[go: up one dir, main page]

WO2009095752A1 - Dérivés de pyrazole condensés en tant que modulateurs du récepteur cannabinoïde - Google Patents

Dérivés de pyrazole condensés en tant que modulateurs du récepteur cannabinoïde Download PDF

Info

Publication number
WO2009095752A1
WO2009095752A1 PCT/IB2009/000083 IB2009000083W WO2009095752A1 WO 2009095752 A1 WO2009095752 A1 WO 2009095752A1 IB 2009000083 W IB2009000083 W IB 2009000083W WO 2009095752 A1 WO2009095752 A1 WO 2009095752A1
Authority
WO
WIPO (PCT)
Prior art keywords
chlorophenyl
pyrazolo
pyridine
carboxamide
dichlorophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2009/000083
Other languages
English (en)
Inventor
Sachin Sundarlal Chaudhari
Abraham Thomas
Ganesh Bhausaheb Gudade
Neelima Khairatkar-Joshi
Pallavi Karnik
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ichnos Sciences SA
Original Assignee
Glenmark Pharmaceuticals SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glenmark Pharmaceuticals SA filed Critical Glenmark Pharmaceuticals SA
Publication of WO2009095752A1 publication Critical patent/WO2009095752A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel cannabinoid receptor modulators, in particular, cannabinoid 1 (CBl) or cannabinoid 2 (CB2) receptor modulators, and uses thereof for treating diseases, conditions and/or disorders mediated by a cannabinoid receptor such as pain, neurodegenerative disorders, eating disorders, weight loss or control, and obesity.
  • the present invention also relates to processes for preparing cannabinoid receptor modulators, synthetic intermediates, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders mediated by cannabinoid receptors.
  • 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, Obes. Man., (2005), 5-19,).
  • Anandamide which is produced postsynaptically, is the main fatty acid involved in the system. It gains access to the extracellular space and activates CBl cannabinoid receptors located on presynaptic nerve terminals. This activation causes presynaptic inhibition of ⁇ -aminobutyric acid or glutamate through inhibition of calcium channels, while simultaneously interfering with vesicle release and activating potassium channels.
  • 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.
  • CB receptor mediated syndromes diseases or disorders which include appetite, metabolism, diabetes, obesity, glaucoma associated intra-ocular pressure, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, inflammation, cell growth disorders, eye- diseases, allergies and allergic reactions, pain, anxiety, psychotic afflictions, pathological states of brain, gastrointestinal disorders, nausea, vomiting, giddiness, urinary and fertility problems, cardiovascular diseases, neuroinflammatory pathologies, diseases of the central nervous system, neurodegenerative syndromes, diseases and disorders, sleep disorders, dermatological disorders, leukocyte activation-associated disorder, autoimmune diseases, nephrological pathologies, delayed or immediate hypersensitivity, infectious parasitic, and viral and bacterial diseases.
  • CB modulators have been characterized as agonists, inverse agonists or antagonists to CBl and/or CB2 receptors.
  • These modulators include naphthalen- l-yl-(4-pentyloxy-naphthalen-l-yl) methanone (SAB-378), 4-(2,4-dichloro-phenylamino)-N- (terahydropyran-4-ylmethyl)-2-trifluromethyl-benzamide (GW-842166X), N-(I -piperidinyl)- 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3 -carboxamide (SRl 41716A) and 3-(4-chlorophenyl-N'-(4-chlorophenyl)sulfonyl-N-methyl-4-phenyl-4,5-dihydro-lH- pyrazole-1 -carboxamide (SLV
  • US 4,048,184 & US 4,260,614 disclose pyridine derivatives.
  • WO 1994/14807 discloses substituted triols as active substances in medicaments.
  • US 5,593,943 discloses pyridine carboxamides as herbicides, and
  • US 6,162,798 discloses pyridine derivatives as inhibitors of atherosclerotic intimal thickening.
  • WO 1989/010365 and JP 05-310700 discloses pyrazolopyridine-type mevalonolactones.
  • JP 06-116239 discloses 7-substituted-3,5- dihydroxyhept-6-ynoic acid compounds as HMG-CoA reductase inhibitors
  • JP 03- 271289 discloses a method of preparation of pyrazolopyridine and dihydropyrazolopyridine derivatives.
  • the present invention relates to CB receptor modulators of the formula (I):
  • Formula (I) and pharmaceutically acceptable salt thereof, an N-oxide thereof, an analog thereof, a tautomer thereof, a regioisomer thereof, and stereoisomer thereof, wherein, the dotted line [ — ] in the ring represents an optional bond; when dotted line [ — ] in the ring is absent, then X is NR 1 and R 2 represents an oxo group ( O); when dotted line [ — ] in the ring represents a bond, then X is N and R 2 is as defined beolw; each occurance of X is N or NR 1 each occurance of R 1 is hydrogen, substituted or unsubstituted alkyl, haloalkyl, acyl, alkoxyalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkynylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • R c and R d when bound to a common atom, are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which optionally include one or more heteroatoms selected from O, NR e and S(O) q , each occurence of 'q' is 0, 1 or 2; each occurence of 'm' is 0, 1, 2, 3, 4 or 5; each occurence of 'n' is 0, 1, 2, 3, 4 or 5 and each occurance of 't' is 1, 2, 3 or 4.
  • the compounds of formula (I) may involve one or more embodiments.
  • One embodiment of the present invention comprises a compound of formula (Ia)
  • each occurrence of R 2 is hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, -OR a , -NR a R b , - S(O) q NHR a , -NHS(O) q R a ; each occurrence of R 3 is hydrogen, nitro, cyano, alkyl, haloalkyl, alkoxy, acyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl
  • R c and R d when bound to a common atom, are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which optionally include one or more heteroatoms selected from O, NR e and S(0) q , each occurrence of 'q' is 0, 1 or 2; each occurence of 'm' is 0, 1, 2, 3, 4 or 5 and each occurence of 'n' is 0, 1, 2, 3, 4 or 5.
  • Another embodiment of the present inventon comprises a compound of formula (Ib)
  • R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, acyl, alkoxy, alkoxyalkyl, cyanoalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkynylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl or -(CR a R b ) t ⁇ R a R b ; each occurrence of R 3 is hydrogen, nitro, cyano, alkyl, haloalkyl, alkoxy, acyl, alkenyl
  • R 1 is hydrogen, substituted or unsubstituted alkyl, haloalkyl, alkoxyalkyl, -(CR a R b ) t NR a R b or cycloalkylalkyl.
  • R 1 is substituted or unsubstituted alkyl, wherein substitutent is one or more halogens.
  • R 1 is substituted or unsubstituted alkyl, wherein substitutent is cyano or alkoxy preferably methoxy or ethoxy.
  • R 1 is substituted or unsubstituted cycloalkylalkyl preferably cyclopropylmethyl or cyclohexylmethyl.
  • R 2 is substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkoxy, or substituted or unsubstituted heterocyclyl.
  • R 2 is substituted or unsubstituted alkyl preferably methyl and the substiutituent is selected from one or more halogens.
  • R 2 is substituted or unsubstituted aryl preferably phenyl and the substitutent is selected from halogen or haloalkyl.
  • R 2 is substituted or unsubstituted arylalkoxy preferably benzyloxy and the substituent is selected from one or more halogens.
  • R 2 is substituted or unsubstituted heterocyclyl preferably pyrrolidinyl.
  • R 3 is hydrogen, cyano, alkyl, haloalkyl, cycloalkyl, -CONR a R b , COOR a and NHCONR c R d .
  • R a and R b are independently selected from hydrogen, alkyl, haloalkyl, alkoxy, alkoxyalkyl, alkylaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl or heterocyclyl.
  • R a and R b together form pyrrolidinyl ring.
  • R c and R d independently are hydrogen and alkyl.
  • R 3 is hydrogen, -CN, -COOCH 2 CH 3 , -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -CONHOCH 3 , CONHCH 2 CH 2 OCH 3 -CONHCH 2 CN, pyrrolidin-lylcarbonyl, -CONH-pyrrolidinyl, -CONH-(N-ethylpyrrolidine), -NHCONHCH 3 , -CONH-(cyclopropyl), -CONH-(cyclopropylmethyl), -CONH-(cyclobutyl), -CONH- (cyclopentyl), -CONHCH 2 CH 3 , CONHCH 2 CH 2 CH 3 , -CONHCH(CH 3 ) 2 ,
  • R is hydrogen or halogen. According to another embodiment, R is chlorine. According to another embodiment, m is 1. According to another embodiment, n is 1 or 2.
  • X is NR and R represents an oxo group
  • the present invention excludes the substituents at the 4-position of the pyridine ring of formula (I) disclosed in WO 1994/14807 and US 4,260,614.
  • Representative compounds of the present invention include those specified below and pharmaceutically acceptable salts, N-oxides, tautomers, regioisomers, and stereoisomers thereof.
