WO2009116074A2

WO2009116074A2 - Substituted benzimidazoles as cannabinoid modulator

Info

Publication number: WO2009116074A2
Application number: PCT/IN2009/000099
Authority: WO
Inventors: Harikishore Pingali; Mukul R. Jain; Pankaj M. Makadia
Original assignee: Cadila Healthcare Limited
Priority date: 2008-02-13
Filing date: 2009-02-12
Publication date: 2009-09-24
Also published as: WO2009116074A3

Abstract

The present invention relates to novel compounds of general formula (I), their stereoisomers, regioisomers, tautomeric forms and novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. The present invention also relates to a process of preparing novel compounds of general formula (I), their stereoisomers, regioisomers, their tautomeric forms, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutical compositions containing them, and novel intermediates involved in their synthesis.

Description

iUBSTITUTED BENZIMIPAZOLES AS CANNABINOID MODULATORS IELD OF INVENTION

The present invention relates to novel compounds of general formula (I), their stereoisomers, egioisomers, tautomeric forms and novel intermediates involved in their synthesis, their •harmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical ompositions containing them. The present invention also relates to a process of preparing novel ompounds of general formula (I), their stereoisomers, regioisomers, their tautomeric forms, their (harmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutical compositions :ontaining them, and novel intermediates involved in their synthesis.

5ACKGROUND AND PRIOR ART OF THE INVENTION

(-)-δ-Tetrahydrocannabinol (δ-THC), the major psychoactive constituent of marijuana, exerts i broad range of biological effects through its interactions with the two cannabinoid (CB) receptor subtypes, CBi and CB₂. CBi receptors are highly expressed in the central nervous system and to a lesser degree in the periphery in a variety of tissues of the cardiovascular and gastrointestinal systems, By contrast, CB₂ receptors are most abundantly expressed in multiple lymphoid organs and cells of the immune system, including spleen, thymus, tonsils, bone marrow, pancreas and mast cells.

Tire psychotropic effects caused by δ⁹-THC and other nonselective CB agonists are mediated by CBi receptors. These CB₁ receptor-mediated effects, such as euphoria, sedation,, hypothermia, catalepsy, and anxiety, have limited the development and clinical utility of nonselective CB agonists. Recent studies have demonstrated that CB₂ modulators are analgesic in pre-clinical models of nociceptive and neuropathic pain without causing the adverse side effects associated with CBi receptor activation. Therefore, compounds that selectively target CB₂ receptors are an attractive approach for the development of novel analgesics.

Pain is the most common symptom of disease and the most frequent complaint which patients present to physicians. Pain is commonly segmented by duration {acute vs. chronic), intensity (mild, moderate, and severe), and type (nociceptive vs neuropathic). Nociceptive pain is the most well known type of pain, and is caused by tissue injury detected by nociceptosis at the site of injury. After the injury, the site becomes a source of ongoing pain and tenderness This pain and tenderness are considered "acute" nociceptive pain. This pain and tenderness gradually diminish as healing progresses and disappear when healing is complete. Examples of acute nociceptive pain include surgical procedures (post-op pain) and bone fractures Even though there may be no permanent nerve damage, "chronic" nociceptive pain results from some conditions when pain extends beyond six months Examples of chronic nociceptive pain include osteoarthritis, rheumatoid arthritis, and musculoskeletal conditions (e.g., back pain), cancer pain, etc

Neuropathic pain is defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system" by the International Association for the Study of Pain, Neuropathic pain is not associated with nociceptive stimulation, although the passage of nerve impulses that is ultimately perceived as pain by the brain is the same in both nociceptive and neuropathic pain, The term neuropathic pain encompasses a wide range of pain syndromes of diverse etiologies. The three most commonly diagnosed pain types of neuropathic nature are diabetic neuropathy, cancer neuropathy, and HTV pain In addition, neuropathic pain is diagnosed in patients with a wide range of other disorders, including trigeminal neuralgia, post-herpetic neuralgia, traumatic neuralgia, phantom limb, as well as a number of other disorders of ill-defined or unknown origin.

Managing the spectrum of pain etiologies remains a major public health problem and both patients and clinicians are seeking improved strategies to effectively manage pain. No cuπently available therapies or drugs effectively treat all types of nociceptive and neuropathic pain states. The compounds of the present invention are novel CB₂ receptor modulators that have utility in treating pain, including nociceptive and neuropathic pain.

The location of CB₂ receptors on the surface of immune cells suggests a role for these receptors in immunomodulation and inflammation. Recent studies have demonstrated that CB₂ receptor ligands have immunomodulatory and antiinflammatory properties. Therefore, compounds that interact with CB₂ receptors offer a unique pharmacotherapy for the treatment of immune and inflammatory disorders.

International patent applications WO2006/052190, WO2006033629, WO2006052189 discloses benzimidazole derivatives as cannabinoid receptor modulators. However, the therapeutic potential of these compounds to treat diseases has not yet been proved and so there remains the need to develop newer medicines which are better or of comparable efficacy with the present treatment regimes, have lesser side effects and require a lower dosage regime.

We herein disclose novel compounds of formula (I) useful as cannabinoid receptor modulators in the treatment of pain, including nociceptive and neuropathic pain, immunomodulation and inflammation. OBJECTS OF THE INVENTION

The main objective of the present invention is to provide novel substituted benzimidazole derivatives represented by the general formula (I), their tautomeric forms, their stereoisomers, regioisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures thereof. Another object of the present invention is to provide for a process for the preparation of novel substituted benzimidazole derivatives represented by the general formula (I), their tautomeric forms, their stereoisomers, regioisomers, their pharmaceutically acceptable salts.

Yet another object of the present invention is to provide for pharmaceutical compositions containing compounds of the general formula (I), their tautomeric forms, their stereoisomers, regioisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions. SUMMARY OF THE INVENTION

Accordingly, the present invention relates to compounds of formula (I) their tautomeric forms, their stereoisomers, regioisomers, their pharmaceutically ^• acceptable salts, and pharmaceutical compositions containing them wherein

Ri at each occurrence independently represents optionally substituted alkyl group selected from propyl and isopropyl group, aryl, heteroaryl, heterocyclyl; cycloalkyl, or bicycloalkyl groups;

X represents O, S, or optionally substituted groups selected from CH₂, SO or SO₂, or the group representing N-R₂ were R₂ represents optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl or bicycloalkylalkyl groups, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl or sulfonyl derivatives; Y represents CH or N; Z represents NH or O.

In a preferred embodiment of the . invention, R₁ represents phenyl, napthyl, pyridyl, thiophenyl, furanyl, piperidine, piperazine, morpholine, thiomorpholine or C₃ to C₇ membered cycloalkyl group.

In another preferred embodiment of the invention R₂ represents optionally substituted groups selected from Ci to C₄ linear or branched alkyl, C₃ to C₇ cycloalkyl, phenyl, pyridyl, piperidine, Ci to C₄ linear or branched alkylsulfonyl, phenyl sulfonyl or pyridyl sulfonyl groups.

In yet another preferred embodiment of the invention substituents on Ri and R₂ are independently selected from hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aiyl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid or its derivatives.

In yet another preferred embodiment of the invention the substituents on Ri & R₂ are independently selected from C₁ to C₄ linear or branched alkyl, Ci to C₄ linear or branched alkoxy, halo, phenyl, C₁-C₄ linear or branched alkylthio, Ci-C₄ linear or branched alkylsulfonyl, Ci-C₄ linear or branched alkylsulfenyl, carboxyl, nitro, trifluoromethyl, trifluoro methoxy, cyano, hydroxyl, oxo or acyl group, each of these groups, are further optionally substituted with one or more groups from those described above.

In a preferred embodiment of the invention the compound of formula (I) are selected from:

( 1 -Isopropyl-2-phenylamino 1 H-benzDimidazol-5-yl)-moφholin-4-yl-methanone;

Morpholino(2-phenoxy- 1-phenyl- 1 H-benzoimidazDl-5-yl)methanone; l-Isopropyl-2-(phenylamino)-N^(ljetrahydro-2H^yran^yl)methyl)-lH-ben2o[d]imidazole-5- carboxamide;

( l-Isopropyl-2-φhenylamino)- 1 H-benzo[d]imidazol-5-yiχthiomoφholino)methanone;

( 1 -Isopropyl-2-(phenylamino)- 1 H-ben2D[d]imidazol-5-yiXpiperidin- 1 -y l)methanone; Morpholino( 1 - phenyl-2-(phenylamino)- 1 H-benzo[d]imidazol-5-yl)methanone;

( l-Phenyl-2-(phenylamino)- 1 H-benzo[d]imidazol-5-yiχthiomoφholino)me1hanone;

(l-Phenyl-2-(phenylaπiino)-lH-benzo[d]imida2ol-5-yiXpiperidin-'l-yl)metiianone;

(4-Methylpiperazin- 1-yiχi -phenyl-2-(phenylamino)- 1 H-benzo[d]imidazol-5-yl)methanσne;

(2-(3-Chlorophenylamino)-l-phenyHH-benzo[d]imidazol-5-yiχmoφholino)methanone;

(2^3^hlorophenylamino)-l-phenyl-lH-benzD[d]imida2Dl-5-yiχthiomoφhoIino)methanone;

(2^3-Chlorophenylamino)-l-phenyl-lH-benzo[d]imida2Dl-5-ylXpiperidin-l-yl)mettianone;

(2^3-Chlorophenylamino)-l-phenyl-lH-benzo[d]iniidazol-5-yiχ4-methylpiperazin-l-yl)methanone;

(2-(3-Chlorophenylamino)- 1 -phenyl- 1 H-benzotd]imidazDl-5-yiχ6,7-dihydrothieno[3₁₎2-c]pyridin-5(4H)- yl)methanone;

(2-(4-Methoxyphenylamino)- 1 -phenyl- 1 H-ben2o[d]imidazDl-5-yiχmoφholino)methanone; (2-(ΦMethoxyphenylamino)- 1 -phenyl- 1 H-benzo[d]imidazol-5-yiχthiomoφholino)methanone; (2-(4-Methoxyphenylamino)-l-phenyl-lH-benzo[d]imida-X)l-5-yl)(piperidin-l-yl)methanone; (2-(4-Methoxyphenylamino)- 1 -phenyl- 1 H-benzo[d]imidazol-5-yiχ4-methyIpiperazin- 1 -yl)methanone; (6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yiχ2-(4-methoxyphenylamino)-l-phenyl-lH- benzo[d]imidazol-5-yl)methanone;

(l-(3-ChlorOphenyl)-2-(phenylamLno)-lH-benzo[d]imida2Dl-5-yiχmoφholino)methanone; ( 1 -(3-Chlorophenyl)-2-(phenylamino)- 1 H-benzD[d]imidazol-5-yiχthiomoφholino)methanone; (l-CS-Chlorophenyl^^phenylaminoVlH-benzotdjimidazol-S-ylXpiperidin-l-yOmethanone; ( 1 -(3-Chlorophenyl)-2-(phenylamino)- 1 H-benzo[d]imidazoI-5-yiχ4-methylpiperazin- 1 -yl)methanone; (l^-Chlorophenyl^^phenylaminoVlH-benzofdlimidazol-S-ylXόJ-dihydrothienoP^-cJpyridin- 5(4Hhyl)methanone;

