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WO2025117930A1 - Déshydrogénation et lactonisation bimodales catalysées par le cuivre de liaisons c(sp3)-h - Google Patents

Déshydrogénation et lactonisation bimodales catalysées par le cuivre de liaisons c(sp3)-h Download PDF

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WO2025117930A1
WO2025117930A1 PCT/US2024/058036 US2024058036W WO2025117930A1 WO 2025117930 A1 WO2025117930 A1 WO 2025117930A1 US 2024058036 W US2024058036 W US 2024058036W WO 2025117930 A1 WO2025117930 A1 WO 2025117930A1
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alkyl
saturated
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Jin-Quan Yu
Shupeng ZHOU
Zi-jun ZHANG
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Scripps Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
    • B01J23/72—Copper
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C07B43/06—Formation or introduction of functional groups containing nitrogen of amide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
    • C07C319/12—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols by reactions not involving the formation of mercapto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C07C2601/20—Systems containing only non-condensed rings with a ring being at least seven-membered the ring being twelve-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the application provides a method of copper-catalyzed bimodal dehydrogenation of N-methoxyamides via radical abstraction of ⁇ -aliphatic C ⁇ H bonds.
  • the application further provides the above method, wherein the dehydrogenation alternatively occurs according to the following scheme: NH 2 wherein: R a , R b , and R c are independently H, -(C 1 -C 6 ) alkyl, -(C 3 -C 14 ) cycloalkyl, -(C 3 -C 14 ) heterocycloalkyl, -NPhth, -OAc, or Ph; R d and R e are independently H, -(C 1 -C 6 ) alkyl, -(C 3 -C 14 ) cycloalkyl, -(C 3 -C 14 ) heterocycloalkyl, -NPhth, -OAc, or Ph; or R d and R e together form -(C 2 -C 6 ) alkenyl.
  • the application further provides the above method, wherein the dehydrogenation alternatively occurs according to the following scheme: NH 2 R 5 wherein: Q is saturated or partially unsaturated (C 3 -C 16 ) cycloalkyl, saturated or partially unsaturated (C 3 -C 14 ) heterocycloalkyl, -(C 5 -C 10 ) heteroaryl, or -(C 6 -C 10 ) aryl; R 1 is H, halo, oxo, or -OAc; or R 1 and R 5 together form partially unsaturated (C 3 -C 16 ) cycloalkyl or saturated or partially unsaturated (C 3 -C 14 ) heterocycloalkyl, optionally substituted with one or more R 1’; R 1’ is -OH, -CN, halo, oxo, (C 1 -C 6 ) alkyl, -OAc, or -(C 2 -C 6 ) alkenyl; R 2 is R
  • the application additionally provides a method of copper-catalyzed bimodal lactonization of N-methoxyamides via radical abstraction of the ⁇ -aliphatic C ⁇ H bonds.
  • N-methoxyamides have become a major class of practically useful substrates in Pd(II)- and Rh(III)-catalyzed C ⁇ H activation reactions 17 since their first introduction 18 . They can be readily prepared in large quantities from carboxylic acids in a single step and are bench-stable for long-term storage. It was hoped to achieve a reductive cleavage of the N ⁇ O bond to generate the amidyl radical.
  • reaction was also found to tolerate a wide range of functionality, including alkyl acetates (B3, B6, and B28), pre-existing olefins (B2, B20, and B26), alkynes (B21), (thio)ethers (B10, B22, B24, and B25), carbamates (B19), heterocycles (B11, B22, and B23), and potential cross coupling partners for downstream elaborations such as aryl halides (B13, B14, and B18) and boronic esters (B15). Moreover, pre-existing stereocenters at the ⁇ - and ⁇ -positions remained intact (B3, B27, and B28).
  • N-Methoxyamide derivatives of natural products and pharmaceuticals also proved amenable to dehydrogenation (B51-B65).
  • the exclusive formation of mono-desaturation product B52 from valproic acid derivative A52 offers a particularly notable example, as our internal oxidant strategy, unlike the use of external oxidant, prevents further dehydrogenation. Site-selectivity became somewhat more complicated with polycyclic substrates.
  • Betulinic acid derivative B62 offers a particularly informative example wherein high yields of a single product were obtained despite the presence of four competing ⁇ -C ⁇ H bonds.
  • the major product was formed by HAT at an unactivated methine rather than the allylic ⁇ -methine, indicating that geometric factors can outweigh the intrinsic reactivity of the competing C ⁇ H bonds.
  • the reaction displayed a remarkable tolerance for sensitive functionality such as the conjugated triene system formed in B59, though migration of the pre-existing double bond was observed in B64 and B65.
  • abietane-type structures are TSRI 2216.1PC widely found in nature and are also precursors of many complex terpenes, it was decided to test a large-scale reaction on the derivative of dehydroabietic acid.
  • the carbon-centered radical Int-1 formed by 1,5-H-abstraction rearranged via an opening of the adjacent cyclopropane, forming the primary allylic radical Int-2, which can subsequently undergo oxidative elimination to afford diene B66.
  • these results support a mechanism initiated by Cu(I)-catalyzed oxidation of the N-methoxyamide to afford an amidyl radical, which then rearranges to a carbon-centered radical at the ⁇ -position via 1,5-HAT.
