WO2007143597A2 - Organic compounds - Google Patents

Organic compounds Download PDF

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Publication number
WO2007143597A2
WO2007143597A2 PCT/US2007/070293 US2007070293W WO2007143597A2 WO 2007143597 A2 WO2007143597 A2 WO 2007143597A2 US 2007070293 W US2007070293 W US 2007070293W WO 2007143597 A2 WO2007143597 A2 WO 2007143597A2
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WO
WIPO (PCT)
Prior art keywords
carboxamide
oxopyridin
methyl
group
benzyl
Prior art date
Application number
PCT/US2007/070293
Other languages
French (fr)
Other versions
WO2007143597A9 (en
WO2007143597A3 (en
Inventor
Natalie Dales
Julia Fonarev
Jianmin Fu
Duanjie Hou
Rajender Kamboj
Vishnumurthy Kodumuru
Natalia Pokrovskaia
Vandna Raina
Shaoyi Sun
Zaihui Zhang
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
Xenon Pharmaceuticals Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=38802273&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2007143597(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to DE602007010287T priority Critical patent/DE602007010287D1/en
Priority to AU2007256708A priority patent/AU2007256708B2/en
Priority to KR1020087029648A priority patent/KR101124070B1/en
Priority to CA002653655A priority patent/CA2653655A1/en
Priority to AT07798049T priority patent/ATE486862T1/en
Priority to EP07798049A priority patent/EP2029572B1/en
Priority to MX2008015229A priority patent/MX2008015229A/en
Application filed by Novartis Ag, Novartis Pharma Gmbh, Xenon Pharmaceuticals Inc. filed Critical Novartis Ag
Priority to BRPI0712902A priority patent/BRPI0712902A2/en
Priority to US12/303,490 priority patent/US8501746B2/en
Priority to CN2007800204238A priority patent/CN101460476B/en
Priority to JP2009514484A priority patent/JP5043105B2/en
Priority to RU2008151051/04A priority patent/RU2491285C2/en
Priority to PL07798049T priority patent/PL2029572T3/en
Publication of WO2007143597A2 publication Critical patent/WO2007143597A2/en
Publication of WO2007143597A3 publication Critical patent/WO2007143597A3/en
Publication of WO2007143597A9 publication Critical patent/WO2007143597A9/en
Priority to US13/942,404 priority patent/US20140024583A1/en

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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • 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
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    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
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Definitions

  • the present invention relates generally to the field of inhibitors of stearoyl-CoA desaturase, such as heterocyclic derivatives, and uses for such compounds m treating and/or preventing various human diseases, including those mediated by stearoyl-CoA desaturase (SCD) enzymes, preferably SCDl, especially diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome, d ⁇ ratological disorders and the like.
  • SCD stearoyl-CoA desaturase
  • Acyl desaturase enzymes catalyze the formation of a double bond in fatty acids derived from either dietary sources or de HOVD synthesis in the liver.
  • fatty acids derived from either dietary sources or de HOVD synthesis in the liver.
  • SCDs Stearoyl-CoA desaturases
  • cofactors other agents
  • other agents such as NADPH, cytochrome b5, cytochrome b5 reductase, Fe, and molecular O2 to introduce a double bond into the C9-C10 position (delta 9) of saturated fatty acids, when conjugated to Coenzyme A (CoA).
  • the preferred substrates are palmitoyl-CoA (16:0) and stearoyl- CoA (18:0), which are converted to palmitoleoyl-CoA (16:1) and oleyl-CoA(18:l), respectively
  • the resulting mono-unsaturated fatty acids are substrates foi further metabolism by fittty acid elongases or incorporation into phospholipids, triglycerides, and cholesterol esters.
  • a number of mammalian SCD genes have been cloned For example, two genes have been identified in humans (h SCDl and hSCD5) and four SCD genes have been isolated from mouse (SCDl, SCD2, SCD3, and SCD4).
  • hSCD 1 by Brownlie et al., FCT published patent application, WO 01/62954, the disclosure of which is hereby incorporated by reference in its entirety
  • hSCD2 PCT published patent application, WO 02/26944, incorporated herein by reference in its entirety.
  • sterculic acid 8-(2 octylcyclopropenyOoctanoic acid) and malvalic acid (7-(2-oclylcyclopropenyl)hepta ⁇ oic acid
  • agents that may inhibit SCD activity include thia-fatty acids, such as 9-thiastearic acid (also called 8-nonylthiooctanoic acid) and other fatty acids with a thioestcr moiety
  • the present invention solves this problem by presenting new drug-like classes of compounds that are useful in modulating SCD activity and regulating lipid levels, especially plasm, lipid levels, and which arc useful in the treatment of SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, especially diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like.
  • the present invention provides heterocyclic derivatives that modulate the activity of ⁇ tearoyl-CoA de ⁇ atura ⁇ e. Methods of using such derivatives to modulate the activity of Stearoyl-CoA desaturase and pharmaceutics] compositions comprising such derivatives are also encompassed.
  • the invention provides compounds of Formula (I):
  • V is selected from -N(R 5 )C(O)-, -C(O)N(R*)-, -OC(O)N(R 5 )-, -N(R 5 )C(O)O-,
  • W is selected fiom -N(R 5 )C(0>, -C(O)N(R 5 )-, -OC(O)N(R 5 )-, -N(R 5 )C(0)0-,
  • X is selected from C(H) or N;
  • Y is selected from S, O, N(H) or N(CH)); p is O, 1, 2, or 3; t is 1 or 2;
  • R' is selected from the group consisting of lydrogen, alkyl, alkenyl, alkynyl,alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralk/L heterocyclyl, heteroeydylalkyl, heteroaryl, and hctcroarylalkyl; or R 1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl Mid heteroaryl and where some or all of the rings may be fused to each other; R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydro ⁇ yalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, hetero
  • R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, trihaloalkoxyl, cyano and -N(R 5 ) 2 j
  • R 4 is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkylalkyl, aralkyl, halo, haloalkyl, -OCF 3 , -OC(H)F 2 , and cyano; or two adjacent R 4 groups, together with the carbon atoms to which they are attached, may form a cycloalkyl, heterocyclyl, sryl or heteroaryl and the remaining R 4 groups, if present, are as described R is selected from the group consisting of hydrogen, alkyl, alkeny
  • R ⁇ a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
  • the invention provides methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, wherein the methods comprise administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention as set forth above.
  • the invention provides compounds or pharmaceutical compositions useful in treating, preventing and/or diagnosing a disease or condition relating to SCD biological activity such as the diseases encompassed by cardiovascular disorders andior metabolic syndrome (including dyslipidemia, insulin resistance and obesity).
  • a disease or condition relating to SCD biological activity such as the diseases encompassed by cardiovascular disorders andior metabolic syndrome (including dyslipidemia, insulin resistance and obesity).
  • the invention provides methods of preventing or treating a disease or co ⁇ cM on related to elevated lipid levels, such as plasma lipid levels, especially elevated triglyceride or cholesterol levels, in a patient afflicted with such elevated levels, comprising administering to said patient a therapeutically or prophylacticaliy effective amount of a composition as disclosed herein.
  • the present invention also relates to novel compounds having therapeutic ability to reduce lipid levels in an animal, especially triglyceride and cholesterol levels.
  • the invention provides pharmaceutical compositions comprising
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the inye ⁇ tion in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level, or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient.
  • the patient has an elevated lipid level, such as elevated plasma triglycerides or cholesterol, before administration of said compound and said compound is present in an amount effective to reduce said lipid level,
  • the invention proridcs methods for treating a patient for, or protecting a patient from developing, a disease or condition mediated by stearoyl-CoA desaturase (SCD), which methods comprise administering to a patient afflicted with such disease or condition, or at risk of developing such disease or condition, a therapeutically effective amount of a compound that inhibits activity of SCD in a patient when administered [hereto.
  • SCD stearoyl-CoA desaturase
  • the invention provides methods for treating a range of diseases involving lipid metabolism and/or lipid homeostasis utilizing compounds identified by the methods disclosed herein.
  • a range of compounds having said activity based on a screening assay for identifying, from a library of test compounds, a therapeutic agent which modulates the biological activity of said SCD and is useful in treating a human disorder or condition relating to serum levels of lipids, such as triglycerides, VLDL, HDL, LDL, and/or total cholesterol.
  • the invention provides the use of the compounds of the invention, as set forth above, in the preparation of a medicament for the treatment of SCD-mediated disease or condition in a mammal, preferably a human.
  • PCTFublished Patent Application WO 01/6045S; PCTFublished Patent Application, WO 01/60369; PCTFublished Patent Application, WO 94/26720; European Published Patent Application, 0438 230; European Published Patent Application, 1 184 442; CA 2,1 14,178; and US Patent No.5,334,328; US Patent No.5,310,499; and US Published Patent Application, 2003/0127627.
  • C 7 -Ci 2 alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms
  • C 4 -Ci 2 Cyclodk ⁇ la]kyl describes a cyclcalkylalkyl group, as defined below, having a total of X to 12 carbon atoms.
  • the total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.
  • Haldroxy refers to the -OH radical
  • Niro refers to the -NO 2 radical
  • Amino refers to the -NR 14 or NR 13 radical
  • Trifluoromethyl refers to the — CFj radical
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms or one to six caibon atoms,
  • an alkyl group may be optionally substituted by one or more of the following groups: alkyl, alkenyl, halo, cyano, aryl, cycloalkyl, heterocyclyl, heteroaryl, -Si(CH 3 J 2 C(CHj) 3 , -OR 14 , -OC(O)-R 14 , - N(R 14 ) 2 , -C(O)R 14 , -C(O)OR", -C(O)N(R 14 J 2 , -N(R 14 )C(O)0R 16 , -N(R 14 )C(O)R 16 , - N(R 14 JS(O) 1 R 1 ', -S-, -S(O) 1 OR 16 , -S(O) 1 R 16 , and -S(OXN(R 14 J 2 and each R" is independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atmns, containing at least one double bond, having from two to twelve carbon atoms, preferably two to eight carbon atoms or two to six carbon atoms and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop.l.e ⁇ yl, but-1-enyl, pent-1-enyl, penta-l,4-dienyl, and the like.
  • an alkenyl group may be optionally substituted by one or more of the following groups: alkyl, alkenyl, halo, haloalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, - OR 14 , -OC(O)-K 14 -N(R 14 J 2 , -C(O)R 14 , -C(O)OR 14 , -C(O)N(R 14 J 2 , -N(R 14 JC(O)OR 16 , - N(R 14 JC(O)R 16 , -N(R 14 )S(0),R l ⁇ , -S-, -S(O] 1 OR 16 , -S(O) 1 R 16 , and -S(O) 1 N(R 14 J 2 and each R 14 , -OC(O)-K 14
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to twelve carbon atoms, preferably two to eight carbon atoms or two to six carbon atoms and which is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted by one or more of the following groups: alkyl, alkenyl, halo.
  • Alkylene and “alkylene chain” refer to a straight or branched divalent hydrocarbon chain, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons or one to six carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, end the like.
  • the alkylene chain may be attached to the rest of the molecule and to the radical group through one caibon within the chain or through any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain may be optionally substituted by one or more of the following groups: alkyl. alkenyl.
  • each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalky], cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R 16 is independently hydrogen, alkyl, haloalkyl, cycloalky], cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R 16 is independently hydrogen, alkyl, haloalkyl, cycloalky], cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R 16 is independently hydrogen, alkyl, haloalkyl, cycloalky], cycloalkylalkyl, aryl, aralkyl, heterocycly
  • alkenylene and alkenylene chain refer to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms or two to six carbon atoms, e.g. ethenylene, propenylene, n-butenylene, and the like.
  • an alkenylene chain may be optionally substituted by one or more of the following groups: alkyl, alkenyl, halo, cyano, aryl, cycloalkyl, heterocyclyl, heteroaryl, -OR 14 , -0C ⁇ 0)-R 14 , -T)(R 1 V - C(O)R 14 , -C(O)OR 14 , -C(O)N(R 14 ),, -N(R 14 )C(O)OR" ⁇ -N0l l4 )C(0)R le .
  • Alkynylene and Alkynylene chain refer to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one triple bond and having from two to twelve carbon atoms or two to six carbon atoms, e.g.
  • an alkynylene chain may be optionally substituted by one or more of the following groups: alkyl, alk;n> I, halo, cyano, aryl, cycloalkyl, lictcrocyclyl, heteroaryl, -OR 14 , -OC(O)-R 1 ', -N(R I4 ) 2 , -C(O)R 14 , - C(O)OR 14 , -C(O)N(R 14 ) 2> -N(R l4 )C(0)0R", -N(R 14 JC(O)R 16 , -N(R 14 )S(O)iR 16 , -S-, - S(O) 1 OR 16 , -S(O) 1 R 16 , and -S(O),N(R 14 ) 2 , arid each R 14 is independently hydrogen,
  • AIkOKy refers to a radical of the formula -OR, where R. is an alkyl radical as generally defined above.
  • R. is an alkyl radical as generally defined above.
  • the alkyl part of the alkoxy radical may be optionally substituted as defined above for an alkyl radical.
  • Alkoityalkyl refers to a radical of ihe formula -R b -O-R 3 where Rj, is an alkylene chain as defined above and R, is an alkyl radical as defined above.
  • the oxygen atom may be bonded to any carbon in the alkylene chair and in the alkyl radical.
  • the allcyl part of the alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group.
  • the alkylene chain part of the alkoxyalkyl radical may be optionally substituted as defined above for an alkylene chain.
  • Aryl refers to aromatic monocyclic O ⁇ multicyclic hydrocarbon ring system consisting only of hydrogen and carbon and containing from 6 to 19 carbon atoms, preferably 6 to 10 carbon atoms, where the ling system may be partially saturated.
  • Aryl groups include, but are not limited to groups such as fluorenyl, phenyl, indenyl and naphthyl.
  • the terra "aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substitucnts selected from the group consisting of alkyl, aUcenyl, alkynyl,
  • Aralkyl refers to a radical of the formula -R 1 R b where R, is an allcylene chain as defined above and R b is one or more aryl radicals as defined above, e.g., benzyl, diphenylmeihyl and the like.
  • the aryl part of the aralkyl radical may be optionally substituted as described above For an aryl group.
  • the alkylene chain part of the aralkyl radical may be optionally substituted as defined above for an alkyl group.
  • Alkenyl refers to a radical of the formula -R a R b where R 2 is an alkenylene chain as defined above and R b i ⁇ one or more aryl radicals a ⁇ defined above, which may be optionally substituted as described above.
  • the aryl part of the aralkenyl radical may be optionally substituted as described above for an aryl group.
  • the alkenylene chain of the aralkenyl radical may be optionally substituted as defined above for an alkenyl group.
  • Aryloxy refers to a radical of the formula -OR b where R b is an aryl group as defined above.
  • R b is an aryl group as defined above.
  • the aryl part of the aryloxy radical may be optionally substituted as defined above.
  • Cycl ⁇ alkyl refers to a stable non-arcmatic monocyclic or polyeyeHc hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, preferably having from three to twelve carbon atoms or from three to six atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl and the like.
  • eycloalkyl is meant to include cycloalkyl radicals which are optionally substituted by one or more ⁇ ubstituent ⁇ selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, cyano, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
  • heterocydylalkyl heter ⁇ aryl, heteroarylalkyl, -R ls -0R 14 , -R 1 ⁇ OC(O)-R 1 ", -R 15 -N(R 14 ) 2 , - R ⁇ -C(O)R 1 ', -R IS -C(O)OR", -R 1S -C(0)N(R%, -R 15 -N(R 14 )C(O)OR 16 , -R 15 - N(R u )C(0)R 16 , -R IS -N(R U )S(O),R 16 , -S-, -R ls -S(O)OR 1 ⁇ , -R 1S -S(O),R 16 , and -R ]i - S(O),N(R 14 ) 2 and each R 14 is independently hydrogen, alky], haloalkyl, cycloalkyl, cycl ⁇ alkylal
  • each R 1 ' is alkyl, tialoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
  • Cycloalkylalkyl refers to a radical of the formula -R,Rj where R n is an alkylene chain as defined above and Rj is a cycloalkyl radical as defined above.
  • the alkylene chain and the cycloalkyl radical may be optionally substituted as defined above.
  • fused refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention
  • the fused ring is a heterocyclyl ring or a heteioaryl ring
  • any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom
  • Halo refers to bromo, chloro, fluoro or iodo.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluororaethyl, trichloromethyl, 2,2,2-trifluoroethyl, l-fluoioinethyl-2-fluoroethyl, 3-bromo-2- fluoropropyl, 1 -bromomethyl-2-bromoethyl, and the like.
  • the alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group.
  • Heteiocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical which consists of carbon atoms and from ore to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the het ⁇ rocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally alkylated/substituted; and the heterocyclyl radical may be partially or fully saturated.
  • aieh heterocyclyl radicals include, but are not limited to, dioxolanyl, decahydroisoquiriolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, lsomolidinyl,
  • morpholinyl octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidirryl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidi ⁇ yl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, l-oxo-thiomorpholinyl, and 1,1-dioxc- thiomorpholinyl.
  • heterocyclyl is meant to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents selected from the groupconsisting of alkyl, alkenyl, halo, haloalkyl, cyano, oxo, thioxo, aryl, aralkyl, cycloalkyl, cycloalkylallcyl, heterocyclyl. lieterocyclylalkyl.
  • heteroaryl, heteroarylalkyl -R IS -OR 14 , -R I S -0C(0)-R", -R 15 -N(R 14 ) 2 , -R I5 -C(O)R U , -R.
  • each R 14 is independently hydrogen, alkyl, haloalkyl, cyclcalkyl, cycloalkylalkyl, aryl, aialkyl, heterocycly], heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R 16 is alkyl, haloalkyl, cyclcalkyl, cycloalkylallcyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
  • Heterocyclylalkyl refers to a radical of the formula -R a R c where R 3 is an alkylene chain as defined above and R* is a heterocyclyl radical as defined above, and if the heterocycly! is a nitrogen-containing heteiocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom.
  • the alkyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for an alkyl group.
  • the heterocyclyl part of the heierocyclylalkyl radical may be optionally substituted as defined above for a heterocyclyl group.
  • Heteroaryl refers to a 5- to 18-membered aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heteroaryl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused cr bridged ring systems; and the nitrogen, carbon or sulfur stems in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally alkylated/substituted Examples include, but are rot limited to, az ⁇ pi ⁇ yl, acridiriyl, benzimidazolyl, benzthiazolyl,
  • Heteroarylalkyl refers to a radical of the formula -R 11 R f where R a is an alkylene chain as defined above and R f is a heteroaryl radical as defined above TTie heteroaryl part of the hetercarylallcyl radical may be optionally substituted as defined alove for a heteroaryl group.
  • the alkyl part of the heterD-rylalkyl radical may be optionally substituted as defined above for an alkyl group
  • Hydroxyalkyl refers to a radical of the formula -R 8 -OH where R 1 is an alkylene chain as defined above The hydroxy group may be attached to the alkyl radical on any carbon within the alkyl radical. The alkyl part of the hydroxyalkyl group may be optionally substituted as defined above for an alkyl group.
  • Trihaloalkoxy refers to a radical of ttie formula -0R e where R 8 is a hsloalkyl group as defined above where three
  • halo are substituted on an alky 1.
  • the trihaloalkyl part of the trihaloalkoxy group may be optionally substituted as defined above for a tialoalkyl group.
  • a multi-ring structure refers to a multicyclic ring system comprised of two to four rings wheiein the rings are independently selected from cycloalkyl, aryl, heterocyclyl or rieteroaryl as defined above
  • Each cycloalkyl may be optionally substituted as defined above for a cycloalkyl group.
  • Each aryl may be optionally substituted as defined above for an aryl group.
  • Each heterocyclyl may be optionally substituted as defined above for a heterocyclyl group.
  • Each heteroaryl may be optionally substituted as defined above for a heteroaryl sroup.
  • the rings may be attached to each other through direct bonds or some or all of the rings may be fused to each other.
  • prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
  • prodrug refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed m vivo to yield the parent compound of the invention, for example, by hydrolysis in blood or conversion in the gut or liver.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp.
  • prodrugs are provided in Higuchi, T., et of., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, Anglican Pharmaceutical Association arid Pergamon Press, 1987, both of which are incorporated in full by reference herein.
  • prodrug is also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • Prodrugs include compounds of the invention wherein a hydroxy, amino or mcrcapto or acid group is bonded to any group that, when the prodrug
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amides of amine functional groups in the compounds of the invention and the like.
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from areaction mixture, and formulation into an efficacious therapeutic agent.
  • “Mammal” includes humans and domestic animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like.
  • Optional or “optionally” means that the subsequently described event of circumstances may or may not occur, and tliat the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties cf the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidcbenzoic acid, camphoric acid, camphor-10-sulfonic acid, capik acid, caproic acid, caprylic acid, carbonic acid, cin ⁇ amic acid, citric acid, cyclamic acid,
  • dodecylsulfiiric acid ethane-l,2-disulfonic acid, ethanesulfonic acid, 2- hydroxyeihanesulfonlc acid, formic acid, njmarfc acid, galactaric acid, gent ⁇ sic acid, glu ⁇ hcptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutatic acid, 2-oxo- glutaric acid, glycerophosphorirc acid, glycolic acid, hippuiic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-], 5-disulfonic acid, naphthalene-2- sulfonic acid, l-hjdroxy-2-naphthoic acid, nicotinic acid, oleic acid
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties cf the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamirie, diethanolamine, ethanolamine, deanol, 2- dimethylaininoethanol, 2-diethylaminoethait ⁇ l, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabami ⁇ e, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, JV-ethylpiperidine, polyamine resins and the like. Particularly
  • solvate refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent.
  • solvent may be water, in which case the solv ⁇ te may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or he a mixture of water plus some adventitious solvent.
  • a “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., hutnatis.
  • a medium includes all pharmaceutically acceptable carriers, diluents orexcipients thereof.
  • “Therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of an SCO-mediated disease or condition in the mammal, preferably a human.
  • the amount of a compound of the invention which constitutes s. "therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age and body weight of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Treating covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or disorder of interest, and includes: (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it; (H) inhibiting the disease or condition, i.e., airesting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving the symptoms resulting from the disease or condition, i.e., relieving the symptoms without addressing the underlying disease or condition.
  • the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have aUnown causative agent (so that etiology has not yet been worked out) and it is therefore not yet
  • the compounds of the invention, or their pharmaceutically acceptable salts may contain one 01 more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereo isomeric forms that may be defined, in terms of absolute stereochemistry, as [R)- or [S)- or, as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and ⁇ S ⁇ -, or (D)- and (L)- isomers may be prepared using chiral synthon ⁇ or ch ⁇ ral reagents, or resolved using conventional techniques, such as HPLC using a chiral column
  • the compounds described herein contain olef ⁇ nic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • all tautomeric Forms are also intended to be included
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • a ' tautorner refers to a proton shift from one atom ⁇ f a molecule tc another atom of the same molecule.
  • the present invention includes tautomers of any said compounds.
  • One embodiment of the invention is the compounds of Formula -(I):
  • V is selected from -N(R 5 )C(O)-, -C(O)N(R 3 )-, -OC(O)N(R 5 )-, -N(R 5 )C(O)O-,
  • W is selected from -N(R 5 )C(0)-, -C(O)N(R 5 )-, -OC(O)N(R 5 )-, -N(R 5 JC(O)O-,
  • X is selected from C(H) or N;
  • Y is selected from S, O, N(H) or N(CHj); p is O, 1, 2, or 3; t is 1 or 2;
  • R 1 is selected from the group consisting of hydrogen, alkyl, alke ⁇ yl, alkyryl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyi, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, hctcrocyclylalkyl, heteroaryl, and heteroarylalkyl, or R 1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyi, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydro ⁇ yalkyl, alkoxyalkyl, cycloalkiyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylal
  • K 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, haloalkoiyl, cyano and -N(R 5 > 2 ;
  • R 4 is selected fiotn the group consisting of alkyl, hydroxyalkyl, cycloalkylalkyl, aralkyl, halo, haloalkyl, -OCF 3 , , -OC(H)F 3 , and cyano; or two adjacent R 4 groups, together with the carbon atoms to which they attached, may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R 4 groups, if present, are as
  • R 5a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
  • V is selected from -O- or a direct bond
  • W is selected from -N(R 5 )C(0)-, -C(O)N(R 5 )-, -C(O)O- or a direct bond; p is 0, 1, 2, or 3;
  • R 1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heterocyclyl, neterocyclylalkyl, heteroaryl, and heteroarylalkyl;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkj/lalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
  • R 3 is selected from the group consisting of hydrogen and alky]
  • R 4 is alkyl or haloalkyl
  • R s is selacted from the group consisting of hydrogen or alkyl
  • V is selected from -O- or a direct hold
  • W is selected from -N(R 5 JC(O)-, -C(C)N(R S )-, -C(O)O- or a direct bond; p is O, I 1 2, or 3;
  • R 1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heterocycl yl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylaflcyl, heteroaryl and heteroarylaHcyl; or R 3 is a multi-ring structure havlti£ 2 to 3 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocydyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
  • R 3 is selected from the group consisting of hydrogen and alkyl
  • R 4 is alkyl or CF 3 ;
  • R 5 is selected from the group consisting of hydrogen or alkyl.
  • Another embodiment is a compound of Formula (I), wherein X is N and Y is N-CH 3 or NH;
  • V is selected from -O- or a direct bond
  • W is selected from -N(R s )C(0)-, -C(CI)N(R 5 )-, -OC(O)-, -C(O)O- oi a direct bond; p is O, 1, 2, or 3;
  • R' isselected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heterocycly], heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
  • R is selected from the group consisting of hydrogen, alkyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cygloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
  • R ! Is selected from the group consisting of hydrogen and alkyl
  • R' IS alkyl, halo and haloalkyl; or two adjacent R 4 groups, together with the carbon atoms to which they attached, may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R 4 groups, if present, are as described above;
  • R 5 is selected from the group consisting of hydrogen or alkyl.
  • Y is selected from S. O, N(H) or N(CHj):
  • V is selected from -O- or a direct bond
  • W is selected from -N(R 5 )C(0)-, -C(O)N(R 5 )-, -C(O)O- or a direct bond; p is 0, 1, 2, or 3;
  • R 1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkoxy, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloallcyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R z is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
  • R 3 is selected from the group consisting of hydrogen and alkyl
  • R 4 is ⁇ lkyl or haloalkyl
  • R s is selected from the group consisting of hydrogen or alkyl
  • Another embodiment is a compound of Formula (1), wherein X is selected from CH or N;
  • Y is selected from S, O, N(H) or N(CHj);
  • V is selected from -O- or a direct bond
  • W is selected from -N(R S )C(O)-, or -C(O)O-; p is 9, 1, 2, or 3;
  • R 1 is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
  • R 2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R 1 is a multi-ring structure having 2 to 3 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other,
  • R 3 is selected from the group consisting of hydrogen and alkyl
  • R 1 is rialcalkl, or alkyl
  • R 5 is selected from the group consisting of hydrogen or alkyl.
  • Another embodiment is a compound of Formula (I), wherein X is selected from CH or N;
  • Y is selected from S, O, N(H) or N(CHj);
  • V is selected from -O- or a direct bond
  • W is selected from -N(R S )C(O)-, or -C(O)O-; p is C, 1, 2, or 3;
  • R' is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
  • R 2 is selected from the group consisting of hydrogen, alkyl, hydroiyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R J is a multi-ring structure having 2 to 3 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
  • R 3 is selected from the group consisting of hydrogen and alkyl
  • R 4 ishal ⁇ alkyl, or alkyl
  • R 5 is selected from the group consisting of hydrogen or alkyl.
  • Another embodiment is a compound of Formula CI), wherein
  • X is selected from CH or N;
  • V is selected from S, O, NH or N-CH 3 ;
  • V is selected from -O- or a direct bond
  • W is selected from -N(R 5 )C(0)-, or -C(O)O-; p is 0, 1, 2, or 3;
  • R' is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
  • R 2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cyclDalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 3 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other,
  • R 3 is selected from the group consisting of hydrogen and alkyl
  • R 4 is alkyl or haloalkyl
  • R 5 is selected from the group consisting of hydrogen or alkyl
  • Another embodiment is a compound of Formula (1), wherein
  • V is selected from -O- or a direct bond
  • W is selected from -N(R S )C(O)-, or -C(O)O-; p is O, I 1 2, or 3;
  • R 1 is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
  • R J is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R : is a multi-ring structure having 2 to 3 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and h ⁇ teroaryl and where some or all of the rings may be ftised to each other;
  • R J is selected from the group consisting of hydrogen and alkyl
  • R 4 is halcalkyl or alkyl
  • R 5 is selected from the group consisting of hydrogen or alkyl.
  • the methods of 1he invention are directed towards the treatment and/or prevention of diseases mediated by stearoyl-CoA desatiuase (SCD), especially human SCD (hSCD), preferably diseases related to dyslipidemiaand disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome, dermatolog ⁇ cal disorders and the like by administering an effective amount of a compound of the invention.
  • SCD stearoyl-CoA desatiuase
  • hSCD human SCD
  • diseases related to dyslipidemiaand disorders of lipid metabolism preferably diseases related to dyslipidemiaand disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome, dermatolog ⁇ cal disorders and the like by administering an effective amount of a compound of the invention.
  • the present invention also relates to pharmaceutical composition containing the compounds of tie Invention.
  • the invention relates to 2 composition comprising compounds of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient.
  • the patient has an elevated lipid level, such as elevated triglycerides or cholesterol, before administration of said compound of the invention and the compound of the invention is present in an amount effective to reduce said lipid leveL
  • the present invention relates to compounds, pharmaceutical compositions and methods of using the compounds and pharmaceutical compositions for the treatment and/or prevention of diseases mediated by stearoyl-CoA desaturase (SCD), especially human SCD (liSCD), preferably diseases related to dyslipidemia and disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, especially cardiovascular disease, diabetes, obesity, metabolic syndrome, dermatologieal disorders and the like, by administering to a patient in need of such treatment an effective amount of an SCD modulating, especially inhibiting agent.
  • SCD stearoyl-CoA desaturase
  • liSCD human SCD
  • diseases related to dyslipidemia and disorders of lipid metabolism preferably diseases related to dyslipidemia and disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, especially cardiovascular disease, diabetes, obesity, metabolic syndrome, dermatologieal disorders and the like, by administering to a patient in need of such treatment an effective amount of an SCD modulating, especially inhibiting agent.
  • the present invention provides a method for treating a patient for, or protecting a patient from developing, a disease related to dyslipidemia and/or a disorder oflipid metabolism, wherein lipid levels in an animal, especially a human being, are outside the normal range (i.e., abnormal lipid level, such as elevated plasma lipid levels),
  • lipid-relaterj condition or disease is an SCD-mediated disease or condition, comprising administering to an animal, such as a mammal, especially a human patient, a therapeutically effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention wherein the compound modulates the activity of SCD, preferably human SCDl .
  • the compounds of the invention modulate, preferably inhibit, the activity of human SCD enzymes, especially human SCDl.
  • the general value of the compounds of the invention in modulating, especially inhibiting, the activity of SCD can be determined using the assay described below in Example 28.
  • the general value of the compounds in treating disorders and diseases may be established in industry standard animal models for demonstrating the efficacy of compounds in treating obesity, diabetes or elevated triglyceride or cholesterol levels or for improving glucose tolerance.
  • Such models include Zucker obese /a/fa rats (available from Harlan Sprague Dawley, Inc. (Indianapolis, Indiana)), or the Zucker diabetic fatty rat (ZDF/GmiCrl- ⁇ fe) (available from Charles River Laboratories (Montreal, Quebec)), and Sprague Dawley rate (Charles Rivers), as used in models for diet-induced obesity (Ohibaudi, L. etal., (2»C2), Obns. Res. Vol. 10, pp.956-963). Similar models have also been developed for mice.
  • the compounds of the instant invention are inhibitors of delta- 0 de ⁇ aturaees and are useful for treating diseases and disorders in humans and other organisms, including all those human diseases and disorders which are the result of aberrant delta-9 desaturase biological activity or which may be amelicr-ted by modulation of delta-9 desaturase biological activity.
  • an SCD-mediated disease or condition is defined as any disease or condition in which the activity of SCD is elevated and/or where inhibition of SCD activity can be demonstrated to bring about symptomatic improvements for the individual so treated.
  • an SCD-mediated disease or condition includes
  • dysl ⁇ pidemias including but not limited to disorders of serum levels of triglycerides, hypertriglyceridemia, VLDL, HDL, LDL, fatty acid Desaturation Index (e.g. the ratio of 18:1/18:0 fatty acids, or other fatty acids, as defined elsewhere herein), cholesterol, and total cholesterol, hypercholesterolemia, as well as cholesterol disorders (including disorders characterized by defective reverse cholesterol transport), familial combined hyperlipidemia, coronary artery disease, atherosclerosis, heart disease, cerebrovascular disease (including but not limited to stroke, ischemic stroke and transient ischemic attack (TIA)), peripheral vascular disease, and ischemic retinopathy.
  • TIA transient ischemic attack
  • An SCD-mediated disease or condition also includes metabolic syndrome (including bul not limited to dyslipidem ⁇ a, obesity and insulin resistance, hypertension, microalbuminem ⁇ a, hyperuricemia, and hypercoagulability), Syndrome X s diabetes, insulin resistance, decreased glucose tolerance, non -insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, body weight disorders (including bul not limited to obesity, overweight, cachexia and anorexia), weight loss, body mass index and leptin related diseases
  • metabolic syndrome including bul not limited to dyslipidem ⁇ a, obesity and insulin resistance, hypertension, microalbuminem ⁇ a, hyperuricemia, and hypercoagulability
  • Syndrome X s diabetes insulin resistance, decreased glucose tolerance, non -insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, body weight disorders (including bul not limited to obesity, overweight, cachexia and anorexia), weight loss, body mass index and leptin related diseases
  • compounds of the invention will be used to treat diabetes me
  • metabolic syndrome is a recognized clinical term used to describe a condition comprising combinations of Type Il diabetes, impaired glucose tolerance, insulin resistance, hypertension, obesity, increased abdominal girth, hypertriglyceridemia, low HDL, hyperuricemia, hypercoagulability and/or micro album ineinia.
  • the American Heart Association has published guidelines for the diagnosis of metabolic syndrome, Grundy, S., et. aJ. f (3006) Cardiol. Rev. Vol. 13, No.6, pp. 322-327.
  • An SCD-mediated disease or condition also includes fatty liver, hepatic steatosis, hepatitis, non-alcoholic hepatitis, non-alcoholic steatohepatitis (NASH) 5 alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, erythrohepaiic protoporphyria, iron overload disorders, hereditary hemochromatosis, hepatic fibrosis, hepatic cirrhosis, hepatoma and conditions related thereto.
  • NASH non-alcoholic steatohepatitis
  • An SCD-mediated disease or condition also includes but is not limited to a disease or condition which is, or is related to primary hypertriglyceridemia, or
  • hypertriglyceridemia secondary to another disorder or disease such as hyperlipoproteinemias, familial histiocytic reticulosis, lipoprotein lipase deficiency, apolipoprotein deficiency (such as ApoCII deficiency or ApoE deficiency), and the like, or hypertriglyceridemia of unknown or unspecified etiology.
  • An SCD-ttiediated disease or condition also includes a disorder of polyunsaturated fatty acid (PUFA) disorder, ⁇ r a dermatoiogical disorder, including but not limited to eczema, acne, psoriasis, keloid scar formation or prevention, diseases related to production or secretions from mucous membranes, such as monounsaturated fasy acids, wax esters, and the like.
  • PUFA polyunsaturated fatty acid
  • ⁇ r a dermatoiogical disorder, including but not limited to eczema, acne, psoriasis, keloid scar formation or prevention, diseases related to production or secretions from mucous membranes, such as monounsaturated fasy acids, wax esters, and the like.
  • the compounds of the invention inhibition of SCD acitivity can prevent or attenuate keloid scar formation by reduction of excessive sebum production that typically results in their Formation.
  • An SCD-mediated disease or condition also includes inflammatica sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, cystic fibrosis, and premenstrual syndrome.
  • An SCD-mediated disease or condition also includes but is not limited to a disease or condition which is, or is related to cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the like.
  • An SCD-mediated disease or condition also includes a condition where increasing lean body mass or lean muscle mass is desired, such as is desirable in enhancing performance through muscle building.
  • Myopathies and lipid myopathies such as carnitine palmitoyltransferase deficiency (CPT I or CPT II) are also included herein.
  • CPT I or CPT II carnitine palmitoyltransferase deficiency
  • bovine, porcine or avian domestic animals or any other animal to reduce triglyceride production andJ ⁇ r provide leaner meat products and/or healthier animals.
  • An SCD-mediated disease or condition also includes a disease or condition that is, or is related to, neurological diseases, psychiatric disorders, multiple sclerosis, immune disorders and eye diseases, including but not limited to, disorders characterized by excessive or inappropriate lipid production by meiobium glands..
  • An SCD-mediated disease or condition also includes a disease or condition which is, or is related to, viral diseases or infections including but not limited to all positive strand RNA viiuses, c ⁇ ronaviruses, SARS virus, SARS-associated corona ⁇ irus, Togavlruses, Picornaviruses, Coxsackievirus, Yellow Fever virus, Flaviviridae, ALPHAVIRUS (TOGAVIRIDAE) including Rubella virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Sindbis virus, Semliki forest virus, Chikungunya viius, O'nyong'nyong virus, Ross river virus, Mayaro virus, Alphaviruses; ASTROVIRIDAE including Astrovirus, Human Astroviruses; CALICIVIRIDAE including Vesicular exanthema of swine virus, Norwalk virus, CaliciviruE, Bovine calici
  • Treatable viral infections include those where the virus employs an RNA intermediate as part of the replicative cycle (hepatitis or HIV); additionally it can be a disease or infection caused by or linked to RNA negative strand viruses such as influenza and parainfluenza viruses.
  • the compounds identified in the instant specification inhibit the desaturation of various fatty acids (such as the C 9 -C 10 desaturation of stearoyl-CoA), which is accomplished by delta-9 desaturases, such as stearoyl-CoA desaturase I (SCDl). As such these compounds inhibit the formation of v ⁇ rious fatty acids and downstream metabolites thereof. This may lead to an accumulation of 5t ⁇ aroyl-CoA or palmitoyl-CoA and olher upstream precursors of various fatty acids; which may possibly result in anegative feedback loop causing an overall change in fatty acid metabolism. Any cf these consequences may ultimately be responsible for the overall therapeutic benefit provided by these compounds.
  • a successful SCD inhibitory therapeutic agent will meet some or all of the following criteria.
  • Oral availability should be at or above 20%
  • Animal model efficacy is less than about 20 rng/Kg, 2 mg/Kg, 1 mg/Kg, or 0.5 mg/Kg and tile target human dose is between 10 and 250 mg/70 Kg, although doses outside of this range may be acceptable.
  • mg/Kg means milligrams of compound per kilogram of body mass of the subject to whom it is being administered.
  • the required dosage should preferably be no more than about once or twice a day or a! meal times.
  • the therapeutic index (or ratio of toxic dose to therapeutic dose) should be greater than 10.
  • the IC 50 is a measure of the amount of compound required to achieve 50% inhibition of SCD activity, over a specific time period, in an SCD biological activity assay. Any process for measuring the activity of SCD enzymes, preferably mouse or human SCD enzymes, may be utilized to assay the activity of the compounds useful in the methods of the invention in inhibiting said SCD activity.
  • Compounds of the invention demonstrate an IC 50 ("Inhibitoty Concentration of 50%") in a 15 minute microsomal assay of preferably less than 10 ⁇ M, less than S ⁇ M, less than 2.5 ⁇ M, less than 1 ⁇ M, less than 750 nM, less than 50D nM, less than 250 nM, less than 100 nM, less than 50 ⁇ M, and most preferably less than 20 nM.
  • IC 50 Inhibitoty Concentration of 50%
  • SAR structure-activity relationship
  • this is accomplished by administering said chemical agent to an animal afflicted withatriglyceride (TG)- or very low density lipoprotein (VLDL)-related disorder and subsequently detecting a change in plasma triglyceride level in said animal thereby identifying a therapeutic agent useful in treating a triglyceride (-T ( Jy. or very low density lipoprotein (VLDL)-related disorder.
  • the animal may be a human, such as a human patient afflicted with such a disorder and in need of treatment of said disorder.
  • said change in SCDl activity in said animal is a decrease in activity, preferably wherein said SCDl modulating agent d ⁇ es not substantially inhibit the biological activity of a delta-5 desaturase, delta-6 desaturase or fatty acid synthetase or other enzymes containing Fe at the active site.
  • the model systems useful for compound evaluation may include, but are not
  • liver microsomes such as from mice that have been maintained on a Mgh carbohydrate diet or from human donors, including persons suffering from obesity- Immortalized cell lines, such as HepG2 (from human liver), MCF-7 (ftom human breast cancer) and 3T3-L1 (from mouse adipocytes) may also be used.
  • Primary cdl lines, such as mouse primary hepatocytes, are also useAil in testing the compounds of the invention.
  • mice used as a source of primary hepatocyte cells may also be used wherein the mice have been maintained on a high carbohydrate diet to increase SCD activity in mirocrosomes and/or to elevate plasma triglyceride levels (i.e., the 1S:1/18:0 ratio); alternatively mice on anormal diet or mice with normal triglyceride levels may be used.
  • Mouse models employing transgenic mice designed foi hypertriglyceridemia are also available. Ratbili and hamsters ate also useful as animal models, especially those expressing CETP (cholesterol ester transfer protein).
  • Another suitable method for determining the in vivo efficacy of the compounds of the invention is to indirectly measure their impact on inhibition of SCD enzyme by measuring a subject's Desaturation Index after administration of the compound.
  • “Desaturation Index” as employed in lhis specification means the ratio of the product over lhc substrate for the SCD enzyme as measured from a given tissue sample. This may be calculated using three different equations 18:ln-9/18:0 (oleic ⁇ cid over stearic acid); 16;ln-7/16:0 (palmitoleic acid over palmitic acid); and/or 16: ln-7 + 18:ln- 7/16:0 (measuring all reaction products of 16:0 desaturation over 16:0 substrate).
  • Desatiiration Index is primarily measured in liver or plasma triglycerides, but may also be measured in other selected lipid fractions from a variety of tissues. Desaturation Index, generally sneaking, is a tool for plasma lipid proflling.
  • a number of human diseases and disorders are the result of aberrant SCDI biological activity and may be ameliorated by modulation of SCDl biological activity using the therapeutic agents of the invention.
  • Inhibition of SCD expression may also affect the fatty acid composition of membrane phospholipids, as well as production or levels of triglycerides and cholesterol esters.
  • the fatty acid composition of phospholipids ultimately determines membrane fluidity, with a subsequent modulation of the activity of multiple enzymes present within the membrane, while the effects on the composition of triglycerides and cholesterol esters
  • Another format can be used to measure the effect of SCD inhibition on sebaceous gland function.
  • oral, intravenous or topical formulations of the SCD inhibitor are administered to a rodent for a period of 1 to 8 days.
  • Skin samples are taken and prepared for histological assessment to determine sebaceous gland number, size, or lipid content
  • a reduction of sebaceous gland size, number or function would indicate that the SCD inhibitor would have a beneficial impact on acne vulgaris, (Clark, S.B. et at "Pharmacological modulation of sebaceous gland activity: mechanisms and clinical applications", De/r ⁇ to/. Clin. (2007) Vol.25, ND 2, pp 137-46. Geiger, J.M , "Retinoids and sebaceous gland activity” Dermatology (1995), Vol. 191, No.4, pp 3C5-10).
  • the present invention also relates to pharmaceutical composition containing the compounds of the invention disclosed herein.
  • the present invention relates to a composition comprising compounds of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient.
  • the patient has an elevated lipid level, such as elevated triglycerides or
  • cholesterol before administration of said compound of the invention and the compound of the invention is present in an amount effective to reduce said lipid level.
  • compositions useful herein also contain a pharmaceutically acceptable carrier, including any suitable diluent or excipient, which includes any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
  • Pharmaceutically acceptable carriers include, but are not limited to, liquids, such as water, saline, glycerol and ethanol, and the like.
  • Therapeutic doses are generally identified through a dose ranging sludy in humans based on preliminary evidence derived frorn animal studies. Doses must be sufficient to result in a de&ited therapeutic benefit without causing unwanted ⁇ ide effects For the patient
  • the preferred dosage range for an ⁇ nimal is 0.001 mg/Kg to 10,000 mg/Kg, including 0.5 mg/Kg, 1.0 mg/Kg, 2.0 mg/Kg 5,0 mg/Kg and 10 mg/Kg, though doses outside this range may be acceptable.
  • the dosing schedule may be once or twice per day, although more often or less often may be satisfactory.
  • the compounds ofthe invention can be used in in vitro or in vivo studies as exemplary agents for comparative purposes to find other compounds also useful in treatment of, or protection from, the various diseases disclosed herein.
  • compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal, topical, and parenteral administration to mammals, including man, to inhibit stearo yl-CoA desaturase, and for the treatment of
  • compositions comprise a therapeutically effective amount of a pharmacologically active compound of the instant invention, alone or In combination with one or more pharmaceutically acceptable carriers.
  • the pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising a therapeutically effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application.
  • excipients or carriers suitable for either enteral or parenteral application.
  • Such pharmaceutical compositions may comprise, for example, 1he active ingredient together with diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethvleneglycol), and for tablets also comprises binders (e.g , magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone) and disintegrants (eg-, starches, agar, alginie acid or its sodium salt) or effervescent mixtures and absorbanis, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or gly
  • the compounds may be in the form of injectable compositions, e.g. preferably aqueous isotonic solutions or suspensions, and suppositories, which can be advantageously prepared from fatty emulsions or suspensions.
  • the compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • the compositions may be prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1- 75%, preferably about 1-50%, of the active ingredient.
  • transdermal devices are in the form of a bsntJage comprising a backing member, a reservoir containing the compound
  • a rate controlling barrier to deliver the compound of the skin of the host at a controlled and pie-determined rate over a prolonged period of time, and means to secure the device to the skin.
  • the compounds of the invention may be usefully combined with one or more other therapeutic agents for the treatment of SCD-mediated diseases and conditions
  • the other therapeutic agent is selected from antidiabetics, hypolipidemic agents, anti-obesity agents, anti-hypertensive agents or inotropic agents.
  • an additional aspect of the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention in combination with one or more other therapeutic agents.
  • the composition can be formulated to comprise a therapeutically effective amount of a compound of the invention as defined above, in combination with anothei therapeutic agent, each at an effective therapeutic dose as reported in the art.
  • Such therapeutic agents may, for example, include insulin, insulin derivatives and mimetics; insulin secretogogues, such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands, such as meglitinides, e.g., nateglinide and repaglinide; PPAR ⁇ and/or PPARot (peroxisome proliferator-activated receptor) ligands such as MCC-555, MK767, L-165041, GW7282 or thiazolidinediones such as rosiglitazone, pioglitazone, troglttazone; insulin sensitizers, such as protein tyrosine phosphatase- IB (PTP-IB) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase- 3) inhibitors such as SB
  • coenzyme A HMG-CoA reductase inhibitors, e.g., lovastatin, p avastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastat ⁇ n, dalva ⁇ tatin, atorvastatin, rosuvastatin, flmndostat ⁇ n and rivastatin, squalene synthase inhibitors or FXR (farnesoid X receptor) and LXR (liver X receptor) Ugands, cholestyramine, fibrates, nicotinic acid and aspirin; anti-obesity agents, such as orlisiat, anti-hypertensive agents, inotropic agents and hypolipidemic agents, e.g., loop diuretics, such as ethacrynic acid, furosemide and torsemide; angiotensin converting enzyme (ACE) inhibitor
  • a compound of the present invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
  • compositions as described above for production of a medicament for the treatment of SCD-mediated disease or conditions.
  • compositions or combination as described above for the preparation of a medicament for the treatment of conditions associated with stearoyi-CoA desatruase activity.
  • Suitable protecting groups include hydroxy, amino, mercapto and carboxylic add.
  • Suitable protecting groups for hydroxy include trialkylsih/l or diarylalkylsilyl (e g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethykilyl), tetrahydropyranyl. benzyl, and the like.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, ben ⁇ yloxycarbonyl, and the like.
  • Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aiylalkyl), p-methoxybenzyl, trityl and the like.
