WO2014018764A1 - Spiro - fused piperidine derivatives for use as inhibitors of the renal outer medullary potassium channel - Google Patents
Spiro - fused piperidine derivatives for use as inhibitors of the renal outer medullary potassium channel Download PDFInfo
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- WO2014018764A1 WO2014018764A1 PCT/US2013/052079 US2013052079W WO2014018764A1 WO 2014018764 A1 WO2014018764 A1 WO 2014018764A1 US 2013052079 W US2013052079 W US 2013052079W WO 2014018764 A1 WO2014018764 A1 WO 2014018764A1
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- 0 C=*N1CCC1 Chemical compound C=*N1CCC1 0.000 description 8
- BTUTXBBWOYIDDS-UHFFFAOYSA-N C=C1OCc2c1ccc1c2CCOC1CN(CC1)CCC1(CCN1C(CO2)=CC2=O)C1=O Chemical compound C=C1OCc2c1ccc1c2CCOC1CN(CC1)CCC1(CCN1C(CO2)=CC2=O)C1=O BTUTXBBWOYIDDS-UHFFFAOYSA-N 0.000 description 1
- PFAHXGOUGVDUTC-UHFFFAOYSA-N CC(C(OC1)=O)=C1N(CCC12CCN(CCc(c(C)c3CO4)ccc3C4=O)CC1)C2=O Chemical compound CC(C(OC1)=O)=C1N(CCC12CCN(CCc(c(C)c3CO4)ccc3C4=O)CC1)C2=O PFAHXGOUGVDUTC-UHFFFAOYSA-N 0.000 description 1
- PUEPIDZESLFCSE-UHFFFAOYSA-N CC(C(OC1)=O)=C1N(CCC12CCN(CCc(cc3)c(C)c(CO4)c3C4=C)CC1)C2=O Chemical compound CC(C(OC1)=O)=C1N(CCC12CCN(CCc(cc3)c(C)c(CO4)c3C4=C)CC1)C2=O PUEPIDZESLFCSE-UHFFFAOYSA-N 0.000 description 1
- KENAEDJVZYYZBV-UHFFFAOYSA-N O=C(C1(CC2)CCNCC1)N2C(CO1)=C(C2CC2)C1=O Chemical compound O=C(C1(CC2)CCNCC1)N2C(CO1)=C(C2CC2)C1=O KENAEDJVZYYZBV-UHFFFAOYSA-N 0.000 description 1
- OGCLAMFWJOMCGL-UHFFFAOYSA-N O=C(C1(CC2C3CC3)CCNCC1)N2C(CO1)=CC1=O Chemical compound O=C(C1(CC2C3CC3)CCNCC1)N2C(CO1)=CC1=O OGCLAMFWJOMCGL-UHFFFAOYSA-N 0.000 description 1
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Definitions
- ROMK Renal Outer Medullary Potassium channel
- ROMK participates in potassium recycling across the luminal membrane which is critical for the function of the Na + /K + /2C1 " co-transporter, the rate- determining step for salt reuptake in this part of the nephron.
- ROMK provides a pathway for potassium secretion that is tightly coupled to sodium uptake through the amiloride- sensitive sodium channel (see Reinalter, S.C., et al., Pharmacotyping of hypokalaemic salt-losing tubular disorders, Acta Physiol Scand, 2004, 181(4): p.
- ROMK channel also referred to herein as inhibitors of ROMK or ROMK inhibitors
- ROMK inhibitors are expected to represent novel diuretics for the treatment of hypertension and other conditions where treatment with a diuretic would be beneficial with potentially reduced liabilities (i.e., hypo- or hyperkalemia, new onset of diabetes, dyslipidemia) over the currently used clinical agents (see Lifton, R.P., A.G. Gharavi, and D.S. Geller, Molecular mechanisms of human hypertension, Cell, 2001, 104(4): p. 545-56).
- Patent application publication number WO2010/129379 published November 11, 2010 having common representative Merck Sharp & Dohme Corp., (also published as
- R5 and R6 are independently -H, -Cl-6 alkyl, -C3-6 cycloalkyl, -CF3, -CHF2, -CH2F or -CH2OH;
- X is -H, -OH,-OCl-3alkyl, -F, oxo, NH 2 or-CH3; and
- Xl is -H or -CH3.
- Patent application publication number WO2012/058134 published May 3, 2012, having common representative Merck Sharp & Dohme Corp., describes ROMK inhibitors having the generic formula:
- a and B are mono and/or bicyclic aromatic groups
- R2 is -H, -Cl-6 alkyl, -C3-6 cycloalkyl, CF3, -CH2OH, or -CO2R, or R2 can be joined to R1 or RlOa to form a ring
- R3 is -H, -Cl-6 alkyl, -C3-6 cycloalkyl, -OH, -F, -OCl-3 alkyl, or -CH2OH, or R3 can be joined to RlOb to form a ring.
- Patent application publication number WO2012/058116 published May 3, 2012, having common representative Merck Sharp & Dohme Corp., describes ROMK inhibitors having the
- R5 and R6 are independently -H, -Ci-6 alkyl or -C(0)OCi-3alkyl; and X, X 1 , Y and Y 1 are independently -H or-Ci-galkyl; or Yl can be joined together with Z2 to form a fused ring system.
- the compounds of Formula I and salts thereof of this invention are selective inhibitors of the ROMK channel and could be used for the treatment of hypertension, heart failure and other conditions where treatment with a diuretic or natriuretic would be beneficial.
- the present invention provides compounds of Formula I
- the compounds of Formula I are inhibitors of the ROMK (Kir 1.1) channel.
- the compounds of Formula I could be used in methods of treatment, inhibition or amelioration of one or more disease states that could benefit from inhibition of ROMK.
- the compounds of this invention could be used in methods of treatment which comprise administering a therapeutically or prophylactically effective amount of a compound of Formula I to a patient in need of a diuretic and/or natriuretic agent. Therefore, the compounds of Formula I could be valuable pharmaceutically active compounds for the therapy, prophylaxis or both of medical conditions, including, but not limited to, cardiovascular diseases such as hypertension and heart failure as well as chronic kidney disease, and conditions associated with excessive salt and water retention.
- the compounds of this invention could further be used in combination with other therapeutically effective agents, including but not limited to, other drugs which are useful for the treatment of hypertension, heart failure and conditions associated with excessive salt and water retention.
- the invention furthermore relates to processes for preparing compounds of Formula I, and pharmaceutical compositions which comprise compounds of Formula I.
- the present invention is directed to compounds having structural Formula I:
- R1 is -H, halo particularly -F, -OH, or -OCl-3alkyl particularly -OCH3;
- n is an integer selected from zero (R3b is absent) and 1 (R3b is present);
- n is an integer selected from 1 or 2;
- R.3a and R3b are joined together with the carbon to which they are both attached to form
- R2 and R3a can be joined together with the carbons to which they are each
- R5 is (a) -H, (b) halo, particularly -CI or -F, (c) -Cl-3alkyl optionally substituted with
- R6 is -H or -Cl-3alkyl
- R7 is -H or -Cl-3alkyl optionally substituted with -OH, -OCH3 or 1 to 3 of-F;
- R7 is -H or -C 1 -3alkyl
- R7a and R7b are joined together with the carbon to which they are both attached to form
- R8 is -H, halo particularly-F, or -Cl-3alkyl
- R9 is -H, -F, -OH, -OCi_3alkyl, -C3 ⁇ 4OH, -NH-R13 or ;
- RlO is -H, halo, -CN, -C3_4cycloalkyl, or -Ci_3alkyl optionally substituted with 1 to 3 of -F; or R9 is -O- and is joined together with RlO to represent -CH2-CH2-O- ; Rll is -H, -CH2OH, -CH2OCH3, or -Ci_3alkyl optionally substituted with 1 to 3 of-F;
- Rll and Rl2 are joined together to represent -CH2-CH2- , -CH2-N(CH3)-CH2- or
- Rl3 is -H, -(CH 2 )o-2-C3-6cycloalkyl, -(CH 2 )i_2-OC3-6cycloalkyl, -(CH 2 )i.2-OCi-3alkyl,
- the dashed bond (“ ”) represents a single, double or aromatic bond, provided that
- m is 1 (which includes but is not limited to compounds wherein R2 and R3a are joined to represent cyclopropyl fused to the pyrrolidine ring), or
- n 1 and m is 1, and each of the variables Rl, R2, R3a R3b R4 R5 ? R6 ? R7a R8 ? R9 RIO, Rl 1, Rl2 and Rl3 and all other variables therein are as defined in Formula I.
- n 1 and m is zero, and each of the variables Rl, R2, R3a R4 R5, R6, R7a R8, R9, RIO, R11, Rl2 and Rl3 and all other variables therein are as defined in Formula I, and wherein the double bond between R2 and R3a represents a non-aromatic double bond, or an aromatic bond when R2 and R3a are joined together with the carbons to which they are each attached to form a phenyl ring.
- n 2 and m is 1, and each of the variables Rl, R2, R3a ? R3b R4 ? R5, R6, R7a ? R8, R9, RIO, Rl 1, Rl2 and Rl3 and all other variables therein are as defined in Formula I.
- Rl is -H, -F, -OH or -OCH3;
- n is an integer selected from zero (R3b is absent) and 1 (R3b is present);
- n is an integer selected from 1 or 2;
- R3a and R3 are joined together with the carbon to which they are both attached to form cyclopropyl or cyclobutyl;
- R2 and R3a can be joined together with the carbons to which they are each
- R5 is -H, -CI, -F, -Ci-3alkyl, -C3_6cycloalkyl or heterocycle optionally substituted with -F, -CI or -Ci_3alkyl;
- R6 is -H or -Ci_3alkyl
- R7a is -H or -Ci_3alkyl optionally susbtituted with -OH, -OCH3 or 1 to 3 of -F;
- R8 is -H, -F or -Ci_3alkyl
- R9 is -H, -F, -OH, -OCl-3alkyl, -C3 ⁇ 4OH, -NH-R13 or
- RIO is -H, halo, -CN, -C3-4cycloalkyl, or -Cl-3alkyl optionally substituted with 1 to 3 of-F; or R9 is -O- and is joined together with RIO to represent -CH2-CH2-O- ;
- Rll is -H, -CH2OH, -CH2OCH3, or -Cl-3alkyl optionally substituted with 1 to 3 of-F;
- Rl2 is -H, -CH2OH, -CH2OCH3, or -Cl-3alkyl optionally substituted with 1 to 3 of-F;
- Rll and Rl2 are joined together to represent -CH2-CH2- , -CH2-N(CH3)-CH2- or
- Rl3 is -H, -(CH2)o-2-C3-6cycloalkyl, -(CH2)i_2-OC3-6cycloalkyl, -(CH2)i_2-OCl-3alkyl, -(CH2)i-2-CN, -C(0)OCl-3alkyl, -SO2CH3 or -Cl-3alkyl optionally substituted with one to three of-F; and
- n 2 and the dashed bond is a single bond and m is 1 , or n is 1 and the dashed bond is a single bond and m is 2, or the dashed bond is a double bond and m is 1;
- R1 is -H, -F, -OH or -Cl- 3alkyl;
- R5 is -H or -Cl-3alkyl;
- R8 is -H or -Cl-3alkyl;
- R9 is -OH, -OCl-3alkyl or - NHR13;
- RIO is as defined;
- Rll and Rl2 are -H; and all other variables are as defined in Formula I.
- compounds of Formula I wherein the dashed bond represents a double bond or an aromatic bond.
- Formulas II and IV depict examples of embodiments wherein the dashed bond is a single bond.
- R1 is H or F, and more particularly it is -H.
- R.3a is -H, -Ci_3alkyl, cyclopropyl, and more particularly it is -H or -CH3.
- R.3b is -H or -Ci_3alkyl, and more particularly it is -H, or R3b is absent when the dashed bond is a double bond or an aromatic bond.
- R5 is (a) -H, (b) halo, and particularly -CI or -F, (c) -Ci_3alkyl (d) -C3_6cycloalkyl, and more particularly it is -H or -CH3.
- R6 is -H or -CH3, and more particularly it is -H.
- R7a is -H or -Ci_3alkyl optionally substituted with -OH, -OCH3 or 1 to 3 of-F, and more particularly it is -H or -CH3.
- R7b is -H or -Ci_3alkyl, and more particularly it is -H.
- RH is -H or -Ci_3alkyl, and more particularly it is -H.
- Rl2 is -H or -Ci-3 alkyl, and more particularly it is -H; or RH and Rl2 are joined together to represent -CH2-CH2-, -CH2-N(CH3)-CH2- or -CH2OCH2-.
- R.13 is -H or -Ci_3alkyl, and more particularly it is -H.
- Embodiment B In a class thereof are compounds of Embodiment A, referred to as Embodiment B, wherein R1 is -H; R2 is -H at each occurrence; R3b is -H (for compounds of Formula I, II or IV); R6 is -H; R8 is -H; Rll is -H; and Rl2 is -H.
- alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout the specification.
- Cycloalkyl is a cyclized alkyl ring having the indicated number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- Halo means -F, -CI, -Br, or -I.
- Heterocycle is intended to include pyridyl (all isomers), pyrazinyl, pyridazinyl or pyrimidinyl.
- double bond refers to a covalent bond where two pairs of electrons are shared between two atoms.
- aromaticity is likewise well-known in the art, as exemplified by benzene and phenyl which are commonly drawn as having 3 alternating double bonds, but may also be considered as having carbon-carbon bonds which are each a hybrid of a single bond and a double bond.
- an "aromatic bond” refers to the aromatic nature of the double bond between -C(R2)- and -C(R3a). when R2 and R3a are joined together to form a phenyl ring fused to the pyrrolidinyl ring as defined in Formulas I, III and V.
- variables depicted in a structural formula with a "floating" bond, such as R$, are permitted on any available carbon atom in the ring to which the variable is attached.
- the compounds of Formula I may have one or more chiral (asymmetric) centers.
- the present invention encompasses all stereoisomeric forms of the compounds of Formula I. Centers of asymmetry that are present in the compounds of Formula I can all independently of one another have (R) or (S) configuration.
- bonds to a chiral carbon are depicted as straight lines in the structural Formulas of the invention, or when a compound name is recited without an (R) or (S) chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of each such chiral carbon, and hence each enantiomer or diastereomer and mixtures thereof, are embraced within the Formula or by the name.
- the production of specific stereoisomers or mixtures thereof may be identified in the Examples where such stereoisomers or mixtures were obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof from being within the scope of this invention.
- the invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios.
- enantiomers are a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios.
- the invention includes both the cis form and the trans form as well as mixtures of these forms in all ratios.
- the preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis.
- a derivatization can be carried out before a separation of stereoisomers.
- the separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formula I or it can be done on a final racemic product.
- Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Alternatively, absolute stereochemistry may be determined by
- VCD Vibrational Circular Dichroism
- the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
- the present invention is meant to include all suitable isotopic variations of the compounds of Formula I.
- different isotopic forms of hydrogen (H) include protium (IF!) and deuterium (3 ⁇ 4).
- Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
- Isotopically-enriched compounds within Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the
- the invention also includes the corresponding pharmaceutically acceptable salts.
- the compounds of Formula I which contain acidic groups can be used according to the invention as, for example but not limited to, alkali metal salts, alkaline earth metal salts or as ammonium salts.
- alkali metal salts alkaline earth metal salts or as ammonium salts.
- salts include but are not limited to sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
- Compounds of Formula I which contain one or more basic groups i.e.
- the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula I by customary methods which are known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts.
- the present invention also includes all salts of the compounds of Formula I which, owing to low
- physiological compatibility are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of
- compounds of the present invention may exist in amorphous form and/or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula I are intended to be included within the scope of the present invention.
- some of the compounds of the instant invention may form solvates with water (i.e., a hydrate) or common organic solvents.
- solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this invention, along with un-solvated and anhydrous forms.
- esters can optionally be made by esterification of an available carboxylic acid group or by formation of an ester on an available hydroxy group in a compound.
- labile amides can be made.
- Pharmaceutically acceptable esters or amides of the compounds of this invention may be prepared to act as pro-drugs which can be hydrolyzed back to an acid (or -COO- depending on the pH of the fluid or tissue where conversion takes place) or hydroxy form particularly in vivo and as such are encompassed within the scope of this invention.
- Examples of pharmaceutically acceptable pro-drug modifications include, but are not limited to, -Ci_6alkyl esters and -Ci_6alkyl substituted with phenyl esters.
- the compounds within the generic structural formulas, embodiments and specific compounds described and claimed herein encompass salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms thereof and any combination of these forms, as well as the salts thereof, pro-drug forms thereof, and salts of pro-drug forms thereof, where such forms are possible unless specified otherwise.
- the compounds of Formula I according to the invention are inhibitors of ROMK, and therefore could be used as diuretic and/or natriuretic agents.
- ROMK inhibitors may be used to help to increase urination and increase urine volume and also to prevent or reduce reabsorption of sodium in the kidneys leading to increased excretion of sodium and water. Therefore, the compounds could be used for treatment or prophylaxis or both of disorders that benefit from increased excretion of water and sodium from the body. Accordingly, the compounds of this invention could be used in a method for inhibiting ROMK comprising administering a compound of Formula I in a ROMK-inhibitory effective amount to a patient in need thereof. This also encompasses the use of the compounds for inhibiting ROMK in a patient comprising
- ROMK ROMK
- this invention also relates to the use of the compounds of Formula I or salts thereof to validate in vitro assays, for example but not limited to the Thallium Flux and
- the compounds of this invention could be used in a method for causing diuresis, natriuresis or both, comprising administering a compound of Formula I in a therapeutically effective amount to a patient in need thereof. Therefore, the compounds of Formual I of this invention could be used in methods for treatment of, prevention of or reduction of risk for developing medical conditions that benefit from increased excretion of water and sodium, such as but not limited to one or more of hypertension, such as essential hypertension (also known as primary or idiopathic hypertension) which is a form of hypertension for which no cause can be found, heart failure (which includes both acute heart failure and chronic heart failure, the latter also known as congestive heart failure) and/or other conditions associated with excessive salt and water retention.
- hypertension such as essential hypertension (also known as primary or idiopathic hypertension) which is a form of hypertension for which no cause can be found
- heart failure which includes both acute heart failure and chronic heart failure, the latter also known as congestive heart failure
- the compounds could also be used to treat hypertension which is associated with any of several primary diseases, such as renal, pulmonary, endocrine, and vascular diseases, including treatment of patients with medical conditions such as heart failure and/or chronic kidney disease.