  • alkyl chloride A67 was treated with AgBF 4 for in-situ carbocation generation (Fig.4d). Contrary to the regioselectivity of our reaction, this reaction afforded the ⁇ , ⁇ - and ⁇ , ⁇ -olefins in a 10:1 mixture. Thus, our copper- catalyzed dehydrogenation unlikely proceeds via a cation intermediate, and the second pathway involving organocopper(III) species is more plausible 37,38 . Additionally, the nearly exclusive ⁇ , ⁇ -selectivity may be attributed to the coordination of the amide to the copper to form a metallocycle, favoring the elimination of an exocyclic ⁇ -H rather than an endocyclic ⁇ -H 39 .
  • Embodiment 1 A method of copper-catalyzed bimodal dehydrogenation of N- methoxyamides via radical abstraction of ⁇ -aliphatic C ⁇ H bonds.
  • Embodiment 2 A method of copper-catalyzed bimodal lactonization of N- methoxyamides via radical abstraction of the ⁇ -aliphatic C ⁇ H bonds.
  • Embodiment 3 The method of either Embodiment 1 or Embodiment 2, wherein the copper catalyst is a Cu(I) catalyst.
  • Embodiment 4. The method of Embodiment 3, wherein the Cu(I) catalyst is [Cu(MeCN) 4 ]BF 4 .
  • Embodiment 5. The method of Embodiment 3, wherein the Cu(I) catalyst is [(CH 3 CN) 4 Cu]PF 6 .
  • Embodiment 3 wherein the Cu(I) catalyst is CuBr.
  • Embodiment 7 The method of Embodiment 1, wherein the copper catalyst is a Cu(II) catalyst.
  • Embodiment 8 The method of any one of Embodiments 1-7, wherein the Cu(II) catalyst is CuF 2 .
  • Embodiment 9 The method of any one of Embodiments 1-7, wherein the Cu(II) catalyst is Cu(OTFA) 2 •H 2 O.
  • R a , R b , and R c are independently H, -(C 1 -C 6 ) alkyl, -(C 3 -C 14 ) cycloalkyl, -(C 3 -C 14 ) heterocycloalkyl, -NPhth, -OAc, or Ph;
  • R f and R g are independently H, (C 1 -C 6 ) alkyl, -(C 3 -C 14 ) cycloalkyl, -(C 3 -C 14 ) heterocycloalkyl, Ph, -NPhth, or
  • Embodiment 11 The method of Embodiment 1, wherein the dehydrogenation occurs according to the following scheme: NH 2 wherein: R a , R b , and R c are independently H, -(C 1 -C 6 ) alkyl, -(C 3 -C 14 ) cycloalkyl, -(C 3 -C 14 ) heterocycloalkyl, -NPhth, -OAc, or Ph; R d and R e are independently H, -(C 1 -C 6 ) alkyl, -(C 3 -C 14 ) cycloalkyl, -(C 3 -C 14 ) heterocycloalkyl, -NPhth, -OAc, or Ph; or R d and R e together form -(C 2 -C 6 ) alkenyl.
  • Embodiment 13 The method of Embodiment 1, wherein the dehydrogenation occurs according to the following scheme: NH 2 R 5 wherein: Q is saturated or partially unsaturated (C 3 -C 16 ) cycloalkyl, saturated or partially unsaturated (C3-C14) heterocycloalkyl, -(C5-C10) heteroaryl, or -(C6-C10) aryl; R 1 is H, halo, oxo, or -OAc; or R 1 and R 5 together form partially unsaturated (C 3 -C 16 ) cycloalkyl or saturated or partially unsaturated (C 3 -C 14 ) heterocycloalkyl, optionally substituted with one or more R 1’; R 1’ is -OH, -CN, halo, oxo, (C 1 -C 6 ) alkyl, -OAc, or -(C 2 -C 6 ) alkenyl; R 2 is R 2a or R 2
  • Embodiment 14 The method of any one of Embodiments 10-13, wherein the Cu(II) catalyst is CuF 2 .
  • Embodiment 15 The method of any one of Embodiments 10-13, wherein the Cu(II) catalyst is Cu(OTFA)2•H2O.
  • Embodiment 16 The method of any one of Embodiments 10-15, wherein the solvent is dioxane.
  • Embodiment 17 The method of any one of Embodiments 10-15, wherein the solvent is dioxane/MeNO 2 .
  • Embodiment 18 The method of any one of Embodiments 10-15, wherein the solvent is MeNO 2 .
  • Embodiment 19 The method of any one of Embodiments 10-13, wherein the Cu(II) catalyst is CuF 2 .
  • Embodiment 15 The method of any one of Embodiments 10-13, wherein the Cu(II) catalyst is Cu(OTFA)2•H2O.
  • Embodiment 16 The method
  • Embodiment 20 The method of any one of Embodiments 10-15, wherein the solvent is DCE.
  • Embodiment 20 The method of any one of Embodiments 10-15, wherein the solvent is PhMe.
  • Embodiment 21 The method of any one of Embodiments 10-15, wherein the solvent is AcOH.
  • Embodiment 22 The method of any one of Embodiments 10-15, wherein the solvent is THF.
  • Embodiment 23 The method of any one of Embodiments 10-22, wherein the solvent is approximately 0.2M.
