WO2009095752A1 - Fused pyrazole derivatives as cannabinoid receptor modulators - Google Patents

Fused pyrazole derivatives as cannabinoid receptor modulators Download PDF

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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
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Prior art keywords
chlorophenyl
pyrazolo
pyridine
carboxamide
dichlorophenyl
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PCT/IB2009/000083
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French (fr)
Inventor
Sachin Sundarlal Chaudhari
Abraham Thomas
Ganesh Bhausaheb Gudade
Neelima Khairatkar-Joshi
Pallavi Karnik
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Glenmark Pharmaceuticals, S.A.
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Publication of WO2009095752A1 publication Critical patent/WO2009095752A1/en

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    • 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.

Abstract

The present invention relates to novel cannabinoid receptor modulators of formula (I), in particular cannabinoid 1 (CB1) or cannabinoid 2 (CB2) receptor modulators, and uses thereof for 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

FUSED PYRAZOLE DERIVATIVES AS CANNABINOID RECEPTOR
MODULATORS
Related applications
This application claims the benefit of Indian Patent Application No. 205/MUM/2008 filed on January 29, 2008 and U.S. Provisional Application No. 61/028,580 filed on February 14, 2008, all of which are hereby incorporated by reference.
Field of the Invention
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.
Background
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 γ-aminobutyric acid 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.
CONFIRMATION COF ftC There is 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, (1999), 142, 302-308 and Gallate J E et al, Eur. J. Pharmacol, (1999), 370, 233-240). 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 TC, Physiol. Behav., 2002, 76, 241-250).
Current data reveals that cannabinoids mediate suppression of inflammation in vitro and invivo through stimulation of CB2 receptors (Ehrhart J, et.al. J. Neuroinflammation, (2005), 2, 29). 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.
Compounds capable of modulating the cannabinoid (CB) receptor activity can be used in the treatment of 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.
At present, various 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-319). 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 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, and JP 03- 271289 discloses a method of preparation of pyrazolopyridine and dihydropyrazolopyridine derivatives.
There still exists a need for a more effective and safe therapeutic treatment of diseases, conditions and/or disorders modulated by cannabinoid receptors, including those modulated by the CBl and CB2 cannabinoid receptors.
Summary of the Invention
The present invention relates to CB receptor modulators of the formula (I):
Figure imgf000004_0001
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 NR1 and R2 represents an oxo group (=O); when dotted line [ — ] in the ring represents a bond, then X is N and R2 is as defined beolw; each occurance of X is N or NR1 each occurance of R1 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 cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl or -(CRaRb)tNRaRb; each occurrence of R2 is hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, -ORa, -NRcRd, -S(O)qNHRa, - NHS(O)qRa; each occurrence of R3 is hydrogen, nitro, cyano, alkyl, haloalkyl, alkoxy, acyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, - NRaC(O)NRaRb, -NRaRb, N-acyl, -C(O)NRaRb, -C(O)OR3 or -NRaS(O)qRb, -S(O)qNRaRb; each occurrence of R is hydrogen, halogen, alkyl, alkoxy, -NRaRb, -NRaC(=B)Rb, -C(O)OR3, -C(O)NRaRb, - NRaS(O)qRb, or -S(O)qNR3Rb; each occurrence of B is O, S or NRa; each occurrence of R3 and Rb are independently hydrogen, halogen, formyl, acyl,
-(CH2)2N(CH3)2, -(CEb)2OCH3, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -S(O)qRc, -S(O)qNRcRd, - NRcRd, substituted or unsubstituted alkyl, haloalkyl, cyanoalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl or a protecting group, or
Ra and Rb when bound to a common atom, are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated ring, which optionally includes one or more heteroatoms selected from O, NRd and S(O)q; each occurrence of Rc, Rd and Re is independently hydrogen, halogen, cyano, formyl, azide, acetyl, oxo, thio, a protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylakyl, cycloalkenyl, cycloalkenylalkyl, heterocyclic ring, heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or