- the compounds of Formula I could be used in methods for treatment of, prevention of or reduction of risk for developing one or more disorders such as pulmonary hypertension, particularly pulmonary arterial hypertension (PAH), cardiovascular disease, edematous states, diabetes mellitus, diabetes insipidus, post-operative volume overload, endothelial dysfunction, diastolic dysfunction, systolic dysfunction, stable and unstable angina pectoris, thromboses, restenosis, myocardial infarction, stroke, cardiac insufficiency, pulmonary hypertonia, atherosclerosis, hepatic cirrhosis, ascitis, pre-eclampsia, cerebral edema,
- PAH pulmonary arterial hypertension
- cardiovascular disease edematous states
- diabetes mellitus diabetes
- nephropathy glomerulonephritis, nephrotic syndrome
- acute kidney insufficiency chronic kidney insufficiency (also referred to as chronic kidney disease, or more generally as renal impairment)
- chronic kidney disease also referred to as chronic kidney disease, or more generally as renal impairment
- acute tubular necrosis hypercalcemia, idiopathic edema, Dent's disease, Meniere's disease, glaucoma, benign intracranial hypertension, and other conditions for which a diuretic or natriuretic or both would have therapeutic or prophylactic benefit.
- the compounds of the invention may be administered to a patient having, or at risk of having, one or more conditions for which a diuretic or natriuretic or both would have therapeutic or prophylactic benefit such as those described herein.
- the compounds of Formula I may potentially have reduced liabilities (for example, hypo- or hyperkalemia, new onset of diabetes, dyslipidemia, etc.) over currently used clinical agents. Also the compounds may have reduced risk for diuretic tolerance, which can be a problem with long-term use of loop diuretics.
- compounds that are ROMK inhibitors can be identified as those compounds which, when tested, have an IC50 of 5 ⁇ or less, preferably 1 ⁇ or less, and more preferably
- Electrophysiology Assay These assays are described in more detail further below.
- the dosage amount of the compound to be administered depends on the individual case and is, as is customary, to be adapted to the individual circumstances to achieve an optimum effect. Thus, it depends on the nature and the severity of the disorder to be treated, and also on the sex, age, weight and individual responsiveness of the human or animal to be treated, on the efficacy and duration of action of the compounds used, on whether the therapy is acute or chronic or prophylactic, or on whether other active compounds are administered in addition to compounds of Formula I. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is expected that the compound will be administered chronically on a daily basis for a length of time appropriate to treat or prevent the medical condition relevant to the patient, including a course of therapy lasting days, months, years or the life of the patient.
- a daily dose of approximately 0.001 to 100 mg/kg, preferably 0.001 to 30 mg/kg, in particular 0.001 to 10 mg/kg (in each case mg per kg of bodyweight) is appropriate for administration to an adult weighing approximately 75 kg in order to obtain the desired results.
- the daily dose is preferably administered in a single dose or can be divided into several, for example two, three or four individual doses, and may be, for example but not limited to, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 2 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, etc., on a daily basis.
- the compound may be formulated for immediate or modified release such as extended or controlled release.
- patient includes animals, preferably mammals and especially humans, who use the instant active agents for the prohylaxis or treatment of a medical condition.
- Administering of the drug to the patient includes both self-administration and administration to the patient by another person.
- the patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for developing said disease or medical condition or developing long-term complications from a disease or medical condition.
- therapeutically effective amount is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
- a prophylactically effective amount is intended to mean that amount of a
- preventing refers to administering a compound to a patient before the onset of clinical symptoms of a condition not yet present in the patient. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of hypertension, and a prophylactically effective amount, e.g., for prevention or reduction of risk of myocardial infarction or prevention or reduction of risk for complications related to hypertension.
- the ROMK inhibitors may be administered via any suitable route of administration such as, for example, orally, parenterally, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
- parenteral as used herein includes subcutaneous injections, intravenous (IV), intramuscular, intrasternal injection or infusion techniques.
- Oral formulations are preferred for treatment of chronic indications such as hypertension or chronic heart failure, particularly solid oral dosage units such as pills, tablets or capsules, and more particularly tablets. IV dosing is preferred for acute treatment, for example for the treatment of acute heart failure.
- compositions comprised of a compound of Formula I and a pharmaceutically acceptable carrier which is comprised of one or more excipients or additives.
- An excipient or additive is an inert substance used to formulate the active drug ingredient.
- the pharmaceutical compositions of this invention containing the active ingredient may be in forms such as pills, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
- Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
- Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- the excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, mannitol, calcium phosphate or sodium
- granulating and disintegrating agents for example, corn starch, or alginic acid
- binding agents for example starch, gelatin or acacia
- lubricating agents for example, magnesium stearate, stearic acid or talc.
- compositions may also contain other customary additives, for example but not limited to, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.
- Oral immediate-release and time-controlled release dosage forms may be employed, as well as enterically coated oral dosage forms. Tablets may be uncoated or they may be coated by known techniques for aesthetic purposes, to mask taste or for other reasons. Coatings can also be used to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water or miscible solvents such as propylene glycol, PEGs and ethanol
- an oil medium for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
- Sweetening agents and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti -oxidant such as ascorbic acid.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
- therapeutically effective amount of a compound of this invention can be used for the preparation of a medicament useful for inhibiting ROMK, for causing diuresis and/or natriuresis, and/or for treating, preventing or reducing the risk for any of the medical conditions described herein, in dosage amounts described herein.
- the amount of active compound of Formula I and/or its pharmaceutically acceptable salts in the pharmaceutical composition may be, for example but not limited to, from about 0.1 mg to 1 g, particularly 0.1 mg to about 200 mg, more particularly from about 0.1 mg to about 100 mg, and even more particularly from about 0.1 to about 50 mg, per dose on a free acid/free base weight basis, but depending on the type of the pharmaceutical composition, potency of the active ingredient and/or the medical condition being treated, it could also be lower or higher.
- compositions usually comprise about 0.5 to about 90 percent by weight of the active compound on a free acid/free base weight basis.
- the compounds of Formula I inhibit ROMK. Due to this property, apart from use as pharmaceutically active compounds in human medicine and veterinary medicine, they can also be employed as a scientific tool or as aid for biochemical investigations in which such an effect on ROMK is intended, and also for diagnostic purposes, for example in the in vitro diagnosis of cell samples or tissue samples.
- the compounds of Formula I can also be employed as intermediates for the preparation of other pharmaceutically active compounds.
- One or more additional pharmacologically active agents may be administered in combination with a compound of Formula I.
- the additional active agent (or agents) is intended to mean a medicinal compound that is different from the compound of Formula I, and which is a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs, for example esterified forms, that convert to pharmaceutically active form after administration, and also includes free-acid, free-base and pharmaceutically acceptable salts of said additional active agents when such forms are sold commercially or are otherwise chemically possible.
- any suitable additional active agent or agents including but not limited to anti-hypertensive agents, additional diuretics, anti-atherosclerotic agents such as a lipid modifying compound, antidiabetic agents and/or anti-obesity agents may be used in any combination with the compound of Formula I in a single dosage formulation (a fixed dose drug combination), or may be
- thiazide-like diuretics e.g., hydrochlorothiazide (HCTZ or HCT); angiotensin converting enzyme inhibitors (e.g, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril); dual inhibitors of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) such as omapatrilat
- ACE angiotensin converting enzyme
- NEP neutral endopeptidase
- eprosartan e.g., eprosartan mesylate (TEVETAN®), irbesartan (AVAPRO®), losartan, e.g., losartan potassium (COZAAR®), olmesartan, e.g, olmesartan medoximil
- a thiazide-like diuretic such as hydrochlorothiazide (e.g., HYZAAR®, DIOVAN HCT®, ATACAND HCT®), etc.); potassium sparing diuretics such as amiloride HCl, spironolactone, epleranone, triamterene, each with or without HCTZ; carbonic anhydrase inhibitors, such as acetazolamide; neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon); aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors (e.g.
- urea derivatives of di- and tri-peptides See U.S. Pat. No. 5,116,835), amino acids and derivatives (U.S. Patents 5,095,119 and 5,104,869), amino acid chains linked by non-peptidic bonds (U.S. Patent 5,114,937), di- and tri-peptide derivatives (U.S. Patent 5,106,835), peptidyl amino diols (U.S. Patents 5,063,208 and 4,845,079) and peptidyl beta-aminoacyl aminodiol carbamates (U.S. Patent 5,089,471); also, a variety of other peptide analogs as disclosed in the following U.S.
- Patent 5,066,643 enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017; aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4- hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamid hemifumarate) SPP600, SPP630 and SPP635); endothelin receptor antagonists; vasodilators (e.g.
- calcium channel blockers e.g., amlodipine, nifedipine, verapamil, diltiazem, , felodipine, gallopamil, niludipine, nimodipine, nicardipine, bepridil, nisoldipine
- potassium channel activators e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam
- sympatholitics e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartate, nadolol, propranolol, sotalol, timolol
- alpha adrenergic blocking drugs e.g., doxazocin, prazocin or alpha methyldopa
- central alpha adrenergic agonists e.g. doxazocin, prazocin or alpha methyldopa
- peripheral vasodilators e.g. hydralazine
- nitrates or nitric oxide donating compounds e.g.
- lipid lowering agents e.g., HMG-CoA reductase inhibitors such as simvastatin and lovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drug form and function as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoA reductase inhibitors such as atorvastatin (particularly the calcium salt sold in LIPITOR®), rosuvastatin (particularly the calcium salt sold in CRESTOR®), pravastatin (particularly the sodium salt sold in PRAVACHOL®), and fluvastatin (particularly the sodium salt sold in LESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®), and ezetimibe in combination with any other lipid lowering agents such as the HMG-CoA reductase inhibitors noted above and particularly with simvastatin (VYTORIN®) or with atorvastatin calcium; niacin
- niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists
- metabolic altering agents including insulin sensitizing agents and related compounds for the treatment of diabetes such as biguanides (e.g., metformin), meglitinides (e.g., repaglinide, nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones also referred to as glitazones (e.g., pioglitazone, rosiglitazone), alpha glucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors, (e.g.,
- bromocriptine combination medications such as JANUMET® (sitagliptin with metformin), and injectable diabetes medications such as exenatide and pramlintide acetate; phosphodiesterase-5 (PDE5) inhibitors such as sildenafil (Revatio, Viagra), tadalafil (Cialis, Adcirca) vardenafil HC1 (Levitra); or with other drugs beneficial for the prevention or the treatment of the above- mentioned diseases including but not limited to diazoxide; and including the free-acid, free-base, and pharmaceutically acceptable salt forms, pro-drug forms (including but not limited to esters), and salts of pro-drugs of the above medicinal agents where chemically possible.
- PDE5 phosphodiesterase-5
- Compound IA which is substituted at the benzylic position with an OH group, can be prepared following the sequence detailed in Scheme 1. Coupling of epoxide 1 to spirocyclic amines 2 at elevated temperatures leads to the formation of alcohols IA (Nomura, Y. et al. Chemical & Pharmaceutical Bulletin, 1995, 43(2), 241-6). The reaction can be carried out with conventional heating, or by heating using a microwave apparatus. A number of solvents can be used in this reaction, for example, ethanol and 2-propanol. Spirocyclic amines may be free bases, or they may be salts, in which case a base such as triethylamine or N;N- diisopropylethylamine may be added.
- chiral HPLC separation of enantiomers or diastereomers of IA may be performed to provide single enantiomers or diastereomers.
- Aldhehydes or ketones 3 may be used in reductive alkylation reactions of spirocyclic amines 2 to afford ROMK inhibitors of the formula IB by using various reductive amination conditions (for example using sodium cyanoborohydride, sodium triacetoxy borohydride, or titanium tetra- isopropoxide, followed by sodium borohydride or sodium cyanoborohydride).
- the epoxides 1 (and single enatiomers (R)-l and (S)-l) can be prepared following the method detailed in Scheme 3.
- Treatment of 4 (where X is chloride, bromide, iodide, or trifluoromethane sulfonate) with commercially available potassium vinyl trifluoroborate (Molander, G.; Luciana, A. Journal of Organic Chemistry, 2005, 70(10), 3950-3956) under palladium catalyzed coupling conditions with an appropriate phosphine ligand gives rise to styrene 5 (Molander, G.; Brown, A. Journal of Organic Chemistry, 2006, 71(26), 9681-9686).
- styrenes 5 can be converted to the corresponding epoxides 1 under various epoxidation conditions, for example, with mCPBA (Fringuelli, F. et al. Organic Preparations and Procedures International, 1989, 21(6), 757-761).
- mCPBA Frringuelli, F. et al. Organic Preparations and Procedures International, 1989, 21(6), 757-761).
- the racemic epoxide 1 can be resolved under chiral HPLC chromatography conditions to afford its enantiomers, which can be used in place of 1 according to Scheme 1.
- enantiopure epoxides (R)-l or (S)-l can be prepared as shown in Scheme 4.
- 4 where X is bromide, iodide, or trifluoromethane sulfonate
- a suitable ligand for example Pd(OAc) 2 , DPPP
- Pd(OAc) 2 , DPPP a suitable ligand
- Enol ethers may be prepared using other methods known to the chemist.
- Treatment of the resulting enol ethers 7 with NBS or other similar reagents affords the corresponding bromomethyl ketones 8.
- Aldehydes 3A may be prepared in numerous ways, with two approaches described in Scheme 5. Treatment of 4 (where X is bromide, iodide, or trifluoromethane sulfonate) with bromo(l ,3-dioxolan-2-ylmethyl)zinc in the presence of an appropriate palladium catalyst and ligand, such as palladium(II) acetate and tri-t-butylphosphine-BF4 complex, provides the corresponding aryl l ,3-dioxolan-2-ylmethyl derivative 9. Then the aldehydes 3 A may be obtained by treatment with HC1 in the presence of water and an organic solvent. Alternatively, reaction of 4 (where X is bromide, iodide, or trifluoromethane sulfonate) with
- Oxidation for example with ozone, followed by dimethyl sulfide, provides aldehydes 3A.
- diamines or amino lactams (where R and R together represent a carbonyl group) 11, protected as appropriate (Greene, T.; Wuts, P. G. M. protective Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, NY 1991), can be coupled to furanone triflates or bromides 12 using a palladium catalyst and ligand, for example palladium acetate and 4,5-Bis(diphenylphosphino)- 9,9-dimethylxanthene.
- a palladium catalyst and ligand for example palladium acetate and 4,5-Bis(diphenylphosphino)- 9,9-dimethylxanthene.
- Spirocyclic amino lactams 11 A can be prepared in numerous ways, including those described in Scheme 7.
- Commercially available aminoesters 14 can be alkylated with
- bromoacetonitrile 15 using a base such as lithium diisopropylamide to afford nitrile intermediates 16.
- Reduction for example using platinum oxide and hydrogen, or Raney Nickel, produces lactams 11 A.
- aminoesters may be alkylated with allyl halides 17 using a base such as lithium diisopropylamide to furnish allyl intermediates 18.
- Oxidative cleavage employing, for example, osmium tetroxide and sodium periodate provides ketones and aldehydes 19.
- Reductive amination with tandem lactam cyclization to 11A can be accomplished in several ways, including by treatment with ammonium acetate and sodium cyanoborohydride in a solvent such as methanol, as shown.
- the subject compounds may be prepared by modification of the procedures disclosed in the Examples as appropriate. Starting materials are commercially available or made by known procedures or as illustrated. The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.
- reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents.
- the progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with E. Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC-MS).
- TLC analytical thin layer chromatography
- LC-MS liquid chromatography-mass spectrometry
- the analytical LC-MS system used consisted of a Waters ZQ platform with electrospray ionization in positive ion detection mode with an Agilent 1100 series HPLC with autosampler.
- the column was usually a Water Xterra MS C 18, 3.0 x 50 mm, 5 ⁇ .
- the flow rate was 1 mL/min, and the injection volume was 10 L.
- UV detection was in the range 210-400 nm.
- the mobile phase consisted of solvent A (water plus 0.06% TFA) and solvent B (acetonitrile plus 0.05% TFA) with a gradient of 100% solvent A for 0.7 min changing to 100% solvent B over 3.75 min, maintained for 1.1 min, then reverting to 100% solvent A over 0.2 min.
- Preparative HPLC purifications were usually performed using a mass spectrometry directed system. Usually they were performed on a Waters Chromatography Workstation configured with LC-MS System Consisting of: Waters ZQ single quad MS system with
- Electrospray Ionization Waters 2525 Gradient Pump, Waters 2767 Injector / Collector, Waters 996 PDA Detector, the MS Conditions of: 150-750 amu, Positive Electrospray, Collection Triggered by MS, and a Waters Sunfire C-18 5 micron, 30 mm (id) x 100 mm column.
- the mobile phases consisted of mixtures of acetonitrile (10-100%) in water containing 0.1%TFA. Flow rates were maintained at 50 mL/min, the injection volume was 1800 /zL, and the UV detection range was 210-400 nm. Mobile phase gradients were optimized for the individual compounds.
- Chiral analytical chromatography was usually performed on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA, or Chiralcel OJ columns (250 x 4.6 mm) (Daicel Chemical Industries, Ltd.) with noted percentage of either ethanol in hexane (%Et/Hex) or isopropanol in heptane (%IP A/Hep) as isocratic solvent systems.
