WO2009118596A2 - Phthalimide derivatives as trpa1 modulators - Google Patents

Phthalimide derivatives as trpa1 modulators Download PDF

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Publication number
WO2009118596A2
WO2009118596A2 PCT/IB2009/000523 IB2009000523W WO2009118596A2 WO 2009118596 A2 WO2009118596 A2 WO 2009118596A2 IB 2009000523 W IB2009000523 W IB 2009000523W WO 2009118596 A2 WO2009118596 A2 WO 2009118596A2
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Prior art keywords
substituted
unsubstituted
methyl
dioxo
dihydro
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PCT/IB2009/000523
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French (fr)
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WO2009118596A3 (en
Inventor
Meyyappan Muthuppalniappan
Sukeerthi Kumar
Abraham Thomas
Neelima Khairatkar-Joshi
Indranil Mukhopadhyay
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Glenmark Pharmaceuticals, S. A.
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Publication of WO2009118596A2 publication Critical patent/WO2009118596A2/en
Publication of WO2009118596A3 publication Critical patent/WO2009118596A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • TRP Transient Receptor Potential
  • TRPC canonical
  • TRPV vanilloid
  • TRPM melastatin
  • TRPP polycystin
  • TRPML mucolipin
  • TRPA ankyrin, ANKTMl
  • TRPN TRPN
  • TRPV5 and TRPV6 are more closely related to each other than to TRPVl, TRPV2, TRPV3, or TRPV4.
  • TRPAl is most closely related to TRPV3, and is more closely related to TRPVl and TRPV2 than to TRPV5 and TRPV6.
  • the TRPM family has 8 members.
  • Constituents include the following: the founding member TRPMl (melastatin or LTRPCl), TRPM3 (KIAA1616 or LTRPC3), TRPM7 (TRP-PLIK, ChaK(l), LTRPC7), TRPM6 (ChaK2), TRPM2 (TRPC7 or LTRPC2), TRPM8 (TRP-p8 or CMRl), TRPM5 (MTRl or LTRPC5), and TRPM4 (FLJ20041 or LTRPC4).
  • TRPMl melastatin or LTRPCl
  • TRPM3 KAA1616 or LTRPC3
  • TRPM7 TRP-PLIK, ChaK(l), LTRPC7
  • TRPM6 ChoK2
  • TRPM2 TRPC7 or LTRPC2
  • TRPM8 TRP-p8 or CMRl
  • TRPM5 MTRl or LTRPC5
  • TRPM4 FLJ20041 or LTRPC4
  • TRPP family consists of two groups of channels: those predicted to have six transmembrane domains and those that have eleven.
  • TRPP2 PPD2
  • TRPP3 PPD2L1
  • TRPP5 PPD2L2
  • TRPPl PPDl, PCl
  • PKD-REJ PKD-REJ
  • PKD-ILl The sole mammalian member of the TRPA family is ANKTMl.
  • TRPAl is expressed in nociceptive neurons.
  • the nociceptive neurons of the nervous system sense the peripheral damage and transmit a pain signal.
  • TRPAl is activated by a variety of noxious stimuli, including cold temperatures
  • TRPAl is membrane bound and most likely acts as a heterodimeric voltage gated channel. It is believed to have a particular secondary structure: its N-terminus is lined with a large number of ankyrin repeats which are believed to form a spring-like edifice. Most receptors have intricate pockets which are specific to certain kind of ligand, and the slightest alteration of either the pocket or the ligand has drastic effects.
  • TRPAl responds to a variety of stimuli it works through different system. It forms covalently linked adducts with electrophilic compounds. The difference with other TRP receptors is that TRPAl ligand binding persists for hours. The physiological response (e.g., pain) is greatly prolonged. Hence to dissociate the electrophile an effective antagonist is required.
  • WO 2008/0949099, WO 2007/073505, WO 2004/055054, and WO 2005/089206 describe the TRP channels as the targets for the treatment of pain and related conditions.
  • R 2 is independently hydrogen, cyano, nitro, -NR x R y , halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heterocyclylalkyl, -C(O)OR", -OR X , -C(0)NR x R y , - C(0)R x , -S
  • R 1 is independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, (CR x R y ) n OR 3 , COR X , C00R x , CONR x R y , S(O) m NR x R y , NR x R y , NR x (CR x R y ) n OR 3 , NR x (CR x R y ) n CN (CH 2 ) n NR x R y , (CH 2 ) n CHR x R y , (CR ⁇ NR ⁇ , NR x (CR x R y ) n CONR x R y , (CH 2 )
  • R 3 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heterocyclylalkyl
  • R a and R b are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted
  • R c is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, (CR x R y ) n OR 3 ,
  • ring A is phenyl
  • R 2 is alkyl preferably isopropyl
  • R 1 is methyl
  • ring A is substituted or unsubstituted phenyl, where in substituent is selected from halogen and/or halomethyl, preferably at each occurrence halogen is independently selected from chlorine, fluorine or bromine, and halomethyl is independently selected from trifluoromethyl and R 1 is methyl.
  • ring A is substituted or unsubstituted phenyl, wherein substituent is selected from phenyl or halophenyl, preferably bromophenyl and R 1 is methyl.
  • ring A is phenyl
  • R 2 is substituted or unsubstituted phenoxy where in substituent is selected from alkyl preferably methyl and R 1 is methyl.
  • ring A is 6-membered heteroaryl.
  • ring A is pyridine
  • R 2 is substituted or unsubstituted phenyl where in substituent is selected from halogen and R 1 is methyl.
  • ring A is thiazole
  • R 2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen and R 1 is alkyl preferably methyl ethyl or propyl.
  • ring A is 5-membered heteroaryl.
  • R 2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen preferably bromine and R 1 is COOR wherein R is ethyl.
  • ring A is 5-membered heteroaryl.
  • R 2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen and alkyl, preferably at each occurrence halogen is independently selected from chlorine and alkyl is independently selected from methyl and R 1 is methyl .
  • ring A is 5-membered heteroaryl.
  • R 2 is substituted or unsubstituted phenyl, where in substituent is selected from alkyl preferably (Ci-C 4 )alkyl, haloalkyl preferably trifiuoromethyl or nitrile and R 1 is methyl.
  • ring A is 5-membered heteroaryl.
  • ring A is thiazole and R 2 is optionally substituted alkyl or cycloalkyl.
  • ring A is 5-membered heteroaryl.
  • R 2 is selected from alkyl and substituted or unsubstituted phenyl, preferably at each occurance alkyl is selected from methyl and substituted phenyl is selected from chlorophenyl and R 1 is methyl.
  • ring A is 5-membered heteroaryl.
  • R 2 is substituted or unsubstituted phenyl and the substituent is selected from halogen and/or methyl or trifiuoromethyl and R 1 is hydrogen or methyl.
  • ring A is 5-membered heteroaryl.
  • R 2 is substituted or unsubstituted phenyl and the substituent is selected from halogen and/or difluoromethoxy, trifluoromethoxy or trifluoroethoxy and R 1 is hydrogen or methyl.
  • ring A is fused heteroaryl.
  • ring A is substituted or unsubstituted 4,5-dihydronaphtho[l,2,-d][l,3]thiazol wherein substituent is selected from halogen preferably chlorine and R 1 is methyl.
  • ring A is 5-membered heteroaryl.
  • R 2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen preferably bromine and R 1 is methyl.
  • ring A is 5-membered heteroaryl.
  • R 2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen preferably chlorine or bromine, R a and R b is independently selected from hydrogen or alkyl preferably methyl.
  • ring A is 5-membered heteroaryl.
  • ring A is optionally oxidized pyrazole more preferably pyrazolone
  • R 2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen preferably chlorine or bromine and R 1 is methyl.
  • ring A is 5-membered heteroaryl.
  • R 2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen preferably chlorine or bromine, R c and R 1 is independently selected from hydrogen or alkyl preferably methyl.
  • N 1 -(4-isopropylphenyl)-2-(2-methyl- 1 ,3-dioxo-2,3 -dihydro- 1 H-4-isoindolyl) acetamide (Example 1); Nl-(4-Bromophenyl)-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-4-isoindolyl) acetamide (Example 2);
  • Nl-(4-Chlorophenyl)-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-4-isoindolyl) acetamide (Example 3); N 1 -(4-Chloro-2-fluorophenyl)-2-(2-methyl- 1 ,3 -dioxo-2,3 -dihydro- 1 H-4- isoindolyl)acetamide (Example 4);
  • N 1 -[4-(2,4-Dichlorophenyl)- 1 ,3-thiazol-2-yl]-2-(2-methyl- 1 ,3-dioxo-2,3-dihydro- lH-4-isoindolyl)acetamide (Example 31); Nl-[4-(3,4-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro- lH-4-isoindolyl)acetamide (Example 32);
  • 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 TRPAl receptors, which modulation is believed to be related to a variety of disease states.
  • the present patent application further provides a method of inhibiting TRPAl 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.
  • phthalimide derivatives which may be used as TRPAl modulators, and processes for the synthesis of these compounds.
  • Pharmaceutically acceptable salts, enantiomers, diastereomers, of these compounds that may have the same type of activity are also provided.
  • Pharmaceutical compositions containing the described compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by TRPAl are further provided.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, 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, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1- dimethylethyl (t-butyl).
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, and 2-butenyl.
  • alkynyl refers to a straight or branched chain 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), e.g., ethynyl, propynyl, and butynyl.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH 3 and -OC 2 H 5 .
  • halogen or halo includes fluorine, chlorine, bromine, or iodine.
  • haloalkyl is used to denote a group comprised of an alkyl group substituted with halogen atom, where alkyl group is as defined above and halogen is used to denote fluorine, chlorine, bromine or iodine, an example of such group is trifluoromethyl, difluoromethyl.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, tetrahydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
  • 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.
  • 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.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H 5 C 6 H 5 .
  • heterocyclyl and “heterocyclic ring” refer to a stable 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 monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidin
  • 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.
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • 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.
  • 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.
  • the substituents in the aforementioned "substituted” groups cannot be further substituted.
  • the substituent on “substituted alkyl” is "substituted aryl”
  • the substituent on “substituted aryl” cannot be “substituted alkenyl”.
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • 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.
  • Certain compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the Formula (I), the present patent application extends to these stereoisomeric forms and to mixtures thereof.
  • the pharmaceutical composition provided in the present patent application includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to inhibit TRPAl receptor in a subject.
  • the inhibitory activity of compounds falling within the formula (I) may be measured by an assay provided herein below.
  • the subjects contemplated include, for example, a living cell and a mammal, including human mammal.
  • the compound of 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.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing oxmetic 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 conventional techniques known in the art (Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003, Lippincott Williams & Wilkins).
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier 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), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, 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.
  • the sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to this harmful stimulus are termed as "nociceptors". Nociceptors are primary sensory afferent (C and A ⁇ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH ⁇ 6) modalities.
  • Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain. Chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. The pain is typically well localized, constant, and often with an aching or throbbing quality. Visceral pain is the subtype of nociceptive pain that involves the internal organs. It tends to be episodic and poorly localized.
  • Nociceptive pain is usually time limited, meaning when the tissue damage heals, the pain typically resolves (arthritis is a notable exception in that it is not time limited).
  • the present patent application provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders modulated by TRPAl antagonists.
  • TRPAl activity and are believed to be of potential use for the treatment or prophylaxis of certain diseases or disorders mediated or associated with the activity of TRPAl receptor, including disorders such as 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, urinary incontinence, cystitis, burns, psoriasis, eczem
  • disorders such as pain, chronic pain,
  • Scheme 1 depicts a method for preparing isoindolylacetic acid of the formula (6) from commercially available 3-nitrophthalimide of formula (1).
  • the compound of formula (3) wherein X is halogen and R 1 is alkyl was prepared from 3-nitrophthalimide (1) by a sequence of transformations comprising of reduction of nitro group to the amino group (A. J. Hannaford et al, Vogel 's Textbook of Practical organic Chemistry (2006) 5 th Ed. 890-897), diazotization followed by halide substitution of the resulting diazo compound (A. J. Hannaford et al, Vogel 's Textbook of Practical organic Chemistry (2006) 5 th Ed., 920-946) and N-alkylation.
  • Scheme 2 describes an alternative approach for the synthesis of compounds of the formula (3) by a sequence of transformations known in the art of organic synthesis.
  • N-alkylation of 3-nitrophthalimide of formula (1) followed by catalytic reduction affords an amine of formula (7) (Hannaford, A. J.; et al, Vogel's Textbook of Practical organic Chemistry, (2006), 5 th Ed., 890-897).
  • Diazotization of compound of formula (7) followed by halide substitution of the resulting diazo compound yields compound of formula (3) (Hannaford, A. J.; et al, Vogel's Textbook of Practical organic Chemistry, (2006), 5 th Ed..936-937).
  • compounds of formula (6) can be accomplished using the synthetic sequence depicted in the Scheme 3.
  • the compound of the formula (7) can be reacted with an allyl bromide, in the presence of an appropriate alkyl nitrite such as tert-butyl nitrite, in an organic solvent such as acetonitrile or tetrahydrofuran to give compounds of formula (5).
  • This conversion is similar to the one described by Fredrik et. al, in J. Org. Chem. (2003), 68, 1911-1918.
  • Conversion of compounds of formula (5) to compounds of formula (6) can be accomplished by oxidative cleavage methods as described in Scheme 1.
  • Scheme 4 depicts a potential synthetic route to compounds of the formula (6a).
  • Compounds of formula (6) can be reacted with an alkylating agent such as an alkyl halide in the presence of a base, to form esters of type (8), which on hydrolysis to give compound of the formula (6a).
  • Scheme 5 depicts a method for preparing the compounds described by general formula (Ia).
  • compound of formula (6) is reacted with oxalyl chloride to afford an acid chloride of the formula (9) which on coupling with an appropriate amine of formula (10) yields compound of formula (Ia)
  • compound of formula (9) can be coupled with amine of formula (10) in the presence of a suitable base such as N,N-diisopropylamine and 4- Dimethylaminopyridine (DMAP) in a suitable solvent to give compound of formula (Ia) as depicted in Scheme 6.
  • a suitable base such as N,N-diisopropylamine and 4- Dimethylaminopyridine (DMAP) in a suitable solvent
  • Scheme-7 describes alternative method for synthesis of compounds of the formula (Ia) by direct coupling of carboxylic acid derivative (6) with amine of the formula (10) using a suitable coupling agent.
  • coupling of compound of formula (6) with amine of formula (10) in the presence of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole monohydrate (HOBt) or l-hydroxy-7- azabenzotriazole (HOAt) afford compounds of the formula (Ia).
  • Scheme 10 depicts the synthesis of 2-amino-4-aryl thiazoles.
  • the compounds of the formula (11) react with oxalyl chloride in the presence of DMF to give acid chloride of the formula (12), which can be reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of triethyl amine to afford the compounds of formula (13).
  • Addition of a Grignard reagent such as methylmagnesium iodide affords compounds of formula (14).
  • the thiazole amine of the formula (16) can be prepared in one step by the the reaction of ketone (14) with thiourea in the presence of iodine in refluxing ethanol.
  • the compounds of formula (16) can be also prepared alternatively by the reaction of compounds of formula (14) with bromine in acetic acid and subsequently treated with thiourea in THF at reflux condition to give compounds of the formula (16).
  • Scheme 11 describes a method for the preparation of compounds of the formula (19).
  • the compounds of the formula (17) is reacted with acrylonitrile in the presence of sodium ethoxide in ethanol to give compounds of the formula (18), which can be converted into compounds of the formula (19) by the reaction with N-bromosuccinimide. This conversion is similar to that described by Duffin; Kendall et. al, J. Chem. Soc. (1954), 408-415.
  • Scheme 12 depicts the preparation of the compounds of the formula (21).
  • the compounds of the formula (20) reacted with ethyl cyanoacetate in the presence of sodium ethoxide in ethanol to give compounds of the formula (21). This conversion is similar to that described by Weissberger, A.; Porter, H., D., J. Am. Chem. Soc. (1942), 2133-2136.
  • DMSO-J 6 Hexadeuterodimethyl sulfoxide
  • DMF N,N-dimethylformamide
  • M.P. Melting point
  • J Coupling constant in units of Hz
  • RT or rt room temperature (22-26°C).
  • Aq. aqueous AcOEt: ethyl acetate; equiv. or eq.: equivalents
  • TLC thin layer chromatography.
  • Step 1 4-Amino-l,3-isoindolinedione
  • a ⁇ 3.6M aqueous solution of sodium nitrite was added at 0°C to a -2.0M solution of the product obtained from step 1 in concentrated hydrochloric acid. After stirring the mixture at the same temperature for 10 min., a ⁇ 3.39M aqueous solution of potassium iodide was added to it, allowed to warm up to RT and then heated at 80 0 C for 2h. After cooling to
  • Step 3 4-Iodo-2-methyl-l ,3-isoindolinedione
  • Step 4 4-Allyl-2-methyl-l ,3-isoindolinedione
  • Step 5 (2-methyl-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl)acetic acid
  • Step 1 4-Nitro-2-ethyl-l ,3-isoindolinedione
  • Step 2 4-Amino-2-ethyl- 1 ,3-isoindolinedione
  • the title compound was prepared according to the procedure described for Intermediate 1 step 1 by using compound obtained from above step 1 in ethylacetate in the presence of 10% palladium on charcoal gave the crude product (91%) which was used without purification in the next step.