  • Embodiment 24 The method of any one of Embodiments 10-23, wherein the Cu catalyst is added at approximately 10 mol%. [0054] Embodiment 25.
  • Embodiment 26 The method of Embodiment 25, wherein Ligand (L) is selected from the group consisting of: N . L
  • Embodiment 27 The method of Embodiment 26, wherein Ligand (L) is 8- methoxyquinoline.
  • Embodiment 28 The method of any one of Embodiments 10-27, wherein the Ligand (L) is added at approximately 20 mol%.
  • Embodiment 29 The method of any one of Embodiments 10-28, wherein the AcOH is added at approximately 8 equivalents.
  • Embodiment 30 The method of any one of Embodiments 10-28, wherein the AcOH is added at approximately 8 equivalents.
  • Embodiment 31 The method of any one of Embodiments 10-30, wherein the reaction time is approximately 2-20 h.
  • Embodiment 32 The method of Embodiment 1, wherein the dehydrogenation occurs according to the following scheme: CuF (10 mol%) 2 R a R d R e O Ligand (L) (20 mol%) Ra d e AcOH (8 equiv.) R R O R b R b NH , c g 2 R R f R 125 °C, 2-20 h .
  • Embodiment 33 Embodiment 33.
  • Embodiment 32 wherein Ligand (L) is 8- methoxyquinoline.
  • Embodiment 34 The method of Embodiment 32, wherein Ligand (L) is absent.
  • Embodiment 35 The method of Embodiment 10, wherein the dehydrogenation occurs according to the following scheme: NH 2 g , ( 0.1 mmol) .
  • Embodiment 36 The method of Embodiment 35, wherein the solvent is dioxane.
  • Embodiment 37 The method of Embodiment 35, wherein the solvent is DCE. TSRI 2216.1PC [0067] Embodiment 38.
  • Embodiment 39 The method of any one of Embodiments 35-37, wherein the acid is AcOH (8 equiv.).
  • Embodiment 40 The method of any one of Embodiments 35-37, wherein the acid is TsOH•H2O (0.5 eq.).
  • Embodiment 41 The method of any one of Embodiments 35-40, wherein the product is selected from the group consisting of: O O NH2 NH2 O 57% O NH2 . 69% [0071] Embodiment 42.
  • Embodiment 43 The method of any one of Embodiments 35-40, wherein the product is selected from the group consisting of: TSRI 2216.1PC C Me O O Me Me ONH 2 Me C ONH 2 73% O OMe NH Me C ONH2 Me . a cid [0073]
  • Embodiment 44 Embodiment 44.
  • Embodiment 45 The method of Embodiment 44, wherein the solvent is dioxane.
  • Embodiment 46 The method of Embodiment 44, wherein the solvent is approximately (1:1) dioxane/MeNO 2 .
  • Embodiment 47 The method of Embodiment 44, wherein the solvent is AcOH.
  • Embodiment 48 The method of Embodiment 44, wherein the solvent is MeNO 2 .
  • Embodiment 49 The method of any one of embodiments 44-48, wherein the solvent is approximately 0.2M. [0079] Embodiment 50.
  • Embodiment 51 The method of any one of embodiments 44-49, wherein the Cu catalyst is [Cu(MeCN) 4 ]BF 4.
  • Embodiment 51 The method of any one of embodiments 44-49, wherein the Cu catalyst is CuF 2 .
  • Embodiment 52 The method of any one of embodiments 44-51, wherein the Cu catalyst is approximately 10 mol%.
  • Embodiment 53 The method of any one of embodiments 44-52, wherein the acid additive is CSA.
  • Embodiment 54 The method of any one of embodiments 44-52, wherein the acid additive is TFA.
  • Embodiment 55 The method of any one of embodiments 44-52, wherein the acid additive is TSOH.
  • Embodiment 56 The method of any one of embodiments 42-52, wherein the acid additive is AcOH.
  • Embodiment 57 The method of any one of embodiments 44-52, wherein the acid additive is added at approximately 0.5-5 equivalents.
  • Embodiment 58 The method of any one of embodiments 44-57, wherein the reaction temperature is approximately 125 °C.
  • Embodiment 59 The method of any one of embodiments 44-58, wherein the reaction time is approximately 2-20 h.
  • Embodiment 60 The method of any one of embodiments 44-58, wherein the reaction time is approximately 3-5 h.
  • Embodiment 61 The method of any one of embodiments 42-52, wherein the acid additive is AcOH.
  • Embodiment 57 The method of any one of embodiments 44-52, wherein the acid additive is added at approximately 0.5-5 equivalents.
  • Embodiment 58 The method of any one of embodiments 44-57, wherein the reaction temperature is approximately 125 °C.
  • Embodiment 62 The method of Embodiment 61, wherein the solvent is dioxane.
  • Embodiment 63 The method of Embodiment 61, wherein the solvent is AcOH.
  • Embodiment 64 The method of any one of Embodiments 61-63, wherein the Cu catalyst is [Cu(MeCN) 4 ]BF 4.
  • Embodiment 65 The method of any one of Embodiments 61-63, wherein the Cu catalyst is CuF 2 .
  • Embodiment 66 The method of any one of Embodiments 61-65, wherein the acid additive is CSA (0.2-0.5 equiv.).