- Abbreviations and acronyms used herein include: -C(0)CH3 (Ac); -OC(0)CH3 (OAc); acetic acid (AcOH; HO Ac); 1-chloroethylchloro formate (ACE-Cl); 2,2'-bis(diphenylphosphino)- ⁇ , ⁇ -binaphthyl (BINAP); t-butyloxycarbonyl (Boc or BOC); di-i-butyl dicarbonate ((BOQ2O, B0C2O); benzyloxycarbonyl (Cbz); Cyclopentyl methyl ether (CPME); Carbonyldiimidazole
- CDI Diethylaminosulfur trifluoride
- DAST Diethylaminosulfur trifluoride
- DBU 1,8- Diazabicyclo[5.4.0]undec-7-ene
- DCE Diethylaminosulfur trifluoride
- DCM dichloromethane
- DME dimethoxyethane
- DIBAL-H Diisobutylaluminium hydride
- DIEA N,N-diisopropylethylamine
- DIPEA DIPEA, Hunig's base
- DIP A di-isopropylamine
- dppf , DPPF
- DMP Dess-Martin Periodinane
- DMP 1,1,1 -Triacetoxy- 1 , 1 -dihydro- 1 ,2-benziodoxol- 3(lH)-one
- DMS dimethylsulfide
- Pd(dppf)Cl2 or PdCl2(dppf) is l, -Bis(diphenylphosphino)ferrocene]dichloropalladium(II) which may be complexed with CH2CI2; tetra-n-butylammonium fluoride (TBAF); tert- butyldimethylsilyl chloride (TBS-C1); triethylamine (TEA); trifluoroacetic acid (TFA); -SO2CF3
- Tf trifluoromethanesulfonic acid
- TfOH trifluoromethanesulfonic anhydride
- Tf 2- tetrahydrofuran
- TEDA Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
- X-Phos Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
- XtalFluor-E® Diethylaminodifluorosulfinium tetrafluoroborate
- Xantphos 4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene
- SM starting material
- RB round-bottom flask
- aqueous aq
- saturated aqueous saturated aqueous sodium chloride solution
- Brine medium pressure liquid chromatography
- HPLC high pressure liquid chromatography
- HPLC preparative HPLC
- FC liquid chromatography
- SFC supercritical fluid chromatography
- TLC thin layer chromatography
- MS liquid chromatography-mass spectrometry
- LC-MS, LCMS or LC/MS column volume (CV); room temperature (rt, r.t. or RT); hour(s) (h or hr); minute(s) (min);
- R t retention time
- CELITE® is a trademark name for diatomaceous earth
- SOLKA FLOC® is a trademark name for powdered cellulose.
- X or x may be used to express the number of times an action was repeated (e.g., washed with 2 x 200 mL IN HC1), or to convey a dimension (e.g., the dimension of a column is 30 x 250mm).
- a chiral center in a compound may exist in the "S" or “R” stereoconfigurations, or as a mixture of both.
- compounds having a chiral center were separated into single stereoisomers (for example, referred to as Isomer A and Isomer B, or faster/slower eluting isomers), or each was derived synthetically from a single isomer intermediate. Except for a defined chiral center in the parent mixture, absolute stereochemistry (R or S) of each of the separated isomers was not determined, unless specifically noted otherwise.
- Step A 5-(13-Dioxolan-2-ylmethyl)-2-benzofuran-l(3H)-one: A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-l(3H)-one (100 g, 470 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge.
- tri-t-butyl phosphonium tetrafluoroborate 500 mg, 1.72 mmol
- palladium (II) acetate 250 mg, 1.1 mmol
- 5-bromo-2-benzofuran-l(3H)-one
- bromo(l ,3-dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 °C for 5 h. Analysis by HPLC-MS indicated the reaction was not complete. The mixture was stirred at 85 °C for 5 more h. The mixture was then allowed to return to room temperature for overnight. 2-methylTHF (2L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgS0 4 , filtered, and concentrated.
- Step B (l-Oxo-l,3-dihydro-2-benzofuran-5-yl)acetaldehyde: 5-(l ,3-Dioxolan-2-ylmethyl)-2- benzofuran-l(3H)-one (61 g, 280 mmol) was combined with water (2.2 L) in a 5 L round bottomed flask equipped with a Claisen adapter, thermocouple, stir bar and nitrogen bubbler. Aqueous HCl solution (2M, 1.14 L, 2.29 mol) was added and the resulting mixture was heated at 40 °C for 8 h. Then the mixture was stirred overnight at room temperature. The mixture was extracted three times with 2 L of ethyl acetate.
- Step B 5-bromo-4-methyl-2-benzofuran-l(3H)-one: To a flask charged with (3-bromo-2- methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of thallium
- Step A 4-Methyl-5-prop-2-en-l-yl-2-benzofuran-l(3H -one: To a flask charged with 5-bromo- 4-methyl-2-benzofuran-l(3H)-one (320 mg, 1.409 mmol) and a stir bar was added allyl tri-n- butyltin (0.655 mL, 2.1 1 mmol), Pd(PPh 3 ) 4 (244 mg, 0.21 1 mmol), lithium chloride (179 mg, 4.23 mmol), and toluene (15 mL). The reaction was purged with nitrogen 2 times then was heated at reflux for 4 hours. The product was separated by silica gel chromatography to give 4- methyl-5-prop-2-en- 1 -yl-2-benzofuran- 1 (3H)-one.
- Step B (4-Methyl-l -oxo- 1 , 3 -dihydro-2-benzofuran-5 -yDacetaldehyde: A solution of the above olefin (220 mg, 1.2 mmol) in MeOH (20 mL) was cooled to -78 °C. To this solution was bubbled ozone until the reaction turned blue. Nitrogen was bubbled through the reaction to drive off excess ozone, followed by addition of DMS (0.870 mL, 1 1.7 mmol). The reaction was allowed to warm up to RT. The crude product was purified by flash chromatography to afford the title compound.
- Step A 5-ethenyl-4-methyl-2-benzofuran-l(3H)-one: 5 -Bromo-4-methyl-2-benzofuran- 1 (3H)- one (598 mg, 4.47 mmol), potassium vinyl trifluoroborate (507 mg, 2.23 mmmol), PdCl 2 (dppf)- CH 2 Cl 2 Adduct (182 mg, 0.223 mmmol), and TEA (0.622 mL, 4.47 mmol) were added to 10 mL ethanol in a 20 mL microwave tube. The tube was sealed and degassed, then heated to 140 °C for 20 min. Analysis by LC-MS showed product peak.
- the reaction mixture was diluted with ethyl acetate, washed with brine twice, dried and evaporated to dryness.
- the crude product was purified by MPLC chromatography using a 120g Redi-sep column and 0-80% EtOAc/Hexane solvent system to yield 5-ethenyl-4-methyl-2-benzofuran-l(3H)-one.
- Step B 4-methyl-5-oxiran-2-yl-2-benzofuran-l(3H -one: 5 -ethenyl-4-methyl-2-benzofuran- l(3H)-one (1.46 g, 8.38 mmol) was added to DCM (25 mL) at 0 °C then mCPBA (2.89 g, 16.8 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was washed once each with saturated aqueous Na 2 S203, NaHC0 3 , and brine. The organic layer was dried over Na 2 S0 4 , filtered, and evaporated to dryness.
- Racemic 4-methyl-5-oxiran-2-yl-2-benzofuran-l(3H)-one was resolved on a ChiralPak® AD-H column (5x25cm)under supercritical fluid chromatography (SFC) conditions on a Berger MGIII preparative SFC instrument.
- the racemate was diluted to 50 mg/mL in 1 : 1 DCM:MeOH.
- the separation was accomplished using 10% EtOH/C02, flow rate 200 mL/min, 100 bar, 25 °C. 500ul Injections were spaced every 2.12 mins.
- the resolution could also be achieved using a mobile phase of 8%>MeOH / 98% C0 2 with a flow rate of lOOmL/min.
- the sample was prepared by dissolving in methanol, 20mg/mL, and using a 1 mL volume per injection. After separation, the fractions were dried off via rotary evaporator at bath temperature 40°C.
- StepA 3-hydroxymethyl-2-methyl phenol: To a 5L 3 neck RB equipped with overhead stirrer was charged NaBH4 (87.0 g, 2.30 mol) and THF (3.0 L) and the resulting slurry was cooled to 10 °C. To the slurry was then added 3 -hydroxy-2 -methyl benzoic acid (175 g, 1.15 mol)
- the batch was cooled to ⁇ 10 °C then quenched with 1 N HC1 (1.5 L) to get a homogeneous solution (pH solution ⁇ 1), which was aged for 30 min and then the organic solvents were removed by rotary evaporation to approximately 1.8 L of total reaction volume (bath temperature was set to 50 °C; internal temp of concentrate after rotary evaporation was ⁇ 40 °C).
- the slurry was held at 45 °C for 30 min then cooled slowly to 15 °C.
- the solids were filtered and washed with cold (15 °C) water (2 x 300 mL), providing 3-hydroxymethyl-2-methyl phenol.
- Step B 4-Bromo-3-hydroxymethyl-2-methyl phenol: 3 -Hydroxymethyl-2 -methyl phenol (113.9 g, 824.0 mmol) was dissolved in a mixture of acetonitrile (850 mL) and trifluoroacetic acid
- the layers were separated.
- the aqueous layer was diluted with water (500 mL) and extracted with MTBE (1 L) + EtOAc (500 mL), and then MTBE (500 mL) + EtOAc (250 mL).
- the combined organic layers were washed with water (240 mL) and dried over sodium sulfate.
- the sodium sulfate was removed by filtration, washed with additional MTBE and concentrated under reduced pressure.
- MTBE (684 mL, 2 volumes) was added, and the suspension was heated to 40 °C to produce a homogeneous solution. The solution was allowed to cool to room temperature. Six volumes of heptane were added, and the supension was stirred overnight.
- Step C 5 -Hydroxy-4-methyl-3H-isobenzofuran- 1 -one : To a 2 L 3 neck flask equipped with overhead stirrer, N2 inlet, and condenser were charged 4-bromo-3-hydroxymethyl -2 -methyl phenol (100 g, 461 mmol), CuCN (83.0 g, 921 mmol), and DMF (500 mL). The solution was sparged with N 2 for 15 min then heated to 145 °C to obtain a homogeneous solution. The solution was aged at 145 °C for 2h, then the reaction mixture was cooled to 95 °C. 41.5 mL water was added (sparged with N 2 ), and the reaction aged for 20 h.
- Step D 4-methyl- 1 -oxo- 1 ,3 -dihydroisobenzofuran-5 -yl trifluoromethanesulfonate
- the biphasic mixture was filtered over SOLKA FLOC®, washing with additional dichloromethane, and transferred to a separatory funnel, whereupon it was diluted with additional water (300 mL). The layers were separated, and the organic layer was washed with water (500 mL) and 10% brine (200 mL).
- dichloromethane solution was dried over sodium sulfate, filtered and evaporated.
- the solid was adsorbed onto silica gel (27.5 g) and eluted through a pad of silica gel (271 g) with 25% ethyl acetate/hexanes.
- the resulting solution was concentrated under vacuum with the product crystallizing during concentration.
- the suspension was filtered, the solid washed with heptane and dried under vacuum and nitrogen, providing trifluoromethanesulfonic acid 4-methyl- 1-oxo- l,3-dihydro-isobenzofuran-5-yl ester.
- HBr (48 %, 0.241 mL) was added and the reaction was aged at RT for approximately 1 h after which 236 mL water was then added to the batch. A water bath is used to maintain temp at 20 °C. Another 315 mL of water was added (solvent composition 1 :2 THF: water) and the slurry was cooled to 15 °C. The resulting solids were filtered and washed with cold 1 :2 THF:water (15 °C): 150 mL displacement wash followed by 100 mL slurry wash. The solids were dried under vacuum at RT to provide 5-(2-bromo-acetyl)-4-methyl-3H-isobenzofuran-l-one.
- KRED MIF-20 (2.44 g) (available from Codexis, Inc., 200 Penobscot Drive, Redwood City, CA 94063, www.codexis.com, tel. 1- 650-421-8100) was added to the erlenmeyer flask and the mixture was swirled to dissolve the solids. The resulting solution was added to the 5 L round bottom, which was then heated to 28 °C and aged for 6 hours, at which point the reaction was cooled to RT and triethylamine (50.2 mL, 360 mmol) was added. The resulting solution was aged at 40 °C for 1 h. The light slurry solution was cooled to RT, after which 122 g NaCl was added.
- IP Ac isopropyl acetate
- the aqueous layer was re-extracted with 400 mL IP Ac and the combined organics were washed with 400 mL 20 % brine solution, dried over MgS0 4 , filtered and concentrated by rotary evaporation. The resulting solids were taken up in 100 mL IP Ac (thick slurry). Hexanes were added (400 mL) and the suspension aged at RT then filtered and washed w/ 5: 1 HexanesTPAc solution (150 mL).
- Step A (R)-5 -(2 -Hydroxy- 1 -methoxyethyl)-4-methylisobenzofuran- 1 (3H)-one: To a solution of (5)-4-methyl-5-(oxiran-2-yl)isobenzofuran-l(3H)-one (2.00 g, 10.5 mmol) in MeOH (20 mL) was added p-toluenesulfonic acid monohydrate (0.100 g, 0.526 mmol). After heating at 80°C for 48 h, the reaction mixture was cooled to RT and then concentrated. The crude product was purified by column chromatography eluting with 0- 45% EtOAc/Hexane. LC-MS (IE, m/z): 223.2 (M+l) + .
- Step B (i?)-2-Methoxy-2-(4-methyl- 1 -oxo- 1 ,3 -dihydroisobenzofuran-5 -yOacetaldehyde : (R)-5- (2-Hydroxy-l-methoxyethyl)-4-methylisobenzofuran-l(3H)-one (500 mg, 2.25 mmol) was dissolved in DCM (10 mL) and treated with Dess-Martin periodinane (954 mg, 2.25 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight. The crude product was used directly. LC-MS (IE, m/z): 239.2 (M+H 2 0+1) + .
- Step A (E)-4-Methyl-5-(prop-l-en-l-vnisobenzofuran-l(3H)-one: To Pd(dppf)Cl 2 (0.220 g,
- Step B 5-(l ,2-Dihydroxypropyl)-4-methylisobenzofuran-l(3H)-one: To (E)-4-methyl-5-(prop-l- en-l-yl)isobenzofuran-l(3H)-one (300 mg, 1.59 mmol) in acetonitrile/water (10/1 , 18 mL) was added NMO (243 mg, 2.07 mmol) and potassium osmate(VI) dihydrate (29.4 mg, 0.080 mmol) at 0 °C. The reaction mixture was allowed to warm to rt and stirred at rt for 2 h. TLC showed the reaction completed. The reaction mixture was filtered through a pad of silica gel, rinsed with 10% MeOH/DCM. The crude product was purified with column chromatography (0-10%
- Step C 5-(2-hydroxyethyl)-6-iodo-2-benzofuran-l(3H)-one: To a cooled (0 °C) solution of 5- (2-hydroxyethyl)-2-benzofuran-l(3H)-one (9.00 g, 50.6 mmol) in 100 mL of TfOH was added NIS (12.5 g, 55.6 mmol), then the mixture was stirred at 0 °C for 2 hrs and then poured into ice- water (500 mL). The solution was extracted three times with 500 mL of EtOAc and the combined organic layers were washed with saturated NaHC0 3 and brine, dried over anhydrous sodium sulfate, filtered and concentrated.
- Step D 5-(2-hydroxyethyl)-6-methyl-2-benzofuran-l(3H -one: To a flask charged with 5-(2- hydroxyethyl)-6-iodo-2-benzofuran-l(3H)-one (6.00 g, 19.7 mmol) and a stir bar was added Pd 2 (dba) 3 (452 mg,0.493 mmol), PPh 3 (1 g, 4 mmol) and NMP (50 mL). The mixture was purged with N 2 and heated to 50 °C for 10 min, followed by addition of Cul (375 mg, 1.97 mmol).
- Step E 2-(6-methyl-l-oxo-l,3-dihydro-2-benzofuran-5-yl)ethyl methanesulfonate: To a solution of 5-(2-hydroxyethyl)-6-methyl-2-benzofuran-l(3H)-one (1.20 g, 6.25 mmol) and TEA (2.5 g, 25 mmol) in DCM (100 mL) was added MsCl (1.40 g, 12.5 mmol) at 0 °C. The mixture was stirred at ambient temperature overnight, then was washed with water and brine. The organic layer was dried and concentrated to dryness. The collected title compound was used for the next step without any purification.
- Step F 5-ethenyl-6-methyl-2-benzofuran-l(3H)-one: To a mixture of 2-(6-methyl-l-oxo-l,3- dihydro-2-benzofuran-5-yl)ethyl methanesulfonate (2.00 g, 7.41 mmol) and TEA (5 mL) in DCM (50 mL) was added DBU (5 mL) slowly at 0 °C. The mixture was stirred at r.t. overnight, and then was diluted with 50 mL of DCM, washed with 2 N HC1 in three times and brine. The organic layer was dried and concentrated to dryness. The residue was purified by prep-TLC to give 5-ethenyl-6-methyl-2-benzofuran- 1 (3H)-one.
- Step G 6-methyl-5-oxiran-2-yl-2-benzofuran-l(3H)-one: To a solution of 5-ethenyl-6-methyl- 2-benzofuran-l(3H)-one (1.00 g, 5.75 mmol) in 50 mL of DCM was slowly added mCPBA (3.50 g, 17.4 mmol) in 50 mL of DCM at 0 °C. The mixture was warmed to room temperature, and stirred for 2 days. The mixture was washed with aqueous Na 2 S0 3 until KI indicator paper didn't change color. The organic layer was washed with brine and then concentrated. The residue was purified via silica column to give the title compound. LC-MS M+l (calc. 191, found 191).
- Step A 5-bromo-4-iodo-2-benzofuran-l(3H]-one: To a solution of 5-bromo-2-benzofuran- l(3H)-one (5.00 g, 23.5 mmol) at 0 °C in TfOH (100 mL) was added NIS (5.55 g, 24.6 mmol). The mixture was stirred at room temperature over night; LC analysis of the reaction mixture indicated completion of the reaction. The reaction mixture was then poured slowly into ice-water (1 L) with stirring.
- Step B 5-bromo-4-prop-2-en-l-yl-2-benzofuran-l(3H)-one: A mixture of 5-bromo-4-iodo-2- benzofuran- 1 (3H]-one (2.42 g, 7.13 mmol), allyltributyltin (2.36 g, 7.13 mmol), LiCl (1.50 g, 35.7 mmol) and Pd (PPh 3 ) 4 (200 g, 0.173 mmol) in toluene (50 mL) was heated at 90-100 °C under N 2 overnight; LC indicated that reaction had gone to completion, to the solution was poured EtOAc (100 mL) and washed with brine. The organic layer was dried over Na 2 S0 4 , filtered and concentrated to dryness, absorbed into silica gel and was then separated over silica gel column to give the title compound.
- Step C 5 -bromo-4-(2-hydroxyethyl)-2-benzofuran- 1 (3H)- one : To a solution of 5-bromo-4- prop-2-en-l-yl-2-benzofuran-l(3H)-one (1.27 g, 5.02 mmol) in MeOH (50 mL) and DCM (50 mL) was bubbled O3 at -78 °C until the solution turned blue; excess ozone was removed on high vacuum. After the solution's color changed to colorless, NaBH 4 (0.8 g, 20 mmol) was added to the reaction mixture and it was subsequently stirred at room temperature for 30 min. LC and TLC indicated that reaction had gone to completion.
