WO2010103381A1

WO2010103381A1 - Spirocyclic piperidine derivatives as trpm 8 modulators

Info

Publication number: WO2010103381A1
Application number: PCT/IB2010/000501
Authority: WO
Inventors: 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.
Priority date: 2009-03-13
Filing date: 2010-03-10
Publication date: 2010-09-16

Abstract

The present invention provides Transient Receptor Potential subfamily M, member 8 (TRPM8) modulators of formula (I). In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPM8. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by TRPM8.

Description

SPIROCYCLIC PIPERIDINE DERIVATIVES AS TRPM 8 MODULATORS

Related applications

This application claims the benefit of Indian Provisional Applications 551 /MUM/2009, filed on Mar 13, 2009; 1345/MUM/2009, filed on Jun 3, 2009; and 2038/MUM/2009, filed on Sep 7, 2009; and U.S. Provisional Applications 61/162,872, filed on Mar 24, 2009; 61/218,240, filed on Jun 18, 2009; and 61/247,765, filed on Oct 1 , 2009; all of which are hereby incorporated by reference in their entirety.

Technical Field

The present patent application relates to spirocyclic piperidine derivatives with TRPM-8 activity.

Background of the Invention

Transient receptor potential (TRP) family of ion channels act as sensors of the physical and chemical environment (Clapham, 2003). These channels are activated by temperature, light and touch etc. They have been classified into seven subfamilies: TRPC ('Canonical', short), TRPV (vanilloid), TRPM (long, melastatin), TRPP (polycystins), TRPML (mucolipins), TRPA (ANKTMl, Ankyrin) and TRPN (WOMPC) families. The TRPC family can be divided into 4 subfamilies (TRPCl, TRPC2, TRPC3, 6, 7 and TRPC4, 5) based on sequence functional similarities. Currently the TRPV family has 6 members. 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). The TRPML family consists of the mucolipins, which include TRPMLl (mucolipin 1), TRPML2 (mucolipin 2) and TRPML3 (mucolipin 3). The TRPP family consists of two groups of channels: those predicted to have six transmembrane domains and those that have 11. TRPP2 (PKD2), TRPP3 (PKD2L1), TRPP5 (PKD2L2) are all predicted to have six transmembrane domains. TRPPl (PKDl, PCl), PKD-REJ and PKD-ILl are all thought to have 1 1 transmembrane domains. Several 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, WO 2007/017092 Al, WO 2007/017093 Al, WO 2007/017094 Al and WO 2007/080109 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.

Summary

In accordance with one aspect, the present patent application provides compounds of the formula (I):

(D wherein,

R¹ is selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, alkoxy, aryl, heteroaryl, and heterocyclyl; at each occurrence, R² is independently selected from hydrogen, hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocyclyl, -NR⁵R⁶, -NR⁵C(O)R⁹, -NR⁵C(S)R⁹, -OCOR⁹, -OC(O)OR⁹, -COR⁹, -COOR⁹, -CONR⁵, and -SR⁵;

R³ is a hydrogen, -(CH₂)_r-L-NR⁵R⁶ or -(CH₂)_r-CN;

R⁴ 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 -(CH₂)_r-SO₂R¹²; X is -(CR⁷R⁸VCH₂-, -(CR⁷)=CH-, -(CR⁹R¹ °)_P-O- or -(CR⁹R ^IO)-NR⁵-;

L is a bond or -C(O)-; at each occurrence, R⁵ and R⁶ are independently selected from hydrogen and lower alkyl; at each occurrence, R⁷ and R⁸ are each independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkoxy, haloalkyl, aryl, arylalkyl, arylalkyloxy, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, - (CH₂)_q-OR⁵, -(CH₂)_r-NR⁵Rⁿ, -(CH₂VCO-NR⁵R¹ ', -(CH₂)_r-CO-NR⁵-SO₂R¹², -(CH₂V COOR⁶, -(CH₂)_r-SO₂R¹², and -(CH₂VSO₂-NR⁵R¹²; alternatively, R⁷ and R⁸ at each occurrence can combine together with the carbon atom to which they are attached to form a >C=0 group, >C=N0R⁵ or cycloalkyl ring; at each occurrence, R⁹ and R¹⁰ are independently selected from hydrogen, halogen, cyano and lower alkyl; alternatively, R⁹ and R¹⁰ at each occurrence can combine with the carbon atom to which they are attached to form a >C=0 group or cycloalkyl ring; with another proviso that when X is -(CR⁷)=CH-, R⁷ is not hydroxyl; at each occurrence, R¹¹ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, -CO-R¹², -SO₂-R¹², and -CO-NR⁵R¹²; at each occurrence, R¹² is independently selected from substituted or unsubstituted alkyl, haloalkyl or aryl;

'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; and

'r' is an integer selected from O to 3; both inclusive; or pharmaceutically acceptable salt thereof.

According to one embodiment, there is provided a compound of the formula (II):

(H) wherein, dotted line [ — ] in the ring represents an optional bond;

R⁴ 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 -(CH₂)_r-SO₂R¹²; at each occurrence, R⁵ and R⁶ 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;

"7 β alternatively, R and R can combine together with the carbon atom to which they are attached to form a >C=0 group, >C=N0R⁵ or cycloalkyl ring; at each occurrence, R⁹ is independently selected from hydrogen, halogen, cyano and lower alkyl; at each occurrence, R¹¹ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, -CO-R¹², -SO₂-R¹², and -CO-NR⁵R¹²; at each occurrence, R¹² is independently selected from substituted or unsubstituted alkyl, haloalkyl or aryl;

'n' is an integer selected from O to 2, both inclusive;

'q' is an integer selected from 1 to 3; both inclusive; and

'r' is an integer selected from O to 3; both inclusive; or pharmaceutically acceptable salt thereof. According to another embodiment, specifically provided are compounds of formula (I), or formula (II) and salts thereof, that inhibit TRPM8 function with an IC50 value of less than 250 nM, preferably, less than 100 nM, more preferably, less than 50 nM with respect to TRPM-8 activity as measured by method as described here in below.

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). Preferably, 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.

Detailed Description of the Invention

The invention is defined by the claims and not limited by the description provided herein below. The terms used in the appended claims are defined herein in this glossary section, with the proviso that the claim terms may be used in a different manner if so defined by express recitation.

The terms "halogen" or "halo" means fluorine, chlorine, bromine, or iodine

The term "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). The term "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.

The embodiments below are illustrative of the present invention and are not intended to limit the scope to the specific embodiments exemplified below.

According to one embodiment, specifically provided are compounds of the formula (II) in which the dotted line [ — ] in the ring is an optional bond.

According to another embodiment, specifically provided are compounds of the formula (II) in which R¹ is halogen, for example Cl, Br or F.

According to another embodiment, specifically provided are compounds of the formula (II) in which R¹ is substituted or unsubstituted aryl, for example cyanophenyl.

According to another embodiment, specifically provided are compounds of the formula (II) in which R¹ is substituted or unsubstituted heteroaryl, for example fluoropyridyl.

According to another embodiment, specifically provided are compounds of the formula (II) in which R² is hydrogen or halogen; and 'n' is 0 or 1.

According to another embodiment, specifically provided are compounds of the formula (II) in which R⁴ is substituted or unsubstituted aryl (for example phenyl), heteroaryl (for example thiazole, thiadiazole, pyridine, benzthiazole or benzoxazole) and heterocyclyl. In this embodiment 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)₂CF₃.

According to another embodiment, specifically provided are compounds of the formula (II) in which both of R⁷ and R⁸ is hydrogen.

According to another embodiment, specifically provided are compounds of the formula (II) in which one of R⁷ and R⁸ is hydrogen and the other is halogen, hydroxyl, NH₂, or -NHC(O)CH₃.

According to another embodiment, specifically provided are compounds of the formula (II) in which R⁷ and R⁸ can combined together to form >C(O), >N-0H or >N- OCH₃. carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting examples of 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.

The term "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.

The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH₃ and -OC₂H₅. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "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.

The term "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 (-OCF₂CF₃), trifluoro-t-butoxy, hexafluoro-t-butoxy, perfluoro-t-butoxy(-OC(CF₃)₃) and the like. Unless otherwise specified, an haloalkoxy group typically has from 1 to 20 carbon atoms.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of 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.

The term "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.

The term "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.

The term "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.

The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂C₆H₅ and -C₂H₄C₆H₅. Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted. The term "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. In addition, 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). Examples of such 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, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The 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.

The term "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.

The term "heteroaryl" unless otherwise specified 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. Examples of such 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, indolizinyl, acridinyl, phenazinyl and phthalazinyl. Unless set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be substituted or unsubstituted.

The term "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.

Unless otherwise specified, the term "substituted" as used herein refers to a group or moiety having one or more of the substituents attached to the structural skeleton of the group or moiety, including, but not limited to such substituents as hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR", -C(O)R", -C(S)R", -C(0)NR^xR^y, -C(0)0NR^xR^y, -NR^xCONR^yR^z, - N(R^x)SOR^y, -N(R^x)SO₂R^y, -(=N-N(R^x)R^y), -NR^xC(0)0R^y, -NR^xR^y, -NR^xC(0)R^y, - NR^xC(S)R^y, -NR^xC(S)NR^yR^z, -SONR^xR^y, -SO₂NR^xR^y, -OR^X, -0R^xC(0)NR^yR^z, - 0R^xC(0)0R^y, -OC(O)R", -0C(0)NR^xR^y, -R^xNR^yC(O)R^z, -R^xOR^y, -R^xC(0)0R^y, - R^xC(O)NR^yR^z, -R^xC(O)R^y, -R^xOC(O)R^y, -SR^X, -SOR^X, -SO₂R^X, and -ONO₂, wherein R\ R^y and R^z are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".

The term "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.

The term "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).

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. With respect to the overall compounds described by the Formula (I), the present patent application extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, 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.

Pharmaceutical Compositions

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). Preferably, 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.

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.

The pharmaceutical 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). For example, 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. When 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.

The pharmaceutical 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.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Methods of Treatment

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. The compounds and pharmaceutical compositions of the present invention can be administered to treat any disorder, condition or disease treatable by inhibition of TRPM8.

For instance, 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, pruritus, prostate cancer, benign prostatic hyperalgesia, overactive bladder, painful bladder, dental pain and cold hypersensitivity of teeth.

General Methods of Preparation

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. These compounds can be purified by any of the methods for purification of organic compounds known in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible stereoisomers are envisioned within the scope of this invention.

Compounds of the general formula (I) where R¹, R², R³, R⁴, X and 'n' are as defined above, can be prepared as described in Scheme 1. Various spirocyclic amine intermediate of a general formula (1) can be prepared by following literature procedures. For example, spirochromene-2,4'-piperidine (X = -CH₂-CH₂-) and its derivatives of a general formula (1) are prepared by adopting the following a literature procedures: (a) Fletcher, S. R. et al J. Med. Chem. 2002, 45, 492-503; (b) Yang, L. et al Bioorg. Med. Chem. Lett. 1998, 8, 107-112 and references cited therein; (c) Chandrasekhar, S. et al Tetrahedron Lett. 2005, 46, 6991-6993; (d) Lau, C. K. et al J. Org. Chem. 1989, 54, 491- 494. 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, N₁N- diisopropylethylamine) in a suitable solvent (T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991). Reaction of spirocyclic amine (1) with carbamate (2) using suitable base (e.g., triethylamine, N,N-diisopropylethylamine) in a suitable solvent (e.g., dimethyl sulfoxide, tetrahydrofuran) affords urea derivative of the formula (3) (Pandey, A. et al J. Med. Chem. 2002, 45, 3772-3793). The compounds of the formula (3) is then alkylated with a suitable alkylating agents like alkyl halide of the formula (4) under suitable conditions gives compounds of the general formula (I).

Scheme 1

(1) (3) (I)

An approach for the synthesis of compounds of general formula (Ha) to (lid) where R¹,

R² and n are as defined above can be prepared as described in Scheme 2. Thus, 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 /ert-butoxycarbonyl (BOC) group of intermediate (6) is deprotected under acidic conditions (e.g., HCl in EtOAc, trifluoroacetic acid) and the free amine thus obtained was coupled with aryl carbamate of the formula (7) in the presence of a suitable base (e.g., triethylamine) and in a suitable solvent (e.g., dimethyl sulfoxide, tetrahydrofuran) to afford urea derivative of a formula (Ha). Spirocyclic racemic hydroxy compound of the general formula (lib) is obtained by the reduction of compound of formula (Ha) with suitable reducing agent like sodium borohydride. Dehydration of compound (lib) under acidic condition affords olefinic compounds of the general formula (lie). Deoxygenation of alcohol of general formula (lib) using triethylsilane in trifluoroacetic acid gives compound of general formula (Hd).

Scheme 2

did) (lib)

(Hc)

An. approach for the synthesis of spirochromane oxime the general formula (He) where R is a hydrogen or a lower alkyl group and R¹, R² and 'n' are as defined, is prepared as described in Scheme 3. Spirocyclic 4-oxo-carboxamides of the formula (Ha) is converted into its oxime of general formula (lie) by reaction with hydroxylamine or a suitable derivative of hydroxylamine in the presence of a suitable base like NaHCO₃ and in a suitable solvent like ethanol.

Scheme 3

An approach for the synthesis of urea derivatives of the general formula (Ilf) where R¹ is an aryl and heteroaryl group is described in Scheme 4. Suzuki coupling of intermediate (Hd) (when R¹ is Br) with suitable aryl boronic acid in the presence of a palladium (O) catalyst in a suitable solvent (e.g., ethanol, toluene, water) or a mixture of solvents affords compound of general formula (Ilf).

Scheme 4

(lid) (Hf) R¹ = Br R >1 - = aryl, heteroaryl

An approach for the synthesis of fluorinated compounds of the general formula (Hg) is as described in Scheme 5. Reduction of spirocyclic ketone of general formula (6) using appropriate reducing agent (e.g., sodium borohydride) give corresponding racemic or pure enantiomeric hydroxy intermediate which on fluorination using appropriate fluorinating agents like (diethylamino)sulfurtrifluoride (DAST), tetrabutylammonium fluoride (TBAF) etc. gives compounds of the general formula (8). The fluorinated intermediate (8) is coupled with carbamate of a formula (7) as described in Scheme 2 to afford compounds of general formula (Hg).

Scheme 5

(6) (8) (Ug)

An approach for the synthesis of amino derivatives of the general formula (Hh) and (Hi) is as described in Scheme 6. Spirocyclic alcohol of general formula (9) is obtained by the reduction of ketone (6) with a reducing agents (e.g., sodium borohydride) as described in Scheme 3. Mitsunobu reaction of spirocyclic alcohol of general formula (9) with phthalimide followed by deprotection affords corresponding phthalimido compound of general formula (10). The phthalimide derivative (10) is then coupled with carbamate (7) as described in Scheme 2 affords the corresponding urea derivative of the general formula (1 1). Finally, phthalimide group of intermediate (11) is cleaved to the free amine using hydrazine hydrate to give compounds of the general formula (Hh).

An approach for the synthesis of acetamide (Hi) is also described in Scheme 6. Thus, Ritter reaction of spirocyclic alcohol (9) using concentrated sulfuric acid/acetonitrile combination followed by deprotection gives spirocyclic acetamido compound of formula (12). The intermediate (12) was then coupled with carbamate of the formula (7) as described in Scheme 2 to afford corresponding urea derivative of a formula (Hi).

Scheme 6

An approach for optical resolution of compounds of the general formula (lib) is depicted in synthetic Scheme 7 via .its diasteriomeric esters using an appropriate chiral carboxylic acid. Esterification of racemic spirocyclic alcohol of general formula (lib) with suitable //-protected amino acid (e.g., (25)-2-{[(benzyloxy)carbonyl]amino}-3-(lH- indol-3-yl)propanoic acid) using EDCI (N-ethyl-iV'-(3-dimethylaminopropyl) carbodiimide hydrochloride) and DMAP (4-dimethylaminopyridine) in suitable solvent (e.g., dichloromethane, dichloroethane) gives diastereomeric mixture of esters. 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 (e.g., sodium hydroxide, lithium hydroxide) affords the optically pure alcohols of the formula (Hj) and (Ilk).

Scheme 7

(Hj) (+) (IIk) (-)

All the intermediates and examples described in the present invention are prepared according to the methods described in Synthetic Schemes 1 to 7.

