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WO2010103381A1 - Dérivés de pipéridine spirocycliques en tant que modulateurs de trpm8 - Google Patents

Dérivés de pipéridine spirocycliques en tant que modulateurs de trpm8 Download PDF

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Publication number
WO2010103381A1
WO2010103381A1 PCT/IB2010/000501 IB2010000501W WO2010103381A1 WO 2010103381 A1 WO2010103381 A1 WO 2010103381A1 IB 2010000501 W IB2010000501 W IB 2010000501W WO 2010103381 A1 WO2010103381 A1 WO 2010103381A1
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WO
WIPO (PCT)
Prior art keywords
piperidine
dihydro
chromene
carboxamide
spiro
Prior art date
Application number
PCT/IB2010/000501
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English (en)
Inventor
Sachin Sundarlal Chaudhari
Abraham Thomas
Ashok Bhausaheb Kadam
Bharat Gangadhar Adik
Sachin Vasantrao Dhone
Neelima Khairatkar-Joshi
Indranil Mukhopadhyay
Original Assignee
Glenmark Pharmaceuticals S.A.
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Publication date
Application filed by Glenmark Pharmaceuticals S.A. filed Critical Glenmark Pharmaceuticals S.A.
Publication of WO2010103381A1 publication Critical patent/WO2010103381A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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]

Definitions

  • the present patent application relates to spirocyclic piperidine derivatives with TRPM-8 activity.
  • TRP Transient receptor potential
  • TRPC Transient receptor potential
  • TRPC2 'Canonical', short
  • TRPV vanilloid
  • TRPM long, melastatin
  • TRPP polycystins
  • TRPML mucolipins
  • TRPA ANKTMl, Ankyrin
  • TRPN WOMPC
  • TRPV5 and TRPV6 are more closely related to each other than to TRPVl , TRP V2, TRPV3 or TRP V4.
  • TRPAl is most closely related to TRPV3, and is more closely related to TRPVl and TRP V2 than to TRPV5 and TRPV6.
  • the TRPM family has 8 members.
  • Constituents include the following: the founding member TRPMl (Melastatin or LTRPCl), TRPM3 (KIAAl 616 or LTRPC3), TRPM7 (TRP-PLIK, ChaK(l), LTRPC7), TRPM6 (ChaK2), TRPM2 (TRPC7 or LTRPC2), TRPM8 (Trp-p8 or CMRl), TRPM5 (Mtrl or LTRPC5) and TRPM4 (FLJ20041 or LTRPC4).
  • TRPMl Mellastatin or LTRPCl
  • TRPM3 KAAl 616 or LTRPC3
  • TRPM7 TRP-PLIK, ChaK(l), LTRPC7
  • TRPM6 ChoK2
  • TRPM2 TRPC7 or LTRPC2
  • TRPM8 Trp-p8 or CMRl
  • TRPM5 Mtrl or LTRPC5
  • TRPM4 FLJ20041 or LTRPC4
  • TRPP family consists of two groups of channels: those predicted to have six transmembrane domains and those that have 11.
  • TRPP2 PPD2
  • TRPP3 PPD2L1
  • TRPP5 PPD2L2
  • TRPPl PPDl, PCl
  • PKD-REJ PKD-ILl
  • TRP channels are thermosensitive and together they confer the ability to sense temperature throughout the range from noxious cold to noxious heat.
  • TRPM8 (McKemy DD et al., Nature, 2002, 416(6876): 52-58) also called cold-menthol receptor- 1 (CMR-I) expressed on a subpopulation of somatic sensory nerves on dorsal root ganglion and trigeminal ganglia, which causes sensory nerve excitation.
  • the receptor is known to be stimulated by cool to cold temperatures as well as synthetic cooling compounds such as menthol and icilin, which may be responsible for the therapeutic cooling sensation that these agents evoke.
  • WO 2006/040136 Al describes substituted benzyloxy derivatives as cold menthol receptor- 1 (CMR-I) antagonists for the treatment of urological disorders.
  • WO 2007/134107 Al describes phosphorous bearing compounds as TRPM8 antagonists useful for treating TRPM8 mediated disorders.
  • R 1 is selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, alkoxy, aryl, heteroaryl, and heterocyclyl; at each occurrence, R 2 is independently selected from hydrogen, hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocyclyl, -NR 5 R 6 , -NR 5 C(O)R 9 , -NR 5 C(S)R 9 , -OCOR 9 , -OC(O)OR 9 , -COR 9 , -COOR 9 , -CONR 5 , and -SR 5 ;
  • R 3 is a hydrogen, -(CH 2 ) r -L-NR 5 R 6 or -(CH 2 ) r -CN;
  • R 4 is selected from hydrogen, substituted or unsubstituted aryl, heteroaryl, and heterocyclyl; wherein the substituent(s) may be one or more are independently selected from halogen, hydroxyl, cyano, nitro, amino, -COOH, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, and -(CH 2 ) r -SO 2 R 12 ;
  • L is a bond or -C(O)-; at each occurrence, R 5 and R 6 are independently selected from hydrogen and lower alkyl; at each occurrence, R 7 and R 8 are each independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkoxy, haloalkyl, aryl, arylalkyl, arylalkyloxy, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, - (CH 2 ) q -OR 5 , -(CH 2 ) r -NR 5 R n , -(CH 2 VCO-NR 5 R 1 ', -(CH 2 ) r -CO-NR 5 -SO 2 R 12 , -(CH 2 V COOR 6 , -(CH 2 ) r -SO 2 R 12 , and -(CH 2 VSO 2 -NR 5 R 12 ; alternatively, R 7 and R
  • 'n' is an integer selected from O to 2, both inclusive;
  • 'p' is an integer selected from O to 1, both inclusive;
  • 'q' is an integer selected from 1 to 3; both inclusive;
  • 'r' is an integer selected from O to 3; both inclusive; or pharmaceutically acceptable salt thereof.
  • R 1 is selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, alkoxy, aryl, heteroaryl, and heterocyclyl; at each occurrence, R 2 is independently selected from hydrogen, hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocyclyl, -NR 5 R 6 , -NR 5 C(O)R 9 , -NR 5 C(S)R 9 , -OCOR 9 , -OC(O)OR 9 , -COR 9 , -COOR 9 , -CONR 5 , and -SR 5 ;
  • R 4 is selected from hydrogen, substituted or unsubstituted aryl, heteroaryl, and heterocyclyl; wherein the substituent(s) may be one or more are independently selected from halogen, hydroxyl, cyano, nitro, amino, -COOH, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, and -(CH 2 ) r -SO 2 R 12 ; at each occurrence, R 5 and R 6 are independently selected from hydrogen and lower alkyl; at each occurrence, R and R are each independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkoxy, haloalkyl, aryl, arylalkyl, arylalkyloxy, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
  • 'n' is an integer selected from O to 2, both inclusive;
  • 'q' is an integer selected from 1 to 3; both inclusive;
  • 'r' is an integer selected from O to 3; both inclusive; or pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described in the present patent application may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions of the present invention are useful for modulating TRPM receptors, which modulation is believed to be related to a variety of disease states.
  • the present patent application further provides a method of inhibiting TRPM8 receptors in a subject in need thereof by administering to the subject one or more compounds described herein in an amount effective to cause inhibition of such receptor.
  • halogen or halo means fluorine, chlorine, bromine, or iodine
  • alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, M-propyl, 1-methylethyl (isopropyl), «-butyl, «-pentyl, and 1,1- dimethylethyl (t-butyl).
  • C 1-6 alkyl refers to an alkyl chain having 1 to 6 It should be understood that the formulas (I), and (II), structurally encompasses all geometrical isomers, stereoisomers, enantiomers and diastereomers, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.
  • R 1 is halogen, for example Cl, Br or F.
