+1 ): 183.3.
Preparation of 1-(tert-butyldimethylsilyloxy)-3-((2S,3R)-3-(tert- butyldimethylsilyloxy) butan-2-yloxy)benzene
Figure imgf000090_0002
To a stirred solution of 3-((2S,3R)-3-hydroxybutan-2-yloxy)phenol (510 mg, 2.80 mmol) and imidazole (762 mg, 11.2 mmol) in dichloromethane (7.0 mL) was added ferf-buty-dimethylsilyl chloride (1.27 g, 8.4 mmol) and the mixture was stirred at room temperature overnight. The reaction was diluted with dichloromethane, filtered through celite, washed with water 2 times and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1.26 g of the crude product which was flash
chromatographed eluting with a 0-30% gradient of ethyl acetate in heptanes to afford the title compound (890 mg, 77.4%) as a clear colorless oil. 1H NMR (400 MHz, CDCI3) δ ppm 0.01 - 0.07 (m, 6 H), 0.18 (s, 6 H), 0.86 (s, 9 H), 0.97 (s, 9 H), 1.15 (d, J=6.24 Hz, 3 H), 1.19 (d, J=6.44 Hz, 3 H), 3.90 - 3.98 (m, 1 H), 4.16 - 4.24 (m, 1 H), 6.36 - 6.42 (m, 2 H), 6.47 - 6.53 (m, 1 H), 7.04 - 7.10 (m, 1 H). MS (M+1): 411.7.
Preparation of 2-(3-(tert-butyldimethylsilyloxy)-5-((2S,3R)-3-(tert- butyldimethyl silyloxy)butan-2-yloxy)phenyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane
Figure imgf000091_0001
A microwave tube was charged with bis(pinacolato)diboron (389 mg, 1.52 mmol), (1 ,5-cyclooctadiene)(methoxy)iridium(l) dimer (14.6 mg, 0.022 mmol), and 4 ,4'-d i-iert-buty I-2 ,2'-d i py ridy I (11.5 mg, 0.043 mmol). The mixture was stirred for 10 minutes in methyl-ferf-butyl ether at room temperature until a deep red solution was observed. Then 1-(tert- butyldimethylsilyloxy)-3-((2S,3R)-3-(tert-butyldimethylsilyloxy) butan-2- yloxy)benzene (890 mg, 2.17 mmol) was added in one portion. The tube was sealed and the reaction stirred for 10 hours at 100°C in a microwave reactor. The mixture was filtered through a plug of silica gel eluting with 500 mL of 30% ethyl acetate in heptanes. Concentration of the eluent afforded the crude title compound (1.373 g) 1H NMR indicated the material was approximately 50% title compound. This material was used in the next step without further purification or characterization.
Preparation of 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-((2S,3R)-3-(tert- butyldimethyl silyloxy)butan-2-yloxy)phenol
Figure imgf000092_0001
A large microwave reactor vial containing crude 2-(3-(tert-butyldimethyl silyloxy)-5-((2S,3R)-3-(tert-butyldimethyl silyloxy)butan-2-yloxy)phenyl)- 4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolane (540 mg, 50% pure, 0.50 mmol), 4- (4-methoxybenzyloxy)-2-chloropyrimidine (168 mg, 0.604 mmol), 1 M aqueous sodium carbonate (1.50 ml_, 1.50 mmol) and acetonitrile (2.2 ml_) was purged with nitrogen. 1 ,1 '-Bis(diphenylphosphino) ferrocene)- dichloropalladium (II) (26 mg, 0.035 mmol) was then added in one portion and the mixture heated for 30 minutes in the microwave at 140°C. The reaction was concentrated under reduced pressure, then 1 M citric acid was added and the mixture was extracted twice with ethyl acetate. A dark precipitate was removed by filtration and rinsed with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered through a pad of silica gel and concentrated under reduced pressure to give 563 mg of crude product as a dark oil. This was flash
chromatographed eluting with a 0-60% gradient of EtOAc in heptane to afford the title compound (169 mg, 64%) as an off white solid. 1H NMR (400 MHz, CDCI3) 5 ppm 0.03 (s, 3 H), 0.08 (s, 3 H), 0.85 (s, 9 H), 1.18 (d, J=6.25 Hz, 3 H), 1.24 (d, J=6.25 Hz, 3 H), 3.80 (s, 3 H), 3.94 - 4.01 (m, 1 H), 4.30 - 4.38 (m, 1 H), 5.40 - 5.53 (m, 2 H), 6.58 (t, J=2.25 Hz, 1 H), 6.66 (d, J=5.86 Hz, 1 H), 6.88 - 6.93 (m, 2 H), 7.38 - 7.42 (m, 2 H), 7.54 - 7.61 (m, 2 H), 8.48 (d, J=5.86 Hz, 1 H). MS (M-1 ): 509.2.
Preparation of 2-(3,5-bis(tert-butyldimethylsilyloxy)phenyl)-4-(4- methoxybenzyloxy)-5-methylpyrimidine
Figure imgf000093_0001
A flask containing 2-(3,5-bis(tert-butyldimethylsilyloxy)phenyl)-4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane (1800 mg, crude, 3.874 mmol, 70-80% pure), 4-(4-methoxy benzyloxy)-2-chloro-5-methylpyrimidine (1030 mg, 3.87 mmol, >95% purity), sodium carbonate (821 mg, 7.75 mmol) and 1 ,1'- Bis(diphenylphosphino)ferrocene)-dichloropalladium (II) (207 mg, 0.283 mmol) was evacuated and refilled with nitrogen three times. Dimethoxy ethane (10 mL) and water (3.3 mL) were added. The mixture was heated at 70°C overnight. The mixture was diluted with water and saturated aqueous ammonium chloride solution (pH~8). The mixture was extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford the title compound (2.62 g) of as a dark syrup. This crude material was used in the subsequent deprotection step without further purification or characterization.
Preparation of 5-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2-yl)benzene-
1 ,3-diol
Figure imgf000093_0002
Tetrabutyl ammonium fluoride (8.0 mL, 1 M in tetrahydrofuran, 8.0 mmol) was added to the solution of the crude 2-(3,5-bis(tert-butyldimethyl silyloxy)phenyl)-4-(4-methoxy benzyloxy)-5-methylpyrimidine (5.229 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 90 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous ammonium chloride solution. The aqueous layer was back- extracted twice with EtOAc (50 ml_). The combined organic layers were dried over sodium sulfate and concentrated to afford 2.61 grams of crude product. The crude product was purified by flash chromatography eluting with a 0 to 100% gradient of EtOAc in heptane to give an oily residue which was crystallized from EtOAc/heptanes to afford the title compound (475 mg) as a white solid. 1H NMR (400 MHz, CDCI3) δ ppm 1.99 (s, 3 H), 3.65 (s, 3 H), 5.35 (s, 2 H), 6.36 (t, J=2.25 Hz, 1 H), 6.70 - 6.78 (m, 2 H), 7.26 - 7.33 (m, 4 H), 8.12 (d, J=0.98 Hz, 1 H), 8.60 (br. s., 2 H). MS (M+1): 339.5. Preparation of 3-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2-yl)-5-(4- (methylsulfonyl)phenoxy)phenol
Figure imgf000094_0001
A sealable tube was charged with 5-(4-(4-methoxybenzyloxy)-5- methylpyrimidin-2-yl)benzene-1 ,3-diol (350 mg, 1.03 mmol), potassium carbonate (286 mg, 2.07 mmol), (4-fluorophenyl)-methylsulfone (234 mg, 1.34 mmol) and dimethylformamide (5.2 ml_). Tube sealed and reaction heated at 120°C overnight. Reaction cooled down to room temperature. Ethyl Acetate was added and the mixture washed with HCI 1 N (aq.).
Aqueous layer washed once with EtOAc. Combined organic layers washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude residue. The residue was purified by flash column chromatography (S1O2); 0-10% methanol / dichloromethane) to provide 3-(4-(4- methoxy benzy loxy )-5-methy I py ri m idi n-2-y I )-5-(4-(methy Isu Ifony I )
phenoxy)phenol (104 mg, 20%) as a colorless gum. MS (M+1 ): 493.0. Preparation of (2S)-2-(3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-(4- (methylsulfonyl)phenoxy)phenoxy)propan-1-ol
Figure imgf000095_0001
In a sealed tube, a solution of 4-Fluorophenylmethylsulfone (17.4 mg, 0.10 mmol) and (S)-3-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol (45 mg, 0.091 mmol) in N,N- dimethyl formamide (0.5 ml_) was stirred at 120°C overnight. The reaction mixture was cooled down to room temperature and partitioned between EtOAc and saturated aqueous ammonium chloride solution. The aqueous layer was extracted with more EtOAc. Combined organics were washed twice with water, once with brine, dried over sodium sulfate, filtered and evaporated to give 45 mg of crude product as an amber residue. This was flash chromatographed eluting with a 50-100% gradient of EtOAc in heptane to afford the title compound (36 mg, 74%) as a white solid foam. 1H NMR (400 MHz, CDCI3) δ ppm 1.33 (d, 3 H), 3.03 (s, 3 H), 3.75 - 3.81 (m, 5 H), 4.60 - 4.70 (m, 1 H), 5.45 (s, 2 H), 6.69 (d, J=5.67 Hz, 1 H), 6.78 (t, J=2.25 Hz, 1 H), 6.84 - 6.90 (m, 2 H), 7.12 - 7.18 (m, 2 H), 7.33 - 7.40 (m, 2 H), 7.76 (dd, J=2.25, 1.47 Hz, 1 H), 7.87 - 7.92 (m, 2 H), 7.99 (br. s., 1 H), 8.49 (d, J=5.86 Hz, 1 H). MS (M+1 ): 537.3.
Preparation of (3-hvdroxy-5-iodophenyl)(pyrrolidin-1 -yl)methanone
Figure imgf000095_0002
To a solution of 3-hydroxy-5-iodobenzoic acid (200 mg, 0.758 mmol) in DMF (5 ml_), was added 1-Hydroxybenzotriazole, HOBT (133 mg, 0.985 mmol), 1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride, EDCI (189 mg, 0.985 mmol) at room temperature. After the addition, the mixture was stirred for 60 minutes at room temperature. The diisopropylethylamine (490 mg, 3.79 mmol) and pyrrolidine (162 mg, 2.27 mmol) was added to the reaction mixture in one portion at 0°C and stirred overnight at room temperature. TLC (dichloromethane: methanol = 10:1 ) indicated the reaction was complete, the reaction mixture was poured into dichloromethane (20 mL), and the organic layers were concentrated under reduced pressure to give the crude material. The crude product was purified by chromatography on silica gel (dichloromethane:methanol = 100:1) to provide (3-hydroxy-5- iodophenyl)(pyrrolidin-1-yl)methanone (190 mg, yield: 79%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.26-7.24 (dd, 2 H), 6.86 (t, 1 H), 3.54 (t, 2 H), 3.41 (t, 2 H), 1.99-1.88 (m, 4 H).
Preparation of (3-iodo-5-(4-(methylsulfonyl)phenoxy)phenyl)(pyrrolidin-1 - vQmethanone
Figure imgf000096_0001
To a solution of (3-hydroxy-5-iodophenyl)(pyrrolidin-1-yl)methanone (190 mg, 0.599 mmol) in DMF (8 mL) was added 1-fluoro-4-(methylsulfonyl) benzene (156 mg, 0.898 mmol) and Cs2CO3 (390 mg, 1.2 mmol). Then the mixture was heated to 80 °C for 18 hr. TLC (dichloromethane:methanol = 10:1 ) showed the reaction was complete. To the mixture was added water (10 mL) and extracted with EtOAc (10 mL once). The aqueous was acidified with 1 N HCI until pH=1-2 and extracted with EtOAc (10 mL X 3). The organic layers were dried and concentrated under reduced pressure to give the crude material. The crude product was purified by chromatography on silica gel (dichloromethane:methanol = 100:1 ) to provide (3-iodo-5-(4- (methylsulfonyl)phenoxy)phenyl)(pyrrolidin-1-yl)methanone (230 mg, yield : 81.5%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.67 (d, 2 H), 7.43 (s, 1 H), 7.28 (s, 1 H), 6.94-6.91 (m, 3 H), 3.25 (t, 2 H), 3.13 (t, 2 H), 2.82 (s, 3 H), 1.68-1.59 (m, 4 H).
Preparation of (3-(4-(methylsulfonyl)phenoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-
Figure imgf000097_0001
To a solution of (3-iodo-5-(4-(methylsulfonyl)phenoxy)phenyl)
(pyrrolidin-l-yl)methanone (100 mg, 0.212 mmol), Bis(pinacolato)diboron (162 mg, 0.636 mmol), potassium acetate (104 mg, 1.06 mmol), Pd(dppf)CI2 (8.00 mg, 0.011 mmol) in DMF (3 ml_), was stirred in a 10 ml_ round bottom flask. The flask was purged with nitrogen. Then reaction mixture was heated to 80°C under nitrogen and stirred for overnight. The resulting mixture was concentrated to remove DMF. Then the crude product was filtered through a plug of silica gel with dichloromethane and concentrated in vacuo. The crude material was purified by flash chromatography to provide (3-(4- (methylsulfonyl)phenoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)(pyrrolidin-1-yl)methanone (60 mg, yield: 60%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (t, 2 H), 7.75 (s, 1 H), 7.52 (t, 1 H), 7.40-7.38 (m, 1 H), 7.22-7.19 (m, 2 H), 3.61 (t, 2 H), 3.48 (t, 2 H), 3.14 (s, 3 H), 2.03-1.94 (m, 4 H), 1.37 (s, 12 H).
Preparation of (3-(4-(benzyloxy)-5-methylpyrimidin-2-yl)-5-(4- (methylsulfonyl)phenoxy)phenyl)(pyrrolidin-1-yl)methanone
Figure imgf000098_0001
A 10 mL round bottom flask was charged with (3-(4-(methylsulfonyl) phenoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)(pyrrolidin-1- yl)methanone (50 mg, 0.11 mmol), 4-(benzyloxy)-2-chloro-5- methylpyrimidine (24.9 mg, 0.106 mmol), Na2C03 (16.9 mg, 0.159 mmol), Pd(PPh3)4 (12.7 mg, 0.011 mmol), Toluene-/PrO (1 :3, 5mL) and H20 (0.3 mL). The flask was purged with nitrogen and then, the reaction mixture was heated to 80°C under nitrogen and stirred for overnight. TLC
(dichloromethane:methanol = 10:1) showed the reaction completion. The resulting mixture was concentrated to remove solvent. Then, the crude product was filtered through a plug of silica gel with dichloromethane and concentrated in vacuo. The crude material was purified by flash
chromatography to provide (3-(4-(benzyloxy)-5-methylpyrimidin-2-yl)-5-(4- (methylsulfonyl)phenoxy)phenyl) (pyrrolidin-l-yl)methanone (35 mg, yield: 58 %) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 8.28 (t, 2 H), 8.06 (s, 1 H), 7.90-7.87 (q, 2 H), 7.29-7.26 (m, 3 H), 7.18-7.16 (m, 2 H), 6.70 (d, 2 H), 5.39 (s, 2 H), 3.67 (s, 3 H), 3.52 (t, 2 H), 3.42 (t, 2 H), 3.00 (s, 3 H), 2.09 (s, 3 H), 1.99-1.78 (m, 4 H).