Experimental

Unless otherwise stated, work-up implies the following operations: distribution of the reaction mixture between the organic and aqueous phase, separation of layers, drying the organic layer over sodium sulfate, filtration and evaporation of the organic solvent. Purification, unless otherwise mentioned, implies purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. The following abbreviations are used in the text: DMSO-^₆: hexadeuterodimethyl sulfoxide; DMF: N,N-dimethylforrnamide, J: coupling constant in units of Hz; RT: room temperature (22-26°C). aq.: aqueous AcOEt: ethyl acetate; equiv.: equivalents.

Preparation of Intermediates

Intermediate 1

8-Chloro-3, 4-dihydrospiro[chromene-2,4'-piperidine]

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. The 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 (Na₂SO₄) and concentrated under reduced pressure. The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 25 % ethyl acetate in petroleum ether to afford 42.18 g of the product as a pale yellow solid; ¹H NMR (300 MHz, OMSO-d₆) δ 1.40 (s, 9H), 1.64-1.68 (m, 2H), 1.88-1.99 (m, 2H), 2.92 (s, 2H), 3.06 (br s, 2H), 3.79-3.83 (m, 2H), 6.07 (t, J = 7.8 Hz, IH), 7.70 (d, J = 7.8 Hz, IH), 7.76 (d, J = 7.5 Hz, IH); APCI-MS (m/z) 252.17 (M-IOO)⁺.

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). The combined organic layers were washed with water (150 mL), brine (100 mL), dried (Na₂SO₄) and concentrated under reduced pressure to afford 36.0 g of the product as an off-white solid; ¹H NMR (300 MHz, DMSO-^₅) δ 1.40 (s, 9H), 1.51-1.71 (m, 3H), 1.77-1.81 (m, 2H), 2.09-2.16 (m, IH), 3.02-3.16 (m, 2H), 3.69-3.78 (m, 2H), 4.68-4.75 (m, IH), 5.53 (d, J= 6.8 Hz, IH), 6.90 (t, J = 7.8 Hz, IH), 7.28 (d, J= 6.9 Hz, IH), 7.37 (d, J = 6.9 Hz, I H); ESI-MS (m/z) 238.23 (M+H)⁺.

Step 3 8-Chloro-3 ,4-dihydrospiro [chromene-2,4'-piperidine] hydrochloride :

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 NaHCO₃ solution and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine, dried (Na₂SO₄) and concentrated under reduced pressure to afford 6.21 g of the product as an off-white solid; ¹H NMR (300 MHz, OMS0-d₆) δ 1.76-1.93 (m, 6H), 2.78-2.80 (m, 2H), 3.02-3.09 (m, 2H), 3.24-3.28 (m, 2H), 6.86 (t, J = 7.8 Hz, IH), 7.10 (d, J = 7.2 Hz, I H), 7.23 (d, J = 7.5 Hz, IH), 8.64 (br s, IH); APCI-MS (m/z) 238.24 (M+H)⁺.

Intermediate 2

8-Bromo-3,4-dihydrospiro[chromene-2,4'-piperidine] trifluoroacetate

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; ¹H NMR (300 MHz, CDCl₃) δ 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, 2H), 7.01 (t, J = 7.8 Hz, IH), 7.73 (d, J = 7.8 Hz, I H), 7.89 (d, J= 7.5 Hz, IH); APCI-MS (m/z) 296.20 (M-IOO)⁺.

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; ¹H NMR (300 MHz, OMSO-d₆) δ 1.40 (s, 9H), 1.62-1.66 (m, 4H), 1.82-1.88 (m, 2H), 2.88-2.96 (m, 2H), 3.77-3.83 (m, 2H), 4.70-4.76 (m, I H), 5.53 (d, J = 5.4 Hz, I H, exchangeable with D₂O), 6.85 (t, J = 12 Hz, IH), 7.42 (t, J = 7.8 Hz, 2H); APCI-MS (m/z) 298.19 (M- 10O)⁺.

Step 2 8-Bromo-3,4-dihydrospiro[chromene-2,4'-piperidine] trifluoroacetate:

Deoxygenation and deprotection of 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; ¹H NMR (300 MHz, DMSO-J₆) δ 1.75-1.93 (m, 6H), 2.77-2.84 (m, 2H), 3.05-3.15 (m, 2H), 3.25-3.30 (m, 2H), 6.81 (t, J = 7.2 Hz, I H), 7.13 (d, J = 7.2 Hz, IH), 7.40 (d, J = 7.8 Hz, IH), 8.49 (br s, IH, exchangeable with D₂O), 8.66 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 282.29 (M+H)⁺.

Intermediate 3 8-Chloro-6-fluoro-3,4-dihydrospiro[chromene-2,4'-piperidine] trifluoroacetate

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 (Na₂SO₄) and concentrated. The crude product obtained after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography using 10 % ethyl acetate in petroleum ether to afford 5.25 g of the product as a pale yellow solid; ¹H NMR (300 MHz, OMSO-d₆) δ 1.46 (s, 9H), 1.56-1.66 (m, 2H), 2.00-2.06 (m, 2H), 2.75 (s, 2H), 3.20-3.26 (m, 2H), 3.94-4.00 (m, 2H), 7.36 (dd, J = 3.3, 7.5 Hz, IH), 7.47 (dd, J = 3.3, 7.8 Hz, IH); APCI-MS (m/z) 368.10 (M-H)-.

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) was reduced with sodium borohydride (0.511 g, 13.520 mmol) in ethanol (50.0 mL) according to the procedure given in Intermediate 1 , Step 2 to obtain a crude product which was used directly for the next step without purification.

Step 3 8-Chloro-6-fluoro-3,4-dihydrospiro[chromene-2,4'-piperidine] trifluoroacetate: Deoxygenation and deprotection of Step 2 intermediate (4.5 g, 12.102 mmol) was carried out with triethylsilane (5.629 g, 48.409 mmol) and trifluoroacetic acid (50.0 mL) according to the procedure described in Intermediate 1, Step 3 to afford 4.80 g of the desired product as an off-white solid; ¹H NMR (300 MHz, DMSO-Cf₆) δ 1.44-1.47 (m, 2H), 1.58-1.62 (m, 2H), 1.70-1.78 (m, 2H), 2.68-2.82 (m, 6H), 6.94 (d, J = 6.3 Hz, IH), 7.20 (d, J= 6.0 Hz, IH); APCI-MS (m/z) 256.22 (M+H)⁺.

Intermediate 4 8-Chlorospiro[chromene-2,4'-piperidin]-4(3H)-one hydrochloride

To a stirred solution of Step 1, Intermediate 1 (2.0 g, 5.688 mmol) in ethyl acetate (5.0 mL) was added dropwise a saturated solution of hydrochloric acid in ethyl acetate (25 mL) at 0⁰C. The reaction mixture was then slowly warmed to room temperature. After 2 h stirring at the same temperature the excess of solvent was evaporated. The residue was taken into water, basified with potassium carbonate solution (pH = 9) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na₂SO₄) and filtered. The filtrate was concentrated to afford 1.6 g of the product as an off-white solid; ¹H NMR (300 MHz, DMSCwZ₆) δ 1.90-1.99 (m, 2H), 2.10-2.18 (m, 2H), 2.56-2.62 (m, 2H), 2.97-3.03 (m, 2H), 3.20-3.28 (m, 2H), 7.12 (t, J = 7.8 Hz, IH), 7.72 (d, J = 7.8 Hz, IH), 7.80 (d, J = 7.8 Hz, IH), 9.19 (br s, IH, exchangeable with D₂O), 9.50 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 252.16 (M+H)⁺._.

Intermediate 5 8-Bromospiro [chromene-2,4'-piperidin]-4(3H)-one hydrochloride:

Compound obtained in Step 1, Intermediate 2 (2 g, 5.047 mmol) was deprotected with saturated solution of hydrochloride in ethyl acetate (25 mL) according to the procedure described in Intermediate 4 to obtain 1.65 g of the product as an off- white solid; ¹H NMR (300 MHz, DMSO-cfe) δ 1.91-1.97 (m, 2H), 2.10-2.16 (m, 2H), 2.95-3.05 (m, 4H), 3.25- 3.31 (m, 2H), 7.06 (t, J= 7.8 Hz, IH), 7.76 (d, J= 7.5 Hz, IH), 7.93 (d, J = 7.8 Hz, IH), 9.16 (br s, IH, exchangeable with D₂O), 9.25 (br s, IH, exchangeable with D₂O); APCI- MS (m/z) 296.26 (M+H)⁺. Intermediate 6 8-Fluorospiro [chromene-2,4'-piperidin]-4(3H)-one hydrochloride

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; ¹H NMR (300 MHz, DMSO-J₆) δ 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), 7.00-7.08 (m, IH), 7.52-7.60 (m, 2H); APCI-MS (m/z) 334.13 (M-H).

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; ¹H NMR (300 MHz, DMSO-J₆) δ 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 D₂O); APCI-MS (m/z) 236.20 (M+H)⁺.

Intemediate 7 (±) 8-Chloro-4-fluoro-3,4-dihydrospiro[chromene-2,4'-piperidine] hydrochloride

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 (-40⁰C) 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. After overnight stirring at the same temperature the reaction mixture was quenched with cold saturated solution of NaHCO₃ and then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine and dried (Na₂SO₄). The solvent was evaporated to obtain a crude residue which was purified by silica gel column chromatography using 10 % ethyl acetate in petroleum ether to afford 1.91 g of the product as a colorless viscous liquid; ¹H NMR (300 MHz, DMSO-4) δ 1.40 (s, 9H), 1.51-1.57 (m, IH), 1.73 (br s, 2H), 1.82-1.89 (m, IH), 2.24-2.32 (m, 2H), 2.93-2.98 (m, IH), 3.11-3.17 (m, IH), 3.74-3.81 (m, 2H), 5.69 (d, J = 50.4 Hz, IH), 6.93-6.99 (m, IH), 7.28-7.37 (m, IH), 7.38-7.46 (m, I H); APCI-MS (m/z) 256.16 (M-IOO)⁺.

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; ¹H NMR (300 MHz, OMSO-dβ) δ 1.91-2.09 (m, 2H), 2.32-2.38 (m, 2H), 2.86-2.99 (m, IH), 3.14-3.18 (m, 2H), 3.27-3.36 (m, 3H), 5.75 (d, J= 52.5 Hz, IH), 7.04 (t, J = 7.2 Hz, IH), 7.42 (d, J = 6.9 Hz, IH), 7.51 (d, J= 6.9 Hz, IH), 9.23 (br s, 2H); APCI-MS (m/z) 256.16 (M+H)⁺.

Intemediate 8

(±)-8-Bromo-4-fluoro-3,4-dihydrospiro[chromene-2,4'-piperidine] hydrochloride:

The titled compound was prepared in two steps according to the procedure described in Intermediate 7 by using Step 2, Intermediate 2 (470 mg, 1.180 mmol) and DAST (286 mg, 1.770 mmol) in 1 ,2-dichloroethane (10 mL) to afford 360 mg of the

8- bromo-4-fluoro-3,4-dihydro-l 'H-spiro[chromene-2,4'-piperidine]-l '-carboxylate as a colorless viscous liquid. This N-Boc compound (340 mg, 0.849 mmol) was then deprotected with saturated solution of hydrochloric acid in ethyl acetate (5 mL) to obtain 282 mg of the product as an off-white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.86-2.14 (m, 4H), 2.27-2.38 (m, 2H), 2.87-3.05 (m, IH), 3.16-3.20 (m, 2H), 3.29-3.35 (m, I H), 5.74 (d, J = 51.9 Hz, IH), 6.98 (t, J = 7.2 Hz, IH), 7.46 (d, J = 7.2 Hz, IH), 7.66 (d, J = 7.2 Hz, IH), 9.07 (br s, 2H); APCI-MS (m/z) 300.21 (M+H)⁺. Intermediate 9 (350-ABK-026) 8-Chlorospiro[chromene-2,4'-piperidine] hydrochloride

Step 1 ter/-Butyl 8-chloro-rH-spiro[chromene-2,4'-piperidine]-r-carboxylate: To a stirred solution of 50 % HCl (20 mL) was added Step 2, Intermediate 1 (2.0 g, 5.652 mmol) portion wise at room temperature. After overnight refluxing, at the same temperature the reaction mixture was cooled to O⁰C and basified with 1 N NaOH (pΗ = 10). The reaction mixture was then extracted with ethyl acetate (2 x 75 mL).The organic layer was washed with water (50 mL), brine (25 mL), dried (Na₂SO₄) and filtered. The filtrate was evaporated under reduced pressure and the crude obtained was directly used for the next step.

Step 2 8-Chlorospiro[chromene-2,4'-piperidine] hydrochloride: The above step 1 crude product obtained was deprotected with saturated solution of hydrochloric acid in ethyl acetate (10 mL) according to the procedure described in Intermediate 4 to obtain 1.21 g of the product as an off-white solid; ¹H NMR (300 MHz, DMSO-J₆) δ 1.98-2.08 (m, 4H), 3.10-3.22 (m, 4H), 5.90 (d, J = 9.9 Hz, IH), 6.61 (d, J = 9.6 Hz, IH), 6.94 (t, J = 7.8 Hz, IH), 7.13 (d, J= 6.9 Hz, IH), 7.30 (d, J= 7.2 Hz, IH), 9.22 (br s, 2H, exchangeable with D₂O); APCI-MS (m/z) 300.21 (M+H)⁺.

Intemediate 10 (350-ABK-066)

(±)-2-(8-Chloro-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl)-lH-isoindole- 1,3(2//)- dione hydrochloride

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 TΗF (50 mL) was added diethyl azodicarboxylate (DEAD) (3.2 g, 18.370 mmol) followed by triphenylphosphine (5.5 g, 21.196 mmol). A solution of phthalimide (2.1 g, 14.131 mmol) in THF was added dropwise to the above reaction mixture at room temperature. After overnight stirring at the same temperature, the reaction mixture was diluted with ethyl acetate (150 mL) and water (100 mL). Two layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with 1 N HCl (25 mL), followed by the saturated solution OfNaHCO₃ (25 mL), water (25 mL). The organic layer was dried (Na₂SO₄), filtered and concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 15 % ethyl acetate in petroleum ether to obtain 810 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.41 (s, 9H), 1.72-1.86 (m, 4H), 2.15-2.29 (m, IH), 2.92 (s, 2H), 3.58-3.86 (m, 3H), 5.48-5.54 (m, IH), 6.80 (t, J = 7.8 Hz, IH), 7.04 (d, J= 7.2 Hz, IH), 7.32 (d, J= 7.8 Hz, IH), 7.81-7.91 (m, 4H); APCI- MS (m/z) 383.09 (M-IOO)⁺.

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; ¹H NMR (300 MHz, DMSO-c/₆) δ 1.98-2.1 1 (m, 4H), 2.18-2.25 (m, IH), 2.50 (s, 2H), 2.78-2.85 (m, IH), 3.25-3.31 (m, 2H), 5.50-5.56 (m, IH), 6.84 (t, J = 7.8 Hz, IH), 7.09 (d, J = 8.1 Hz, IH), 7.35 (d, J = 7.5 Hz, IH), 7.81-7.91 (m, 4H), 9.01 (br s, 2H, exchangeable with D₂O); APCI-MS (m/z) 383.16 (M+H)⁺.

Intemediate 1 1 (350-ABK-082)

(±)-N-(8-Chloro-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl)acetamide hydrochloride

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. H₂SO₄ (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 (Na₂SO₄) and filtered. The filtrate was evaporated under reduced pressure to give crude product. This crude was treated with EtOAc saturated with HCl to give 435 mg of the desired compound as a white solid; ¹H NMR (300 MHz, OMSO-dβ) δ 1.21-1.45 (m, 2H), 1.48-1.56 (m, IH), 1.60-1.69 (m, 4H), 1.75- 1.80 (m, 2H), 2.06-2.13 (m, IH), 2.66-2.74 (m, 2H), 2.97-3.16 (m, IH), 5.05-5.15 (m, IH), 6.87 (t, J = 7.2 Hz, IH), 7.08 (d, J = 7.8 Hz, IH), 7.30 (d, J = 7.8 Hz, IH), 8.27 (br s, I H, exchangeable with D₂O); APCI-MS (m/z) 295.26 (M+H)⁺. General procedure for the preparation of phenyl carbamate

To a stirred solution of commercially available amine (substituted anilines, 2- aminothiazoles, 2-aminobenzothiazoles) (1.0 eq) in THF (5 vol) was added pyridine (2.0 eq) at 0°C. After stirring for 5 min, phenyl chloroformate (1.1 eq) was added slowly. Reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with ethyl acetate and water. Two layers were separated. The aqueous layer was extracted 2-3 times with ethyl acetate. The combined organic layers were washed with water, brine, dried (Na₂SO₄) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was stirred in pet ether. Solid obtained was filtered, washed 2-3 times with pet ether and then dried well to obtain the product as a white solid.