(l-(3-Chlorophenyl)-2-(p-tolylamino)-lH-benzD[d]iniidazol-5-yiχmoφholino)methanone; ( 1 -(3-Chlorophenyl)-2-(p-tolylamino)- 1 H-benzo[d]imidazol-5-yiχthiomoφholbo)methanone; (l-(3-Chlorophenyl)-2-{p-tolylamino)-lH-benzo[d]iniidazol-5-ylXpiperidin-l-yl)meihanone; (l-(3-ChlorophenyI)-2-(p-tolylamino)-lH-benzo[d]imidazoI-5-yiχ4-methyIpiperazin-l-yl)methanone; (l-(3^Morophenyl)-2-(Φmethoxyphenylamino)-lH-benzo[d]imiclazol-5-yiχmoφholino)me1hanone; (l-{3-Chlorophenyl)-2-(4-me1hojQφhenylamino)-lH-benzo[d]uήϊdazol-5- yiχthiomoφholino)methanone;

( 1 -(3-Chlorophenyl)-2-(4-methoxyphenylamino)- 1 H-benzo[d]imidazol-5-yiχpiperidin- 1 -yl)methanone; (1 -(3-Chlorophenyl)-2-{4-methoxyphenylamino> 1 H-benzo[d]imidazDl-5-yiχ4-methylpiperazin- 1 - yl)methanone;

(l-(3-Chlorophenyl)-2-(4^hlorophenylammo)-lH-benzo[d]imidazDl-5-yiχmoφhoIino)methanone; (l-(3-Chlorophenyl)-2-(4-chlorophenylamino)-lH-benzo[d]imidazol-5-yiχfliiomoφholino)methanone; (l-(3-Chlorophenyl)-2^4-chlorophenylamino)-lH-ben2θ[d]imidazol-5-yiXpiperidin-l-yl)methanone; (l-(3-Chlorophenyl)-2-(4-chlorophenylainino)-lH-benzo[d]imidazol-5-yiχ4-methylρiperazin-l- yl)methanone;

(l-(3-Chlorophenyl)-2-(4-chlorophenylamino)-lH-benzo[d]imidazol-5-yiχ4-(methylsulfonyl)piperazin- l-yl)methanone;

(l-(3-Chlorophenyl)-2-{3-chlorophenylamino)-lH-benzo[d]imidazDl-5-yiχmoφholino)methanone; (l-(3-Chlorophenyl)-2-(3-chlorophenylamino)-lH-benzD[d]imidazDl-5-yiχthiomoφholino)methanone; (HS-Chlorophenyl^^S-chlorophenylamino^lH-beπzDtdJimidazol-S-ylXpiperidin-l-yOmethanone; (l-(3-Chlorophenyl)-2-(3-chlorophenylamino)-lH-benzD[d]imidazol-5-yiχ4-methylpiperazin-l- yl)me(hanone;

(l-(3-Chlorophenyl)-2-{3,4-dichlorophenylamino)-lH-ben2θ[d]imida2Dl-5-yiχnioφholino)metnanone; (2-Phenoxy- 1 -phenyl- 1 H-benzo[d] imida2iol-5-yiχthiomoφholino)methanone; (2-Phenoxy-l-phenyl-lH-benzo[d]!midazol-5-yiχpiperidin-l-yl)methanone; (4-Methylpiperazin- 1 -y^-phenoxy- 1 -phenyl- 1 H-benzo[d]imidazol-5-yl)methanone;

Mθφholinc<3-phenyl-2-(phenylamino)-3H-imiclazo[4,5-b]pyridin-6-yl)methanone;

(3-Phenyl-2-(phenylamino)-3H-imidazo[4,5-b]pyridin-6-yiχthiomoφholino)methanone;

(3-Phenyl-2-(phenylamino)-3H-iniidazo[4,5-b]pyridin-6-yiXpiperidin-l-yl)methanone.

The present invention also relates to a process for preparing compound of formula (I) ;uch as herein described comprising, reacting a compound of formula (X) with compound of brmula (XI), where Ri, X, Y, Z are as defined above:

The present invention further relates to pharmaceutical composition comprising compound of formula (I) suchas herein above decsribed along with suitable excipients.

In a preferred embodiment the said pharmaceutical compositions are used for the treatment of inflammation and neuropathic pain.

In accordance with the preferred embodiments the invention also relates to a method of treating inflammation and neuropathic pain comprising compounds of formula (I) or its pharmaceutical compositions. DETAILED DESCRD7TION OF THE INVENTION

Accordingly, the present invention relates to compounds of the general formula (I),

their tautomeric forms, their stereoisomers, regioisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein

Ri at each occurrence independently represents optionally substituted alkyl group selected from propyl and isopropyl group, aryl, heteroaryl, heterocyclyl, cycloalkyl, or bicycloalkyl groups;

X represents CH₂, O, S, SO or SO₂, or the group representing N-R₂ were R₂ represents optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl or bicycloalkylalkyl groups, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl or sulfonyl derivatives; Y represents CH or N;

Z represents NH or O;

In a preferred embodiment, Ri represents phenyl, napthyl, pyridyl, thiophenyl, furanyl, piperidine, piperazine, morpholine, thiomorpholine or C₃ to C₇ membered cycloalkyl group;

R₂ represents optionally substituted groups selected from Ci to C₄ linear or branched alkyl, C₃ to C₇ cycloalkyl, phenyl, pyridyl, piperidine, Ci to C₄ linear or branched alkylsulfonyl, phenyl sulfonyl or pyridyl sulfonyl groups;

When either of Ri or R₂ is substituted the substituent may be selected from hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkdxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives.

When the substituents on either of 'Ri' or 'R₂' are further substituted, those substituents are selected from hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives.

Preferred substituents on Ri & R₂ may be independently selected from Cj to C₄ linear or branched alkyl, Ci to C₄ linear or branched alkoxy, halo, phenyl, CpC₄ linear or branched alkylthio, Ci-C₄ linear or branched alkylsulfonyl, Ci-C₄ linear or branched alkylsulfenyl, carboxyl, nitro, trifluoromethyl, trifluoro methoxy, cyano, hydroxyl, oxo or acyl group, each of these groups, when applicable, may be optionally substituted with one or more groups from those described above;

The various groups, radicals and substituents used anywhere in the specification are described in the following paragraphs. In a further preferred embodiment the groups, radicals described above may be selected from: the "alkyl" group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, «-propyl, /so-propyl, ra-butyl, sec-butyl, tert-butyl, amyl, /-amyl, n-pentyl, n-hexyl, and the like; the "alkenyl" group used either alone or in combination with other radicals, is selected from a radical containing from two to six carbons, more preferably groups selected from vinyl, allyl, 2- butenyl, 3-butenyI, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and the like; the "alkenyl" group includes dienes and trienes of straight and branched chains wherever applicable; the "alkynyl" group used either alone or in combination with other radicals, is selected from a linear or branched radical containing two to six carbon atoms, more preferably thynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, 1-hexynyl, and the like. The term "alkynyl" includes di- and tri-ynes wherever applicable; the "cycloalkyl", or "alicyclic" group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; The terms "bicycloalkyl" means more than one cycloalkyl groups fused together; the "cycloalkenyl" group used either alone or in combination with other radicals, are preferably selected from cyclopropenyl, 1-cyclobutenyl, 2-cylobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3- cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl and the like; The terms

"bicycloalkenyl" means more than one cycloalkenyl groups fused together; the "alkoxy" group used either alone or in combination with other radicals, is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, f-butoxy, iso-butoxy, pentyloxy, hexyloxy, and the like; the "alkenoxy" group used either alone or in combination with other radicals, is selected from groups containing an alkenyl radical, as defined above, attached to an oxygen atom, more preferably selected from vinyloxy, allyloxy, butenoxy, pentenoxy, hexenoxy, and the like; the "haloalkyl" group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as perhaloalkyl, more preferably, perfluoro (Ci-Cβjalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups; the "haloalkoxy" group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like; the "perhaloalkoxy" group is selected from a suitable perhaloalkyl radical, as defined above, directly attached to an oxygen atom, more preferably groups selected from trifluoromethoxy, trifluoroethoxy, and the like; the "aryl" or "aromatic" group used either alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like; the "heterocyclyl" or "heterocyclic" group used either alone or in combination with other radicals, is selected from suitable saturated, partially saturated or unsaturated aromatic or non aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3- oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazoHdinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, and the like; the "heteroaryl" or "heteroaromatic" group used either alone or in combination with other radicals, is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyiTolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofiiranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl and the like; the groups "heteroaryloxy", "heteroaralkoxy", "heterocycloxy", "heterocylylalkoxy" are selected from suitable heteroaryl, heteroarylalkyl, heterocyclyl, heterocylylalkyl groups respectively, as defined above, attached to an oxygen atom; the "acyl" group used either alone or in combination with other radicals, is selected from a radical containing one to eight carbons, more preferably selected from formyl, acetyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted; the "acyloxy" group used either alone or in combination with other radicals, is selected from a suitable acyl group, as defined above, directly attached to an oxygen atom, more preferably such groups are selected from acetyloxy, propionyloxy, butanoyloxy, isø-butanoyloxy, benzoyloxy and the like; the "acylamino" group used either alone or in combination with other radicals, is selected from a suitable acyl group as defined earlier, attached to an amino radical, more preferably such groups are selected from CH₃CONH, C₂H₅CONH, C₃H₇CONH, C₄H₉CONH, C₆H₅CONH and the like, which may be substituted; the "mono-substituted amino" group used either alone or in combination with other radicals, represents an amino group substituted with one group selected from (Ci-CβJalkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups as defined earlier, more preferably such groups are selected from methylamine, ethylamine, n-propylamine, n-butylamine, n-pentylamine and the like; the 'disubstituted amino" group used either alone or in combination with other radicals, represents an amino group, substituted with two radicals that may be same or different selected from (Ci-C₆)alkyl, substituted alkyl, aryl, substituted aryl, or arylalkyl groups, as defined above, more preferably the groups are selected from dimethylamino, methylethylamino, diethylamino, phenylmethyl amino and the like; the "arylamino" used either alone or in combination with other radicals, represents an aryl group, as defined above, linked through amino having a free valence bond from the nitrogen atom, more preferably the groups are selected from phenylamino, naphthylamino, N-methyl anilino and the like; the "oxo" or "carbonyl" group used either alone (-C=O-) or in combination with other radicals such as alkyl described above, for e.g. "alkylcarbonyl", denotes a carbonyl radical (-C=O-) substituted with an alkyl radical described above such as acyl or alkanoyl; the "carboxylic acid" group, used alone or in combination with other radicals, denotes a -COOH group, and includes derivatives of carboxylic acid such as esters and amides; the "ester" group used alone or in combination with other radicals, denotes -COO- group, and includes carboxylic acid derivatives, more preferably the ester moieties are selected from alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which may optionally be substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which may optionally be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may optionally be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group, is as defined above, which may optionally be substituted; heterocyclyloxycarbonyl, where the heterocyclic group, as defined earlier, which may optionally be substituted; the "amide" group used alone or in combination with other radicals, represents an aminocarbonyl radical