Example 1 : 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6-oxo- 1 ,6-dihvdropyrimidine-5-carbonitrile
Figure imgf000099_0001
To a stirred solution of 3-isopropoxy-5-(4-(methylsulfonyl)phenoxy) benzamidine (35 mg, 0.10 mmol) and ethyl (ethoxymethylene)cyanoacetate (16.9 mg, 0.10 mmol) in anhydrous ethanol (0.3 mL) was added sodium ethoxide (0.112 mL, 0.3 mmol, 21% in ethanol) dropwise at 0 °C. The vessel was sealed and heated at 70 °C overnight. Purification by column
chromatography eluting with 0 - 100% ethyl acetate in hexane gave the title compound 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6-oxo-1 ,6- dihydropyrimidine-5-carbonitrile (5.1 mg, 12%) as a white solid. 1H NMR (400 MHz, DMSO-de) δ ppm 8.58 (s, 1 H), 7.92 (d, J = 8.8 Hz, 2 H), 7.60 (m , 1 H), 7.42(m, 1 H), 7.22 (d, J = 8.8 Hz, 2 H), 6.94 (m, 1 H),4.72 (m, 1 H), 3.18 (s, 3 H), 1.27 (d, J = 6.0 Hz, 6 H). MS (M-1 ): 424.4.
Example 2: 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-5- methylpyrimidin-4(3H)-one
Figure imgf000099_0002
The title compound (53 mg, 45%) was prepared by a method analogous to that described for Example 1 using ethyl 2-methyl-3- oxopropanoate (48.5 mg, 0.373 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.71 (br s, 1 H), 7.91 (d, J = 8.8 Hz, 2 H), 7.88 (s , 1 H), 7.53 (m, 1 H),7.37 (m, 1 H), 7.21 (d, J = 8.8 Hz, 2 H), 6.86 (m, 1 H), 4.73 (m, 1 H), 3.17 (s, 3 H), 1.92 (s, 3 H), 1.27 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 415.3. Example 3: 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)pyrimidin- 4(3H)-one
Figure imgf000100_0001
The title compound (58 mg, 25%) was prepared by a method analogous to that described for Example 1 using ethyl propiolate (116 μΙ_,
1.15 mmol). 1H NMR (400 MHz, CDCI3) δ ppm 8.09 (d, J = 6.6 Hz, 1 H), 7.92 (d, J = 8.8 Hz, 2 H), 7.56 (t, J = 1.7 Hz, 1 H), 7.44 (t, J = 1.7 Hz, 1 H),
7.16 (d, J = 8.8 Hz, 2 H), 6.79 (t, J = 1.7 Hz, 1 H), 6.30 (d, J = 6.6 Hz, 1 H), 4.74 (heptet, J = 6.0 Hz, 1 H), 3.05 (s, 3 H), 1.38 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 401.4.
Example 4: 5-ethyl-2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)
phenyl)pyrimidin-4(3H)-on
Figure imgf000100_0002
The preparation of Example 4 is representative of the general method of pyrimidinone preparation from amidines with 1 ,3-dicarbonyl equivalent prepared in situ. To a stirred suspension of sodium hydride (91.8 mg, 60% in oil, 2.29 mmol) in anhydrous ether (1 mL) was added ethyl butyrate (0.152 mL, 1.15 mmol) and ethyl formate (0.092 mL, 1.15 mmol). The mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. 3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)benzamidine (100 mg, 0.287 mmol) and ethanol (1 mL) was then added. The suspension was heated at 75 °C overnight. Water was added followed by 3-4 drops of 37% hydrochloric acid to adjust pH to about 2. The mixture was extracted with EtOAc. The organic layer was dried over sodium sulfate and
concentrated. Purification by column chromatography eluting with 0 - 50% ethyl acetate in hexane gave the title compound 2-(3-isopropoxy-5-(4- (methylsulfonyl) phenoxy) phenyl)-6-oxo-1 ,6-dihydropyrimidine-5-carboxylate to afford the title compound 5-ethyl-2-(3-isopropoxy-5-(4-(methylsulfonyl) phenoxy)phenyl)pyrimidin-4(3H)-one (24.2 mg, 20%). 1H NMR (400 MHz, DMSO-d6) 5 ppm 13.22 (br s, 1 H), 7.92 (s, 1 H), 7.89 (d, J = 8.8 Hz, 2 H), 7.67 (m , 1 H), 7.58 (m, 1 H), 7.12 (d, J = 8.8 Hz, 2 H), 6.72 (m, 1 H), 4.73 (m, 1 H), 3.03 (s, 3 H), 2.47 (q, J = 7.6 Hz, 2 H),1.35 (d, J = 6.0 Hz, 6 H), 1.15 (t, J = 7.6 Hz, 3 H). MS (M+1): 429.4.
Example 5: 5-chloro-2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy) phenyl)pyrimidin-4(3H)-one
Figure imgf000101_0001
The title compound (56 mg, 45%) was prepared by a method analogous to that described for Example 4 using ethyl chloroacetate (0.183 ml_, 1.72 mmol) and ethyl formate (0.138 ml_, 1.72 mmol). 1H NMR (400 MHz, DMSO-de) δ ppm 13.30 (br s, 1 H), 8.29 (s, 1 H), 7.93 (d, J = 8.8 Hz, 2 H), 7.53 (m, 1 H), 7.37 (m, 1 H), 7.23 (d, J = 8.8 Hz, 2 H), 6.92 (m, 1 H), 4.74 (m, 1 H), 3.19 (s, 3 H), 1.28 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 435.4.
Example 6: 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-5- methoxypyrimidin-4(3H)-one
Figure imgf000102_0001
The title compound (42 mg, 17%) was prepared by a method analogous to that described for Example 4 using ethyl-2-methoxyacetate (0.269 mL, 2.29 mmol) and ethyl formate (0.184 mL, 2.29 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.79 (br s, 1 H), 7.91 (d, J = 8.8 Hz, 2 H), 7.62 (s, 1 H), 7.47 (m, 1 H), 7.32 (m, 1 H), 7.21 (d, J = 8.8 Hz, 2 H), 6.82 (m, 1 H),4.72 (m, 1 H), 3.74 (s, 3 H), 3.18 (s, 3 H), 1.27 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 431.4.
Example 7: 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-5- (methoxymethyl)pyrimidin- -one
Figure imgf000102_0002
The title compound (1.5 mg, 1.2%) was prepared by a method analogous to that described for Example 4 using methyl acrylate (0.414 mL) and ethyl formate (0.738 mL). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (br s, 1 H), 8.12 (s, 1 H), 7.92 (d, J = 8.8 Hz, 2 H), 7.48 (m, 1 H), 7.38 (m, 1 H), 7.15 (d, J = 8.8 Hz, 2 H), 6.76 (m, 1 H), 4.67 (m, 1 H), 3.43 (s, 3 H), 3.06 (s, 3 H), 1.38 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 445.0.
Example 8: Ethyl 2-(2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl) - 6-oxo- 1 , 6-d i h yd ro p yri m id i n-5-yl )acetate
Figure imgf000103_0001
The title compound (32 mg, 23%) was prepared by a method analogous to that described for Example 4 using diethyl succinate (0.385 ml_, 2.29 mmol) and ethyl formate (0.184 ml_, 2.29 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.91 (br s, 1 H), 8.05 (s, 1 H), 7.90 (d, J = 8.8 Hz, 2 H), 7.59 (m, 1 H), 7.50 (m, 1 H), 7.15 (d, J = 8.8 Hz, 2 H), 6.74 (m, 1 H), 4.69 (m, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 3.46 (s, 2 H), 3.04 (s, 3 H), 1.37 (d, J = 6.0 Hz, 6 H), 1.35 (t, J = 7.2 Hz, 3 H). MS (M+1): 487.4.
Example 9: 2-(2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6-oxo- 1 ,6-dihvdropyrimidin-5-yl)acetic acid
Figure imgf000103_0002
Sodium hydroxide (5 N, 0.248 ml_, 1.24 mmol) was added to a solution of ethy 2-(2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6- oxo-1 ,6-dihydropyrimidin-5-yl)acetate (30 mg, 0.062 mmol) in methanol (0.3 ml_). The mixture was stirred at 75 °C for 1 hour. The mixture was diluted with ethyl acetate, washed with hydrochloric acid and brine, dried over sodium sulfate, and concentrated to afford the title compound 2-(2-(3- isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6-oxo-1 ,6- dihydropyrimidin-5-yl)acetic acid (22 mg, 27%). 1H NMR (400 MHz, DMSO- d6) δ ppm 8.08 (s, 1 H), 7.88 (d, J = 8.8 Hz, 2 H), 7.48 (m, 1 H), 7.41 (m, 1 H), 7.13 (d, J = 8.8 Hz, 2 H), 6.73 (m, 1 H), 4.66 (m, 1 H), 3.50 (s, 2H), 3.04 (s, 3 H), 1.34 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 459.0.
Example 10: 2-(3-isopropoxy-5-(1 -(methylsulfonyl)pyrrolidin-3-yloxy)phenyl)- 5-methylpyrimidin-4(3H)-o
Figure imgf000104_0001
To a stirring solution of 3-isopropoxy-5-(1-(methylsulfonyl)pyrrolidin-3- yloxy)benzamidine (50 mg, 0.15 mmol), ethyl 2-methyl-3-oxopropanoate (57.0 mg, 0.438 mmol) in anhydrous ethanol (0.5 ml_) in a small vial was added sodium ethoxide (0.163 ml_, 0.438 mmol, 21 percent in ethanol) dropwise at room temperature. The vial was sealed and heated at 85 °C overnight. LCMS indicated the desired product was generated with some starting material left. Water was added followed by 3-4 drops of 37% hydrochloric acid to adjust PH~2. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography eluting with 0 - 80% ethyl acetate in hexane gave the title compound 2-(3-isopropoxy-5-(1-(methylsulfonyl) pyrrolidin-3-yloxy)phenyl)-5-methylpyrimidin-4(3H)-one (19 mg, 32%) as a white solid. 1H NMR (400 MHz, CDCI3) δ ppm 12.86 (br s, NH, 1 H), 7.98 (s, 1 H), 7.42 (m, 1 H), 7.29 (m, 1 H), 6.53 (m, 1 H), 5.11 (br m, 1 H), 4.76 (heptet, J = 6.0 Hz, 1 H), 3.70 (m, 1 H), 3.62 (m, 2 H), 3.49 (m, 1 H), 2.84 (s, 3 H), 2.35 (m, 1 H), 2.22 (m, 1 H), 2.11 (s, 3 H), 1.36 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 408.5.
Example 11 : 2-(3-isopropoxy-5-(1-(methylsulfonyl)pyrrolidin-3- yloxy)phenyl)pyrimidin-4(3H)-one
Figure imgf000105_0001
The title compound was prepared by a method analogous to that described for Example 10, using ethyl propiolate instead of ethyl 2-methyl-3- oxopropanoate. 1H NMR (400 MHz, CDCI3) δ ppm 13.27 (br s, NH, 1 H), 8.13 (d, J = 6.8 Hz, 1 H), 7.45 (m, 1 H), 7.33 (m, 1 H), 6.57 (m, 1 H), 6.38 (d, J = 6.8 Hz, 1 H), 5.12 (m, 1 H), 4.76 (heptet, J = 6.0 Hz, 1 H), 3.69 (m, 2 H), 3.62 (m, 1 H), 3.59 (m, 1 H), 2.85 (s, 3 H), 2.37 (m, 1 H), 2.23 (m, 1 H), 1.37 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 394.5.
Example 12: (S)-2-(3-(1 -methoxypropan-2-yloxy)-5-(4-(methylsulfonyl) phenoxy)phenyl)-5-methylpyrimidin-4(3H)-one
Figure imgf000105_0002
The title compound was prepared by a method analogous to that described for Example 2, using (S)-3-(1-methoxypropan-2-yloxy)-5-(4- (methylsulfonyl)phenoxy)benzamidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (s, 1 H), 7.86 (d, J = 9.0 Hz, 2 H), 7.69 (m, 1 H), 7.59 (m, 1 H), 7.12 (d, J = 9.0 Hz, 2 H), 6.80 (m, 1 H), 4.75 (m, 1 H), 3.59 (dd, J = 10.2, 6.0 Hz, 1 H), 3.50 (dd, J = 10.2, 4.0 Hz, 1 H), 3.37 (s, 3 H), 3.04 (s, 3 H), 1.99 (s, 3 H), 1.33 (d, J = 6.4 Hz, 3 H). MS (M+1 ): 445.2.
Example 13: 5-ethyl-2-(3-r(1S)-2-hvdroxy-1-methylethoxy1-5-r4- (methylsulfonyl)phenoxylphenyl)pyrimidin-4(3H)-one
Figure imgf000106_0001
A mixture of (S)-2-(3-(1-(benzyloxy)propan-2-yloxy)-5-(4- (methylsulfonyl)phenoxy)phenyl)-5-ethylpyrimidin-4(3H)-one (48 mg, 0.09 mmol) and 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone (61.3 mg, 0.27 mmol) in dichloromethane (0.4 ml_) and water (40 μΙ_) was heated at 58°C over the weekend. The solvent escaped to dryness. Dichloromethane (0.5 ml_) was added. LCMS of an aliquot indicated -25% conversion to the desired product. The mixture was heated at 64°C for another 24 hours. LCMS of an aliquot indicated -50% conversion to the desired product. The solvent was removed and the crude residue was purified by preparative HPLC, to provide the title compound (17.8 mg, 44.5%). MS (M+1 ): 445.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA (trifluoroacetic acid) 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.4 min. Example 14: (S)-5-(3-(1-hvdroxypropan-2-yloxy)-5-(6-oxo-1 ,6- dihvdropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide
Figure imgf000106_0002
A mixture of 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-((S)-1-(tert- butyldimethylsilyloxy)propan-2-yloxy)phenol (151 mg, 0.304 mmol), 5-chloro- N,N-dimethylpyrazine-2-carboxamide (73.1 mg, 0.394 mmol), potassium carbonate (126 mg, 0.91 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 75 °C for 4 h. TLC indicated the starting material was consumed. The mixture was diluted with ethyl acetate and washed with water, dried over sodium sulfate and concentrated. The crude residue was dissolved in tetrahydrofuran (2 ml_) and tetrabutylammonium fluoride (0.456 ml_, 1 M in tetrahydrofuran, 0.456 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate and washed with ammonium chloride (saturate aqueous). The organic layer was dried over sodium sulfate and concentrated. The crude was dissolved in dichloromethane (2 ml_) and trifluoroacetic acid (469 μΙ_, 6.09 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc and washed with sodium bicarbonate
(saturated aqueous), dried over sodium sulfate and concentrated.