  • Step 3 4-Allyl-2-ethyl-l ,3-isoindolinedione
  • Step 4 (2-methyl-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl)acetic acid
  • Step 1 Methyl 2-(2-methyl-l ,3-dioxo-2,3-dihydro-lH-4-isoindolyl)propanoate
  • Step 2 2-(2-Methyl-l,3-dioxo-2,3-dihydro-lH-4-isoindolyl) propanoic acid
  • the reaction mixture was refluxed overnight.
  • the mixture was concentrated to ca. half its initial volume and extracted into ethyl acetate, the organic layers were washed with water, dried over Na 2 SO 4 and the solvent evaporated to give the title compound in 97% yield.
  • Step-1 Oxalyl chloride (1.2 equiv) was added at 0 C to a solution of benzoic acid (1.0 equiv) in dichloromethane followed by the addition catalytic amount of DMF and stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane and added slowly to a solution of N,O- dimethylhydroxylamine hydrochloride (1.2 equiv) and Et 3 N (2.4 equiv) in dichloromethane at 0 C and the mixture was stirred at RT for 2 h. The reaction mixture was distributed between water and dichloromethane and the organic extracts were washed with brine and dried over Na 2 SO 4 . The evaporation and purification by column chromatography to give amide.
  • Step-2 Grignard reagent was generated from iodomethane (5.0 equiv) and magnesium turnings (5.0 equiv) in dry diethyl ether and was treated drop-wise to a solution of the product obtained from above step 1 (1.0 equiv) in dry diethyl ether and the reaction mixture was stirred at room temperature for 2 h. An aqueous saturated NH 4 Cl solution was added and extracted with ethyl acetate. The organic layers were washed with brine, Na 2 SO 4 and the solvent evaporated. The purification of the crude product by chromatography gave acetophenones.
  • General Procedure for the preparation of thiazole amine :
  • Method A A solution of acetophenone (1.0 equiv), thiourea (2.0 equiv) and iodine (1.0 equiv) in dry ethanol (1.5M) were refluxed for 24h.
  • the reaction mixture was diluted with ethylacetate, washed with saturated solution of sodium thiosulphate and organic layer was treated with IN HCl, precipitated salt collected by filtration.
  • the salt was then treated with saturated solution of NaHCO 3 and extracted with dichloromethane, washed with brine and dried over sodium sulphate and the solvent was evaporated to afford the aminothiazole derivative.
  • Method B To a solution of acetophenone (1.0 equiv) in glacial acetic acid (1.0 M), liquid bromine (1.0 equiv) was added at 0°C and reaction was stirred at room temperature for 2h. The reaction mixture was diluted with water and extracted with ethyl acetate, washed with brine and dried over Na 2 SO 4 . The crude product obtained upon concentration was dissolved in dry THF (0.4M) and thiourea (2.0 equiv) was added and refluxed for overnight. The reaction mixture was diluted with ethylacetate, washed with saturated solution of sodium thiosulphate and organic layer was treated with IN HCl, precipitated salt collected by filtration.
  • 4,5-Dihydonaptho[l,2-d]thiazole-2-ylamine were prepared from appropriate tetralones according to the procedure described by Norman, L.; Edward, S. J., J. Org. Chem. (1962), 27, 70-76.
  • Method A A 0.15-0.3M solution of the carboxylic acid Intermediate in dichloromethane was treated with oxalyl chloride (0.7 equiv.) and catalytic quantity of DMF. After stirring the mixture at RT for 30 min., the solvent was evaporated and the residue dissolved in the same volume as dichloromethane of 1,4-dioxane. The corresponding amine (2 equiv.) was added stirred at RT until TLC indicated complete consumption of the acid chloride. Aq. IN HCl was added. Wherever precipitates were formed, they were collected by filtration and when filtration was not possible, work-up using AcOEt was employed. Purification of the precipitate or the residue after work-up gave the crude products.
  • Method B Similar to method A, but 1.0 equiv. of the amine coupling partner and 1.3 equiv. of N,N-dimethylaniline were employed in the coupling stage. In some cases DMAP (0.1 equiv.) was also used.
  • Method C A mixture of the carboxylic acid Intermediate (1 equiv.), the corresponding amine (1 equiv.), l-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.2 equiv.), 1-Hydroxybenzotriazole or l-Hydroxy-7-azabenzotriazole (0.3 equiv.) and DMAP (0.1 equiv.) in 1 ,2-dichloroethane (volume required to make the concn. of carboxylic acid ca. 0.1 M) was stirred at RT overnight.
  • EDCI l-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
  • 1-Hydroxybenzotriazole or l-Hydroxy-7-azabenzotriazole 0.3 equiv.
  • DMAP 0.1 equiv.
  • the crude products were purified either by column chromatographic techniques using ethylacetate-chloroform mixture of a suitable polarity as the mobile phase or by repeated crystallizations from methanol or isopropanol.
  • TRPAl receptor activation was followed as inhibition of allyl isothiocyanate (AITC) induced cellular uptake of radioactive calcium.
  • AITC allyl isothiocyanate
  • Test compounds were dissolved in 100% DMSO to prepare 20 mM stock and then diluted using plain medium with 0.1% BSA and 1.8 mM CaCl 2 to get desired concentration. Final concentration of DMSO in the reaction was 0.5% (v/v).
  • TRPAl expressing CHO cells were grown in F- 12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, 400 ⁇ g / 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 AITC at a final concentration of 30 ⁇ M and 5 ⁇ Ci/ml 45 Ca +2 for 3 minutes. Cells were washed and lysed using buffer containing 1% Triton X-100, 0.1 % deoxycholate and 0.1% SDS.
  • Radioactivity in the lysate was measured in Packardt Top count after addition of liquid scintillant. (Toth A, et al, Life Sciences, (2003) 73, 487-498; McNamara CR et al, Proceedings of the National Academy of Sciences, (2007), 104, 13525-13530)
  • Concentration response curves were plotted as a % of maximal response obtained in the absence of test antagonist.
  • IC 50 values ' can be calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software. The title compounds of the examples were tested in the biological test described above and the results were expressed as percent inhibition at various concentrations.
  • IC 50 (nM) values of the compounds are set forth in Table 3 wherein "A” refers to an IC 50 value of less than 250.00 nM, “B” refers to IC 50 value in range of 250.01 to 500.00 nM, “C” refers to an IC 50 value in range of 500.01 to 1000.00 nM and “D” refers to an IC 50 value of greater than 1000.01 nM.

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Abstract

The present invention provides TRPA (Transient Receptor Potential subfamily A) modulators. In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPAl (Transient Receptor Potential subfamily A, member 1) modulators. 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 TRPAl.

Description

PHTHALIMIDE DERIVATIVES AS TRPAl MODULATORS
Related applications
This application claims the benefit of Indian Patent Application No. 645/MUM/2008 filed on March 26, 2008; 1669/MUM/2008 August 5, 2008 and U.S. Provisional Application Nos 61/043,966 filed on April 10, 2008 and 61/092,310 filed on August 27, 2008 all of which are hereby incorporated by reference.
Background
The Transient Receptor Potential (TRP) channels or receptors are pain receptors. They have been classified into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin, ANKTMl) and TRPN (NOMPC) families. The TRPC family can be divided into 4 subfamilies (i) TRPCl (ii) TRPC2 (iii) TRPC3, TRPC6, TRPC7 and (iv) TRPC4, TRPC5 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, TRPV2, TRPV3, or TRPV4. TRPAl is most closely related to TRPV3, and is more closely related to TRPVl and TRPV2 than to TRPV5 and TRPV6. The TRPM family has 8 members. Constituents include the following: the founding member TRPMl (melastatin or LTRPCl), TRPM3 (KIAA1616 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 eleven. 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 eleven transmembrane domains. The sole mammalian member of the TRPA family is ANKTMl.
It is believed TRPAl is expressed in nociceptive neurons. The nociceptive neurons of the nervous system sense the peripheral damage and transmit a pain signal. TRPAl is activated by a variety of noxious stimuli, including cold temperatures
(activated at 17°C), pungent natural compounds (e.g., mustard, cinnamon and garlic), and environmental irritants (MacPherson LJ et al, Nature, (2007), 445; 541-545). Noxious compounds activate TRPAl ion channels through covalent modification of cysteines. TRPAl is membrane bound and most likely acts as a heterodimeric voltage gated channel. It is believed to have a particular secondary structure: its N-terminus is lined with a large number of ankyrin repeats which are believed to form a spring-like edifice. Most receptors have intricate pockets which are specific to certain kind of ligand, and the slightest alteration of either the pocket or the ligand has drastic effects. Since TRPAl responds to a variety of stimuli it works through different system. It forms covalently linked adducts with electrophilic compounds. The difference with other TRP receptors is that TRPAl ligand binding persists for hours. The physiological response (e.g., pain) is greatly prolonged. Hence to dissociate the electrophile an effective antagonist is required.
WO 2008/0949099, WO 2007/073505, WO 2004/055054, and WO 2005/089206 describe the TRP channels as the targets for the treatment of pain and related conditions.
In efforts to discover better analgesics for the treatment of both acute and chronic pain and to develop treatments for various neuropathic and nociceptive pain states, there exists a need for a more effective and safe therapeutic treatment of diseases, conditions and/or disorders modulated by TRPAl .
Summary 0 The present patent application relates to compounds of the formula (I):
Figure imgf000004_0001
(I) or tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein, ring A is aryl, heteroaryl, heterocyclyl or cycloalkyl;
R2 is independently hydrogen, cyano, nitro, -NRxRy, halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heterocyclylalkyl, -C(O)OR", -ORX, -C(0)NRxRy, - C(0)Rx, -S(O)m-Rx, -S(O)m-NRxRy; Rx and Ry are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heterocyclylalkyl;
R1 is independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, (CRxRy)nOR3, CORX, C00Rx, CONRxRy, S(O)mNRxRy, NRxRy, NRx(CRxRy)nOR3, NRx(CRxRy)nCN (CH2)nNRxRy, (CH2)nCHRxRy, (CR^NR^, NRx(CRxRy)nCONRxRy, (CH2)nNHC0Rx and (CH2)nNH(CH2)nSO2Rx, (CH2)nNHSO2Rx;
R3 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heterocyclylalkyl Ra and Rb are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heterocyclylalkyl; or Ra and Rb may be joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least one heteroatom such as O and S or group selected from NRd, C(O) and S(O)0-2;
Rc is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, (CRxRy)nOR3,
CORX, C00Rx, CONRxRy, S(0)mNRxRy, NRxRy, NRx(CRxRy)nOR3, NRx(CRxRy)nCN
(CH2)nNRxRy, (CH2)nCHRxRy, (CR]R3)NRxRy, NRx(CRxRy)nCONRxRy, (CH2)nNHC0Rx and (CH2)nNH(CH2)πSO2Rx, (CH2)nNHSO2Rx; each occurrence of Rd is hydrogen or substituted or unsubstituted alkyl; each occurrence of 'm' is independently selected from 0-2; each occurrence of 'n' is independently selected from 0-5.
The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is phenyl, R2 is alkyl preferably isopropyl, and R1 is methyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is substituted or unsubstituted phenyl, where in substituent is selected from halogen and/or halomethyl, preferably at each occurrence halogen is independently selected from chlorine, fluorine or bromine, and halomethyl is independently selected from trifluoromethyl and R1 is methyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is substituted or unsubstituted phenyl, wherein substituent is selected from phenyl or halophenyl, preferably bromophenyl and R1 is methyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is phenyl, R2 is substituted or unsubstituted phenoxy where in substituent is selected from alkyl preferably methyl and R1 is methyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 6-membered heteroaryl. In this embodiment, preferably, ring A is pyridine, R2 is substituted or unsubstituted phenyl where in substituent is selected from halogen and R1 is methyl. According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 5-membered heteroaryl. In this embodiment, preferably, ring A is thiazole, R2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen and R1 is alkyl preferably methyl ethyl or propyl. According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 5-membered heteroaryl. In this embodiment, preferably, ring A is thiazole, R2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen preferably bromine and R1 is COOR wherein R is ethyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 5-membered heteroaryl. In this embodiment, preferably, ring A is thiazole, R2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen and alkyl, preferably at each occurrence halogen is independently selected from chlorine and alkyl is independently selected from methyl and R1 is methyl .
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 5-membered heteroaryl. In this embodiment, preferably, ring A is thiazole, R2 is substituted or unsubstituted phenyl, where in substituent is selected from alkyl preferably (Ci-C4)alkyl, haloalkyl preferably trifiuoromethyl or nitrile and R1 is methyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 5-membered heteroaryl. In this embodiment, preferably, ring A is thiazole and R2 is optionally substituted alkyl or cycloalkyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 5-membered heteroaryl. In this embodiment, preferably, ring A is thiazole, R2 is selected from alkyl and substituted or unsubstituted phenyl, preferably at each occurance alkyl is selected from methyl and substituted phenyl is selected from chlorophenyl and R1 is methyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 5-membered heteroaryl. In this embodiment, preferably, ring A is thiazole, R2 is substituted or unsubstituted phenyl and the substituent is selected from halogen and/or methyl or trifiuoromethyl and R1 is hydrogen or methyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 5-membered heteroaryl. In this embodiment, preferably, ring A is thiazole, R2 is substituted or unsubstituted phenyl and the substituent is selected from halogen and/or difluoromethoxy, trifluoromethoxy or trifluoroethoxy and R1 is hydrogen or methyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is fused heteroaryl. In this embodiment, preferably, ring A is substituted or unsubstituted 4,5-dihydronaphtho[l,2,-d][l,3]thiazol wherein substituent is selected from halogen preferably chlorine and R1 is methyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 5-membered heteroaryl. In this embodiment, preferably, ring A is thiadiazole, R2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen preferably bromine and R1 is methyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 5-membered heteroaryl. In this embodiment, preferably, ring A is thiazole, R2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen preferably chlorine or bromine, Ra and Rb is independently selected from hydrogen or alkyl preferably methyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 5-membered heteroaryl. In this embodiment, preferably, ring A is optionally oxidized pyrazole more preferably pyrazolone, R2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen preferably chlorine or bromine and R1 is methyl.
According to one embodiment, specifically provided are compounds of the formula (I) in which, ring A is 5-membered heteroaryl. In this embodiment, preferably, ring A is thiazole, R2 is substituted or unsubstituted phenyl, where in substituent is selected from halogen preferably chlorine or bromine, Rc and R1 is independently selected from hydrogen or alkyl preferably methyl.
Below are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention.
