WO2016069376A1 - Novel methyl-piperidine compounds useful for inhibiting microsomal prostaglandin e2 synthase-1 - Google Patents

Novel methyl-piperidine compounds useful for inhibiting microsomal prostaglandin e2 synthase-1 Download PDF

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WO2016069376A1
WO2016069376A1 PCT/US2015/056960 US2015056960W WO2016069376A1 WO 2016069376 A1 WO2016069376 A1 WO 2016069376A1 US 2015056960 W US2015056960 W US 2015056960W WO 2016069376 A1 WO2016069376 A1 WO 2016069376A1
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mmol
mixture
add
methyl
patient
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PCT/US2015/056960
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French (fr)
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Matthew Joseph Fisher
Steven Lee Kuklish
Peter Rudolph Manninen
Katherine Marie PARTRIDGE
Matthew Allen Schiffler
Alan M. Warshawsky
Jeremy Schulenburg York
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Eli Lilly And Company
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Priority to NZ730724A priority Critical patent/NZ730724A/en
Priority to AU2015339644A priority patent/AU2015339644B2/en
Priority to CA2963321A priority patent/CA2963321C/en
Priority to SI201531036T priority patent/SI3230278T1/en
Priority to DK15791432.6T priority patent/DK3230278T3/en
Priority to BR112017007011-1A priority patent/BR112017007011B1/en
Priority to LTEP15791432.6T priority patent/LT3230278T/en
Priority to CN201580058595.9A priority patent/CN107074829B/en
Priority to JP2017522866A priority patent/JP6393830B2/en
Priority to EP15791432.6A priority patent/EP3230278B1/en
Priority to EA201790766A priority patent/EA032428B1/en
Priority to PL15791432T priority patent/PL3230278T3/en
Priority to RS20200015A priority patent/RS59783B1/en
Priority to MX2017005659A priority patent/MX2017005659A/en
Priority to KR1020177011303A priority patent/KR101898829B1/en
Priority to ES15791432T priority patent/ES2773439T3/en
Priority to US15/520,462 priority patent/US9962375B2/en
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Publication of WO2016069376A1 publication Critical patent/WO2016069376A1/en
Priority to ZA2017/02198A priority patent/ZA201702198B/en
Priority to US15/972,699 priority patent/US20180250282A1/en
Priority to CY20201100076T priority patent/CY1122534T1/en
Priority to HRP20200216TT priority patent/HRP20200216T1/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
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Abstract

The present invention provides compounds of Formula (1), or a pharmaceutically acceptable salt thereof, formula (1), where R, R1, and G are as described herein; methods of preparing the compounds; and use of the compounds to treat pain and/or inflammation associated with arthritis or osteoarthritis.

Description

Novel Methyl-Piperidine Compounds Useful for Inhibiting
Microsomal Prostaglandin E2 Synthase- 1
The present invention relates to novel compounds; to pharmaceutical compositions comprising the compounds; methods of using the compounds to treat pain and/or inflammation associated with arthritis; and intermediates and processes useful in the synthesis of the compounds.
Arthritis involves inflammation of the joints and is often accompanied by pain and stiffness. Osteoarthritis, the most common form of arthritis, is a complex degenerative disease of the joints characterized by progressive destruction of articular cartilage; peri- articular structures including bones, synovium, and associated fibrous joint tissues; and varying degrees of inflammation. Existing drug therapies using non-steroidal, anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 inhibitors (COX-2 inhibitors) can reduce pain associated with
osteoarthritis, but may be only moderately effective over time and each has variable risk/benefit considerations.
The NSAIDs and COX-2 inhibitors reduce inflammation and pain through inhibition of the COX-2 enzymes. In response to pro-inflammatory stimuli, the COX-2 enzymes metabolize arachidonic acid to prostaglandin H2 (PGH2). PGH2 is further metabolized by a variety of enzymes to other eicosanoids including prostaglandin E2 (PGE2), prostaglandin I2 (PGI2), prostaglandin F2a (PGF2a), prostaglandin D2 (PGD2), and thromboxane A2 (TXA2). These metabolites are known to induce physiological and pathophysiological effects. It is thought that a drug-mediated imbalance of PGI2 and TXA2 may explain why NSAIDs and COX-2 inhibitors produce deleterious gastrointestinal and cardiovascular side-effects. Consequently, these classes of drugs may be contraindicated for many patients due to pre-existing or emergent
cardiovascular and/or gastrointestinal conditions. Additionally, patients can become refractory over time to specific drug treatments.
Of the arachidonic acid metabolites, PGE2has been identified as an important mediator of conditions associated with osteoarthritis; for example, fever, pain and inflammation.
Prostaglandin E2 is specifically produced through the metabolism of PGH2 by microsomal prostaglandin E2 synthase-1 (mPGES-1). It is thought that selectively inhibiting mPGES-1 may provide a new treatment option for patients suffering from arthritis.
Publication WO 2013/146970 discloses tri- substituted quinoline compounds and suggests that the disclosed compounds may be useful for treating inflammatory diseases inter alia.
However, that publication does not disclose compounds as claimed in this application.
There remains a need for additional options to treat the inflammation and alleviate the pain associate with arthritis. The present invention provides novel compounds that inhibit mPGES-1 and that may be beneficial for treating patients suffering from arthritis and
osteoarthritis.
The present invention provides compounds according to Formula 1, or pharmaceutically acceptable salts thereof,
Figure imgf000003_0001
1,
where Rl is H or -CH3; R is selected from:
Figure imgf000003_0002
Figure imgf000004_0001
2,
Figure imgf000005_0001
where: Rl is H or -CH3; R is selected from:
Figure imgf000005_0002
and
G is selected from:
Figure imgf000005_0003
Figure imgf000006_0001
The present invention also provides compounds according to Formulae 1 or 2, or pharmaceutically acceptable salts thereof, where Rl is -CH3.
For preferred compounds of Formulae 1 or 2, or pharmaceutically acceptable salts thereof, R is selected from:
Figure imgf000006_0002
Figure imgf000007_0001
For still more preferred compounds of Formulae 1 or 2, or pharmaceutically acceptable salts thereof, R is selected from:
Figure imgf000008_0001
For preferred compounds of Formulae 1 or 2, or pharmaceutical salts thereof, G is:
Figure imgf000008_0002
or
The present invention also provides a compound according to Formula 3, or a pharmaceutically acceptable salt thereof.
Figure imgf000008_0003
3 In one embodiment, compounds of Formulae 1, 2, or 3 are provided as a neutral species. In another embodiment, the compounds are provided as pharmaceutically acceptable salts. In one preferred salt form, the compound of Formula 3 is provided as hydrochloride salt.
The present invention also provides a pharmaceutically acceptable composition that includes a compound according Formulae 1, 2, or 3, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
The present invention also provides a method of treating a patient in need of treatment for pain associated with arthritis or osteoarthritis. The method comprises administering to the patient an effective amount of a pharmaceutically acceptable composition that includes a compound according Formulae 1, 2, or 3, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
The present invention also provides a method of treating a patient in need of treatment for arthritis or osteoarthritis. In one form, the present invention provides a method of treating a patient for the signs and/or symptoms of osteoarthritis. The method comprises administering to the patient an effective amount of a compound according to Formulae 1, 2, or 3, or a
pharmaceutically acceptable salt thereof.
The present invention also provides a method of treating a patient in need of treatment for inflammation associated with arthritis or osteoarthritis. The method comprises administering to the patient an effective amount of a pharmaceutically acceptable composition that includes a compound according to Formulae 1, 2, or 3, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
The present invention also provides a method of treating a patient in need of treatment for pain associated with arthritis. The method comprises administering to the patient an effective amount of a compound according to Formulae 1, 2, or 3, or a pharmaceutically acceptable salt thereof. The present invention further provides a method of treating a patient for pain associated with osteoarthritis. The method comprising administering to the patient an effective amount of a compound according compound according to Formulae 1, 2, or 3, or a pharmaceutically acceptable salt thereof.
The present invention provides a compound according Formulae 1, 2, or 3 for use as a medicament. The medicament or compound can be used for therapy. The therapy can include the treatment of the patient for arthritis or osteoarthritis. In one embodiment the therapy can be the treatment of pain or inflammation associated with arthritis or osteoarthritis.
The present invention also provides the use of a compound for the manufacture of a medicament to treat arthritis or osteoarthritis. In one form, the medicament is used to treat pain or inflammation associated with arthritis or osteoarthritis.
As used herein, the terms "treating" or "to treat" includes stopping or reducing the severity of an existing symptom or disorder, in particular the pain and/inflammation, associated with arthritis or osteoarthritis.
As used herein, the term "patient" refers to a mammals, such as a guinea pigs, rats, dogs, cats, cows, horses, sheep, goats or humans; or fowl such as a chickens or ducks. The preferred patient is a mammal, more preferably a human.
The exemplified compounds of the present invention can be formulated into
pharmaceutical compositions in accordance within accepted practices. Examples of
pharmaceutically acceptable carriers, excipients, and diluents can be found in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co. Easton Pa. 1990. Non-limiting examples include the following: starch, sugars, mannitol, and silica derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, glycerol monostearate;
adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium, and magnesium stearate, and solid polyethyl glycols. In one form, the pharmaceutical formulation includes 20% Captisol in 25 mM phosphate buffer pH 2.
Preferred pharmaceutical compositions can be formulated as a tablet or capsule for oral administration or as an injectable solution. The tablet, capsule, or solution will include a compound of the present invention in an amount effective for treating a patient in need of treatment.
As used herein, the term "effective amount" refers to the amount or dose of a compound of the invention, or a pharmaceutically acceptable salt thereof, which, upon a single or multiple dose administration to the patient, provides the desired effect, such as, the reduction or elimination of pain and/or inflammation the patient under diagnosis or treatment.