  • Embodiment 67 The method of any one of Embodiments 61-65, wherein the acid additive is TFA (0.25-0.5 equiv.).
  • Embodiment 68 The method of any one of Embodiments 61-65, wherein the acid additive is TsOH•H 2 O (0.5 equiv.). TSRI 2216.1PC
  • Embodiment 69 The method of any one of Embodiments 61-68, wherein the product is selected from the group consisting of: O O D . O NPhth d.r.4:5 O O 2 3% .
  • Embodiment 70 Embodiment 70.
  • Embodiment 71 The method of any one of Embodiments 61-68, wherein the product is selected from the group consisting of: O O 64% , 78% 60% O O 53% [00100] Embodiment 71.
  • Embodiment 72 The method of Embodiment 61, wherein the product is selected from the group consisting of X O H 56% [00102]
  • Embodiment 73 The method of Embodiment 61, wherein the product is selected from the group consisting of:
  • Embodiment 74 The method of Embodiment 1, wherein the dehydrogenation occurs on a gram scale according to the following scheme: , Me , Me , A58, 1.65g, 5.0 mmol .
  • Embodiment 75 Any method disclosed in the instant application. Definitions [00105]
  • the phrase “a” or “an” entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.
  • each instance of that R group is separately identified as one member of the set which follows in the definition of that R group.
  • each R 1 and R 2 is independently selected from carbon and nitrogen” means that both R 1 and R 2 can be carbon, both R 1 and R 2 can be nitrogen, or R 1 or R 2 can be carbon and the other nitrogen or vice versa.
  • “optionally substituted” means that the “optionally substituted” moiety may incorporate a hydrogen or a substituent.
  • the phrase “optional bond” means that the bond may or may not be present, and that the description includes single, double, or triple bonds. If a substituent is designated to be a "bond” or “absent”, the atoms linked to the substituents are then directly connected. TSRI 2216.1PC [00115] The term “about” is used herein to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.
  • Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate an individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule.
  • keto form predominates while; in phenols, the enol form predominates.
  • a “pharmaceutically acceptable salt” is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound described herein.
  • Representative pharmaceutically acceptable salts include, e.g., alkali metal salts, alkali earth salts, ammonium salts, water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresor
  • a pharmaceutically acceptable salt can have more than one charged atom in its structure.
  • the pharmaceutically acceptable salt can have multiple counterions.
  • a TSRI 2216.1PC pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterions.
  • phenylalkyl refers to an alkyl group having one to two phenyl substituents, and thus includes benzyl, phenylethyl, and biphenyl.
  • An “alkylaminoalkyl” is an alkyl group having one to two alkylamino substituents.
  • “Hydroxyalkyl” includes 2-hydroxyethyl, 2-hydroxypropyl, 1-(hydroxymethyl)-2- methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth. Accordingly, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups defined below.
  • -(ar)alkyl refers to either an unsubstituted alkyl or an aralkyl group.
  • the term (hetero)aryl or (het)aryl refers to either an aryl or a heteroaryl group.
  • alkyl as used herein denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 12 carbon atoms.
  • TSRI 2216.1PC lower alkyl or “C 1 -C 6 alkyl” as used herein denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms.
  • C 1-12 alkyl refers to an alkyl composed of 1 to 12 carbons.
  • alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
  • alkyl When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically- named group.
  • phenylalkyl denotes the radical R'R"-, wherein R' is a phenyl radical, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene radical.
  • arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl.
  • arylalkyl or “aralkyl” are interpreted similarly except R' is an aryl radical.
  • (het)arylalkyl or “(het)aralkyl” are interpreted similarly except R' is optionally an aryl or a heteroaryl radical.
  • C 1–6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 alkyl.
  • Alkyl refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1–20 alkyl”).
  • an alkyl group has 1 to 15 carbon atoms (“C 1–15 alkyl”). In some embodiments, an alkyl group has 1 to 14 carbon atoms (“C 1–14 alkyl”). In some embodiments, an alkyl group has 1 to 13 carbon atoms (“C 1–13 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1–12 alkyl”). In some embodiments, an alkyl group has 1 to 11 carbon atoms (“C 1–11 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1–9 alkyl”).
  • an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1–2 alkyl”).
  • an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to TSRI 2216.1PC 6 carbon atoms (“C 2–6 alkyl”). Examples of C 1–6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n–propyl (C 3 ), isopropyl (C 3 ), n–butyl (C 4 ), tert–butyl (C 4 ), sec–butyl (C 4 ), iso–butyl (C 4 ), n– pentyl (C 5 ), 3–pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3–methyl–2–butanyl (C 5 ), tertiary amyl (C 5 ), and n–hexyl (C 6 ).
  • alkyl groups include n–heptyl (C 7 ), n– octyl (C 8 ) and the like.
  • Alkenyl or “olefin” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds (“C 2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2–7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2–6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl).
  • Examples of C 2–4 alkenyl groups include ethenyl (C 2 ), 1–propenyl (C 3 ), 2–propenyl (C 3 ), 1– butenyl (C 4 ), 2–butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2–6 alkenyl groups include the aforementioned C 2–4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • alkenyl examples include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • Alkynyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C 2–10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2–8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C 2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2–5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
  • the one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl).