  • Suitable protecting groups for ca ⁇ bo ⁇ ylic acid include alkyl, aryl or arylalkyl esters.
  • the protecting group may also be a polymer re&in such as a Wang resin or a 2-chlorotrityl-cliloride resin
  • starting components may be obtained from sources such as Sigma Aldricri, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepered as described in this invention.
  • the compounds of Formula (I) of this invention can be synthesized following the general procedure as described it Reaction Scheme 1 where W is - N(R 5 JC(O)- and p, R 1 , R 2 , R 3 , R 4 , R ! , W , V, X and Y are defined as in the Specification unless specifically defined otherwise.
  • R' is a protecting group.
  • Compound (101) is coupled with compound (102) under metal catalyzed reaction conditions to generate compound (103) which undergoes a standard hydrolysis procedure known to one skilled in the art to generate the carboxylic acid (104). Coupling between compounds (1*4) and (105) under standard amide bond formation conditions known to th ⁇ one skilled in the art affords compounds of Formula (I) of the invention where W is - N(R 5 )C(O)-.
  • the compounds of Formula (I) of this invention can be synthesized following the general procedure as described in Reaction Scheme 2 where W is - N(R 5 JC(O)-, ani p, X, Y, V, R 1 , R 2 , R 3 , R 4 ami R 5 are defined as in the Specification unless specifically defined otherwise.
  • the starting compound (201) undergoes coupling reaction with amine (105) under standard amide bond formation conditions known to one skilled in the art Io afford compound (201).
  • Compound (202) is then coupled with compound (102) under metal catalyzed reaction conditions to generate compounds of Formula (I) where W is - N(R 5 )C(O>.
  • the compounds of Formula (I) of this invention can be synthesized following the general procedure as described in Reaction Scheme 3 where W is - N(R 5 )C(O>, V is -O- or direct bond and p, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 are defined as in the Specification unless specifically defined otherwise. R' and R" are protecting groups.
  • the compounds of Foiniula (I) of this invention can be synthesized following the general procedure as described in Reaction Scheme 4 where W is - N(R 5 )C(O)-, V is -N(H)C(O)- and p, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 are defined as in the Specification unless specifically defined otherwise.
  • R" is a protecting group.
  • Compound (301) is coupled with compound (401) under metal catalyzed reaction conditions to generate compound (402) which undergoes a standard hydrolysis procedure known to one skilled in the art to generate the carboxylic acid (403). Coupling between compound (403) and amine (105) under standard amide bond formation conditions known to one skilled in the art affords the compound (404).
  • Compound (404) is used as a key intermediate to generate compounds of Fo ⁇ nula (1) under the conditions of (a) reductive aminition or (b) amide bond formation.
  • reaction mixture was stirred at ambient temperature for 1 hour, then diluted with chloroform (100 mL) and filtered through Celite. The filtrate was concentrated in vacuo. The residue was dissolved in a mixture of methanol/chloroform 1/10 (30 mL).
  • TTie reaction mixture was stirred at ambient temperature for 5 hours and N,N-dimethylformarnide was removed in vacuo. The residue was dissolved in ethyl acetate (15 mL) and urashed with saturated aqueous sodium bicarbonate (2 x 5 mL) and brine (5 mL). The organic layer was dried over anhydrous
  • the reaction mixture was kept stirring for 2 hours it ambient temperature, then another portion of benzaldehyde (0.10 mL, 0.98 mmol) and tricthylsilanc (0, 15 mL, 1.00 mmol) was added.
  • the reaction mixture was ic «pt stirring for another 2 houis at ambient temperature.
  • DMSO-A 8 167.9. 162.0. 151.6, 154.1, 150.2, 139.9, 132. «, 128.7, 127.7, 127.2, 123.6, 104.4, 98.0, 43.1, 17.5, MS (ES+) m/z 342.2 (M + 1).
  • reaction mixture was heated at 100 0 C for 6 hours and then diluted with ethyl acetate (25 inL), washed with 14% aqueous ammonium hydroxide (2 x 7 mL) and brine (7 mL).
  • ethyl acetate 25 inL
  • 14% aqueous ammonium hydroxide 2 x 7 mL
  • brine 7 mL
  • the or ⁇ nic layer was dried over anhydrous sodium sulfate, filtered concentrated in vacuo to afford as a yellowish solid (0.45 g, 66%)- 'H NMROOO MHz.
  • the reaction mixture was heated at reflux for 1 S hours, cooled to ambient temperature and ethyl acetate (30 mL) was added. The mixture was washed with saturated ammonium chloride (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated m vacuo.
  • dimethylfo ⁇ namide (8 mL) was added cesium carbonate (0.32 g, 0.99 mmol) and catalytic amount of w-tetrabutylammon jura iodide, followed by the addition of 2- (chloromethyl)-5-phenyl-l ,3,4-oxadiazole (0.15 g, 0.76 mmol).
  • the reaction mixture was heated at 80 0 C for 20 hours and concentrated in vacuo, followed by the addition of dichloromethane (100 mL). The mixture was washed with water (70 mL). The organic layer was dried over anhydrous sodium sulfite and filtered. The solvent was concentrated in vacuo.

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Abstract

The present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed.

Description

ORGANIC COMPOUNDS
FIELD OF THE INVENTION
The present invention relates generally to the field of inhibitors of stearoyl-CoA desaturase, such as heterocyclic derivatives, and uses for such compounds m treating and/or preventing various human diseases, including those mediated by stearoyl-CoA desaturase (SCD) enzymes, preferably SCDl, especially diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome, døπratological disorders and the like.
BACKGROUND OF THE INVENTION
Acyl desaturase enzymes catalyze the formation of a double bond in fatty acids derived from either dietary sources or de HOVD synthesis in the liver. In mammals, at least three fatty acid desaturases exists, each with differing specificity: delta-9, delta-6, and delιa-3, which Introduce a double bond at the 9-10, 6-7, and 5-6 positions respectively.
Stearoyl-CoA desaturases (SCDs) act with cofactors (other agents) such as NADPH, cytochrome b5, cytochrome b5 reductase, Fe, and molecular O2 to introduce a double bond into the C9-C10 position (delta 9) of saturated fatty acids, when conjugated to Coenzyme A (CoA). The preferred substrates are palmitoyl-CoA (16:0) and stearoyl- CoA (18:0), which are converted to palmitoleoyl-CoA (16:1) and oleyl-CoA(18:l), respectively The resulting mono-unsaturated fatty acids are substrates foi further metabolism by fittty acid elongases or incorporation into phospholipids, triglycerides, and cholesterol esters. A number of mammalian SCD genes have been cloned For example, two genes have been identified in humans (h SCDl and hSCD5) and four SCD genes have been isolated from mouse (SCDl, SCD2, SCD3, and SCD4). While the basic biochemical role of SCD has been known in rats and mice since the 1970's (Jeffcoat, R. el al., Eur J. hiaehem (1979), Vol. 101, No. 2, pp. 439-445; de Antueno, R. etal., Lipids (1993), VoI 28, No. 4, pp. 285-290), it has only recently been directly implicated in human disease processes.
The two human SCD genes have been previously described: hSCD 1 by Brownlie et al., FCT published patent application, WO 01/62954, the disclosure of which is hereby incorporated by reference in its entirety and hSCD2, PCT published patent application, WO 02/26944, incorporated herein by reference in its entirety.
To date, the only small-molecule, drug-like compounds known that specifically inhibit or modulate SCD activity are found in the following PCT Published Patent Applications: WO 06/034338, WO 06/034446, WO 06/034441, WO 06/034440, WO 06/034341, WO 96/034315, WO 06/034312, WO 06/034279, WO 06/014158, WO 05/011657, WO 05/011556, WO 05/011655, WO 05/011654 and WO 05/01 1653 SCD inhibitors have also been described in by Zliao el al., Biorganic and Medicinal Chemistry Letters, 2007, and PCT Published Patent Applications WO 06/130986 and WO 07/009236.
Before the discovery of the above compounds, only certain long-chain hydrocarbons, analogs of the substrate stearic acid, had been used to studj SCD activity. Known examples include thia-fatty acids, cyclopropenoid fatty acids, and certain conjugated linαleic acid isomers Specifically, eis-12, trans-] 0 conjugated linoleic acid is believed to inhibit SCD enzyme activity and reduce the abundance of SCD 1 mRNA, while cis-9, trans-11 isomer of conjugated linoleic acid does not have this biological activity. Cyclopropenoid fatty acids, such as those found in stercula and cotton seeds, are also known to inhibit SCD activity. For example, sterculic acid (8-(2 octylcyclopropenyOoctanoic acid) and malvalic acid (7-(2-oclylcyclopropenyl)heptaπoic acid) are CIS and Cl 6 derivatives of sterculoy] and malvaloyl fatty acids, respectively, having cyclopropene rings at their C9-C 10 position These agents must be coupled to CoA to act as inhibitors and are believed to inhibit SCD enzymatic activity by direct interaction with the enzyme complex, thus inhibiting delta-9 desaruration. Other agents that may inhibit SCD activity include thia-fatty acids, such as 9-thiastearic acid (also called 8-nonylthiooctanoic acid) and other fatty acids with a thioestcr moiety
There is a major unmet need for smεll molecule inhibitors of SCD enzyme activity because evidence is now compelling that SCD activity is directly implicated in common human disease processes1 See e g , Attie, A D et al, "Relationship between stearoyl-CoA desaturase activity and plasma iriglycerides in human and mouse
hypertriglyceridemia", J. Lipid Res. (2002), Vol.43, No. 11, pp 1899-907; Cohen, P. et al., "Role for stearoyl-CoA desaturase-1 in leplin mediated weight loss". Science (2002), Vol. 297, No.5579, pp. 240-3, Ntambi, J. M. et al, "Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity", Prcc, Natl. Acad. Sci. U.S.Λ. (2002), Vol.99, No. 7, pp. 1 1482-6, Gutierrez-Juarez, R. et al "Critical role of stearoyl CoA desaturaβe-1 (SCDl) in the onset of diet-induced hepatic insulin resistance", 7. Clin. Invest. (2006), VoI 116, No. S, pp. 1686-95, Dobrzyn A. and Dobrzyn P. "Stearoyl-CoA desaturase - a new player in skeletal muscle metabolism regulation", J. Physiol Pharmacol (2006), VoI 57 Suppl 10, pp.31-42, Sampath, H. et al, "Stearoyl-CoA Desaturase-1 mediates the pro-lipogenio effects of dietary saturated fat", J. Biol. Chem., (2007), VoI 282, No.4, pp 2483-93, Xu H UaL, "Hepatic knockdown of stearoyl-CoA desaturase 1 via RNA interference in obese mice decreases lipid content and change sfatty acid composition", Front Biosci. (2007), Vol. 12, pp 3781-94.
The present invention solves this problem by presenting new drug-like classes of compounds that are useful in modulating SCD activity and regulating lipid levels, especially plasm, lipid levels, and which arc useful in the treatment of SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, especially diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like.
SUMMARY OF THE INVENTION
The present invention provides heterocyclic derivatives that modulate the activity of εtearoyl-CoA deεaturaεe. Methods of using such derivatives to modulate the activity of Stearoyl-CoA desaturase and pharmaceutics] compositions comprising such derivatives are also encompassed.
Accordingly, in one aspect, the invention provides compounds of Formula (I):
Figure imgf000005_0001
wherein,
V is selected from -N(R5)C(O)-, -C(O)N(R*)-, -OC(O)N(R5)-, -N(R5)C(O)O-,
-N(R5)C(O)N(R5)-, -0-, -N(RS)-, -S-, -S(O),-, -N(R5JS(O)1-, -S(O)JN(R5)-, - OS(O)2-, -OS(O)2N(R5)-, -C(O)-, -OC(O)-, -C(O)O-, -N(R5)C(-N(R5a))NR5-, - N(R!)C[=S)NR'-, -N(R3)((R3a)N=)C^ -C(=N(R:"))N(R;!)-, alkylene, dkenyleπe, alkynylene, aryl, heteroaryl, a cycloilkyl, a heterocyclyl, or a direct bond;
W is selected fiom -N(R5)C(0>, -C(O)N(R5)-, -OC(O)N(R5)-, -N(R5)C(0)0-,
-N(R5JC(O)N(R5)-, -0-, -N(RS>, -S-, -S(O)1-, -N(R5)S(0)r, -S(O)1N(R5)-, - OS(O)2N(R5)-, -C(O)-, -OC(O)-, -C(O)O-, -N(R5)C(-N(R5B))NR5-, - N(Rs)((RSa)N=)C-, -C(=N(R5a))N(R.s)-, aryl, a heteroaryl, heterocyclyl, alkynjlene, alkenyleπe, alkylεπε or a direct bond;
X is selected from C(H) or N;
Y is selected from S, O, N(H) or N(CH)); p is O, 1, 2, or 3; t is 1 or 2;
R' is selected from the group consisting of lydrogen, alkyl, alkenyl, alkynyl,alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralk/L heterocyclyl, heteroeydylalkyl, heteroaryl, and hctcroarylalkyl; or R1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl Mid heteroaryl and where some or all of the rings may be fused to each other; R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydro∑yalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 riugs wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryi and heteroaryl
and where some or all of the rings may be fused to each other; R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, trihaloalkoxyl, cyano and -N(R5)2j R4 is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkylalkyl, aralkyl, halo, haloalkyl, -OCF3, -OC(H)F2, and cyano; or two adjacent R4 groups, together with the carbon atoms to which they are attached, may form a cycloalkyl, heterocyclyl, sryl or heteroaryl and the remaining R4 groups, if present, are as described
Figure imgf000006_0001
R is selected from the group consisting of hydrogen, aryl, alkyl, heteroaryl, heterocyclyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl;
R≤a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
In another aspect, the invention provides methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, wherein the methods comprise administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention as set forth above.
In another aspect, the invention provides compounds or pharmaceutical compositions useful in treating, preventing and/or diagnosing a disease or condition relating to SCD biological activity such as the diseases encompassed by cardiovascular disorders andior metabolic syndrome (including dyslipidemia, insulin resistance and obesity).
In anodier aspect, the invention provides methods of preventing or treating a disease or coπcM on related to elevated lipid levels, such as plasma lipid levels, especially elevated triglyceride or cholesterol levels, in a patient afflicted with such elevated levels, comprising administering to said patient a therapeutically or prophylacticaliy effective amount of a composition as disclosed herein. The present invention also relates to novel compounds having therapeutic ability to reduce lipid levels in an animal, especially triglyceride and cholesterol levels.
In another aspect, the invention provides pharmaceutical compositions comprising
the compounds of the invention as set forth above, and pharmaceutically acceptable excipients. In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the inyeπtion in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level, or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient. In an enrfecdiment of such composition, the patient has an elevated lipid level, such as elevated plasma triglycerides or cholesterol, before administration of said compound and said compound is present in an amount effective to reduce said lipid level,
In another aspect, the invention proridcs methods for treating a patient for, or protecting a patient from developing, a disease or condition mediated by stearoyl-CoA desaturase (SCD), which methods comprise administering to a patient afflicted with such disease or condition, or at risk of developing such disease or condition, a therapeutically effective amount of a compound that inhibits activity of SCD in a patient when administered [hereto.
In another aspect, the invention provides methods for treating a range of diseases involving lipid metabolism and/or lipid homeostasis utilizing compounds identified by the methods disclosed herein. In accordance therewith, there is disclosed herein a range of compounds having said activity, based on a screening assay for identifying, from a library of test compounds, a therapeutic agent which modulates the biological activity of said SCD and is useful in treating a human disorder or condition relating to serum levels of lipids, such as triglycerides, VLDL, HDL, LDL, and/or total cholesterol. In another aspect, the invention provides the use of the compounds of the invention, as set forth above, in the preparation of a medicament for the treatment of SCD-mediated disease or condition in a mammal, preferably a human.
It is understood that the scope of the invention as it relates to compounds of Formula (I) is rot intended to encompass compounds which are known, including, but not limited to, any specific compounds which are disclosed and/or claimed in tie following publications:
PCT Published Patent Application, WO 00/25768;
PCT Published Patent Application, WO 99/47507;
PCTFublished Patent Application, WO 01/6045S; PCTFublished Patent Application, WO 01/60369; PCTFublished Patent Application, WO 94/26720; European Published Patent Application, 0438 230; European Published Patent Application, 1 184 442; CA 2,1 14,178; and US Patent No.5,334,328; US Patent No.5,310,499; and US Published Patent Application, 2003/0127627.
DETAILED DESCRIPTION QF THE INVENTION DEFINITIONS
Certain chemical groups named herein are preceded by a shorthand notation indicating the total number of carbon atoms that are to be found in the indicated chemical group. For example, C7-Ci2alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms, and C4-Ci2Cyclodkγla]kyl describes a cyclcalkylalkyl group, as defined below, having a total of X to 12 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.
Accordingly, as used in the specification and appended claims, unless specified to the contrary, 1hθ following terms have the meaning indicated:
"Cyaro" refers to the -CN radical;
"Hydroxy" refers to the -OH radical;
"Nitro" refers to the -NO2 radical;
"Amino" refers to the -NR14 or NR13 radical;
"Mercapto" refers to the -SR radical;
"Add™ refers to the -COOH radical;
"Trifluoromethyl" refers to the — CFj radical;
"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms or one to six caibon atoms,
and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n- propyl. 1-mettiylethyl (jso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (/-butyl), and the like. Unless slated otherwise specifically in the specification, an alkyl group may be optionally substituted by one or more of the following groups: alkyl, alkenyl, halo, cyano, aryl, cycloalkyl, heterocyclyl, heteroaryl, -Si(CH3J2C(CHj)3, -OR14, -OC(O)-R14, - N(R14)2, -C(O)R14, -C(O)OR", -C(O)N(R14J2, -N(R14)C(O)0R16, -N(R14)C(O)R16, - N(R14JS(O)1R1', -S-, -S(O)1OR16, -S(O)1R16, and -S(OXN(R14J2 and each R" is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heteroeyclylalkyl, heteroaryl orheteroarylalkyl; and each R.16 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteraaryl or heteroarylallcyl
"Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atmns, containing at least one double bond, having from two to twelve carbon atoms, preferably two to eight carbon atoms or two to six carbon atoms and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop.l.eπyl, but-1-enyl, pent-1-enyl, penta-l,4-dienyl, and the like. Unless Etatβd otherwise specifically in the specification, an alkenyl group may be optionally substituted by one or more of the following groups: alkyl, alkenyl, halo, haloalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, - OR14, -OC(O)-K14 -N(R14J2, -C(O)R14, -C(O)OR14, -C(O)N(R14J2, -N(R14JC(O)OR16, - N(R14JC(O)R16, -N(R14)S(0),Rlδ, -S-, -S(O]1OR16, -S(O)1R16, and -S(O)1N(R14J2 and each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, lieterocyclylalkyl, heteroaryl cr heteroarylalkyl; and each RB is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, liaerocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl
"Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to twelve carbon atoms, preferably two to eight carbon atoms or two to six carbon atoms and which is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted by one or more of the following groups: alkyl, alkenyl, halo.
haloalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl. heteroarylalkyl, -ORU, -OC(O)-R."1 -N(R1V -C(O)R1", -C(O)OR1', - C(O)N(R1V -N(R14)C(O)OR15, -N(RI4)C(O)R16, -N(RI4)S(O),R16, -S-, -S(O),OR16, - S(O)1R16, and -S(O),N(R14)2 and each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl aralkyl, heierocyclyl, hetcrocyclylalkyl, heteroaryl or heteroarylalkyl, and each R16 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
"Alkylene" and "alkylene chain" refer to a straight or branched divalent hydrocarbon chain, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons or one to six carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, end the like. The alkylene chain may be attached to the rest of the molecule and to the radical group through one caibon within the chain or through any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain may be optionally substituted by one or more of the following groups: alkyl. alkenyl. halo, cyaπo. aryl. cycloalkyl. heterocyclyl, heteroaryl, -OR14, -OC(O)-R14, -N(R14J2, -C(O)R14, -C(O)OR14, ■ C(O)N(R14)2, -N(R14)C(O)OR16, -N(R14)C(O)R16, -N(R14)S(O),Rle,-S-, -S(O)1OR16, - S(O)1R16, and -S(O),N(R14)2 and each R14 is independently hydrogen, alkyl, haloalkyl, cycloalky], cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R16 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl
"Alkenylene" and "alkenylene chain" refer to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms or two to six carbon atoms, e.g. ethenylene, propenylene, n-butenylene, and the like. Unless stated otherwise specifically in the specification, an alkenylene chain may be optionally substituted by one or more of the following groups: alkyl, alkenyl, halo, cyano, aryl, cycloalkyl, heterocyclyl, heteroaryl, -OR14, -0C<0)-R14, -T)(R1V - C(O)R14, -C(O)OR14, -C(O)N(R14),, -N(R14)C(O)OR"\ -N0ll4)C(0)Rle. - N(R14)S(O),R1(i, -S-, -S(O)1OR16, -S(O)1R ls, and -S(O)1N(R1V and each RM is
independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, hεterocyclyl, tirterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R16 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, hctcrσcyclyl, hctcrocyclylalkyl, hsteroaryl or heteroarylalkyl "Alkynylene" and "Alkynylene chain" refer to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one triple bond and having from two to twelve carbon atoms or two to six carbon atoms, e.g. propynylene, n butynylene, and the like. Unless stated otherwise specifically in the specification, an alkynylene chain may be optionally substituted by one or more of the following groups: alkyl, alk;n> I, halo, cyano, aryl, cycloalkyl, lictcrocyclyl, heteroaryl, -OR14, -OC(O)-R1', -N(RI4)2, -C(O)R14, - C(O)OR14, -C(O)N(R14)2> -N(Rl4)C(0)0R", -N(R14JC(O)R16, -N(R14)S(O)iR16, -S-, - S(O)1OR16, -S(O)1R16, and -S(O),N(R14)2, arid each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocydylalkyl, heteroaryl or heteroarylalkyl; and each R" is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
"AIkOKy" refers to a radical of the formula -OR, where R. is an alkyl radical as generally defined above. The alkyl part of the alkoxy radical may be optionally substituted as defined above for an alkyl radical.
"Alkoityalkyl" refers to a radical of ihe formula -Rb-O-R3 where Rj, is an alkylene chain as defined above and R, is an alkyl radical as defined above. The oxygen atom may be bonded to any carbon in the alkylene chair and in the alkyl radical. The allcyl part of the alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group. The alkylene chain part of the alkoxyalkyl radical may be optionally substituted as defined above for an alkylene chain.
"Aryl" refers to aromatic monocyclic OΪ multicyclic hydrocarbon ring system consisting only of hydrogen and carbon and containing from 6 to 19 carbon atoms, preferably 6 to 10 carbon atoms, where the ling system may be partially saturated. Aryl groups include, but are not limited to groups such as fluorenyl, phenyl, indenyl and naphthyl. Unless stated otherwise specifically in the specification, the terra "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substitucnts selected from the group consisting of alkyl, aUcenyl, alkynyl,
halo, haloalkyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalky], heierocyclyl, heterocyclylaBcyl, heteroaryl, heteroarylalkjl, -R15-OR14, -R1S.OC(O)-R14, .R"-N(R14)2j - R15-C(O)R14, -R1^CCO)OR1", -RIS-C(O)N(R14)2, -R15-N(Ru)C(0)0R", -R15- N(R14)C(O)RI6 ( -R1S-N(R14)S(O),R16, -S-, -R15-S(O)OR16, -R15-S(O)tR16, and -R15- S(O)tN(R14); ind each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylslkyl each R15 is independently a direct bond or a straight or branched alkylene or alkenylene chain, and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
"Aralkyl" refers to a radical of the formula -R1Rb where R, is an allcylene chain as defined above and Rb is one or more aryl radicals as defined above, e.g., benzyl, diphenylmeihyl and the like. The aryl part of the aralkyl radical may be optionally substituted as described above For an aryl group. The alkylene chain part of the aralkyl radical may be optionally substituted as defined above for an alkyl group.
"Aralkenyl" refers to a radical of the formula -RaRb where R2 is an alkenylene chain as defined above and Rb iε one or more aryl radicals aε defined above, which may be optionally substituted as described above. The aryl part of the aralkenyl radical may be optionally substituted as described above for an aryl group. The alkenylene chain of the aralkenyl radical may be optionally substituted as defined above for an alkenyl group.
"Aryloxy" refers to a radical of the formula -ORb where Rb is an aryl group as defined above. The aryl part of the aryloxy radical may be optionally substituted as defined above.
"Cyclόalkyl" refers to a stable non-arcmatic monocyclic or polyeyeHc hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, preferably having from three to twelve carbon atoms or from three to six atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl and the like. Unless otherwise stated specifically in the specification, the term "eycloalkyl" is meant to include cycloalkyl radicals which are optionally substituted by one or more εubstituentε selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, cyano, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocydylalkyl. heterαaryl, heteroarylalkyl, -Rls-0R14, -R1^OC(O)-R1", -R15-N(R14)2, - R^-C(O)R1', -RIS-C(O)OR", -R1S-C(0)N(R%, -R15-N(R14)C(O)OR16, -R15- N(Ru)C(0)R16, -RIS-N(RU)S(O),R16, -S-, -Rls-S(O)OR1δ, -R1S-S(O),R16, and -R]i- S(O),N(R14)2 and each R14 is independently hydrogen, alky], haloalkyl, cycloalkyl, cyclσalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaryhlkyl; each Rl ! is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R1' is alkyl, tialoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
"Cycloalkylalkyl" refers to a radical of the formula -R,Rj where Rn is an alkylene chain as defined above and Rj is a cycloalkyl radical as defined above. The alkylene chain and the cycloalkyl radical may be optionally substituted as defined above.
"Fused" refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention When the fused ring is a heterocyclyl ring or a heteioaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom
"Halo" refers to bromo, chloro, fluoro or iodo.
"Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluororaethyl, trichloromethyl, 2,2,2-trifluoroethyl, l-fluoioinethyl-2-fluoroethyl, 3-bromo-2- fluoropropyl, 1 -bromomethyl-2-bromoethyl, and the like. The alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group.
"Heteiocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical which consists of carbon atoms and from ore to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heterocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the hetεrocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally alkylated/substituted; and the heterocyclyl radical may be partially or fully saturated. Examples of aieh heterocyclyl radicals include, but are not limited to, dioxolanyl, decahydroisoquiriolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, lsomolidinyl,
morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidirryl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidiπyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, l-oxo-thiomorpholinyl, and 1,1-dioxc- thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents selected from the groupconsisting of alkyl, alkenyl, halo, haloalkyl, cyano, oxo, thioxo, aryl, aralkyl, cycloalkyl, cycloalkylallcyl, heterocyclyl. lieterocyclylalkyl. heteroaryl, heteroarylalkyl -RIS-OR14, -RI S-0C(0)-R", -R15-N(R14)2, -RI5-C(O)RU, -R.I5-C(O)ORU, -R15-C(O)N<KI4)2, -R15-
Figure imgf000014_0001
-R15- S(O)1R-16, and -R15-S(O),N(R14)2 and each R14 is independently hydrogen, alkyl, haloalkyl, cyclcalkyl, cycloalkylalkyl, aryl, aialkyl, heterocycly], heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R16 is alkyl, haloalkyl, cyclcalkyl, cycloalkylallcyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
"Heterocyclylalkyl" refers to a radical of the formula -RaRc where R3 is an alkylene chain as defined above and R* is a heterocyclyl radical as defined above, and if the heterocycly! is a nitrogen-containing heteiocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. The alkyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for an alkyl group. The heterocyclyl part of the heierocyclylalkyl radical may be optionally substituted as defined above for a heterocyclyl group.
"Heteroaryl" refers to a 5- to 18-membered aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused cr bridged ring systems; and the nitrogen, carbon or sulfur stems in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally alkylated/substituted Examples include, but are rot limited to, azεpiπyl, acridiriyl, benzimidazolyl, benzthiazolyl,
benzindolyl, benzothiadiazolyl, beπzonaphttiofiiranyl, beπzoxazolyl, beii2Ddioxolyl, benzodioxinyl, benzopyranyl, benzopyranoiijil, benzofuranyl, benzofiiranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, beπzo[+,<5]imidazo[l,2--]pyridiπyl, carbazolyl, cinrolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triizolyl, tetrazolyl, triazinyl, and thiophenyl Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include tieteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyciyl, heterocyclyklkyl, heteroaryl, heteroarylalkyl, -RI S-OR14, -R15-OC(O)-R14, -R15-N(R14)2, -R^-C(O)R14, - R'5-C(O)ORU, -RI5-C(O)N(R14)2, -R15-N(R14)C(O)OR16, -R15-N(R14)C(O)R16, -R15- N(R1+)S(O)1R16, .S-, -R15-S(O)OR16, -R1S-S(O),R", and -R13.S(O)tN(R")2 and each R14 is mdependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyciyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R15 is independently a direct bond or a straight or branched alkylere or alkenylene chain; and each Rls is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aialkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
"Heteroarylalkyl" refers to a radical of the formula -R11Rf where Ra is an alkylene chain as defined above and Rf is a heteroaryl radical as defined above TTie heteroaryl part of the hetercarylallcyl radical may be optionally substituted as defined alove for a heteroaryl group. The alkyl part of the heterD-rylalkyl radical may be optionally substituted as defined above for an alkyl group
"Hydroxyalkyl" refers to a radical of the formula -R8-OH where R1 is an alkylene chain as defined above The hydroxy group may be attached to the alkyl radical on any carbon within the alkyl radical. The alkyl part of the hydroxyalkyl group may be optionally substituted as defined above for an alkyl group. "Trihaloalkoxy" refers to a radical of ttie formula -0Re where R8 is a hsloalkyl group as defined above where three
halo are substituted on an alky 1. The trihaloalkyl part of the trihaloalkoxy group may be optionally substituted as defined above for a tialoalkyl group.
"A multi-ring structure" refers to a multicyclic ring system comprised of two to four rings wheiein the rings are independently selected from cycloalkyl, aryl, heterocyclyl or rieteroaryl as defined above Each cycloalkyl may be optionally substituted as defined above for a cycloalkyl group. Each aryl may be optionally substituted as defined above for an aryl group. Each heterocyclyl may be optionally substituted as defined above for a heterocyclyl group. Each heteroaryl may be optionally substituted as defined above for a heteroaryl sroup. The rings may be attached to each other through direct bonds or some or all of the rings may be fused to each other.
A "prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly transformed m vivo to yield the parent compound of the invention, for example, by hydrolysis in blood or conversion in the gut or liver. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et of., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, Anglican Pharmaceutical Association arid Pergamon Press, 1987, both of which are incorporated in full by reference herein.
The term "prodrug" is also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention wherein a hydroxy, amino or mcrcapto or acid group is bonded to any group that, when the prodrug
of the compound of the invention is administered to a mammalian subject, cleaves to form a fixe hydroxy, free amino or free mercapto or acid group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amides of amine functional groups in the compounds of the invention and the like.
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from areaction mixture, and formulation into an efficacious therapeutic agent.
"Mammal" includes humans and domestic animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like.
"Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and tliat the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution
"Pharmaceutically acceptable carrier, diluent or excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
"Pharmaceutically acceptable salt" includes both acid and base addition salts
"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties cf the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidcbenzoic acid, camphoric acid, camphor-10-sulfonic acid, capik acid, caproic acid, caprylic acid, carbonic acid, cinπamic acid, citric acid, cyclamic acid,
dodecylsulfiiric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2- hydroxyeihanesulfonlc acid, formic acid, njmarfc acid, galactaric acid, gentϊsic acid, glu∞hcptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutatic acid, 2-oxo- glutaric acid, glycerophosphorirc acid, glycolic acid, hippuiic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-], 5-disulfonic acid, naphthalene-2- sulfonic acid, l-hjdroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyrogliitamic acid, pyruvic acid, salicylic acid.4-aminosalιcylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyaπic acid, ^-toluenesulfonic acid, tritluoroacetic acid, undecylenic acid, and the like.
"Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties cf the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamirie, diethanolamine, ethanolamine, deanol, 2- dimethylaininoethanol, 2-diethylaminoethaitαl, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamiπe, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, JV-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diettaylainine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
Often crystallizations produce a solvate of the compound of the invention. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent. The
solvent may be water, in which case the solvεte may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or he a mixture of water plus some adventitious solvent.
A "pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., hutnatis. Such a medium includes all pharmaceutically acceptable carriers, diluents orexcipients thereof.
"Therapeutically effective amount" refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of an SCO-mediated disease or condition in the mammal, preferably a human. The amount of a compound of the invention which constitutes s. "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age and body weight of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
"Treating" or "treatment" as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or disorder of interest, and includes: (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it; (H) inhibiting the disease or condition, i.e., airesting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving the symptoms resulting from the disease or condition, i.e., relieving the symptoms without addressing the underlying disease or condition.
As used herein, the terms "disease" and "condition" may be used interchangeably or may be different in that the particular malady or condition may not have aUnown causative agent (so that etiology has not yet been worked out) and it is therefore not yet
recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
The compounds of the invention, or their pharmaceutically acceptable salts may contain one 01 more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereo isomeric forms that may be defined, in terms of absolute stereochemistry, as [R)- or [S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and {S}-, or (D)- and (L)- isomers may be prepared using chiral synthonε or chϊral reagents, or resolved using conventional techniques, such as HPLC using a chiral column When the compounds described herein contain olefϊnic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric Forms are also intended to be included
A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
A ' tautorner" refers to a proton shift from one atom αf a molecule tc another atom of the same molecule. The present invention includes tautomers of any said compounds.
Also within the scope of the invention are intermediate compounds of Formula (I) and all polymorphs of the aforementioned species and crystal habits thereof.
The chemical naming protocol and structure diagrams used herein employ and rely on the chemical naming features as utilized by ChemDraw Version 10.0 software program (available from Cambridgesoft® Corp., Cambridge, MA),
EMBODIMENTS OF THE INVENTION
One embodiment of the invention is the compounds of Formula -(I):
Figure imgf000021_0001
wherein,
V is selected from -N(R5)C(O)-, -C(O)N(R3)-, -OC(O)N(R5)-, -N(R5)C(O)O-,
-N(R5)C(O)N(R5)-, -0-, -N(R5)-, -S-, -S(O)1-, -N(R3)S(O)r, -S(O)1N(R')-, - OS(O)2N(R5)-, -C(O)-, -OC(O)-, -C(O)O-, -N(R5)C(=N(RS'))NRS-, - N(RJ)C(=S)NR3-, -N(R3)((R3a)N=)C- -C(-N(R5l))N(R5)-, alkylcne, dkcnylcnc, alkynylene, aryl, heteroaryl, cycloalkyi, heterocyclyl or a direct bend;
W is selected from -N(R5)C(0)-, -C(O)N(R5)-, -OC(O)N(R5)-, -N(R5JC(O)O-,
-N(R5)C(O)N(R5)-, -0-, -N(R5)-, -S-, -S(O)1-, -N(R5)S(0),-, -S(O)1N(R5)-, - OS(O)2N(R5)-, -C(O)-, -OC(O)-, -C(O)O-, -N(R5)C(=N(R5a))NR5-, - N(RS)((R5")N=)C-, -C(=N(R5a))N(Rs)-, aryl, heteroaryl, heterocyclyl, alkynylene, alkcnylerie, alkylene or a direct bond;
X is selected from C(H) or N;
Y is selected from S, O, N(H) or N(CHj); p is O, 1, 2, or 3; t is 1 or 2;
R1 is selected from the group consisting of hydrogen, alkyl, alkeπyl, alkyryl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyi, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, hctcrocyclylalkyl, heteroaryl, and heteroarylalkyl, or R1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyi, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydro∑yalkyl, alkoxyalkyl, cycloalkiyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, hetercaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyi, heterocyclyl, aryl and heteroaryl
and where some or all of the rings may be fused to«ach other; K3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, haloalkoiyl, cyano and -N(R5>2; R4 is selected fiotn the group consisting of alkyl, hydroxyalkyl, cycloalkylalkyl, aralkyl, halo, haloalkyl, -OCF3, , -OC(H)F3, and cyano; or two adjacent R4 groups, together with the carbon atoms to which they attached, may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R4 groups, if present, are as described above; R5 is selected from the group consisting of hydrogen, aryl, alkyl, heteroaryl, heterocyclyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl;
R5a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
Another emhediment is represented by Formula (I), wherein X is C(H) and Y is S;
V is selected from -O- or a direct bond;
W is selected from -N(R5)C(0)-, -C(O)N(R5)-, -C(O)O- or a direct bond; p is 0, 1, 2, or 3;
R1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heterocyclyl, neterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkj/lalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alky];
R4 is alkyl or haloalkyl; and
Rs is selacted from the group consisting of hydrogen or alkyl,
Another embodiment is represented by Formula (I), wherein X is N and Y is S;
V is selected from -O- or a direct hold;
W is selected from -N(R5JC(O)-, -C(C)N(RS)-, -C(O)O- or a direct bond; p is O, I1 2, or 3;
R1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heterocycl yl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylaflcyl, heteroaryl and heteroarylaHcyl; or R3 is a multi-ring structure havlti£ 2 to 3 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocydyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl;
R4 is alkyl or CF3; and
R5 is selected from the group consisting of hydrogen or alkyl.
Another embodiment is a compound of Formula (I), wherein X is N and Y is N-CH3 or NH;
V is selected from -O- or a direct bond;
W is selected from -N(Rs)C(0)-, -C(CI)N(R5)-, -OC(O)-, -C(O)O- oi a direct bond; p is O, 1, 2, or 3;
R' isselected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heterocycly], heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R is selected from the group consisting of hydrogen, alkyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cygloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R! Is selected from the group consisting of hydrogen and alkyl;
R' IS alkyl, halo and haloalkyl; or two adjacent R4 groups, together with the carbon atoms to which they attached, may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R4 groups, if present, are as described above; and
R5 is selected from the group consisting of hydrogen or alkyl.
Another embodiment is represented by Formula (I), wherein X is selected from CH or N;
Y is selected from S. O, N(H) or N(CHj):
V is selected from -O- or a direct bond;
W is selected from -N(R5)C(0)-, -C(O)N(R5)-, -C(O)O- or a direct bond; p is 0, 1, 2, or 3;
R1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkoxy, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloallcyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or Rz is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl;
R4 is εlkyl or haloalkyl; and
Rs is selected from the group consisting of hydrogen or alkyl
Another embodiment is a compound of Formula (1), wherein X is selected from CH or N;
Y is selected from S, O, N(H) or N(CHj);
V is selected from -O- or a direct bond;
W is selected from -N(RS)C(O)-, or -C(O)O-; p is 9, 1, 2, or 3;
R1 is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R1 is a multi-ring structure having 2 to 3 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other,
R3 is selected from the group consisting of hydrogen and alkyl;
R1 is rialcalkl, or alkyl; and
R5 is selected from the group consisting of hydrogen or alkyl.
Another embodiment is a compound of Formula (I), wherein X is selected from CH or N;
Y is selected from S, O, N(H) or N(CHj);
V is selected from -O- or a direct bond;
W is selected from -N(RS)C(O)-, or -C(O)O-; p is C, 1, 2, or 3;
R' is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, hydroiyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or RJ is a multi-ring structure having 2 to 3 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl;
R4 ishalαalkyl, or alkyl; and
R5 is selected from the group consisting of hydrogen or alkyl.
Another embodiment is a compound of Formula CI), wherein
X is selected from CH or N;
V is selected from S, O, NH or N-CH3;
V is selected from -O- or a direct bond;
W is selected from -N(R5)C(0)-, or -C(O)O-; p is 0, 1, 2, or 3;
R' is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cyclDalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 3 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other,
R3 is selected from the group consisting of hydrogen and alkyl;
R4 is alkyl or haloalkyl; and
R5 is selected from the group consisting of hydrogen or alkyl
Another embodiment is a compound of Formula (1), wherein
V is selected from -O- or a direct bond;
W is selected from -N(RS)C(O)-, or -C(O)O-; p is O, I1 2, or 3;
R1 is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
RJ is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R: is a multi-ring structure having 2 to 3 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and hεteroaryl and where some or all of the rings may be ftised to each other;
RJ is selected from the group consisting of hydrogen and alkyl;
R4 is halcalkyl or alkyl; and
R5 is selected from the group consisting of hydrogen or alkyl.
In ore embodiment, the methods of 1he invention are directed towards the treatment and/or prevention of diseases mediated by stearoyl-CoA desatiuase (SCD), especially human SCD (hSCD), preferably diseases related to dyslipidemiaand disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome, dermatologϊcal disorders and the like by administering an effective amount of a compound of the invention.
The present invention also relates to pharmaceutical composition containing the compounds of tie Invention. In one embodiment, the invention relates to 2 composition comprising compounds of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient. In an embodiment of such composition, the patient has an elevated lipid level, such as elevated triglycerides or cholesterol, before administration of said compound of the invention and the compound of the invention is present in an amount effective to reduce said lipid leveL
UTILITY AND TESTING OF THE COMPOUNDS OF THE INVENTION
The present invention relates to compounds, pharmaceutical compositions and methods of using the compounds and pharmaceutical compositions for the treatment and/or prevention of diseases mediated by stearoyl-CoA desaturase (SCD), especially human SCD (liSCD), preferably diseases related to dyslipidemia and disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, especially cardiovascular disease, diabetes, obesity, metabolic syndrome, dermatologieal disorders and the like, by administering to a patient in need of such treatment an effective amount of an SCD modulating, especially inhibiting agent.
In general, the present invention provides a method for treating a patient for, or protecting a patient from developing, a disease related to dyslipidemia and/or a disorder oflipid metabolism, wherein lipid levels in an animal, especially a human being, are outside the normal range (i.e., abnormal lipid level, such as elevated plasma lipid levels),
especially levels higher than normal, preferably where said lipid is a fatty acid, such as a free or complexed fatty acid, triglycerides, phospholipids, or cholesterol, such as where LDL-cholesterol levels are elevated or HDL-ctiolesterol levels are reduced, or any combination of these, where said lipid-relaterj condition or disease is an SCD-mediated disease or condition, comprising administering to an animal, such as a mammal, especially a human patient, a therapeutically effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention wherein the compound modulates the activity of SCD, preferably human SCDl .
The compounds of the invention modulate, preferably inhibit, the activity of human SCD enzymes, especially human SCDl.
The general value of the compounds of the invention in modulating, especially inhibiting, the activity of SCD can be determined using the assay described below in Example 28.
Alternatively, the general value of the compounds in treating disorders and diseases may be established in industry standard animal models for demonstrating the efficacy of compounds in treating obesity, diabetes or elevated triglyceride or cholesterol levels or for improving glucose tolerance. Such models include Zucker obese /a/fa rats (available from Harlan Sprague Dawley, Inc. (Indianapolis, Indiana)), or the Zucker diabetic fatty rat (ZDF/GmiCrl-^fe) (available from Charles River Laboratories (Montreal, Quebec)), and Sprague Dawley rate (Charles Rivers), as used in models for diet-induced obesity (Ohibaudi, L. etal., (2»C2), Obns. Res. Vol. 10, pp.956-963). Similar models have also been developed for mice.
The compounds of the instant invention are inhibitors of delta-0 deεaturaees and are useful for treating diseases and disorders in humans and other organisms, including all those human diseases and disorders which are the result of aberrant delta-9 desaturase biological activity or which may be amelicr-ted by modulation of delta-9 desaturase biological activity.
As defined herein, an SCD-mediated disease or condition is defined as any disease or condition in which the activity of SCD is elevated and/or where inhibition of SCD activity can be demonstrated to bring about symptomatic improvements for the individual so treated. As defined herein, an SCD-mediated disease or condition includes
but is not limited to a disease or condition which is, or is related to} cardiovascular disease, dyslϊpidemias (including but not limited to disorders of serum levels of triglycerides, hypertriglyceridemia, VLDL, HDL, LDL, fatty acid Desaturation Index (e.g. the ratio of 18:1/18:0 fatty acids, or other fatty acids, as defined elsewhere herein), cholesterol, and total cholesterol, hypercholesterolemia, as well as cholesterol disorders (including disorders characterized by defective reverse cholesterol transport), familial combined hyperlipidemia, coronary artery disease, atherosclerosis, heart disease, cerebrovascular disease (including but not limited to stroke, ischemic stroke and transient ischemic attack (TIA)), peripheral vascular disease, and ischemic retinopathy.
An SCD-mediated disease or condition also includes metabolic syndrome (including bul not limited to dyslipidemϊa, obesity and insulin resistance, hypertension, microalbuminemϊa, hyperuricemia, and hypercoagulability), Syndrome Xs diabetes, insulin resistance, decreased glucose tolerance, non -insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, body weight disorders (including bul not limited to obesity, overweight, cachexia and anorexia), weight loss, body mass index and leptin related diseases In a preferred embodiment, compounds of the invention will be used to treat diabetes mellitus and/or obesity.
As used herein, the term "metabolic syndrome" is a recognized clinical term used to describe a condition comprising combinations of Type Il diabetes, impaired glucose tolerance, insulin resistance, hypertension, obesity, increased abdominal girth, hypertriglyceridemia, low HDL, hyperuricemia, hypercoagulability and/or micro album ineinia. The American Heart Association has published guidelines for the diagnosis of metabolic syndrome, Grundy, S., et. aJ.f (3006) Cardiol. Rev. Vol. 13, No.6, pp. 322-327.
An SCD-mediated disease or condition also includes fatty liver, hepatic steatosis, hepatitis, non-alcoholic hepatitis, non-alcoholic steatohepatitis (NASH)5 alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, erythrohepaiic protoporphyria, iron overload disorders, hereditary hemochromatosis, hepatic fibrosis, hepatic cirrhosis, hepatoma and conditions related thereto.
An SCD-mediated disease or condition also includes but is not limited to a disease or condition which is, or is related to primary hypertriglyceridemia, or
hypertriglyceridemia secondary to another disorder or disease, such as hyperlipoproteinemias, familial histiocytic reticulosis, lipoprotein lipase deficiency, apolipoprotein deficiency (such as ApoCII deficiency or ApoE deficiency), and the like, or hypertriglyceridemia of unknown or unspecified etiology.
An SCD-ttiediated disease or condition also includes a disorder of polyunsaturated fatty acid (PUFA) disorder, αr a dermatoiogical disorder, including but not limited to eczema, acne, psoriasis, keloid scar formation or prevention, diseases related to production or secretions from mucous membranes, such as monounsaturated fasy acids, wax esters, and the like. Preferably, the compounds of the invention inhibition of SCD acitivity can prevent or attenuate keloid scar formation by reduction of excessive sebum production that typically results in their Formation. The investigation of the role of SCD inhibitors in the treatment of acne was advanced by the discovery that rodents lacking a functional SCD 1 gene had changes 10 the condition of their eyes, skin, coat (Zheng Y., et al. "SCDl is expressed in sebaceous glands and is disrupted in the asebia mouse", JVa/. Genet. (1999) 23:268-270. Mjyazaki, M., "Targeted Disruption of Stearoyl-CoA Desaturase 1 Gene in Mice Causes Atrophy of Sebaceous and Meibomian Glands and Depletion of Wax Esters in the Eyelid", J. Nutr. (2001), Vol. 131 , pp 2260- 68., Binczek, E. etal., "Obesity resistance of the Stearoyl-CoA desaturase-defrcient mouse results from disruption of the epidermsl lipid barrier and adaptive thermoregulation", Biol. Chem. (2007) Vol.3SX No.4, pp 405-18).
An SCD-mediated disease or condition also includes inflammatica sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, cystic fibrosis, and premenstrual syndrome.
An SCD-mediated disease or condition also includes but is not limited to a disease or condition which is, or is related to cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the like.
An SCD-mediated disease or condition also includes a condition where increasing lean body mass or lean muscle mass is desired, such as is desirable in enhancing performance through muscle building. Myopathies and lipid myopathies such as carnitine palmitoyltransferase deficiency (CPT I or CPT II) are also included herein Such treatments are useful in humans and in animal husbandry, including for administration to
bovine, porcine or avian domestic animals or any other animal to reduce triglyceride production andJαr provide leaner meat products and/or healthier animals.
An SCD-mediated disease or condition also includes a disease or condition that is, or is related to, neurological diseases, psychiatric disorders, multiple sclerosis, immune disorders and eye diseases, including but not limited to, disorders characterized by excessive or inappropriate lipid production by meiobium glands..
