WO2009053799A1 - Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation - Google Patents

Abstract

The present invention relates to compounds of f formula (I) as cannabinoid receptor modulators, in particular cannabinoid 1 (CB1) or cannabinoid 2 (CB2 ) receptor modulators, and uses thereof f or treating diseases, conditions and/or disorders modulated by a cannabinoid receptor ( such as pain, neurodegenrative disorders, eating disorders, weight loss or control, and obesity).

Description

NOVEL CANNABINOID RECEPTOR LIGANDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND PROCESS FOR THEIR

PREPARATION

Related applications

This application claims the benefit of Indian Patent Application Nos. 2111 /MUM/2007 filed on October 24, 2007; 2566/MUM/2007 filed on December 26, 2007; and 492/MUM/2008 filed on March 11, 2008 and U.S. Provisional Application Nos. 61/015,325 filed on December 20, 2007; 61/023,551 filed on January, 25, 2008; and 61/051,157 filed on May 07, 2008, all of which are hereby incorporated by reference.

Field of the Invention

The present invention relates to novel cananbinoid receptor modulators, pharmaceutical compositions thereof and uses thereof for treating diseases, conditions and/or disorders modulated by a cannabinoid receptor.

Background of the Invention

The endogenous cannabinoid system comprises two main receptors, CBl and CB2, and a number of ligands including Anandamide and Virodhamine which demonstrate the greatest activity at the cannabinoid receptor (Jonathan A W & Louis J A, Obesity Management, 15-19, 2005). Anandamide, which is produced postsynaptically, is the main fatty acid involved in the system. It gains access to the extra cellular space and activates CBl cannabinoid receptors located on presynaptic nerve terminals. This activation causes presynaptic inhibition of γ-aminobutyric acid (GABA) or glutamate through inhibition of calcium channels, while simultaneously interfering with vesicle release and activating potassium channels.

However, Anandamide is prone to rapid enzymatic hydrolysis. This represents a serious drawback in its use as a drug because, inter alia, substances which are susceptible to hydrolytic cleavage may undergo changes in the gastrointestinal tract.

CBl receptors are predominantly located in the brain and other neurons, while CB2 receptors are predominantly located in immune cells. Stimulation of these receptors is known to affect the central and peripheral action on lipid and glucose metabolism in adipose tissue and most notably, helps to regulate food intake, energy balance and nicotine dependence as well as regulate fear and anxiety. There are evidence suggesting that CBl agonists or antagonists, respectively, increase or decrease the motivation to work for palatable ingesta (Gallate J E and McGregor I S, Psychopharmacology, 142, 302-308, 1999 and Gallate J E, Saharov T, Mallet P E and McGregor I S, 1999, Eur. J. Pharmacol, 370, 233-240, 1999). Cannabinoids appear to directly stimulate eating by actions on appetitive processes, making food stimuli more salient and rapidly inducing eating even in satiated animals (Williams C M and Kirkham T C, Physiol. Behav., 76, 241-250, 2002).

Current data reveals that cannabinoids mediate suppression of inflammation in vitro and in vivo through stimulation of CB2 receptors (Ehrhart J, et al, J. Neuroinflammation, 2, 29, 2005). The inflammatory mediators such as nitric oxide, cytokines and chemokines play an important role in microglial cell-associated neuron cell damage. Activated microglial cells have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease, multiple sclerosis, HIV and dementia.

Known CB modulators include naphthalen-lyl-(4-pentyloxy-naphthalen-l-yl) methanone (S AB-378), 4-(2,4-dichlorophenylamino)-N-(terahydro-pyran-4- ylmethyl)-2-trifluromethyl-benzamide (GW-842166X), N-(I -piperidinyl)-5-(4- chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SRl 41716A), 3-(4-chlorophenyl-N'-(4-chlorophenyl)sulfonyl-N-methyl-4-phenyl- 4,5-dihydro-lH-pyrazole-l-carboxamide (SLV-319), and (R)-(+)-[2,3-dihydro-5- methyl-3-[4-moφholinylmethyl]-pyrrolo-[l ,2,3-de]-l ,4-benzoxazin-6-yl](l -naphthyl) methanone (WIN 55212-2).

These modulators have reached advanced stages of clinical trials for the treatment of pain, neurodegenerative disorders, psychotic disorders, neurological syndromes, diseases or disorders, eating disorders, Alzheimer's disease, alcohol dependency, diabetes, obesity and/or smoking cessation.

US 7,056,917; US 2002/077486; EP 1227084; EP 0856255; EP135367; PCT publications WO 06/124874, WO 06/045096, WO 98/27080 and WO 00/069827 disclose fused pyridone or pyrimidone compounds.

Other cannabinoid receptor modulating compounds are disclosed in Patent Nos. US 4,973,587, US 5,013,837, US 5,081,122, US 5,112,820, US 5,292,736, and US 5,532,237, and PCT Publication Nos. WO 97/29079, WO 98/37061, WO 99/02499, WO 00/10967, WO 00/10968, WO 01/58869, WO 01/70700, WO 02/076949, WO 03/026647, WO 03/026648, WO 03/027069, WO 03/027076, WO 03/027114, WO 03/077847, WO 03/088968, WO 04/13120, WO 04/69837, WO 04/058145, WO 04/26301, WO 04/058744, WO 04/096763 and WO 06/030124.

There exists an unmet need for treatment of alcohol abuse. Health risks associated with alcoholism include impaired motor control and decision making, cancer, liver disease, birth defects, heart disease, drug-drug interactions, pancreatitis and interpersonal problems. Studies have suggested that endogenous cannabinoid tone plays a critical role in the control of ethanol intake. The endogenous CBl receptor antagonist SR-141716A has been shown to block voluntary ethanol intake in rats and mice. (Arnone, M et al, Psychopharmacol, 132, 104-106, 1997; Hungund, B. L and Basavarajappa, B S, Alcohol & Alcoholism, 35(2), 126-133, 2000).

Current treatments for alcohol abuse or dependence generally suffer from non- compliance or potential hepatotoxicity. There is an unmet need for more effective treatments of alcohol abuse/dependence. A drug candidate should have good pharmacokinetic properties enabling a suitable dosage regimen for the required pharmacodynamic action.

There still exists a need for safer and more effective therapeutic treatments for diseases, conditions and/or disorders modulated by cannabinoid receptors (such as pain and obesity), including those modulated by CBl or CB2 receptors.

Summary of the Invention

The present invention relates to cannabinoid receptor modulators of formula (I):

I and esters thereof, tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein

Ring A is aryl or heteroaryl;

D is selected from -C≡C-, substituted or unsubstituted arylene, and a 5 or 6- membered substituted or unsubstituted heteroarylene; Z is O or S;

W is N or CR^a;

R¹ is 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 aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -C(=Z)-R^a, -S(O)_m-R^a, - S(O)_m-NR^aR^b, -(CH₂)_nR^aR^b, -(CR^xR^y)_nNR^aR^b and -(CR^xR^y)_nNCONR^aR^b; each occurrence of Z is independently selected from O, S and NR^a; each occurrence of R^a and R^b is independently selected from hydrogen, nitro, halo, cyano, -OR, -SR, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group, heterocyclylalkyl, - C(=Z^')-R^', -C(O)O-R, -C(O)NRR^", -S(O)_m-R^', -S(O)_1n-NRR ^" and -NR^'R^"; each occurrence of R' and R is independently selected from hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heterocyclylalkyl, and heteroarylalkyl; or

R and R may be joined together with nitrogen to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NR and S; each occurrence of R^x and R^y is independently selected from hydrogen, halo, cyano, -OR, -SR, -NRR , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group and heterocyclylalkyl ; each occurrence R² and R³ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, -SR⁴, -SOR⁴, -SO₂R⁴, -SO₂NR⁴R⁵, -CO₂NR⁴R⁵ _, CO₂R⁴ _, C(O)R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each occurrence of R⁴ and R⁵ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, and substituted or unsubstituted heterocyclylalkyl; each occurrence of 'm' is an integer from 0 to 2; and each occurrence of 'n' is an integer from 0 to 4.

According to one preferred embodiment, the cannabinoid receptor modulator is a compound of formula (II):

(H) and esters thereof, tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein

R¹ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted heterocyclyl; each occurrence of R² and R³ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, -SR⁴, -SOR⁴, -SO₂R⁴, -SO₂NR⁴R⁵, -CO₂NR⁴R⁵ CO₂R⁴, C(O)R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each occurrence of R⁴ and R⁵ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, and substituted or unsubstituted heterocyclylalkyl; and

'n' is an integer from O to 4. Another embodiment is a compound of formula (II), wherein R² is branched or unbranched, substituted or unsubstituted alkyl, where one or more substituents are hydroxy.

Another embodiment is a compound of formula (II), wherein R is substituted or unsubstituted cycloalkyl, where one or more substituents are hydroxy.

Another embodiment is a compound of formula (II), wherein R is substituted or unsubstituted aryl, preferably phenyl.

Another embodiment is a compound of formula (II), wherein R¹ is branched or unbranched, substituted or unsubstituted alkyl.

Another embodiment is a compound of formula (II), wherein R¹ is substituted or unsubstituted cycloalkylalkyl.

Another embodiment is a compound of formula (II), wherein R¹ is substituted or unsubstituted arylalkyl, preferably benzyl. In another embodiment, R¹ is benzyl substituted with one or more halogens, preferably fluoro.

According to another preferred embodiment, the cannabinoid receptor modulator is a compound of formula (III):

(III) and esters thereof, tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein;

W is CH or N;

Z is O or S;

Ring Y is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted heterocyclyl; each occurrence of R² and R³ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, formyl, -SR⁴, -SOR⁴, -SO₂R⁴, -SO₂NR⁴R⁵, - CO₂NR⁴R⁵ _, CO₂R⁴ _, C(O)R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstiruted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each occurrence of R⁴ and R⁵ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, and substituted or unsubstituted heterocyclylalkyl; and

'n' is an integer from O to 4.

Another embodiment is a compound of formula (III), wherein W is CH.

Another embodiment is a compound of formula (III), wherein W is N.

Another embodiment is a compound of formula (III), wherein Z is O.

Another embodiment is a compound of formula (III), wherein Z is S.

Another embodiment is a compound of formula (III), wherein ring Y is aryl, preferably phenyl.

Another embodiment is a compound of formula (III), wherein ring Y is heteroaryl, preferably oxazolyl or thiazolyl.

Another embodiment is a compound of formula (III), wherein R² is formyl, acetyl, or substituted or unsubstituted alkyl (e.g. ethyl or propyl), wherein one or more substituents are hydroxy.

Another embodiment is a compound of formula (III), wherein R² is branched or unbranched alkyl, preferably tert-butyl.

Another embodiment is a compound of formula (III), wherein R¹ is branched or unbranched alkyl, preferably n-pentyl.

Another embodiment is a compound of formula (III), wherein R¹ is cycloalkylalkyl, preferably cyclohexylmethyl.

Another embodiment is a compound of formula (III), wherein R¹ is substituted or unsubstituted arylalkyl, preferably benzyl. In another embodiment, benzyl is substituted with one or more halogens, preferably fluoro. Another embodiment is a compound of formula (III), wherein R¹ is substituted or unsubstituted aryl, preferably phenyl. In another embodiment, phenyl is substituted with one or more halogens, preferably fluoro or chloro.

Representative examples of compounds of the present invention are provided below. These compounds are illustrative in nature only and do not limit to the scope of the invention.

3-(3,3-Dimethyl-l-butynyl)-l-propyl-l,4-dihydro-4-cinnolinone (compound 1); 3-(3,3-Dimethyl-l-butynyl)-l-(wo-propyl)-l,4-dihydro-4-cinnolinone (compound 2); 1 -Butyl-3-(3 ,3-Dimethyl- 1 -butynyl)- 1 ,4-dihydro-4-cinnolinone (compound 3); 3-(3,3-Dimethyl-l-butynyl)-l-isobutyl-l,4-dihydro-4-cinnolinone (compound 4); 3 -(3 ,3-Dimethyl- 1 -butynyl)- 1 -pentyl- 1 ,4-dihydro-4-cinnolinone (compound 5); 3-[2-(l -Hydroxycyclohexyl)- 1 -ethynyl)- 1 -pentyl- 1 ,4-dihydro- 1 H-cinnolin-4-one (compound 6); 3-(3 -Hydroxy-3 -Methyl- 1 -butynyl)- 1 -pentyl- 1 ,4-dihydro-4-cinnolinone (compound

7);

3 -(3, 3 -Dimethyl- 1 -butynyl)- 1 -neopentyl-1 ,4-dihydro-4H-cinnolinone (compound 8);

3-(2-Cyclopentyl- 1 -ethynyl)- 1 -cyclopropylmethyl- 1 ,4-dihydro-4-cinnolinone

(compound 9); l-Cyclopropylmethyl-3-(3,3-Dimethyl-l -butynyl)- 1 ,4-dihydro-4-cinnolinone

(compound 10);

1 -Cyclopropylmethyl-3-(2-phenyl-l -ethynyl)-l ,4-dihydro-4-cinnolinone (compound i i); l-(Cyclohexylmethyl)-3 -(3, 3 -Dimethyl- 1 -butynyl)- l,4-dihydro-4-cinnolinone

(compound 12);

1 -(2,4-Difluorobenzyl)-3 -(3, 3 -Dimethyl- 1 -butynyl)- 1 ,4-dihydro-4-cinnolinone

(compound 13);

3 -(4-Oxo- 1 -pentyl- 1 ,4-dihydro-3 -cinnolinyl)benzaldehyde (compound 14);

1 -[(4-Oxo-l -pentyl- 1 ,4-dihydro-3-cinnolinyl)phenyl]- 1 -ethanol (compound 15); l-[(4-Oxo-l-pentyl-l,4-dihydro-3-cinnolinyl)phenyl]-l-ethanone (compound 16);

3 -[3 -(I -hydroxy- 1 -methyl ethyl)phenyl]-l -pentyl- 1 ,4-dihydro-4-cinnolinone

(compound 17);

3-[5-(ter?-Butyl)-oxazol-2-yl]-l-pentyl-l,4-dihydro-4-cinnolinone (compound 18);

3-[5-(ter?-Butyl)-thiazol-2-yl]-l-cyclohexylmethyl-l,4-dihydro-4-cinnolinethione

(compound 19); 3-[5-(tert-Butyl)-thiazol-2-yl]-l-n-pentyl-l,4-dihydro-4-cinnolinethione (compound

20);

3-[5-(/ert-Butyl)-oxazol-2-yl]-l-(4-fluorobenzyl)-l,4-dihydro-4-cinnolinone

(compound 21);

3-[5-(tert-Butyl)-thiazol-2-yl]-l-(4-fluorobenzyl)-l,4-dihydro-4-cinnolinethione

(compound 22);

3-[5-(tert-Butyl)-oxazol-2-yl]- 1 -phenyl- 1 ,4-dihydro-4-cinnolinone (compound 23);

3-[5-(tert-Butyl)-oxazol-2-yl]-l-(2,4-difluorophenyl)-l,4-dihydro-4-cinnolinone

(compound 24);

3-[5-(tert-Butyl)-thiazol-2-yl]- 1 -(4-fluorobenzyl)- 1 ,4-dihydro-4-cinnolinone

(compound 25);

3-[5-(tert)-Butyl-l,3-oxazol-2-yl]-l-(4-chlorophenyl)-l,4-dihydro-4-quinolinone

(compound 26);

3-[5-(tert)-Butyl-l,3-oxazol-2-yl]-7-chloro-l-(4-chlorophenyl)-l,4-dihydro-4- quinolinone (compound 27);

3-[5-(tert)-Butyl-l,3-oxazol-2-yl]-l-(«-pentyl)-l ,4-dihydro-4-quinolinone (compound

28); and esters thereof, tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a pharmaceutical composition comprising at least one compound of the present invention and a 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 of the present invention.

Yet another embodiment is a method for preventing, ameliorating or treating a cannabinoid receptor mediated disease, disorder or syndrome (such as a disease, disorder or syndrome mediated by interaction with the CBl or CB2 receptor) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the present invention.

Such diseases, disorders, and symptoms include, but are not limited to, appetite disorders, metabolism disorders, catabolism disorders, diabetes, obesity, ophthalmic diseases, social related disorders, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, pain and neurodegenerative related syndromes.