  • Examples of C 2–4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1–propynyl (C 3 ), 2–propynyl (C 3 ), 1–butynyl (C 4 ), 2–butynyl (C 4 ), and the like.
  • Examples of C 2–6 alkenyl TSRI 2216.1PC groups include the aforementioned C 2–4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • alkynyl examples include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • haloalkyl or “halo-lower alkyl” or “lower haloalkyl” refers to a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms wherein one or more carbon atoms are substituted with one or more halogen atoms.
  • alkylene or "alkylenyl” as used herein denotes a divalent saturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g., (CH 2 ) n )or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g., -CHMe- or -CH 2 CH(i-Pr)CH 2 -), unless otherwise indicated. Except in the case of methylene, the open valences of an alkylene group are not attached to the same atom.
  • alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2-ethylbutylene.
  • alkoxy as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t- butyloxy, pentyloxy, hexyloxy, including their isomers.
  • “Lower alkoxy” as used herein denotes an alkoxy group with a “lower alkyl” group as previously defined.
  • “C 1-10 alkoxy” as used herein refers to an-O-alkyl wherein alkyl is C 1-10 .
  • hydroxyalkyl denotes an alkyl radical as herein defined wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups.
  • cycloalkyl refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • C 3-7 cycloalkyl refers to an cycloalkyl composed of 3 to 7 carbons in the carbocyclic ring.
  • carboxy-alkyl refers to an alkyl moiety wherein one, hydrogen atom has been replaced with a carboxyl with the understanding that the point of TSRI 2216.1PC attachment of the heteroalkyl radical is through a carbon atom.
  • carboxy or “carboxyl” refers to a –CO 2 H moiety.
  • heteroaryl or “heteroaromatic” as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing four to eight atoms per ring, incorporating one or more N, O, or S heteroatoms, the remaining ring atoms being carbon, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring.
  • heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character.
  • heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazol, isoxazole, thiazole, isothiazole, triazoline, thiadiazole and oxadiaxoline which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino,dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbon
  • bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole and benzisothiazole.
  • Bicyclic moieties can be optionally substituted on either ring; however the point of attachment is on a ring containing a heteroatom.
  • heterocyclyl denotes a monovalent saturated cyclic radical, consisting of one or more rings, preferably one to two rings, including spirocyclic ring systems, of three to eight atoms per ring, incorporating one or more ring heteroatoms (chosen from N,O or S(O) 0-2 ), and which can optionally be independently substituted with one or more, preferably one or two substituents selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkyls
  • heterocyclic radicals include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl.
  • Heterocyclyl refers to a group or radical of a 3– to 14– membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon– carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”).
  • a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”).
  • a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5–membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, TSRI 2216.1PC dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione.
  • Exemplary 5– membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6–membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6–membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro–1,8–naphthyridinyl, octahydropyrrolo[3,2–b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H–benzo[e][
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6–14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl ( ⁇ -naphthyl) and 2–naphthyl ( ⁇ -naphthyl)).
  • C 10 aryl e.g., naphthyl such as 1–naphthyl ( ⁇ -naphthyl) and 2–naphthyl ( ⁇ -naphthyl)).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • Heteroaryl refers to a radical of a 5–14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–14 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”).
  • a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”).
  • a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”).
  • the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 5–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5–membered heteroaryl TSRI 2216.1PC groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5–membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5–membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6–membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6–membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7–membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6– bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • “Saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.
  • Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted.
  • Optionally substituted refers to a group which may be substituted or unsubstituted.
  • substituted means that at least one hydrogen present on a group is replaced with a non-hydrogen substituent, and which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • Heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and/or non-hydrogen substituents which satisfy the valencies of the heteroatoms and results in the formation of a stable compound.
  • Halo or “halogen” refers to fluorine (fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, –Br), or iodine (iodo, –I).
  • composition is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combination of the specified ingredients.
  • Salt includes any and all salts.
  • “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19.
  • Pharmaceutically acceptable salts include those derived from inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, TSRI 2216.1PC quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC).
  • Compounds with such isotopically enriched atoms are useful, for example, as analytical tools or probes in biological assays.
  • Certain isotopically-labelled compounds e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes, for example, those labeled with positron-emitting isotopes like 11 C or 18 F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123 I can be useful for application in Single Photon Emission Computed Tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • PTT Positron Emission Tomography
  • SPECT Single Photon Emission Computed Tomography
  • substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and hence, may be preferred in some circumstances.
  • isotopic substitution at a site TSRI 2216.1PC where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time.
  • Isotopically labeled compounds of Formula (I), in particular those containing isotopes with longer half- lives (t 1/2 >1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.
  • an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.
  • the structures and names may be represented as single enantiomers to help describe the relative stereochemistry.
  • Those skilled in the art of organic synthesis will know if the compounds are prepared as single enantiomers from the methods used to prepare them.
  • Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F254 using UV light for visualization and aqueous ammonium cerium nitrate/ammonium molybdate or basic aqueous potassium permanganate as developing agent.
  • 1 H NMR spectra were recorded on Bruker AMX-400, Bruker AV-500, or Bruker DRX-600 instruments.
  • 13 C NMR spectra were recorded on Bruker AV-500, or Bruker DRX-600 and were fully decoupled by broad band proton decoupling.