  • the examples below are illustrative in nature and the present invention should not be construed to be limited by them.
  • Another aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the present invention and one or more pharmaceutically acceptable excipients, diluents or carriers.
  • Yet another aspect of the present invention is a method for preventing, ameliorating or treating diseases, disorders or syndromes mediated by cannabinoid (CB) receptors in a subject in need thereof by administering to the subject therapeutically effective amounts of one or more compounds of the present invention or a pharmaceutical composition of the present invention.
  • Yet another aspect of the present invention is a method for preventing, ameliorating or treating a disease, disorder or syndrome mediated by the cannabinoid 1 (CBl) and/or cannabinoid 2 (CB2) receptor in a subject in need thereof by administering to the subject a therapeutically effective amount of one or more compounds of the present invention, or combination thereof, or a pharmaceutical compoisiton the present invention.
  • a preferred method of treatment includes administering a compound of the present invention having one or more of the embodiments as specified for formula I above.
  • the cannabinoid (CB) receptor modulator is a CBl or CB2 cannabinoid receptor modulator
  • the CB receptor modulator is an agonist, antagonist, partial agonist or inverse agonist.
  • the CB receptor mediated disease is obesity or dyslipidemia, such as obesity or dyslipidemia mediated by CBl.
  • the disease, condition and/or disorder is selected from appetite disorder, metabolism disorder, cardiovascular disease, catabolism disorder, diabetes, obesity, dyslipidemia, glaucoma-associated intraocular pressure, social related disorder, mood disorder, seizures, substance abuse, learning disorder, cognition disorder, memory disorder, organ contraction, muscle spasm, respiratory disorder, locomotor activity disorder, movement disorder, immune disorder (such as autoimmune disorder), inflammation, cell growth, pain and neurodegenerative related syndromes, disorders and diseases.
  • appetite disorder is selected from appetite disorder, metabolism disorder, cardiovascular disease, catabolism disorder, diabetes, obesity, dyslipidemia, glaucoma-associated intraocular pressure, social related disorder, mood disorder, seizures, substance abuse, learning disorder, cognition disorder, memory disorder, organ contraction, muscle spasm, respiratory disorder, locomotor activity disorder, movement disorder, immune disorder (such as autoimmune disorder), inflammation, cell growth, pain and neurodegenerative related syndromes, disorders and diseases.
  • obesity cardiovascular diseases or complications thereof.
  • a method for treating diabetes or diabetes-related obesity is provided.
  • Yet another aspect of the present invention is a process for preparing the compounds of the present invention.
  • the present invention relates to novel cannabinoid receptor modulators, pharmaceutically acceptable salts,,N-oxides, tautomers, regioisomers, stereoiosmers, and processes for their preparation.
  • the present invention also relates to pharmaceutical compositions containing the compounds of the present invention, together with pharmaceutically acceptable carriers, excipients or diluents, useful for the treatment of a disease, condition or disorder mediated by a cannabinoid (CB) receptor, such as CBl or CB2.
  • CBD cannabinoid
  • alkyl refers to an optionally substituted straight or branched saturated hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to ten carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
  • haloalkyl refers to alkyl group substituted with one or more halogen atoms.
  • alkenyl refers to an optionally substituted aliphatic hydrocarbon group containing a carbon-carbon double bond, 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-1-propenyl, 1-butenyl, and 2-butenyl.
  • alkynyl refers to a optionally substituted 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.
  • alkynylalkyl refers to an alkynyl group attached via to an alkynyl group as defined herein.
  • the alkylaryl can be attached to the main structure at any atom in the aryl group.
  • alkoxy refers to an alkyl group attached via an oxygen bond to the rest of the molecule.
  • the alkyl group is as defined above. Representative examples of such groups are -OCH 3 and -OC 2 H 5 .
  • alkyl is defined as above.
  • alkoxyalkyl refers to an alkoxy group attached via alkyl group.
  • the alkyl and the alkoxy group are as defined above. Representative examples of such groups are
  • cycloalkyl refers to an optionally substituted non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl.
  • cycloalkylalkyl refers to an optionally substituted 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.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • cycloalkenyl refers to an optionally substituted 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.
  • cycloalkenylalkyP refers to an optionally substituted cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkenyl group.
  • the cycloalkenylalkyl can be attached to the main structure at any carbon atom in the alkenyl group.
  • aryl refers to an optionally substituted aromatic radical having 6 to 14 carbon atoms, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H 5 C 6 H 5 .
  • alkylaryl refers to an alkyl group as defined above directly bonded to an aryl group as defined above.
  • the alkylaryl can be attached to the main structure at any atom in the aryl group.
  • heterocyclic ring or heterocyclyl refers to an optionally substituted stable 3- to 20-membered ring radical which consists of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, dioxolanyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, indolizinyl, naphthyridinyl, pyridyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisouinolyl, imidazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidiny
  • heterocyclylalkyl refers to an optionally substituted 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.
  • heteroaryl refers to an optionally substituted aromatic heterocyclic ring radical.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom.
  • heteroarylalkyl refers to an optionally substituted heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group.
  • acyl refers to a carbonyl attached to an alkyl, alkenyl, aryl, cycloalkyl, heteroaryl or heterocyclyl.
  • protecting group refers to a substituent that is employed to block or protect a particular functionality while other functional groups on the compound may remain reactive.
  • 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 "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxy-protecting groups include, but are not limited to, acetyl, benzyl, tetrahydropyranyl and silyl.
  • 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, -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p- nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)ethyl, and nitroethyl.
  • protecting groups and their use see, T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
  • cannabinoid receptor refers to any one of the known or heretofore unknown subtypes of the class of cannabinoid receptors, including the CBl and CB2 cannabinoid receptors that may be bound by a cannabinoid modulating compound.
  • modulator or “modulating compound” refers to a compound capable of acting as a receptor agonist, partial agonist, antagonist or inverse-agonist.
  • analog refers to a chemical compound that differs structurally from a parent compound by a single atom or moiety. For example, the replacement of one atom by a different atom or the replacement of one functional group by a different functional group.
  • stereoisomer refers to compounds that have identical chemical composition, but differ with regard to arrangement of their atoms and substituent groups in space. These include enantiomers, diastereomers, geometrical isomers, atropisomers or comformational isomers. All the stereoisomers of the compounds described herein are within the scope of this invention. Racemic mixtures are also encompassed within the scope of this invention.
  • tautomers refers to compounds that differ in the location of hydrogen atoms and location of double bonds. Tautomeric forms of the compound are in equibilrium, but may or may not be isolable in their pure form. All tautomeric forms of the compounds described herein are within the scope of this invention.