- Step D 5-ethenyl-4-(2-hydroxyethyl)-2-benzofuran-l(3H)-one: A mixture of 5-bromo-4-(2- hydroxyethyl)-2-benzofuran-l(3H)-one (0.460 g, 1.78 mmol), tributyl(vinyl)tin (0.676 g, 2.13 mmol), LiCl (0.224 g, 5.33 mmol) and Pd (PPh 3 )4 (0.10 g, 0.087 mmol) in toluene (50 mL) was heated at 100-110 °C under N 2 overnight after which TLC indicated that the reaction had gone to completion.
- Step E 4-(2-hydroxyethyl)-5-oxiran-2-yl-2-benzofuran-l(3H)-one: 5-Ethenyl-4-(2-hydroxyethyl)-2- benzofuran-l(3H)-one (1.2 g, 5.9 mmol) was added to a flask containing a stir bar. To the flask was thi added dichloromethane (20 mL).
- Step F (3-oxo-3,6,8,9-tetrahydro-lH-furo[3,4-f
- Step A ethyl 4-bromo-2-methyl-3-oxobutanoate: To a solution of ethyl 2-methyl-3-oxobutanoate (5.05 g, 35.0 mmol) in water (10 mL) at 0 °C was added bromine (1.81 mL, 35.0 mmol) dropwise over 2h. The resulting solution was stirred at rt for 16 h. The reaction mixture was extracted with ethyl acetate, the organic phase was dried over sodium sulfate and concentrated to give ethyl 4-bromo-2-methyl-3-oxobutanoate.
- 1 HNMR 500 MHz, CDC1 3 ), 54.322-4.274 (m, 2H), 2.455(s, 2H), 1.991 (s, 3H), 1.337-1.309 (t, 3H).
- Step B 4-hydroxy-3-methylfuran-2(5H -one: Ethyl 4-bromo-2-methyl-3-oxobutanoate (7.81 g, 35 mmol) was treated with hydrogen bromide (0.040 mL, 48%, 0.35 mmol) and the mixture was heated at 100 °C for 6 h. The precipitate was collected by filtration followed by washing with ethyl acetate to give 4-hydroxy-3-methylfuran-2(5H)-one.
- 1 HNMR 500 MHz, CDC1 3 ), 54.595 (s, 2H), 3.314 (s, 1H), 1.668 (s, 3H).
- Step C 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate: To a solution of 4- hydroxy-3-methylfuran-2(5H)-one (400 mg, 3.51 mmol) in dichloromethane (10 mL) at -78 °C was added 2,6-lutidine (0.612 mL, 5.26 mmol) and triflic anhydride (0.711 mL, 4.21 mmol) dropwise. The reaction temperature was maintained at -78 °C for 0.5 h before being warmed to rt for lh.
- Step B tert-Butyl 4-formypiperidinecarboxylate: The solution of 200 mL of DMSO in CH 2 C1 2 cooled to -78 °C, 118 mL of (COCl) 2 was added drop-wise. Then 255 g of tert-butyl 4-
- Step D tert-Butyl 3,8-diazaspiro[5,51undecane-3-carboxylate: 73 ⁇ 4rt-butyl 4-formyl-4- propylpiperidinecarboxylate (30 g) was dissolved in a saturated solution of ammonia in methanol, and 15 g of Raney Ni was added. The reaction mixture was heated to 110 °C at 80 atmospheres pressure in a 2 L high-pressure autoclave. The mixture was filtered to remove the catalyst and the filtrate was concentrated to give residue which was purified by column chromatography to afford tert-butyl 3,8-diazaspiro[5,5]undecane-3-carboxylate.
- tert-Butyl l-oxo-2,8-diazaspiro[4.51decane-8-carboxylate The title compound is commercially available from a number of vendors, for example, Shanghai AQ BioPharma Co., Ltd, catalog
- Step A 1 -tert-Butyl 4-methyl 4-(cyanomethyl)piperidine-l,4-dicarboxylate: To a solution of commercially available 1 -tert-butyl 4-methyl piperidine-l,4-dicarboxylate (200 g, 0.82 mol) in anhydrous THF (2 L) was added LDA (2M in THF, 575 mL, 1.15 mol) drop-wise at -65 °C under N 2 . The mixture was stirred at -65 °C for 1.5 h. To the mixture was added bromoacetonitrile (148 g, 1.23 mol) in anhydrous THF (500 mL) at -65 °C.
- Step B tert-Butyl l-oxo-2,8-diazaspiro[4.51decane-8-carboxylate: A suspension of 1 -tert-butyl 4-methyl 4-(cyanomethyl)piperidine-l,4-dicarboxylate (70.0 g, 247.9 mmol) and Raney Ni (60 g) in MeOH (1500 mL) and ⁇ 3 ⁇ 2 0 (80 mL) was stirred at 2 MPa of hydrogen pressure at 50 °C for 18 h.
- Step A tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-l-carboxylate: Into a 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a suspension of NaH (74.0 g, 2.16 mol 1.05 equiv, 70%) in tetrahydrofuran (2000 mL) at 0°C, then ethyl 2-(diethoxyphosphoryl)acetate (514 g, 2.06 mol, 1.05 equiv, 98%>) was added dropwise with stirring at 0°C.
- Step B tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-(nitromethyl)piperidine-l-carboxylate: Into a 3000- mL 4-necked round-bottom flask was placed potassium carbonate (93.2 g, 662 mmol, 0.50 equiv) and DMSO (2000 mL). The resulting solution was heated to 80°C.
- Step C 3-oxo-2,8-diaza-spiro[4,51decane-8-carboxylic acid tert-butylester: A mixture of tert- butyl 4-(2-ethoxy-2-oxoethyl)-4-(nitromethyl)piperidine-l-carboxylate (330 g, 990 mmol, 1.00 equiv, 99%>) and Ni (40 g, 0.15 equiv) in ethanol (1200 mL) was stirred for 24 h under a hydrogen atmosphere at room temperature. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product was purified by re-crystallization from ether to afford the title compound.
- Step A 1 -fert-Butyl 4-methyl 4-(2-methylallyl)piperidine- 1 ,4-dicarboxylate: A solution of N- Boc-piperidine-4-carboxylic acid methyl ester (2.00 g, 8.22 mmol) in THF (40 mL) was cooled to -78 °C . Under nitrogen, a 2.0 M THF solution of LDA (6.17 mL, 12.3 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 30 minutes before a solution of 3- bromo-2-methylpropene (1.60 g, 11.9 mmol) in THF (2 mL) was added.
- Step B 1 -tert-Butyl 4-methyl 4-(2-oxopropyl)piperidine-l ,4-dicarboxylate: To a solution of 1- tert-butyl 4-methyl 4-(2-methylallyl)piperidine-l,4-dicarboxylate (2.2 g, 7.4 mmol) in dioxane/water(60 mL, 1/1) under nitrogen was added osmium tetroxide (0.038g, 0.15 mmol) and sodium periodate (2.88 g, 13.5 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was then diluted with dichloromethane (50 mL), and washed with 20% Na 2 S 2 0 3 (20 mL).
- Step C tert-Butyl 3-methyl- l-oxo-2,8-diazaspiro
- the faster eluting isomer was determined to be (S)- tert-Butyl 3-methyl-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate and the slower eluting isomer was (i?)-tert-Butyl 3-methyl-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate based on Vibrational Circular Dichroism (VCD) spectroscopy analysis.
- Step A tert-Butyl 2-(5-oxo-2,5-dihydrofuran-3-yl)-2,9-diazaspiro[5.51undecane-9-carboxylate
- Hunig's Base 275 ⁇ , 1.57 mmol
- tert-butyl 3,8-diazaspiro[5,5]undecane-3- carboxylate 200 mg, 0.786 mmol.
- the reaction mixture was stirred at 76 °C overnight, concentrated and purified by column chromatography (0-10% MeOH in DCM) to afford the title compound.
- LC/MS: [(M+l)] + 337
- Step B 4-(2,9-Diazaspiro[5.51undecan-2-yl)furan-2(5H)-one: To tert-butyl 2-(5-oxo-2,5- dihydrofuran-3-yl)-2,9-diazaspiro[5.5]undecane-9-carboxylate (266 mg, 0.792 mmol) in DCM (2 mL) was added TFA (2 mL, 26.0 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure, then placed on the high vacuum. The residue was dissolved in MeOH and loaded onto a 2 g Bond Elut SCX column (pre -rinsed with MeOH).
- Step B 2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one: To a solution of tert- butyl l-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (5.70 g, 16.9 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (26.1 mL, 339 mmol) and the resulting solution was stirred at rt for lh.
- Step A tert-Butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.51decane-8- carboxylate: To a mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (I- 1 1 , 80.0 g, 315 mmol) and 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (1-9, 85.2 g, 346 mmol), Xantphos (13.6 g, 23.6 mmol), CS 2 CO 3 (153.7 g, 471.8 mmol) in toluene (1200 mL), was added Pd 2 (dba) 3 (7.20 g, 7.86 mmol) under N 2 .
- Step B 2-(4-Methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one: To a mixture of of tert-butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.5]decane-8- carboxylate (57.0 g, 163 mmol) in EtOAc (180 mL) was added saturated HCl(g)/ EtOAc (712 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h.
- Step B 2-(5-Oxo-2,5-dihydrofuran-3-yl)-2,9-diazaspiro[5.5]undecan- 1 -one: tert- utyl 1 -oxo-2- (5-0X0-2, 5-dihydrofuran-3-yl)-2,9-diazaspiro[5.5]undecane-9-carboxylate (100 mg, 0.285 mmol) in DCM (2 mL) was treated with TFA (660 ⁇ , 8.56 mmol) at 0 °C to give TFA salt.
- Step A tert-Butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,9-diazaspiro[5.51undecane- 9-carboxylate: A microwave vial was charged with commercially available tert-butyl l-oxo-2,9- diazaspiro[5.5]undecane-9-carboxylate (Shanghai AQ BioPharma Co., Ltd, catalog # ABP3640, 100 mg, 0.373 mmol), 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (110 mg, 0.447 mmol), Pd 2 (dba) 3 (17 mg, 0.019 mmol), Xantphos (32 mg, 0.056 mmol), and cesium carbonate (182 mg, 0.559 mmol).
- Step B 3-methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one: ter t- utyl 3- methyl- l-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (90 mg, 0.257 mmol) was dissolved in dichloromethane (2 mL) and treated with TFA (1 mL). After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated to remove excess of the reagent and co-evaporated with dichloromethane three times to give the title compound.
- Step A ethyl 4-bromo-2-ethyl-3-oxobutanoate: To a solution of ethyl 2-ethyl-3-oxobutanoate (5.17 g, 32.7 mmol) in water (10 mL) at 0°C was added bromine (1.684 mL, 32.7 mmol) dropwise over 2h. The resulting solution was stirred at rt for 16 h. The mixture was extracted with ethyl acetate (100 mL) and the organic phase was dried over sodium sulfate and
- Step B 3-ethyl-4-hydroxyfuran-2(5H)-one: A mixture of ethyl 4-bromo-2-ethyl-3-oxobutanoate and hydrogen bromide (48%, 0.037 mL, 0.327 mmol) was heated at 100 °C for 20 h. After cooling to rt, the solid was collected by filtration followed by diethyl ether washing to give 3- ethyl-4-hydroxyfuran-2(5H)-one. LC/MS: (M+l) + : 129.05.
- Step C 4-ethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate: To a solution of 3-ethyl- 4-hydroxyfuran-2(5H)-one (400 mg, 3.12 mmol) in dichloromethane (10 mL) at -78 °C was added 2,6-lutidine (0.545 mL, 4.68 mmol) and triflic anhydride (0.633 mL, 3.75 mmol) dropwise. The reaction solution was stirred at -78 °C for lh before being warmed to rt for 2h.
- Step D tert-butyl 2-(4-ethyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.51decane-8- carboxylate: A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 4-ethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (246 mg, 0.944 mmol), Xantphos (45.5, 0.079 mmol), palladium (II) acetate (8.8 mg, 0.039 mmol), water (0.043 mL, 2.4 mmol), and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was heated at 60 °C for 16 h. After filtration through CEL
- Step E 2-(4-ethyl-5 -oxo-2,5 -dihydrofuran-3 -yl)-2, 8-diazaspiro [4.5] decan- 1 -one : To a solution of tert-butyl 2-(4-ethyl-5-oxo-2,5-dihydrofuran-3-yl)- 1 -oxo-2,8-diazaspiro[4.5]decane-8- carboxylate (0.34 g, 0.93 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (2.16 mL, 28 mmol) and the resulting solution was stirred at rt for lh.
- Step A ethyl 4-bromo-2-isopropyl-3-oxobutanoate: To a solution of ethyl 2-acetyl-3- methylbutanoate (5.10 g, 29.6 mmol) in water (10 mL) at 0 °C was added bromine (1.53 mL, 29.6 mmol) dropwise over 2h. Chloroform (30 mL) was added and the resulting solution was stirred at rt for 16h. Ethyl acetate (300 mL) was added to the reaction solution and the organic phase was dried over sodium sulfate and concentrated to give the title compound.
- Step B 4-hydroxy-3-isopropylfuran-2(5H)-one: A mixture of ethyl 4-bromo-2-isopropyl-3- oxobutanoate (7.1 g, 28 mmol) and hydrogen bromide (48%, 0.032 mL, 0.28 mmol) was heated at 100 °C for 8h. After cooling to rt, the solid was collected by filtration followed by diethyl ether washing to give 4-hydroxy-3-isopropylfuran-2(5H)-one. LC/MS: (M+l) + : 143.09.
- Step C 4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate: To a solution of 4- hydroxy-3-isopropylfuran-2(5H)-one (400 mg, 2.81 mmol) in methylene chloride (10 mL) at -78 °C was added 2,6-lutidine (0.492 mL, 4.22 mmol) and triflic anhydride (0.570 mL, 3.38 mmol) dropwise, and the reaction temperature was maintained at -78 °C for lh before warmed to rt for 2h. The mixture was partitioned between methylene chloride and 1 N hydrogen chloride.
- Step D tert-butyl 2-(4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.51decane- 8-carboxylate: A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (I-l 1) (200 mg, 0.786 mmol), 4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (259 mg, 0.944 mmol), Xantphos (46 mg, 0.079 mmol), palladium (II) acetate (8.8 mg,
- Step E 2-(4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one: To a solution of tert-butyl 2-(4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (195 mg, 0.515 mmol) in methylene chloride was added trifluoroacetic acid at rt and the resulting solution was stirred at rt for lh.
- Step A tert-Butyl 2-(4-bromo-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.51decane-8- carboxylate: tert-Butyl l-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8- carboxylate (1-16, Step A) (784 mg, 2.33 mmol) was dissolved in DCM (20 mL) and was treated with NBS (498 mg, 2.80 mmol) at 25°C for 12 hours.
- the reaction mixture was diluted with DCM (20 mL), washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrates were concentrated and the crude product was purified by column chromatography (IS CO 40 g silica gel column), eluting with 50-100% ethyl acetate/hexane gradient to give the title compound.
- Step B tert-Butyl 2-(4-cyclopropyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8- diazaspiro [4.5] decane- 8 -carboxylate : In a microwave vial, tert-butyl 2-(4-bromo-5-oxo-2,5- dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (90 mg, 0.22 mmol) was dissolved in toluene (2 mL) and water (0.2 mL).
- Step C 2-(4-cyclopropyl-5 -oxo-2,5 -dihydrofuran-3 -yO-2, 8-diazaspiro [4.5] decan- 1 -one :
- the title compound can be prepared in a similar fashion to that described for 2-(4-isopropyl-5-oxo-2,5- dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-l-one (1-24) above using TFA.
- Step A ethyl 4-bromo-3-oxopentanoate: To a solution of ethyl 3-oxopentanoate (5.00 g, 34.7 mmol) in chloroform (27 mL) at 0 °C was added bromine (1.79 mL, 34.7 mmol) in chloroform (10 mL) drop-wise. The resulting solution was stirred at rt for 16 h. The solution was washed with water, dried over sodium sulfate, concentrated to give ethyl 4-bromo-3-oxopentanoate.
- Step B 4-hydroxy-5-methylfuran-2(5H)-one: Ethyl 4-bromo-3-oxopentanoate (7.49 g, 33.6 mmol) was treated with potassium hydroxide (5.03 g, 90 mmol) in water (36 mL) at 0 °C. The resulting mixture was vigorously stirred at 0°C for 4h. The reaction mixture was extracted with methylene chloride (twice with 100 mL). The alkaline phase was acidified to pH ⁇ 1 by 6N hydrogen chloride. The acidic phase was extracted with methylene chloride (3x100 mL). The latter combined organic phase was dried over sodium sulfate and concentrated to give the title compound.
- 1 HNMR 500 MHz, CDC1 3 ), 55.064 (s, 1H), 4.949-4.878(m, 1H), 3.251-3.239 (m, 1H), 1.566-1.547 (m, 3H).
- Step C 2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate: To a solution of 4- hydroxy-5-methylfuran-2(5H)-one in methylene chloride (10 mL) at -78 °C was added 2,6- lutidine (0.612 mL, 5.26 mmol) and triflic anhydride (0.711 mL, 4.21 mmol) drop-wise. The reaction temperature was maintained at -78 °C for 0.5 h before being warmed to rt for lh. The mixture was washed with hydrogen chloride (IN, three times 100 mL), diluted sodium bicarbonateand dried over sodium sulfate to give the title compound.
- Step D tert-butyl 2-(2-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.51decane-8- carboxylate: A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (232 mg, 0.944 mmol), Xantphos (45.5 mg, 0.079 mmol), palladium (II) acetate (8.83 mg, 0.039 mmol), water (0.043 mL, 2.359 mmol), and potassium carbonate (217 mg, 1.573 mmol) in toluene (20 mL) was degassed by nitrogen
- Step E 2-(2-methyl-5 -oxo-2,5 -dihydrofuran-3 -yl)-2, 8-diazaspiro [4.5] decan- 1 -one : To a solution of tert-butyl 2-(2-methyl-5-oxo-2,5-dihydrofuran-3-yl)- 1 -oxo-2,8-diazaspiro[4.5]decane-8- carboxylate (127 mg, 0.362 mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (1.396 mL, 18.12 mmol), the resulting solution was stirred at rt for lh.