N 1 -(4-isopropylphenyl)-2-(2-methyl- 1 ,3-dioxo-2,3 -dihydro- 1 H-4-isoindolyl) acetamide (Example 1); Nl-(4-Bromophenyl)-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-4-isoindolyl) acetamide (Example 2);
Nl-(4-Chlorophenyl)-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-4-isoindolyl) acetamide (Example 3); N 1 -(4-Chloro-2-fluorophenyl)-2-(2-methyl- 1 ,3 -dioxo-2,3 -dihydro- 1 H-4- isoindolyl)acetamide (Example 4);
N 1 -(4-Fluoro-2-chloro)-2-(2-methyl- 1 ,3 -dioxo-2,3 -dihydro- 1 H-4-isoindolyl) acetamide (Example 5);
N 1 -(4-Chloro-3 -trifluoromethylphenyl)-2-(2-methyl- 1 ,3 -dioxo-2,3-dihydro- 1 H-4- isoindolyl)acetamide (Example 6);
N 1 -(4-phenylphenyl)-2-(2-Methyl- 1 ,3 -dioxo-2,3-dihydro- 1 H-4-isoindolyl) acetamide (Example 7);
Nl-[3-(4-Bromophenyl)phenyl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-4- isoindolyl)acetamide (Example 8); Nl-[4-(3-Bromophenyl)phenyl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-4- isoindolyl)acetamide (Example 9);
N 1 -[4-(4-Bromophenyl)phenyl]-2-(2-methyl- 1 ,3-dioxo-2,3-dihydro- 1 H-4- isoindolyl)acetamide (Example 10);
2-(2-Methyl-l,3-dioxo-2,3-dihydro-lH-4-isoindolyl)-N-[4-(4- methylphenoxy)phenyl] acetamide(Example 11);
Nl-[5-(4-Chlorophenyl)-2-pyridyl]-2-(2-Methyl-l,3-dioxo-2,3-dihydro-lH-4- isoindolyl)acetamide (Example 12);
N 1 -[4-Cyclohexyl- 1 ,3 -thiazol-2-yl]-2-(2-methyl- 1 ,3 -dioxo-2,3 -dihydro- 1 H-4- isoindolyl)acetamide (Example 13); N 1 -[4-(4-Methylphenyl)- 1 ,3-thiazol-2-yl]-2-(2-methyl- 1 ,3-dioxo-2,3-dihydro- 1 H-
4-isoindolyl)acetamide (Example 14);
Nl-[4-(4-ter/-Butylphenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro- lH-4-isoindolyl)acetamide (Example 15); Nl-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH- 4-isoindolyl)acetamide (Example 16);
Nl-[4-(4-Iodophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-4- isoindolyl)acetamide (Example 17); Nl-[4-(4-Bromophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-
4-isoindolyl)acetamide (Example 18);
Nl-[4-(4-Bromophenyl)-l,3-thiazol-2-yl]-2-( -l,3-dioxo-2-ethyl-2,3-dihydro-lH- 4-isoindolyl)acetamide (Example 19);
Nl -[4-(4-Bromophenyl)-l ,3-thiazol-2-yl]-2-(l ,3-dioxo-2-propyl-2,3-dihydro- 1 H- 4-isoindolyl)acetamide (Example 20);
Nl -[4-(3-Chlorophenyl)- 1 ,3-thiazol-2-yl]-2-(2-methyl-l ,3-dioxo-2,3-dihydro- 1 H- 4-isoindolyl)acetamide (Example 21);
Nl -[4-(4-Fluorophenyl)- 1 ,3-thiazol-2-yl]-2-(2-methyl-l ,3-dioxo-2,3-dihydro- 1 H- 4-isoindolyl)acetamide (Example 22); Nl-[4-(3-Trifluoromethylphenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3- dihydro-lH-4-isoindolyl)acetamide (Example 23);
Nl-[4-(3-Trifluoromethoxyphenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3- dihydro-lH-4-isoindolyl)acetamide (Example 24);
Nl -[4-(4-Cyanophenyl)- 1 ,3-thiazol-2-yl]-2-(2-methyl- 1 ,3-dioxo-2,3-dihydro- 1 H- 4-isoindolyl)acetamide (Example 25);
Nl-[4-(4-Bromophenyl)-l,3-thiazol-2-yl]-2-(2-ethoxycarbonyl-l,3-dioxo-2,3- dihydro-lH-4-isoindolyl)acetamide (Example 26);
Nl-[4-(4-Bromophenyl)-l,3-thiazol-2-yl]-2-(l,3-dioxo-2,3-dihydro-lH-4- isoindolyl) acetamide (Example 27); Nl-[4-(4-Bromophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-
4-isoindolyl)propanamide (Example 28);
Nl -[4-(4-Chlorophenyl)- 1 ,3-thiazol-2-yl]-2-(2-methyl- 1 ,3-dioxo-2,3-dihydro- 1 H- 4-isoindolyl)propanamide (Example 29); Nl-[4-(4-Chlorophenyl)-l ,3-thiazol-2-yl]-Nl -methyl-2-(2-methyl-l ,3-dioxo-2,3- dihydro-lH-4-isoindolyl)acetamide (Example 30);
N 1 -[4-(2,4-Dichlorophenyl)- 1 ,3-thiazol-2-yl]-2-(2-methyl- 1 ,3-dioxo-2,3-dihydro- lH-4-isoindolyl)acetamide (Example 31); Nl-[4-(3,4-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro- lH-4-isoindolyl)acetamide (Example 32);
Nl-[4^4-Chloro-3-Methylphenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3- dihydro-lH-4-isoindolyl)acetamide (Example 33);
N 1 - {4-[3-Fluoro-4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl} -2-(2-methyl- 1 ,3- dioxo-2,3-dihydro-lH-isoindol-4-yl)acetamide (Example 34);
Nl-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(2-methyl- l,3-dioxo-2,3-dihydro-lΗ-isoindol-4-yl)acetamide (Example 35);
Nl-{4-[3,5-Difluoro, 4-difluoromethoxy)- phenyl]- l,3-thiazol-2-yl}-2-(2-methyl- l,3-dioxo-2,3-dihydro-lH-4-isoindolyl)acetamide (Example 36); Nl-[4-(4-Chlorophenyl)-5-methyl-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3- dihydro-lH-4-isoindolyl)acetamide (Example 37);
Nl-[4,5-Dihydronaphtho[l,2-d][l,3]thaiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3- dihydro-lH-4-isoindolyl)acetamide (Example 38);
Nl -[7-Chloro-4,5-dihydronaphtho[ 1 ,2-d] [ 1 ,3]thaiazol-2-yl]-2-(2-methyl- 1 ,3- dioxo-2,3-dihydro-lH-4-isoindolyl)acetamide (Example 39);
Nl-[I -(4-Bromophenyl)- 1 H-3-pyrazolyl]-2-(2-Methyl- 1 ,3-dioxo-2,3-dihydro- 1 H- 4-isoindolyl)acetamide (Example 40);
Nl-[l-(4-Chlorophenyl)-lH-3-pyrazolyl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH- 4-isoindolyl)acetamide (Example 41); Nl-[3-(4-Chlorophenyl)-lH-5-pyrazolyl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-
4-isoindolyl)acetamide (Example 42);
Nl-[l-(4-Chlorophenyl)-5-oxo-4,5-dihydro-lH-3-pyrazolyl]-2-(2-methyl-l,3- dioxo-2,3-dihydro-lH-4-isoindolyl)acetamide (Example 43); Nl-[5-(4-Bromophenyl)-l,3,4-thiadiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3- dihydro-lH-4-isoindolyl)acetamide (Example 44); or tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof, The present patent application 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 TRPAl receptors, which modulation is believed to be related to a variety of disease states.
The present patent application further provides a method of inhibiting TRPAl 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 present patent application provides phthalimide derivatives, which may be used as TRPAl modulators, and processes for the synthesis of these compounds. Pharmaceutically acceptable salts, enantiomers, diastereomers, of these compounds that may have the same type of activity are also provided. Pharmaceutical compositions containing the described compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by TRPAl are further provided.
The following definitions apply to the terms as used herein:
The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, 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, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1- dimethylethyl (t-butyl).
The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, and 2-butenyl.
The term "alkynyl" refers to a straight or branched chain 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), e.g., ethynyl, propynyl, and butynyl.
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.
The terms "halogen" or "halo" includes fluorine, chlorine, bromine, or iodine.
The term "haloalkyl" is used to denote a group comprised of an alkyl group substituted with halogen atom, where alkyl group is as defined above and halogen is used to denote fluorine, chlorine, bromine or iodine, an example of such group is trifluoromethyl, difluoromethyl.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, tetrahydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
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.
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. The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H5C6H5. The terms "heterocyclyl" and "heterocyclic ring" refer to a stable 3- to 15- membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic 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; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4- piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, naphthothaiazolyl and isochromanyl. 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.
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. The term "heteroaryl" refers to an aromatic heterocyclic ring radical. 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.
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 otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, 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 cycloalkenylalkyl, 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, -COORX, -C(O)RX, -C(S)R", -C(O)NRxRy, -C(O)ONRxRy, -NRxC0NRyRz, - N(Rx)SORy, -N(Rx)SO2Ry, -(=N-N(Rx)Ry), -NRxC(O)ORy, -NRxRy, -NRxC(O)Ry, - NRxC(S)Ry, -NRxC(S)NRyRz, -SONRxRy, -SO2NRxRy, -ORX, -ORxC(O)NRyRz, - ORxC(O)ORy, -OC(O)R", -0C(0)NRxRy, -RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, - RxC(0)NRyRz, -RxC(0)Ry, -RxOC(O)Ry, -SR", -SORX, -SO2RX, and -ONO2, wherein Rx, Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkyl, 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. According to one embodiment, 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 effect such treatment. 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. Certain compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). 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 provided in the present patent application includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).Preferably, the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to inhibit TRPAl receptor in a subject. The inhibitory activity of compounds falling within the formula (I) may be measured by an assay provided herein below.
The subjects contemplated include, for example, a living cell and a mammal, including human mammal. The compound of 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.
Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. The carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing oxmetic 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 conventional techniques known in the art (Remington: The Science and Practice of Pharmacy, 20th 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), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, 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
Pain can be acute or chronic. While acute pain is usually self-limiting, chronic pain persists for 3 months or longer and can lead to significant changes in a patient's personality; lifestyle, functional ability and overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine; J. C. Bennett & F. Plum (eds.), 20th ed. (1996) 100-107). N The sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to this harmful stimulus are termed as "nociceptors". Nociceptors are primary sensory afferent (C and Aδ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH<6) modalities. Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain. Chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. The pain is typically well localized, constant, and often with an aching or throbbing quality. Visceral pain is the subtype of nociceptive pain that involves the internal organs. It tends to be episodic and poorly localized. Nociceptive pain is usually time limited, meaning when the tissue damage heals, the pain typically resolves (arthritis is a notable exception in that it is not time limited). The present patent application provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders modulated by TRPAl antagonists. The compounds described herein and pharmaceutical formulations thereof have TRPAl activity and are believed to be of potential use for the treatment or prophylaxis of certain diseases or disorders mediated or associated with the activity of TRPAl receptor, including disorders such as 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, urinary incontinence, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus. The connection between therapeutic effect and inhibition of TRPAl is illustrated, for example, in Story GM et al, Cell, (2003), U2, 819-829; McMahon SB and Wood JN, Cell, (2006), 124, 1123-1125; Voorhoeve PM et al, Cell, (2006), 124, 1169-1181; Wissenbach U, Niemeyer BA and Flockerzi V, Biology of the Cell, (2004), 96, 47-54; Dayne YO, Albert YH & Michael X, Expert Opinion on Therapeutic Targets (2007), 11(3), 391-401 and the references cited therein. General method of preparation
The compounds described herein, including compounds of general formula I and specific examples, are prepared using techniques known to one skilled in the art through the reaction sequences depicted in Schemes 1-12 as well as by other methods. 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 part of the present invention. The compounds obtained by using the general reaction sequences may be of insufficient purity. These compounds can be purified by using any of the methods for purification of organic compounds known to persons skilled 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.
Scheme 1 depicts a method for preparing isoindolylacetic acid of the formula (6) from commercially available 3-nitrophthalimide of formula (1). The compound of formula (3) wherein X is halogen and R1 is alkyl was prepared from 3-nitrophthalimide (1) by a sequence of transformations comprising of reduction of nitro group to the amino group (A. J. Hannaford et al, Vogel 's Textbook of Practical organic Chemistry (2006) 5th Ed. 890-897), diazotization followed by halide substitution of the resulting diazo compound (A. J. Hannaford et al, Vogel 's Textbook of Practical organic Chemistry (2006) 5th Ed., 920-946) and N-alkylation. Compound of formula (3) was reacted with allyl boronic acid of formula (4) in the presence of a palladium catalyst, such as bis(triphenylphosphine)-palladium dichloride or tetrakis(triphenylphosphine)palladium(0) (e.g. a procedure similar to the Suzuki-Miyaura Coupling described by Kotha et. al, in Synlett (2005), .12, 1877-1890) to yield a compound of formula (5). Transformation of compounds of formula (5) to compounds of formula (6) can be accomplished by oxidative cleavage methods known in the art, such as the methods reviewed by D. G. Lee and T. Chen in Comprehensive Organic Transformations Edited by B. M. Trost, I. Fleming and S. V. Ley, Pergamon Press, (1991), pp 541-591. Scheme-1
Figure imgf000021_0001
Scheme 2 describes an alternative approach for the synthesis of compounds of the formula (3) by a sequence of transformations known in the art of organic synthesis. Thus, N-alkylation of 3-nitrophthalimide of formula (1) followed by catalytic reduction affords an amine of formula (7) (Hannaford, A. J.; et al, Vogel's Textbook of Practical organic Chemistry, (2006), 5th Ed., 890-897). Diazotization of compound of formula (7) followed by halide substitution of the resulting diazo compound yields compound of formula (3) (Hannaford, A. J.; et al, Vogel's Textbook of Practical organic Chemistry, (2006), 5th Ed..936-937).
Scheme 2
Figure imgf000021_0002
Alternatively, compounds of formula (6) can be accomplished using the synthetic sequence depicted in the Scheme 3. The compound of the formula (7) can be reacted with an allyl bromide, in the presence of an appropriate alkyl nitrite such as tert-butyl nitrite, in an organic solvent such as acetonitrile or tetrahydrofuran to give compounds of formula (5). This conversion is similar to the one described by Fredrik et. al, in J. Org. Chem. (2003), 68, 1911-1918. Conversion of compounds of formula (5) to compounds of formula (6) can be accomplished by oxidative cleavage methods as described in Scheme 1. Scheme-3
RuC13-3H2Q / NaICV solvent
Figure imgf000022_0001
Figure imgf000022_0002
(7) (5) (6)
Scheme 4 depicts a potential synthetic route to compounds of the formula (6a). Compounds of formula (6) can be reacted with an alkylating agent such as an alkyl halide in the presence of a base, to form esters of type (8), which on hydrolysis to give compound of the formula (6a).
Scheme 4
Scheme 5 depicts a method for preparing the compounds described by general formula (Ia). In this scheme, compound of formula (6) is reacted with oxalyl chloride to afford an acid chloride of the formula (9) which on coupling with an appropriate amine of formula (10) yields compound of formula (Ia)
Scheme 5
Figure imgf000022_0004
Alternatively, compound of formula (9) can be coupled with amine of formula (10) in the presence of a suitable base such as N,N-diisopropylamine and 4- Dimethylaminopyridine (DMAP) in a suitable solvent to give compound of formula (Ia) as depicted in Scheme 6.
Scheme 6
Figure imgf000023_0001
Scheme-7 describes alternative method for synthesis of compounds of the formula (Ia) by direct coupling of carboxylic acid derivative (6) with amine of the formula (10) using a suitable coupling agent. Thus, coupling of compound of formula (6) with amine of formula (10) in the presence of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole monohydrate (HOBt) or l-hydroxy-7- azabenzotriazole (HOAt) afford compounds of the formula (Ia).
Scheme 7
Figure imgf000023_0002
The coupling of compound of the formula (6a) with respective amines of formula (10) by a standard amide coupling method gives compounds of formula (Ib) as depicted in scheme 8.
Scheme 8
Figure imgf000023_0003
Compounds of formula (Ib) can be N-alkylated with alkyl halide of formula R0X to form compounds of formula (I) as shown in scheme 9.
Scheme 9
Figure imgf000023_0004
Scheme 10 depicts the synthesis of 2-amino-4-aryl thiazoles. The compounds of the formula (11) react with oxalyl chloride in the presence of DMF to give acid chloride of the formula (12), which can be reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of triethyl amine to afford the compounds of formula (13). Addition of a Grignard reagent such as methylmagnesium iodide to compounds of formula (13) affords compounds of formula (14). The thiazole amine of the formula (16) can be prepared in one step by the the reaction of ketone (14) with thiourea in the presence of iodine in refluxing ethanol. This conversion is similar to that described by Carroll King et. al, J. Am. Chem. Soc. (1950), 3722 and Naik, S. J.; Halkar, U. P. ARKIVOC, (2005) xm, 141-149. The compounds of formula (16) can be also prepared alternatively by the reaction of compounds of formula (14) with bromine in acetic acid and subsequently treated with thiourea in THF at reflux condition to give compounds of the formula (16).
Scheme 10
(
Figure imgf000024_0001
<16>
Scheme 11 describes a method for the preparation of compounds of the formula (19). The compounds of the formula (17) is reacted with acrylonitrile in the presence of sodium ethoxide in ethanol to give compounds of the formula (18), which can be converted into compounds of the formula (19) by the reaction with N-bromosuccinimide. This conversion is similar to that described by Duffin; Kendall et. al, J. Chem. Soc. (1954), 408-415. Scheme 11
NaOEt
Figure imgf000025_0002
EtOH1 reflux
Figure imgf000025_0001
(17) (18) (19)
Scheme 12 depicts the preparation of the compounds of the formula (21). The compounds of the formula (20) reacted with ethyl cyanoacetate in the presence of sodium ethoxide in ethanol to give compounds of the formula (21). This conversion is similar to that described by Weissberger, A.; Porter, H., D., J. Am. Chem. Soc. (1942), 2133-2136.
Scheme 12
ethyl cyanoacetate / NaOEt N
Figure imgf000025_0004
EtOH, reflux
Figure imgf000025_0003
(20) (21)
Experimental Unless otherwise stated, work-up implies distribution of the reaction mixture between the organic and aqueous phase indicated within paranthesis, separation of layers and drying the organic layer over sodium sulphate, filteration and evaporation of the 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. Use of a different eluent system is indicated within paranthesis.
The following abbreviations are used in the text: DMSO-J6: Hexadeuterodimethyl sulfoxide; DMF: N,N-dimethylformamide, M.P.: Melting point; J: Coupling constant in units of Hz; RT or rt: room temperature (22-26°C). Aq.: aqueous AcOEt: ethyl acetate; equiv. or eq.: equivalents; TLC: thin layer chromatography.