An effective amount can be readily determined by the attending diagnostician by using known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for a patient, a number of factors can be considered by the attending diagnostician, including, but not limited to: the species of mammal, its size, age, and general health; the severity of the symptoms; the response of the individual patient; the mode of administration; the bioavailability characteristics of the compound of Formula 1, 2, or 3 or its pharmaceutically acceptable salt form, as a formulated drug product in the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
In one embodiment, the effective amount can be from about 0.0005 mg/kg of body weight to about 100 mg/kg. More preferably, the effective amount can be from about 0.001 mg/kg to about 50 mg/kg. Still more preferably, the effective amount can be from about 0.001 mg/kg to about 20 mg/kg.
A compound of the present invention can be combined with other treatment methods and/or additional therapeutic agents. Preferably a compound of the present invention can be combined with other agents that also are effective for the treatment of arthritis or osteoarthritis. Examples of these additional therapeutic agents include: NSAIDs or COX-2 inhibitors such as ibuprofen, aspirin, acetaminophen, celecoxib, naproxen, and ketoprofen; opioids such as oxycodone, and fentanyl; and corticosteroids such as hydrocortisone, prednisolone, and prednisone.
The compound of the invention and the additional therapeutic agent(s) can be
administered either together through the same delivery route and device such as a single pill, capsule tablet, or solution; or separately administered either at the same time in separate delivery devices or administered sequentially.
The compound of the present invention can be provided as a pharmaceutically acceptable salt. "Pharmaceutically- acceptable salt" refers to salts of the compound of the invention considered to be acceptable for clinical and/or veterinary use. Pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, (VCHA/Wiley-VCH, 2002); S.M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.
The compound of the present invention, or a salt thereof, may be prepared by a variety of procedures known in the art, some of which are illustrated in the Schemes, Preparations, and Examples below. One of ordinary skill in the art recognizes that the specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare compounds of the invention, or salts thereof. The products of each step in the schemes below can be recovered or purified by conventional methods, including extraction, evaporation, precipitation, chromatography, supercritical fluid chromatography, filtration, trituration, and crystallization.
Individual isomers, enantiomers, or diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of Formula 1 by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions" , John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen," Stereochemistry of Organic Compounds", Wiley- Interscience, 1994). Additionally, the intermediates described in the following preparations contain nitrogen and oxygen protecting groups. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example "Greene 's Protective Groups in Organic Synthesis", Fourth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).
The reagents and starting materials are generally readily available to one of ordinary skill in the art. Others may be made by standard techniques of organic and heterocyclic chemistry and the procedures described in the Preparations and the Examples below.
The depiction of a bond with a line through it as illustrated below indicates the point of attachment of the substituent to the rest of the molecule.
Figure imgf000012_0001
The abbreviations used herein are defined according to Aldrichimica Acta, Vol. 17, No. 1, 1984. Other abbreviations are defined as follows: "δ" refers to part per million down-field from tetramethylsilane; "ATCC" refers to American type culture collection; "BOP" refers to
(benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; "BSA" refers to Bovine Serum Albumin; "CDI" refers Ι,Γ-carbonyldiimidazole; "DCC" refers to 1,3- dicyclohexylcarbodiimide; "DCM" refers to dichloromethane; "DIC" refers to 1,3- diisopropylcarbodiimide; "DMF" refers to dimethylformamide; "DMSO" refers to
dimethylsulfoxide; "EDCI" refers to l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; "EDTA" refers to ethylenediaminetetraacetic acid; "ee" refers to enantiomer excess; "EIA" refers to enzyme immunoassay; "EIMS" refers to electron ionized mass spectrometry; "ESMS" refers to electrospray mass spectrometry; "EtOAc" refers to ethyl acetate; "EtOH" refers to ethanol or ethyl alcohol; "Ex. No." refers to Example Number;
"HATU" refers to (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate); "HBTU" refers to (lH-benzotriazol-l-yloxy)(dimethylamino)-N,N- dimethylmethaniminium hexafluorophosphate; "HO AT" refers to l-hydroxy-7- azobenzotriazole; "HOBT" refers to 1-hydroxylbenzotriazole hydrate; "IC50" refers to the concentration of an agent that produces 50% of the maximal inhibitory response possible for that agent; "i-PrOH" refers to isopropanol or isopropyl alcohol; "LPS" refers to lipopolysaccharide; "MeOH" refers to methanol; "min" refers to minutes; NSAIDs" refers to nonsteroidal anti- inflammatory drugs; "PBS" refers to Phosphate Buffered Saline; "PGE2" refers to prostaglandin E2; "PGH2" refers to prostaglandin H2; "PGI2" refers to prostaglandin I2; "PyBOP" refers to (benzotiiaz.ol-l -yl-oxytripyrrolidinophosphonium hexafluorophosphate); "PyBrOP" refers to bromo(tri-pyrrolidinyl)phosphoniumhexafluorophosphate; "rhIL-Ιβ" refers to recombinant human interleukin 1β; "SCF" refers to supercritical fluid; "SFC" refers to supercritical fluid chromatography; "TBME" refers to i-butyl ether methyl ether; "THF" refers to tetrahydrofuran; and "tR" refers to retention time.
General LCMS Methods. All analyses are performed using an Agilent 1200 Infinity Series Liquid Chromatography (LC) system, consisting of a 1260 HiP degasser (G4225A), 1260 Binary Pump (G1312B), 1290 auto-sampler (G4226A), 1290 thermo-stated column compartment (G1316C) and a 1260 Diode Array Detector (G4212B) coupled to an Agilent 6150 single quadrupole mass spectrometry (MS) detector. The MS is operated with an electro-spray ionization source (ESI) in both positive & negative ion mode. The nebulizer pressure is set to 50 psi, the drying gas temperature and flow to 350 °C and 12.0 L/min respectively. The capillary voltages used are 4000 V in positive mode and 3500 V in negative mode. Data acquisition is performed with Agilent Chemstation software. HPLC Method 1. Analyses are carried out on a Daicel ChiralPak AD-3R column (100 mm length, 4.6 mm internal diameter, 3 μιη particle size). The mobile phase used is: A2=Water with 10 mM ammonium bicarbonate, adjusted to pH 9 with ammonium hydroxide; and B2 = acetonitrile. The run is performed at a temperature of 25 °C and a flow rate of 1.5 mL/min with a gradient elution from 50 % to 95 % (B2) over 3.0 min followed by a 3.0 min hold at 95 % (B2). The UV (DAD) acquisition is performed at 40 Hz, with a scan range of 190-400 nm (by 5 nm step). A 1 : 1 flow split is used before the MS detector. The MS acquisition range is set to 100- 800 m/z with a step size of 0.2 m/z in both polarity modes. Fragmentor voltage is set to 70 (ESI+) or 120 (EST), Gain to 0.40 (ESI+) or 1.00 (EST) and the ion count threshold to 4000 (ESI+) or 1000 (EST). The overall MS scan cycle time is 0.15 s/cycle.
SFC Method 1. Analyses are carried out on a Daicel ChiralPak OJ-H column (100 mm length, 4.6 mm internal diameter, 5 μιη particle size). The mobile phase is: 8 % (20 mM NH3 in j-PrOH) and 92 % C02(SCf) at a pressure of 100 bar. The run is performed at a temperature of 35 °C and a flow rate of 3 mL/minute. The UV (DAD) acquisition is performed at a wavelength of 220 nm.
SFC Method 2. Analyses are carried out on a Daicel ChiralPak AS-H column (100 mm length, 4.6 mm internal diameter, 5 μιη particle size). The mobile phase is: 20 % (20 mM NH3 in j-PrOH) and 80 % C02(SCf) at a pressure of 100 bar. The run is performed at a temperature of 35 °C and a flow rate of 5 mL/minute. The UV (DAD) acquisition is performed at a wavelength of 220 nm.
The following Schemes further illustrate the invention.
Scheme 1
Figure imgf000015_0001
1. Hydrogenation
PG=protecting group Step 3 2. Deprotect
Figure imgf000015_0002
In Scheme 1, Step 1, a trifluoromethyl sulfonyl group is installed on the piperidine to act as a leaving group in the subsequent reaction of Step 2. "PG" is a protecting group developed for the amino group, such as carbamates and amides. The product of Step 1 is then subjected to carbonylation using a palladium catalyst to give the ester product of Step 2. The double bond in the tetrahydropyridine can be reduced under hydrogenation conditions. In Step 3, substep 2, the piperidine amine can be deprotected under acidic conditions. The piperidine product of Step 3 can then be reacted with a halogen substituted G group under conditions suitable for nucleophilic aromatic substitution give the product of Step 4. For example, an inorganic base such as K2C03 or an organic base such as Ν,Ν-diisopropylethylamine, pyridine, or triethylamine can be used to give the product of Step 4, substep 1. Alternatively, the piperidine product of step 3 can be reacted with a quinolone N-oxide using an activating agent, such as PyProp, to give the product of Step 4. Deprotection of the piperidine carboxy group can be accomplished under standard conditions with an inorganic base such as aqueous sodium hydroxide or lithium hydroxide to give the product of Step 4, substep 2 or under acidic conditions using 4 M HC1 or aqueous sulfuric acid. Scheme 2
R'N H2 +
Figure imgf000016_0001
1
In Scheme 2, the piperidine carboxylic acid product of Step 4 can be coupled with an appropriate amine, R-NH2, under amidation conditions using an organic base such as triethylamine or diisopropylethylamine, a coupling reagent such as EDCI, and a coupling additive such as HOBT to give the compounds of Step 5, substep 1. One skilled in the art will recognize that there are a number of methods and reagents for amide formation resulting from the reaction of carboxylic acids and amines. For example, the reaction of the amine compound with an appropriate carboxylic acid in the presence of a coupling reagent with or without an organic base can provide a compound of Formula 1. Coupling reagents include carbodiimides, such as DCC, DIC, EDCI or a carbonyldiimidazole such as CDI. Amide coupling additives, such as HOBT and HO At can also be used to enhance the reaction. Additionally, uronium or phosphonium salts of non-nucleophilic anions, such as HBTU, HATU, BOP, PyBOP, and PyBrOP could be used in place of the more traditional coupling reagents. An additive such as DMAP may be used to enhance the reaction. The product of Step 5, substep 1 can then be deprotected, if necessary, under standard conditions with an inorganic base such as aqueous sodium hydroxide or lithium hydroxide in a solvent such as MeOH and THF to give compounds of Formula 1.