Rc and Rd, 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, NRe 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)
Figure imgf000006_0001
Formula (Ia) and pharmaceutically acceptable salt thereof, an N-oxide thereof, an analog thereof, a tautomer thereof, a regioisomer thereof, and stereoisomer thereof, wherein, each occurrence of R2 is hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, -ORa, -NRaRb, - S(O)qNHRa, -NHS(O)qRa ; each occurrence of R3 is hydrogen, nitro, cyano, alkyl, haloalkyl, alkoxy, acyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, -NRaC(O)NRaRb, -NRaRb, N-acyl, -C(O)NRaRb, -C(O)OR3 or -NRaS(O)qRb, -S(O)qNRaRb; each occurrence of R is hydrogen, halogen, alkyl, alkoxy, -NRaRb, -NRaC(=B)Rb, -C(O)ORa, -C(O)NRaRb, - NRaS(O)qRb, or -S(O)qNRaRb; each occurrence of B is O, S or NRa; each occurrence of Ra and Rb are independently hydrogen, halogen, formyl, acyl,
-(CH2)2N(CH3)2, -(CH2)2OCH3) -C(O)R0, -C(O)OR0, -C(O)NR°Rd, -S(O)qRc, -S(O)qNRcRd, - NRcRd, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl or a protecting group, or
Ra and Rb when bound to a common atom, are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated ring, which optionally includes one or more heteroatoms selected from O, NR and S(O)q; each occurrence of Rc, Rd and Re is independently hydrogen, halogen, cyano, formyl, azide, acetyl, oxo, thio, a protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylakyl, cycloalkenyl, cycloalkenylalkyl, heterocyclic ring, heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or
Rc and Rd, 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, NRe 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)
Figure imgf000007_0001
Formula (Ib) and pharmaceutically acceptable salt thereof, an N-oxide thereof, an analog thereof, a tautomer thereof, a regioisomer thereof, and stereoisomer thereof, wherein, each occurance of R1 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 -(CRaRb)tΝRaRb; each occurrence of R3 is hydrogen, nitro, cyano, alkyl, haloalkyl, alkoxy, acyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, -NRaC(O)NRaRb, -NRaRb, N-acyl, -C(O)NRaRb, -C(O)OR3 or -NRaS(O)qRb, -S(0)qNRaRb; each occurrence of R is hydrogen, halogen, alkyl, alkoxy, -NRaRb, -NRaC(=B)Rb, -C(O)OR3, -C(0)NRaRb, - NRaS(O)qRb, or -S(O)qNRaRb; each occurrence of B is O, S or NRa; each occurrence of Ra and Rb are independently hydrogen, halogen, formyl, acyl,
-(CH2)2N(CH3)2, -(CH2)2OCH3; -C(O)RC, -C(O)OR0, -C(O)NR°Rd, -S(O)qR°, -S(0)qNRcRd, -NRcRd, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl or a protecting group, or
Ra and Rb when bound to a common atom, are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated ring, which optionally includes one or more heteroatoms selected from O, NRd and S(O)q; each occurrence of R°, Rd and Re is independently hydrogen, halogen, cyano, formyl, azide, acetyl, oxo, thio, a protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylakyl, cycloalkenyl, cycloalkenylalkyl, heterocyclic ring, heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or Rc and Rd, 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, NR6 and S(O)q, each occurrence 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.
According to another embodiment, R1 is hydrogen, substituted or unsubstituted alkyl, haloalkyl, alkoxyalkyl, -(CRaRb)tNRaRb or cycloalkylalkyl.
According to another embodiment, R1 is substituted or unsubstituted alkyl, wherein substitutent is one or more halogens.
According to another embodiment, R1 is substituted or unsubstituted alkyl, wherein substitutent is cyano or alkoxy preferably methoxy or ethoxy.
According to another embodiment, R1 is substituted or unsubstituted cycloalkylalkyl preferably cyclopropylmethyl or cyclohexylmethyl.
According to another embodiment, R2 is substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkoxy, or substituted or unsubstituted heterocyclyl.
According to another embodiment, R2 is substituted or unsubstituted alkyl preferably methyl and the substiutituent is selected from one or more halogens.
According to another embodiment, R2 is substituted or unsubstituted aryl preferably phenyl and the substitutent is selected from halogen or haloalkyl.
According to another embodiment, R2 is substituted or unsubstituted arylalkoxy preferably benzyloxy and the substituent is selected from one or more halogens.
According to another embodiment, R2 is substituted or unsubstituted heterocyclyl preferably pyrrolidinyl.
According to one embodiment, R3 is hydrogen, cyano, alkyl, haloalkyl, cycloalkyl, -CONRaRb, COORa and NHCONRcRd. According to another embodiment, Ra and Rb are independently selected from hydrogen, alkyl, haloalkyl, alkoxy, alkoxyalkyl, alkylaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl or heterocyclyl.