- Step A ethyl 4-bromo-2-methyl-3-oxopentanoate: To a solution of ethyl 2-methyl-3- oxopentanoate (5.0 g, 34.7 mmol) in chloroform at 0 °C was added bromine (1.79 mL, 34.7 mmol) in chloroform (10 mL) drop-wise. The resulting solution was stirred at rt for 16 h. The solution was washed with water, dried over sodium sulfate, and concentrated to give the title compound.
- Step B 4-hydroxy-3,5-dimethylfuran-2(5H)-one: To ethyl 4-bromo-2-methyl-3-oxopentanoate (7.49 g, 31.6 mmol) was added cold potassium hydroxide (4.7 g, 84 mmol) in water (36 mL) at 0 °C, the resulting mixture was vigorously stirred at 0 °C for 4h. The reaction mixture was extracted with methylene chloride (2x100 mL), the alkaline phase was acidified to ph 1 by 6N hydrogen chloride followed by extraction with methylene chloride (3 times 100 mL).
- Step C 2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate: To a solution of 4- hydroxy-3,5-dimethylfuran-2(5H)-one (400 mg, 3.12 mmol) in methylene chloride (10 mL) at - 78 °C was added 2,6-lutidine (0.545 mL, 4.68 mmol) and triflic anhydride (0.633 mL, 3.75 mmol) drop-wise. The reaction temperature was maintained at -78 °C for lh before warming to rt for 2h.
- Step D tert-butyl 2-(2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8- diazaspiro [4.5] decane- 8 -carboxylate : A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8- carboxylate (200 mg, 0.786 mmol), 2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl
- Step E 2-(2 ⁇ -dimethyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one: To a solution of tert-butyl 2-(2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8- diazaspiro [4.5] decane- 8 -carboxylate (195 mg, 0.535 mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (2.06 mL, 26.8 mmol) and the resulting solution was stirred at rt for lh.
- Step A tert-butyl 2-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.51decane-8- carboxylate: To a solution of tert-butyl l-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8- diazaspiro [4.5] decane- 8 -carboxylate (1-16, Step A) (2.1 g, 6.2 mmol) in chloroform (50 mL) was added NCS (1.00 g, 7.49 mmol) at rt and the resulting solution was heated at 60 °C overnight. After removing the volatiles the residue was purified on silica gel column using EtOAc/hexane as eluting solvents to give the title compound. LC/MS: (M+l) + : 371.11, 372.99.
- Step B 2-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one: To a solution of tert-butyl 2-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.5]decane-8- carboxylate (2.26 g, 6.09 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (9.39 mL, 122 mmol) and the resulting solution was stirred at rt for lh.
- Step A 3-bromo-4-ethoxy-3-fluoro-4-hydroxydihydrofuran-2(3H -one: To a solution of 4- hydroxyfuran-2(5H)-one (2.25 g, 22.5 mmol) in ethanol (20 mL) was added NBS (4.00 g, 22.5 mmol), and the resulting solution was stirred at rt for 40 min. Then l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (7.97 g, 22.5 mmol) was added and the resulting mixture was stirred at rt overnight.
- Step B 3-fluoro-4-hydroxyfuran-2(5H)-one: To a solution of 3-bromo-4-ethoxy-3-fluoro-4- hydroxydihydrofuran-2(3H)-one (4.39 g, 18.1 mmol) in tetrahydrofuran (20 mL) was added tri-n- butyltin hydride (9.39 mL, 35.0 mmol) at 0 °C under N2- The resulting solution was stirred at rt overnight. After removing the volatiles, the residue was stirred in 30 mL 50% acetic acid and 30 mL hexane at rt for 30 min.
- the acidic phase was washed with hexane (3x30 mL) before concentration.
- the reside was dissolved in sodium carbonate (50 mL, 2N), extracted with 40%> EtOAc/hexane (4x50 mL), the alkaline phase was acidified to pH ⁇ 1 by 1 N hydrogen chloride.
- the acidic phase was then extracted with ethyl acetate (8 times 60 mL).
- the combined organic phase was dried over sodium sulfate, concentrated to give 3-fluoro-4-hydroxyfuran-2(5H)-one.
- Step C 4-fluoro-2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate: To a solution of 3-fluoro-4-hydroxyfuran-2(5H)-one (400 mg, 3.39 mmol) in methylene chloride (10 mL) at - 78°C was added 2,6-lutidine (0.592 mL, 5.08 mmol) and trifiic anhydride (0.687 mL, 4.07 mmol) drop-wise, the reaction temperature was maintained at -78°C for 1 h before warmed to rt for 2h.
- Step D tert-butyl 2-(4-fluoro-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.51decane-8- carboxylate: A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (150 mg, 0.590 mmol), 4-fluoro-2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (148 mg, 0.590 mmol), xantphos (34.1 mg, 0.059 mmol), water (0.032 mL, 1.77 mmol) in toluene (20 mL) was degassed by nitrogen followed by addition of palladium acetate (6.6 mg, 0.029 mmol).
- Step E 2-(4-fluoro-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one: To a solution of tert-butyl 2-(4-fluoro-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.5]decane-8- carboxylate (109 mg, 0.308 mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (1.896 mL, 24.61 mmol) and the resulting solution was stirred at rt for lh.
- octane-3,,8-dicarboxylate To a solution of (li?,3s,55)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2. l]octane-3-carboxylic acid (5.00 g, 19.6 mmol) in a mixture solvent of dry MeOH (60 mL) and DCM (60.0 mL) was added (trimethylsilyl)diazomethane (19.6 mL, 39.2 mmol). The mixture was stirred for 0.5 hr. AcOH (5 mL) was added.
- Step B (lR,3r,5S)-%-tert-butyl 3-methyl 3-(cyanomethyl)-8-azabicyclo
- Step D (lR,3r,5S)-tert-butyl 2'-oxo-8-azaspiro[bicyclo [3.2.11octane-3,3'-pyrrolidinel-8- carboxylate: A mixture of (li?,3r,55)-8-tert-butyl 3-methyl 3-(2-aminoethyl)-8- azabicyclo[3.2.1]octane-3,8-dicarboxylate (4.2 g, 13.4 mmol) and potassium carbonate (9.29 g, 67.2 mmol) in MeOH (50 mL) was heated at 60 °C for 1 hr. The mixture was concentrated, and DCM (50 mL) was added.
- Step E ( ⁇ R3r,5S)-tert-butYl ⁇ -(4 ⁇ 6& ⁇ 1-5- ⁇ -2,5- ⁇ -3- ⁇ -2'- ⁇ -8- azaspiro[bicyclo[3.2.11octane-3,3'-pyrrolidinel-8-carboxylate: A mixture of 4-methyl-5-oxo-2,5- dihydrofuran-3-yl trifluoromethanesulfonate (1.861 g, 7.56 mmol), ⁇ R, r,5S)-tert- vXy ⁇ 2'-oxo- 8-azaspiro[bicyclo[3.2.1]octane-3,3'-pyrrolidine]-8-carboxylate (1.63 g, 5.81 mmol),
- Step F (li?,3r,56 - -(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-8-azaspiro[bicyclo[3.2.11octane- 3 ,3 '-pyrrolidinl -2'-one : A solution of ⁇ R, r,5S)-tert- vXy ⁇ l'-(4-methyl-5-oxo-2,5-dihydrofuran- 3-yl)-2'-oxo-8-azaspiro[bicyclo [3.2.1]octane-3,3'-pyrrolidine]-8-carboxylate in DCM (50 mL) and TFA (10 mL) was stirred at rt for lh.
- Step A (lR,5S,Z)-tert-butyl 3-(l-cyano-2-methoxy-2-oxoethylidene)-8-azabicyclo[3.2.11octane- 8-carboxylate: Methyl 2-cyanoacetate (3.63 g, 36.6 mmol), commercially available ( ⁇ R,5S)-tert- butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (5.5 g, 24.41 mmol), ammonium acetate (2.51 mL, 36.6 mmol), acetic acid (5.59 mL, 98 mmol) and toluene (100 mL) were placed in a 500-mL round-bottomed flask attached to a Dean-Stark constant water separator which was connected to a reflux condenser.
- the flask was heated in an oil bath at 150 °C, and the water that distilled out of the mixture with the refluxing toluene was removed from the separator at intervals (overnight). Solvent was removed under reduced pressure. The residue was dissolved in EtOAc (150 mL). The solution was washed with brine, dried (MgS0 4 ), and concentrated. The residue was purified by column chromatography on silica gel (hexane in EtOAc 0-60 % gradient).
- Step B (lR,3r,5S)-tert-butyl 3-(l-cyano-2-methoxy-2-oxoethyl)-3-vinyl-8-azabicyclo-
- octane-8-carboxylate To a suspension of ⁇ R,5S,Z)-tert-bvXy ⁇ 3-(l-cyano-2-methoxy-2- oxoethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylate (7.17 g, 23.4 mmol) and copper(I) iodide (2.229 g, 11.70 mmol) in THF (150 mL) was added vinylmagnesium bromide (35.1 mL, 35.1 mmol) by injection at -10 °C.
- Step C (lR,3s,5S)-tert-butyl 3-(cyanomethyl)-3-vinyl-8-azabicyclo[3.2.11octane-8-carboxylate: A suspension of ⁇ R,3r,5S)-tert-bvXy ⁇ 3-(l-cyano-2-methoxy-2-oxoethyl)-3-vinyl-8- azabicyclo[3.2.1]octane-8-carboxylate (7.2 g, 21.53 mmol) and sodium chloride (1.258 g, 21.53 mmol) in DMSO (40 mL) and water (4 mL) was heated in an 160 °C oil bath for 2 h, then cooled down to RT.
- Step D (lR,3s,5S)-tert-butyl 3-(cyanomethyl)-3-formyl-8-azabicyclo[3.2.11octane-8-carboxylate: To a suspension of (lR,3s,5S)-tert-butyl 3-(cyanomethyl)-3-vinyl-8-azabicyclo[3.2.1]octane-8- carboxylate (4.00 g, 14.5 mmol, water (15 mL) and sodium periodate (12.4 g, 57.9 mmol) in dioxane (45 mL) was added osmium tetroxide (0.184 g, 0.724 mmol). The suspension was stirred for 17 hr at rt.
- Step E (li?,3 ,56 -8-(tert-butoxycarbonyl)-3-(cyanomethyl)-8-azabicyclo[3.2. l]octane-3- carboxylic acid: To a solution of (lR,3s,5S)-tert-butyl 3-(cyanomethyl)-3-formyl-8- azabicyclo[3.2.1]octane-8-carboxylate (5.10 g, 18.3 mmol) in t-BuOH/H20 (2: 1) was added sodium dihydrogenphosphate hydrate (7.59 g, 55.0 mmol) and 2-methylbut-2-ene (9.7 mL, 92 mmol).
- Step F (lR,3s,5S)-%-tert-butyl 3-methyl 3-(cyanomethyl)-8-azabicyclo
- Step G (lR.3s.5S)-S-tert-butyl 3-methyl 3-(2-aminoethyl)-8-azabicvclor3.2.11octane-3.8- dicarboxylate: A mixture of (lR,3s,5S)-8-tert-butyl 3-methyl 3-(cyanomethyl)-8- azabicyclo[3.2.1]octane-3,8-dicarboxylate (3.5 g, 11.4 mmol) and platinum(iv) oxide (0.258 g, 1.14 mmol) in ethanol (20 mL) and AcOH (20 mL), was hydrogenated on a shaker (45 psi hydrogen ) at rt for 48 hr. The catalyst was filtered off through a CELITE® pad. The filtration was concentrated and the residue was used directly in the next step. LCMS 313.25 (+1), 257.25 (+1-56).
- Step H (lR,3s,5S)-tert-butyl 2 , -oxo-8-azaspiro[bicyclo[3.2.11octane-3,3'-pyrrolidinel-8- carboxylate: A mixture of (lR,3s,5S)-8-tert-butyl 3-methyl 3-(2-aminoethyl)-8- azabicyclo[3.2. l]octane-3,8-dicarboxylate (3.50 g, 11.2 mmol) and potassium carbonate (7.74 g, 56.0 mmol) in MeOH (50 mL) was heated at 60 °C for 1 hr. The mixture was concentrated, and DCM (50 mL) was added.
- Step I (lR.3s.5S)-tert-butyl l'-(4-methyl-5-oxo-2.5-dihvdrofi ran-3-yl)-2'-oxo-8- azaspiro[bicyclo[3.2.11octane-3,3'-pyrrolidinel-8-carboxylate: A mixture of (lR,3s,5S)-tert-butyl 2'-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3'-pyrrolidine]-8-carboxylate (2.00 g, 7.13 mmol), 4- methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (1.93 g, 7.85 mmol),
- Step J (li?j ,56 - -(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-8-azaspiro[bicyclo[3.2.11octane- 3 ,3 '-pyrrolidinl -2'-one : (lR,3s,5S)-tert-butyl 2'-oxo-8-azaspiro[bicyclo[3.2. l]octane-3,3'- pyrrolidine] -8-carboxylate was stirred with TFA (5 mL) in DCM (30 mL) at rt for lh. Volatiles were removed under reduced pressure.
- Step A (lR,3r,5S)-8-tert-butyl 3-methyl 8-azabicyclo[3.2.1 "
- Step B (lR n5S)-8-tert-butyl 3-methyl 3-(2-methylallylV8-azabicvclor3.2.11octane-3,8- dicarboxylate: To a solution of diisopropylamine (5.94 mL, 41.7 mmol) in tetrahydrofuran (5 mL) at 0 °C was added n-butyllithium (16.7 mL, 41.7 mmol) drop-wise, and the resulting solution was stirred at 0°C for 0.5h. This solution was added dropwise to a solution of the compound of Step A (7.48 g, 27.8 mmol) in tetrahydrofuran (90mL) at -78°C.
- Step C ( ⁇ R3r,5S)-8-tert-butYl 3-methyl 3-(2-oxopropyn-8-azabicvclor3.2.11octane-3.8- dicarboxylate: To a solution of (li?,3r,55)-8-tert-butyl 3-methyl 3-(2-methylallyl)-8- azabicyclo[3.2.1]octane-3,8-dicarboxylate (7.99 g, 24.7 mmol) in dioxane (100 mL) and water (50 mL) was added sodium periodate (10.6 g, 49.4 mmol) and osmium tetroxide (0.126 g, 0.494 mmol).
- Step D (lR,3r,5S)-tert-butyl S'-methyl- '-oxo-S-azaspiro bicyclo S. . lloctane-SJ'-pyrrolidinel- 8-carboxylate: To a solution of (lR,3r,5S)-%-tert-butyl 3-methyl 3-(2-oxopropyl)-8- azabicyclo[3.2.1]octane-3,8-dicarboxylate (7.90 g, 24.3 mmol) in methanol (50 mL) was added magnesium sulfate (5.84 g, 48.6 mmol), ammonium acetate (3.74 g, 48.6 mmol), and sodium cyanoborohydride (3.05 g, 48.6 mmol).
- Step E (lR.3r.5S)-tert-butyl 5'-methyl-2' ⁇ xo '-(5 ⁇ xo-2.5-dihvdrofuran-3-yl)-8- azaspiro[bicyclo[3.2.11octane-3,3'-pyrrolidinel-8-carboxylate.
- Step F (l ⁇ Jr ⁇ -S'-methyl- -fS-oxo ⁇ -dihydrofuran-S-yn-S-azaspiro bicyclo [3.2.1 "
- Isomer A and Isomer B TFA (3.27 mL, 42.5 mmol) was added to a solution of ⁇ R,3r,5S)-tert-bvXy ⁇ 5'-methyl-2'-oxo-l'-(5-oxo-2,5-dihydrofuran-3-yl)-8- azaspiro[bicyclo[3.2.1]octane-3,3'-pyrrolidine]-8-carboxylate
- Isomer (A) (0.80 g, 2.1 mmol) in methylene chloride (5 mL) and the resulting solution was stirred at rt for lh.
- Step A (lR.5S -ter?-butyl 3-methyl-7-(((trifluoromethyl)sulfonyl)oxy)-3.9- diazabicyclo[3.3.1 ]non-6-ene-9-carboxylate: To a solution of commercially available (IR,5S)- tert-butyl 3-methyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (10.0 g, 39.3 mmol) in tetrahydrofuran (100 mL) was added LDA solution (23.6 mL, 47.2 mmol) at -78 °C drop-wise.
- Step B (lR.5S -9-terf-butyl 7-methyl 3-methyl-3.9-diazabicvclor3.3. Hnon-6-ene-7.9- dicarboxylate: To a solution of (lR,5S)-tert-butyl 3-methyl-7-(((trifluoromethyl)sulfonyl)oxy)- 3,9-diazabicyclo[3.3.1]non-6-ene-9-carboxylate (14 g, 36 mmol) and diisopropylethylamine (9.47 mL, 54.3 mmol) in methanol (100 mL) and DMF (100 mL) was triphenylphosphine (0.95 g, 3.62 mmol) and palladium (II) acetate (0.407 g, 1.81 mmol).
- Step C (lR,5S)-9-tgrt-butyl 7-methyl 3-methyl-3,9-diazabicyclo[3.3.11nonane-7,9-dicarboxylate: To a solution of (lR,5S)-9-tert-butyl 7-methyl 3-methyl-3,9-diazabicyclo[3.3.1]non-6-ene-7,9- dicarboxylate (4.69 g, 15.8 mmol) in methanol (50 mL) was added palladium on carbon (10%, 1.684 g, 1.583 mmol) and the resulting mixture was subjected to hydrogenation under 40 psi for three days. After filtration through CELITE® under nitrogen the filtrate was concentrated to give the title compound. LC/MS: (M+l) + : 299.1.
- Step D (lR.5S s)-9-tert-butyl 7-methyl 7-(cvanomethyl)-3-methyl-3.9- diazabicyclo[3.3.1 ]nonane-7,9-dicarboxylate: To a solution of diisopropylamine (3.28 mL, 23.02 mmol) in tetrahydrofuran ( 5 mL) was added n-butyllithium (11.51 mL, 23.02) dropwise at 0 °C, and the resulting solution was stirred at 0 °C for 0.5 h.
- Step E (lR.5S s)-9-tert-butyl 7-methyl 7-(2-aminoethyl)-3-methyl-3.9- diazabicyclo[3.3.1 lnonane-7,9-dicarboxylate: To a solution of ⁇ R,5S,1 s)-9-tert-bvXy ⁇ 7-methyl 7-(cyanomethyl)-3-methyl-3,9-diazabicyclo[3.3.1]nonane-7,9-dicarboxylate (4.39 g, 13.0 mmol) in methanol (30 mL) was added platinum (IV) oxide (0.207 g, 0.911 mmol) and the resulting mixture was hydrogenated at 40 psi for 16 h. After filtration through CELITE® under nitrogen, the filtrate was concentrated to give the title compound. LC/MS: (M+l) + : 342.2.