Purification by column chromatography eluting with 0-100% EtOAc in hexane followed by 5% methanol in EtOAc gave the title compound (50 mg, 39.6% over 3 steps) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.45 (d, J = 1.4 Hz, 1 H), 8.40 (d, J = 1.4 Hz, 1 H), 8.05 (d, J = 6. 8 Hz, 1 H), 7.55 (m, 1 H), 7.45 (m, 1 H), 7.08 (m, 1 H), 6.40 (d, J = 6. 8 Hz, 1 H), 4.60 (m, 1 H), 3.68 (m, 2 H), 3.14 (s, 3 H), 3.12 (s, 3 H), 1.31 (d, J = 6.2 Hz, 3 H). MS (M+1 ): 412.5.
Example 15: (S)-2-(3-(1 -hvdroxypropan-2-yloxy)-5-(4-(methylsulfonyl) phenoxy)phenyl)pyrimidin-4(3H)-one
Figure imgf000107_0001
The title compound was prepared by a method analogous to that described for Example 14, using 1-fluoro-4-(methylsulfonyl)benzene to replace 5-chloro-N,N-dimethylpyrazine-2-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (d, J = 6.8 Hz, 1 H), 7.95 (d , J = 8.8 Hz, 2 H), 7.50 (m, 1 H), 7.33 (m, 1 H), 7.23 (d, J = 8.8 Hz, 2 H), 6.95 (m, 1 H), 6.41 (d, J = 6.8 Hz, 1 H), 4.59 (m, 1 H), 3.68 (d, 2 H), 3.10 (s, 3 H), 1.30 (d, J = 6.2 Hz, 3 H). MS (M+1 ): 417.4.
Example 16: (S)-2-(3-(4-(ethylsulfonyl)phenoxy)-5-(1-hvdroxypropan-2-
Figure imgf000108_0001
The title compound was prepared by a method analogous to that described for Example 14, using 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5- ((S)-1 -(triisopropylsilyloxy)propan-2-yloxy)phenol and 1 -fluoro-4- (ethylsulfonyl)benzene. MS (M+1 ): 431.1. Column: Waters Atlantis d C18 4.6x50 mm, 5 μιη; Modifier: TFA 0.05%; Gradient: 90% H20 / 10% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 2.06 min.
Example 17: (S)-4-(3-(1-hvdroxypropan-2-yloxy)-5-(6-oxo-1 ,6- dihvdropyrimidin-2-yl)phenoxy)-N,N-dimethylbenzenesulfonamide
Figure imgf000108_0002
The title compound was prepared by a method analogous to that described for Example 14, using 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5- ((S)-1 -(triisopropylsilyloxy)propan-2-yloxy)phenol and 4-fluoro-A/,A/- dimethylbenzenesulfonamide. MS (M+1 ): 446.1. Column: Waters Atlantis d C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 90% H20 / 10% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.24 min. Example 18: N,N-dimethyl-5-(3-(1 -methyl-2-oxopyrrolidin-3-yloxy)-5-(6-oxo- 1 ,6-dihvdropyrimidin- -yl)phenoxy)pyrazine-2-carboxamide
Figure imgf000109_0001
A mixture of 5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)benzene-1 ,3- diol (220 mg, 0.678 mmol), 3-bromo-1-methylpyrrolidin-2-one (121 mg, 0.678 mmol) and potassium carbonate (141 mg, 1.02 mmol) in N,N-dimethyl formamide (2 ml_) was stirred at 60 °C over the weekend. LCMS of an aliquot indicated a little bit desired product was generated with majority of the starting material left. 282 mg of potassium carbonate was added and the mixture was heated at 90°C for 6 h. LCMS indicated more desired product was generated. 5-chloro-N,N-dimethylpyrazine-2-carboxamide (126 mg, 0.678 mmol) was added. The mixture was heated at 60 °C overnight. TFA (0.5 ml_) was then added slowly. The mixture was stirred for 1 hour, diluted with EtOAc and washed with sodium bicarbonate (saturated aqueous). The organic layer was dried over sodium sulfate and concentrated. Purification by HPLC (high pressure liquid chromatography) gave the title compound 2- (3-isopropoxy-5-(1-methyl-2-oxopyrrolidin-3-yloxy)phenyl) pyrimidin-4(3H)- one (19 mg, 6.2%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 8.46 (d, J = 1.4 Hz, 1 H), 8.40 (d, J = 1.4 Hz, 1 H), 8.05 (d, J = 6.7 Hz, 1 H), 7.62 (m, 1 H), 7.52 (m, 1 H), 7.17 (m, 1 H), 6.39 (d, J = 6.7 Hz, 1 H), 5.13 (t, J = 7.6 Hz, 1 H), 3.61-3.43 (m, 2 H), 3.13 (s, 3 H), 3.11 (s, 3 H), 2.90 (s, 3 H), 2.70 (m, 1 H), 2.13 (m, 1 H). MS (M+1): 451.5.
Example 19: 5-(3-isopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)- N , N-d i methyl pyri m id i ne-2-carboxam ide
Figure imgf000110_0001
A sealed tube was charged with 3-isopropoxy-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol (100 mg, 0.273 mmol),5-bromo- N,N-dimethylpyrimidine-2-carboxamide (81.7 mg, 0.355 mmol), cesium carbonate (142 mg, 0.437 mmol), CuCI (27.1 mg, 0.273 mmol) and DMF (1 mL). 2,2,6,6-tetramethylheptane-3,5-dione (0.056 mL, 0.273 mmol) was then added, the tube sealed and the reaction mixture heated at 120 °C overnight. To the reaction mixture was added DCM (1.5 mL) and TFA (3.0 mL) and after 10 minutes, the deprotection was completed. Reaction mixture transfered with ethyl acetate into a separately funnel containing an HCI solution (1 N, aq.) (10 mL) ca. pH 2-3 and extracted with ethyl acetate (3 X 20 mL). Combined organic layers were washed with water (1 X 10mL), brine (1 X 10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column
chromatography (S1O2, 0%-20% methanol / ethyl acetate) to provide 5-(3- isopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-A/,A/- dimethylpyrimidine-2-carboxamide as a white solid (28.5 mg, 24.3%). Rf = 0.24 (8%MeOH/ethyl acetate). 1H NMR (400 MHz, CD3OD) δ 1.34 (d, 6 H), 2.98 (s, 3 H), 3.13 (s, 3 H), 4.72 (spt, J = 5.86 Hz, 1 H), 6.39 (d, J = 6.64 Hz, 1 H), 6.98 (t, J = 2.25 Hz, 1 H), 7.31 - 7.38 (m, 1 H), 7.45 - 7.52 (m, 1 H), 8.05 (d, J = 6.64 Hz, 1 H), 8.64 (s, 2 H); MS (M+1 ): 396.5.
Example 20: 2-(3-(2-(azetidine-1-carbonyl)pyrimidin-5-yloxy)-5- isopropoxyphenyl)pyrimidin-4(3H)-one
Figure imgf000111_0001
The title compound was prepared by a method analogous to that described for Example 19 using azetidin-1-yl(5-bromopyrimidin-2- yl)methanone. MS (M+1 ): 408.1 ; Column: Waters Atlantis d C18 4.6x50 mm, 5 pm; Modifier: TFA 0.05%; Gradient: 90% H20 / 10% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.14 min.
Example 21 : 2-(3-isopropoxy-5-(2-(pyrrolidine-1-carbonyl)pyrimidin-5- yloxy)phenyl)pyrimidin- -one
Figure imgf000111_0002
The title compound was prepared by a method analogous to that described for Example 19 using (5-bromopyrimidin-2-yl)(pyrrolidin-1- yl)methanone. MS (M+1 ):408.1 ; Column: Waters Atlantis dC18 4.6 x 50 mm, 5 pm; Modifier: TFA 0.05%; Gradient: 90% H20 / 10% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.21 min.
Example 22: 3-fluoro-5-(3-isopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)-N,N-dimethylpicolinamide
Figure imgf000112_0001
In a sealed tube, were dissolved in DMF, 3-isopropoxy-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol (50 mg, 0.14 mmol), 3,5-difluoro- N,N-dimethylpicolinamide (33 mg, 0.18 mmol) and potassium carbonate (34 mg, 0.25 mmol). The tube was sealed and the reaction mixture was stirred overnight at 100°C. TFA (0.5 ml_) was added to the reaction mixture and stirred for 15 minutes. Organics were removed under reduced pressure and the residue was dissolved in DMSO (0.9 ml_) for preparative HPLC
purification. MS (M+1 ): 413.2; Column: Waters Atlantis dC18 4.6 x 50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 85% H20 / 15% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min.; Flow: 2.0ml_ / min.; RT: 2.05 min.
Example 23: 2-(3-(6-(azetidine-1 -carbonyl)-5-fluoropyridin-3-yloxy)-5- isopropoxyphenyl)pyrimidin-4(3H)-one
Figure imgf000112_0002
The title compound was prepared by a method analogous to that described for Example 22 using azetidin-1-yl(3,5-difluoropyridin-2-yl) methanone. MS (M+1 ): 425.1. Column: Waters Atlantis dC18 4.6 x 50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min.; Flow: 2.0mL / min.; RT: 2.43 min.
Example 24: 2-(3-(5-(azetidine-1-carbonyl)pyrazin-2-yloxy)-5- isopropoxyphenyl)pyrimidin-4(3H)-one
Figure imgf000113_0001
The title compound was prepared by a method analogous to that described for Example 22 using azetidin-1-yl(5-chloropyrazin-2- yl)methanone. MS (M+1 ): 408.1. Column: Waters Atlantis dC18 4.6 x 50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min.; Flow: 2.0ml_ / min.; RT: 2.48 min.
Example 25: 5-(3-isopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)- N.N-dimethylpyrazine-2-carboxamide
Figure imgf000113_0002
A mixture of 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5- isopropoxyphenol (64.1 mg, 0.175 mmol), 5-chloro-N,N-dimethylpyrazine-2- carboxamide (48.6 mg, 0.262 mmol), potassium carbonate (72.6 mg, 0.525 mmol) in acetonitrile (1 ml_) was stirred at 75 °C for 4 h. The mixture was diluted with ethyl acetate and washed with 1 N hydrochloric acid, dried over sodium sulfate and concentrated. The crude was dissolved in
dichloromethane (0.5 ml_) and trifluoroacetic acid (0.27 ml_, 3.5 mmol) was added. The mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and washed with sodium bicarbonate (saturated aqueous), dried over sodium sulfate and concentrated.
Purification by column chromatography eluting with 0 - 100% ethyl acetate in hexane followed by 5% methanol in ethyl acetate gave the title compound 5-(3-isopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrazine-2-carboxamide (41 mg, 59% over 2 steps) as a white solid. 1H NMR (400 MHz, CDCI3) 5 ppm 13.31 (s, 1 H), 8.53 (d, J = 1.3 Hz, 1 H), 8.38 (d, J = 1.3 Hz, 1 H), 8.10 (d, J = 6.8 Hz, 1 H), 7.48 (m, 1 H), 7.46 (m, 1 H), 6.91 (m, 1 H), 6.40 (d, J = 6.8 Hz, 1 H), 4.74 (heptet, J = 6.0 Hz, 1 H), 3.17 (s, 3 H), 3.14 (s, 3 H), 1.39 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 396.5.
Example 26: 4-(3-isopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)benzenesulfonamide
Figure imgf000114_0001
A mixture of 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5- isopropoxyphenol (65 mg, 0.18 mmol), 4-fluorobenzenesulfonamide (57.0 mg, 0.325 mmol) and cesium carbonate (115 mg, 0.354 mmol) in 1- methylpyrrolidin-2-one (0.7 ml_) was heated at 135 °C for 20 h. This was follwed by deprotection under acidic conditions. LCMS indicated the desired product was produced. HPLC (high pressure liquid chromatography) purification gave the title compound 4-(3-isopropoxy-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)benzenesulfonamide (14.6 mg, 21%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J = 6.7 Hz, 1 H), 7.91 (d, J = 8.8 Hz, 2 H), 7.42 (m, 1 H), 7.27 (m, 1 H), 7.16 (d, J = 8.8 Hz, 2 H), 6.83 (m, 1 H), 6.38 (d, J = 6.7 Hz, 1 H), 4.69 (heptet, J = 6.1 Hz, 1 H), 1.34 (d, J = 6.1 Hz, 6 H). MS (M+1 ): 402.1.
Example 27: 4-(3-isopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)-N- methylbenzenesulfonamide
Figure imgf000114_0002
The title compound was prepared by a method analogous to that described for Example 26, using 4-fluoro-N-methylbenzenesulfonamide. 1H NMR (400 MHz, CDCI3) δ ppm 8.04 (d, J = 6.7 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 2 H), 7.44 (m, 1 H), 7.30 (m, 1 H), 7.18 (d, J = 8.8 Hz, 2 H), 6.85 (m, 1 H), 6.38 (d, J = 6.7 Hz, 1 H), 4.71 (heptet, J = 6.0 Hz, 1 H), 2.52 (s, 3 H), 1.34 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 416.4.
Example 28: 4-(3-isopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)-
Figure imgf000115_0001
The title compound was prepared by a method analogous to that described for Example 22 using fert-butyl 4-fluoro-2- methylphenylsulfonyl(methyl)carbamate. MS (M+1 ): 430.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05% Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 2.81 min.
Example 29: 5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)- N , N-d i methyl pyri m id i ne-2-carboxam ide
Figure imgf000115_0002
The title compound was prepared by a method analogous to that described for Example 19, using 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5- sec-butoxyphenol. 1H NMR (400 MHz, CDCI3) δ ppm 8.60 (br s, 2 H), 8.11 (d, J = 6.6 Hz, 1 H), 7.61 (m, 1 H), 7.47 (m, 1 H), 6.82 (m, 1 H), 6.38 (d, J = 6.6 Hz, 1 H), 4.55 (m, 1 H), 3.13 (s, 3 H), 2.98 (s, 3 H), 1.77-1.67 (m, 2 H), 1.34 (d, J = 6.1 Hz, 3 H), 1.01 (t, J = 7.5 Hz, 3 H). MS (M+1 ): 410.5.
Example 30: 5-(3-isopropoxy-5-(5-methyl-6-oxo-1 ,6-dihvdropyrimidin-2-yl)
Figure imgf000116_0001
The title compound was prepared by a method analogous to that described for Example 19, using 3-(4-(4-methoxybenzyloxy)-5- methylpyrimidin-2-yl)-5-isopropoxyphenol. 1H NMR (400 MHz, CD3OD) δ ppm 8.95 (very broad s, 2 H, the bottom pyrimidine H), 7.94 (s, 1 H), 7.44 (m, 1 H), 7.31 (m, 1 H), 6.96 (m, 1 H), 4.74 (heptet, J = 6.0 Hz, 1 H), 3.13 (s, 3 H), 2.99 (s, 3 H), 2.06 (s, 3 H), 1.35 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 410.2. Example 31 : 3-fluoro-5-(3-isopropoxy-5-(5-methyl-6-oxo-1 ,6-
Figure imgf000116_0002
The title compound was prepared by a method analogous to that described for Example 22, using 3-(4-(4-methoxybenzyloxy)-5- methylpyrimidin-2-yl)-5-isopropoxyphenol. MS (M+1 ): 427.1 ; Column:
Waters Atlantis dC18 4.6 x 50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min.; Flow: 2.0mL / min.; RT: 2.52 min.