  • R 1 is substituted or unsubstituted aryl, for example cyanophenyl.
  • R 1 is substituted or unsubstituted heteroaryl, for example fluoropyridyl.
  • R 4 is substituted or unsubstituted aryl (for example phenyl), heteroaryl (for example thiazole, thiadiazole, pyridine, benzthiazole or benzoxazole) and heterocyclyl.
  • the substituents may be one or more and are independently selected from cyano, halogen (Cl, Br or F), alkyl (tert-buty ⁇ ), haloalkyl (trifluoromethyl), haloalkoxy (trifluoromethoxy or trifluoroethoxy), and S(O) 2 CF 3 .
  • alkenyl refers to a hydrocarbon chain containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), wo-propenyl, 2-methyl-l- propenyl, 1 -butenyl, and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a hydrocarbyl radical having at least one carbon- carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred).
  • Non-limiting examples of alkynyl groups include ethynyl, propynyl, and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH 3 and -OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkyl refers to a group containing at least one halogen and an alkyl portion as define above, that is, a haloalkyl is a substituted alkyl group that is substituted with one or more halogens. Unless otherwise specified, all structural isomers of a given structure, for example, all enantiomers and all diasteriomers, are included within this definition. Exemplary haloalkyl groups include fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, trifluoromethyl and the like. Unless otherwise specified, a haloalkyl group has from 1 to 20 carbon atoms.
  • haloalkoxy refers to an alkoxy group with a halo substituent, where alkoxy and halo groups are as defined above.
  • exemplary haloalkoxy groups include fiuoromethoxy, chloromethoxy, trifluoromethoxy, trichloroethoxy, fluoroethoxy, chloroethoxy, trifloroethoxy, perfiuoroethoxy (-OCF 2 CF 3 ), trifluoro-t-butoxy, hexafluoro-t-butoxy, perfluoro-t-butoxy(-OC(CF 3 ) 3 ) and the like.
  • an haloalkoxy group typically has from 1 to 20 carbon atoms.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., sprio(4,4)non-2-yl. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H 4 C 6 H 5 . Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heterocyclic ring or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrol
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heteroaryl refers to substituted or unsubstituted 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indoli
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non- domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to cause the effect in the subject which is the purpose of the administration.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the compound described in the present patent application may form salts.
  • Non- limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases, salts of organic bases, salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
  • the present patent application extends to these stereoisomeric forms and to mixtures thereof.
  • the different stereoisomeric forms of the present patent application may be separated from one another by the method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
  • the pharmaceutical composition of the present invention includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition includes the compound(s) described herein in an amount sufficient to inhibit TRPM in a subject (e.g., a human).
  • the inhibitory activity of compounds falling within the Formula (I) may be measured by an assay provided below.
  • the compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient such as a carrier or a diluent
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.
  • the pharmaceutical composition may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • compositions may be prepared by techniques known in the art, e.g. as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound can be mixed with a carrier or diluted by a carrier or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • the oral route is preferred.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), troches and lozenges. Tablets or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Non-limiting examples of carriers for tablets or capsules include lactose, cornstarch and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • the compounds of the present inventions are useful for treatment of Urological diseases such as detrusor overactivity (overactive bladder), urinary incontinence, neurogenic detrusor overactivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia and lower urinary tract symptoms.
  • Urological diseases such as detrusor overactivity (overactive bladder), urinary incontinence, neurogenic detrusor overactivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia and lower urinary tract symptoms.
  • the compounds and pharmaceutical compositions of the present invention can be administered to treat any disorder, condition or disease treatable by inhibition of TRPM8.
  • the compounds and pharmaceutical compositions of the present invention are suitable for treatment or prophylaxis of the following diseases, conditions, and disorders mediated or associated with the activity of TRPM8 receptors: pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV-related neuropathy, postherpetic neuralgia, fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer, pr
  • the compounds described herein, including compounds represented by the general formula (I), (Ha) to (Ilk) can be prepared by techniques known to one in the art, for example, through the reaction Schemes 1 to 7 depicted below. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof are envisioned as a part of the present invention. The compounds obtained by using the general reaction schemes may be of insufficient purity.
  • Carbamate intermediates of formula (2) required for the synthesis are prepared using appropriate chloroformate (e.g., phenyl chloroformate) and commercially available amine (e.g., aniline) in the presence of suitable base (e.g., triethylamine, N 1 N- diisopropylethylamine) in a suitable solvent (T. W.
  • chloroformate e.g., phenyl chloroformate
  • suitable base e.g., triethylamine, N 1 N- diisopropylethylamine
  • R 2 and n are as defined above can be prepared as described in Scheme 2.
  • appropriately substituted hydroxy acetophenone of the formula (5) is reacted with N- BOC-4-piperidone in the presence of pyrrolidine and in a suitable solvent like methanol to give N-BOC spirocyclic amine of general formula (6).
  • the diasteromeric esters are separated by silica gel column chromatography to afford pure isomers (13) and (14).
  • Saponification of isomers (13) (+) and (14) (-) with a suitable base affords the optically pure alcohols of the formula (Hj) and (Ilk).
  • Step 1 tert-Butyl 8-chloro-4-oxo-3,4-dihydro-l 'H-spiro[chromene-2,4'-piperidine]-l '- carboxylate: To a stirred solution of 3-chloro-2-hydroxyacetophenone (26 g, 152.439 mmol) and pyrrolidine (12.66 mL, 152.439 mmol) in methanol (260 mL) was added N- /er/-butoxycarbonyl-4-piperidone (30.37 g, 152.439 mmol) at room temperature over 20 min. The reaction mixture was stirred at the same temperature for 24 h.
  • reaction mixture was concentrated and partitioned between ethyl acetate (500 mL) and 2N hydrochloric acid (250 mL). Two layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • Step 2 ter/-Butyl 8-chloro-4-hydroxy-3,4-dihydro-l 'H-spiro[chromene-2,4'-piperidine]- l '-carboxylate: To a stirred solution of Step 1 intermediate (38 g, 108.009 mmol) in ethanol (380 mL) was added sodium borohydride (4.00 g, 108.009 mmol) at room temperature over 30 min. The reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with ethyl acetate (400 mL) and water (250 mL). Two layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 150 mL).
  • Triethylsilane (13.14 g, 113.048 mmol) was added to a stirred solution of above Step 2 intermediate (10 g, 28.262 mmol) in trifluoroacetic acid (100 mL) and the resulting mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure to obtain a crude residue. The residue was dissolved in water (100 mL), neutralized with saturated NaHCO 3 solution and extracted with ethyl acetate (2 x 100 mL).
  • Step 1 /ert-Butyl bromo-4-oxo-3,4-dihydro-l 'H-spiro[chromene-2,4'-piperidine]-l '- carboxylate:
  • This compound was prepared according to the procedure described in Step 1 , Intermediate 1, by using 3 -bromo-2 -hydroxy acetophenone (7.0 g, 32.552 mmol), pyrrolidine (2.70 ml, 32.552 mmol) and iV-/ert-butoxycarbonyl-4-piperidone (6.4 g, 32.552 mmol) in methanol (70 mL) to obtain 9.93 g of the product as a off-white solid;
  • 1 H NMR 300 MHz, CDCl 3 ) ⁇ 1.40 (s, 9H), 1.60-1.67 (m, 2H), 1.82-1.94 (m, 2H), 2.91 (s, 2H), 3.09 (br s, 2H), 3.80-3.86 (m
  • Step 2 ter/-Butyl 8-Bromo-4-hydroxy-3,4-dihydro-l 'H-spiro[chromene-2,4'-piperidine]- l '-carboxylate:
  • the Step 1 intermediate (7.5 g, 18.926 mmol) was reduced with sodium borohydride (0.75 g, 18.926 mmol) in ethanol (75 mL) according to the procedure described in Intermediate 1, Step 2 to obtain 8.10 g of product as viscous liquid;
  • Step 2 intermediate (7.90 g, 19.834 mmol) was carried out with triethylsilane (12.60 mL, 79.339 mmol) and trifluoroacetic acid (80 mL) according to the procedure described in Intermediate 1, Step 3 to afford 6.82 g of the desired product as an off-white solid;
  • Step 1 tert-Buty ⁇ 8-chloro-6-fluoro-4-oxo-3,4-dihydro-l 'H-spiro[chromene-2,4'- piperidine]-l'-carboxylate: To a stirred solution of 3-chloro-5-fluoro-2- hydroxyacetophenone (8.0 g, 42.422 mmol) in AfN-dimethylformamide (80 mL) was added N-tert-butoxycarbonyl-4-piperidone (8.45 g, 42.422 mmol) followed by L-proline (1.46 g, 12.727 mmol) at room temperature. The reaction mixture was heated to 80°C for 15 h.