Intermediate 1
Preparation of (2-methyl-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl)acetic acid :
Figure imgf000025_0005
Step 1 : 4-Amino-l,3-isoindolinedione
A solution of 3-nitrophthalimide in ethylacetate was treated with 10% palladium on charcoal (10 wt. %) and hydrogenated at 20 psi for 2h. The catalyst was filtered through celite and the filterate was evaporated to give the crude product (97%) which was used without purification in the next step. 1H-NMR (δ ppm, DMSO-J6, 300 MHz): 10.85 (br. s, IH); 7.39 (t, J = 7.8, IH); 6.93 (d, J = 8.4, IH); 6.88 (d, J = 6.9); 6.38 (br. s, 2H).
Step 2: 4-Iodo-l,3-isoindolinedione
A ~3.6M aqueous solution of sodium nitrite was added at 0°C to a -2.0M solution of the product obtained from step 1 in concentrated hydrochloric acid. After stirring the mixture at the same temperature for 10 min., a ~3.39M aqueous solution of potassium iodide was added to it, allowed to warm up to RT and then heated at 800C for 2h. After cooling to
RT, work-up (AcOEt/H2O) afforded the title compound in 82% yield. 1H-NMR (δ ppm,
DMSO-J6, 300 MHz): 11.48 (br. s, IH); 8.17 (d, J = 7.8, IH); 7.79 (d, J = 8.4, IH); 7.48 (t, J = 6.9, IH).
Step 3: 4-Iodo-2-methyl-l ,3-isoindolinedione
Sodium hydride (1.1 equiv.) was added portion wise to a ~0.5M solution of compound obtained from step 2 (1.0 equiv.) in DMF at 0°C. After stirring the mixture for 15 min. Iodomethane (1.1 equiv.) was added slowly and stirred at RT until TLC monitoring indicated complete conversion of starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. Organic layer was then washed with water, brine and dried over Na2SO4. Purification of the crude product by SiO2 column chromatography gave the title compound as a pale yellow solid in 91% yield. 1H-NMR (δ ppm, DMSO-J6, 300 MHz): 8.16 (d, J = 8.1, IH); 7.82 (d, J = 8.2, IH); 7.48 (t, J = 6.9, IH).
Step 4: 4-Allyl-2-methyl-l ,3-isoindolinedione
A 0.1 M solution of product obtained from step 3 containing cesium fluoride (2.0 equiv.) and allyl boronic acid pinacol ester (1.8 equiv) in 1,4-dioxane was treated with tetrakis(triphenylphosphine)palladium(0) (10 mol%) in an inert atmosphere at 100°C overnight. The reaction mixture was cooled to RT and diluted with water, extracted with ethylacetate and organic layers were separated, washed with brine and dried over Na2SO4. Purification of crude product by SiO2 column chromatography gave the title compound in 73% yield.
Step 5: (2-methyl-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl)acetic acid
A 1.35M aqueous solution of sodium metaperiodate (6.0 equiv.) was added to a 0.47M solution of product obtained in above step 4 (1.0 equiv.) in carbon tetrachloride and acetonitrile (1 :1) containing ruthenium (III) chloride trihydrate (2 mol%). After stirring for 2Oh, the mixture was concentrated to remove the organic solvents. Work-up (AcOEt) gave the product in 83% yield. 1H-NMR (δ ppm, DMSO-^6, 300 MHz): 12.47 (br. s, IH); 7.80-7.60 (m, 3H); 4.05 (s, 2H); 3.00 (s, 3H). MS (m/z): 220.15 ([M+H]+). Intermediate 2
Preparation of 2-(2-Ethyl-l,3-dioxo-2,3-dihvdro-lH-4-isoindolyl)acetic acid
Figure imgf000027_0001
Step 1 : 4-Nitro-2-ethyl-l ,3-isoindolinedione
The title was prepared according to the procedure described in the step 3 intermediate 1 by using 3-nitrophthalimide (1.0 equiv.), sodium hydride (1.4 equiv.) and ethyl bromide (1.6 equiv.) in DMF to give the title compound as a pale yellow solid in 78% yield. 1H- NMR (δ ppm, CDCl3, 300 MHz): 8.10-8.00 (m, 2H); 7.87 (t, J = 7.8, IH); 3.77 (q, J = 7.2, 2H); 1.29 (t, J = 7.2, 3H). MS (m/z): 221.36 ([M+H]+).
Step 2: 4-Amino-2-ethyl- 1 ,3-isoindolinedione The title compound was prepared according to the procedure described for Intermediate 1 step 1 by using compound obtained from above step 1 in ethylacetate in the presence of 10% palladium on charcoal gave the crude product (91%) which was used without purification in the next step. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.37 (t, J = 7.8, IH); 7.11 (d, J = 7.2, IH); 6.81 (d, J = 8.1, IH); 5.18 (br. s, 2H); 3.67 (q, J = 7.2, 2H); 1.25 (t, J = 6.9, 3H).
Step 3 : 4-Allyl-2-ethyl-l ,3-isoindolinedione
To a 0.5M solution of tert-butyl nitrite (1.5 equiv) and allyl bromide (15.0 equiv) in acetonitrile, product obtained above from step 2 (1.0 equiv.) was added portion wise. The reaction mixture was stirred for 30 min. After removal of solvents and excess of allyl bromide by distillation under reduced pressure, the residue was diluted with ethylacetate, washed with water and dried over Na2SO4. The crude product was purified by SiO2 column chromatography give the title compound in 61% yield. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.67 (d, J = 7.2, IH); 7.58 (t, J = 7.5, IH); 7.49 (d, J = 7.2, IH); 6.05-5.85 (m, IH); 5.15-5.05 (m, 2H); 3.88 (d, J = 6.9, 2H); 3.71 (q, J = 6.9, 2H); 1.27 (t, J = 6.9, 3H).
Step 4: (2-methyl-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl)acetic acid
The title compound was prepared according to the procedure described for Intermediate 1 step 5 using product obtained in above step 3 (1.0 equiv.), sodium metaperiodate (6.0 equiv.) in carbon tetrachloride and acetonitrile gave title compound in 83% yield. 1H- NMR (δ ppm, DMSO-Cf6, 300 MHz): 12.44 (br. s, IH); 7.80-7.60 (m, 3H); 4.06 (s, 2H); 3.56 (t, J = 7.2, 2H); 1.15 (t, J = 7.2, 3H). MS [(m/z)]: 234.05 ([M+H]+).
Intermediate 3 Preparation of 2-(2-Propyl-l,3-dioxo-2,3-dihvdro-lH-4-isoindolyl')acetic acid
Figure imgf000028_0001
The title compound was prepared according to the procedure described in Intermediate 2 by using 3-nitrophthalimide, propyl bromide, Pd/C, tert-butyl nitrite, allyl bromide, sodium metaperiodate and ruthenium (III) chloride trihydrate. Yield: 79%. 1H-NMR (δ ppm, DMSO-J6, 300 MHz): 12.40 (br. s, IH); 7.75-7.60 (m, 3H); 4.06 (s, 2H); 3.50 (t, J = 6.9, 2H); 1.58 (sextet, J = 7.2, 2H); 0.85 (t, J = 7.5, 3H). MS [(m/z)]: 248.15 ([M+H]+).
Intermediate 4 Preparation of 2-(2-Ethoxycarbonyl-l,3-dioxo-2,3-dihvdro-lH-4-isoindolyl)acetic acid
Figure imgf000028_0002
The title compound was prepared according to the procedure described in Intermediate 2 by using 3-nitrophthalimide, ethyl chloroformate, Pd/C, tert-butyl nitrite, allyl bromide, sodium metaperiodate and ruthenium (III) chloride trihydrate. Yield: 73%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 12.51 (br. s, IH); 7.90-7.70 (m, 3H); 4.34 (q, J = 6.9, 2H); 4.06 (s, 2H); 1.31 (t, J = 6.9, 3H). MS [(m/z)]: 278.04 ([M+H]+).
Intermediate 5
Preparation of 2-(2-Methyl- 1 ,3 -dioxo-2,3-dihydro- 1 H-4-isoindolyl)Propanoic acid
Figure imgf000029_0001
Step 1: Methyl 2-(2-methyl-l ,3-dioxo-2,3-dihydro-lH-4-isoindolyl)propanoate
A 0.46M solution of Intermediate 1 (1 equiv.) in dry DMF was treated with K2CO3 (3.5 equiv.) and iodomethane (3.5 equiv.) and stirred at RT overnight. The mixture was diluted with ethyl acetate, filtered and the filtrate was washed with water and the organic layer was dried and concentrated and the residue subjected to purification to give the title compound in 44% yield. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.80-7.45 (m, 3H); 4.94 (q, J = 6.9, IH); 3.68 (s, 3H); 3.16 (s, 3H); 1.56 (d, J = 6.9, 3H).
Step 2: 2-(2-Methyl-l,3-dioxo-2,3-dihydro-lH-4-isoindolyl) propanoic acid To a 0.2 M solution of compound obtained from above step 1 in 1 : 1 aqueous dioxane was added 3N H2SO4. The reaction mixture was refluxed overnight. The mixture was concentrated to ca. half its initial volume and extracted into ethyl acetate, the organic layers were washed with water, dried over Na2SO4 and the solvent evaporated to give the title compound in 97% yield. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.80-7.55 (m, 3H); 4.96 (q, J = 7.2, IH); 3.16 (s, 3H); 1.59 (d, J = 7.2, 3H).
General Procedure for the preparation of acetophenone: o
Step-1 : Oxalyl chloride (1.2 equiv) was added at 0 C to a solution of benzoic acid (1.0 equiv) in dichloromethane followed by the addition catalytic amount of DMF and stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane and added slowly to a solution of N,O- dimethylhydroxylamine hydrochloride (1.2 equiv) and Et3N (2.4 equiv) in dichloromethane at 0 C and the mixture was stirred at RT for 2 h. The reaction mixture was distributed between water and dichloromethane and the organic extracts were washed with brine and dried over Na2SO4. The evaporation and purification by column chromatography to give amide.
Step-2: Grignard reagent was generated from iodomethane (5.0 equiv) and magnesium turnings (5.0 equiv) in dry diethyl ether and was treated drop-wise to a solution of the product obtained from above step 1 (1.0 equiv) in dry diethyl ether and the reaction mixture was stirred at room temperature for 2 h. An aqueous saturated NH4Cl solution was added and extracted with ethyl acetate. The organic layers were washed with brine, Na2SO4 and the solvent evaporated. The purification of the crude product by chromatography gave acetophenones. General Procedure for the preparation of thiazole amine:
Method A: A solution of acetophenone (1.0 equiv), thiourea (2.0 equiv) and iodine (1.0 equiv) in dry ethanol (1.5M) were refluxed for 24h. The reaction mixture was diluted with ethylacetate, washed with saturated solution of sodium thiosulphate and organic layer was treated with IN HCl, precipitated salt collected by filtration. The salt was then treated with saturated solution of NaHCO3 and extracted with dichloromethane, washed with brine and dried over sodium sulphate and the solvent was evaporated to afford the aminothiazole derivative.
Method B: To a solution of acetophenone (1.0 equiv) in glacial acetic acid (1.0 M), liquid bromine (1.0 equiv) was added at 0°C and reaction was stirred at room temperature for 2h. The reaction mixture was diluted with water and extracted with ethyl acetate, washed with brine and dried over Na2SO4. The crude product obtained upon concentration was dissolved in dry THF (0.4M) and thiourea (2.0 equiv) was added and refluxed for overnight. The reaction mixture was diluted with ethylacetate, washed with saturated solution of sodium thiosulphate and organic layer was treated with IN HCl, precipitated salt collected by filtration. The salt was then treated with saturated solution of NaHCO3 and extracted with dichloromethane, washed with brine and dried over sodium sulphate and the solvent was evaporated to give the aminothiazole in quantitative yield. The following 2-aminothiazole Intermediates were synthesized by using above procedures and their characterization data is given in Table 1. Table 1 : Structural details and 1H NMR data of selected 2-aminothiazole intermediates
Figure imgf000031_0001
Figure imgf000032_0001
4,5-Dihydonaptho[l,2-d]thiazole-2-ylamine were prepared from appropriate tetralones according to the procedure described by Norman, L.; Edward, S. J., J. Org. Chem. (1962), 27, 70-76.
Table 2: Structural details and 1H NMR data of dihydronaptho[l,2-d]thiazole-2-ylamines
Figure imgf000033_0001
EXAMPLES
The examples described herein were synthesized by coupling of acid intermediate 1-5 with the appropriate amine, according to table 1 , using one of the procedures described below: General procedure for amide coupling reactions:
Method A: A 0.15-0.3M solution of the carboxylic acid Intermediate in dichloromethane was treated with oxalyl chloride (0.7 equiv.) and catalytic quantity of DMF. After stirring the mixture at RT for 30 min., the solvent was evaporated and the residue dissolved in the same volume as dichloromethane of 1,4-dioxane. The corresponding amine (2 equiv.) was added stirred at RT until TLC indicated complete consumption of the acid chloride. Aq. IN HCl was added. Wherever precipitates were formed, they were collected by filtration and when filtration was not possible, work-up using AcOEt was employed. Purification of the precipitate or the residue after work-up gave the crude products.
Method B: Similar to method A, but 1.0 equiv. of the amine coupling partner and 1.3 equiv. of N,N-dimethylaniline were employed in the coupling stage. In some cases DMAP (0.1 equiv.) was also used. Method C: A mixture of the carboxylic acid Intermediate (1 equiv.), the corresponding amine (1 equiv.), l-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.2 equiv.), 1-Hydroxybenzotriazole or l-Hydroxy-7-azabenzotriazole (0.3 equiv.) and DMAP (0.1 equiv.) in 1 ,2-dichloroethane (volume required to make the concn. of carboxylic acid ca. 0.1 M) was stirred at RT overnight. Methanol was added to the mixture and if the product precipitated it was filtered and washed with methanol to obtain the crude product. Where the product did not precipitate, the mixture was subjected to work-up (AcOEt or CHC13/Aq. IN HCl) to obtain the crude product.
The crude products were purified either by column chromatographic techniques using ethylacetate-chloroform mixture of a suitable polarity as the mobile phase or by repeated crystallizations from methanol or isopropanol.
Example 1 N 1 -(4-isopropylphenyl)-2-(2-methyl- 1 ,3 -dioxo-2,3 -dihvdro- 1 H-4-isoindolvPacetamide
Figure imgf000034_0001
The title compound was prepared according to the general procedure described in method A by coupling Intermediate 1 (50 mg, 0.228 mmol) with 4-isopropylaniline (61 mg, 0.456 mmol) in 1,4-dioxane (2 ml) to give 42 mg of the product as a white solid. M. P.: 183- 185°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.62 (br. s, IH); 7.80-7.59 (m, 3H); 7.40 (d, J = 8.4, 2H); 7.12 (d, J = 8.4, 2H); 4.07 (s, 2H); 3.19 (s, 3H); 2.81 (quintet, J = 6.8, IH); 1.2 (d, J = 6.9, 6H). IR (cm"1, KBr): 3285 (m), 2961 (w), 2925 (w), 1766 (w), 1708 (s), 1660 (s), 1598 (w), 1526 (m), 1444 (w), 1429 (w), 1412 (w), 1381 (m), 1345 (w), 1304 (w), 1279 (w), 1256 (w), 1006 (m), 969 (w), 825 (w), 725 (w). MS [(m/z)]: 335.19 ([M- H]-).
Example 2 N 1 -(4-Bromophenyl)-2-(2-methyl- 1 ,3 -dioxo-2,3 -dihydro- 1 H-4-isoindolyl)acetamide
The title compound was prepared according to the general procedure described in method A by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-bromoaniline (157 mg, 0.912 mmol) in 1,4-dioxane (5 ml) to give 116 mg of the product as an off-white solid. M.P.: 235-238°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.78 (br. s, IH); 7.80-7.60 (m, 3H); 7.38 (br. s, 4H); 4.06 (s, 2H); 3.20 (s, 3H). IR (cm"', KBr): 3246 (w), 3182 (w), 3112 (w), 3064 (w), 1766 (m), 1708 (s), 1663 (s), 1606 (m), 1545 (m), 1486 (m), 1448 (w), 1427 (w), 1394 (w), 1381 (w), 1346 (w), 1300 (w), 1253 (w), 1072 (w), 1007 (m), 962 (w), 827 (m), 731 (m). MS [(m/z)]: 373.29 ([M-H]").