- Step F (lR,3's,5S)-tert-butyl 3-methyl-2'-oxo-3,9-diazaspiro[bicyclo[3.3.11nonane-7,3'- pyrrolidinel-9-carboxylate: To a solution of ⁇ R,5S,1 s)-9-tert-bvXy ⁇ 7-methyl 7-(2-aminoethyl)-3- methyl-3,9-diazabicyclo[3.3.1]nonane-7,9-dicarboxylate (4.44 g, 13.0 mmol) in methanol (100 mL) was added potassium carbonate (10.8 g, 78 mmol), and the resulting solution was heated at reflux for 8h.
- Step G (lR.3's.5S)-tert-butyl 3 ⁇ 6& ⁇ 1- ⁇ -(4 ⁇ 6& ⁇ 1-5- ⁇ -2,5- ⁇ -3- ⁇ -2'- ⁇ -3,9- diazaspiro[bicyclo[3.3.11nonane-73'-pyrrolidine "
- -9-carboxylate A mixture of (lR,3's,5S)-tert- butyl 3-methyl-2'-oxo-3,9-diazaspiro[bicyclo[3.3.1 ]nonane-7,3'-pyrrolidine]-9-carboxylate (4.0 g, 12.9 mmol), 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (3.82 g, 15.5 mmol), Xantphos (0.748 g, 1.29 mmol), and potassium carbonate (3.57 g, 25.9 mmol) in toluene (100 m
- Step H (li?,3 , ,5 t ⁇ -3-methyl-r-(4-methyl-5-oxo-2,5-dihvdrofuran-3-vn-3,9- diazaspiro[bicyclo[3.3.1 lnonane-7,3'-pyrrolidinl-2 , -one: To a solution of the compound of Step G (2.63 g, 6.49 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (10 mL, 130 mmol) and the resulting solution was stirred at rt for lh. After removing the volatiles the residue was basified on ion exchange column washed with methanol followed by 1 N ammonia/methanol to give the title compound. LC/MS: (M+l) + : 306.09.
- Step A Ethyl l-benzyl-4-(cyanomethyl)-3-oxopiperidine-4-carboxylate: To a flask charged with ethyl l-benzyl-3-oxopiperidine-4-carboxylate (1.0 g, 3.8 mmol) and a stir bar was added K2CO3 (1.06 g, 7.6 mmol), bromoacetonitrile (0.92 g, 7.6 mmoO, and acetone (15 mL). The reaction was allowed to stir at RT for 2 hours. LC showed slow reaction. It was then heated to 45 °C for 3 hours. LC showed complete reaction at that point. The reaction was quenched with NH4CI, extracted with EtOAc, dried over Na2SC"4, filtered and concentrated. The crude product was purified by MPLC to furnish the title compound. LCMS: mlz 301 (M+H) + .
- Step B 8-Benzyl-6-hydroxy-2,8-diazaspiro[4.51decan- 1-one: To a flask charged with ethyl 1- benzyl-4-(cyanomethyl)-3-oxopiperidine-4-carboxylate (900 mg, 3.0 mmol) and a stir bar was added platinum oxide (100 mg, 0.44 mmol), MeOH (20 mL) and acetic acid (20 mL). The mixture was allowed to stir vigorously under an atmosphere of hydrogen for 24 hours. LC indicated complete reaction at that point. The catalyst was removed by filtration through a pad of CELITE®, and the filtrate was concentrated under reduced pressure.
- Step C 8-Benzyl-6-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan- 1-one: To a flask charged with 8-benzyl-6-hydroxy-2,8-diazaspiro[4.5]decan- 1-one (520 mg, 2.0 mmol) and a stir bar was added palladium acetate (22 mg, 0.10 mmol), K2CO3 (550 mg, 4.00 mmol), Xantphos (120 mg, 0.20 mmol), 4-methyl-5-oxo-2,5-dihydrofuran-3-yl
- Step D 6-Hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one
- 8-benzyl-6-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8- diazaspiro[4.5]decan-l-one 150 mg, 0.42 mmol
- MeOH mL
- the mixture was allowed to stir under an atmosphere of hydrogen for 16 hours.
- LC indicated complete reaction.
- the catalyst was filtered off, and the crude material was used without further purification.
- Step A 8-benzyl-6-fluoro-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan- 1 - one Isomers A and B):
- Step B-l 6-Fluoro-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan- 1 -one (Isomer B, I-36B): To a solution of Isomer B from Step A (100 mg, 0.28 mmol) in DCE (2 mL) was added ACE-C1 (0.15 mL, 1.4 mmol). The mixture was heated to 80 °C for 3 hours. The solvent was then removed, and the residue was pumped under high vacuum for 15 minutes. The residue was then dissolved in MeOH (5 mL) and heated to reflux for 30 minutes. LC showed formation of the desired product.
- Step B-2 6-Fluoro-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one (Isomer A, 1-36 A): The title intermediate (which is I-36A) was prepared following the same method as described in Step B-l, but starting from Isomer A from Step A). LCMS: mlz 269 (M+H) + .
- Step A 1-tert-butyl 4-methyl 4-(2-((tert-butoxycarbonyl)amino)-l-hydroxyethyl)piperidine-l,4- dicarboxylate: To a solution of LDA (prepared by adding n-butyllithium (20.0 mL, 49.3 mmol) to diisopropylamine (5.16 mg, 51.0 mmol) in THF (40 mL) at 0 °C, stirred for 30 min) was added 1-tert-butyl 4-methyl piperidine-l,4-dicarboxylate (4.00 g, 16.4 mmol) in TMEDA (15 mL, 99 mmol) drop-wise via syringe pump at -78 °C for 10 min.
- LDA prepared by adding n-butyllithium (20.0 mL, 49.3 mmol) to diisopropylamine (5.16 mg, 51.0 mmol) in THF (40 mL) at 0
- Step B tert-Butyl 4-hydroxy-l-oxo-2,8-diazaspiro[4.51decane-8-carboxylate: To a solution of
- Step C tert-Butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8- diazaspiro[4.51decane-8-carboxylate.
- Step D 4-hydroxy-2-(4-methyl-5 -oxo-2,5 -dihydrofuran-3 -yl)-2, 8-diazaspiro [4.5] decan- 1 -one.
- Isomer A and Isomer B The title compounds were prepared from Isomers A and B of tert-Butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)- 1 -oxo-2,8-diazaspiro[4.5]decane-8- carboxylate, respectively, using TFA in a similar fashion as described previously for 1-19.
- Step A tert-Butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l,4-dioxo-2,8- diazaspiro [4.5] decane- 8 -carboxylate : To tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5- dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1-37, Step C) (200 mg, 0.546 mmol) in DCM (2.8 mL) was added sodium bicarbonate (68.8 mg, 0.819 mmol) and Dess-Martin periodinane (347 mg, 0.819 mmol).
- Step B 2-(4-Methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decane-l,4-dione:
- the title compound was prepared from tert-Butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l ,4-dioxo- 2,8-diazaspiro[4.5]decane-8-carboxylate in a similar fashion as described in 1-19.
- LC/MS: [(M+l)] + 265
- Step A fert-Butyl 4-methoxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8- diazaspiro
- Step B 4-methoxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one, Isomer A and Isomer B: The individual isomers of the title compound were prepared from each of the single Enantiomers from the previous step in a similar fashion as described for 1-19, Step B, using TFA.
- Step A tert-Butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.51dec-3- ene- 8 -carboxylate: To a solution of tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3- yl)-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (300 mg, 0.819 mmol) in DCM (8.2 mL) at 0 °C was added DBU (370 ⁇ , 2.46 mmol), and XtalFluor-E® (562 mg, 2.46 mmol).
- Step A tert-Butyl 4-hydroxy-l-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decane- 8-carboxylate: To a round bottom flask was charged tert-butyl 4-hydroxy-l-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (300 mg, 1.11 mmol), 4-bromofuran-2(5H)-one (271 mg, 1.66 mmol), Pd(OAc)2 (24.9 mg, 0.111 mmol), Xantphos (96 mg, 0.166 mmol), and K 2 C0 3 (307 mg, 2.22 mmol).
- Step B tert-Butyl l-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51dec-3-ene-8- carboxylate: To a solution of tert-butyl 4-hydroxy-l-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8- diazaspiro[4.5]decane-8-carboxylate (210 mg, 0.596 mmol) in DCM (6 mL) at 0 °C was added DBU (269 ⁇ , 1.79 mmol), and XtalFluor-E® (409 mg, 1.79 mmol).
- Step A 1-tert-butyl 4-ethyl 4-(2-bromoallyl)piperidine-l,4-dicarboxylate:
- Lithium diisopropylamide (29.1 mL, 58.3 mmol) was added dropwise at -78 °C
- a solution of 1-tert-butyl 4-ethyl piperidine-l,4-dicarboxylate (9.56 mL, 38.9 mmol) in THF (200 mL), and stirred at this temperature for 50 min.
- 2,3-Dibromoprop-l-ene (5.47 mL, 56.0 mmol) in THF (10 mL) was added to the reaction mixture slowly and the resulting mixture was stirred for 1.5 hr at -78 °C.
- reaction mixture was queched with NH4CI solution (15 mL) and was allowed to warm to room temperature and the aqueous layer was extracted with EtOAc (30 mL X 3). The combined organics were washed with brine (30 mL), dried over MgS04 and concentrated to get the crude product which was purified by silica gel column chromatography (RediSep 220g Gold column) using (0-30)% EtO Ac/Hex anes as mobile phase to give the title compound.
- Step B 1-tert-butyl 4-ethyl 4-(2-methylenebutyl)piperidine-l,4-dicarboxylate: To a solution of 1-tert-butyl 4-ethyl 4-(2-bromoallyl)piperidine-l,4-dicarboxylate (5.0 g, 13.3 mmol) in THF (80 mL) in a sealed tube was added BINAP (3.31 g, 5.32 mmol), diethylzinc (15.95 mL, 15.95 mmol) and Pd(OAc) 2 (0.597 g, 2.66 mmol) and the resuting mixture was degassed and heated for 16 hours at 100 °C.
- reaction mixture was evaporated to remove solvent under reduced pressure and the crude product was purified by silica gel column chromatography (RediSep 220g Gold column) using (0-30)% EtOAc/Hexanes as mobile phase and the title compound was isolated.
- Step C 1-tert-butyl 4-ethyl 4-(2-oxobutyl)piperidine-l,4-dicarboxylate: Potassium
- tetrahydroxydioxidoosmium (0.041 g, 0.111 mmol) was added to a solution of 1-tert-butyl 4- ethyl 4-(2-methylenebutyl)piperidine-l,4-dicarboxylate (1.0 g, 3.07 mmol) in acetone (20 mL) and water (20 mL) and stirred for 10 min. Solid sodium periodate (2.62 g, 12.26 mmol) was added in four portions during 1 hour and the reaction temperature was maintained below 40°C using an ice-bath. The resulting mixture was stirred for 1 hour at room temperature. At this point LCMS showed incomplete reaction. Another 0.036 eq.
- Step D tert-butyl 3-ethyl-l-oxo-2,8-diazaspiro[4.51decane-8-carboxylate: To a stirred solution of 1 -tert-butyl 4-ethyl 4-(2-oxobutyl)piperidine-l,4-dicarboxylate (0.78 g, 2.38 mmol) in ethanol
- Steps E and F 3-ethyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one:
- Step A 1 -tert-butyl 4-ethyl 4-(2-cyclopropylallyl)piperidine-l,4-dicarboxylate: 1 -tert-butyl 4- ethyl 4-(2-bromoallyl)piperidine-l,4-dicarboxylate (1.0 g, 2.66 mmol), potassium
- Step A tert-butyl 2-(4-bromo-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.51decane-8- carboxylate: tert-butyl l-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8- carboxylate (1-16, Step A) (2.73 g, 8.12 mmol) was dissolved in DCM (70 mL) and was treated with N-bromosuccinimide (1.73 g, 9.74 mmol) at 25 °C and the resulting mixture was stirred overnight at room temperature.
- reaction mixture was diluted with DCM and was washed with water and brine then dried over Na2SC"4. Removing solvent gave crude product that was purified by silica gel column chromatography (80g RediSep Gold Column) using (25- 80)% EtOAc/Hexanes as mobile phase to afford the title compound.
- Step B tert-butyl l-oxo-2-(5-oxo-4-vinyl-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decane-8- carboxylate: tert-butyl 2-(4-bromo-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (2.2 g, 5.30 mmol), potassium trifluoro(vinyl)borate (1.06 g,
- Step C tert-butyl 2-(4-formyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.51decane-8- carboxylate: tert-butyl 1 -oxo-2-(5-oxo-4-vinyl-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane- 8-carboxylate (1.6 g, 4.4 mmol) was dissolved in acetone (36 mL) and water (36 mL), then
- Step D tert-butyl 2-(4-(hydroxymethyl)-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8- diazaspiro [4.5] decane- 8 -carboxylate : tert-butyl 2-(4-formyl-5-oxo-2,5-dihydrofuran-3-yl)- 1 -oxo- 2, 8 -diazaspiro [4.5 ]decane- 8-carboxylate (1.18 g, 3.24 mmol) was dissolved in THF (13 mL) and MeOH (13 mL) and the mixture was cooled to -78 °C and stirred for 15 min.
- Step E tert-butyl 2-(4-(methoxymethyl)-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8- diazaspiro [4.5] decane- 8 -carboxylate : tert-butyl 2-(4-(hydroxymethyl)-5-oxo-2,5-dihydrofuran-3- yl)-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.42 g, 1.15 mmol), silver oxide (0.292 g, 1.26 mmol) and methyl iodide (0.358 mL, 5.73 mmol) were taken up in DCM (5 mL) and stirred over night at room temperature under nitrogen.
- Step F 2-(4-(methoxymethyl)-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan- 1 -one:
- the title compound was prepared from tert-butyl 2-(4-(methoxymethyl)-5-oxo-2,5-dihydrofuran- 3-yl)-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate in an analogous fashion as described for 3- methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-l-one (1-22, last step).
- Step A 1-tert-Butyl 4-methyl 4-(2-((tert-butoxycarbonyl)amino)-l-hydroxypropyl)piperidine- 1 ,4-dicarboxylate: To a solution of LDA (prepared by adding n-BuLi (27.7 mL, 55.5 mmol) to diisopropylamine (8.04 mL, 57.3 mmol) in THF (40 mL) at 0 °C, stir for 30 min) was added 1- tert-butyl 4-methyl piperidine-l,4-dicarboxylate (4500 mg, 18.5 mmol) in TMEDA (16.6 mL, 111 mmol) dropwise via syringe pump at -78 °C for 20 min.
- LDA prepared by adding n-BuLi (27.7 mL, 55.5 mmol) to diisopropylamine (8.04 mL, 57.3 mmol) in THF (40 mL) at
- Step B tert-Butyl 4-hydroxy-3-methyl-l-oxo-2,8-diazaspiro[4.51decane-8-carboxylate: To a solution of 1 -tert-butyl 4-methyl 4-(2-((tert-butoxycarbonyl)amino)- 1 -hydroxypropyl)piperidine- 1 ,4-dicarboxylate (8000 mg, 19.2 mmol) in DCM (190 mL) was added TFA (44.4 mL, 576 mmol) at 0 °C and the resulting solution was stirred for 2 h.
- Step C tert-Butyl 4-hydroxy-3-methyl-l-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8- diazaspiro [4.5] decane- 8 -carboxylate : To a round bottom flask was charged tert-butyl 4-hydroxy- 3-methyl-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1000 mg, 3.52 mmol), 4-bromofuran- 2(5H)-one (860 mg, 5.28 mmol), Pd(OAc) 2 (79 mg, 0.352 mmol), Xantphos (305 mg, 0.528 mmol), and K 2 CO 3 (972 mg, 7.03 mmol).
- Step D tert-butyl 4-iodo-3-methyl-l-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8- diazaspiro [4.5] decane- 8 -carboxylate : To a solution of the compound of step C (370 mg, 1.01 mmol) in toluene (20 mL) at rt was added PPI13 (397 mg, 1.515 mmol), imidazole (137 mg, 2.02 mmol), and I 2 (384 mg, 1.515 mmol). The mixture was stirred for 10 h at 100 °C, and quenched with NaHC0 3 aqueous solution.
- Step E 4-iodo-3-methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one:
- Step F 3-methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51dec-3-en-l-one: To a solution of the compound of Step E (180 mg, 0.478 mmol) in THF (4.8 mL) at rt was added 10- ethyl-2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (polymer-bound, 1.15 mmol/g, 2.5 g resin).
- Step A tert-Butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l,4-dioxo-2,8- diazaspiro [4.5] decane- 8 -carboxylate : To tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5- dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (see example I-37A and I- 37B, Step C, racemate prior to chiral HPLC separation)(200 mg, 0.546 mmol) in DCM (2.8 mL) was added sodium bicarbonate (68.8 mg, 0.819 mmol) and Dess-Martin periodinane (347 mg, 0.819 mmol).
- Step B tert-butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-4- (((trifluoromethyl)sulfonyl)oxy)-2 , 8 -diazaspiro [4.5] dec-3 -ene- 8 -carboxylate : To a flask containing tert-butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)- 1 ,4-dioxo-2,8- diazaspiro [4.5 ]decane- 8 -carboxylate (200 mg, 0.549 mmol) in THF (3 mL) was added NaHMDS (1.10 mL, 1 M in THF, 1.10 mmol) dropwise over 5 min at -78 °C.
- Step C tert-butyl 4-methyl-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8- diazaspiro [4.5] dec-3 -ene- 8 -carboxylate : tert-Butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l- oxo-4-(((trifluoromethyl)sulfonyl)oxy)-2,8-diazaspiro[4.5]dec-3-ene-8-carboxylate (180 mg, 0.363 mmol) was dissolved in THF (3.6 mL), and Pd(Ph 3 P)4 (209 mg, 0.181 mmol) was added, followed by trimethylaluminum (3.6 mL, 7.25 mmol) at 0 °C.
- Step D 4-methyl-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51dec-3-en-l-one tert-Butyl 4-methyl-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.5]dec-3- ene-8-carboxylate (130 mg, 0.359 mmol) in DCM (1.8 mL) was treated with TFA (0.8 mL, 10.7 mmol) at 0 °C to remove the Boc group which provided the TFA salt.