(H₂N-C=O), wherein the amino group is mono- or di-substituted or unsubstituted, more preferably the groups are selected from methyl amide, dimethyl amide, ethyl amide, diethyl amide, and the like; the "aminocarbonyl" group used either alone or in combination with other radicals, may be selected from 'aminocarbonyl', 'aminocarbonylalkyl", "n-alkylaminocarbonyl", "N- arylaminocarbonyl", "N,N-dialkylaminocarbonyl", "N-alkyl-N-arylaminocarbonyl", "N-alkyl-N- hydroxyaminocarbonyl", and "N-alkyl-N-hydroxyaminocarbonylalkyl", each of them being optionally substituted. The terms "N-alkylaminocabonyl" and "N,N-dialkylaminocarbonyl" denotes aminocarbonyl radicals, as defined above, which have been substituted with one alkyl radical and with two alkyl radicals, respectively. Preferred are "lower alkylaminocarbonyl" having lower alkyl radicals as described above attached to aminocarbonyl radical. The terms "N- arylaminocarbonyl" and "N-alkyl-N-arylaminocarbonyl" denote amiocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl, and one aryl radical. The term "aminocarbonylalkyl" includes alkyl radicals substituted with aminocarbonyl radicals; the "hydroxyalkyl" group used either alone or in combination with other radicals, is^' selected from an alkyl group, as defined above, substituted with one or more hydroxy radicals, more preferably the groups are selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like; the "aminoalkyl" group used alone or in combination with other radicals, denotes an amino (- NH₂) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted aminoalkyl. The term "alkylamino" used herein, alone or in combination with other radicals, denotes an alkyl radical, as defined above, attached to an amino group, which may be substituted, such as mono- and di-substituted alkylamino; the "alkoxyalkyl" group used alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an alkyl group as defined above, more preferably the groups may be selected from methoxymethyl, ethoxymethyl, methoxyethyl, efhoxyethyl and the like; the "alkylthio" group used either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from methylthio, ethylthio, propylthio, butylthio, pentylthio and the like or cyclic alkylthio selected from cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, which may be optionally substituted; the "thioalkyl" group used either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula -SR', where R' represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally substituted. the "alkoxycarbonylamino" group used alone or in combination with other radicals, is selected from a suitable alkoxycarbonyl group, as defined above, attached to an amino group, more preferably methoxycarboήylamino, ethoxycarbonylamino, and the like; the "aminocarbonylamino", "alkylaminocarbonylamino", "dialkylaminocarbonylamino" groups used alone or in combination with other radicals, is a carbonylamino (-CONH₂) group, attached to amino(NH₂), alkylamino group or dialkylamino group respectively, where alkyl group is as defined above; the "amidino" group used either alone or in combination with other radicals, represents a -

C(=NH)-NH₂ radical; the "alkylamidino" group represents an alkyl radical, as described above, attached to an amidino group; the "alkoxyamino" group used either alone or in combination with other radicals, represents a suitable alkoxy group as defined above, attached to an amino group; the "hydroxyamino" group used either alone or in combination with other radicals, represents a —

NHOH moiety, and may be optionally substituted with suitable groups selected from those described above; the "sulfenyl" group or "sulfenyl derivatives" used alone or in combination with other radicals, represents a bivalent group, -SO- or. R_xSO, where R_x .is an .optionally substituted alkyl, aryl, heteroaryl, heterocyclyl, group selected from those described above; the "sulfonyl" group or "sulfones derivatives" used either alone or in combination with other radicals, with other terms such as alkylsulfonyl, represents a divalent radical -SO₂-, or R_xSO₂-, where R_x is as defined above. More preferably, the groups may be selected from "alkylsulfonyl" wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, "arylsulfonyl" wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like.

Suitable groups and substituents on the groups may be selected from those described anywhere in the specification. Particularly useful compounds may be selected from:

(l-Isopropyl-2-phenylammo-lH-benzoimidazόl-5-yl)-mθφhόlin-4-yl-methanone;Mθφholino(2-phenoxy-

1 -phenyl- 1 H-benzoimidazol-5-yl)methanone; l-Isopropyl-2-φhenylamino)-N-{(tetrahydrc)-2H-pvran-4-yl)methyl)-lH-benzo[d]imidazole-5- carboxamide;

( 1 -Isopropyl-2-(phenylamino)- 1 H-benzo[d]imidazol-5-yiχthiomoφholino)methanone;

(l-Isopropyl-2-φhenylamino)-lH-benzo[d]irnidbazol-5-yiχpiperidin-l-yl)memanone;Moφholino(l- phenyl-2-{phenylamino)-lH-benzo[d]imidazol-5-yl)methanone;

( 1 -Phenyl-2-(phenylamino)- 1 H-benzotdlimidazDUS-ylXthiomoφholino^methanone;

(l-Phenyl-2-{phenylamino)-lH-ben2o[d]imida2ol-5-ylXpiperidin-l-yl)methanone;

(4-Methylpiperazin- 1 -yiχ 1 -phenyl-2-(phenylamino)- 1 H-benzo[d]imidazol-5-yl)methanone;

(2-(3-Chlorophenylamino)-l-phenyl-lH-benzo[d]imidazol-5-yiχmoφholino)methanone;

(2-(3<^hlorophenylamino)-l-phenyl-lH-rjenzD[d]imidazDl-5-yiχthiomoφholino)memanone;

(2-(3-Chlorophenylamino)- 1 -phenyl- 1 H-benzo[d]imidazDl-5-yl)φiperidin- 1 -yl)methanone;

(2-(3-CWorophenylamino)-l-phenyl-lH-benzo[d]imida2Dl-5-yiχ4-memylpirjerazin-l-yl)methanone; (2^3-Chlorophenylammo)-l-phenyl-lH-ben2D[d]imidazDl-5-yiχ6,7κlihydrothieno[3^]pyridin-5(4H)- yl)methanone;

(2^4-Methoxypheny lamino)- 1 -phenyl- 1 H-benzo[d] imidazol-5-yiχmoφholino)methanone;

(2-{4-Methoxyphenylamino)- 1 -phenyl- 1 H-benzD[d]imidazol-5-yiχthiomoφholino)methanone;

(2-(4-MethoxyphenyIamino)- 1 -phenyl- 1 H-benzo[d]imidazoI-5-yiχpiperidin- 1 -yl)methanone;

(2-(4-Methoxyphenylamino)- 1 -phenyl- 1 H-benzo[d]imidazol-5-yiχ4-methylpiperazin- 1 -yl)methanone;

(6,7-Dihydrolhieno[3,2-c]pyridin-5(4H)-yiχ2-(Φmethojςyphenylamino)-l-phenyl-lH-tenzo[d]imidaziol-

5-yl)methanone;

(l-(3-Chlorophenyl)-2-(phenylamino)-lH-ben2θ[d]imida2θl-5-yiχmoφholino)methanone;

(l-(3-Chlorophenyl)-2-{phenylamino)-lH-ben2D[d]imidazol-5-yiχthiomoφholino)methanone;

(l-(3-Chlorophenyl)-2-(phenylamino)-lH-benzo[d]imidazol-5-yiχpiperidin-l-yl)methanone;

( 1 -(3-Chlorophenyl)-2-(phenylamino)- 1 H-benzo[d]imidazol-5-yiχ4-methylpiperazin- 1 -yl)methanone;

(!-(3-CUorophenyl)-2-φhenylamino)-lH-benzo[d]imidazol-5-yiχ6J-dihydrothieno[3^κ;]pyridin-5(4H)- yl)methanone;

(l-<3-Chlorophenyl)-2-(p-tolylamino)-lH-benzo[d]imidazol-5-yiχmoφholino)methanone;

(l-(3-Chlorophenyl)-2-(p-tolylamino)-lH-benzD[d]imidazol-5-yiχfhiomoφholino)methanone;

(l-(3-Chlorophenyl)-2-{p-tolylamino)-lH-ben2o[d]imidazol-5-ylXpiperidin-l-yl)meftanone;

( 1 -(3-Chlorophenyl)-2-(p-tolylamino)- 1 H-benzo[d]imidazol-5-yiχ4-methylpiperazin- 1 -yl)methanone;

(l-(3-Chlorophenyl)-2-(4-metiioxyphenylamino)-lH-benzo[d]imidazol-5-yiχmoφholino)methanone;

(l-(3^hlorophenyl)-2-(4-metiioxyphenylamino)-lH-ben2D[d]imidazol-5-yiχthiomoφholino)melhanone;

( 1 -(3-Chlorophenyl)-2-(4-ineflio3Qphenylamino)- 1 H-benzo[d] imidazol-5-yiXpiperidin- 1 -yl)methanone;

(l-(3^hlorophenyl)-2-(4-methθ5-yphenylamino)-lH-benzD[d]imiclazol-5-yiχ4-melhylpiperaz-n-l- yl)methanone;

(l-(3-CUorophenyl)-2-(4-chlorophenylamino)-lH-benzo[d]imidazol-5-yiχmoφholino)methanone;

(l-(3-Chlorophenyl)-2-(4-chlorophenylamino)-lH-ben2θ[d]imiclazol-5-yiχihiomoφholino)meflianone;

(l-(3-Chlorophenyl)-2-(4-chlorophenylamino)-lH-ben2θ[d]imidazol-5-yiXpiperidin-l-yl)methanone;

( 1 -(3-Chlorophenyl)-2-(4-chlorophenylamino)- 1 H-benzo[d]imidazol-5-yiχ4-methylpiperazin- 1- yl)methanone;

( 1 -(3-Chlorophenyl)-2-(4-chlorophenyIamino)- 1 H-benzD[d]imidazøl-5-yiχ4-(methylsulfonyl)piperazin- 1 - yl)methanone;

(KS-Chlorophenyl^-CS-chlorophenylaminoyiH-benzotdJimidazol-S-ylXmoφholino^ethanone;

(l-(3-Chlorophenyl)-2-(3-chlorophenyIamino)-lH-benzD[d]imidazol-5-yiχthiomoφholino)melnanone;

(HS-Chlorophenyl^^-chlorophenylamino^lH-benzotdjimiclazøl-S-ylXpiperidin-l-yl^ethanone;

(H3-Chlorophenyl)-2^3-chlorophenylamino)-lH-benzo[d]imidazol-5-yiχ4-methylpiperazin-l- yl)methanone;

(l-(3-Chlorophenyl)-2-(3,4^ichloiOphenylamino)-lH-benzD[d]imidazol-5-yiχmoφholino)methanone; (2-PhenojQ'-l-phenyl-lH-benzo[d]imidazol-5-yiχthiomoφholino)methanone; (2-Phenoxy- l-phenyHH-benzo[d]imidazol-5-yiXpiperidin- l-yl)methanone; (4-Methylpiperazin- 1 -yiχ2-phenoxy- 1 -phenyl- 1 H-benzo[d]imidazDl-5-yl)methanone; Moφholino(3-phenyl-2-(phenylamino)-3H-imidazo[4,5-b]pyridin-6-yl)methanone; (3-Phenyl-2-(phenylamino)-3H-imidazo[4,5-b]pyridin-6-yiχthiomorpholino)methanone; (3-Phenyl-2-(phenylamino)-3H-imidazo[4,5-b]pyridin-6-ylXpiperidin-l-yl)methanone.