Examples

General procedure for the preparation of urea derivatives:

To a stirred solution of spiro chromene piperidine hydrochloride (1.0 eq) in anhydrous DMSO (5 vol), was added phenyl carbamate (1.0 eq) followed by triethylamine (2.0 eq). The resulting mixture was stirred for 2 h. The reaction mixture was diluted with ethyl acetate and washed with water, followed by brine. Organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 5% ethyl acetate in petroleum ether to obtain the product as white to off-white solid. Example 1 8-Chloro-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]- 1 '-carboxamide

To a stirred solution of Intermediate 1 (500 mg, 2.103 mmol) in anhydrous DMSO (5.0 mL) was added triethyl amine (1.0 g, 10.516 mmol) and stirred at room temperature for 20 min. under nitrogen atmosphere. Then a solution of phenyl [4- (trifiuoromethyl)phenyl]carbamate (650 mg, 2.313 mmol) in anhydrous DMSO (4.0 mL) was added and resulting mixture was stirred at the same temperature for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2 x 25 mL) followed by brine (25 mL). Organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 15% ethyl acetate in petroleum ether to obtain 748 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-J₆) δ 1.60-1.67 (m, 2H), 1.74-1.85 (m, 4H), 2.74-2.81 (m, 2H), 3.17-3.26 (m, 2H), 3.96-4.02 (m, 2H), 6.84 (t, J = 7.8 Hz, IH), 7.08 (d, J = 7.2 Hz, IH), 7.25 (d, J = 7.8 Hz, IH), 7.58 (d, J = 8.7 Hz, 2H), 7.68 (d, J= 8.1 Hz, 2H); APCI-MS (m/z) 425.19 (M+H)⁺.

Example 2

8-Chloro-./V-(4-cyanophenyl)-3 ,4-dihydro- 1 ' H-spiro [chromene-2,4 ' -piperidine] - 1 ' - carboxamide

Coupling reaction of Intermediate 1 (100 mg, 0.420 mmol) with phenyl (4- cyanophenyl)carbamate (1 10 mg, 0.462 mmol) in the presence of triethylamine (213 mg, 2.103 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1, gave 108 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.64-1.70 (m, 2H), 1.74-1.84 (m, 4H), 2.75-2.84 (m, 2H), 3.18-3.27 (m, 2H), 3.95-4.08 (m, 2H), 6.84 (t, J= 7.8 Hz, IH), 7.07 (d, J = 7.5 Hz, IH), 7.23 (d, J = 7.8 Hz, IH), 7.64- 7.70 (m, 4H), 9.05 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 382.24 (M+H)⁺.

Example 3 8-Chloro-N-(4-tert-butylphenyl)-3,4-dihydro-rH-spiro[chromene-2,4'-piperidine]-l '- carboxamide

Coupling reaction of Intermediate 1 (100 mg, 0.420 mmol) with phenyl (4-tert- butylphenyl)carbamate (124 mg, 0.462 mmol) in the presence of triethylamine (213 mg, 2.103 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1, gave 87 mg of the product as a white solid; ¹H NMR (300 MHz, DMSOtZ₆) δ 1.25 (s, 9H), 1.57-1.76 (m, 4H), 1.80-1.88 (m, 2H), 2.75-2.82 (m, 2H), 3.15-3.23 (m, 2H), 3.91-3.99 (m, 2H), 6.83 (t, J= 7.8 Hz, IH), 7.07 (d, J= 7.5 Hz, I H), 7.23 (d, J= 8.4 Hz, 3H), 7.35 (d, J = 8.4 Hz, 2H), 8.48 (br s, I H, exchangeable with D₂O); APCI-MS {m/z) 413.28 (M+H)⁺.

Example 4

8-Chloro-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide

Coupling reaction of Intermediate 1 (100 mg, 0.420 mmol) with phenyl [4- (trifluoromethoxy)phenyl]carbamate (137 mg, 0.462 mmol) in the presence of triethylamine (213 mg, 2.103 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1, gave 151 mg of the product as a white solid; ¹H NMR (300 MHz, DMSCW₆) δ 1.62-1.72 (m, 4H), 1.78-1.85 (m, 2H), 2.75-2.81 (m, 2H), 3.17- 3.24 (m, 2H), 3.94-4.00 (m, 2H), 6.83 (t, J = 7.2 Hz, IH), 7.07 (d, J = 6.9 Hz, IH), 7.23 (d, J = 7.8 Hz, 3H), 7.55 (d, J = 8.4 Hz, 2H), 8.77 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 441.18 (M+H)⁺. Example 5 8-Bromo-jV-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide

Coupling reaction of Intermediate 2 (200 mg, 0.504 mmol) with phenyl [4- (trifluoromethyl)phenyl]carbamate (156 mg, 0.555 mmol) in the presence of triethylamine (255 mg, 2.523 mmol) in anhydrous DMSO (6.0 mL) according to the procedure described in Example 1, gave 164 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-J₆) δ 1.60-1.66 (m, 2H), 1.74-1.84 (m, 4H), 2.74-2.81 (m, 2H), 3.18- 3.28 (m, 2H), 3.97-4.05 (m, 2H), 6.79 (t, J - 7.8 Hz, IH), 7.11 (d, J - 7.2 Hz, IH), 7.38 (d, J = 7.8 Hz, IH), 7.58 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 8.96 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 469.15 (M+H)⁺.

Example 6

8-(6-Fluoropyridin-3-yl)-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH- spiro [chromene-2,4 ' -piperidine] - 1 ' -carboxamide

To a stirred solution of Example 5 (50 mg, 0.106 mmol) in toluene (2 mL) was added Pd[(Ph₃)P]₄ (5 mg, 0.004 mmol) followed by the solution of Na₂CO₃ (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). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated to afford a crude product which was purified by silica gel column chromatography by using 20 % ethyl acetate in pet ether to obtain 1 1 mg of the product as a white solid; ¹H NMR (300 MHz, CDCl₃) δ 1.63-1.70 (m, 2H), 1.85-1.91 (m, 4H), 2.86-2.93 (m, 2H), 3.00-3.06 (m, 2H), 3.76-3.84 (m, 2H), 6.55 (br s, IH, exchangeable with D₂O), 6.98 (d, J- 7.2 Hz, 2H), 7.15 (d, J = 6.3 Hz, 2H), 7.43-7.52 (m, 4H), 7.94-8.00 (m, IH), 8.37-8.43 (m, I H); APCI-MS (m/z) 486.28 (M+H)⁺.

Example 7 8-Bromo-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide

Coupling reaction of Intermediate 2 (200 mg, 0.504 mmol) with phenyl [4- (trifluoromethoxy)phenyl]carbamate (165 mg, 0.555 mmol)) in the presence of triethylamine (255 mg, 2.523 mmol) in anhydrous DMSO (6.0 mL) according to the procedure described in Example 1, gave 161 mg of the product as a white solid; Η NMR (300 MHz, DMSO-^₆) δ 1.60-1.65 (m, 2H), 1.70-1.76 (m, 2H), 1.82-1.88 (m, 2H), 2.76- 2.81 (m, 2H), 3.16-3.26 (m, 2H), 3.96-4.04 (m, 2H), 6.78 (t, J = 7.5 Hz, IH), 7.11 (d, J = 12 Hz, IH), 7.23 (d, J = 8.1 Hz, 2H), 7.38 (d, J= 7.8 Hz, IH), 7.55 (d, J= 8.7 Hz, 2H), 8.77 (br s, I H, exchangeable with D₂O); APCI-MS (m/z) 485.23 (M+H)⁺.

Example 8

8-(4-Cyanophenyl)-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro[chromene- 2,4'-piperidine]-r-carboxamide

Suzuki coupling reaction of Example 7 (48 mg, 0.098 mmol) with 4-cyanophenyl boronic acid (22 mg, 0.148 mmol) in the presence of Pd[(Ph₃)P]₄ (5 mg, 0.0039 mmol) and a solution OfNa₂CO₃ (63 mg, 0.593 mmol) in water (1 mL) in a mixture of solvents toluene and ethanol (2:1, 3.0 mL) according to the procedure described in Example 6 gave 6.05 mg of title compound as an off white solid; ¹H NMR (300 MHz, CDCl₃) δ 1.60-1.70 (m, 2H), 1.84-1.94 (m, 4H), 2.84-2.91 (m, 2H), 2.98-3.05 (m, 2H), 3.74-3.82 (m, 2H), 6.38 (br s, IH, exchangeable with D₂O), 6.97 (t, J= 7.5 Hz, IH), 7.10-7.20 (m, 4H), 7.34 (d, J = 8.7 Hz, 2H), 7.65-7.72 (m, 4H); APCI-MS (m/z) 508.23 (M+H)⁺. Example 9

8-Chloro-N-(5-cyanopyridin-2-yl)-3,4-dihydro-rH-spiro[chromene-2,4'-piperidine]-r carboxamide

Coupling reaction of Intermediate 1 (57 mg, 0.210 mmol) with phenyl (5-cyanopyridin-2- yl)carbamate (55 mg, 0.232 mmol) in the presence of triethylamine (106 mg, 1.051 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1 , gave 56 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.58-1.71 (m, 4H), 1.83 (t, J = 6.3 Hz, 2H), 2.77 (t, J = 6.0 Hz, 2H), 3.15-3.25 (m, 2H), 3.95-4.03 (m, 2H), 6.81 (t, J = 7.8 Hz, IH), 7.04 (d, J = 7.2 Hz, IH), 7.20 (d, J = 7.5 Hz, IH), 7.87 (d, J = 8.7 Hz, IH), 8.08 (d, J = 6.9 Hz, IH), 8.65 (s, IH), 9.90 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 381.36 (M-H).

Example 10 8-Chloro-N- [3 -fluoro-4-(trifluoromethyl)pheny 1] -3 ,4-dihydro- 1 ' H-spiro [chromene-2,4 ' - piperidine]-l '-carboxamide

Coupling reaction of Intermediate 1 (100 mg, 0.420 mmol) with phenyl [3-fluoro-4- (trifluoromethyl)phenyl] carbamate (138 mg, 0.462 mmol) in the presence of triethylamine (213 mg, 2.103 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1, gave 158 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.64-1.74 (m, 2H), 1.80-1.88 (m, 4H), 2.78-2.85 (m, 2H), 3.19- 3.26 (m, 2H), 3.96-4.03 (m, 2H), 6.84 (d, J = 7.5 Hz, IH), 7.08 (d, J = 6.9 Hz, I H), 7.24 (d, J = 7.2 Hz, I H), 7.42 (d, J = 7.8 Hz, IH), 7.60-7.72 (m, 2H), 9.18 (br s, IH, exchangeable with D₂O); ESI-MS (m/z) 441.29 (M-H)^".

Example 11

8-Chloro-N-[4-fluoro-3-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-! '-carboxamide

Coupling reaction of Intermediate 1 (75 mg, 0.315 mmol) with phenyl [4-fluoro-3- (trifluoromethyl)phenyl] carbamate (104 mg, 0.347 mmol) in the presence of triethylamine (160 mg, 1.577 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1, gave 130 mg of the product as a white solid; ¹H NMR (300 MHz, CDCl₃) δ 1.62-1.68 (m, 2H), 1.73-1.79 (m, 2H), 1.82-1.88 (m, 2H), 2.75-2.81 (m, 2H), 3.18-3.26 (m, 2H), 3.95-4.02 (m, 2H), 6.84 (t, J = 7.8 Hz, IH), 7.07 (d, J = 7.5 Hz, IH), 7.23 (d, J = 7.8 Hz, IH), 7.36-7.43 (m, IH), 7.62-7.68 (m, IH), 7.91-7.98 (m, IH), 8.91 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 443.17 (M+H)⁺.

Example 12

8-Chloro-jV-[2-chloro-4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide

Coupling reaction of Intermediate 1 (75 mg, 0.315 mmol) with phenyl [2-chloro-4- (trifluoromethyl)phenyl] carbamate (1 10 mg, 0.347 mmol) in the presence of triethylamine (160 mg, 1.577 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1, gave 1 13 mg of the product as a white solid; ¹H NMR (300 MHz, CDCl₃) δ 1.65-1.70 (m, 2H), 1.75-1.85 (m, 4H), 2.76-2.82 (m, 2H), 3.20-3.26 (m, 2H), 3.93-3.99 (m, 2H), 6.84 (t, J= 7.5 Hz, IH), 7.08 (d, J= 7.5 Hz, IH), 7.24 (d, J = 7.8 Hz, IH), 7.65 (d, J = 7.8 Hz, IH), 7.79-7.86 (m, 2H), 8.50 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 459.16 (M+H)⁺.

Example 13

8-Chloro-yV-[4-chloro-3-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide

Coupling reaction of Intermediate 1 (75 mg, 0.315 mmol) with phenyl [4-chloro-3- (trifluoromethyl)phenyl] carbamate (110 mg, 0.347 mmol) in the presence of triethylamine (160 mg, 1.577 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1, gave 131 mg of the product as a white solid; ¹H NMR (300 MHz, CDCl₃) δ 1.63-1.70 (m, 2H), 1.75-1.85 (m, 4H), 2.74-2.81 (m, 2H), 3.18-3.26 (m, 2H), 3.95-4.04 (m, 2H), 6.84 (t, J= 7.2 Hz, IH), 7.08 (d, J= 6.9 Hz, IH), 7.23 (d, J = 7.8 Hz, I H), 7.57 (d, J = 8.4 Hz, IH), 7.75-7.82 (m, IH), 8.05 (s, IH), 9.01 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 457.20 (M-H)^'.

Example 14 8-Bromo-N-[3-fluoro-4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide

Coupling reaction of Intermediate 2 (200 mg, 0.504 mmol) with phenyl [3-fluoro-4- (trifluoromethyl)phenyl] carbamate (166 mg, 0.555 mmol) in the presence of triethylamine (255 mg, 2.523 mmol) in anhydrous DMSO (6.0 mL) according to the procedure described in Example 1, gave 171 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.60-1.67 (m, 2H), 1.73-1.79 (m, 2H), 1.82-1.88 (m, 2H), 2.73- 2.79 (m, 2H), 3.14-3.22 (m, 2H), 3.97-4.06 (m, 2H), 6.79 (t, J = 7.8 Hz, IH), 7.11 (d, J = 7.5 Hz, I H), 7.37-7.44 (m, 2H), 7.59-7.71 (m, 2H), 9.17 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 489.06 (M+H)⁺.

Example 15 δ-Chloro-ό-fluoro-iV- [4-(trifluoromethyl)phenyl] -3 ,4-dihydro- 1 ' //-spiro [chromene-2,4 ' - piperidine]-l '-carboxamide:

Coupling reaction of Intermediate 3 (100 mg, 0.391 mmol) with phenyl [4- (trifluoromethyl)phenyl]carbamate (121 mg, 0.430 mmol) in the presence of triethylamine (198 mg, 1.955 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1, gave 104 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.57-1.72 (m, 4H), 1.84 (t, J = 6.3 Hz, 2H), 2.75-2.82 (m, 2H), 3.16-3.24 (m, 2H), 3.94-4.03 (m, 2H), 7.01 (d, J = 6.3 Hz, IH), 7.25 (dd, J = 5.4, 7.8 Hz, IH), 7.58 (d, J= 8.7 Hz, 2H), 7.68 (d, J= 8.4 Hz, 2H), 8.97 (br s, IH, exchangeable with D₂O); ESI-MS (m/z) 443.21 (M+H)⁺.