  • ligands L1-L4 which are commonly used in copper-catalyzed reactions, were first tried but no desired product was obtained.
  • the library of ligands available in our lab for Pd-catalyzed reactions (L5-L15) were screened, and L8 was found to increase the catalytic efficiency the most. It was speculated that L8 may be able to enhance the reducing ability of the Cu center, promoting the N ⁇ O bond reductive cleavage.
  • a later screen of ligands bearing similar structures as L8 revealed that the simplified L16 achieved a similar result, and the best yield (70%) was obtained when L18 was used, which has the methoxy TSRI 2216.1PC substituent moved to the 8- position of the quinoline.
  • the reaction time was reduced to 10 h (see entry 11, in Table S4 for comparison).
  • the ligand can improve the conversion, it is not necessary for every substrate as it may also lead to less optimal regioselectivity in some cases.
  • Conditions with and without the ligand are usually tested to determine the best conditions, and the labeled substrates are those that require the ligand, see Fig.2.
  • Table S6 Some additional conditions screened for ⁇ -dehydrogenation. Standard r eaction conditions: CuF 2 (10 mol%), L18 (20 mol%), AcOH (8.0 eq.), dioxane (0.2 M), 125 °C, 10 h. Isolated yields are reported. *The substrate could be partially recovered.
  • TSRI 2216.1PC Scheme S10-1 Representative examples of bimodal oxidation. Isolated yields are reported. * The solvent is dioxane.
  • Scheme S10-2 Representative examples of bimodal oxidation. Isolated yields are reported.
  • Toluene is a complementary solvent (or can be a cosolvent with dioxane) for the lactonization.
  • the yields in toluene are generally lower than those when dioxane is the solvent, but entry 2 (C28) is an exception.
  • TsOH•H2O is a complementary acid additive for lactonization, especially for benzylic C ⁇ H (eg. entry 11) but may cause the hydrolysis of some substrates.
  • the combination of CuF2 (10 mol%) and AcOH (0.2 M) is an alternative for some substrates that require higher reaction temperatures. (entry 14 and 17). Synthesis of Carboxylic Acids Note: all reactions for the synthesis of substrates are unoptimized.
  • SA13-2 was directly used in the next step without further purification.
  • a flame-dried 50 mL round-bottom flask was charged with SA13-2 (472 mg, 1.5 mmol, 1.0 equiv), Pd(OAc) 2 (16.8 mg, 0.075 mmol, 0.05 equiv), 1,1’- bis(diphenylphosphino)ferrocene (166 mg, 0.3 mmol, 0.2 equiv), and KOAc (883 mg, 9.0 mmol, 6.0 equiv).
  • the flask was capped with a septum stopper, then dry DMF (7.5 mL) was added. The flask was purged with carbon monoxide (CO balloon) for 5 min. The reaction mixture was allowed to stir at 60 °C for 16 h under carbon monoxide atmosphere (CO balloon) before it was cooled to room temperature. Saturated aq. NH 4 Cl (30 mL) was added, and the resultant mixture was extracted with EtOAc (3 ⁇ 40 mL). The combined organic phases were washed with brine (40 mL), dried over Na 2 SO 4 , filtered, and concentrated under vacuum.
  • Carboxylic acid SA14 was prepared from 4-bromo-5,6,7,8-tetrahydro-1- naphthalenol following the method used to obtain SA13. [00166] The title compound was synthesized according to a published procedure (2) with minor alteration.
  • the tube was evacuated and refilled with argon three times before 1,4-dioxane (8 mL) was added.
  • the resultant aqueous solution was extracted with EtOAc (3 ⁇ 20 mL).
  • the combined organic phases were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum.
  • the residue was subjected to flash column chromatography for purification using hexane/acetone (2:1) as eluent to give SA19.
  • a Schlenk tube was charged with carboxylic acid SA18 (604 mg, 2.0 mmol, 1.0 equiv), 1-ethynyl-4-methoxybenzene (396 mg, 3.0 mmol, 1.5 equiv), (PPh 3 ) 2 PdCl 2 (70 mg, 0.1 mmol, 0.05 equiv), and CuI (38 mg, 0.2 mmol, 0.1 equiv).
  • the tube was evacuated and refilled with argon three times before a solution of Et 3 N (102 mg, 1.4 mL, 10 mmol, 5.0 equiv) in dry tetrahydrofuran (10 mL) was added at 22 °C.
  • Carboxylic acid SA35 was prepared from cycloheptanecarbaldehyde following the method used to prepare SA38.
  • C O2H [00181]
  • Carboxylic acid A36 was prepared from cyclooctanecarboxaldehyde following the method used to to prepare SA38.
  • CO 2 H [00182]
  • Carboxylic acid SA37 was prepared from cyclohexylketone following the method used to prepare SA38.
  • Carboxylic acid SA40 was prepared from 3-aminopentanoic acid following the procedure used to obtain SA39.
  • Carboxylic acid SA41 was prepared from pregabalin following the method used to obtain SA39.
  • Carboxylic acid SA42 was prepared from homophenyalanine following the method used to obtain SA39.
  • C O 2 H [00187]
  • Carboxylic acid SA43 was prepared from norleucine following the procedure used to obtain SA39.
  • Carboxylic acid SA44 was prepared from 1-aminocyclohexanecarboxylic acid following the method used to obtain SA45.