Example 32: 4-(3-isopropoxy-5-(5-methyl-6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)-N-methylbenzenesulfonamide
Figure imgf000117_0001
The title compound was prepared by a method analogous to that described for Example 27, using 3-(4-(4-methoxybenzyloxy)-5- methylpyrimidin-2-yl)-5-isopropoxyphenol. MS (M+1 ): 430.1. Column:
Waters XBridge C18 4.6x50 mm, 5 μηη; Modifier: ammonium hydroxide 0.03%; Gradient: 85% H20 / 10% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 1.89 min.
Example 33: (S)-5-(3-sec-butoxy-5-(5-methyl-6-oxo-1 ,6-dihvdropyrimidin-2-
Figure imgf000117_0002
The title compound was prepared by a method analogous to that described for Example 22, using (S)-3-seobutoxy-5-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)phenol and 5-chloro-N,N- dimethylpyrazine-2-carboxamide. MS (M+1 ): 424.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.63 min.
Example 34: (S)-5-(3-sec-butoxy-5-(5-methyl-6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide
Figure imgf000118_0001
The title compound was prepared by a method analogous to that described for Example 19, using (S)-3-seobutoxy-5-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)phenol and 5-bromo-N,N- dimethylpyrimidine-2-carboxamide. MS (M+1): 424.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 2.53 min.
Example 35: (S)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide
Figure imgf000118_0002
The title compound was prepared by a method analogous to that described for Example 22, using (S)-3-seobutoxy-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol and 5-chloro-N,N-dimethylpyrazine- 2-carboxamide. MS (M+1 ): 410.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.49 min.
Example 36: (S)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide
Figure imgf000118_0003
The title compound was prepared by a method analogous to that described for Example 19, using (S)-3-seobutoxy-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol and 5-bromo-N,N- dimethylpyrimidine-2-carboxamide. MS (M+1): 410.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 2.39 min.
Example 37: N,N-dimethyl-3-(5-methyl-6-oxo-1 ,6-dihvdropyrimidin-2-yl)-5-
Figure imgf000119_0001
Step 1 : A sealed tube was charged with 3-hydroxy-5-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)-N,N-dimethylbenzamide (30 mg, 0.076 mmol), (4-fluorophenyl)-methylsulfone (19.9 mg, 0.114 mmol), potassium carbonate (21.0 mg, 0.152 mmol) and dimethylformamide (0.4 ml_). The tube was sealed and the reaction stirred at 120 °C overnight. EtOAc added to the reaction mixture and was washed once with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford the crude material. MS (M+1 ): 548.4.
Step 2: The crude material from Step 1 was dissolved in
dichloromethane (0.39ml_) and TFA (0.18ml_, 2.31 mmol) was added in one portion. The reaction was stirred at room temperature for 2 hours. DCM and TFA removed under reduced pressure and crude product dissolved in DMSO for preparative HPLC purification. MS (M+1): 428.2. Column:
Waters Atlantis C184.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.07 min. Example 38: 3-(4-(ethylsulfonyl)phenoxy)-N,N-dimethyl-5-(5-methyl-6-oxo-
Figure imgf000120_0001
The title compound was prepared by a method analogous to that described for Example 37, using 1-(ethylsulfonyl)-4-fluorobenzene. MS (M+1): 442.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 2.21 min.
Example 39: 3-(4-(isopropylsulfonyl)phenoxy)-N,N-dimethyl-5-(5-methyl-6- oxo-1 ,6-dihvdropyrimidi -2-yl)benzamide
Figure imgf000120_0002
The title compound was prepared by a method analogous to that described for Example 37, using 1-fluoro-4-(isopropylsulfonyl)benzene. MS (M+1): 456.0. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.31 min.
Example 40: (S)-2-(3-(1 -hvdroxypropan-2-yloxy)-5-(4-(methylsulfonyl) phenoxy)phenyl)-5-methylpyrimidin-4(3H)-one
Figure imgf000121_0001
Step 1 : A sealed tube was charged with K2C03 (132 mg, 0.955 mmol),(4-fluorophenyl)-methylsulfone (99.8 mg, 0.573 mmol), (S)-3-(1-(fert- butyldimethylsilyloxy)propan-2-yloxy)-5-(4-(4-methoxybenzyloxy)-5- methylpyrimidin-2-yl)phenol (195 mg, 0.382 mmol) and DMF (1.9 mL). The reaction mixture was stirred at 120°C overnight. Reaction completed (TBS totally deprotects because of the fluoride ion formed during the process). Reaction mixture dissolved in ethyl acetate and washed with water / citric acid 1N (2/1 ; ca. pH 3). The organic layer was washed two times with water, dried over sodium sulfate, filtered and concentrated to afford the crude material. The residue was purified by flash column chromatography (Si02, 80%-100% ethyl acetate / heptane) to provide (S)-2-(3-(4-(4- methoxy benzy loxy )-5-methy I py ri m id i n-2-y I )-5-(4-(methy Isu Ifony I )
phenoxy)phenoxy)propan-1-ol (194 mg, 92%) as a white solid. 1H NMR (400 MHz, CDCI3) δ ppm 1.31 (d, 3 H), 2.15 (d, J=0.78 Hz, 3 H), 2.29 (br. s., 1 H), 3.02 (s, 3 H), 3.71 - 3.77 (m, 2 H), 3.78 (s, 3 H), 4.52 - 4.64 (m, 1 H), 5.44 (s, 2 H), 6.72 (t, J=2.34 Hz, 1 H), 6.82 - 6.89 (m, 2 H), 7.10 - 7.17 (m, 2 H), 7.32 - 7.39 (m, 2 H), 7.72 (dd, J=2.24, 1.27 Hz, 1 H), 7.83 - 7.90 (m, 3 H), 8.27 (d, J=0.98 Hz, 1 H). MS (M+1 ): 551.5.
Step 2: A 20 dram vial was charged with (S)-2-(3-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)-5-(4-(methylsulfonyl)phenoxy) phenoxy)propan-1-ol (190 mg, 0.345 mmol) and dissolved in 0.5M
HCI/MeOH solution (4 mL) and stirred at room temperature overnight. The reaction was not totally complete. 0.8 mL of 4N HCI in dioxane was added to the reaction mixture and stirred an extra 3 hours after which time the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (Biotage KP-NH column, 5%- 25% ethyl acetate / heptane) to provide (S)-2-(3-(1-hydroxypropan-2-yloxy)- 5-(4-(methylsulfonyl)phenoxy)phenyl)-5-methylpyrimidin-4(3H)-one (95mg, 64%) as a white solid (trituration with ethyl ether help to provide a nice white solid). 1H NMR (400 MHz, CD3OD) δ ppm 1.29 (d, 3 H), 2.05 (d, J=0.98 Hz, 3 H), 3.10 (s, 3 H), 3.66 (d, J=5.08 Hz, 2 H), 4.51 - 4.63 (m, 1 H), 6.91 (t, J=2.15 Hz, 1 H), 7.18 - 7.24 (m, 2 H), 7.29 (t, J=1.66 Hz, 1 H), 7.42 - 7.47 (m, 1 H), 7.89 - 7.96 (m, 3 H). MS (M+1 ): 431.5.
Example 41 : (S)-2-(3-(4-(ethylsulfonyl)phenoxy)-5-(1-hvdroxypropan-2- yloxy)phenyl)-5-methylpyrimidin-4(3H)-one
Figure imgf000122_0001
The title compound was prepared by a method analogous to that described for Example 40, using 1-(ethylsulfonyl)-4-fluorobenzene and (S)-3- (1-hydroxypropan-2-yloxy)-5-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2- yl)phenol. However, the final deprotection (para-methoxybenzyl removal) was done without isolation of the intermediate after step 1. MS (M+1 ):
445.0. Column: Waters Atlantis C18 4.6 x 50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 2.34 min.
Example 42: (S)-2-(3-(4-(cvclopropylsulfonyl)phenoxy)-5-(1 -hvdroxypropan- 2-yloxy)phenyl)-5-methylpyrimidin-4(3H)-one
Figure imgf000123_0001
The title compound was prepared by a method analogous to that described for Example 40, using 1-(cyclopropylsulfonyl)-4-fluorobenzene and (S)-3-(1-hydroxypropan-2-yloxy)-5-(4-(4-methoxybenzyloxy)-5- methylpyrimidin-2-yl)phenol. However, the final deprotection (PMB removal) was done without isolation of the intermediate after step 1. MS (M+1 ):
457.0. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 2.41 min. Example 43: (S)-4-(3-(1-hvdroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6-
Figure imgf000123_0002
The title compound was prepared by a method analogous to that described for Example 40, using 4-fluoro-N,N-dimethylbenzenesulfonamide. However, the final deprotection (PMB removal) was done without isolation of the intermediate after step 1. MS (M+1 ): 460.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μιη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.49 min.
Example 44: (S)-3-fluoro-5-(3-(1 -hvdroxypropan-2-yloxy)-5-(5-methyl-6-oxo- 1 ,6-dihvdropyrimidin-2-yl)phenoxy)-N,N-dimethylpicolinamide
Figure imgf000124_0001
The title compound was prepared by a method analogous to that described for Example 40, using 3,5-difluoro-N,N-dimethylpicolinamide. However, the final deprotection (para-methoxybenzyl removal) was done without isolation of the intermediate after step 1. MS (M+1 ): 443.1. Column: Waters Atlantis C184.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 80% H20 / 20% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 1.34 min.
Example 45: (S)-5-(3-(1-hvdroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6-
Figure imgf000124_0002
The title compound was prepared by a method analogous to that described for Example 40, using 5-chloro-N,N-dimethylpyrazine-2- carboxamide. However, the final deprotection (para-methoxybenzyl removal) was done without isolation of the intermediate after step 1. MS (M+1): 426.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 80% H20 / 20% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 1.24 min.
Example 46: (S)-5-(3-(1-hvdroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6- dihvdropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide
Figure imgf000125_0001
The title compound was prepared by a method analogous to that described for Example 19, using (S)-3-(1-hydroxypropan-2-yloxy)-5-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)phenol. MS (M+1): 426.1.
Column: Waters Atlantis C18 4.6x50 mm, 5 pm; Modifier: TFA 0.05%;
Gradient: 80% H20 / 20% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 1.16 min. Example 47: (S)-4-(3-(1-hvdroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6-
Figure imgf000125_0002
The title compound was prepared by a method analogous to that described for Example 40, using tert-butyl 4-fluorophenylsulfonyl
(methyl)carbamate and (S)-3-(1-hydroxypropan-2-yloxy)-5-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)phenol. However, the final deprotection (para-methoxybenzyl removal) was done directly on the reaction mixture of step 1 with 40 equiv. of TFA at room temperature for 1 hour. MS (M+1 ): 446.1. Column: Waters Atlantis C18 4.6x50 mm, 5 pm; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.27 min. Example 48: (S)-3-fluoro-5-(3-(1-hvdroxypropan-2-yloxy)-5-(6-oxo-1 ,6-
Figure imgf000126_0001
The title compound was prepared by a method analogous to that described for Example 40, using 3,5-difluoro-N,N-dimethylpicolinamide and (S)-3-(1 -(tert-butyldimethylsilyloxy) propan-2-yloxy)-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol. The final deprotection (PMB removal) was done with TFA in dichloromethane at room temperature. MS (M+1): 429.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 1.85 min.
Example 49: (S)-2-(3-(1 -hvdroxypropan-2-yloxy)-5-(4-(isopropylsulfonyl) phenoxy)phenyl)pyrimidi -4(3H)-one
Figure imgf000126_0002
The title compound was prepared by a method analogous to that described for Example 40, using 1-fluoro-4-(isopropylsulfonyl)benzene and (S)-3-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol. The final deprotection (para- methoxybenzyl removal) was done with TFA in dichloromethane at room temperature. MS (M+1): 445.1. Column: Waters Atlantis C18 4.6 x 50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.33 min.
Example 50: (S)-2-(3-(4-(cvclopropylsulfonyl)phenoxy)-5-(1 -hvdroxypropan- 2-yloxy)phenyl)pyrimidin- -one
Figure imgf000127_0001
The title compound was prepared by a method analogous to that described for Example 40, using 1-(cyclopropylsulfonyl)-4-fluorobenzene and (S)-3-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol. The final deprotection (para- methoxybenzyl removal) was done with TFA in dichloromethane at room temperature. MS (M+1): 443.1. Column: Waters Atlantis C18 4.6 x 50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.3 min.
Example 51 : (S)-4-(3-(1-hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6-
Figure imgf000127_0002
The title compound was prepared by a method analogous to that described for Example 40, using tert-butyl 4-fluorophenylsulfonyl(methyl) carbamate and (S)-3-(1-(tert-butyldimethyl silyloxy)propan-2-yloxy)-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol. The final deprotection (para- methoxybenzyl removal) was done with addition of TFA in the reaction mixture of step 1. MS (M+1): 432.1. Column: Waters Atlantis C184.6x50 mm, 5 pm; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.12 min.
Example 52: (S)-2-(3-(1-hvdroxypropan-2-yloxy)-5-(3-methyl-4-
Figure imgf000128_0001
The title compound was prepared by a method analogous to that described for Example 40, using 4-fluoro-2-methyl-1-(methylsulfonyl) benzene and (S)-3-(1-(ferf-butyldimethylsilyloxy) propan-2-yloxy)-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol. The final deprotection (para- methoxybenzyl removal) was done with addition of TFA in the reaction mixture of step 1. MS (M+1 ): 431.1. Column: Waters XBridge C18 4.6 x 50 mm, 5 pm; Modifier: TFA 0.05%; Gradient: 45% H20 / 55% MeCN linear to 70% H20 / 30% MeCN over 3.75 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 1.89 min.
Example 53: (S)-5-(3-(1-hvdroxypropan-2-yloxy)-5-(6-oxo-1 ,6- dihvdropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide
Figure imgf000128_0002
The title compound was prepared by a method analogous to that described for Example 19, using (S)-3-(1-(tert-butyldimethylsilyloxy)propan- 2-yloxy)-5-(4-(4-methoxybenzyloxy) pyrimidin-2-yl)phenol. MS (M+1 ): 412.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%;
Gradient: 90% H20 / 10% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 1.5 min. Example 54: 2-(3-(1 -hvdroxybutan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy) phenyl)pyrimidin-4(3H)-o
Figure imgf000129_0001
A sealable tube was charged with PPh3 (162 mg, 0.616 mmol) and the solid was dissolved in THF (1.3 mL). DIAD (0.1 mL, 0.5 mmol) was then added in one portion and the solution was stirred 15 minutes at room temperature. The reactive ylid formed crashed out of solution. 1-(tert- butyldimethylsilyloxy)butan-2-ol (102 mg, 501 mmol) and 3-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)-5-(4-(methylsulfonyl)phenoxy)phenol (184 mg, 395 mmol) are then added to the mixture which becomes a solution again in less than 30 minutes and the reaction stirred overnight at room temperature. No more starting material is observed by LCMS. TFA (1 mL) added and the reaction stirred for 30 minutes at room temperature. EtOAc added and mixture washed 1 time with water / NH4CI aq. sat (1/1 ) then 1 time with brine, dried over sodium sulfate, filtered and concentrated to afford the crude mixture containing the desired product. Purification with
preparative HPLC. MS (M+1 ): 431.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.26 min. Example 55: 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-5- isopropylpyrimidin-4(3 -one
Figure imgf000130_0001
Step 1 : 1-isopropoxy-3-(4-(methylsulfonyl)phenoxy)benzene (2.78 g,
9.07 mmol) was charged into a round bottom flask. Bispinacolatodiboron (1.38 g, 5.44 mmol), di- -methoxybis(1 ,5-cyclooctadiene)diiridium (I) (180 mg, 0.272 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (146 mg, 0.544 mmol) were added. A reflux condenser with an outlet to a double manifold, nitrogen/vacuum, was attached, and the apparatus was evacuated and filled with nitrogen 3 times. 2-Methyltetrahydrofuran (20 ml_) was added via syringe then nitrogen was bubbled into the solution for about 10 minutes. The reaction was heated at reflux about 30 hours. Analysis by GCMS indicated about 25% starting material remaining, but the reaction was called complete at this time. The reaction was concentrated to remove the solvent, the residue was redissolved in EtOAc-heptane (approx. 1 :1 ; 5ml_) and the crude product was filtered through a pad of silica gel (42 g). The filtrate was concentrated to afford the desired product as a light red foam (3.76 g, 96%; -3:1 mixture of borylated products). Crude product used whitout further purification.