Scheme 1: Compounds of general formula (I) may be prepared according to the scheme described here.

♦

Method E

Method

Method A: Compounds of formula IV where Rj and Y are .as defined earlier may be prepared by heating a mixture of compound II where Ri and Y are as defined earlier and L represents F or Cl and amine of formula in where R| is as defined earlier in an appropriate solvent such as toluene, dioxane, dimethyl sulfoxide and the like or the mixtures there of. The reaction may be carried out at the temperatures ranging from 20 ⁰C to the boiling point of the solvents) used. The reaction may be carried out in an inert atmosphere. The reaction time may range from 2 hours to 2 days. Method B: Nitro compounds of formula IV where R₂ and Y are as defined earlier may be reduced to corresponding amine of formula V employing the reducing agents such as SnCb, iron metal/HCl, Zn/ HCl, Pd/C-H₂ and the like. Suitable solvents such as alcohols like methanol, ethanol and the like may be used. Reaction temperatures ranging from 30 ⁰C to the boiling point of the solvent(s) used may be employed. Reaction time may range from one hour to one day.

Method C: Compounds of formula VI where R₂ and Y are as defined earlier may be prepared by cyclisation of compounds of formula V employing appropriate reagents like phosgene, triphosgene and the like in presence of appropriate base like triethyl amine and the like. Suitable solvents such as tetrahydrofuran, toluene and the like may be used. Reaction temperatures ranging from 0⁰C to the boiling point of the solvents) used may be employed. Reaction time may range from 2 hour to 2 days.

Method D: Compounds of formula VII where R₂ and Y are as defined earlier may be prepared by the reaction of compounds of formula VI with phosphorous oxychloride, PCl₅, SOCl₂, HCl and the like and the mixture there of. Reaction temperatures ranging from 30⁰C to the boiling point of reagent(s) may be employed. Reaction time may range from one hour to one day.

Method E: Compounds of formula IX where R_t, Y and Z are as defined earlier may be prepared by heating a mixture of compounds of formula VII and compounds of formula VIII in presence of appropriate base like triethyl amine, diisopropyl amine, Cs₂Cθ₃, K₂CC»₃ and the like in an appropriate solvent such as toluene, dioxane, aceto nitrile, methanol, ethanol and the like or the mixtures there of. The reaction may be carried out at the temperatures ranging from 20 ⁰C to the boiling point of the solvents) used. The reaction may be carried out in an inert atmosphere. The reaction time may range from 2 hours to 2 days.

Method F: Compounds of formula X where R), Y and Z are as defined earlier may be prepared from corresponding esters of formula IX using appropriate base such as NaOH, KOH, LiOH and the like. Suitable solvent such as alcohols like ethanol, methanol.and the .like, THF and water or the mixtures there of. The reaction may be carried out at the temperatures ranging from 20 ⁰C to the boiling point of the solvents) used. The reaction time may range from 2 hours to 2 days.

Method G: Compounds of formula (I) where R₁, X, Y and Z are as defined earlier may be prepared by coupling of compounds of formula X and compounds of formula XI using methods available in the literature for standard peptide coupling.

IH NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Bruker A VANCE-400) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is DMSO-Dc using tetramethyl silane as the internal standard. EXAMPLES

Example 1

(l-Isopropyl-2-phenylamino-lH-benzoimidazol-5-yl)-morpholin-4-yl-methanone

Step 1: Ethyl 4-isopropylamino-3-nitro-benzoate

To a solution of ethyl 4-fluoro-3-nitrobenzoate (10.0 g) in DMSO (50 mL) was added isopropyl amine (8.1 ml) and the reaction mixture was stirred at 80 ⁰C for 3 hours under nitrogen atmosphere. Rection mixture was cooled and poured into ice cold water. Solid separated was filtered and dried under vaccum to yield 1 1.0 g of product.

¹H NMR, CDCl₃: 1.31-1.35 (m, 9H}, 3.92-1.93 (m, IH), 4.32 (q, J= 7.2 Hz, 2H), 6.81 (d, J= 9.2 Hz, IH), 8.02 (dd, J= 9.0 & 1.8 Hz, IH), 8.81 (s, IH). Yield: 93% Step 2: Ethyl 3-amino-4-isopropylamino-benzoate

To a solution of ethyl 4-isopropylamino-3-nitro-benzoate (11.0 g) in ethanol (100 mL) was added SnCl₂.2H₂O (49.0 gm) and the reaction mixture was refluxed for 3 hours. The reaction mixture was cooled and solvent was evapourated under reduced pressure. The residue was dissolved in ethyl acetate (500 ml) and neutralised by Hq. NH₃. Off white solid seperated was filtered and washed with ethyl acetate. The combined filtrate was washed with water and brine, dried over Na₂SO₄ evapourated under reduced pressure to yield 9.5 gm of product as thick liquid.

¹H NMR, CDCl₃: 1.21-1.25 (m, 6H), 1.30-1.35 (m, 3H), 3.72-3.77 (m, IH), 4.30 (q, J= 7.2 Hz, 2H), 6.61 (d, J= 8.4 Hz, IH), 7.42 (s, IH), 7.66 (dd, J= 8.4 & 2.0 Hz, IH). Yield: 98% Step 3: Ethyl 1 -isopropyl-2-oxo-2,3-dihydro- 1 H-benzoimidazole-5-carboxylate

To a solution of ethyl 3-amino-4-isopropylamino-benzoate (4.0 g) in THF (50 mL) was added Et₃N (9.0 ml) followed by dropwise addition of phosgene solution (20% in toluene) (10.6 ml) and the reaction mixture was refluxed for 3 hours. The reaction mixture was cooled and solvent was evapourated under reduced pressure. The residue was diluted with ice cold water. Off white solid seperated was filtered and washed with water dried over P₂Os under vacuum to yield 3.3 gm of product. ¹H NMR, CDCl₃: 1.41 (t, J= 7.4 Hz, 3H), 1.61 (d, J= 7.2 Hz, 6H), 4.42 (q, J= 7.2 Hz, 2H), 4.80-4.82 (m, IH), 7.14 (d, J= 8.4 Hz, IH), 7.80 (m, 2H), 10.13 (s, NH). Yield: 75% Step 4: Ethyl 2-chloro-l -isopropyl- 1 H-benzoimidazole-5-carboxylate

HCl gas was passed through a solution of ethyl l-isopropyl-2-oxo-2,3-dihydro-lH- benzoimidazole-5-carboxylate (3.3 g) in POCl₃ (30 mL) under refluxing condition for 4 hours. Excess POCl₃ was distilled out from the reaction mixture, residue was diluted with ice cold water and neutralised with sodium bicarbonate solution. Off white solid seperated was filtered and washed with water & dried over P₂O₅ under vacuum to yield 3.0 gm of product.

¹H NMR, CDCl₃: 1.42 (t, J= 7.2 Hz, 3H), 1.61 (d, J= 6.8 Hz, 6H), 4.42 (q, J= 7.2 Hz, 2H), 4.91-4.93

(m, IH), 7.50 (d, J= 8.8 Hz, IH), 7.91-7.92 (m, IH), 8.30 (d, J= 1.2 Hz, IH).

Yield: 85%

Step 5: Ethyl l-isopropyl-2-phenylamino- 1 H-benzoimidazole-5-carboxylate

To a solution of ethyl 2-chloro-l-isopropyl-l H-benzoimidazole-5-carboxylate (1.0 g) in 1,4- dioxane (10 mL), aniline (383 mg) was added and reaction mixture was refluxed for 18 hours. Solvent was evapourated from the reaction mixture under vacuum, the residue was diluted with water (50 ml) and extracted by ethyl acetate. The combined ethyl acetate extract was washed with water and brine, dried over Na₂SC^ and evaporated in vacuum to yield 460 mg of product as off white solid. ¹HNMR₅ CDCl₃: 1.21 (t, J= 7.2 Hz, 3H), 1.61 (d, J= 6.8 Hz, 6H), 4.42 (q, J= 7.2 Hz, 2H), 4.62-4.63 (m, IH), 6.20 (s, NH), 7.01 (t, J= 7.4 Hz, IH), 7.33 (m, 3H), 7.52-7.55 (m, 2H), 7.81 (d, J= 8.4 Hz, IH), 8.32 (s, IH). Yield: 38% Step 6: l-Isopropyl^-phenylamino-lH-benzoimidazole-S-carboxylic acid

To a solution of ethyl l-isopropyl-2-phenylamino-lH-benzoimidazole-5-carboxylate (460 mg) in ethanol (10 mL), a solution of NaOH (1 14 mg) in H₂O (5 ml) was added and reaction mixture was stirred at 60 ⁰C for 18 hours. Solvent was evapourated from the reaction -mixture under vacuum, the residue was diluted with water (50 ml), neutralised by dil. HCl and extracted by ethyl acetate. The combined ethyl acetate extract was washed with water and brine, dried over Na₂ SO₄ and evapourated in vacuum to yield 173 mg of product as off white solid.