  • the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (500 mL) and water (250 mL). Two layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na 2 SO 4 ) and concentrated.
  • Step 2 tert-Butyl 8-chloro-6-fluoro-4-hydroxy-3,4-dihydro-l 'H-spiro[chromene-2,4'- piperidine]-l'-carboxylate:
  • the Step 1 above intermediate 5.0 g, 13.520 mmol
  • sodium borohydride 0.511 g, 13.520 mmol
  • ethanol 50.0 mL
  • Step 1 tert-Butyl 8-fluoro-4-oxo-3,4-dihydro-l 'H-spiro[chromene-2,4'-piperidine]-l '- carboxylate:
  • the compound was prepared according to the procedure described in Step 1 , Intermediate 1 by using 3-fluoro-2-hydroxyacetophenone (3.50 g, 5.514 mmol), pyrrolidine (392 mL, 5.514 mmol) and N-tert-butoxycarbonyl-4-piperidone (1.1 g, 5.514 mmol) in methanol (10 mL) to obtain 1.64 g of the product as a pale yellow solid;
  • 1 H NMR 300 MHz, DMSO-J 6 ) ⁇ 1.40 (s, 9H), 1.58-1.70 (m, 2H), 1.87-1.98 (m, 2H), 2.92 (s, 2H), 3.05-3.13 (m, 2H), 3.69-3.76 (m, 2H), 7.00
  • Step 2 8-Fluorospiro [chromene-2,4'-piperidin]-4(3H)-one hydrochloride: The Step 1 Intermediate (2.0 g, 5.047 mmol) was deprotected with saturated solution of hydrochloric acid in ethyl acetate (10 mL) according to the procedure described in Intermediate 4 to obtain 1.25 g of the product as an off-white solid; 1 H NMR (300 MHz, DMSO-J 6 ) ⁇ 1.90-1.98 (m, 2H), 2.10-2.18 (m, 2H), 2.98-3.06 (m, 4H), 3.18-3.24 (m, 2H), 7.04-7.12 (m, IH), 7.55-7.65 (m, 2H), 8.95 (br s, IH, exchangeable with D 2 O); APCI-MS (m/z) 236.20 (M+H) + .
  • Step 1 ( ⁇ )-tert-Butyl 8-chloro-4-fluoro-3,4-dihydro-l 'H-spiro[chromene-2,4'- piperidine]-l '-carboxylate: To a stirred and cooled (-40 0 C) solution of Step 2, Intermediate 1 (2.0 g, 5.652 mmol) in 1 ,2-dichloroethane (20 mL) was added (diethylamino)sulfurtrifluoride (DAST) (1.4 g, 8.847 mmol) under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature.
  • DAST diethylamino)sulfurtrifluoride
  • reaction mixture was quenched with cold saturated solution of NaHCO 3 and then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine and dried (Na 2 SO 4 ).
  • Step 2 ( ⁇ )-8-chloro-4-fluoro-3,4-dihydrospiro[chromene-2,4'-piperidine] hydrochloride:
  • the Step 1 intermediate (1.90 g, 5.339 mmol) was deprotected with saturated solution of hydrochloric acid in ethyl acetate (25 mL) according to the procedure described in Intermediate 4 to afford 1.46 g of the product as white solid;
  • Step 1 ( ⁇ )-ter/-Butyl 8-Chloro-4-(l ,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-3,4-dihydro- l'H-spiro[chromene-2,4'-piperidine]-r-carboxylate: To a stirred solution of Step 1, Intermediate 1 (5.0 g, 14.131 mmol) in anhydrous T ⁇ F (50 mL) was added diethyl azodicarboxylate (DEAD) (3.2 g, 18.370 mmol) followed by triphenylphosphine (5.5 g, 21.196 mmol).
  • DEAD diethyl azodicarboxylate
  • Step 2 ( ⁇ )-2-(8-Chloro-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl)-lH-isoindole- 1 ,3(2H)-dione hydrochloride:
  • the Step 1 Intermediate (800 mg, 1.656 mmol) was then deprotected with saturated solution of hydrochloric acid in ethyl acetate (10 mL) according to the procedure described in Intermediate 4 to obtain 522 mg of the product as an off-white solid;
  • Step 2 To a stirred and cooled (0°C) solution of Step 2, Intermediate 1 (1.0 g, 2.826 mmol) in acetonitrile (10.0 mL) was added cone. H 2 SO 4 (5.0 mL) dropwise and the resulting mixture was slowly warmed to room temperature. After stirring for 4 h the reaction mixture was poured onto crushed ice and basified with 2 M NaOH solution. The mixture was then extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with water (50 mL), brine (25 mL), dried (Na 2 SO 4 ) and filtered. The filtrate was evaporated under reduced pressure to give crude product.
  • Example 5 To a stirred solution of Example 5 (50 mg, 0.106 mmol) in toluene (2 mL) was added Pd[(Ph 3 )P] 4 (5 mg, 0.004 mmol) followed by the solution of Na 2 CO 3 (68 mg, 0.639 mmol) in water (1 mL). A solution of 2-fluoro-5-pyridylboronic acid (21 mg, 0.149 mmol) in ethanol (1 mL) was added to the reaction mixture and refluxed for 1.5 h. Excess of solvent was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (50 mL) and water (25 mL).
  • Example 25 To a stirred solution of Example 25 (50 mg, 0.1 14 mmol) in ethanol (1 mL) was slowly added sodium borohydride (4.4 mg, 0.1 14 mmol) at room temperature over 30 min. The reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was then diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with water and dried (Na 2 SO 4 ).