  • treating or “treatment” of a state, disease, disorder or condition includesr(a) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder or condition in a subject that may be afflicted with or predisposed to the state, disease, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder or condition; (b) inhibiting the state, disease, disorder or condition, i.e., arresting or reducing the development of the state, disease, disorder or condition, or at least one clinical or subclinical symptom thereof; or (c) relieving the state, disease, disorder or condition, 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 a statistically significant, or at least perceptible difference, in the state, disease, disorder or condition to the subject or to the physician or caregiver.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including horses, cats, dogs, fishes or birds) and non- domestic animals (such as cattle, sheep, goats or wildlife).
  • domestic animals e.g., household pets including horses, cats, dogs, fishes or birds
  • non- domestic animals such as cattle, sheep, goats or wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the state, disease disorder or condition being treated, its severity and the age, weight, physical condition and responsiveness of the subject being treated.
  • Pharmaceutically acceptable salts include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn 3 and Mn), salts of organic bases (such as N 5 N 1 - diacetylethylenediamine, glucamine, triethylarnine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine), salts of chiral bases (such as alkylphenylamine, glycinol, and phenyl glycinol), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine), salts of non-natural amino acids (such as D-isomers or
  • salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • acid addition salts such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • solvates include hydrates and other solvents of crystallization (such as alcohols).
  • the compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.
  • the pharmaceutical composition of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable excipient, such as a carrier, diluent, or mixture thereof.
  • a pharmaceutically acceptable excipient such as a carrier, diluent, or mixture thereof.
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention.
  • the compound(s) of the present invention may be associated with a pharmaceutically acceptable excipient, such as a carrier or diluent, or a mixture thereof, in the form of capsule, sachet, paper or other container.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing oxmetic 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.
  • compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 21 st Ed., 2005 (Lippincott Williams & Wilkins).
  • the active compound is mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound is adsorbed on a granular solid container, for example, in a sachet.
  • Suitable doses of the compounds for use in treating the diseases, disorders and conditions, treated by the compounds of the present invention can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therepautic benefit without causing unwanted side effects. Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All such changes and modifications are envisioned within the scope of the present invention.
  • the present invention comprises 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 receptor (CB), especially those modulated by the CBl or CB2 receptor including those discussed below.
  • CBD cannabinoid receptor
  • the present invention further comprises a method of treating a disease, disorder and/or condition 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.
  • CBD cannabinoid receptor
  • Diseases, disorders, and/or conditions that are modulated by a CB receptor include, but are not limited to, appetite disorders, metabolism disorders, catabolism disorders, diabetes, obesity, glaucoma-associated intraocular pressure, 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, diseases, disorders and conditions.
  • Appetite related syndromes, diseases, disorders or conditions 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, diseases, disorders, and conditions include, but are not limited to, reduced activity.
  • Metabolism related syndromes, diseases, disorders or conditions include, but are not limited to, metabolic syndrome, dyslipidemia, elevated blood pressure, diabetes, insulin sensitivity or resistance, hyperinsulinemia, hypercholesterolemia, hyperlipidemias, hypertriglyceridemias, arteriosclerosis, atherosclerosis, other cardiovascular diseases, osteoarthritis, dermatological diseases, sleep disorders, cholelithiasis, hepatomegaly, steatosis, abnormal alanine aminotransferase levels, polycystic ovarian disease, inflammation, and the like.
  • Diabetes related syndromes, diseases, disorders or conditions include, but are not limited to, glucose dysregulation, insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity, hyperglycemia and the like.
  • Catabolism related syndromes, diseases disorders or conditions 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.
  • Social or mood related syndromes, diseases, disorders or conditions include, but are not limited to, depression, anxiety, psychosis, social affective disorders, cognitive disorders and the like.
  • Substance abuse related syndromes, diseases, disorders or conditions 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, cocaine, hallucinogens, inhalants, opioids, heroin abuse, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, combinations of any of the foregoing.
  • the compounds and pharmaceutical compositions can also be used to treat withdrawal symptoms and substance-induced anxiety or mood disorder.
  • 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.
  • dementias are diseases that include memory loss and additional intellectual impairment separate from memory.
  • the 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, diseases, disorders or conditions include, but are not limited to, multiple sclerosis, cerebral palsy and the like.
  • Locomotor activity and movement syndromes, diseases, disorders or conditions include, but are not limited to, stroke, Parkinson's disease, multiple sclerosis, epilepsy and the like.
  • Respiratory related syndromes, diseases, disorders or conditions include, but are not limited to, diseases, disorders and conditions of the respiratory tract, chronic pulmonary obstructive disorder, emphysema, asthma, bronchitis and the like.
  • Autoimmune or inflammation related syndromes, diseases, disorders or conditions 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, rhumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel
  • Cell growth related syndromes, diseases, disorders or conditions include, but are not limited to, dysregulated mammalian cell proliferation, breast cancer cell proliferation, prostrate cancer cell proliferation and the like.
  • Pain related syndromes, diseases, disorders or conditions include, but are not limited to, central and peripheral pathway mediated pain, bone and joint pain, migraine headache associated pain, cancer pain, menstrual cramps, labor pain and the like.
  • Neurodegenerative related syndromes, diseases, disorders or conditions 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, Alzheimer's disease, Huntington's disease, Tourett's syndrome, plaque sclerosis, spinal cord injury, and the like.
  • the compounds of the present invention may be used alone or in combination with other pharmaceutical agents in the manufacture of a medicament for the therapeutic applications described herein.
  • the compounds of the present invention including compounds of general formula (I), formula (Ia), formula (Ib) and specific examples, may be prepared by techniques known to one of ordinary skill in the art.
  • the compounds of the present invention may be prepared by following the reaction sequences as depicted in Schemes 1-4 wherin R, R 1 , R , R 3 , 'm' and 'n' are as previously defined for formula (I), formula (Ia) or formula (Ib) unless otherwise stated.
  • a compound of formula (2) (wherein R is halogens, R 4 is alkyl and 'm' and 'n' are 1 or 2) by halogenation with a suitable halogenating agent [e.g., N-bromosuccinimide ( ⁇ BS), or N-iodosuccinimide (NIS)] in a suitable solvent (e.g., carbon tetrachloride, dichloromethane, dichloroethane, dibromoethane, chloroform or a mixture thereof), followed by hydrolysis in one or more solvents (e.g., ethanol, methanol, dimethylsulfoxide, dimethylformamide, diethylformamide, acetonitrile, water or a mixture thereof).
  • a suitable halogenating agent e.g., N-bromosuccinimide ( ⁇ BS), or N-iodosuccinimide (NIS)
  • a suitable solvent e.g., carbon tetrachlor
  • the halogenation reaction in step-1 is performed in the presence of a radical initiator, [e.g., azobisisobutyronitrile, l,l'-Azobis(cyclohexanecarbonitrile), benzoyl peroxide, methyl ethyl ketone peroxide, peroxyacetone, or triacetone triperoxide].