¹H NMR: 1.62-1.63 (d, J= 6.8 Hz, 6H), 4.81-4.83 (m, IH), 7.03 (t, J= 7.0 Hz, IH), 7.32-7.36 (m, 2H), 7.63-7.66 (m, 2H), 7.80 (d, J= 8.4 Hz, IH), 8.01 (s, IH), 8.22 (s, IH). Yield: 41% Step 7: (l-Isopropyl-2-phenylamino-lH-benzoimidazol-5-yl)-moφholin-4-yl-methanone

To a solution of l-isopropyl^-phenylamino-lH-benzoimidazole-S-carboxylic acid (500 mg) in DMF (5 mL), morpholine (154 mg), HOBT (357 mg), EDCI (390 mg) and N-ethyl morpholine (0.64 ml) were added and reaction mixture was srirred at 25 ⁰C for 2 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water. Off white solid seperated was filtered and washed with water dried over P₂O₅ under vacuum to yield 479 mg of product. 1HNMR: 1.57 (d,J=6.8 Hz; 6H> 3.52 (br,4H> 3.59 (br, 4H> 4.904.97 (m, lHfc 6.96 ft J= 7.4 Hz, IHX 7.08 (dd, J= 7.6 & 1.6

Yield: 74% Example 2

Morpholino(2-phenoxy- 1 -phenyl- 1 H-benzoimidazol-5-yl)methanone Step 1 : ethyl 2-phenoxy-l -phenyl- lH-benzo[d]imidazoIe-5-carboxylate

To a solution of ethyl 2-chloro-l-phenyl-lH-benzo[d]imidazole-5-carboxylate (prepared as per the procedure given in example 1, step 1 to 4) (2.1 g) in DMF (10 ml) was added phenol (0.688 gm) and Cs₂CO₃ (4.34 gtn) at 20 ⁰C and the reaction mixture was stirred at 60 ⁰C for 18 hours under nitrogen atmosphere. Reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined extract was washed with water and brine, dried over sodium sulphate and evaporated in vaccum to yield 2.43 gm of product as off white solid.

¹H NMR, CDCl₃: 1.37 - 1.40 (t, J = 7.2 Hz, 3H), 4.35 - 4.40 (m, 2H), 7.24 - 7.28 (m, 2H), 7.36 -7.39 (m, 2H), 7.41 - 7.45 (m, 2H), 7.48 - 7.52 (m, IH), 7.56 - 7.62 (m, IH), 7:92 - 7.95 (dd, J = 8.4 & 1.6 Hz, 1 H), 8.35 (d, J = 1.2 Hz, 1 H). Yield: 95% Step 2: 2-Phenoxy-l-phenyl-lH-benzo[d]imidazoIe-5-carboxylic acid

To a solution ethyl 2-phenoxy- 1 -phenyl- lH-benzo[d]imidazole-5-carboxylate (2.43 gm) in ethanol (10 mL), a solution of NaOH (536 mg) in H₂O (5 ml) was added and reaction mixture was stirred at 60 ⁰C for 18 hours. Solvent was evaporated from the reaction mixture under vacuum, the residue was diluted with water (50 ml) and neutralised by dil. HCl. Solid separated was filtered and dried over P₂Os under vaccum to yield 2.1 gm of product as off white solid.

¹H NMR: 7.28 - 7.32 (m, 2H), 7.42 - 7.49 (m, 4H), 7.28 - 7.32 (m, 2H), 7.53 - 7.59 (m, IH), 7.63 - 7.72 (m, 2H), 7.72 - 7.75 (m, 2H), 7.81 - 7.84 (dd, J = 8.4 & 1.4 Hz, 1H),,8.O3 (d, J = 1.2 Hz, IH), 12.74 (s, OH). Yield: 94% Step 3: morpholino(2-phenoxy-l-phenyl-lH-benzoimidazol-5-yl)methanone

To a solution of 2-Phenoxy-l -phenyl- l H-benzo[d]imidazole-5-carboxylic acid (500 mg) in DMF (5 mL), morpholine (139 mg), HOBT (319 mg), EDCl (349 mg) and N-ethyl morpholine (576 μl) were added and reaction mixture was srirred at 25 ⁰C for 2 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water. Off white solid seperated was filtered and washed with water & dried over P₂O₅ under vacuum to yield 490 mg of product. 1HNMR: 400MHz, 3.49-3.58 (m, 8H), 7.23-7.31 (m, 3H), 7.41-7.49 (m, 4H), 7.53-7.56 (m, 2H), 7.63-7.67 (m, 2H), 7.71-7.73 (m, 2H). Yield: 81%

The following examples were prepared following the general procedures given in EXAMPLE 1-2, with suitable modifications, alterations and other process variations which are within the scope of a person skilled in the art. Example 3

1 -Isopropyl-2-{phenylamino)-N-((tetrahydro-2H-pyran-4-yl)methyl)- 1 H-benzo[d] imidazole-5-carboxamide

¹H NMR: 1.14-1.24 (m, 2H), 1.50-1.60 (m, 8H), 1.77-1.83 (m, IH), 3.17 (t, J = 6.2 Hz, 2H), 3.28 (t, J = 11.2 Hz, 2H), 3.85 (dd, J = 1 1.2 & 2.0 Hz, 2H), 4.90-4.97 (m, 1 H), 6.96 (t, J = 7.2 Hz, IH), 7.32 (t, J = 7.8 Hz, 2H), 7.53-7.58 (m, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.94 (s, IH), 8.3 (t, J = 5.6 Hz, NH), 8.90 (s, IH).

Example 4

(l-Isopropyl-2-(phenylamino)-lH-benzo[d]imidazol-5-yl)(thiomoφholino)methanone

¹H NMR, CDCl₃: 1.65 (d, J = 7.2 Hz, 6H), 2.66 (br, 4H), 3.90 (br, 4H), 4.55-4.61 (m, IH), 7.04 (t, J =

7.2 Hz, IH), 7.22 (d, J = 8.4 Hz, IH), 7.33-7.44 (complex, 5H), 7.57 (s, IH).

Example 5

( 1 -IsopropyI-2-(phenylamino)- 1 H-benzo[d] imidazol-5-yl)(piperidin- l-yl)methanone 1H NMR: 1.50-1.57 (ra, 12H), 3.46 (bs, 4H), 4.91-4.94 (m, IH), 6.92-7.03 (m, 2H), 7.28-7.33 (m, 3H), 7.55 (d, J = 8.0 Hz, IH), 7.78 (d, J = 7.6 Hz, 2H), 8.88 (s, NH).

Example 6

Morpholino(l-phenyl-2-(phenylamino)-lH-benzo[d]imidazol-5-yl)methanone 1H NMR: 3.51-3.59 (m, 8H), 6.9.-6.98 (m, 2H), 7.07-7.10 (m, IH), 7.27 (t, J=8.0 Hz, 2H), 7.43 (s, IH), 7.56-7.60 (m, 3H), 7.64-7.68 (m, 2H), 7.76 (d, J=8.0 Hz,.2H),.8.89 (s, NH).

Example 7

( 1 -Phenyl-2-(phenylamino)- 1 H-benzo[d] imidazol-5-yl)(thiomorpholino)methanone 1HNMR- 2.63 (bs, 4H), 3.74 (bs, 4H), 6.92-6.96 (m, 2H), 7.04 (dd, J = 8.0 &,l2Hz, IH), 726 (t, J = 8.0 Hz, 2H), 7.45 (d, J = 12 Hz, IH), 7.56-7.60 (m, 3H), 7.64-7.66 (m, 2H), 7.77 (d, J = 7.6 Hz, 2H), 8.75 (s, NH).

Example 8

(l-Phenyl-2-(phenylamino)-lH-benzo[d]imidazol-5-yl)(piperidin-l_ryl)methanone 1HNMR: 1.50 (m, 4H), 1.60-1.61 (m, 2H), 3.46-3.53 (m, 4H), 6.92-6.96 (m, 2H), 7.02 (dd, J = 8.4 & 1.2 Hz, IH), 7.26 (t, J = 8.0 Hz, 2H), 7.42 (s, IH), 7.56-7.59 (m, 3H), 7.64-7.68 (m, 2H), 7.77 (d, J = 7.6 Hz, 2H), 8.73 (s, NH).

Example 9

(4-Methylpiperazin- 1 -yl)( 1 -phenyl-2-(phenylamino)- 1 H-benzo[d] imidazol-5-yl)methanone 1H NMR: 2.18 (s, 3H), 2.31 (bs, 4H), 3.50 (bs, 4H), 6.92-6.96 (m, 2H), 7.04 (dd, J = 8.2 & 1.4 Hz, IH), 7.26 (t, J = 7.8 Hz, 2H), 7.43 (d, J = 0.8 Hz, IH), 7.56-7.59 (m, 3H), 7.64-7.68 (m, 2H), 7.77 (d, J = 8.0 Hz, 2H), 8.75 (s, NH).

Example 10

(2-(3 -Chlorophenylamino)- 1 -phenyl- 1 H-benzo[d] imidazol-5-yl)(morpholino)methanone 1HNMR S-Sl (bs, 4H), 3.59 (bs, 4H), 6.94-7.00 (m, 2H), 7.12 (dd, J = 8.2 & 1.4 Hz, IH), 728 (U = 82 Hz, IH), 7.53-7.61 (m, 4H), 7.64 (t, J = 7.4 Hz, 2H), 7.74 (dd, J = 8.4 & 1.2 Hz, IH), 8.00 (t, J = 1.4 H₂, IH), 8.99 (s, NH). Example 11

(2-(3-chlorophenylamino)-l-phenyMH-benzo[d]imidazol-5-yl)(thiomoφholino)methanone 1H NMR: 2.63 (bs, 4H), 3.74 (bs, 4H), 6.94-6.99 (m, 2H), 7.08 (dd, J = 8.0 & 1.6 Hz, IH), 7.28 (t, J = 8.0 Hz, IH), 7.51 (d, J = 1.2 Hz, IH), 7.56-7.61 (m, 3H), 7.64-7.68 (m, 2H), 7.73 (dd, J = 8.2 & 1.4 Hz, IH), 8.00 (t, J = 2.0 Hz, IH), 8.99 (s, NH).

Example 12

(2-(3-Chlorophenylamino)-l-phenyI-lH-benzo[d]imidazol-5-yl)(piperidin-l-yl)methanone 1H NMR: 1.50 (bs, 4H), 1.61 (bs, 2H), 3.46 (bs, 4H), 6.93 (d, J = 8.0 Hz, IH), 6.98 (dd, J = 8.0 & 1.2 Hz, IH), 7.06 (dd, J = 8.0 & 1.6 Hz, IH), 7.28 (t, J = 8.0 Hz, IH), 7.47 (d, J = 0.8 Hz, IH), 7.56-7.61 (m, 3H), 7.64-7.68 (m, 2H), 7.74 (dd, J = 8.4 & 1.6 Hz, IH), 7.99 (t, J = 2.0 Hz, IH), 8.98 (s, NH).

Example 13

(2-(3-Chlorophenylamino)- 1 -phenyl- 1 H-benzo[d] imidazol-5-yl)(4-methylpiperazin- 1 -y l)methanone ¹H NMR: 2.22 (s,3H), 2.37 (bs, 4H), 3.52 (bs, 4H), 6.95 (d, J = 8.4 Hz, IH), 6.98 (m, IH), 7.09 (dd, J = 8.0 & 1.6 Hz, IH), 7.28 (t, J = 8.2 Hz, IH), 7.50 (d, J = 1.2 Hz, IH), 7.56-7.61 (m, 3H), 7.65-7.68 (m, 2H), 7.74 (dd, J = 8.2 & 1.4 Hz, IH), 8.00 (t, J = 2.0 Hz, IH), 8.98 (s, NH).