- Step A 5-bromo-4-ethyl-2-benzofuran-l(3H)-one: A mixture of 5-bromo-4-vinyl-2-benzofuran- l(3H)-one (2.0 g, 8.37 mmol) and Pd/C (400 mg) in 50 mL of MeOH was stirred at rt. under H 2 (1 atm) overnight, and then filtered. The filtrate was concentrated. The resulting oil was purified by column chromatography to give 5-bromo-4-ethyl-2-benzofuran-l(3H)-one.
- Step B 4-ethyl-5-vinyl-2-benzofuran-l(3H)-one: A mixture of 5-bromo-4-ethyl-2-benzofuran- l(3H)-one (1.81 g, 7.51 mmol), potassium vinyltrifluoroborate (1.21 g, 9.01 mmol) and
- Step C 4-ethyl-5-oxiran-2-yl-2-benzofuran-l(3H)-one: To a solution of 4-ethyl-5-vinyl-2- benzofuran-l(3H)-one (1.1 g, 5.85 mmol) in 50 mL of DCM was slowly added mCPBA (3.60 g, 85% purity, 17.6 mmol) in 50 mL of DCM at 0 °C. The mixture was warmed to room
- Step A 5-bromo-4-iodo-2-benzofuran-l(3H)-one: To a cooled (0 °C) solution of 5-bromo-2- benzofuran-l(3H)-one (50 g, 0.235 mol) in trifluoromethanesulfonic acid (400 mL) was added N-iodosuccinimide (55.5 g, 0.247 mol). The resulting mixture was stirred at room temperature overnight, then poured slowly into ice water (2 L), filtered and the filtrate extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated to give
- Step B 5-bromo-4-vinyl-2-benzofuran-l(3H)-one: A mixture of 5-bromo-4-iodo-2-benzofuran- l(3H)-one (1 g, 2.95 mmol), potassium vinyltrifluoroborate (474 mg, 3.54 mmol) and
- Step C 5-bromo-4-cyclopropyl-2-benzofuran-l(3H -one: To a cooled (0 °C) mixture of 5- bromo-4-vinyl-2-benzofuran-l(3H)-one (2.2 g, 9.21 mol) and Pd(OAc) 2 (100 mg) in EtOAc (50 mL) was added a solution of CH 2 N 2 in ether (100 mL) slowly. The resulting mixture was stirred at room temperature overnight, then quenched with acetic acid, filtered and the filtrate washed with water and brine, dried and concentrated to provide title compound.
- Step D 4-cyclopropyl-5-vinyl-2-benzofuran-l(3H -one: A mixture of 5-bromo-4-cyclopropyl-2- benzofuran-l(3H)-one (760 mg, 3.004 mmol), potassium vinyltrifluoroborate (805 mg, 6.01 mmol) and Pd(dppf)Cl 2 (100 mg) in 20 mL of TEA and 20 mL of EtOH was heated to reflux under N 2 for 8 hours. After TLC showed complete reaction, then most of the solvent was removed and the residue was dissolved in EtOAc (100 mL). The solution was washed with 0.1 N HCl, sodium bicarbonate, and brine, dried over sodium sulfate, filtered and concentrated. The resulting oil was purified by column chromatography to give the title compound.
- Step E 4-cyclopropyl-5-oxiran-2-yl-2-benzofuran-l(3H)-one: _To a solution of 4-cyclopropyl-5- vinyl-2-benzofuran-l(3H)-one (440 mg, 2.2 mmol) in 50 mL of DCM was slowly added mCPBA (1.14 g, 6.6 mmol) in 50 mL of DCM at 0 °C. After warming to room temperature, the mixture was stirred for 12 hours. The mixture was washed with aqueous Na 2 S0 3 until KI paper didn't change color. The organic layers were combined, washed with brine and then concentrated. The residue was purified via prep-TLC to give the title compound.
- Step A 2-chloro-3-(hvdroxymethyl)phenol: To a solution of 2-chloro-3-hydroxybenzaldehyde (8.10 g, 51.7 mmol) in MeOH was added NaBH 4 (1.96 g, 51.7 mmol) at 0 °C. The reaction was allowed to stir for 30 minutes. The reaction was then diluted with EtOAc (400 mL), washed with water and brine, dried over sodium sulfate, and concentrated. The crude product was used in Step B without further purification.
- Step B 4-bromo-2-chloro-3-(hvdroxymethyl)phenol: To a flask charged with 2-chloro-3- (hydroxymethyl)phenol and a stir bar was added NBS (10.8 g, 60.5 mmol) and TFA (50 mL). The reaction was allowed to stir for 16 hours at RT, then the solvent was removed under vacuum. The residue was re-dissolved in EtOAc, washed with water, and purified by silica gel flash chromatography. A pair of regio-isomers was collected from the separation. The less polar spot was the desired 4-bromo-2-chloro-3-(hydroxymethyl)phenol according to NMR analysis.
- Step C 4-chloro-5-hydroxy-2-benzofuran-l(3H -one: To a flask charged with 4-bromo-2- chloro-3-(hydroxymethyl)phenol (2.44 g, 10.3 mmol) and a stir bar, was added CuCN (2.76 g, 30.8 mmol) and DMF (25 mL). The flask was fitted with a condenser and purged three times with Nitrogen. The solution was then heated to 145 °C for 2 hours. At that point, water (0.555 mL, 30.8 mmol) was added to the reaction via a syringe, and the reaction was kept at 100 °C for another 24 hours. The reaction was cooled to RT, diluted with DCM (100 mL), and filtered through a pad of CELITE® to remove the solids. The filtrate was washed with saturated
- Step D 4-chloro-5-ethenyl-2-benzofuran-l(3H)-one: To a cold solution of 4-chloro-5-hydroxy- 2-benzofuran-l(3H)-one (1.39 g, 7.53 mmol) in DCM (25 mL) was added Hunig's Base (3.29 mL, 18.8 mmol) and trif uoromethanesulfonic anhydride (2.54 mL, 15.1 mmol). The mixture was allowed to stir for 16 hours. Analysis by TLC showed complete consumption of all SM. The reaction was diluted with hexane and washed with water.
- Step E 4-chloro-5-oxiran-2-yl-2-benzofuran-l(3H)-one: To a solution of 4-chloro-5-ethenyl-2- benzofuran-l(3H)-one (1.1 g, 5.7 mmol) in DCM (40 mL) was added mCPBA (1.9 g, 8.5 mmol). The solution was allowed to stir at RT for 16 hours. Analysis by TLC and LC showed formation of the desired product. The reaction was diluted with DCM (200 mL), washed with aqueous Na 2 S 2 0 3 and Na 2 C0 3 , dried over sodium sulfate, concentrated, and purified by silica gel flash chromatography to afford title compound.
- Step B 4-fluoro-5-vinyl-3H-isobenzofuran-l-one: A mixture of 5-bromo-4-fluoro-2-benzofuran- l(3H)-one (5.0 g, 21.6 mmol), potassium vinyltrifluoroborate (4.4 g, 32.5 mmol) and
- Step C 4-fluoro-5-oxiranyl-3H-isobenzofuran-l-one: To a solution of 4-fluoro-5-vinyl-3H- isobenzofuran-l-one (4.0 g, 17.3 mmol) in 100 mL of DCM was slowly added mCPBA (6.0 g, 85% purity, 34.6 mmol) in 50 mL of DCM at 0 °C. After warming to room temperature, the mixture was stirred overnight. The mixture was washed with aqueous Na 2 S0 3 until KI paper didn't change color. The organic layers were washed with brine and then concentrated.
- mCPBA 6.0 g, 85% purity, 34.6 mmol
- Step A (li?,56',E)-tert-butyl 7-(l-cyano-2-methoxy-2-oxoethylidene)-3-oxa-9- azabicyclo[3.3.1 ]nonane-9-carboxylate: A solution of methyl 2-cyanoacetate (4.39 mL, 49.7 mmol), (li?,55)-tert-butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (8 g, 33.2 mmol), ammonium acetate (3.83 g, 49.7 mmol), and acetic acid (7.59 ml, 133 mmol) in toluene (100 ml) was heated at 150 °C overnight and the water generated was separated by Dean-Stark trap.
- Step B (lR,5SJs)-tert-butyl 7-(l-cyano-2-methoxy-2-oxoethyl)-7-vinyl-3-oxa-9- azabicyclo[3.3.1 "
- nonane-9-carboxylate To a suspension of (li?,55',E)-tert-butyl 7-(l-cyano-2- methoxy-2-oxoethylidene)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (10.82 g, 33.6 mmol) and copper(I) iodide (6.39 g, 33.6 mmol) in tetrahydrofuran at 0°C was added vinylmagnesium bromide (50.3 ml, 50.3 mmol) slowly over 2h.
- Step C 2-((li?,56',7s)-9-(tert-butoxycarbonyl)-7-vinyl-3-oxa-9-azabicyclo[3.3.1 "
- Step D (lR,5S,7r)-tert-butyl 7-(cyanomethyl)-7-vinyl-3-oxa-9-azabicyclo[3.3.11nonane-9- carboxylate: A solution of 2-((li?,55',7s)-9-(tert-butoxycarbonyl)-7-vinyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-2-cyanoacetic acid (1.10 g, 3.27 mmol) in DMF (10 mL) was heated at 130 °C for 20 min.
- Step E (lR,5S,7r)-tert-butyl 7-(cyanomethyl)-7-formyl-3-oxa-9-azabicyclo[3.3.1 ]nonane-9- carboxylate: To a solution of (lR,5S,7r)-tert-butyl 7-(cyanomethyl)-7-vinyl-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate (0.66 g, 2.257 mmol) in dioxane (10 ml) and water (3 ml) was added sodium periodiate (1.931 g, 9.03 mmol) and osmium tetroxide (0.035 ml, 0.113 mmol).
- Step G (l ⁇ ⁇ -g-tert-butyl 7-methyl 7-(cyanomethyl)-3-oxa-9-azabicyclo[3.3.1 ]nonane-7,9- dicarboxylate: To a solution of (li?,55',7r)-9-(tert-butoxycarbonyl)-7-(cyanomethyl)-3-oxa-9- azabicyclo[3.3.1]nonane-7-carboxylic acid (646 mg, 2.082 mmol) in methanol (10 ml) was added TMS-diazomethane (5.20 ml, 10.41 mmol) dropwise until there was no bubble generation, and then the reaction was quenched by addition of acetic acid (a few drops). The mixture was concentrated to give the title compound. LC/MS: (M+23) + : 346.98.
- Step H (lR,5S r)-9-tert-butyl 7-methyl 7-(2-aminoethyl)-3-oxa-9-azabicyclo[3.3. l]nonane-7,9- dicarboxylate: A mixture of (li?,55',7r)-9-tert-butyl 7-methyl 7-(cyanomethyl)-3-oxa-9- azabicyclo[3.3.1]nonane-7,9-dicarboxylate (0.58 g, 1.788 mmol) and platinum(IV) oxide (0.082 g, 0.358 mmol) in methanol (10 ml) and acetic acid (10 ml) was hydrogenated at 45 Psi over the weekend. After filtration through CELITE® under nitrogen, the filtrate was concentrated to give the title compound. LC/MS: (M+l) + : 329.04.
- Step I (lR3'r,5S)-tert-butyl 2 , -oxo-3-oxa-9-azaspiro[bicyclo[3.3.11nonane-7,3'-pyrrolidinel-9- carboxylate: A mixture of (li?,55',7r)-9-tert-butyl 7-methyl 7-(2-aminoethyl)-3-oxa-9- azabicyclo[3.3.1]nonane-7,9-dicarboxylate (0.59 g, 1.797 mmol) and potassium carbonate (1.490 g, 10.78 mmol) in methanol (50 ml) was heated at reflux for 4h.
- Step J (lR.3'r.5S -tert-butyl r-(4-methyl-5-oxo-2,5-dihvdrofuran-3-vn-2 , -oxo-3-oxa-9- azaspiro[bicyclo[3.3.1 lnonane-7,3 , -pyrrolidinel-9-carboxylate: To a mixture of (li?,3'r,55)-tert- butyl 2'-oxo-3-oxa-9-azaspiro[bicyclo[3.3.1]nonane-7,3'-pyrrolidine]-9-carboxylate (0.42 g, 1.417 mmol) and 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifiuoromethanesulfonate (0.454 g,
- Step K (li?,3 , r,5 t ⁇ -r-(4-methyl-5-oxo-2,5-dihvdrofuran-3-vn-3-oxa-9- azaspiro[bicyclo[3.3.1 Inonane ⁇ J'-pyrrolidinl ⁇ '-one: To a solution of (li?,3'r,55)-tert-butyl ⁇ - (4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2'-oxo-3-oxa-9-azaspiro[bicyclo[3.3.1]nonane-7,3'- pyrrolidine]-9-carboxylate (0.22 g, 0.561 mmol) in methylene chloride (4 mL) was added trifluroroacetic acid (4 ml, 51.9 mmol), and the resulting solution was stirred at rt for 2h. After removing the volatiles the residue was basified on an i
- Step A ethyl 1 -benzyl-4-(cyanomethyl)-3-oxopiperidine-4-carboxylate: Into a 250-mL 3-necked round-bottom flask was placed a solution of ethyl l-benzyl-3-oxopiperidine-4-carboxylate (10 g, 38.27 mmol, 1.00 equiv) in tetrahydrofuran (80 mL).
- Step B ethyl 4-(2-aminoethyl)- 1 -benzyl-3 -hydroxypiperidine-4-carboxylate :
- a solution of ethyl l-benzyl-4-(cyanomethyl)-3- oxopiperidine-4-carboxylate 180 g, 599.30 mmol
- acetic acid/methaol 1 : 1, 5.4L
- platinum oxide 27 g, 118.90 mmol
- Step C 8-benzyl-6-hydroxy-2,8-diazaspiro
- Step D cis-tert-butyl 6-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8- diazaspiro [4.5] decane- 8 -carboxylate : Into a 2000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 8-benzyl-6-hydroxy- 2,8-diazaspiro[4.5]decan-l-one (46.3 g, 177.85 mmol, 1.00 equiv), Cs 2 C0 3 (115.9 g, 354.62 mmol, 1.99 equiv), Xantphos (6.17 g, 10.66 mmol, 0.06 equiv), Pd 2 (dba) 3 (5.52 g, 6.03 mmol, 0.03 equiv) and 4-methyl-5-oxo-2,5-dihydrofuran-3-
- Step D tert-butyl 6-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2,8- diazaspiro [4.5] decane- 8 -carboxylate (CIS) : To a solution of 8-benzyl-6-hydroxy-2-(2-methyl-3- oxocyclopent-l-en-l-yl)-2,8-diazaspiro[4.5]decan-l-one (CIS) (10 g, 28.2 mmol) and di-tert- butylcarbonate (7.21 ml, 31.0 mmol) in methanol (50 ml) was added palladium on carbon (1.501 g, 1.411 mmol), and the resulting mixture was subjected to hydrogenation at 45 Psi at rt over the weekend.
- CIS 8-benzyl-6-hydroxy-2-(2-methyl-3- oxocyclopent-l-en-l-y
- Step E tert-butyl 6-methoxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)- 1 -oxo-2,8- diazaspiro[4.51decane- 8 -carboxylate (CIS, faster) and tert-butyl 6-methoxy-2-(4-methyl-5-oxo- 2,5-dihydrofuran-3-yl)-l-oxo-2,8-diazaspiro[4.51decane-8-carboxylate (CIS, slower).
- Step F 6-methoxy-2-(4-methyl-5 -oxo-2,5 -dihydrofuran-3 -yl)-2, 8-diazaspiro [4.5] decan- 1 -one (CIS, faster): To a solution of tert-butyl 6-methoxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l- oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (CIS, faster) (2.17 g, 5.70 mmol) in methylene choride (7 mL) was added trifluoroacetic (7 mL, 91 mmol) and the resulting solution was stirred at rt for 2h.
- isomer “A” and isomer “B,” refer to the faster eluting and slower eluting diastereomers, respectively, based on the observed elution order of the individual diastereomers upon separation from its isomer mixture. Except for a defined chiral center in the parent isomer mixture, absolute stereochemistry of each of the separated isomers was not determined unless stated otherwise.
- an asterisk may be used in the associated chemical structure drawing that indicates the location of the unassigned chiral center.
- Example 6 The product of Example 6 was resolved using SFC eluting with 30% MeOH (0.2%DEA)/ C02 on Chiralcel OD column to give Isomer 6A (faster eluting) :LC-MS (IE, m/z): 441.3; and Isomer 6B (slower eluting): LC-MS (IE, m/z): 441.3 (M+l) + .
- Step A 8-r(2 ⁇ -2-hvdroxy-2-(4-methyl -oxo -dihvdro-2-benzofuran-5-vnethyl1-2-(4-methyl- 5 -oxo-2,5 -dihydrofuran-3 -yO-2, 8-diazaspiro [4.5] decan- 1 -one : To a suspension of 4-methyl-5- [(25)-oxiran-2-yl]-2-benzofuran-l(3H)-one (I-4A)(200 mg, 1.05 mmol) and 2-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-l-one (300 mg, 1.05 mmol) in 10 mL of EtOH was added DIPEA (271 mg, 2.10 mmol).
- Step B 8-r(2i? -2-fluoro-2-(4-methyl-l-oxo-1 -dihvdro-2-benzofuran-5-vnethyl1-2-(4-methyl- 5 -oxo-2,5 -dihydrofuran-3 -yl)-2, 8-diazaspiro [4.5] decan- 1 -one : To a solution of the product of Step A, (170 mg, 0.39 mmol) in 5 mL of DCM was added Et 3 N 3HF (10 drops) and DAST (5 drops) at -78 °C. The mixture was stirred overnight and quenched with aqueous NaHC0 3 .
- Step A (5V8-(2-chloro-2-(4-methyl- 1 -oxo- 1 ,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5- oxo-2,5-dihydromran-3-yl)-2,8-diazaspiro[4.5 "
- decan-l-one To a solution of 8-[(2i?)-2-hydroxy- 2-(4-methyl- 1 -oxo- 1 ,3 -dihydro-2-benzofuran-5 -yl)ethyl] -2-(4-methyl-5 -oxo-2,5 -dihydrofuran-3 - yl)-2,8-diazaspiro[4.5]decan-l-one (Example 7) (1.1 g, 2.5 mmol) and methanesulfonyl chloride (0.584 mL, 7.49 mmol) in DCM (30 mL) was
- Step B 8-r(2i? -2-methoxy-2-(4-methyl-l-oxo-l,3-dihvdro-2-benzofuran-5-vnethyll-2-(4- methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo-2-aza-8-azoniaspiro[4.51decane:
- One small piece of sodium metal in methanol (20 mL) was stirred until the sodium disappeared.