  • sodium borohydride 4.4 mg, 0.1 14 mmol
  • Step 1 8-Chloro-4-oxo-N-[4-(tert-butyl)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l'-carboxamide: Coupling reaction of Intermediate 4 (135 mg, 0.471 mmol) with phenyl [4-(ter/-butyl)phenyl]carbamate (152 g, 0.566 mmol) in the presence of triethylamine (238.8 mg, 2.358 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 125 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO-4) ⁇ 1.24 (s, 9H), 1.70-1.78 (m, 2H), 1.90-1.98 (m, 2H), 2.95 (s, 2H), 3.10-3.20 (m, 2H), 3.93-3.99 (m, 2H), 7.08
  • Step 2 ( ⁇ )-8-Chloro-4-hydroxy-N-[4-(tert-butyl)phenyl]-3,4-dihydro-l 'H-spiro[chromene -2,4'-piperidine]-l '-carboxamide:
  • the Step 1 intermediate (70 mg, 0.163 mmol) was reduced with sodium borohydride (7 mg, 0.196 mmol) in ethanol (1 mL) as described in Example 26, to obtain 50 mg of the product as a white solid;
  • Step 1 8-Bromo-4-oxo-jV-[4-(tert-butyl)phenyl]-3,4-dihydro- 1 'H-spiro[chromene-2,4'- piperidine]-l'-carboxamide: Coupling reaction of Intermediate 5 (275 mg, 0.675 mmol) with phenyl [4-(ter/-butyl)phenyl]carbamate (218 g, 0.810 mmol) in the presence of triethylamine (341.51 mg, 3.375 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 201 mg of the product as a white solid; 1 H NMR (300 MHz, DMSCwZ 6 ) ⁇ 1.24 (s, 9H), 1.68-1.75 (m, 2H), 1.90-1.98 (m, 2H), 2.94 (s, 2H), 3.12-3.22 (m, 2H), 3.96-4.02 (m
  • Step 2 ( ⁇ )-8-Bromo-4-hydroxy-N-[,4-(ter;-butyl)phenyl]-3,4-dihydro-rH-spiro[chromene -2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate (100 mg, 0.212 mmol) was reduced with sodium borohydride (9 mg, 0.254 mmol) in ethanol (1 mL) as described in Example 26, to obtain 60 mg of the product as a white solid;
  • Step 1 8-Bromo-4-oxo-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene- 2,4'-piperidine]-l '-carboxamide: Coupling reaction of Intermediate 5 (1.50 g, 4.707 mmol) with phenyl [4-(trifluoromethyl)phenyl]carbamate (1.45 g, 5.178 mmol) in the presence of triethylamine (2.38 g, 23.537 mmol) in anhydrous DMSO (10.0 mL) according to the procedure described in Example 1, gave 1.89 g of the product as a white solid; 1 H NMR (300 MHz, DMSO-J 6 ) ⁇ 1.70-1.78 (m, 2H), 1.92-2.00 (m, 2H), 2.95 (s, 2H), 3.16-3.26 (m, 2H), 4.00-4.06 (m, 2H), 7.03 (t, J
  • Step 2 ( ⁇ )-8-Bromo-4-hydroxy-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro- 1 'H-spiro [chromene-2,4'-piperidine]-l '-carboxamide:
  • the Step 1 intermediate (150 mg, 0.310 mmol) was reduced with sodium borohydride (12 mg, 0.310 mmol) in ethanol (1 mL) as described in Example 26, to obtain 131 mg of the product as a white solid;
  • Step 1 8-Fluoro-4-oxo-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene- 2,4'-piperidine]-l '-carboxamide: Coupling reaction of Intermediate 6 (300 mg, 1.104 mmol) with phenyl [4-(trifluorornethyl)phenyl]carbamate (341 mg, 1.214 mmol) in the presence of triethylamine (558 mg, 5.520 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1 , gave 445 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO-J 6 ) ⁇ 1.74-1.81 (m, 2H), 1.93-2.01 (m, 2H), 2.96 (s, 2H), 3.15-3.26 (m, 2H), 3.90-3.98 (m, 2H), 7.02-7.10 (m
  • Step 2 ( ⁇ )-8-Fluoro-4-hydroxy-jV-[4-(trifluoromethyl)phenyl]-3,4-dihydro-l 'H-spiro [chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate (100 mg, 0.236 mmol) was reduced with sodium borohydride (9 mg, 0.236 mmol) in ethanol (1 mL) as described in Example 26, to obtain 95 mg of the product as a white solid;
  • 1 H NMR 300 MHz, OMSO-d ⁇ ) ⁇ 1.66-1.92 (m, 5H), 2.13-2.20 (m, IH), 3.12-3.22 (m, 2H), 3.86-3.92 (m, 2H), 4.70-4.76 (m, IH), 5.50-5.56 (br s, IH), 6.85-6.91 (m, IH), 7.04-7.12 (m, IH), 7.21-7.26 (m, 2H), 7.57
  • Step 1 8-Chloro-4-oxo-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro [chromene -2,4'-piperidine]-l '-carboxamide: Coupling reaction of Intermediate 4 (1.50 g, 4.707 mmol) with phenyl [4-(trifluoromethoxy)phenyl]carbamate (1.45 g, 5.178 mmol) in the presence of triethylamine (2.38 g, 23.537 mmol) in anhydrous DMSO (10.0 mL) according to the procedure described in Example 1, gave 1.89 g of the product as a white solid; 1 H NMR (300 MHz, DMSCW 6 ) ⁇ 1.73-1.77 (m, 2H), 1.94-1.98 (m, 2H), 2.95 (s, 2H), 3.14-3.22 (m, 2H), 3.97-4.01 (m, 2H), 7.11 (t
  • Step 2 ( ⁇ )-8-Chloro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-l '-carboxamide:
  • the Step 1 intermediate (150 mg, 0.329 mmol) was reduced with sodium borohydride (12 mg, 0.329 mmol) in ethanol (1 mL) as described in Example 26, to obtain 131 mg of the product as a white solid;
  • Step 1 CBZ-L-Tryptophan ester: To a magnetically stirred solution of Example 31 (2.1 g, 4.596 mmol) in DCM (20.0 mL) was added (25)-2- ⁇ [(benzyloxy)carbonyl] amino ⁇ -3- (lH-indol-3-yl)propanoic acid (1.86 g, 5.515 mmol), EDCI (1.05 g, 5.515 mmol) and 4- dimethylaminopyridine (DMAP) (0.673 g, 5.515 mmol) at room temperature and stirred for 18 h. The reaction mixture was concentrated and the residue obtained was diluted with ethyl acetate (100 mL) and water (50 mL).
  • DMAP 4- dimethylaminopyridine
  • Step 2 (+)-8-Chloro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-l '-carboxamide: To a solution of Step 1 less polar distereomer (1.50 g, 1.927 mmol), in a mixture of T ⁇ F (20 mL), MeOH (4.0 mL), and water (4.0 mL) was added LiOH (0.162 g, 3.855 mmol) and stirred for 1 h at room temperature. The solvent was evaporated under reduced pressure and residue obtained was dissolved in water (50 mL).
  • Step 2 Saponification of more polar diastereomer (0.975 g, 1.254 mmol) using LiOH (0.1 18 g, 2.509 mmol) in a mixture of THF (20 mL), MeOH (4.0 mL), and water (4.0 mL) as described in Example 32, Step 2 afforded 500 mg of (-)-8-chloro-4-hydroxy-N-[4- (trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'-piperidine]-r- was added LiOH (0.162 g, 3.855 mmol) and stirred for 1 h at room temperature.
  • Step 2 Saponification of more polar diastereomer (0.975 g, 1.254 mmol) using LiOH (0.1 18 g, 2.509 mmol) in a mixture of THF (20 mL), MeOH (4.0 mL), and water (4.0 mL) as described in Example 32, Step 2 afforded 500 mg of (-)-8-chloro-4-hydroxy-N-[4- (trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'-piperidine]-r-
  • Step 2 ( ⁇ )-8-Bromo-4-hydroxy-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-l '-carboxamide:
  • the Step 1 intermediate (100 mg, 0.201 mmol) was reduced with sodium borohydride (7.5 mg, 0.201 mmol) in ethanol (1 mL) as described in Example 26, to obtain 74 mg of the product as a white solid;
  • Step 1 CBZ-L-Tryptophan ester was prepared by coupling compound obtained in Example 34 (660 mg, 1.316 mmol) with (2S>2- ⁇ [(benzyloxy)carbonyl] amino ⁇ -3-(1H- indol-3-yl)propanoic acid (534 mg, 1.579 mmol) in the presence of EDCI (302 mg, 1.579 mmol) and DMAP (193 mg, 1.579 mmol) in DCM (4.0 mL) according to the procedure described in Example 32, Step 1 to yield 722 mg of mixture of diastereomers.
  • Example 36 Spectral data of more polar diastereomer is given in Example 36, Step 1.