Example 14

(2{3<MorophenylamnoH-phatyl-lH4«^

¹H NMR, CDCl₃: 2.97 (bs, 2H), 3.84-4.06 (m, 2H), 4.75 (bs,.2H), 6.38 (s, NH), 6.82 (s, IH), 7.00- 7.05 (m, 2H), 7.13 (s, IH), 7.24-7.29 (m, 2H), 7.48-7.50 (m, 2H), 7.54 (dd, J = 8.2 & 1.8 Hz, IH), 7.61-7.63 (m, IH), 7.66-7.70 (m, 2H), 7.73-7.75 (m, 2H).

Example 15

(2-(4-Methoxyphenylamino)-l-phenyl-lH-benzo[d]imidazol-5-yl)(moφholino)methanone 1H NMR: 3.51-3.59 (m, 8H), 3.71 (s, 3H), 6.86-6.90 (m, 3H), 7.03 (dd, J = 8.2 & 1.4 Hz, IH), 7.41 (d, J = 1.2 Hz, IH), 7.54-7.59 (m, 3H), 7.64-7.68 (m, 4H), 8.54 (s, NH).

Example 16

(2-(4-Methoxyphenylamino)-l-phenyl-l H-benzo[d]imidazol-5-yl)(thiomoφhoIino)tnethanone ¹H NMR: 2.62 (bs, 4H), 3.71 (m, 7H), 6.86-6.90 (m, 3H), 7.00 (dd, J = 8.0 & 1.6 Hz, IH), 7.39 (d, J = 1.2 Hz, IH), 7.55-7.59 (m, 3H), 7.64-7.68 (m, 4H), 8.55 (s, NH).

Example 17

(2-(4-Methoxyphenylamino)- 1 -phenyl- 1 H-benzo[d] imidazol-5-y l)(piperidin- 1 -yl)methanone 1H NMR: 1.59-1.60 (m, 6H), 3.45 (bs, 4H), 3.71 (s, 3H), 6.85-6.89 (m, 3H), 6.98 (dd, J = 8.0 & 1.2 Hz, IH), 7.35 (d, J = 1.2 Hz, IH), 7.55-7.59 (m, 3H), 7.63-7.67 (m, 4H), 8.53 (s, NH).

Example 18

(2-(4-Methoxyphenylamino)- 1 -phenyl- 1 H-benzo[d]imidazol-5-yiχ4-methylpiperazin- 1 -yl)methanone ¹H NMR: CDCl₃, 400MHz, 232 (s, 3H), 2.43 (bs, 4H), 3.73 (bs, 4H), 3.80 (s, 3H), 6.15 (s, NH), 6.88-6.92 (m, 2H), 6.98-7.00 (m, lH), 7.17(dd, J=82 & 1.4Hz, IH), 7.49-7.54 (m, 4H), 7.56-7.60 (m, 2H), 7.64-7.68 (m, 2H). Example 19

(6,7-I^ydradiieno[3,2-c]pyridin-5^ l-pheπyl- lH-benzo[d]imidazDW5-yl)mertianone

¹H NMR: 2.86-2.87 (m, 2H), 3.71-3.76 (m, 5H), 4.63 (bs, 2H), 6.87-6.92 (m, 4H), 7.07 (dd, J = 8.2 & 1.4 Hz, IH), 7.32 (s, IH), 7.45 (d, J = 0.8 Hz, IH), 7.56-7.59 (m, 3H), 7.64-7.69 (m, 4H), 8.56 (s, NH).

Example 20

( l-(3-Chlorophenyl)-2-(phenyIamino)- 1 H-benzo[d]imidazol-5-yl)(moφholino)methanone 1H NMR: 3.51-3.55 (m, 4H), 3.60 (bs, 4H), 6.94-6.97 (m, 2H), 7.07 (dd, J = 8.2 & 1.4 Hz, IH), 7.27 (t, J = 5.0 Hz, 2H), 7.47 (d, J = 1.2 Hz, IH), 7.53-7.56 (m, IH), 7.64-7.69 (m, 2H), 7.74-7.79 (m, 3H), 8.55 (s, NH).

Example 21

(l-(3-chIorophenyl)-2-(phenylamino)-lH-benzo[d]imidazol-5-yl)(thiomoφholino)methanone ¹H NMR: 2.63 (bs, 4H), 3.73 (bs, 4H), 6.94-6.98 (m, 2H), 7.05 (dd, J = 8.0 & 1.2 Hz, IH), 7.27 (t, J = 8.0 Hz, 2H), 7.45 (d, J = 0.8 Hz, IH), 7.54-7.56 (m, IH), 7.64-7.69 (m, 2H), 7.75-7.78 (m, 3H), 8.84 (s, NH).

Example 22

( 1 -(3-Chlorophenyl)-2-(phenylamino)- 1 H-benzo[d3imidazol-5-yl)(piperidin- 1 -yl)methanone 1H NMR: 1.50 (bs, 4H), 1.60 (m, 2H), 3.45 (bs, 4H), 6.94-6.97 (m, 2H), 7.03 (dd, J = 8.0 & 1.2 Hz, IH), 7.27- 7.31 (m, 2H), 7.41 (d, J = 0.8 Hz, 1 H), 7.54-7.56 (m, 1 H), 7.58-7.69 (m, 2H), 7.75-7.78 (m, 3H), 8.82 (s, NH).

Example 23

( 1 -(3-Chlorophenyl)-2-(phenylamino)- 1 H-benzo[d]imidazol-5-yl)(4-methylpiperazin- 1 -yl)methanone ¹HNMR: 220 (s, 3H), 232 (bs, 4H), 3.50 (bs, 4H), 6.94-6.98 (m, 2H), 7.05 (dd, J = 8.2 & 1.4 Hz, IH), 7.27 (t, J = 5.0 Hz, 2H), 7.43 (d, J = 1.2 Hz, IH), 7.53-7.56 (m, IH), 7.64-7.69 (m, 2H), 7.74-7.79 (m, 3H), 8.83 (s, NH).

Example 24

¹HNMR: 2.87 (bs, 2H), 3.76-3.99 (m, 2H), 4.94 (bs, 2H), 6.65-6.99 (m, 3H), 7.14 (d, J = 8.4 Hz, IH), 7.28 (t, J = 7.4 Hz, 3H), 7.51-7.57 (m, 2H), 7.66 (t, J = 7.2 Hz, 2H), 7.76-7.80 (m, 3H), 8.85 (s, NH).

Example 25

(l-(3-Chlorophenyl)-2-(p-tolylamino)-lH-benzo[d]imidazol-5-yl)(morpholino)methanone 1H NMR: 2.25 (s, 3H), 3.51 (bs, 4H), 3.59 (bs, 4H), 6.95 (d, J = 8.0 Hz, 2H), 7.05-7.11 (m, 3H), 7.44 (d, J = 1.2 Hz, IH), 7.52-7.55 (m, IH), 7.64-7.69 (m, 4H), 7.73 (d, J = 1.6 Hz, IH), 8.73 (s, NH).

Example 26

(l-(3-chlorophenyl)τ2-(p-tolylamino)-lH-benzo[d]imidazol-5ⁱyl)(thiomorpholino)methanone 1H NMR: 2.25 (s, 3H), 2.63 (bs, 4H), 3.74 (bs, 4H), 6.94 (d, J = 8.0 Hz, IH), 7.03 (dd, J = 8.0 & 1.6 Hz, IH), 7.09 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 0.8 Hz, IH), 7.52-7.56 (m, IH), 7.64-7.69 (m, 4H), 7.73 (d, J = 1.6 Hz, IH), 8.73 (s, NH).

Example 27 ( 1 -(3-Chlorophenyl)-2-(p-tolylamino)- 1 H-benzo[d]imidazol-5-yl)(piperidin- 1 -yl)methanone ¹H NMR: 1.49 (bs, 4H), 1.61 (bs, 2H), 2.24 (3 H, s), 3.55 (bs, 4H), 6.92 (d, J = 8.0 Hz, 2H), 7.01 (dd, J = 8.0 & 1.6 Hz, IH), 7.09 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 1.2 Hz, IH), 7.53-7.56 (m, IH), 7.64-7.69 (m, 4H), 7.74 (d, J = 1.6 Hz, IH), 8.72 (s, NH).

Example 28

( 1 -(3-Chlorophenyl)-2-(p-tolylamino)- 1 H-benzo[d] imidazol-5-yI)(4-methyIpiperazin- 1 -yl)methanone ¹H NMR: 2.18 (s, 3H), 2.25 (s, 3H), 2.30 (bs, 4H), 3.50 (bs, 4H), 6.92 (d, J = 8.0 Hz, IH), 7.03 (dd, J = 8.0 & 1.2 Hz, IH), 7.09 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 1.2 Hz, IH), 7.53-7.55 (m, IH), 7.64-7.69 (m, 4H), 7.74 (d, J = 1.6 Hz, IH), 8.73 (s, NH).

Example 29

(l-(3-Chlorophenyl)-2-(4-methoxyphenylamino)-lH-benzo[d]imidazol-5-yiχmoφholino)methanone ¹H NMR: 3.50-3.59 (m, 8H), 3.72 (s, 3H), 6.88 - 6.91 (m, 2H), 6.93 (s, IH), 7.04 (dd, J = 8.0 & 1.6 Hz, IH), 7.41 (d, J = 1.2 Hz, IH), 7.53-7.55 (m, IH), 7.64-7.67 (m, 4H), 7.73 (d, J = 1.6 Hz, IH), 8.65 (s, NH).

Example 30

(l-(3-Chlorophenyl)-2-(4-methoxyphenylamino)-lH-benzo[d]imidazol-5-yiχthiomoφholino)methanone ¹H NMR: 2.62 (bs, 4H), 3.71 (bs, 7H), 6.87-6.90 (m, 2H), 6.92 (s, IH), 7.01 (dd, J = 8.2 & 1.4 Hz, IH), 7.39 (d, J = 1.2 Hz, IH), 7.53-7.56 (m, IH), 7.65-7.67 (m, 4H), 7.73 (t, J = 1.8 Hz, IH), 8.65 (s, NH).

Example 31

( 1 -(3-Chlorophenyl)-2-(4-methoxyphenylamino)- 1 H-benzo[d] imidazol-5-yl)(piperidin- 1 -y l)methanone ¹H NMR: 1.49 (bs, 4H), 1.59 (bs, 2H), 3.45 (bs, 4H), 3.71 (s, 3H), 6.87-6.92 (m, 3H), 6.99 (dd, J = 8.0 & 1.2 Hz, IH), 7.34 (d, J = 1.2 Hz, IH), 7.53-7.56 (m, IH), 7.63-7.69 (m, 4H), 7.73 (d, J = 12 Hz, IH), 8.64 (s, NH).