A preferred disorder is pain, ophthalmic diseases, respiratory disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, or neurodegenerative related syndromes.

Yet another embodiment is a method for preventing, ameliorating or treating an appetite disorder, social related disorder, autoimmune or inflammation, pain or neurodegenerative related syndrome, disorder or disease, or substance abuse, in a subject in need thereof by administering to the subject a therapeutically effective amount of at least one compound of the present invention.

Yet another embodiment is a method for preventing, ameliorating or treating an appetite related disease, disorder or syndrome, such as obesity, an overweight condition, anorexia, bulimia, cachexia, dysregulated appetite, an obesity related syndrome, disorder, disease or symptom (including, but not limited to, obesity as a result of genetics, diet, food intake volume, metabolic syndrome, disorder or disease, hypothalmic disorder or disease, age, abnormal adipose mass distribution, abnormal adipose compartment distribution, a compulsive eating disorder, or a motivational disorder which includes the desire to consume sugars, carbohydrates, alcohols or drugs or any ingredient with hedonic value, and/or reduced activity) in a subject in need thereof by administering to the subject a therapeutically effective amount of at least one compound of the present invention.

Yet another embodiment is a method for preventing, ameliorating or treating a social related disease, disorder or syndrome, including, but not limited to, depression and its types, bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, and/or cognitive disorders, in a subject in need thereof by administering to the subject a therapeutically effective amount of at least one compound of the present invention.

Yet another embodiment is a method for preventing, ameliorating or treating an autoimmune or inflammation related disease, disorder or syndrome, including, but not limited to, psoriasis, lupus erythematosus, diseases of the connective tissue, Sjogren's syndrome, ankylosing spondylarthritis, rheumatoid arthritis, reactional arthritis, undifferentiated spondylarthritis, Behcet's disease, autoimmune hemolytic anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, graft rejection or diseases affecting the plasma cell line, allergic diseases (such as delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis or allergic conjunctivitis infectious parasitic), viral or bacterial diseases (such as AIDS and meningitis), inflammatory diseases (such as diseases of the joints including, but not limited to, arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)) and osteoporosis in a subject in need thereof by administering to the subject a therapeutically effective amount of at least one compound of the present invention.

Yet another embodiment is a method for preventing, ameliorating or treating pain or a neurodegenerative related syndrome, disorder or disease, including, but not limited to, central and peripheral pathway mediated pain, bone and joint pain, migraine headache associated pain, cancer pain, dental pain, menstrual cramps, labor pain, chronic pain of the inflammatory type, pain associated with allergies, rheumatoid arthritis, dermatitis or immunodeficiency, chronic neuropathic pain (including pain associated with diabetic neuropathy, sciatica, non specific lower back pain, fibromyalgia, and HIV-related neuropathy), post herpetic neuralgia, trigeminal neuralgia, pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions, Hodgkin's disease, myasthenia gravis, nephrotic syndrome, scleroderma and thyroiditis, in a subject in need thereof by administering to the subject a therapeutically effective amount of at least one compound of the present invention.

Yet another embodiment is a method for preventing, ameliorating or treating a substance abuse related syndrome, disorder or disease including, but not limited to, drug abuse and drug withdrawal in which, for example, the substance of abuse or dependence is alcohol, amphetamines, amphetamine like substances, caffeine, cannabis, ***e, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin abuse, barbiturates, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics, benzodiazepines, or combinations of substances of abuse, in a subject in need thereof by administering to the subject a therapeutically effective amount of at least one compound of the present invention. Yet another embodiment is a method for reducing tobacco craving in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention.

Yet another embodiment is a method for treating nicotine dependency, addiction, withdrawal or aiding in the cessation or lessening of tobacco use in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention.

Detailed Description of the Invention Definitions

The term "aryl" refers to aromatic radicals having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term "arylene" refers to a bivalent aromatic radical having 6 to 14 carbon atoms.

The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂C₆Hs and -C₂HsC₆Hs.

The terms "heterocyclic ring" and "heterocyclyl" 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 sulphur 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, tetrazolyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamoφholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, 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 "heteroarylene" refers to a bivalent 5- to 14-membered aromatic ring radical which consist of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulphur.

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 from the alkyl group 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 "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 -methyl ethyl (isopropyl), n-butyl, n-pentyl, and 1,1 -dimethyl ethyl (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 term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl and norbomyl groups, bridged cyclic groups or 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 "protecting group" refers to a substituent that is employed to block or protect a particular functionality. Other functional groups on the compound may remain reactive. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethylenoxycarbonyl (Fmoc). A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Suitable carboxy-protecting groups include, but are not limited to, -CH₂CH₂SO₂Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p- toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, and nitroethyl. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

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 cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR_x, - C(O)R_x, -C(S)R_x, -C(O)NR_xR_x, -C(O)ONR_xR_y, -NR_xCONR_yR_z, -N(R_x)SOR_y, - N(R_x)SO₂R_y, -(=N-N(R_x)R_y), -NR_xC(O)OR_y, -NR_xR_y, -NR_xC(O)Ry, -NR_xC(S)Ry, - NR_xC(S)NR_yR₂, -SONR_xR_y, -SO₂NR_xR_y, -OR_x, -OR_xC(O)NR_yR_z, -OR_xC(O)OR_y, - OC(O)R_x, -OC(O)NR_xR_y, -R_xNR_yC(O)R_z, -R_xOR_y, -R_xC(O)OR_y, -R_xC(O)NR_yR_z, - R_xC(O)R_y, -R_xOC(O)Ry, -SR_x, -SOR_x, -SO₂R_x, and -ONO₂, wherein R_x, R_y and R_z 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 "cannabinoid receptor" refers to any one of the known or heretofore unknown subtypes of the class of cannabinoid receptors, including CBl and/or CB2 receptors, that may be bound by a cannabinoid modulator compound of the present invention.

The term "modulator" further refers to the use of a compound of the invention as a CB (e.g., CBl and/or CB2) receptor agonist, partial agonist, antagonist or inverse-agonist.

The term "treating" or "treatment" of a state, disorder or condition includes:

(1) 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;

(2) 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

(3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician.

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 compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.

Compounds 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

Pharmaceutically acceptable solvates include hydrates and other solvents of crystallization (such as alcohols). Compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.

Pharmaceutical Compositions

The pharmaceutical composition of the present invention comprises at least one compound of the present invention and a 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 of the present invention. Compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. 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, hydroxymethyl cellulose 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 osmetic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing methods known in the art.

The pharmaceutical compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20^th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.

The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.

The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is preferred. Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), 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.

A typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride

Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.

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

Methods of Treatment

The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment, amelioration, and/or prevention of diseases, conditions and/or disorders modulated by a cannabinoid (CB) receptor, especially those modulated by the CBl or CB2 receptor including those discussed below.

The present invention further provides a method of treating a disease, condition and/or disorder modulated by a cannabinoid receptor (CB), and in particular the CBl or CB2 receptor, in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.

Diseases, conditions, and/or disorders that are modulated by a CB receptor, include, but are not limited to, appetite disorders, metabolism disorders, catabolism disorders, diabetes, obesity, social related disorders, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, pain (such as neuropathic pain) and neurodegenerative related syndromes, disorders and diseases.

Appetite related syndromes, disorders or diseases include, but are not limited to, obesity, overweight conditions, anorexia, bulimia, cachexia, dysregulated appetite and the like. Obesity related syndromes, disorders or diseases include, but are not limited to, obesity as a result of genetics, diet, food intake volume, metabolic syndrome, disorder or disease, hypothalmic disorder or disease, age, abnormal adipose mass distribution, abnormal adipose compartment distribution, compulsive eating disorders, motivational disorders which include the desire to consume sugars, carbohydrates, alcohols or drugs or any ingredient with hedonic value and the like. Symptoms associated with obesity related syndromes, disorders, and diseases include, but are not limited to, reduced activity.

Metabolism related syndromes, disorders or diseases include, but are not limited to, metabolic syndrome, dyslipidemia, elevated blood pressure, insulin sensitivity or resistance, hyperinsulinemia, hypercholesterolemia, hyperlipidemias, atherosclerosis, hypertriglyceridemias, arteriosclerosis, other cardiovascular diseases, osteoarthritis, dermatological diseases, sleep disorders (disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), cholelithiasis, hepatomegaly, steatosis, abnormal alanine aminotransferase levels, polycystic ovarian disease, inflammation, and the like.

Diabetes related syndromes, disorders or diseases include, but are not limited to, glucose dysregulation, insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity, hyperglycemia and the like.

Catabolism related syndromes, disorders or diseases include, but are not limited to, catabolism in connection with pulmonary dysfunction and ventilator dependency; cardiac dysfunction, e.g., associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure.

Ophthalmic diseases include, but are not limited to, glaucoma, glaucoma- associated intraocular pressure retinitis, retinopathies, uveitis, and acute injury to the eye tissue (e.g. Conjunctivitis).

Social or mood related syndromes, disorders or diseases include, but are not limited to, depression (including, but not limited to, bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, cognitive disorders and the like).

Substance abuse related syndromes, disorders or diseases include, but are not limited to, drug abuse and drug withdrawal. Abused substances include, but are not limited to, alcohol, amphetamines (or amphetamine like substances), caffeine, cannabis, ***e, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin abuse, barbiturates, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics, benzodiazepines, or combinations of any of the foregoing. Compounds and pharmaceutical compositions can also be used to treat withdrawal symptoms and substance-induced anxiety or mood disorder.

The present invention further provides a method of treating nicotine dependency, addiction, withdrawal or aiding in the cessation or lessening of tobacco in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.

Learning, cognition or memory related syndromes, disorders or diseases which can be treated with compounds of the present invention include, but are not limited to, memory loss or impairment as a result of age, disease, side effects of medications (adverse events) or the like. Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld- Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline. Generally, dementias are diseases that include memory loss and additional intellectual impairment separate from memory. Compounds and pharmaceutical compositions of the present invention are also useful in treating cognitive impairments related to attentional deficits, such as attention deficit disorder.

Muscle spasm syndromes, disorders or diseases include, but are not limited to, multiple sclerosis, cerebral palsy and the like.

Locomotor activity and movement syndromes, disorders or diseases include, but are not limited to, stroke, Parkinson's disease, multiple sclerosis, epilepsy and the like. Respiratory related syndromes, disorders or diseases include, but are not limited to, diseases of the respiratory tract, chronic obstructive pulmonary disorder, emphysema, asthma, bronchitis and the like.

Kidney dysfunction nephritis which can be treated with the modulators of the present invention includes, but is not limited to, mesangial proliferative glomerulonephritis, nephritic syndrome, liver dysfunction (hepatitis, cirrhosis).

Autoimmune or inflammation related syndromes, disorders or diseases include, but are not limited to, psoriasis, lupus erythematosus, diseases of the connective tissue, Sjogren's syndrome, ankylosing spondylarthritis, rheumatoid arthritis, reactional arthritis, undifferentiated spondylarthritis, Behcet's disease, autoimmune hemolytic anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, graft rejection or diseases affecting the plasma cell line; allergic diseases: delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis or allergic conjunctivitis infectious parasitic, viral or bacterial diseases (such as AIDS and meningitis), inflammatory diseases (such as diseases of the joints including, but not limited to, arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)) and osteoporosis.

Cell growth related syndromes, disorders or diseases include, but are not limited to, dysregulated mammalian cell proliferation, breast cancer cell proliferation, prostrate cancer cell proliferation and the like.

Pain related syndromes, disorders or diseases include, but are not limited to, central and peripheral pathway mediated pain, bone and joint pain, migraine headache associated pain, cancer pain, dental pain, menstrual cramps, labor pain, chronic pain of the inflammatory type, allergies, rheumatoid arthritis, dermatitis, immunodeficiency, chronic neuropathic pain, (e.g. pain associated with diabetic neuropathy, sciatica, non specific lower back pain, fibromyalgia; HIV-related neuropathy; post herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions), hodgkin's disease, myasthenia gravis, nephrotic syndrome, scleroderma, thyroiditis and the like.

Neurodegenerative related syndromes, disorders or diseases include, but are not limited to, Parkinson's disease, multiple sclerosis, epilepsy, ischemia or secondary biochemical injury collateral to traumatic head or brain injury, brain inflammation, eye injury or stroke and the like.

Compounds of the present invention (including the pharmaceutical compositions and processes used therein) may be used alone or in combination with other pharmaceutical agents in the manufacture of a medicament for the therapeutic applications described herein.

General method of preparation

Compounds described herein, including compounds of general formula (I), (II) and (III) and specific examples are prepared using techniques known to one of ordinary skill in the art. Compounds described herein are prepared through the reaction sequences as depicted in Schemes 1-8. Further, in the following schemes, where specific bases, acids, reagents, solvents, cyclizing agents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, cyclizing agents, coupling agents, etc., known to one of ordinary skill in the art may also be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combination thereof, are envisioned as part of the present invention. All possible stereoisomers are also envisioned within the scope of this invention.

The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, the compounds according to the present invention may be prepared in the below reaction scheme as follows, wherein all symbols are as defined above.

A general approach for the synthesis of compound of formula (II) is described in synthetic scheme 1. A compound of formula (1) can be cyclised by following a general diazotization procedure with sodium nitrite in the presence of an acid (e.g., hydrochloric acid) to form a compound of formula (2). The compound of formula (2) can be halogenated to form a compound of formula (3) by using a general halogenation reagent, for example, bromination with bromine in acetic acid and sodium acetate; or iodination with N-iodosuccinimide in DMF. The compound of formula (3) (wherein X is halogen) can be alkylated with an alkylating agent, such as an alkyl halide or an alkyl sulfonate, in the presence of a base, such as alkali metal hydrides (e.g., NaH), to afford a compound of formula (4). The compound of formula

(4) can be coupled (e.g., Sonogashira coupling) with a terminal acetylene compound, for example in the presence of a palladium catalyst such as bis(triphenylphosphine)palladium(II)chloride and a copper halide such as CuI and suitable solvent combination (for example, DMF and/or triethyl amine), to afford a compound of formula (II).

Scheme 1

(a) Diazotisation (b) Halogenation; (c) Alkylation; (d) Coupling reaction

Compounds of formula (III) can be prepared as described in scheme 2. A compound of formula (5) (wherein X is halogen) can be coupled with boronic acid derivative of formula (6) in the presence of a coupling reagent, such as a palladium catalyst, for example, tetrakis(triphenylphosphine)palladium(0); and an alkali metal carbonate (e.g., sodium carbonate) and suitable solvent combination (e.g., dioxane and/or water (2:1)) to afford a compound of formula (III).

⁵ (HI)

(a) Coupling reaction

Compounds of formula (III) where R² is formyl can be transformed to give compounds of formulas (Ilia), (IHb), and (IHc) as depicted in scheme 3.

A compound of formula (III) where R² is formyl [or formula (HIx)] can be coverted to form a compound of formula (Ilia) by using Grignard reagent of formula (a) (e.g., the Grignard reagent may be prepared from magnesium and alkyl halide in diethylether). The compound of formula (Ilia) can be oxidized, for example using a general oxidation reagent (such as pyridinium dichromate) and a suitable solvent (such as dichloro methane), to afford a compound of formula (HIb). The compound of formula (HIb) can be converted to form a compound of formula (HIc) by using a Grignard reagent of formula (c).