Example 3 N 1 -(4-Chlorophenyl V2-(2-methyl- 1.3 -dioxo-2.3 -dihvdro- 1 H-4-isoindolvOacetamide
Figure imgf000035_0001
The title compound was prepared according to the general procedure described in method A by coupling Intermediate 1 (50 mg, 0.228 mmol) with 4-chloroaniline (58 mg, 0.456 mmol) in 1,4-dioxane (2 ml) to give 35 mg of the product as an off-white solid. M.P.: 223-226°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.79 (br. s, IH); 7.80-7.60 (m, 3H); 7.44 (d, J = 8.7, 2H); 7.30-7.10 (2H, under CHCl3 signal); 4.06 (s, 2H); 3.20 (s, 3H). IR
(cm"', KBr): 3249 (w), 3187 (w), 3119 (w), 3066 (w), 1767 (w), 1708 (s), 1662(m), 2607 (m), 1594 (m), 1548 (s), 1489 (m), 1447 (w), 1428 (w), 1399 (w), 1382 (w), 1346 (w), 1301 (w), 1278 (w), 1253 (w), 1197 (w), 1091 (w), 1008 (w), 962 (w), 829 (w), 731 (w). Example 4
N 1 -f 4-Chloro-2-fluorophenvn-2-(2-methyl- 1.3 -dioxo-2.3-dihydro- 1 H-4-isoindolvn acetamide
Figure imgf000035_0002
The title compound was prepared according to the general procedure described in method A by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-chloro-2-fluoroaniline (132 mg, 0.912 mmol) in 1,4-dioxane (2 ml) to give 62 mg of the product as an off-white solid. M.P.: 209-212°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.73 (br. s, IH); 8.18 (t, J = 9.0,
IH); 7.80-7.65 (m, 3H); 7.06 (t, J = 7.2, 2H); 4.14 (s, 2H); 3.20 (s, 3H). IR (cm"1, KBr): 3254 (m), 3188 (m), 3116 (m), 3053 (m), 2977 (w), 1765 (s), 1704 (s), 1671 (s), 1613 (s), 1600 (s), 1539 (s), 1488 (s), 1444 (m), 1428 (m), 1404 (m), 1381 (m), 1346 (m), 1304 (m), 1276 (w), 1250 (w), 1197 (s), 1118 (w), 1075 (w), 1017 (m), 1006 (s), 956 (m), 891 (m), 852 (m), 820 (w), 732 (s). MS [(m/z)]: 347.20 ([M+H]+).
Example 5 N 1 -(4-Fluoro-2-chloro)-2-(2-ml- 1.3 -dioxo-2,3-dihvdro- 1 H-4-isoindolyl)acetamide
Figure imgf000036_0001
The title compound was prepared according to the general procedure described in method A by coupling Intermediate 1 (100 mg, 0.456 mmol) with 2-chloro-4-fluoroaniline (132 mg, 0.912 mmol) in 1,4-dioxane (5 ml) to give 115 mg of the product as an off-white solid. M.P.: 201-203°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.52 (br. s, IH); 8.25-8.15 (m, IH); 7.80-7.60 (m, 3H); 7.10-7.05 (m, IH); 6.95-6.85 (m, IH); 4.19 (s, 2H); 3.19 (s, 3H). IR (cm"', KBr): 3245 (m), 3096 (w), 3027 (w), 2932 (w), 1767 (w), 1704 (s), 1659 (s), 1614 (w), 1532 (s), 1492 (w), 1447 (w), 1431 (w), 1386 (w), 1343 (w), 1287 (w), 1259 (w), 1193 (w), 1008 (m), 917 (w), 861 (w), 818 (w), 796 (w), 728 (w). MS [(m/z)]: 347.15 ([M+H]+).
Example 6 Nl-("4-Chloro-3-trifluoromethylphenvπ-2-(2-methyl-1.3-dioxo-2.3-dihvdro-lH-4- isoindolvDacetamide
Figure imgf000036_0002
The title compound was prepared according to the general procedure described in method
A by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-chloro-3- trifluoromethylaniline (178 mg, 0.912 mmol) in 1,4-dioxane (5 ml) to give 128 mg of the product as an off-white solid. M.P.: 188-1900C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.01 (br. s, IH); 7.86-7.80 (m, 5H); 7.38 (t, J = 8.7, IH); 4.08 (s, 2H); 3.21 (s, 3H). IR
(cm"1, KBr): 3315 (m), 3209 (w), 3136 (w), 3069 (w), 1765 (s), 1707 (s), 1678 (s), 1594 (s), 1544 (s), 1484 (m), 1446 (m), 1419 (m), 1386 (m), 1345 (w), 1327 (w), 1270 (m), 1249 (w), 1182 (s), 1146 (w), 1120 (s), 1032 (w), 1019 (w), 1008 (m), 956 (w), 887 (w), 848 (m), 731 (m), 703 (w). MS [(m/z)]: 397.31 ([M+H]+).
Example 7 N 1 -B iphenyl-4-yl-2-(2 -methyl- 1 ,3-dioxo-2,3-dihydro- 1 H-isoindol-4-yl)acetamide
Figure imgf000037_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with biphenyl-4-amine (85 mg, 0.501 mmol) in the presence of N,N-dimethylaniline (72 mg, 0.593 mmol) and DMAP (5 mg, 0.045 mmol) in 1,4-dioxane (5 ml) to give 90 mg of the product as an off-white solid. M.P.: 273°C (Decomposes). 1H-NMR (δ ppm, CDCl3, 300 MHz): 10.33 (br. s, IH); 7.80- 7.55 (m, 9H); 7.42 (t, J = 7.4, 2H); 7.30 (t, J = 7.5, IH); 4.23 (s, 2H); 3.01 (s, 3H). IR (cm'
', KBr): 3302 (m), 1769 (m), 1704 (s), 1660 (s), 1591 (m), 1575 (w), 1526 (s), 1488 (m), 1446 (w), 1429 (w), 1404 (w), 1382 (w), 1343 (w), 1271 (w), 1252 (w), 1202 (w), 1003 (m), 828 (w), 759 (w), 725 (w). MS [(m/z)]: 371.11 ([M+H]+).
Example 8
N 1 -(4'-Bromobiphenyl-3-vn-2-(2-methyl- 1.3-dioxo-2,3-dihydro- 1 H-4-isoindolvn acetamide
Figure imgf000037_0002
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4'-bromobiphenyl-3-amine (124 mg, 0.501 mmol) in the presence of N,N-dimethylaniline (72 mg, 0.593 mmol) in 1,4- dioxane (5 ml) to give 108 mg of the product as an off-white solid. M. P.: 208°C. 1H- NMR (δ ppm, CDCl3, 300 MHz): 10.35 (br. s, IH); 7.93 (s, IH); 7.80-7.68 (m, 3H); 7.63 (d, J = 8.4, 2H); 7.55-7.50 (m, 3H); 7.41-7.28 (m, 2H); 4.22 (s, 2H); 3.00 (s, 3H). IR (cm"
\ KBT): 3261 (w), 3029 (w), 1768 (w), 1705 (s), 1663 (s), 1661 (m), 1608 (w), 1591 (w), 1535 (w), 1476 (w), 1430 (w), 1384 (m), 1340 (w), 1221 (w), 1007 (m), 781 (w). MS [(m/z)]: 449.10 ([M+H]+).
Example 9
N 1 -(3 '-Bromobiphenyl-4-vO-2-(2-methyl- 1 ,3 -dioxo-2.3-dihvdro- 1 H-4-isoindolyl) acetamide
Figure imgf000038_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with 3'-bromobiphenyl-4-amine (124 mg, 0.501 mmol) in the presence of N,N-dimethylaniline (72 mg, 0.593 mmol) and DMAP (5 mg, 0.045 mmol) in 1,4-dioxane (5 ml) to afford 88 mg of the product as an off-white solid. M.P.: 2080C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.85 (br. s, IH); 7.85- 7.65 (m, 4H); 7.58 (d, J = 8.4, 2H); 7.55-7.35 (m, 4H); 7.30-7.20 (IH under CHCl3); 4.10
(s, 2H); 3.22 (s, 3H). IR (cm"', KBr): 3281 (w), 1767 (w), 1705 (s), 1664 (m), 1594 (w), 1526 (m), 1473 (w), 1445 (w), 1428 (w), 1383 (w), 1262 (w), 1194 (w), 1007 (m), 828 (w), 781 (w).
Example 10
N 1 -(4'-Bromobiphenyl-4-vO-2-(2-methyl- 1 ,3-dioxo-2.3-dihvdro- 1 H-isoindol-4- vQacetamide
Figure imgf000038_0002
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4'-bromobiphenyl-4-amine (124 mg, 0.501 mmol) in the presence of N,N-dimethylaniline (72 mg, 0.593 mmol) and DMAP (5 mg, 0.045 mmol) in 1,4-dioxane (5 ml) afforded 86 mg of the product as an off-white solid. M.P.: 264.7°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.83 (br. s, IH); 7.82-7.62 (m, 3H); 7.58 (d, J = 7.8, 2H); 7.51 (d, J = 8.1, 2H); 7.46 (d, J = 8.1, 2H); 7.38
(d, J = 7.8, 2H); 4.01 (s, IH); 3.21 (s, 3H). IR (cm"1, KBr): 3289 (w), 1766 (w), 1704 (s), 1663 (m), 1598 (w), 1531 (m), 1481 (w), 1428 (w), 1414 (w), 1382 (w), 1346 (w), 1264 (w), 1190 (w), 1112 (w), 1002 (m), 812 (w). Example 11
2-(2 -Methyl- 1 ,3 -dioxo-2,3-dihydro- 1 H-4-isoindo IyI)-N- |"4-(4-methylphenoxy)phenyl] acetamide
Figure imgf000039_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(4-methylphenoxy)aniline (99 mg, 0.501 mmol) in the presence of N,N-dimethylaniline (72 mg, 0.593 mmol) and DMAP (5 mg, 0.045 mmol) in 1,4-dioxane (5 ml) to afford 102 mg of the product as an off-white solid. M.P.: 201-2030C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.66 (br. s, IH); 7.80-7.60 (m, 3H); 7.43 (d, J = 8.7, 2H); 7.07 (d, J = 8.1, 2H); 6.89 (d, J = 8.7, 2H); 6.82 (d, J = 8.1, 2H); 4.07 (s, 2H); 3.20 (s, 3H); 2.30 (s, 3H). IR (cm'1, KBr): 3257 (w), 3201 (m), 3138 (w), 3081 (w), 2923 (w), 1767 (w), 1709 (s), 1662 (m), 1610 (w), 1554 (m), 1498 (s), 1444 (w), 1428 (w), 1408 (w), 1382 (w), 1347 (w), 1303 (w), 1280 (w), 1237 (m), 1223 (m), 1168 (w), 1104 (w), 1005 (w), 963 (w), 931 (w), 874 (w), 857 (w), 828 (w), 815 (w), 795 (w), 729 (m). MS [(m/z)]: 401.18 ([M+H]+). Example 12
N 1 -r5-(4-Chlorophenvn-2-pyridyll-2-(2-Methyl- 1.3-dioxo-2.3-dihvdro- 1 H-4- isoindolvDacetamide
Figure imgf000040_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (300 mg, 1.368 mmol) with 5-(4-chlorophenyl)pyridin-2- amine (308 mg, 1.505 mmol) in the presence of N,N-dimethylaniline (215 mg, 1.774 mmol) and DMAP (16 mg, 0.136 mmol) in 1,4-dioxane (5 ml) to give 155 mg of the product as a white solid. M.P.: 220-2220C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.05 (br. s, IH); 8.46 (s, IH); 8.17 (d, J = 8.4, IH); 7.83-7.75 (m, 2H); 7.73-7.63 (m, 2H); 7.44 (d,
J = 9.0, 2H); 7.39 (d, J = 8.7, 2H); 4.11 (s, 2H); 3.21 (s, 3H). IR (cm"', KBr): 3312 (m), 1773 (m), 1711 (s), 1585 (w), 1568 (w), 1528 (w), 1495 (w), 1446 (w), 1432 (w), 1409 (w), 1383 (m), 1308 (w), 1293 (w), 1184 (w), 1090 (w), 1011 (w), 833 (w), 814 (w). MS [(m/z)]: 406.19 ([M+H]+).
Example 13
Nl-r4-Cvclohexyl-1.3-thiazol-2-yll-2-(2-methyl-l,3-dioxo-2,3-dihvdro-lH-4- isoindolvOacetamide
Figure imgf000040_0002
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (150 mg, 0.684 mmol) with 4-cyclohexyl-l,3-thiazol-2- amine (124 mg, 0.684 mmol) in the presence of N,N-dimethyl aniline (207 mg, 1.711 mmol) and DMAP (8 mg, 0.068 mmol) in 1,4-dioxane (8 ml) to give 40 mg of the product as an off-white solid. M.P.: 201-203°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.75 (br. s, IH), 7.85-7.75 (m, IH); 7.75-7.60 (m, 2H); 6.46 (s, IH); 4.22 (s, 2H); 3.20 (s, 3H); 2.50-2.30 (m, IH); 2.10-1.90 (m, 2H); 1.90-1.55 (m, 2H); 1.50-1.10 (m, 6H). IR
(cm"', KBr): 3235 (m), 2923 (m), 2850 (m), 1771 (m), 1709 (s), 1693 (s), 1550 (s), 1447 (m), 1431 (w), 1382 (m), 1343 (w), 1268 (m), 1162 (w), 1009 (m), 922 (w), 853 (w), 727 (w). MS [(m/z)]: 384.28 ([M+H]+).
Example 14 Nl-r4-(4-MethylphenylV1.3-thiazol-2-yll-2-(2-methyl-1.3-dioxo-2.3-dihvdro-lH-4- isoindolvDacetamide
Figure imgf000041_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(4-methylphenyl)-l,3-thiazol- 2-amine (86 mg, 0.456 mmol) in the presence of N,N-dimethylaniline (138 mg, 1.140 mmol) and DMAP (5 mg, 0.045 mmol) in 1 ,4-dioxane (5 ml) to afford 46 mg of the product as an off-white solid. M.P.: 265°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 10.05 (br. s, IH); 7.85-7.65 (m, 5H); 7.19 (d, J = 7.8, 2H); 7.04 (s, IH); 4.21 (s, 2H); 3.21 (s, 3H); 2.36 (s, 3H). IR (cm"', KBr): 3254 (m), 3225 (w), 3105 (w), 3071 (w), 2980 (w), 2921 (w), 1767 (m), 1703 (s), 1691 (s), 1612 (w), 1549 (s), 1489 (w), 1448 (w), 1431 (w), 1385 (m), 1346 (w), 1322 (w), 1271 (w), 1165 (w), 1062 (w), 1012 (w), 968 (w), 924 (w), 905 (w), 854 (w), 824 (w), 730 (w). MS [(m/z)]: 392.52 ([M+H]+).
Example 15 N 1 -r4-(4-tert-butvbhenylV 1.3-thiazol-2-yl1-2-(2-methyl- 1.3-dioxo-2.3-dihydro- 1 H-4- isoindolvDacetamide
Figure imgf000041_0002
The title compound was prepared according to the general procedure described in method C by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(4-tert-butylphenyl)-l,3- thiazol-2-amine (105 mg, 0.456 mmol) in the presence of EDCI hydrochloride (104 mg, 0.547 mmol), HOBt (18 mg, 0.136 mmol) and DMAP (5 mg, 0.045 mmol) in 1,2- dichloroethane (5 ml) gave 92 mg of the product as white solid. M.P.: 260-2620C. 1H- NMR (δ ppm, CDCl3, 300 MHz): 12.60 (br. s, IH); 7.84-7.74 (m, 5H); 7.54 (s, IH); 7.44 (d, J = 8.4, 2H); 4.32 (s, 2H); 3.00 (s, 3H); 1.31 (s, 9H). MS [(m/z)]: 433.52 ([M+H]+). Example 16 Nl-r4-(4-ChloroDhenvn-1.3-thiazol-2-yl1-2-r2-methyl-l,3-dioxo-2.3-dihvdro-lH-4- isoindolvDacetamide
Figure imgf000042_0001
The title compound was prepared according to the general procedure described in method A by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(4-chlorophenyl)-l,3-thiazol-
2-amine (192 mg, 0.912 mmol) in 1,4-dioxane (5 ml) to afford 38 mg of the product as an off-white solid. M.P.: 198-2000C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 10.00 (br. s, IH);
7.85-7.70 (m, 5H); 7.37 (d, J = 8.4, 2H); 7.10 (s, IH); 4.25 (s, 2H); 3.24 (s, 3H). IR (cm"1, KBr): 3276 (w), 3093 (w), 2923 (w), 1768 (w), 1691 (s), 1550 (m), 1477 (w), 1451 (w), 1429 (w), 1382 (w), 1343 (w), 1291 (w), 1275 (w), 1165 (w), 1090 (w), 1005 (m), 837 (w), 734 (w), 726 (w). MS [(m/z)]: 412.31 ([M+H]+).