An SCD-mediated disease or condition also includes a disease or condition which is, or is related to, viral diseases or infections including but not limited to all positive strand RNA viiuses, cαronaviruses, SARS virus, SARS-associated coronaυirus, Togavlruses, Picornaviruses, Coxsackievirus, Yellow Fever virus, Flaviviridae, ALPHAVIRUS (TOGAVIRIDAE) including Rubella virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Sindbis virus, Semliki forest virus, Chikungunya viius, O'nyong'nyong virus, Ross river virus, Mayaro virus, Alphaviruses; ASTROVIRIDAE including Astrovirus, Human Astroviruses; CALICIVIRIDAE including Vesicular exanthema of swine virus, Norwalk virus, CaliciviruE, Bovine calicivirus, Pig cakivirus, Hβpatitie E; CORONA VIRIDAE including Coronavirus, SARS virus, Avian infectious bronchitis virus, Bovine coroπavirus, Canine coronavirus, Feline infectious peritonitis virus, Human coronavirus 299E, Human coronavirus OC43, Murine hepalitϊs virus, Porcine epidemic diarrhea virus, Porcine hemagglutinating encephalomyelitis virus, Porcine transmissible gastroenteritis virus, Rat coronavirus, Turkey coronavirus, Rabbit coronavirus, Berne virus, Breda virus; FLAVIVIRIDAE including Hepatitis C virus, West Nile virus, Yellow Fever virus, St. Louis encephalitis virus, Dengue Group, Hepatitis G virug, Japanese B encephalitis virus, Murray Valley encephalitis virus, Central European tick-borne encephalitis virus, Far Eastern tick-borne encephalitis virus, Kyasanur forest virus, Louping ill virus, Powassan virus, Omsk hemorrhagic fever virus, Kumilinge virus, Absetarov anzalovahypr virus, ITheus virus, Rocϊo encephalitis virus, Langal "virus, Pestivirus, Bovine viral diarrhea, Hog cholera virus, Rio Bravo Group, Tyuleniy Group, Ntaya Group, Uganda S Group, Modoc Group; PICORNA VIRIDAE including Coxsackie A virus, Rhino-virus, Hepatitis A virus, EncejΛalomyocarditis virus, Mengovirus, ME virus, Human poliovirus 1, Coxsackie B; POCYVIRIDAE including Potyvirus, Rymovirus, Bymovirus. Additionally
it can be a disease or infection caused by orlinked to Hepatitis viruses, Hepatitis B virus, Hepatitis C virus, human immunodeficiency virus (HIV) and the like. Treatable viral infections include those where the virus employs an RNA intermediate as part of the replicative cycle (hepatitis or HIV); additionally it can be a disease or infection caused by or linked to RNA negative strand viruses such as influenza and parainfluenza viruses.
The compounds identified in the instant specification inhibit the desaturation of various fatty acids (such as the C9-C10 desaturation of stearoyl-CoA), which is accomplished by delta-9 desaturases, such as stearoyl-CoA desaturase I (SCDl). As such these compounds inhibit the formation of vεrious fatty acids and downstream metabolites thereof. This may lead to an accumulation of 5tεaroyl-CoA or palmitoyl-CoA and olher upstream precursors of various fatty acids; which may possibly result in anegative feedback loop causing an overall change in fatty acid metabolism. Any cf these consequences may ultimately be responsible for the overall therapeutic benefit provided by these compounds.
Typically, a successful SCD inhibitory therapeutic agent will meet some or all of the following criteria. Oral availability should be at or above 20% Animal model efficacy is less than about 20 rng/Kg, 2 mg/Kg, 1 mg/Kg, or 0.5 mg/Kg and tile target human dose is between 10 and 250 mg/70 Kg, although doses outside of this range may be acceptable. ("mg/Kg" means milligrams of compound per kilogram of body mass of the subject to whom it is being administered). The required dosage should preferably be no more than about once or twice a day or a! meal times. The therapeutic index (or ratio of toxic dose to therapeutic dose) should be greater than 10. The IC50 ("Inhibitory Concentration - 50%") is a measure of the amount of compound required to achieve 50% inhibition of SCD activity, over a specific time period, in an SCD biological activity assay. Any process for measuring the activity of SCD enzymes, preferably mouse or human SCD enzymes, may be utilized to assay the activity of the compounds useful in the methods of the invention in inhibiting said SCD activity. Compounds of the invention demonstrate an IC50 ("Inhibitoty Concentration of 50%") in a 15 minute microsomal assay of preferably less than 10 μM, less than S μM, less than 2.5 μM, less than 1 μM, less than 750 nM, less than 50D nM, less than 250 nM, less than 100 nM, less than 50 πM, and most preferably less than 20 nM. Compounds of the invention may show
reversible inhibition (i.e., competitive inhibition) and preferably do not inhibit other iron binding proteins
The identification of compounds of the invention as SCD inhibitors was readily accomplished using the SCD enzyme and microsomal assay procedure described in Shanklin J. and Summerville C, Proc. Natl Acad. Sd. USA (1591), Vol. SS, pp.2510- 2514. When tested in this assay, compounds of the invention had less than 50% remaining SCXl activity at 10 μM concentration of the test compound, preferably less than 40% remaining SCD activity at 10 μM concentration of the test compound, more preferably less than 30% remaining SCD activity at 10 μM concentration offlie test compound, and even more preferably less than 20% remaining SCD activity at 10 μM concentration of the test compound, thereby demonstrating that the compounds of the invention are potent inhibitors of SCD activity.
These results provide the basis for analysis of the structure-activity relationship (SAR) between test compounds and SCD. Certain-groups tend to provide more potent inhibitory compounds. SAR analysis is one of the tools those skilled in the lit may employ to Identify preferred embodiments of the compounds of the invention for use as therapeutic agents. Other methods of testing the compounds disclosed herein are also readily available to those skilled in the art. Thus, in addition, the determination of the ability of a compound to inhibit SCD may be accomplished in vivo. In one such embodiment this is accomplished by administering said chemical agent to an animal afflicted withatriglyceride (TG)- or very low density lipoprotein (VLDL)-related disorder and subsequently detecting a change in plasma triglyceride level in said animal thereby identifying a therapeutic agent useful in treating a triglyceride (-T(Jy. or very low density lipoprotein (VLDL)-related disorder. In such embodiment, the animal may be a human, such as a human patient afflicted with such a disorder and in need of treatment of said disorder.
In specific embodiments of such in vivo processes, said change in SCDl activity in said animal is a decrease in activity, preferably wherein said SCDl modulating agent dαes not substantially inhibit the biological activity of a delta-5 desaturase, delta-6 desaturase or fatty acid synthetase or other enzymes containing Fe at the active site.
The model systems useful for compound evaluation may include, but are not
limited to, the use of liver microsomes, such as from mice that have been maintained on a Mgh carbohydrate diet or from human donors, including persons suffering from obesity- Immortalized cell lines, such as HepG2 (from human liver), MCF-7 (ftom human breast cancer) and 3T3-L1 (from mouse adipocytes) may also be used. Primary cdl lines, such as mouse primary hepatocytes, are also useAil in testing the compounds of the invention. Where whole animals are used, mice used as a source of primary hepatocyte cells may also be used wherein the mice have been maintained on a high carbohydrate diet to increase SCD activity in mirocrosomes and/or to elevate plasma triglyceride levels (i.e., the 1S:1/18:0 ratio); alternatively mice on anormal diet or mice with normal triglyceride levels may be used. Mouse models employing transgenic mice designed foi hypertriglyceridemia are also available. Ratbili and hamsters ate also useful as animal models, especially those expressing CETP (cholesterol ester transfer protein).
Another suitable method for determining the in vivo efficacy of the compounds of the invention is to indirectly measure their impact on inhibition of SCD enzyme by measuring a subject's Desaturation Index after administration of the compound.
"Desaturation Index" as employed in lhis specification means the ratio of the product over lhc substrate for the SCD enzyme as measured from a given tissue sample. This may be calculated using three different equations 18:ln-9/18:0 (oleic εcid over stearic acid); 16;ln-7/16:0 (palmitoleic acid over palmitic acid); and/or 16: ln-7 + 18:ln- 7/16:0 (measuring all reaction products of 16:0 desaturation over 16:0 substrate).
Desatiiration Index is primarily measured in liver or plasma triglycerides, but may also be measured in other selected lipid fractions from a variety of tissues. Desaturation Index, generally sneaking, is a tool for plasma lipid proflling.
A number of human diseases and disorders are the result of aberrant SCDI biological activity and may be ameliorated by modulation of SCDl biological activity using the therapeutic agents of the invention.
Inhibition of SCD expression may also affect the fatty acid composition of membrane phospholipids, as well as production or levels of triglycerides and cholesterol esters. The fatty acid composition of phospholipids ultimately determines membrane fluidity, with a subsequent modulation of the activity of multiple enzymes present within the membrane, while the effects on the composition of triglycerides and cholesterol esters
can affect lipoprotein metabolism and adiposity.
In carrying out the procedures of the present invention it is of couise to be understood that reference to particular buffers, media, reagents, cells, culture conditions and the like aie not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented.
For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve tlieir purposes in using the methods and procedures disclosed herein.
Alternatively, another format can be used to measure the effect of SCD inhibition on sebaceous gland function. In a typical study using ridnets, oral, intravenous or topical formulations of the SCD inhibitor are administered to a rodent for a period of 1 to 8 days. Skin samples are taken and prepared for histological assessment to determine sebaceous gland number, size, or lipid content A reduction of sebaceous gland size, number or function would indicate that the SCD inhibitor would have a beneficial impact on acne vulgaris, (Clark, S.B. et at "Pharmacological modulation of sebaceous gland activity: mechanisms and clinical applications", De/røto/. Clin. (2007) Vol.25, ND 2, pp 137-46. Geiger, J.M , "Retinoids and sebaceous gland activity" Dermatology (1995), Vol. 191, No.4, pp 3C5-10).
PHARMACEUTICAL COMPOSITIONS Of THE INVENTION AND ADMINISTRATION
The present invention also relates to pharmaceutical composition containing the compounds of the invention disclosed herein. In one embodiment, the present invention relates to a composition comprising compounds of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient. In an embodiment of such composition, the patient has an elevated lipid level, such as elevated triglycerides or
cholesterol, before administration of said compound of the invention and the compound of the invention is present in an amount effective to reduce said lipid level.
The pharmaceutical compositions useful herein also contain a pharmaceutically acceptable carrier, including any suitable diluent or excipient, which includes any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity. Pharmaceutically acceptable carriers include, but are not limited to, liquids, such as water, saline, glycerol and ethanol, and the like. A thorough discussion of pharmaceutically acceptable carriers, diluents, and other excipients is presented in REMINGTONS PHARMACEUTICAL SCIENCES (Mack Pub. Co., NJ. current edition).
Those skilled in the art know how to determine suitable doses of the compounds for use in trusting the diseases and disorders contemplated herein.
Therapeutic doses are generally identified through a dose ranging sludy in humans based on preliminary evidence derived frorn animal studies. Doses must be sufficient to result in a de&ited therapeutic benefit without causing unwanted εide effects For the patient The preferred dosage range for an εnimal is 0.001 mg/Kg to 10,000 mg/Kg, including 0.5 mg/Kg, 1.0 mg/Kg, 2.0 mg/Kg 5,0 mg/Kg and 10 mg/Kg, though doses outside this range may be acceptable. The dosing schedule may be once or twice per day, although more often or less often may be satisfactory.
Those skilled in the art are also familiar with determining administration methods (oral, intravenous, inhalation, sub-cutaneous, transdermal, topical, etc.), dosage forms, suitable pharmaceutical excipients and other matters relevant to the delivery ofthe compounds to a subject in need thereof.
In an alternative use ofthe invention, the compounds ofthe invention can be used in in vitro or in vivo studies as exemplary agents for comparative purposes to find other compounds also useful in treatment of, or protection from, the various diseases disclosed herein.
The pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal, topical, and parenteral administration to mammals, including man, to inhibit stearo yl-CoA desaturase, and for the treatment of
conditions associated with stearoyl desaturase activity. In general, the pharmaceutical compositions comprise a therapeutically effective amount of a pharmacologically active compound of the instant invention, alone or In combination with one or more pharmaceutically acceptable carriers.
The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising a therapeutically effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application. For enteral orparenteral application, it is preferred to administer an effective amount of a pharmaceutical composition according to the invention as tablets or gelatin capsules. Such pharmaceutical compositions may comprise, for example, 1he active ingredient together with diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethvleneglycol), and for tablets also comprises binders (e.g , magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone) and disintegrants (eg-, starches, agar, alginie acid or its sodium salt) or effervescent mixtures and absorbanis, colorants, flavors and sweeteners.
In another aspect of the present invention the compounds may be in the form of injectable compositions, e.g. preferably aqueous isotonic solutions or suspensions, and suppositories, which can be advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions may be prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1- 75%, preferably about 1-50%, of the active ingredient.
Suitable formulations for transdermal and topical application induct a therapeutically effective amount of a compound of the invention with carrier Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. Characteristically, transdermal devices are in the form of a bsntJage comprising a backing member, a reservoir containing the compound
optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and pie-determined rate over a prolonged period of time, and means to secure the device to the skin.
The most suitable route will depend on the nature and severity of the condition being treated. Those skilled in the art are also familiar with determining administration methods, dosage forms, suitable pharmaceutical excipients and other matters relevant to the delivery of the compounds to a subject in need thereof.
The compounds of the invention may be usefully combined with one or more other therapeutic agents for the treatment of SCD-mediated diseases and conditions Preferrably, the other therapeutic agent is selected from antidiabetics, hypolipidemic agents, anti-obesity agents, anti-hypertensive agents or inotropic agents.
Thus, an additional aspect of the present invention concerns a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention in combination with one or more other therapeutic agents. For example, the composition can be formulated to comprise a therapeutically effective amount of a compound of the invention as defined above, in combination with anothei therapeutic agent, each at an effective therapeutic dose as reported in the art. Such therapeutic agents may, for example, include insulin, insulin derivatives and mimetics; insulin secretogogues, such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands, such as meglitinides, e.g., nateglinide and repaglinide; PPARγ and/or PPARot (peroxisome proliferator-activated receptor) ligands such as MCC-555, MK767, L-165041, GW7282 or thiazolidinediones such as rosiglitazone, pioglitazone, troglttazone; insulin sensitizers, such as protein tyrosine phosphatase- IB (PTP-IB) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase- 3) inhibitors such as SB-517955, SB-4195052, SB-216763, NN-57-05441, NN-57-05445 or RXR ligands such as GW-0791, AGN-194204; sodium-dependent glucose cotransporter inhibitors, such as T-1095, glycogen phosphotylase A inhibitors, such as BAY R3401 ; biguanides, such as metformin; alpha-glucosidase inhibitors, such as acarbose; GLP-I (glucagon like peptide-1), GLP-I analogs, such as Exendin-4, and GLP- 1 mimetics; DPPlV (dipeptidyl peptidase IV) inhibitors such as LAF237 (Vildagliptin ) or MK-0431 (Stiagliptin); hypolipidemic agents, such as 3-hydroxy-3-metflyl-glutaryl
coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin, p avastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatϊn, dalvaεtatin, atorvastatin, rosuvastatin, flmndostatϊn and rivastatin, squalene synthase inhibitors or FXR (farnesoid X receptor) and LXR (liver X receptor) Ugands, cholestyramine, fibrates, nicotinic acid and aspirin; anti-obesity agents, such as orlisiat, anti-hypertensive agents, inotropic agents and hypolipidemic agents, e.g., loop diuretics, such as ethacrynic acid, furosemide and torsemide; angiotensin converting enzyme (ACE) inhibitors, such as benazepril, captopril, enalapril, fosinopril; lisinopril, inoexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPae« membrane pump, euch as digoidn; neutralendopeptidase (NEP) inhibitors; ACEiNEP inhibitors, such as omapatrilat, sampatrilat and fasidotril; angiotensin II antagonists, such as candesartan, φrosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan; β-adrenergic receptor blockers, such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agents, such as digoxin, dobutaπime and milrinone; calcium channel blockers, such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, niaoldipine and verapamil. Other specific antidiabetic compounds are described by Patel Mona {Expert Opin Irtvestig Drugs. (2003) Apr; 12(4):623-33) in the figures 1 to 1, which are herein incorporated by reference. A compound of the present invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
The structure of the active agents identified by code nos., generic oi trade names may be taken from the actual edition of the siandard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications). Die corresponding content thereof is hereby incoipαrated by reference.
In another aspect is the use of the pharmaceutical composition as described above for production of a medicament for the treatment of SCD-mediated disease or conditions.
In another aspect is the use of a pharmaceutical composition or combination as described above for the preparation of a medicament for the treatment of conditions associated with stearoyi-CoA desatruase activity.
A pharmaceutical composition as described above for the treatment of conditions
associated with the inhibition of stearoyl-CoA desaturase.
PREPARATION OF THE COMPOUNDS OF THE INVENTION
The Following Reaction Schemes illustrate methods to make compounds of the invention, i.e., compounds of Formula (I): :
Figure imgf000040_0001
wherein p, V, W, X, Y, R1, R2, R3 and R4 aie as defined above in the Summary of the Invention for compounds of Formula (I), as a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
It is understood that in the following description, combinations of substituents and/or variables of the depicted formulae aie permissible only if such ccntrifcutions result in stable compounds.
It will slso be appreciated by those skilled in the art that in the process described below the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic add. Suitable protecting groups for hydroxy include trialkylsih/l or diarylalkylsilyl (e g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethykilyl), tetrahydropyranyl. benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benεyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aiylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for caτboκylic acid include alkyl, aryl or arylalkyl esters.
Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein.
The use of protecting groups is described in detail in Greene, T. W. ϊnd P.G.M.
Wuts, Protective Groups in Organic Synthesis (2006), 4th Ed., Wiley. The protecting group may also be a polymer re&in such as a Wang resin or a 2-chlorotrityl-cliloride resin
It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this invention may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds of this invention are included within the scope of the invention.
The following reaotion schemes illustrate methods to make compounds of this invention, ft is understood that those skilled in the art would be able to make these compounds by similar methods or by methods known to one skilled in the art. In general, starting components may be obtained from sources such as Sigma Aldricri, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepered as described in this invention.
In general, the compounds of Formula (I) of this invention can be synthesized following the general procedure as described it Reaction Scheme 1 where W is - N(R5JC(O)- and p, R1, R2, R3, R4, R!, W , V, X and Y are defined as in the Specification unless specifically defined otherwise. R' is a protecting group.
REACTION SCHEME 1
Figure imgf000042_0001
(102) (103)
Figure imgf000042_0002
The starting materials for the above reaction scheme are commercially available or can be prepared according io methods known to one skilled in the an or by methods disclosed herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows:
Compound (101) is coupled with compound (102) under metal catalyzed reaction conditions to generate compound (103) which undergoes a standard hydrolysis procedure known to one skilled in the art to generate the carboxylic acid (104). Coupling between compounds (1*4) and (105) under standard amide bond formation conditions known to thε one skilled in the art affords compounds of Formula (I) of the invention where W is - N(R5)C(O)-.
Altemati-vely, the compounds of Formula (I) of this invention can be synthesized following the general procedure as described in Reaction Scheme 2 where W is - N(R5JC(O)-, ani p, X, Y, V, R1 , R2, R3, R4 ami R5 are defined as in the Specification unless specifically defined otherwise.
REACTION SCHEME 2
Figure imgf000043_0001
(ZUI) (1OS) (802)
Figure imgf000043_0002
(102)
The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, the compounds of the invention are prepared tithe above reaction scheme as follows:
The starting compound (201) undergoes coupling reaction with amine (105) under standard amide bond formation conditions known to one skilled in the art Io afford compound (201). Compound (202) is then coupled with compound (102) under metal catalyzed reaction conditions to generate compounds of Formula (I) where W is - N(R5)C(O>.
Alternatively, the compounds of Formula (I) of this invention can be synthesized following the general procedure as described in Reaction Scheme 3 where W is - N(R5)C(O>, V is -O- or direct bond and p, X, Y, R1, R2, R3, R4 and R5 are defined as in the Specification unless specifically defined otherwise. R' and R" are protecting groups.
REACTION SCHEME 3
Figure imgf000044_0001
The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein In general, the compounds of the invention are prepared in the above reaction scheme as follows:
Compound (301) is coupled with compound (302) under metal catalyzed reaction
conditions to generate compound (303) which undergoes a standard hydrolysis procedure known to ore skilled in the art to generate the carboxylic acid (304) Coupling between compound (ΪI4) and amine (105) under standard amide bond formation conciticms known to one skilled in the art affords the compound (305). Deprotectioπ of the R' group (R' = benzyl) under palladium catalyzed hydrogenation conditions known to one skilled in the art affords compound (306). Compound (306) is used as a key intermediate to generate compounds of Formula (I) underthe conditions of (a) metal catalyzed coupling reaction when R! is aryl, or (b) alkylation when R2 is akyl or (c) triflate formation to generate compound (307), followed by Suzuki coupling.
Alternatively, the compounds of Foiniula (I) of this invention can be synthesized following the general procedure as described in Reaction Scheme 4 where W is - N(R5)C(O)-, V is -N(H)C(O)- and p, X, Y, R1, R2, R3, R4 and R5 are defined as in the Specification unless specifically defined otherwise. R" is a protecting group.
REACTION SCHEME 4
Figure imgf000046_0001
The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, the compounds cf the invention are prepared in the above reaction scheme as follows:
Compound (301) is coupled with compound (401) under metal catalyzed reaction conditions to generate compound (402) which undergoes a standard hydrolysis procedure known to one skilled in the art to generate the carboxylic acid (403). Coupling between compound (403) and amine (105) under standard amide bond formation conditions known to one skilled in the art affords the compound (404). Compound (404) is used as a key intermediate to generate compounds of Foπnula (1) under the conditions of (a) reductive aminition or (b) amide bond formation.
Although anyone skilled in thε art is capable of preparing the compounds of the
invention accoiding to the general techniques disclosed above, more specific details on synthetic techniques for compounds of the invention are provided elsewhere in this specification for convenience. Again, all reagents and reaction conditions employed in synthesis are known to those skilled in the art and are available from ordinary commercial sources.
PREPARATION 1
Preparation of 4-Phenylpyridin-2-ol
A solution of 4-phenylpyridine-l-oxide (200 g, 0.012 mol) in acetic anhydπde(6 mL) was heated at reflux for 48 hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (80 mL) and washed with saturated iqueous sodium bicarbonate (2 x i5 mL} and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methanol (20 mL) and potassium carbonate (0.32 g, 0.002 mol) was added to the solution. The reaction mixture was stirred at ambient temperature for 1 hour, then diluted with chloroform (100 mL) and filtered through Celite. The filtrate was concentrated in vacuo. The residue was dissolved in a mixture of methanol/chloroform 1/10 (30 mL). The title compound was precipitated with trieadditioπ of hexanes (30 mL) as a white solid which was collected by filtration (1.2C g, 60%): 1H NMR (300 MHz, DMSO-J6) S 7.66-7.62 (m, 2H), 7.48-7.37 (m, 4H), 6.51 (d, /= 1.2 Hz, IH), 6.44 (dd, / = 6.7, 1.8 Hz, IH); MS (ES+-) mk 172.5 (M + 1).
PREPARATION 2
Preparation of A^-Benzyl-2-bromo-4-methylthiazole-5-carboxamide
Toamixture of 2-bromo-4-methyltrιiazole-5-carboxylic acid (10.00 g, 45.03 mmol) and l-(3-dimethyl)aminopropyl)-3-ethylcarbodiimide hydrochloride (12.09 g, 63.04 mmol) in tetrahydrofuran (170 mL) under nitrogen atmosphere was added diisopropylethylamine (17.46 g, 135.0 mmcl). After the mixture was stirred at ambient temperature for 30 minutes, 1-hydroxybenzotriazole (8.52 g, 63.04 mmol) and benzylamine {6.76 g, 6.88 mL, 63.04 mmol) were added. The mixture was stirred at ambient tempemture for 16 hours and then concentrated in vacuo The residue was
dissolved in dichloromethane (500 mL), washed with water (2 x 100 mL) and brine (2 x 100 mL). The organic layer was dried over anhydrous sodium sulfite and Filtered. The filtrate was concentrated m vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether, 2/1) to afford the title compound (U .91 g, 85%): 1H NMR (300 MHz, DMSO-40 δ 9.92 (t, J = 6.0 Hr, IH), 7.34-7.25 (m, 5H), 4.46 (d, J= 6.0 Hz, 2H), 2.53 (S, 3H); MS (ES+) m/z 298.1 (M + I), 300.1 (M + 1)
PREPARATIONS
Preparation of 3-(Bθnzyloxy)pyridin-2-oi
To a stirred solution of potassium hydroxide (2.52 g, 45.00 mmol) in methanol (30 mL), was added pyridine-2,3-diol (5.00 g, 45.0 mmol) in 3 portions and a clear red solution was obtained. To this clear red solution was added benzyl bromide (7.70 g, 5.35 mL, 45.00 mmol), The reaction mixture was kept stirring at ambient temperature for 30 minutes, then at 40 0C for 2 hours. The solvent was removed in vacuo and 1he residue was dissolved in dichloromethane (100 mL), and washed with water (10OmL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from methanol (20 mL) to afford the title compound (4.60 g, 51%): 1H NMR (300 MHz, DMSCW6) δ 11.63 (s, IH), 7.44- 7.33 (m, 5H), «.96-6.88 (m, 2H), 6.07 (t, /= 6,0 Hz, IH), 5.00 (a, 2H); MS (ES+) m/z 202.2 (M + 1).
PREPARATION 4
Preparation of 5-(Benzyloxy)pyridin-2(l.ff)-oric
To a solution of 5-hydroxypyridin-2(li/)-one (4.44 g, 40,0 mmol) in methanol (50 mL) was added potassium hydroxide (2.64 g, 40.0 mmol). The reaction mkture was stirred for 30 minutes at ambient temperature, followed by the addition of kenzyl bromide (5.2 mL, 44 mmol). The reaction mixture was kept stirring at ambient temperature for 2 hours and then heated at 45-50 0C for 1 hour The solvent was removed ia vacuo, and the residue was washed with water, dichloromethane and then recrystallized from methanol to afford the title compound (5 39 g, 67%): 1H NMR (300 MHz. DMSO-*) 8 11.08 (s, IH), 7.42-7.26 (m, 6H), 7.09 (., ./= 3.0Hz, IH), 6.30 (d,J = 9.6 Hz, IH), 489<s, 2H);
MS (ES+) m/2 202.3 (M + 1).
PREPARATION S
Preparation of 5-(Benzyloxy)isoquinolin-l(2i/)-one
5-Hydroxyisoquinolin- 1 (2Λ)-one (065 g, 4.04 mmol) was added in portions to a solution of potassium hydroxide (0.23 g, 4.04 mtnol) in methanol (15 mL). The mixture was stirred at ambient temperature for 10 minutes, then benzyl bromide [0.69 g, 0.4S mL, 4.04 mmol) was added. The mixture was stirred at ambient temperature for 30 minutes and then at 40 0C for 2 hours. The solvent was removed in vacuo. The residua was dissolved in dichloromethane (100 mL) and washed with water (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from methanol (10 mL) to afford the title compound (040 g, 40%)- mp 165-168 "C; MS (ES+) m/z 252,1 (M + 1)
PREPARATION 6
Preparation of 5-(Bcπiylσsy)quiiiσlin-2(lfϊ)-oric
Following the synthetic procedure as described in Preparation 5, making variations only as required to use 6-hydroxyquinolin-2(l/7)-oπe in place of 5- hydroxyisoquinclin- 1 (2//)-one, the title compound was obtained (0.42 g, 42%): MS (ES+) m/z 2522 (M + 1)
PREPARATION 7
Preparation of fV-Bcπzyl-5-bromothiophcnc-3-carboxamide
A. To a stirred solution of 3-thiophenecarboxylic acid (1.00 g, 7.80 mmol) in glacial acetic acid (9 mL) at ambient temperature under nitrogen atmosphere was slowly added bromine (0.39 mL, 7.53 mmol) in glacial acetic acid (6 mL). The reaction mixture was stirred for 15 minutes, then quenched with cold water (50 mL). The precipitate was filtered, washed with water and dried in vacuum oven at 50 0C to afford f -bromo-3- thiophenecarboxylic acid as a colorless solid {0.78 g, 50%): mp 133-135 "C; 1HNMR (300 MHz, CDClj) S 8.12 (d, /= 1.5 H2, IH), 751 (d, J= 1.5 Hz, IH).
B. To a stirred solution of 5-bromo-3-thiophenecarboxyiic acid <0.50 g, 2.42
Figure imgf000050_0001
mL, 7.46 mmol), i-hydroxybenzotriazole (0.49 g, 2.61 mmol), and l-ethyl-3^3. dimethylaminopropyOcarbodiimide hydrochloride (0.69 g, 3.62 mmol) Beizylamine (0.26 mL, 2.41 mmol) was added 5 minutes later. The reaction mixture was stirred at ambient temperature for 16 h, then diluted with ethyl acetate (75 mL). The organic layer was washed with 10% aqueous hydrochloric acid (25 mL), saturated aqueous sodium bicarbonate (2 x 25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated m vacuo to afford the title compound as a colorless solid (C.57 g, 80%): 1H NMR (300 MHZ, CDCl5) 3 7.77 (d, J= 1.5 Hz, IH), 7.37-7.31 (m, 6H), 6.14 (br s, IH), 4.59 (d, / = 5 7Hz, 2H).
PREPARATION 8
Preparation of JV-Benzyl-5-bromo-3-methylthiophene-2-carboxamide
To a stirred solution of ΛMrenzyl-a-mrthylthiophene^-carboxamide (0.74 g, 3.18 mmol) in acetonitrile (15 mL) was added JV-bromosucrinimide (0.57 g, 3.18 mmol). The reaction mixture was stirred for 1 S h, and then concentrated in vacuo. The residue was purified by column chromatography elutiπg with 5-35% ethyl acetate in liexane to afford the title compound as a colorless solid (0.69 g, 69%): 1H NMR (300 MHz, CDCl5) δ 7.38-7.30 (m, 5H), 6.87 (s, IH), 4.59 (d, J= 5.5 Hz, 2H), 246 (s, 3H); MS (ES+) m/z 310.1 (M + 1), 312.1 (M + 1).
PKEPARATION 9
Preparation of 2-Cyclopropylethyl 4-Methylbenzenesulfonaie
To a stirred solution of 2-cyclopropylethanol (5.00 g, 58.05 mmol) in dichloromethaiie (20 mL) was added pyridine (7.03 mL, 86.92 mmol), followed byp- toluenesulfonyl chloride (10.50 g, 55.07 mmol). The reaction mixture was stirred for 16 h, and then partitioned between dichloromethane (100 mL) and water (50 rnL). The organic layer was washed with 10% aqueous hydrochloric acid (50 mL), saturated aqueous sodium bicarbonate (50 mL) and rjrme{50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated m vacuo to afford 2-cycbpropylethyl 4- rnethylbenzenesulfon.te as a colorless oil (1 1.90 g, 96%): 1H NMR (300 MHz, CDCl3) 6
7.S0 (d, J= 8.3 Hz, 2H), 7.34 (d, J= 8.3 Hz, 2H), 4.09 (t, J= 6.6 Hz, 2H), 2.45 (s, 3H), 1 57-1.48 (m, 2H), 0.74-0.59 (m, IH), 0.45-0.36 (m, 2H), O.Q8-0.06 (m, 2H].
PREP AHATlON 10
Preparation of Fhenethyl 4-Methylbenzenesαlfonate
To a stirred solution of phenethyl alcohol (0.50 mL, 4.17 mmol) in pyridine (4 mL) at 0 0C was added /)-toluenesulfonyl chloride (0.80 g, 4.18 mmol). The reaction mixture was stiired for 16 h, and then diluted with ethyl acetate (75 mL). The organic solution was weshed with 10% aqueous hydrochloric acid (2 x 25 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (25 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluting with 0-20% ethyl acetate in hexane to afford the title compound as a light yellow liquid (0.59 g, 51%): 1HNMR (300 MHz, CDCIj)S 7.69 (d, J- 8.3 Hz, 2H), 7.31-7.20 (m, 5H), 7.11 (dd,/= 7.4,1.7 Hz, 2H), 4.21 (t, /=7.1 Hz, 2H), 2.96 (t,J= 7.1 Hz, 2H), 2.43 (s, 3H); MS (ES+) mil 299.2 (M + 23).
PREPARATION 11
Preparation of2-Hydroxy-N-phenylisonicctinainide
A. To a solution of 2-methoxyisonicotinic acid (2.00 g, 13.06 mmol) in anhydrous tetrahjdrofuran (SO mL) was added 4-methyl morphαline^l.84 g, 18.28 mmol). After cooling to 00C, isobutyl chloroformate (2 31 g, 16.98 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 6 hours, followed by ttie addition of aniline (1.70 g. 18.28 mmol). The resulting mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (15OnL) and washed with saturated aqueous sodium bicarbonate (2 x 50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford 2- methoxy-N-phenylisonicotinamide (2.50 g, 86%) as a colorless solid: 1HNMR (300 MH2, CDCl3) S 11 85 (s, IH), 10.31 (s, IH), 7.75-7.60 (m, 2H), 7.47 (d, /=4.6 Hz, IH), 7.35-7.20 (in, 2H), 7.12-7 04 (m, IH), 6 83-6.80 (m, IH), 6 S4-6.42 (m, IH)5MS (ES4)
Figure imgf000051_0001
+• 1).
B. To a solution of 2-raethoxy-iV"-phenylisonicotinamide (1.00 g, 4.38 mmol) in anhydrous chloroform (60 mL) was added iodotrimethylsilane (17.50 g, $7.50 mmol). The reaction mixture was stirred at reflux for 16 hours. After cooling to ambient temperature, methanol (10 mL) was added dropwise to quench the reaction. The solvent was removed m vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 100 mL) and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrate in vacuo. The brawn crude product was recrystallised from ethyl acetate and methanol to afford the title compound as a colourless solid (0.35 g. 19%): 1H NMK OCI(J MHz, DMSO-d<o a l l.S8 (br s, IH), 10.31 (s, IH)1 7.73-7.08 (m, 2H), 7.47 (d, J- 6.8 Hz, IH), 7.31 (t, J= 7.9 Hz, 2H), 7.10-7 05 (m, IH), 6.81 (s, IH), 6.49 (dd, J= 6.8, 1.7 Hz, IH); MS (ES+) m/i 215.2 (M + 1).
PREPARATION 12
Preparation of 2-Oxo-Λ'-phenyl-l,2-dihydropyiidine-3-carboxamide
To a solution of 2-oxo- 1 ,2-dihydropj;iidine-3-carboxylic acid (1.08 g, 7.18 mmol) in anhydrous tettahydrofuran (40 mL) was added 4-methyl morpholine (1,01 g, 10.06 mmol). After cooling to 90C, isobutyl chloroformate (1.27 g, 9.34 mmol) was added to the reaction mixture. The mixture was stirred at ambient temperature for 6 hours followed by the addition of aniline (0.87 g, 9.34 mmol]. The resulting mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacua The residue was dissolved in ethyl acetate (100 mL), and washed with saturated aqueous sodium bicarbonate (2 K 50 mL) and brine (SO mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated m vacuo to afford the title compound as a colorless solid (1.50 g, 97%): 1H NMR (300 MHz, DMSO-c/6) 8 12.71 (bi s, IH), 12.14 (s, IH), 8.46-838 (m, IH), 7.S0-7.52 (m, IH), 7.65-7.62 (m, 2H), 7.35-7.29 (m, 2H), 7.10-6.95 (m, IH), 6.58-6.45 (m, IH); MS (ES+) m/z 215.2 (M + 1).
PREPARATION 13
Preparation of Ethyl 2-Bromo-l,4-dimethjl-lff-imidazole-5-carboxylat« and Ethyl 2- Bromo-1 ,5-dimethyl- l/f-imidazole-4-caτboκylate
A. To a stirred suspension of ethyl 4-methyl-l»imidazole-5-C£rboxylate (2.00 g, 13.0 mmol) in acetonitrile (25 mL) and chloroform (25 mL) was added N- bromosucciBimide (2.31 g, 13.0 mmol). The reaction mixture was stirred under nitrogen atmosphere fcr 20 h, then concentrated in vacua The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate,
Figure imgf000053_0001
The residue was purified by column chromatography eluting with 50% ethyl acetate in hexanes to afford ethyl 2-broino-4-methyl-l-B-imidazo]e-5-carboxylate as a light yellow solid (1.88 g, 62%): 1H NMR (300 MHz, CECl,) δ 4.35 (q, J= 7.1 Hz, 2H), 2.51 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); MS (ES+) m/z 233.1 (M + 1), 235.1 (M + 1).
B. To a stirred suspension of ethyl 2-bromo-4-methyl-l//-imidazole-5- carboxylate (0.90 g, 3.86 mmol) and potassium carbonate (1.07 g, 7.74 mmol) in NrN- dimethylformamide (15 mL) under nitrogen atmosphere was added iodomethane (0.73 mL, 11 ,6 mmol). The reaction mixture was stirred for 1.5 h, and diluted with ethyl acetate (75 mL). The organic layer was washed with water (25 mL) and brine (25 πiL), dried over sodium sulfate, filtered and concentrated m vacuo. The residue was purified by column chromatography eluting with 10-60% ethyl acetate in hexanes to afford the title compounds. Fitst fraction: ethyl 2-bromo-l ,4-dimethyl-l/7-imidazole-5-carboxylate (0.61 g, 64%): 1H NMR (300 MHz, CDCI3) S 4.33 (q, J= 7.1 Hz, 2H), 3.86 (s, 3H), 2.46 (s, 3H), 1.38 (t, J= 7 1 Hz, 3H); MS (ES+) m/i 247.1 (M + 1). Second fraction: ethyl 2- bromo-1 ,5-dimcthyI-ltf-imidazolc-4-carbo∑ykte (0.30 g, 32%). 1H NMR (300 MHz, CDCl3) 6435 (n, J- 7.1 Hz, 2H), 3.54 (s, 3H), 2.56 (s, 3H), 1.38 (t, J- 7.1 Hz, 3H); MS (ES+) m/i 247.1 (M + 1).
PREPARATION 14
Preparation of 2-Bromo-Λ^-(4-fluorobenzyl)-4-inethylthiazole-5-carboxamide
To amlxture of 2-bromo-4-ιnetliyltMazole-5-caruoxyllc acid (2.00 £.9,00 mmol) in anhydrous tetrahydrofuran (40 mL) was added N,N-dU5opropylethylaminc (4.67 mL,
27.0 mmol) and l-ethyl-3-(3-dimethylamincprcpyl)carbodiimide hydrochloride (2.41 g, 12.6 mmol). The reaction mixture was stiπed at ambient temperature for 30 minutes, followed by the addition of l-hydroxybenzotπazole (1.70 g, 12.60 mmol) and (4- fluoroρhenyl)inbthanamine (2.50 g, 12.60 mrnol). The reaction mixture was stirred at ambient temperature for 18 hours The solvent was concentrated to half in vacuo. The residue was dinted with ethyl acetate (200 rnL), washed sequentially with 10% aqueous hydrochloric acid (50 mL), saturated bicarbonate solution (50 tnL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo The residue was recrystallized in ethyl acetate and hexane to afford the title compound as a colorless solid (2.38 g, 81%]: 1H NMR (300 MHz, CDCIj) i 7.30-7.26 (m, 2H), 7.05-7.00 (m, 2H)1 5.99-5.87 (m, IH), 4.54 (d, J= 5.7 Hz, 2H), 2.63 (s, 3H).
PREPARATION 14.1
Preparation of 2-Bromo-JV-(3,4-difluorobenzyl)-4-methylthiazole-5-carboxaniide
Following the procedure as described in Preparation 15, making variations only as requires to us« {3,4-difluoroρhenyl)methanamine to replaoe (4-fluoroρhenyl)- methanamine tc react with 2-bromo-4-memylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 50% yield: 1H NMR (300 MHz, CDCh) 8 7.16-7.01 (m, 3H), 6.08-5.94 (m, IH), 4.52 (d, /= 5.9 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 347.2 (M + 1), 349,2 (M + 3).
PREPARATION 15
Preparation of 2-Bromo-4-methyl-?/-(pyri<iin-3-ylmethyl)thiazo]e-5-carboxamide
To a solution of 2-bromo-4-methylthiazole-5-carboxylic acid (1000 g, 45.00 mmol) and 4-methylmorpholine (6.5 mL, 55.0 mmol) in tetrahydrofiiran(l 50 mL) was added isobutyi chloroformate (6.5 mL, 49.6 mmol) at 00C. The resulting mixture was stirred at room temperature for 1 hour then 3-(aminomethyl)pyπdine (5.2 mL, 51.4 mmol) was added. The reaction mixture was stirred at ambient temperature for 17 hours, then concentrated in vacuo. The residue was purified by column chromatography to afford 2-bτomo-4-mcthγl-Λf-(pyridin-3-ylmGtbjl)thiazolc-5-carboxamidc in 52% yield (7.3 g): 1H NMR (300 MHz, CDCI3) δ 8,39-8.80 (m, 2H), 7,80-7.72 <m, IH), 7.40-7.35
(m, IH), 6.47 (br s, IH), 4.60 (d, /= 6.0 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 312.1, 314. HM + 1).
PREPARATION 16
Preparation of 4-(Phenoxymethyl)pyridin-2( lH)-one
A. To a solution of tributylphospMne (4.57 g, 22.63 mmol) in anhydrous tetrahydrofuren (20 mL) was added diisoprcpyl azodicarboxylate (4.57 g, 22.63 mmol) at 00C. The reaction mixture was stirred for 10 minutes at 00C, then added to a solution of (2-chloropyridiϊi-4-yl)methanol and phenol in anhydrous tetrahydrofurari (SO mL) at 0 °C. The reaction mixture was stirred at 00C for 20 minutes then at ambient temperature for 16 hours. The reaction was quenched with saturated ammonium chloride solution (10 mL). The solvent was evaporated m vacuo. The residue was diluted with ethyl acetate (350 mL), washed with 1 N sodium hydroxide solution (3 x 40 mL), dried ever anhydrous sodium sulfate, filtered and concentrated In vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/9) to afford 2-chloro-4- (phenoxymetrιyl)pyridine as a gummy solid in 51 % yield (2.34 g): 1H NMH (300 MHz, CDCl5) δ 8.36 «1 7= 5.1 Hz, IH), 7.40 (s, IH), 7.32-7 24 (m, 3H), 7.01-6.91 (m, 3H), 5.05 (s, 2H); MS (ES+) m/z 220.2 (M + 1).
B. To a solution of 2-chloro-4-(phenoxymethyl)pyridine (2.34 g, 10.68 mmol) in antijdrous methanol (30 mL) in a steel bomb was added sodium hydroxide (3.20 g, 80.11 mmol). The reaction mixture was stirred at 1700C for 16 hours, cooled to 00C and neutralized with cold concentrated hydrochloric acid, followed by the addition of methanol (10 rnL) and filtration. The filtrate was concentrated in vacuo and the residue was washed with methanol and hexane. The title compound was obtained as a colorless solid in 93% (2 g): 1H NMR (300 MHz, CDCI3) δ 13.00 (br s, 1 H), 7.35-7,25 (m, 3H), 6.99-6.90 (m, 3H), 6.64 (s, IH), 6.34 (d, /=6.6 Hz, IH), 4.93 (s, 2H); MS (ES+) mk 202.2 (M + 1)
PREPARATION 17
Preparation of jy-Benzyl-3-mcthylfuran-2-carboxamidc
To a mixture of 3-methyifuran-2-carbo?(ylic acid (0.79 g, 6.28 mmol), 1-
hydroxybenzotnazole (1.27 g, 9.42 mmol) and 1 -ethyl-3-(3-dimethylaminopropyl)- carbodiimide hydrochloride (1.81 g, 9.42 mmol) in Λ^JV-dimethylformamide (6 mL) was added JV.Λf-diisopropylethylamine (3.30 mL, L 8.94 miral) and benzylamϊne (069 mL, 6.28 mmol). The reaction mixture was stirred for 16 hours, and then diluted with ethyl acetate (75 mL). The organic layer was washed with 10% aqueous hydrochloric acid (2 x 25 mL), saturated aqueous sodium bicarbonate (2 x 25 mL), dried over sodium sulfate, filtered and concentrated m vacuo to afford JV-benzyl-3-methylfuran-2-carboxamide as a light brown solid (0 57 g, 80%): 1H NMR (300 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 7.27 ia, J= 1.5 Hz, IH). 6.61 (br s, IH), 6.34 (d, J= 1.5 Hz, IH), 4.59 (d, /= 1» Hz, 2H), 2.42 (s, 3H); MS (ES+) m/z 216.2 (M + 1),
PREPARATION 17.1
Preparation of N-^-FluorαbenzylJJ-methyltliiophene-Σ-carboxamide
Following the procedure as described in Preparation 18, making variations only as required to use 3-methylthiophene-2-carboκylic acid in place of 3-πletr]ylfLlran-2- carboxylicaci(lto react with 4-fluorofienzylamlne In place of benzylamine, JV-(4- flucrobenzyl)-3-inethylthiophene-2-carboxsrmde was obtained as a colorless solid in 94% yield 1H NMR (300 MHz, CDCIj) δ 7.37-7.26 (m, 3H), 7.08-7.00 (in, 2H), 6.90 (d, J = 5.0 Hz, IH), 609 (br s, IH), 4.57 (d, J= 5.8 Hz, 2H), 2.52 (s, 3H); MS (ES+) m/z 250.2 (M + 1).
PHEPARATtON 17.2
Preparation of N-(3-Fluorobenzyl)-3-metliyltlilophene-2-carboxamide
Following the procedure as described in Preparation 18, making variations only as required to use 3-methylthiophene-2-carbo>ylic acid in place of 3-methylfuran-2- carboxylic acid to react with 3-fluorobenzylainine in place of benzylamins, K-(3- fluorobenzyl>3-methylthiophene-2-carboxamide was obtained as a colorless solid in 96% yield: 1H NMR (300 MHz, CDCl3) δ 7.35-7.25 (m, 2H), 7.15-6.94 (m, 3H), 6.90 (d, J= 5.0 Hz, IH), 6.14 (br s, IH), 4.61 (d, J= 5.9 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 250.2 (M+ 1).
PREPARATION 17.3
Preparation of N-ethyl-3-methylthiophene-2-carboxamide
Following the procedure as described in Preparation 18, making variations only as required to use J-methylthiophene^-carboxylic acid in place of 3-methylftiran-2- carboxylic acid to react with ethylamine in place of benzylamine, JV-ethyi-3- methylthiophene-2-carboxamide was obtained as a colorless liquid in 92% yield: 1H NMR (300 MHz, CDCl3) δ 7.24 (d, J = 5.0 H-, IH), 6.88 (d, J= 5.0 Hz, IH), 5.77 (br s, IH), 3.51-3.4(1 (m, 2H), 2.51 (s, 3H), 1.24 ft / = 7.3 Hz, 3H); MS (ES+) m/z 170.2 (M + I)-
PREPARATION 18
Preparation of N-Benzyl-5-bromo-3-methylfuran-2-carboxamide
To a stirred solution of JV-benzyl-3-methylfuran-2-carboxamide (1 ,18 g, 5.49 mmol) in acetonitrile (25 mL) was added Λ'-brorrjOsuccinimide (0 98 g, 5.49 mmol). The reaction mixture was stirred for 16 hours, and then partitioned between ethyl acetate (100 mL) and water (75 mL). The organic layer was washed with 1 N sodium hydroxide solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-20% ethyl acetate in hexares to afford JV-benzyl-5-broino-3-methylfuran-2-carboxaniide as a colorless solid (0.18 g, 11%): 1H NMR (300 MHz, CDCl5) δ 7.38-7.27 (m, 5H), 6.54 (br s, IH), 6.28 (s, 1 H), 4.58 (d, J - 5.9 Hz, 2H), 2.40 (s, 3H); MS (ES+) mi 294.1 (M + 1), 296.1 (M + 1)
PREPARATION 18.1
Preparation of 5-bramo-N-(4-fiuorobenzyl)-3-rnethylthiophene-2-carboxainide
Following the procedure as described in Preparation 19, making variations only as required to use V-(4-fluorobenzyl)-3-methylthiopheπe-2-carboxamide) in place of ./V- benzyl-3-metriylfιiran-2-carboxamide to react with JV-bromosucciπimide, 5-bromo-N-(4- fluorobenzyl)-3-methylthiophene-2-carboxamide was obtained as a colorless solid in 87% yield: 1H NMR (300 MHz, CD3CN) δ 738-7.32 On, 2H). 7.10-7.03 (m, 2H), 6.97 (s, IH), 4.45 (d, J- 6.1 Hz, 2H), 2.40 (s, 3H); MS (ES+) mfz 328.1 (M + 1), 330.1 (M +
I)-
PREPARATION 18.2
Preparation of 5-Bromo-N-(3-fluorobenzyl)-3-inethylthiophene-2-carboxaniide
Following the procedure as described in Preparation 19, making variations only as required to use /V-(3-fluorobenzyl)-3-methy]thiophene-2-carboxamide) in place of N- benzyl-3-methylfuran-2-carboxamide to react with JV-bromosuccinimide, 5-bromo-N-(3- fluorobenzy^-S-methylthiophene^-carbosamide was obtained as a colorless solid in 89% yield: 'H NMR (300 MHz, CD3CN) S 7.39-7.31 <m, IH), 7.16 (d, J = 76 Hz, IH), 7.08 (d, J= 10.2 Hz, IH), 7.02 (dd, J= 8.5, 25 Hz, IH), 6.98 (s, IH), 4.4* (d, J= 6.1 Hz, 2H), 2.42 (s, 3H); MS (ES+) m/z 328.1 (M 4 I), 330.1 (M + 1).