According to another embodiment, Ra and Rb together form pyrrolidinyl ring. According to another embodiment, Rc and Rd independently are hydrogen and alkyl.
According to another embodiment, R3 is hydrogen, -CN, -COOCH2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHOCH3, CONHCH2CH2OCH3 -CONHCH2CN, pyrrolidin-lylcarbonyl, -CONH-pyrrolidinyl, -CONH-(N-ethylpyrrolidine), -NHCONHCH3, -CONH-(cyclopropyl), -CONH-(cyclopropylmethyl), -CONH-(cyclobutyl), -CONH- (cyclopentyl), -CONHCH2CH3, CONHCH2CH2CH3, -CONHCH(CH3)2,
-CONHCH2CH(CH3)2, -CONHCH2CH2CH(CH3)2 -CONHCH(CH3)CH(CH3)2,
-CONHC(CH3)2CH2CH3, -CONHC(CH3)3, -CONHCH(CH3)CH2CH3,
-CONHC(CHS)2CH2OH, -CONHCH2CH2F or -CONHCH2CH2N(CHS)2.
According to another embodiment, 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.
According to another embodiment, when dotted line [ — ] in the ring is absent, then X is NR and R represents an oxo group;
According to another embodiment, 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.
2-(2-Chlorophenyl)-3-(4-chloroρhenyl)-6-(trifluoromethyl)-2H"-ρyrazolo[3,4- b]pyridine-5-carboxamide (Compound No. 1),
2-(2-Chloroρhenyl)-3-(4-chlorophenyl)-iV-methyl-6-(trifiuoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 2), 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-eώyl-6-(trifluoromethyl)-2H-pyrazolo[3,4- b]pyridine-5-carboxamide (Compound No. 3),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-propyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-&]pyridine-5-carboxamide (Compound No. 4),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-isopropyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 5),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-(isobutyl)-6-(trifluoromethyl)-2H- pyrazolo[3,4-Z?]pyridine-5-carboxamide (Compound No. 6),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-(5ec-butyl)-6-(trifluoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide(Compound No. 7),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-iV-(tert-butyl)-6-(trifluoromethyl)-2H- pyrazolo[3,4-έ]pyridine-5-carboxamide (Compound No. 8),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-ό]pyridine-5-carboxamide (Compound No. 9),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropylmethyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-έ]pyridine-5-carboxamide (Compound No. 10),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclobutyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 11),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-iV-(2-dimethylaminoethyl)-6- (trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 12),
(2-Chlorophenyl)-3-(4-chlorophenyl)-N-(2-methoxyethyl)-6-(trifluoromethyl)-2H- pyrazolo[3,4-Z?]pyridine-5-carboxamide (Compound No. 13),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-iV-(2-fluoroethyl)-6-(trifluoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 14),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-6-(2-fluorophenyl)-N-methyl-2H- pyrazolo[3,4-&]pyridine-5-carboxamide (Compound No. 15),
2,3-Bis(4-chlorophenyl)-iV-methyl-6-(1xifluorometliyl)-2H-pyrazolo[3,4-Z?]pyridine-5- carboxamide (Compound No. 16), 6-(4-Bromophenyl)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4- b]pyridine (Compound No. 17),
3-(4-Chlorophenyl)-2-(2,4-dichloroρhenyl)-6-[3-(trifluoromethyl)phenyl]-2H- pyrazolo[3,4-b]pyridine (Compound No. 18),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(trifluoromethyl)-2H-pyrazolo[3,4- b]pyridine-5-carboxamide (Compound No. 19),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(trifluoromethyl)-2H-pyrazolo[3,4- έ]pyridine-5-carbonitrile (Compound No. 20),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-isopropyl-6-methyl-2H-pyrazolo[3,4- Z?]pyridine-5-carboxamide (Compound No. 21),
3-(4-Chloroρhenyl)-2-(2,4-dichlorophenyl)-6-methyl-iV-(tert-butyl)-2H-ρyrazolo[3,4- b]pyridine-5-carboxamide (Compound No. 22),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 23),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-ethyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-έ]pyridine-5-carboxamide (Compound No. 24),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7Vr-isopropyl-6-(trifluoromethyl)-2Hr- pyrazolo[3,4-δ]pyridine-5-carboxamide (Compound No. 25),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-propyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-έ]pyridine-5-carboxamide (Compound No. 26),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-isobutyl-6-(trifluoromethyl)-2/iT- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 27),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(tert-butyl)-6-(trifluoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 28),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-5ec-butyl-6-(trifluoroniethyl)-2H- pyrazolo[3,4-δ]pyridine-5-carboxamide (Compound No. 29),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-isopentyl-6-(trifluoromethyl)-2/f- pyrazolo[3,4-b]ρyridine-5-carboxamide (Compound No. 30), 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-iV-(l,2-dimethylpropyl)-6- (trifluoromethyl)-2H-pyrazolo[3,4-b]ρyridine-5-carboxamide (Compound No. 31),