Example 32

(l-(3-Chlorophenyl)-2-(4-methoxyphenylamino)-lH-benzo[d]imidazDl-5-ylX4-methylpiperazin-l-yl)m 1H NMR: 2.20 (s, 3H), 2.32 (bs, 4H), 3.53 (bs, 4H), 3.71 (s, 3H), 6.87-6.90 (m, 2H), 6.92 (s, IH), 7.01 (dd, J = 8.0 & 12 Hz, IH), 7.37 (s, IH), 7.53-7.57 (m, IH), 7.63-7.69 (m, 4H), 7.73 (d, J =..1.6 Hz, IH), 8.65 (s, NH).

Example 33

Jl-(3-Chlorophenyl)-2-(4-chlorophenylamino)-lH-benzo[d]imidazol-5-yl)(moφholino)methanone ¹H NMR: 3.51 (bs, 4H), 3.59 (bs, 4H), 6.96 (d, J = 8.0 Hz, 1 H), 7.09 (d, J = 8.0 Hz, IH), 7.34 (d, J = 8.8 Hz, ZH), 7.48 (s, IH), 7.54-7.56 (m, IH), 7.66-7.70 (m, 2H), 7.76 (s, IH), 7.83 (d, J = 8.8 Hz, 2H), 9.00 (s, NH).

Example 34 l-(3^hlorophenyl)-2-(4-chlorophenylamino)-lH-benzo[d]imidazol-5-yiχthiomoφholino)methanone H NMR: 2.63 (bs, 4H), 3.73 (bs, 4H), 6.95 (d, J = 8.4 Hz, IH), 7.06 (d, J = 8.4 Hz, IH), 7.34 (d, J = 8.8 Hz, IK), 7.46 (s, IH), 7.54-7.58 (m, IH), 7.66-7.70 (m, 2H), 7.76 (s, IH), 7.83 (d, J = 9.2 Hz, 2H), 9.00 (s, NH).

Example 35

( 1 -(3-Chlorophenyl)-2-(4-chlorophenylamino)- 1 H-benzo[d]imidazol-5-yl)(piperidin- 1 -yl)methanone HNMR: 1.50 (bs, 4HX 1.60 (bs, 2H), 3.42 (bs, 4H), 6.94 (d, J =8.0 Hz, IH), 7.04 (dd, J= 82 & 1.0 Hz, lH),733 (d, J =8.8 Hz, 2H), 7.42(S, IH), 7.54-7.58 (m, IH), 7.64-7.69 (m, 2H), 7.76 (s, IH), 7.83 (d, J =8.8 Hz, 2H), 8.99 (s, NH). Example 36

(l-(3-cMorophenyl)-2^4-chlorophenylammoHH-ben^

¹HNMR: 2.18 (s, 3H), 230 (bs, 4H), 3.49 (bs, 4H), 6.95 (d, J = 8.4 Hz, IH), 7.06 (d, J = 8.0 Hz, IH), 733 (d, J = 8.8

Hz, 2H), 7.44(s, IH), 7.54-7.56 (m, IH), 7.66 (d, J =6.4 Hz, 2H), 7.76 (s, IH), 7.83 (d, J = 8.8 Hz, 2H), 9.04 (s, NH).

Example 37

(H3-chlorophenyl)-2-(4-cMorophenylam

¹H NMR: 2.90 (s, 3H), 3.16 (bs, 4H), 3.69 (bs, 4H), 7.08 (d, J = 8.4 Hz, IH), 7.24 (d, J = 8.4 Hz, IH), 7.48-7.50 (m, 3H), 7.65-7.71 (m, 3H), 7.72-7.76 (m, 2H), 7.88 (s, IH).

Example 38

(l-(3-chlorophenyl)-2-(3-chlorophenylamino)-l H-benzo[d]imidazol-5-yl)(moφholino)methanone ¹H NMR: 3.51-3.54 (m, 4H), 3.60 (bs, 4H), 6.97-7.01 (m, 2H), 7.10 (d, J = 8.4 Hz, IH), 7.30 (t, J = 8.0 Hz, IH), 7.53-7.56 (m, 2H), 7.67-7.73 (m, 3H), 7.77 (s, IH), 8.01 (s, IH), 9.07 (s, NH).

Example 39

(l-(3-chlorophenyl)-2-(3-chlorophenyIamino)-lH-benzo[d]imidazol-5-yl)(thiomorpholino)methanone ¹H NMR: 2.64 (bs, 4H), 3.74 (bs, 4H), 6.97-7.01 (m, 2H), 7.10 (d, J = 8.0 Hz, IH), 7.30 (t, J = 8.0 Hz, IH), 7.51 (s, IH), 7.55-7.56 (m, IH), 7.67-7.73 (m, 3H), 7.78 (s, IH), 8.01 (s, IH), 9.07 (s, NH).

Example 40

( 1 -(3-chlorophenyl)-2-(3 -chloropheny lamino)- 1 H-benzo[d] imidazol-5-y l)(piperidin- 1 -yl)methanone ¹HNMR: 1.49 (bs, 4H), 1.60 (bs, 2H), 338-3.42 (m, 4H), 6.96-7.01 (m, 2H), 7.05-7.09 (m, IH), 7.33 (t, J = 8.0 Hz, IH), 7.47 (s, IH), 7.55-7.57 (m, IH), 7.67-7.73 (m, 3H), 7.78 (s, IH), 8.01 (s, IH), 9.06 (s, NH).

Example 41

(l-(3-cMorophenyl)-2-(3-chlorophenylaminoHH-ben^

¹HNMR: 2.18 (s, 3H), 2.32 (bs, 4H), 3.49 (bs, 4H), 6.96-7.01 (m, 2H), 7.07-7.09 (m, IH), 7.30 (t, J = 8.0 Hz,

IH), 7.48 (s, IH), 7.55-7.57 (m₅ IH), 7.67-7.71 (m, 3H), 7.78 (s, IH), 8.01 (s, IH), 9.06 (s, NH).

Example 42

(l-(3-chlorophenyl)-2-(3,4-dichlorophenylamino)-lH-benzo[d]imidazol-5-yl)(moφholino)methanone ¹H NMR: 3.51 (bs, 4H), 3.59 (bs, 4H), 6.97 (d, J = 8.0 Hz, IH), 7.11 (d, J = 7.6 Hz, IH), 7.54-7.57 (m, 3H), 7.67 (d, J = 5.2 Hz, 2H), 7.78-7.82 (m, 2H), 8.19 (d, J = 2.4 Hz, IH), 9.17 (s, NH).

Example 43

(2-phenoxy- 1 -phenyl- 1 H-benzo[d]imidazol-5-yl)(thiomorpholino)methanone 1H NMR: 2.62 (bs, 4H), 3.72 (bs, 4H), 7.20-7.31 (m, 3H), 7.41-7.48 (m, 4H), 7.51-7.62 (m, 2H), 7.64-7.66 (m, 2H), 7.71-7.73 (m, 2H).

Example 44

(2-phenoxy-l-phenyl-lH-benzo[d]imidazol-5-yl)(piperidin-l-yl)methanone

¹H NMR: CDCl₃, 400MHz, 1.59-1.66 (m, 6H), 3.54-3.65 (m, 4H), 7.23-7.24 (m, IH), 7.28-7.31 (m, 2H), 735-7.37 (m, 2H), 7.40-7.45 (m, 2H), 7.47-7.51 (m, IH), 7.55-7.61 (m, 4H), 7.64 (d, J = 0.4 Hz, IH). Example 45

(4-Methylpiperazin-l-yl)(2-phenoxy-l-phenyl-lH-benzo[d]imidazol-5-yl)methanone

¹H NMR: 2.17 (s, 3H), 2.29 (bs, 4H), 3.47 (bs, 4H), 7.20-7.22 (d, J = 8.4 Hz, IH), 7.26-7.31 (m, 2H),

7.41-7.49 (m, 5H), 7.53-7.56 (m, IH), 7.63-7.66 (m, 2H), 7.71-7.73 (d, J = 8.4 Hz, 2H).

Example 46

Moφholino(3-phenyl-2-(phenylamino)-3H-imidazo[4,5-b]pyridin-6-yl)methanone 1H NMR: 3.60 (bs, 8H), 6.98-7.01 (t, J = 7.2 Hz, IH), 7.28-7.32 (m, 2H), 7.57-7.65 (m, 5H), 7.78- 7.72 (m, 3H), 8.01 (s, IH), 8.99 (s, NH).

Example 47

(3-Phenyl-2-(phenylamino)-3H-imidazo[4,5-b]pyridin-6-yl)(thiomoφholino)methanone 1H NMR: 2.65 (bs, 4H), 3.73 (bs, 4H), 6.98 (t, J-= 7.4- Hz, IH), 7.28 (t,-J = 7.6 Hz, 2H), 7.55-7.65 (m, 5H), 7.76-7.81 (m, 3H), 7.99 (d, J = 1.6Hz, IH), 8.98 (s, NH)

Example 48

(3-Phenyl-2-(phenylamino)-3H-imidazo[4,5-b]pyridin-6-yI)(piperidin-l-yl)methanone 1H NMR: 1.51-1.60 (m, 6H), 3.37-3.55 (m, 4H), 6.97 (t, J = 7.4 Hz, IH), 7.28 (t, J = 7.6 Hz, 2H), 7.57-7.65 (m, 5H), 7.71 (d, J = 2.0 Hz, IH), 7.79-7.81 (m, 2H), 7.96 (d, J = 1.6 Hz, IH), 8.97 (s, NH).

The biological activity of the compounds of the present invention may be tested in the following in vitro model mentioned herein below.

Jn vitro cAMP Assay: Fatty acid-free BSA, IBMX, (Iso butyl methyl xanthine), RO20-1724 {4-[(3-butoxy-4-methoxyphenyl) methyl]-2-imidazololidinone}, forskolin and DMSO (hybrimax) were purchased from Sigma Chemical Co. cAMP detection ELISA kit was from Assay Designs, USA. Tissue culture reagents were procured from Sigma, and Hi-media. -Other reagents used, were all of analytical grade. AU the compounds were dissolved in DMSO.

In vitro cAMP Assay for CB2: The cAMP assay was carried out using Chinese Hamster Ovary (CHO) cells (CHOK 1) stably expressing human CB2 receptor. cAMP assay was performed following the method of Bouaboula et alP Cells grown to 80% confluence were maintained in HAM'S F12 medium containing 10% fetal bovine serum at 1.0 mg/mL G-418 pressure and were seeded at a density of 50, 000 cells/well in 24 well plate. Cells were then incubated in plain HAM'S F12 containing 0.5% fatty acid free BSA at 37 °C/5% CO₂. Before addition of the compounds, cells were preincubated with phosphodiesterase inhibitors - IBMX (0.1 mM) and RO20-1724 (0.1 mM). Compounds and forskolin (at a final concentration of 4μM) were added simultaneously. The reaction was terminated by washing once with PBS and adding 200μL 0.1 N HCl and 0.1% Triton-X 100. Supernatant of the cell lysate was used for detection of cAMP. ELISA carried out using Assay Designs cAMP kit as per the manufacturer's instructions.