  • a radical initiator e.g., azobisisobutyronitrile, l,l'-Azobis(cyclohexanecarbonitrile), benzoyl peroxide, methyl ethyl ketone peroxide, peroxyacetone, or triacetone triperoxide.
  • the compound of formula (2) is then oxidzed using one or more oxidizing agents, such as 2,2,6,6- tetramethylpiperidine-iV-oxyl [Miller, R. A. et al.. Org. Lett.
  • Formyl ester thus obtained is hydrolysed in suitable polar protic solvents ⁇ e.g., 009/000083 methanol, ethanol, isopropanol or a mixture thereof) in the presence of a suitable base (e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide) to obtain compound of formula (3).
  • suitable polar protic solvents e.g., 009/000083 methanol, ethanol, isopropanol or a mixture thereof
  • a suitable base e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide
  • the compound of formula (3) is converted into mixed anhydride using suitable alkyl chloroformates (e.g., ethyl chloroformate, methyl chloroformate) and suitable bases (e.g., triethylamine, pyridine) followed by reaction with alkali metal azide (preferably sodium azide) in suitable solvent (e.g., acetone, acetonitrile, dioxane) to obtain acyl azide of formula (4) (Haddad, M. E. et al.. J. Het. Chem. (2000), 37, 1247-1252 and reference cited therein).
  • suitable alkyl chloroformates e.g., ethyl chloroformate, methyl chloroformate
  • suitable bases e.g., triethylamine, pyridine
  • alkali metal azide preferably sodium azide
  • suitable solvent e.g., acetone, acetonitrile, dioxane
  • Curtius rearrangement of compound of formula (4) gives corresponding isocyanate, which is reacted with alcohol, R 5 OH (e.g, tert-butyl alcohol, benzyl alcohol) in suitable solvent (e.g., toluene, xylene) to afford an ⁇ /-protected compound of a formula (5).
  • R 5 OH e.g, tert-butyl alcohol, benzyl alcohol
  • suitable solvent e.g., toluene, xylene
  • Deprotection of compound of formula (5) under acidic conditions e.g., trifiuoroacetic acid, hydrochloric acid
  • Intermediate (1) can also be prepared by direct hydrolysis of an acyl azide of formula (4).
  • Intermediate (1) is allowed to react with a compound of the formula R 2 COCH 2 R 3 , in the presence of suitable base (e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, and piperidine) in suitable solvent (e.g., methanol, ethanol, isopropanaol, t-butanol, dioxane, and tetrahydrofuran) to afford compound of a general formula (Ia-I) (Jachak, M. et al.. J. Het. Chem. (2005), 42, 1311-1319 and reference cited therein).
  • suitable base e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, and piperidine
  • suitable solvent e.g., methanol, ethanol, isopropanaol, t-butanol, dioxane, and tetrahydro
  • Pyridine carboxylic acid of a general formula (6) is converted into compound of general formula (Ia-3) by coupling with NH 4 OH using coupling agent (e.g., EDCI hydrochloride) followed by dehydration of amide using suitable dehydrating agent [e.g., trifluoroacetic anhydride (TFAA)].
  • coupling agent e.g., EDCI hydrochloride
  • suitable dehydrating agent e.g., trifluoroacetic anhydride (TFAA)
  • Pyridine carboxylic acid of a general formula (6) is convered into compound of a general formula (Ia-4) using Cu catalyzed decarboxylation (Fossa, P. et al. Bioorg. & Med. Chem. (2002), 10, 743-751).
  • pyridine carboxylic acid of a general formula (6) is converted into urea of general formula (Ia-5) by classical curtius rearrangement followed by reaction of amine, R 3 R 11 NH with isocyanate thus formed (Helene, L. et al.. Org. Lett. (2006), 8(25), 5717-5720 and reference cited therein).
  • Compound of general formula (8) is then converted into compound of a general formula (Ia- 6) by ester hydrolyis followed by coupling with suitable amine R 8 R 11 NH (wherein R a and R b are as difined in formula (I)) using suitable coupling agent (e.g., BOP reagent, EDCI hydrochloride).
  • suitable coupling agent e.g., BOP reagent, EDCI hydrochloride
  • Compound of general formula (7) is converted into compound of a general formula (9) by reaction with POCl 3 followed by appropriate amine, R°R d NH in the presence of a suitable base (e.g, triethyl amine, pyridine) and solvent (e.g., dimethyl formamide, acetonitrile).
  • Compound of general formula (Ia-7) is prepared by ester hydrolysis of compound of general formula (9) followed by coupling of acid thus formed with suitable amine, R c R d NH using suitable coupling agent (e.g., BOP reagent, EDCI hydrochloride).
  • suitable coupling agent e.g., BOP reagent, EDCI hydrochloride
  • compound of general formula (Ia-7) is also prepared by ester hydrolysis of compound of general formula (7) followed by coupling of carboxylic acid thus formed with suitable amine, R ⁇ 15 NH.
  • the cyclic amide thus obtained is then converted into compound of general formual (Ia-7) either by reaction with POCl 3 to afford corresponding imidoyl chloride followed by reaction with a suitable amine, R c R d NH (wherein R c and R are as difined in formula (I) or reaction with BOP reagent in the presence of suitable base [e.g., triethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and suitable amine, R c R d NH (Zhao-kui Wan et al.. Org. Lett. (2006), 8(11). 2425-2428).
  • suitable base e.g., triethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and suitable amine, R c R d NH (Zhao-kui Wan et al.. Org. Lett. (2006),
  • N- alkylation cyclic amide of a general formula 7 using suitable electrophile R X (wherein X is a halogen) in the presence of suitable base (e.g., cesium carbonate, sodium hydride) and suitable solvent (e.g., dimethyl formamide, tetrahydrofuran) affords N-alkylated compound of a general formula (10) as a major regiomer and O-alkylated compound of a general formula (11) as a minor regiomer.
  • Both compounds of general formula (10) and (11) are further converted into compounds of general formula (Ib-3) and (Ia-8) respectively by ester hydrolysis followed by coupling with suitable amine, R a R b ⁇ H.
  • Compound of general formula (10) is also converted into urea of general formula (Ib-2) by ester hydrolysis followed by classical Curtius rearrangement followed by reaction of amine, R 8 R 13 NH with isocyanate thus formed (Helene, L. et al.. Org. Lett. (2006), 8(25), 5717-5720 and references cited therein).
  • the present invention encompasses all isomers of compounds of formula (I), formula (Ia) and formula (Ib), and all pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g., racemic mixtures). Where additional chiral centres are present in thecompounds of formula (I), formula (Ia) and formula (Ib), 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), formula (Ia) and formula (Ib), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the most abundant atomic mass or mass number found in nature, for that atom type.
  • isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine and chlorine, for example 3 H, 11 C, 14 C, 18 F, 123 I and 125 I.
  • Isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as H, C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • 11 C and 8 F isotopes are particularly useful in PET (positron emission tomography), and 125 I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all of the isotopes are useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, are preferred in some circumstances.
  • Isotopically labeled compounds of the present invention can generally be prepared by carrying out the procedures disclosed in the schemes above, or in the examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • Stepl Ethyl 4-bromomethyl- 1 -(2-chlorophenyl)-5-(4-chlorophenyl)- 1 H-3-pyrazole- carboxylate: To a magnetically stirred solution of ethyl l-(2-chlorophenyl)-5-(4- chlorophenyl)-4-methyl-lH-3-pyrazolecarboxylate (14.60 g, 38.902 mmol) in carbon tetrachloride (150 ml) was added N-bromosuccinimide (7.62 g, 42.813 mmol) and 2,2'- azobisisobutyronitrile (AIB ⁇ ) (0.128 g, 0.779 mmol).
  • N-bromosuccinimide 7.62 g, 42.813 mmol
  • AIB ⁇ 2,2'- azobisisobutyronitrile
  • Step 2 Ethyl 1 -(2-chlorophenyl)-5-(4-chlorophenyl)-4-hydroxymethyl-lH-3-pyrazole- carboxylate: To a solution of Step 1 intermediate (18 g, 39.631 mmol) was added 90 ml of dimethyl sulfoxide: water (5:1). The mixture was stirred at 60 0 C for 3 h. After cooling to room temperature, water (300 ml) was added. The organic layer was extracted with ethyl acetate (3 x 100 ml) and dried (Na 2 SO 4 ).
  • Step 3 Ethyl 1 -(2-chlorophenyl)-5-(4-chlorophenyl)-4-formyl- lH-3-pyrazole-carboxylate: To a solution of Step 2 intermediate (15 g, 38.334 mmol) in toluene (150 ml) at room temperature was added 0.76 JV aqueous NaHCO 3 (150 ml). Solid iodine (19.4 g, 76.672 mmol) was then added in one portion to the reaction mixture followed by solid 2,2,6,6- tetramethyl-1-piperidinyloxy, free radical (1.1 g, 7.667 mmol). The reaction mixture was then stirred vigorously for 24 h at room temperature.