PREPARATION 18.3
Preparation of S-bromo-N-ethyl-S-methyltbjophene^-carboxamide
Following the procedure as described in Preparation 19, making variations only as required to u3e ?V-ethyl-3-methylthiophene-2-oarboxamide in place of N-bβΛzy[-3 methylfuran-2-carboxamide to react with Λ^broraosuccinimide, 5-bromo-.V-ethyl-3- methylthiophere-2-carboxamide was obtained as a colorless oil in 92% yield 1H NMR (300 MHz, CDCI3) δ 6.85 (s, IH), 5.65 (br s, IH), 3.48-3.38 (m, 2H), 2.45 (s, 3H), 1.22 (t, J= 7.3 Hz, 3H); MS (ES+) m/z 248.1 (M + 1), 250.1 (M + 1).
PREPARATION 19
Preparation of ethyl 5-bromo-3-mcthylthiophcnc-2-carboxylatc
A. To a stirred solution of S-methylthiophene-l-carboxylic acid (1.84 g, 12.9 mmol) in ethanol (20 mL) was added thionyl chloride (0.94 mL, 12.9 mmol). The resulting reaction mixture was stirred at reflux For 20 h, and then allowed tc cool to ambient temperature and concentrated in \acvc. The residue was taken up in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (2 x 100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl S-methytthicpheπe^-carboxylate as light yellow liquid (1.89 g, 86%) 1H NMR (300 MHz, CDCl3) 67.37 (d, J= 5.0 Hz, IH), 6.90 (ά, J= 5.0 Hz, IH), 4.32 (q, J= 1 1
Hz, 2H), 2,55 (s, 3H), 1.37 (t, J ■= 7.1 Hz, 3H).
B. To a stirred solution of ethy] 3-methylthiophene-2-carhoxylate (1.89 g, 11.10 mmol) in acetonitrile (20 mL) was added «-bromosuccinimide (1 98 g, 11.12 mml). The teaction mixture was stirred for 20 h, and then concentrated in vacuo. The residue was purified by column chromatography eluted with 0-5% ethyl acetate in hexanes to afford a mixture of ethyl 5-bromo-3-methylthiophene-2-carbθ)cj'late and ethyl 4-bromo-3-methylthiophene-2-carbαxylate as colorless liquid (2.04 g, 72%): 1H NMR (300 MHz, CDCl3) δ 6.89 (s, IH), 4.39-4.2« (m, 2H), 2.55 (s, 3H), 1.43-1 ,31 (in, 3H).
Although anyone skilled in the art is capable of preparing the compounds of the invention according to the general techniques disclosed above, more specific details on synthetic techniques for compounds of the invention are provided elsewhere in this specification for convenience. Again, all reagents and reaction conditions employed in synthesis are known to those skilled in the art and are available from ordinary commercial sources.
The syntheses of compounds of this invention are illustrated by, but not limited to the following examples.
EXAMPLE 1
Synthesis of Λ'-bennM-mcthyl-2-(2-oxo-4-plicnylpyridin-l(2//)-jl)thiamle-5- carboxamide
Figure imgf000059_0001
To a solution of 4-methyl-2-(2-oxo-4-pheπylpyridin- 1 (2H)-yl)thiaiole-5- carboxylic acid (0.20 g, 0.64 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added 1-hydrcxybenzotriazole (0.23 g, 1.67 mmol), N-(3-dimethylaminoprcpyl)-N'- ethylcarbodiimide (0.1 S g, 0.77 mmol), "N.N-diisopropylethylamine (0.11 g, 0.83 mmol), and benzylamine (0.084 mL, 0.77 mmol). TTie reaction mixture was stirred at ambient temperature for 5 hours and N,N-dimethylformarnide was removed in vacuo. The residue was dissolved in ethyl acetate (15 mL) and urashed with saturated aqueous sodium bicarbonate (2 x 5 mL) and brine (5 mL). The organic layer was dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid (0.12 g, 47%); mp 235-237 0C (ethyl acetate); 1H NMR (300 MHz, DMSO- d6) δ 8.83 (t, J = 5.8 Hz, IH), 8.77 (d, J= 7.6 Hz, 1 H), 7.87-7.77 (m, 2H), 7.52-749 (m, 3H), 7.34-7.18 (m, 5H), 7.08-7.00 (m, 2H), 4.40 (d, / = 5.8 Hz, 2H), 2.59 (s, 3H); 13CNMR (75 MHz, DMSD- d6) 5 161.9, 160.4, 153.7, 151.4, 150.6, 139.9, 135.9, 131.6, 130.9, 129.7, 128.8, 127.8, 127.5, 127.3, 124.5, 432, 17.6; MS (ES+) m/z 402.5 (M + 1).
EXAMPLE Ll
Synthesis of ΛT-Bcπiyl-2-(4-(cyclopropylaiethra) r)-2-oxopyridiπ-l(2fl)-yl)-4- methylthiazole-5-carboxamide
Figure imgf000060_0001
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(eyclopropylmethoxy)-2-oxopyridin-l(2H)-y])-4-met]ιy]thiazo]e-5- carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenyIpyπdm-](2.H)-yl)t]ιia2θle-5- carboxylic acid to react with benzylamine, the title compound was obtained as a white solid in 58% yield: mp 218-220 0C (hexane/ethyl acetate); 1H NMR (300 MHz, DMSO- dt) δ 8.77 (t, /= 5.9 Hz, IH), 8.58 (d, J = 8 1 Hz, IH), 7.35-7.18 (m, 5H), 6.34 {dd,J = 8.1, 2.7 Hz, IH), 6.05 (d, J- 2.7 Hz, IH), 433 {A, J= 5.9 Hz, 2H), 3.88 (d, /= 7.2 Hz, 2H), 2.53 (s, 3H), 1.26-1.10 (m, IH), 0.52-050(m, 2H), 0.32-0.27 <m, 2H); 11C NMR (75 MHz1 DMSO-If6) 8 167.8, 161.9, 161.«, 153.S, 150.3, 139.9, 131.9, 1287, 127.7, 127.2, 123.6, 104.4, 96.8, 73.9, 43.1, 17.5, 9.9, 3.6; MS (ES+) m/z 396.2(M + 1).
EXAMPLE L2
Synthesis of iV-Benssyl-2-(4-methoxy-2-i)x«pyridin-l(2fl)-yl)-4-ιnetliylthla20le-S- carboxamlde
N
Cu /=\ /
1 0
Following the procedure as described m Example 1 , making variations only as required to use 2-{4-methoxy-2-oxopyridin-l(2H)-yI)-4-methylthiazole-5-carboxylic acid in place of4-methyl-2-(2-oxo-4-phenylpyridin-l(2H)-yl)thiazole-5-carboxjlicacid to react with benzylamine, the title compound was obtained as a colorless solid in 17% yield: mp 205-208 αC (hexane/ethyl acetate); 1H NMR (300 MHz, DMSO-rf«) 58.78 (t, J = 6.0 Bz , IH), 8.59 (d, /= 8.1 Hz, IH), 7.35-7.17 (m, 5H), 6.33 (dd, J= S.I, 2.7 Hz, IH), 6.11 (d, / = 2.7 Hz, IH), 4.38 (d, J = 60Hz, 2H), 3.81 (s, 3H), 2.54 (s, 3H); 13C NMR (75 MHz1 DMSO- di) B 168.6, 161.9, 161.6, 153.9, 150.3, 139.9, 13ZC, 128.7, 127,2, 123.7, 104.2, 86.5, 56,8, 43.1, 17.5, M3 (ES+) m/z 356.2 (M + 1).
EXAMPLE 1.3
Synthesis of iV-Benzyl-2-(4-(2-c)'clopropyleth«xy)-2-oxopyridin-l(2fl)-yl)-*- methylthiazolc-S-carboxamide
Figure imgf000061_0001
Following the procedure as described in Example 1, making variations only as required to use 2.(4-(2-cyclopropylethoxy)-2-oxopyridin-l(2//)-yl)-4-πietriyltlHazole-5- carboxylio acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-l (2/f)-yl)thiazole-5- carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 1 TA yield: mp 172-174 0C (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) 8 8.64 (A, J= t.\ Hz, IH), 7.37-7.26 (m, 5H), S.16 (dd, .7= 8.1, 2.5 Hz, IH), 6.09<t, J = 5.6 Hz, IH), 5.97 (d, J= 2.5 Hz, IH), 4.58 <dt /= 5.6 Hz, 2H), 4 03 (t, J= 6,6 Hz, 2H), 2.68 (s, 3H), 1.58 (q, J= 6.6 Hz, 2H), 0.89-0.72 (m, IH), 0.52-0.46 (m, 2H), 0.13-0.08 (m, 2H); 11C NMR (75 MHz, CDCl3) B 1678, 162.2, 162.1, 153.6, 152.1, 137.7, 131.3, 128.8, 127.9, 127.7, 122.2, 104.1, 96.6, 69.1, 44.1, 33.6, 17 3, 7.5, 4.2; MS (ES+) m/. 410.2 (M + 1).
EXAMPLE 1.4
Synthesis of 2-(4-(2-Cyclopro pyle»hoxy)-2-oxopyridin-l(2H)-yl)-Λr-(4-tluorobeiizj'l)- 4-methylthiaz<]le-5-carboxaimde
Figure imgf000062_0001
Following the procedure as described in Example 1, making variations only as required to use 4-fluorbenzylamine in place of benzylamine to react with 2-(4-(2- cyclopropy]ethoxy>2-oxopyiiain-lC2fl)-ylH-methylthiazole-5-carboxyllc acid, the title compound was obtained as a colorless solid in 30% yield: mp 172-1740C (ethyl acetate), 1H NMR (300 MHz, CDCl3)O 8.64 (d, J= t.l Hz, IH), 8.32-8.27 (m, 2H), 7.05-7.00 (m, 2H), 6.17-6.08 (m, 2H), 5.97 (t, J= 2.5 Hz, IH), 4.54 (d,/= 5.7 Hz, 2H), 4.03 (t, J= 6.6 Hz, 2H), 2.67 (s, 3H), 1.68 (q, J= 6.6 Hz, 2H), 0.87-0.93 (m, IH), 0.54-046 (m, 2H), 0.13-0.08 (m, 2H); '3C NMR (75 MHz, CDCI3) 5 167.9, 163.9, 162.2, 160.6, 153.6, 152.4, 133.6, 131.3, 129.5, 122.0, 115.8, 1042, 96.6, 69.1, 43.3, 33.6, 17.3, 7.5, 4.2; MS (ES+) mlz 428.2 (M + 1).
EXAMPLE 1.5
Synthesis of 2-(4-(2-Cyclopropylethoxy)-2-oϊopyridin-l(2Λ)-yl)-4-raeHiyl-iV- (pyridin-3-ylmethyl)thiazole-5-carboxami<le
Figure imgf000062_0002
Following the procedure as described in Example 1 , making variations only as required to usepyτidin-3-ylmethanamine in place of benzylamine to react with 2-(4-(2- cyclopropyIethoxy)-2-oxopyridin-l(2H)-yl)-4-rnethylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 47% yield: rap 170-172 0C (ethyl acetate); 1H NMR (300 MHz, CDCl3) S 8.63 (d, J = 8.1 Hz, 2H), 8.55 (s, IH), 7.77 id, /= 7.8 Hz, IH), 7.37-7.27 (m, IH), 6.43 (t, J= 5.7 Hz, IH), 6.16 (dd, J= 8.1, 2.6 Hz, IH), S.96 (d, J = 2.6 Hz, IH), 4.62 (d, J= 5.7 Hz, 2H), 4.03 CA J= 6.6 Hz, 2H), 2.67 (s, 3H), 1.68 (q, J=
6 6 Hz, 2H), O.86-0.74 (m, IH), 0.52-0.46 (in, 2H), 0.13-0.08 (m, 2H); 13C NMR (75 MHz, CDCIj) S 167.9, 162.5, 162.1, 153.7, 152.«, 148.6, 148.3, 136.3, 131.3, 121.7, 104.2, 96.6, 69.1 , 41.4, 33.6, 17.3, 7.56, 4.2; MS (ES+) m/z 411 2 (M 4 1).
EXAMPLE 1«
Synthesis of /^-(4-Fluorobenzyl)-2-(4-hydrαxy-2-oxopyridiπ-l(2.ff)-yl)-4- mcthylthiuzolc-J-carboxamidc
Figure imgf000063_0001
Following the procedure as described in Example 1, making variations only as required to use 4-fluorobcnzylamine in place of benzylamine to react with 2-(4-hydroxy- 2-oxopyridiri-l(2ft)-yl)-4-methylthiazo]e-5-carbcxylic acid, the title compound was obtained as a colorless solid in 37% yield: mp 280-282 0C (methanol/ethyl acetate); 1H NMR (300 MHl. DMSO-Cf4) S 8 74 (t. J= 5 9 Hz, IH), 8 56 (d, J= S Q Hs, IH), 7 34. 7.29 (m, 2H), 7.12 (t, J = S.9 Hz, 2H), 6.22 (da, J= 8.0, 2.5 Hz, IH), 5.75 (d, J= 2 5 Hz, IH), 4.35 (d, J= S.8 Hz, 2H), 2 52 (s, 3H); 15C NMR (75 MHz, DMSCW6) 5 167.9, 162.0, 161 6, 154.1, 150.2, 139.9, 132.6, 128.7, 127.7, 127.2, 123.6, 104.4, 98.0, 43.1, 17.5; MS (ES+) m/z- 360.1 (M + 1).
EXAMLPE 1.7
Synthesis of JV-Benzyl-2-(4-(benayloKy)-2-aiopyridin-l(2B)-yl)-4 mβthyl-lff imiύazole-S-c-rboxainide
Figure imgf000063_0002
Following the procedure as described in Example 1 , making variations only as required lo use 2-[4-(benzyloxy)-2-oxopyridιn-K2Λ)-yl)-4-methyl-lfl"-imida2ole-5- carboxylic acid in place of 4-mcthyl-2-(2-oxD-4-phenylpyπdin-l(2.£f)-yl)trιi-zolε-5-
carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 59»/o yield: mp 183-184 0C; 1H NMR (300 MHz, CDCI3) S 11.86 (br 3, IH), 8.42 (d, J = 8.0 Hz, IH), 7.43-7.26 (m, 10H), 6.18 (dd, J= 8.0, 2 6 Hz, IH), 6.04 (d, J= 2.6 Hz, IH), 5.05 (s, 2H), 4.61 (d, /= 6.0 Hz, 2H), 2,65 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 163 6, 163.4, 138.8, 134.6, 132.2, 129.5, 128.8, 128.7, 128.6, 127.8, 127.8, 127.3, 126.9, 103.5, 98.4, 70.7, 42.7, 11.0; MS (ES+) m/z 415.2 (M + 1).
EXAMPLE 1.8
Synthesis of 2-(<t-(Benzyloxy)-2-oxopy rl<lln-l(2.fl)-yl)-*-πierhyl-/V-(py ridin-3- ylmelby X)-IH- imidazole-5-carboxamide
Figure imgf000064_0001
Following the procedure as described in Example 1, making variations only as required to use 2 (4-(benzyloxy)-2-oxopjτidim-l (2H)-yl)-4-meth)1-lH-imιclazolc-5- carboxylic acii in place of 4-methyl-2-(2-ojso-4-phenylpyridin-l(2H)-yl)tlιiazole-5- carboxylic acid to react with S^arninomethyl^yridine, the title compound was obtained as a colorless solid in 63% yield: mp 203-20* 0C; 1H NMR (300 MHz, DMSO- d6) δ 12.70 (brs, IH), 8.58-8.51 (m, 2H), 8.43 (d, J= 3.9 Hz, IH), 8.01 (d, J= T.J Hz, IH), 7.70 (d, J= 7.S Hz, IH), 7.50-7.29 (m, 6H), 623 (dd, /= 7.8, 2.6 Hz, IH), 6.07 (d, J= 2.6 Hz, 1 H), 5.16 (s, 2H), 4.40 (d, J= 6.3 Hi.2H), 2.47 (s.3H): 13C NMR. (75 MHz, DMSO- d6) 5 167.2, 162.9, 162.0, 148.8, 147.8, 137.3, 135.9, 135.6, 133.4, 133.1, 130.8, 128.5, 128.2, 128.0, 127.4, 123.3, 101.6, 97.5, 70.0, 10.5; MS {ES+) m/z41S.3<M + 1).
EXAMPLE 1.9
Synthesis oϋV-Benzyl-2-(4-(benzyloxy)-2-iκepy rid in-l(2H)-yl)-l,4-(liiii ethyl- IH- imidazole-5-carfcoxamide
Figure imgf000065_0001
Following the procedure as described in Example 1, making variations only as required to use 2<4-(benzyloxy)-2-oxopyridirι-l(2//)-yl)-l,4-dimethyl-lfl-irmdazole-5- carboxylic acid in place of 4-methy]-2-(2-oxo-4-phenylpyridin-l(2/f)->'I)thiazole-5- carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 62% yield: mp 232-233 0C; 1H NMR (300 MHz, CDCl3) S 7.43-729 (m, 10H), 7 19 (d, J= 7.7 Hz, IH), 6.17 (t, J= 5.6 Hz, IH), 6.09 (dd, J= 7.7, 2.5 Hz, IH), 5.96 (d, J = 2.5 Hz, IH)1 5.02 (s, 2H), 4.62 (d, J= 5.6 Hz, 2H), 3.67 (s, 3H), 2.39 (s, 3H); 13C NMR (75 MHz, CDC]3) 5 168.3, 163.3, 160.9, 141.5, 138.0, 137.8, 136.8, 134.7, 128.84, 128.8, 128.6, 127,7, 127.7, 127.6, 123.5, 102.8, 97.8, 70.6, 43.6, 32,7, 15.2; MS (ES+) mlz 429.3 (M + 1).
EXAMPLE 1.10
Synthesis of 7y-Beozyl-2-(4-{benzyloxy)-2-ox»pyridin-l(2fl)-yl)-l,S-dimethyl-lfi- imidazole-4-carboxamide [Not covered b> Formula (I)]
Figure imgf000065_0002
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(benzyloxy)-2-oxopyridin-l (2ff>-y')-l,5-dimethyl-lfl-iniidazole-4- carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-l(2iϊ)-yl)thiazole-5- carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 76»/o yield, mp 190-191 0C; 1H NMR (300 MHz, CDCl3) S 7.43-729 (m, 10H), 7,21 (d, J= 7.7 Hz, IH), 6.08 (dd, J= 7.7, 2,5 Hz, IH), 5.98 (d, J= 2.5 Hz, IH), 5.04{s, 2H), 4.56 (d, J = 6.1 Hz, 2H), 3.39 (S, 3H), 2.63 (S, 3H); 15C NMR (75 MHz, CDCl3) θ 168.3, 163,4, 1«3.1, 138.6, 138.4, 137.1, 134.7, 133.5, 129.1, 128.8, 128.7, 128.5, 127.8,
127.7, 127.2, 1C2.7, 97.8, 70.6, 42.7, 30.6, 100; MS (ES+) m/z 429.3 (M +■ 1).
EXAMPLE 111
Synthesis of 2-(4-Methoxy-2-oxopyridiπ-l(2Λ)-yl)-4-methyl-iV-(pyri<lin-3- ylmethyl)thLaz»le-S-carboxamide
Figure imgf000066_0001
Following the procedure as described in Example 1 , making variations only as required to use 2-(4-methoxy-2-oxopyridin-l(2H)-yl)-4-methylthiazole-5-c.rboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyiidin-l(2Λ)-yl)thia™le-5-carbθϊylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 58% yield: mp 200-202 0C (dichloromethane/methanol); 1H NMR (300 MHz, CDCIj) 68.64 (d, / = 8 1 Hz, IH), 8.60-8.59 (m, IH), 8.52-8.51 (m, lH), 7.51-7.68<m, IH), 7.29-7.24 (m, IH), 6.30 (t, J- 5.8 Hz, IH), 6.17 (dd, J- 8.1, 2.6 Hz, IH), 5.W (d, J= 2.6 Hz, IH), 461 (d, J= 5.8 Hz, 2H), 3.82 (s, 3H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.4, 162.4, 162.1, 153.6, 152.6, 149.2, 149,0, 135.7, 133.7, 131 4, 123.6, 121.8, 103.9, 96.2, 5SO, 41.4, 17.3; MS (ES+) mlz 357.2 (M + 1).
EXAMPLE 1.12
Synthesis of ♦-Mcthyl-l^I-oxo^-rtS-CtrifuoromethylJfnran^-yOniethcxyjpyridiπ- l(2//)-y])-Λr-<pyrϊdin-3-ylmcthyl)thiazole-5-<arboxaιnide
Figure imgf000066_0002
Following the procedure as described in Example 1, making varialions only as required to use Φ-methyl-l^-oxo^-^S^triflLioromethy^fuian^-ylJmethox^pyridin- l(2H)-yl)thiazole-5-carboxyhc acid in place of 4-methyl-2-(2-oxo-4-ρhenylpyridin- l(2H)-yl)th]azole-5-carbϋxyliC acid to react with pyrϊdϊn-3-ylmethanamine the title compound was obtained as a colorless solid in 90% yield: mp 240-242 0C
(dichloromefliane/methanol); 1H NMR (300 MHz, CDCl5) 8 8.69 (d, J= 8.1 Hz, IH), 8.60 (a, IH), S.52 (d, J= 5.8 Hz, IH), 7.70 jd, /- 7.7 Hz, IH), 7.28-7.26 (rα, IH), 6.81- 6.79 (m, IH), 6.57-6.56 (m, IH), 6.38 (br s, IH), 6.25-6.18 (m, IH), 6.05 (Irs, IH), 5.00 (s, 2H), 4.61 (d, /= 5.8 Hz, 2H), 2.67 (s, 3H), 13CNMR (75 MHz, CDCI3) 5 166.6, 162.3, 161.7, 153.4, 152.5, 150.5, 149.3, 149.1, 135.6, 133.6, 131.8, 123.6, 122.1, 112.4, 111.7, 103.7, 97.1, 62.1, 41.5, 17.3; MS (ES+) tn/z 491.3 (M + 1).
EXAMPLE 1.13
Synthesis of 2-(4-(4-Fluorobenzyloxy)-2-ox()pyrlflin-l(2fll-yl)-4-nietliyIJV-Cpyndin-
S-ylmethyOtliiazole-S-carboxarnide
Figure imgf000067_0001
Following the procedure as described in Example 1, making variations only as required tα use --(4-(4-fluorobenzylox5')-2-oxopyrldln-l(2/f)-yll-4-methyltiiazole-5- carboxylic acid in place of 4-methyl-2-(2-ojco-4 -phenylpyridin-l(2/7)-y])t.lii_zole-5- carboxylic acid to react with pyridin-3-ylmethanamine, the title compound wis obtained as a colorless solid in 52% yield: mp 231-2330C (dichloromethane/methancl); 1H NMR (300 MHz, DMSCWs) 8 8.83 (t, J= 5.6 Hz, 1 H), 8.60 (d, J= 8.1 Hz, IH), 8.50 (s, IH), 8.43 (d, J= 4.2 Hz, IH), 7.69 (d, J= 7.9 Hz, IH), 7.51-7.47 <m, 2H), 7.37-7.29 (m, IH), 722 ((,./= 8.8 Hz, 2H), 6.41-6.35 (m, IH), 5.23 (s, IH), 5 13 (s, 2H) 4.40 (ά, J = 4.2 Hz, 2H). 2.53 Cs.3H); 13C NMR (75 MHz, DMSG-*) S 167 i, 164 1, 162.0, 161.6, 160.9, 154.0, 150.6, 149.3, 148.5, 135.6, 132.1, 131.0, 130.9, 123.9, 116.0, 115.7, IC4.4, 97.5, 70.1, 42 2, 175, MS (ES+) mh 451.3 (M + 1).
Example 1.14
Synthesis of Λr-(4-Fluorobenzyl)-2-(4-(4-tliiβrobenzyloxy)-2-oxopyridii-l(2fl)-yl)-4- methylthiazole-S-carboxamide
Figure imgf000068_0001
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(4-fluorobenzyloxy)-2-o>opyridin-l(2fl)-yl)-4-methylthiazole-5- carboxylic acid in place of 4-methyl-2-(2-03«>4-phenylpyridin-l(2//)-yl)thiazole-5- carboxylic acid to react with (4-fluoropherryl)methanamine, the title compound was obtained as a colorless solid in 34% yield: rap 249-251 0C (hexaπεs/ethyl acetate), 1H NMR (300 MHz, DMSO-C/6) δ 8.78 (t, J - 5.9 Hz, IH), 8.60 <d, J- 8.1 Hz, IH), 7.51- 7.47 (m, 2H), 734-7.29 (m, 2H), 7.25-7.08 (m, 4H), 6.37 (dd, J= 8.1, 2.7 Hz, 1 H), 6.23 (d, J = 2.7 Hz1 IH), 5.14 (s, 2H), 4.35 id, J= 5.9Hz, 2H), 2.53 fs, 3H); '3C NMR (75 MHz, DMSO-<i) δ 167.4, 164.1, 163.2, 161.9, 160.9, 153.9, 150.4, 136.1, 132.1, 131.0, 130.9, 129-8, 123.6, 116.0, 115.7, 104.3, 975, 70.1, 42.4, 17.5; MS (ES+) mJz 468.3 (M + 1).
EXAMPLE 1.15
Synthesis of JV-(3-Fluorobenzyl)-2-(4-hydroxy-2-oxopyridin-l (2fl)-yl)-4- iiiethylthiazoU-5-carhoxaniide
Figure imgf000068_0002
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridiiι-l<2fl)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-l(2fl)-yl)thiazole-5-carbcκylic acid to react with (3-fluorophenyl)methan_mine, tile title compound was obtained as a colorless solid in 44% yield: mp 250-252 °C (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO- <k) S 11.50(br s, IH), 8.78 (t, 7= 6.0 Hz, IH), 8.59 (d, J= 8.0 Hz, IH), 7.39-7.30 (m, IH), 7.13-7,00 (m, 3H), 6.26 (dd, J= 8.0, 2.5 Hz, IH), 5 82 <d, J= 2.5 Hi, IH), 4,39 <d, J = 5.9 Hz, 2H), 2.53 (s, 3H); 13C NMR (75MHz, DMSO-(Z6) δ 167.9, 164.2, 162.1, 161.6,
154.2, 142.9, [42.8, 132.6, 130.7, 123.7, 123.+, 114.5, 114.1, 104.4, 98.0, 42.«, 17.5; MS (ES+) Wz: 360.2 (M + 1)
EXAMPLE 1.16
Synthesis of .(V-(Cy clopropylmethyl)-2-(4-hydroxy-2-oxopyridin-l(2iT)-yl)-4- methylthiazole-5-carboxaπiide
Figure imgf000069_0001
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyτidin-l(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyri<lin-l(2H)-yl)thiazole-5-carbθλylic acid to react with cyclopropylmethanamme, the title compound was obtained as a colorless solid in 76% yield: mp 240-242 0C (ethyl acetate/hexanes); 1H NMR (300 MHi, DMSO-rfj) δ 11.56 (br s, IH), 8 58 (d, J= 8.0 Hz, IH), 8.26 (t, J= 5.6 Hz, IH), 6.25 (dd, J = 8.0, 2.5 Hz. IH). 3.Sl H, J= 2.5 Hz, IH), 3.05 (m, 2H), 2 51 (S, 3H), 1.05-0.92 (m, IH), 0.43- 0.36 (m, 2H), 020-0.15 (m, 2H); 13C NMR (75MHz, DMSOrfs) B 167.9, 161.8, 161.6, 153 9, 149 7, 132.6, 124.0, 104 3, 98.0, 43.9, 17.4, 11.4, 3.7; MS (ES+) m/z: 306.2 (M + I)-
EXAMPLE 1.17
Synthesis of Λ'-(2-Cyclopropyle*liyl)-2-(4-lij'<lroxy-2-oxoρyridiπ-l(2a)-jl)-4-
■nethylthiazDle-5-carboxamide
V~ ϊ > ~
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-l(2i/)-yl)-4-niethylthiazole-5-carboxy]ic acid in place of4-methyl-2-(2-oxo-4-phenylpyridiii-l(2//)-yl)thiazole-5-carbo3iylic acid to react with 2-cycloρropyJethanamine, the title compound was obtained as a colorless solid
in 64% yield: mp 234-236 "C (ethyl acetateΛiexanes); 1H NMR (300 MHz, DMSO-^6) δ 11.47 (s, 1H), 8.5S (d,J= 8.0 Hz, IH), 8.16 (t, J= 5.6 Hz, IH), 6.25 (dd, /- 8.0, 2.6 Hz, IH), 5.81 (d, / = 2.5 Hz, IH), 3.26-3.20 (m, 2H), 2.50 (B, 3H), 1.40-1.34 (m, 2H), 0.76- 0.59 (m, IH), O.39-0.33 (m, 2H), 0.03-0.01 [m, 2H); 13C NMR (75 MHz, DMSO-d4) δ 167.8, 161.8, 161.6, 153.9, 149.4, 132.6, 1242, 104.3, 98.0, 39.9, 34.4, 17.4, 9.0, 4.6; MS (ES+) ffi/z 320.2 (M + 1).
EXAMPLE 1.18
Synthesis of Λ^-FluorπphenethyO-Σ-^-kydroxy-Z-oxopyrldiπ-llZffl-JlM- methylthiazole-S-carboxamide
Figure imgf000070_0001
Following the procedure as described in Example 1 , making variations only as required to use 2-(4-hydroxy-2-oxopyridin- 1 (2i/)-y])-4-mcthylthiazD]ε-5-C2rboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-l(2/r)-yl)thiazole-5-carboxylic acid to react with 2-(4-fluoropheny])ethanamine, the title compound was obtained as a colorless solid in 69% yield' mp 225-2270C (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO- ds) δ 11.47 (s, IH), 8.57 (d, J= 8.0 Hϊ, IH), 8.23 (t, J= 5.5 Hz, IH), 7.25-7.18 (m, 2H), 7 12-7.04 (m, 2H), 6.25 (dd, J= 8.0, 2.6 Hz, IH), 5.81 (d, J= 2.5 Hz, IH)1 3.42-3.35 (m, 2H), 2 78 (UJ= 7.2 Hz, 2H), 2.50 (s, 3H); 11C NMR (75 MHz, DMSO-4,) S 167.8, 161.9, 1(51 ,6, 139.«, 154.1, 149 6, 136.0. 132.9, 130.9, 124.0, 115 5, 1013, S8.0, 41.2, 34.5, 17.3; MS (ES+) m!z 374.2 (M + 1).
EXAMPLE L19
Synthesis ofiV-(3,4-Difluorobeiizyl)-2-(4-liydroxy-2-oxopyridin-l(2H)-yl)-4- methylthiazn]e-5-carboxainide
Figure imgf000071_0001
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-l{2.y)-yl)-4-rnethylthiazole-5-carboxylic acid in place of 4-mettiyl-2-(2-oxo-4-phenyIpytidm-l(2Λ)-yl)thiazole-5-carbθϊylfc acid to react with (3,4-dif3uorophenyl)methanamine, the title compound was obtained as a colorless solid in 88% yield: mp 294-2960C (ethyl -cetate/hexanee); 1H NMR (300 MHz, OMSO-di) δ 11.50 (br s, IH), 8.77 (t, J= 5.8 Hz, IH), 8.59 (d, J= 8.0 Hz, IH), 7.40-7.28 (m, 2H), 7.15-7 10 (m, IH), 626 (dd, J= 8.0, 2.6 Hz, IH), 5.82 (d, J= 2.6 Hz, IH), 4.35 (d, J= 5.8 Hz, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, DMSO-4,) δ 167.9, 152.1, 161.6, 154.2, 150.5, 137.7, 132.6, 124.5, 123.3, 117.3, 117.6, 116.8, 116.6, 104.4, 98.0, 42.2, 17.5; MS (ES+) mix 378.2 (M + 1).
EXAMPLE 1.20
Synthesis of 2-(4-Hydroxy-2-oxopyridin-l(ia)-yl)-4-αiethyl-Λ'-(|)}τitliii-4- ylmethyl)thiazι>le-5-carboxaniide
Figure imgf000071_0002
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyπdin-l(2J/)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridiii-l(2Λ)-yl)thiazole-5-carbθJ<ylic acid to react with pyridiri-4-ylmethanamine, the title compound was obtained as acolorless solid in 46% yield: mp 275-278 0C (dichloromethane/methanol); 1H NMR (300 NtHz, DMSO- d6) i 11.59 (bi E, IH), 8.88-8.78 (m, IH), 8.58 (t, J= 8.9 Hz, IH), 8.47-8.44 (m, 2H), 7.26-7.23 (m, 2H), 6.27-6.22 (m, IH), 5.85-5.80 (m, IH), 4.44-4.30 (m, 2H), 2.56 (s, 3H); 13C NMR (75 MHz, DMSO-i4) 6 167.S, 162.2, 161.5, 154.2, 150.6, 149.9, 148.«, 132.6, 123.2, 122.6, 104.4, 98.0, 42.2, 17.5; MS (ES+) mk 343.2 (M + 1).
EXAMPLE 1.21
Synthesis of I-^-Hydroxy-Z-oxopyridin-Kliri-yO^-methyl-iV-CCS-metliylpyrazin-Z- yl)methyl)thiazole-5-carboxamide
Figure imgf000072_0001
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-K-J?l-yl)-4-methylthiazole-5-t_rtioxylic acid in place of 4-metliyl-2-(2-oxo-4-pheπylpyridiii-l (2/f)-yl)thiazolc-5-carbo!(ylio acid to react with (5-methy]pyrazin-2-yl)methanamine, the title compound was obtained as a colorless solid in 14% yield: 1H NMR (300 MHz, DMSCW4) δ 11.49 (s, IH), 8.80 (t, J- 5 2 Hz, IH), 8.59 (d, J= 7.8 Hz IH), 8.44 (s, 2H), 6.26 (d, J = 7.8 Hz, IH), 5.81 (s, IH), 4.47 (d, J= 5.2 Hz, 2H), 2.52 (s, 3H), 2.43 (s, 3H); MS (ES+) m/z 358.1 (M+ 1).
EXAMPLE 1.22
Synthesis of 2-(4-Hydroxy-2-oxopyridin-l(2.ff)-yl)-4-niethyl-JV-(oxaϊol-2- yl mef hy])thiaz(»]e-5-carboj£ani ide
Figure imgf000072_0002
Following the procedure as described In Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-l(2#)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridra-l{2.H)-yl)thiazole-5-carboj(y]ic acid to react with oxazol-2-ylmethanamine, the title compound was obtained as a colorless solid in 25% yield: 1H NMR (300 MHz, DMSOV5) S 11.51 (s, IH), 8.84 (t, J= 5.7 Hz, IH), 8 59 (d, J= 8.0 Hz, IH), 8.02 (s, IH), 7.12 (s, IH), 6.26 (dd, J= 8.0, 2.5 Hz, IH), 5.82 (d, J= 2.5 Hz1 IH), 4.48 (d, J= 5.7 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 333.2 (M + 1 ).
EXAMPLE 1.23
Synthesis of 5-(4-(Benzyloxy )-2-oxopy ridin-l(2fl)-yl)-3-methyl-iV-(py ridiπ-3- ylιnethyl)thiθ|}lieiie>2-carboxaniide
Figure imgf000073_0001
Following the procedure as described ill Example 1, making variations only as required to use 5-(4-(benzyloxy)-2-oxopyτidin-l(2H)-yl)-3-m«thylthiopliene-2-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-l(2/0-yl)Λiaz°le-5-caiboxy]ic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 39°/. yield: mp 165-167 0C; 1H NMR (300 MHz, CDCl3) δ 8.61 (d, /= 1.5 Hz, IH), 8.54 (dd, J = 4.7, 1.5 Hz, IH), 7.71 (dt J= 7.8, 1.5 Hz, IH), 7.57 (d, J- 7.8 Hz, IH), 7.43-7.27 (m, 6H), 6 85 {s, IH), 6.30 (1, /= 5.8 Hz, IH), 6.15 (dd, J = 7,8, 2.7 Hz, IH), 6.06 <d, / = 2.7 Hz, IH), 5.04 (s, 2H), +.51 (d, J= 5.8 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, DMSO-Cf6) 8 166.2, 162.6, 160.9, 138.8, 137.5, 135.4, 135.0, 128.5, 128,2, 128.0, 126.9, 120.5, 102.6, 97.3, 70.0, 15.5; MS (ES+) m/z432.2 (M + 1).
EXAMPLE 1.24
Synthssis ofΛ'-Benzyl-2-(4-(4-fluorobenzylojy)-2-oxopyridin-l(2jff)-yl)-J*" methyUhiazole-5-carboxamidG
Figure imgf000073_0002
Following the procedure as described in Example 1, making variations only as required to use 4-methyl-2-(2-oxo-4-(4-(trif]uστomethyl)beπzyloxy)pyriditi-l(2H)- y])thiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-prienylpyridirι-i(2fl)- y])thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 8% yield: mp 243-245 <C; 1H NMR (300 MHz, CDCb) 8 8.7 (d, J = 8.1 Hz, IH), 1J9-7.06 (m, 9H).6.23-6.05 (m, 3H), 5.28 (s, 2H), 4.60 (d, J = 54 Hz, 2H), 2.68 (5, 3H), 13C NMR (75 MHz, CDCI3) δ 192.8, 167.2, 162.3, 162.2, 153.5, 152.1, 137.7, 131.7, 130.4, 129.9, 129.7, 128.9, 127.9, 127.7, 122.4, 116.0, 115.7, 1C4.0, 97.4,
70.1, 44.1, 173; MS (ES+) m/z 450.3 (M + 1).
EXAMPLE 2
Synthesis of Af-Benzyl-2-(4-(beDzyloxy)-2-osβpyridiιi-l(2a)-yl)-4-πiethylfhiazole-5- carboxamide
Figure imgf000074_0001
To a solution of 4-methyl-2-(4-(bemyloxy)-2-oxopyridin-l(2fl)-yDmiazole-5- carboxylic acid (0.10 g, 0.29 mmol) and 4-methylmorpholine (0.032 itiL, 0.29 mmol) in anhydrous dichloromethane (6 mL) was added isobutylchloroformate (0.044 inL, 0.34 mmol) dropwise at 0 0C. After stirring at ambient temperature for 2 hours, the reaction mixture was cooled to 0 °C and benzylamine (0.032 mL, 0.29 mmol) was added dropwise. Stirring at ambient temperature was continued for IS hours, then the reaction mixture was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL) and brine (3O mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of ethyl acetate/dichloromethane 1/1 (10 mL) to afford the title compound as a white solid (0.055 g, 44%) • tup 219-220 0C (ethyl acetate/dichloromethane); 1H NMR (300 MHz, CDCl,) B 8.67 (d, J= S.1 Hz, IH), 7.47-7.15 (m, 10H), 6.22 (dd, J= 8.1, 2.6 Hz, IH), 6.14 (t, /= 5.6 Hz, IH), 6.D5 (d, J= 2.6 Hz, IH), 5.03 (s, 2H), 4.58 (d, J = 5.6 HZ.2H) 2.58 (S, 3H); 13C NMR (75 MHz, CDCl3) 5 1674, 162 3, 1S2 0, 153 5, 152.2, 137.8, 134.6, 131.6, 12S.9, 128.8, 127.9, 127.8, 127.7, 122.4, 104 1, 97.4, 70.S, 44.1, 17.3; (ES+) mJz 432.2 (M + 1).
EXAMPLE 3
Synthesis of 2-{4-Amino-2-oxopyridin-l (2A>5 l)-.V-hcnzy]-4-methyltlii:iMle-5- carboxamide
Figure imgf000075_0001
To a degassed solution of JV-benzy]-2-bromo-4-methylthiazole-5-carboxamide (1.58 g, 5.00 iπiπol), 4-amiπopyridiπ-2(lfl)-one (0.72 g, 6.50 mmol), potassium carbonate (2.C0 g, 14.40 mmol) and 8-hydroxyquinoline (0.Q8 g, 0.50 mmol) in dimethyl sulfoxide (3D mL) was added copper{[) iodide (0.10 g, 0.50 mmol). The reaction mixture was heated at 75-80 DC for 16 hours, then cooled to ambient temperature. Water (300 mL) was added to the mixture and the crude product was precipitated and collected by filtration The crude product was subjected to column chromatography to afford the title compound as a white solid (0.84 g, 49%): mp 171-172 °C; 1H NMR (300 MHz, DMSO- dt) fi 8.68 (t, J= 5 7 Hz, IH), 8 40 (d, J= 7.8 Hz, IH), 7.32-7.19 (m, 5H), 680{s, 2H), 6.07 (dd, J= 7.8, 1.8, Hz, IH), 5.38 (d, J= 1.8 Hz, IH), 4.37 (d, J= 5.7 Hz1 2H), 2.50 (s, 3H); 13C NMR (75 MHz1 DMSO-^) δ 162.2, 160.8, 157.7, 154.6, 150.0, 140.0, 131.5, 128 7, 127.7, 127.1, 122 9, 103 4, 90 5, 430, 175; MS (ESf) m/z 341 2 (M4 1)
EXAMPLE 3.1
Synthesis of /V.Beni>l-l-mctliyl-2-(3-ilιctli>l-2-oxopyra/in-1(2H;)-yl|thitznle-5- carboxamide [Not covered by Formula (I)]
Figure imgf000075_0002
Following the procedure as described in Example 3, making variations only as required to use 3-methylpyrazin-2(l//)-one m place of 4-aminopvridin-2(liO-one to react with Λr-benEyl-2-bromo-4-niethylthiazole-5-catboxamide, the title compound was obtained as a white solid in 5% yield: mp 186-1870C; 1H NMR {300 MHz, CDCI3) 8 8.44 (s, IH), 7.45-7.25 (m, 6H), 6.12 (s, IH), 4.59 (d,./- 5.7 Hz, 2H), 2.6? (s, 3H), 2.55 (s, 3H); 13C NMR (75 MHz, CDCI3) S 161.«, 159.2, 153.4, 152.4, 152.0, 1375, 128.8,
127.9, 127.8, 124.5, 123.5, 119.3, 44.2, 20.8, 17.3; MS (ES+) m/z 341.2 (M + 1).
EXAMPLE 3.2
Synthesis of JV-Benzyl-2-(5-(benzyloxy)-2-oxopyridin-l(2fl)-yl)-4-metliylthiazole-5- carboxamide
Figure imgf000076_0001
Following the procedure as described in Example 3, making variations only as required to use5-(benzyloxy)pyridin-2(l/f)-one in place of4-aminopyridin-2(l//)-one to react with iV-benzyl-2-bromo-4-methylthia2o]e-5-carboxamide, the title compound was obtained as a white solid in 32% yield: mp 166-167 °C; 1H NMR (300 MHz, CDCl3) 6 8.36 (d, J = 27Hz5 IH), 7.48-7.22 (m, HH), 6.61 (d, J = 9.9 Hz, IH), 645 (t, J= 5.4 Hz, IH), 4.98 (s, 2 H), 4.56 (d, J= 5 4 Hz, 2H), 210 (s, 3H); 13C NMR (75 MHz, CDCl3) Z 1(52.2, 138.7, 153.3, 152.1, 143.3, 137.8, 136 1, 135.5, 128.7, 128.6, 127.9. 127.8, 127.6, 121.7, 112.0, 71.3, 44.0, 17.3; MS (ES+) m/z 432.2 (M + 1).
EXAMPLE 3.3
Synthesis of JV-Benzyl-2-(S-chloro-2-oxopyrirlin-l(2Λ)-yl)-4-methylthiflZ(ile-5- carboxamide
Figure imgf000076_0002
Following the procedure as described in Example 3, making variations only as required to use 5-chloro-2-hydroxypyridine in place of 4-aminopjτidin-2(lfl)-one to react with ΛUjeπzyl-2-bromo-4-methyhhiazole-5-carbo?ςamide, the title compound was obtained as a white solid in 39% yield: mp 173-174 0C; 1H NMR (300 MHz, CDCl3) S
8.79 (d, ./ = 2.4 Hz, 1H), 7.36-7.23 (m, 6 H), 6,61 (d, J= 9.9 Hz, IH), 6.43 (s, IH), 4.55 (d, J- 5.4 Hz, 2H), 2.66 (s, 3H); '3C NMR. (75 MHz, CDCl3) δ 161.9, 158.8, 152.4, 152.0, 141.0, 131.7, 128.7, 128.5, 127.8, 1276, 123.8, 121.9, 115.5, 44.1, 17.2; MS (ES+) m/z36D.l (M + 1), 362, 1 (M + 1).
EXAMPLE $A
Synthesis of ?VBenzyl-4-inethyl-2-(2-oxo-5-<trifliioromethyl)pyridiιi-:l (2.H)- yl)thiazole-5-carboxamide
Figure imgf000077_0001
Following the procedure as described in Example 3, making variations only as required to iise2-hydroxy-5-(1rifluoromethyl)pyridine in place of 4-ammopyridin-2(l//)- one to react with A^ benzyl-2-bromo-4-methylthiazo]e-5-oarboxQmide, the title compound was obtained as a white solid in 60% yield: mp 148-149 0C; 1H NMR (300 MHz, CDCl3) δ 9.19 (br s, IH), 7.53 (dd, J= 9.6, 2.7 Hz, IH), 7.37-7.25 (m, 5H), 6.78 (d, /= 9.6 Hz, IH), 6.27 (t, / = 5.7 Hz, IH), 4.58 (d, J= 5.7Hz, 2H), 2.69 (s, 3H); 13C NMR (75 MHz, CDCl3) 8 161.7, 159.6, 152 4, 151.9, 137.5, 1352, 131 1, 128.8, 127.9, 124.6, 124.5, 122.1, 121.1, 111.8, 44.2, 17.2; MS (ES+) mJz 394.2 (M + 1).
EXAMPLE 3.5
Synthesis of \-Ben/yl-4-methyl-2-(2-oxc>-3-(trifluoroιncthyl)pjridiii-l(2//)- yllthiazole-5 carboxumidc
Figure imgf000077_0002
Following the procedure as described in Example 3, making variations only as
required to use 2-hydroxy-3-(trifluoromethyl)pyridine in place of 4-aminopyridiπ-2(lΛ)- oneto react ™thAM«nzyl-2-bromo-4-methyltMazole-5-carboxamide, the title compound was obtained as a white solid in 37% yield: mp 203-204 "C; 1H NMR (303 MHz, CDCl3) 8 9.01 (d, J= 7.2 Hz, IH), 7.87 (d, J = 7.2Hz, IH), 7.36-7.23 (m, 5H), 6.53 it, J= 7.2 Hz, IH), 6.10 (s, IH), 4.57 (d, J= 5.4 Hz, 2H), 2.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 156.6, 152.2, 152.1, 139.3, 139.2, 137.4, 135.1, 128.9, 128.8, 127.8, 123.8, 121.9, 106.0, 44.2, 17.2; MS (ES+) m/z 3942 (M + 1).