Example 17
Nl-r4-(4-Iodophenvn-l,3-thiazol-2-yll-2-(2-methyl-l,3-dioxo-2.3-dihvdro-lH-4- isoindolyPacetamide
Figure imgf000042_0002
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(4-iodophenyl)-l,3-thiazol-2- amine (137 mg, 0.456 mmol) in the presence of N,N-dimethylaniline (138 mg, 1.140 mmol) and DMAP (5 mg, 0.045 mmol) in 1,4-dioxane (5 ml) to give 38 mg of the product as an off-white solid. M.P.: 252-255°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.99 (br. s, IH); 7.85-7.75 (m, IH); 7.75-7.65 (m, 4H); 7.55 (d, J = 8.7, 2H); 7.10 (s, IH);
4.22 (s, 2H); 3.22 (s, 3H). IR (cm"', KBr): 3353 (w), 3289 (w), 2947 (w), 1764 (m), 1706 (s), 1618 (w), 1605 (w), 1565 (m), 1547 (s), 1474 (w), 1447 (w), 1428 (m), 1395 (w), 1376 (m), 1357 (w), 1339 (m), 1318 (w), 1219 (w), 1202 (w), 1177 (w), 1161 (w), 1066 (w), 1005 (m), 904 (w), 855 (w), 845 (w), 832 (w), 826 (w), 796 (w), 735 (m). MS (m/z): 504.04 ([M+H]+). Example 18
Nl-r4-(4-BromophenylVi.3-thiazol-2-yll-2-(2-methyl-1.3-dioxo-2J-dihvdro-lH-4- isoindolvDacetamide
Figure imgf000043_0001
The title compound was prepared according to the general procedure described in method A by coupling Intermediate 1 (50 mg, 0.228 mmol) with 4-(4-bromophenyl)-l,3-thiazol- 2-amine (116 mg, 0.456 mmol) in 1,4-dioxane (400 ml) to afford 45 mg of the product as an off-white solid. M.P.: 210-2130C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 10.00 (br. s, IH); 7.85-7.75 (m, IH); 7.75-7.62 (m, 4H); 7.49 (d, J = 8.1, 2H); 7.09 (s, IH); 4.23 (s, 2H); 3.22 (s, 3H). IR (cm"1, KBr): 3295 (m), 1763 (m), 1708 (s, shoulder), 1688 (s), 1572 (m), 1549 (s), 1473 (m), 1448 (m), 1430 (m), 1384 (m), 1344 (m), 1291 (m), 1277 (m), 1177 (w), 1161 (w), 1073 (w), 1064 (w), 1009 (m), 837 (w), 733 (m).
Example 19
Nl -r4-(4-Bromophenyl)- 13-thiazol-2-yll-2-( -1.3-dioxo-2-ethyl-2.3-dihvdro- 1 H-4- isoindolvDacetamide
Figure imgf000043_0002
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 2 (100 mg, 0.428 mmol) with 4-(4-bromophenyl)-l,3-thiazol- 2-amine (109 mg, 0.428 mmol) in the presence of N,N-dimethylaniline (68 mg, 0.566 mmol) in 1,4-dioxane (5 ml) to give 32 mg of the product as an off-white solid. M.P. 204- 2070C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 10.02 (br s, IH); 7.85-7.65 (m, 5H); 7.49 (d, J = 8.1, 2H); 7.09 (s, IH); 4.23 (s, 2H); 3.78 (q, J = 7.2, 2H); 1.31 (t, J = 7.2, 3H). IR (cm'
\ KBr): 3373 (w), 3251 (w), 3112 (w), 3105 (w), 3067 (w), 2978 (w), 2923 (w) 1769 (w), 1710 (s), 1693 (s), 1620 (w), 1571 (w), 1546 (s), 1474 (w), 1399 (m), 1378 (w), 1343 (w), 1289 (w), 1269 (w), 1231 (w), 1204 (w), 1168 (w), 1100 (w), 1071 (w), 1062 (w), 1039 (w), 1010 (w), 975 (w), 903 (w), 879 (w), 859 (w), 831 (w) 736 (w). Example 20
Nl -r4-(4-BromophenylV 13-thiazol-2-yl]-2-a 3-dioxo-2-propyl-2.3-dihydro-l H-4- isoindolvDacetamide
Figure imgf000044_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 3 (100 mg, 0.404 mmol) with 4-(4-bromephenyl)-l,3-thiazol- 2-amine (103 mg, 0.404 mmol) in the presence of N,N-dimethylaniline (63 mg, 0.525 mmol) in 1,4-dioxane (5 ml) to give 43 mg of the product as an off-white solid. M.P.: 172-175°C (Decomposes). 1H-NMR (δ ppm, CDCl3, 300 MHz): 10.12 (br. s, IH); 7.87- 7.65 (m, 5H); 7.50 (d, J = 7.8, 2H); 7.10 (s, IH); 4.24 (s, 2H); 3.70 (t, J = 7.8, 2H), 1.74
(q, J = 7.8, 2H); 0.99 (t, J = 7.8, 3H). IR (cm"1, KBr): 3377 (w), 3254 (w), 3216 (w), 3106 (w), 3067 (w), 2964 (w), 2924 (w), 2876 (w), 2853 (w), 1767 (w), 1713 (m), 1696 (s), 1571 (w), 1546 (s), 1473 (w), 1444 (w), 1467 (m), 1398 (m), 1382 (w), 1344 (m), 1316 (w), 1289 (w), 1272 (w), 1230 (w), 1199 (w), 1182 (w), 1163 (w), 1071 (w), 1053 (w), 1010 (w), 967 (w), 904 (w), 832 (w), 796 (w), 781 (w), 735 (m). MS [(m/z)]: 484.37 ([M+H]+).
Example 21
Nl-r4-(3-Chlorophenvn-l,3-thiazol-2-yl1-2-(2-methyl-1.3-dioxo-2.3-dihvdro-lH-4- isoindolvDacetamide
Figure imgf000044_0002
The title compound was prepared according to the general procedure described in method C by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(3-chlorophenyl)-l,3-thiazol- 2-amine (96 mg, 0.456 mmol) in the presence of EDCI hydrochloride (104 mg, 0.547 mmol), HOAt (18 mg, 0.136 mmol) and DMAP (5 mg, 0.045 mmol) in 1,2- dichloroethane (4 ml) to give 48 mg of the product as an off-white solid. M.P.: 199- 202°C. 1H-NMR (δ ppm, DMSO-^6, 300 MHz): 10.04 (br. s, IH); 7.90-7.75 (m, 2H); 7.75-7.65 (m, 2H); 7.35-7.20 (m, 3H); 7.12 (s, IH); 4.24 (s, 2H); 3.23 (s, 3H). IR (cm"', KBr): 3246 (w), 3221 (w), 3074 (w), 2924 (w), 1776 (w), 1707 (s), 1693 (s), 1597 (w), 1553 (m), 1474 (w), 1450 (m), 1474 (w), 1450 (w), 1384 (w), 1344 (w), 1273 (w), 1163 (w), 1075 (w), 1012 (w), 854 (w), 790 (w), 743 (w), 726 (m). MS (m/z): 412.42 ([M+H]+)
Example 22
Nl-r4-(4-Fluorophenvn-1.3-thia2ol-2-yll-2-(2-methyl-1.3-dioxo-2,3-dihydro-lH-4- isoindolvDacetamide
Figure imgf000045_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(4-fluorophenyl)-l,3-thiazol- 2-amine (97 mg, 0.501 mmol) in the presence of N,N-dimethylaniline (138 mg, 1.140 mmol) and DMAP (5 mg, 0.045 mmol) in 1,4-dioxane (5 ml) to give 90 mg of the product as an off-white solid. M.P.: 2080C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.95 (br. s, IH); 7.85-7.60 (m, 5H); 7.15-7.00 (m, 3H); 4.23 (s, 2H); 3.22 (s, 3H). IR (cm"', KBr): 3258 (w), 3225 (w), 3100 (w), 3066 (w), 2973 (w), 2917 (w), 1773 (w), 1698 (s), 1608 (w), 1548 (s), 1489 (m), 1449 (m) 1431 (m), 1410 (w) 1384 (m), 1345 (w), 1316 (w), 1271 (m), 1252 (w), 1239 (m), 1155 (m), 1098 (w), 1065 (w), 1009 (m), 967 (w), 923 (w), 905 (w), 841 (w), 731 (m). MS [(m/z)]: 396.35 ([M+H]+).
Example 23 Nl-r4-(3-TrifluoromethylphenylV1.3-thiazol-2-yll-2-(2-methyl-l,3-dioxo-2.3-dihvdro- 1 H-4-isoindolyl')acetamide
Figure imgf000045_0002
The title compound was prepared according to the general procedure described in method
C by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(3-trifluoromethylphenyl)- l,3-thiazol-2-amine (111 mg, 0.456 mmol) in the presence of EDCI hydrochloride (104 mg, 0.547 mmol), HOAt (18 mg, 0.136 mmol) and DMAP (5 mg, 0.045 mmol) in 1,2- dichloromethane (4 ml) to give 32 mg of the product as an off-white solid. M.P.: 190- 193°C. 1H-NMR (δ ppm, DMSO-^6, 300 MHz): 10.06 (br. s, IH); 8.08 (s, IH); 7.98 (d, J = 6.6, IH); 7.85-7.75 (m, 3H); 7.75-7.65 (m, 2H); 7.19 (s, IH); 4.25 (s, 2H); 3.22 (s, 3H).
IR (cm'1, KBr): 3448 (w), 3274 (w), 3112 (w), 2924 (w), 2853 (w), 1766 (w), 1702 (w), 1616 (w), 1549 (s), 1447 (w), 1430 (w) 1384 (w), 1343 (m), 1261 (m), 1161 (w), 1094 (m), 1007 (m), 971 (w), 967 (w), 901 (w), 853 (w), 804 (w), 733 (m). MS (m/z): 446.27 ([M+H]+)
Example 24
N 1 - [4-(3 -trifluoromethoxy)phenyl)- 1.3-thiazol-2-yll-2-(2-methyl- 1.3 -dioxo-2.3 -dihvdro- 1 H-4-isoindolvπacetamide
Figure imgf000046_0001
The title compound was prepared according to the general procedure described in method C by coupling Intermediate 1 (250 mg, 1.14 mmol) with 4-(3-trifluoromethoxyphenyl)- l,3-thiazol-2-amine (296 mg, 1.14 mmol), EDCI hydrochloride (262 mg, 1.30 mmol), HOBt (46 mg, 0.34 mmol) and DMAP (13 mg, 0.01 mmol) in 1 ,2-dichloromethane to give 119 mg of the product as an off-white solid. M.P.: 223-225°C. 1H-NMR (δ ppm, DMSO-.4, 300 MHz): 12.64 (br. s, IH); 7.92 (d, J = 7.2, IH); 7.87 (s, IH); 7.86-7.70 (m, 4H); 7.58 (t, J = 7.8, IH); 7.33 (d, J = 7.2, IH); 4.34 (s, 2H); 3.00 (s, 3H). MS (m/z): 462.12 ([M+H]+). Example 25
Nl-r4-(4-Cvanophenvπ-1.3-thiazol-2-yll-2-(2-methyl-1.3-dioxo-2.3-dihydro-lH-4- isoindolvDacetamide
Figure imgf000046_0002
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(2-amino-l,3-thiazol-4- yl)benzonitrile (110 mg, 0.547 mmol) in the presence of N,N-dimethylaniline (138 mg, 1.140 mmol) and DMAP (5 mg, 0.045 mmol) in 1,4-dioxane (5 ml) to give 40 mg of the product as a pale yellow solid. M.P.: 250-253°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 12.63 (br. s, IH); 8.07 (d, J = 8.1, 2H); 7.95-7.85 (m, 3H); 7.85-7.60 (m, 3H); 4.33 (s, 2H); 2.99 (s, 3H).
Example 26
Nl-r4-(4-Bromophenyl)-l,3-thiazol-2-yl1-2-(2-ethoxycarbonyl-l,3-dioxo-2,3-dihydro- 1 H-4-isoindolyl)acetamide:
Figure imgf000047_0001
The title compound was prepared according to the general procedure described in method C by coupling Intermediate 4 (200 mg, 0.721 mmol) with 4-(4-bromophenyl)-l,3-thiazol-
2-amine (183 mg, 0.721 mmol) in the presence of EDCI hydrochloride (165 mg, 0.865 mmol), HOAt (29 mg, 0.216 mmol) and DMAP (8 mg, 0.072 mmol) in 1,2- dichloroethane (6 -ml) to give 38 mg of the product as an off-white solid. 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.82 (br. s, IH); 7.95-7.85 (m, IH); 7.80-7.70 (m, 2H); 7.66 (d, J = 8.4, 2H); 7.49 (d, J = 8.7, 2H); 7.10 (s, IH); 4.90 (q, J = 6.9, 2H); 4'25 (s, 2H); 1.47 (t, J
= 6.9, 3H).
Example 27
Nl-r4-r4-Bromophenvn-13-thiazol-2-yll-2-(13-dioxo-2.3-dihvdro-lH-4-isoindolyl) acetamide
Figure imgf000047_0002
Ammonia gas was passed through a solution of Nl-[4-(4-Bromophenyl)-l,3-thiazol-2- yl]-2-(2-ethoxycarbonyl-l,3-dioxo-2,3-dihydro-lH-4-isoindolyl)acetamide (example 17- 38 mg, 0.074 mmol) in dry THF (ImL) for about 25 min. The product precipitated was filtered off and solid obtained washed with dry THF to give 17 mg of the product as an off-white solid. M.P.: 331.3°C. 1H-NMR (δ ppm, DMSCwZ6, 300 MHz): 12.54 (br. s, IH); 11.28 (br. s, IH); 7.90-7.55 (m, 8H); 4.30 (s, 2H). MS (m/z): 442.32 ([M+H]+). Example 28
Nl -r4-(4-Bromophenyl)- 13-trύazol-2-yl1-2-f2-methyl-l 3-dioxo-23-dihvdro-l H-4- isoindolyDpropanamide
Figure imgf000048_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 5 (100 mg, 0.428 mmol) with 4-(4-bromophenyl)-l,3-thiazol- 2-amine (120 mg, 0.471 mmol) in the presence of N9N, dimethylaniline (67 mg, 0.557 mmol) and DMAP (5 mg, 0.042 mmol) in 1,4-dioxane (5 ml) to give 62 mg of the product as a pale yellow solid. M.P.: 165-168°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.87 (br. s, IH); 7.87-7.65 (m, 5H); 7.48 (d, J = 7.8, 2H); 7.08 (s, IH); 5.07 (q, J = 6.9,
IH); 3.22 (s, 3H); 1.69 (d, J = 6.9, 3H). IR (cm"', KBr): 3270 (w), 3222 (w), 2924 (m), 1764 (w), 1698 (s), 1682 (s), 1556 (m), 1537 (m), 1450 (w), 1427 (w), 1382 (w), 1266 (w), 1157 (w), 1068 (w), 1008 (w), 821 (w), 740 (w). MS [(m/z)]: 472.05 ([M+H]+).
Example 29 Nl-r4-(4-ChloroDhenvn-l,3-thiazol-2-yll-2-('2-methyl-l,3-dioxo-2.3-dihvdro-lH-4- isoindolvDpropanamide
Figure imgf000048_0002
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 5 (100 mg, 0.428 mmol) with 4-(4-chlorophenyl)-l,3-thiazol- 2-amine (99 mg, 0.504 mmol) in the presence of N,N-dimethylaniline (72 mg, 0.596 mmol) and DMAP (5 mg, 0.042 mmol) in 1,4-dioxane (5 ml) to give 30 mg of the product as a pale yellow solid. M.P.: 125-128°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.85 (br. s, IH); 7.81-7.65 (m, 5H); 7.32 (d, J = 8.1, 2H); 7.06 (s, IH); 5.06 (q, J = 6.8,
IH); 3.22 (s, 3H); 1.69 (d, J = 6.8, 3H). IR (cm"', KBr): 3272 (w), 3105 (w), 3072 (w), 2925 (m), 1768 (m), 1705 (s), 1540 (s), 1478 (m), 1443 (m), 1428 (m), 1403 (w), 1382 (m), 1265 (m), 1177 (w), 1161 (w), 1090 (w), 1006 (m), 854 (w), 834 (w), 740 (w). MS [(m/z)]: 426.38 ([M+H]+).
Example 30
N 1 -r4-(4-ChlorophenylV 1.3 -thiazol-2-vπ-N 1 -methyl-2-(2-methyl- 1.3 -dioxo-2.3 -dihvdro- 1 H-4-isoindolyl)acetamide
Figure imgf000049_0001
To a stirred solution of example 16 (160 mg, 0.388 mmol) in DMF(1.94 mL) was added sodium hydride (60% dispersion in mineral oil, 16 mg, 0.427 mmol) at RT and reaction mixture was stirred for 30 min. Iodomethane was added (32 μL, 0.51 mmol) drop wise and stirring continued for 3h. The reaction mixture was quenched in water; precipitated crude product was collected by filtration and subjected to purification (AcOEt/CHCl3 as eluent) to give 58 mg of the product as an off-white solid. M.P.: 211-213°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.85-7.75 (m, 3H); 7.67 (t, J = 7.8, IH); 7.58 (d, J = 7.8, IH);
7.36 (d, J = 9.0, 2H); 7.14 (s, IH); 4.51 (s, 2H); 3.99 (s, 3H); 3.13 (s, 3H). IR (cm"1, KBr): 2921 (w), 2851 (w), 1766 (m), 1706 (s), 1657 (m), 1522 (w), 1488 (m), 1444 (w), 1428 (m), 1404 (w), 1379 (m), 1325 (w), 1294 (w), 1275 (w), 1249 (w), 1200 (w), 1172 (w), 1122 (w), 1090 (w), 1056 (w), 1005 (w), 929 (w), 855 (w), 839 (w), 825 (w), 748 (w), 735 (w), 723 (w). MS [(m/z)]: 426.45 ([M+H]+).