  • Step 2 Saponification of step 1 less polar distereomer (360 mg, 0.438 mmol), using LiOH (37 mg, 0.876 mmol) in a mixture of THF (4.0 mL), MeOH (1.0 mL), and water (1.0 mL) according to the procedure described in Example 32, Step 2 afforded 177 mg (+)-8-bromo-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide as a white solid; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.62-1.92 (m, 5H), 2.10-2.18 (m, IH), 3.08-3.17 (m, 2H), 3.22-3.28 (m, IH), 3.93-3.99 (m, 2H), 4.70-4.80 (m, IH), 5.54 (br s, IH), 6.86 (
  • Step 2 Saponification of more polar diastereomer (300 mg, 0.365 mmol) using LiOH (30 mg, 15.606 mmol) in a mixture of THF (4.0 mL), MeOH (1.0 mL), and water (1.0 mL) according to the procedure described in Example 32, Step 2 afforded 130 mg of (-)-8- bromo-4-hydroxy-iV-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide as a white solid; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.67-1.87 (m, 5H), 2.10-2.16 (m, IH), 3.08-3.17 (m, 2H), 3.22-3.30 (m, IH), 3.94-4.00 (m, 2H), 4.70-4.78 (m, IH), 5.54 (br s, IH), 6.86 (d
  • Step 1 8-Fluoro-4-oxo-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-l 'H-spiro [chromene -2,4'-piperidine]-l '-carboxamide: Coupling reaction of Intermediate 6 (300 mg, 1.104 mmol) with phenyl [4-(trifluoromethoxy)phenyl]carbamate (360 g, 1.214 mmol) in the presence of triethylamine (558 mg, 5.520 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1 , gave 440 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.72-1.81 (m, 2H), 1.93-2.00 (m, 2H), 2.96 (m, 2H), 3.15-3.25 (m, 2H), 3.88-3.95 (m, 2H), 7.00-7.08
  • Step 2 ( ⁇ )-8-Fluoro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro- 1 'H- spiro[chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate (100 mg, 0.228 mmol) was reduced with sodium borohydride (8.6 mg, 0.228 mmol) in ethanol (1 mL) as described in Example 26, to obtain 94 mg of the product as a white solid;
  • 1 H NMR 300 MHz, DMSCW 6 ): ⁇ 1.65-1.85 (m, 5H), 2.10-2.20 (m, IH), 3.10-3.25 (m, 2H), 3.84-3.90 (m, 2H), 4.70-4.75 (m, IH), 5.52 (br s, IH), 6.85-6.91 (m, IH), 7.04-7.11 (m, IH) 5 7.20- 7.26 (m, 3H),
  • Stepl CBZ-L-Tryptophan ester was prepared by coupling compound obtained in Example 37 (320 mg, 0.726 mmol) with (25)-2- ⁇ [(benzyloxy)carbonyl]amino ⁇ -3-(lH- indol-3-yl)propanoic acid (295 mg, 0.871 mmol) in the presence of EDCI (166 mg, 0.871 mmol) and DMAP (106 mg, 0.871 mmol) in DCM (4.0 mL) according to the procedure described in Example 32, Step 1, to yield 575 mg of mixture of diastereomers.
  • Step 2 Saponification of Step 1 less polar distereomer (170 mg, 0.223 mmol), using LiOH (19 mg, 0.446 mmol) in a mixture of THF (4.0 mL), MeOH (1.0 mL), and water (1.0 mL) according to the procedure described in Example 32, Step 2 afforded 83 mg (+)- 8 -fluoro-4-hydroxy-N- [4-(trifluoromethoxy)pheny 1] -3 ,4-dihydro- 1 'H-spiro [chromene- 2,4'-piperidine]-l'-carboxamide as a white solid; 1 H NMR (300 MHz, DMSO-c/ 6 ): ⁇ 1.64- 1.85 (m, 5H), 2.12-2.21 (m, IH), 3.12-3.24 (m, 2H), 3.85-3.91 (m, 2H), 4.68-4.76 (m, IH), 5.52 (br s, IH), 6.84-6.91 (
  • Step 2 Saponification of more polar diastereomer (145 mg, 0.190 mmol) using LiOH (16 mg, 0.381 mmol) in a mixture of THF (4.0 mL), MeOH (1.0 mL), and water (1.0 mL) according to the procedure described in Example 32, Step 2 afforded 68 mg of (-)-8- fluoro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l'-carboxamide as a white solid; 1 H NMR (300 MHz, DMSO-c/ 6 ): ⁇ 1.64-1.90 (m, 5H), 2.12-2.20 (m, IH), 3.12-3.27 (m, 2H), 3.82-3.90 (m, 2H), 4.70-4.76 (m, IH), 5.52 (br s, IH), 6.82-6.90 (m, IH), 7.04
  • Step 1 8-Chloro-4-oxo-jV-[4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydro- 1 '//-spiro [chromene-2,4'-piperidine]-l '-carboxamide: Coupling reaction of Intermediate 4 (100 mg, 0.346 mmol) with phenyl [4-(2,2,2-trifluoroethoxy)phenyl]carbamate (129 g, 0.416 mmol) in the presence of triethylamine (175.05 mg, 1.73 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 140 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.66-1.76 (m, 2H), 1.90-1.98 (m, 2H), 2.95 (s, 2H), 3.10-3.20 (m, 2H), 3.94-4.00 (m,
  • Step 2 ( ⁇ )-8-Chloro-4-hydroxy-jV-[4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydro-r//- spiro[chromene-2,4'-piperidine]-l '-carboxamide:
  • the Step 1 intermediate 120 mg, 0.255 mmol
  • sodium borohydride (1 1 mg, 0.307 mmol) in ethanol (3 mL) as
  • Step 1 8-Bromo-4-oxo-N-[4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-r-carboxamide: Coupling reaction of Intermediate 5 (100 mg, 0.337 mmol) with phenyl [4-(2,2,2-trifluoroethoxy)phenyl]carbamate (126 g, 0.405 mmol) in the presence of triethylamine (170.50 mg, 1.688 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 150 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.70-1.75 (m, 2H), 1.90-1.98 (m, 2H), 2.94 (s, 2H), 3.12-3.23 (m, 2H), 3.96-4.02 (m, 2H), 4.