A pharmaceutically acceptable salt of the compounds of the invention, such as a hydrochloride salt, can be formed, for example by reaction of an appropriate free base of Formula 1 and an appropriate pharmaceutically acceptable acid, such as hydrochloric acid, in a suitable solvent such as diethyl ether under standard conditions. Additionally, the formation of such salts can occur simultaneously upon deprotection of a nitrogen protecting group. The formation of such salts is well known and appreciated in the art. See, for example, Gould, P.L., "Salt selection for basic drugs," International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R.J., et al. "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4: 427-435 (2000); and Berge, S.M., et ah, "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66: 1-19, (1977).
The following Preparations and Examples further illustrate the invention.
Preparation 1
ieri-Butyl 3,3-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine- 1 (2H)- carbox late
Figure imgf000017_0001
Under a nitrogen atmosphere, cool a solution of diisopropylamine (260 mL, 1.85 mol) in THF (1.0 L) to -20 °C then add a solution of w-butyllithium (2.50 M in hexanes, 650 mL, 1.60 mol) drop- wise over 30 minutes. Allow the mixture to warm to -10 °C and stir for 1 hour. Cool the mixture to -74 °C and add a solution of ieri-butyl 3,3-dimethyl-4-oxopiperidine-l- carboxylate (260 g, 1.14 mol) in THF (1.0 L mL) drop-wise over 60 minutes. Stir the mixture at -74 °C for 2 hours, and then add a solution of N-phenylbis(trifluoromethanesulfonimide) (430 g, 1.20 mol) in THF (1.0 L). Warm the mixture to 0 °C and stir for 2 hours. Allow the mixture to warm to room temperature and stir overnight. Quench the reaction with saturated aqueous
NH4CI (1.0 L); dilute with water (2.0 L); separate the layers; and extract the aqueous layer with EtOAc (2 x 2 L). Combine the organic extracts; dry over Na2S04; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Subject the resulting crude material to silica gel flash chromatography, eluting with a gradient of 0 % to 15 % TBME in hexanes, to provide the title compound as an orange oil in about 75% purity by mass as estimated by 1H NMR (430 g, 78%). 1H NMR (400 MHz, DMSO-J6) δ 1.05 (s, 6H), 1.40 (s, 9H), 3.36 (s, 2H), 4.02 (d, / = 3.4 Hz, 2H), 5.82 (br s, 1H). Preparation 2
01 -ieri-Butyl-04-methyl 3,3-dimethyl-2,6-dihydropyridine- 1 ,4-dicarboxylate
Figure imgf000018_0001
Combine palladium(II) acetate (4.40 g, 20.0 mmol), 1,1'- bis(diphenylphosphino)ferrocene (13.3 g, 22.8 mmol), ieri-butyl 3,3-dimethyl-4-
(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-l(2H)-carboxylate (72.0 g, 150 mmol), anhydrous acetonitrile (850 mL), anhydrous MeOH (570 mL), and triethylamine (36.0 mL, 245 mmol) in a 2-L PARR™ autoclave fitted with a mechanical stirrer. Seal the autoclave. Purge and then pressurize the autoclave with carbon monoxide to 689 kPa. Heat the mixture to 65 °C for 2.25 hours; cool the mixture to room temperature; and carefully vent the autoclave.
{Caution! Poison gas!). Concentrate under reduced pressure to give crude material. Combine this material with five other batches of material prepared by an analogous procedure on similar scales. Subject the combined material to silica gel flash chromatography, eluting with a gradient of 0 % to 20 % TBME in hexanes, to give the title compound as a yellow oil in about 83% purity by mass (260 g, 88%). MS (m/z): 214 (M - ί-Bu + 2H)+.
Preparation 3
(±)-01 -ieri-Butyl-04-methyl 3,3-dimethylpiperidine- 1 ,4-dicarboxylate
Figure imgf000018_0002
Suspend palladium (10 wt% on carbon, 5.4 g, 5.1 mmol) in MeOH (700 mL) then add a solution of Oi-ie/ -butyl-04-methyl 3,3-dimethyl-2,6-dihydropyridine-l,4-dicarboxylate (130 g, 396 mmol) dissolved in MeOH (700 mL) in a 2.25 L PARR™ reactor. Seal the reactor and purge it first with nitrogen gas then with hydrogen gas. Pressurize the reactor to 414 kPa with hydrogen and stir the mixture at room temperature for 1.5 hours. Release the pressure and filter the mixture to remove the catalyst. Combine the filtrate with that obtained from another essentially identical reaction and concentrate under reduced pressure to give the title compound as a yellow oil in about 85% purity by mass (240 g, 95%). MS (m z): 216 (M - ί-Bu + 2H)+.
Preparation 4
(+)-Methyl 3,3-dimethylpiperidine-4-carboxylate hydrochloride
Figure imgf000019_0001
Add HC1 (4.0 M solution in 1,4-dioxane, 2.0 L, 8.0 mol) to a solution of 01-tert-bvXy\- 04-methyl 3,3-dimethylpiperidine-l,4-dicarboxylate (240 g, 752 mmol) in 1,4-dioxane (500 mL). Stir the resulting mixture at room temperature overnight and concentrate under reduced pressure. Dilute the residue with TBME (500 mL) and collect the resulting solids by filtration. Rinse the filter cake with TBME (2 x 400 mL) and dry the solid in a vacuum oven at 35 °C overnight to give the title compound as a white solid (144 g, 92%). MS (m/z): 172 (M + H)+.
Preparation 5
(-)-Methyl (4lS')-3,3-dimethyl-l-(8-methyl-2-quinolyl)piperidine-4-carboxylate
Figure imgf000019_0002
Add K2CO3 (210 g, 1.52 mol) to a mixture of methyl 3,3-dimethylpiperidine-4- carboxylate hydrochloride (144 g, 693 mmol) and 2-chloro-8-methylquinoline (125 g, 704 mmol) in DMSO (1.4 L). Stir the resulting mixture over night at 131 + 1 °C. Cool the mixture to room temperature; filter to remove the solids; collect the filtrate; dilute the filtrate with water (2 L); then extract with EtOAc (2 x 3 L). Wash the combined organic extracts with water (3 x 1.5 L); dry over Na2S04; filter; collect and concentrate the filtrate under reduced pressure.
Subject the resulting crude material to silica gel flash chromatography, eluting with a gradient of 25 % to 30 % (10 % TBME in DCM) in hexanes, to provide the racemate of the title compound. Dissolve this material in MeOH (7.5 L) and filter. Subject the material to chiral SFC (Chiralpak OJ-H, 50 mm x 250 mm x 5 μιη) using 15 % (0.2 % dimethylethylamine in j-PrOH) in C02(SCf) as the mobile phase at a flow rate of 400 g/min, by injecting 5 mL of solution every 95 seconds until all of the material has been subjected. For each injection, collect the first fraction to elute (¾ = 2.57 min by SFC Method 1). Combine the collected fractions with those from a previous reaction prepared similarly to provide 98 g of crude methyl 3,3-dimethylpiperidine-4-carboxylate hydrochloride. Concentrate mixture under reduced pressure and recrystallize the material from hot EtOH (1.38 L). Collect the crystals and dry the crystalline material in a vacuum oven at 40 °C overnight to give the title compound as a white crystalline solid (156 g, 43 % yield on a batch-proportional basis). MS (m z): 313 (M + H)+, [a]20 D -45° (c 0.21, DCM). ee = >99 % as determined by SFC Method 1.
Preparation 6
(-)-(4lS')-3,3-Dimethyl-l-(8-methyl-2-quinolyl)piperidine-4-carboxylic acid
Figure imgf000020_0001
Treat methyl (4lS')-3,3-dimethyl-l-(8-methyl-2-quinolyl)piperidine-4-carboxylate (154 g, 493 mmol) with sulfuric acid (10% v/v in water, 2.31 L, 2.75 mol) and reflux the mixture overnight. Cool the mixture to room temperature and add NaOH (50 wt% in water) until the pH reaches 13. Add TBME (500 mL) to provide a triphasic mixture. Label the layers from top to bottom as: "Layer A," "Layer B," and "Layer C." Remove Layer C (the bottom layer). Add water (600 mL) to Layers A and B and separate the aqueous layer from the organic layers. Set aside the organic layers (A and B). Combine the aqueous layer with Layer C. Extract the combined aqueous layers with TBME (500 mL); separate the layers; and set aside the organic extracts. Add HCl (5.0 M) to the aqueous layer until the pH is 6.5. Extract the resulting aqueous mixture with TBME (2 x 400 mL). Combine all of the organic extracts (including Layers A and B); dry over MgS04; filter; collect and concentrate the filtrate under reduced pressure to give the title compound as a white solid in 96 % purity (145 g, 95%). MS (m z): 299 (M + H)+. [a]20 D - 59.6° (c 3.12, CH3OH). Preparation 7
(±)-2-((Benzyloxy)methyl)-2,3-dihydro-4H-pyran-4-one
Figure imgf000021_0001
Add a solution of ZnCl2 in THF (0.5 M, 1.21 L, 607 mmol) to a cold (0 °C) solution of (E)-l-methoxy-3-(trimethylsilyl)oxy- l,3-butadiene (95% pure, 100 g, 551 mmol) and
(benzyloxy)acetaldehyde (97 % pure, 80 mL, 551.370 mmol) in toluene (551 mL) over 90 minutes while maintaining the internal temperature of the reaction mixture below 10 °C. Allow the mixture to warm to room temperature and stir overnight. Divide the reaction mixture into two equal portions; perform the following procedures on each portion. Add trifluoroacetic acid (35 mL, 457 mmol) in four portions. After 20 minutes, concentrate the resulting mixture under reduced pressure; dilute with EtOAc; add excess saturated NaHC03; filter to remove the solids; collect the filtrate; separate and collect the organic layer. Wash the organic solution with saturated aqueous NaCl; isolate the organic extracts; dry over MgS04; filter; collect the filtrate; and concentrate under reduced pressure. Combine the resulting material from each of the previously separated portions. Subject the resulting material to silica gel flash chromatography, eluting with a gradient of 20% to 50% EtOAc in hexanes, to give the title compound as an orange oil in 92% purity (96 g, 73%). 1H NMR (400 MHz, CDC13) δ 7.40-7.28 (m, 6H), 5.42 (d, / = 6.0 Hz, 1H), 4.65-4.56 (m, 3H), 3.74-3.67 (m, 2H), 2.75 (dd, / = 16.8, 14.3 Hz, 1H), 2.42 (dd, / = 16.9, 3.2 Hz, 1H).