3-(4-Chloroρhenyl)-2-(2,4-dichloroρhenyl)-iV-(l,l-dimethylρroρyl)-6- (trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 32),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-iV-cyclopropyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 33),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-iV-cyclopropylmethyl-6-(trifluoromethyl)- 2H~pyrazolo[3,4-&]pyridine-5-carboxamide (Compound No. 34),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-cyclobutyl-6-(trifluoromethyl)-2i/- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 35),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-cyclopentyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-6]pyridine-5-carboxamide (Compound No. 36),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7V:-cyanomethyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-έ]pyridine-5-carboxamide (Compound No. 37),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-iV-methoxy-6-(trifluoromethyl)-2H- pyrazolo[3,4-ό]pyridine-5-carboxamide (Compound No. 38),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-jV-(2-methoxyethyl)-6-(trifluoromethyl)- 2/-r-pyrazolo[3,4-Z?]pyridine-5-carboxamide (Compound No. 39),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(2-dimethylaminoethyl)-6- (trifluoromethyl)-2H-pyrazolo[3,4-6]pyridine-5-carboxamide (Compound No.40),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(2-pyrrolidin-l-ylethyl)-6- (trifluoromethyl)-2H-pyrazolo[3,4-ό]pyridine-5-carboxamide (Compound No. 41),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-(pyrrolidin-l-ylcarbonyl)-6- (trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine (Compound No. 42),
3-(4-CMorophenyl)-2-(2,4-dichlorophenyl)-N-pyrrolidin-l-yl-6-(trifluoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 43), l-[3-(4-Chloroρhenyl)-2-(2,4-dichlorophenyl)-6-(trifluoromethyl)-2H-ρyrazolo[3,4- b]pyridin-5-yl]-3-methylurea (Compound No. 44), 2-(2-CMorophenyl)-3-(4-chlorophenyl)-7-(3,3,3-trifluoropropyl)-6,7-dihydro-2H- pyrazolo[3,4-b]pyridin-6-one (Compound No. 45),
2-(2-Chloroρhenyl)-3-(4-chlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro- 2H-ρyrazolo[3,4-b]ρyridine-5-carboxamide (Compound No. 46),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-methyl-6-oxo-7-propyl-6,7-dihydro-2H- pyrazolo[3,4-&]pyridme-5-carboxaniide (Compound No. 47),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-6-oxo-7-propyl-6,7-dihydro- 2H-pyrazolo[3,4-δ]pyridine-5-carboxamide (Compound No. 48),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-isobutyl-N-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 49),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-7-isobutyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-Z)]pyridine-5-carboxamide (Compound No. 50),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-cyclopropylmethyl-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-ό]pyridine-5-carboxamide (Compound No. 51),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7V-cyclopropyl-7-cyclopropylmethyl-6-oxo- 6,7-dihydro-2H-pyrazolo[3,4-έ]pyridine-5-carboxamide (Compound No. 52),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(isopentyl)-N-methyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-δ]pyridine-5-carboxamide (Compound No. 53),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-iV-methyl-7-neopentyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 54),
2-(2-Chloroρhenyl)-3-(4-chlorophenyl)-N-methyl-6-oxo-7-(3,3,3-trifluoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-6]pyridine-5-carboxamide (Compound No. 55),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-ethyl-6-oxo-7-(3,3,3-trifluoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 56),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-iV-isopropyl-6-oxo-7-(3,3,3-trifluoropropyl)- 6,7-dihydro-2H-pyrazolo[3,4-6]pyridine-5-carboxamide (Compound No. 57),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-6-oxo-7-(3,3,3-trifluoro- propyl)-6,7-dihydro-2H-pyrazolo[3,4-δ]pyridine-5-carboxamide (Compound No. 58), 3-(4-Chlorophenyl)-2-(2-chlorophenyl)-N-cyclopropyl-6-(3,3,3-trifluoropropoxy)-2H- pyrazolo[3,4-&]pyridine-5-carboxamide (Compound No. 58.1),
2-(2-Chloroρhenyl)-3-(4-chloroρhenyl)-N-(2-fluoroethyl)-6-oxo-7-(3,3,3-trifluoro- propyl)-6,7-dihydro-2H-pyrazolo[3,4-6]pyridine-5-carboxamide (Compound No. 59),