  • Step 2 ( ⁇ )-8-Bromo-N-[4-(2,2,2-trifluoroethoxy)phenyl]-4-hydroxy-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate 130 mg, 0.253 mmol
  • sodium borohydride 11 mg, 0.303 mmol
  • ethanol 3 mL
  • Step 2 ( ⁇ )-8-Chloro-N-(3,4-difluorophenyl)-4-hydroxy-3,4-dihydro- 1 'H-spiro[chromene- 2,4'-piperidine]-l '-carboxamide:
  • the Step 1 intermediate 120 mg, 0.294 mmol
  • sodium borohydride 13 mg, 0.353 mmol
  • ethanol 3 mL
  • 1 H NMR 300 MHz, DMSO- ⁇ 4 ⁇ 1.59-1.90 (m, 5H), 2.10-2.17 (m, IH), 3.05-3.25 (m, 2H), 3.93-3.98 (m, 2H), 4.68-4.78 (m, IH), 5.54 (br s, IH), 6.91 (t, J- 7.8 Hz, IH), 7.20-7.40 (m, 4H), 7.58- 7.65 (m, IH), 8.75 (br s)
  • Step 1 8-Chloro-4-oxo-jV-[(4-t-?r/-butyl)-l,3-thiazol-2-yl]-3,4-dihydro-l'H-spiro [chromene-2,4'-piperidine]-r-carboxamide: Coupling reaction of Intermediate 4 (100 mg, 0.346 mmol) with phenyl (4-tert-butyl-l,3-thiazol-2-yl)carbamate (115 mg, 0.416 mmol)
  • Step 2 ( ⁇ )-8-Chloro- ⁇ 4(4-ter/-butyl)-l ,3-thiazol-2-yl]-4-hydroxy-3,4-dihydro-l 'H-spiro [chromene-2,4'-piperidine]-l'-carboxamide:
  • the Step 1 intermediate (100 mg, 0.230 mmol) was reduced with sodium borohydride (10 mg, 0.275 mmol) in ethanol (2 mL) as described in Example 26, to obtain 100 mg of the product as a white solid;
  • Step 1 8-Chloro-4-oxo-N-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-3,4-dihydro-l'H-spiro [chromene-2,4'-piperidine]-r-carboxamide: Coupling reaction of Intermediate 4 (100 mg, 0.346 mmol) with phenyl [4-(trifluoromethyl)-l,3-thiazol-2-yl]carbamate (1 19 g, 0.416 mmol) in the presence of triethylamine (175.05 mg, 1.73 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 160 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.70-1.78 (m, 2H), 1.92-2.00 (m, 2H), 2.94 (s, 2H), 3.15-3.26 (m, 2H), 4.04-4.12
  • Step 2 ( ⁇ )-8-Chloro-4-hydroxy-N-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate 150 mg, 0.335
  • Step 1 8-Chloro-4-oxo-N-[6-(trifluoromethyl)-l,3-benzothiazol-2-yl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide: Coupling reaction of Intermediate 4 (100 mg, 0.346 mmol) with phenyl [5-(ter/-butyl)-l,3,4-thiadiazol-2-yl]carbamate (115 g, 0.416 mmol) in the presence of triethylamine (175.05 mg, 1.73 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1 , gave 60 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.34 (s, 9H), 1.65-1.74 (m, 2H), 1.92-2.05 (m, 2H), 2.93 (s, 2H),
  • Step 2 ( ⁇ )-8-Chloro-4-hydroxy-N-[5-(/ert-butyl)-l,3,4-thiadiazol-2-yl]-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate 50 mg, 0.1 15 mmol
  • sodium borohydride 5 mg, 0.138 mmol
  • ethanol 1 mL
  • 1 H NMR 300 MHz, OMSO-d ⁇
  • Step 1 S-Chloro ⁇ -oxo-N-fS-CtrifluoromethyO-l ⁇ -thiadiazol ⁇ -y ⁇ -S ⁇ -dihydro-l'H- spiro[chromene-2,4'-piperidine]-l '-carboxamide: Coupling reaction of Intermediate 4 (100 mg, 0.346 mmol) with phenyl [5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]carbamate (1 19 g, 0.416 mmol) in the presence of triethylamine (175.05 mg, 1.73 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 138 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO-J 6 ) ⁇ 1.71-1.81 (m, 2H), 1.96-2.02 (m, 2H), 2.94 (s, 2H), 3.20-3.26 (m, 2H),
  • Step 2 ( ⁇ )-8-Chloro-4-hydroxy-N-[5-(trifluoromethyl)- 1 ,3,4-thiadiazol-2-yl]-3,4-dihydro- rH-spiro[chromene-2,4'-piperidine]-l '-carboxamide:
  • the Step 1 intermediate 120 mg, 0.269 mmol
  • sodium borohydride (12 mg, 0.322 mmol) in ethanol (2 mL) as described in Example 26, to obtain 110 mg of the product as a white solid
  • Step 1 8-Chloro-4-oxo-iV-(6-fluoro-l ,3-benzothiazol-2-yl)-3,4-dihydro-l 'H-spiro [chromene-2,4'-piperidine]-l '-carboxamide: Coupling reaction of Intermediate 4 (300
  • Step 2 ( ⁇ )-8-Chloro-N-(6-fluoro-l,3-benzothiazol-2-yl)-4-hydroxy-3,4-dihydro-l'H-spiro [chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate (75 mg, 0.168 mmol) was reduced with sodium borohydride (7 mg, 0.168 mmol) in ethanol (1 mL) as described in Example 26, to obtain 65 mg of the product as a white solid;
  • Step 1 8-Bromo-4-oxo-N-(6-fluoro-l ,3-benzothiazol-2-yl)-3,4-dihydro-l 'H-spiro [chromene-2,4'-piperidine]-l '-carboxamide: Coupling reaction of Intermediate 5 (250 mg, 0.751 mmol) with phenyl (6-fluoro-l,3-benzothiazol-2-yl)carbamate (238 mg, 0.826 mmol) in the presence of triethylamine (380 mg, 3.758 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1 , gave 352 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.70-1.78 (m, 2H), 1.92-2.00 (m, 2H), 2.94 (s, 2H), 3.16-3.26 (m, 2H), 4.1 1-4.
  • Step 2 ( ⁇ )-8-Bromo-N-(6-fluoro-l,3-benzothiazol-2-yl)-4-hydroxy-3,4-dihydro-17/-spiro [chromene-2,4'-piperidine]-l'-carboxamide:
  • the Step 1 intermediate (100 mg, 0.203 mmol) was reduced with sodium borohydride (8 mg, 0.203 mmol) in ethanol (1 mL) as described in Example 26, to obtain 67 mg of the product as a white solid;
  • Step 1 8-Chloro-4-oxo-N-[6-(trifluoromethyl)-l,3-benzothiazol-2-yl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide: Coupling reaction of Intermediate 4 (100 mg, 0.346 mmol) with phenyl [6-(trifluoromethyl)-l,3-benzothiazol-2-yl]carbamate (140 g, 0.416 mmol) in the presence of triethylamine (175.05 mg, 1.73 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 179 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.70-1.80 (m, 2H), 1.90-2.05 (m, 2H), 2.95 (s, 2H), 3.24-3.29 (m, 2H
  • Step 2 ( ⁇ )-8-Chloro-4-hydroxy-jV-(6-trifluoromethyl-l,3-benzothiazol-2-yl)-3,4-dihydro- rH-spiro[chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate (170 mg, 0.343 mmol) was reduced with sodium borohydride (16 mg, 0.412 mmol) in ethanol (2 mL) as described in Example 26, to obtain 120 mg of the product as a white solid;
  • Step 1 8-Chloro-N-(4,6-difluoro-l,3-benzothiazol-2-yl)-4-oxo-3,4-dihydro-l'H-spiro [chromene-2,4'-piperidine]-r-carboxamide: Coupling reaction of Intermediate 4 (100 mg, 0.346 mmol) with phenyl (4,6-difluoro-l ,3-benzothiazol-2-yl)carbamate (127 g, 0.416 mmol) in the presence of triethylamine (175.05 mg, 1.73 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 162 mg of the product as a white solid; 1 H NMR (300 MHz, DMSCW 6 ) ⁇ 1.72-1.81 (m, 2H), 1.94-2.02 (m, 2H), 2.95 (s, 2H), 3.18-3.28 (m, 2H), 4.10
  • Step 2 ( ⁇ )-8-Chloro-4-hydroxy-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate (150 mg, 0.323 mmol) was reduced with sodium borohydride (15 mg, 0.388 mmol) in ethanol (2 mL) as described in Example 26, to obtain 140 mg of the product as a white solid;
  • Step 1 8-Chloro-4-oxo-7V- ⁇ 4-[4-(trifluoromethyl)phenyl]-l ,3-thiazol-2-yl ⁇ -3,4-dihydro- l 'H-spiro[chromene-2,4'-piperidine]-l '-carboxamide: Coupling reaction of Intermediate
  • Step 2 ( ⁇ )-8-Chloro-iV- ⁇ 4-[4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl ⁇ -4-hydroxy-3,4- dihydro-rH-spiro[chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate 200 mg, 0.383 mmol
  • sodium borohydride 14 mg, 0.383 mmol
  • ethanol 2 mL
  • Step 1 8-Chloro-4-oxo-iV- ⁇ 4-[(trifluoromethyl)sulfonyl]phenyl ⁇ -3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-r-carboxamide: Coupling reaction of Intermediate 4 (90 mg, 0.312 mmol) with phenyl ⁇ 4-[(trifluoromethyl)sulfonyl]phenyl ⁇ carbamate (129 mg, 0.374 mmol) in the presence of triethylamine (157.95 mg, 1.561 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 108 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.72-1.81 (m, 2H), 1.95-2.02 (m, 2H), 2.96 (s, 2H), 3.18-3.28 (m, 2H), 3.98-4.