Preparation 8
(+)-2-(Benzyloxymethyl)tetrahydropyran-4-one
Figure imgf000021_0002
Stir a mixture of EtOAc (880 mL), (+)-2-((benzyloxy)methyl)-2,3-dihydro-4H-pyran-4- one (96 g, 0.440 mol), triethylamine (123 mL, 0.882 mol), and palladium (10% on carbon, 4.68 g, 4.40 mmol) under an atmosphere of hydrogen at room temperature for 73 hours. Filter the mixture through diatomaceous earth; rinse the filter cake with EtOAc (250 mL); and sequentially wash the filtrate with aqueous HC1 (0.1 M), saturated aqueous NaHC03, and saturated aqueous NaCl. Dry the organic layer over MgS04; filter; collect the filtrate; and concentrate under reduced pressure to give the title compound as a light yellow material (81.4 g, 84%). LC/MS (ESI+): 221 [M+H]+, 238 [M+NH4]+, 243 [M+Na]+.
Preparation 9
(2S,4R)-2-(Benzyloxymethyl)tetrahydropyran-4-ol
Figure imgf000022_0001
Cool a solution of (+)-2-(benzyloxymethyl)tetrahydropyran-4-one (40.6 g, 184 mmol) in THF (1.08 L) to -78 °C. Add a solution of LiAlH4 (1.0 M in THF, 240 mL, 240 mmol) drop- wise over 15 minutes. Allow the mixture to warm to 0 °C after the addition is complete and slowly add water (8.4 mL) drop- wise. After stirring the mixture for 5 minutes, add a solution of NaOH (15 mass % in water, 8.4 mL) and stir for an additional 5 minutes. Then add water (3 x 8.4 mL) and allow the mixture to warm to room temperature. After 30 minutes, filter the suspension to remove the solids and concentrate the filtrate under reduced pressure to provide the title compound as a colorless oil. Rinse the solids once with THF; filter; and concentrate the filtrate under reduced pressure. Combine this material with those obtained from previously reactions performed essentially according to the same procedure starting with 40 g, 22 g, and 45 g of (+)-2-(benzyloxymethyl)tetrahydropyran-4-one. Dissolve the combined material in i-PrOH (637 mL). Subject the material to chiral SFC (Chiralpak AS-H, 50 mm x 150 mm x 5 μιη) using 25% j-PrOH in C02(SCf) as the mobile phase at a flow rate of 300 g/min, by injecting 1.35 g of solution every 114 seconds until all of the material has been injected. For each injection, collect the first fraction to elute (major isomer). Combine all of the collected fractions to give the title compound in >99 % ee as determined by SFC Method 2 (62.8 g, 42 % yield on a batch proportional basis). LC/MS (ESI): 223 [M+H]+, 240 [M+NH4]+, 245 [M+Na]+, 467 [2M+Na]+. Preparation 10
((2S,4R)-2-(Benzyloxymethyl)tetrahydropyran-4-yl)methanesulfonate
Figure imgf000023_0001
Drop-wise add a solution of methanesulfonyl chloride (11.7 mL, 150.6 mmol) in DCM (70 mL) to a mixture of (2S,4R)-2-(benzyloxymethyl)tetrahydropyran-4-ol (31 g, 139.5 mmol), DCM (1.40 L), and N,N-diisopropylethylamine (73.0 mL, 418.4 mmol) at 0 °C. Allow the mixture to warm to room temperature and stir it overnight. Thereafter add a solution of methanesulfonyl chloride (0.537 mL, 6.98 mmol) in DCM (5 mL) and stir the mixture for 5 minutes at room temperature. Cool the mixture to 0 °C, pour it into water; separate; and collect the organic layer. Wash the organic layer with water (500 mL); combine the organic layer with organic layers/extracts obtained from other, essentially identical reactions. Dry the combined organic solutions over MgS04; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound as a light orange oil (84.7 g, 97 % yield on a batch proportional basis). 1H NMR (400 MHz, J6-DMSO) δ 7.36-7.24 (m, 5H), 4.86-4.77 (m, 1H), 4.47 (s, 2H), 3.96 (dd, / = 7.6, 4.4 Hz, 1H), 3.60-3.54 (m, 1H), 3.48-3.36 (m, 3H), 3.18 (s, 3H) 2.05 (d, 7 = 7.8 Hz, 1H), 1.98 (d, 7 = 7.8 Hz, 1H), 1.58 (app qd, / = 12.0, 4.8 Hz, 1H), 1.40 (app q, J = 11.8 Hz, 1H).
Preparation 11
((2S,4S)-4-Aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride
Figure imgf000023_0002
H- CI
Add sodium azide (12.85 g, 191.7 mmol) to a solution of ((25,4R)-2- (benzyloxymethyl)tetrahydropyran-4-yl)methanesulfonate (32.0 g, 106.5 mmol) in DMF (304 mL). Heat the resulting mixture to 100 °C and stir it for 4 hours. Cool the reaction mixture to room temperature. Pour the mixture into water (400 mL) and then extract with EtOAc (2 x 400 mL). Combine organic extracts and wash with saturated aqueous NaCl (3 x 200 mL). Dry the organic extracts over MgS04; filter; and collect the filtrate. Concentrate filtrate under reduced pressure to about 100 mL total volume. Dissolve resulting mixture in EtOAc (700 mL) and add it to a PARR™ vessel containing Pt02 (2.7 g, 12 mmol) and EtOAc (700 mL). Purge the vessel with nitrogen; then pressurize it with hydrogen to 414 kPa. Agitate the mixture for 4 hours at room temperature. Filter the mixture and concentrate the colorless filtrate under reduced pressure to provide 23.2 g of a colorless oil. Combine with 36.2 g of material from a previous reaction prepared by essentially the same procedure. Dissolve the combined material in EtOH (600 mL) and add HCl (37 wt% in H20, 50 mL). Add the resulting mixture to a PARR™ vessel which contains Pd (10% on carbon, 10.0 g, 9.40 mmol) and EtOH (600 mL). Purge the reactor with nitrogen and pressurize it with hydrogen to 414 kPa. Agitate the mixture at room temperature for 1 hour. Filter the mixture; collect the filtrate; and concentrate the colorless filtrate under reduced pressure to give the title compound as a dark, thick oil in about 72 % purity (54.2 g, 85 %). LC/MS (ESI): 132 [M+H]+.
Preparation 12
(+)-(Methyl 3,3-dimethyl-l-[4- trifluoromethyl)phenyl]piperidine-4-carboxylate
Figure imgf000024_0001
Add K2C03 (460 mg, 3.33 mmol) to a mixture of methyl 3,3-dimethylpiperidine-4- carboxylate hydrochloride (300 mg, 1.44 mmol), l-fluoro-4-(trifluoromethyl)benzene (475 mg, 2.89 mmol) and DMSO (2 mL). Stir the resulting mixture at 130 °C for 2 days. Cool the mixture to room temperature and stir for 3 days. Subject the resulting material to reverse-phase flash chromatography on C18 silica gel, eluting with a gradient of 10 % to 100 % acetonitrile (0.1 % formic acid) in water (0.1 % formic acid), to give the title compound as a yellow oil (113 mg, 25 %). MS (m z): 316 (M + H)+.
Preparation 13
(±)-3,3-Dimethyl-l-[4-(trifluorometh l)phenyl]piperidine-4-carboxylic acid.
Figure imgf000024_0002
Add 2M aqueous NaOH (1 mL, 2 mmol) to a mixture of methyl (+)-3,3-dimethyl-l-[4-
(trifluoromethyl)phenyl]piperidine-4-carboxylate (113 mg, 0.36 mmol), MeOH (1 mL), and THF (5 mL). Stir the resulting mixture at 50 °C overnight. Cool the mixture to room temperature, and add HCl (33 wt % in water) until the pH of the mixture is 3. Concentrate the mixture under reduced pressure to give the title compound as a yellow solid in 88 % purity (123 mg, 99 % yield). MS (m z): 302 (M + H)+.
Preparation 14
(±)-3,3-Dimethyl-l-[5-(trifluorometh l)pyrimidin-2-yl]piperidine-4-carboxylic acid
Figure imgf000025_0001
Add triethylamine (7.65 mL, 54.9 mmol) to a mixture of (+)-methyl 3,3- dimethylpiperidine-4-carboxylate hydrochloride (8.55 g, 41.2 mmol), 2-chloro-5- (trifluoromethyl)pyrimidine (5.0 g, 27.4 mmol), and acetonitrile (67 mL). Heat the mixture in a microwave to 180 °C for 1 hour; then cool the mixture to room temperature; and concentrate under reduced pressure. Add MeOH (40 mL), THF (80 mL), and 2 M aqueous NaOH (40 mL, 80 mmol). Stir the resulting mixture for 2 days at 50 °C. Add 2 M aqueous NaOH (45 mL, 90 mmol) and stir the resulting mixture for 4 hours at 50 °C. Cool the mixture to room temperature, and then add HCl (33 wt % in water) until the pH reaches 3. Concentrate under reduced pressure. Dilute with 1 N aqueous HCl (100 mL) and extract with EtOAc (2 x 100 mL). Wash the combined organic extracts with brine (100 mL); dry over Na2S04; filter; collect the filtrate; and concentrate under reduced pressure to give the title compound (7.60 g, 61 %). MS (m/z): 302 (M + H)+.