Scheme 3

(Mix) (Ilia) (MIb) (MIc)

(a) R⁰MgX; (b) oxidation; (c) R^dMgX

Compounds of formula (8) can be prepared by following sequential transformations as depicted in scheme 4. The first step in this sequence is coupling of a compound of formula (4a) (wherein X is halogen) with a metal cyanide (such as cuprous cyanide) in a suitable solvent (such as DMF), to afford a compound of formula (7), which is hydrolysed in the presence of an acid (e.g., H₂SO₄) or a base to give a compound of formula (8). Alternatively, compounds of formula (8) can be prepared from a compound of formula (9) by following procedure as described by R. A. Coburn and D. Gala in J. HeL Chem. 1982, 19, 757-759. A compound of formula (10) (wherein R is alkyl) can be prepared from the compound of formula (9) by esterifϊcation, which is well known in the art of organic synthesis. Alkylation of the compound of formula (10), for example by reacting with an alkyl halide of formula (d) (wherein R¹ is substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; and X is halogen) in the presence of a base (such as sodium hydride), yields a compound of formula (11), which is hydrolysed to give a compound of formula (8). Scheme 4

(b)

(a) Metal-CN; (b) hydrolysis; (c) esterifϊcation; (d) R¹X, base;

Compounds of formula (8) can also be prepared as dipicted in scheme 5. A compound of formula (12) (wherein X is halogen; and R is alkyl) can be prepared by methods well known in the art, e.g., as described by Katritzky et al in J. Org. Chem. 2004, 69, 6617-6622 {inter alia). The compound of formula (12) is converted to a compound of formula (13) by reacting with a compound of formula (a) (wherein arene diazonium salts were obtained in situ by diazotization of anilines of formula R¹NH₂ and NaNO₂ in the presence of acid). Treatment of the compound of formula 13 (wherein X is halogen; and R is alkyl) with a base, such as a metal hydride (e.g., sodium hydride), optionally in a suitable solvent (such as dioxane or THF) at an elevated temperature, affords a compound of formula (14) (wherein R is alkyl), which upon hydrolysis yields the compound of formula (8).

Scheme ₅

12 13 14

(a) R'NH₂/NaNO₂, H⁺; (b) Base; (c) hydrolysis

Compounds of formula 8a can be prepared according to scheme 6. A compound of formula (12) (wherein X is halogen; and R is alkyl) can be treated with amide acetals of formula (a) to afford a compound of formula (15), which can be further treated with an amine of formula R¹NH₂ to afford a compound of formula (16) (wherein X is halogen; and R is alkyl). Cyclisation of the compound of formula (16) in the presence of a strong base, such as a metal hydride (e.g., sodium hydride), produces a compound of formula (17) (wherein R is alkyl). Hydrolysis of the compound of formula (17) gives the compound of formula (8a).

Scheme 6

12 15 16

17 8a

(a) R³RVCH(OR)₂,; (I))R¹NH₂; (c) base, (d) hydrolysis

Scheme 7 depicts the synthesis of a compound of formula (HId). A compound of formula (8b) is coupled with a free or salt form of R²C(O)CH₂NH₂ through an amide coupling procedure well known in the art, [e.g., BOP (Benzotriazole-1-yl-oxy- tris-(dimethylamino)-phosphonium hexafluorophosphate) and DMF] to afford a compound of formula (18). The compound of formula 18 can be cyclised by treating with dehydrating agents, for example POCl₃, to give compounds of formula (HId).

8b 18 iπd

(a) amide coupling, (b) dehydration

Scheme 8 depicts the synthesis of a compound of formula (HIf) from a compound of formula (18). The compound of formula (18) can be converted to a compound of formula (IHe) by reacting with a thionating reagent, such as P₂S₅ or Lawesson's reagent. The compound of formula (IHe) can be reacted with a thiophilic reagent, such as a mercuric salt (e.g., Hg(OAc)₂), to form the compound of formula

(HIf).

Scheme 8

(a) thionation; (b) thiophilile

It is to be understood that the present invention encompasses all isomers of compounds of formula (I), (II) and (III) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in a compound of formula (I), the present invention includes within its scope all possible diastereoismers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.The subject invention also includes isotopically-labeled compounds, which are identical to those recited in formula (I), (II) or (III) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nikogen, oxygen, phosphorous, fluorine, iodine, and chlorine such as ³H, ¹¹C, ¹⁴C, ¹⁸0, ³²P, ³³P, ¹⁸F, ³⁷Cl ¹²³I and ¹²⁵I.

Compounds of the present invention and pharmaceutically acceptable salts of compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H, ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. ¹¹C and ⁸F isotopes are particularly useful in PET (positron emission tomography), and ¹²⁵I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e, 2H, can afford therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of formula (I), (II) or (III) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

Compounds of formula (I), (II) and (III) may be prepared in crystalline or noncrystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.

Embodiments of the present invention are illustrated by the following examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.

Experimental Intermediates

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: sat.: saturated; DMSO: Dimethyl sulphoxide; DMSCW₆: Hexadeuterodimethyl sulfoxide; THF: Tetrahydrofuran; DMF: N,N-dimethylformamide; M. P.: Melting point; TLC: thin layer chromatography; AcOEt: ethyl acetate; J: Coupling constant in units of Hz. Various alkyl 2-haloaroylacetates employed herein as starting materials were prepared by methods well known in the art of organic synthesis, e.g., according to Katritzky et al J. Org. Chem. 2004, 69, 6617-6622. 4-Oxo-l,4-dihydro-3-cinnolinone carboxylic acid was prepared by the route described by R. A. Coburn and D. Gala in J. Heterocycl. Chem. 1982, 19, 757-759. Intermediate 1 : Preparation of 1.4-Dihvdro-4-cinnolinone:

A solution of sodium nitrite (4.0 g, 59 mmol) in water (10 ml) was added over 20 minutes to a stirred mixture of 2 -aminoacetophenone (5.0 g, 37.03 mmol) and concentrated hydrochloric acid (31 ml) cooled in an ice bath. The resulting mixture was stirred at the same temperature for 2h and then at room temperature overnight. The mixture was concentrated under reduced pressure. Work-up (AcOEt/brine) after neutralization of the residue with aqueous sodium acetate gave the title compound (1.25 g, 23%). ¹H-NMR (δ ppm, OMSO-d₆, 300 MHz): 13.48 (br. s, IH); 8.01 (d, J = 8.1, IH); 7.82-7.73 (m, 2H); 7.57 (d, J = 8.1, IH); 7.41 (t, J = 7.8, IH). Intermediate 2: Preparation of 3-Bromo-l,4-dihydro-4-cinnolinone:

Bromine (0.8 ml) in acetic acid (10 ml) was added to a mixture of cinnolin-4- one (1.5 g, 10.27 mmol), sodium acetate (1.51 g, 18.49 mmol) and acetic acid (15 ml) maintained at 100 ⁰C and stirred at that temperature for Ih. The mixture was concentrated under reduced pressure to half the initial volume and poured into water. The precipitated solid was filtered, washed with water and dried under reduced pressure. Yield: 64%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 13.87 (br. s, IH); 8.06 (d, J = 7.8, IH); 7.84-7.80 (m, IH); 7.61 (d, J = 8.7, IH); 7.49 (t, J = 7.8, IH). Intermediate 3: Preparation of 3-Iodo-l,4-dihydro-4-cinnolinone:

A solution of cinnolinone and N-iodosuccinimide in DMF was stirred at 60°C for 3h. The mixture was poured into water and the precipitated product was collected by filtration and dried under vacuum. Appearance: Off-white powder. Yield: 80%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 13.90 (br. s, IH); 8.02 (d, J = 7.8, IH); 7.82 (t, J = 6.9, IH); 7.58 (d, J = 8.1, IH); 7.48 (t, J = 7.5, IH). General Procedure for alkylation of intermadiate 2 and intermediate 3: To an approximately 0.8M solution of the 3-halocinnolinone (intermediate 2 or intermediate 3, 1.0 equivalent) in DMF, sodium hydride (60% dispersion, 1.2 equivalent) and catalytic amount of tetra-«-butylammonium iodide were added at 0^°C. After stirring at room temperature for 30 min, the corresponding alkyl bromide (606 mg, 1.15 equivalent) was added and stirred until TLC indicated completion of the reaction. Work-up (AcOEt/H₂O, brine) and purification of the residue gave the corresponding l-alkyl-3-halocinnolinone. Intermediates 4 to 12 were prepared according to this procedure. Modifications are mentioned wherever applied. Intermediate 4: 3-Iodo-l-propyl-l,4-dihvdro-4-cinnolinone:

Yield from intermediate 3: 66%. Off-white solid. M.P.: 114-116°C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.33 (d, J = 8.4, IH); 7.75 (t, J = 8.1, IH); 7.50-7.37 (m, 2H); 4.39 (t, J = 7.7, 2H); 1.96 (sextet, J = 7.5, 2H); 1.03 (t, J = 7.5, 3H). Intermediate 5: 3-Iodo-l-(iso-propyl)-l,4-dihydro-4-cinnolinone:

The alkylating agent was isopropyl iodide and tetra-«-butylammonium iodide was not employed. Yield from intermediate 3: 45%. Yellow solid. M.P.: 105-108°C. ¹H-NMR (6 ppm, CDCl₃, 300 MHz): 8.36 (d, J = 8.4, IH); 7.75 (t, J = 7.8, IH); 7.54 (d, J = 8.7, IH); 7.44 (t, J = 7.8, IH); 4.96 (septet, J = 6.3, IH); 1.56 (d, J = 6.6, 6H). Intermediate 6: 3-Iodo-l-(»-butyl)-l,4-dihydro-4-cinnolinone:

Yield from intermediate 3: 72%. Yellow solid. M.P.: 65⁰C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.33 (d, J = 7.8, IH); 7.75 (t, J = 7.8, IH); 7.45-7.35 (m, 2H); 4.42 (t, J = 7.8, 2H); 1.90 (pentet, J = 7.8, 2H); 1.44 (sextet, J = 7.8, 2H); 1.00 (t, J = 7.8, 3H).

Intermediate 7: 3-Iodo-l-fao-butyl)-l,4-dihydro-4-cinnolinone:

Yield from intermediate 3: 70%. Flesh coloured solid. MP. : 78.8°C. ¹H-NMR (6 ppm, CDCl₃, 300 MHz): 8.34 (d, J = 7.8, IH); 7.74 (t, J = 7.8, IH); 7.45-7.35 (m, 2H); 4.23 (d, J = 7.8, 2H); 2.45-2.25 (m, IH); 1.00 (d, J = 6.3, 6H). Intermediate 8: 3-Bromo-l-(n-pentyl)-l,4-dihydro-4-cinnolinone:

Yield from intermediate 2: 64%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.37 (d, J = 9.0, IH); 7.75 (t, J = 7.2, IH); 7.48-7.41 (m, 2H); 4.40 (t, J = 7.8, 2H); 2.00-1.82 (m, 2H); 1.42-1.35 (m, 4H); 0.95-0.86 (m, 3H). Intermediate 9: 3-Iodo-l-(neo-pentyl)-l,4-dihydro-4-cinnolinone:

The reaction was conducted at 100°C. Yield from intermediate 3: 15%. Yellow solid. M.P.: 99-101°C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.34 (d, J = 7.5, IH); 7.71 (t, J = 7.8, IH); 7.50 (d, J = 8.7, IH); 7.43 (t, J = 7.2, IH); 4.26 (s, 2H); 1.03 (s, 9H). Intermediate 10: S-Iodo-l-cyclopropylmethyl-l ,4-dihydro-4-cinnolinone:

Yield from intermediate 3: 62%. Yellow solid. M.P.: 142-145°C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.34 (d, J = 8.1, IH); 7.76 (t, J - 7.8, IH); 7.52 (d, J = 9.0, IH); 7.46 (t, J = 7.5, IH); 4.31 (d, J = 6.9, 2H); 1.47-1.30 (m, IH); 0.75-0.58 (m, 2H); 0.58-0.47 (m, 2H).

Intermediate 11 : S-Iodo-l-cyclohexylmethyl-M-dihydro^-cinnolinone:

The reaction was conducted at 60-65°C. Yield from intermediate 3: 59%. Off- white powder. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.33 (d, J = 7.8, IH); 7.74 (t, J = 7.5, IH); 7.50-7.35 (m, 2H); 4.25 (d, J = 7.2, 2H); 2.05-1.90 (m, IH); 1.80-1.50 (m, 3H); 1.25-1.00 (m, 7H).

Intermediate 12: 3-Iodo-l-2,4-difluorobenzyl-l,4-dihydro-4-cinnolinone:

Yield from intermediate 3: 83%. Off-white solid. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.32 (d, J = 9.0, IH); 7.70 (t, J = 9.0, IH); 7.50-7.30 (m, 2H); 7.20-7.08 (m, IH); 7.93-7.68 (m, 2H); 5.61 (s, 2H).

Intermediate 13: 4-Oxo-l-pentyl-l,4-dihydro-3-cinnolinone carboxylic acid: Step 1 : 4-Oxo-l-pentyl-l,4-dihydro-3-cinnolinone carboxonitrile:

A mixture of intermediate 8 (1.4 g, 4.74 mmol), cuprous cyanide (488 mg,

5.40 mmol), and DMF (10 ml) was stirred at 100-110 °C for 18h and then concentrated to dryness under reduced pressure. To this residue were added ethylenediamine (4 ml), water (25 ml) and chloroform (50 ml). The resulting mixture was stirred for 2h. The organic phases separated and dried over Na₂SO₄. The title compound (550 mg, 48%) obtained by evaporation of solvent was used in the next step without purification. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.40 (d, J = 8.1, IH); 7.84 (t, J = 6.9, IH); 7.62-7.50 (m, 2H); 4.47 (t, J = 7.5, 2H); 2.05-1.85 (m, 2H); 1.42-

1.35 (m, 4H); 0.95-0.86 (m, 3H). IR (cm^"', KBr): 2958 (m), 2934 (m), 2858 (m), 2233 (w), 1682 (m), 1637 (s), 1602 (s), 1574 (m), 1497 (m), 1475 (m), 1459 (m), 1445 (s), 1323 (m), 1300 (m), 1 192 (m), 1201 (m). Step 2: 4-Oxo-l-pentyl-l,4-dihvdro-3-cinnolinone carboxylic acid:

The product of step 1 (550 mg, 2.28 mmol) and concentrated sulphuric acid (5 ml, 50%) were heated at 100-110 °C for 12h. The reaction was then diluted with water, solid obtained was filtered and dried (Yield: 390 mg, 66%). ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 14.59 (br. s, IH); 8.50 (d, J = 7.8, IH); 7.98-7.90 (m, IH); 7.75- 7.64 (m, 2H); 4.69 (t, J = 7.8, 2H); 2.06-1.97 (m, 2H); 1.44-1.34 (m, 4H); 0.92 (t, J = 6.9, 3H). Intermediate 14: Ethyl 4-Oxo-l,4-dihydro-3-cinnolinone carboxylate:

A solution of 4-oxo-l,4-dihydro-3-cinnolinone carboxylic acid (16.5 g, 86.8 mmol) in ethanol (165 niL) was treated with cone. H₂SO₄ (8 raL) and the mixture was refluxed overnight. The crystals of un-reacted starting material were filtered off and the filtrate was subjected to work-up (AcOEt/aq. Sat. NaHCO₃) to afford the title compound (6g, 31%). ¹H-NMR (δ ppm, DMSO-J₆₅ 300 MHz): 13.80 (br. s, IH); 8.08

(d, J = 8.1, IH); 7.84 (t, J = 7.5, IH); 7.67 (d, J = 8.4, IH); 7.51 (t, J = 7.5, IH); 4.30

(q, J = 7.2, 2H); 1.31 (t, J = 7.2, 3H).

Intermediate 15 : Ethyl 4-Oxo- 1 -cvclohexylmethyl- 1 ,4-dihydro-3 -cinnolinone carboxylate:

A solution of intermediate 14 (1.0 g, 4.59 mmol) in DMF ( 6 mL) was cooled in an ice-bath and treated with sodium hydride (60% dispesion, 132 mg, 5.5 mmol) and stirred at RT for 15 minutes. Bromomethylcyclohexane (742 μL, 5.32 mmol) and tetra-«-butylammonium iodide (356 mg, 0.92 mmol) were added to the mixture and stirring continued at RT overnight. Work-up and purification afforded the title compound (330 mg, 23%). Η-NMR (δ ppm, DMSO-J₆₅ 300 MHz): 8.16 (d, J = 6.6,

IH); 7.98 (d, J = 9.0, IH); 7.89 (t, J = 7.2, IH); 7.57 (t, J = 7.8, IH); 4.40-4.41 (m, 4H); 2.00-1.95 (m, IH); 1.70-1.50 (m, 5H); 1.30 (t, J = 7.2, 3H); 1.25-1.00 (m, 5H). Intermediate 16: Ethyl 4-Oxo-l-(4-fluorobenzyl)-l,4-dihvdro-3-cinnolinone carboxylate:

A procedure similar to that described for the previous intermediate was employed. Starting from intermediate 14 (1.0 g), DMF (6.0 mL), sodium hydride (60% dispesion, 132 mg, 5.5 mmol), 4-fluorobenzyl bromide (658 μL) and tetra-n- butylammonium iodide (338 mg, 0.92 mmol), the title compound (1.08g) was obtained in 72% yield. ¹H-NMR (δ ppm, DMSCW₆₅ 300 MHz): 8.17 (d, J = 8.4, IH);

7.84 (br. s, 2H); 7.60-7.50 (m, IH); 7.40-7.30 (m, 2H); 7.17 (t, J = 8.7, 2H); 5.77 (s,

2H); 4.32 (q, J = 7.2, 2H); 1.31 (t, J = 7.2, 3H).