2-(2-Chloroρhenyl)-3-(4-chlorophenyl)-N-[2-(dimethylamino)ethyl]-6-oxo-7- (3,3,3-trifluoropropyl)-6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 60),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-methoxyeihyl)-N-methyl-6-oxo-6,7- dihydro-2if-pyrazolo[3,4-6]pyridine-5-carboxamide (Compound No. 61),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-7-(2-methoxyethyl)-6-oxo- 6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 62),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-ethoxyethyl)-iV-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-Z?]pyridine-5-carboxamide (Compound No. 63),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-ethoxyethyl)-iV-isopropyl-6-oxo-6,7- dihydro-2//-pyrazolo[3,4-έ>]pyridine-5-carboxamide (Compound No. 64),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-cyanoethyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 65),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-cyanoethyl)-N-cyclopropyl-6-oxo-6,7- dihydro-2iJ-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 66),
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N,N-dimethyl-6-oxo-7-(3,3,3-trifluoro- propyl)-6,7-dihydro-2H-pyrazolo[3,4-&]pyridine-5-carboxamide (Compound No. 67),
2,3-Bis(4-chlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 68),
2,3-Bis(4-chlorophenyl)-iV-cyclopropyl-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro- 27i-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 69),
N-tert-Butyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 70),
3 -(4-Chlorophenyl)-2-(2,4-dichloroρhenyl)-N-(2-hydroxy- 1 , 1 -dimethylethyl)-6-oxo- 6,7-dihydro-2H-pyrazolo[3,4-έ]pyridine-5-carboxamide (Compound No. 71), 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carbonitrile (Compound No. 72),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-iV,7-diinethyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-&]pyridine-5-carboxamide (Compound No. 73),
3-(4-Chlorophenyl)-7-cyclopropylmethyl-2-(2,4-dichlorophenyl)-iV-methyl-6-oxo- 6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 74),
7-Butyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-Z>]pyridine-5-carboxamide (Compound No. 75),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-isobutyl-N-methyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-&]pyridine-5-carboxamide (Compound No. 76),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-isopentyl-N-methyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-&]pyridine-5-carboxamide (Compound No. 77),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-7-neopentyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-&]pyridine-5-carboxamide (Compound No. 78),
3-(4-Chlorophenyl)-7-cyclohexylmethyl-2-(2,4-dichlorophenyl)-iV:-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-Z?]pyridine-5-carboxamide (Compound No. 79),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-Λ/"-methyl-6-oxo-7-(2,252-trifluoroethyl)- 6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 80),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoroρropyl)-6,7- dihydro-2H-pyrazolo[3,4-Z?]pyridine-5-carboxamide (Compound No. 81),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-6-oxo-7-(3,3,3-trifluoropropyl)- 6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 82),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(3,3-difluoropropyl)-iV-methyl-6-oxo- 6,7-dihydro-2H-pyrazolo[3,4-ό]pyridine-5-carboxamide (Compound No. 83),
3-(4-Chlorophenyl)-2-(2,4-dichloroρhenyl)-7-(4-fluorobutyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 84),
3-(4-Chlorophenyl)-2-(2,4-dichloroρhenyl)-7-(2-methoxyethyl)-N-methyl-6-oxo-6,7- dihydro-2//-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 85),
3-(4-Chloroρhenyl)-2-(2,4-dichlorophenyl)-7-(2-ethoxyethyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 86), 3-(4-Chlorophenyl)-7-(2-cyanoethyl)-2-(2,4-dichlorophenyl)-N-metliyl-6-oxo-657- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 87),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(3-cyanopropyl)-iV-metliyl-6-oxo-6,7- dihydro-27i-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 88),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-dimethylaminoethyl)-N-methyl-6- oxo-6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 89), l-[3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-£]pyridin-5-yl]-3-methylurea (Compound No. 90),
Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-2H"- pyrazolo[3,4-&]pyridine-5-carboxylate (Compound No. 91),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-2H- pyrazolo[3,4-&]pyridine-5-carbonitrile (Compound No. 92),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-iV-methyl-2H- pyrazolo[3,4-Z?]pyridine-5-carboxamide (Compound No. 93),
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(4-fluorobenzyloxy)-iV-methyl-2H"- pyrazolo[3,4-ό]pyridine-5-carboxamide (Compound No. 94),
Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-(l-pyrrolidinyl)-2/i-pyrazolo[3,4- b]pyridine-5-carboxylate (Compound No. 95),
3 -(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-6-pyrrolidin- 1 -yl-2H- pyrazolo[3,4-b]pyridine-5-carboxamide (Compound No. 96), and pharmaceutically acceptable salt thereof, an iV-oxide thereof, an analog thereof, a tautomer thereof, a regioisomer thereof, and stereoisomer thereof.