Preparation 15
5,8-Dimethylquinoline- 1-oxide
Figure imgf000025_0002
Add 3-chloroperoxybenzoic acid (5.96 g, 24.1 mmol) to a mixture of 5,8- dimethylquinoline (2 g, 12.1 mmol) and DCM (80 mL) maintained at 0 °C. After 1 hour, add Na2S04 (5 g) and filter the mixture. Collect the filtrate. Stir the resulting mixture at room temperature overnight. Dilute with DCM (100 mL); wash with 1 N aqueous NaOH (3 x 50 mL); dry over Na2S04; filter; collect the filtrate; and concentrate to dryness under reduced pressure. Subject the resulting crude material to reverse-phase flash
chromatography on C18 silica gel, eluting with a gradient of 15 % to 70 % acetonitrile (10 mM ammonium bicarbonate) in water (lOmM ammonium bicarbonate) to give the title compound (372 mg, 18 %). MS (m z): 327 (M + H)+.
Preparation 16
(+)-Methyl l-(5,8-dimethyl-2-quinolyl)-3,3-dimethyl-piperidine-4-carboxylate.
Figure imgf000026_0001
Add N,N-diisopropylethylamine (2.02 mL, 11.6 mmol) and PyBroP (1.75 g, 3.75 mmol) to a mixture of (+)-methyl 3,3-dimethylpiperidine-4-carboxylate hydrochloride (600 mg, 2.89 mmol), 5,8-dimethylquinoline-l-oxide (678 mg, 3.91 mmol), and DCM (15 mL). Stir the resulting mixture at room temperature for 3 days. Subject the crude reaction to reverse-phase flash chromatography on C18 silica gel, eluting with a gradient of 10% to 100% acetonitrile (0.1% formic acid) in water (0.1% formic acid). Combine the fractions containing the desired product and concentrate under vacuum to approximately 30 mL volume. Adjust the pH to 6 with addition of a IN aqueous NaOH solution. Extract the aqueous solution with EtOAc (2 x 30 mL), wash with a pH 6 aqueous buffer solution (4 x 30 mL), dry over MgS04; filter; and concentrate under reduced pressure to give the title compound (166 mg, 18%). MS (m z): 327 (M + H)+.
Preparation 17
(+)-l-(5,8-Dimethyl-2-quinolyl)-3,3-dimethyl-piperidine-4-carboxylic acid.
Figure imgf000026_0002
Combine a mixture of methyl (+)-l-(5,8-dimethyl-2-quinolyl)-3,3-dimethyl-piperidine-4- carboxylate (166 mg, 0.51 mmol), MeOH (0.1 mL), THF (0.5 mL), and 1 M aqueous NaOH (2.5 mL, 2.5 mmol) in a microwave vessel. Heat the resulting mixture at 120 °C for 2 hours in a microwave reactor. Cool the mixture to room temperature and add 1 N aqueous HCl until the pH is 6. Extract with CHC13 (2 x 25 mL); dry over Na2S04; filter; collect the filtrate; and concentrate under reduced pressure to give the title compound (135 mg, 85 %). MS (m/z): 312 (M + H)+.
Preparation 18
(+)-Methyl l-(8-chloro-2-quinolyl)-3,3-dimethyl-piperidine-4-carboxylate.
Figure imgf000027_0001
Add K2C03 (1.07 g, 7.75 mmol) to a mixture of methyl (+)-3,3-dimethylpiperidine-4- carboxylate hydrochloride (700 mg, 3.37 mmol), 2,8-dichloroquinoline (876 mg, 4.38 mmol), and DMSO (4.5 mL). Stir the resulting mixture at 130 °C overnight. Cool the mixture to room temperature; filter to remove the solids; dilute with water (5 mL); and extract with EtOAc (4 x 20 mL). Wash the combined organic extracts with water (20 mL) then brine (20 mL). Dry the organic extracts over MgS04; filter; collect the filtrate; and concentrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel, eluting with a gradient of 0 % to 40 % EtOAc in hexanes, to give the title compound (1.1 g, 98 %). MS (m z): 332 (M + H)+.
Preparation 19
(+)-l-(8-Chloro-2-quinolyl)-3,3-dimethyl-piperidine-4-carboxylic acid
Figure imgf000027_0002
Combine a mixture of (+)-methyl l-(8-chloro-2-quinolyl)-3,3-dimethyl-piperidine-4- carboxylate (1.1 g, 3.3 mmol), MeOH (0.8 mL), THF (3.3 mL), and 1 M aqueous NaOH (3.3 mL, 17 mmol) in a microwave vessel. Heat the resulting mixture at 120 °C for 2 hours in a microwave. Cool the mixture to room temperature and then add 5 N aqueous HCl until the pH is 6. Extract the mixture with EtOAc (3 x 10 mL). Combine the organic extracts; dry over Na2S04; filter; collect the filtrate; and concentrate under reduced pressure to give the title compound (815 mg, 77 %). MS (m z): 318 (M + H)+.
Preparation 20
Methyl 4-anilino-2,5-dih drofuran-3-carboxylate
Figure imgf000028_0001
Add /7-toluenesulfonic acid (500 mg, 3.16 mmol) to a mixture of (+)-methyl 4- oxotetrahydrofuran-3-carboxylate (6.6 g, 45.8 mmol), aniline (4.3 mL, 47.2 mmol) and toluene (70 mL). Fit the reaction vessel with a Dean-Stark trap and heat to 140 °C. Stir the resulting mixture at room temperature overnight. Heat the reaction to 140 °C and stir for 2 hours. Cool the mixture and add diethyl ether (100 mL) and water (100 mL). Extract the mixture with diethyl ether (3 x 50 mL); dry over MgS04; filter; collect the filtrate; and concentrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel, eluting with a gradient of 0 % to 100 % EtOAc in heptane, to give the title compound (6.7 g, 67 %). MS (m z): 220 (M + H)+.
Preparation 21
(+)-Methyl-3-(iodometh l)-4-phenylimino-tetrahydrofuran-3-carboxylate
Figure imgf000028_0002
Add a solution of (+)-methyl 4-anilino-2,5-dihydrofuran-3-carboxylate (3.6 g, 16.4 mmol) and 18-crown-6 (4.8 g, 18 mmol) in toluene (15 mL) to a mixture of potassium tert- butoxide (2.0 g, 17.8 mmol) and toluene (15 mL). Stir the resulting mixture at room temperature for 30 minutes. Add diiodomethane (4 mL) and stir the reaction at room temperature overnight. Add water (50 mL) and extract with diethyl ether (2 x 50 mL). Collect the organic extracts and wash with brine (50 mL). Dry the organic extracts over MgS04; filter; collect the filtrate; and concentrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel, eluting with a gradient of 0 % to 60 % EtOAc in heptane, to give the title compound (1.0 g, 17 %). MS (m z): 359 (M + H)+.
Preparation 22
(+)-Methyl 5-oxotetrahydropyran-3-carboxylate
Figure imgf000029_0001
Heat a mixture of tri-/i-butyltin hydride (1.12 mL, 4.18 mmol), 2,2'-azobis(2- methylpropionitrile) (35 mg, 0.21 mmol) and toluene (10 mL) to reflux. Add a solution of (+)- methyl-3-(iodomethyl)-4-phenylimino-tetrahydrofuran-3-carboxylate (1.0 g, 2.78 mmol) in toluene (50 mL) drop- wise over three hours. Stir the resulting mixture at reflux for 3 hours. Concentrate the reaction under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel, eluting with a gradient of 0 % to 80 % EtOAc in heptane, to give the title compound (0.37 g, 84 %). 1H NMR (400 MHz, CDC13) δ 4.09-3.99 (m, 4H), 3.72 (s, 3H), 3.16 (m, 1H), 2.82 (dd, J= 7.2, 16.9 Hz, 1H), 2.66 (dd, J= 6.3, 16.9 Hz, 1H).
Preparation 23
(+)-Methyl ira«5,-5-(benzylamino)tetrahydropyran-3-carboxylate
Figure imgf000029_0002
Add sodium triacetoxyborohydride (0.96 g, 4.53 mmol) to a mixture of (+)-methyl 5- oxotetrahydropyran-3-carboxylate (0.33 g, 2.08 mmol), benzylamine (0.31 mL, 2.84 mmol) and 1,2-dichloroethane (5 mL). Stir the resulting mixture at room temperature for 2.5 hours. Add a saturated aqueous solution of sodium bicarbonate (10 mL); extract with DCM (3 x 10 mL); separate organic layer; wash with brine (10 mL); dry over MgS04; filter; collect the filtrate; and concentrate under reduced pressure. Subject the resulting crude material to flash
chromatography on silica gel, eluting with a gradient of 0 % to 60 % EtOAc in heptane, to give the title compound (0.085 g, 16 % yield). MS (m z): 250 (M + H)+.
Preparation 24 (+)-Methyl ira/is-S-aminotetrahydropyran-S-carboxylate
Figure imgf000030_0001
Add 10 % palladium on carbon (0.07 g, 0.66 mmol) to a mixture of (+)-methyl trans-5- (benzylamino)tetrahydropyran-3-carboxylate (0.085 g, 0.34 mmol) and ethanol (8 mL). Purge the mixture with hydrogen and stir the resulting mixture at room temperature under hydrogen (1 atm) overnight. Filter the mixture and concentrate under reduced pressure to give the title compound (0.045 g, 83 % yield). 1H NMR (400 MHz, CDC13) δ 3.82-3.77 (m, 2H), 3.68 (m, 4H), 3.38-3.31 (m, IH), 3.11-3.08 (m, IH), 2.85-2.80 (m, IH), 2.17-2.11 (m, IH), 1.78-1.71 (m, 3H).