Step 2: The crude 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy) phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane from step 1 (614 mg, 1.42 mmol) was charged into a round bottom flask. 2-chloro-5-isopropyl-4-(4- methoxy-benzyloxy)-pyrimidine (416 mg, 1.42 mmol), dichloro[1 ,2- bisdiphenylphosphino)ferrocene]palladium (II) (116 mg, 0.142 mmol) and sodium carbonate (452 mg, 4.26 mmol) were added. A reflux condenser with outlet to a double manifold (nitrogen/vacuum) was attached and the apparatus was evacuated and filled with nitrogen 3 times. Dioxane (5 ml_) and water (1 mL) were added and the mixture was refluxed under nitrogen for about 18 hours overnight. Analysis by LCMS indicated that the reaction was complete. The reaction was diluted with water, and the aqueous was extracted with EtOAc (2 x 75 mL). The combined extracts were washed with an equal volume of brine, dried over sodium sulfate and concentrated to an oily residue. The residue was purified by flash column chromatography (Si02, 0%-40% ethyl acetate / heptane) to provide 2-(3-isopropoxy-5-(4- (methylsulfonyl)phenoxy)phenyl)-5-isopropyl-4-(4-methoxybenzyloxy) pyrimidine (80 mg, 10%). 1H NMR (400 MHz, CDCI3) δ ppm 1.25(d J=6.05 Hz, 6 H), 1.37(d, J=6.05 Hz, 6 H), 3.03 (s, 3 H), 3.05 -3.13 (m, 1 H), 3.79 (s, 3 H), 4.60 - 4.71 (m, 1 H), 5.46 (s, 3 H), 6.69 (t, J=2.34 Hz, 0 H), 6.85 - 6.89 (m, 2 H), 7.12 - 7.17 (m, 2 H), 7.34 - 7.40 (m, 2 H), 7.70 (dd, J=2.24, 1.27 Hz, 1 H), 7.85 (dd, J=2.34, 1.37 Hz, 1 H), 7.86 - 7.91 (m, 2 H), 8.35 (s, 1 H).
Step 3: 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-5- isopropyl-4-(4-methoxybenzyloxy)pyrimidine (90 mg, 0.16 mmol) was charged into a round bottom flask and dissolved in dichloromethane (3 mL). Trifluoroacetic acid (60 μί, 0.80 mmol) was added and the homogeneous solution was stirred overnight at room temperature. The reaction was diluted with MTBE (60 mL), transferred into a separatory funnel and washed with sodium bicarbonate solution (sat. aq.; 2 x 50mL). The organic phase was dried over sodium sulfate and concentrated to an oily residue, which upon trituration with diethyl ether/heptane yielded 2-(3-isopropoxy-5-(4- (methylsulfonyl)phenoxy)phenyl)-5-isopropylpyrimidin-4(3H)-one as a tan waxy solid (54 mg, 76%). 1H NMR (400 MHz, CDCI3) δ ppm 1.20 - 1.29 (m, 6 H), 1.36 (d, J=6.06 Hz, 6 H), 3.05 (s, 3 H), 3.06 - 3.12 (m, 1 H), 4.54 - 4.71 (m, 1 H), 6.69 - 6.79 (m, 1 H), 7.13 (d, J=8.79 Hz, 2 H), 7.40 - 7.46 (m, 1 H), 7.46 - 7.55 (m, 1 H), 7.86 - 7.96 (m, 3 H). MS (M+1 ): 443.2.
Example 56: 2-(3-(4-(ethylsulfonyltohenoxy)-5-((2S.3R)-3-hvdroxybutan-2- yloxy)phenyl)pyrimidin-4(3H)-one
Figure imgf000132_0001
In a sealed tube, a solution of 1-(ethylsulfonyl)-4-fluorobenzene (19 mg, 0.10 mmol) and 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-((2S,3R)-3-(tert- butyldimethyl silyloxy)butan-2-yloxy)phenol (34 mg, 0.067 mmol) in N,N- dimethyl formamide (0.35 mL) was stirred at 120 °C overnight. The reaction was cooled to room temperature and the solvent evaporated under reduced pressure. The residue was partitioned between ethyl acetate and 1 M citric acid solution. The aqueous layer was extracted with more ethyl acetate. Combined organic layers were washed twice with water, once with brine, dried over sodium sulfate, filtered and evaporated to afford 42 mg of crude protected product as an amber residue. This material was taken up in 2 mL methanol to which was added 2 mL of 4N hydrochloric acid in 1 ,4-dioxane and stirred at room temperature for 3 hours. The mixture was evaporated 3 times from methanol and dried under high vacuum to give 42 mg of crude deprotected product. This material was purified by HPLC to afford the title compound (9.3 mg, 31%). MS (M+1 ): 445.05. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 minutes, HOLD at 5% H20 / 95% MeCN to 5.0 minutes. Flow: 2.0ml_/min.; RT: 2.33 min.
Example 57: 5-methyl-2-{3-i4-(methylsulfonyl)phenoxy1-5-(tetrahvdrofuran- 3-yloxy)phenyl}pyrimidin-4(3H)-one
Figure imgf000132_0002
A mixture of 5-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2-yl)benzene-1 ,3- diol (125 mg, 0.369 mmol), 3-bromotetrahydrofuran (55 mg, 0.369 mmol) and potassium carbonate (102 mg, 0.738 mmol) in N,N-dimethylformamide (1 ml_) was stirred at 80°C overnight. The reaction mixture was cooled to room temperature. 4-Fluorophenylmethylsulfone (65 mg, 0.369 mmol) and additional potassium carbonate (102 mg, 0.738 mmol) were then added to the reaction. The reaction mixture was stirred at 80°C for 2 days. The cooled reaction mixture was treated with trifluoroacetic acid (0.75 ml_) for 3 hours, then diluted with EtOAc and washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and purified by HPLC to afford the title compound (11.3 mg, 19%). MS (M+1): 443.1. Column:
Waters Atlantis C184.6mm x 50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 minutes HOLD at 5% H20 / 95% MeCN to 5.0 minutes. Flow: 2.0 mL / min.; RT: 2.43 min. Example 58: 5-methyl-2-(3-(1 -methyl-2-oxopyrrolidin-3-yloxy)-5-(4-
Figure imgf000133_0001
The title compound (6.7 mg, 16%) was prepared by a method analogous to that described for Example 57 using 3-bromo-N-methyl pyrolidinone (65 mg, 0.369 mmol) instead of 3-bromotetrahydrofuran. MS (M+1 ): 470.13. Column: Waters Atlantis C18 4.6 mm x 50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 minutes, HOLD at 5% H20 / 95% MeCN to 5.0 minutes. Flow: 2.0 mL/min.; RT: 2.22 minutes
Example 59: (S)-2-(3-(1 -methoxypropan-2-yloxy)-5-(4-(methylsulfonyl) phenoxy)phenyl)pyrimidin-4(3H)-one
Figure imgf000134_0001
To a solution of (2S)-2-(3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-(4- (methylsulfonyl) phenoxy)phenoxy)propan-1-ol (35 mg, 0.065 mmol) in tetrahydrofuran (1.0 mL) was added sodium hydride (4 mg, 1.5 equiv, 60% dispersion in mineral oil) and the mixture was stirred for 10 minutes at room temperature. Subsequently methyl iodide (10.2 mg, 1.1 equiv) was added to the reaction mixture, which was then heated to 55°C for 3 hours. LCMS indicated the methylation had proceeded about 65%, so an additional 5 mg of sodium hydride and another 5 μΙ_ of methyl iodide were added and the mixture heated to 55°C for an hour, then cooled to room temperature and partitioned between saturated aqueous ammonium chloride solution and diethyl ether. The aqueous layer was extracted with a second portion of diethyl ether. Combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to give 40 mg of 4-(4- methoxybenzyloxy)-2-(3-((S)-1-methoxypropan-2-yloxy)-5-(4- (methylsulfonyl)phenoxy)phenyl)pyrimidine. MS ( M+1 ): 551.1. This material was taken up in methanol (2 mL) and 4N hydrochloric acid in dioxane (2 mL) was added and the mixture stirred at room temperature overnight. Solvents were evaporated and the residue chased twice with methanol before purifying by HPLC to afford the title compound (14.7 mg, 47%). MS (M+1 ): 431.04. Column: Waters Atlantis C18 4.6 mm x 50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 minutes, HOLD at 5% H20 / 95% MeCN to 5.0 minutes. Flow:
2.0mL/min.; RT: 2.44 min.
Example 60: 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5-(tetrahvdro-2H- pyran-4-yloxy)phenyl)pyrimidin-4(3H)-one
Figure imgf000135_0001
In a sealed tube tube was stirred together PPh3 (40.1 mg) and DIAD (30.0 μΙ_) in THF (0.5 ml_) at room temperature for 30 minutes. After a white solid crashed out of the solution, both tetrahydro-2H-pyran-4-ol (20.8 mg) and 3-(4-(4-methoxybenzyloxy)-5-methylpyrimidin-2-yl)-5-(4-(methylsulfonyl) phenoxy)phenol (50.0 mg) are then added to the heterogeneous mixture and the resulting mixture which became a solution in less than 5 minutes is stirred overnight at 50 °C in an oil bath with the tube sealed. The reaction was then cooled down to room temperature. Silica gel was added to the reaction mixture and solvents are concentrated under reduced pressure. The silica gel containing the crude material was loaded directly onto a silica gel column. This was flash chromatographed eluting with a 0-10% gradient of methanol in dichloromethane to afford 4-(4-methoxybenzyloxy)-5-methyl- 2-(3-(4-(methylsulfonyl)phenoxy)-5-(tetrahydro-2H-pyran-4- yloxy)phenyl)pyrimidine. The final deprotection (PMB removal) was done with TFA in dichloromethane at room temperature until complete
deprotection. After removal of the solvents under reduced pressure, the title compound was dissolved in DMSO and purified by preparative HPLC to provide 5-methyl-2-(3-(4-(methylsulfonyl) phenoxy)-5-(tetrahydro-2H-pyran- 4-yloxy)phenyl)pyrimidin-4(3H)-one. MS (M+1 ): 457.0. Column: Waters Atlantis C18 4.6 x 50 mm, 5 pm; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 2.52 min.
Example 61 : 5-ethyl-2-(2-isopropoxy-6-(4-(methylsulfonyl)phenoxy)pyridin-4- yl)pyrimidin-4(3H)-one
Figure imgf000136_0001
Step 1 : In an oven dried microwave tube, bispinacolatodiboron (175 mg, 0.683 mmol), 4,4'-di-tert-butyl-2,2,-bipyridine (5.4 mg, 0.02 mmol) and (1 ,5-cyclooctadiene) (methoxy)iridium(l) dimer (6.6 mg, 0.01 mmol) dissolved in MTBE (0.5 ml_) and stirred (~10min.) until a deep red color is observed. 2-isopropoxy-6-(4-(methylsulfonyl)phenoxy)pyridine is then dissolved in MTBE (0.6 ml_) and transfered to the previous mixture in one portion. The tube was sealed and heated in the microwave at 100 °C for 10 hours. Reaction mixture filtered through a short pad of silica gel (100 ml_ of 50% ethyl acetate / heptane solution). Organics concentrated to provide 2- isopropoxy-6-(4-(methylsulfonyl)phenoxy)-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine as a crude light orange gum (602 mg). MS (APCI) of the mixture confirm the presence of starting material, desired product and also over-reaction of the product with a second boronate ester. Next step done without any further purification.
Step 2: In a sealed tube, 2-isopropoxy-6-(4-(methylsulfonyl)phenoxy)- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (175 mg, 0.40 mmol), 2-chloro-5-ethyl-4-(4-methoxybenzyloxy)pyrimidine (135 mg, 0.48 mmol), Na2C03 (1.2 ml_; 1 M in water) and acetonitrile (2.0 ml_) was purged with nitrogen for 10 minutes. [1 ,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium (II) (14.6 mg, 5 mol%) was added in one portion and the mixture heated at 140 °C for 30 minutes in a microwave oven. LC-MS analysis show the formation of the desired specie. EtOAc added to the reaction mixture and citric acid 1 M (aq.) to ~pH 3. Aqueous extracted with EtOAc three times, combined organic layers washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude material. The residue was purified by flash column chromatography (S1O2 , 40%-100% EtOAc / heptane) to provide 5-ethyl-2-(2-isopropoxy-6-(4-(methylsulfonyl) phenoxy)pyridin-4-yl)-4-(4-methoxybenzyloxy)pyrimidine (35 mg) as an orange gum. MS (M+1 ): 550.5. 1H NMR (400 MHz, CDCI3) δ ppm 1.18 - 1.24 (m, 3 H), 1.27 (d, J=6.24 Hz, 6 H), 2.61 (q, J=7.54 Hz, 2 H), 3.06 (s, 3 H), 3.81 (s, 3 H), 4.96 - 5.08 (m, 1 H), 5.48 (s, 2 H), 6.88 - 6.93 (m, 2 H), 7.29 - 7.34 (m, 2 H), 7.37 - 7.41 (m, 2 H), 7.45 (d, J=0.98 Hz, 1 H), 7.49 (d, J=0.98 Hz, 1 H), 7.91 - 7.97 (m, 2 H), 8.34 (s, 1 H).
Step 3: In a 20 dram vial, 5-ethyl-2-(2-isopropoxy-6-(4- (methylsulfonyl)phenoxy)pyridin-4-yl)-4-(4-methoxybenzyloxy)pyrimidine (35 mg) dissolved in dioxane (1.3 mL) and 4N HCI / dioxane (1 mL) added in one portion. 0.3 mL of methanol added to the mixture and reaction stirred at room temperature overnight. Reaction completed following LCMS. Volatiles are removed under reduced pressure. The crude compound was dissolved in DMSO and purified by preparative HPLC to provide of 5-ethyl-2-(2- isopropoxy-6-(4-(methylsulfonyl)phenoxy)pyridin-4-yl)pyrimidin-4(3H)-one (9.3 mg, 33%). MS (M+1 ): 430.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 3.01 min.