Example 16 8-Chloro-6-fluoro-N-(4-tert-butylphenyl)-3,4-dihydro-l 'H-spiro[chromene-2,4'- piperidine]-l '-carboxamide

Coupling reaction of Intermediate 3 (130 mg, 0.508 mmol) with phenyl (4-tert- butylphenyl)carbamate (150 mg, 0.559 mmol) in the presence of triethylamine (257 mg, 2.541 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1 , gave 90 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.24 (s, 9H), 1.60-1.70 (m, 4H), 1.75-1.85 (m, 2H), 2.78-2.85 (m, 2H), 3.12-3.20 (m, 2H), 3.90-3.98 (m, 2H), 7.00 (d, J = 8.4 Hz, IH), 7.23 (d, J = 8.4 Hz, 3H), 7.34 (d, J = 8.4 Hz, 2H), 8.48 (br s, IH, exchangeable with D₂O); ESI-MS (m/z) 431.34 (M+H)⁺.

Example 17 8-Chloro-N- [4-(trifluoromethy I)- 1 ,3 -thiazol-2-y 1] -3 ,4-dihydro- 1 ' H-spiro [chromene-2 ,4 ' - piperidine]-l '-carboxamide

Coupling reaction of Intermediate 1 (250 mg, 1.051 mmol) with phenyl[4- (trifluoromethyl)-l,3-thiazol-2-yl] carbamate (333 mg, 1.156 mmol) in the presence of triethylamine (532 mg, 5.258 mmol) in anhydrous DMSO (8.0 mL) according to the procedure described in Example 1, gave 199 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.63-1.76 (m, 4H), 1.80-1.86 (m, 2H), 2.75-2.81 (m, 2H), 3.19- 3.26 (m, 2H), 4.03-4.10 (m, 2H), 6.84 (t, J = 8.1 Hz, IH), 7.07 (d, J = 7.5 Hz, IH), 7.23 (d, J = 7.2 Hz, IH), 7.80 (s, IH), 1 1.42 (br s, I H, exchangeable with D₂O); ESI-MS (m/z) 430.24 (M-Hy. Example 18

S-Bromo-N-fS-CtrifluoromethyO-l^-thiazol^-y^-S^-dihydro-rH-spirofchromene-Z^'- piperidine]-l '-carboxamide

Coupling reaction of Intermediate 2 (200 mg, 0.504 mmol) with phenyl [5- (trifluoromethyl)-l,3-thiazol-2-yl]carbamate (160 mg, 0.555 mmol) in the presence of triethylamine (255 mg, 2.523 mmol) in anhydrous DMSO (6.0 mL) according to the procedure described in Example 1, gave 180 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.66-1.71 (m, 4H), 1.76-1.83 (m, 2H), 2.73-2.80 (m, 2H), 3.20- 3.26 (m, 2H), 4.06-4.12 (m, 2H), 6.79 (t, J = 7.2 Hz, IH), 7.1 1 (d, J = 7.2 Hz, IH), 7.36 (d, J = 7.2 Hz, IH), 7.80 (s, IH), 1 1.41 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 476.01 (M+H)⁺.

Example 19

8-Chloro-6-fluoro-jV-(5-methyl-l,3-thiazol-2-yl)-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide

Coupling reaction of Intermediate 3 (100 mg, 0.391 mmol) with phenyl (5-methyl-l,3- thiazol-2-yl)carbamate (100 mg, 0.430 mmol) in the presence of triethylamine (198 mg, 1.955 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1, gave 86 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.54-1.61 (m, 2H), 1.66-1.74 (m, 2H), 1.80-1.86 (m, 2H), 2.25 (s, 3H), 2.75-2.82 (m, 2H), 3.16-3.21 (m, 2H), 4.04-4.1 1 (m, 2H), 6.96-7.03 (m, 2H), 7.24 (d, J = 6.9 Hz, I H), 10.75 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 394.14 (M-H)^".

Example 20

AM ^-Benzothiazol^-yl-S-chloro-S^-dihydro-l 'H-spirofchromene^^'-piperidinej-r- carboxamide

Coupling reaction of Intermediate 1 (1.0 g, 4.206 mmol) with phenyl l ,3-benzothiazol-2- ylcarbamate (1.25 g, 4.627 mmol) in the presence of triethylamine (2.12 g, 21.033 mmol) in anhydrous DMSO (20.0 mL) according to the procedure described in Example 1 , gave 2.10 g of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.58-1.65 (m, 2H), 1.69-1.76 (m, 2H), 1.80-1.88 (m, 2H), 2.77-2.81 (m, 2H), 3.19-3.25 (m, 2H), 4.12- 4.18 (m, 2H), 6.84 (t, J = 7.5 Hz, IH), 7.08 (d, J = 7.2 Hz, IH), 7.20-7.26 (m, 2H), 7.32- 7.38 (m, IH), 7.58-7.65 (m, IH), 7.80-7.88 (m, IH), 1 1.28 (br s, IH, exchangeable with D₂O); ESI-MS (m/z) 414.16 (M+H)⁺.

Example 21 N-I ,3-Benzothiazol-2-yl-8-bromo-3,4-dihydro-l 'H-spiro[chromene-2,4'-piperidine]-l '- carboxamide

Coupling reaction of Intermediate 2 (200 mg, 0.504 mmol) with phenyl 1,3-benzothiazol- 2-ylcarbamate (150 mg, 0.555 mmol) in the presence of triethylamine (255 mg, 2.523 mmol) in anhydrous DMSO (6.0 mL) according to the procedure described in Example 1 , gave 136 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-4) δ 1.60-1.68 (m, 2H), 1.78-1.85 (m, 4H), 2.73-2.80 (m, 2H), 3.22-3.28 (m, 2H), 4.12-4.18 (m, 2H), 6.79 (t, J = 7.2 Hz, IH), 7.12 (d, J = 7.2 Hz, IH), 7.18-7.24 (m, IH), 7.33-7.40 (m, 2H), 7.57-7.62 (m, IH), 7.80-7.88 (m, IH), 11.28 (br s, IH, exchangeable with D₂O); APCI- MS (m/z) 458.09 (M+H)⁺.

Example 22 8-Chloro-N-(6-trifluoromethoxy-l,3-benzothiazol-2-yl)-3,4-dihydro-rH-spiro

[chromene-2,4'-piperidine]-l '-carboxamide

Coupling reaction of Intermediate 1 (250 mg, 1.051 mmol) with phenyl [6- (trifluoromethoxy)-l, 3 -benzothiazol-2-yl] carbamate (410 mg, 1.156 mmol) in the presence of triethylamine (532 mg, 5.258 mmol) in anhydrous DMSO (7.0 mL) according to the procedure described in Example 1, gave 205 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-ύ?₆) δ 1.65-1.78 (m, 4H), 1.80-1.90 (m, 2H), 2.75-2.83 (m, 2H), 3.22-3.28 (m, 2H), 4.09-4.15 (m, 2H), 6.84 (t, J = 7.5 Hz, IH), 7.08 (d, J = 6.9 Hz, IH), 7.24 (d, J = 7.8 Hz, IH), 7.35 (d, J= 8.4 Hz, IH), 7.66-7.71 (m, IH), 7.98-8.03 (m, IH), 11.42 (br s, IH, exchangeable with D₂O); ESI-MS (m/z) 496.28 (M- H)-.

Example 23 8-Chloro-N-(6-fluoro-l,3-benzothiazol-2-yl)-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine] - 1 ' -carboxamide

Coupling reaction of Intermediate 1 (75 mg, 0.315 mmol) with phenyl (6-fluoro-l,3- benzothiazol-2-yl)carbamate (100 mg, 0.347 mmol) in the presence of triethylamine (160 mg, 1.577 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1, gave 133 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-Uf₆) δ 1.64-1.74 (m, 4H), 1.78-1.87 (m, 2H), 2.72-2.79 (m, 2H), 3.22-3.28 (m, 2H), 4.05-4.1 1 (m, 2H), 6.84 (t, J = 7.8 Hz, IH), 7.08 (d, J = 7.5 Hz, IH), 7.21-7.27 (m, 2H), 7.60-7.66 (m, IH), 7.78-7.84 (m, IH), 11.30 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 432.26 (M+H)⁺.

Example 24

N-l^-Benzoxazol^-yl-S-chloro-S^-dihydro-rH-spirofchromene^^'-piperidineJ-l '- carboxamide

Coupling reaction of Intermediate 1 (75 mg, 0.315 mmol) with phenyl l,3-benzoxazol-2- ylcarbamate (88 mg, 0.347 mmol) in the presence of triethylamine (160 mg, 1.577 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1 , gave 125 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.62-1.70 (m, 2H), 1.77-1.84 (m, 4H), 2.75-2.81 (m, 2H), 3.12-3.18 (m, 2H), 4.14-4.20 (m, IH), 4.30- 4.36 (m, IH), 6.83 (t, J = 7.2 Hz, IH), 7.07 (d, J= 8.1 Hz, IH), 7.15-7.25 (m, 4H), 7.30- 7.39 (m, I H), 12.18 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 396.26 (M-H)^".

Example 25

8-Chloro-4-oxo-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide

Coupling reaction of Intermediate 4 (1.07 g, 3.817 mmol) with phenyl [4- (trifluoromethyl)phenyl]carbamate (1.07 g, 3.817 mmol) in the presence of triethylamine (1.75 g, 17.350 mmol) in anhydrous DMSO (10.0 mL) according to the procedure described in Example 1 , gave 1.32 g of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.70-1.80 (m, 2H), 1.92-2.02 (m, 2H), 2.93-2.98 (m, 2H), 3.15-3.25 (m, 2H), 3.97-4.05 (m, 2H), 7.09 (t, J - 7.8 Hz, IH), 7.58 (d, J= 8.1 Hz, 2H), 7.64-7.73 (m, 3H), 7.78 (d, J = 7.2 Hz, IH), 8.98 (br s, I H, exchangeable with D₂O); APCI-MS (m/z) 439.12 (M+H)⁺.

Example 26

(±)-8-Chloro-4-hydroxy-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene- 2,4'-piperidine]-l '-carboxamide

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 (Na₂SO₄). The organic layer was evaporated and the residue obtained was purified by silica gel column chromatography by using 2 % methanol in chloroform to obtain 38 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-J₆) δ 1.61-1.88 (m, 4H), 3.10-3.18 (m, 2H), 3.30-3.40 (m, 2H), 3.93-3.99 (m, 2H), 4.70-4.75 (m, IH), 5.55 (d, J = 6 Hz, IH), 6.92 (t, J- 7.8 Hz, IH), 7.30 (d, J= 7.2 Hz, IH), 7.39 (d, J= 7.2 Hz, IH), 7.58 (d, J= 9 Hz, 2H), 7.68 (d, J= 8.4 Hz, 2H), 8.95 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 441.07 (M+H)⁺.

Example 27 (±)-8-Chloro-4-hydroxy-N-[4-(terr-butyl)phenyl]-3,4-dihydro-l'H-spiro[chromene-2,4'- piperidine]- 1 '-carboxamide

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; ¹H NMR (300 MHz, DMSO-4) δ 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 (t, J = 7.5 Hz, IH), 7.20-7.26 (m, 2H), 7.31- 7.36 (m, 2H), 7.69-7.79 (m, 2H), 8.50 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 427.10 (M+H)⁺.

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; ¹H NMR (300 MHz, DMSO-^₆) δ 1.22 (s, 9H), 1.62-1.75 (m, 4H), 1.80-1.85 (m, 2H), 2.10-2.18 (m, IH), 3.08- 3.26 (m, IH), 3.89-3.96 (m, 2H), 4.70-4.76 (m, IH), 5.54 (br s, IH), 6.91 (t, J = 7.5 Hz, I H), 7.23 (d, J = 8.1 Hz, 2H), 7.28-7.40 (m, 4H), 8.47 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 429.35 (M+H)⁺. Example 28

(±)-8-Bromo-4-hydroxy-N-[4-(/ert-butyl)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]- 1 '-carboxamide

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; ¹H NMR (300 MHz, DMSCwZ₆) δ 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, 2H), 7.02 (t, J = 7.2 Hz, IH), 7.23 (d, J = 8.1 Hz, 2H), 7.32-7.38 (m, 2H), 7.75 (d, J = 7.8 Hz, IH), 7.91 (d, J = 7.2 Hz, IH), 8.50 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 471.19 (M+H)⁺.

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; ¹H NMR (300 MHz, DMSCM₆) δ 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, 2H), 4.70-4.78 (m, IH), 5.53 (br s, IH), 7.02 (t, J = 7.2 Hz, IH), 7.23 (d, J= 8.1 Hz, 2H), 7.32-7.38 (m, 2H), 7.75 (d, J= 7.8 Hz, IH), 7.91 (d, J= 7.2 Hz, IH), 8.50 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 473.13 (M+H)⁺.

' Example 29

(±)-8-Bromo-4-hydroxy-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-l '-carboxamide

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; ¹H NMR (300 MHz, DMSO-J₆) δ 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 = 7.8 Hz, IH), 7.58 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 7.8 Hz, IH), 7.92 (d, J = 8.7 Hz, IH), 8.99 (br s, I H, exchangeable with D₂O); APCI-MS (m/z) 483.01 (M+H)⁺.

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; ¹H NMR (300 MHz, DMSO-J₆) δ 1.60-1.90 (m, 4H), 2.11-2.18 (m, IH), 3.10-3.18 (m, 2H), 3.95-4.04 (m, 2H), 4.70-4.78 (m, IH), 5.54 (br s, IH), 6.87 (t, J = 7.8 Hz, IH), 7.44 (t, J = 6.9 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 8.95 (br s, I H, exchangeable with D₂O); APCI-MS (m/z) 485.04 (M+H)⁺.

Example 30

(±)-8-Fluoro-4-hydroxy-N- [4-(trifluoromethyl)phenyl] -3 ,4-dihydro- 1 'H-spiro [chromene- 2,4'-piperidine]- 1 '-carboxamide

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; ¹H NMR (300 MHz, DMSO-J₆) δ 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, IH), 7.52-7.60 (m, 4H), 7.64-7.70 (m, 2H), 8.97 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 423.1 1 (M+H)⁺. 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; ¹H NMR (300 MHz, OMSO-dβ) δ 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 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 7.8 Hz, 2H), 8.94 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 425.10 (M+H)⁺.

Example 31

(±)-8-Chloro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]- 1 '-carboxamide

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; ¹H NMR (300 MHz, DMSCW₆) δ 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, J = 7.8 Hz, IH), 7.23 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 9.3 Hz, 2H), 7.71 (d, J = 7.2 Hz, IH), 7.77 (d, J = 7.8 Hz, IH), 8.78 (s, I H, exchangeable with D₂O); APCI-MS (m/z) 455.10 (M+H)⁺.

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; ¹H NMR (300 MHz, DMSCW₆) δ 1.60-1.92 (m, 5H), 2.12-2.19 (m, IH), 3.09-3.12 (m, IH), 3.23-3.27 (m, IH), 3.88-3.96 (m, 2H), 4.73-4.75 (m, IH), 5.54 (d, J = 6.3 Hz, IH), 6.91 (t, J = 7.6 Hz, IH), 7.23 (d, J= 8.4 Hz, 2H), 7.30 (d, J= 7.2 Hz, IH), 7.39 (d, J= 7.2 Hz, IH), 7.56 (d, J = 9.0 Hz, 2H), 8.75 (s, IH, exchangeable with D₂O); APCI-MS (m/z) 457.26 (M+H)⁺.

Example 32

(+)-8-Chloro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]- 1 '-carboxamide

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). Combined organic layers were washed with water, saturated sodium bicarbonate (NaHCO₃) solution, brine and filtered. The filtrate was evaporated to yield 3.51 g of crude product. This crude was a mixture of diastereomers which was then separated using column chromatography 30 % ethyl acetate in petroleum ether (double run) to afford 1.55 g of less polar diastereomer (eluted first) as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.60-1.74 (m, 2H), 1.85-1.95 (m, 2H), 2.20-2.30 (m, 2H), 3.07-3.17 (m, 6H), 3.85-3.99 (m, 2H), 4.08-4.15 (m, IH), 4.25- 4.35 (m, IH), 4.97 (s, 2H), 5.80-5.86 (m, IH), 6.58 (t, J = 7.5 Hz, IH), 6.78 (t, J = 7.8 Hz, IH), 6.96 (t, J= 6.9 Hz, IH), 7.06 (t, J= 7.2 Hz, IH), 7.17-7.38 (m, 6H), 7.47 (d, J = 7.8 Hz, IH), 7.55 (d, J = 8.7 Hz, 2H), 7.89 (d, J= 6.6 Hz, IH), 8.77 (s, IH), 10.89 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 111.16 (M+H)⁺; HPLC: Chiral PAK IA 250 mm, 97.94 (de); Retention time: 14.68 min. Further elution with increasing amounts of ethyl acetate in petroleum ether gave 1.14 g of more polar diastereomer (eluted second) as a white solid. Spectral data of more polar diastereomer is given in Example 33, Step 1.