Another aspect of the present invention is 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.
Preferred methods include one or more of the following embodiments, hi one embodiment, the cannabinoid (CB) receptor modulator is a CBl or CB2 cannabinoid receptor modulator, hi another embodiment, the CB receptor modulator is an agonist, antagonist, partial agonist or inverse agonist. In another embodiment, the CB receptor mediated disease is obesity or dyslipidemia, such as obesity or dyslipidemia mediated by CBl. In yet another embodiment, 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. In a preferred embodiment, there is provided a method for treating obesity or cardiovascular diseases or complications thereof. In yet another preferred embodiment is provided a method for treating diabetes or diabetes-related obesity.
Yet another aspect of the present invention is a process for preparing the compounds of the present invention.
Detailed Description of the 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.
Definitions The term "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).
The term "haloalkyl" refers to alkyl group substituted with one or more halogen atoms.
The term "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.
The term "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.
The term "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.
The term "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 -OCH3 and -OC2H5. The term alkyl is defined as above.
The term "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
-CH2CH2OCH3, -CH2CH2OCH2CH3, etc.
The term "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. Examples of 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.
The term "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.
The term "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.
The term "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.
The term "aryl" refers to an optionally substituted aromatic radical having 6 to 14 carbon atoms, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H5C6H5.
The term "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.
The term "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. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, 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-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofortyl, tetrahydropyranyl, thienyl, benzothienyl, ihiamoφholinyl, 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.
The term "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.
The term "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.
The term "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.
The term "acyl" as used herein, alone or in combination, refers to a carbonyl attached to an alkyl, alkenyl, aryl, cycloalkyl, heteroaryl or heterocyclyl.
Unless otherwise specified, the term "optionally substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), azide, haloalkyl, 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 cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COORX, -C(O)R", - C(S)RX, -C(0)NRxRy, -C(O)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)SO2Ry, -(=N- N(Rx)Ry), -NRxC(O)ORy, -NRxRy, -NRxC(O)Ry, -NRxC(S)Ry, -NRxC(S)NRyRz, -SONRxRy, - SO2NRxRy, -ORX, -ORxC(O)NRyRz, -ORxC(O)ORy, -OC(O)RX, -OC(O)NRxRy, -RxC(O)ORy, -RxORy, -RxNRyC(0)Rz, -RxC(O)NRyRz, -RxC(O)Ry, -RxOC(O)Ry, -SRX, -SORX, -SO2RX, and -ONO2, wherein Rx, Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted eycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cyclo alkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted amino. 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 "protecting group" or "PG" refers to a substituent that is employed to block or protect a particular functionality while 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). Similarly, 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, -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.
The term "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.
The term "modulator" or "modulating compound" refers to a compound capable of acting as a receptor agonist, partial agonist, antagonist or inverse-agonist. The term "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.
The term "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.
The term "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.
The term "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.
The term "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).
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, Zn3 and Mn), salts of organic bases (such as N5N1- 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 substituted amino acids), salts of guanidine, salts of substituted guanidine (wherein the substituents are selected from nitro, amino, alkyl, alkenyl, or alkynyl), ammonium salts, substituted ammonium salts, and aluminum salts. Other pharmaceutically acceptable 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. Yet other pharmaceutically acceptable salts include, but are not limited to, quaternary ammonium salts of the compounds of invention with alkyl halides or alkyl sulphates (such as MeI or (Me)2SO4).