EXAMPLE 3.«
Synthesis of MBenzyM-methyl-2-(2-oi«-4-(trifluoromethyl)pyridin-l(2Λ)- yl)thiazole-5-carboxamide
Following the procedure as described in Example 3, making variations only as required to use 2-hydroxy-4-(trifluorometliyl)pyridine in place of 4-aminopyridin-2(l//)- one to react with Λf-benzyl^-bromo^-mefhyltliiazole-S-carboxamide, the title compound was obtained as a white solid in 9% yield: mp 197-198 0C; 1H NMR (300 MHz, CDCl3) δ S.93 (d, J= 78 Hz, IH), 7.39-7.25 (m, 5H), 7.00 (d, J = 0.6 Hz, IH), 6.57-6.54 (m, IH), 6.17 (s, IH), 4.59 (d, J= 5.7 Hz, 2H), 2.70 (s, 3H); '3C NMR (75 MHz, CDCl3) 8 161.7, 159.3, 152.4, 141.0, 137.5, 133.1, 128.8, 127.9, 127.8, 124.1, 119.1, 103,0, 44.2, 17.3; MS (ES+) m/2 394.2 (M + 1 ). EXAMPLE 3.7
Synthesis of iV-Benzyl-2-(3-(benzyloxy)-ϊ-oxo|iyridiii-l(2fl)-yl)-4-metlylβiiazole-5- carhoxamlde
Figure imgf000078_0002
Following the procedure as described in Example 3, making variations only as required to
Figure imgf000079_0001
with JV-benzyl-Z-bromo^-methylthiazoIe-S-carboxamide, the title compound was obtained as a white solid in 7% yield: mp 198-201 0C; 1H NMR (300 MHz, CDCl3) δ 8.45 (dd, J= 6.0, 3.0 Hz, IH), 7.46-7.29 (in, 10H), 6.73 (d, J= 6.0 Hz, IH), 6.32 (t, J= 6.0 Hz, IH), 6.13 (br, IH), 5.15 (s, 2H), 4.61 (AJ= 6.0 Hz, 2H), 2.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 187.9, 162.1, 152.1, 148.9, 137.7, 135.5, 128.8, 128.7, 128.3, 127.8, 127.7, 127.3, 122.9, 114.8, 106.7, 106.7, 96.8, 71 1, 44.1, 17.3; MS (ES+) mJz 432.2 (M + 1).
EXAMPLE 3.8
Synthesis of, V-Btιizyl-2-(5-(lκMiiylα.vy)-l-υxui»ϋquinolin-2(l//)-yl)-4-!niMhylthiαzole- 5-carboxamide
Figure imgf000079_0002
Following the procedure as described in Example 3, making variations only as required to use 5-(benzyloxv)isoquinol]n-l(2i/)-one in place of 4-aminopyridin-2(l.r7)- one to react with Λ'-benzyl-2-bromo-4-methyltliiazole-5-carboxaιnide, the title compound was obtained as - white solid in 2% yield: nip 225-226 0C; 1H NMR (300 MHz, CD3OD) S 7.77 (d, J- 60 Hz, IH), 7.41-7.25 (m, HH), 7.10-7.08 (m, 2H), 6.99 (d, /- 9.0 Hz, IH), 4.55 (s, 2H), 4.50 (s, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, DMSO-<fe) 5162.0, 159.6, 153.5, 151.3, 136.7, 135.0, 128.3, 127.2, 126.8, 126.7, 126.6, 126.4, 125.6, 125.4, 125.3, 125.2, 124.2, 115.5, 114.3, 99.9, 41.7, 31.1, 14.1; MS (ES+) m/z 48Z3 (M + l).
EXAMPLE 3.9
Synthesis of Λ'-Hcnz>M-2-(6-(benzylo\y)-2-ov()<|uinolin-](2//)-ylH-mclhyltliia™]le-;. carboxamiύe
Figure imgf000080_0001
Following the procedure as described in Example 3, making variations only as required to use 6-(benzyloxy)quinolin-l (2Λ)-one in place of 4-amiπopyridin-2(l J¥)-one to react with Λf-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound waε obtained as awhile solid in 3% yield- mp 213-216 "C; 1H NMR (300 MHz1 CDjOD) S 7.85 (d, /= 12.0Hz, IH), 7.41-7.23 (m, HH), 7.11 (d, J = 3.0 Hz), IH), 7.1)8 (d, J= 3.0 Hz, IH), 7.02 (d, J= 3.0 Hz, IH), 6.58 (d. J= 9.0 Hz, IH), 4.55 (ε, 2H), 4.51 (s, 2H), 2.57 (s, 3H); '3C NMR (75 MHz, DMSO-ctø δ 161.4, 159.7, 154.4, 151.9, 139.6, 138.8, 137.9, 135.8, 132.1, 129.9, 129.2, 128.3, 1282, 127.2, 126.8, 121.9, 1 19.9, 119.7, 116.1, 111.4, 42.8, 34.5, 16.8; MS (ES+) m/z 482.3 (M+ 1).
EXAMPLE 3.1»
Synthesis of \-Benz\l-4-methyl-2-(2-oxop3πdin-l(2//)-yl)thiazole-S-carl)θϊamicle
Figure imgf000080_0002
Following the procedure as described in Example 3, making variations only as required to use pyridin-2(l/f)-one in place of 4-aminopyridin-2(l/fl-one to react with JV- benzyl-2-bromo-4-methylthiazole-5-carboxainide, the title compound was obtained as a colorless solid in 48% yield: mp 180-182 °C (nexane/ethyl acetate); 1HNMR(SOO MHz, CDCl3) δ 8.83 (t, J= 5.9 Hz, IH), 8.71 (dd, J= 7.3 ,1.7 Hz, IH), 7.65-7.59 (m, IH), 7.37- 7.18 (m, 5H), 6.74 (d, J= 9.3 Hz, IH), 660-6.55 (m, IH), 4.39 (d, J= 5 B Hz, 2H), 2.56 (S. 3H); 11C INMR (75 MHz, CDCl3) S 167.9, 162.0, 161 6, 154.1, 1502, 13SLQ, 132.6, 128.7, 127.7, 127.2, 123.6, 104.4, 98.0, 43.1 , 17.5; (ES+) m/z 326.1 (M + 1).
EXAMPLE 3.11
Synthesis of JV-(4-Fluorobemϊyl)-4-methyl-2-(2-o]topyridin-l(2fl)-j'l)tliiaH>lβ-S- carboxamidc
Figure imgf000081_0001
Following the procedure as described in Example 3, making variations only as required to usepyridin-2(l#)-one in place of 4-aminopyridin-2(l//)-one to react with 2- bromo-iV-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide in place of N-benzyl-2- bromo^-methylthiazole-S-carboxamide, the title compound was obtained as a colorless solid in 45% yield: nip 170-172 °C (hexaiie'tfhy] acetate), 1HNMR (300 MHz, CDCl3) 5 8.80-8.77 (m, IH), 7.47-7.42 (m, IH), 7.34-7.28 (m, 2H), 7.03 (t, J= 8.6 Hz, 2H), 6.75 (d, J= 9.4 Hz, IH), 6.44 Cd, J= 6.9 Hz, IH), 6.06 Ct, /= 5.6 Hz, IH), 4.56 (d, /= 5.6 Hz, 2H), 2.70 (s, 3H); 13C NMR (75 MHz, CDCl]) 6 163.9, 162.1, 160.6, 153.2, 152.5, 139.9, 133.5, 131.2, 129.6, 129.5, 122.9, 121.3, 1 15.8, 115.5, 107.8, 43.4, 17.3; (ES+) m/z 344.2 (M + 1).
EXAMPLE J.12
Synthesis of 2-(4-(Benzyloxy)-2-oxopyridiri-l(2.H)-yl)-Λ-(4-fluorobenzyl)-4- methylthiazole-S-carboxaiπide
Figure imgf000081_0002
Following the procedure as described in Example 3, making variδtions only as required to use-4-(benzyIoxy)pyridιii-2(li-r)-one in place of 4-aminopyridir-2(lW)-one to react with 2-bramo-jV-(4-fluoroben2yl)-4-rτiethylthiazole-5-carboxamide in place of .W-
benzyl-2-bronic-4-raethylthiazole-5-carbo)camide, the title compound was obtained as a colorless solid in 92% yield: mp 223-225 0C (hexαnβΛsthyl acetate); 1H NMR (300 MHz, CDCl3) S 8.« (t,J= 8.1 Hz, IH), 7.38-7.35 (m, SH), 7.32-7.27 (m, 2H), 7.01 M= 8.6 Hz, 2H), 6.23 (dd, J= 8.1, 2.3 Hz, IH), 6.11 (t, J= 5.5 Hz, IH), 6.06 (d, J = 2.3 Hz, IH), 5.03 (s, 2H), 4.54 (d, J= 5.5 Hz, 2H), 2.67 (s, 3H); '3C NMR (75 MHz, CDCl3) δ 167.4, 163.9, 162.2, 160.6, 153.5, 152.3, 134.5, 133.6, 131.5, 129.6, 128.8, 128.7, 127.7, 122.1, 115.8, 104.1, 97.3, 70.8, 43.3, 17.3; (ES+) ra/j +50.2 CM + 1).
EXAMPLE 3.13
Synthesis of MBeπzyl-4-methyl-2-(2-oxo-4-(phenylcarb_πioyl)py]-idiiι-l(2fl)- yl)thiazole-5-carboxamide
Figure imgf000082_0001
Following the procedure as described in Example 3, making variations only as required to use2-hydroxy-JV-pherylisonico1inamide in place of 4-aminopyridin-2(lH)- one to react with iV-benzyi-2-bromo-4-methylthiazole-5-carboxarnide, the title compound was obtained as a colorless solid in 20% yield: mp 243-245 0C (hexane/ethyl acetate); 1H NMR (300 MHz, DMSCW6) δ 10.53 (s, IH), 8.88 (t, J = 5.8 Hz, IH), 8.83 (d,7= 7.6 Hz, IH), 7.72 (d, /= 7.6 Hz, 2H), 7.36-7.19 (m, 8H), 7.10 (X, J= 7.3 Hz, IH), 6.98 <dd, J= 7.6. 1.8 Hz, IH).4.40 (d. J= 3.8 Hz.2H).2.59 (S, 3H); 13C NMK (75 MHz, DMSO-rfe) d 163.0, 161.7, 180.2, 153.5, 150.7, 139.8, 1320, 129.1, 128.7, 127.7, 127.2, 124.7, 124.6, 123.6, 121.0, 119.5, 107.0, 106.1, 43.2, 17.5; (ES+) m/z 445.1 <M + 1)
EXAMPLE 3.14
Synthesis nf 'V-nenzy]-4-iiieth>l-2 -(2-OXO- J-(phenylcarbanioyl)pyridin-lt2//)- yl)thiazole-5-carbύxatnide
Figure imgf000083_0001
Following the procedure as described in Example 3, making variations only as required to use 2-oxo-A^phenyl-l,2-dihydrcpyridine-3-carboxamide in place of 4- aminopyridin-2(l-H)-one to react with Λf-benzyl-2-t>romo-4-methylthiazole-5- carboxamide, the title compound was obtained as a colorless solid in 15% yield: mp 225- 227 °C (hraaac/cthyl acetate); 1H NMR (300 MHz, DMSCW0) S 13.14 (a, IH), 8.64-8.5S (m, 2H), 8.18 (dd, J= 6.6, 2.1 Hz, IH), 7.SJ-7.47 (m, SH), 7.32-7.26 (m, 4H), 7.24-7.17 (m, IH), 6.75-6.70 (m, IH), 4.37 (d, J= 5.9 Hz, 2H), 2.44 (s, 3H); 13C NMR (75 MHz, DMSO-afc) 5 162.0, 161.8, 156.0, 151.4, 1460, 145.7, 140.2, 140.0, 129.7, 129.5, 128.7, 127.6, 127.2, 127.2, 120.1, 118.4, 107 8, 43.1 , 17.4; (ES+) ra/z 445.1 (M *- 1).
EXAMPLE 3.15
Synthesis Cf Λ-Benzyl-4-melliyl-2-(2-oxo-S-(phenylcarbamoyl)pyridiπ-l(2fl)- yl)thiazole-5-carboxamide
Figure imgf000083_0002
Following the procedure as described in Example 3, making variations only as required to use 6-oxo-JV-phenyl-l,6-dlhydrop:yrl_lne-3-caΛoxamide in place of 4- aminopyridirι-2(l/J)-one to react with JV-bensy]-2-bromo-4-methylthiazole-5- carboxamide, the title compound was obtained as a colorless solid in 31% yield: mp 223- 225 °C (hexane/ethyl acetate); 1H -NMR (300MHz, DMSO-tfe) S 10.39 (S1 IH), 9.40 (d, J= 2.5 Hz, IH), 8.89 (t, J= 5.9 Hz, IH), 8.14 (,άd, J= 9.6, 2.5 Hz, IH), 7.70-7.68 (m, 2H ), 7.36-7.28 (m, 6H), 7.26-7.18 (m, IH), 7.11-7.07 (ro, IH), 6.86 (d, J= 9.6 Hz, IH), 4.41 (d,J- 5.9 Hz, 2H), 2.61 (s, 3H); 13C NMR (75 MHz, DMSO-.4) S 162.4, KU, 160.1, 153.5, 150.5, 139.7, 139.3, 139.1, 134.0, 126.1, 128.7, 127.7, 127.3, 125.3, 124.4, 121.0,
120.2, 116.2, 43.2, 17.5; (ES+) m/z 445.1 (M *■ 1).
EXAMPLE 3.1«
Synthesis of 4-Methyl-2-(2-oxopyridin-l(2,H)-yl)-JV-(pyridin-3-ylinethyl)tliiazole-5- carboxamide
Figure imgf000084_0001
Following the procedure as described in Example 3, making variations only as required to use pyridin-2(l//)-one in place of4-aminopyridin-2(l//)-one to react with 2- bromo-4-methj4-N-<pyridin-3-ylmethyl)Λiεzole-5-carboxamide, the title compound was obtained as a colorless solid in 21 % yield: mp 218-2200C {ethyl acetate/hexεπes); 1H NMR (300 MHz1 DMSO-dj) δ 8.87 (t, J= 5.6 Hz, IH), 8.71 (dd, J = 7.3, 13 Hz, IH), 8.56-8.43 (m,2H), 7.71 (d, J = 7.3 Hz, IH), 7.68-7.59 {ra, IH), 7.38 (br s, IH), 6.74 (d, J = 9.2 Hz, IH), 5.60-6.55 (m, IH), 4.42 (d, J= 5.7 Hz, 2H), 2.56 (s, 3H); "C NMR (75 MHz, DMSO-*) δ 161.9, 160.2, 153.8, 150 S, 149 3, 148.4, 141.4. 135.5, 131.5, 124.2, 120.9, 108.7, 41.0, 17.5; MS (ES+)m/z 327.2 (M + 1).
EXAMPLE 3.17
Synthesis of Z-(4-(Benzy]oxy)-2-oxopyridin-l(2//)-y])-JV-(3,4-dinuorobenzyl).4- methylthiazolt-5-carbαxainide
Figure imgf000084_0002
Following the procedure as described in Example 3, making variations only as required to use4-(benzyloxy)pyridin-2(lΛ)-one in place of 4-aminopyridin-2{lW)-one to react with 2-bromo-iV-(3,4-difluorobenzyl)4-methylthiazole-5-carboxamide, the title compound wis obtained as a colorless solid in 85% yield: mp 225-2270C (ethyl acetate/heκaπe:); 1H NMR (300 MHz, CDCl3) S 8.67 (d, J= 7.9 Hz, 1 H), 7.43-7.35 (m,
5H), 7.17-7.05 (m, 3H), 6.35-6.19 (m, 2H), 6.Q5 (s, IH), 5.03 (s, 2H), 4.52 [a, 2H), 2.67 (s, 3H), 13C NMR (75 MHz, CDCl3) δ lCT.4, 162.3, 162.0, 153.5, 1S2.6, 152.1, 151.5, 148.8, 135.0, 134.5, 131.5, 128.8, 127.7, 123.7, 121.8, 117.6, 116.9, 104.1, 97.3, 70.8, 42.9, 17.3; MS (ES+) m/z 468.3 (M + 1).
EXAMPLE 3.18
Synthesis of MBenzyl-4-methyl-2-(2-oxo-4-(phenoxymethyl)pyridin-l(2i?)- yl)thiazole-5-carboxamide
Figure imgf000085_0001
Following the procedure as described in Example 3, making variations only as required to use4-(benzyloxy)pyridin-2(U/)-oiie in place of 4-amiπopyridin-2(l//)-one to react withW-benzyl-2-bromo-4-methylthiaiole-5-carboxamide, the title compound was obtained as a colorless solid in 12% yield: mp 173-177 °C (methanol); 1H TJMR (300 MHz, CDCI3) 5 S.78 (d, /= 7.6 Hz, IH), 737-7.26 (m, 7H), 7.01-6.91 (m, 3H), 6.83-6.82 (m, IH), 6.48 (d_, J= 7.6, 1.8 H2, IH), 6.10 (t, /= 5.3 Hz, IH ), 4.96 (s, 2H), 4.59 (d, J= 5.6 Hz, 2H), 2.70 (m, 3H); 15C NMR (75 MHz, CDCl3) δ 162.0, 160.3, 157.7, 153.2, 152.3, 150.8, 1376, 131.2, 129.7, 128.8, 127.5, 127.7, 123.1, 121.7, 117.2, 114.7, 106.3, 67.3, 44.1, 17.3; MS (ES+) m/z 432.3 (M + l).
EXAMPLE J.19
Synthesis cf iV-Benzyl-5-(4-(benzyloxy)-2-»sopyridiii-l(2fl)-yl)-3-me1hylfuran-2- carboxamide
Figure imgf000085_0002
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(l//)-one in place of 4-aminopyiidin-2(l/f)-onc to
react with Λ'-ben2yl-5-broπio-3-methylfuran-2-carboxainide in place of λ^benzyl^- bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 22% yield: mp 191-192 0C; 1HNMR (300 MHz, DMSO-cfe) δ 8.92(1, /= 6.2 Hz, IH), 8.23 (d, /= 7.9 Hz, IH), 7.49-7.20 (m, 10H), 6.78 (s, IH), 6.25 (dd, J= 7.9, 2.7 Hz, IH), 6.06 (d, J = 2.7 Hz, IH), 5.15 (s, 2H), 4.43 (d, J= 6.2 Hz, 2H), 2.33 (s, 3H); 13C KMR (75 MHz1 DMSOd6) δ 166.4, 160.7, 158.3, 143.7, 139.6, 137.1, 135.4, 134.5, 128.4, 128.3, 128.2, 128.0, 127.2, 126.7, 105.3, 101.8, 97.6, 69.9, 41.5, l l.*; MS<ES+) JWΪ 415.3 (M + 1).
EXAMPLE 3.1«
Synthesis of Ethyl 5-(4-(Benz> toxy)-2-oi< |i>ridin-l(2H)-yl)-3-me(hylth ophene-2- carboxylate
Figure imgf000086_0001
Following the procedure as described in Example 3, making variations only as required to use4-(benzyloxy)ρyridin-2(lΛ)-one in place of 4-aminopyridin-2(liϊ)-one to react with ethyl 5-bromo-3-methylthiophene-2-carboxylate in place of ΛT-benzyl-2- bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 26% yield: 1H NMR (300 MHz1 CDCl,) 6 7.55 (d, J= 7.8 Hz, IH), 7.44-7.36 (m, 5H), 6.87 (s, IH), 6.13 (dd, J = 7.8, 2.7 Hz, IH), 6.07 (d, J = 2.7 Hz, IH), 5.04 <s, 2H), 4.32 (Q. /=7.1 Hz. 2H).2.35 (S, 3H), 1.36 Ct1 /= 7.1 Hz, 3H); MS (ES+) iwi 370.2 (M + 1).
EXAMPLE 3.21
Synthesis of S-(4-(Benzyloxy)-2-oxopyridin-l(2H)-yl)-Λr-(4-fluorobeiiiyl)-3- methylthiophene-2-carboxamide
Figure imgf000086_0002
Following the procedure as described in Example 3, making variations only as required to use i.(benzyloxy)pyridin-2(lΛ).one in place of 4-aminopyridin-2(l//)-one to react with S-brcmo-iV-^-fluorobenzyO-S-methylthiophene-Z-carboxamide in place of JV- benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in.28% yield: mp 175-177 0C; 1H NMR (300 MHz, CDCIj) c 7.55 (d, J = 7.8 Hz, IH), 7.43-7.36 (m, 5H), 7.31 (dd, / = 8,S, 5.6 Hz, 2H), 7.02 (άd,J= 8.5, 8.5 Hz, 2H), 6.84 (s, IH), 6.20 (t, J= 5.4 Hz, IH), 6.14 (dd, J= 7.8, 2.4 Hz, IH), 6.05 (d, /= 24 Hz, IH), 5,03 (s, 2H), 4.54 (d, /= 5.4 Hz, 2H), 2.53 (s, 3H), 13C NMR (75 MHz, CDCb) δ 166.8, 162.9, 1S2.2, 139.8, 139.7, 134.7, 134,4, 133.8 (JC-F- 3.3 Hz), 129.5 ( /C-f - 8.1 Hz), 128.8, 127.8, 126.8, 121.9, 115.6 (Jt-F = 21.4 Hz), 103.4, 98.1, 70Λ, 43.2, 15.9; MS (ES+) m/z 449.3 (M + 1).
EXAMPLE 3.22
Synthesis of 5-(4-(Benzyloxy)-2-oxopyridin-l(2Jf0-yl)-iV-(3-nuoroberzj'l)-3- methylthiophene-2-carboxamide
Figure imgf000087_0001
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridtn-2(l//)-one in place of 4-aminopyridin-2(lifl-one to react with 5-bromo-Λr-(3-fluorobeπzyl)-3-inethy]thiophene-2-carboxamide in place ofiV- benzyl-2-bromo-4-rnethylthiazole-5-carboxarrιide, the title compound was obtained as a colorless solid in 45% yield: mp 140-U1 0C; 1H NMR (300 MHz, CDCl,) ϊ 7.56 (d, J = 7.8 Hz, IH), 7.43-7.27 (m, 6H), 7.11 (d, /=7.8 Hz, IH), 7.04 (d, /= 9.6 Hz, IH), 7.00- 6.92 (m, IH), 684 (s, IH), 6.29 (t, /= 5.7 Hz1 IH), 6.14 (dd, J= 7.8, 2 7 Hz, IH), 6.05 (d, /= 2.7 Hz, 1 H), 5.02 (s, 2H), 4.58 (d, J = 5.7 Hz, 2H), 2.54 (s, 3H); 15C NMR (75 MHz, CDCl,)δ 166.8, 164.6, 163.0,163.0 (d, Jc-F= 246.6 Hz), 162.2, 161.3, l«.7 (d, /c. F= 7.0 Hz), 13S.9, 139.7, 134.7, 134.4, 1302 (d,Jc.F= 8.2 Hz), 128.8, 12S.7, 127.8, 126.7, 123.2 (i, JC.F = 2.9 Hz), 121.9, 114.6(d,/c.F= 15.2 Hz), 114.3 (4 JcF= 14.4 Hz), 103.4, 98.1, 70.6, 43.3, 15.9; MS (ES+) ra/z4Φ9.3 (M + 1).
EXAMPLE 3.23
Synthesis of S-^-CBenzyloϊyJ-l-oxopyridin-lCZ/O-ylJ-^V-ethyl-S-metliϊlthlophene-Σ- carboxamide
Figure imgf000088_0001
Following the procedure a9 described in Example 3, mating variations only as required to use4-(benzyloxy)pyridin-2(l/fH)rιe in place of 4-aminopyridiπ-2(l/f)-one to react with S-bromo-iV-ethyl-S-methylthiopriene^-carboxamide in place of .V-benzyl-2- bromo^-methylthiazole-S-carboxamide, the title compound was obtained as a light yellow solid in 45% yield: mp 158-160 0Q1H NMR (300 MHz, CDCl3) S 7.54 (d, J= 7.8 Hz, IH), 7.43-7.36 (m, 5H), 6.82 (s, IH), 6 13 (dd, J= 7.8, 2.7 Hz, IH), 6.06 (d, J= 2.7 Hz, IH), 5.84 (br s, IH), 5.04 (s, 2H), 3.4?-3.38 (m, 2H), 2.51 (s, 3H), 1.22 (t, J= 7.3 Hz, 3H); 13C NMR (75 MH2, CDCl3) 6 166.8, 162.9, 162.3, 139.4, 139.0, 134.8, 134.7, 128.8, 128.6, 127.7, 127.5, 122.2, 103.2, »«.2, 70.6, 34.8, 15.8, 14.9; MS (ES+) mlz 369.3 (M+ 1).
EXAMPLE 324
Synthesis cf 4-Methyl-2-(2-oxo-4-(trUl«croinethyl)pyridin-l(2fl)-yl)-/V-(pyridin -3- ylmethyl)tlιiaz»le-S-carbDxamide
Figure imgf000088_0002
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(]fl)-one in place of 4-aminopyridin-2(liϊ)-one to react with 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carbonamide in place of JV-bcπzyl-2-bromo-4-mcthylthiazolc-5-c_rrx«amide, the title compound was obtained as a colorless solid in 52% yield: mp 172-173 0C; 1H NMR (300 MHz, CDCl3) 8 8.93 (d, J
= 7.2 Hz, IH), $.13 (br s, IH), 7.12-6.54, (ra.3H), 4.92 (br s, 2H), 2.69 (s, 3H); 13C NMR
(75 MHz, CDCl3) 8 162.1, 159.3, 152.7, 152.6, 141.5, 141.0, 133.1, 127 1, 123.7, 119.9,
119.1, 119.0, 103.1, 44.2, 17.4; MS (ES-OWr 395.2 (M + 1).
EXAMPLE 3.25
Synthesis of ϊ-(4-(Benzj'loxy)-2-oxopyriιlin-l(2fl)-yl)-4-niethyl-Λr-(py ridiπ-3- ylmethyl)thi-2θIe-5-carboxamide
Figure imgf000089_0001
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyndin-2(l J/J-one in place of 4-aminopyridin-2(lW)-one to react with 2-bromo-4-methyl-jV-(pyridin-3-y]methyl)thiazole-5-carboxatni4e in place of Af-benzyl^-bromo^-methylthiazole-S-carboxamide, the title compound was obtained as a colorless solid in 47% yield: mp 208-209°C; 1H -NMR (300 MHz, DMSO-cfe) δ 8.86 (br s, IH)1 8.68-8,60 (m, IH), 7.81-7.72 (m, IH), 7.51-7.33 (m, 7H), 635-6.18 (m, IH), 6.27 (s, IH), S 19 (s, 2H), 4.47 (s, IH), 2.52 (s, 3H); 13C NMR (75MHz, DMSO-&) δ 167.0, 161.5, 161.1, 153 5, 150.1, 135.2, 131.6, 128.5, 128 3, 128.0, 122.9, 103.9, 97.0, 70.3, 17.0; MS (ES+) m/z: 433.3 (M + 1).
EXAMPLE 4
Synthesis of 2-(4-Benzamido-2-oxopyridiπ-l(2fl)-yl)-Λ'-beπϊyl-4-metliylthiazole-5- carboxamide
Figure imgf000089_0002
To a mixture of 2-(4-amino-2-oxopyridin-l(2Λ)-yl)-Λ'-benzyl-4-inethylthiazole-5- carhoxamide (O 17 g, 0.50 mmol) and 4-dimethylaminopyridine (0.01 g) in pyridinc{10 mL) was added benzoyl chloride (0.07 mL, 0.S0 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 6 hours, and water \ 100 mL) was added. The title
compound was precipitated as a solid which was collected by filtration and washed with water and J-butγlmethyl εthεr (0.17 g, 76Η): mp 246-248 0C; 1H NMR (300 MHz, DMSOd6) a 10.66 (s, IH), 8.78 (t, J- 5.7 Hz, IH), 8.67 (d, J= 7.8 Hz, IH), 7.95-7.90 (m, 2H), 7 S5-7.47 (m, 3H), 7.35-7.18 (m, 6H), 6.94 (dd, J= 7.8, 2.1 Hz, IH), 4.39 (d, J = 5.7 Hz, 2H), 2.55 (s, 3H), 13C NMR (75 MHz, DMSO-*) 5 167.4, 161.9, 161.0, 153.8, 150.3, 149.4, 139.8, 134.1, 132.9, 131.6, 129.0, 128.7, 128.4, 127.7, 127.2, 123.9, 104.2, 103.9, 43.1, 175; MS (ES+) mfz 445.3 (M + 1).
EXAMPLE 5
Synthesis of Λl-benzyl-2-(4-(lκnzylamino)-2-oxopyridin-l(2i/)-yl)-4-m<*hylthiazofe-
5-carboxflmide
Figure imgf000090_0001
To a solution of 2-(4-amino-2-oxopyridin-l(2//)-yl)-JV-ben2yl-4- methylthiazole-5-carboxamide (0.30 g, 0.88 mmol) and trifluoroacetic acid (15 mL) in chloroform (20 mL) was added benzaldehyde (0.10 mL, 0.98 mmol). The reaction mixture was stirred for 15 minutes at ambient temperature, then triethylsilane (0.15 mL, 1.00 mmol) was added. The reaction mixture was kept stirring for 2 hours it ambient temperature, then another portion of benzaldehyde (0.10 mL, 0.98 mmol) and tricthylsilanc (0, 15 mL, 1.00 mmol) was added. The reaction mixture was ic«pt stirring for another 2 houis at ambient temperature. The solvent was removed in vacuo, and the residue was washed with saturated aqueous sodium bicarbonate solution, water and f- butylmethyl ether to afford the title compound (0.30 g, 79%): mp 253-255 CC; 1H NMR (300 MHz, DMSCW6) S 8.68 (t, J= 5 7 Hi, IH), 8.39 {d, J= 7.8 Hz, IH), 7.87 (s, IH), 7.44-7.21 (m, 10H), 6.21 (d, /= 7.8 Hz, IH), 5.31 (s, IH), 4.36 (d, J- 57 Hz, 2H), 4.31 (d, J= 4.5 Hz1 2H), 2.50 (s, 3H); 13C NMR (75 MHz, DMSO-A) 6 162.1 , 160.9, 155.9, 154.5, 1502, U0.0, 138.3, 130.6, 128.9, 12S.7, 127.7, 127.6, 127.1, 122.8, 103.6, 88.6, 46.0, 43.0, 17.5; MS (ES+) Wi 431.2 (M + 1).
EXAMPLE t
Synthesis ofAT-Benzy l-4-mrthyl-2-(2-oxo-l-(pyridin-3-ylmethoxy)pyridiii-l(2fl)- yl)lli iaiok-5-Cii rboxamide
Figure imgf000091_0001
To a solution ofAf-benzyl-2-(4-hydroxy-2-oxopyridin-l(2//)-yl)-4- methylthiazole-5-carboxaπiide (0.10 g, 0.29 mmol) in iV.iV-dimethylfornianiide (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.028 g, 0.70 mmol) slowly at 0 0C. The reaction mixture was stirred for 5 minutes and then 3-(bromotnethyl)ρyridine hydrobromide (0.096 g, 0.38 mmol) and tetra-»-butylammonium iodide (0.0C5 g, 0.014 mrnol) were added at 0 °C. After stirred at ambient temperature for 16 hours, the reaction mixture was concentrated in yacuσ to yield a solid residue. The crude product was purified by column chromatography eluted with ethyl acetate/hexanes (50/50 to 100/0) to afford the title compound as a white solid (0.0 IS g, 14% yield): mp 214-216 °C; 1H NMR (300 MHz, DMSCW6) δ 8.81-8.61 (m, 4H), 7.98 (d, J= 7.8 Hz, IH), 7.55-7.51 (m, IH), 7.33-7.19 (m, 5H), 6.42-6.39 (m, IH), 628 (d, J= 2.7 Hz, IH), 5.25 (s,2H), 5.39 (d, J= 5.7 Hz, 2H), 2.55 (s, 3H); 13C NMR (75 MHz, DMSO-tfj) 8 167.3, 161.9, 161.6, 153.9, 150.3, 149.1, 148.7, 139.9, 137.8, 1323, 128.8, 127.7, 127.2, 124.7, 123.8, 104.3, 97.7, 68.3, 17.5; MS (ES+) mh 433 2 (M 4 1)
EXAMPLE 5.1
Synthesis of /V-Benzyl-4-methyl-2-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-l(2fl)- yl)thiazole-5-carboxamide
Figure imgf000092_0001
Following the procedure as described in Example 6, making variations only as required to use 2-(bromomethyl)pyridine hydrobromide in place of 3- (bromometriyl)pyridine hydrobroinide to react with JV-benzyl-2-(4-hydroxy-2-oxopyridin- l(2i/)-yi)-4-m«thylthiazole-S-carboxamide, the title compound was obtained as a white solid in 11% yield: mp 202-205 0C; 1HNMR (300 MHz, Ct)CyCD3OD) δ 8.69 (m, IH), 8.53 (m, IH), Z89-7.84 (m, IH), 7.56-7 A9(m, 2H), 7.39-7.35 (m, IH), 7.28-7.17 (m, 5H), 6.36-6.32 (m, IH), 6.07 (d, J= 2.7 Hz1 IH), 5.18 (s, 2H), 4.46 (s, 2H), 2.56{s, 3H); 13C NMR (75 MHz, CDCIJZCD3OD) δ 170,1, 165.7, 164.9, 156.7, 156.3, 154.0, 150.6, 141.9, 140.9, 134.7, 131.1, 130.0, 129.8, 126.8, 126.0, 125.5, 106.6, 100.1, 72.6, 46.2, 19.4; MS (ES+) m/i 433.3 (M + 1).
EXAMPLE 7
Synthesis of/V-Benzyl-2-(3-hydroxy-2-«sopyridiii-l(2B)-yl)-4-n>e«hylt*'a2θle-5- carboxamide
Figure imgf000092_0002
A mixture of W-benzy]-2-(3-(benzyloxy)-2-oxopyridin-l(2fl)-yl)-4- methylthiazcle-5-carboxamide (0.14 g, 0.32 mmol) and 20 wt.% palladium on activated carbon (0.10 g) in methanol (50 mL) was slirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography followed by recrystallization from methanol (10 mL) to afford the title compound (0.027 g, $%): mp 225-228 °C; 1H NMR (300 MHz,
CD3OD) B 8.63 (d, J = 7.6 Hz, IH), 7.42-725 (in, 5H), 6.20-6.10 (m, IH), 5.57-5.83 (m, IH), 4.36 (d, /-6.0 Hz, 2H), 2.58 (s, 3H), MS (ES+) m/z 342.2 (M + 1).
EXAMPLE 7.1
Synthesis of JV-Benzyl-2-(5-hydroxy-l-oxoi»oquinolin-2(lfl)-yl)-4-methylthiazole-5- carboxamide
Figure imgf000093_0001
Following the procedure as described in Example 7, making variations only as required to use N-benzyl-2-(5-(benzyIoxy)- 1 -oxoisoqumolin-2(l_H)-yl)-4-methy]thiazo]e- 5-carboxamide in place of Λr-benzyl-2-(3-(benzyloxy)-2-oxopyridin-l(2a)-y])-4- methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 18% yield: mp 218-221 0C; 1H NMR (300 MH2, CD3OD) S 7.74 (d, J= 6.0 Hz, IH), 7.35- 7.23 (m, 6H), 7.12-7.08 (m, 2H), 6.97 (d, / = 60 Hz, IH), 4.50 (s, 2H), 2.57 (s, 3H); '3C NMR (75 MHz, CD3OD) δ 162.1, 159.6, 153.5, 151.3, 136.7, 134.9, 128.3, 126.7, 126.6, 125.6, 125.4, 125.3, 125.3, 124.2, 115.5, 1142, 99.8, 41.7, 14.1; MS (ES+) m/z 392.3 (M + 1).
EXAMPLE 7.2
Synthesis of JV-BcnEyl-2-(6-hydroxy-l-ox»isoquinoHn-2(l/?)-yl)-4-mcΛιylthiacolc-5- carboxamide
Figure imgf000093_0002
Following the procedure as described in Example 7, making variations only as required to use 7V-benzyl-2-(6-(benzyloxy)-l-oicoisoquinolin-2(l/i)-yl)-4-metliylthia«ile- 5-carboxamide in place of JV-benzyl-2-(3-(henzyloxy)-2-oxopyridin- l<2/ϊ)-yl)-4-
methylthιazole-5-carboxamide, the title compound was obtained as a white solid in 18% yield: mp 225-2280C; 1H NMR (300 MHz1CD3OD) S 7.84 (d, J = 9.0 Hz, IH), 734- 7.22 (m, 6H), 7.10-7.06 (m, IH), 7.01 (m, IH), «.58 (d. J= 9.0 Hz, IH), 4.50 (s, 2H), 2.58 (s, 3H), 13CNMR (75 MHz, DMSO-(Z6) 5 161.3, 159.7, 154.5, 151.9, 139.6, 138.9, 132.1, 129.9, 128.3, 127.2, 126.9, 121.9, 119,9, 119.7, 116.1, 111.4, 42.8, 16.8; MS (ES+) m/z 392.2 (M + 1).
EXAMPLE 7.Ϊ
Synthesis of iV-Benzyl-5-(4-hyflr<)xy-2-ox[)pyridlii-l(2/r>yi)tliiopheiie-3- carboxamlde
Figure imgf000094_0001
Following the procedure as described in Example 7, making variations only as required to use Λr.benzyl-5-(4-(taenzy]oxy)-2-OXODyridin-l(Z.ffl-yl)Ihlophene-3- carboxamide in place of iV-berizyl-2-(3-(benzyloxy)-2-oxop)T[diii-l(2fl)-yl)-4- methylthiazole-5-carboxamιde, the title compound was obtained as a white solid in 10% yield- mp 1500C (dec); 1H NMR (300 MHz, DMSO-dJ,) B 8.83 (t, J= 5.B Hz, IH), 7.93 (s, IH), 7.91 (s, IH), 7.61 (s, IH), 7.37-720 (m, 5H), 6.00 (d, J = 6.8 Hz, IH), 5.55 (s, IH), 4.45 (d, J= 5.8 Hz, 2H); MS (ES+) m/i 327.2 (M + 1).
EXAMPLE 7.4
Synthesis »fΛr-Benzyl-5-(4-hydroxy-2-Oϊopyrldiii-l(2ff)-yl)-3-metliyltliiopliene-2- carboxamide
Figure imgf000094_0002
Following the procedure as described in Example 7, making -varMcns only as required tc use iY-benzyl-5-(4-(benzyloxy)-2-oxopyridin-l(2Λ)-yl)-3-methylthioρhene-2-
caiboxamide inplace ofΛr-benzyl-2-(3-(benzybxy)-2-cxopyridin-l(2/f)-J'l)-+- mcthylthiαcolc-5-carboxamide, the title compound was obtained as a whits solid in 87% yield: mp 98 0C (dec); 1H NMR (300 MHz, DMSO-^6) S 8.54 (t, J= 5.9 Hz, 1H), B.1O (d, /■= 7.8 Hz, IH), 7.37-7.22 (m, 5H), 7.20 (s, IH), 6.12 (dd, J= 7.8, 2.5 Hz, IH), 5.75 (ά, J= 2.5 Hz, IH), 4.40 {ά,J= 5.9 Hz, 2H), 2.41 (s, 3H); '3C NMR (75 MHz, DMSO- <fc) a 166.8, 152.5, 161.1, 139.7, 139.1, 137 I1 135.4, 128.2, 127.1, 126.6, 120.1, 102.8, 97.8, 42.5, 15.6; MS (ES+) mfz 341.1 (M + I].
EXAMPLE 7.5
Synthesis of JV-Benzyl-2-(4-hydroxy-2-oxβpyridin-l(2H)-yl)-4-methyltMazole-5- carboxamide
Figure imgf000095_0001
Following the procedure as described in Example 7, making variations only as required to use Λ>-benzyl-2-(4-(benzyloxy)-2-oxopyridin- 1 (2iϊ)-yl)-4-metfιylthiazole-5- carboxamide in place of Λi-benzyl-2-(3-(benzy]oxy)-2-oxopyridin-l(2Λ)-yl)-4- methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 89% yield, mp 240-243 0C (methanol); 1H NMR (300 MHz, DMSO-rfj) 8 11.51 tbr 3, IH), 8.76 (t, /= 5.9 Hz, IH), 8.59 (d, J= S.0 Hz, IH), 7.39-7.16 (m, 5H), 6.26 (dd, J- 8.0, 2.5 Hz, IH), 5.81 (d, J= 2.5 Hz, lH),4.3S <d, J= 5.9 Hz, 2H), 2.53<s, 3H); 13C NMR (75 MHz. DMSO-A) 8 167.9. 162.0. 151.6, 154.1, 150.2, 139.9, 132.«, 128.7, 127.7, 127.2, 123.6, 104.4, 98.0, 43.1, 17.5, MS (ES+) m/z 342.2 (M + 1).
EXAMPLE 7.6
Synthesis of 5-(4-Hydroxy-2-oxopyridin-l(2fl) yl)-3-methyl-/V-(pyriaiii-3- ylmethyI)thiophene-2-carboxamide
Figure imgf000095_0002
Following the procedure as described in Example 7, making variations only as required to _sc 5-(4-(benzyloκy)-2-oxopyridiii-l (2Λ)-yl)-3-methykV-(pyri<tin-3- ylmethyl)thioj>hene-2-carboxamide in place of /V-benzyl-Z-β-CπenzyloiqO-l-oxopyridJn- ip.ffl-yri^-inetriylthiazole-S-carboxamide, the title compound was obtained as an off- white solid in 14»/. yield: mp 110 0C (dec); 1H NMR (300 MHz, CD3OD) 8 8.56 (s, IH), 8.44 (S, IH), 7.89 (d, J= 7.8 Hz, IH), 7.85 (d, /= 7.8 Hz, IH), 7.42 <dd, J= 7.8, 4.9 Hz, IH), 7.07 (s, IH), 6.20 (dd, J= 7.8, 2.6 Hz, IH), 5.87 (d, J= 2.6 Hz, IH), 4.56<s, 2H), 2.47 (s, 3H); 13CNMR (75 MHz, CD3OD) 5 169.8, 165.7, 164.8, 149.5, 148.8, 141.9, 1405, 137.73, 137.7, 128.9, 123.3, 125.3, 124.0, 104.8, 99.4, 42.0, 15.9, MS{ES+) m/. 342.2 (M + 1).
EXAMPLE 7.7
Synthesis of (V-(4-Fluorobenzyl)-5-(4-hj€iroiy-2-oiopyriaiii-l(2fl)-yl)-3- ιnethylthioplune-2-carbox-mide
Figure imgf000096_0001
Following the procedure as described in Example 7, making variations only as required to use 3-(4-(benzyloxy)-2-oxopyridm-l(2Λ)-yl)-Λf-(4-fluorohenEyl)-3- methylthiophene-2-carboxamide in place of ΛM>enzyl-2-(3-(benzyloxy)-2-oxopyridin- 1 (2/0-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as an off- white solid in 76% yield: mp 95 0C (dec), 1H NMR (300 MHz, DMSO-(A) S 11.22 (br s, IH), 8.53 (t, J- 6.0 Hz, IH), 8.10 (d, J= IS Hz, IH), 7.39-7.30 (m, 2H), 7.21 -7.11 (m, 3H), 6.13 (dd, J= 7.9, 2.6 Hz, IH), 5.76 {d, /= 2.6 Hz, IH), 4.38 <d, /= 6.0 Hz, 2H), 2.41 (s, 3H); 1!C NMR (75 MHz, DMS(W6) 3 166.5, 162.5, 161.0, 161.0 [ά, Jc.F= 242.0 Hz), 139.1, 137.2, 135.9 (ά, Jc-F = 2.9 Hz)1 135.5, 129.1 {ά, J0-F - 8-1 H4 127.1, 120.2, 114.9 (d, Jc-F = 21.3 Hz), 102.6, 97.9, 41.8, 15.5; MS (ES+) m/z 359.2 (M + 1).
EXAMPLE 7.8
Synthesis of iV-(3-Fluorobenzyl)-5-(4-hydrosy-2-oxopyridin-l(2i0-yl)-3- met-iylthiophene-2-earboxamide
Figure imgf000097_0001
Following the procedure as described in Example 7, making variations only as required to use 5-(4-(benzyloxy)-2-oxopyriditi-l(2/J)-yl)-Jv'-(3-fluorobenzyl)-3- methylthiophene-2-carbαxamide in place of ff-benzyl-2-(3-(benzyloxy)-2-exopyridin- 1(2r7)-y])-4-methylthiazolε-5-tarboxamidc, the title compound was obtained as a colorless solid in 76% yield: mp 140-142 "C; 1HNMR (300 MHz, DMSCW6) S 11.24 (br s, IH), 8.56 (t, J= 6.0 Hz, 1H), 8.11 (d, /= 7.9 Hz, IH), 7.42-7.34 (m, IHX 7.21 (s, IH), 7.18-7.02 (m, 3H), 6.13 (dd, J= 7.9, 2.6 Hz, IH), 5.77 (d, J = 2.6 Hz, IH), 4,41 (d, J= 6.0 Hz, 2H), 2.42 (., 3H); 13C NMR (75 MHJ, DMSO-J6) S 166.5, 162.S, 162.1
Figure imgf000097_0002
241.5 Hz), 161.0, 142.7 (d, Jc-F= 7.0 Hz), 1392, 137.3, 135.4, 130.1 (d, /C-f= 8-3 Hz), 126.9, 123.1 [i, JC.F= 2.6 Hz), 120.2, 113.8 <d, /c.r= 21.S Hz), 113.4 (d, Jc.F= 20.9 Hz), 102.6, 97.9, 42.1, 15.5; MS (ES+) mil 359.2 (M + 1).
EXAMPLE 7.9
Synthesis of /V-Etftyl-S-fJ-hydroxy-J-oxopyridin-lβi^-ylJJ-methylttmphene-Z- carboxamidβ
\ °
Following the procedure as described in Example 7, making variations only as required to use 5-(4-(benzyloxy)-2-oxopyridin-l(2Λ)-yl)-Λr-ethyl-3-methylthiopheπe-2- carboxamide in place of Λ'-benzyl-2-(3-(benzyloxy)-2-oxopyπdin- 1 (2H)-yl)-4- methylthiazαle-5-carboxamide, the title compound was obtained as an off-white solid in 80% yield- mp 183-184 °C; 1H NMR (300 MHz, DMSCWi) δ 11.8 (bt S. IH). 8.07 £d, J= 7 S Hz, IH), 794 (t. J = 5.5 Hz. IH), 7.1« (s IH).6.12 (dd./= 7.9.2.6 Hz, IH), 5.76 (d, J= 2.6 Hz, IH), 3.27-3.16 (m, 2H), 2.39 (s, 3H), 1.09 (t, J- 7.2 Hz, 3H), '3C NMR (75
MHz, DMSO-*) δ 166.5, 162.2, 161.0, 1389, 136.4, 135.6, 127.8, 120.2, 102.5, 97.9, 33.9, 15.4, 14.B1 MS (ES+) m/z 279.2 (M+ 1)
EXAMPLE 7.10
Synthesis of 2-(4-iIydrox>-2-oϊopyri(liιi-t(2W)-yl)-4-mt1thyl-Λ'-(μvriιJiιi-3- ylmethyl)thiaεole-5-carboxaιnide cuco-p-
Following the procedure as described in Example 7, making variations only as required to use 2-(4-(benzyloxy>2-oxopyridin-l (2/f)-yl)-4-methyl-A'-(pyrιdin-3- ylmethyl)thi[i2θle-5-carboxatnide in place ofΛr-benzyl-2-(3-(benzyloκy)-2-oxopyridin- 1 (2W)-yl)-4-nπetriylthi_zole-5-caιtoxamide, the title compound was obtained as yellowish solid in 34% yield: mp 238-240 °C; 1H NMR (300 MHz, DMSO-rfe) δ 8.78 (t, /= 4.8 Hz, IH), 8.55 (d, J = 7.9 Hz, IH), X.53 (br s, IH), 7.74-7.64 <m, 2H), 7.35 (br s, IH), 6.22 (dd, J= 7.9, 1.3 Hz, IH), 5.74 (d, J= 1.3 Hz, IH), 4.49 (d, J= 4.8 Hz, 2H), 232 (S, 3H); '3C NMR (75MHz, DMSO-ife) 6 168.9, 162.2, 161.7, 154.4, 150.5, 132.4, 123.2, 105.2, 97.7, 40.9, 176; MS (ES+) mk: 343.2 (M + 1).