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 TΗF (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). This mixture was acidified with 1 N HCl to pH 4 and extracted with ethyl acetate (2 x 100 mL). Organic layer was washed with water, brine, and dried (Na₂SO₄). Evaporation of solvent under reduced pressure afforded 789 mg of (+)-8-chloro-4- hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l'-carboxamide as a white solid; ¹H NMR (300 MHz, DMSO-fifc) δ 1.62-1.87 (m, 5H), 2.10-2.18 (m, IH), 3.08-3.18 (m, 2H), 3.22-3.28 (m, IH), 3.93-4.01 (m, 2H), 4.70-4.81 (m, IH), 5.54 (br s, IH), 6.91 (t, J= 7.8 Hz, IH), 7.23 (d, J= 9.0 Hz, 2H), 7.30 (d, J = 7.8 Hz, IH), 7.39 (d, J = 7.8 Hz, IH), 7.55 (d, J = 8.7 Hz, 2H), 8.75 (br s, I H, exchangeable with D₂O); APCI-MS (m/z) 457.11 (M+H)⁺; HPLC: CHIRALPAK AD-H 250 mm, 94.98 % (ee); Retention time: 16.25 min; Specific optical rotation: [α]_D : +3.72°, c = 0.1% in chloroform.

Example 33

(-)-8-Chloro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-r-carboxamide

Step 1 Spectral data for more polar diastefeomer (eluted second) from Example 32, Step 1 : ¹H NMR (300 MHz, DMSO-^₆) δ 1.00-1.23 (m, 2H), 1.40-1.46 (m, 3H), 1.60-1.68 (m, 2H), 2.02-2.08 (m, IH), 2.98-3.23 (m, 4H), 3.78-3.85 (m, IH), 3.93-4.00 (m, IH), 4.23- 4.32 (m, IH), 5.00 (s, IH), 5.87 (br s, IH, exchangeable with D₂O), 6.89-7.03 (m, 4H), 7.10 (d, J = 7.8 Hz, 1 H), 7.17-7.31 (m, 6H), 7.40 (d, J = 7.5 Hz, 1 H), 7.48 (d, J = 7.2 Hz, IH), 7.59 (d, J = 9.0 Hz, 2H), 7.95 (d, J = 6.3 Hz, IH), 8.75 (s, IH), 10.90 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 777.16 (M+H)⁺; HPLC: Chiral PAK IA 250 mm, 99.50 (de); Retention Time: 1 1.14 min.

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. The solvent was evaporated under reduced pressure and residue obtained was dissolved in water (50 mL). This mixture was acidified with 1 N HCl to pH 4 and extracted with ethyl acetate (2 x 100 mL). Organic layer was washed with water, brine, and dried (Na₂SO₄). Evaporation of solvent under reduced pressure afforded 789 mg of (+)-8-chloro-4- hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l'-carboxamide as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.62-1.87 (m, 5H), 2.10-2.18 (m, IH), 3.08-3.18 (m, 2H), 3.22-3.28 (m, IH), 3.93-4.01 (m, 2H), 4.70-4.81 (m, IH), 5.54 (br s, IH), 6.91 (t, J= 7.8 Hz, IH), 7.23 (d, J= 9.0 Hz, 2H), 7.30 (d, J = 7.8 Hz, IH), 7.39 (d, J = 7.8 Hz, IH), 7.55 (d, J = 8.7 Hz, 2H), 8.75 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 457.11 (M+H)⁺; HPLC: CHIRALPAK AD-H 250 mm, 94.98 % (ee); Retention time: 16.25 min; Specific optical rotation: [α]_D : +3.72°, c = 0.1% in chloroform.

Example 33

(-)-8-Chloro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-l'H-spiro [chromene-2,4'-piperidine]- 1 '-carboxamide

Step 1 Spectral data for more polar diastereomer (eluted second) from Example 32, Step 1 : ¹H NMR (300 MHz, DMSO-^₆) δ 1.00-1.23 (m, 2H), 1.40-1.46 (m, 3H), 1.60-1.68 (m, 2H), 2.02-2.08 (m, IH), 2.98-3.23 (m, 4H), 3.78-3.85 (m, IH), 3.93-4.00 (m, IH), 4.23- 4.32 (m, IH), 5.00 (s, IH), 5.87 (br s, IH, exchangeable with D₂O), 6.89-7.03 (m, 4H), 7.10 (d, J = 7.8 Hz, IH), 7.17-7.31 (m, 6H), 7.40 (d, J= 7.5 Hz, IH), 7.48 (d, J = 7.2 Hz, IH), 7.59 (d, J = 9.0 Hz, 2H), 7.95 (d, J = 6.3 Hz, IH), 8.75 (s, IH), 10.90 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 777.16 (M+H)⁺; HPLC: Chiral PAK IA 250 mm, 99.50 (de); Retention Time: 1 1.14 min.

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-

46 carboxamide as a white solid; ¹H NMR (300 MHz, DMSO-J₆) δ 1.64-1.92 (m, 5H), 2.10- 2.18 (m, IH), 3.08-3.16 (m, IH), 3.22-3.28 (m, I H), 3.93-4.00 (m, 2H), 4.70-4.80 (m, IH), 5.54 (br s, IH), 6.91 (t, J = 7.8 Hz, IH), 7.24 (d, J = 9.0 Hz, 2H), 7.30 (d, J = 7.8 Hz, IH), 7.39 (d, J= 7.8 Hz, IH), 7.55 (d, J= 8.7 Hz, 2H), 8.75 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 457.14 (M+H)⁺; HPLC: CHIRALPAK AD-H 250 mm, 95.62 % (ee); Retention time: 9.47 min; Specific optical rotation: [α]p : -3.27°, c = 0.1% in chloroform.

Example 34

(±)-8-Bromo-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-r//- spiro[chromene-2,4'-piperidine]-r-carboxamide

Step 1 8-Bromo-4-oxo-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro- 1 'H-spiro[chromene- 2,4'-piperidine]-r-carboxamide: Coupling reaction of Intermediate 5 (300 mg, 0.901 mmol) with phenyl [4-(trifluoromethoxy)phenyl]carbamate (268 g, 0.992 mmol) in the presence of triethylamine (456 g, 4.501 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1, gave 426 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.68-1.76 (m, 2H), 1.92-2.00 (m, 2H), 2.92-2.99 (m, 2H), 3.12-3.26 (m, 2H), 3.98-4.06 (m, 2H), 7.03 (t, J = 7.8 Hz, IH), 7.23 (d, J= 8.4 Hz, 2H), 7.54 (d, J= 8.7 Hz, 2H), 7.75 (d, J= 7.8 Hz, IH), 7.92 (d, J= 8.7 Hz, IH), 8.78 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 499.16 (M+H)⁺.

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; ¹H NMR (300 MHz, DMSO-^₆) δ 1.67-1.87 (m, 5H), 2.11-2.18 (m, IH), 3.10-3.18 (m, 2H), 3.95-4.04 (m, 2H), 4.70-4.78 (m, IH), 5.54 (d, J= 6.6 Hz, IH), 6.86 (t, J= 7.8 Hz, IH), 7.23 (t, J = 7.8 Hz, 2H), 7.39-7.47 (m, 2H), 7.55 (d, J = 8.7 Hz, 2H), 8.75 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 500.97 (M+H)⁺.

Example 35

47 (+)-8-Bromo-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide

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. These diastereomers were separated by silica gel column chromatography using 30 % ethyl acetate in petroleum ether (double run) to afford 397 mg of less polar diastereomer (eluted first) as a white solid; ¹H NMR (300 MHz, OMSO-d₆) δ 1.55-1.79 (m, 3H), 1.88- 1.96 (m, 2H), 2.10-2.30 (m, IH), 3.06-3.17 (m, 4H), 3.89-4.02 (m, 2H), 4.23-4.33 (m, IH), 4.97 (s, 2H), 5.78-5.85 (m, IH), 6.62 (d, J = 7.2 Hz, IH), 6.73 (t, J = 7.8 Hz, IH), 6.96 (t, J = 7.2 Hz, IH), 7.07 (t, J = 7.8 Hz, IH), 7.17-7.38 (m, 8H), 7.45-7.58 (m, 4H), 7.88 (br s, IH, exchangeable with D₂O), 8.77 (br s, IH, exchangeable with D₂O), 10.89 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 820.95 (M+H)⁺. Further elution with increasing amounts of ethyl acetate in petroleum ether gave 325 mg of more polar diastereomer (eluted second) as a white solid. 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; ¹H NMR (300 MHz, DMSO-^₆) δ 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 (d, J= 7.8 Hz, IH), 7.23 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 6.9 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 8.75 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 500.97 (M+H)⁺; HPLC: CHIRALPAK AD-H

48 250 mm, 96.56% (ee); Retention Time: 17.13 min; Specific optical rotation: [α]_D : + 0.39°, c = 0.1% in chloroform.

Example 36 (-)-8-Bromo-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro

[chromene-2 ,4'-piperidine] - 1 '-carboxamide

Step 1 Spectral data for more polar diastereomer (eluted second) from Example 35, Step 1 : ¹H NMR (300 MHz, DMSO-J₆) δ 1.10-1.60 (m, 3H), 1.65-1.75 (m, 2H), 2.23-2.31 (m, IH), 2.98-3.25 (m, 4H), 3.79-3.86 (m, IH), 3.95-4.02 (m, IH), 4.25-4.31 (m, IH), 5.00 (s, 2H), 5.84-5.90 (m, IH), 6.86 (t, J = 7.8 Hz, IH), 6.90-7.04 (m, 2H), 7.10-7.20 (m, 3H), 7.25-7.33 (m, 6H), 7.48 (d, J = 7.8 Hz, IH), 7.53-7.63 (m, 3H), 7.95 (br s, IH, exchangeable with D₂O), 8.75 (br s, IH, exchangeable with D₂O), 10.89 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 820.97 (M+H)⁺

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; ¹H NMR (300 MHz, DMSO-^₆) δ 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, J= 7.8 Hz, IH), 7.23 (d, J= 8.4 Hz, 2H), 7.46 (d, J = 7.5 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 8.75 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 501.03 (M+H)⁺; HPLC: CHIRALPAK AD-H 250 mm, 97.04% (ee); Retention Time: 9.79 min; Specific optical rotation: [α]o: -1.21°, c = 0.1% in chloroform.

Example 37

(±)-8-Fluoro-4-hydroxy-iV-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide

49 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; ¹H NMR (300 MHz, DMSO-^₆) δ 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 (m, IH), 7.23 (d, J = 8.4 Hz, 2H), 7.53-7.62 (m, 4H), 8.78 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 439.13 (M+H)⁺.

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; ¹H NMR (300 MHz, DMSCW₆): δ 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), 7.56 (d, J= 9.3 Hz, 2H), 8.74 (br s, IH, exchangeable with D₂O); APCI- MS (m/z) 441.11 (M+H)⁺.

Example 38

(+)-8-Fluoro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3 ,4-dihydro- 1¹H- spiro[chromene-2,4'-piperidine]-r-carboxamide

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. These diastereomers were separated by silica gel column chromatography using 30 % ethyl acetate in petroleum ether (double run) to afford 209 mg of less polar diastereomer (eluted first) as a white solid; ¹H NMR (300 MHz, DMSO-^₆): δ 1.68-1.88 (m, 3H), 1.95-

50 2.00 (m, 2H), 2.20-2.26 (m, IH), 3.00-3.25 (m, 4H), 3.80-3.93 (m, 2H), 4.25-4.35 (m, IH), 4.98 (s, 2H), 5.80-5.86 (m, IH), 5.57 (d, J= 7.8 Hz, IH), 6.70-6.80 (m, IH), 6.95 (d, J = 7.2 Hz, IH), 6.98 (t, J = 7.2 Hz, IH), 7.10-7.29 (m, 8H), 7.45 (d, J = 7.8 Hz, IH), 7.55 (d, J = 8.7 Hz, 2H), 7.89 (br s, IH, exchangeable with D₂O), 8.77 (br s, IH, exchangeable with D₂O), 10.89 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 761.1 1 (M+H)⁺; HPLC: Chiral PAK IA 250 mm, 98.34% (de); Retention Time: 14.52 min). Further elution with increasing amounts of ethyl acetate in petroleum ether gave 169 mg of more polar diastereomer (eluted second) as a white solid. Spectral data of more polar diastereomer is given in Example 39, Step 1.

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; ¹H NMR (300 MHz, DMSO-c/₆): δ 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 (m, IH), 7.04-7.12 (m, IH), 7.22 (d, J= 7.8 Hz, 3H), 7.56 (d, J = 9.3 Hz, 2H), 8.74 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 441.10 (M+H)⁺; HPLC: Chiral PAK IA 250 mm, 98.06 (ee); Retention Time: 35.73 min; Specific optical rotation: [α]o : + 8.1 1°, c = 0.1% in chloroform.

Example 39

(-)-8-Fluoro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide

Step 1 Spectral data for more polar diastereomer (eluted second) from Example 38, Step 1 : ¹H NMR (300 MHz, DMSO-^₆): δ 1.24-1.30 (m, 3H), 1.40-1.46 (m, IH), 1.50-1.58 (m, IH), 1.68-1.73 (m, 2H), 1.97-2.03 (m, IH), 3.00-3.23 (m, 4H), 3.72-3.80 (m, IH), 3.84-3.91 (m, IH), 4.23-4.32 (m, IH), 5.01 (s, 2H), 5.84-5.90 (m, IH), 6.78-7.02 (m, 4H), 7.15-7.23 (m, 8H), 7.49 (d, J= 7.2 Hz, IH), 7.59 (d, J= 8.7 Hz, 2H), 7.96 (br s, IH, exchangeable with D₂O), 8.75 (br s, IH, exchangeable with D₂O), 10.90 (br s, IH,

51 exchangeable with D₂O); APCI-MS (m/z) 761.10 (M+H)⁺; HPLC: Chiral PAK IA 250 mm, 99.38% (de); Retention Time: 10.47 min.

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; ¹H NMR (300 MHz, DMSO-c/₆): δ 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), 7.04-7.12 (m, IH), 7.22 (d, J = 8.1 Hz, 3H), 7.55 (d, J = 8.7 Hz, 2H), 8.74 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 441.09 (M+H)⁺; HPLC: Chiral PAK IA 250 mm, 96.4% (ee); Retention Time: 40.72 min; Specific optical rotation: [α]o : -1.19°, c = 0.1% in chloroform.

Example 40

(±)-8-Chloro-4-hydroxy-jV-(4-2,2,2-trifluoroethoxyphenyl)-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide

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; ¹H NMR (300 MHz, DMSO-^₆) δ 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, 2H), 4.67 (q, J = 9.0 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 7.08 (t, J = 7.8 Hz, IH), 7.37 (d, J = 9.3 Hz, 2H), 7.71 (d, J= 6.6 Hz, IH), 7.77 (d, J= 7.8 Hz, IH), 8.51 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 467.12 (M-H)^".

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) was reduced with sodium borohydride (1 1 mg, 0.307 mmol) in ethanol (3 mL) as

52 described in Example 26, to obtain 70 mg of the product as a white solid; ¹H NMR (300 MHz, OMSO-dβ) δ 1.60-1.78 (m, 3H), 1.82-1.91 (m, 2H), 2.10-2.20 (m, IH), 3.06-3.14 - (m, IH), 3.20-3.30 (m, I H), 3.90-3.96 (m, 2H), 4.62-4.78 (m, 3H), 5.52 (br s, IH), 6.87- 6.97 (m, 3H), 7.30 (d, J = 7.8 Hz, IH), 7.38 (d, J = 8.1 Hz, 3H), 8.47 (br s, IH, exchangeable with D₂O); ESI-MS (m/z) 471.12 (M+H)⁺.