Example 31 Nl-r4-(2,4-Dichlorophenvn-L3-thiazol-2-yl1-2-r2-methyl-1.3-dioxo-2,3-dihvdro-lH-4- isoindolyl)acetamide
Figure imgf000049_0002
The title compound was prepared according to the general procedure described in method
B by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(2,4-dichlorophenyl)-l,3- thiazol-2-amine (111 mg, 0.456 mmol) in the presence of N,N-dimethylaniline (138 mg,
1.140 mmol) and DMAP (5 mg, 0.045 mmol) in 1,4-dioxane (5 ml) to give 29 mg of the product as an off-white solid. M.P.: 213-216°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 10.07 (br. s, IH); 7.85-7.75 (m, 2H); 7.75-7.65 (m, 2H); 7.45-7.40 (m, 2H); 7.30-7.20 (lHunder CHCl3 signal); 4.23 (s, 2H); 3.20 (s, 3H). IR (cm'1, KBr): 3289 (m), 3138 (w), 3070 (w), 2924 (w), 2953 (w), 1769 (w), 1716 (s), 1683 (m), 1677 (m), 1590 (w), 1558 (m), 1547 (m), 1468 (w), 1446 (w), 1430 (w), 1380 (w), 1342 (w), 1306 (w), 1273 (w), 1232 (w), 1196 (w), 1180 (w), 1157 (w), 1122 (w), 1104 (w), 1084 (w), 1042 (w), 1007 (w), 926 (w), 910 (w), 864 (w), 823 (w), 789 (w), 756 (w), 737 (w). MS [(m/z)]: 446.26 ([M+H]+).
Example 32 Nl-r4-(3.4-Dichlorophenvn-1.3-thiazol-2-yll-2-(2-methyl-1.3-dioxo-2.3-dihvdro-lH-4- isoindolvDacetamide
Figure imgf000050_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(3,4-dichlorophenyl)-l,3- thiazol-2-amine (134 mg, 0.547 mmol) in the presence of N,N-dimethylaniline (138 mg, 1.140 mmol) and DMAP (5 mg, 0.045 mmol) in 1,4-dioxane (5 ml) to give 98 mg of the product as a pale yellow solid. M.P.: 190-1930C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 10.04 (br. s, IH); 7.91 (s, IH); 7.85-7.75 (m, IH); 7.75-7.55 (m, 3H); 7.43 (d, J = 9.0,
IH); 7.11 (s, IH); 4.23 (s, 2H); 3.23 (s, 3H). IR (cm'1, KBr): 3311 (w), 3109 (w), 3047 (w), 2948 (w), 1763 (m), 1700 (s), 1606 (w), 1562 (m), 1539 (s), 1478 (w), 1442 (m), 1386 (m), 1302 (m), 1271 (w), 1253 (w), 1205 (w), 1183 (w), 1164 (w), 1138 (w), 1124 (w), 1065 (w), 1055 (w), 1028 (w), 1006 (m), 935 (w), 914 (w), 861 (w), 839 (w), 832 (w), 790 (w), 769 (w), 735 (m). MS (m/z): 446.21 ([M+H]+).
Example 33 Nl-|"4-(4-Chloro-3-methylphenyl)-1.3-thiazol-2-yll-2-(2-methyl-13-dioxo-2.3-dihvdro- 1 H-4-isoindolyl)acetamide
Figure imgf000051_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(4-chloro-3-methylphenyl)- l,3-thiazol-2-amine (122 mg, 0.547 mmol) in the presence of N,N-dimethylaniline (138 mg, 1.140 mmol) and DMAP (5 mg, 0.045 mmol) in 1,4-dioxane (5 ml) to give 68 mg of the product as an off-white solid. M.P.: 214-217°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 10.00 (br. s, IH); 7.85-7.75 (m, IH); 7.75-7.60 (m, 3H); 7.55 (d, J = 7.8, IH); 7.32 (d, J =
8.1, IH); 7.06 (s, IH); 4.22 (s, 2H); 3.21 (s, 3H); 2.40 (s, 3H). IR (cm"1, KBr): 3252 (w), 3223 (w), 3102 (w), 3068 (w), 2853 (w), 1772 (m), 1705 (s), 1693 (s), 1547 (s), 1476 (w), 1449 (w), 1412 (w), 1385 (m), 1344 (w), 1317 (m), 1265 (w), 1200 (w), 1158 (m), 1073 (w), 1049 (w), 1011 (m), 974 (w), 855 (w), 829 (w), 743 (w), 730 (m). MS (m/z): 424.52 ([M-H]").
Example 34
N 1 - (4-f 3-Fluoro-4-(trifluoromethvnphenvn- 1 ,3-thiazol-2-yll -2-(2-methyl- 1.3-dioxo-2.3- dihydro- 1 H-isoindol-4-vQacetamide
Figure imgf000051_0002
The title compound was prepared according to the general procedure described in method C by coupling Intermediate 1 (200 mg, 0.912 mmol) with 4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (239 mg, 0.912 mmol) in the presence of EDCI hydrochloride (210 mg, 1.095 mmol), ΗOBt (36 mg, 0.273 mmol) and DMAP (1 1 mg, 0.091 mmol) in 1 ,2-dichloroethane (10 ml) to give 80 mg of the product as an off- white solid. M.P.: 206-2080C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 12.71 (br. s, IH); 8.03-7.92 (m, 3H); 7.86 (d, J = 8.1, IH); 7.76-7.70 (m, 3H); 4.34 (s, 2H); 3.00 (s, 3H). MS (m/z): 464.06 ([M+H]+). Example 35
Nl-{4-r3,5-Difluoro-4-rtrifluoromethvπphenvn-1.3-thiazol-2-vU-2-('2-methyl-1.3-dioxo- 2,3-dihvdro-lH-isoindol-4-yl)acetamide
Figure imgf000052_0001
The title compound was prepared according to the general procedure described in method C by coupling Intermediate 1 (117 mg, 0.535 mmol) with 4-[3,5-difluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (150 mg, 0.535 mmol) in the presence of EDCI hydrochloride (123 mg, 0.642 mmol), HOBt (21 mg, 0.160 mmol) and DMAP (6.54 mg, 0.053 mmol) in 1,2-dichloroethane (5.3 ml) to give 52 mg of the product as an off-white solid. M.P.: 224-226°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 12.68 (br. s, IH); 8.39-8.33 (m, 2H); 7.80-7.70 (m, 2H); 7.63 (s, IH); 7.52 (d, J = 8.4, IH); 4.34 (s, 2H); 3.00 (s, 3H). MS (m/z): 482.09 ([M+H]+).
Example 36
Nl-{4-[4-(3,5-Difluoro. 4-difluoromethoxyphenyll-1.3-thiazol-2-vU-2-(2-methyl-1.3- dioxo-2,3-dihydro- 1 H-4-isoindolyl)acetamide
Figure imgf000052_0002
The title compound was prepared according to the general procedure described in method C by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-[3,5-difluoro, 4- difluoromethoxy phenyl]-l,3-thiazol-2-amine (126 mg, 0.456 mmol) in the presence of EDCI hydrochloride (104 mg, 0.547 mmol), HOBt (18 mg, 0.136 mmol) and DMAP (5 mg, 0.045 mmol) in 1,2-dichloroethane (4 ml) to give 29 mg of the product as an off- white solid. M.P.: 216-2180C. 1H-NMR (δ ppm, OMSO-d6, 300 MHz): 12.68 (br. s, IH); 7.88 (s, IH); 7.81-7.70 (m, 5H); 7.28 (d, J = 72.3, IH); 4.33 (s, 2H); 3.31 (s, 3H); 3.00 (s, 3H). Example 37
Nl-r4-(4-Chlorophenyl)-5-methyl-1.3-thiazol-2-yl1-2-(2-methyl-1.3-dioxo-2.3-dihvdro- 1 H-4-isoindolvDacetamide
Figure imgf000053_0001
The title compound was prepared according to the general-procedure described in method A by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4-(4-chlorophenyl)-5-methyl- l,3-thiazol-2-amine (205 mg, 0.912 mmol) in 1,4-dioxane (5 ml) to give 80 mg of the product as a yellow solid. M.P.: 223-226°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.90 (br. s, IH); 7.80-7.75 (m, IH); 7.70-7.60 (m, 2H); 7.51 (d, J = 8.4, 2H); 7.36 (d, J = 5.5, 2H); 4.16 (s, 2H); 3.19 (s, 3H); 2.45 (s, 3H). IR (cm"1, KBr): 3221 (m), 3239 (m), 2921 (w), 1771 (s), 1702 (s), 1683 (s), 1569 (w), 1547 (s), 1486 (w), 1448 (s), 1429 (m), 1399 (w), 1382 (m), 1337 (w), 1276 (m), 1263 (m), 1157 (w), 1096 (w), 1008 (s), 966 (w), 854 (w), 834 (w), 731 (w). MS [(m/z)]: 426.51 ([M+H]+).
Example 38 Nl -r4,5-Dihvdronaphthori .2-diπ .31thaiazol-2-yl1-2-(2-methyl- 1.3-dioxo-2.3-dihydro- 1 H-4-isoindolyl)acetamide
Figure imgf000053_0002
The title compound was prepared according to the general procedure described in method A by coupling Intermediate 1 (100 mg, 0.456 mmol) with 4,5-dihydronaphtho[l,2- </][l,3]thiazol-2-amine(101 mg, 0.501 mmol) in the presence of N, N-dimethylaniline (71 mg, 0.593 mmol) in 1,4-dioxane (5 ml) to give 45 mg of the product as an off-white solid. M.P.: >290°C (Decomposes). 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.86 (br. s, IH); 7.77-
7.68 (m, 3H); 7.03-7.01 (m, 4H); 4.22 (s, 2H); 3.21 (s, 3H); 3.05-2.85 (m, 4H). IR (cm"1, KBr): 3448 (w), 3255 (w), 3226 (m), 3074 (w), 2954 (w), 1767 (m), 1702 (m), 1689 (s), 1549 (s), 1446 (w), 1430 (w), 1384 (m), 1339 (w), 1365 (m), 1163 (w), 1008 (m), 771 (w) 762 (w), 729 (w). MS [(m/z)]: 404.22 ([M+H]+).
Example 39
Nl-r7-Chloro-4.5-dihvdronaphthori.2-diri.31thaiazol-2-yll-2-('2-methyl-1.3-dioxo-2.3- dihvdro- 1 H-4-isoindolvπacetamide
Figure imgf000054_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (150 mg, 0.684 mmol) with 7-chloro-4,5- dihydronaphtho[l,2-fiT][l,3]thiazol-2-amine (178 mg, 0.752 mmol) in the presence of N,N-dimethylaniline (108 mg, 0.889 mmol), DMAP (8 mg, 0.068 mmol) in 1,4-dioxane (5 ml) to give 102 mg of the product as an off-white solid. M.P.: 201-203°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 12.50 (br. s, IH); 7.85-7.55 (m, 4H); 7.34 (s, 2H); 4.30 (s, 2H);
3.10-2.80 (m, 4H); 2.99 (s, 3H). IR (cm'", KBr): 3244 (m), 3225 (m), 3074 (w), 2983 (w), 2942 (w), 2919 (w), 2906 (w), 1770 (m), 1704 (s), 1688 (s), 1610 (w), 1550 (s), 1486 (w), 1446 (m), 1430 (w), 1402 (w), 1384 (m), 1363 (w), 1346 (w), 1271 (m), 1233 (w), 1197 (w), 1164 (w), 1131 (w), 1097 (w), 1062 (w), 1009 (m), 973 (w), 923 (w), 910 (w), 882 (w), 874 (w), 854 (w), 824 (w), 810 (w), 770 (w), 729 (m). MS (m/z): 438.38 ([M+H]+).
Example 40
N 1 - r 1 -(4-Bromophenvn- 1 H-3 -pyrazolyl1-2-(2-Methyl- 1 ,3-dioxo-2,3 -dihvdro- 1 H-4- isoindolvDacetamide
Figure imgf000054_0002
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with l-(4-bromophenyl)-lH- pyrazol-3-amine (119 mg, 0.501 mmol) in the presence of N, N-dimethylaniline (71 mg, 0.593 mmol) and DMAP (5.5 mg, 0.045 mmol) in 1,4-dioxane (5 ml) to give 102 mg of the product as a yellow solid. M.P.: 229-231°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.88 (br. s, IH), 7.80-7.20 (m, 4H); 7.52 (d, J = 9.0, 2H); 7.47 (d, J = 9.0, 2H); 6.87 (d, J = 1.8, IH); 4.16 (s, 2H); 3.21 (s, 3H). IR (cm"', KBr): 3446 (w), 3273 (s), 3047 (w), 2925 (w), 1761 (m), 1697 (s), 1563 (s), 1491 (w), 1446 (m), 1429 (w), 1419 (w), 1404 (s), 1385 (s), 1268 (w), 1250 (w), 1204 (m), 1198 (w), 1162 (w), 1050 (w), 1020 (w), 1062 (w), 1004 (s), 944 (w), 830 (w), 826 (w), 749 (m). MS (m/z): 439.39 ([M+H]+).
Example 41
Nl-ri-(4-Chlorophenvn-lH-3-pyrazolyll-2-r2-methyl-1.3-dioxo-2.3-dihvdro-lH-4- isoindolvDacetamide
Figure imgf000055_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (100 mg, 0.456 mmol) with l-(4-chlorophenyl)-lH-pyrazol- 3-amine (102 mg, 0.501 mmol) in the presence of N, N-dimethylaniline (138 mg, 1.140 mmol) and DMAP (5 mg, 0.045 mmol) in 1,4-dioxane (5 ml) to give 68 mg of the product as an off-white solid. M.P.: 212-214°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.95 (br. s, IH); 7.80-7.60 (m, 4H); 7.53 (d, J = 8.7, 2H); 7.37 (d, J = 8.7, 2H); 6.86 (d, J
= 1.8, IH); 4.16 (s, 2H); 3.20 (s, 3H). IR (cm"', KBr): 3273 (m), 3041 (w), 2924 (w), 2852 (w), 1763 (w), 1699 (s), 1663 (s), 1588 (w), 1563 (m), 1550 (m), 1493 (m), 1476 (m), 1446 (m), 1429 (w), 1386 (m), 1268 (m), 1252 (w), 1233 (w), 1195 (w), 1100 (w), 1051 (w), 1005 (m), 967 (w), 945 (w), 926 (w), 854 (w), 832 (w), 806 (w), 796 (w), 750 (m), 726 (m). MS [(m/z)]: 395.41 ([M+H]+). •
Example 42
Nl-r3-r4-ChlorophenylVlH-5-pyrazolyll-2-r2-methyl-l,3-dioxo-2,3-dihvdro-lH-4- isoindolvDacetamide
Figure imgf000055_0002
The title compound was prepared according to the general procedure described in method C by coupling Intermediate 1 (100 mg, 0.456 mmol) with 3-(4-chlorophenyl)-lH-pyrazol- 5-amine (88 mg, 0.456 mmol) in the presence of EDCI hydrochloride (104 mg, 0.547 mmol), HOAt (18 mg, 0.136 mmol) and DMAP (5 mg, 0.045 mmol) in 1,2- dichloroethane (4 ml) to give 94 mg of the product as an off-white solid. M.P.: 175- 178°C. 1H-NMR (δ ppm, DMSO-J6, 300 MHz): 7.85-7.75 (m, 4H); 7.66 (t, J = 8.6, IH); 7.56 (d, J = 8.6, IH); 7.38 (d, J = 7.2, 2H); 5.53 (br. s, 2H); 4.99 (s, 2H); 3.15 (s, 3H). IR
(cm"', KBr): 3479 (m), 3376 (m), 3074 (w), 2959 (w), 2936 (w), 2851 (w), 1771 (m), 1715 (s), 1703 (s), 1619 (s), 1580 (w), 1512 (w), 1480 (m), 1441 (s), 1411 (s), 1381 (s), 1352 (w), 1285 (m), 1243 (w), 1212 (w), 1109 (w), 1021 (w), 1012 (w), 992 (w), 942 (w), 911 (3w), 838 (w), 792 (w), 764 (w), 751 (w), 734 (m). MS (m/z): 395.34 ([M+H]+). Example 43
Nl-ri-(4-Chlorophenvn-5-oxo-4.5-dihvdro-lH-3-pyrazolvn-2-(2-methyl-l,3-dioxo-2.3- dihydro- 1 H-4-isoindolyl)acetamide
Figure imgf000056_0001
The title compound was prepared according to the general procedure described in method B by coupling Intermediate 1 (200 mg, 0.912 mmol) with 5-amino-2-(4-chlorophenyl)- 2,4-dihydro-3H-pyrazol-3-one (210 mg, 1.003 mmol) in the presence of N, N- dimethylaniline (143 mg, 1.185 mmol) and DMAP (11 mg, 0.091 mmol) in 1,4-dioxane (5 ml) to give 55 mg of the product as an off-white solid. M.P.: 247-249°C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.28 (br. s, IH); 7.82-7.68 (m, 3H); 7.68-7.63 (m, 2H); 7.13 (d, J = 7.8, 2H); 4.10 (s, 2H); 3.96 (s, 2H); 3.22 (s, 3H). IR (cm"', KBr): 3258 (w), 3222 (w), 3188 (w), 3100 (w), 2975 (w), 1767 (w), 1698 (s), 1632 (s), 1597 (w), 1494 (s), 1444 (m), 1383 (w), 1348 (m), 1257 (w), 1204 (w), 1178 (w), 1159 (w), 1141 (w), 1008 (m), 836 (w). MS [(m/z)]: 411.23 ([M+H]+).