EXAMPLE 8
Synthesis of Λr-Btnzyl-5-(4-(lpeπΛvl(>.\y)-2-oι.)p\ridin-l(2^)-yl)thiophtre-3- carboxamide
Figure imgf000098_0001
A mixture of Λf-beπzyl-5-bromothiαj>rιene-3-carboxamide (0.57 g, 1.91 mmol), 4- (benzyloxy)pyridin-2(lΛ)-one (0.42 g, 2.10 mmol), copper(l) iodide (0.055 g, 0.29 mmol), 8-hydrcxyquinoline (0.042 g, 0.29 mmol) and potassium carbonate (0.40 g, 2.87 mmol) in ΛΛ'-<iimethylformamide (15 mL) was stirred at 130 0C for 17 Ii under nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature, and then
diluted with eihyl acetate (50 mL). The organic layer was washed with water (2 x 25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated !n vacuo and the residue was purified by column chromatography eluting with 10-80% ethyl acetate in hexanes to affoidthe title compound as awhite solid (0.14 g, 18%): mp 162-163 °C; 1H NMR (300 MHz, DMSO-4) δ 8.55 (t, J= 6.0 Hz, IH), 8.07 (d, J= 7.9 Hz, IH), 8.00 (d, J= 1.5 Hz, IH), 7.71 (d, J= 1.5 Hz, IH), 7.4S-7.20 (m, 10H), 6.26 (dd, J = 78, 2.7 Hz, IH), 6.11 (d, J = 2.7 Hz, IH), 5.16 (s, 2H), 4.46 (d, J= 6.0 Hz, 2H); MS (ES+) mlz 417.2 (M + 1).
EXAMPLE 8.1
Synthesis of JV-Ben_yl-5-(4-(benzyloxy)-2-oϊopyridin-l(2H)-yl)-3-metliylthiopliene-
2-carboxami<ie
Figure imgf000099_0001
Following the procedure as described in Example 8, making variations only as required to use -λ^benzyl-5-bromo-3-rnethyl1hιophene-2-carboxamide in place of JV- benzyl-5-bromothiophene-3-carboxamide to react with 4-(benzyloxy)pyridin-2(lΛ)-one, the title compound was obtained as colorless solid in 49% yield: mp 153-154 0C; 1H NMR (300 MHi, CDCl3) δ 7.55 (d, J= 7.9 Hz, IH), 7.43-7.27 (m, 1 OH), 6.14 (s, IH), 6.20-6.11 (m, 2H), 6.05 (d, J = 2.7 Hz, IH), 5.03 (s, 2H), 4.59 (d, /- 5.7 Hz, 2H), 2.54 (s, 3H); 13C NVIR (75 MHz, CDCl3) S 166.4, 162.5, 161.9, 139.2, 137.6, 134,2, 128.43, 128.40, 128.3, 127.5, 127.4, 127.2, 126.7, 121.8, 102.9, 97 8, 70.3, 43.6, 15.6; MS (ES+) m/z 431.3 (M + 1).
EXAMPLE 9
Synthesis of ^-Benzyl-5-(4-(2-cyclopropyleth9icy)-2-oxopyridin-l(2fl)-yl)-3- mcthylthioplittie-2-caι irosamide
Figure imgf000100_0001
To a stirred solution of iV-benzyl-5-(4-hydroxy-2-oxopyridiπ-l(2W)-yl)-3- methylthiophene-2-carboxamide (0.20 g, 0.59 mmol) in ACAT-dimethylformamide (4 raL) at ambient temperature was added potassium carbonate (0.082 g, 0.59 mmol), followed by the addition of 2-cyclopropylethyl 4-methylbenzenesulfonate (0.13 g, G.59 mmol). The reaction mixture was stirred at 70 0C for 2 hours, and then allowed to cool to ambient temperature and partitioned between ethyl acetate (50 ml) and water (25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with 40% ethyl acetate in hexanes to afford the title compound as a colorless solid (0.14 g, 58%): mp 134-1360C; 1HNMR (300 MHz, CDCl3) S 7.52 (d, J = 7.8 Hz, IH), 7.36-7.27 (m, 5H), 6.83 (s, IH), 6.18 (t, J= 5.6 Hz, IH), 5.05 (dd, J = 7.8, 2.6 Hz, IH), 5.95 (d, J- 2.7 Hz, IH), 4.58 (d, /= S.6 Hz, 2H), 4.02 (t, J= t.S Hz, 2H), 2.53 (s, 3H), 1.72-1.64 (m, 2H), 0.89-0.73 (m, IH), 0.55-0.45 (m, 2H), 0.15-0.08 (m, 2H); '3C NMR(75 MHz, CDCl3) δ 167.2, 162.9, 162.3, 139 7, 139.6, 138.0, 134.3, 128.7, 127.8, 127.5, 126.9, 121.9, 103.4, 97.4, S8.8, 43.9, 33.6, 15.9, 7.6, 42; MS (ES+) mlz 409.3 (M+ 1). EXAMPLE M
Synthesis of JV-Benzyl-3-methyl-5-(2-oxo-4-(4-(trifluoroinethyl)beiizy]o>ry)pyridiii- l(2/f>vl)llιic|)liene-2-caι hoxamidc
Figure imgf000100_0002
Following the procedure as described in Example 9, making variations only as required to use l-(bromoinethyl)-4-(trifluorDui_thyl)beπzene in place of 2- cyclopropylεthyl 4-mcthylbeπzεncsulfonatc to react with Λ'-bcπzyl-S-(4-hydroxγ-2- oxopyridin-1 {2//)-yl)-3-methylthiophene-2-carboxamide, the title compound was
obtained as a colorless solid in 42% yield: mp 225-227 0C, 1H NMR (300 MHz, DMSO- ck) S 8.56 (t,J- 5.0 Hz, IH), 8.18 (ά, J- 7.9 Hz, IH), 7.80 (ά,J- 8.2 Hz, 2H), 7.68 (d, J - 8.1 Hz, 2H), 7.37-7.20 <m, 6H), 6.32 (dd, /= 7.9, 2.8 Hz, IH), 6.14 (d, J- 2.8 Hz, IH), 5.30 (s, 2H), 4.41 (d, J= 6.0 Hz, 2H), 2.42 (s, 3H), 13C NMR (75 MHz, DMSO-cfe) S 166 0, 1624, 160.9, 140 3, 139.6, 138 7, 137.2, 135.2, 128.2 (d, JC-F = 37 Hz), 127.4, 127.1, 126.6, 125.4 (d, Jc.F= 3 8 Hz), 1207, 102.4, 97.5, 690, 42.5, 15.5; MS(ES+) m/z 499.3 (M+l).
EXAMPLE 9.1
Synthesis of iy-Benzyl-S-^-^-fluornbenzyloiy^-oxopyridin-lC/fl-yD-S- methylthiopliene-2-carboxaniide
Figure imgf000101_0001
Following the procedure as described in Example 9, making variations only as required to use 1 -(bromomethyl)-4-fluorobenzene in place of 2-cyclopropylethyl 4- methylbenzenesulfonate to react with Λr-benzyl-5-(4-hydroxy-2-oxopyridin-l(2//)-yl)-3- methylthiophene-2-carboxamide, the title compound was obtained as a pale yellow solid in 43% yield: mp 195-1970C; 1H NMR (3«0 MHz, DMSCW6) δ 8.56 (t, /= 6.0 Hz, IH), 8.16 (d, / = 8.0 Hz, IH), 7.55-7.49 (m, 2H), 7.37-7.20 (m, 8H), 6.28 (dd, 7= 7.9, 2.7 Hz. IH). 6 15 (&.J= 2.7 Hz. IH), 5.14 Cs.2H), 4.41 (d. J= 6.0 Hz. 2H).2.42 (S. 3H); 13C NMR (75 MHz, DMSO-*,) 6 166.2, 162.4, lόC.9, 139.6, 138.8, 137.2, 1352, 135.1, 131.7 {i,Jc.F= 3.0 Hz), 1304 (d, JC.F= 84 Hz), 128.2, 127.3, 127.1, 1266, 120.6, 1 15.3 (d, /c.jT = 21.5 Hi), 102.5, 97.3, 69.3, 42.5, 15.5; MS (ES+) mlz 449.3 (M+l)
EXAMPLE 9.3
Synthesis of MBeπzyl-5-(4-(4-(diπuorometnoxy)beπzyloxy)-2-oxopyridiii-l(2/7)-yl)-
3-methylthiophcπe-2-carbox9niide
Figure imgf000102_0001
Following the procedure as described in Example 9, making variations only as required to use 1 -(bromomethyl)-4-(difluoroniethoxy)benzene in place of 2- cyclopropylethyl 4-methylbenzenesulfoπateto react with Λ'-benzyl-5-(4-hydrDxy-2- oxopyridin- 1 (2.tø)-yl)-3-methylthiophene-2-carbι>xamide, the title compound was obtained as a pinkish solid in 35°/. yield: mp 178.180 0C; 1H NMR (300 MHz, DMSO- 4) 5 8.55 (t, J = 6.0 Hz, IH), «.16 (d, J= 8.0 Hz, IH), 7.53 <d, J= 8.5 Hz1 2H) 7.38-7.20 (m, 9H), 6,28 (to, J- 7.9, 2.7 Hz, IH), €.14 (d, /= 2.7 Hz, IH), 5.16 (s, 2H), 4.41 (d, J= 6.0 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-^) S 166.1, 162.4, 150.9, 150.8, 139.6, 138.8, 137.2, 135.1, 132.4, 129.9, 1282, 127.3, 1274, 127.1, 126.6, 120.6, 118.7, 116.2, 102.5, 97.3, 69.2, 42.5, 15.5; MS (ES+) m/z 497.3 (M+l).
EXAMPLE ».4
Synthesis of .V-Bcnzjl-3-πieth>l-5-(2-oϊ<p-t-])hcncthoxypyridiπ-1(2//)-yl)thiophene- 2-carbcraanιiie
Figure imgf000102_0002
Following the procedure as described in Example 9, making variations only as required to iisephenethyl 4-methylbenzenesulfonate in place of 2-cycloproj>y]ethyl 4- methylbenzsmesulfonate to react with /V-berizyl-5-(4-hydroxy-2-oxopyrici in- l(2i/)-yl)-3- methylthiophεne-2-carboxamide, the title compound was obtained as a colorless solid in 59% yield: rap 159-160 0C; 1H NMR (300 MHz, DMSCM;) δ 8.55 (t, J= 5.9 Hz, IH), 8.12 (d, J = 79 Hz, IH), 7.35-7.20{m, HH), 6.18 (dd, J= 7.9, 2.6 Hz, IHX 6.06 {d, J = 2.6 Hz. IH). 4.41 (d, J= 6.0 Hz, 2H), 4.27 tt, J = 6.7 Hz, 2H), 3.04 (t, J= tA Hz, 2H), 2.42 (s, 3H), 13CNMR (75 MHz, DMSO-dJ) β 166.3, 162.4, 161.0, 139.6, 138.8, 137.7,
137.1, 135 D, 128.8, 128.3, 128.2, 127.3, 127.1, 126.6, 126.3, 120.5, 102.4, 96.8, 68.8, 42.5, 34.2, 15 5; MS (ES+) m/z 445.3 (M + 1).
EXAMPLE 9.5
Synthesis of JV-Beπzyl-S-(4-(cyclopropylmeth«xy)-2-oxopyridin-l(2fi)-jl)-3- methylthioptiene-Z-carboxamide
Figure imgf000103_0001
Following the procedure as described in Example 9, making variations only as required to use cyclopropylmethyl bromide in place of 2-cyclopropylethyl 4- methylbenzenesulfonate to react with iV-benzyl-5-(4-hj'droxy-2-oxopyridin-l(2/f)-yl)-3- methyltbiophene-2-carboxamide, the title compound was obtained as a tclorless solid in 62% yield: nip 175-1770C; 1H NMR (300 MHz, DMSCW6) δ 8.54 (t, J= 6.0 Hz, IH), S.13 (d, J = 8.0 Hz, IH), 7.35-7.20 (m, 6H)1 6.2. (dd, J= 8 0, 2 7 Hz, IH), 597 (d, J= 2.7 Hz, IH), 4.41 (d, J = 6.0 Hz, 2H), 3.S8 (d, /= 7.2 Hz, 2H), 2.42 (s, 3H), 1.27-1.14 (m, IH), 0.63-0.54 (m, 2H), 0.37-0.29 (m, IH); '3C NMR (75 MHz, DMSO-rf6) 8 166.5, 162.4, 161.0, 139.6, 138.8, 137.2, 1349, 128.2, 127.2, 127.1, 126.6, 120.4, 102.5, 96.6, 73.1, 42.3, 15.5, 9.5, 3.1; MS (ES+) m/z 395.2 (M + 1).
EXAMPLE ?.6
Sjn thesis of 5-(4-(3 -(fcrt-ButyldimethylsOyloxytøropoxyJ-J -oxopy riain-l(2.H)-yl)-./V-
(S-fluorobenzyl^-RiethyUhiophene-l-carboxamide
Figure imgf000103_0002
Following the procedure as described in Example 9, making variations only as required to use (3-bromopropoxy)(rer/-bιιtyl)dimethylsϊlane in place of 2-
cyclopropylethjl 4-methylbenzenesulfonateto react with JV-(3-fluorabenz/l)-5-(4- hydroxy-2-oxopyridin-l(2/0-yl)-3-meth)'ltHophenβ-2-oarboxaraidβ, the title compound was obtained as ε yellowish viscous oil in quantitative yield: 1H NMR ^300 MHz, CDCIj) δ 7.54 (d, J= 7.8 Hz, IH), 7.35-7.27 (m, IH), 7.12 (d, J= 7 8 Hz, IH), 7.05 (d, J= 9.6 Hz, IH), 7 00-6.94 (ra, IH), 6.85 <s, IH), 6.15 {t, J= 5.8 Hz, IH), 6.07 (AA, J= 7.8, 2 7 Hz, IH), 5.98 (d, J= 2.7 Hz, IH), 4.59 (d, J= 5.8 Hz, 2H), 4.07 (t, J= 6,0 Hz, 2H), 3,77 (t, J= 6.0 Hε, 2H), 3.52 (t, J= 6.0 Hz, 2H), 254 (s, 3H), 0.88 (s, 9H), 0.04 (s, 6H); MS (ES+) m/z 531.5 (M H- I).
EXAMPLE 9.7
Synthesis of jV-Ben_yl-4-methyl-2-(2Hκo-4 -((5-(trifluoromethyl)fϊι ran-2- yl)methoxy)pyridin-l(2fl)-yl)tliiazole-5-c-rl)ox_iiH<le
^v^Hrc
Following the procedure as described in Example 9, making variations only as required to use 2-(bromomethyl)-5-(trifluorDinethyl)fύran in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with JV-benzy]-2-(4-hydroxy-2-oxopyridi]i-[(2.£fι-yl)- 4-methylthia2θle-5-carboxamide, the title compound was obtained as a colorless solid in 16% yield- mp 214-216 0C; ' H NMR (300 MHz, DMSO-<y δ S 71-8.68 (m, 1 H), 7.38- 7.26 (m, 5H)1 6.S1-6.79 (m, IH), 6.57-6.56 (m, IH), 6.22-6.06 (m, 3H), 5.C0 (s, 2H), 4.59 (d, 7= 5.7 Hz, 2H), 2.68 (s, 3H); 13C NMR. (75 MHz, DMSO-d5) S 166.8, 1«1 9, 161.5. 153.0, 152.5, 1504, 139.9, 132.3, 128.8, 127.7, 127.2, 123.S, 114.6, 113.2, 107.5, 104.1, 97.6, 62.9, 62.4,43.1, 17.5; MS (ES+) m/z 490.3 (M + 1).
EXAMPLE 9,8
Synthesis of /y-Benzyl-4-methyl-2-(2-oxo-4-(4-(trifluoromethyl)benzylcxy)pyridin- l(2//)-yl)tMii2ult-5-car|]oxamide
Figure imgf000105_0001
Following the procedure as described in Example 9, making variations only as required to use 4-trifluoromethylbenzyl bromide in place of 2-cyclopropylethyl 4- methylbenzenesulfonate to react with Λr-ber]zyl-2-(4-hydroxy-2-oxopyridin-l(2.H)-yl)-'t- methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 21% yield: mp 278-280 0C; 1H NMR (300 MHz, DMS(W1,) S 8.78 (br s, IH), 8.65-8.62 (m, IH), 7.78-7.64 (m, 4H), 7.30-7.29 (m, 5H), 6.44-6.41 (m, IH), 6.23 (d, J= 2.7 Hz, IH), 5.30 (s, 2H), 4.38 (d, J = 6.0 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MH-,DMSO-d«) δ 167.3, 161.9, 161.6, 153.9, 150.4, 140.7, 1399, 132.3, 128.8, 128.7, 127.7, 127.2, 126.4, 126.0, 125.9, 123.8, 104.3, 97.7, 69.8,43 1, 17.5; MS (ES+) m/z 500.3 (M + 1).
Same as Example 1.24
EXAMPLE 9.9
Synthesis of 2-(4-(4-(Diπuoroinethoxy)benzyloxy)-2-oxopyridiii-l(2.ff)-yl)-ΛH4- fluorobenzy^-l-methylthiazole-S-carbosamide
Figure imgf000105_0002
Following the procedure as described in Example 9, making variation only as required to use 4-(difluoromethoxy)benzyl bromide in place of 2-cyclopropylethyl A- methylbenzeresulfonate to react with Λr-(4-fluorobenzyl)-2-(4-hydroxy-2-cκopyridin- l(2Jϊ)-yl)-4-rnethylthiazole-5<arboxamide, the title compound was obtained as a colorless solid in 25% yield: mp 242-244 "C (dichloromethaπe/methanol), 1H NMR (300 MHz, DMSO-<f0) δ 8.78 (t,«? = 5.8 Hz, IH), 8.60 (dd, ./= 8.1, 3.0 Hz, IH), 7.56-7.47 <m, 2H), 7.34-7.08 (in, 7H), 6.43-6.32 (m, 1 H), 622 (s, IH), 5.15 (s, 2H), 4.34 (J, J= 5.8 Hz, 2H), 2 52 (s, 3H); 13C NMR (75 MHz, DMSO-4) & 167.4, 163.2, 161.9, 1600, 151.4,
150.4, 136.1, 133.7, 132.7, 130.5, 129.8, 123.5, 120.1, 1 19.2, 116.7, 115.6, 113.3, 104.3, 97.5, 70.1, 44,6, 17.5; MS (ES+) m/z 516.4 (M + 1).
EXAMPLE 9.10
Synthesis »fλr-Beπzyl-2-(4-(cyclopentylinelhoxy)-2.oxopyridiii-l(2fl)-yl)-4- methylthiazole-S-carboxamide
Figure imgf000106_0001
Following the procedure as described in Example 9, making variation only as required to use cyclopentylmetbyl 4-methylbenzenesulfonate in place of 2- cyclopropylethyl 4-methylbenzenesulfonate to react with iVLbβnzyl-2-(4-hydroxy-2- oxopyridir-l(2H)-yl)-4-methylthia2θle-5-carboxamide, the title compound was obtained as a colorless solid in 57% yield: mp 196-198 0C (methanol); 1H NMR (3«C MHz, CDCl3) B % .Si (d, J= 8 1 Hz, IH), 7.40-7 25 Cm, 5H), 6.16 (d, J = 8.1 , 2.6 Hz, IH).6.09- 6.05 [m. IH), 5.94 (d, J = 2.6 Hz, IH), 4.38 (d, J= 5.6 Hz, 2H), 3.83 H, J = 7.0 Hz, 2H), 2.68 (s, 3H) 2.41-2.27 (m, IH), 1.87-1.77 (m, 4H), 1.66-1.58 (m, 4H); 13C NMR (75 MHz, CDCl3) 5 167.9, 162.2, 162.1, 153.6, 152.2, 137.7, 131.3, 128.8, 1279, 127.7, 122.1, 104.2, 956, 73.3, 44.1, 3S.4, 29.3, 25.3, 17.3; MS (ES+) m/z 4243 (M + 1).
EXAMPLE ?.ll
Synthesis of N-<3)4-Difluorobenzyl)-2-(4-metlioxy-2-oxopyridiii-l(2,H)-)'l)-4- methylthiazcle-5-carboxamide
Figure imgf000106_0002
Following the procedure as described in Example 9, making variation only as required to use iodomethane in place of 2-cyelopropylethyl 4-methylbenzenesulfonate to react with JV-(3,4-difluorobenzyl)-2-(4-hy[lroxy-2-oxopyridin-l(2Jϊ)-yl)-4- methyIthiazole-5-carboxamide, the title compound was obtained as a colorless solid in
66% yield: mp 183-185 °C (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl1) δ 8.«5 (d, J= 8.1 Hz1 IH), 7.18-7.05 (m, 3H), 6.20-6.15 (m, 2H), 5.97 id, J- 2,5 Hi, IH), 4.53 (d, J= 5.8 Hz1 2H), 3.82 (m, 3H), 2.68 {m, 3H); 13C NMR (75 MHz, CDCl3)δ 168.4, 162.3, 162.1, 153.6, 152.7, 135.0, 131.4, 123.7, 121.8, 117.6, 117.4, 116.9, 116.7, 104.0, 96.2, 56.0,430, 17.3; MS (ES+) m/z 392.2 (M+ 1).
EXAMPLE 9.12
Synthesis of Λf-Benzyl-4-methyl-2-(2-oxθJt-((<etrahy(l rofuran-2-yl)metkoxy)pyri(iin- l(Z.ff)-yl)tliιazole-5-carboxamide
Figure imgf000107_0001
Following the procedure as described in Example 9, making variation only as required to use 2-(bromomethyl)tetrahydrofuran in place of 2-cyclopropylethyl 4- methylbcnzenesiilfonate to react with iV-berzy]-2-(4-hydroxy-2-oxopyridin-l(2/?)-yl)-4- methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 42% yield: mp 181-183 T (ethyl acetatefliexanes); 1H NMR (300 MHz, CDCIj) δ 8.66- 8.62 (m, IH), 7.38-7.26 (m, 5H), 6.22-6.18 (m, IH), 6.14-6.12 (m, IH), 5 95-5.94 (m, IH), 4.58-4.54 (in, 2H), 4.33-4.20 (m, IH), 399-3.78(m, 4H), 2.67 (s, 3H)1 2.13-1.90<m, 3H), 1.77-1.65 (m, IH); MS (ES+) m/z 4263 (M + 1), 448.3 {M + 23).
EXAMPLE 1C
Synthesis of ^-Bcnzyl-2-(4-(4-cliloropheiiyl)-2-oxopyridin-l(2fl)-yl)-4- methylthiazflle-5-carboxamide
Figure imgf000107_0002
An oven-dried flask was charged with ethyl 1 -(5-(benzylcarbamoyI)-4- methylthiazoL2-y])-2-oκo.l;2-dihydropyridin-i.yl trifluoramethanesulfonate (0.10 g, 0.21 mmol), 4-chlorophenylboronic acid (0036 g, 0.23 mmol),
tetrakis(triplieny]phosphine)palladium(0) (0.012 g, 0.01 mmol), potassium phosphate (0.067 g, 0.31 mmol) and potassium bromide (0.027 g, 0.23 mmol). The mixture was then purged with nitrogen, followed by the addition of anhydrous dioxane (7 mL). The reaction mixture was heated to reflux for 16 hours, then ethyl acetate (20 mL) was added and the mixture was washed with saturated ammonium chloride (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The brown residue was purified by column chromatography eluting with ethyl acetate/hexane (1/1) and then recrystallized from ether to afford (he title compound as a colorless solid (0.090 g, 99%). mp 265-267 "C (ether), 1H NMR (300 MHz, DMSO-tfs) 8 8.89 (t, /= 5.4 Hz, IH), 8.81 (d, 7 = 7.7 Hz, IH), 7.91-7.88 (m,2H), 7.64-7.58 (m, 2H), 7.35-723 (m, 5H), 7.15 (d, J= 1.7 Hz, IH), 7.05 (dd, J= 7.7, Z 1 Hz, IH), 4.44 (d, J= 5.2 Hz, 2H), 2.62 (s, 3H); 13C hMR (75 MHz, DMSO-*) 6 161.8, 160.2, 153.6, 150.6, 150.0, 139.8, 135.7, 134,6, 131.7, 129.6, 129.3, 128.7, 127.7, 127.2, 124.5, 1 16.3, 107.5, 43.1, 17.5; MS (ES-t-J ffl/z 436.0 (M + 1).
EXAMPLE 11
Synthesis of l-(5-(Benϊylcarbamoyl)-4-raetliylthiazol-2-yl)-2-oxo-l,2- dihydropyridin-4-yl Trifluoromelhanesiilfcnate
Figure imgf000108_0001
To a solution of jV-benzy]-2-(4-iiydroxy-2-oxopyridin-l(2/f)-yl)-4- methylthiazole-5-carboxamide (1.00 g, 2.92 rnmol) in anhydrous pyridine (20 rnL) was added trifluorαmethanesulfonic anhydride ai -75 °C. The mixture was stirred at -50 °C for 20 minutes followed by the addition of ethyl acetate (30 mL), and subsequently washed with water (2 « 5 mL). The organic layer wεs separated and concentrated m vacuo. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (3/2) to afford the title compound as a yellow solid in 58% yield (0.81 g): 1H NMR (300 MHz, ΩMSO-de) S t.iS (ά, J= 8.1 Hz, IH), 7.40-7.26 (m, 5H), 6.69 (d, J= 2.6 Hs, IH), 6.45 (dd, J = 8.1 , 2.6 Hz, IH), 6.08 (t, /= 5.6 Hz1 IH), 4.60 (d, J= 5.6 Hz, 2H), 2.69 (s, 3H);
MS CES+) mfi 4744 (M + 1).
EXAMPLE 12
Synthesis of Ethyl 4-Methyl-2-(2-oxo-4-pkenyIpyridin-l(2/2)-yl)thiazoIe-5- carboxylate
Figure imgf000109_0001
To asolution of ethyl 2-bromo^l-nietliy[thiazol€-5-cβrboxylate (0.50 g, 2.00 mmol) in anhydrous A^JV-dimethylformamide (10 raL) was added 4-phenylpyridin-2-ol (0.31 g, 1.80 mmol), copper(I) iodide (0.053 g, 0.28 mmol), 8-hydroxyquinoline (0.041 g, 0.28 mmol), and potassium carbonate (0.39 g, 2.80 mmol) The mixture was degassed and the flask was filled with nitrogen. The reaction mixture was heated at 100 0C for 6 hours and then diluted with ethyl acetate (25 inL), washed with 14% aqueous ammonium hydroxide (2 x 7 mL) and brine (7 mL). The orønic layer was dried over anhydrous sodium sulfate, filtered concentrated in vacuo to afford as a yellowish solid (0.45 g, 66%)- 'H NMROOO MHz. DMSO-^ δ S.SS-S.TS (m, IH), 7.88-7.81 <m, 2H), 7.60-7.50 (m, 3H), 7.14-703 (m, 2H), 4.26 (q, J= 7.0Hz, 2H), 2.64 (s, 3H), 1.28 (t, J= 7.0 Hz, 3H); MS (ES-O wi/j 341,6 (M + 1).
EXAMPLE 12.1
Synthesis of l.thyl 2-(4-(Benzyloxy).2-oxopyr idin.l(2 H)-yl)-4-mothylHiJZole-;- carboxylate
Figure imgf000109_0002
Following the procedure as described in Example 12, making variations only as required to use 4-fl)enzyloxy)pyridin-2(lfl)-one in place of4-phenylpyridin-2-oI to react with ethyl 2-brorno-4-methylthiazole-5-carbDijlate, the title compound was obtained as a
yellow solid in 80% yield: 1H NMR (300 MHz, CDCIj) S 8.65 (d, J= 7.9 Hz, IH), 7.42- 7.26 (m, 5H], S.18 (d, J= 7.Q Hz, IH), 6.07 (s, IH), 5.01 (s, 2H), 4.28 (q, /= 7.1 Hz, IH), 2.65 (s, 3H), 1.32 (t, J= 7.1 Hz, 3H); MS (ES+) mlz 371.1 (M + 1).
EXAMPLE 12.2
Synthesis of Elhyl 2-(4-(benzyloxy)-2-oxopyridin-l(2/Q-yl)-4-methyl-:l.ff-iinidazole-
5-carboxyiate
Figure imgf000110_0001
Following the procedure as described m Example 12, making variations only as required to use 4-(benzyloxy)pyridin-2(lfl)-one in place of 4-phenylpyridiri-2-ol to react with ethyl 2-brorno-4-methyl-l//-imidazole-5-carboxylate in place of ethyl 2-bromo-4- methylthiazole-5-carboxylate at 130 0C for 54 hours, the title compound was obtained as u colorless solid m 26% yield: mp 135-13« "C; 1H NMR (300 UHt, CDCl3) 5 12.01 {s, IH), 8.60-8.50 (m, IH), 7.44-7.36 (en, 5H), S->1 (dd, J= 8.0, 2.6 Hz, IH), 6.04 (d, J = 2.6 Hz, IH), 5.06 (s, 2H), 4.44-4.29 (m, 2H), 2.59-2.51 (m, 3H), 1.44-1.34 (in, 3H); MS (ES+) mk 354.2 (M + 1).
EXAMPLE 12.3
Synthesis of Ethyl 2-(4-(Beπzyloxy)-2-osopyridin-l(2.^-ylH,4-dimetlijl-:lJϊ- imidazolc-S-«arboxylαtc
Figure imgf000110_0002
Following the procedure as described in Example 12, making variations only as required to use 4-(benzyloxy)pyridin-2(l/7)-one in place of 4-phenylpyridin-2-ol to react with ethyl 2-bromo-l,4-dimethyl-l/-r-imidazcle-5-carboxylate in place of elhyl 2-bromo- 4-methyltliiazole-5-carboxylate at 125 0C fcr 64 hours, the title compound was obtained
as a colorless solid in 24% yield: 1H NMR (3OC MHz, CDCl5) δ 7.44-7.36 (m, 5H), 7.22 (d, J- 7.7 Hz1 IH), 6.09 (άά, J- 7.7, 2.5 Hz, IH) 5.98 (ά,J = 2,5 Hs, IH], 5.04 (a, 2H), 4.35 (q, J= 7.1 Hz, 2H), 3.69 (s, 3H), 2.49 (s, 3H), 1.38 (t, J= 7.1 Hz, 3H); MS (ES+) mlz 368.2 (M 4- 1),
EXAMPLE 12.4
Synthesis of Ethyl 2-(4-(Benzyloxy)-2-oxop>τidin-l(2.φ-yl)-l,5-dinietliyl-l.ff- iπiidazole-4-carboxylate
Not covered \rf Formula (I)
Figure imgf000111_0001
Following the procedure as described in Example 12, making variations only as required to use 4-(benzyloxy)pyridin-2(l/i>one in place of 4-phenylpyndin-2-ol to react with ethyl 2-bromo-l,5-dimcthyl-l//-imidαxclc-4-carboxylate in place of ethyl 2-bromo- 4-methylthiazole-5-carboxylate at 125 0C for 28 hours, the title compound was obtained as a colorless solid in 30% yield: 1H NMR (3DO MHz, CDCl3) δ 7.43-7.38 (m, 5H), 7.31 (d, J = 7.7 Hz, IH), 6.07 (dd, J= 7.7, 2.5 HE, IH) 5.96 <d, J= 2,5 Hz, IH), 5,04 (s, 2H), 4.37 (q, J = 69 Hz, 2H), 3.42 (s, 3H), 2.58 (s 3H), 1.38 (t, J = 7.1 Hz, 3H); MS (ES+) mlz 368.3 (M+ 1).
EXAMPLE 13
Synthesis of 4-Methyl-2-(2-oxo-4-phenylpyridin-l(2//)-yl)thiazole-5-c.rbraylic Acid
Figure imgf000111_0002
Toa solution of ethyl 4-methyl-2-(2-cxo-4-phenylpyridin-l{2//)-yl)thiazole-5- carboxylatc (0.25 g, 0.74 mmol) in a mixture of tetrahydrofuran (4 mL) and water (4 mL) was added lithium hydroxide (0.14 g, 3.68 mjtiol). The reaction mixture was heated at 50
0C for 4 hours, (hen cooled to ambient temperature and acidified to pH 6 with acetic acid. The solid obtained wag collected by filtration, washed with water and dried in air. The title compound was obtained as a yellowish solid {0.20 g, 87%): MS (ES4) m/z 313.5 {M + 1).
EXAMPLE 13.1
Synthesis of 2-(4-(Benzyloxy)-2-oxopy ridin-l(2^)-yl)-4-methyltbiazolc-5-carboxylic acid
Figure imgf000112_0001
Following the procedure as described in Example 13» making variations only as required to use ethyl 2-(4-(ben2yloxy)-2-oxorjyridin-l(2Z/)-yl)-4-methy]thiazole-5- carboxylate in place of ethyl 4-methyl-2-(2-o>;o-4-phenylpyridin-l(2/fl-yl)tliiazole-5- cαrboxylatc, the title compound was obtained as a yellowish solid in 72% yield. MS (ES+) m/z 343.2 (M + 1).
EXAMPLE 13,2
Synthesis of2-(4-(Cyclopropylmethoxy)-2-oxopyridin-l(2//)-yl)-4-methyltliiazole-5- carboxylic Acid
Figure imgf000112_0002
Following the procedure as described in Example 13, making variations only as required to use ethyl 2-(4-(cyclopropylmetlioxy)-2-oxopyridin-l(2./7)-yl)-4- raethylthiazole-5-carboxylate in place of ethyl 4-methyl-2-(2-oxo-4-phenylpyridin-l(2/0- yl)thiazole-5-cart)θxylate, the title compound was obtained as a yellowish soiid in 73% yield: MS (ES+) mil 307.4 (Mt I).
Ill
EXAMPLE 13.3
Synthesis »f l-(4-(2-Cyclopropylethoxy)-2-»xopyridin-l(2fl)-j'l)-4-inethylthiiιzole-5- carboxylic Aeid
Figure imgf000113_0001
Following the procedure as described in Preparation 13, making variations only as required to use ethyl 2-(4-(2-cyclopropylethDxy)-2-oxopyridiπ-l(2/f)-yl>4- methylthiazole-5-carboxylate in place of ethyl 4-methyl-2-(2-oxo-4-phenylpyridin-l(2/^)- yl)thiazole-5-carboxylate, the title compound was obtained as a pale yellow solid in 85% yield: MS (ES+) m/r. 321.4 (M + 1).
EXAMPLE ]3.4
Synthesis of J^-Methoiy-l-oxopyridin-^IiO-ylM-rnethylthiazole-S-carboitylic
Acid
Figure imgf000113_0002
Following the procedure as described in Example 13, making variations only as required to use ethyl 2-(4-methoxy-2-oxopyridin-l(2//)-yl)-4-methylthiazole-5- carboxylate in place of ethyl 4-methyl-2-(2-Dxo-4-phenylpyridin-l(2i/)-j'l)thia?ole-5- carboxylate, the title compound was obtained as a yellowish solid in 80% yield: MS (ES+) m/z 267.3 (M + 1).
EXAMPLE 13.5
Synthesis of 2-(4-Hydroxy-2-oxopyridin-l(2tf)-yl)-4-rnethylthiazole-S-carboxylic Acid
Figure imgf000113_0003
Following the procedure as describe! in Example 13 , making variations only as required to use ethyl 2-(4-hydκm}-2-oxopyridin-l(2.β)-yl)-4-mettiylthiaEole-5- carboxylate ir place of ethyl 4-methyl-2-(2-oxo-4-phenylpyτidin-l(2,H)-y])(hiazole-5- carboxylate, the title compound was obtained as a colorless solid in 92% yield; MS (ES+) m/z 253.2 (M+ 1).
EXAMPLE 13.«
Synthesis of 4-Methyl-2-(2-oio-4-((5-(ti-ifluoromethyl)furan-2-yl)metlicxy)pyriiJin- l(lff)-yl)»lilazole-3-cartH>xyltc acid
Figure imgf000114_0001
Following the procedure as described in Example 13, making variations only as required to use ethyl 4-methyl-2-(2-oxo-4-((f-(trifluorcmethyl)furan-2- yl)mcthoi4y)pyridin-l(2W)-yl)thi_zolβ-S-oaιboxylate in place of ethyl 4-methyl-2-(_-oxo- 4-phenylpyridin-l(2.H)-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 75% yield: mp 261-263 0C (water/acetone); 1H NMR (300 MHz, DMSO-4s) S 13J24 (br s, IH), 8.61 (d, J= 8.1 Hz, IH), 7.25-7.23 (m, IH], 690 (d, J= 3.2 Hz, IH), 6.39 (dd, J= S.I, 2.7 Hz, IH), 6.32 (d, /= 2.7 Hz, IH), 5.250, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, DMSO-4,) δ 1Θ6.8, 164.0, 161.6, 155.8, 154.4, 152.6, 141.3, 132.1, 121.1, 117 6, 114.5, 113 1, 104.1, 97.6, 62.4, 17.4; MS (ES+) m/i 401.1 (M + 1).
EXAMPLE 13.7
Synthe$siof2-(l-(4-Fluorabenzyloxy)-2-«sopyridin-l(10)-yl)-4-πiethyltliiazole-5- carboxylic acid
Figure imgf000114_0002
Following the procedure as described in Example 13, making variations only as
required to use ethyl 2-(4-(4-fluorobenzyloxy)-2-oxopyridin-l(2Λ)-yl)-4-ιτiethylthiazole- 5-carboxylata in place of εthyl 4-mcthyl-2-(2-oxo-4-phenylpyridin-l(2fl)-yl)ttiiazole-5- carboxylate,tHe title compound was obtained as a colorless solid in 79% yield; mp >300 0C (water/acetone); 1H NMR (300 MHz, DMSO-rfβ) δ 8.60 <d, J = 8.1 Hz, IH), 7.52-7.47 (m, 2H), 7,27-7.16 (m, 2H), 6.90 (d, J = 3.2 Hz, IH), 6.37 (dd, J= 8.1, 2.7 Hz, IH), 6.21 (d, J = 2.6 Hz1 IH), 5.14 (s, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, DMSO-rf^ 5 167.4, 164,1, 161.7, 160.9, 155.9, 154.4, 132.0, 131.9, 130.9, 120.8, 116.0, 115.7, 104.1, 97.5, 70.1, 17.4;MS (ES+) m/z 361.3 (M+ 1).
EXAMPLE 13.8
Synthesis of 5-(4-(Benzyloxy)-2-oiopy ri(lin-l(2i/)-yl)-3-metliylthiophcne-2- carboxylic arid
. Vw^rO
HOY^S' y
Following the procedure as described in Example 13, making variations only as required to use ethyl 5-(4-(benzyloxy)-2-oxopyridin-l(2.tf)-yl)-3-methylthicphene-2- carboxylate in place of ethyl 4-methyl-2-(2-oio-4-phenylpyridm-l(2//)-yl)thiazole-5- carboxylate, the title compound was obtained as a colorless solid in 92% yield: 1H NMR (300 MHz, DMSO-*) δ 12.82 (br s, IH), 8.20 (d, J= 8.0 Hz, IH), 7.50-7.32 (in, 6 H), 6 30 (dd, J= «.0, 2.6 Hz, IH), 6.14 (d, / = 2,6 Hz, IH), 5.17 (s, 2H), 2.46 (s, 3H); MS (ES+) m/ϊ 343 α (M+l)
EXAMPLE 14
Synthesis of Ethyl 2-(4-Hydroxy-2-oxopyridiii-l(2fl)-yl)-4-methylthiazol«-5- carboxylate
^c >,.* -κ ' ■> " -°H
A mixture of ethyl 2-(4-(benzyloxy)-2-oxopyridin-l (2fl)-yl)-4-metliylthiazole-5- carboxylate (7.00 g, 18.0 mmol) and 20 wt.% palladium on activated carbon (3 g) in anhydrous tetrahydrofuran (300 mL) was stiπed under an atmosphere of hydrogen for 2 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo The residue was recrystallized from ethyl acetate to afford the title compound as a colorless solid (4.00 g, 80%): mp 270-273 0C (ethyl acetate); 1H NMR (300 MHz, DMS0-.4) i 1 1.57 (s, IH), 8.58 (d, J = 8.0 Hz, IH), 6.27 (dd, J= 8.0, 2.5 Hz, IH), 5.81 (d, J= 2.5 Hz1 IH), 4.24 (q, J= 7.1 Hz, 2H), 2.58 (s, 3H), 1.26 (t, J= 7.1 Hz, 3H); 13C KMR (73 MHz, DMSO-&) 6 168.0, 162.3, 1*1.7, 136.3. 133.3, 132.4, 119.0, 104.7. 97.9, 61.2, 176, 14.6; MS (ES+) m/∑ 281.0 (M+ 1).
EXAMPLE 15
Synthesis of Ethyl 2-(4-(Cyclopropylmetlioi;y)-2-oxopyridiii-l(2fl)-yl)-4- methylthiazole-5-carboxylate
Figure imgf000116_0001
of ethyl 2-(4-hydroxy-2-oxopyridin-l(2fl)-ylM- methylthiazol£-5-carboxylate (1.00 g, 3.56 mmol) in W,Λf-dύnethylformamidc (10 mL) at 00C was added sodium hydride (0.14 g, 5.70 mmol). The reaction mixture was stirred at 00C for 30 mirutes, then (bromomethyl)cyclopropane (0.58 g, 4.28 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 hours. The sol-vent was removed at high vacuum and the residue was diluted with dichloromethane (30 mL), washed with brine (25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate/hexane (1/1) to afford the title compound as a colorless solid (1.15 g, 97%): mp 180-183 0C (hexane/ethyl acetate); 1H NMR (300 MHz, CDCI3) δ 8.68-8.65 (m, IH), 6.19-6.16 (m, IH), 5.93 (d, J= 2.6 Hz, IH), 4.31 (q, J= 7.1 Hz, 2H), 3.81<d, J = 7.1 Hz, 2H), 2.68 (s, 3H), 1.33 (t, J= 7.1 Hz, 3H), 1.31-1.19 (ItI, IH), 0.70-0.64 (in, 2H). 0.38- 0.33 (m, 2H); 11C NMR (75 MHz, CDCl3) 6 167.6, 162.9, 162.2, 156.6, 155.-6, 131.3,
119.6, 104.5, 96.7, 60.9, 17.3, 14.3, 9.8, 9.5, 3.3; MS (ES+) m/z 335.1 (M+ 1),
EXAMPLE 15.1
Synthesis of Ethyl 2-(4-Metho]ty-2-OM>py riain-l(2fl)-yl)-4-methylthiazβle-S- carboxylate
-d
,C J>P*
Following the procedure as describe! in Example 15, making variations only as required to use methyl iodide in place of (bromomethyl)cyclopropane to react with ethyl 2-(4-hydroxy-2-oxopyridin-l(2^-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a yellowish solid in 54% yield; mp 163-165 "C (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) S 8.67 (d, J= 8. I Hz , IH), 6.16 (dd, J= 8.1, 2.7 Hz, IH),
6.00 (d, J= Z 7Hz , IH), 4.32 (q, J= 7.1 Hi , 2H), 3.83 (s, 3H), 2.68 (s, 3H), 1.36 (t, J =
7.1 Hz, 3H), 13CNMR (75 MHz, CDCI5) δ 168.3. 162.9, 1S2.2. 156.6. 155.7. 131.3. 119.7, 103.8, 96.3, 60.9, 56.0, 17.3, 14.3; MS (ES+) m/z 295.2 (M + 1 ).
EXAMPLE 15.2
Synthesis of Ethyl 2-(4-(2-Cyclopropyletlioxy)-2-oxopyridin-l(2H)-yl)-4- methylthiazαlc-5-carboxylate
- Following tαhe procedure as described in Example 15, making variations only as required to use 2-cyclopropylethyl-4-methylbenzenesulfonate in place of (bromomethyl)cyclopropane to react with ethyl 2-(4-hydroxy-2-oxopyridin-l(2//)-)'l)-4- methylthiazole-5-carboxylate, the title compound was obtained as a colorless 1SoHd in 35% yield: mp 1 S8-190 "C (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8 67
Figure imgf000117_0001
8.1, 1.1 Hz , IH), 6.17-6.13 (m. 1 H).600-5.99 Cm, IH).4.35-4.27 [m.2H). 4.04 (t, J= 6.6 Hz, 2H), 2.68 (s, 3H), 1.68 (q,^= 6.6 Hz, 2H), 1.35 (dt, J = 7.1, 1.3 Hz, 3H),
0.90-0.68 (m, IH), 0.52-0.44 (m, 2H), 0.14-0.09 (m, 2H); 13C NMR (75 MHz, CDCI3) 8 167.8, 162.9, 162.2, 156.6, 155.6, 131.3, 119.7, 104.1, 96.7, 69.1, 60.9, 33.6,17.3, 14.3, 7.5, 4.2; MS (ES+) mk 349.2 (M + 1).
EXAMPLE 16
Synthesis of 2-(4-(Beπzyloxy)-2-oxopyridin-l(2/7)-yl)-4-methyl-lff-imidazo]e-5- carboxylic Acid
Figure imgf000118_0001
A suspension of ethyl 2-(4-(benzyloxy)-2-oxopyridin-l(2Λ)-yl)-':l-methyl-l//- imidazole-5-c«rboxylate (0.10 g, 0.28 mmol) in 1 N aqueous sodium hydroxide (2 mL) was stirred al +5 0C for 16 h, and then at 65 "C for 5 h. The reaction mixture was cooled to 0 °C then acidified with 10% aqueous hydrochloric acid to pH ~ 2. The precipitate was filtered, washed with water, and then with acetone into a separate flask. The acetone filtrate was concentrated in vacuo and co-concentrated with methanol to dryness (x 2). The residue was combined with the solid to afford the title compound (O.OSO g, 65%): MS (ES-) mk 324.2 (M - 1).
EXAMPLE 16.1
Synthesis of 2-l4-(Benzyloxy)-2-n\opyridiri-l(2//)-yl)-l,4-dimethyl-li/-imidiiiolc-5- iar turn Hc Add
Figure imgf000118_0002
Following the procedure are described in Exmaple 16, making variations only as required to use ethyl 2-(4-(benzyloxy)-2-oxcpyridin-l(2fl)-y])-l,4-dimethyl-U7- imidazole-5-cart)oxylate In place of ethyl 2-(4-tøenzyloxy)-2-oxopyridin-l(2Λ>yl)-4- methyl-l/f-iinida_ole-5-carboxylate, the title compound was obtained as a colorless ϊolid
in 97% yield: 1H NMR (300 MHz, DMSO</()δ 13.03 (br s, IH), 7.54 (dd, J= 7.8, 1.4 HZ, IH). 7.51-7.37 (m. 5H). 6.18 Cd. / = 7.8 Hz. IH). 6.03 (s, IH). 3.1d (S, 2H), 3.30 (s, 3H), 2.38 (S, 3H); MS (ES+) m/z 340.2 (M -i- 1).
EXAMPLE 16.2
Synthesis of 2-(4-(Benzyloxy)-2-oxopyri(liπ-l(2H)-yl)-l,5-dimethyl-2,3-(llhydro-llf- imidazole-4-carboxyllc Acid
Figure imgf000119_0001
Following the procedure as described in Example 16, making variations only as required to use ethyl 2-(4-(benzyloxy)-2-oxopjridin-l(2Λ)-yl)-l,5-dimetliyl-l/ϊ- imidazole-4-carboxylate in place of ethyl 2-(4-(benzyloxy)-2-oxopyridin-l(2fl)-yl)-4- methyl-l//-iraidazole-5-carboxylate, the title compound was obtained as a colorless solid in 86% of yield- 1H NMR (3QO MHz, DMSO-rf,) S 12 24 (br s, IH), 756-7.34 (m, 6H). 6.18 (d, J= 73 Hz, IH), 6.04 (s, IH), 5.16 (S1 2H), 3.30 (S, 3H), 3.17 (S, J = 4.7 Hz, 3H); MS (ES+) m/z 340.2 (M + 1).