  • CO 2 H [00190]
  • Carboxylic acid SA46 was prepared from gabapentin following the method used to obtain SA39.
  • Carboxylic acid SA47 was prepared from 3-amino-4-methylpentanoic acid following the procedure used to obtain SA39. Et 3 N CO 2 H phthalic CO 2 H toluene, 125 NPhth SA49 [00192] Carboxylic acid SA49 was prepared from L-cyclohexylalanine following the method used to prepare SA45.
  • Carboxylic acid SA73 was prepared from 1,4-dimethyl-2- naphthalenecarboxaldehyde via a Pinnick oxidation following the method used in the synthesis of SA10. O OH Ph [00206] A flame-dried 50 mL round-bottom flask was charged with 1,3-diethyl 2-(2- phenylethyl)propanedioate (1.32 g, 5.0 mmol, 1.0 equiv) in dry dimethylformamide (5 mL) at 0 °C.
  • Carboxylic acid SA83 was prepared from ⁇ -oxobenzenepentanoic acid via a Wittig reaction following the method used to obtain SA81.
  • SA86 is prepared from ( ⁇ S)- ⁇ -aminocyclopentaneacetic acid following the method used to obtain SA45.
  • Decylmagnesium bromide (6.0 mL, 1.0 M in Et 2 O, 6.0 mmol, 1.2 equiv) was then slowly added. The mixture was warmed to 22 °C and allowed to stir at that temperature for 4 h before saturated aq. NH 4 Cl (30 mL) was added. The resultant aqueous solution was extracted with EtOAc (3 ⁇ 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using hexane/Et 2 O (2:1) as eluent to give intermediate TSRI 2216.1PC SA90-1.
  • Carboxylic acid SA90 was prepared from SA90-1 via a Wittig reaction following the method used to obtain SA81.
  • CO 2 H [00213]
  • Carboxylic acid SA94 was prepared from citronellal following the method used to obtain SA10.
  • CO 2 H [00214] A 50 mL round-bottom flask was charged with mycophenolic acid (641 mg, 2.0 mmol, 1.0 equiv) and palladium on carbon (64.1 mg, 10 wt%) in MeOH (10 mL) at 22 °C. The flask was purged with hydrogen (H 2 balloon) for 5 min. The reaction mixture was allowed to stir at 22 °C for 16 h under H 2 atmosphere (H 2 balloon) before it was filtered through Celite ® .
  • HMRS [M+H] + calcd for C 12 H 16 NO 3 + 222.1130, found 222.1131.
  • the title compound was prepared according to general procedure A from SA17. Purification by flash column chromatography afforded A17 (225 mg, 89%, 1.1 mmol scale) as a white powder.
  • reaction mixture was heated at 125 °C until complete consumption of the substrate (2-20 hours) was observed (by TLC). Then the reaction was cooled to room temperature, the solvents were removed under reduced pressure and the residue was purified by flash column chromatography or preparative TLC to afford the desired product C.
  • Method B-D in Schlenk tubes under the protection of argon. The reaction mixture was degassed by two successive freeze-pump-thaw operations before heating.
  • Solution 1 A mixture of [Cu(MeCN) 4 ]BF 4 (3.2 mg, 0.010 mmol) and DCE (0.50 mL) was stirred at 22 ⁇ C for 5 min. (0.02 M)
  • Solution 2 A mixture of CuF 2 (2.0 mg, 0.020 mmol), CSA (23.2 mg, 0.10 mmol) and dioxane (10.0 mL) was heated at 80 ⁇ C for 30 min. (0.002 M)
  • Solution 3 A mixture of CuF 2 (2.0 mg, 0.020 mmol) and AcOH (10.0 mL) was heated at 80 ⁇ C for 5 min.
  • Solution 4 A mixture of CuF 2 (2.0 mg, 0.020 mmol) and TFA (0.80 mL) was heated at 80 ⁇ C for 5 min. (0.025 M) [00335]
  • [Cu(MeCN) 4 ]BF 4 shows relatively good solubility in DCE. Although we found that DCE could suppress the formation of lactone (Table S8, entry 2 and entry 10), when it was used as a cosolvent with dioxane ( ⁇ 1/10, v/v), the yield of lactone did not decrease, as shown by the low catalyst loading experiment that yields C29.
  • TSRI 2216.1PC N H2 [00348] The compound was prepared following the general procedure (Method B, 3 h, 0.5 mL dioxane and 40 ⁇ L TFA) and was purified by flash column chromatography using hexane/acetone (4:1) as eluent to give B13 (12.4 mg, 60%) as a white foam.
  • TSRI 2216.1PC NH 2 [00359] The compound was prepared following the general procedure (Method B, 2 h, 0.5 mL dioxane and 40 ⁇ L TFA) and was purified by flash column chromatography using hexane/acetone (2:1) as eluent to give B24 (14.5 mg, 49%) as a white powder.
  • the compound was prepared following the general procedure (Method B, 3 h, 0.5 mL dioxane and 45 ⁇ L AcOH) and was purified by flash column chromatography using hexane/acetone (3:1) as eluent to give B32 (10.3 mg, 51%) as a white powder.