Preparation 25
(+)-Methyl ira/i5-5-[[(4S)-3,3-dimethyl-l-(8-methyl-2-quinolyl)piperidine-4- carbon l] amino] tetrahydropyran-3 -carboxylate
Figure imgf000030_0002
Add EDCI (0.087 g, 0.45 mmol) to a mixture of (-)-(45 3,3-dimethyl-l-(8-methyl-2- quinolyl)piperidine-4-carboxylic acid (0.087 g, 0.29 mmol), (±)-methyl-ira/i5,-5- aminotetrahydropyran-3-carboxylate (0.045 g, 0.28 mmol), HOBT (9 mg, 0.06 mmol), triethylamine (0.15 mL, 1.08 mmol), in DCM (5 mL). Stir the resulting mixture at room temperature for 3 hours. Subject the resulting mixture to flash chromatography on silica gel, eluting with a gradient of 5 % to 100 % EtOAc in heptane, to give the title compound (0.085 g, 66 %). MS (m z): 439 (M + H)+. Preparation 26
(+)-Methyl ira/i5,-3-(dibenzylamino)cyclohexanecarboxylate
Figure imgf000031_0001
Add potassium carbonate (3.53 g, 25.6 mmol) and benzyl bromide (1.9 mL, 15.9 mmol) to a mixture of (+)-methyl-ira/is,-3-aminocyclohexanecarboxylate (1.07 g, 6.8 mmol) in acetonitrile (40 mL). Heat the resulting mixture to 80 °C and stir for 5 hours. Cool the mixture and add acetonitrile (40 mL). Filter through diatomaceous earth and concentrate the filtrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel, eluting with a gradient of 0 % to 20 % EtOAc in hexanes, to give the title compound (1.6 g, 70 %). MS (m/z): 338 (M + H)+.
Preparation 27
(+)-2-[ira/i5'-3-(Dibenzylamino)cyclohexyl]propan-2-ol
Figure imgf000031_0002
Add methylmagnesium bromide (3.0 M solution in diethyl ether, 16 mL, 48 mmol) to a mixture of (+)-methyl-ira/is,-3-(dibenzylamino)cyclohexanecarboxylate (1.6 g, 4.7 mmol) and THF (50 mL), maintained at 0 °C. Allow the reaction to warm to room temperature and stir overnight. Add water (25 mL) and filter through diatomaceous earth. Collect the aqueous filtrate. Extract the resulting aqueous material with EtOAc (50 mL). Collect the organic extracts; dry over Na2S04; filter; collect the filtrate; and concentrate under reduced pressure. Add EtOAc (50 mL); wash with saturated aqueous NH4C1 (2 x 25 mL); dry over Na2S04; filter; collect the filtrate; and concentrate under reduced pressure to give the title compound (1.1 g, 69 %). MS (m z): 338 (M + H)+.
Preparation 28
2-[(lS,3S)-3-(Dibenzylamino)cyclohexyl]propan-2-ol
Figure imgf000032_0001
Dissolve (±)-2-[/ra/is,-3-(dibenzylamino)cyclohexyl]propan-2-ol (1.1 g, 3.26 mmol) in ethanol (13 mg/mL). Subject the material to chiral SFC (Chiralpak IA, 2 cm x 15 cm) using 12 % (0.1 % dimethylethylamine in i-PrOH) in C02(SCf) as the mobile phase at 220 nm and a flow rate of 70 mL/minute. Collect and combine the first fraction to elute and concentrate under reduced pressure, to provide the title compound (0.54 g, 49 %), ee = >99 %. MS (m/z): 338 (M + H)+. SFC Analytical method (Chiralpak IA, (15 cm x 0.46 cm) using 10 % (0.1 %
dimethylethylamine in i-PrOH) in C02(SCf) as the mobile phase at 220 nm and a flow rate of 3 mL/minutes).
Preparation 29
2-[(lS,3S)-3-Aminocyclohexyl]propan-2-ol hydrochloride
Figure imgf000032_0002
2
HCI
Add palladium hydroxide (20% on carbon, 0.51 g, 3.7 mmol) to a mixture of 2-[(lS,3S)- 3-(dibenzylamino)cyclohexyl]propan-2-ol (0.54 g, 1.6 mmol) in MeOH (20 mL) in a Parr™ shaker vessel. Purge and pressurize the vessel with hydrogen to 414 kPa. Shake mixture for 4 days at room temperature. Filter the mixture through diatomaceous earth and concentrate the filtrate under reduced pressure. Dilute the mixture in diethyl ether (25 mL) and DCM (25 mL). Add HCl (4.0 M solution in 1,4-dioxane, 0.8 mL) and concentrate under reduced pressure to give the title compound (0.24 g, 77 %). MS (m z): 158 (M + H)+.
Preparation 30
tert-Butyl N-[(lRS,2RS,4SR,6RS)-6-(hydroxymethyl)norbornan-2-yl]carbamate
Figure imgf000033_0001
Combine (acetylacetonato)dicarbonylrhodium (10 mg, 0.03 mmol), 1,1'- bis(diphenylphosphino)ferrocene (27 mg, 0.05 mmol), methyl bicyclo[2.2.1]hept-2-ene-5- carboxylate (2.5 g, 11.9 mmol) and ieri-butanol (25 mL) to a PARR™ autoclave with
mechanical stirrer. Purge and pressurize the vessel with Syngas (1: 1 mix of carbon monoxide and hydrogen, 310 kPa). Stir overnight. Concentrate the mixture under reduced pressure.
Dilute in DCM (29 mL) and MeOH (2.9 mL). Add sodium borohydride (0.26 g, 6.9 mmol) and stir for 20 min at room temperature. Add DCM (60 mL) and wash with saturated aqueous sodium carbonate (2 x 25 mL) and brine (25 mL). Dry the organic layer over Na2S04; filter; collect the filtrate; and concentrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel eluting with a solution of 30 % DCM, 30 % ieri-butyl methyl ether and 40 % hexanes, to give the title compound as a mixture of diastereomers (0.58 g, 21 %). 1H NMR (400 MHz, CDC13) δ 4.71-4.59 (m, 1H), 3.92-3.81 (m, 1H), 3.46-3.45 (m, 2H), 2.36 (d, J= 3.0 Hz, 1H), 2.21-2.05 (m, 3H), 1.55 (br s, 1H), 1.49-1.25(m, 12H), 1.16-1.09 (m, 1H), 0.68 (ddd, J= 12.9, 4.5, 2.4 Hz, 1H).
Preparation 31
[(lRS,2RS,4SR,6RS)-6-Aminonorbornan-2-yl]methanol hydrochloride
Figure imgf000033_0002
HCl
Add HCl (4.0 M solution in 1,4-dioxane, 2.1 mL, 8.3 mmol) to a mixture of ieri-butyl N- [(lRS,2RS,4SR,6RS)-6-(hydroxymethyl)norbornan-2-yl]carbamate (0.2 g, 0.83 mmol) in DCM (8 mL) maintained at 0 °C. Allow the resulting mixture to warm to room temperature and stir for 3 hours. Concentrate the mixture under reduced pressure to give the title compound (0.15 g, 100%). 1H NMR (400 MHz, CDC13) δ 8.17-8.02 (m, 3H), 4.93-4.90 (br, IH), 3.47-3.45 (m, IH), 3.19-3.15 (m, 2H), 2.31 (m, IH), 2.14-2.12 (m, IH), 2.01- 1.94 (m, IH), 1.92-1.88 (m, IH), 1.44- 1.35 (m, 2H), 1.22 (m, IH), 1.04-0.98 (m, 2H).
Preparation 32
ie/ -Butyl ((ci5,-4-((ieri-butoxycarbonyl)amino)cyclohexyl)methyl)(sulfamoyl)carbamate
Figure imgf000034_0001
Add diisopropyl azodicarboxylate (1.6 mL, 7.8 mmol) to a mixture of tert-butyl cis-A- (hydroxymethyl)cyclohexylcarbamate (1.5g, 6.5 mmol), ieri-butyl N-sulfamoylcarbamate (1.9 g, 9.8 mmol), triphenylphosphine (2.1 g, 7.8 mmol), and EtOAc (33 mL). Stir overnight at room temperature. Add water (50 mL); extract with EtOAc (2 x 50 mL); collect the organic extracts. Wash the organic extracts with brine (25 mL); dry over MgS04; filter; collect the filtrate; and concentrate under reduced pressure. Subject the resulting crude material to flash
chromatography on silica gel, eluting with a gradient of 10 % to 80 % EtOAc in hexane, to give the title compound (1.78 g, 67 %). MS (m/z): 430 (M + Na)+.
Preparation 33
ci5,-l-amino-4-[(sulfamoylamino)methyl]cyclohexane hydrochloride
Figure imgf000034_0002
HCI
Add HCI (4.0 M solution in 1,4-dioxane, 15 mL, 60 mmol) to tert-butyl ((cis-A-((tert- butoxycarbonyl)amino)cyclohexyl)methyl)(sulfamoyl)carbamate (1.78 g, 4.37 mmol). Stir the resulting mixture overnight at room temperature. Concentrate under reduced pressure. Dilute in MeOH (10 mL) and add drop-wise diethyl ether (150 mL) while vigorously stirring. Collect the resulting white precipitate by vacuum filtration to give the title compound (0.68 g, 56 %). MS (m/z): 208 (M + H)+.
Preparation 34
Methyl (lR5,3R5)-3-((5)-3,3-dimethyl-l-(8-methylquinolin-2-yl)piperidine-4- carboxamido)cyclohexane- 1 -carboxylate
Figure imgf000035_0001
Add triethylamine (0.9 mL, 7 mmol) to a mixture of (-)-(4S)-3,3-dimethyl- l-(8-methyl- 2-quinolyl)piperidine-4-carboxylic acid (0.8 g, 3 mmol), (+)-methyl trans- - aminocyclohexanecarboxylate hydrochloride (0.5 g, 3 mmol), BOP (2.0 g, 3 mmol) and DMF (5 mL). Stir the resulting mixture at room temperature overnight. Add a saturated aqueous solution of sodium bicarbonate (20 mL) and extract with EtOAc (2 x 25 mL). Collect the organic extracts; wash with brine (25 mL); dry over MgS04; filter; collect the filtrate; and concentrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel, eluting with a gradient of 10 % to 90 % EtOAc in hexanes, to give the title compound (1.00 g, 80 %). MS (m/z) 438 (M + H)+.