Pharmaceutically acceptable 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.
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 carrier, diluent, or mixture thereof. Preferably, 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.
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, 21st Ed., 2005 (Lippincott Williams & Wilkins). For example, 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. 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 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.
Methods of Treatment
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.
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.
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.
Learning, cognition or memory related syndromes, diseases, disorders or conditions 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. 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 disease (IBD) and irritable bowel syndrome (IBS)), osteoporosis, pain, chronic pain of the inflammatory type, allergies, rheumatoid arthritis, dermatitis, immunodeficiency, chronic neuropathic pain and the like.
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, including pharmaceutical compositions, combinations 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 Methods of Preparation
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. In addition, the compounds of the present invention may be prepared by following the reaction sequences as depicted in Schemes 1-4 wherin R, R1, R , R3, 'm' and 'n' are as previously defined for formula (I), formula (Ia) or formula (Ib) unless otherwise stated. Further in the following schemes, where specific bases, acids, reagents, solvents, oxidizing agents, reducing agents, fluorinating agents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, oxidizing agents, reducing agents, coupling agents, fluorinating 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 a combination thereof, are envisioned as part of the present invention. All possible stereoisomers are also envisioned within the scope of this invention.
Scheme 1
Figure imgf000029_0001
(Ia-I) Intermediate 1
Compound of formula (Ia-I) is prepared by the process described in Scheme 1. Thus, compound of formula (1) (prepared by following the procedure as described in Murray, W. V. et al.,.J. Het. Chem. (1989), 26, 1389 or Seltzman, H. H. et al.. J. Chem. Soc. Chem. Commun. (1995), 1549) is converted to a compound of formula (2) (wherein R is halogens, R4 is alkyl and 'm' and 'n' are 1 or 2) by halogenation with a suitable halogenating agent [e.g., N-bromosuccinimide (ΝBS), 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). Preferably, 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]. 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. (2003), 5(3J1 285], bis-4,41- (2,2,6,6-tetramethylpiperidine-N-oxyl) oxamide, bis-3,3'-(2,2,5,5-tetramethylpyrrolidine-N- oxyl)oxamide), pyridinium chlorochromate, manganese dioxide, sodium hypochlorite, selenium dioxide or Dess-Martin periodinane in suitable solvents to obtain corresponding formyl ester. 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). 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). Curtius rearrangement of compound of formula (4) gives corresponding isocyanate, which is reacted with alcohol, R5OH (e.g, tert-butyl alcohol, benzyl alcohol) in suitable solvent (e.g., toluene, xylene) to afford an Λ/-protected compound of a formula (5). Deprotection of compound of formula (5) under acidic conditions (e.g., trifiuoroacetic acid, hydrochloric acid) affords an Intermediate (1) Alternatively; 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 R2COCH2R3, 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).
Scheme 2
Figure imgf000030_0001
Compounds of formula (Ia-2), (Ia-3), (Ia-4), and (Ia-5) are synthesized by the process shown in Scheme 2. Intermediate (1) is allowed to react with an ester of formula R2COCH2CO2R6, ( wherein R6 is alkyl), in the presence of suitable base (e.g., pyridine, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, and potassium ethoxide) and suitable solvent (e.g., methanol, ethanol, isopropanol, t-butanol, tetrahydrofuran, ethyl acetate, chloroform, dioxane) to obtain pyridine ester (Jachak, M. et IB2009/000083 al.. J. Het. Chem. (2005), 42, 1311-1319 and reference cited therein) which upon hydrolysis affords pyridine carboxylic acid of a general formula (6). Coupling of carboxylic acid of a general formula (6) with suitable amine, R11R13NH (wherein Ra and Rb are as difined in formula (I)) in the presence of coupling agent [e.g., benzotriazol-l-yloxytris(dimethylamino) phosphoniurnhexafluorophosphate (BOP), iV-ethyl-N'-(3 -dimethylaminopropyl)carbodiimide hydrochloride (EDCI)] affords compound of a general formula (Ia-2). Pyridine carboxylic acid of a general formula (6) is converted into compound of general formula (Ia-3) by coupling with NH4OH using coupling agent (e.g., EDCI hydrochloride) followed by dehydration of amide using 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). Further, 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, R3R11NH with isocyanate thus formed (Helene, L. et al.. Org. Lett. (2006), 8(25), 5717-5720 and reference cited therein).