EXAMPLE 17
Synthesis of eihyl 4-Methyl-2-(2-oxo-4-<(5-(trifluoromethyl)furaιi-2- yl)methoxy)pyridin-l(2H)-yl)thiazole-5-carl>oxy]ate
Figure imgf000119_0002
To a stirred solution of ethyl 2-(4-hydroxy-2-oxopyridiπ-l(2i/)-y]>-4- methylthiazoIe-5-carboxylate (1.00 g, 3.56 tnrnol) in ΛζΛr-dimetiiylform amide (20 mL) at O 0C was added sodium hydride (0.15 g, 6.42 mmoi). The mixture was stirred at O 0C for 30 minutes, followed by the addition of 2-(bromomethyl)-S-(trifluoromethyl)furan (1.06 g, 4.63 ramol). The reaction mixture was stiπed at ambient temperature for 16 hours. The
solvent was removed in vacuo and the residue was diluted with dichloromethane (250 mL), washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized in ethyl acetate and hexane to afford the title compound asacolorless solid in 68% yield (1.04 g): mp 196-198 0C (ethyl acetate/hexenes): 1H NMR (300 MHz, CDCl3) S 8.72-8.70 (m, IH), 6.8C-6.79 (m, IH), 6.37 (d, J = 32Hz, IH), 6.21-6.17 (m, IH), 6.09 (d, J= 2.5 Hz, IH), 5.02 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.68 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.5, 162.8, 1SI .8, 156.3, 155.7, 150.6, 143.1, 131.8, 120.4, 119.9, 1 12.4, 111.7, 103.6, 97.2, 62.1, 61.C, 17.3, 14.3; MS CES+) mfl 429.Z (M + 1).
EXAMPLE 17.1
Synhtesls of Ethyl 2-(4-(4-Fluorobenzytoiy).2-oxopyridin-l(2ff|-yl)-4- mcthylthiazclt-5-carboxylatc
Figure imgf000120_0001
Following the procedure as described in Example 17, making variations only as required to use ethyl l-(bromomethyl)-4-fliiorobenzene in place of 2-(bromomethyl)-5- (trifluorometllyl)furan to react with ethyl 2-(4-hydroxy-2-oxopyridin-l(2i/)-yl)-4- methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid in 70% yield: mp 214-2170C (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCI3) 8 8.70 (d, J= 8 1 Ha, IH), 7.42.7.3d (m, 2H), 7.13-7.Oi (m, 2H), 6.20 (dd, J = S 1, 2.7 Hz, IH), 6.07 (d, / = 2.7 Hz, IH), 5.01 (S, 2H), 4.32 (q, /= 7.1 Hz, 2H), 2.6S (s, 3H], 1.36 (t, J = 7.1 Hz, 3H); 13CNMR (75 MHz, CDCl3) S 157.1 , 164.5, 162.8, 161.2, 1565, 155.6, 131.5, 130.4, 129.8, 119.8, 115.9, 103.9, 97.4, 70.1, 61.9, 17.3, 14.3; MS (ES4) m/2 389.2 (M + 1).
EXAMPLE 18
Synthesis of JV-BenzyM-methyl-i p-oxo ^-phenoxy pyridin-l{ZH)-yl)tlii»zole-5- carboxamide
Figure imgf000121_0001
To a solution ofN-benzyl-2-(4-hydroxy-2-oxopyridin-l(2//)-yl)-4- methylthiazok-5-carboxamide (0.20 g, 0.58 mmol) and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.19 g, 0.64 mmol) in anhydrous acetonitrile (10 mL) was added cesium fluoride (0.22 g, 1.46 mmof). The reaction mixture was heated at 600C for 16 hours, followed by the addition of ethyl acetate (30 mL). The mixture WES "washed with saturated ammonium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography elutcd with ethyl acetate/hexane (1/1) and farther purified by recrystallization in ether to afford the title compound as a colorless solid in 14% yield (0.032 g): mj> 67-70 0C (ether); 1H NMR (300 MHz, CDCI3) 88.76 (d, J= 8.1 Hz, IH), 7.45-7.25 (m, SH), 7.11-7.08 (m, 2H), 6.35 (dd, J= S.I, 2.7 Hz, IH), 6.05 (t, /= 5 6 Hz1 IH), 5.81 (d, J= 2.6 Hz, IH), 4.38 (d, J= 5.5 Hz, 2H), 2.69 (S, 3H); 13C NMR (75 MHZ. CDCl3) δ 167.8, 162.1, 161.8, 153.3, 152.8, 152.1, 137.7, 132.2, 130.3, 12S.8, 127.9, 127.7, 126.4, 122.5, 121.1, 103.4, 100.2, 44.1, 17.3; MS (ES+) ra/z 418.2 (M -H).
EXAMPLE 19
SyDthesis of7V-benzyl-4-methyl-2-(2-oxo-4-phcnethylpyridin-l(2fi)->'l)tkiazole-S- carbαxamide
Figure imgf000121_0002
To an sealed tube undernitrogen atmosphere was added 1 -(5- (benzylcarbamoyl)-4-methylthiazol-2-yl)-2-«xo-l,2-dihydropyridin-4-yl trifluoromethanesulfonate (020 g, 0.42 mmol), phenethylboronic acid (0.069 g, 0.46 mmol), I,l'-Ms(αiphenylphosphino)reiτocene]dichloropalladium(ll) (0.06S %, 0.084 mmol) and potassium carbonate (0.18 g, 1.2( mmol), followed by the addidion of
tetrahydrofuren(lO mL) and water (1 mL). The reaction mixture was heated at reflux for 22 hours, and cooled to ambient temperature. Ethyl acetate (20 mL) was added and the mixture was washed with saturated ammonium chloride (10 mL), dried over anhydrous sodium sulfate ind filtered. The filtrate was concentrated in vacuo. The brown residue was purified by column chromatography elυted with ethyl acetate/hexane ( ] /1 ) to afford the title compound as a colorless solid in 33% yield (0.060 g): mp 149-150 °C (ethyl acetate/hexanes); 1H NMR (300 MHz, CDQ3) S 8.66 (d, J= 7.5 Hz, 1 H), 734-7.25 (m, 7H), 7.21-7.14 (m, 3H), 6.49 (s, IH), 6.25 (drJ, /= 7.5, 1.8 Hz, IH), 6.11 <t,J= 5.6 Hz, IH), 4.59 (d, /- 5.6 Hr, 2H), 2.95-2.89 (rn,2H), 2.84-2.76 (m, 2H), 2.69 (a, 3H), 13C NMR (75 MHz, CDCl3) δ 162.1, 160.5, 155.2, 153.3, 152.3, 140.0, 137.7, 1302, 128,8, 128.6, 128.3, 127.9 127.7, 1,26.4, 122.8, 1 18.6, 109.7, 44.1, 37.0, 35.0, 173; MS CES+) mh 430.3 (M + 1).
EXAMPLE 19.1
Synthesis nfAf-Benzyl-2-(4-cyclopropyI-2-oxopyridin-l(2//)-yl)-4-roet]ijltliiazole-5- carbαxamltie
Figure imgf000122_0001
Following the procedure as described in Example 19, making variations only as required to use cyclopropylboronic acid in place of phenethylboronic acid to react with - (5-(benzylearl)anioyl)-4-methylthi_zol-2-yl)-2-oxo-l,2-dihydropjτidin-4-jl tπfluoromethanesulfonate, the title compound was obtained as a colorless solid in 54% yield: mp 149-151 °C (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 58.63 (d, J= 7.6 Hz, IH), 7.39-7.25 (m, 5H), 6.39 (d, /- 1.5 Hz, IH), 6.10-6.05 (m, 2H), 4.58 (d, J= 5.6 Hz, 2H), 2.69 (s, 3H), 1.81-1 72 (m, IH)1 I 14-1 07 (m, 2H), 0.86-0.81 <m,2H); 13C NMR (75 MHz1 CDCl3) 6 162.2, 160.3, 158.8, 153.4, 152.3, 137.7, 130.3, 128.8, 127.9, 127.6, 127.7, 1 14.7, 106.6, 44.1, 17.3, 15.4, 10.4; MS (ES+) m/z 366.1 (M + 1).
EXAMPLE 20
Synthesis of IV-Benzyl-4-metliyl-2-(4-methyl-2-oxopy ridln-l(2^f)-yl)th iazole-5- carbσxamidc
Figure imgf000123_0001
To an oven-dried sealed tube under nitrogen atmosphere was added l-(5- (benzylcarbajnoyl)-4-methylthiazol-2-yl)-2 -αxo-1, 2-dihydropyridin-4-yl trifluoromεthiinesulfonate (0.27 g, O.5<5 iπmol), irimeitiylboroxlne (0.07 g, 0.Θ2 mmol), tetrakis(triphenylphosphinc)palladium(0) (C.13 g, 0.11 mmol) and potassium carbonate (0.23 g, 1.69 mrnol), followed by the addidioti of dimethoxyethane (10 mL) and water (1 mL). The reaction mixture was heated at reflux for 1 S hours, cooled to ambient temperature and ethyl acetate (30 mL) was added. The mixture was washed with saturated ammonium chloride (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated m vacuo. The brown residue was purified by column chromatoirarjhy elured with ethyl acetate/hexane (4/1) to afford the title compound as a colorless solid in 54% yield (0.13 g): mp 145-1470C (ethyl acetate/hexanes); 1HNMR (300 MHz, CDCl3) S 8.65 (d, J = 7.5 Hz, 1 HX 737-7.25 (m, 5H), 6.50 (s, IH), 6.27 (dd, J - 7.5, 1.7 Hz, IH), 6.12 (t, J- 5.6 Hz, IH), 4.58 (ά, J= 5.6 Hz, 2H), 2.69 <s, 3H), 2.24 (s, 3H); 13CNMR (75 MHz, CDCl3) δ 162.2, 160.4, 153.4, 152.2, 152.1, 137.7, 130.0, 128.8, 127.9, 127.7, 122.8, 119.1, 110.6, 44.1, 21.5, 17.3; MS (ES+) m/z 340 1 (M + 1).
EXAMPLE 21
Synthesis of JV-Benzyl-4-methyl-2-(2-oϊi)-4-((5-plienyl-l,3,4-o)[adiaz»l-2- yl)methoxy)pyridin-l(2/J)-yl)thiazole-5-carrjoxainide
Figure imgf000123_0002
To a solution ofΛJ-benzyl-2-(4-hydπ>xy-2-oxopyridin-l(2fl)-yl)-4- methylthiazole-5-carboxamide (0.20 g, 0.58 mrnol) in anhydrous KN-
dimethylfoπnamide (8 mL) was added cesium carbonate (0.32 g, 0.99 mmol) and catalytic amount of w-tetrabutylammon jura iodide, followed by the addition of 2- (chloromethyl)-5-phenyl-l ,3,4-oxadiazole (0.15 g, 0.76 mmol). The reaction mixture was heated at 800C for 20 hours and concentrated in vacuo, followed by the addition of dichloromethane (100 mL). The mixture was washed with water (70 mL). The organic layer was dried over anhydrous sodium sulfite and filtered. The solvent was concentrated in vacuo. The residue was recrystallized m ethyl acetate and hexane. The solid was collected by filtration and washed with methanol and hexanes to afford the title compound as i colorless solid in 38% yield [C.1 1 g). 1H NMR (300 MHi, DMSCWn) 8 8.84 (t, J = 5.9 Hz, IH), 8.69 (d, J= 8.0 H-, IH), 8.04-8.01 (m, 2H), 7.69-757 (m, 3H), 7.37-7.29 (m, 4H), 7.27-7.21 (m, IH), 6.50-S.43 (m, 2H), 5.64 (s, 2H)1442 (d, J= 5.9 Hz, 2H), 2.58 (s, 3H); MS (ES+) m/z 500.2 <M + 1), 522.2 (M + 23).
EXAMPLE 21.1
Synthesis i)f /vr-lienzvi-2-(4-((5-(4-chloropheiiyl)-I,3,4-o\adiazol-2-\l)iutttiu_\v)-2- orøpyridin-l(2fl)-yl)-4-rπethylthiazole-5-carboxaπiide
Figure imgf000124_0001
Following the procedure as described in Example 21, making variation only as required to use 2-(chloromcthyl)-5-(4-chlorophcnyl)-l,3,4-oxadiazole in place of 2- (chloromethyl)-5-prιenyl-l,3,4-oxadiazolet<! react with ΛLbenzyl-2-(4-hydroxy-2- oxopyridin-l{2i/)-yl)-4-rrιethylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 32% yield: 1H NMR (300 MHz, DMSO-rfj) δ S.80 (t, J= 5.8 Hz, IH), 8.65 (d, J = 7.8 Hz, 1 H), 8.0 (d, J = 8.6 Hz, 2H), 7.66 (d, /= 8.5 Hz, 2H), 7.32-7.19 (m, 5H), 6.46-639 (m, 2H), 5 60 (s, 2H), 4.38 (d, J= 5.8 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 534.1 (M + 1).
EXAMPLE 21.2
Synthesis of JV-Benzyl-2-(4-((8-chloro-6-(trifluoromethyl)πaphthaleπ-2-yl)πiethoxy)- 2-oxopyi*idin-l(2/j)-yl)-4-me<hylthiazole-5-carboxamide
Figure imgf000125_0001
Following the procedure as described in Example 21 , making variation only as required to use 6-(brornomethyl)-4-chloro-2-(trifluoromethy])quinoline in place of 2- (thlororaethyl)-5-pheπyl-l,3,4-ox_diazoleto reacι wiihΛr-benzyl-2-C4-hy4roxy-2- oxopyridin- 1 (2fl)-yl)-4-mεthylthiazole-5-rart>oxamide, the title compound was obtained as a colorless solid in 27% yield: 1H NMR (300 MHz, DMSO-dj) δ 8.79 (t, J= 5.9 Hz, IH), 8.65 (d, / = 8.1 Hz, IH), 8.42-8.40 (m, IH), 8.34-8.27 (m, 2H), 8.07-804 (m, IH), 7.34-7.26 (m,4H), 7.23-7.17 (m, IH), 6.49 (dd, /= 8.1, 2.6 Hz, IH), 6.32(d, J = 2.6 Hz, IH), 5.52 (s, 2H), 4 38 (d, /= 5.9 Hz, 2H), 2.54 (s, 3H); MS<ES+) mfz 585 1 (M + 1).
EXAMPLE 21.3
Synthesis of jV-Benzyl-4-methyl-2-(2-oϊθ-l-((6-(trifluoroπiβthyl)pyri(lιn-3- yl)methoxy)iiyridin-l(2H)-yl)thiazDle-5-cuboxamide
Figure imgf000125_0002
Following the procedure as described in Example 21. making variation only as required to use 5-(chloromethyI)-2-(trifluorcmethyl)pyridine in place of 2- (chloromethyl)-5-phenyl-l ,3,4-oxadiazole to react with W-benzyl-2-(4-hydroxy-2- oxopyridin-l(2i7)-yl)-4-methylthiazole-5-carbcxamide, the title compound was obtained as a colorless solid in 49% yield: 1H NMR (300 MHz, DMSO-rfs) δ 8.85 (s, IH), 8.79 (t, /= 5.9 Hz, IH), 8.64 (d, J= 8.1 Hz, IH), S. H-8.14 (m, IH), 7.95 (d, J= 8.1 Hz, IH), 7 38-7 17 (m, 5H), 6.43 (dd, J = 8.1, 2.7 Hz, IH), 6.28 (d, J= 2.7 Hz, IH), 5.35 (s, 2H), 438 Qi, J= 5.9 Hz, 2H), 2.54 (s, 3H); MS (ES4) m/z 501.2 (M + 1).
EXAMPLE 11.4
Synthesis of JV-Benzyl-4-methyl-2-(2-ojc»-4-(thi«zol-4-ylmcthoxy)pj'ri(lin-l(2fl)- yl)thiazole-5-carboxamide
Figure imgf000126_0001
Following the procedure as described in Example 21 , making \arMcn only as required to use 4-(chloromethyl)thiazole in place of 2-(chloromethyl)-5-pbenyl-l,3,4- oxadiazole to react with iV-benzyl-2-(4-hydroxy-2-oxopyridin-l(2.H)-yl)-4- methylthiazoIe-5-carboxamide, the title compound was obtained as a colorless solid in 29% yield: 1H NMR (300 MHz, DMSCM,) δ 9.12 (d, J = 1.9 Hz, IH), 8.79 (t, J = 5.9 Hz, IH), 8.61 (d, /= 8.0 Hz, IH), 7.89 (d, J= 1.9 Hz, IH), 7.33-7.27 (m, 4H), 7.25-7.17 (m, IH), 6.38-6.32 {ra, 2H), 5.27 (s, 2H), 438 (d, J- 5.9 Hz, 2H), 2.54 (s, JH); MS (ES+) m/z 439.1 (M + 1).
EXAMPLE 21.5
Synthesis of rV-Benzyl-4-meUiyl-2-(2-oiπ>-4-((tetrahydro-2Jff-pyran-2- y])ιnethθ3y)pyridiπ-l(2i7)-yl)thiazole-5-cart>oxaιiiide
Figure imgf000126_0002
Following the procedure as described in Example 21 , making "variation only as required to use 2-(bromomethyl)tetrahydro-2H-pyran in place of 2-(chloromcthyl)-5- phenyl-l,3,4-oxadiazole to react with iV-bcnzyl-2-(4-hydroxy-2-oxopyrid]n-l<2/f)-yl)-4- methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 66% yield: 1H NMR (300 MHz, DMSO-d«) o 8.77 ft J= 5.9 Hz, IH), 8.58<d, J= 8.1 Hz, IH), 7.36-7.26 (m, 4H), 7.23-7.18 (m, 1 H), 6.34 (dd, J = 8.1 , 2.7 Ha, 1 H), 6.11 (d, J = 2.6 Hz, IHX 438 (d, J= 5.9 Hz, 2H), 4.D3-3 S4 (m, 2H), 3.86-3.82 (m, IH), 3.62-3.55 (m, IH), 3.38-3.31 (m, IH), 2.53 (s, 3H), 1.76-1.69 (m, IH), 1.59-1.20<m, 5H); MS
(ES+) m/z 440.2 (M + 1).
EXAMPLE IU
Synthesis of JV-Benzyl-4-methyl-2-(4-((5-ιnethyli5θxazol-3-yl)niethoxy)-2-oxαpyridin- l(2fl)-yl)thiazole-5-c_rboxainide
Figure imgf000127_0001
Following the procedure as described in Example 21 , making variation only as required to use 3-(bromomethyl)-5-methylisoκazole in place of 2-(chloromethyl)-5- phenyl-l,3,4-oxadiazole to react with JV-benzyl-2-(4-hydroxy-2-oxopyridin- l(2i7)-yl)-4- methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 47% yield: 1H NMR (300 MHz, DMSO-</4) δ 8.79 (t, J = 5.9 Hz, IH), 8.62 (d, J= 8.1 Hz, IH), 7.35-7.18 (m, 5H), 6.38-6.35 (m, 2H), 6.26 (d, J = 2.6 Hz, IH), 5.22 (s, 2H), 4.38 (d, J- 5.9 Hz, 2H), 2.54 (s, 3H), 2.38 ts.3tϋ; MS (ES+) Wl 4372 (M + 1).
EXAMPLE 21.7,
Synthesis »fΛr-Beπzyl-2-(4-((5-chlorothioph«n-2-yl)methoxy)-2-osopyrirliii-l(2fl)- yl^-methyltliiazole-S-carboxaniide
Figure imgf000127_0002
Following the procedure as described in Example 21, making variation only as required to use 2-ch!oro-5-(chloromethyl)thiophene in place of 2-(chloromel:hyl)-5- phenyl-l,3,4-oxadiazole to react with N-bcnzj'l-2-(4-hydroxy-2-oxopyridin-l{2H)-yl)-4- methylthiazo]e-5-carboxamide, the title compound was obtained as a coloiless solid in 40% yield: 1HNMR (300 MHz, DMSO-^) S 878 (t, J= 5.9 Hz, IH), 8.60 (d, J= 8, 1 Hz, IH), 7.30-7 18 (m, 5H), 7.15 (d, J= 3.8 Hz, IH), 7.05 (d, J= 3.8 Hz, IH). 6.34 (dd, J = 8.1, 2.7 Hz, IH), 6.28 (d, J- 2.7 Hz, IH), 5 30 (s, 2H), 4.38 (ά,J- 5.9 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 471.9 (M + 1), 473 8 (M + 3).
EXAMPLE 11.«
Synthesis of 2-(4-(Benzo[rf]tliiazol-2-y]methoxy)-2-oiopyridiii-l(2B)-yl)-JV-benzyl-4- methylthiazole-5-carboxamide
Figure imgf000128_0001
Following the procedure as described in Example 21, making variation only as required to usa 2-(bromomethyl)benzo[d]thiazole in place of 2-(chlorotneihyl)-5-phenyl- 1,3,4-oxadiazole to react with iV-benzyl-2-{4-hyclroxy-2-oxopyridiπ-l(2i/}-)'l)-4- methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 14% yield: 1H NMR (300 MHz, DMSO^)S 8.79 (1,7= 5.9 Hz, IH), 8.6S (d, J= 8.1 Hz, IH), 8.13-8.11 (m, IH), 8.03-8.00 (m, IH), 7.55-7.42 (m, 2H), 7.34-7 18 (m, 5H), 6.48 (dd, J= J.I, 2.7 Hz, IH), 6.34 (d, .7 = 2.7 Hz, IH), 5.68 (s, 2H), 4.38 (d, J= S.9 Hz, 2H), 2.54 (S, 3H); MS (ES+) mil 489.1 CM + 1).
EXAMPLE 21.9
Synthesis of Λf-Bemyl-Z^-tp-isopropyltliiaiol^-yOinethoxyJ-l-oxopyridin-HlΛ)- ylH-niethyltliiazole-5-carhnxaιiHcle
Figure imgf000128_0002
Following the procedure as described in Example 21 , making variation only as required to use 4-(chloromethyl)-2-isopropylthiazole in place of 2-(chloroiriethyl)-5- phenyl-l,3,4-oj(a(liazole to react with Λf-beneyI-2-(4-hydroxy-2-oxopyridin-l(2Λ)-yl)-4- methylthiazole-5-carboxamide, the title compound was obtained as a coloiless solid in 36% yield: 1HNMR (300 MHz, CDCl3) 8 867 (d, J= 8.1 Hz, 1 H), 7.34-723.(m, 5H), 7.21 (s, IH), fi.28-6.20 (m, IH), 6.10-6.04 Cm, 2H), 5.12 (S. 2H), 4.59 (d, J= 5.6 Hz, 2H), 3.38-3.27 (m, 1 H), 2.68 (s, 3H), 1.45-1.35 (m, -H); MS (ES+) m/z 481.2 (M + 1).
EXAMPLE 21.10
Synthesis of /V-BenzyI-2-(4<(6-ehlorop\ridin-3-yl)niethoxy)-2-oxopyri<lin-l(2/7)-yl)-
4-nieth)]tliiazjle-S-carl«)xaniiJe
Figure imgf000129_0001
Following the procedure as described in Example 21 , making variation only as required to use 2-chloro-5-(chloromcthyl)pyridine in place of 2-(chloromettiyl)-5-phenyl- 1 ,3,4-oxadiazole to react with JV-benzy]-2-(4-hydroxy-2-oxopyridin-l{2,ft)-yl)-4- methylthiazoIe-5-carboxamide, the title compound was obtained as a colorless solid in 73% yield: 1H NMR (300 MHz, DMSO-cfe) B 8.79 (t, J= 5.9 Hz, IH), 862(d, J = 8 1 Hz, IH), 8.51 (d, / = 2.4 Hz, IH), 7.95 (di,J= 8.3, 2.5 Hz, IH), 7.57-7.54 (m, IH), 7.35- 7.16 (m, 5H), 6.39 (dd, J= 8.1, 2.7 Hz, IH), 6.26 (d, J = 2.7 Hz, IH), 5.22 {s, 2H), 4.38 (d, J = 5 9 H2, 2H), 2.54 (s, 3H); MS (ES4) mh 467.0 (M + 1).
EXAMPLE 11.11
Synthesis of Λ'-Benzyl-4-methyl-2-(4-((2-methylthiazol-4-yl)methoxy)-2-oxopyridin- l(2/7)-yl)thiazole-5-carboxamide
Figure imgf000129_0002
Following the procedure as described in Example 21, making variation only as required to use 4-(chloromethyl)-2-methyltfιiazole in place of 2-(chloromct]iyl)-5-phenyl- 1,3,4-oxadiazoleto react with /V-benzyl-2-(4-hydroxy-2-oxopyridin-l(2i/)-yl)-4- methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 20% yield: 1H NMR (300 MHz, CDCI3) δ 8.67 (d, J= 8.1 Hz, IH), 7.34-7.26 (m, 5H), 7.20 (s, IH), 6.24 (dd, /= 8.1, 2.7 Hz, IH), 6.13-6.07 (m, 2H), 5.10 (s, 2H), 4.59 (d, J= 5.6 Hz, 2H), 2.73 (a, 3H), 2.67 (s, 3H); MS (ES+) m/z 453.1 (M + 1).
EXAMPLE 21.12
Synthesis of _-(4-((l,2,4-Oxadiazol-3-yl)mtthoxy)-2-oxopyridin-l(2.H)-yl)-iV-benzyl-
4-methylthiazαle-S-carboxamide
Figure imgf000130_0001
Following the procedure as described in Example 21, making variation only as required to useS-CchloromethylH^-oxadiazole in place ofZ-fchloromethyO-S-phenyl- l,3,4-oxa_iazole to react with.A^-benzyl-2-(4-hydroxy-2-oxopyridin-l(2fl)-yl)-4- methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 20% yield: 1H NMR (300 MHz, DMSO-*) δ 8.81 (t, J= 5,9 Hz, IH), 8.66 (d, /" 8.1 Hz, IH), 7.36-7.17 (m, 6H), 6.42 (dd, J= 8.1, 2.8 Hz, IH), 6.33 (d, J= 2.8 Hz, IH), 5.26 (s, 2H), 4.38 (d, J= 5.9 Hz, 2H), 2.55 (s, 3H]; MS (ES+) m/z 424.1 (M -I- I).
EXAMPLE 21.13
Synthesis of N-bαiiyl-2-(4-((3^-dimεth}rli5θxaz.ol-4-yl)niethoiy)-2-oiro[jjridiπ- l(2H)-yl)-4-methylthiazole-5-carboxaiπide
Figure imgf000130_0002
Following the procedure as described in Example 21, making variation only aa required to use 4-(chloromethyl)-3,5-dimet]iylisoxazole in place of 2-(chlorornethyl)-5- phenyl-l,3,4-oxadiazole to react with ΪV-benzyl-2-(4-hydroxy-2-oxopyridiii-i (2//)-yl)-4- methylthiazole-5 -carboxamide, the title compound was obtained as a colorless -solid in 10% yield: 1H NMR (300 MHz, CDCI3) g Ϊ.69 (d, J= 8.1 Hz, IH), 7.41-72S{m, 5H), 6.16-6.06 (m 3H), 4.76 (s, 2H), 4.59 (d, J- 5.5 Hz, 2H), 2.68 (s, 3H), 2.41 (s, 3H), 2.27 (s, 3H); MS (ESt-) m/z 451.1 (M + 1).
EXAMPLE 22
Synthesis of \-(Deii2«[*]thiophen-2-ylni<lliyD-2-(4-(bcnzyloxy)-2-oϊcpyridin-l(2i/)- yl)-4-meth^lthiazole-S-carbDxamide
Figure imgf000131_0001
To a solution of 2-(4-(benzyloxy)-2-αxopyridin-l(2H)-yl)-4-metriylthiazole-5- carboxylic acid (0.20 g, 0.58 mmol) in anhydrous JV,JV-dimethylformamide (10 mL) was added /fyV-diisopropylethylamine (0.27 g, 2.10 mmπl) and N-(3-dimettiylair]iiiopτopyl)- W-ethylcarbodiimide (0.18 g, 0.93 mmol). The mixture was stirred for 30 minutes, followed by the addition of 1-hydroxybenzotriazole (0.11 g, 0.81 mmol) arid benzo[δ]thioplien-2-ylmethanamine (0.14 mL, 0.87 mmol). The reaction mixture was stirred at ambient temperature for 24 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (2 x 5 mL) and brine ( 10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate and hexane. The solid was collected by filtration and washed with methanol and hexane. The title compound was oblained as a colorless solid in 78% yield (0.22 g): 1H NMR (300 MHz, DMSO-rfj) δ 8.98 (t, J= 5.8 Hz, IH), 8.61 (d, J = 8.1 Hz, IH), 7.82-7.85 (m, IH), 7.76-7.73 (m, IH), 7.51-7.23 (m, 8H), S.34 (dd, / = 8.1 , 2.7 Hz, IH), 6.23 (d, J = 2.7 Hz, IH), 5. ] 6 (s, 2H), 4.65-4.63 (m, 2H), 256 (s, 3H); MS (ES+) fflA48S.l (M + l).
EXAMPLE 22.1
Synthesis of 2-(4-(Benzyloxy)-2-oxopyridiii-l(2fl)-yl)-4-methyl-JV-((J- methylthiopticn^-y^methy^thiazαle-S-cirboxamide
Figure imgf000131_0002
Following the procedure as described in Example 22, making variation only as
required to use (3-methylthiophen-2-yl)meth&namine in place of benzo[i>]tlύophen-2- ylmethanamine to react with 2-(4.-(benzyloxy)-2-oxopyridin-l(2/f)-yl)-4-methy]thiazole- 5-carboxylic acid, the title compound was obtained as a colorless solid in 52% yield: 1H NMR (300 MHz, OMSO-d6) 6 S.81 (t, J= 5.8 Hz, IH), 8.60 (d, J= 8.1 H-, IH), 7.45- 7.30 (m, 5H), 7.24 (d, J= 5.1 Hz, IH), 6.79 (d, J= 5.1 Hz, IH), 6.38 (dd, J= 8.1, 2.7 Hz, IH), 6.22 (d, / = 2.7 Hz, IH), 5.15 (s, 2H), 4.Φ5-4.43 (m, 2H), 2.53 (s, 3H), 2.17 (s, 3H); MS (ES+) m/z 452.1 (M + 1).
EXAMPLE 11.2
Synthesis or l^-tBenzyloxy^-oxopyridin-Ul^-ylt-JV-C∑^-dihydro-lfl-indeiiJ- yl)-4-methylfhiazole-5-carboxamide
Figure imgf000132_0001
Following the procedure as described in Example 22, making variation only as required to use 2,3-dihydro-l//-iπden-2-ain]ne in place of benzo[i]thiophen-2- ylmethanaπine to react with 2-(4-(benzyloxy)-2-oxopyridin-l(2Λ)-yl)-4-itiethylthiazole- 5-carboxylic acid, the title compound was obtained as a colorless solid in 27% yield: 1H NMR (300 MHz, DMSCWe) δ 8.61 (d, J= S.I Hz, IH), 8.51 (d, J= 7.0 Hz, IH), 7.50- 7.31 (m, 5H), 7.20-7.09 (m, 4H), 6.38 (dd, J- 8.1, 2.7 Hz, IH), 6.22 (d, J- 2.7 Hz, IH), 5,15 (s, 2H), +.56-4.58 (m, IH), 3.24-3.11 (m, 2H), 2.95-2.84 (m, 2H), 2.52 <s, 3H); MS (ES+) mJz 458.2 (M + 1).
EXAMPLE 22.3
Synthesis of .-(4-(Benzyloxy )-2-oxopy riilin-l(2fl)-yl)-*-'nethyl-^-((5-niet hylpyrazin-
2-yl)methyl)lhiazole-5-carboxamide
-ζu^>} ~>U~O
Following the procedure as described in Example 22, making variation only as required to use (5-methylpyrazin-2-yl)metharιamine in place of benzo{&]thiophen-2- ylmetbanamine to react with 2-(4-(benzylo!<y)-2-oxopyridin-l(2//)-yl)-4-inethylthiazole- 5-carboxylic acid, the title compound was oblained as a colorless solid in 4-2% yield: 1H NMR (300 MHz, DMSOV5) δ 8.83 (t, /- 5.7 Hc, IH), 8.61 (d, J- 8.1 HE, IH), 8.44 (s, 2H), 7.48-7.31 (m, 5H), 6.39 (dd, J= 8.1, 27 Hz, IH), 6.23 (d, J- 2.7 Hz, IH), 5.16 (s, 2H), 4.48 (d, / = 5.7 Hz, 2H), 2.54 (m, 3H), Z43 (s, 3H); MS (ES+) Wz 448.2 (M + 1).
EXAMPLE 22.4
Synthesis of 2-t4-(Benzyloxy)-2-oxopyridiii-l(2fl)-yl)-4-methyl-iV-(oxsz3l-2- ylmethyl)thiazαle-5-carboxamide
Figure imgf000133_0001
Following the procedure as described in Example 22, making variation only as required to use oxazol-2-ylmethanamine in place of benzo[fi]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-l(2i?)-yl)-4-methylthiazole-5-tarboxylic acid, the title compound was obtained as acolorless solid in 62% yield: 1H NMR (300 MHz, DMSO-4) S 8.87 (t, J= 5.7 Hz, IH), 861 (d, J= 8.1 Hz, IH), 8.02 (*, IH), 7.45- 7 30 (m, 5H), 7,13 (s, IH), 6.39 (dd, J= 8.1, 2.7 Hz, IH), 6.23 (d, J= 2.7 HE, IH), 5.16 (s, 2H), 4.49 (d, J= 5.7 Hz, 2H), 2.54 (m, 3H); MS (ES+) mά 423.2 (M -H).
EXAMPLE 22,5
Synthesis of 2-(4-(Benzy loxy)-2-oxopyridin- l(2H)-yl)-4-methyl-N-((5-inethyl-2-
(triflui)rϋmtt,i;i)furiin-J-} l)nicthjl)thiazult-5-L-arlιιnaιlli(]t
Figure imgf000134_0001
Following the procedure as described in Example 22, making variation only as required to use (5-methyl-2-(trifluoromethyl)furan-3-yl)methanamine in plice of benzo[i]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-l(2//)- yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 28% yield: 1HNMR (300 MHz, DMSO-cfø 6 8.75 (t, J- 5.7 Hz, 1 H), 8.61 <d, J - 8.1 Hz, IH), 7.52-7.30 (m, 5H), 6.39 (dd, J- 8.1, 2.7 Hz, IH), 6.26 (s, IH), 6.23 (i,J = 2.7 Hz, IH), 5.16 (s, 2H), 4.30 (d, J= 5.7 Hz1 2H), 2.53 {m, 3H), 2.26 (in 3H); MS (ES+) mi 504.2 (M + 1).
EXAMPLE 22.5
Synthesis of -•(4-(Benϊyloϊy)-2-oxopyridiii-l(2JΪ)-yl)-4-metliyl-Λf-(thiaϊCil-2- ylmetlrvOtliiazolc-J-carboxaiπiik
Figure imgf000134_0002
Following the procedure as described in Example 22, making variation only as required to usethiazol-2-ylmethanatnine in place of benzo[6]thiophen-2-ylmethanamine to react with 2-(4-Cbenzyloxy)-2-oxopyridiii-l(2fl)-yl)-4-metliylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 71 % yield: HNMR (300 MHz, DMSO-rfβ) 69.1 1 (t, /= 5.9 Hz, IH)1 8.Sl (d, J= 8.1 Hz, IH), 7.70 (d, /= 3.3 Hz, IH), 7.60 (A, J= 3.3 Hz, IH), 7.45-7.33 (in, 5H), 6.39 (dd, J= 8.1, 2.7 Hz, IH), 6.23 (d, J = 2.7 Hz, IH), 5.16 (s, 2H), 4.66 (d, J- 59 Hz, 2H), 2.56 (m, 3H); MS (ES+) m/z 439.1 (M + 1).
EXAMPLE 22.7
Synthesis of l-(4-(Benzyloxy)-2-oiopyridiιi-l(2fl)-yI)-4-riiet]iyl-iV-((5- methylthiι>i)litiι-2-yllτiieth\l)tliiazole-5-ι:arl)i)\iiιiιidi;
& :vtκ ^ r /=-\
Following the procedure as described in Example 22, making variation only as required to use (5-methylthiophen-2-yl)me1hanamine in replace of benzo^Z>]thiophen-2- ylmethanamine to react with 2-(4-(benzylo:ty>2-oxopyπdln-l(2fl>yl)-4-irιetliyltn.iazole- 5-carboxylic acid, the title compound was obtained as a colorless solid in 43% yield: H NMR (300 MHz, DMSO-rfβ) S 8.82 (t, J = 5.8 Hz, IH), 8 60 (d, J= 8.1 Hz, IH), 7.45- 7 30 (m, 5H), 6.73 (d, J= 3.3 Hz, IH), 7.59-6.57 (m, IH), 6.38 (dd, / = 8.1, 2.7 Hz, IH), 6.22 (d, /=2.7 Hz, IH), 5.16 (s, 2H), 443 (d, J= 5.8 Hz, 2H), 2.53 (s, 3H), 2.34 (s, 3H); MS (ES+) Wz 452.1 (M + 1).
EXAMPLE 22.8
Synthesis of 2-(4-(Bεnzyloxy)-2-oxopyridin-l(2Λ)-yl)-4-methyl-/V-((4- inethylthiophen-Z-y^metliyfythiazole-S-carboxamide
Figure imgf000135_0001
Following the procedure as described in Example 22, making variation only as required to use (4-methy]thiophen-2-yl)metbanamine in place of benzo[Λ]lhiophen-2- ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-l(2fl)-yl)-4-methylthiazole- 5-carboxylic acid, the title compound was obtained as a colorless solid in 46% yield: 1H NMR (300 MHz, DMSO-rfβ) 6 8.83 (t, J = 5 8 Hz, 1 H), 8.60 (d, J= 8.1 Hz, IH), 7.50- 7 31 (m, 5H), S 91 (s, IH), 6.77 (s, IH), 6.38 (dd, J= 8.1, 2.6 Hz, IH), 622 (i,J= 2.6 Hz. IH), 5.15 (S, 2H), 4.46 (d, J= 5.7 Hz, 2H), 2.53 (s, 3H), 2.12 (s, 3H); MS (ES+) m/z 452.2 (M + 1)
EXAMPLE 22.9
Synthesis of l-(4-(Benzyloxy)-2-oxopyridιπ-l(2fl)-yl)-Λ;-((l,5-diiuethjιl.lJΪ-pyrrol.2- yl)niethyl)-4-r>*fhylthiazole-5-e:irboxaniidc
Figure imgf000136_0001
Following the procedure as described in Example 22, making wialion only as required to u3c (l,5-dimcthyl-l//-pyrτol-2-j'l)methanamine in place ofbetizo[fr]thioρhen- 2-ylmethanamine to react with 2-(4-(benzyloxj')-2-oxopyridin-l(2fl)-yl)-4- methylthia2ole-5-carboxylic acid, the title compound was obtained as a colorless solid in 33% yield: 1H NMR (300 MHz, DMSO-cfe) S 8.60{d, J= 8.1 Hz, IH), 8.53 (t, J= 5.4 Hz, IH), 7.44-7.33 (m, 5H), 6.37 (dd, / = 8.1, 2.7 Hz, IH), 6.21 (d, J = 2.7Hz, IH), 5.91 (d, /= 3.3 Hz, IH), 5.64-5.63 (m, IH), 5.15 (s, 2H), 4.32 (d, J- 5.4 Hz, 2H), 3.39 (s, 3H), 2.51 (s, 3H), 2.10 (s, 3H); MS (ES+) mk 449.2 (M + 1).
EXAMPLE 2Z.19
Synthesis of 2-(4-(Beπzyloxy)-2-oxopyridi«-l(2fl)-yl)-4-methyl-Λ-((l-metliyl-lH- iιnidazol-5 yl)ιnethyl)thiazole-5-<:arlκ>.\a[i]iιk
Figure imgf000136_0002
Following the procedure as described in Example 22, making variation only as required to use (l-methyl-l/f-imidazol-S-yOmethanamine in place of berizofijthiophen- 2-ylmethanamine to react with 2-(4-(ben2yloxy)-2-oxopyridin-l(2H)-yl)-4- methylthiazok-5-carboxylic acid, the title compound was obtained as a colorless solid in 52% yield: 1HNMR (300 MHz, DMSO-<fø 5 8.65-8.58 (m, 2H), 7.51 (s, IH), 7.44-7.30 (m, 5H), 6.78 [s, 1 H), 6.38 (dd, J= 8.1, 2.t Hz, IH), 6.22 (d, J= 2.6 Hz, IH), 5.15 {s, 2H), 4.36 (d, J = S.3 Hz, 2H), 3.58 (ε, 3H), 2.52 (s, 3H); MS (ES+) Wz 43 S 2 (M 4 1).
EXAMPLE 22.11
Syndesis of Z-(4-(Beπzyloxy)-2-oxopyιϊdiii-l (2fl)-ylH-mcthyl-;V-((l-nietliyl-lff- pyrazol-4-yl)πuthyl)thiazole-5-carboxaιiii<l«
Figure imgf000137_0001
Following the procedure as described in Example 22, making variation only as required to use (l.methyl-liϊ-pyrazol-4.yl>rietlianamine in place of beriZOl*]ltiiophen-2- ylmethanamine to react with 2-(4-(benzyloκy>2-oxopyridin-l(2tf)-yl)-4-πiethylthia_olc- 5-carboxylic acid, the title compound was obtained as a colorless solid in 8% yield: 1H NMR (300 MHz, DMSO-rf0) δ 8.59 (d, /= 8.1 Hz, IH), 8.31 (br s, 2H), 7.69 (s, IH), 7.50-7.30 (m, 5H), 6.30 (dd, J= 8.1, 27 Hz, IH), 6.13 (d, J= 2.7 Hz, IH), 5.13 (s, 2H), 3.82 (s, 2H), 3 77 (s, 3H), 2.52 (s, 3H); MS (ES+) m/z 4-36.1 (M + 1).
EXAMPLE 2Ϊ.12
Synthesis of 2-(4-(Benzy]oxy)-2-oxopyridin-l(2J0-yl)-4-ιnethyl-Λr-((Z-raethylthiazol-
4-yl)methyl)thiazole-5-carboxaιnide
-&*$>
Following the procedure as described in Example 25, making variation only as required to use (2-methylthiazol-4-yl)methanamine in place of benzo[fe]thiophen-2- ylmethanainineto react with 2-(4-(beπzylcxy)-2-oxopyridin-l(2ff)-yl)-4-πκthylthiazolc- 5-carboxylιc acid, the title compound was obtained as a colorless solid in 74% yield: 1H NMR (300 MHz, DMSO-*) δ 8.74 (t, / = 5 7 Hz, IH), 8.61 (d, J= 8.1 Hz, IH), 7.45- 7.31 (m, 5H), 7 16 (s, IH), 6.38 (M, J= 8.1, 2.7 Hz, IH), 6.23 (d, 7= 2.7 Hz, IH), 5.16 (s, 2H), 4.42 (4, J = 5.7 Hz, 2H), 2.59 (s, 3H), 2.54 (S, 3H): MS (ES+) mώ 453.1 (M + 1).
EXAMPLE 22.13
Synthesis of 2-(4-(Benzyloxy)-2-oxopyriJln-l(2H)-yl)-Λf-((5-cyanofuran-2- yI)methyl)-4-metliylthiazole-5-carboxaiiιicU
Figure imgf000138_0001
Following the procedure as described iri Example 22, making variation only as required to use 5-(aminomethyl)furaπ-2-carboiiitrile in place of benzo^lthbphen-2- ylmethanamine K) react with 2-(4-(ben_yloxy)-2-oxnpyridin-l(2/f|-yl)-'(-irιethylthiaz.ok- 5-carboxylic acid, the title compound was obtained as a colorless solid in 72% yield: 1H NMR (300 MHz, DMSO-A) δ S.84 (X, J= 5.6 Hz, IH), 8.61 (d, J= 8.1 Hs, IH), 7.52<d, J = 3.6 Hz, lH), 7.45-7.30 (m, 5H), 6.55 (d,J= 3.6 Hz, IH), 6.39 (dd, J- 8.1, 2.7 Hz, IH), 6.23 (d, / = 2.6 Hz, IH), 5.16 (s, 2H), 4.44 (d, J = 5.6 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 447.1 (M + 1).
EXAMPLE 12.14
Synthesis of \-(Bciizo[(/|oϊazol-2-)lnitthϊl)-2-(4-(lien/Λlnxy|-2-oxθ[iyritlii]-l(2H)- yl)-4-methylthiazole-S-carbαxflinide
Figure imgf000138_0002
Following the procedure as described in Example 22, making variation only as required to usebenzo[rf]oxazol-2-ylmethanmiine in place of benzo[*]thicphen-2- ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-l(2i/)-yl)-4-methylthiazole- 5-carboxylic acid, the title compound was obtained as a colorless solid in 44% yield: 1H NMR (300 MHz, DMSCW«) δ 9.01 (t, J= 5.5 Hz, IH), 8.62 (d, J= 8.1 Hz, IH), 7.72- 7.64 (m, 2H), 7.45-7.31 (m, 7H), 6.40 (dd, / = 8.1, 2.7 Hz, IH), 6.24 (d, J= 2.7 Hz, IH), 5.16 (s, 2H), 4.68 (d, J- 5.5 Hz, 2H), 2.57 (s, 3H); MS (EB+) m/z 473.1 (M + 1).
EXAMPLE 22.15
Synthesis of Ethyl 5-((2-(4-(Benzyloxy)-2κixopyridiιi-l(2fl)-yl)-4-nietriylthiazole-5- carboxinnid«)inethy])furan-2-carboxjlatε
Figure imgf000139_0001
Following the procedure as described in Example 22, making variation only as required to use ethyl 5-(aminomethyl)furan-2-carboxylate in place of benao[(>]thiophen- 2-ylmethanamine to react with 2-(4-(benzykmy)-2-oxopyridin-l(2//)-yl)-4- methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 67% yield: 1H NMR (300 MHz, OMSO-ds) δ 8.85 (t, J = 5.6 Hz, IH), 8.61 (d, /= 8.1 Hz, IH), 7.45-7.33 (m, 5H), 7.20 (d, J= 3.5 Hz, IH), 6.45 (d, J= 3.5 Hz, IH), 6.39 <dd, J = 8.1, 2.7 Hz, IH), 6.23 (d, /= 2.7 Hz, IH)1 5.16 (s, 2H), 4,45 (d, J= 5.5 Hz, 2H), 4.23 (q, 7 = 7.1 H2, 2H), 2.54 (s, 3H), 1.24 (t, 7=7.1 Hz, 3H); MS (ES+) mJz 494.2 (M + 1).
EXAMPLE 12.16
Synthesis of JV-^l/Hndol-l-yOmethyO-Σ ^-tbenzyloϊy^-oxopyridiii-ipHJ-yl) -4- πiethylthiazcle-5-carbαxamide
Figure imgf000139_0002
Following the procedure as descrihed in Example 22. making variation only as required to use (1 J/-indol-2-yl)methanamine in place of benzo[A]thiophen-2- ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridto-l(2/0-yl)-4-n1etny'tn'a OTle- 5-carboxylic acid, the title compound was obtained as a colorless solid in 22% yield: 1H NMR (300 MHz, DMSO-cfe) S 10.91 (s, IH), 8.73 (t, J= 5.6 Hz, IH), 8.62 (ά,J= 8.1 Hz, IH), 7.45-7.29 (m, 7H), 7.01-6.87 (m, 2H), 639(dd, J= 8.1, 2.7 Hz, IH), «.25-6.22 (m, 2H), 5.16 (B, 2H), 4.53 (d, J- 5.6 Hz, 2H), 2.56 (s, 3H); MS (ES+) m/z 471.2 <M + 1).
EXAMPLE 22.17
Synthesis of JV-(Benzo[d]thi_zol-2-ylme<hyl)-2-(4-(benzyloxy)-2-oxopjri<iiιi-l(2fl)- yl)-4-methyllhiazole-5-carboxamidt
Figure imgf000140_0001
Following the procedure as described ill Example 22, making variation only as required to use benzo[W]thiazol-2-ylinetharianiinθ in place of beπzo[i]thioph«n-2- ylmeihananώeto react with 2-(4-(benzylo>y)-2-oxopyridin-l(2Λ)-yl)-4-ιnβthylthi-zole- 5-carboxylic acid, the title compound was obtained as a colorless solid in 59% yield: 1H NMR (300 MHz, DMSO-A) S 9.23 (t, /= 5.8 Hz, IH), 8.63 <d, J= 8.1 H-, IH), 8.04- 8.02 (m, IH), 793-7.91 (m, IH), 7.49-7.31 {m, 7H), 6.40 (dd, J- 8.1, 2.7 Hz, IH), 6.24 (d, J = 2.7 Hz, IH), 5.17 (s, 2H), 4.78 (d, J= 5.8 Hz, 2H), 2.58 (s, 3H); MS (ES+) m/z 489.1 (M + 1>
EXAMPLE 22.18
Synthesis of Λf-((lff-Pyrazol-3-yl)methyl)-2-<4-(benzyloxy)-2-oxopyridii-l(2fl)-yl)-4- methylthiazole-5-c_rboxamide
Figure imgf000140_0002
Following the procedure as described in Example 22, making variation only as required to use ( l/7-pyrazol-3-)<i)methanamine in place of benzo[ft]thiopher-2- ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-l(2fl)-y])-4-metliylthiazole- 5-carboxylic acid, the title compound was obtained as a colorless solid in 43% yield: 1H NMR (300 MHi, DMSO-*) 8 12.63 (br s, IH), 8.74-8.54 (m, 2H), 7.63-731 <m, 6H), 6.38 (dd, /= 8.1, 2.5 Hz, IH), 622 (d, J= 25 Hz, IH), 6.13 (d,/= 1.0 Hz, IH), 5.15 (S, 2H), 4.37 (d, J= 5.6 Hz, 2H), 2.53 (a, 3H); MS (ES+) m'z 422.2 (M + 1).