Example 41 (±)-8-Bromo-N-[4-(2,2,2-trifluoroethoxy)phenyl]-4-hydroxy-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-r-carboxamide

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; ¹H NMR (300 MHz, DMSO-^₆) δ 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), 4.67 (q, J = 9.0 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 7.03 (t, J = 7.8 Hz, IH), 7.37 (d, J = 9.0 Hz, 2H), 7.75 (d, J = 7.5 Hz, IH), 7.91 (d, J= 6.9 Hz, IH), 8.51 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 513.10 (M+H)⁺.

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) was reduced with sodium borohydride (11 mg, 0.303 mmol) in ethanol (3 mL) as described in Example 26, to obtain 100 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.23-1.28 (m, I H), 1.64-1.90 (m, 4H), 2.10-2.20 (m, I H), 3.05-3.26 (m, 2H), 3.92-3.98 (m, 2H), 4.63-4.78 (m, 3H), 5.53 (br s, IH), 6.86 (t, J = 7.8 Hz, IH), 6.93 (d, J = 8.7 Hz, 2H), 7.37-7.46 (m, 4H), 8.47 (br s, IH, exchangeable with D₂O); ESI-MS (m/z) 515.14 (M+H)⁺.

53 Example 42

(±)-8-Chloro-4-fluoro-iV-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene- 2,4'-piperidine]-l '-carboxamide

Coupling reaction of Intermediate 7 (150 mg, 0.503 mmol) with phenyl [4- (trifluoromethyl)phenyl]carbamate (156 mg, 0.553 mmol) in the presence of triethylamine (254 mg, 2.515 mmol) in anhydrous DMSO (2.0 mL) according to the procedure described in Example 1, gave 163 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-J₆) δ 1.63-1.72 (m, IH), 1.80-1.86 (m, 2H), 1.92-1.98 (m, IH), 2.15- 2.21 (m, IH), 2.30-2.37 (m, IH), 3.07-3.14 (m, IH), 3.31-3.38 (m, IH), 3.90-3.95 (m, I H), 4.00-4.08 (m, IH), 5.62-5.68 (m, IH), 5.80-5.86 (m, IH), 7.01 (t, J = 7.5 Hz, I H), 7.40 (d, J = 7.2 Hz, IH), 7.49 (d, J = 7.8 Hz, IH), 7.58 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 8.96 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 443.1 1 (M+H)⁺.

Example 43 (±)-8-Bromo-4-fluoro-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-

2,4'-piperidine]-l '-carboxamide

Coupling reaction of Intermediate 8 (100 mg, 0.297 mmol) with phenyl [4- (trifluoromethyl)phenyl]carbamate (92 mg, 0.326 mmol) in the presence of triethylamine (150 mg, 1.485 mmol) in anhydrous DMSO (2.0 mL) according to the procedure described in Example 1, gave 85 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.62-1.69 (m, IH), 1.78-1.84 (m, IH), 1.92-1.98 (m, IH), 2.17-2.22 (m, I H), 2.32-2.38 (m, IH), 3.07-3.16 (m, IH), 3.31-3.38 (m, IH), 3.90-3.97 (m, IH), 4.02- 4.10 (m, IH), 5.62-5.68 (m, IH), 5.78-5.84 (m, IH), 6.96 (t, J = 7.5 Hz, I H), 7.44 (d, J = 7.5 Hz, IH), 7.55-7.60 (m, IH), 7.62-7.70 (m, 4H), 8.96 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 487.28 (M+H)⁺.

54 Example 44 (±)-8-Chloro-N-(3,4-difluorophenyl)-4-hydroxy-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]- 1 '-carboxamide

Step 1 8-Chloro-4-oxo-iV-(3,4-difluorophenyl)-3,4-dihydro- 1 'H-spiro[chromene-2,4'- piperidine]-l '-carboxamide: Coupling reaction of Intermediate 4 (100 mg, 0.346 mmol) with phenyl (3,4-difluorophenyl)carbamate (95 g, 0.381 mmol) in the presence of triethylamine (175.55 mg, 1.734 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 130 mg of the product as a white solid; ¹H NMR (300 MHz, DMSCM₆) δ 1.68-1.76 (m, 2H), 1.92-2.00 (m, 2H), 2.95 (s, 2H), 3.12-3.23 (m, 2H), 3.94-4.02 (m, 2H), 7.08 (t, J = 7.8 Hz, IH), 7.19-7.25 (m, IH), 7.28-7.34 (m, I H), 7.56-7.65 (m, IH), 7.71 (d, J = 6.6 Hz, IH), 7.77 (d, J = 7.8 Hz, IH), 8.79 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 407.02 (M+H)⁺.

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) was reduced with sodium borohydride (13 mg, 0.353 mmol) in ethanol (3 mL) as described in Example 26, to obtain 80 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-<4) δ 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, IH, exchangeable with D₂O); APCI-MS (m/z) 409.08 (M+H)⁺.

Example 45

8-Chloro-iV- [(4-tert-bulyl)- 1 ,3 -thiazol-2-yl] -4-hydroxy-3 ,4-dihydro- 1 'H-spiro [chromene- 2,4'-piperidine]-l '-carboxamide

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)

55 in the presence of triethylamine (175.55 mg, 1.734 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1 , gave 1 10 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ ¹H NMR (300 MHz, DMSO-J₆) δ 1.24 (s, 9H), 1.65-1.75 (m, 2H), 1.89-1.97 (m, 2H), 2.93 (s, 2H), 3.13-3.23 (m, 2H), 4.04-4.10 (m, 2H), 6.54-6.58 (m, IH), 7.08 (t, J = 7.8 Hz, IH), 7.71 (d, J= 7.8 Hz, IH), 7.77 (d, J = 7.8 Hz, IH), 10.81 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 434.94 (M+H)⁺. Step 2 (±)-8-Chloro-Λ4(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; ¹H NMR (300 MHz, DMSO-^₆) δ 1.24 (s, 9H), 1.55-1.89 (m, 5H), 2.10-2.17 (m, IH), 3.08-3.26 (m, 2H), 4.00-4.08 (m, 2H), 4.70-4.76 (m, IH), 5.54 (br s, IH), 6.50-6.56 (m, IH), 6.91 (t, J = 7.8 Hz, IH), 7.30 (d, J = 7.8 Hz, IH), 7.38 (d, J = 7.8 Hz, IH), 10.79 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 436.1 1 (M+H)⁺.

Example 46

(±)-8-Chloro-4-hydroxy-N-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-r-carboxamide

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; ¹H NMR (300 MHz, DMSO-^₆) δ 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 (m, 2H), 7.09 (t, J = 7.8 Hz, IH), 7.71 (d, J = 7.8 Hz, IH), 7.75-7.81 (m, 2H), 11.44 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 446.06 (M+H)⁺.

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

56 mmol) was reduced with sodium borohydride (14 mg, 0.403 mmol) in ethanol (3 mL) as described in Example 26, to obtain 70 mg of the product as a white solid; H NMR (300 MHz, DMSOcZ₆) δ 1.60-1.92 (m, 4H), 2.10-2.20 (m, 2H), 3.10-3.20 (m, 2H), 4.03-4.09 (m, 2H), 4.70-4.76 (m, IH), 5.53 (br s, IH), 6.92 (t, J= 7.8 Hz, IH), 7.30 (d, J= 7.8 Hz, IH), 7.38 (d, J = 7.8 Hz, IH), 7.80 (s, IH), 1 1.40 (br s, IH, exchangeable with D₂O); ESI-MS (m/z) 446.31 (M-H).

Example 47

(±)-8-Chloro-4-hydroxy-N-[5-(rert-butyl)-l,3,4-thiadiazol-2-yl]-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-r-carboxamide

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; ¹H NMR (300 MHz, DMSO-^₆) δ 1.34 (s, 9H), 1.65-1.74 (m, 2H), 1.92-2.05 (m, 2H), 2.93 (s, 2H), 3.16-3.24 (m, 2H), 4.09-4.13 (m, 2H), 7.08 (t, J = 7.8 Hz, IH), 7.71 (d, J = 7.8 Hz, IH), 7.77 (d, J = 6.3 Hz, IH), 12.89 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 435.20 (M+H)⁺.

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) was reduced with sodium borohydride (5 mg, 0.138 mmol) in ethanol (1 mL) as described in Example 26, to obtain 40 mg of the product as a white solid; ¹H NMR (300 MHz, OMSO-dβ) δ 1.56 (s, 9H), 1.56-1.91 (m, 4H), 2.10-2.17 (m, 2H), 3.10-3.28 (m, 2H), 4.05-4.10 (m, 2H), 4.68-4.77 (m, IH), 5.54 (br s, IH), 6.91 (t, J = 7.8 Hz, IH), 7.30 (d, J = 7.8 Hz, IH), 7.38 (d, J = 7.2 Hz, IH), 1 1.20 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 436.13 (M)⁺.

57 Example 48 (±)-8-Chloro-4-hydroxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide

Step 1 S-Chloro^-oxo-N-fS-CtrifluoromethyO-l^^-thiadiazol^-yη-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; ¹H NMR (300 MHz, DMSO-J₆) δ 1.71-1.81 (m, 2H), 1.96-2.02 (m, 2H), 2.94 (s, 2H), 3.20-3.26 (m, 2H), 4.10-4.16 (m, 2H), 7.09 (t, J = 8.1 Hz, IH), 7.72 (d, J= 7.8 Hz, IH), 7.78 (d, J= 6.9 Hz, IH), 12.10 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 445.50 (M-H)^".

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) was reduced with 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; ¹H NMR (300 MHz, DMSO-^₆) δ 1.64-1.95 (m, 2H), 2.08-2.17 (m, 2H), 3.15-3.33 (m, 4H), 4.05-4.12 (m, 2H), 4.70-4.76 (m, IH), 5.56 (br s, IH), 6.92 (t, J = 7.8 Hz, IH), 7.31 (d, J = 7.5 Hz, IH), 7.38 (d, J = 7.5 Hz, IH), 12.06 (br s, IH, exchangeable with D₂O); APCI- MS (m/z) 447.10 (M-H)^'.

Example 49 (±)-8-Chloro-/V-(6-fluoro-l,3-benzothiazol-2-yl)-4-hydroxy-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-l '-carboxamide

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

58 mg, 1.104 mmol) with phenyl (6-fluoro-l,3-benzothiazol-2-yl)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; ¹H NMR (300 MHz, DMSO-^₆) δ 1.72-1.78 (m, 2H), 1.92-2.00 (m, 2H), 2.95 (s, 2H), 3.20-3.26 (m, 2H), 4.08-4.16 (m, 2H), 7.09 (t, J = 7.8 Hz, IH), 7.20-7.30 (m, 2H), 7.70-7.80 (m, 3H), 1 1.28 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 446.26 (M+H)⁺.

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; ¹H NMR (300 MHz, DMSCM₆) δ 1.74-1.93 (m, 5H), 2.10-2.18 (m, IH), 3.15-3.21 (m, 2H), 4.06-4.12 (m, 2H), 4.70-4.76 (m, IH), 5.55 (br s, IH), 6.92 (t, J= 7.8 Hz, IH), 7.18-7.23 (m, IH), 7.30 (d, J = 7.2 Hz, IH), 7.39 (d, J= 7.2 Hz, IH), 7.58-7.65 (m, IH), 7.75-7.81 (m, IH), 1 1.28 (br s, IH, exchangeable with D₂O); ESI-MS (m/z) 449.16 (M+H)⁺.

Example 50

(±)-8-Bromo-N-(6-fluoro-l,3-benzothiazol-2-yl)-4-hydroxy-3,4-dihydro-r//- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide

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; ¹H NMR (300 MHz, DMSO-^₆) δ 1.70-1.78 (m, 2H), 1.92-2.00 (m, 2H), 2.94 (s, 2H), 3.16-3.26 (m, 2H), 4.1 1-4.18 (m, 2H), 7.03 (t, J = 7.8 Hz, IH), 7.18-7.25 (m, 2H), 7.72-7.80 (m, 2H), 7.91 (d, J= 7.8 Hz, IH), 11.33 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 488.18 (M+H)⁺.

59 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; ¹H NMR (300 MHz, DMSO-J₆) δ 1.72-1.94 (m, 5H), 2.10-2.18 (m, IH), 3.13-3.20 (m, 2H), 4.08-4.14 (m, 2H), 4.72-4.78 (m, IH), 5.54 (br s, IH), 6.87 (t, J = 7.8 Hz, IH), 7.18-7.25 (m, I H), 7.40-7.48 (m, 2H), 7.58-7.64 (m, IH), 7.76-7.82 (m, IH), 1 1.29 (br s, IH, exchangeable with D₂O); ESI-MS (m/z) 490.10 (M-H).

Example 51

(±)-8-Chloro-4-hydroxy-N-(6-trifluoromethyl-l,3-benzothiazol-2-yl)-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide

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; ¹H NMR (300 MHz, DMSO-^₆) δ 1.70-1.80 (m, 2H), 1.90-2.05 (m, 2H), 2.95 (s, 2H), 3.24-3.29 (m, 2H), 4.17-4.21 (m, 2H), 7.09 (t, J = 7.8 Hz, I H), 7.68-7.91 (m, 4H), 8.32-8.38 (m, IH), 1 1.66 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 496.08 (M+H)⁺.

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; ¹H NMR (300 MHz, DMSO-^₆) δ 1.78-1.95 (m, 2H), 2.10-2.17 (m, 2H), 3.15-3.22 (m, 4H), 4.09-4.13 (m, 2H), 4.70-4.78 (m, IH), 5.55 (br s, IH), 6.92 (t, J = 7.8 Hz, IH), 7.31 (d, J = 7.8 Hz, IH), 7.39 (d, J= 7.8 Hz, IH), 7.67 (d, J= 8.4 Hz, IH), 7.75-7.81 (m, IH), 8.38- 8.42 (m, IH), 11.55 (br s, IH, exchangeable with D₂O); ESI-MS (m/z) 498.06 (M)⁺.

60 Example 52

(±)-8-Chloro-N-(4,6-difluoro-l ,3-benzothiazol-2-yl)-4-hydroxy-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide

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; ¹H NMR (300 MHz, DMSCW₆) δ 1.72-1.81 (m, 2H), 1.94-2.02 (m, 2H), 2.95 (s, 2H), 3.18-3.28 (m, 2H), 4.10-4.16 (m, 2H), 7.09 (t, J= 7.8 Hz, IH), 7.28 (d, J = 9.3 Hz, IH), 7.72 (d, J = 7.8 Hz, 2H), 7.78 (d, J = 7.8 Hz, IH), 1 1.59 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 466.07 (M+H)⁺.

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; ¹H NMR (300 MHz, OMSO-d_β) δ 1.62-1.95 (m, 4H), 2.10-2.20 (m, 2H), 3.14-3.47 (m, 2H), 4.05-4.13 (m, 2H), 5.55 (br s, IH), 6.92 (t, J = 7.8 Hz, IH), 7.25-7.42 (m, 2H), 7.39 (d, J= 7.2 Hz, I H), 7.72 (d, J = 7.5 Hz, I H), 1 1.54 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 464.12 (M+H)⁺.

Example 53 (±)-8-Chloro-N- { 4- [4-(trifiuoromethyl)phenyl] - 1 ,3-thiazol-2-yl } -4-hydroxy-3 ,4-dihydro-

1 'H-spiro[chromene-2,4'-piperidine]- 1 '-carboxamide

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

61 4 (250 mg, 0.751 mmol) with phenyl {4-[4-(trifluoromethyl)phenyl]-l,3-thiazol-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; ¹H NMR (300 MHz, DMSOd₆) δ 1.72-1.80 (m, 2H), 1.93-2.00 (m, 2H), 2.95 (s, 2H), 3.15-3.26 (m, 2H), 4.05-4.15 (m, 2H), 7.09 (t, J = 7.8 Hz, IH), 7.70-7.80 (m, 5H), 8.10 (d, J= 7.8 Hz, 2H), 11.18 (br s, 1 H, exchangeable with D₂O); APCI-MS (m/z) 521.99 (M+H)⁺.