Intermediate 17: 4-Oxo-l-cvclohexylmethyl-l,4-dihvdro-3-cinnolinone carboxylic acid:

A 1.4M aqueous solution of KOH (1 mL) was added to a solution of intermediate 15 (330 mg, 1.05 mmol) in ethanol (3.5 mL) and stirred at RT for 5h. After evaporation of ethanol, the mixture was acidified with aq. IN HCl. The precipitated product was filtered and dried to give the title compound (330 mg) in pure form and in quantitative yield. H-NMR (δ ppm, DMSO-J₆₅ 300 MHz): 14.42

(br. s, IH); 8.31 (d, J = 8.4, IH); 8.18 (d, J = 8.7, IH); 8.02 (t, J = 7.5, IH); 7.72 (t, J =

7.5, IH); 4.53 (d, J = 6.9, 2H); 2.05-1.85 (m, IH); 1.50-1.40 (m, 5H); 1.15-1.00 (m,

5H).

Intermediate 18: 4-Oxo-l-(4-fluorobenzyl)-l,4-dihvdro-3-cinnolinone carboxylic acid:

A procedure similar to that described for the previous intermediate was employed. Starting from intermediate 16 (1.Og, 3.07 mmol), the title compound (875 mg) was obtained in 86% yield. ¹H-NMR (δ ppm, DMSO-J₆ 300 MHz): 14.42 (br. s, IH); 8.31 (d, J = 8.1, IH); 8.05-7.80 (m, 2H); 7.66 (t, J = 6.9, IH); 7.45-7.30 (m, 2H); 7.17 (t, J = 8.7, 2H); 5.92 (s, 2H).

Intermediate 19: 4-Oxo-l -phenyl- l,4-dihydro-3-cinnolinone carboxylic acid: Step 1: Ethyl 2-(phenylhvdrazono)-3-(2-fluorophenyl)-3-oxo-propionate:

An aqueous solution (0.9 mL) of sodium nitrite (223 mg, 1.02 mmol) was added slowly to a solution of aniline (0.28 mL, 3.17 mmol) in aq. 35% hydrochloric acid (0.67 mL) while maintaining the mixture below 0°C. The resulting orange solution was added to a slurry of ethyl 2-(2-fluorobenzoyl)acetate (680 mg, 1.02 mmol) and sodium acetate (595 mg, 2.29 mmol) in ethanol (6.32 mL) and water (1.17 mL) at 0⁰C and the mixture was stirred for 3h. Work-up (CHC1₃/H₂O) gave the crude product (1.0 g) as a ca. 7:3 mixture of two geometrical isomers as revealed by its nmr spectrum and was used without purification in the next step. H-NMR (δ ppm, DMSO-J₆^OO MHz): 14.33 (br. s, 0.3H); 12.91 (br. s, 0.7 H); 7.70-7.00 (m, 9H);

4.38 (q, J = 7.5, 1.4H); 4.23 (q, J = 7.2, 0.6H); 1.38 (t, J = 7.5, 2.1H); 1.89 (t, J = 7.2,

0.9H).

Step 2: Ethyl 4-oxo-l -phenyl- l,4-dihydro-3-cinnolinone carboxylate:

Sodium hydride (60% dispersion in mineral oil, 41.66 mg, 1.05 mmol) was added slowly at RT to a solution of the product from step 1 (300 mg, 0.95 mmol) in 1,4-dioxane (3 mL) and reflux ed for 2h. Work-up (AcOEtZH₂O) after cooling to RT gave the crude product (272 mg) which was used in the next step. H-NMR (δ ppm, CDCl₃ 300 MHz): 8.42 (d, J = 8.4, IH); 7.60-7.40 (m, 7H); 7.21 (d, J = 9.0, IH); 4.45

(q, J = 7.2, 2H); 1.41 (t, J = 7.2, 3H). MS (m/z): 295.16 ([M+H]⁺, 100). Step 3: 4-Oxo-l -phenyl- l,4-dihydro-3-cinnolinone carboxylic acid:

An aq. 1.25 M solution of KOH (0.94 mL) was added to a suspension of the product from step 2 in ethanol (3.0 mL) and refluxed for Ih. Ethanol was evaporated and the residue diluted with water and washed with ether. The precipitate formed upon acidification of the aqueous layer with aq. IN HCl was filtered, dissolved in CH₂Cl₂, dried over sodium sulphate, filtered and the solvent was evaporated to give the title compound as an off-white solid in 76% yield. H-NMR (δ ppm, CDCl₃ SOO

MHz): 14.48 (br. s, IH); 8.52 (d, J = 7.8, IH); 7.79 (t, J = 7.2, IH); 7.70-7.45 (m, 6H);

7.40 (d, J = 8.7, IH). MS (m/z): 267.42 ([M+H]⁺, 100).

Intermediate 20: 4-Oxo-l-(2,4-difluorophenvD-l,4-dihvdro-3-cinnolinone carboxylic acid:

Step 1 : Ethyl 2-[(2,4-difluorophenyl)hvdrazonol-3-(2-fluorophenyl)-3-oxo- propionate:

Starting from 2,4-difluoroaniline (602 mg, 4.66 mmol) and ethyl 2- (2fluorobenzoyl)acetate (1.0 g, 4.76 mmol), the title compound (1.5 g, 92%) was obtained as a yellow solid by a procedure similar to that described in step 1 for intermediate 19. ' H-NMR (δ ppm, CDC1_3? 300 MHz): 12.89 (br. s, IH); 7.65 (br. t, J

= 7.2, IH); 7.55-7.45 (m, IH); 7.30-7.10 (m, 2H); 7.08 (t, J = 9.3, IH); 6.95-6.75 (m,

2H); 4.38 (q, J = 7.2, 2H); 1.35 (t, J = 7.2, 3H).

Step 2: 4-Oxo-l-(2,4-difluorophenylVh4-dihvdro-3-cinnolinone carboxylic acid:

A solution of the product from step 1 (1.0 g, 2.85 mmol) in 1,4-dioxane (7.5 mL) was added slowly to suspension of sodium hydride (60% dispersion in mineral oil, 171 mg, 2.85 mmol) in 1,4-dioxane (2.5 mL) and the mixture was heated at reflux for 3h. After cooling to RT, the mixture was subjected to work-up (AcOEt/aq. IN HCl) and the residue subjected to a procedure similar to that described in step 3 for intermediate 19 to give the title compound (810 mg) as an off-white solid. H- NMR (δ ppm, DMSO-4_; 300 MHz): 13.87 (br. s, IH); 8.28 (d, J = 7.8, IH); 8.00-

7.80 (m, 2H); 7.80-7.60 (m, 2H); 7.44 (t, J = 8.1, IH); 7.23 (d, J = 8.4, IH). MS (m/z): 303.28 ([M+H]⁺, 100).

Intermediate 21 : l-(4-Chlorophenyl)-4-oxo-l,4-dihvdroquinoline-3-carboxylic acid: Step 1 : Ethyl (2E/Z)-2-(2-chlorobenzoyl)-3-dimethylamino)prop-2-enoate:

Ethyl 2-chlorobenzoylacetate (1.0 equiv.) was stirred with dimethylformamide dimethyl acetal (3.0 equiv) for 2 hr at RT and then for an additional hr at 60 °C and cooled to RT. Work-up (AcOEt/H₂O) and purification gave the title compound in pure form. Yield: 56%. ¹H-NMR (O ppm, CDC1_3J300 MHz): 7.80 (s, IH); 7.40-7.19

(m, 4H); 3.88 (q, J = 7.2, 2H); 3.23 (br. s, 3H); 2.96 (br. s, 3H); 0.83 (t, J = 7.2, 3H). Step 2: Ethyl (2E/Z)-3-r(4-chlorophenyl)aminol-2-(2-chlorobenzoyl)-prop-2-enoate:

A 0.5M solution of the product form step 1 (1.0 eq.) and 4-chloroaniline (1.1 equiv.) in toluene was heated at 110 °C for 4h. Evaporation of the solvent and purification of the residue gave the product as a 65:35 mixture of two isomers. Yield: 92%. Η-NMR (δ ppm, CDCl₃₅ 300 MHz): 12. 65 (br. d, J = 16, 0.65 H); 11.20 (br. d,

J = 16, 0.35 H); 8.55 (d, J = 12.3, IH); 7.45-7.10 (m, 7H); 4.10-3.90 (m, 2H); 0.93, 0.84 (2t, J = 7.2, 3H).

Step 3: l-(4-Chlorophenyl)-4-oxo-l,4-dihvdroquinoline-3-carboxylic acid:

Sodium hydride was added slowly to a ca. 0.06M solution of the product from step 2 in DME and heated at 80 °C for 4hr. After cooling and work-up [AcOEt/Aq. Sat. NH₄Cl, brine], the residue was dissolved (to ca. 0.25 M) in THF and treated with half a volume of a 0.6M solution of sodium hydroxide and refluxed for 3h. The mixture was diluted water and washed with ether. Acidification of the aqueous layer and extraction into ethyl acetate gave the title carboxylic acid in 75% yield. H- NMR (δ ppm, CDCl₃₅ 300 MHz): 14.73 (br. s, IH); 8.75 (s, IH); 8.55 (d, J = 7.8, IH);

7.80-7.40 (m, 4H); 7.85 (d, J = 7.2, 2H); 7.12 (d, J = 8.1, IH). MS (m/z): 300.49 ([M+H]⁺, 100).

Intermediate 22: l-(n-Pentyl)-4-oxo-l,4-dihvdroquinoline-3 -carboxylic acid: Step 1 : Ethyl (2E/Z)-3-(n-pentylamino)-2-(2-chlorobenzoyl)-prop-2-enoate:

The title compound was prepared from the product of step 1 for intermediate 21 and n-pentylamine using a procedure similar to that described in step 2 for the same intermediate. Yield: 98%. Η-NMR (δ ppm, CDCl₃ 300 MHz): 1 1.06 (br. s, 0.87

H); 9.50 (br. s, 0.13 H); 8.18 (d, J = 13.8, 0.13 H); 8.11 (d, J = 13.8, 0.87 H); 7.35- 7.15 (m, 4H); 4.00-3.85 (m, 2H); 3.43 (q, J = 6.9, 2H); 1.80-1.60 (m, 2H); 1.40-1.30

(m, 4H); 1.00-0.70 (m, 6H). Step 2: l-Cn-PentylM-oxo-M-dihydroquinoline-S-carboxylic acid:

The product from step 1 was converted into the title compound by using a procedure similar to that described in step 3 for intermediate 21. Yield: 78%. H- NMR (δ ppm, CDC1_3;3OO MHz): 14.96 (br. s, IH); 8.74 (s, IH); 8.55 (d, J = 7.8, IH);

7.84 (t, J = 6.9, IH); 7.70-7.50 (m, 2H); 4.31 (t, J = 6.9, 2H); 1.94 (br. s, 2H); 1.40

(br. s, 4H); 0.93 (br. s, 3H).

Intermediate 23 : 7-Chloro- 1 -(4-chlorophenyl)-4-oxo- 1 ,4-dihydroquinoline-3- carboxylic acid:

Step 1 : Ethyl (2E/Z)-2-(2,4-dichlorobenzoyl)-3-(dimethylamino)prop-2-enoate:

The title compound was obtained from ethyl 2,4-dichlorobenzoylacetate using a procedure similar to that described in step 1 for intermediate 21. Yield: 66%. H- NMR (δ ppm, CDCl₃₅300 MHz): 7.80 (s, IH); 7.38-7.20 (m, 3H); 3.92 (q, J = 6.9,

2H); 3.33 (br. s, 3H); 2.95 (br. s, 3H); 0.91 (J = 7.2, 3H).

Step 2: Ethyl (2E/Z)-3-[(4-chlorophenyl)aminol-2-(2,4-dichlorobenzoyl)-prop-2- enoate:

The title compound was prepared from the product of step 1 and 4- chloroaniline using a procedure similar to that described in step 2 for intermediate 21.

Yield: 31%. Η-NMR (δ ppm, CDCl₃^OO MHz): 12.64 (d, J = 13.2, 0.7 H); 11.21 (d,

J = 11.7, 0.3H); 8.55 (d, J = 14.1, IH); 7.41-7.10 (m, 7H); 4.08-3.95 (m, 2H); 1.01 (t, J = 7.5, 2.1H); 0.88 (t, J = 7.2, 0.9H). Step 3: 7-Chloro-l-(4-chlorophenylV4-oxo-l,4-dihydroquinoline-3-carboxylic acid:

The product of step 2 was converted into the title compound by a procedure similar to that described in step 3 for intermediate 21. Yield: 94%. H-NMR (δ ppm, DMSO-J₆₅ 300 MHz): 8.75 (s, IH); 8.41 (d, J = 7.2, IH); 7.79-7.70 (m, 5H); 7.12 (s,

IH).

Intermediate 24: l-Amino-3,3-dimethyl-2-butanone hydrochloride:

Step 1 : l-Azido-3,3-dimethyl-2-butanone:

N₃ O To a solution of sodium azide (399 mg, 6.14 mmol) in dry DMF (5 ml), 1-

O bromo pinacolone (751μl, 5.58 mmol) was added dropwise at 0 C during 15 min. The mixture was allowed to warm up to RT and stirred for 5h. Work-up (AcOEt/hexane 1 : I/water and brine) gave the title azide as a yellow oil (689 mg, 88%). H-NMR (δ ppm, CDCl₃ SOO MHz): 4.08 (s, 2H); 1.19 (s, 9H). IR (cm^"', KBr): 3413 (w), 2971

(m), 2909 (m), 2875 (m), 2104 (s), 1718 (m), 1477 (w), 1282 (m), 1066 (m), 1014

(w), 910 (m).

Step 2: l-Amino-3,3-dimethyl-2-butanone hydrochloride:

Acetyl chloride (131 μl, 1.84 mmol) was added to cooled solution of ethanol (5 ml) and the azide from step 1 (200 mg, 1.41 mmol) was dissolved in it and evacuated and flushed with nitrogen. To the above solution was added 20 mg of palladium on carbon (10%). The resulting slurry was again flushed with nitrogen and stirred under 1 atm of hydrogen for 3h. The reaction mixture was filtered through a pad of celite and solvent was removed under reduced pressure and dried under vacuum to furnish white solid (194 mg, 90%). ¹H-NMR (O ppm, CDCl^OO MHz):

8.39 (br. s, 3H); 4.33 (br. s, 2H); 1.20 (s, 9H). IR (cm^"', KBr): 3431 (s), 2979 (s), 2619 (m), 1719 (s), 1638 (m), 1605 (w), 1480 (s), 1385 (m), 1141 (m), 987 (m), 893(m). Intermediate 25: N3-(3.3-Dimethyl-2-oxobutylV 4-oxo-l-pentyl-1.4-dihvdro-3- cinnolinone carboxamide:

The intermediate 13 (300 mg, 1.15 mmol) was dissolved in dry DMF (2.0 ml), Et₃N (390 μl, 2.76 mmol) and BOP reagent (560 mg, 1.26 mmol) were added to the solution. After stirring at RT for 30 min., Intermediate 24 (192 mg, 1.26 mmol) was added and the mixture was stirred at RT overnight. Work-up (AcOEt/H₂O) followed by purification of the crude product furnished the title compound as a white solid (250 mg, 60%). ¹H-NMR (δ ppm, DMSO-J₆, 300 MHz): 10.04 (br. s, IH); 8.30 (d, J = 7.8, IH); 8.04 (d, J = 8.1, IH); 7.95 (t, J = 6.9, IH); 7.64 (t, J = 7.2, IH); 4.61 (t, J = 7.2, 2H); 4.47 (d, J = 5.4, 2H); 1.96-1.80 (m, 2H); 1.39-1.30 (m, 4H); 1.17 (s, 9H); 0.86 (br. s, 3H).