Example 62: (S)-5-(3-(1-methoxypropan-2-yloxy)-5-(6-oxo-1 ,6- dihvdropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide
Figure imgf000137_0001
To a solution of (S)-5-(3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-(1- methoxypropan-2-yloxy)phenoxy)-N,N-dimethylpyrazine-2-carboxamide (23mg, 0.043 mmol) in THF (1.0 mL) was added NaH (4 mg, 1.5 equiv, 60% dispersion in mineral oil) and the mixture was stirred for 10 minutes at room temperature. Subsequently, methyl iodide (10.2 mg, 1.1 equiv) was added to the reaction mixture, which was then heated to 55 °C for 4 hours. LC-MS indicated the complete methylation. The reaction mix was partitioned between ammonium chloride (aq. sat.) and EtOAc. Combined aqueous layers washed with a second portion of EtOAc. Combined organics were washed with brine, dried over Na2SC>4, filtered and evaporated to give 29 mg of a residue which was taken up in 1 mL of 40:60 TFA/dichloromethane (1 mL) and stirred at room temperature for 35 min. LC-MS shows the desired product as the major peak. Solvents evaporated and the residue chased with methanol. This was taken up in DMSO for preparative HPLC final purification to provide (S)-5-(3-(1-methoxypropan-2-yloxy)-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide. MS (M+1): 426.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.23 min.
Example 63: 3-(4-(cvclopropylsulfonyl)phenoxy)-N,N-dimethyl-5-(5-methyl-6- oxo-1 ,6-dihvdropyrimidin-2-yl)benzamide
Figure imgf000138_0001
The title compound was prepared by a method analogous to that described for Example 37, using 1-(cyclopropylsulfonyl)-4-fluorobenzene. Purification by flash column chromatography (S1O2 , 0%-20% methanol / ethyl acetate) to provide 3-(4-(cyclopropylsulfonyl)phenoxy)-N,N-dimethyl-5- (5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl)benzamide (181 mg, 74%) as a white solid. MS (M+1): 454.1. 1H NMR (400 MHz, CDCI3) δ ppm 0.99 - 1.06 (m, 2 H), 1.30 - 1.36 (m, 2 H), 2.01 (d, J=0.98 Hz, 3 H), 2.44 (tt, J=8.02, 4.85 Hz, 1 H), 3.02 (s, 3 H), 3.10 (s, 3 H), 7.09 - 7.15 (m, 2 H), 7.26 - 7.28 (m, 1 H), 7.83 - 7.88 (m, 2 H), 7.94 (d, J=1.17 Hz, 1 H), 8.01 - 8.04 (m, 1 H), 8.14 (t, J=1.37 Hz, 1 H), 12.70 (br. s., 1 H).
Example 64: 5-(3-cvclobutoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)-
N , N-d i methyl pyri m id i ne-2-carboxam ide
Figure imgf000139_0001
The title compound was prepared by a method analogous to that described for Example 19 using 3-cyclobutoxy-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol to provide 5-(3-cyclobutoxy-5-(6- oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2- carboxamide. MS (M+1): 408.2. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.28 min.
Example 65: 5-(3-cvclobutoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)-
N.N-dimethylpyrazine-2-carboxamide
Figure imgf000140_0001
The title compound was prepared by a method analogous to that described for Example 25 using 3-cyclobutoxy-5-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)phenol to provide 5-(3-cyclobutoxy-5-(6- oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrazine-2- carboxamide. MS (M+1): 408.2. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.38 min.
Example 66: 5-(3-(cvclopentyloxy)-5-(6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide
Figure imgf000140_0002
The title compound 5-(3-(cyclopentyloxy)-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide was prepared by a method analogous to that described for Example 19 using 3- (cyclopentyloxy)-5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)phenol. 1 H NMR (400 MHz, CDCI3) δ ppm 1.62 - 1.73 (m, 2 H), 1.77 - 2.05 (m, 6 H), 2.99 (s, 3 H), 3.16 (s, 3 H), 4.97 (tt, J=5.68, 2.71 Hz, 1 H), 6.39 (d, J=6.63 Hz, 1 H), 6.81 (t, J=2.24 Hz, 1 H), 7.49 (dd, J=2.15, 1.56 Hz, 1 H), 7.58 - 7.63 (m, 1 H), 8.11 (d, J=6.44 Hz, 1 H), 8.62 (s, 2 H), 12.98 (br. s., 1 H). MS (M+1): 422.2. Example 67: 5-(3-(cvclopentyloxy)-5-(6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide
Figure imgf000141_0001
The title 5-(3-(cyclopentyloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide was prepared by a method analogous to that described for Example 25 using 3- (cyclopentyloxy)-5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)phenol. MS (M+1 ): 422.2. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 2.55 min.
Example 68: (single enantiomer) 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)- 5-(tetrahvdrofuran-3-yloxy)phenyl)pyrimidin-4(3H)-one
Figure imgf000141_0002
The title compound 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5- (tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4(3H)-one was prepared by a method analogous to that described for Example 57 using (-)-3-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)-5-(tetrahydrofuran-3- yloxy)phenol. MS (M+1 ): 443.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.41 min. Example 69: (single enantiomer) 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)- 5-(tetrahvdrofuran-3-yloxy)phenyl)pyrimidin-4(3H)-one
Figure imgf000142_0001
The title compound 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5- (tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4(3H)-one was prepared by a method analogous to that described for Example 57 using (+)-3-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)-5-(tetrahydrofuran-3- yloxy)phenol. MS (M+1 ): 443.2. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.41 min.
Example 70: N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)-5-
(tetrahvdrofuran-3-yloxy)phenoxy)pyrimidine-2-carboxamide
Figure imgf000142_0002
The title compound N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihydropyrimidin-2- yl)-5-(tetrahydrofuran-3-yloxy)phenoxy)pyrimidine-2-carboxamide was prepared by a method analogous to that described for Example 19 using (±)- 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-(tetrahydrofuran-3-yloxy)phenol and 5-bromo-N,N-dimethylpyrimidine-2-carboxamide. MS (M+1): 424.2. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 1.86 min.
Example 71 : 2-(3-(4-(methylsulfonyl)phenoxy)-5-(tetrahvdrofuran-3- yloxy)phenyl)pyrimidin-4(3H)-one
Figure imgf000143_0001
The title compound 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5- (tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4(3H)-one was prepared by a method analogous to that described for Example 57 using (±)-3-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)-5-(tetrahydrofuran-3-yloxy)phenol. MS (M+1): 429.1. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.26 min.
Example 72: N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)-5-
(tetrahvdrofuran-3-yloxy)phenoxy)pyrazine-2-carboxamide
Figure imgf000143_0002
The title compound N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihydropyrimidin-2- yl)-5-(tetrahydrofuran-3-yloxy)phenoxy)pyrazine-2-carboxamide was prepared by a method analogous to that described for Example 57 using (±)- 3-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)-5-(tetrahydrofuran-3-yloxy)phenol and 5-chloro-N,N-dimethylpyrazine-2-carboxamide. MS (M+1 ): 424.2.
Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%;
Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 1.91 min.
Example 73: (R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide
Figure imgf000144_0001
The title compound (R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide was prepared by a method analogous to that described for Example 19 using (R)- 3-sec-butoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)phenol and 5-bromo- N,N-dimethylpyrimidine-2-carboxamide. MS (M+1 ): 410.3. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.38 min.
Example 74: (R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide
Figure imgf000144_0002
The title compound (R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide was prepared by a method analogous to that described for Example 57 using (R)- 3-sec-butoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)phenol and 5-chloro- N,N-dimethylpyrazine-2-carboxamide. MS (M+1): 410.2. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 2.48 min.
Example 75: (R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2- yl)phenoxy)-3-fluoro-N,N-dimethylpicolinamide
Figure imgf000145_0001
The title compound (R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-3-fluoro-N,N-dimethylpicolinamide was prepared by a method analogous to that described for Example 22 using (R)- 3-sec-butoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)phenol and 3,5- difluoro-N,N-dimethylpicolinamide. MS (M+1 ): 427.2. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.58 min.
Example 76: (S)-5-(3-(1-methoxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihvdro pyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide
Figure imgf000145_0002
The title compound (S)-5-(3-(1-methoxypropan-2-yloxy)-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide was prepared by a method analogous to that described for Example 19 using (S)- 3-(4-(4-methoxy benzy loxy )py ri m id i n-2-y I )-5-( 1 -methoxy propan-2- yloxy)phenol and 5-bromo-N,N-dimethylpyrimidine-2-carboxamide. MS (M+1 ): 425.4. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 1.99 min.
Example 77: (S)-2-(3-(4-(ethylsulfonyl)phenoxy)-5-(1 -methoxypropan-2- yloxy)phenyl)pyrimidin-4(3H)-one
Figure imgf000146_0001
The title compound (S)-2-(3-(4-(ethylsulfonyl)phenoxy)-5-(1- methoxypropan-2-yloxy)phenyl)pyrimidin-4(3H)-one was prepared by a method analogous to that described for Example 57 using (S)-3-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)-5-(1-methoxypropan-2-yloxy)phenol and 1-(ethylsulfonyl)-4-fluorobenzene. MS (M+1 ): 445.2. Column: Waters Atlantis C18 4.6x50 mm, 5 μιη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.55 min.
Example 78: N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)-5-(pentan-
3-yloxy)phenoxy)pyrazine-2-carboxamide
Figure imgf000146_0002
The title compound N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihydropyrimidin-2- yl)-5-(pentan-3-yloxy)phenoxy)pyrazine-2-carboxamide was prepared by a method analogous to that described for Example 57 using 3-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)-5-(pentan-3-yloxy)phenol and 5-chloro- N,N-dimethylpyrazine-2-carboxamide. MS (M+1): 424.2. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 2.68 min.
Example 79: N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)-5-(pentan-
3-yloxy)phenoxy)pyrimidine-2-carboxamide
Figure imgf000147_0001
The title compound N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihydropyrimidin-2- yl)-5-(pentan-3-yloxy)phenoxy)pyrimidine-2-carboxamide was prepared by a method analogous to that described for Example 19 using 3-(4-(4- methoxybenzyloxy)pyrimidin-2-yl)-5-(pentan-3-yloxy)phenol and 5-bromo- N,N-dimethylpyrimidine-2-carboxamide. MS (M+1 ): 424.2. Column: Waters Atlantis C18 4.6x50 mm, 5 μηη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 mL / min.; RT: 2.57 min.
Example 80: 5-(3-cvclopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)- N , N-d i methyl pyri m id i ne-2-carboxam ide
Figure imgf000148_0001
The title compound 5-(3-cyclopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin- 2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide (white solid; 15.3 mg, 36%) was prepared by a method analogous to that described for Example 19 using 3-cyclopropoxy-5-(4-(4-methoxybenzyloxy)pyrimidin-2-yl)phenol and 5- bromo-N,N-dimethylpyrimidine-2-carboxamide. 1H NMR (400 MHz, CDCI3) δ ppm 0.80 - 0.90 (m, 4 H), 2.99 (s, 3 H), 3.16 (s, 3 H), 3.86 - 3.97 (m, 1 H), 6.40 (d, J=6.63 Hz, 1 H), 6.97 (t, J=2.24 Hz, 1 H), 7.51 (t, J=1.76 Hz, 1 H), 7.73 - 7.80 (m, 1 H), 8.10 (d, J=6.63 Hz, 1 H), 8.62 (s, 2 H). MS (M+1 ):
394.1.
Example 81 : 5-(3-cvclopropoxy-5-(6-oxo-1 ,6-dihvdropyrimidin-2-yl)phenoxy)-
N.N-dimethylpyrazine-2-carboxamide
Figure imgf000148_0002
The title compound 5-(3-cyclopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin- 2-yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide was prepared by a method analogous to that described for Example 57 using 3-cyclopropoxy-5- (4-(4-methoxybenzyloxy)pyrimidin-2-yl)phenol and 5-chloro-N,N- dimethylpyrazine-2-carboxamide. MS (M+1 ): 394.2. Column: Waters Atlantis C18 4.6x50 mm, 5 μιη; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% MeCN linear to 5% H20 / 95% MeCN over 4.0 min, HOLD at 5% H20 / 95% MeCN to 5.0 min. Flow: 2.0 ml_ / min.; RT: 2.21 min. Example 82: 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5-(pyrrolidine-1 - carbonyl)phenyl)pyrimidin-4(3H)-one
Figure imgf000149_0001
A Parr shaker bottle was charged with (3-(4-(benzyloxy)-5-methylpyrimidin- 2-yl)-5-(4-(methylsulfonyl)phenoxy)phenyl)(pyrrolidin-1-yl)methanone (30 mg, 0.052 mmol), Pd/C 10% (water wet, 10 mg) and EtOH (10 ml_). The reaction mixture was shaken under 40 psi of H2(g) at room temperature overnight. TLC (dichloromethane: methanol =10:1 ) indicated the reaction completion and the mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC to give 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5- (pyrrolidine-1-carbonyl)phenyl)pyrimidin-4(3H)-one (32 mg, yield: 40 %) as a white solid. MS (M+1): 454.2. MS (M+23): 476.1. 1H NMR (400 MHz, CD3OD) δ ppm 8.05-8.00 (m, 4 H), 7.90 (s, 1 H), 7.48 (d, 1 H), 7.31-7.29
(dd, 2 H), 3.63 (t, 2 H), 3.53 (t, 2 H), 3.15 (s, 3 H), 2.10 (s, 3 H), 2.02-1.94
(m, 4 H).
Example 83: 5-(hvdroxymethyl)-2-(3-isopropoxy-5-(4-(methylsulfonyl) phenoxy)phenyl)pyrimidin-4(3H)-one
Figure imgf000149_0002
Example 84: 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5-(tetrahydro-2H- Pyran-3-yloxy)phenyl)pyrimidin-4(3H)-one
Figure imgf000150_0001
The title compound 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5- (tetrahydro-2H-pyran-3-yloxy)phenyl)pyrimidin-4(3H)-one was prepared by a method analogous to that described for Example 57 using 3-(4-(4- methoxybenzyloxy)-5-methylpyrimidin-2-yl)-5-(tetrahydro-2H-pyran-3- yloxy)phenol and 1-fluoro-4-(methylsulfonyl)benzene. 1H NMR (400 MHz, CDCI3) δ ppm 1.61 - 1.72 (m, 1 H), 1.80 - 1.99 (m, 2 H), 2.05 (s, 3 H), 2.08 - 2.18 (m, 1 H), 3.08 (s, 3 H), 3.59 - 3.70 (m, 2 H), 3.71 - 3.80 (m, 1 H), 3.93 - 4.01 (m, 1 H), 4.46 - 4.55 (m, 1 H), 6.82 (t, J=2.15 Hz, 1 H), 7.12 - 7.20 (m, 2 H), 7.48 - 7.53 (m, 1 H), 7.61 (d, J=1.95 Hz, 1 H), 7.89 - 7.95 (m, 2 H), 7.95 - 7.98 (m, 1 H), 12.29 (br. s., 1 H). MS (M-1 ): 455.0.