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) was reduced with sodium borohydride (14 mg, 0.383 mmol) in ethanol (2 mL) as described in Example 26, to obtain 134 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.72-1.93 (m, 5H), 2.12-2.18 (m, IH), 3.14-3.22 (m, 2H), 4.05-4.10 (m, 2H), 4.72-4.78 (m, IH), 5.54 (br s, IH), 6.90-6.96 (m, IH), 7.28- 7.40 (m, 2H), 7.70-7.80 (m, 3H), 8.08-8.16 (m, 2H), 11.13 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 522.27 (M-H).

Example 54

(±)-8-Chloro-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-4-hydroxy-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-l'-carboxamide

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; ¹H NMR (300 MHz, DMSO-^₆) δ 1.72-1.81 (m, 2H), 1.95-2.02 (m, 2H), 2.96 (s, 2H), 3.18-3.28 (m, 2H), 3.98-4.06 (m, 2H), 7.09 (t, J = 7.8 Hz, IH), 7.71 (d, J = 7.8 Hz, IH), 7.78 (d, J = 7.8 Hz, IH), 7.86 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 9.0 Hz, 2H), 9.47 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 502.94 (M)⁺.

62 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; ¹H NMR (300 MHz, DMSO-J₆) δ 1.70-1.99 (m, 5H), 2.10-2.20 (m, IH), 3.13-3.34 (m, 2H), 3.95-4.02 (m, 2H), 4.70-4.80 (m, IH), 5.56 (br s, IH), 6.92 (t, J = 7.8 Hz, IH), 7.31 (d, J = 7.5 Hz, IH), 7.39 (d, J= 7.2 Hz, IH), 7.87 (d, J= 9.3 Hz, 2H), 7.96 (d, J= 8.7 Hz, 2H), 9.45 (br s, IH, exchangeable with D₂O); ESI-MS (m/z) 503.31 (M-H).

Example 55

8-Chloro-N-[4-(trifluoromethyl)phenyl]-rH-spiro[chromene-2,4'-piperidine]-r- carboxamide

Coupling reaction of Intermediate 9 (200 mg, 0.734 mmol) with phenyl [4- (trifluoromethyl)phenyl]carbamate (227 mg, 0.808 mmol) in the presence of triethylamine (372 mg, 3.674 mmol) in anhydrous DMSO (4.0 mL) according to the procedure described in Example 1, gave 241 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.65-1.73 (m, 2H), 1.78-1.86 (m, 2H), 2.82-2.90 (m, 2H), 3.15- 3.24 (m, 2H), 3.97-4.03 (m, 2H), 6.87-6.95 (m, IH), 7.58-7.69 (m, 5H), 7.76-7.82 (m, IH), 8.95 (s, IH), 1 1.54 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 421.25 (M- H).

Example 56

(±)-4-Amino-8-chloro-N-(4-trifluoromethylphenyl)-3,4-dihydro-rH-spiro[chromene- 2,4'-piperidine]- 1 '-carboxamide hydrochloride

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

63 mmol) in the presence of triethylamine (603 mg, 5.962 mmol) in anhydrous DMSO (5.0 mL) according to the procedure described in Example 1, gave 610 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-J₆) δ 1.65-1.73 (m, IH), 1.86-2.00 (m, 4H), 2.15-3.30 (m, 2H), 3.00-3.10 (m, IH), 3.99-4.11 (m, 2H), 5.50-5.56 (m, IH), 6.78-6.85 (m, IH), 7.03-7.09 (m, IH), 7.30-7.36 (m, IH), 7.55-7.61 (m, 2H), 7.66-7.72 (m, 2H), 7.85-7.91 (m, 4H), 8.98 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 570.39 (M+H)⁺.

Step 2 (±)-4-Amino-8-chloro-N-(4-trifluoromethyphenyl)-3,4-dihydro-rH-spiro [chromene-2,4'-piperidine]-r-carboxamide: A mixture of Step 1 intermediate (575 mg, 1.088 mmol) and hydrazine hydrate (497 mg, 9.928 mmol) in ethanol (20.0 mL) was stirred at room temperature for 4 h. Excess of solvent was evaporated and the residue was dissolved in water (100 mL), basified with 2 N NaOH (pΗ = 10). The reaction mixture was then extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with water (50 mL), brine (25 mL), dried (Na₂SO₄) and filtered. The filtrate was evaporated under reduced pressure. The residue obtained after the evaporation of the solvent was directly used for the next step. A solution of di-tert-butyl dicarbonate (345 mg, 1.582 mmol) was added dropwise to the stirred solution of this crude intermediate (580 mg, 1.318 mmol) and triethylamine (266 mg, 2.637 mmol) in dichloromethane (10.0 mL) and stirred overnight. The reaction mixture was then diluted with ethyl acetate (25 mL) and water (25 mL). Two layers were separated. 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 (Na₂SO₄) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 20 % ethyl acetate in petroleum ether to obtain 75 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-J₆) δ 1.40-1.50 (m, 12H), 1.60-1.68 (m, IH), 1.75-1.80 (m, 2H), 2.08-2.15 (m, IH), 2.98-3.08 (m, IH), 3.93-4.06 (m, 2H), 4.78-4.83 (m, IH), 6.92 (t, J = 7.2 Hz, IH), 7.1 1 (d, J = 7.2 Hz, IH), 7.28-7.38 (m, I H), 7.55-7.60 (m, 2H), 7.65-7.70 (m, 2H), 8.96 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 538.37 (M-H)^".

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

64 (70 mg, 0.129 mmol) in ethyl acetate (1.0 mL) was added dropwise a saturated solution of hydrochloric acid in ethyl acetate (4.0 mL) at 0°C. The reaction mixture was then slowly warmed to room temperature. After 2 h stirring at the same temperature the excess of solvent was evaporated. The residue was taken into water, basified with potassium carbonate solution (pH = 9) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na₂SO₄) and filtered. The filtrate was concentrated to afford 27 mg of the product as a off-white solid; ¹H NMR (300 MHz, DMSO-J₆) δ 1.82-1.90 (m, 2H), 2.35-2.40 (m, 2H), 3.95-3.1 1 (m, 2H), 4.62-4.68 (m, IH), 7.04 (d, J = 7.5 Hz, IH), 7.47 (d, J = 7.5 Hz, IH), 7.58 (d, J = 8.7 Hz, 2H), 7.69 (d, J= 7.8 Hz, 2H), 8.72 (br s, 3H₅ exchangeable with D₂O), 9.04 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 438.30 (M-H)^'.

Example 57

(±)-8-Chloro-4-(acetylamino)-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide

Coupling reaction of Intermediate 11 (200 mg, 0.603 mmol) with phenyl [4- (trifluoromethyl)phenyl]carbamate (186 mg, 0.664 mmol) in the presence of triethylamine (305 mg, 3.018 mmol) in anhydrous DMSO (2.0 mL) according to the procedure described in Example 1, gave 236 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-J₆) δ 1.60-1.68 (m, IH), 1.75-1.82 (m, 5H), 1.91 (s, 3H), 2.08-2.16 (m, I H), 3.04-3.10 (m, I H), 3.92-4.00 (m, 2H), 5.09-5.15 (m, IH), 6.92 (t, J = 7.2 Hz, IH), 7.10-7.16 (m, IH), 7.30-7.36 (m, IH), 7.55-7.60 (m, 2H), 7.65-7.70 (m, 2H), 8.28- 8.35 (m, IH), 8.97 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 480.19 (M-H)^".

Example 58

(4E)-8-Chloro-4-(hydroxyimino)-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide

65 Hydroxylamine hydrochloride (288 mg, 4.138 mmol) was added to a stirred solution of Example 25 (200 mg, 0.413 mmol) and NaHCO₃ (348 mg, 4.138 mmol) in ethanol (4.0 mL) at room temperature. The reaction mixture was refluxed. After overnight refluxing, excess of ethanol was evaporated and the residue obtained was diluted with ethyl acetate (25 mL) and water (25 mL). Two layers were separated. The aqueous layer was washed with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (15 mL), brine (10 mL) dried over anhydrous Na₂SO₄, filtered and concentrated. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 1.5% methanol in chloroform to obtain 33 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-J₆) δ 1.66-1.72 (m, 2H), 1.78-1.84 (m, 2H), 2.87 (s, 2H), 3.15-3.25 (m, 2H), 3.97-4.03 (m, 2H), 6.92 (t, J = 7.8 Hz, IH), 7.58-7.69 (m, 5H), 7.79 (d, J = 7.5 Hz, IH)₅ 8.95 (br s, IH, exchangeable with D₂O), 11.54 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 498.26 (M+H)⁺.

Example 59

(4£)-8-Chloro-4-(methoxyimino)-jV-[4-(trifluoromethyl)phenyl]-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-r-carboxamide

The title compound was prepared by using Example 25 (100 mg, 227 mmol), NaHCO₃ (191 mg, 2.278 mmol) and methoxyamine hydrochloride (190 mg, 4.278 mmol) in ethanol (4.0 mL) as per the procedure described in Example 58 to give 52 mg the product a white solid; ¹H NMR (300 MHz, DMSO-^₆) δ 1.66-1.74 (m, 2H), 1.78-1.85 (m, 2H), 2.85-2.95 (m, 2H), 3.10-3.20 (m, 2H), 3.94 (s, 3H), 3.98-4.04 (m, 2H), 6.98 (t, J = 8.7 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 1 H), 7.57 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 7.8 Hz, IH), 8.95 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 468.10 (M+H)⁺.

Example 60

(±)-8-Chloro-N-[3-fluoro-4-(trifluoromethyl)phenyl]-4-hydroxy-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide

66

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 solidΗ NMR (300 MHz, DMSO-^₆) δ 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 (t, J = 7.8 Hz, IH), 7.41 (d, J = 8.7 Hz, IH), 7.58-7.65 (m, 2H), 7.71 (d, J= 8.4 Hz, IH), 7.77 (d, J = 7.5 Hz, IH), 9.20 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 455.25 (M+H)⁺. 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; ¹H NMR (300 MHz, DMSOcZ₆) δ 1.61-1.94 (m, 5H), 2.12-2.19 (m, IH), 3.10-3.20 (m, 2H), 3.93-3.99 (m, 2H), 4.70-4.78 (m, IH), 5.52-5.58 (m, IH), 6.92 (t, J = 7.8 Hz, I H), 7.30 (d, J = 7.8 Hz, I H), 7.35-7.45 (m, 2H), 7.58-7.71 (m, 2H), 9.16 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 457.35 (M-H)^".

Example 61

(±)-8-Chloro-4-hydroxy-N-(4-difluoromethoxyphenyl)-3,4-dihydro-l'H-spiro[chromene- 2,4'-piperidine]- 1 '-carboxamide

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

67 white solid; ¹H NMR (300 MHz, DMS0-<4) δ 1.65-1.77 (m, 2H), 1.90-2.06 (m, 2H), 2.95 (s, 2H), 3.13-3.23 (m, 2H), 3.95-4.03 (m, 2H), 7.00-7.08 (m, 3H), 7.10 (t, J = 74.1 Hz, IH), 7.46 (d, J= 9.3 Hz, 2H), 7.71 (d, J = 7.8 Hz, IH), 7.78 (d, J = 6.9 Hz, IH), 8.66 (br s, I H, exchangeable with D₂O); APCI-MS (m/z) 437.25 (M+H)⁺. 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; ¹H NMR (300 MHz, DMSO-cfe) δ 1.67-1.91 (m, 3H), 2.10-2.15 (m, 2H), 3.05-3.22 (m, IH), 3.90-3.96 (m, 2H), 4.70-4.78 (m, IH), 5.50-5.56 (m, IH), 6.85-6.95 (m, 2H), 7.03-7.1 1 (m, 2H), 7.30 (d, J= 7.8 Hz, IH), 7.38 (d, J= 7.8 Hz, IH), 7.47 (d, J = 8.7 Hz, 2H), 8.62 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 439.10 (M)⁺.

Example 62

(±)-8-Bromo-N-[4-(difluoromethoxy)phenyl]-4-hydroxy-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide

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; ¹H NMR (300 MHz, DMSO-^₆) δ 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, 3H), 7.10 (X, J = 74.1 Hz, IH), 7.47 (d, J= 9.3 Hz, 2H), 7.74 (d, J= 7.8 Hz, IH), 7.91 (d, J= 7.8 Hz, IH), 8.66 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 481.00 (M+H)⁺. 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; ¹H NMR (300

68 MHz, DMSO-c/₆) δ 1.60-1.87 (m, 5H), 2.10-2.15 (m, I H), 3.05-3.16 (m, 2H), 3.93-3.99 (m, 2H), 5.50-5.56 (m, IH), 6.84 (t, J = 7.8 Hz, IH), 7.02-7.07 (m, IH), 7.10 (t, J = 73.8 Hz, IH), 7.35-7.49 (m, 4H), 8.63 (br s, IH, exchangeable with D₂O); APCI-MS (Wz) 483.06 (M+H)⁺.

Example 63

(±)-8-Chloro-N-[4-(difluoromethoxy)-3-fluorophenyl]-4-hydroxy-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-l'-carboxamide

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; ¹H NMR (300 MHz, DMSO-^₆) δ 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), 7.05-7.10 (m, IH), 7.12 (t, J = 73.2 Hz, IH), 7.18-7.26 (m, 2H), 7.54-7.62 (m, IH), 7.72 (d, J = 7.8 Hz, IH), 7.77 (d, J = 7.8 Hz, IH), 8.85 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 455.10 (M+H)⁺. 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) was reduced with 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; ¹H NMR (300 MHz, OMSO-dβ) δ 1.59-1.92 (m, 5H), 2.10-2.18 (m, IH), 3.06-3.16 (m, IH), 3.20- 3.28 (m, IH), 3.91-3.99 (m, 2H), 4.71-4.78 (m, IH), 5.51-5.56 (m, IH), 6.89 (X, J = 7.8 Hz, I H), 7.12 (t, J= 73.8 Hz, IH), 7.18-7.29 (m, IH), 7.38 (d, J = 8.1 Hz, IH), 7.56-7.63 (m, I H), 8.82 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 457.06 (M+H)⁺.

Example 64

(±)-8-Bromo-4-hydroxy-N-[4-(difluoromethoxy)-3-fluorophenyl]-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide

69

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; ¹H NMR (300 MHz, DMSO-J₆) δ 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 (m, 2H), 7.03 (t, J = 7.8 Hz, IH), 7.12 (t, J= 73.8 Hz, IH), 7.23-7.28 (m, 2H), 7.55-7.61 (m, IH), 7.75 (d, J= 7.8 Hz, IH), 7.91 (d, J= 7.8 Hz, IH), 8.85 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 499.1 1 (M-H)^".

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) was reduced with 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; ¹H NMR (300 MHz, DMSO-^₆) δ 1.58-1.87 (m, 5H), 2.10-2.18 (m, IH), 3.08-3.18 (m, IH), 3.22-3.28 (m, IH), 3.93-3.99 (m, 2H), 4.72-4.78 (m, IH), 5.51-5.56 (m, IH), 6.82-6.90 (m, IH), 7.12 (t, J = 73.8 Hz, IH), 7.18-7.26 (m, 2H), 7.40-7.47 (m, 2H), 7.56-7.63 (m, I H), 8.82 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 501.02 (M+H)⁺.

Example 65

(±)-8-Bromo-N-[3-fluoro-4-(trifluoromethyl)phenyl]-4-hydroxy-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide

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,

70 0.243 mmol) in the presence of triethylamine (102 mg, 1.01 1 mmol) in anhydrous DMSO (3.0 mL) according to the procedure described in Example 1, gave 96 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-J₆) δ 1.68-1.78 (m, 2H), 1.94-2.00 (m, 2H), 2.95 (s, 2H), 3.12-3.26 (m, 2H), 3.98-4.06 (m, 2H), 7.03 (t, J= 7.8 Hz, IH), 7.40 (d, J = 9.0 Hz, IH), 7.58-7.66 (m, 2H), 7.73 (d, J = 7.8 Hz, IH), 7.91 (d, J = 7.8 Hz, IH), 9.20 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 501.02 (M+H)⁺. Step 2 (±)-8-Bromo-iV- [3 -fluoro-4-(trifluoromethyl)phenyl] -4-hydroxy-3 ,4-dihydro- 1¹H- 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; ¹H NMR (300 MHz, DMSO-^₆) δ 1.63-1.94 (m, 5H), 2.10-2.18 (m, IH), 3.10-3.20 (m, 2H), 3.97-4.02 (m, 2H), 4.73-4.78 (m, 2H), 5.54-5.58 (m, IH), 6.87 (t, J = 7.8 Hz, IH), 7.40-7.47 (m, 3H), 7.58-7.73 (m, 2H), 9.17 (br s, IH, exchangeable with D₂O); APCI-MS (m/z) 503.20 (M+H)⁺.