  • Reaction mixture was cooled to 0 0 C, diluted with ethyl acetate (300 ml) and quenched at 0 0 C by adding an aqueous solution of Na 2 SO 3 (250 ml) . Layers were separated. Organic layer was washed with saturated aqueous KHCO 3 (250 ml) followed by brine (250 ml) and dried (Na 2 SO 4 ).
  • Step 4 l-(2-Chlorophenyl)-5-(4-chlorophenyl)-4-fonnyl-li7-pyrazole-3-carboxylic acid: To a solution of Step 3 intermediate (11 g, 28.262 mmol) in methanol (150 ml) was added 1.1 TV KOH (50 ml) and the mixture was refluxed for 1 h under stirring. Methanol was evaporated under reduced pressure. The residue was diluted with water (250 ml) and the mixture was acidified with IN HCl to pH 2.0. The mixture was extracted with ethyl acetate (2 x 300 ml), washed with brine and dried (Na 2 SO 4 ).
  • Step 5 3-Amino-l-(2-chlorophenyl)-5-(4-chloro ⁇ henyl)-lH-pyrazole-4-carbaldehyde: To a solution of Step 4 intermediate (18.8 g, 52.051 mmol) in tetrahydrofuran (300 ml) at 0 0 C was added triethylamine (10 ml, 76.51 mmol). While maintaining the temperature at 0 0 C, ethyl chloroformate (11.5 ml, 121.271 mmol) was added slowly.
  • Step 1 Ethyl 2-(2-chlorophenyl)-3 -(4-chlorophenyl)-6-(trifluoromethyl)-2 J H-pyrazolo[3 ,4- b]pyridine-5-carboxylate: A solution of Intermediate 1 (0.25 g, 0.752 mmol), ethyl 4,4,4- trifluoroacetoacetate (0.11 ml, 0.752 mmol) and piperidine (0.186 ml, 1.881 mmol) in ethanol (20 ml) was heated under reflux for 4 h.
  • Step 2 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-6-(trifluoromethyl)-2H " - ⁇ yrazolo[3,4-b] pyridine-5-carboxylic acid: Step 1 intermediate (0.30 g, 0.625 mmol) in methanol (15 ml) was added 0.41 N KOH (3 ml) and the mixture was refluxed for 1 h under stirring. Excess methanol was evaporated under reduced pressure and the residue was diluted with water (50 ml).
  • Step 1 Ethyl 4-bromomethyl-l,5-bis(4-chlorophenyl)-lH-pyrazole-3-carboxylate: To a magnetically stirred solution of ethyl l,5-bis(4-chlorophenyl)-4-methyl-lH-pyrazole-3- carboxylate (8.8 g, 23.452 mmol) in carbon tetrachloride (100 ml) was added N- bromosuccinimide (4.5 g, 25.282 mmol) and AIBN (0.077 g, 0.468 mmol). The resulting mixture was refluxed overnight. After cooling to room temperature, diethyl ether (200 ml) was added to get a clear solution.
  • Step 2 Ethyl l,5-bis(4-chlorophenyl)-4-hydroxymethyl-lH-pyrazole-3-carboxylate: To a solution of Step 1 intermediate (11 g, 24.223 mmol) was added 70 ml of dimethyl sulfoxide: water (5:1). The mixture was stirred at 60 0 C for 3 h. After cooling to room temperature, water (300 ml) was added. The organic layer was extracted with ethyl acetate (2 x 100 ml) and dried (Na 2 SO 4 ).
  • Step 3 Ethyl l,5-di(4-chlorophenyl)-4-formyl-l ⁇ /-pyrazole-3-carboxylate: To a solution of Step 2 intermediate 2 (10 g, 25.551 mmol) in toluene (100 ml) at room temperature was added 1 N aqueous NaHCO 3 (75 ml). Solid iodine (12.9 g, 51.102 mmol) was then added in one portion to the reaction mixture followed by solid TEMPO free radical (0.79 g, 5.103 mmol). The reaction mixture was then stirred vigorously for 24 h at room temperature.
  • Reaction mixture was cooled to 0 0 C, diluted with ethyl acetate (3 x 100 ml) and quenched at 0 °C by adding an aqueous solution OfNa 2 SO 3 (250 ml). Layers were separated. Organic layer was washed with saturated aqueous KHCO 3 (250 ml) followed by brine (250 ml) and dried (Na 2 SO 4 ).
  • Step 4 l,5-bis(4-Chlorophenyl)-4-formyl-lH-pyrazole-3-carboxylic acid: To a solution of Step 3 intermediate (8.79 g, 22.353 mmol) in methanol (100 ml) was added 1 TVKOH (45 ml) and the mixture was refluxed for 1 h under stirring. Methanol was evaporated under reduced pressure. The residue was diluted with water (200 ml) and the mixture was acidified with IN HCl (100 ml) to pH 2.0. The mixture was extracted with ethyl acetate (2 x 200 ml), washed with brine and dried (Na 2 SO 4 ).
  • Step 5 3-Amino-l,5-bis(4-chlorophenyl)-4-formyl-lH : -pyrazole-3-carbaldehyde: To a solution of Step 4 intermediate (2 g, 5.531 mmol) in tetrahydrofuran (30 ml) at 0 0 C was added triethylamine (1.12 ml, 8.102 mmol). While maintaining the temperature at 0 0 C, ethyl chloroformate (1.25 ml, 12.903 mmol) was added slowly. The mixture was stirred for 30 min at 0 0 C followed by dropwise addition of a solution of sodium azide (0.96 g, 14.762 mmol) in water (6 ml).
  • Step 6 Ethyl 2,3-bis(4-chlorophenyl)-6-(trifluoromethyl)-2/]r-pyrazolo[3,4-b]pyridine-5- carboxylate: A solution of Step 5 intermediate (0.5 g, 1.501 mmol), ethyl 4,4,4- trifluoroacetoacetate (0.2 ml, 1.462 mmol) and piperidine (0.37 ml, 3.753 mmol) in ethanol (5 ml) was heated under reflux for 4 h.
  • Step 7 2,3-bis(4-Chlorophenyl)-6-(trifluoromethyl)-2i/-pyrazolo[3,4-Z?]pyridine-5-carboxylic acid: Hydrolysis of Step 6 intermediate (0.50 g, 1.043 mmol) using IN KOH (2 ml) in methanol (6 ml) according to the procedure described in Step 2 of Intermediate 2 gave 0.37 g of the product as a yellow solid; IR (KBr) 3443, 2958, 1714, 1612, 1496, 834 cm “1 ; 1 H ⁇ MR (300 MHz, DMSO-J 6 ) ⁇ 7.45-7.65 (m, 8H), 8.73 (s, IH), 12.43 (s, IH); ESI-MS (m/z) 452.19 [60%, (M+H) + ].
  • Step 1 Ethyl 4-bromomethyl-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-lf/-pyrazole-3- carboxylate: To a magnetically stirred solution of ethyl 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylate (6 g, 14.643 mmol) in carbon tetrachloride (60 ml) was added N-bromosuccinimide (3.40 g, 19.102 mmol) and AIB ⁇ (0.072 g, 0.438 mmol). The resulting mixture was refluxed overnight.
  • Step 2 Ethyl 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-hydroxymethyl- lH-pyrazole-3 - carboxylate: To a solution of Step 1 intermediate (8.7 g, 17.831 mmol), 52 ml of dimethyl sulfoxide: water (5:1) was added. The mixture was stirred at about 60 0 C for about 3 h. After cooling to room temperature, water (100 ml) was added. The organic layer was extracted with ethyl acetate (100 ml) and dried (Na 2 SO 4 ).
  • Step 3 Ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-formyl-lH-pyrazole-3- carboxylate: To a solution of Step 2 intermediate (0.2 g, 0.471 mmol) in toluene (2 ml) at room temperature was added 0.7 N aqueous NaHCO 3 (20 ml). Solid iodine (0.238 g, 0.941 mmol) was then added in one portion to the reaction mixture followed by solid TEMPO free radical (0.0148 g, 0.094 mmol). The reaction mixture was then stirred vigorously for about 24 h at room temperature.
  • Reaction mixture was cooled to about 0 0 C, diluted with ethyl acetate (50 ml) and quenched at 0 0 C by adding an aqueous solution of sodium sulfite (50 ml). Layers were separated. Organic layer was washed with saturated aqueous KHCO 3 (50 ml) followed by brine (50 ml) and dried (Na 2 SO 4 ).
  • Step 4 5-(4-Chlorophenyl)-l-(2,4-dichlorophenyl)-4-formyl-lH-pyrazole-3-carboxylic acid: To a solution of Step 3 intermediate (1.70 g, 4.019 mmol) in methanol (30 ml) was added 1.6 N KOH (5.0 ml) and the mixture was refluxed for about 1 h under stirring. Methanol was evaporated under reduced pressure. The residue was diluted with water (100 ml) and the 000083
  • Step 5 3-Amino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-li ⁇ -pyrazole-4-carbaldehyde: To a solution of Step 4 intermediate (0.75 g, 1.898 mmol) in acetone (10 ml) at about 0 0 C was added triethylamine (0.26 ml, 1.898 mmol). While maintaining the temperature at 0 0 C, ethyl chloroformate (0.18 ml, 1.898 mmol) was added slowly.
  • Step 1 Ethyl 3-(4-chloro ⁇ henyl)-2-(2,4-dichlorophenyl)-6-methyl-2H-pyrazolo[3,4-b] pyridine-5-carboxylate: A solution of Intermediate 4 (0.18 g, 0.492 mmol) and ethyl acetoacetate (0.062 ml, 0.492 mmol) in ethanol (2 ml) and piperidine (0.122 ml 1.23 mmol) was heated under reflux for 4 h.
  • Step 2 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-methyl-2H-pyrazolo[3,4- ⁇ ]pyridine-5- carboxylic acid: To a solution of Step 1 intermediate (0.17 g, 0.371 mmol) in methanol (5 ml) was added 0.7 N potassium hydroxide (1 ml) and the mixture was refluxed for 1 h under stirring. The methanol was evaporated under reduced pressure and the residue was diluted with water (50 ml).
  • Step 1 Ethyl 3-(4-chloro ⁇ henyl)-2-(2,4-dichlorophenyl)-6-(trifluoromethyl)-2H-pyrazolo [3,4-&]pyridine-5-carboxylate: A solution of Intermediate 4 (0.175 g, 0.478 mmol), ethyl 4,4,4-trifluoroacetoacetate (0.071 ml, 0.478 mmol) and piperidine (0.12 ml, 1.195 mmol) in ethanol was heated under reflux for 4 h.
  • Step 2 3-(4-Chlorophenyl)-2-(2,4-dichloro ⁇ henyl)-(6-(trifluoromethyl))-2H " -pyrazolo[3,4-b] pyridine-5-carboxylic acid: To a solution of Step 1 intermediate (0.12 g , 0.234 mmol) in methanol (5 ml) was added 0.5 JV KOH (1 ml) and the mixture was refluxed for 1 h under stirring. Methanol was evaporated under reduced pressure and the residue was diluted with water (50 ml). The mixture was acidified with INHCl to pH 2.0.