Intermediate 26: N3-(3,3-Dimethyl-2-oxobutyl)-4-oxo- 1 -cvclohexylmethyl- 1 A- dihydro-3-cinnolinone carboxamide:

A procedure similar to that described for the previous intermediate was employed. Starting from intermediate 17 (290 mg, 1.01 mmol), DMF (6.0 mL), Et₃N (156 μL, 1.1 1 mmol), BOP reagent (470 mg, 1.06 mmol) and intermediate 24 (227 mg, 1.52 mmol) title compound (250 mg) was obtained in 64% yield. H-NMR (δ ppm, DMSO-J, 300 MHz): 10.05 (br. s, IH); 8.29 (d, J = 7.8, IH); 8.08 (d, J - 8.7, IH); 7.94 (t, J - 7.5, IH); 7.63 (t, J = 7.8, IH); 4.55-4.40 (m, 4H); 2.05-1.95 (m, IH); 1.75-1.35 (m, 5H); 1.30-1.00 (m, 14 H).

Intermediate 27: N3-(3,3-Dimethyl-2-oxobutyl)-4-oxo-l-(4-fluorobenzyl)-l,4- dihydro-3 -cinnolinone carboxamide:

A procedure similar to that described for intermediate 25 was employed. Starting from intermediate 18 (475 mg, 1.59 mmol), DMF (10.0 mL), Et₃N (590 μL, 4.19 mmol), BOP reagent (734 mg, 1.66 mmol) and intermediate 24 (380 mg, 2.38 mmol) the title compound (400 mg) was obtained in 63% yield. H-NMR (δ ppm, DMSO-^300 MHz): 10.02 (t, J = 4.8, IH); 8.29 (d, J = 8.1, IH); 7.95-7.80 (m, 2H);

7.60 (t, J = 7.2, IH); 7.40-7.25 (m, 2H); 7.16 (t, J = 8.7, 2H); 5.87 (s, 2H); 4.50 (d, J = 4.8, 2H); 1.18 (s, 9H).

General procedure for amidation of 4-oxo-l,4-dihvdroquinoline-3-carboxylic acids and l-aryl-4-oxo-K4-dihvdrocinnoline-3-carboxylic acids:

A solution of the carboxylic acid (any of intermediates 19 to 23, 1.0 eq.) in DMF was treated with BOP reagent (1.1 eq.), and triethylamine (2.4 eq.) at RT for 0.5h and then intermediate 24 (1.1 eq.) was added and the mixture stirred overnight. The solids formed upon dilution with water were collected and purified. The following intermediates were prepared by this procedure:

Intermediate 28: N3-(3,3-Dimethyl-2-oxobutyl)-4-oxo-l-phenyl-l,4-dihydro-3- cinnolinone carboxamide:

Satrting from intermediate 19, the title compound was obtained in 59% yield. ¹H-NMR (δ ppm, CDCl₃ 300 MHz): 10.50 (br. s, IH); 8.50 (d, J = 7.8, IH); 7.75-7.45 (m, 7H); 7.28 (d, J = 8.7, IH); 4.55 (d, J = 4.5, 2H); 1.25 (s, 9H). Intermediate 29: N3-π3-Dimethyl-2-oxobutyl)-4-oxo-H2Λ-difluorophenyl)-1.4- dihydro-3-cinnolinone carboxamide:

Satrting from intermediate 20, the title compound was obtained in 70% yield. ¹H-NMR (δ ppm, CDC1_3J300 MHz): 9.83 (br. s, IH); 8.32 (d, J = 7.8, IH); 7.98-7.80

(m, 2H); 7.80-7.60 (m, 2H); 7.44 (t, J = 8.1, IH); 7.22 (d, J = 9.3, IH); 4.47 (d, J =

4.8, 2H); 1.49 (s, 9H). MS (m/z): 400.22 ([M+H]⁺, 100).

Intermediate 30: l-(4-Chlorophenyl)-N-(3,3-dimethyl-2-oxobutyl)-4-oxo-l,4- dihydroquinoline-3 -carboxamide:

Starting from intermediate 21, the title compound was obtained in 99% yield. ¹H-NMR (δ ppm, CDCl₃^OO MHz): 10.54 (br. s, IH); 8.72 (s, IH); 8.57 (d, J = 6.3,

IH); 7.65-7.55 (m, 3H); 7.47 (t, J = 6.3, IH); 7.36 (d, J = 7.2, 2H); 7.02 (d, J = 8.1, IH); 4.49 (d, J = 4.8, 2H); 1.25 (s, 9H). MS (m/z): 397.49 ([M+H]⁺, 100). Intermediate 31 : N-(3 ,3 -Dimethyl-2-oxobutyl^')-4-oxo- 1 -(n-pentvP- 1 ,4- dihydroquinoline-3-carboxamide:

Starting from intermediate 22, the title compound was obtained in 65% yield. ¹H-NMR (δ ppm, CDCl₃ SOO MHz): 10.57 (br. s, IH); 8.70 (s, IH); 8.56 (d, J = 7.8,

IH); 7.70 (t, J = 7.8, IH); 7.52-7.40 (m, 2H): 4.48 (d, J - 4.5, 2H); 4.23 (t, J = 7.0, 2H); 2.00-1.85 (m, 2H); 1.38 (br. s, 4H); 1.24 (s, 9H); 0.91 (br. s, 3H). Intermediate 32: 7-Chloro-l -(4-chlorophenyl)-N-(3,3-dimethyl-2-oxobutyl)-4-oxo- 1 ,4-dihydroquinoline-3 -carboxamide:

Starting from intermediate 23, the title compound was obtained in 89% yield.

¹H-NMR (O ppm, CDC1₃₎3OO MHz): 10.41 (br. s, IH); 8.68 (s, IH); 8.49 (d, J = 7.8,

IH); 7.61 (d, J = 8.1, 2H); 7.43-7.35 (m, 3H); 6.98 (s, IH); 4.48 (br. s, 2H); 1.24 (s, 9H).

Examples

General Procedures for Sonogashira coupling reactions:

Procedure A: To a solution of a l-alkyl-3-halocinnolinone (1.0 equiv.) and a terminal alkyne (1.5 to 3 equiv.) in 1 :1 mixture of DMF and triethylamine were added catalytic amount of bis-[triphenylphosphine]palladium(II) chloride (2 mol %) and copper(I)iodide (1 mol %). After stirring the mixture at RT until TLC indicated completion of the reaction, solvent was removed and the residue subjected to silica gel column chromatography to furnish the corresponding l-alkyl-3-alkynyl cinnolinone.

Procedure B: As per procedure A with the following modification: Only 1.5 equivalents of the alkyne were employed with triethylamine as the solvent. One of these procedures, as indicated, was used to prepare examples 1 to 13: Example 1: 3 -(33 -Dimethyl- 1-butwvD-l -propyl- lΛ-dihydro-4-cinnolinone:

Procedure A. Yield from intermediate 4 and 3,3-dimethyl-l-butyne: 70%. Brown solid. M.P.: 38°C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.33 (d, J = 7.2, IH); 7.68 (t, J = 7.2, IH); 7.45-7.32 (m, 2H); 3.37 (t, J = 7.5, 2H); 2.02-1.84 (m, 2H); 1.40 (s, 9H); 1.02 (t, J = 7.8, 3H). IR (cm^"', CHCl₃): 2969 (s), 293 l(m), 2899(m), 2973(m), 2221 (w), 1626 (s), 1607 (s), 1481 (s), 1463 (m), 1457 (m), 1361 (m), 1331 (s), 1304 (m), 1258 (w), 1242 (w), 1208 (m), 1124 (w), 977 (m), 862 (m), 758 (s). MS (m/z): 269.1 ([M+H]⁺). Example 2 : 3-(3 ,3 -Dimethyl- 1 -butynyl)- 1 -(/so-propyl)- 1 ,4-dihydro-4-cinnolinone:

Procedure A. Yield from intermediate 5 and 3, 3 -dimethyl- 1-butyne: 46%. Pale brown solid. M.P.:120-123°C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.35 (d, J = 7.2, IH); 7.68 (t, J = 8.1, IH); 7.54 (d, J = 8.7, IH); 7.37 (t, J = 7.5, IH); 4.96 (septet, J =

6.5, IH); 1.56 (d, J = 6.5, 6H); 1.40 (s, 6H). IR (cm^'1, CHCl₃): 2971 (s), 2927 (m), 2877 (w), 2220(w), 1626 (s), 1610 (s), 1481 (m), 1463 (m), 1363 (m), 1310 (s), 1266 (w), 1253 (w), 1208 (s), 1164 (w), 1136 (w), 1095 (w), 1039 (w), 978 (w), 864 (w), 744 (m). MS (m/z): 269.1 ([M+H]⁺). Example 3: l-Butyl-3-(3,3-Dimethyl-l-butvnyl)-l,4-dihydro-4-cinnolinone:

Procedure A. Yield from Intermediate 6 and 3,3-dimethyl-l-butyne: 73%. Pale yellow solid. M.P.: 40°C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.33 (d, J = 8.4, IH); 7.66 (t, J = 7.8, IH); 7.44-7.32 (m, 2H); 4.40 (t, J = 7.5, 2H); 2.00-1.80 (m, 2H); 1.52-

1.35 (m, 2H); 1.40 (s, 9H); 0.99 (t, J = 7.5, 3H). IR (cm^"', CHCl₃): 2967 (s), 293 l(m), 2973(m), 2869(m), 222 l(w), 1627 (s), 1607 (s), 1481 (s), 1465 (m), 1457 (m), 1361 (m), 1334 (s), 1304 (s), 1259 (w), 1236 (m), 1201 (m), 1124 (w), 980 (w), 862 (m), 758 (s). MS (m/z): 283.2 ([M+H]⁺). Example 4: 3-(3,3-Dimethyl-l-butvnyl)-l-isobutyl-l,4-dihvdro-4-cinnolinone:

Procedure A. Yield from intermediate 7 and 3,3-dimethyl-l-butyne: 85%. Pale yellow solid. 60-63 °C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.33 (d, J = 8.4, IH); 7.67 (t, J = 7.8, IH); 7.48-7.32 (m, 2H); 4.21 (d, J = 7.2, 2H); 2.40-2.20 (m, IH); 1.39

(s, 9H); 0.98 (t, J = 6.6, 6H). IR (cm^"1, KBr): 2967 (m), 2955 (m), 2899 (w) 2870 (w),

2218 (w), 1625 (s), 1605 (s), 1481 (m), 1467 (m), 1363 (w), 1343 (m), 1326 (s), 1299

(m), 1242 (s), 1211 (m), 1135 (w), 979 (w), 862 (w), 759 (m). MS (m/z): 283.2

([M+H]⁺).

Example 5: 3-(3,3-Dimethyl-l-butvnyl)-l-pentyl-l,4-dihvdro-4-cinnolinone:

Procedure B. Yield from intermediate 8 and 3,3-dimethyl-l-butyne: 40%. ¹H- NMR (δ ppm, CDCl₃, 300 MHz): 8.33 (d, J = 7.8, IH); 7.69 (t, J = 7.8, IH); 7.45-7.23 (m, 2H); 4.39 (t, J = 7.8, 2H); 1.98-1.82 (m, 2H); 1.45-1.30 (m, 4H); 1.39 (s, 9H);

0.95-0.86 (m, 3H). IR (cm^"', KBr): 2966 (s), 2931 (s), 2869 (m), 2218 (w), 1711 (m), 1626 (s), 1607 (s), 1481 (s), 1467 (s), 1266 (m), 1230 (m), 1 198 (s), 1 135 (w), 1123 (w), 1064 (w), 968 (w), 863 (m), 758 (s). MS (m/z): 297.4 ([M+H]⁺). Example 6: 3-[2-(l -Hydroxycyclohexyl)- 1 -ethynyl)- 1 -pentyl- 1 ,4-dihydro- 1 H- cinnolin-4-one:

Procedure B. Yield from intermediate 8 and 1 -ethynyl cyclohexanol: 29%. Waxy solid. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.34 (d, J = 7.5, I H); 7.71 (t, J = 7.5, IH); 7.50-7.30 (m, 2H); 4.40 (t, J = 6.9, 2H); 2.80 (br. s, IH); 2.10 (br. s, 2H); 1.92 (br. s, 4H); 1.82-1.50 (m, 4H); 1.50-1.12 (m, 6H); 0.92 (br. s, 3H). IR (cm^" , KBr): 3466 (br. s,), 3227 (br. m), 2933 (s), 2859 (m), 1618 (s), 1606 (s), 1482 (m), 1465 (m), 1455 (m), 1354 (m), 1333 (s), 1310 (m), 1271 (w), 1259 (w), 1231 (w), 1209 (w), 1192 (w), 1132 (w), 1115 (w), 1072 (m), 1037 (w), 991 (w), 967 (m), 904 (w), 756 (m), 746 (w). MS (m/z): 339.2 ([M+H]⁺). Example 7: 3-(3-Hydroxy-3-Methyl-l -butynyl)-! -pentyl-1 ,4-dihydro-4-cinnolinone:

Procedure B. Yield from intermediate 8 and α,α-dimethyl propargyl alcohol: 69%. Waxy solid. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.34 (d, J = 8.4, IH); 7.73 (t, J = 7.8, IH); 7.50-7.35 (m, 2H); 4.41 (t, J = 7.5, 2H); 3.40 (br. s, IH, exchanges with D₂O); 2.00-1.80 m, 2H); 1.67 (s, 6H); 1.52-1.32 (m, 4H); 0.92 (t, J = 6.3, 3H). IR (cm^"

\ KBr): 3390 (br. s); 2980 (s), 2961 (s), 2932 (s), 2872 (m) 2861 (m), 2230 (w), 1715 (w), 1608 (s), 1606 (s), 1484 (m), 1464 (m), 1375 (m), 1361 (m), 1333 (s), 1304 (m), 1263 (w), 1231 (m), 1194 (m), 1168 (s), 1047 (w), 989 (w), 965 (w), 950 (m), 875 (w), 758 (s). MS (m/z): 299.3 ([M+H]⁺). Example 8: 3-(3,3-Dimethyl-l-butynyl)-l-neopentyl-l,4-dihydro-4-H-cinnolinone:

Procedure A. Yield from intermediate 9 and 3,3-dimethyl-l-butyne: 46%. Pale brown solid. M.P.: 100-103°. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.33 (d, J = 8.4, IH); 7.64 (t, J = 7.1, IH); 7.51 (d, J = 8.7, IH); 7.36 (t, J = 7.2, IH); 4.25 (s, 2H); 1.39

(s, 9H); 1.03 (s, 9H). ). IR (cm^"1, KBr): 2965 (m), 2955 (m), 2899 (w) 2866 (w), 2219 (w), 1622 (s), 1599 (s), 1492 (w), 1474 (m), 1449 (m), 1367 (w), 1349 (w), 1337 (m), 1302 (m), 1232 (m), 1192 (w), 1 183 (w), 979 (w), 862 (w), 762 (w). MS (m/z): 297.2 ([M+H]⁺). Example 9: 3-(2-Cyclopentyl- 1 -ethynyl)- 1 -cyclopropylmethyl- 1 ,4-dihydro-4- cinnolinone:

Procedure A. Yield from intermediate 10 and ethynyl cyclopentane: 44%. Pale brown solid. M.P.: 86-89°. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.35 (d, J = 8.4, IH); 7.70 (t, J = 7.8, IH); 7.53 (d, J = 9.0, IH); 7.39 (t, J = 7.8, IH); 4.29 (d, J = 6.9, 2H); 3.01-2.85 (m, IH); 2.12-1.97 (m, 2H); 1.90-1.72 (m, 4H); 1.51-1.69 (m, 2H); 1.45-

1.31 (m, IH); 0.67-0.48 (m, 4H). IR (cm^"1, KBr): 2952 (m), 2868 (w), 2225 (w), 1623

(s), 1602 (s), 1528 (w), 1478 (m), 1461 (m), 1444 (w), 1386 (w), 1345 (m), 1328 (m),

1296 (m), 1250 (w), 1222 (w), 1017 (w), 932 (w), 904 (w) 830 (w), 757 (m). MS

(m/z): 293.3 ([M+H]⁺).