Pharmacological activity

The illustrative examples of the present invention are screened for TRPM8 antagonist activity according to a modified procedure described in Tόth, 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.

Screening for TRPM8 antagonist using ⁴⁵Calcium uptake assay:

In this assay, inhibition of TRPM8 receptor activation was followed as inhibition of agonist induced cellular uptake of radioactive calcium using hTRPM8/CHO cells. Test compounds were dissolved in dimethylsulfoxide (DMSO) to prepare 10 mM stock and then diluted using plain medium containing 0.1% bovine serum albumin (BSA) and 1.8 mM CaCl₂ to obtain the desired concentration. Final concentration of DMSO in the reaction was 0.5% (v/v). Human TRPM8 expressing CHO cells were grown in F- 12 Dulbecco's Modified Eagle Medium (DMEM) with 10% fetal bovine serum (FBS), 1% penicillin-streptomycin solution and 400 μg/ml of G-418. Cells were seeded 24 h prior to the assay in 96 well plates so as to get -50,000 cells per well on the day of experiment. Cells were treated with test compounds for 10 minutes followed by addition of icilin or

71 menthol at a pre-defined concentration and 5 μCi/ml of ⁴⁵Ca⁺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. IC₅₀ values were calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software.

The IC_5O (nM) values of the compounds are set forth in Table 1 wherein "A" refers to an IC₅₀ value of less than 20 nM, "B" refers to IC₅₀ value in range of 20.01 - 100 nM, "C" refers to an IC₅₀ value in range of 100.01 - 500 nM and "D" refers to an IC₅₀ value of more than 500 nM. Table 1 : In-vitro screening results of compounds of invention

72

73

74

Claims

CLAIMS:

1. A compound of the formula (I):

(I) wherein,

R³ is a hydrogen, -(CH₂) -L-NR⁵R⁶ or -(CH₂)_r-CN;

R⁴ 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 -(CH₂)_r-SO₂R¹²;

X is -(CR⁷R⁸)_p-CH₂-, -(CR⁷)=CH-, -(CR⁹R^l0)_p-O- or -(CR⁹R¹⁰)-NR⁵-;

L is a bond or -C(O)-; at each occurrence, R⁵ and R⁶ are independently selected from hydrogen and lower alkyl; at each occurrence, R⁷ and R⁸ are each independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkoxy, haloalkyl, aryl, arylalkyl, arylalkyloxy, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, - (CH₂)_q-OR⁵, -(CH₂X-NR⁵R^{1 1}, -(CH₂)_r-CO-NR⁵R^π, -(CH₂)_r-CO-NR⁵-SO₂R¹², -(CH₂)_r- COOR⁶, -(CH₂VSO₂R¹², and -(CH₂X-SO₂-NR⁵R¹²; alternatively, R and R can combine together with the carbon atom to which they are attached to form a >C=0 group, >C=N0R⁵ or cycloalkyl ring; at each occurrence, R and R¹⁰ are independently selected from hydrogen, halogen, cyano, and lower alkyl;

75 alternatively, R⁹ and R¹⁰ at each occurrence can combine with the carbon atom to which they are attached to form a >C=O group or cycloalkyl ring; with another proviso that when X is -(CR⁷)=CH-, R⁷ is not hydroxyl; at each occurrence, R^{1 1} is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, -CO-R¹², -SO₂-R¹², and -CO-NR⁵R¹²; at each occurrence, R¹² is independently selected from substituted or unsubstituted alkyl, haloalkyl, and aryl;

'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; and

2. The compound of claim 1 having the formula (II):

(H) wherein, dotted line [ — ] in the ring represents an optional bond;

76 at each occurrence, R⁵ and R⁶ are independently selected from hydrogen, and lower alkyl; at each occurrence, R⁷ and R⁸ are each independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkoxy, haloalkyl, aryl, arylalkyl, arylalkyloxy, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; alternatively, R and R can combine together with the carbon atom to which they are attached to form a >C=O group, >C=NOR⁵ or cycloalkyl ring; at each occurrence, R⁹ is independently selected from hydrogen, halogen, cyano, and lower alkyl; at each occurrence, R^{1 1} is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, -CO-R¹², -SO₂-R¹², and -CO-NR⁵R¹²; at each occurrence, R¹² is independently selected from substituted or unsubstituted alkyl, haloalkyl or aryl;

'n' is an integer selected from O to 2, both inclusive;

'q' is an integer selected from 1 to 3; both inclusive; and

V is an integer selected from O to 3; both inclusive; or pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein R¹ is hydrogen or halogen.

4. The compound of claim 1 or 2, wherein R¹ substituted or unsubstituted aryl, heteroaryl,

5. The compound of claim 1 or 2, wherein R² is halogen and 'n' is 0 or 1.

6. The compound of claim 1, wherein X is -(CR⁷R⁸)_P-CH₂-.

7. The compound of claim 6, wherein both of R⁷ and R⁸ are hydrogen.

8. The compound of claim 6, wherein one of R⁷ and R⁸ is hydrogen and the other is halogen and 'p' is 1.

9. The compound of claim 6, wherein one of R and R is hydrogen and the other is hydroxyl and 'p' is 1.

10. The compound of claim 6, wherein one of R⁷ and R⁸ is hydrogen and the other is NH₂ or NHC(O)CH₃ and 'p' is 1.

77

1 1. The compound of claim 6, wherein R⁷ and R⁸ are combined together with the carbon atom to which they are attached to form >C=O, >C=N-OH, or >C=N- OCH₃.

12. The compound of claim 1, wherein R³ is hydrogen.

13. The compound of claim 1, wherein R⁴ is substituted or unsubstituted aryl, heteroaryl, or heterocyclyl.

14. The compound of claim 13, wherein aryl substituted phenyl.

15. The compound of claim 13, wherein heteroaryl is selected from substituted or unsubstituted thiazole, thiadiazole, pyridine, benzthiazole or benzoxazole.

16. The compound of claim 13, 14 or 15, wherein substitutents may be one or 2 are independently selected from cyano, halogen, alkyl, haloalkyl, haloalkoxy, and S(O)₂CF₃.

17. The compound of claim 1 selected from:

8-Chloro-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]- 1 '-carboxamide;

8-Chloro-N-(4-cyanophenyl)-3,4-dihydro-rH-spiro[chromene-2,4'-piperidine]-r- carboxamide;

8-Chloro-N-(4-tert-butylphenyl)-3,4-dihydro-rH-spiro[chromene-2,4'-piperidine]- 1 '-carboxamide;

8-Chloro-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide;

8-Bromo-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide;

8-(6-Fluoropyridin-3-yl)-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-l '-carboxamide;

8-Bromo-N-[4-(trifiuoromethoxy)phenyl] -3 ,4-dihydro- 1 ' H-spiro [chromene-2 ,4 ' - piperidine]-l '-carboxamide;

8-(4-Cyanophenyl)-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH-spiro[chromene- 2,4'-piperidine]- 1 '-carboxamide;

8-Chloro-N-(5-cyanopyridin-2-yl)-3,4-dihydro-rH-spiro[chromene-2,4'-piperidine]- 1 ' carboxamide;

78 8-Chloro-N-[3-fluoro-4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-

2,4'-piperidine]-r-carboxamide;

S-Chloro-jV-^-fluoro-S^trifluoromethyOphenylJ-S^-dihydro-rH-spirotchromene-

2,4^"-piperidine]-l ^'-carboxamide;

8-Chloro-N-[2-chloro-4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-

2,4'-piperidine]-l '-carboxamide;

S-Chloro-N-^-chloro-S-^rifluoromethyOphenyll-S^-dihydro-rH-spirofchromene-

2,4' -piperidine] - 1 ' -carboxamide;

8-Bromo-N-[3-fluoro-4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-

2,4'-piperidine]-l '-carboxamide;

8-Chloro-6-fluoro-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-

2,4'-piperidine]-l '-carboxamide;

8-Chloro-6-fluoro-N-(4-ter/-butylphenyl)-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide;

S-Chloro-N-^-CtrifluoromethyO-l^-thiazol^-y^-S^-dihydro-rH-spirofchromene-

2,4'-piperidine]-l '-carboxamide;

8-Bromo-jV-[5-(trifluoromethyl)-l,3-thiazol-2-yl]-3,4-dihydro-rH-spiro[chromene-

2,4 ' -piperidine]- 1 ' -carboxamide;

S-Chloro-o-fluoro-N-CS-methyl-l ^-thiazol^-y^-S^-dihydro-l 'H-spirofchromene-

2,4'-piperidine]-l '-carboxamide;

N- 1 ,3 -Benzothiazol-2-yl-8-chloro-3 ,4-dihydro- 1 ' H-spiro [chromene-2,4 ' -piperidine] -

1 '-carboxamide;

A^-l ,3-Benzothiazol-2-yl-8-bromo-3,4-dihydro-l 'H-spiro[chromene-2,4'-piperidine]-

1 '-carboxamide;

8-Chloro-N-(6-trifluoromethoxy-l,3-benzothiazol-2-yl)-3,4-dihydro-l 'H-spiro

[chromene-2,4'-piperidine]- 1 '-carboxamide;

8-Chloro-N-(6-fluoro-l,3-benzothiazol-2-yl)-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide;

N-l,3-Benzoxazol-2-yl-8-chloro-3,4-dihydro-rH-spiro[chromene-2,4'-piperidine]-

1 '-carboxamide;

79 8-Chloro-4-oxo-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH-spiro[chromene-2,4'- piperidine]-l '-carboxamide;

(±)-8-Chloro-4-hydroxy-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH- spiro [chromene-2 ,4 ' -piperidine] - 1 ' -carboxamide;

(±)-8-Chloro-4-hydroxy-N-[4-(tert-butyl)phenyl]-3,4-dihydro-l'H-spiro[chromene-

2,4'-piperidine]-l '-carboxamide;

(±)-8-Bromo-4-hydroxy-N-[4-(/er/-butyl)phenyl]-3,4-dihydro-l 'H-spiro[chromene-

2,4'-piperidine]- 1 '-carboxamide;

(±)-8-Bromo-4-hydroxy-N- [4-(trifluoromethy l)pheny 1] -3 ,4-dihydro- 1 ' H-spiro

[chromene-2,4'-piperidine]-r-carboxamide;

(±)-8-Fluoro-4-hydroxy-jV-[4-(trifluoromethyl)phenyl]-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(±)-8-Chloro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-l 'H-spiro

[chromene-2,4'-piperidine]- 1 '-carboxamide;

(+)-8-Chloro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(-)-8-Chloro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(±)-8-Bromo-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-l 'H- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide;

(+)-8-Bromo-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide;

(-)-8-Bromo-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(±)-8-Fluoro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(+)-8-Fluoro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide;

(-)-8-Fluoro-4-hydroxy-N-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-l'H- spiro [chromene-2 ,4'-piperidine] - 1 '-carboxamide ;

80 (±)-8-Chloro-4-hydroxy-N-(4-2,2,2-trifluoroethoxyphenyl)-3,4-dihydro-l 'H- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide;

(±)-8-Bromo-N-[4-(2,2,2-trifluoroethoxy)phenyl]-4-hydroxy-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-r-carboxamide;

(±)-8-Chloro-4-fluoro-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(±)-8-Bromo-4-fluoro-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-r-carboxamide;

(±)-8-Chloro-N-(3,4-difluorophenyl)-4-hydroxy-3,4-dihydro-rH-spiro[chromene-

2,4'-piperidine]- 1 '-carboxamide;

8-Chloro-jV-[(4-^rt-butyl)-l,3-thiazol-2-yl]-4-hydroxy-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(±)-8-Chloro-4-hydroxy-N-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(±)-8-Chloro-4-hydroxy-yV-[5-(/er/-butyl)-l,3,4-thiadiazol-2-yl]-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide;

(±)-8-Chloro-4-hydroxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]-3,4-dihydro-

1 'H-spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(±)-8-Chloro-N-(6-fluoro-l ,3-benzothiazol-2-yl)-4-hydroxy-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-r-carboxamide;

(±)-8-Bromo-N-(6-fluoro-l ,3-benzothiazol-2-yl)-4-hydroxy-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide;

(±)-8-Chloro-4-hydroxy-N-(6-trifluoromethyl-l ,3-benzothiazol-2-yl)-3,4-dihydro- rH-spiro[chromene-2,4'-piperidine]-r-carboxamide;

(±)-8-Chloro-N-(4,6-difluoro-l,3-benzothiazol-2-yl)-4-hydroxy-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(±)-8-Chloro-N-{4-[4-(trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}-4-hydroxy-3,4- dihydro-rH-spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(±)-8-Chloro-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-4-hydroxy-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide;

81 8-Chloro-N-[4-(trifluoromethyl)phenyl]- 1 'H-spiro[chromene-2,4'-piperidine]- 1 '- carboxamide;

(±)-4-Amino-8-chloro-N-(4-trifluoromethylphenyl)-3,4-dihydro-r//-spiro[chromene- 2,4'-piperidine]- 1 '-carboxamide hydrochloride;

(±)-8-Chloro-4-(acetylamino)-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(4E)-8-Chloro-4-(hydroxyimino)-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]-l '-carboxamide;

(4E)-8-Chloro-4-(methoxyimino)-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide;

(±)-8-Chloro-N-[3-fluoro-4-(trifluoromethyl)phenyl]-4-hydroxy-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide; (±)-8-Chloro-4-hydroxy-N-(4-difluoromethoxyphenyl)-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide;

(±)-8-Bromo-N-[4-(difluoromethoxy)phenyl]-4-hydroxy-3,4-dihydro-l'H- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide;

(±)-8-Chloro-N-[4-(difluoromethoxy)-3-fluorophenyl]-4-hydroxy-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide;

(±)-8-Bromo-4-hydroxy-N-[4-(difluoromethoxy)-3-fluorophenyl]-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide; and

(±)-8-Bromo-N-[3-fluoro-4-(trifluoromethyl)phenyl]-4-hydroxy-3,4-dihydro-rH- spiro[chromene-2,4'-piperidine]- 1 '-carboxamide or pharmaceutically acceptable salts thereof.

18. Use of the compound according to any one of claim 1 to 17, in the preparation of medicament for the prevention, amelioration or treatment of a disease, disorder or syndrome mediated by melastatin receptor in a subject in need thereof.

19. Use of a compound according to claim 18 in the preparation of medicament, wherein the symptoms of a disease, disorder, syndrome or condition associated with TRPM8 function is selected from the group consisting of pain, acute pain, chronic pain, nociceptive pain, neuropathic pain, post-operative pain, dental pain, cancer pain, cardiac pain arising from an ischemic myocardium, pain due to migraine, arthralgia,

82 neuropathies, neuralgia, trigeminal neuralgia nerve injury, diabetic neuropathy,neurodegeneration, retinopathy, neurotic skin disorder, stroke, urinary bladder hypersensitiveness, urinary incontinence, vulvodynia, gastrointestinal disorders such as irritable bowel syndrome, gastro-esophageal reflux disease, enteritis, ileitis , stomach- duodenal ulcer, inflammatory bowel disease, Crohn's disease, celiac disease, an inflammatory disease such as pancreatitis, a respiratory disorder such as allergic and non- allergic rhinitis, asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, dermatitis, pruritic conditions such as uremic pruritus, fervescence, muscle spasms, emesis, dyskinesias, depression, Huntington's disease, memory deficits, restricted brain function, amyotrophic lateral sclerosis (ALS), dementia, arthritis, rheumatoid arthritis, osteoarthritis, diabetes, obesity, urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis, anxiety disorders and benign prostate hyperplasia.

20. Use of compound according to any one of claim 1 to 17, in the preparation of medicament for the treatment of pain in a subject in need thereof comprising administering to the subject with a therapeutically effective amount.

83