Example 85: Ethyl 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6- oxo-1 ,6-d i h yd ropyri m id i ne-5-carboxylate
Figure imgf000150_0002
To a stirred solution of 3-isopropoxy-5-(4 (methylsulfonyl)phenoxy) benzamidine (100 mg, 0.287 mmol), diethyl ethoxymethylenemalonate (57.6 uL, 0.287 mmol) in anhydrous ethanol (0.3 ml_) was added sodium ethoxide (0.321 ml_, 0.86 mmol, 21 % in ethanol) dropwise at room temperature. The vessel was sealed and heated at 70 °C overnight. The solvent was evaporated under reduced pressure. Water was added followed by 3-4 drops of 37% hydrochloric acid to adjust the pH~2. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography eluting with 0 - 65% ethyl acetate in hexane gave the title compound 2-(3- isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6-oxo-1 ,6- dihydropyrimidine-5-carboxylate (40 mg, 29%) as a white solid. 1H NMR (400 MHz, DMSO-de) δ ppm 11.77 (br s, 1 H), 8.97 (s, 1 H), 7.89 (d, J = 8.8 Hz, 2H), 7.82 (m, 1 H), 7.69 (m, 1 H), 7.13 (d, J = 8.8 Hz, 2 H), 6.78 (m, 1 H), 4.69 (m, 1 H), 4.44 (q, J = 7.2 Hz, 2 H), 3.04 (s, 3 H), 1.42 (t, J = 7.2 Hz, 3 H), 1.36 (d, J = 6.0 Hz, 6 H). MS (M+1 ): 473.4. RT = 2.6 min.
PHARMACOLOGICAL TESTING
The practice of this invention for the treatment of diseases modulated by the activation of the glucokinase enzyme can be evidenced by activity in at least one of the protocols described herein below.
Representative compounds of this invention were evaluated in biochemical assays (Assay 1 or Assay 2) to characterize their glucokinase activation properties.
The recombinant human glucokinase protein utilized in both assays was prepared and purified as described below.
Beta Cell Glucokinase His-Tag Growth and Induction Conditions:
BL21 (DE3) cells (Invitrogen Corporation, Carlsbad, CA) containing pBCGK (C or N His) vector were grown at 37°C (in 2XYT) until the OD600 was between 0.6-1.0. Expression was induced by addition of
isopropylthiogalactoside to a final concentration of 0.1-0.2 mM to the cells which were then incubated overnight at 23°C. The next day, cells were harvested via centrifugation at 5000 rpm for 15 minutes at 4°C. The cell pellet was stored at -80°C for future purification. Beta Cell Glucokinase His-Tag Purification Conditions: A Ni-NTA (Quigan, Germantown, MD) column (15-50 mL) was used for separation. Two buffers were prepared, 1 ) a lysis/nickel equilibration and wash buffer and 2) a nickel elution buffer. The lysis/equilibration/wash buffer was prepared as such: 25 mM HEPES buffer at pH 7.5, 250 mM NaCI, 20 mM imidazole, and 14 mM β-mercaptoethanol as final concentrations. The elution buffer was prepared as such: 25 mM HEPES at pH 7.5, 250 mM NaCI, 400 mM imidazole, and 14 mM β-mercaptoethanol as final concentrations. The buffers were each filtered with a 0.22 μιτη filter prior to use. The cell pellet (1 L culture) was resuspended in 300 mL of the lysis/equilibration buffer. The cells were then lysed (3 times) with a Microfluidics Model 1 10Y microfluidizer (Microfluidics Corporation, Newton, MA). The slurry was centrifuged with a Beckman Coulter Model LE-80K ultracentrifuge (Beckman Coulter, Fullerton, CA) at 40,000 rpm for 45 minutes at 4°C. The supernatant was transferred to a chilled flask. A volume of 20 μΙ was saved for gel analysis. A Pharmacia AKTA (GMI, Inc., Ramsey, MN) purification system was used for separation. The prime lines were purged with lysis/equilibration buffer. The Ni-NTA column was equilibrated with 200 mL of the lysis/equilibration buffer at a flow rate of 5 mL/minute. The supernantant was loaded over the column at 4 mlJminute and the flow-through was collected in a flask. The unbound proteins were washed with lysis/equilibration buffer at a flow rate of 5 mlJminute until the ultraviolet reaches baseline. The protein was then eluted from the column with the imidazole elution buffer via imidazole gradient 20 mM to 400 mM over 320 mL. The column was then stripped of any additional protein with 80 mL of the elution buffer. The elution fractions were each 8 mL, for a total yield of 50 samples. Fractions were analyzed by sodium dodecyl sulfate polyacrylamide (SDS-PAGE) and the fractions containing protein of interest were pooled and concentrated to 10 mL using ultrafiltration cell with a 10,000 molecular weight cut-off (MWCO) Millipore membrane (Sigma-Aldrich, St. Louis, MO) under nitrogen gas (60 psi).
Protein was further purified by size exclusion chromatography (SEC) using a Sedex 75 evaporative light scattering detector (320 ml_) (Amersham
Pharmacia, Uppsala, Sweden). SEC was equilibrated with 450 ml_ sizing buffer containing 25mM HEPES pH 7.0, 50 mM NaCI, and 5 mM
dithiothreitol. Concentrated protein was then loaded over SEC and elution with 400 ml_ sizing buffer was performed overnight at 0.5 mL/minute. The elution fractions were 5 ml_ each. The fractions were analyzed by SDS- PAGE and protein containing fractions were pooled. Concentration was measured using Bradford Assay/BSA Standard. Purified protein was stored in small aliquots at -80°C.
Assay 1 : Evaluating activator potency and maximum activation at 5 mM glucose
Full-length glucokinase (beta cell isoform) was His-tagged at the N- terminus and purified by a Ni column followed by size exclusion
chromatography as described above. Glucose was obtained from
Calbiochem (San Diego, CA) and other reagents were purchased from Sigma-Aldrich (St. Louis, MO).
All assays were performed in a Corning 384-well plate using
Spectramax PLUS spectrophotometer (Molecular Devices, Sunnyvale, CA) at room temperature. The final assay volume was 40 μL· The buffer conditions used in this assay were as follows: 50 mM HEPES, 5 mM glucose, 2.5 mM ATP, 3.5 mM MgCI2, 0.7 mM NADH, 2 mM dithiothreitol, 1 unit/mL pyruvate kinase/lactate dehydrogenase (PK/LDH), 0.2 mM phosphoenolpyruvate, and 25 mM KCI. The buffer pH was 7.1. The test compound in dimethylsulfoxide solution was added to the buffer and mixed by a plate shaker for 7.5 minutes. The final concentration of
dimethylsulfoxide introduced into the assay was 0.25%.
Glucokinase was added to the buffer mixture to initiate the reaction in the presence and absence of compound. The reaction was monitored by absorbance at 340 nm due to the depletion of NADH. The initial reaction velocity was measured by the slope of a linear time course of 0-300 seconds. The percentage of maximum activation was calculated by the following equation:
% Maximum Activation = (Va/Vo - 1) x 100; wherein each of Va and Vo is defined as the initial reaction velocity in the presence and absence of the tested compound, respectively.
To determine the EC50 (half maximal effective concentration) and %maximum activation, compounds were serially diluted in dimethylsulfoxide by 3-fold. The glucokinase activities were measured as a function of compound concentrations. The data were fitted to the equation below to obtain the EC50 and %max activation values:
Va/Vo = 1 + (%max activation/100)/(1 + ECso/compound
concentration).
Assay 2: Evaluating activator potency in a matrix assay at multiple glucose concentrations
As described by Bebernitz and coworkers (Bebernitz, G.R. et. al., J. Med. Chem. 2009, 52, 6142-6152) the potency of a glucokinase activator and its modulation of the glucokinase enzyme's Km (for glucose) and Vmax can be characterized using a matrix assay wherein multiple combinations of activator and glucose concentrations are simultaneously evaluated. Utilizing an adaptation of this method, representative compounds of the current invention were evaluated at 22 different concentrations and 16 different glucose concentrations in a coupled enzyme assay system that detects glucokinase activity via depletion of β-NADH. The readout is absorbance at 340 nm, and is captured asAA340/Atime.
Initially, a 1.0 L volume of assay buffer (at 5 times (5X) final concentration) was prepared utilizing the following reagents (reagent used, formula weight of reagent, 5X concentration of reagent ([5X]), final concentration of reagent after dilution ([Final], and mass of reagent): HEPES, FW = 238.3 g/mol, [5X] = 250 mM, [Final] = 50 mM, 59.58 g; MgCI2, FW = 203.3 g/mol, [5X] = 17.5 mM, [Final] = 3.5 mM, 3.56 g; KCI, FW = 74.55 g/mol, [5X] = 125 mM, [Final] = 25 mM, 9.32 g; and BSA, n/a, [5X] = 0.5%; [Final] = 0.1 %.
Compounds are tested against 16 concentrations of glucose. The glucose titration is made at 2 times (2X) the final concentration. The final glucose concentrations used are: 0 mM, 0.05 mM, 0.1 mM, 0.3 mM, 0.625 mM, 1.25 mM, 2.5 mM, 5 mM, 7.5 mm, 10 mM, 15 mM, 20 mM, 40 mM, 60 mM, 80 mM and 100 mm. Plates are stored at 4°C. The glucokinase activator compounds of Formula (I) of the current invention are evaluated at 22 different compound concentrations. The final compound concentrations that are employed are: 0.001 M, 0.0005 M, 0.00025 M, 0.000125 M,
0.0000625 M, 0.00003125 M, 0.000015625 M, 7.81 x 10"6 M, 3.91 x 10"6 M, 1.95 x 10"6 M, 9.77 x 10"7 M, 4.88 x 10"7 M, 2.44 x 10"7 M, 1.22 x 10"7 M, 6.10 x 10"8 M, 3.05 x 10"8 M, 1.53 x 10"8 M, 7.63 x 10"9 M, 3.81 x 10"9 M, 1.91 x 10" 9 M, 9.54 x 10"10 M and 4.77 x 10"10 M.
The assay reagents and final concentrations of the reagents are as follows (reagent, final concentration): GK, 10 nM; Buffer, 1X; ddH20; DTT, 2 mM; PEP, 0.8 mM; NADH, 0.7 mM; ATP, 2.5 mM; and PK/LDH, 8 U/mL. The DTT is stored as a frozen 1 M stock. PEP, NADH, and ATP are weighed out as powders. The assay reagents are made up fresh daily, and in two separate components.
The enzyme mix and the substrate mix is outlined as follows. The enzyme mix consists of GK, Buffer (5X), water and DTT. The substrate mix consists of Buffer (5X), water, DTT, PEP, NADH, ATP and PK/LDH. Each mix is made up at 4 times the concentration of the final concentration used.
Assay Protocol: The assay volume is 40 μΙ_ per well: 20 μΙ_ from glucose, 10 μΙ_ from enzyme, and 10 μΙ_ from substrate. The final assay plates have 1 μΙ_ of compound solution or control in DMSO. When running multiple plates simultaneously on multiple readers, read triplicates on the same reader to decrease variability. The procedure for carrying out the assay is as follows: Add 20 μΙ_ of glucose to each well and centrifuge (1000 rpm, 10 seconds). Add 10 μΙ_ of the enzyme mix. Shake plates on plate shaker (900 revolutions per minute) at room temperature (22°C) for 7 minutes to mix in the compound. Add 10 μΙ_ of substrate mix. Shake briefly at room temperature to mix, about 10 seconds and centrifuge to remove bubbles. Examine plate for residual bubbles, and remove them with ethanol vapor. The assay plates are read on a SpectraMax reader (Molecular Devices) using SoftMaxPro 4.8 software. The reader should be configured to read absorbance at wavelength 340 nm, in kinetic mode, read every 30 seconds for 10 minutes. Automix and blanking are off and autocalibrate is set to once.
These data were analyzed by fitting curves to the rates observed for each combination of substrate and activator. This enabled determination of the glucokinase Km (for glucose) and Vmax of at each concentration of activator. Plotting the resulting Km values for each concentration of activator and fitting a curve enabled determination of an intrinsic potency for a given activator determined as the concentration of compound affording a 50% reduction in the enzyme's Km. These intrinsic EC50 values are reported for representative compounds in the Biological Activity Table below.
Biological Activity Table: EC50 of representative examples determined by the method of Assay 1 or 2.
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001

Claims

We Claim:
1. A compound of Formula (I)
Figure imgf000159_0001
or a pharmaceutically acceptable salt thereof, wherein
R1 is H, (Ci-C6)alkyl, (Ci-C6)alkoxy, halo, C02H, C02(Ci-C6)alkyl or cyano; wherein said (Ci-C-6)alkyl and (Ci-Ce)alkoxy are optionally substituted with one to three halo or one (d-C4)alkoxy, hydroxy, C02H or C02(Ci-C4)alkyl; R2 is OR4 or C(0)NR5R6;
R3 is phenyl, 3 to 7 membered heterocyclyl or 5 to 6 membered heteroaryl; wherein said phenyl, 3 to 7 membered heterocyclyl or 5 to 6 membered heteroaryl are optionally substituted with one to three S(0)2R7, C(0)NR8R9, halo, (Ci-C4)alkyl, or (Ci-C4)alkoxy;
R4 is (Ci-C6)alkyl, (C3-C7)cycloalkyl or 3 to 7 membered heterocyclyl;
wherein said (Ci-C-6)alkyl or (C3-C7)cycloalkyl is optionally substituted with one to two hydroxy, (Ci-C4)alkoxy or (C3-C7)cycloalkyl;
R5 and R6 are each indepependently hydrogen, (Ci-C6)alkyl, (C3- C7)cycloalkyl or (Ci-C6)alkyl(C3-C7)cycloalkyl or R5 and R6 taken together with the nitrogen to which they are attached form an azetidine, pyrrolidine, morpholine or piperidine ring;
R7 is (Ci-C6)alkyl, (C3-C7)cycloalkyl, (Ci-C6)alkyl(C3-C7)cycloalkyl or NR8R9, wherein said (Ci-C6)alkyl, (C3-C7)cycloalkyl or (Ci-C6)alkyl(C3-C7)cycloalkyl is optionally substituted with one to three halo; and R and R are each indepependently hydrogen, (Ci-C6)alkyl, (C3- C7)cycloalkyl or (Ci-C6)alkyl(C3-C7)cycloalkyl, each optionally substituted with one to three halo, or R8 and R9 taken together with the nitrogen to which they are attached form an azetidine, pyrrolidine, morpholine or piperidine ring.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or methyl.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl or 5 to 6 membered heteroaryl; wherein said phenyl or 5 to 6 membered heteroaryl is substituted with S(0)2R7 or
C(0)NR8R9 and is optionally substituted with halo or (Ci-C4)alkyl.
4. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein R3 is phenyl or a 5 to 6 membered heteroaryl selected from pyridinyl, pyrimidinyl or pyrazinyl; wherein said phenyl, pyridinyl, pyrimidinyl or pyrazinyl is substituted with S(0)2R7 or C(0)NR8R9 and is optionally substituted with fluoro or methyl.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R2 is OR4; and R4 is isopropyl, 1-hydroxypropan-2-yl, 1- methoxypropan-2-yl, 1-hydroxybutan-2-yl, 3-hydroxybutan-2-yl,
tetrahydrofuran-3-yl or 1-methyl-2-oxopyrrolidin-3-yl.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R2 is C(O)NR5R6.
7. The compound of claim 6 or a pharmaceutically acceptable salt thereof wherein R5 and R6 are each methyl.
8. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein R3 is phenyl or a 5 to 6 membered heteroaryl selected from pyridinyl, pyrimidinyl or pyrazinyl; wherein said phenyl, pyridinyl, pyrimidinyl or pyrazinyl is substituted with S(0)2R7 or C(0)NR8R9 and is optionally substituted with fluoro or methyl.
9. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein R7 is methyl, ethyl, isopropyl or NR8R9; and R8 and R9 are independently hydrogen or methyl.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R1 is hydrogen, methyl or ethyl; R2 is OR4; and R4 is isopropyl, 1-hydroxypropan-2-yl, 1-methoxypropan-2-yl, 1-hydroxybutan-2-yl, 3-hydroxybutan-2-yl, tetrahydrofuran-3-yl or 1-methyl-2-oxopyrrolidin-3-yl; and R3 is phenyl or a 5 to 6 membered heteroaryl selected from pyridinyl, pyrimidinyl or pyrazinyl; wherein said phenyl, pyridinyl, pyrimidinyl or pyrazinyl is substituted with S(O)2R7 or C(O)NR8R9and is optionally substituted with fluoro or methyl.
11. The compound of claim 10 or a pharmaceutically acceptable salt thereof wherein R7 is methyl, ethyl, isopropyl or NR8R9; and R8 and R9 are independently hydrogen or methyl.
12. The compound of claim 11 or a pharmaceutically acceptable salt thereof wherein R4 is isopropyl or 1-hydroxypropan-2-yl.
13. A compound of claim 1 selected from the group consisting of 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6-oxo-1 ,6- dihydropyrimidine-5-carbonitrile;
2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-5-methylpyrimidin- 4(3H)-one; 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)pyrimidin-4(3H)-one;
5-ethyl-2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)pyrimidin-
4(3H)-one;
5-chloro-2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy) phenyl)pyrimidin- 4(3H)-one;
2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-5-methoxypyrimidin- 4(3H)-one;
2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-5- (methoxy methyl )pyri m idi n-4(3 H )-one ;
Ethyl 2-(2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl) -6-oxo-1 ,6- d i hyd ro py ri m id i n-5-y I )acetate ;
2-(2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6-oxo-1 ,6- d i hydropy ri m id i n-5-y I )acetic acid ;
2-(3-isopropoxy-5-(1-(methylsulfonyl)pyrrolidin-3-yloxy)phenyl)-5- methylpyrimidin-4(3H)-one;
2-(3-isopropoxy-5-(1-(methylsulfonyl)pyrrolidin-3-yloxy)phenyl)pyrimidin- 4(3H)-one;
(S)-2-(3-(1-methoxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy)phenyl)-5- methylpyrimidin-4(3H)-one;
5-ethyl-2-{3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl) phenoxy]phenyl}pyrimidin-4(3H)-one;
(S)-5-(3-(1-hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide;
(S)-2-(3-(1-hydroxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy) phenyl)pyrimidin-4(3H)-one;
(S)-2-(3-(4-(ethylsulfonyl)phenoxy)-5-(1-hydroxypropan-2- yloxy)phenyl)pyrimidin-4(3H)-one;
(S)-4-(3-(1-hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N,N-dimethylbenzenesulfonamide; N,N-dimethyl-5-(3-(1-methyl-2-oxopyrrolidin-3-yloxy)-5-(6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)pyrazine-2-carboxamide;
5-(3-isopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrimidine-2-carboxamide;
2-(3-(2-(azetidi ne- 1 -carbony I )py ri m id i n-5-y loxy )-5- isopropoxyphenyl)pyrimidin-4(3H)-one;
2- (3-isopropoxy-5-(2-(pyrrolidine-1-carbonyl)pyrimidin-5- yloxy)phenyl)pyrimidin-4(3H)-one;
3- fluoro-5-(3-isopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpicolinamide;
2-(3-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-5-isopropoxyphenyl) pyrimidin-4(3H)-one;
2- (3-(5-(azetidine-1-carbonyl)pyrazin-2-yloxy)-5-isopropoxyphenyl)pyrimidin- 4(3H)-one;
5-(3-isopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- d i methyl py razi ne-2-carboxamide ;
4- (3-isopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)benzene sulfonamide;
4-(3-isopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N- methylbenzenesulfonamide;
4- (3-isopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,2- dimethylbenzenesulfonamide;
5- (3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrimidine-2-carboxamide;
5-(3-isopropoxy-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl) phenoxy)-N,N- dimethylpyrimidine-2-carboxamide;
3- fluoro-5-(3-isopropoxy-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N,N-dimethylpicolinamide;
4- (3-isopropoxy-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N- methylbenzenesulfonamide; (S)-5-(3-sec-butoxy-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)- N,N-dimethylpyrazine-2-carboxamide;
(S)-5-(3-sec-butoxy-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)- N , N-d i methyl py ri m id i ne-2-carboxam ide ;
(S)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- d i methyl py razi ne-2-carboxamide ;
(S)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrimidine-2-carboxamide;
N , N-d i methy l-3-(5-methy I-6-0X0- 1 ,6-d i hydropy ri m id i n-2-y I )-5-(4- (methylsulfonyl)phenoxy)benzamide;
3-(4-(ethylsulfonyl)phenoxy)-N,N-dimethyl-5-(5-methyl-6-oxo-1 ,6- dihydropyrimidin-2-yl)benzamide;
3-(4-(isopropylsulfonyl)phenoxy)-N,N-dimethyl-5-(5-methyl-6-oxo-1 ,6- dihydropyrimidin-2-yl)benzamide;
(S)-2-(3-(1-hydroxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy)phenyl)-5- methylpyrimidin-4(3H)-one;
(S)-2-(3-(4-(ethylsulfonyl)phenoxy)-5-(1-hydroxypropan-2-yloxy)phenyl)-5- methylpyrimidin-4(3H)-one;
(S)-2-(3-(4-(cyclopropylsulfonyl)phenoxy)-5-(1-hydroxypropan-2- yloxy)phenyl)-5-methylpyrimidin-4(3H)-one;
(S)-4-(3-(1-hydroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-
2-yl)phenoxy)-N,N-dimethylbenzenesulfonamide;
(S)-3-fluoro-5-(3-(1-hydroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6- dihydropyrimidin-2-yl)phenoxy)-N,N-dimethylpicolinamide;
(S)-5-(3-(1-hydroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-
2-y I )phenoxy )-N , N-d i methy I py razi ne-2-carboxam ide ;
(S)-5-(3-(1-hydroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-
2-yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide;
(S)-4-(3-(1-hydroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-
2-yl)phenoxy)-N-methylbenzenesulfonamide; (S)-3-fluoro-5-(3-(1-hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N,N-dimethylpicolinamide;
(S)-2-(3-(1-hydroxypropan-2-yloxy)-5-(4-(isopropylsulfonyl)phenoxy)phenyl) pyrimidin-4(3H)-one;
(S)-2-(3-(4-(cyclopropylsulfonyl)phenoxy)-5-(1-hydroxypropan-2- yloxy)phenyl)pyrimidin-4(3H)-one;
(S)-4-(3-(1-hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N-methylbenzenesulfonamide;
(S)-2-(3-(1-hydroxypropan-2-yloxy)-5-(3-methyl-4-(methylsulfonyl)phenoxy) phenyl)pyrimidin-4(3H)-one;
(S)-5-(3-(1-hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide;
2-(3-(1-hydroxybutan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy)phenyl) pyrimidin-4(3H)-one;
2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-5-isopropylpyrimidin- 4(3H)-one;
2-(3-(4-(ethylsulfonyl)phenoxy)-5-((2S,3R)-3-hydroxybutan-2- yloxy)phenyl)pyrimidin-4(3H)-one;
5-methyl-2-{3-[4-(methylsulfonyl)phenoxy]-5-(tetrahydrofuran-3- yloxy)phenyl}pyrimidin-4(3H)-one;
5-methyl-2-(3-(1-methyl-2-oxopyrrolidin-3-yloxy)-5-(4-(methylsulfonyl) phenoxy)phenyl)pyrimidin-4(3H)-one;
(S)-2-(3-(1-methoxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy)phenyl) pyrimidin-4(3H)-one;
5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5-(tetrahydro-2H-pyran-4- yloxy)phenyl)pyrimidin-4(3H)-one;
5-ethyl-2-(2-isopropoxy-6-(4-(methylsulfonyl)phenoxy)pyridin-4-yl)pyrimidin- 4(3H)-one;
(S)-5-(3-(1-methoxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N,N-dimethylpyrazine-2-carboxamide; 3-(4-(cyclopropylsulfonyl)phenoxy)-N,N-dimethyl-5-(5-methyl-6-oxo-1 ,6- dihydropyrimidin-2-yl)benzamide;
5-(3-cyclobutoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrimidine-2-carboxamide;
5-(3-cyclobutoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- d i methy I py razi ne-2-carboxam ide ;
5-(3-(cyclopentyloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrimidine-2-carboxamide;
5-(3-(cyclopentyloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- d i methy I py razi ne-2-carboxam ide ;
(single enantiomer) 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5-
(tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4(3H)-one;
(single enantiomer) 5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5-
(tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4(3H)-one;
N , N-d i methy l-5-(3-(6-oxo- 1 ,6-d i hyd ropy ri m id i n-2-y I )-5-(tetrahyd rof u ran-3- yloxy)phenoxy)pyrimidine-2-carboxamide;
2-(3-(4-(methylsulfonyl)phenoxy)-5-(tetrahydrofuran-3- yloxy)phenyl)pyrimidin-4(3H)-one;
N , N-d i methy l-5-(3-(6-oxo- 1 ,6-d i hyd ropy ri m id i n-2-y I )-5-(tetrahyd rof u ran-3- yloxy)phenoxy)pyrazine-2-carboxamide;
(R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrimidine-2-carboxamide;
(R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- d i methy I py razi ne-2-carboxam ide ;
(R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-3-fluoro- N,N-dimethylpicolinamide;
(S)-5-(3-(1 -methoxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihydro pyrimidin-2- yl)phenoxy)-N,N-dimethylpyrimidine-2-carboxamide;
(S)-2-(3-(4-(ethylsulfonyl)phenoxy)-5-(1-methoxypropan-2- yloxy)phenyl)pyrimidin-4(3H)-one; N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihydropyrimidin-2-yl)-5-(pentan-3- yloxy)phenoxy)pyrazine-2-carboxamide;
N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihydropyrimidin-2-yl)-5-(pentan-3- yloxy)phenoxy)pyrimidine-2-carboxamide;
5-(3-cyclopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrimidine-2-carboxamide;
5-(3-cyclopropoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- d i methyl py razi ne-2-carboxam ide ;
5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5-(pyrrolidine-1-carbonyl) phenyl)pyrimidin-4(3H)-one;
5-(hydroxymethyl)-2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)
phenyl)pyrimidin-4(3H)-one;
5-methyl-2-(3-(4-(methylsulfonyl)phenoxy)-5-(tetrahydro-2H-pyran-3- yloxy)phenyl)pyrimidin-4(3H)-one; and
Ethyl 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-6-oxo-1 ,6- dihydropyrimidine-5-carboxylate;
or a pharmaceutically acceptable salt thereof.
14. A compound of claim 13 selected from the group consisting of 2-(3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)phenyl)-5-methylpyrimidin- 4(3H)-one;
(S)-2-(3-(1-methoxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy)phenyl)-5- methylpyrimidin-4(3H)-one;
(S)-2-(3-(4-(ethylsulfonyl)phenoxy)-5-(1-hydroxypropan-2-yloxy)phenyl) pyrimidin-4(3H)-one;
(S)-4-(3-(1-hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N,N-dimethylbenzenesulfonamide;
5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- d i methyl pyri m id i ne-2-ca rboxa m ide ;
4-(3-isopropoxy-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N- methylbenzenesulfonamide; 3-(4-(ethylsulfonyl)phenoxy)-N,N-dimethyl-5-(5-methyl-6-oxo-1 ,6- dihydropyrimidin-2-yl)benzamide;
3-(4-(isopropylsulfonyl)phenoxy)-N,N-dimethyl-5-(5-methyl-6-oxo-1 ,6- dihydropyrimidin-2-yl)benzamide;
(S)-2-(3-(1-hydroxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy) phenyl)pyrimidin-4(3H)-one;
(SH-(3-(1-hydroxypropan-2-yloxy)-5-(5-methyl-6-oxo-1 ,6-dihydropyrimidin- 2-yl)phenoxy)-N-methylbenzenesulfonamide;
(S)-3-fluoro-5-(3-(1-hydroxypropan-2-yloxy)-5-(6-oxo-1 ,6-dihydropyrimidin-2- yl)phenoxy)-N,N-dimethylpicolinamide;
(S)-2-(3-(1-hydroxypropan-2-yloxy)-5-(4-(isopropylsulfonyl)phenoxy)phenyl) pyrimidin-4(3H)-one;
(S)-2-(3-(4-(cyclopropylsulfonyl)phenoxy)-5-(1-hydroxypropan-2- yloxy)phenyl)pyrimidin-4(3H)-one;
2- (3-(4-(ethylsulfonyl)phenoxy)-5-((2S,3R)-3-hydroxybutan-2- yloxy)phenyl)pyrimidin-4(3H)-one;
(S)-2-(3-(1-methoxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy)phenyl) pyrimidin-4(3H)-one;
3- (4-(cyclopropylsulfonyl)phenoxy)-N,N-dimethyl-5-(5-methyl-6-oxo-1 ,6- dihydropyrimidin-2-yl)benzamide;
(R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- dimethylpyrimidine-2-carboxamide;
(R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-N,N- d i methyl py razi ne-2-carboxam ide ;
(R)-5-(3-sec-butoxy-5-(6-oxo-1 ,6-dihydropyrimidin-2-yl)phenoxy)-3-fluoro- N,N-dimethylpicolinamide;
(S)-2-(3-(4-(ethylsulfonyl)phenoxy)-5-(1-methoxypropan-2- yloxy)phenyl)pyrimidin-4(3H)-one;
N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihydropyrimidin-2-yl)-5-(pentan-3- yloxy)phenoxy)pyrazine-2-carboxamide; and N,N-dimethyl-5-(3-(6-oxo-1 ,6-dihydropyrimidin-2-yl)-5-(pentan-3- yloxy)phenoxy)pyrimidine-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of claim 1 ; or a pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable excipient, diluent, or carrier.
16. A method for treating or delaying the progression or onset of Type 2 diabetes and diabetes-related disorders in animals comprising the step of administering to an animal in need of such treatment a
therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of claim 1.
PCT/IB2011/052462 2010-06-18 2011-06-06 2-(3,5-disubstitutedphenyl)pyrimidin-4(3h)-one derivatives WO2011158149A1 (en)

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