Example 10: l-Cvclopropylmethyl-3-(3,3-Dimethyl-l-butynyl)-l,4-dihydro-4- cinnolinone:

Procedure A. Yield from intermediate 10 and 3,3-dimethyl-l-butyne: 55%. Off-white solid. M.P. 106-108°C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.34 (d, J =

7.8, IH); 7.69 (t, J = 7.8, IH); 7.52 (d, J = 8.7, IH); 7.39 (t, J = 7.5, IH); 4.29 (d, J =

6.9, 2H); 1.42-1.30 (m, IH); 1.40 (s, 9H); 0.67-0.54 (m, 2H); 0.54-0.55 (m, 2H). IR

(cm^"', KBr): 2968 (m), 2923 (m), 2898 (w) 2867 (w), 2219 (w), 1626 (s), 1604 (s), 1495 (w), 1481 (m), 1460 (m), 1443 (w), 1352 (m), 1333 (s), 1297 (m), 1261 (m), 1244 (m), 1222 (m), 1 193 (w), 1169 (w), 1 140 (w), 1049 (w), 1021 (w), 970 (m), 929 (w), 861 (m), 830 (m), 762 (m), 756 (m). MS (m/z): 281.2 ([M+H]⁺). Example 11 : l-Cyclopropylmethyl-3-(2-phenyl-l -ethynyl)- 1 ,4-dihydro-4- cinnolinone:

Procedure A. Pale brown solid. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.41 (d, J = 8.4, IH); 7.74 (t, J = 8.4, IH); 7.70-7.55 (m, 2H); 7.59 (d, J = 9.0, IH); 7.44 (t, J = 7.5, IH); 7.38-7.25 (m, 3H); 4.35 (d, J = 6.9, 2H); 1.60-1.35 (m, IH); 0.70-0.60 (m,

2H); 0.60-0.50 (m, 2H). IR (cm^'1, KBr): 3078 (w), 3000 (w), 2961 (w) 2215 (w), 1627

(s), 1608 (s), 1482 (m), 1457 (m), 1443 (w), 1390 (w), 1346 (s), 1297 (w), 1256 (w),

1238 (w), 1221 (m), 1 180 (w), 1168 (w), 1143 (w), 1070 (w), 1020 (w), 949 (w), 840

(w), 818 (w), 774 (m), 752 (m). MS (m/z): 301.26 ([M+H]⁺).

Example 12: l-(Cvclohexylmethyl)-3-(3,3-Dimethyl-l-butvnyl)-l,4-dihvdro-4- cinnolinone:

Procedure A. Yield from intermediate 11 and 3, 3 -dimethyl- 1-butyne: 73%.Off-white solid. M.P.: 123-126°C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.33 (d, J = 8.4, IH); 7.68 (t, J = 7.5, IH); 7.50-7.35 (m, 2H); 4.23 (d, J = 7.5, 2H); 2.05-1.95

(m, IH); 1.80-1.50 (m, 4H); 1.40 (s, 9H); 1.30-1.00 (m, 6H). IR (cm^"1, KBr): 2968

(m), 2924 (s), 2851 (m), 2222 (w), 1626 (s), 1606 (s), 1482 (m), 1466 (w), 1450 (w),

1350 (w), 1328 (m), 1302 (m), 1313 (m), 1255 (w), 1201 (w), 983 (w), 863 (w), 764

(w). MS (m/z): 323.2 ([M+H]⁺).

Example 13: 1 -(2.4-Difluorobenzyl)-3-(3,3-Dimetfayl-l -butynvD-1 ,4-dihydro-4- cinnolinone:

The title compound was obtained as an off-white solid in 78% yield from intermediate 12 and 3, 3 -dimethyl- 1-butyne using Procedure A. M.P.: 195-198°C. ¹H- NMR (δ ppm, CDCl₃, 300 MHz): 8.32 (d, J = 8.4, IH); 7.62 (t, J = 7.5, IH); 7.40-7.26

(m, 2H); 7.16-7.00 (m, IH); 6.90-6.70 (m, 2H); 5.60 (s, 2H); 1.41 (s, 9H). IR (cm^"1, KBr): 3063 (m), 2970 (m), 2217 (w), 1634 (s), 1608 (s), 1509 (m), 1493 (m), 1483 (m), 1465 (w), 1450 (w), 1429 (w), 1333 (s), 1313 (w), 1298 (w), 1257 (w), 1243 (w), 1162 (w), 1148 (w),l 124 (w), 1094 (m), 966 (m), 890 (w), 860 (w), 809 (w), 758 (m). MS (m/z): 353.3 ([M+H]⁺). Example 14: 3-(4-Oxo-l-pentyl-l,4-dihvdro-3-cinnolinyl)benzaldehyde:

A solution of intermediate 8 (200 mg, 0.67 mmol), 3-formylphenyl boronic acid (152 mg, 1.01 mmol) and sodium carbonate (358 mg, 3.38 mmol) in dioxane- water (2:1 ; 7.5mL) was degassed with nitrogen for 10 min. Tetrakis(triphenylphosphine)-palladium(0) (39 mg, 0.03 mmol) was added and to the o mixture and heated at 100 C for overnight. Dioxane was evaporated and the residue was subjected to work-up (AcOEt/H₂O) followed by purification to give the title compound as a pale yellow solid (150 mg, 69%). M.P.: 82-85°C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 10.08 (s, IH); 8.72 (s, IH); 8.52 (d, J = 7.8, IH); 8.46 (d, J = 6.9, IH); 7.91 (d, J = 7.8, IH); 7.78-7.72 (m, IH); 7.60 (t, J = 7.8, IH); 7.54-7.44 (m, 2H); 4.51 (t, J = 7.8, 2H); 2.02-1.95 (m, 2H); 1.50-1.38 (m, 4H); 0.93 (t, J = 6.9, 3H). IR

(cm^"', KBr): 2949 (m), 2930 (m), 2857 (w) 1689 (s), 1620 (m), 1598 (s), 1479 (m), 1423 (w), 1180 (m), 1 158 (m), 809 (w), 788 (m). MS (m/z): 321.4 ([M+H]⁺). Example 15: l-fC^Oxo-l-pentyl-l^-dihydro-S-cinnolinvDphenyll-l-ethanol:

A solution of Methyl Magnesium Iodide formed from Magnesium (125 mg) and iodomethane (300 μl) in diethyl ether (3 ml) was added to a solution of 3-(4- Oxo-l-pentyl-l,4-dihydro-3-cinnolinyl)benzaldehyde (example 14, 750 mg) in diethyl ether (2 ml) at 0°C and stirred at RT overnight. Work-up (AcOEt/aq. IN HCl) and purification gave the title compound (450 mg, 62%). ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.44 (d, J = 6.9, IH); 8.16 (s, IH); 8.04 (br. t, J = 8.7, IH); 7.72 (t, J = 7.0, IH); 7.55-7.35 (m, 4H); 4.98 (q, J = 6.3, IH); 4.49 (t, J = 7.5, 2H); 2.05-1.90 (m, 2H); 1.55 (d, J = 6.6, 3H); 1.50-1.35 (m, 4H); 0.93 (t, J = 7.2, 3H). MS (m/z): 337.1 ([M+H]⁺).

Example 16: l-[(4-Oxo-l-pentyl-L4-dihvdro-3-cinnolinyl)phenyll-l-ethanone:

A solution of l-[(4-Oxo-l-pentyl-l,4-dihydro-3-cinnolinyl)phenyl]-l-ethanol (example 15) in CH₂Cl₂ was treated with pyridinium dichromate (1.2 equivalents) at RT overnight. The mixture was filtered through celite and the filtrate was subjected to work-up (CHCl₃/aq. IN HCl) and purification to give the title compound as a yellow solid (87%). M.P.: 84-86 °C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.80 (s, IH); 8.45 (d, J = 8.1, IH); 8.42 (d, J = 7.8, IH); 7.98 (d, J = 7.8, IH); 7.55-7.40 (m, 3H); 7.74 (t, J = 7.8, IH); 4.51 (t, J = 7.5, 2H); 2.68 (s, 3H); 2.07-1.90 (m, 2H); 1.55-1.30 (m, 4H);

0.93 (t, J = 6.6, 3H). ). IR (cm^"', KBr): 2949 (m), 2930 (m), 2867 (w), 1672 (s), 1617

(m), 1596 (s), 1500 (w), 1480 (m), 1459 (w), 1413 (w), 1355 (w), 1337 (w), 1304 (w),

1271 (w), 1260 (m), 1210, 1163 (w), 1085 (m), 1067, 1023 (m), 962 (m), 916 (m),

862 (m), 809 (w), 792 (w), 754 (s).

Example 17: 3 - [3 -(I -hydroxy- 1 -methyl ethvDphenyll - 1 -pentyl- 1 ,4-dihvdro-4- cinnolinone:

The title compound was prepared by a procedure similar to that described in example 15. From l-[(4-Oxo-l-pentyl-l,4-dihydro-3-cinnolinyl)phenyl]-l-ethanone (example 16), it was obtained in 28% yield as a yellow solid. M.P.: 99 °C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.44 (d, J = 7.8, IH); 8.29 (s, IH); 8.00 (d, J - 7.8, IH); 7.72 (t, J = 8.0, IH); 7.58-7.35 (m, 4H); 4.49 (t, 7.75, 2H); 2.08-1.90 (m, 2H); 1.65 (s,

6H); 1.55-1.37 (m, 4H); 0.93 (t, J - 7.1, 3H). IR (cm^"', KBr): 3377 (br. m), 2957 (w), 2932 (w), 2860 (w), 1599 (s), 1590 (s), 1568 (m), 1491 (m), 1458 (m), 1363 (w), 1339 (m), 1298 (w), 1253 (w), 1217 (w), 1147 (w), 1141 (m), 1075 (w), 963 (w), 910 (w), 790 (w), 765 (m). MS (m/z): 351.5 ([M+H]⁺). Example 18: 3-r5-(tert-Butyl)-oxazol-2-yπ- 1 -pentyl- 1 ,4-dihydro-4-cinnolinone:

A solution of intermediate 25 (240 mg, 0.67 mmol) and POCl₃ (95 μl, 1.00 mmol) in dry toluene (5 ml) was refluxed overnight. Work-up (AcOEt/aq. satd. NaHCO₃, brine) after cooling to room temperature and purification of the crude product furnished the title compound as a yellow oil (23 mg 10%). ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.47 (d, J = 7.8, IH); 7.75 (t, J = 7.2, IH); 7.54-7.43 (m, 2H); 6.91 (br. s, IH); 4.52 (t, J = 7.2, 2H); 2.15-1.90 (m, 2H); 1.48-1.31 (m, HH); 1.30-1.21 (m, 2H); 1.00-0.90 (m, 3H). MS (m/z): 340.50 ([M+H]⁺).

Example 19: 3-[^"5-(/ert-Butyl)-thiazol-2-yl]-l -cyclohexylmethyl-l ,4-dihydro-4- cinnolinethione:

A mixture of intermediate 26 (120 mg, 0.31 mmol) and P₂S₅ (104 mg, 0.47 mmol) were heated at 170-180°C for 2h. Work-up (AcOEt/aq. IN NaOH) and purification afforded the title compound (80 mg) as a pale green solid in 64% yield. M.P.: 163-165°C. ¹H-NMR (δ ppm, DMSO-J₆, 300 MHz): 8.71 (d, J = 7.8, IH); 8.18 (d, J = 9.0, IH); 7.95 (t, J = 7.8, IH); 7.76 (s, IH); 7.69 (t, J = 8.1, IH); 4.58 (d, J = 6.3, 2H); 2.10-1.90 (m, IH); 1.75-1.60 (m, 5H); 1.42 (s, 9H); 1.25-1.00 (m, 5H). IR

(cm^"1, KBr): 2938 (m), 2917 (s), 2846 (m), 1606 (m), 1567 (m), 1455 (m), 1422 (s),

1362 (m), 1324 (w), 1267 (w), 1246 (w), 1227 (s), 1170 (w), 1149 (m), 1134 (w),

1100 (s), 1083 (w), 1032 (m), 991 (w), 944 (w), 853 (m), 758 (s). MS (m/z): 398.34

([M+H]⁺).

Example 20: 3-r5-(fer?-Butyl)-thiazol-2-yl1-l-n-pentyl-l,4-dihydro-4-cinnolinethione:

By using a procedure similar to that described for the previous example, from intermediate 25 (90 mg, 0.25 mmol) and P₂S₅ (78 mg, 0.35 mmol), the title compound (42 mg) was obtained as a pale yellow solid in 45% yield. M.P.: 87-89°C. ¹H-NMR (δ ppm, DMSO-J₆, 300 MHz): 8.70 (d, J = 8.1, IH); 8.15 (s, J = 8.7, IH); 7.95 (t, J = 7.8, IH); 7.75 (s, IH); 6.69 (t, J = 7.5, IH); 4.72 (t, J - 7.5, 2H); 2.00-1.85 (m, 2H);

1.50-1.30 (m, 4H); 1.42 (s, 9H); 0.86 (br. s, 3H). IR (cm^"', KBr): 3077 (w), 2956 (s), 2934 (w), 2868 (w), 1604 (w), 1565 (m), 1509 (w), 1481 (s), 1470 (s), 1412 (m), 1386 (w), 1366 (w), 1329 (w), 1295 (w), 1228 (m), 1202 (w), 1167 (w), 1091 (s), 1028 (w), 963 (w), 986 (w), 870 (w), 858 (w), 754 (s),. MS (m/z): 372.25 ([M+H]⁺). Example 21 : 3-|^"5-(tert-Butyl)-oxazol-2-yl1-l-(4-fluorobenzyl)-l,4-dihvdro-4- cinnolinone:

The title compound was obtained by employing a procedure similar to that described for example 18. Starting from intermediate 27 (50 mg, 0.126 mmol), the product (17 mg) was obtained as an off-white solid in 35% yield. M.P.: 111-113°C. ¹H-NMR (δ ppm, DMSO-J₆, 300 MHz): 8.21 (d, J = 8.1, IH); 7.90-7.75 (m, 2H); 7.54 (t, J = 7.2, IH); 7.45-7.35 (m, 2H); 7.17 (t, J = 8.7, 2H); 7.02 (s, IH); 5.80 (s,

2H); 1.32 (s, 9H). MS (m/z): 378.50 ([M+H]⁺).

Example 22: 3-f5-(tert-Butyl)-thiazol-2-yl1-l -(4-fluorobenzyl)-L4-dihvdro-4- cinnolinethione:

A solution of intermediate 27 (100 mg, 0.25 mmol) in xylenes (1 mL) was treated with P₂S₅ (85 mg, 0.38 mmol) and refluxed for 2h. Work-up (CH₂Cl₂/aq. IN NaOH) and purification gave the title compound (65 mg, 62%) as a green solid. M.P.: 180-182⁰C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.86 (d, J = 8.4, IH); 7.77 (s, IH); 7.65 (t, J = 7.5, IH); 7.55-7.45 (m, 2H); 7.30-7.20 (m, 2H); 7.00 (t, J = 8.7, 2H); 5.87 (s, 2H); 1.49 (s, 9H). MS (m/z): 410.59 ([M+H]⁺). Example 23: 3-r5-(fert-Butyl)-oxazol-2-yll-l-phenyl-l,4-dihydro-4-cinnolinone:

The title compound was obtained by employing a procedure similar to that described for example 18. Starting from intermediate 28 (130 mg, 0.36 mmol), POCl₃ (39μL) and toluene (1.8 mL) the product (50 mg, 40%) was obtained as an off-white solid. For purification, CHCl₃/AcOEt mixtures were used as mobile phase. M. P.: 187-189°C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.47 (d, J = 7.5, IH); 7.65-7.40 (m, 7H); 7.30-7.20 (IH under CHCl₃ signal); 6.88 (s, IH); 1.37 (s, 9H). MS (m/z): 346.33 ([M+H]⁺).