Example 44 N 1 -r5-(4-BromophenylV 1.3.4-thiadiazoI-2-yl1-2-(2-methyl- 1.3 -dioxo-2.3-dihvdro- 1 H-4- isoindolvDacetamide
Figure imgf000057_0001
The title compound was prepared according to the general procedure described in method C by coupling Intermediate 1 (100 mg, 0.456 mmol) with 5-(4-bromophenyl)-l,3,4- thiadiazol-2-amine (116 mg, 0.456 mmol) in the presence of EDCI hydrochloride (104 mg, 0.547 mmol), HOBt (18 mg, 0.136 mmol) and DMAP (5 mg, 0.045 mmol) in 1,2- dichloroethane (4 ml) to give 61 mg of the product as a white solid. M.P.: >265°C. 1H- NMR (δ ppm, OMSO-d6, 300 MHz): 13.01 (s, IH); 7.84 (d, J = 9.0, 2H); 7.75-7.65 (m,
5H); 4.36 (s, 2H); 2.99 (s, 3H). IR (cm'', KBr): 3157 (w), 2921 (w), 2853 (w), 2727 (w), 1767 (w), 1711 (s), 1589 (w), 1556 (m), 1489 (w), 1441 (m), 1379 (m), 1348 (m), 1204 (w), 1176 (w), 1071 (w), 1005 (w), 985 (w), 730 (w). MS [(m/z)]: 458.94 ([M+H]+).
Example 45: Screening for TRPAl antagonist using the 45Calcium uptake assay
The inhibition of TRPAl receptor activation was followed as inhibition of allyl isothiocyanate (AITC) induced cellular uptake of radioactive calcium.
Test compounds were dissolved in 100% DMSO to prepare 20 mM stock and then diluted using plain medium with 0.1% BSA and 1.8 mM CaCl2 to get desired concentration. Final concentration of DMSO in the reaction was 0.5% (v/v). Human
TRPAl expressing CHO cells were grown in F- 12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, 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 AITC at a final concentration of 30 μM and 5 μCi/ml 45Ca+2 for 3 minutes. Cells were washed and lysed using buffer containing 1% Triton X-100, 0.1 % deoxycholate and 0.1% SDS.
Radioactivity in the lysate was measured in Packardt Top count after addition of liquid scintillant. (Toth A, et al, Life Sciences, (2003) 73, 487-498; McNamara CR et al, Proceedings of the National Academy of Sciences, (2007), 104, 13525-13530)
Concentration response curves were plotted as a % of maximal response obtained in the absence of test antagonist. IC50 values' can be calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software. The title compounds of the examples were tested in the biological test described above and the results were expressed as percent inhibition at various concentrations.
The IC50 (nM) values of the compounds are set forth in Table 3 wherein "A" refers to an IC50 value of less than 250.00 nM, "B" refers to IC50 value in range of 250.01 to 500.00 nM, "C" refers to an IC50 value in range of 500.01 to 1000.00 nM and "D" refers to an IC50 value of greater than 1000.01 nM.
Table 3: In- vitro screening results of compounds of invention
Figure imgf000058_0001
Figure imgf000059_0001
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

WE CLAIM:
1. A compound of Formula (I)
Figure imgf000061_0001
(I) tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein, ring A is aryl, heteroaryl, heterocyclyl or cycloalkyl;
R2 is independently hydrogen, cyano, nitro, -NRxRy, halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heterocyclylalkyl, -C(O)OR", -ORX, -C(0)NRxRy, - C(O)RX, -S(O)m-Rx, -S(O)m-NRxRy;
Rx and Ry are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heterocyclylalkyl;
R1 is independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,
(CRxRy)nOR3, CORX, COOR", C0NRxRy, S(O)mNRxRy, NRxRy, NRx(CRxRy)nOR3, NRx(CRxRy)nCN (CH2)nNRxRy, (CH2)nCHRxRy, (CR1R3)NRxRy, NRx(CRxRy)nCONRxRy, (CH2)nNHCORx and (CH2)nNH(CH2)nSO2Rx, (CH2)nNHSO2Rx;
R3 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted. arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heterocyclylalkyl Ra and Rb are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heterocyclylalkyl; or
Ra and Rb may be joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least one heteroatom such as O and S or group selected from NRd, C(O) and S(O)0-2; Rc is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, (CRxRy)nOR3, CORX, COOR", C0NRxRy, S(0)mNRxRy, NRxRy, NRx(CRxRy)nOR3, NRx(CRxRy)nCN (CH2)nNRxRy, (CH2)nCHRxRy, (CR'R3)NRxRy, NRx(CRxRy)nCONRxRy, (CH2)nNHC0Rx and (CH2)nNH(CH2)nSO2Rx, (CH2)nNHSO2Rx; each occurrence of Rd is hydrogen or substituted or unsubstituted alkyl; each occurrence of 'm' is independently selected from 0-2; each occurrence of 'n' is independently selected from 0-5.
2. A compound according to claim 1, wherein ring A is substituted or unsubstituted phenyl.
3. A compound according to claim 1, wherein ring A is substituted or unsubstituted pyridine.
4. A compound according to claim 1, wherein ring A is substituted or unsubstituted thiazole.
5. A compound according to claim 1, wherein ring A is substituted or unsubstituted pyrazole.
6. A compound according to claim 1 , wherein ring A is substituted or unsubstituted pyrazolone
7. A compound according to claim 1 , wherein ring A is substituted or unsubstituted thiadiazole.
8. A compound according to any of the claim 1 to 7, wherein R1 is hydrogen.
9. A compound according to to any of the claim 1 to 7, wherein R1 is alkyl.
10. A compound according to to any of the claim 9, wherein alkyl is methyl.
11. A compound according to to any of the claim 9, wherein alkyl is ethyl.
12. A compound according to to any of the claim 9, wherein alkyl is propyl.
13. A compound according to any of the claim 1 to 12, wherein R2 is substituted or unsubstituted alkyl and/or halogen.
14. A compound according to any of the claim 1 to 12, wherein R2 is substituted or unsubstituted phenyl.
15. A compound according to any of the claim 1 to 12, wherein R2 is substituted or unsubstituted cycloalkyl.
16. A compound according to any of the claim 1 to 14, wherein Ra, Rb and Rc are hydrogen.
17. A compound according to any of the claim 1 to 14, wherein Ra or Rb is methyl.
18. A compound according to any of the claim 1 to 16, wherein Rc is methyl.
19. A compound selected from, Nl -(4-isopropylphenyl)-2-(2-methyl- 1 ,3-dioxo-2,3-dihydro- 1 H-4-isoindolyl) acetamide,
Nl-(4-Bromophenyl)-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-4-isoindolyl) acetamide, N 1 -(4-Chlorophenyl)-2-(2-methyl- 1 ,3 -dioxo-2,3-dihydro- 1 H-4-isoindolyl) acetamide,
Nl -(4-Chloro-2-fluorophenyl)-2-(2-methyl-l ,3-dioxo-2,3-dihydro- 1 H-4- isoindolyl)acetamide, N 1 -(4-Fluoro-2-chloro)-2-(2-methyl- 1 ,3 -dioxo-2,3-dihydro- 1 H-4-isoindolyl) acetamide,
N 1 -(4-Chloro-3-trifluoromethylphenyl)-2-(2-methyl- 1 ,3-dioxo-2,3-dihydro- 1 H-4- isoindolyl)acetamide,
N 1 -(4-phenylphenyl)-2-(2-Methyl- 1 ,3-dioxo-2,3-dihydro- 1 H-4- isoindolyl)acetamide,
Nl-[3-(4-bromophenyl)phenyl]-2-(2-Methyl-l,3-dioxo-2,3-dihydro-lH-4- isoindolyl)acetamide,
N 1 -[4-(3-Bromophenyl)phenyl]-2-(2-Methyl- 1 ,3-dioxo-2,3-dihydro- 1 H-4- isoindolyl)acetamide, Nl-[4-(4-bromophenyl)phenyl]-2-(2-Methyl-l,3-dioxo-2,3-dihydro-lH-4- isoindolyl)acetamide,
2-(2-Methyl-l,3-dioxo-2,3-dihydro-lH-4-isoindolyl)-N-[4-(4-methylphenoxy) phenyl]acetamide,
N 1 -[5-(4-Chlorophenyl)-2-pyridyl]-2-(2-Methyl- 1 ,3-dioxo-2,3-dihydro- 1 H-4- isoindolyl)acetamide,
Nl-[4-Cyclohexyl-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-4- isoindolyl)acetamide,
N 1 -[4-(4-Methylphenyl)- 1 ,3-thiazol-2-yl]-2-(2-methyl- 1 ,3-dioxo-2,3-dihydro- 1 H- 4-isoindolyl)acetamide, N 1 -[4-(4-tert-butylphenyl)- 1 ,3-thiazol-2-yl]-2-(2-methyl- 1 ,3-dioxo-2,3-dihydro-
1 H-4-isoindolyl)acetamide
Nl-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH- 4-isoindolyl)acetamide, N 1 -[4-(4-Iodophenyl)- 1 ,3-thiazol-2-yl]-2-(2-methyl- 1 ,3-dioxo-2,3-dihydro- 1 H-4- isoindolyl)acetamide,
Nl-[4-(4-Bromophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH- 4-isoindolyl)acetamide, N 1 -[4-(4-Bromophenyl)- 1 ,3-thiazol-2-yl]-2-( - 1 ,3-dioxo-2-ethyl-2,3-dihydro- 1 H-
4-isoindolyl)acetamide,
Nl-[4-(4-Bromophenyl)-l,3-thiazol-2-yl]-2-(l,3-dioxo-2-propyl-2,3-dihydro-lH- 4-isoindolyl)acetamide,
Nl-[4-(3-Chlorophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH- 4-isoindolyl)acetamide,
Nl-[4-(4-Fluorophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH- 4-isoindolyl)acetamide,
Nl-[4-(3-Trifluoromethylphenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-~ dihydro- 1 H-4-isoindolyl)acetamide, Nl-[4-(3-trifluoromethoxy)phenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3- dihydro-1 H-4-isoindolyl)acetamide ,
Nl-[4-(4-Cyanophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH- 4-isoindolyl)acetamide,
Nl-[4-(4-Bromophenyl)-l,3-thiazol-2-yl]-2-(2-ethoxycarbonyl-l,3-dioxo-2,3- dihydro- 1 H-4-isoindolyl)acetamide,
N 1 - [4-(4-Bromophenyl)- 1 ,3-thiazol-2-yl]-2-( 1 ,3 -dioxo-2,3 -dihydro- 1 H-4- isoindolyl) acetamide,
Nl-[4-(4-Bromophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH- 4-isoindolyl)propanamide, Nl-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH-
4-isoindolyl)propanamide,
N 1 -[4-(4-Chlorophenyl)- 1 ,3-thiazol-2-yl]-N 1 -methyl-2-(2-methyl- 1 ,3-dioxo-2,3- dihydro- 1 H-4-isoindolyl)acetamide, Nl-[4-(2,4-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3-dihydro- 1 H-4-isoindolyl)acetamide,
N 1 - [4-(3 ,4-Dichlorophenyl)- 1 ,3 -thiazol-2-yl]-2-(2-methyl- 1 ,3 -dioxo-2,3-dihydro- 1 H-4-isoindolyl)acetamide, Nl-[4-(4-Chloro-3-Methylphenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3- dihydro- 1 H-4-isoindolyl)acetamide,
N 1 - {4- [3 -Fluoro-4-(trifluoromethyl)phenyl]- 1 ,3 -thiazol-2-yl } -2-(2-methyl- 1,3- dioxo-2,3-dihydro-lH-isoindol-4-yl)acetamide,
N 1 - {4- [3 ,5-difluoro-4-(trifluoromethyl)phenyl]- 1 ,3 -thiazol-2-yl } -2-(2-methyl- 1,3- dioxo-2,3 -dihydro- 1 Η-isoindol-4-yl)acetamide,
N 1 - {4-[3 ,5-difluoro, 4-difluoromethoxy)- phenyl]- 1 ,3-thiazol-2-yl} -2-(2-methyl- 1 ,3-dioxo-2,3-dihydro- 1 H-4-isoindolyl)acetamide,
Nl-[4-(4-chlorophenyl)-5-methyl-l,3-thiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3- dihydro- 1 H-4-isoindolyl)acetamide, Nl-[4,5-dihydronaphtho[l ,2-d][l ,3]thaiazol-2-yl]-2-(2-methyl-l ,3-dioxo-2,3- dihydro- 1 H-4-isoindolyl)acetamide,
Nl-[7-Chloro-4,5-dihydronaphtho[l,2-d][l,3]thaiazol-2-yl]-2-(2-methyl-l,3- dioxo-2,3-dihydro- 1 H-4-isoindolyl)acetamide,
Nl-[I -(4-Bromophenyl)- 1 H-3-pyrazolyl]-2-(2-Methyl- 1 ,3-dioxo-2,3-dihydro- 1 H- 4-isoindolyl)acetamide,
Nl-[I -(4-Chlorophenyl)- 1 H-3-pyrazolyl]-2-(2-methyl- 1 ,3 -dioxo-2,3 -dihydro- 1 H- 4-isoindolyl)acetamide,
Nl-[3-(4-Chlorophenyl)-lH-5-pyrazolyl]-2-(2-methyl-l,3-dioxo-2,3-dihydro-lH- 4-isoindolyl)acetamide, Nl-[l-(4-Chlorophenyl)-5-oxo-4,5-dihydro-lH-3-pyrazolyl]-2-(2-methyl-l,3- dioxo-2,3-dihydro- 1 H-4-isoindolyl)acetamide,
Nl-[5-(4-Bromophenyl)-l,3,4-thiadiazol-2-yl]-2-(2-methyl-l,3-dioxo-2,3- dihydro- 1 H-4-isoindolyl)acetamide, or tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof.
20. A process for the preparation of compounds of formula (I)
Figure imgf000067_0001
(I) tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein, ring A, R1, R2, Ra, Rb, and Rc are defined as in claim 1 ; the process comprising of,
(a) alkylating compound of formula (6) with alkylating agent such as RaX and/or RbX followed by hydrolysis to obtain compound of formula (6a),
Figure imgf000067_0002
(6) (6a)
(b) reacting compound of formula (6) with oxalyl chloride to obtain compound of formula (9),
Figure imgf000067_0003
(c) coupling compound of formula (6) or formula (9) with an amine of formula (10) in presence of a catalyst to obtain compound of formula (Ia),
Figure imgf000067_0004
(Ia)
(d) coupling of compound of formula (6a) with an amine of formula (10) to obtain compound of formula (Ib),
Figure imgf000068_0001
(e) alkylating compound of formula (Ib) with alkyl halide to obtain compound of formula (I).
21. A pharmaceutical composition comprising a compound according to any of claims 1- 20 either as a free base or in pharmaceutically acceptable salt form and a pharmaceutically acceptable excipient.
22. A method for treating disease or condition associated with TRPAl function in a subject in need thereof comprising administering to the subject an effective amount of a compound according to any of claims 1-20.
23. A method according to claim 22, wherein the symptoms of a disease or condition associated with TRPAl function is selected from 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, post-herpetic 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, urinary incontinence, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus.
24. A method according to claim 22, wherein the symptoms of a disease or condition is associated with chronic pain.
25. A method according to claim 22, wherein the symptoms of a disease or condition is associated with neuropathic pain.
26. A method according to claim 22, wherein the symptoms of a disease or condition is associated with rheumatoid arthritic pain or osteoarthritic pain.
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