  • the compound was prepared following the general procedure (Method B, 5 h, 10 mg CuF 2 , 0.5 mL dioxane and 45 ⁇ L AcOH) and was purified by pTLC (hexane/acetone 2:1) to give B54 (13.3 mg, 51%) as a white powder.
  • the compound was prepared following the general procedure (Method B, heated at 135 ⁇ C for 12 h, 0.5 mL dioxane and 45 ⁇ L AcOH) and was purified by flash column chromatography using hexane/acetone (4:1) as eluent to give B60 (24.7 mg, 77%) as a white powder.
  • the compound was prepared following the general procedure (Method B, 2 h, 0.5 mL dioxane and 11.6 mg CSA) and was purified by by flash column chromatography using CH 2 Cl 2 /acetone (5:1) as eluent to give B63 (32.8 mg, 70%) as a white foam.
  • B66 [00404] The compound was prepared following the general procedure (Method A, 6 h) and was purified by flash column chromatography using CH 2 Cl 2 /acetone (8:1) as eluent to give B66 (6.5 mg, 43%) as a white powder.
  • the compound was prepared following the general procedure (Method C, 0.5 mL AcOH and 40 ⁇ L TFA, 20 h) and was purified by flash column chromatography using hexane/ethyl acetate (10:1) as eluent to give C2 (12.3 mg, 73%) as a colorless oil.
  • Me OMe C 10 [00416] The compound was prepared following the general procedure (Method C, 3.2 mg [Cu(MeCN) 4 ]BF 4 , 0.5 mL dioxane and 40 ⁇ L TFA, 5 h) and was purified by flash column chromatography using hexane/ethyl acetate (8:1) as eluent to give C10 (13.0 mg, 71%) as a white powder.
  • N HTs [00428] The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 9.5 mg TsOH ⁇ H 2 O, 4 h)) and was purified by flash column chromatography using hexane/EtOAc (1:1) as eluent to give C22 (24.3 mg, 80%) as white powder.
  • the compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ⁇ L TFA, 2 h) and was purified by flash column chromatography using hexane/EtOAc (1:1) as eluent to give C25 (14.1 mg, 71%) as white powder.
  • Low catalyst loading experiment The compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ⁇ L solution 4, 24 h) and was purified by flash column chromatography using hexane/EtOAc (1:1) as eluent to give C25 (14.5 mg, 73%) as white powder.
  • the compound was prepared following the general procedure (Method C, 101 mg CuF 2 , 0.5 mL dioxane and 40 ⁇ L TFA, 24 h) and was purified by flash column chromatography using hexane/EtOAc (4:1) as eluent to give C37 (14.0 mg, 73%) as a white foam.
  • Me Me Me Me [00452] The compound was prepared following the general procedure (Method C, 3.2 mg [Cu(MeCN) 4 ]BF 4 , 0.5 mL dioxane and 40 ⁇ L TFA, 1 h) and was purified by pTLC (hexane/acetone 4:1) to give C45 (17.6 mg, 49%) as a white powder.
  • the compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 40 ⁇ L TFA, 3 h) and was purified by flash column chromatography using hexane/EA (20:1 ⁇ 10:1) as eluent to give D46 (10.0 mg, 55%) as a colorless oil.
  • the compound was prepared following the general procedure (Method C, 0.5 mL dioxane and 20 ⁇ L TFA, 12 h) and was purified by flash column chromatography using hexane/EA (5:1) as eluent to give C52 (21.5 mg, 45%, d.r.5:4) as a white powder.

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Abstract

La présente invention concerne des procédés de déshydrogénation et de lactonisation bimodales catalysées par le cuivre de N-méthoxyamides par abstraction de radicaux γ-C-H.
PCT/US2024/058036 2023-12-01 2024-12-02 Déshydrogénation et lactonisation bimodales catalysées par le cuivre de liaisons c(sp3)-h Pending WO2025117930A1 (fr)

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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
TAO LIU; MICHAEL C. MYERS; JIN€QUAN YU: "Copper‐Catalyzed Bromination of C(sp3)−H Bonds Distal to Functional Groups", ANGEWANDTE CHEMIE, VERLAG CHEMIE, HOBOKEN, USA, vol. 56, no. 1, 29 November 2016 (2016-11-29), Hoboken, USA, pages 306 - 309, XP072095726, ISSN: 1433-7851, DOI: 10.1002/anie.201608210 *
TROYANSKII E.I., I. V. SVITAN'KO, G. I. NIKISHIN: "Reaction of N-hydroxy(alkoxy)amidyl and amidoxy radicals in the sodium peroxydisulfate-copper chloride oxidizing system", BULLETIN OF THE ACADEMY OF SCIENCES OF THE USSR, DIVISION OF CHEMICAL SCIENCES., SPRINGER NEW YORK LLC, US, vol. 33, 1 September 1984 (1984-09-01), US , pages 1887 - 1891, XP093334236, ISSN: 0568-5230 *
ZHANG HONGWEI, ZHOU YULU, TIAN PEIYUAN, JIANG CUIYU: "Copper-Catalyzed Amide Radical-Directed Cyanation of Unactivated C sp 3 –H Bonds", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 21, no. 6, 15 March 2019 (2019-03-15), US , pages 1921 - 1925, XP093334237, ISSN: 1523-7060, DOI: 10.1021/acs.orglett.9b00553 *

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