- the product of Step A (45 mg, 0.098 mmol) was added to the solution. The mixture was stirred at rt for 20 min. 3 mL I N HCl was added, and the mixture was concentrated.
- the reaction mixture was concentrated and purified by column chromatography (0-10% MeOH/DCM) to separate the syn and anti isomers.
- Step A 8-(2-(4-methyl- 1 -oxo- 1 ,3-dihydroisobenzofuran-5-yl)-2-oxoethyl)-2-(4-methyl-5-oxo- 2,5-dihydromran-3-yl)-2,8-diazaspiro
- Step B 8-(2-(cyclopropylamino)-2-(4-methyl-l-oxo-l,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4- methyl-5 -oxo-2,5 -dihydrofuran-3 -yl)-2, 8-diazaspiro [4.5] decan- 1 -one : To a mixture of 8-(2-(4- methyl- 1 -oxo- 1 ,3-dihydroisobenzofuran-5-yl)-2-oxoethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-
- Step A (5V8-(2-azido-2-(4-methyl- 1 -oxo- 1 ,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5- oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one: To a suspension of 8-[(2i?)-2- hydroxy-2-(4-methyl- 1 -oxo- 1 ,3 -dihydro-2-benzofuran-5 -yl)ethyl] -2-(4-methyl-5 -oxo-2,5 - dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-l-one (Example 7, 300 mg, 0.68 mmol) and diphenylphosphoryl azide (578 mg, 1.36 mmol ) in a mixed solvent of toluene and
- Step B (y)-8-(2-amino-2-(4-methyl-l-oxo-l,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5- oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one: To a solution of (5)-8-(2-azido-2-(4- methyl- 1 -oxo- 1 ,3-dihydroisobenzofuran-5-yl) ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)- 2,8-diazaspiro[4.5]decan-l-one (200 mg, 0.43 mmol) in a mixed solvent of tetrahydrofuran and water (v:v, 12: 1, 20 mL) was added triphenylphosphine (225 mg, 0.86 m
- Step A (i?)-8-(2-azido-2-(4-methyl-l-oxo-l ,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5- oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one: To a suspension of 8-[(25)-2- hydroxy-2-(4-methyl- 1 -oxo- 1 ,3 -dihydro-2-benzofuran-5 -yl)ethyl] -2-(4-methyl-5 -oxo-2,5 - dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-l-one (Example 8, 500 mg, 1.13 mmol)
- Step C (i?)-8-(2-amino-2-(4-methyl- 1 -oxo- 1 ,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5- oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one: To a solution of (i?)-8-(2-azido-2-(4- methyl- 1 -oxo- 1 ,3-dihydroisobenzofuran-5-yl) ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)- 2,8-diazaspiro[4.5]decan-l-one (250 mg, 0.54 mmol) in a mixed solvent of tetrahydrofuran and water (v : v, 12 : 1, 20 mL) was added triphenylphosphine (2
- Step A (R)- 1 '-(2-hydroxy-2-(4-methyl- 1 -oxo-1 ,3-dihydroisobenzofuran-5- yl)ethyl)spiro[indoline-3,4'-piperidinl -2-one:
- Commercially available spiro [indoline-3, 4'- piperidin] -2-one hydrochloride 500 mg, 2.10 mmol
- 4-methyl-5-[(25)- oxiran-2-yl]-2-benzofuran-l(3H)-one (I-4A) (398 mg, 2.10 mmol) and DIEA (439 ⁇ , 2.51 mmol) in ethanol (7 mL) and heated at 80 °C for 3 h.
- the reaction mixture was concentrated and purified by MPLC eluting first with 30% ethyl acetate/hexanes and then with 10%
- Step B r-r(2i? -2-hvdroxy-2-(4-methyl-l-oxo-1 -dihvdro-2-benzofuran-5-vnethyl1-2-oxo-l-(5- oxo-2,5-dihydromran-3-yl)-l ,2-dihydrospiro[indole-3,4'-piperidiniuml : (R)- 1 '-(2-hydroxy-2-(4- methyl- 1 -oxo- 1 ,3 -dihydroisobenzofuran-5 -yl)ethyl)spiro [indoline-3 ,4'-piperidin] -2-one (502 mg, 1.28 mmol), 4-bromofuran-2-one (250 mg, 1.53 mmol), cesium carbonate (625 mg, 1.92 mmol), Pd(dba) 2 (37 mg, 0.064 mmol), Xantphos
- Step B 5 -(3 -((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl)-4-methylisobenzofuran- 1 (3H)- one : To a solution of 5-(2,3-dihydroxypropyl)-4-methylisobenzofuran-l(3H)-one (2.00 g, 9.0 mmol) in dry DMF (20 mL) was added imidazole (1.20 g, 18.0 mmol) and TBSC1 (1.50 g, 9.9 mmol).
- reaction mixture was diluted with CH2CI2 (50 mL) and washed with H2O (3 X 20 mL) and saturated NaHC0 3 (3 X 20 mL). The combined aqueous layers were extracted five times with CH 2 CI 2 (20 mL). The combined organic layers were washed with brine (3 X 30 mL), dried over Na2SC"4, filtered and concentrated. The residue was purified by flash column chromatography (0-60% ethyl acetate in petroleum ether) to give the title compound.
- Step C 5 -(3 -((tert-butyldimethylsilyl)oxy)-2-oxopropyl)-4-methylisobenzofuran- 1 (3H)- one : To a solution of 5-(3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl)-4-methylisobenzofuran-l(3H)- one (1.00 g, 3.0 mmol) in CH 2 CI 2 (30 mL) was added Dess-Martin periodinane (6.30 g, 15.0 mmol).
- Step D 8 -( 1 -((tert-butyldimethylsilyl)oxy)-3 -(4-methyl- 1 -oxo- 1 ,3 -dihydroisobenzofuran-5 - yl)propan-2-yl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one: To a solution of 5-(3-((tert-butyldimethylsilyl)oxy)-2-oxopropyl)-4-methylisobenzo furan-l(3H)-one (0.50 g, 1.5 mmol) in methanol (20 mL) was added 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)- 2,8-diazaspiro[4.5]decan-l-one (1-17) (0.45 g, 1.8 mmol) and titanium(
- Step E 8-(l -hydroxy-3 -(4-methyl- 1 -oxo-1 ,3-dihydroisobenzoi ran-5-yl)propan-2-yl)-2-(4- methyl-5 -oxo-2,5 -dihydro furan-3 -yl)-2, 8-diazaspiro [4.5] decan- 1 -one : To a solution of 8-(l- ((tert-butyldimethylsilyl)oxy)-3 -(4-methyl- 1 -oxo- 1 ,3 -dihydro isobenzofuran-5 -yl)propan-2-yl)-2- (4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-l-one (0.10 g, 0.18 mmol) in DCM (3 mL) was added trifluoroacetic acid (3 mL) at m
- Step A 2,8-diazaspiror4.51decan-l-one: To a solution of tert-butyl l-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (I- 1 1) (5.0 g, 19.7 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (15.2 mL, 197 mmol) and the resulting solution was stirred at rt for lh. After evaporating the volatiles the residue was basified on ion exchange column washed with methanol followed by 1 N ammonia in methanol to give 2,8-diazaspiro[4.5]decan-l-one. LC/MS: (M+l) + : 155.1 1
- Step B ethyl 2-methyl-2-(l-oxo-2,8-diazaspiro[4.51decan-8-yl)propanoate: A mixture of 2,8- diazaspiro[4.5]decan-l-one (3.03 g, 19.65 mmol), triethylamine (5.48 ml, 39.3 mmol) and ethyl 2-bromo-2-methylpropanoate (5.77 ml, 39.3 mmol) was heated at 80 °C overnight. The reaction mixture was partitioned between methylene chloride (200 mL) and saturated sodiun bicarbonate, the alkaline phase was extracted with methylene chloride (3x100 mL). The combined organic phase was dried over magnesiun sulfate, concentrated and the residue was purified on silica gel using methanol/methylene chloride to give the title compound. LC/MS (M+l) + : 269.4
- Step C 2-methyl-2-(l-oxo-2,8-diazaspiror4.51decan-8-yl)propanal: .To a solution of ethyl 2- methyl-2-(l-oxo-2,8-diazaspiro[4.5]decan-8-yl)propanoate (3.77 g, 14.1 mmol) in toluene (100 mL) at -78 °C was added DIBAL-H (45.0 mL, 45.0 mmol) dropwise.
- Step D 4-methyl-5 -(trimethylstannyl)isobenzofuran- 1 (3H - one :
- Step E 5-bromo-4-methylisobenzofuran-l(3H)-one: To a solution of 4-methyl-5-
- Step F 5-bromo-4-methyl-l ,3-dihydroisobenzofuran-l-ol: To a solution of 5-bromo-4- methylisobenzofuran-l(3H)-one (3.45 g, 15.19 mmol) in toluene (100 mL) at -78°C was added DIBAL-H (21.27 mL, 21.27 mmol) dropwise. After stirring at -78 °C for 2h, the reaction was quenched by methanol at -78°C, then warmed to rt , then 20 mL of saturated sodium sulfate was added and the mixture was vigorously stirred at rt for 30 min.
- Step G ((5-bromo-4-methyl- 1 ,3-dihydroisobenzofuran- 1 -yl)oxy)(tert-butyl)dimethylsilane
- Step H 8 -( 1 -( 1 -((tert-butyldimethylsilyl)oxy)-4-methyl- 1 ,3 -dihydroisobenzofuran-5 -yl)- 1 - hydroxy-2-methylpropan-2-yl)-2,8-diazaspiro[4.51decan- 1 -one: To a solution of ((5-bromo-4- methyl- l,3-dihydroisobenzofuran-l-yl)oxy)(tert-butyl)dimethylsilan (3.9 g, 11.36 mmol) in tetrahydrofuran (50 ml) at -78 °C was addded N-butyllithium (5.00 ml, 12.50 mmol).
- Step I 8-(l-(l -((tert-butyldimethylsilyl)oxy)-4-methyl- 1 ,3 -dihydroisobenzofuran-5 -yl)- 1 - hydroxy-2-methylpropan-2-yl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8- diazaspiro [4.5] decan- 1 -one : To a mixture of 8-(l-(l-((tert-butyldimethylsilyl)oxy)-4-methyl-l,3- dihydroisobenzofuran-5-yl)- 1 -hydroxy-2-methylpropan-2-yl)-2,8-diazaspiro[4.5]decan- 1 -one (1.35 g, 2.76 mmol), 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (1-9) (0.884
- Step J 8 -( 1 -hydroxy- 1 -( 1 -hydroxy-4-methyl- 1 ,3 -dihydroisobenzofuran-5 -yl)-2-methylpropan-2- yl)-2-(4-methyl-5 -oxo-2,5 -dihydrofuran-3 -yl)-2, 8-diazaspiro [4.5] decan- 1 -one : To a solution of the product of Step 1 (1.282 g, 2.192 mmol) in tetrahydrofuran (50 ml) was added TBAF (2.63 mL, 2.63 mmol) at 0 °C, and the resulting solution was stirred at 0 °C for 2h. After
- Step K 8-(l -hydroxy-2 -methyl- 1 -(4-methyl- 1 -oxo- 1 ,3-dihydroisobenzofuran-5-yl)propan-2-yl)- 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan-l-one:
- PCC 311 mg, 1.45 mmol
- reaction mixture was partitioned between methylene chloride and saturated bicarbonate, and the alkaline phase was extracted with methylene chloride (3x50 mL). The combined organic phase was dried over sodium sulfate, concentrated and the residue was purified on TLC using 10%
- Step L 8-( 1 -hydroxy-2 -methyl- 1 -(4-methyl- 1 -oxo- 1 ,3 -dihydroisobenzofuran-5 -yl)propan-2-yl)- 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.51decan- 1 -one (separated single isomers): The title compound (an isomer mixture) (100 mg, 0.213 mmol) was separated by SFC on OJ column to give two isomers.
- HEK293 cells stably expressing hROMK (hKi r l .l) were grown at 37°C in a 10%CO 2 humidified incubator in complete growth media: Dulbecco's Modified Eagle
- Reagent preparation FluxOR Working Solutions • 1000X FluxORTM Reagent: Reconstitute a vial of component A in 100 ⁇ DMSO; Mix well; Store 10 ⁇ aliquots at -20°C
- Loading Buffer (per microplate): 10 ⁇ 1000X FluxORTM Reagent; 100 ⁇ component C; 10 mL Probenecid/ Assay Buffer
- Compound Buffer (per microplate): 20 mL Probenecid/ Assay Buffer; 0.3 mM ouabain (10 mM ouabain in water can be stored in amber bottle/aluminum foil at room temperature); Test compound
- Stimulant Buffer prepared at 5X final concentration in IX FluxORTMChloride-Free Buffer: 7.5 mM Thallium sulfate and 0.75 mM Potassium sulfate (to give a final assay concentration of 3 mM Thallium/ 0.3 mM Potassium). Store at 4°C when not in use. If kept sterile, this solution is good for months.
- Assay protocol- The ROMK channel functional thallium flux assay is performed in 384 wells, using the FLIPR-Tetra instrument. HEK-hKirl .1 cells are seeded in Poly-D-Lysine microplates and kept in a 37°C-10%CO 2 incubator overnight. On the day of the experiment, the growth media is replaced with the FluxORTM reagent loading buffer and incubated, protected from light, at ambient temperature (23-25°C) for 90 min. The loading buffer is replaced with assay buffer ⁇ test compound followed by 30 min incubation at ambient temperature, where the Thallium/Potassium stimulant is added to the microplate.
- control compound is included to support that the assay is giving consistent results compared to previous measurements, although the control is not required to obtain the results for the test compounds.
- the control can be any compound of Formula I of the present invention, preferably with an IC50 potency of less than 1 ⁇ in this assay.
- the control could be another compound (outside the scope of Formula I) that has an IC50 potency in this assay of less than 1 ⁇ .
- test pulse consisting of a 100 ms step to 0 mV from a holding potential of -70 mV, followed by a 100 ms voltage ramp from -70 mV to +70 mV, was applied before and after a 6 min compound incubation period.
- Test compounds were prepared by diluting DMSO stock solutions into the bath solution at 3x the final concentration and placed in the instrument in 96-well polypropylene plates. Current amplitudes were measured using the Ion Works software.
- control compound is included to support that the assay is giving consistent results compared to previous measurements, although the control is not required to obtain the results for the test compounds.
- the control can be any compound of Formulas I-V of the present invention, preferably with an IC50 potency of less than
- control could be another compound (outside the scope of Formulas I-V) that has an IC50 potency in this assay of less than 1 ⁇ .
- Data collected for compounds in the Examples of the present invention using the Thallium Flux Assay and the Electrophysiology Assay are shown in Table 5 below. All of the tested final product compounds in the Examples (diastereomeric mixtures and individual diastereomers) had IC50 potencies less thanl ⁇ in one or both of the Thallium Flux Assay and the Electrophysiology Assay.
- the spontaneously hypertensive rat exhibits age-dependent hypertension that does ire administration of exogenous agents to elevate blood pressure nor does it require the high salt diet to elevate blood pressure. Thus it resembles human essential hypertension and provides an opportunity to assess the dose-dependence of novel agents for their ability to lower blood pressure.
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EP13745315.5A EP2877471B1 (en) | 2012-07-26 | 2013-07-25 | Spiro-fused piperidine derivatives for use as inhibitors of the renal outer medullary potassium channel |
KR20157001566A KR20150036142A (en) | 2012-07-26 | 2013-07-25 | Spiro - fused piperidine derivatives for use as inhibitors of the renal outer medullary potassium channel |
CN201380039265.6A CN104540826B (en) | 2012-07-26 | 2013-07-25 | The piperidine derivative of the spiro-condensed of inhibitor as kidney medulla externa potassium channel |
RU2015106139A RU2642066C2 (en) | 2012-07-26 | 2013-07-25 | Spiro-fused piperidine derivatives for application as inhibitors of external medullar layer potassium channel |
MX2015001115A MX365986B (en) | 2012-07-26 | 2013-07-25 | Spiro - fused piperidine derivatives for use as inhibitors of the renal outer medullary potassium channel. |
AU2013295722A AU2013295722B2 (en) | 2012-07-26 | 2013-07-25 | Spiro - fused piperidine derivatives for use as inhibitors of the renal outer medullary potassium channel |
BR112015001419A BR112015001419A8 (en) | 2012-07-26 | 2013-07-25 | compound, pharmaceutical composition, and use of a compound or a pharmaceutically acceptable salt thereof |
CA2876508A CA2876508A1 (en) | 2012-07-26 | 2013-07-25 | Spiro-fused piperidine derivatives for use as inhibitors of the renal outer medullary potassium channel |
ES13745315.5T ES2606016T3 (en) | 2012-07-26 | 2013-07-25 | Spiro condensed piperidine derivatives for use as inhibitors of renal external medullary potassium channel |
JP2015524451A JP6166783B2 (en) | 2012-07-26 | 2013-07-25 | Spiro-fused piperidine derivatives used as inhibitors of renal medullary outer layer potassium channels |
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BR112015001419A2 (en) | 2017-07-04 |
KR20150036142A (en) | 2015-04-07 |
JP6166783B2 (en) | 2017-07-19 |
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MX2015001115A (en) | 2015-04-08 |
EP2877471B1 (en) | 2016-11-02 |
CN104540826A (en) | 2015-04-22 |
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TW201410675A (en) | 2014-03-16 |
RU2642066C2 (en) | 2018-01-24 |
AU2013295722A1 (en) | 2015-01-15 |
BR112015001419A8 (en) | 2019-07-30 |
AU2013295722B2 (en) | 2017-12-07 |
CN104540826B (en) | 2018-04-20 |
AR092031A1 (en) | 2015-03-18 |
CA2876508A1 (en) | 2014-01-30 |
RU2015106139A (en) | 2016-09-20 |
ES2606016T3 (en) | 2017-03-17 |
US9206198B2 (en) | 2015-12-08 |
US8952166B2 (en) | 2015-02-10 |
EP2877471A1 (en) | 2015-06-03 |
US20140031349A1 (en) | 2014-01-30 |
US20150099729A1 (en) | 2015-04-09 |
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