  • Step 2 ( ⁇ )-8-Chloro-4-hydroxy-N- ⁇ 4-[(trifluoromethyl)sulfonyl]phenyl ⁇ -3,4-dihydro- rH-spiro[chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate (100 mg, 0.198 mmol) was reduced with sodium borohydride (9 mg, 0.238 mmol) in ethanol (2 mL) as described in Example 26, to obtain 60 mg of the product as a white solid;
  • Step 1 ( ⁇ )-8-Chloro-4-pthalimido-N-(4-trifluoromethylphenyl)-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-l '-carboxamide: Coupling reaction of Intermediate 10 (510 mg, 1.192 mmol) with phenyl [4-(trifluoromethyl)phenyl]carbamate (368 mg, 1.31 1
  • Step 2 ( ⁇ )-4-Amino-8-chloro-N-(4-trifluoromethyphenyl)-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-r-carboxamide:
  • Step 1 intermediate 575 mg, 1.088 mmol
  • hydrazine hydrate 497 mg, 9.928 mmol
  • ethanol 20.0 mL
  • the reaction mixture was then extracted with ethyl acetate (2 x 50 mL).
  • the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (15 mL), brine (10 mL) dried (Na 2 SO 4 ) and filtered. The filtrate was concentrated under reduced pressure.
  • Step 3 4-Amino-8-chloro-N-(4-fluorophenyl)-3,4-dihydro-r//-spiro[chromene-2,4'- piperidine]-l'-carboxamide hydrochloride: To a stirred solution of Step 2 intermediate
  • Step 1 8-Chloro-N-[3-fluoro-4-(trifluoromethyl)phenyl]-4-oxo-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-r-carboxamide: Coupling reaction of Intermediate 4 (60 mg, 0.208 mmol) with phenyl [3 -fluoro-4-(trifluoromethyl)phenyl] carbamate (62 g, 0.208 mmol) in the presence of triethylamine (105.23 mg, 1.04 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 102 mg of the product as a white solid ⁇ NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.70-1.80 (m, 2H), 1.94-2.02 (m, 2H), 2.95 (s, 2H), 3.15-3.22 (m, 2H), 3.96-4.05 (m, 2H), 7.08 (
  • Step 2 ( ⁇ )-8-Chloro-7V-[3-fluoro-4-(trifluoromethyl)phenyl]-4-hydroxy-3,4-dihydro- 1 'H- spiro[chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate (91 mg, 0.199 mmol) was reduced with sodium borohydride (9 mg, 0.239 mmol) in ethanol (2 mL) as described in Example 26, to obtain 55 mg of the product as a white solid;
  • Step 1 8-Chloro-N-[3-fluoro-4-(trifluoromethyl)phenyl]-4-oxo-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-r-carboxamide: Coupling reaction of Intermediate 4 (60 mg, 0.208 mmol) with phenyl (4-difluoromethoxyphenyl)carbamate (62 mg, 0.208 mmol) in the presence of triethylamine (105.23 mg, 1.04 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 102 mg of the product as a
  • Step 2 ( ⁇ )-8-Chloro-N-[3-fluoro-4-(trifluoromethyl)phenyl]-4-hydroxy-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate (91 mg, 0.199 mmol) was reduced with sodium borohydride (9 mg, 0.239 mmol) in ethanol (2 mL) as described in Example 26, to obtain 55 mg of the product as a white solid;
  • Step 1 8-Bromo-N-[4-(difluoromethoxy)phenyl]-4-oxo-3,4-dihydro-l 'H-spiro[chromene- 2,4'-piperidine]-l '-carboxamide: Coupling reaction of Intermediate 5 (100 mg, 0.300 mmol) with phenyl [4-(difluoromethoxy)phenyl]carbamate (92 mg, 0.330 mmol) in the presence of triethylamine (151 mg, 1.500 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 120 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.65-1.75 (m, 2H), 1.90-1.98 (m, 2H), 2.94 (s, 2H), 3.15-3.22 (m, 2H), 3.97-4.03 (m, 2H), 7.00-7.07 (m,
  • Step 2 ( ⁇ )-8-Bromo-N-[4-(difluoromethoxy)phenyl]-4-hydroxy-3,4-dihydro-l'H-spiro [chromene-2,4'-piperidine]-l '-carboxamide:
  • the Step 1 intermediate (1 10 mg, 0.228 mmol) was reduced with sodium borohydride (10 mg, 0.274 mmol) in ethanol (2 mL) as described in Example 26, to obtain 60 mg of the product as a white solid;
  • Step 1 8-Chloro-N-[4-(difluoromethoxy)-3-fluorophenyl]-4-oxo-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-r-carboxamide: Coupling reaction of Intermediate 4 (100 mg, 0.346 mmol) with phenyl [4-(difluoromethoxy)-3-fluorophenyl]carbamate (113 mg, 0.381 mmol) in the presence of triethylamine (175 mg, 1.73 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 128 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.70-1.78 (m, 2H), 1.90-2.00 (m, 2H), 2.95 (s, 2H), 3.12-3.23 (m, 2H), 3.95-4.01 (m, 2H),
  • Step 2 ( ⁇ )-8-Chloro-N-[4-(difluoromethyl)-3-fluorophenyl]-4-hydroxy-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate 120 mg, 0.261 mmol
  • sodium borohydride (12 mg, 0.313 mmol) in ethanol (3.0 mL) as described in Example 26, to obtain 65 mg of the product as a white solid
  • Step 1 8-Bromo-N-[4-(difluoromethoxy)-3-fluorophenyl]-4-oxo-3,4-dihydro- 1 'H-spiro [chromene-2,4'-piperidine]-r-carboxamide: Coupling reaction of Intermediate 5 (100 mg, 0.337 mmol) with phenyl [4-(difluoromethoxy)-3-fluorophenyl]carbamate (110 mg, 0.371 mmol) in the presence of triethylamine (170.50 mg, 1.685 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1 , gave 125 mg of the product as a white solid; 1 H NMR (300 MHz, DMSO-J 6 ) ⁇ 1.70-1.78 (m, 2H), 1.92-2.00 (m, 2H), 2.94 (s, 2H), 3.12-3.23 (m, 2H), 3.97-4.03
  • Step 2 ( ⁇ )-8-Bromo-4-hydroxy-N-[4-(difluoromethoxy)-3-fluorophenyl]-3,4-dihydro- 1 'H-spiro [chromene-2,4'-piperidine]-l'-carboxamide:
  • the Step 1 intermediate 120 mg, 0.240 mmol
  • sodium borohydride (1 1 mg, 0.288 mmol) in ethanol (2 mL) as described in Example 26, to obtain 75 mg of the product as a white solid
  • Step 1 8-Bromo-N-[3-fluoro-4-(trifluoromethyl)phenyl]-4-oxo-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-l '-carboxamide: Coupling reaction of Intermediate 5 (60 mg, 0.202 mmol) with phenyl [3-fluoro-4-(trifluoromethyl)phenyl]carbamate (72.74 mg,
  • Step 2 ( ⁇ )-8-Bromo-iV- [3 -fluoro-4-(trifluoromethyl)phenyl] -4-hydroxy-3 ,4-dihydro- 1 1 H- spiro[chromene-2,4'-piperidine]-r-carboxamide:
  • the Step 1 intermediate (90 mg, 0.179 mmol) was reduced with sodium borohydride (8 mg, 0.215 mmol) in ethanol (2 mL) as described in Example 26, to obtain 35 mg of the product as a white solid;
  • the illustrative examples of the present invention are screened for TRPM8 antagonist activity according to a modified procedure described in T ⁇ th, A. et al. Life Sciences (2003), 73, 487-498.