Example 1
(lS')-N-((25,4lS,)-2-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-3,3-dimethyl-l-(8-methylquinolin-
2-yl)piperidine-4-carboxamide
Figure imgf000035_0002
Add benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (153 g, 293 as a slurry in DMF (152 mL) to a cold (10 °C) mixture of (-)-(45 3,3-dimethyl-l-(8- methyl-2-quinolyl)piperidine-4-carboxylic acid (76.0 g, 245 mmol), ((2S,4S)-4-aminotetrahydro- 2H-pyran-2-yl)methanol hydrochloride (72 % pure, 57.37 g, 246 mmol), triethylamine (153 mL, 1.10 mol), and DMF (380 mL) while maintaining the internal reaction temperature below 20 °C. Thereafter allow the mixture to warm to room temperature and stir it for 30 minutes. Pour the mixture into ice water (1.5 L) while stirring it. Extract the mixture with DCM (2 x 600 mL) and wash the combined organic extracts with a half- saturated aqueous NaCl solution (1.0 L). Dry the organic solution over MgS04; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give a wet solid. Triturate the wet solid with water and isolate the solid by filtration. Triturate the solid again with water (1.5 L) and isolate the solid by filtration. Wash the solid with water (2 x 250 mL). Set this first batch of isolated solid aside. Collect the aqueous washings; extract with DCM (2 x 800 mL); combine the DCM extracts. Add the first batch of isolated solids to the combined DCM extracts and wash with aqueous HC1 (2.5 M, 2 x 800 mL). Separate the aqueous layer and add 50% aqueous NaOH solution to the aqueous layer until the pH reaches 12 to induce precipitation. Filter the mixture to collect the resulting solid. Rinse the solid with water (2 x 300 mL). Dry the solid in a vacuum oven at 50 °C for 3 hours. Dissolve the solid in MeOH (1.2 L); add mercaptopropyl mesoporous silica scavenging resin (1.2 mmol/g, 715 m /g, 54 μιη average particle size); and stir at 50 °C overnight. Filter to remove the solids collecting the filtrate. Rinse the solid with 1: 1 CH2Cl2:MeOH (2 x 500 mL). Combine the filtrates and concentrate under reduced pressure to give a white solid. Triturate the solid with TBME (1.5 L), and collect the solids. Crystallize the solid from hot EtOH (1.8 L). Dry the solid in a vacuum oven at 50 °C for 2.5 hours to give the title compound as a crystalline, white solid (76.7 g, 76 %). LC/MS (ESI): 412 [M+H]+.
The following Examples in Table 1 can be prepared essentially by the procedure of Preparation 34 using the appropriate starting amine in place of (±)-methyl-ira/i5,-3- aminocyclohexanecarboxylate hydrochloride and the appropriate starting carboxylic acid in place of (-)-(4lS,)-3,3-dimethyl-l-(8-methyl-2-quinolyl)piperidine-4-carboxylic acid.
Table 1
MS
Ex. Purif.-
Structure Chemical Name {mix)
No. Meth
(M+H)
Figure imgf000037_0001
Figure imgf000038_0001
carboxamide
Purification Methods (Purif Meth): A= Crude product is purified by silica gel normal phase column chromatography eluting with gradient of EtOAc in hexanes. B= Crude product is purified by CI 8 reverse phase column chromatography eluting with a gradient of acetonitrile and water. C= Crude product is purified by chiral column chromatography with Chiralpak AS-H, 21 x 150 mm) using 15% IPA in C02 as the mobile phase at a flow rate of 70 mL/min.
Example 13
(4S)-N-[(lS,3S)-3-(l-Hydroxy-l-methyl-ethyl)cyclohexyl]-3,3-dimethyl-l-(8-methyl-2- quinolyl)piperidine-4-carboxamide
Figure imgf000038_0002
Add N,N-diisopropylethylamine (0.7 mL, 4 mmol) and HATU (0.31 g, 0.8 mmol) to a mixture of (-)-(4lS')-3,3-dimethyl-l-(8-methyl-2-quinolyl)piperidine-4-carboxylic acid (0.2 g, 0.67 mmol), 2-[(lS,3S)-3-aminocyclohexyl]propan-2-ol hydrochloride (0.13 g, 0.67 mmol) and DMF (5 mL). Stir the resulting mixture at room temperature for 45 minutes. Subject the resulting reaction mixture to reverse phase flash chromatography on CI 8, eluting with a gradient of 5 % to 80 % ACN in water, to give the title compound (0.26 g, 88 %). MS (m/z): 438 (M + H)+.
Prepare the following Examples in Table 2 essentially by the procedure for Example 13 using the appropriate starting carboxylic acid in place of (-)-(4S)-3,3-dimethyl- l-(8-methyl-2- quinolyl)piperidine-4-carboxylic acid.
Table 2
Figure imgf000039_0001
Prepare the following Examples in Table 3 essentially by the procedure for Preparation 25 using the appropriate starting amine in place of methyl (+)-ira/is,-5-aminotetrahydropyran-3- carboxylate and the appropriate starting carboxylic acid in place of (-)-(4S)-3,3-dimethyl-l-(8- methyl-2-quinolyl)piperidine-4-carboxylic acid.
Table 3
MS
Purifica¬
Ex. (m/z)
Structure Chemical Name tion No. (M+
Method H)
Figure imgf000040_0001
Purification Methods: A= Crude product is purified by silica gel normal phase column chromatography, eluting with a gradient of EtOAc in hexanes. C= Crude product is purified by chiral column chromatography using chiral SFC (Chiralcel OD-H, 21 x 250 mm) using 25% EtOH(0.2% IP Am) in C02(SCf) as the mobile phase at a flow rate of 70 mL/min.
Example 18
(5)-N-((3R5,55R)-5-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)-3,3-dimethyl-l-(8- meth lquinolin-2-yl)piperidine-4-carboxamide
Figure imgf000040_0002
Add a 5 N aqueous NaOH solution (0.5 mL) to a mixture of methyl (3^,5^)-5-((45)- 3,3-dimethyl- l-(8-methyl-2-quinolyl)piperidine-4-carbonyl]amino]tetrahydropyran-3- carboxylate (0.085 g, 0.19 mmol), MeOH (2 mL), and THF (2 mL). Stir the resulting mixture at room temperature for 1 hour. Add a 5 N aqueous HCl solution (0.5 mL) and concentrate. Dilute the crude mixture in THF (6 mL) and cool to 0 °C. Add a 2 M solution of borane-THF complex in THF (0.15 mL, 0.3 mmol) drop-wise. Slowly warm the mixture to room temperature and stir at room temperature overnight. Add a saturated aqueous solution of sodium bicarbonate (10 mL) and extract the mixture with EtOAc (3 x 10 mL). Collect the organic extracts; wash with brine (10 mL); dry over MgS04; filter; collect the filtrate; and concentrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel eluting with 100 % EtOAc to give the title compound (0.046 g, 59 % yield over 2 steps). MS (m/z): 411 (M + H)+.
Example 19
Methyl (lR5,3R5)-3-((5)-3,3-Dimethyl- l-(8-methyl-2-quinolyl)piperidine-4- carbonyl] amino] cyclohexanecarboxylic acid
Figure imgf000041_0001
Add a 5 N aqueous NaOH solution (2.2 mL) to a mixture of methyl (±)-trans-[[(4S)-3,3- dimethyl- l-(8-methyl-2-quinolyl)piperidine-4-carbonyl]amino]cyclohexane-3-carboxylate (1.0 g, 2.2 mmol), MeOH (2 mL), and THF (8 mL). Stir the resulting mixture at room temperature overnight. Add a 5 N aqueous HC1 solution (2.2 mL) to adjust the pH to 6.5. Extract with EtOAc (2 x 25 mL) and collect the organic extracts. Wash the organic extracts with brine (25 mL); dry over MgS04; filter; collect the filtrate; and concentrate under reduced pressure to give the title compound (0.935 g, 98 %). MS (m/z): 424 (M + H)+.
Example 20
(lS')-N-((lRlS,,3RlS,)-3-(Ethylcarbamoyl)cyclohexyl)-3,3-dimethyl- l-(8-methylquinolin-2- yl)piperidine-4-carboxamide
Figure imgf000041_0002
Add triethylamine (0.7 mL, 5 mmol) to a mixture of (±)-ira/is,-3-[[(4S)-3,3-dimethyl-l- (8-methyl-2-quinolyl)piperidine-4-carbonyl]amino]cyclohexanecarboxylic acid (0.9 g, 2 mmol), ethanamine (2 mL, 3 mmol), BOP (1.0 g, 3 mmol) and DMF (4 mL). Stir the resulting mixture at room temperature for 3 hours. Add a saturated aqueous solution of sodium bicarbonate (20 mL). Extract the resulting mixture with EtOAc (2 x 50 mL). Collect the organic extracts; wash with brine (3 x 25 mL); dry over MgS04; filter; collect the filtrate; and concentrate under reduced pressure. Subject the resulting material to reverse-phase flash chromatography on C18 silica gel, eluting with a gradient of 20 % to 80 % acetonitrile (0.1 % formic acid) in water (0.1 % formic acid), to give the title compound (0.25 g, 30 %). MS (m z): 450 (M + H)+.
Biological Assays
Human mPGES-1 enzyme inhibition assay
Human mPGES-1 (Invitrogen™ (Cat# 97002RG, clone ID 6374722)) is subcloned into pcDNA3.1 and transiently expressed in 293E cells. Microsomes are prepared from cell pellets based on published methods (Oullet et al., Purification and characterization of recombinant microsomal prostaglandin E synthase- 1, Protein Expression and Purification, 26 pp 489-495 (2002); and Thoren et al., Human Microsomal Prostanglandin E Synthase- 1, J. Biol Chem.