Example 24: 3-r5-(fert-Butyl)-oxazol-2-yl1-l-(2,4-difluorophenyl)-l,4-dihvdro-4- cinnolinone:

The title compound was obtained by employing a procedure similar to that described for example 18. Starting from intermediate 29 (150 mg, 0.37 mmol), the product (90 mg, 63%) was obtained as an off-white solid. M. P.: 165-167°C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.45 (d, J = 7.8, IH); 7.66-7.53 (m, 2H); 7.47 (t, J = 7.2,

IH); 7.14-1.03 (m, 2H); 6.93 (d, J = 9.0, IH); 6.89 (s, IH); 1.36 (s, 9H). IR (cm^"', KBr): 3067 (w), 3047 (w), 2965 (w), 2932 (w), 2907 (w), 2870 (w), 1642 (s), 1608 (m), 1581 (w), 1537 (w), 1515 (s), 1467 (s), 1435 (w), 1367 (w), 1341 (w), 1321 (w), 1283 (m), 1270 (w), 1251 (w), 1236 (w), 1218 (w), 1179 (w), 1 149 (w), 1087 (m), 1028 (w), 979 (m), 966 (w), 877 (w), 758 (m), 727 (w), 697 (w). MS (m/z): 382.60 ([M+H]⁺).

Example 25: 3-r5-(fe^ButylVthiazol-2-yl1-l-(4-fluorobenzylVl ,4-dihvdro-4- cinnolinone:

Mercuric acetate (24 mg, 73 μmol) was added to a solution of example 22 (30 mg, 73 μmol) in 4:1 THF/H₂O mixture (0.5 mL) and stirred at RT for 2h. Work-up and purification using AcOEt/CHCl₃ mixtures as mobile phase gave the title compound (20 mg, 71%) as an off-white solid. M. P.: 174-176°C. ¹H-NMR (δ ppm, DMSO-J₆, 300 MHz): 8.27 (d, J = 8.1, IH); 7.95-7.80 (m, 2H); 7.76 (s, IH); 7.56 (t, J = 8.1, IH); 7.45-7.35 (m, 2H); 7.15 (t, J = 8.7, 2H); 5.89 (s, 2H); 1.43 (s, 9H). MS (m/z): 394.35 ([M+H]⁺).

Example 26: 3-r5-(tert)-Butyl-1.3-oxazol-2-yll-l-(4-chlorophenyl)-L4-dihydro-4- quinolinone:

The title compound was obtained by employing a procedure similar to that described for example 18. Starting from intermediate 30 (120 mg, 0.30 mmol) and POCl₃ (83 μL), the product (45 mg) was obtained in 39% yield as an off-white solid.

M. P.: 220-223 °C. ¹H-NMR (δ ppm, CDCl₃₅ 300 MHz): 8.57 (d, J = 7.8, IH); 8.36 (s,

IH); 7.62-7.45 (m, 3H); 7.43-7.35 (m, 3H); 6.97 (d, J = 7.5, IH); 6.74 (s, IH); 1.36 (s,

9H). MS (m/z): 379.96 ([M+H]⁺ for ³⁵Cl , 100).

Example 27: 3-r5-(fer/)-Butyl-l,3-oxazol-2-yll-7-chloro-l-(4-chlorophenyl)-1.4- dihydro-4-quinolinone:

The title compound was obtained by employing a procedure similar to that described for example 18. Starting from intermediate 32 (220 mg, 0.51 mmol) and POCl₃ (140 μL, 1.53 mmol), the product (130 mg) was obtained as an off-white solid in 62% yield. M.P.: 260-262 °C. ¹H-NMR (δ ppm, CDCl₃₅ 300 MHz): 8.49 (d, J =

8.7, IH); 8.32 (s, IH); 7.61 (d, J = 8.1, 2H); 7.39 (d, J = 8.1, 2H); 7.35 (d, J = 8.7, IH); 6.93 (s, IH); 6.74 (s, IH); 1.35 (s, 9H). MS (m/z): 413.53 ([M+H]⁺, 100). Example 28: 3-r5-(fert)-Butyl-L3-oxazol-2-yll-l-(n-pentyl)-l,4-dihvdro-4- quinolinone:

The title compound was obtained by employing a procedure similar to that described for example 18. Starting from intermediate 31 (150 mg, 0.42 mmol) and POCl₃ (115 μL, 1.26 mmol), the product (56 mg) was obtained in 39% yield. Yield:

39%. Oil. Η-NMR (δ ppm, CDC1_3? 300 MHz): 8.58 (d, J = 8.4, IH); 8.41 (s, IH);

7.67 (t, J = 7.5, IH); 7.47-7.37 (m, 2H); 6.74 (s, IH); 4.19 (t, J = 7.0, 2H); 1.92 (br. s, 2H); 1.38 (s, 13 H); 0.92 (br. s, 3H). MS (m/z): 339.27 ([M+H]⁺, 100).

Pharmacological activity

Compounds described herein can be tested for their activity for cannabinoid receptors following any procedures known to a person ordinary skill in the art. For example, the following protocols can be employed for testing compounds. These protocols are illustrative and do not limit to the scope of the present invention. Example 29: In-vitro Protocol for rat CBl receptor binding using brain membrane

In this assay, [³H]SRl 41716 A was used to bind the CBl receptor present in a rat brain membrane preparation which can be displaced by unlabeled ligands having affinity to the CBl receptor.

The assay was performed according to the modified method of Thomas et al, J Pharmacol Exp Ther, 285: 285-292, 1998. The total reaction mixture (250 ml) contains Tris-BSA buffer (50 mM Tris, pH 7.4 with 1.5 % BSA) or unlabeled SR141716A (1 mM) or test samples (1 mM), [³H] SR141716A (2 nM) and 100 mg of rat brain membrane. The non-specific binding was defined by 1 mM of SR141716A. The assay mixture was incubated at 37⁰C for 1 hour. The reaction was then stopped by rapid filtration under vaccum using Whatman GF/B-96 micro filter plate. A scintillation cocktail was added and radioactive counts were measured using Topcount beta scintillation counter.

The standard and test sample dilutions were made in an assay buffer containing either ethanol or DMSO at a final concentration of 1 %. The percent (%) displacement by a test ligand was calculated by comparing the specific bound values. Example 30: Protocol for in-vitro assay using hCBl-CHO membranes

In this assay, [³H]-CP-55, 940 was used as the radioligand to bind human CBl receptors expressed on the membranes from CHO cells (the hCBl-CHO cell line was generated in-house) which can be displaced by unlabeled ligands having affinity to the CBl receptor. The assay was performed according to the modified method of Ross et al, Br. J. Pharmacol. 128, 735-743, 1999. The reaction was set up in a total volume of 200 μl in PEI (Poly(ethyleneimine)) (0.2 %) precoated Millipore GFB (Glass Fibre-B) filter plates. ImM stocks of test compounds were prepared in DMSO and tested at a final concentration of 300 nM. The non-specific binding was determined by 0.5 μM CP-55, 940. The total reaction mixture contained Tris-BSA buffer (5OmM Tris, 5 mM MgCl₂, 1 mM EDTA, pH 7.4 with 0.1 % BSA), unlabelled CP-55, 940 (0.5 μM) or test samples, [³H]-CP-55, 940 (0.75 nM ) and 50 μg of human CBl receptor preparation. The assay mixture (with or without the test compound) was incubated at 37 °C for 1 hour. The reaction was stopped by rapid filtration under vacuum and the radioactivity on the filters was measured by liquid scintillation counting using microscint PS. Example 31 : In-vitro Protocol for rat CB2 receptor binding using spleen membrane

In this assay, [³H]CP55,940 was used to bind the CB2 receptor present in a rat spleen membrane preparation which can be displaced by unlabeled ligands having affinity to the CB2 receptor.

The assay was performed according to the modified method of Rinaldi- Carmona et al, J Pharmacol Exp Ther, 284: 644-650, 1998. The total reaction mixture (250 ml) contains Tris-BSA buffer (50 mM Tris, pH 7.4 with 1.5 % BSA) or unlabeled SRl 44528 (1 mM) or test samples (300 nM), [³H]CP55,940 (1 nM) and 100 mg of rat brain membrane. The non-specific binding was defined by 1 mM of SRl 44528. The assay mixture was incubated at 37⁰C for 1 hour. The reaction was then stopped by rapid filtration under vaccum using Whatman GF/B-96 micro filter plate. A scintillation cocktail was added and radioactive counts were measured using Topcount beta scintillation counter. The standard and test sample dilutions were made in an assay buffer containing either ethanol or DMSO at a final concentration of 1%. The percent (%) displacement by a test ligand was calculated by comparing the specific bound values.

Example 32: Protocol for in-vitro radioligand binding assay using CHO-hCB2 membranes:

In this assay, [³H]-CP-55, 940 was used as the radioligand to bind human CB2 receptor expressed on the membranes from CHO cells (hCB2-CHO cell line was procured from Euroscreen) which can be displaced by unlabeled ligands having affinity to the CB2 receptor.

The assay was performed according to the modified method of Ross et al, Br. J. Pharmacol. 128, 735-743, 1999. The reaction was set up in a total volume of 200 μl in PEI (0.2 %) precoated Millipore GF/B filter plates. Tris-BSA buffer containing 50 mM Tris, 5 mM MgCl₂, 1 mM EDTA pH 7.4 with 0.1 % BSA was used as the assay buffer. 0.75 nM [³H]-CP-55, 940 was used as the radioligand. The non-specific binding was determined by cold 0.5 μM Win-55, 212-2. 1 mM stocks of the test compounds were prepared in DMSO. Binding was initiated by the addition of 0.25 μg /100 μl hCB2-CHO membranes, with or without the addition of test compounds and incubation for 1 hour at 37 °C. The reaction was stopped by rapid filtration under vacuum. Radioactivity on the filters was measured by liquid scintillation counting using microscint PS. Data from binding curves was used to calculate IC₅₀ values for the test compounds using Graph Pad Prism software. Reagents and buffer composition: Assay buffer: 50 mM Tris, 5 mM MgCl₂, 1 mM EDTA, 0.1 % FAF- BSA and pH 7.4; washing buffer: 50 mM Tris, 0.5 % FAF-BSA and pH 7.4.

The IC₅₀ (nM) values of the compounds are set forth in Table 1 wherein "A" refers to an IC₅₀ value of less than 25 nM, "B" refers to IC₅₀ value of less than 100 nM, "C" refers to an IC₅₀ value of less than 500 nM and "D" refers to an IC₅₀ value of more than 500 nM.

Table 1:

* o %, Displacement at 1 μM

Claims

WE CLAIM:

1. A compound of Formula (I):

I and esters thereof, tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein:

Ring A is aryl or heteroaryl;

D is selected from -C≡C-, substituted or unsubstituted arylene, and a 5 or 6- membered substituted or unsubstiruted heteroarylene;

Z is O or S;

W is N or CR^a;

R¹ is selected from hydrogen, substituted or unsubstiruted alkyl, substituted or unsubstiruted alkenyl, substituted or unsubstiruted alkynyl, substituted or unsubstiruted cycloalkyl, substituted or unsubstiruted cycloalkylalkyl, substituted or unsubstiruted aryl, substituted or unsubstiruted arylalkyl, substituted or unsubstiruted heteroaryl, substituted or unsubstiruted heteroarylalkyl, substituted or unsubstiruted heterocyclyl, substituted or unsubstiruted heterocyclylalkyl, -C(=Z )-R^a, -S(O)_m-R^a, - S(O)_m-NR^aR^b, -(CH₂)_nR^aR^b, -(CR^xR^y)_nNR^aR^b and -(CR^xR^y)_nNCONR^aR^b; each occurrence of Z is independently selected from O, S and NR^a; each occurrence of R^a and R^b is independently selected from hydrogen, nitro, halo, cyano, -OR, -SR, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -C(=Z)- R, -C(O)O-R^', -C(O)NRR^", -S(O)_1n-R^', -S(O)_1n-NRR. ^" and -NRR ^"; each occurrence of R' and R is independently selected from hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heterocyclylalkyl, and heteroarylalkyl; or R and R may be joined together with nitrogen to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NR" and S; each occurrence of R^x and R^y is independently selected from hydrogen, halo, cyano, -OR, -SR, -NRR , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group, or heterocyclylalkyl; each occurrence R² and R³ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, -SR⁴, -SOR⁴, -SO₂R⁴, -SO₂NR⁴R⁵, -CO₂NR⁴R⁵, CO₂R⁴, C(O)R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each occurrence of R⁴ and R⁵ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, and substituted or unsubstituted heterocyclylalkyl; each occurrence of 'm' is an integer from O to 2; and each occurrence of 'n' is an integer from O to 4.

2. A compound according to claim 1, wherein D is -C≡C-.

3. A compound according to claim 1, wherein D is substituted or unsubstituted arylene.

4. A compound according to claim 1, wherein D is substituted or unsubstituted heteroarylene.

5. A compound according to claim 1, wherein Z is O or S.

6. A compound according to claim 1, wherein W is CH or N.

7. A compound according to claim 1, wherein R¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted cycloalkylalkyl.

8. A compound according to claim 1, wherein R² is hydrogen, acetyl, formyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.

9. A compound according to claim 1, wherein R³ is hydrogen or halogen.

10. A compound of claim 1, comprising the structural formula (II):

(H) and esters thereof, tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein:

R¹ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted heterocyclyl; each occurrence of R and R is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, -SR⁴, -SOR⁴, -SO₂R⁴, -SO₂NR⁴R⁵, -CO₂NR⁴R⁵, CO₂R⁴ _, C(O)R⁴, branched or unbranched, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each occurrence of R⁴ and R⁵ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, and substituted or unsubstituted heterocyclylalkyl; and

'n' is an integer from O to 4.

11. A compound according to claim 10, wherein R² is branched or unbranched, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, or substituted or unsubstituted aryl.

12. A compound according to claim 11, wherein R² is substituted or unsubstituted (Ci-C₅) alkyl.

13. A compound according to claim 11, wherein R² is substituted or unsubstituted (C₃-C₆)cycloalkylmethyl.

14. A compound according to claim 11, wherein R² is substituted or unsubstituted phenyl.

15. A compound according to claim 10, wherein R¹ is hydrogen, branched or unbranched, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, or substituted or unsubstituted arylalkyl.

16. A compound according to claim 15, wherein R¹ is substituted or unsubstituted (Ci-Cs)alkyl.

17. A compound according to claim 15, wherein R¹ is substituted or unsubstituted (C₃-C₆)cycloalkylmethyl .

18. A compound according to claim 15, wherein R¹ is substituted or unsubstituted benzyl.

19. A compound according to claim 10, wherein R³ is hydrogen.

20. A compound of claim 1 comprising the structural formula (III):

(III) and esters thereof, tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein;

W is CH or N;

Z is O or S;

Ring Y is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R¹ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted heterocyclyl; each occurrence of R and R is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, formyl, -SR⁴, -SOR⁴, -SO₂R⁴, -SO₂NR⁴R⁵, - CO₂NR⁴R⁵ _, CO₂R⁴ _, C(O)R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each occurrence of R⁴ and R⁵ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, and substituted or unsubstituted heterocyclylalkyl; and

'n' is an integer from O to 4.

21. A compound according to claim 20, wherein W is N.

22. A compound according to claim 20, wherein W is CH.

23. A compound according to claim 20, wherein Z is O.

24. A compound according to claim 20, wherein Z is S.

25. A compound according to claim 20, wherein ring Y is aryl or heteroaryl.

26. A compound according to claim 25, wherein ring Y is phenyl.

27. A compound according to claim 25, wherein ring Y is oxazolyl or thiazolyl.

28. A compound according to claim 20, wherein R² is hydrogen, acetyl, formyl, or branched or unbranched substituted or unsubstituted alkyl.