  • Examples 1-96 given below represent preferred embodiments of the present invention. It should be understood that there may be other examples which fall within the scope and spirit of this invention.
  • the examples described below are prepared from appropriately substituted pyrazolo[3,4-b]pyridine-5-carboxylic acids or 6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5- carboxylic acids and various amines using methods described in general synthetic schemes 1- 4 using specific coupling agents such as EDCI and BOP. However, the coupling reaction can be performed using various other methods and approaches known in the literature.
  • the compounds of the present invention may be prepared from above acids via its acid chlorides or by activation of the acids using other activating reagents such as chloroformate, HOSu (JV-Hydroxysuccinimide), DCC ( ⁇ N'-Dicyclohexylcarbodiimide), CDI (l,r-Carbonyldiimidazole) and the like followed by treatment with various amines.
  • activating reagents such as chloroformate, HOSu (JV-Hydroxysuccinimide), DCC ( ⁇ N'-Dicyclohexylcarbodiimide), CDI (l,r-Carbonyldiimidazole) and the like followed by treatment with various amines.
  • Examples 3-14 were prepared as described in Example 2 by coupling reaction of Intermediate 2 with appropriate amine and the structural details are given in Table 1.
  • Step 1 Ethyl 2-(2-chlorophenyl)-3-(4-chlorophenyl)-6-(2-fluorophenyl)-2H-pyrazolo[3,4-b] pyridine-5-carboxylate: A solution of Intermediate 1 (0.25 g, 0.753 mmol), ethyl 3-(2- fluorophenyl)-3-oxopropanoate (0.136 ml, 0.753 mmol) and piperidine (0.185 ml, 1.882 mmol) in ethanol (10 ml) was heated under reflux for 4 h.
  • Step 2 2-(2-Chlorophenyl)-3-(4-chloro ⁇ henyl)-6-(2-fluoro ⁇ henyl)-2H " - ⁇ yrazolo[3,4-b] pyridine-5-carboxylic acid: Hydrolysis of Step 1 intermediate (0.29 g, 0.572 mmol) using IiV KOH (1.5 ml) in methanol (10 ml) gave 0.26 g of the product as an off-white solid; IR (KBr) 3430, 2949, 1721, 1674, 1292, 1094, 833 cm “1 ; 1 H NMR (300 MHz, OMSO-d 6 ) ⁇ 7.20-7.36 (m, 2H), 7.42-7.70 (m, 9H), 7.80-7.90 (m, IH), 8.71 (s, IH), 12.43 (s, IH); ESI-MS (m/z) 478 [59%, (M+H) + ].
  • Step 3 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-6-(2-fluorophenyl)-N-methyl-2H-pyrazolo [3,4- ⁇ ]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate (0.08 g, 0.167 mmol) using BOP reagent (0.081 g, 0.184 mmol), triethylamine (0.214 ml, 1.673 mmol) and methylamine hydrochloride (0.012 g, 0.184 mmol) in anhydrous DMF (3 ml) according to the procedure described in Example 2 afforded 0.06 g of the product as a white solid; IR (KBr) 3352, 2927, 1642, 1489, 1092, 766 cm “1 ; 1 H NMR (300 MHz, OMSOd 6 ) ⁇ 2.67 (br s, 3H), 7.18-7.35 (m, 2H), 7.40-7.70 (m, 9H), 7.84
  • Example 19 To a magnetically stirred solution of Example 19 (0.035 g, 0.072 mmol) in dichloromethane (1 ml) was added triethylamine (0.1 ml, 0.721 mmol) and trifluoroacetic anhydride (0.03 ml, 0.214 mmol) at 0 0 C. The resulting mixture was stirred at room temperature overnight. After this time, reaction mixture was diluted with dichloromethane (10 ml) and washed successively with saturated aqueous NaHCO 3 solution (30 ml), brine (30 ml), and dried (Na 2 SO 4 ).
  • Examples 21 to 41 were prepared by coupling reaction of Intermediate 5 and 6 as applicable with appropriate amine as described in Example 2.
  • Step 1 Ethyl 2-(2-chloro ⁇ henyl)-3-(4-chlorophenyl)-6-oxo-7-(3 ,3 ,3 -trifluoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate: To a solution of Intermediate 7 (0.1 g, 0.233 mmol) in dry DMF (3 ml) were added cesium carbonate (0.19 g, 0.583 mmol) and l,l 5 l-trifluoro-3-iodopropane (0.041 ml, 0.351 mmol) at room temperature. The reacton mixture was stirred overnight at 80 °C.
  • reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (25 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were washed with water (50 ml) and dried (Na 2 SO 4 ).
  • Step 2 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro- 2H-pyrazolo[3,4-Z?]pyridine-5-carboxylic acid: To a stirred solution of Step 1 intermediate (325 mg, 0.619 mmol) in methanol (15 ml) and water (3 ml), KOH (69 mg, 1.233 mmol) was added at room temperature. The reaction mixture was refluxed for 2 h. The residue obtained after the evaporation was partitioned between 30 ml of ethyl acetate and 1 N HCl (50:50).
  • Step 3 2-(2-Chlorophenyl)-3 -(4-chlorophenyl)-7-(3 ,3 ,3 -trifluoropropyl)-6,7-dihydro-2H- pyrazolo[3,4-&]pyridm-6-one: A magnetically stirred solution of Step 2 intermediate (0.05 g, 0.101 mmol) in quinoline (1 ml) containing Cu powder (0.005 g) was refluxed for 6 h.
  • Examples 48 to 65 were prepared from Intermediate 7 in the three steps; N-alkylation of the pyridone followed by ester hydrolysis and coupling of the resultant acid with an appropriate amine according to the procedure described in Example 47.
  • Step 3 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-cyclopropylmethyl-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate and methylamine hydrochloride according to the procedure described in Example 47, Step 3 afforded the resultant compound (50%) as a white solid; IR (KBr) 3279, 2927, 2346, 1670, 1612, 1510, 833 cm '1 ; 1 H ⁇ MR (300 MHz, DMSO-J 6 ) ⁇ 0.48 (s, 4H), 1.32-1.42 (m, IH), 2.85 (s, 3H), 4.08 (br s, 2H), 7.38 (d, J- 7.8 Hz, 2H), 7.48-7.80 (m, 6H), 8.58 (s, IH), 9.48 (br s, IH).
  • Step 3 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-methyl-7-neopentyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4- ⁇ ]pyridme-5-carboxarnide: Coupling reaction of Step 2 intermediate and methylamine hydrochloride according to the procedure described in Example 47, Step 3 afforded the resultant compound (50%) as an off-white solid; IR (KBr) 3272, 2958, 1698, 0083
  • Step 1 Ethyl 2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(2-methoxyethyl)-6-oxo-6,7-dihydro- 2if-pyrazolo[3,4-6]pyridine-5-carboxylate:
  • This compound was prepared from Intermediate 7 and 2-bromoethyl methyl ether according to the procedure described in Example 45, Step 1 to afford the resultant compound as an off-white solid:
  • Step 3 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-methoxyethyl)-iV-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4- ⁇ ]pyridine-5-carboxarnide: Coupling reaction of Step 2 intermediate and methylamine hydrochloride according to the procedure described in Example 47, Step 3 afforded the resultant compound (28%) as an off-white solid; IR (KBr) 3323, 2932, 1676, 1613, 1512, 1481, 1161, 1095, 835 cm 1 ; 1 H NMR (300 MHz, DMSO-J 6 ) ⁇ 2.84 (s, 3H), 3.62-3.78 (m, 5H), 4.30-4.40 (m, 2H), 7.28-7.40 (m, 2H), 7.44-7.64 (m, 5H), 7.70-7.82 (m, IH), 8.57 (br s, IH), 9.43 (br
  • Step 3 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-ethoxyethyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate and methylamine hydrochloride according to the procedure described in Example 47, Step 3 afforded the resultant compound (45%) as an off-white solid; IR (KBr) 3285, 2926, 1670, 1611, 1511, 1115, 797 cm “1 ; 1 H ⁇ MR (300 MHz, DMSO-J 15 ) ⁇ 1.03 (s, 3H), 2.58 (s, 3H), 3.40-3.50 (m, 2H), 3.74 (s, 2H), 4.35 (s, 2H) 3 7.30-7.42 (m, 2H), 7.50-7.65 (m, 5H), 7.70-7.84 (m, IH), 8.57 (s, IH), 9.
  • Example 65 The title compound was prepared from Example 65, Step 2 intermediate and cyclopropylamine according to the coupling procedure described in Example 47, Step 3 to afford the resultant compound (35%) as an off-white solid;
  • IR KBr 3090, 2927, 2253, 1650, 1611, 1483, 1091, 769 cm “1 ;
  • Step 1 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro-2H-pyrazolo[3,4- ⁇ ] pyridine-5-carboxylic acid: To a round bottom flask containing Intermediate 9 (0.5 g, 1.081 mmol) was added concentrated HCl (10 ml) and acetic acid (10 ml). The resulting clear solution was heated to reflux for 24 h. After this time, the resulting suspension was cooled to room temperature and poured into ice cold water (20 ml).
  • Step 2 N-(tert-Butyl)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro-2H- ⁇ yrazolo[3,4-b]pyridine-5-carboxarnide: To a stirred solution of Step 1 intemediate (0.1 g, 0.231 mmol) in anhydrous toluene (3 ml) was added thionyl chloride (0.058 ml, 0.807 mmol) 3
  • Step 1 Ethyl 3-(4-chloro ⁇ henyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoropro ⁇ yl)-6,7- dihydro-2H-pyrazolo[3,4-6]pyridine-5-carboxylate: To a magnetically stirred solution of Intermediate 9 (0.2 g, 0.432 mmol) in anhydrous dimethylformamide (3 ml) was added cesium carbonate (0.352 g, 1.081 mmol) at room temperature. Then l,l,l-trifluoro-3- iodopropane (0.145 g, 0.647 mmol) was added.
  • Step 4 3-(4-Chloro ⁇ henyl)-2-(2,4-dichloro ⁇ henyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-&]pyridine-5-carbonitrile:
  • This compound was prepared from Step 3 intermediate (0.022 g, 0.196 mmol), trifiuoroacetic anhydride (0.045 ml, 0.33 mmol) and triethylamine (0.150 ml, 1.085 mmol) in dichloromethane according to procedure described in Example 20 to afford 0.043 g of the product as a white solid;
  • Examples 74 to 89 were prepared in 3 steps from Intermediate 9 by N-alkylation of pyridone followed by ester hydrolysis and subsequent coupling of the resultant acid with an appropriate amine as described in Table 4.
  • Step 3 7-Butyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-iV-methyl-6-oxo-6,7-dihydro-2iy- pyrazolo[3,4-b]pyridme-5-carboxamide:
  • This compound was prepared from Step 2 intermediate and methylamine hydrochloride according to the procedure described in Example 2 to afford the resultant compound (90%) as an off-white solid:
  • Step 2 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-neopentyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-&]pyridine-5-carboxylic acid: Saponification of Step 1 intermediate according to 000083
  • Step 1 Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6 3 7- dihydro-2H-pyrazolo[3,4- ⁇ ]pyridine-5-carboxylate: To a magnetically stirred solution of Intermediate 9 (0.2 g, 0.432 mmol) in anhydrous dimethylformamide (3 ml) was added cesium carbonate (0.352 g, 1.081 mmol) at room temperature. Then l,l,l-trifluoro-3- iodopropane (0.145 g, 0.647 mmol) was added.
  • Step 3 3-(4-Chloro ⁇ henyl)-2-(2,4-dichloro ⁇ henyl)-N-methyl-6-oxo-7-(3 ,3 ,3-trifluoropropyl)- 6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate (0.09 g, 0.169 mmol) using EDCI hydrochloride (0.04 g, 0.209 mmol), ⁇ OBt (0.027 g, 0.199 mmol) in dichloromethane (5 ml) at 0 0 C according to the procedure described in Example 2 afforded 0.04 g of the product (40%) as an off-white solid; IR (KBr) 3323, 2932, 1676, 1613, 1512, 1481, 1257, 1161, 1095, 835 cm “1 ; 1 H NMR (300 MHz, OMSO-ds) ⁇ 2.85 (br s,
  • Step 1 Ethyl 3-(4-chloro ⁇ henyl)-2-(2,4-dichloro ⁇ henyl)-7-(3,3-difluoro ⁇ ro ⁇ yl)-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate:
  • This compound was prepared from Intermediate 9 and 3-bromo-l,l-difluoropropane in presence of cesium carbonate according to the procedure described in Example 45, Step 1 to afford the compound as an off-white solid:
  • Step 2 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(3,3-difiuoro ⁇ ropyl)-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid: Saponification of Step 1 intermediate according to the procedure described in Intermediate 3, Step 4 afforded the acid as an off- white solid which was used as such for the coupling reaction, Step 3.
  • Step 1 Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-methoxyethyl)-6-oxo-6,7- dihydro-2H
  • -pyrazolo[3,4-&]pyridine-5-carboxylate This compound was prepared from Intermediate 9 and 2-bromomethyl methyl ether in presence of cesium carbonate according to the procedure described in Example 45, Step 1 to afford the compound as a white solid;
  • reaction mixture was diluted with ethyl acetate (50 ml), washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure to give 0.145 g of major regiomer, ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)- 2H-pyrazolo[3,4-&]pyridine-5-carboxylate as a white solid.
  • Step 1 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-2H-pyrazolo [3,4- ⁇ ]pyridine-5-carboxylic acid: Saponification of Example 91 (0.12 g, 0.203 mmol) in methanol (5 ml) and water (1 ml) with KO ⁇ (0.023g, 0.411 mmol) as described in Intermediate 3, Step 4 gave 0.11 g of the product as a white solid; IR (KBr) 3444, 3081, 2667, 1725, 1614, 1445, 1284, 1097, 835 cm “1 ; 1 H NMR (300 MHz, DMSO-J 6 ) ⁇ 5.40 (s, 2H), 7.10-8.00 (m, 10H), 8.63 (s, IH), 13.95 (s, IH); ESI-MS (m/z) 560.10 [100%, (M+H) +
  • Step 2 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-2H ' -pyrazolo [3,4-b]pyridine-5-carboxamide: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluoro benzyloxy)-2H-pyrazolo[3,4-6]pyridine-5-carboxylic acid (0.105 g, 0.187 mmol) was reacted with EDCI hydrochloride (0.043 g, 0.224 mmol), ⁇ OBt (0.03 g, 0.222 mmol) in DCM (2 ml) followed by addition of 25% solution of ammonia in water (0.042 ml, 0.559 mmol) at 0 0 C according to the procedure described in Example 1 to afford 0.063 g of the product as an off- white solid; 1 H NMR (300 MHz
  • Step 3 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-2iy-pyrazolo [3,4- ⁇ ]pyridine-5-carbonitrile: Prepared from Step 2 intermediate (0.05 g, 0.089 mmol), trifluoroacetic anhydride (0.057 ml, 0.399 mmol) and triethylamine (0.186 ml, 1.388 mmol) in dichloromethane (3 ml) as described in Example 20 to afford 0.043 g of the product as a white solid; IR (KBr) 3431, 3032, 2228 1663, 1621, 1482, 1286, 1097, 769 cm “1 ; 1 H NMR (300 MHz, DMSO-J d ) ⁇ 5.28 (s, 2H), 7.22-7.30 (m, IH), 7.36-7.60 (br m, 6H), 7.67 (dd,
  • Step 1 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-2H-pyrazolo [3,4-5] pyridine-5-carboxylic acid: Saponification of Example 91 (0.13 g, 0.221 mmol) in methanol (2 ml) with 1NKO ⁇ (0.5 ml) as described in Intermediate 3, Step 4 gave 0.12 g of the product as a white solid; IR (KBr) 3444, 3081, 1725, 1614, 1445, 1284, 1097, 835 cm “1 ; 1 H NMR (300 MHz, DMSO-J 5 ) ⁇ 5.40 (s, 2H), 7.10-8.00 (m, 10H), 8.63 (s, IH), 13.95 (s, IH); ESI-MS (m/z) 560.10 [100%, (MH) + ].
  • Step 2 3 -(4-Chloro ⁇ henyl)-2-(2,4-dichloro ⁇ henyl)-6-(3 ,4-difluorobenzyloxy)-N-methyl-2H- pyrazolo[3,4-&]pyridine-5-carboxarnide: Step 1 intermediate (0.11 g, 0.196 mmol) was reacted with EDCI hydrochloride (0.045 g, 0.235 mmol), HOBt (0.031 g, 0.229 mmol) in dichloromethane (5 ml) followed by addition of 40% solution of methylamine in water (0.045 ml, 0.579 mmol) at 0 °C according to procedure described in Example 2 to afford 0.03 g of the product as a white solid; IR (KBr) 3434, 2927, 1671, 1611, 1514, 1285, 1095, 760 cm “1 ; 1 H NMR (300 MHz, DMSO-J 6 ) ⁇ 2.84 (br
  • Step 1 Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-(4-fluorobenzyloxy)-2if-pyrazolo [3,4-b]pyridine-5-carboxylate:
  • This intermediate was prepared form Intermediate 9 (0.15 g, 0.324 mmol) with 4-fluorobenzyl bromide (0.06 ml, 0.486 mmol) in presence of cesium carbonate (0.265 g, 0.813 mmol) in anhydrous dimethylformamide (2 ml) according to the procedure described in Example 45, Step 1 to afford 0.14 g of the major product, ethyl 3-(4- chlorophenyl)-2-(2,4-dichlorophenyl)-6-(4-fiuorobenzyloxy)-2H-pyrazolo[3,4-b]pyridine-5- carboxylate as an off-white solid; IR (KBr) 3449, 3071, 1737,
  • Step 2 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-6-pyrrolidm-l-yl-2H-pyrazolo [3,4-b]pyridine-5-carboxamide:
  • BOP reagent 0.096 g, 0.217 mmol
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • [ 3 H]-CP-55940 was used as the radioligand to bind human CB1/CB2 receptors expressed on the membranes of CHO cells (the hCBl-CHO cell line was generated in-house and hCB2 cell line was purchased from Perkin Elmer (erstwhile Euroscreen)). Test compounds possessing affinity towards the receptor compete with and displace the radioligand and thus show receptor binding.
  • the assay was performed according to the modified method of Ross et al. 1999 (Br. J. Pharmacol. 128, 735-743). The reaction was set up in a total volume of 200 ⁇ l 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 ⁇ M CP-55, 940.
  • PEI Poly(ethyleneimine)
  • Millipore GFB Glass Fibre-B
  • the total reaction mixture contained Tris-BSA buffer (5OmM Tris, 5 mM MgCl 2 , 1 mM EDTA, pH 7.4 with 0.1 % BSA), unlabelled CP-55, 940 (0.5 ⁇ M) or test samples and [ 3 H]-CP-55,940 (0.75 nM ).
  • Tris-BSA buffer 5OmM Tris, 5 mM MgCl 2 , 1 mM EDTA, pH 7.4 with 0.1 % BSA
  • unlabelled CP-55, 940 0.5 ⁇ M
  • test samples 0.5 ⁇ M
  • [ 3 H]-CP-55,940 0.75 nM
  • IC 5O (nM) values of the compounds are set forth in Table 5 wherein "A” refers to an IC5 0 value of less than 50 nM, “B” refers to IC 50 value of 50.01 to 100 nM, and “C” refers to an IC 50 value of more than 100 nM.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne de nouveaux modulateurs du récepteur cannabinoïde de formule (I), en particulier des modulateurs du récepteur cannabinoïde 1 (CB1) ou cannabinoïde 2 (CB2). L'invention concerne également des utilisations de ceux-ci dans le traitement de maladies, d'états et/ou de troubles modulés par un récepteur cannabinoïde (tels que la douleur, les troubles neurodégénératifs, les troubles de l'alimentation, la perte pondérale ou le contrôle pondéral et l'obésité).
PCT/IB2009/000083 2008-01-29 2009-01-20 Dérivés de pyrazole condensés en tant que modulateurs du récepteur cannabinoïde Ceased WO2009095752A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN205/MUM/2008 2008-01-29
IN205MU2008 2008-01-29
US2858008P 2008-02-14 2008-02-14
US61/028,580 2008-02-14