278(25) pp 22199-22209 (2003)). Briefly, pellets are brought up in homogenization buffer (15 mM Tris-HCl, pH 8.0; 0.25 M sucrose; 0.1 mM EDTA; 1 mM glutathione) and sonicated 5 x 30 seconds on ice. Homogenate is centrifuged at 5,000 x g for 10 minutes at 4 °C. The supernatant fraction is decanted and loaded into Beckman Quick-Seal® tubes and centrifuged at 150,000 x g. for 90 minutes at 4 °C. The supernatant fraction is discarded by decantation and the pellets are re-suspended in assay buffer (10 mM sodium phosphate, pH 7.0; 10% glycerol; 2.5 mM glutathione; Complete Protease Inhibitor Cocktail (Roche)). Protein concentration is determined using the Pierce Coomassie Plus™ reagent.
For the enzyme assay, the microsomes are diluted into assay buffer and 14 μΕΛνεΙΙ of the resulting solution is added to 384 well assay plates. Compound dilution plates (Nunc
Cat#249944) are generated on a Tecan_MC384™ and 4 μΕΛνεΙΙ are added to the assay plates. Prostaglandin H2 (PGH2) is diluted into assay buffer immediately before use and 14 μΕΛνεΙΙ is added to the assay plates. Final concentrations are 6.55 μg/mL microsomes and 1.67 μΜ PGH2. After a 1.5 minute incubation at room temperature, 5 μΕΛνεΙΙ of 1 mg/mL SnCl2 in 0.5 N HC1 is added to stop the reaction. Five μL· of the stopped reaction are transferred to a 384 well plate containing 45 μΐ^ of 0.1% formic acid, and the plates are stored at -80 °C. The plates are shipped to Agilent Technologies, formerly Biocius Lifesciences (Wakefield, MA 01880) for standard LC/MS analysis for PGE2. The data are used to calculate the IC50 (μΜ). The compounds of the Examples inhibit human mPGES-1 with an IC50 μΜ value of less than 100 nM. The exemplified compound of Example 1 inhibits human mPGES- 1 with an IC50 μΜ value of 0.00193, + 0.00064, n=17. This result demonstrates that the exemplified compound of Example 1 is a potent inhibitor of the mPGES- 1 enzyme in an isolated enzyme preparation. Cell Based Assay for measuring Eicosanoid Selectivity
Human epithelial lung carcinoma cell line A549 is obtained from ATCC (CCL- 185) and maintained in Kaighn's F12 cell culture medium + 10% fetal bovine serum (FBS) (plating medium) under standard 5% C02 humidified atmosphere at 37 °C. The cells are passaged at 1 :3 twice per week.
For the assays, cells are released from flasks by washing once with PBS, then once with
Trypsin/EDTA. After 3-5 minutes at 37 °C, the cells are suspended in plating medium and centrifuged at 2,000 rpm, 25 °C, for 5 minutes. The supernatant is aspirated and the cell pellet is resuspended in F12K plating medium. The cell number is determined by counting an aliquot of cells which has been diluted in PBS and Trypan blue on a hemocytometer. Cells are plated at 40,000/well in 96 well Falcon plates 24 hours prior to treatment. Compounds are diluted in
DMSO to 100 x of the final concentration in Screen Mates tubes. The medium is removed from the cells and fresh medium (90 μΕΛνεΙΙ) is added to the cells. The compounds are added at 1 μL· I well, n=2, to give seven concentrations each. Cells are pretreated with compounds for 30 minutes at 37 °C, 5% C02. Prostaglandin E2 production is induced by the addition of recombinant human interleukin (rhIL-Ι β) diluted in plating medium to 10 x final. A 10 μΕΛνεΙΙ aliquot is added to give a final rhIL- Ιβ concentration of 0.1 ng/mL. The treatment period is approximately 18 hours. Conditioned medium is removed to v-bottom polypropylene plates. The conditioned medium is assayed for levels of PGE2 and prostaglandin I2 (PGI2) by specific enzyme immune-assay EIAs, according to the manufacturer's protocols (Cayman). Briefly, conditioned medium (1 is added to each well of a 96 well plate coated with a capture antibody and containing EIA buffer (49 supplied by the manufacturer. The tracer is diluted with the EIA buffer (50 μί). The detection antibody is diluted with the EIA buffer (50 The plate is covered with adhesive sealing film and is incubated for 1 hour at room temperature on an orbital shaker at 100 rpm. The wash buffer is diluted into MILLIPORE purified water, and the plate is washed 5 x 350 μΕΛνεΙΙ, using a plate washer. The substrate (Ellman's reagent) is diluted with MILLIPORE purified water and then added to the plate at 200 μΐ ννεΐΐ. After approximately 90-120 minutes at room temperature on an orbital shaker at 100 rpm, the plates are read at A412 on a plate reader. A standard curve of PGE2 is used to calibrate the unknowns. The exemplified compound of Example 1 inhibits PGE2 formation with an IC50 of 0.00471 μΜ + 0.00301, n=2.
Human Whole Blood Assay
Blood is collected from normal volunteer donors into sodium heparin VACUTAINER tubes. Donors are selected, in part, on their confirmation that they have not taken NSAIDs, aspirin, Celebrex®, or glucocorticoids within two weeks of the donation. All tubes/donor are pooled into 250 mL Corning conical centrifuge tubes and 436.5 μίΛνεΙΙ is distributed into deep well polypropylene plates. Compounds are diluted in DMSO to 100 x final and 4.5 μΕ/well in duplicate or triplicate is added to give 7 point curves. The blood is pretreated with compounds at 37 °C, 5% C02, in a humidified atmosphere, covered with a MicroClime Environmental Microplate lid, for 30 minutes after which 9 μΕ/well of a solution of 5 mg/mL of LPS (Sigma, serotype 0111:B4) in 1 mg/mL BS A/PBS is added to give a final LPS concentration of 100 μg/mL. The plates are incubated for 20-24 hours, at 37 °C, 5% C02, in a humidified
atmosphere. The plates are tightly sealed with the aluminum foil lids and are chilled on ice for approximately 1 hour. Then the plates are centrifuged at 1,800 x g, 10 minutes, 4 °C, in an Eppendorf 5810R centrifuge. Plasma is removed from the cell layer using the Rainin L200 with sterile filtered tips and transferred to v-bottom polypropylene plates. One hundred microliters is quantitatively transferred to Costar cluster tubes blocks and 400 μίΛνεΙΙ of the MeOH stop reagent and internal standards, <i4-PGE2, <i4-PGF2a, and <i4-TXA2p are added. Samples are vortexed for 5 minutes and are placed at -20 °C for at least one hour. Samples are centrifuged for 10 minutes at 4000 rpm in an Eppendorf 5810R.
Solid phase extraction is performed using Waters HLB 30 mg/bed 96 well plates on a vacuum manifold: Step 1, the matrix is washed with MeOH (1 mL), followed by 0.1% formic acid in water (1 mL); Step 2, 400 μΐ^ sample is applied along with 0.1% formic acid in water (900 μ > and allowed to bind for 5 minutes; Step 3, the matrix is washed with 0.1% formic acid in water (600 μί), followed by 80/20 water/MeOH (600 μί); Step 4, the products are eluted with 2-500 μΐ^ volumes of EtOAc; Step 5 the samples are dried under nitrogen and reconstituted in 75/25 water/acetonitrile with 0.1% formic acid (50 μΐ^). The products are analyzed by LC/MS/MS. Example 1 inhibits The PGE2 formation in this assay with an IC50 of 0.00205 + 0.00082, n=l l. This result supports that Example 1 inhibits PGE2 synthesis in human whole blood.

Claims

What is claimed is:
1. A compound of Formula 1 :
Figure imgf000046_0001
1, wherein:
Rl is H or -CH3;
R is selected from:
Figure imgf000046_0002
Figure imgf000047_0001
Figure imgf000047_0002
A compound according to Formula 2
Figure imgf000047_0003
2, wherein:
Rl is H or -CH3;
R is selected from:
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000049_0001
or a pharmaceutically acceptable salt thereof.
3. A compound according claim 1 or 2: wherein:
Rl is H or -CH3;
R is selected from:
Figure imgf000049_0002
Figure imgf000050_0001
G is selected from:
Figure imgf000050_0002
or a pharmaceutically acceptable salt thereof
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is selected from:
Figure imgf000050_0003
Figure imgf000051_0001
Figure imgf000051_0002
6. A compound according any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein G is:
Figure imgf000052_0001
or 7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Rl is -CH3.
8. A compound which is:
Figure imgf000052_0002
or a pharmaceutically acceptable salt thereof.
9. A compound according to claim, which is:
Figure imgf000052_0003
10. A compound according to any one of claims 1 to 9 wherein the pharmaceutically acceptable salt is a hydrochloride salt.
11. A pharmaceutically acceptable composition comprising a compound according to any one o claims 1 to 10 and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
12. A method of treating a patient in need of treatment for pain associated with arthritis or osteoarthritis said method comprising administering to the patient an effective amount of a pharmaceutically acceptable composition according to claim 11.
13. A method of treating a patient in need of treatment for inflammation associated with arthritis or osteoarthritis, said method comprising administering to the patient an effective amount of a pharmaceutically acceptable composition according to claim 11.
14. A method of treating a patient in need of treatment for arthritis or osteoarthritis, said method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 10.
15. A method of treating a patient in need of treatment for pain associated with arthritis, said method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 10.
16. A method of treating a patient in need of treatment for pain associated with osteoarthritis, said method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 10.
17. A method of treating a patient in need of treatment for inflammation associated with arthritis, said method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 10.
18. A method of treating a patient in need of treatment for inflammation associated with osteoarthritis, said method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 10. 19. A compound according to any one of claims 1 to 10 for use as a medicament.
20. A compound according to any one of claims 1 to 10 for use in therapy.
21. A compound according to any one of claims 1 to 10 for use in the treatment of arthritis or osteoarthritis.
22. A compound according to any one of claims 1 to 10 for use in the treatment of pain or inflammation associated with arthritis or osteoarthritis. 23. Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament to treat arthritis or osteoarthritis.
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