EXAMPLE 22.19
Synthesis of l ^-CBenzyloxyJ-ϊ-oxopyridir-lfΣΛt-yO-Λ^rtό-chloropyrWin-S- y])methyl)-4-m«thylthiazole-5-carboxamιde
Figure imgf000141_0001
Following the procedure as described in Example 22, making variation only as required to use (6-chloropyridin 3 y])methenamijie in place of bcnzo[έ]thiophcn-2- ylmethanamine to react with 2-(4-(benzyl(ray)-2-oxopyridin-l(2#)-y])-4-inethyltriiazole- 5-carboxylic acid, the title compound was obtained as a colorless solid in 60% yield: 1H NMR (300 MHz, DMSCW6) δ S.82 (t, J= 5.! Hz, IH), 8.60 (d, J= 8.1 Hs, IH), 8.34 (d, J= 2.1 Hz, IH), 7.77 (dd, J = 8.2, 2.5 Hz, IH), 7.51-7.28 (m, 6H), 6.38 (ddt /= 8.1, 2.7 Hz, IH), 6.23 (i, J = 2.7 Hz, IH), 5.16 (s, 2H), 4.39 (d, J- 5.8 Hz, 2H), 2.53 <s, 3H); MS (ES+) m/z 467.0 (M + 1).
EXAMPLE 12.20
Synthesis of 2-(4-(Benzyloxy)-2-oxopyridin-l(2fl)-ylH-niethyl-iV-((6-
(trifluoromethyfypyridin-S-yfymethyfytriiazole-f-carboxamide
Figure imgf000141_0002
Following the procedure as described in Example 22, making variation only as required to use (6-(trifluoromethyl)pyridin-3-yl)methanamine in place of benzo[ό]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-l(2/τ> yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 38% yield: 1H NMR (300 MHz, DMSO-ώ) δ 8.89 (t, J= 5.6 Hz, IH), 8.69 <br s, IH), 8.61 (d, J- 8.1 Hz IH), 7.9S-7.96 (m, IH), 7.87-7.84 (m, IH), 7.45-7.33 (m, 5H), 6.39 (dd, /- 8.1, 2.6 Hz, IH), 6.23 (d, J= 2.6 Hz, IH), 5.16 (S, 2H), 4.50 (d. /= 5.6 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 501.1 (M+ 1).
EXAMPlE 22.21
Synthesis or2-(4-(Benzyloxy)-2-oxopyri<Jii-l(2fl).yl).4-inethyl-ΛL((5-m«thylfuran-2- yl)methyl)»hi_2ole-5-carboxaitiide
Figure imgf000142_0001
Following the procedure as described in Example 22, making variation only as requiredto u5e(5-methyifuraii-2-yl)inetl]arιainine in place of benzo[Λ]thiophen-2- ylmethanamine to react with 2-(4-φenzylox})-2-oxopyridin-l(2/7)-yl)-4-metriylthiazole- 5-carboxylic acid, the title compound was obtained as a colorless solid in 48% yield: 1H NMR (300 MHz, DMSO-ttø δ 8.68 <t,./= 5.5 Hz, IH), 8.60 (d, J= 8.1 Hz, IH), 7.45- 7.31 (m, 5H), 6.38 (dd, J= 8.1 , 2.7 Hz, IH), 5.22 <d, J = 2 7 Hz, IH), 6.0? (d, J= 3.0 Hz, IH), 5.95 (d, /= 3.0 Hz, IH), 5.16 (s, 2H), 439 (ά, J = 5.6 Hz, 2H), 2.52 (s, 3H), 2.19 (s, 3H); MS (ESH-J mis 436.5 (M + 1).
EXAMPLE 23
Synthesis of l-(5-(benzylcarbamoy l)-4-meHiylth iophen-2-y])-2-oxo-l,2- dihydropyriditι-4-yI trifluαrαπiethanesiιlfonate
Figure imgf000142_0002
To a stirred suspension of JV-benzyI-5-(4-hydroxy-2-oxopyridin-l(2/f)-yl)-3- methylthiopliene-2-carboxamide (0,34 g, 0.98 mmol) in dichloromethane (5 mL) under nitrogen atmosphere at -780C was added triethylamine (040 mL, 2.87 mmol), followed by dropwise addition of trifluoromethanesuMbriic anhydride (0.18 mL, 1 07 mmol). The resulting reaction mixture was stirred at -780C for 15 minutes, and then qnenched with water (25 mL). The aqueous layer was extracted with dichloromethane (SO mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The
residue was purified by column chromatography eluted with 30% ethyl acetate in dichloromethane to afford the title compound as a cream color solid in 74% yield (034 g)- 1H NMR. (300 MHz, CDCl3) δ 7.74 (d,/= 7.9 Hz, IH), 7.38-7.28 Cm, 5H), 6.94 (s, IH), 6.62 (d, 7= 2.7 Hz, IH), 6.35 (dd, J = I 9, 2.7 Hz, IH), 6.15 (X, J= 5.3 Hz, IH), 4.60 (d, ./ = 5.3 Hz, 2H), 2.54 (s, 3H); MS (ES+) raA473.3 (M + 1).
EXAMPLE U
Synthesis of fV-benzyl-3-inethyl-5-(2-oxo-4-phenethylpyridin-l(2β)-}'l)thiophene-2- tarboxanildt
Figure imgf000143_0001
A mixture of l-(5-φenzylcarb_moy])-4-rnethy]thiophen-2-yl)-2-oxc-l,2- dihydropyridin-4-yl trifluoromethanesulfomte (0.15 g, 0.32 mmol), phenetlyl boronic acid (0.047 g,0.31 mmol), t1,l'-biS[diplienylpllosphmo)ferrDcene] dichloiopιιlladium(II), 1:1 complex with dichloromethane (0.023 g, 0.028 mmol) and potassium carbonate (0.13 g, 095 mmol) in tetrahydrofuran (3 mL) and water (0.3 mL) was stirred in a sealed tube at 70 0C for 16 hours under nitrogen atmosphere. The reaction mixture was allowed to cool to ambienttemperature, and was partitioned between ethyl acetate (75 mL) and water (35 mL). The organic layer was washed sequentially with 10% aqueous hydrochloric gcid (30 mL), saturated aqueous sodium bicarbonate solution (2 x 25 mL) and brine (30 mL), then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 20% ethyl acetate in dichloromethane to afford the title compound as a light cream color solid in 40% yield (0.054 g). mj> 145-1460C; 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J= 7.3 Hz, IH), 7.38- 7.15 (m, 10H)1 6.89 (s, IH), 6.48 (s, IH), 6.19 (t, J= 5.8 Hz, IH), 6.16{dd, 7= 7.3, 1.9 Hz, IH), 4.59 (d, J- 5.8 Hz, 2H), 2.96-2.87 (m, 2H), 2.84-2.75 (m, 2H), 2 54(s, 3H); 13C NMR (75 MHE, CDCl3) 6 162.9, 160.7, 1543 140.1. 139.54, 139 5, 137 B, 133.2, 128.7, 128.4, 128.3, 127.8, 127.6, 127.2, 126.4, 121.8, 119.2, 109.3, 439, 36.9.35.1, 15.9; MS (ES4) m/z 4293 (M + l).
EXAMPLE 25
Synthesis of /V-(3-Fluorobenzyl)-5-(4-(3-liydr9xypropoxy)-2-oxopyridiB-l(28)-yl)-3- methylthioplieiie-2-carbox-πιide
Figure imgf000144_0001
A solution of 5-(4-(3-{førf butyldimethχldlyloxy)propoxy)-2-oκopjridii]-l(2/f)- yl)-/V-(3-nuo[Obenzyl)-3-itiethylthiophene-2-sarboxamide (0,368 mmol) in acetic acid (5 mL) was stirred at 60 0C foe 16 hours. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-10% methanol in dichloromethane to afford the title compound as a pinkish solid in 61% yield (0.093 g): mp 135-137 "C; 1HNMR (300 MHz, DMSO- 6) δ 8.58 (t, J= 6.0 Hz, IH), 8.14 (d, J= 7.9 Hz, IH), 7.42-7.33 (m, IH), 7.26 <5, IH), 7.18-7.03 (m, 3H), 6.21 ((Id1 J = IS.2.7 Hz. IH). 6 01 (d,J= 2 7 Hz, IH), 4.60 (br s, IH), 4.42 (d, J= 6.0 Hz, 2H), 4.09<t, J=6.2 Hz, 2H), 3.54 (t, J= 6.2 Hz, 2H), 2.42 (s, 3H), 1.86 (p, J= 6.2 Hz, 2H); 13C NMR (75 MHz, DMSO-rfs) S 166.6, 162.5, 162.1
Figure imgf000144_0002
142.7 (ά, Jc.F= 7.0 Hz), 138.9, 137.4, 134.8, 130.1 <d, Jc-F = 8.3 Hz), 127.0, 123.1 (d,7C-f = 2.7 Hz), 120.4, 113.8 (d, Jc-F= 21.5 Hz), 113.4 (d, Jb-F= 20.9 Hz), 102.6, 96.6, 65.6, 55.9, 42.1, 31 A, 15.5, MS (ES+) m/z 4173 <M + 1).
EXAMPLE 26
S) nthesis of Λ'-Denty l-4-iii el livl-2-(2-o.\o-4-(2-oxoiniillazolidin-l-yl)pyritlir-l|2W)- yl)thi_zυle-5-carboxamide
Figure imgf000144_0003
To a solution of 2-(4-amino-2-oxoρyri<lin-l(2//)-yl)-Λr-bcnzyl-4-rncthylthiazole- 5-carboxamide (0.14 g, 0.41 mmol) in N. N-dimethylformaraide (10 mL) was added 2-
chloroethyl isocyanate (0.05 mL, 0.58 mmol) it ambient temperature. The resulting reaction mixture was heated at 80-90 0C for 7 hours. Potassium carbonate (0.10 g, 0.72 mmol) was added and the reaction mixture was heated for 18 hours. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound in 6% yield (0.01 g): mp >3000C; 1H NMR (300 MHz, DMSCW6) δ 8.76 (t, J- 6.0 Hz, IH), 8.56 (d, J = 8.4 Hz, [H), 7.64-7.17 (ra, 7H), 6.C8 (d, J = 2.1 Hz, IH), 4.38 (ά, J= 6.0 Hz, 2H), 3.85-3.79 (m, 2H), 3.42-3.37 (m, 2H), 260(5, 3H); '5C NMR (75 MHz1 DMSCW6) S 161.9, 160.7, 157.8, 153.8, 150.7, 150.4, 139.?, 130.9, 128.7, 127.7, 127.2, 123.7. 101.4, 98 S, 44 3, 43 1, 36.5, 17.5; MS (ES+) «4 410.2 (M + I)-
EXAMPLE 27
Synthesis of 3{(2-(4-methoxy-2-oxopyri<fin-l(2H)-yl)-4-methyltbirø»le-5-
Figure imgf000145_0001
jSXi
To astiired solution of 2-(4-methox/-2-oxopyridm-l(2/f)-yl)-4-m-thyl-W- (pyridin-3-ylmethyl)thiazole-5-carboxamide <0 10 g, 0.28 mmol) in anhydrous dichloromethεne (10 mL) was added m-chlcroperoxy benzoic acid (0.072 g, 0.42 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 24 hours, diluted with dichloromethaneOOO iπL), washed with saturated bicarbonate solution (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized in ethyl acetate and hexane. The solid was collected by filtration and washed with methanol and hexane to afford the title compound as a colorless solid in 34% yield (0.035 g): mp 255-257 0C (ethyl acetate/tiexaπes); 1H NMR (300 MHz, DMSCW() δ 8.81 (t, J= 5.8 Hz, IH), 8.59 (d, J= 8.1 Hz, IH), 8.13 (s, IH), S.09 (d, J= 6.3 Hz, IH), 7.37-7.23 (m, 2H), 6.33 (dd, J - 8.1, 2.7 Hz, IH), 6.12 (d, /= 2.7 Hz. IH), 434 (d, J= 5 7 Hj, 2H), 3.81 (s, 3H), 2.54 (s, 3H); 13C NMR (75 MHz, DMSCW«) β 1686, 162.2, 161.7, 154.1, 151.0, 139.3, 138 1,
137.7, 131.9, 126.7, 124.9, 123.0, 104.2, 96.5, 56.8, 42.1, 17.5; MS (ES-I-) mlz 373.3 (M + 1), 395.2 (M -1-23).
EXAMPLE 2S
Measuring Stearoyl-C&A Desaturase Inhibition Activity of a Test Compound Using
Mouse Liver Microsomes
The identification of compounds of (he invention as SCD inhibitors was readily accomplished using the SCD microsomal assay procedure described in Shanklin J. and Summβrvillβ C , Proc. Natl. Acad. Sd. USA (1991), Vol. 88, pp. 2510-2514.
Preparation of Mouse Liver Microsomes:
Male ICR outbread mice, on a high-carbohydrate, low fat diet, under light halothane (15'/4 in mineral oil) anesthesia are sacrificed by exsanguinatioπ during periods of high enzyme activity. Livers are immediately rinsed with cold 0.9% NaO solution, weighed and minced with scissors. AU procedures are performed at 4 °C unless specified otherwise. Livers are homogenized in a solution (1/3 w/v) containing 0.25 M sucrose, 62 mM potassium phosphate buffer (pH 7.0), 0. IS M KCl, 15 mM JV-acetyleysteine, 5 mM MgCb, and 9.1 ™M EDTA using 4 strokes of a Potter-Elvehjem tissue homogenize:. The homogenate is centriftiged at 10,400 x g for 20 min to eliminate mitochondria and cellular debris. The supernatant is filtered through a 3-layer cheesecloth and centrifuged at 105,000 xg far 60 min. The microsomal pellet is gently resuspended in the same homogenizalion solution with a small glass/teflon homogenizer and stored at -70 °C. The absence of mitochondrial contamination is cnzymatically assessed. The protein concentration is measured using bovine serum albumin as the standard.
Incubation of Mouse Liver Microsomes with Test Compounds:
Desaturase activity is measured as the release Of5H2O from (9, 10-3H]stearoyl- CoA. Reactions per assay point conditions src as follows: 2 μL 1.5 mM stearoyl-CoA, 0.25 μL 1 mCi/mL 3H stearoyl CoA, 10 μL 20 mM NADH, 36.75 μL 0.1 M PK buffer (K2HPO4ZNaH2PO4, pH 7.2). The test compound or control solution Is added In a 1 UL volume. Reactions are started by adding 50 μL of microsomes (1.25 mg/mL). The plates
are mixed and after 15 mm incubation on aheating block (25 0C), the reactions are stopped by the addition of 10 μL 60% PCA An aliquot of 100 μL is then transferred to a filter plate pretreated with charcoal and the p ate centri&ged at 4000 rpm for 1 minute The flow through containing the H2O relessed by the SCDl desaturation reaction is added to scintillation fluid and the radioactiv ty measured m a Packard TopCount The data is analysed to identify the IC50 for test compounds and reference compounds
Representative compounds of the invention showed activity as inhibitors of SCD when tested in this assay The activity was defined in terms of % SCD enijme activity remaining at 1he desired concentration of the test compound or as the IC50 concentration The IC5O (affin ty) of the example compounds toward the stearoyl CoA desaturase is comprised between around 500 micro Molar and 0 0001 micro Molar or between around 100 micro Molar and 0 002 micro Molar or between around 10 micro Molar and 0 002 micro Molar Some results are shown in Tab e 1 below
TABLE l
Figure imgf000147_0001
Figure imgf000148_0001
Those skilled in the art are aware of a variety of modifications to this assay that can be useful fcrmeasuring inhibition of stearoyl-CoA desaturase activity in microsomes or in cells by test compounds.
All of the U.S patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent pullioatiom referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety.
From the foregoing it will be appreciated that, although specific embodiments of the invention hεve been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of tke invention.
Accordingly, the invention is not limited except as by the appended claims.

Claims

We Claim:
1 A compound of Formula (I):
Figure imgf000149_0001
wherein,
V is selected from -N(RS)C(O)-, -C(O)N(R5)-, -OC(O)N(R5)-, -N(R5)C(O)O-,
-N(R5)C(O)N(R5>, -O-, -N(R5)-, -S-, -S(O)4-, -N(R5)S(O}-, -S(O)1N(R5)-, - OS(O)2-, -OS(O)2N(R5)-, -C(O)-, -OC(O)-, -C(O)O-, -N(R5)C(=N(R5a))NR5-, - N(R5)C(=S)NR5-, -N(R5)((RSa)N=)C-, -C(=N(R5a))N(Rs)-, alkylene, alkenylene, alkynylene, ary], heteroaryl, cycloalkyl, heterocyclyl or a direct bond;
W is selected from -N(R5)C<O)-, -C(O)N(R5)-, -OC(O)N(R5)-, -N(R5)C(O)0-,
-N(R^C(O)N(R5)-, -O-, -N(R5)-, -S-, -S(O)1-, -N(R5)S(O)r, -S(O)1N(R5)-, - OS(O)2N(R5)-, -C(O)-, -OC(O)-, -C(O)O-, -N(R5)C(=N(R5a))NR5-, - N(R5)((R5a)N=)C-, -C(=N(R5a))N(R5)-, aryl, heteroaryl, heterocyclyl, alkynylene, alkenylene, alkylene or a direct bond;
X is selected from C(H) or N;
Y is selected from S, O, N(H) Or N(CH3), p is O, 1, 2, or 3; t is 1 or 2;
R1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and hctcroarylalkyl, or R1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each oilier; R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, haloalkoxyl, cyano and -N(RS)2; R4 is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkylalkyl, aralkyl, halo, haloalky], -OCF3, -OC(H)F2, and cyano; or two adjacent R4 groups, together with the carbon atoms to which they are attached, may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R4 groups, if present, are as described above; R5 is selected from the group consisting of hydrogen, aryl, alkyl, heteroaryl, heterocyclyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl;
R5a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
2. The compound according to claim 1, wherein X is C(H) and Y is S.
3. The compound according to claim 1, wherein X is N and Y is S.
4. The compound according to claim 1, wherein X is N and Y is N(H) or N(CH3).
5. The compound according to claim 1, wherein
V is selected from -O- or a direct bond;
W is selected from -N(R5)C{0)-, -C(O)N(R5)-, -C(O)O- or a direct bond; X is selected from C(H) or N;
Y is selected from S, N(H) OrN(CH3); p is 0, 1, 2, or 3;
R1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkoxy, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkynyl, alkoxyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cyclcalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a mulii-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl;
R4 is alkyl or haloalkyl; and
R5 is selected from the group consisting of hydrogen or alkyl.
6. The compound according to claim 2, wherein
V is selected from -O- or a direct bond;
W is selected from -N(R5)C(0)-, C[O)N(R5)-, -C(O)O- or a direct bond; p is O, 1, 2, or 3;
R1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl;
R4 is alkyl or haloalkyl; and
R5 is selected from the group consisting of hydrogen or alkyl.
7. The compound according to claim 3, wherein
V is selected from -O- or a direct bond; W is selected From -N(R5)C(O)-, -C(O)N(R5)-, -OC(O)-, -C(O)O- or a direct bond; p is O, 1, 2, or 3;
R1 is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alky], alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl;
R4 is alkyl, halo and haloalkyl; or two adjacent R4 groups, together with the carbon atoms to which they attached, may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R4 groups, if present, are as described above; and
R5 is selected from the group consisting of hydrogen or alkyl.
8, The compound according to claim 7, wherein
V is a direct bond;
W is -N(R5)C(0> or -OC(O)-; p is O, 1 or 2;
R1 is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl; R4 is alkyl, halo and haloalkyl; or two adjacent R4 groups, together with the carbon atoms to which they attached, may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R4 groups, if present, are as described above; and
R5 is selected from the group consisling of hydrogen oralkyl.
9. The compound according to claim 7, wherein
V is -O-;
W is -N(R5)C[0)- or -OC(O)-; p is O, 1 or 2;
R1 is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl;
R4 is alkyl, halo and haloalkyl; or two adjacent R4 groups, together with the carbon atoms to which they attached, may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R4 groups, if present, are as described above; and
R5 is selected from the group consisting of hydrogen or alkyl.
10. The compound according to claim 4, wherein
V is selected from -O- or a direct bond;
W is selected from -N(R5)C(O)-, -C(O)N(R5)-, -OC(O)-, -C(O)O- or a direct hond; p is O, 1, 2, or 3; R1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heterocycly], heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyi, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocycly], aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl;
R4 is alkyl, halo and haloalkyl; or two adjacent R4 groups, together with the carbon atoms to which they attached, may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R4 groups, if present, are as described above; and
R5 is selected from the group consisting of hydrogen or alkyl
11. The compound according to claim 1 , wherein
V is selected from -C(O)N(R5)-, -N(R5)-, -O-, -OS(O)2- or a direct bond; W is selected from -N(Rs)C(0)-, -OC(O)- or -C(O)O-;
X is selected from C(H) or N;
Y is selected from S, N(H) or N(CHj); p is O3 1, 2, or 3 ;
R1 is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxy, alkαxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl;
R4 is haloalkyl or alkyl; and R5 is selected from the group consisting of hydrogen or alkyl.
12. The compound according to claim 2, wherein
V is selected From -O-, -N(R5)-, -OS(O)2- or a direct bond; W is selected from -N(R5)C(O)-, or -C(O)O-; p is O, 1, 2, or 3;
R1 is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkcxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heieroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl;
R4 is haloalkyl or alkyl; and
R5 is selected from the group consisting of hydrogen or alkyl.
13. The compound according to claim 3, wherein
V is selected from -C(O)N(R5)-, -N<R5)-, -0-, -OS(O)2- or a direct bond; W is selected from -N(R3)C(0>, -OC(O)- or -C(O)O-; p is O, 1, 2, or 3;
R1 is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl; R4 is alkyl or haloalkyl; and
R5 is selected from the group consisting of hydrogen or alkyl.
14. The compound according to claim 4, wherein
V is selected from -C(O)N(R5)-, -N(R5)-, -O-, -OS(O)2- or a direct bond;
W is selected from -N(RS)C(O)-, -OC(O)- or -C(O)O-; p is O, 1, 2, or 3 ;
R1 is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
R2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxy, εlkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R3 is selected from the group consisting of hydrogen and alkyl;
R4 is haloalkyl or alkyl; and
R5 is selected from the group consisting of hydrogen or alkyl.
15. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
JV-benzyl-4-methyl-2-(2-oxo-4-phenylpyridin-l (2//)-yl)thia?ole-5-carboxamide;
7V-Benzyl-2-(5-(benzyloxy)-2-oxopyridin-l (2//)-yl)-4-methylthiazole-5- carboxamide;
Λ^-Benzyl-2-(4-hydroxy-2-oxopyridin-l(2/f)-yl)-4-methylthiazole-5-carboxamide;
Λ/-benzyl-2-(4-(4-chloropheπyl)-2-oxDpyridin-l(2//)-yl)-4-methylthiazolc-5- carboxamide;
Λr-benzyl-2-(4-(cyclopropylmethoxy)-2-oxopyridin-l(2ffl-yl)-4-methylthiazole-5- carboxamide; iV-benzyl-2-(4-methoxy-2-oxopyridin-l(2//)-yl)-4-methylthiazole-5-carboxamide; Λf-(4-fluoroben2yl)-2-(4-hydroxy-2-oxopyridin-l(2/^-yl)-4-methylthiazole-5- carboxamide;
Λ^-benzyl-2-(4-(2-cyclopropylethoxy)-2-oxopyridin-l(2/r)-yl)-4-methylthiazole-5- carboxamide;
2-(4-amino-2-oxopyridin-l(2//)-yl)-N-benzyl-4-methylthiazole-5-carboxarnide;
7V-benzyl-4-methyl-2-(2-oxopyridin-l(2iϊ)-yl)thiazole-5-carbox3mide;
JV-benzyl-4-methyl-2-(2-oxo-4-(phenylcarbamoyl)pyridin-l(2//)-yl)thiazo]e-5- carboxamide; iV-benzyl-2-(3 -(benzy loxy)-2-oxopyridin- 1 (2//)-yl)-4-methy lthiazole-5- carboxamide; jV-benzyl-2-(3-hydroxy-2-oxopyridin-l(2//)-yl)-4-methylthiazole-5-carboxamide; iV-benzyl-4-methyl-2-(2-oxo-3-(phenylcarbamoyl)pyridin-l(2//)-yl)thiazole-5- carboxamide; iV-benzyl-4-methyl-2-(2-oxo-5-(phenylcarbamoyl)pyridin-l-(2//)-yl)thiazole-5- carboxamide;
2-(4-beπzamidD-2-oxopyridin-l(2/f)-yl)-N-benzyl-4-nieth}/lthiazole-5- carboxamide;
A^-(4-fluorobenzyl)-4-methyl-2-(2-oxopyridin-l(2^0-yl)thiazole-5-carboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l(2F)-yl)-^-(4-fluorobenzyl)-4-methylthiazo]e-5- carboxamide;
2-(4-(2-cyclopropylethoxy)-2-oxopyridin-l(2//)-yl)-iV-(4-fluorDbeπzyl)-4- methylthiazole-5-carbo)camide;
2-(4-(2-cyclopropylethoxy)-2-oxopyridin-l(2//)-yl)-4-me1hyl-Λr-(pyridin-3- ylmethyl)thiazole-5 -carboxamide;
ΛLbenzyl-4-methyl-2-(2-oxo-4-(pyridin-3-ylmethoxy)pyridin-l(2//)-yl)thiazole-5- carboxamide; iV-benzyl-2-(5-hydroxy-l-oxoisoquino]in-2(]i/)-yl)-4-methylthiazole-5- carboxamide;
Λr-benzyl-2-(6-b.ydroxy-2-oxoquinolm-l(2//)-yl)-4-methylthiazole-5- carboxamide; ΛT-benzyl-2-(6-(benzyloxy)-2-oxoquinolin-l(2//)-y])-4-rnethylthiazole-5- carboxamide; iV-benzyl-2-(5-(benzyloxy)-l-oxoisoquinolin-2(l//)-yl)-4-methylthiazole-5- carboxamide;
7V-benzyl-2-(4-(benzyloxy)-2-oxopyridin-l{2//)-yl)-4-rne1hyl-l//-imidazole-5- carboxamide;
7V-benzyl-5-(4-(benzyloxy)-2-oxopyridin-l(2//)-yl)-3-niethylthiophene-2- carboxamide;
JV-benzyl-5-(4-hydroxy-2-oxopyridin-l(2//)-yl)-3-methylthiophene-2- carboxamide; jV-benzyl-2-(4-(benzyloxy)-2-oxoρyπdin-l(2/0-yl)-l!4-<iimethyl-l//-imidazolc-5- carboxamide;
7V-benzyl-2-(4-(benzyloxy)-2-oxopyridin-l(2//)-yl)-l,5-dimethyl-l//-imidazole-4- carboxamide;
Λr-benzyl-5-(4-(2-cyclopropylethoxy)-2-oxopyridin-l(2/3>yl)-3-methy]thiophene- 2-carboxamide; l-(5-(Benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxo-l,2-dihydropyridin-4-yl trifluoromethanesulfonate;
Ethyl 4-methyl-2-(2-oxo-4-phenylpyridin-l(2//)-yl)thiazole-5-carboxy late;
Ethyl 2-(4-(benzyloxy)-2-oxopyridin-l(2//)-yl)-4-methyUhiazol«-5-carboxylate,
Ethyl 2-(4-(benzyloxy)-2-oxopyridin-l(2//)-yl)-4-methyl- 1 H-ϊmidazo]e-'5- carboxylate;
Ethyl 2-(4-(beπzyloxy)-2-oxopyridin-l(2//)-yl)-l,4-dimethyl-l//-imidazole-5- carboxylate;
Ethyl 2-(4-(benzyloxy)-2-oxopyridiπ-l(2//)-yl)-l,5-dimethy]-lJ7-imidazole-4- carboxylate;
4-Methyl-2-(2-oxo-4-ρhenylpyridin-l(2//)-yl)thiazo]€-5-carboxylic acid;
4-Methyl-2-(4-(benzyloxy)-2-oxopyridin-l(2//)-y])thiazol«-5-carboxylic acid;
2-(4-(Cyclopropylmethoxy)-2-oxopyridin-] (2//)-yl)-4-methy]thiazole-5- carboxylic acid; 2-(4-(2-Cyclopropylethoxy)-2-oxopyridin-l(2i7)-yl)-4-methylthiazole-5- carboxylic acid;
2-(4-Methoxy-2-oxopyridin- 1 (2//)-yl)-4-methylthiazole-5-carboxylic acid; 2-(4-Hydroxy-2-oxopyridin- 1 (2//)-yl)-4-methylthiazole-5-carboxylic acid;
Ethyl 2-(4-hydroxy-2-oxopyridin-l(2/i0-yl)-4-methylthiazole-5-carboxylate;
Ethyl 2-(4-(cyclopropylmethoxy)-2-oxopyridin- 1 (2//)-yl)-4-methylthiazole-5- carboxylate;
Ethyl 2-(4-methoxy-2-oxopyridin-l(2//)-yl)-4-methylthiazole-5-carboxylate;
Ethyl 2-(4-(2-cyclopropylethoxy)-2-oxopyridin-l(2//)-yl)-4-methylthiazole-5- carboxylate;
2-(4-(Benzyloxy)-2-oxopyridin-l(2Λ)-yl)-4-methyl-l/f-imidazole-5-carboxylic acid;
2-(4-(Benzyloxy)-2-oxopyridin-l(2i/)-yl)-l,4-dimethyl-lϋ-iinidazole-5- carboxylic acid;
2-(4-(Benzyloxy)-2-oxopyridin-l(2//)-yl)-4-methyl-Λ'-(pyridin-3-ylmethyl)-li/- imidazole-5-carboxamide;
Λ^-Benzyl-2-(4-(benzyloxy)-2-oxopyridin-l(2//)-yl)-4-methylthiazole-5- carboxamide;
Λ^-Benzyl-4-methyl-2-(3-methyl-2-oxopyrazin-l(2//)-yl)thiazole-5-carboxamide;
JV-Benzyl-2-(5-chloro-2-oxopyridin-l(2//)-yl)-4-methylthiazole-5-carboxamide;
JV-Benzyl-4-methyl-2-(2-oxo-5-(trifluoromethyl)pyridin-l(2/ϊ)-yl)thiazole-5- carboxamide;
JV-Benzyl-4-methyl-2-(2-oxo-3-(trifluoromethyl)pyridin-l(2//)-yl)thiazole-5- carboxamide;
7V-Beπzyl-4-methyl-2-(2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)thiazole-5- carboxamide;
JV-benzyl-2-(4-(benzylamino)-2-oxopyridin-l(2//)-yl)-4-methylthiazoIe-5- carboxamide;
Λ^-Benzyl-4-methyl-2-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-l(2//)-yl)thiazole- 5-carboxamide; Λr-Benzyl-2-(6-hydroxy-l-oxoisoquinolin-2(l/f)-yl)-4-methylthiazole-5- carboxamide;
7V-Benzyl-5-(4-hydroxy-2-oxopyridin-l(2/f)-yl)thiophene-3-carboxamide;
A^-Benzyl-5-(4-(benzyloxy)-2-oxopyridin-l(2/f)-yl)thiophene-3-carboxamide;
A^-Benzyl-3-tnethy]-5-(2-oxo-4-(4-(trifluoromethyl)benzyloxy)pyridin-l(2//)- yl)thiophene-2-carboxamide;
Λ^-Benzyl-5-(4-(4-fluorobenzyloxy)-2-oxopyridin-l(2//)-yl)-3-methy]thiophene- 2-carboxamide;
ΛM3enzyl-5-(4-(4-(difluoromethoxy)l>enzyloxy)-2-oxopyπdin-l(2/f)-yl)-3- methylthiophene-2-carboxamide;
Λ^-Beπzyl-3-rπethyl-5-(2-oxo-4-pheneihoxypyridin-1^2ϋ)-yl)thiophene-2- carboxamide;
2-(4-(Benzyloxy)-2-oxopyridin- 1 [2H)-y])- 1 ,5-dimethyl-2,3 -dihydro- 1 H- imidazole-4-carboxylic acid;
Λ^-benzyl-4-me1hyl-2-(2-oxo-5-(trifluoromethyl)pyridin-l(2fl}-y')thiazole-5- carboxamide; yV-benzyl-4-methyl-2-(2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)thiazole-5- carboxamide;
Λr-benzyl-4-methyl-2-(2-oxo-4-((5-(trifluoromethyl)furan-2-yl)methoxy)pyridin- 1 (27ϊ)-yl)thiazole-5-carboxamide; iV-bcnzyl-2-(4-(4-fluorobcπzyloxy)-2-oxopyridiπ-l(2/f)->'l)-4-πiethylthiazole-5- carboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l(2//)-yl)-4-methyl-iV-(pyridin-3- ylmethyl)thiazole-5-caτboxamide; iV-benzyl-4-methyl-2-(2-oxo-4-(4-^trifluoromethyl)benzyloxy)pyridin-l(2/f)- yl)thiazole-5-carboxainide;
2-(4-hydroxy-2-oxopyridin-l{2H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5- carboxamide; iV-(3-fluorobenzyl)-2-(4-hydroxy-2-osopyridin-l(2//)-yl)-4-methylthiazole-5- carboxamide; JV-(cyclopropylmethyl)-2-(4-hydroxy-2-oxopyridin-l(2iJ)-yl)-4-methylthiazole-5- carboxamide;
4-methyl-2-(2-oxopyridin-l(2/f)-yl)-λ'-(pyridin-3-ylmethyl)thiazole-5- carboxamide;
Λr-(2-cyclopropylethyl)-2-(4-hydroxy-2-oxopyridin-l(2//)-yl)-4-methylthiazole-5- carboxamide;
JV-(4-fluorophertethyl)-2-(4-hydroxy-2-oxopyridin- 1 (2//)-yl)-4-methylthiazole-5 - carboxamide;
7V-benzyl-4-metliyl-2-(2-oxo-4-phenethylpyridin-l(2//)-yl)thiazole-5- carboxamide;
Λ^-benzyl-4-metliyl-2-(2-oxo-4-phenoxypyridin-l(2Λ)-yl)thiazole-5-carboxamide;
4-methyl-2-(2-oxo-4-(trifluoromethyl)pyridin-l (2/f)-yI)-?V-(pyridin-3- ylmethyl)thiazole-5 -carboxamide;
JV-(3,4-difluorobenzyl)-2-(4-hydroxy-2-oxopyridin-l(2i7)-yl)-4-methylthiazole-5- carboxamide;
JV-benzyl-4-metliyl-2-(2-oxo-4-(2-oxoimidazolidin- 1 -yl)pyridin- 1 QH)- yl)thiazole-5-carboxamide;
2-(4-hydroxy-2-oxopyridin-l(2//)-yl)-4-methyl-jV-(pyridin-4-ylmethyl)thiazole-5- carboxamide;
2-(4-(4-(difluoromethoxy)benzyloxy)-2-oxopyridin-l(2f/)-yl)-Λr-(4- fluorobenzyl)-4-rnethylthiazole-5-carboxainide;
2-(4-methoxy-2-oxopyridin-l(2//)-yl)-4-methyl-jV-(pyridin-3-ylmethyl)thiazole- 5-carboxamide;
4-methyl-2-(2-oxo-4-((5-(trifluoromethyl)furan-2-yl)methoxy)pyridin-l(2/7)-yl)- jV-(pyridin-3-ylmethyl)thiazole-5-carboxamide;
2-(4-(4-fluorobenzyloxy)-2-oxopyridm-l(2/^-yl)-4-methyl-N-(pyridin-3- ylmethyl)thiazole-5-carboxamide; iV-(4-fluorobenzyl)-2-(4-(4-fluorobeπzyloxy)-2-oxopyridin-l{2//)-yl)-4- methylthiazole-5-carboxamide; iV-benzyl-2-(4-(cyclopentylmethoxy)-2-oxopyridin-l(2/f)-yl)-4-methylthiazole-5- carboxamide; JV-(3,4-difluorobeπzyl)-2-(4-methoxy-2-oxopyridin-l(2/f)-yl)-4-methylthiazo]e-5- carboxamide;
JV-beπzyl-4-methyl-2-(2-oxo-4-(phenoxymethyl)pyridm-l(2//)-yl)thiazole-5- carboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-N-(3,4-difluorobenzyl)-4- methylthiazole-5-carboxamide;
Λ?-benzyl-4-methyl-2-(2-oxo-4-((tetrahydrofuran-2-yl)meihoxy)pyridin-l(2Λ)- yl)thiazole-5-carboxεmide;
3-((2-(4-methcxy-2-oxopyridin-l<2#)-y])-4-methylthiazole-5- carboxamido)methyl)pyridine 1 -oxide; jV-benzy l-4-itiethyl-2-(2-oxo-4-((5-pheπyl- 1 ,3 ,4-oxadiazol-2-yl)methoxy)ρyridin- 1 (2^)-yl)thiazole-5 -carboxamide; jV-benzy]-2-(4-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)methoxy)-2-oxopyridir- ](2//)-yl)-4-methylthiazole-5-carboxamide;
Λ'-benzyl-2-(4-((4-chloro-2-(trifluoromethyl)quinolin-6-yl)methoxy)-2- oxopyridin-l(2//)-yl)-4-inethylthiazole-5-carboxamidc;
7V-benzyl-4-methyl-2-(2-oxo-4-((6-[trifluoromethyl)pyridin-3- yl)methoxy)pyridin-l(2/?)-yl)thiazole-5-carboxamide;
#-benzyl-4-methyl-2-(2-oxo-4-(thiazol-4-ylmethoxy)pyndin-l(2//)-yl)thiazole-5- carboxamide;
ΛA-benzyl-4-methyl-2-(2-oxo-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin- l(2/f)-yl)thiazole-5-carboxamide; iV-(benzo[b]thiophen-2-ylmethyl)-2-(4-(beπzyloxy)-2-oxopyridin-l (2//)-yl)-4- methylthiazole-5-carboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l(2Λ)-yl)-4-methyl-A'-((3-methylthiophen-2- yl)methyl)thiazole-5-carboxamide;
2-(4-(benzyloxy)-2-oxopyridiπ-l(2H)-yl)-iV-(2,3-dihydro-l/ϊ-inden-2-yl)-4- methyIthiazole-5-carboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l(2iϊ)-yl)-4-methyl-Λf-((5-πi€thylpyrazin-2- yl)methyl)thiazole-5-carboxamide; 2-(4-(benzylox><)-2-oxopyπdin- 1 (2//]-yl)-4-methy l-iV-(oxazol-2- ylmethyl)thiazole-5-carboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l(2/f)-yl)-4-methyl-iV-((5-methyl-2- (trifluoromethyl)furan-3-yl)rnethyl)thiazole-5-carboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l(2/f)-yl)-4-methyl-Λf-(thiεzol-2- ylmethyl)thiazole-5-Qarboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l(2^)-yl)-4-methyl-Λr-((5-methylthiophen-2- yl)tnethyl)thiazole-5-carboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l(2ii)-yl)-4-methyl-7Vr-((4-methylthiophen-2- yl)methyl)thiazole-5-carboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l(2 )-yl)-iV-((l,5-dimetliyl-liy-ρyrrol-2- yl)methyl)-4-methylthiazole-5-carboxamids,
2-(4-(benzyloκy)-2-oxopyridin- 1 (2#)-yl)-4-methyl-N-((l-methyl- 1 i/-imidazol-5 - yl)methyl)thiazole-5-carboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l (2/f)-yl)-4-methyl-iV-((l-methyl- 1 //-pyrazol-4- yl)methyl)thiazole-5-carboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l(2iϊ)-yl)-4-methyl-Λ^-((2-methylthiazol-4- yl)methyl)thiazole-5-carboxamide;
2-(4-(benzylox>)-2-oxopyridin-l(2F)-yl)-Λ^-((5-cyanofuiar-2-yl)methyl)-4- methylthiazole-5-carboxamide; jV-(benzo[d]o>s.azol-2-ylmethyl)-2-(4-(benzyloxy)-2-oxopyridin-l(2/f)-yl)-4- methylthiazole-5-carboxamide;
Ethyl-5-((2-(4-(benzyloxy)-2-oxopyπdin-l(2//)-yl)-4-methylthiazole-5- carboxamido)methyl)furan-2-carboxylate;
F-((l/f-indol-2-yl)methyl)-2-(4-(benzyloxy)-2-oxopyridin-l(2//)-yl)-4- methylthiazole-5-carboxamide; iV-(benzo[J]th]azol-2-ylmethyl)-2-(4-(benzyloxy)-2-oxopyridin-l(2if|-yl)-4- methylthiazole-5-carboxamide;
AT-((li/-pyrazol-3-yl)methyl)-2-(4-(benzyloxy)-2-oxopyridin-l<2JW)-yl)-4- methylthiazole-5-carhoxamide; 2-(4-(bcnzyloxy)-2-oxopyridin-l(2i/)-yl)-Λr-(('6-chloropyridin-3-yl)methyl)-4- methylthiazole-5-carboxamide;
2-(4-(benzyloxy)-2-oxopyridin- 1 (2if)-yl)-4-methyl-Λ'-((6- (trifluoromethyl)pyridin-3-yl)methyl)thiazole-5-carboxamide;
2-(4-(benzyloxy)-2-oxopyridin-l(2i0-yl)-4-methyl-Λ'-((5-methylfuran-2- yl)methyl)thiazole-5-carboxamide;
Λr-benzyl-4-methyl-2-(4-((5-methylisoxazol-3-yl)methoxy)-2-oxopyridiπ-l(2if)- yl )thiazole-5-carboxam ide;
Λf-benzyl-2-(4-((5-chlorothiophen-2-yl)methoxy)-2-oxopyridin-l(2/f»-yl)-4- methylthiazole-5-carboxamide;
#-benzyl-2-(4-((5-chlorothiophen-2-yl)methoxy)-2-oxopyridin-l{2/^-yl)-4- methylthiazole-5-carboxamide;
Λ'-benzyl-2-(4-((2-isopropylthiazol-4-yl)methoxy)-2-oxopyridin-l(2//)-yl)"4- methylthiazole-5-carboxamide;
N-benzyl-2-(4-((6-chloropyridin-3 -yl)methoxy)-2-oxopjrridin- 1 (2//)-yl)-4- methy lthiazole-5-carboxam ide ;
W-benzyl-4-methyl-2-(4-((2-methylthiazol-4-yl)methoxy)-2-oxopyridin-l(2H)- yl)thiazole-5-carboxamide;
2-(4-((l,2,4-oxadiazol-3-yl)methoxy)-2-oxopyridin-l(2//)-yl)-Λf-benzyl-4- methylthiazole-5-carboxamide; iV-benzyl-2-(4-((3,5-dimethylisoxa2θl-4-yl)inethoxy)-2-oκopyridin-l(2iϊ)-yl)-4- methylthiazole-5-carboxamide;
2-(4-hydroxy-2-oxopyridin-l(2W)-yl)-4-methyl-Λ^-«6-methylpyrazin-2- yl)methyl)thiazole-5-carboxamide;
2-(4-hydroxy-2-oxopyridin-l(2//)->'l)-4-methyl-Λ'-(oxazDl-2-ylmethyl)thiazole-5- carboxamide; and
Λr-benzyl-2-(4-cyclopropyl-2-oxopyridin-l(2/f)-yl)-4-methylthiazole-5- carboxamide.
16. A pharmaceutical composition, comprising: the compound of formula (I) according to claim 1 and a pharmaceutically acceptable excipient or carrier.
17. A method of inhibiting human stearoyl-CoA desaturase (hSCD) activity comprising contacting a source of hSCD with a compound of Formula (I):
Figure imgf000165_0001
wherein,
V is selected from -N(RS)C(O)-, -C(O)N(R5)-, -OC(O)N(R5)-, -N(R3)C(O)O-,
-N(R5)C(O)N(R5)-, -O-, -N(R5)-, -S-, -S(O),-, -N(R5)S(0)t-, -S(O)1N(R5)-, - OS(O)2-, -OS(O)2N(R5)-, -C(O)-, -OC(O)-, -C(O)O-, -N(R5)C(=N(R5a))NR5-, - N(R5)C(=S)NR5-, -N(R5)((R5a)N=)C-, -C(=N(R5a))N(R5)-, alkylene, alkenylene, alkynylene, aryl, heteroaryl, cycloalkyl, heterocyclyl or a direct bond;
W is selected from -N(R3)C(O)-, -C(O)N(R3)-, -OC(O)N(R5)-, -N(R5)C(0)0-,
-N(R3)C(O)N(R5)-, -0-, -N(R5)-, -S-, -S(O)1-, -N(R5)S(0)t-: -S(O)1N(R5)-, - OS(O)2N(RS)-, -C(O)-, -OC(O)-, -C(O)O-, -N(R5)C(=N(R5a))NR3-, - N(R5)((R5a)N=)C-, -C(=N(R5a))N(R5)-, aryl, heteroaryl, heterocyclyl, alkynylene, alkenylene, alkylene or a direct bond;
X is selected from C(H) or N;
Y is selected from S, O, N(H) or N(CH3); p is O, 1, 2, or 3; t is 1 or 2;
R1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl, and heteroarylalkyl; or R1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, atyl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, haloalkoxyl, cyano and -N(R5)2; R4 is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkylalkyl, aralkyl, halo, haloalkyl, -OCF3, -OC(H)F2, and cyano; or two adjacent R4 groups, together with the carbon atoms to which they attached, may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R4 groups, if present, are as described above; R5 is selected from the group consisting of hydrogen, aryl, alkyl, heteroaryl, heterocyclyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl;
R5a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
18. A method of treating a disease or condition mediated by stearoyl-CoA deεaturase (SCD) in a mammal, comprising: administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) according to claim 1.
19. The method according to claim 18, wherein the disease or condition is metabolic syndrome, Syndrome X, diabetes, insulin resistance, decreased glucose tolerance, non- insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, body weight disorders, weight loss, body mass index or leptin related diseases.
20. The method according to claim 19, wherein the metabolic syndrome is dyslipidemia, obesity, insulin resistance, hypertension, microalbuminemia, hyperuricaemia, or hypercoagulability.
21. The method according to claim 19, wherein the bodyweight disorder is obesity, overweight, cachexia and anorexia.
22. The method according to claim 18, where the disease or condition is a skin disorder.
23. The method according to claim 20, wherein the skin disorder is eczema, acne, psoriasis, or keloid scar formation or prevention.
24. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of claim 1 in combination with a therapeutically effective amount of insulin, insulin derivative or mimetic; insulin sccrctagogue, insulinotropic sulfonylurea receptor ligand; PPAR ligand; insulin sensitizer; biguanide; alpha-glucosidase inhibitors; GLP-I, GLP-I analog or mimetic; DPPIV inhibitor; HMG-CoA reductase inhibitor; squalene synthase inhibitor; FXR or LXR ligand; cholestyramine; fibrates; nicotinic acid; or aspirin.
25. Use of a compound of Formula (I) according to claim 1, for the preparation of a pharmaceutical composition for the treatment of a disorder or disease in a subject mediated by the inhibition of stearoyl-CoA desaturase.
26. A compound of Formula (I) according to claim 1 for use as a medicament.
27. Use of a compound of Formula (I) according to claim 1 , for the preparation of a pharmaceutical composition for the treatment of a disorder or disease in a subject mediated by the inhibition stearoyl-CoA desaturase.
28. A pharmaceutical composition according to claim 1 for use as a medicament.
29. Use of a pharmaceutical composition according to claims 16, 24 or 28 for the preparation of a medicament for the treatment of a disorder or disease in a subject mediated by the inhibition of stearoyl-CoA desaturase.
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