  • Other related methods and procedures may be found in Behrendt, H. J. et al. Br. J. Pharmacol. (2004), 141. 737-745; Anderson, D. A. et al. J. Neuroscience (2004), 24, 5364-5369.
  • menthol at a pre-defined concentration and 5 ⁇ Ci/ml of 45 Ca +2 for 3 minutes.
  • Cells were washed and lysed using buffer containing 1% Triton X-IOO, 0.1% deoxycholate and 0.1% SDS. Radioactivity in the lysate was measured in Packard Top count after addition of liquid scintillant. Concentration response curves were plotted as a percentage of maximal response obtained in the absence of test antagonist. IC 50 values were calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software.
  • IC 5O (nM) values of the compounds are set forth in Table 1 wherein "A” refers to an IC 50 value of less than 20 nM, “B” refers to IC 50 value in range of 20.01 - 100 nM, “C” refers to an IC 50 value in range of 100.01 - 500 nM and “D” refers to an IC 50 value of more than 500 nM.
  • Table 1 In-vitro screening results of compounds of invention

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Abstract

La présente invention porte sur des modulateurs de formule (I) de la sous-famille M à potentiel de récepteur transitoire (TRPM8). En particulier, l'invention porte sur des composés qui sont utiles pour traiter ou prévenir des maladies, des états et/ou des troubles modulés par TRPM8. L'invention porte également sur des procédés de préparation de composés décrits présentement, sur des intermédiaires utilisés dans leur synthèse, sur des compositions pharmaceutiques de ceux-ci et sur des procédés pour traiter et prévenir des maladies, des états et/ou des troubles à modulation par TRPM8.
PCT/IB2010/000501 2009-03-13 2010-03-10 Dérivés de pipéridine spirocycliques en tant que modulateurs de trpm8 WO2010103381A1 (fr)

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WO2012098281A2 (fr) 2011-01-19 2012-07-26 Universidad Miguel Hernández De Elche Peptides modulateurs de récepteurs trp et leurs utilisations
EP2481727A1 (fr) 2011-01-28 2012-08-01 Dompe S.p.A. Antagonistes du récepteur TRPM8
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EP2606888A1 (fr) 2011-12-19 2013-06-26 Dompe' S.P.A. Antagonistes du TRPM8
WO2013092711A1 (fr) 2011-12-19 2013-06-27 Dompe' S.P.A. Antagonistes de trpm8
WO2015136947A1 (fr) 2014-03-14 2015-09-17 Raqualia Pharma Inc. Dérivés azaspiro en tant qu'antagonistes de trpm8
WO2015197640A1 (fr) 2014-06-23 2015-12-30 Dompe' Farmaceutici S.P.A. Dérivés du 2-aryl-4-hydroxy-1,3-thiazole utilisables comme inhibiteurs du trpm8 dans le traitement de la névralgie, de la douleur, de la broncho-pneumopathie chronique obstructive et de l'asthme
WO2016039448A1 (fr) * 2014-09-12 2016-03-17 田辺三菱製薬株式会社 Composé aromatique d'amide d'acide carboxylique
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US20120010135A1 (en) * 2009-04-01 2012-01-12 Xenon Pharmaceuticals Inc. Spiro derivatives for the modulation of stearoyl-coa desaturase
WO2012098281A2 (fr) 2011-01-19 2012-07-26 Universidad Miguel Hernández De Elche Peptides modulateurs de récepteurs trp et leurs utilisations
EP2481727A1 (fr) 2011-01-28 2012-08-01 Dompe S.p.A. Antagonistes du récepteur TRPM8
WO2012101244A1 (fr) 2011-01-28 2012-08-02 Dompe' S.P.A. Antagonistes des récepteurs trpm8
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WO2012161119A1 (fr) * 2011-05-20 2012-11-29 興和株式会社 Nouveau dérivé de spiropipéridine et produit pharmaceutique le contenant
EP2606888A1 (fr) 2011-12-19 2013-06-26 Dompe' S.P.A. Antagonistes du TRPM8
WO2013092711A1 (fr) 2011-12-19 2013-06-27 Dompe' S.P.A. Antagonistes de trpm8
US10562870B2 (en) 2012-03-16 2020-02-18 Biohaven Pharmaceutical Holding Company Ltd. Prodrugs of riluzole and their method of use
US9725427B2 (en) 2012-03-16 2017-08-08 Biohaven Pharmaceutical Holding Company Limited Prodrugs of riluzole and their method of use
US12172974B2 (en) 2012-03-16 2024-12-24 Biohaven Pharmaceutical Holding Company Ltd. Prodrugs of riluzole and their method of use
US10844026B2 (en) 2012-03-16 2020-11-24 Biohaven Pharmaceutical Holding Company Ltd. Prodrugs of riluzole and their method of use
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US10231954B2 (en) 2014-02-04 2019-03-19 Lytix Biopharma As Neurodegenerative therapies
KR20160132041A (ko) * 2014-03-14 2016-11-16 라퀄리아 파마 인코포레이티드 Trpm8 길항제로 사용되는 아자스피로 유도체
KR102425400B1 (ko) 2014-03-14 2022-07-26 라퀄리아 파마 인코포레이티드 Trpm8 길항제로 사용되는 아자스피로 유도체
JP2017507981A (ja) * 2014-03-14 2017-03-23 ラクオリア創薬株式会社 Ｔｒｐｍ８拮抗剤としてのアザスピロ誘導体
EP3116858A4 (fr) * 2014-03-14 2017-11-22 RaQualia Pharma Inc. Dérivés azaspiro en tant qu'antagonistes de trpm8
RU2683309C2 (ru) * 2014-03-14 2019-03-28 Раквалиа Фарма Инк. Азаспиропроизводные в качестве антагонистов trpm8
US10093678B2 (en) 2014-03-14 2018-10-09 Raqualia Pharma Inc. Azaspiro derivatives as TRPM8 antagonists
WO2015136947A1 (fr) 2014-03-14 2015-09-17 Raqualia Pharma Inc. Dérivés azaspiro en tant qu'antagonistes de trpm8
CN106103416A (zh) * 2014-03-14 2016-11-09 拉夸里亚创药株式会社 作为trpm8拮抗剂的氮杂螺衍生物
US11046662B2 (en) 2014-06-23 2021-06-29 Dompé Farmaceutici S.P.A. 2-aryl-4-hydroxy-1,3-thiazole derivatives useful as TRPM8-inhibitors in treatment of neuralgia, pain, COPD and asthma
US10196368B2 (en) 2014-06-23 2019-02-05 Dompé Farmaceutici S.P.A. 2-aryl-4-hydroxy-1,3-thiazole derivatives useful as TRPM8-inhibitors in treatment of neuralgia, pain, COPD and asthma
WO2015197640A1 (fr) 2014-06-23 2015-12-30 Dompe' Farmaceutici S.P.A. Dérivés du 2-aryl-4-hydroxy-1,3-thiazole utilisables comme inhibiteurs du trpm8 dans le traitement de la névralgie, de la douleur, de la broncho-pneumopathie chronique obstructive et de l'asthme
WO2016039448A1 (fr) * 2014-09-12 2016-03-17 田辺三菱製薬株式会社 Composé aromatique d'amide d'acide carboxylique
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US10993939B2 (en) 2016-06-13 2021-05-04 Mitsubishi Tanabe Pharmaceutical Company Compositions for treating or preventing vasomotor symptoms
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