29. A compound according to claim 28, wherein R²is substituted or unsubstituted (Ci-C₄)alkyl.

30. A compound according to claim 20, wherein R¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted arylalkyl.

31. A compound according to claim 30, wherein R'is (C]-C₅)alkyl.

32. A compound according to claim 30, wherein R'is (C₃-C₆)cycloalkylmethyl.

33. A compound according to claim 30, wherein R'is substituted or unsubstituted phenyl.

34. A compound according to claim 30, wherein R'is substituted or unsubstituted benzyl.

35. A compound according to claim 20, wherein R³ is hydrogen or halogen.

36. A compound acoording to claim 1-36, the compound is selected from: 3-(3, 3 -Dimethyl- 1 -butynyl)-l -propyl- 1 ,4-dihydro-4-cinnolinone;

3 -(3, 3 -Dimethyl- 1 -butynyl)- 1 -(iso-pτopyl)- 1 ,4-dihydro-4-cinnolinone;

1 -Butyl-3 -(3, 3 -Dimethyl- 1 -butynyl)- 1 ,4-dihydro-4-cinnolinone;

3-(3,3-Dimethyl- 1 -butynyl)- 1 -isobutyl- 1 ,4-dihydro-4-cinnolinone;

3 -(3, 3 -Dimethyl- 1 -butynyl)- 1 -pentyl-1 ,4-dihydro-4-cinnolinone;

3-[2-( 1 -Hydroxycyclohexyl)- 1 -ethynyl)- 1 -pentyl- 1 ,4-dihydro- 1 H-cinnolin-4-one;

3-(3 -Hydroxy-3 -Methyl- 1 -butynyl)- 1 -pentyl- 1 ,4-dihydro-4-cinnolinone;

3 -(3 ,3 -Dimethyl- 1 -butynyl)- 1 -neopentyl- 1 ,4-dihydro-4-H-cinnolinone;

3-(2-Cyclopentyl- 1 -ethynyl)- 1 -cyclopropylmethyl- 1 ,4-dihydro-4-cinnolinone;

1 -Cyclopropylmethyl-3 -(3 ,3 -Dimethyl- 1 -butynyl)- 1 ,4-dihydro-4-cinnolinone;

1 -Cyclopropylmethyl-3 -(2-phenyl- 1 -ethynyl)- 1 ,4-dihydro-4-cinnolinone; l-(Cyclohexylmethyl)-3 -(3, 3 -Dimethyl- 1 -butynyl)- 1 ,4-dihydro-4-cinnolinone;

1 -(2,4-Difluorobenzyl)-3 -(3 ,3 -Dimethyl- 1 -butynyl)- 1 ,4-dihydro-4-cinnolinone;

3 -(4-Oxo-l -pentyl-1 ,4-dihydro-3-cinnolinyl)benzaldehyde;

1 -[(4-Oxo- 1 -pentyl- 1 ,4-dihydro-3-cinnolinyl)phenyl]- 1 -ethanol;

1 -[(4-Oxo- 1 -pentyl- 1 ,4-dihydro-3-cinnolinyl)phenyl]- 1 -ethanone;

3-[3-(l -hydroxy-1 -methylethyl)phenyl]-l -pentyl-1 ,4-dihydro-4-cinnolinone;

3-[5-(teτt-Butyl)-oxazol-2-yl]-l -pentyl-1, 4-dihydro-4-cinnolinone;

3-[5-(tert-Butyl)-thiazol-2-yl]-l-cyclohexylmethyl-l,4-dihydro-4-cinnolinethione;

3-[5-(ter?-Butyl)-thiazol-2-yl]-l-n-pentyl-l,4-dihydro-4-cinnolinethione;

3-[5-(tert-Butyl)-oxazol-2-yl]-l-(4-fluorobenzyl)-l,4-dihydro-4-cinnolinone;

3-[5-(tert-Butyl)-thiazol-2-yl]- 1 -(4-fluorobenzyl)- 1 ,4-dihydro-4-cinnolinethione;

3-[5-(tert-Butyl)-oxazol-2-yl]-l-phenyl-l,4-dihydro-4-cinnolinone;

3-[5-(ter?-Butyl)-oxazol-2-yl]-l-(2,4-difluorophenyl)-l,4-dihydro-4-cinnolinone;

3-[5-(tert-Butyl)-thiazol-2-yl]- 1 -(4-fluorobenzyl)- 1 ,4-dihydro-4-cinnolinone;

3-[5-(ter0-Butyl-l,3-oxazol-2-yl]-l-(4-chlorophenyl)-l,4-dihydro-4-quinolinone;

3-[5-(ter0-Butyl-l,3-oxazol-2-yl]-7-chloro-l-(4-chlorophenyl)-l,4-dihydro-4- quinolinone;

3-[5-(tert)-Butyl-l,3-oxazol-2-yl]-l-(n-pentyl)-l,4-dihydro-4-quinolinone; and pharmaceutically acceptable salts, esters, tautomers, or stereoisomers thereof,

37. A compound that is selected from:

1 -Butyl-3-(3,3-Dimethyl-l -butynyl)-l ,4-dihydro-4-cinnolinone; 3-(3 ,3-Dimethyl- 1 -butynyl)-l -pentyl- 1 ,4-dihydro-4-cinnolinone;

1 -Cyclopropylmethyl-3 -(3, 3 -Dimethyl- 1 -butynyl)-l ,4-dihydro-4-cinnolinone;

1 -(Cyclohexylmethyl)-3-(3,3-Dimethyl- 1 -butynyl)- 1 ,4-dihydro-4-cinnolinone;

1 -(2,4-Difluorobenzyl)-3 -(3 ,3 -Dimethyl- 1 -butynyl)- 1 ,4-dihydro-4-cinnolinone;

3-[5-(tert)-Butyl-l,3-oxazol-2-yl]-l-(n-pentyl)-l,4-dihydro-4-quinolinone and pharmaceutically acceptable salts, esters, tautomers, or stereoisomers thereof,

38. A process for the preparation of compounds of formula (II)

(H) and esters thereof, tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein:

R¹ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted heterocyclyl; each occurrence of R² and R³ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, -SR⁴, -SOR⁴, -SO₂R⁴, -SO₂NR⁴R⁵, -CO₂NR⁴R⁵, CO₂R⁴ _, C(O)R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each occurrence of R⁴ and R⁵ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, and substituted or unsubstituted heterocyclylalkyl; and 'n' is an integer from O to 4, the process comprising the steps of: (a) diazotizing a compound of formula 1 to form a compound of formula 2

(b) halogenating the compound of formula 2 to form a compound of formula 3

³ (wherein X is halogen);

(c) alkylating the compound of formula 3 with an alkyl halide to form a compound of formula 4

4 ; and

(d) coupling of the compound of formula 4 with a compound of formula

R ^CH to form the compound of formula II.

39. The process according to claim 38, wherein halogenation in step (b) is carried out by using a suitable halogenating agent.

40. The process according to claim 39, wherein the suitable halogenating agent is bromine-acetic acid or N-iodosuccinimide in DMF.

41. The process according to claim 38, wherein the coupling reaction in step (d) is carried out in dimethylformamide and in presence of a base, for example triethylamine.

42. The process according to claim 41, wherein the base is used as a solvent.

43. A process for the preparation of compounds of formula (III)

(III) and esters thereof, tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein:

W is CH or N;

Z is O or S;

Ring Y is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R¹ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted heterocyclyl; each occurrence of R² and R³ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, formyl, -SR⁴, -SOR⁴, -SO₂R⁴, -SO₂NR⁴R⁵, - CO₂NR⁴R⁵ _, CO₂R⁴ _, C(O)R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each occurrence of R⁴ and R⁵ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, and substituted or unsubstituted heterocyclylalkyl; and 'n' is an integer from O to 4. the process comprising the step of:

(a) coupling of a compound of formula 5 with boronic acid derivative of formula 6

5 6 to form the compound of formula III.

44. The process according to claim 43, wherein the coupling reaction is performed in a suitable solvent, preferably a mixture of dioxane and water.

45. A process for the preparation of compounds of formula (IIIc)

me wherein

R^c and R^d are alkyl;

R¹ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted heterocyclyl;

R³ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, formyl, -SR⁴, -SOR⁴, -SO₂R⁴, -SO₂NR⁴R⁵, -CO₂NR⁴R⁵, CO₂R⁴, C(O)R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each occurrence of R⁴ and R⁵ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, and substituted or unsubstituted heterocyclylalkyl; and

Ring Y is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, the process comprising the steps of:

(a) reacting a compound of formula IHx

iπx with a compound of formula R^cMgX (wherein X is halogen) to form a compound of formula Ilia

ma ;

(b) oxidizing the compound of formula Ilia to form a compound of formula IUb

nib ; and

(c) reacting the compound of formula HIb with a compound of formula R^dMgX (wherein X is halogen) to form a compound of formula IHc.

46. The process according to claim 45, wherein the oxidation is carried out by using a suitable oxidizing agent in organic solvent.

47. The process according to claim 46, wherein the oxidizing agent is pyridinium dichromate.

48. A process for the preparation of compounds of formula (HId)

wherein

W is CH or N;

R¹ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted heterocyclyl; each occurrence of R² and R³ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, formyl, -SR⁴, -SOR⁴, -SO₂R⁴, -SO₂N(R⁴)₂, - CO₂N(R⁴)_2; CO₂R⁴, C(O)R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and

'n' is an integer from O to 4, the process comprising the steps of:

(a) coupling a compound of formula 8b

8b with a compound of formula

R^z

H₇N

O to form a compound of formula 18

18 and

(b) cyclizing the compound of formula 18 to form a compound of formula

IHd.

49. The process according to claim 48, wherein the coupling reaction is carried out by using BOP reagent in DMF.

50. The process according to claim 48, wherein the cyclization in step (b) is carried out by using a dehydrating agent, preferably POCl₃.

51. A process for the preparation of compounds of formula (HIf)

iπf wherein

W is CH or N;

R¹ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted heterocyclyl; each occurrence of R² and R³ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, formyl, -SR⁴, -SOR⁴, -SO₂R⁴, -SO₂N(R⁴)₂, - CO₂N(R⁴)_2> CO₂R⁴, C(O)R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and

'n' is an integer from O to 4, the process comprising the step of:

(a) cyclizing a compound of formula 18

18 to form a compound of formula IHe

Me ; and

(b) reacting the compound of formula HIe with a thiophilic agent to form the compound of formula IHf.

52. The process according to claim 51, wherein the cyclization in step (a) is carried out by using a thionating agent, preferably P₂S₅.

53. The process according to claim 51, wherein the thiophilic agent is POCl₃.

54. A pharmaceutical composition comprising a compound according to any of claims 1-37 either as a free base or in pharmaceutically acceptable salt form and a pharmaceutically acceptable excipient.

55. The pharmaceutical composition according to claim 54, wherein the pharmaceutically acceptable excipient is a carrier or diluent.

56. A method for the manufacture of a pharmaceutical composition comprising admixing a compound according to any of claims 1-37 either as a free base or in pharmaceutically acceptable salt form and a pharmaceutically acceptable excipient.

57. A method for preventing, ameliorating or treating a cannabinoid receptor mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject an effective amount of a compound according to any of claims 1-37.

58. The method of claim 57 wherein the cannabinoid receptor mediated disease, disorder or syndrome is selected from appetite disorders, metabolism disorders, catabolism disorders, diabetes, obesity, ophthalmic diseases, social related disorders, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, social related disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, pain, and neurodegenerative related syndromes.

59. The method of claim 58, wherein the cannabinoid receptor mediated disease, disorder or syndrome is selected from obesity; overweight conditions; anorexia; bulimia; cachexia; dysregulated appetite; obesity related syndromes, disorders, diseases or symptoms; and obesity as a result of genetics, diet, food intake volume, metabolic syndrome, disorder or disease, hypothalmic disorder or disease, age, abnormal adipose mass distribution, abnormal adipose compartment distribution, compulsive eating disorders, motivational disorders (such as the desire to consume sugars, carbohydrates, alcohols or drugs or any ingredient with hedonic value), or reduced activity.

60. The method of claim 58, wherein the cannabinoid receptor mediated disease, disorder or syndrome is selected from depression, bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, and cognitive disorders.

61. The method of claim 58, wherein the cannabinoid receptor mediated disease, disorder or syndrome is selected from psoriasis, lupus erythematosus, diseases of the connective tissue, Sjogren's syndrome, ankylosing spondylarthritis, rheumatoid arthritis, reactional arthritis, undifferentiated spondylarthritis, Behcet's disease, autoimmune hemolytic anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, graft rejection or diseases affecting the plasma cell line; allergic diseases: delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis or allergic conjunctivitis infectious parasitic, viral or bacterial diseases (such as AIDS and meningitis), inflammatory diseases (such as diseases of the joints, arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)), and osteoporosis.

62. The method of claim 58, wherein the cannabinoid receptor mediated disease, disorder or syndrome is selected from central and peripheral pathway mediated pain; bone and joint pain; migraine headache associated pain; cancer pain; menstrual cramps; labor pain; chronic pain of the inflammatory type; allergies; rheumatoid arthritis; dermatitis; immunodeficiency; chronic neuropathic pain; pain associated with diabetic neuropathy, sciatica, non specific lower back pain, fibromyalgia, HIV-related neuropathy, post herpetic neuralgia, or trigeminal neuralgia; and pain resulting from physical trauma, dental pain, amputation, cancer, toxins or chronic inflammatory conditions, hodgkin's disease, myasthenia gravis, nephrotic syndrome, scleroderma, or thyroiditis.

63. The method of claim 58, wherein the cannabinoid receptor mediated disease, disorder or syndrome is selected from drug abuse and drug withdrawal in which a substance of abuse or dependence is alcohol, amphetamines, amphetamine like substances, caffeine, cannabis, ***e, hallucinogens, inhalants, opioids, nicotine, heroin, barbiturates, phencyclidine or its derivatives, sedative-hypnotics, benzodiazepines, or combinations thereof.

64. The method of claim 58, wherein the cannabinoid receptor mediated disease, disorder or syndrome is selected from glaucoma, glaucoma-associated intraocular pressure, retinitis, retinopathies, uveitis, and acute injury to the eye tissue.

65. Use of a compound according to any of claims 1-37 for the manufacture of a medicament for preventing, ameliorating or treating a cannabinoid receptor mediated disease, disorder or syndrome.

66. The use according to claim 65, wherein the the cannabinoid receptor mediated disease, disorder or syndrome is selected from appetite disorders, metabolism disorders, catabolism disorders, diabetes, obesity, ophthalmic diseases, social related disorders, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, social related disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, pain, and neurodegenerative related syndromes.

67. The use according to claim 65, wherein the the cannabinoid receptor mediated disease, disorder or syndrome is selected from obesity; overweight conditions; anorexia; bulimia; cachexia; dysregulated appetite; obesity related syndromes, disorders, diseases or symptoms; and obesity as a result of genetics, diet, food intake volume, metabolic syndrome, disorder or disease, hypothalmic disorder or disease, age, abnormal adipose mass distribution, abnormal adipose compartment distribution, compulsive eating disorders, motivational disorders (such as the desire to consume sugars, carbohydrates, alcohols or drugs or any ingredient with hedonic value), or reduced activity.

68. The use according to claim 65, wherein the the cannabinoid receptor mediated disease, disorder or syndrome is selected from depression, bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, and cognitive disorders.

69. The use according to claim 65, wherein the the cannabinoid receptor mediated disease, disorder or syndrome is selected from psoriasis, lupus erythematosus, diseases of the connective tissue, Sjogren's syndrome, ankylosing spondylarthritis, rheumatoid arthritis, reactional arthritis, undifferentiated spondylarthritis, Behcet's disease, autoimmune hemolytic anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, graft rejection or diseases affecting the plasma cell line; allergic diseases: delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis or allergic conjunctivitis infectious parasitic, viral or bacterial diseases (such as AIDS and meningitis), inflammatory diseases (such as diseases of the joints, arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)), and osteoporosis.

70. The use according to claim 65, wherein the the cannabinoid receptor mediated disease, disorder or syndrome is selected from central and peripheral pathway mediated pain; bone and joint pain; migraine headache associated pain; cancer pain; menstrual cramps; labor pain; chronic pain of the inflammatory type; allergies; rheumatoid arthritis; dermatitis; immunodeficiency; chronic neuropathic pain; pain associated with diabetic neuropathy, sciatica, non specific lower back pain, fibromyalgia, HIV-related neuropathy, post herpetic neuralgia, or trigeminal neuralgia; and pain resulting from physical trauma, dental pain, amputation, cancer, toxins or chronic inflammatory conditions, hodgkin's disease, myasthenia gravis, nephrotic syndrome, scleroderma, or thyroiditis.

71. The use according to claim 65, wherein the the cannabinoid receptor mediated disease, disorder or syndrome is selected from drug abuse and drug withdrawal in which a substance of abuse or dependence is alcohol, amphetamines, amphetamine like substances, caffeine, cannabis, ***e, hallucinogens, inhalants, opioids, nicotine, heroin, barbiturates, phencyclidine or its derivatives, sedative-hypnotics, benzodiazepines, or combinations thereof.

72. The use according to claim 65, wherein the the cannabinoid receptor mediated disease, disorder or syndrome is selected from glaucoma, glaucoma-associated intraocular pressure, retinitis, retinopathies, uveitis, and acute injury to the eye tissue.