Publications (1)

Publication Number Publication Date
WO2009095752A1 true WO2009095752A1 (fr) 2009-08-06

Family

ID=40912317

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/000083 Ceased WO2009095752A1 (fr) 2008-01-29 2009-01-20 Dérivés de pyrazole condensés en tant que modulateurs du récepteur cannabinoïde

Country Status (1)

Country Link
WO (1) WO2009095752A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011153588A1 (fr) * 2010-06-10 2011-12-15 Biota Scientific Management Pty Ltd Inhibiteurs de polymérase virale
CN102603637A (zh) * 2012-01-18 2012-07-25 中国药科大学 吡唑化合物及其作为rtk和pi3k双重抑制剂的用途
JP2013544277A (ja) * 2010-12-01 2013-12-12 ファイザー・インク Ｋａｔｉｉ阻害剤
CN105254628A (zh) * 2015-11-13 2016-01-20 南京华威医药科技开发有限公司 吡唑并吡啶类抗肿瘤化合物及其制备方法和应用
CN114380818A (zh) * 2020-10-16 2022-04-22 四川科伦博泰生物医药股份有限公司 吡唑并吡啶类化合物，及其药物组合物、制备方法和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0239191A2 (fr) * 1986-01-30 1987-09-30 Beecham Group Plc Dérivés de pyrazolo[4,3-b]pyridine, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO2004076450A1 (fr) * 2003-02-27 2004-09-10 J. Uriach Y Compañia S.A. Derives de pyrazolopyridine
WO2004080463A1 (fr) * 2003-03-10 2004-09-23 Schering Corporation Inhibiteurs de kinase heterocycliques : procedes d'utilisation et de synthese
WO2005077363A1 (fr) * 2004-02-18 2005-08-25 F. Hoffmann-La Roche Ag Modulateurs heterocycliques du recepteur gaba-a selectifs d'un sous-type
US20070238726A1 (en) * 2006-03-07 2007-10-11 Blake James F Heterobicyclic pyrazole compounds and methods of use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0239191A2 (fr) * 1986-01-30 1987-09-30 Beecham Group Plc Dérivés de pyrazolo[4,3-b]pyridine, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO2004076450A1 (fr) * 2003-02-27 2004-09-10 J. Uriach Y Compañia S.A. Derives de pyrazolopyridine
WO2004080463A1 (fr) * 2003-03-10 2004-09-23 Schering Corporation Inhibiteurs de kinase heterocycliques : procedes d'utilisation et de synthese
WO2005077363A1 (fr) * 2004-02-18 2005-08-25 F. Hoffmann-La Roche Ag Modulateurs heterocycliques du recepteur gaba-a selectifs d'un sous-type
US20070238726A1 (en) * 2006-03-07 2007-10-11 Blake James F Heterobicyclic pyrazole compounds and methods of use

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011153588A1 (fr) * 2010-06-10 2011-12-15 Biota Scientific Management Pty Ltd Inhibiteurs de polymérase virale
JP2013544277A (ja) * 2010-12-01 2013-12-12 ファイザー・インク Ｋａｔｉｉ阻害剤
CN102603637A (zh) * 2012-01-18 2012-07-25 中国药科大学 吡唑化合物及其作为rtk和pi3k双重抑制剂的用途
CN105254628A (zh) * 2015-11-13 2016-01-20 南京华威医药科技开发有限公司 吡唑并吡啶类抗肿瘤化合物及其制备方法和应用
CN114380818A (zh) * 2020-10-16 2022-04-22 四川科伦博泰生物医药股份有限公司 吡唑并吡啶类化合物，及其药物组合物、制备方法和用途

Similar Documents

Publication Publication Date Title
EP2464647B1 (fr) Azaindoles en tant qe modulateurs du recepteur btk et leur utilisation
JP5092402B2 (ja) ピラゾロピリジン誘導体
RU2135471C1 (ru) Гетероциклические соединения, способ их получения, композиция на их основе и способ противодействия тахикининовым рецепторам
JP4764823B2 (ja) キナーゼ阻害剤としての１，６−二置換アザベンゾイミダゾールの調製
CN105829307B (zh) 用作tnf活性调节剂的四氢咪唑并吡啶衍生物
JP5366349B2 (ja) ホスホジエステラーゼ阻害剤として有効な置換ピロロピリジノン誘導体
JP4671104B2 (ja) ピロロピリダジン誘導体
JP5097696B2 (ja) Ｖｒ１拮抗剤としての２，３−置換縮合ピリミジン−４（３ｈ）−オン
WO2005042537A1 (fr) Composes bicycliques a substitution phenyl-aniline utilises comme inhibiteur de la kinase
WO2007096764A2 (fr) Dérivés d'hétéroaryles bicycliques en tant que modulateurs des récepteurs cannabinoïdes
JPH07252256A (ja) 新規複素環誘導体
CN105814051B (zh) 用作tnf活性调节剂的四氢咪唑并吡啶衍生物
NZ205529A (en) Heterocyclic derivatives as antibacterial agents and intermediates
AU2002336172A1 (en) Bicyclic oxopyridine and oxopyrimidine derivatives
WO2003033502A1 (fr) Derives bicycliques d'oxopyridine et d'oxopyrimidine
AU2008248996A1 (en) 2 -heteroaryl- pyrrolo [3, 4-C] pyrrole derivatives and their use as SCD inhibitors
WO2006004636A2 (fr) Inhibiteurs de kinase heterocycliques accoles
HU211275A9 (en) New heterocyclic compounds
WO2007086080A2 (fr) Ligands de recepteur cannabinoide atypique imidazo[1,2-a]pyridine et compositions pharmaceutiques les contenant
AU1719901A (en) Pyrazolo-pyridine derivatives as ligands for gaba receptors
CA2598133A1 (fr) Antagonistes de recepteur de pgd2 pour le traitement des maladies inflammatoires
AU2004212435A1 (en) Process for preparing pyrrolotriazine kinase inhibitors
CZ17988A3 (en) BENZOPYRAN(4,3-c)PYRAZOLE OR BENZOTHIOPYRAN(4,3-c)PYRAZOLE DERIVATIVES, PROCESSES OF THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS IN WHICH THEY ARE COMPRISED
WO2009095752A1 (fr) Dérivés de pyrazole condensés en tant que modulateurs du récepteur cannabinoïde
JPH08337583A (ja) 複素環化合物およびその製造法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09705302

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09705302

Country of ref document: EP

Kind code of ref document: A1