Thus, the compounds are potent CB2 agonists and therefore may be suitable for treatment of inflammation and neuropathic pain.

The compounds of the present invention may be formulated into suitable pharmaceutical compositions by processes known in the art for dosing to a mammal in need of such treatment. Pharmaceutical compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: the Science and Practice of Pharmacy, 19^th Ed., 1995. The compositions may be in the conventional forms, such as capsules, tablets, powders, solutions, suspensions, syrups, aerosols or topical applications. They may contain suitable solid or liquid carriers or in suitable sterile media to form injectable solutions or suspensions. The compositions may contain 0.5 to 20 %, preferably 0.5 to 10 % by weight of the active compound, the remaining being pharmaceutically acceptable carriers, excipients, diluents, solvents and the like. Typical compositions containing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipients which may be 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. When the carrier serves as a diluent, it may be a solid, semisolid, or liquid material, which acts as a vehicle, excipients or medium for the active compound.

Claims

We claim:

1. Compound of formula (I) their tautomeric forms, their stereoisomers, regioisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein

R₁ at each occurrence independently represents optionally substituted alkyl group selected from propyl and isopropyl group, aryl, heterøaryl, heterocyclyl, cycloalkyl, or bicycloalkyl groups;

X represents O, S, or optionally substituted groups selected from CH₂, SO or SO₂, or the group representing N-R₂ were ^"R₂ represents optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl or bicycloalkylalkyl groups, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl or sulfonyl derivatives; Y represents CH or N; Z represents NH or O.

2. The compounds of formula (I) as claimed in claim 1 wherein Ri represents phenyl, napthyl, pyridyl, thiophenyl, furanyl, piperidine, piperazine, morpholine, thiomoφholine or C₃ to C₇ membered cycloalkyl group.

3. The compounds of formula (I) as claimed in claim 1 wherein R₂ represents optionally substituted groups selected from Ci to C₄ linear or branched alkyl, C₃ to C₇ cycloalkyl, phenyl, pyridyl, piperidine, Ci to C₄ linear or branched alk^'ylsulfonyl, phenyl sulfonyl or pyridyl sulfonyl groups.

4. The compound of claim 1 wherein the substituents on Ri and R₂ are independently selected from hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl;-perhaloalkyl;'haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylarnmc>carbonylarnino, alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid or its derivatives.

5. The compounds of any preceding claims wherein the substituents on Rl & R2 are independently selected from C₁ to C₄ linear or branched alkyl, Ci to C₄ linear or branched alkoxy, halo, phenyl, Ci-C₄ linear or branched alkylthio, Cj -C₄ linear or branched alkylsulfonyl, Cj-C₄ linear or branched alkylsulfenyl, carboxyl, nitro, trifluoromethyl, trifluoro methoxy, cyano, hydroxyl, oxo or acyl group, each of these groups, are further optionally substituted with one or more groups from those described above.

6. A compound of any preceding claim selected from: ^•

( 1 -Isopropyl-2-phenylamino- 1 H-benzoimidazol-5-yl)-morpholin-4-yl-methanone;

Morpholino(2-phenoxy- 1 -phenyl- 1 H-benzoimidazol-5-yl)methanone;

1 -Isopropyl-2-(phenylamino)-N-((tetrahydro-2H-pyran-4-yl)methyl)- 1 H-benzo[d]imidazole-5- carboxamide;

( 1 -Isopropyl-2-φhenylamino)- 1 H-benzo[d]imidazol-5-yl)(thiomorpholino)methanone;

( 1 -Isopropyl-2-(phenylamino)- 1 H-benzo[d]imidazol-5-yl)(piperidin- 1 -yl)methanone;

Moφholino( 1 -phenyl-2-(phenylamino)- 1 H-benzo[d]imidazol-5-yl)methanone;

( 1 -Phenyl-2-(phenylamino)- 1 H-benzo[d] imidazol-5-yl)(thiomorpholino)methanone;

(l-Phenyl-2-φhenylammo)-lH-benzo[d]imidazol-5-yl)φiperidin-l-yl)methanone;

(4-Methylpiperazin- 1 -yl)( 1 -phenyl-2-(phenylamino)- 1 H-benzo[d]imidazol-5-yl)methanone;

(2-(3-Chlorophenylamino)- 1 -phenyl-1 H-benzo[d]imidazόl-5-yl)(moφholino)methanone;

(2-{3-Chlorophenylamino)- 1 -phenyl- 1 H-tenzofdJimidazol-S^ylXthiomoφholino^ethanone;

(2-(3-Chlorophenylamino)- 1 -phenyl- 1 H-ben2θ[d]imidazol-5-yiXpiperidin- 1 -yl)methanone;

(2-(3-Chlorophenylamino)- 1 -phenyl- 1 H-benzD[d]irnidazDl-5-yiχ4-methylpiperazin- 1 -yl)methanone;

(2-(3-Chlorophenylamino)- 1 -phenyl- lH-benzo[d]imidazol-5-yiχ6,7-dihydrothieno[3 ,2- c]pyridin-5(4H)-yl)methanone;

(2-(4-Methoxyphenylamino)- 1 -phenyl- 1 H-benzo[d]imidazol-5-yiχmorpholino)methanone;

(2-(4-Methoxyphenylamino)- 1 -phenyl- 1 H-benzo[d]imidazol-5-yiχthiomoφholino)methanone;

(2-(4-Methoxyphenylamino)- 1 -phenyl- 1 H-benzo[d]imidazol-5-yl)(piperidin-l -yl)methanone;

(2-(4-Methoxyphenylamino)- 1 -phenyl- 1 H-benzo[d]imidazol-5-yiχ4-methylpiperazin- 1 - yl)methanone; (6,7-DihydrotWeno[3,2-c]pyridin-5(4H)-yl)(2-(4-methoxyphenylainino)- 1 -phenyl-1 H- benzo[d]imidazol-5-yl)methanone;

(1 -(3-Chlorophenyl)-2-(phenylamino)- 1 H-benzo[d]imidazol-5-yl)(moφholino)methanone;

(l-(3-CUorophenyl)-2-(phenylarnino)-lH-benzo[d]iinidazol-5-yl)(thiomoφholino)methano

(1 -(3-Chlorophenyl)-2-(phenylamino)- 1 H-benzo[d]imidazx3l-5-yl)(piperidin- 1 -yl)methanone;

(l-(3^Moiophαiyl)-2-φhmylamino)-lH-bαizo[d]iinidazDl-5-yiχ4-m

(1 -(3-Chlorophenyl)-2-(phenylamino)- 1 H-benzo[d]imidazol-5-yiχ6,7-dihydrothieno[3,2- c]pyridin-5(4H)-yl)methanone;

( 1 -(3-Chlorophenyl)-2-(p-tolylaπiino)- 1 H-benzo[d]imidazol-5-yl)(moφholino)methanone;

(l-(3-CMorophenyl)-2-(p-tolylaminoHH-benzo[d]i^

( 1 -(3-Chlorophenyl)-2-(p-tolylamino)- 1 H-benzo[d]imidazol-5-yl)(piperidin- 1 -yl)methanone;

(l-(3-QiloiOphenyl)-2-(p-tolylaπiirø

(l-(3-Chlorophenyl)-2-(4-methoxyphenylamino)-lH-benziθ[d]iinidazol-5- yl)(moφholino)methanone;

(1 -(3-Chlorophenyl)-2-(4-methoxyphenylamino)-l H-benzo[d]imidazol-5- yiχthiomoφholino)methanone;

( 1 -(3-Chlorophenyl)-2-(4-methoxyphenylamino)-l H-benzo[d]imidazol-5-yl)(piperidin- 1 - yl)methanone;

(l-(3^Worophenyl)-2-(4-me1hoxyphenylamino)-lH-benzo[d]iniidazol-5-yl)(4- methylpiperazin- 1 -yl)methanone;

(l-(3-CUorophenyl)-2-(4H:Morophenylamino)-lH-beii-TO[d]iinida2ol-5- yiχmoφholino)methanone;

(l-(3-Chlorophenyl)-2-(4-cUoκ)phenylamino)-lH-benzo[d]imidazol-5- yl)(thiomoφholino)methanone;

(l-(3-CWorophenyl)-2-(4-cWorophenylamino)-lH-ben2»[d]imidazol-5-yl)(piperidin-l- yl)methanone;

(l-(3-CHorophenyl)-2-(4-cWorophenylamino)-lH-benzo[d]iinidazol-5-yl)(4-meώylpiper^^ l-yl)methaπone;

(l-(3-Chlorophenyl>2-(4-cUorophenylaiiiino)-lH-baizo[d]imidazol-5-ylX4-

(methylsulfonyl)piperazin- 1 -yl)methanone;

(l-(3-CWorophenyl)-2-(3-cWoiophenylamino)-lH-benzo[d]imidazol-5- yiχmoφholino)methanone; (1 -(3-Chlorophenyl)-2-(3-chloiOphenylamino)- 1 H-benzo[d]imidazol-5- yl)(thiomoφholino)methanone;

(1 -(3-Chlorophenyl)-2-(3-chloiOphenylamino)- 1 H-benzo[d]imidazol-5-yl)(piperidin- 1 - yl)methanone;

(l-(3-CWorophenyl)-2-(3-cUorophenylamino)-lH-benzo[d]irnida2»l-5-yl)(4-methylpiperazin- l-yl)methanone;

( 1 -(3-Chlorophenyl)-2-(3 ,4-dichlorophenylamino)- 1 H-benzo[d]imidazol-5- yl)(moφholino)methanone;

(2-Phenoxy- 1 -phenyl- 1 H-benzo[d]irnidazol-5-yl)(thiomorpholiήo)methanone;

(2-Phenoxy- 1 -phenyl- 1 H-benzo[d]imidazol-5-yl)(piperidin- l-yl)methanone;

(4-Methylpiperazin- 1 -yl)(2-phenoxy- 1 -phenyl- 1 H-benzo[d] imidazol-5-yl)methanone;

Mθφholino(3-phenyl-2-φhenylanτino)-3H-imidazo[4,5-b]pyridin-6-yl)methanone;

(3-Phenyl-2-(phenylamino)-3H-imidaz»[4,5-b]pyridin-6-yl)(tWomoφholino)methanone;

(3-Phenyl-2-(phenylamino)-3H-imidazo[4,5-b]pyridin-6-yl)φiperidin-l-yl)methanone.

7. A process for preparing compound of formula (I) as claimed in any of the preceding claims comprising, reacting a compound of formula (X) with compound of formula (XI), where Rl, X, Y, Z are as defined in claim 1 :

8. A pharmaceutical composition comprising compound of formula (I), as . claimed in any preceding claims along with suitable excipients.

9. The pharmaceutical composition of claim 8 for the treatment of inflammation and neuropathic pain.

10. A method of treating inflammation and neuropathic pain comprising compounds of formula (I) or its pharmaceutical compositions as claimed in any preceding claims.