Scheme 3
Figure imgf000031_0001
Compounds of formula (Ia-6) and (Ia-7) are synthesized by the process depicted in Scheme 3. Reaction of Intermediate (1) with dialkyl malonate (e.g., diethyl malonate, dimethyl malonate) in the presence of suitable base (e.g., piperidine, pyridine, sodium hydroxide, and potassium hydroxide) and polar solvent (e.g., ethanol, methanol, isopropanol, dioxane, and tetrahydrofuran) affords cyclic amide of a general formula (7) (Jachak, M. et al.. J. Het. Chem. (2005), 42, 1311-1319 and reference cited therein) O-benzylation of cylic amide of a general formula (7) using substituted or unsubstituted benzyl halide, RaX in the presence of suitable base (e.g, NaH, Cs2CO3) and polar aportic solvent (e.g., dimethyl formamide, dioxane, acetonitrile, tetrahydrofuran) afford compound of a general formula (8). 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 R8R11NH (wherein Ra and Rb are as difined in formula (I)) using 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 POCl3 followed by appropriate amine, R°RdNH 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, RcRdNH using suitable coupling agent (e.g., BOP reagent, EDCI hydrochloride). Alternatively, 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^15NH. The cyclic amide thus obtained is then converted into compound of general formual (Ia-7) either by reaction with POCl3 to afford corresponding imidoyl chloride followed by reaction with a suitable amine, RcRdNH (wherein Rc 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, RcRdNH (Zhao-kui Wan et al.. Org. Lett. (2006), 8(11). 2425-2428).
Scheme 4
Figure imgf000032_0001
Figure imgf000032_0002
3
Compounds of formula (Ib-I), (Ib-2), (Ib-3), and (Ia-8) are prepared by the process described in Scheme 4. The ester of formula 7 is converted into compound of a general formula (Ib-I) by ester hydrolysis followed by coupling of carboxylic acid thus formed with suitable amine, R8R13NH using coupling agent (e.g., BOP reagent, EDCI hydrochloride). 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, RaRbΝH. 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, R8R13NH 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. Examples of 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 3H, 11C, 14C, 18F, 123I and 125I.
Compounds of the present invention and pharmaceutically acceptable salts of the 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 H, C 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 of the isotopes are useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, 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.
EXPERIMENTAL
Intermediate 1 3-Amino-l-(2-chlorophenyl)-5-(4-chlorophenyl)-lH"-pyrazole-4-carbaldehyde:
Figure imgf000034_0001
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 (AIBΝ) (0.128 g, 0.779 mmol). The resulting mixture was refluxed overnight. After cooling to room temperature, diethyl ether (400 ml) was added to get a clear solution. The organic layer was washed with water (200 ml) followed by brine (200 ml), dried (Na2SO4), filtered and concentrated under reduced pressure to give 18.016 g of the product as a brown solid; IR (KBr) 2979, 1717, 1495, 1266, 1086, 831 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.35 (t, J= 7.2 Hz, 3H), 4.38 (q, J= 7.2 Hz, 2H), 4.73 (s, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.30-7.60 (m, 5H), 7.77 (d, J = 6.9 Hz, IH); ESI-MS (m/z) 455.34 [84%, (M+H)+].
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 0C 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 (Na2SO4). Excess solvent was removed under reduced pressure to afford 14.9 g of the product as an off-white solid; IR (KBr) 2985, 1690, 1600, 1495, 1266, 1191, 1088, 834 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.32 (t, J= 6.9 Hz, 3H), 4.33 (q, J= 6.9 Hz, 2H), 4.53 (br s, 2H), 4.96 (br s, IH), 7.31 (d, J= 8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.53-7.60 (m, 3H), 7.66 (d, J= 6.6 Hz, IH); ESI-MS (rn/z) 391.23 [100%, (M+H)+].
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 NaHCO3 (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 0C, diluted with ethyl acetate (300 ml) and quenched at 0 0C by adding an aqueous solution of Na2SO3 (250 ml). Layers were separated. Organic layer was washed with saturated aqueous KHCO3 (250 ml) followed by brine (250 ml) and dried (Na2SO4). Concentration under reduced pressure afforded 16.2 g of the product as a yellow solid; IR (KBr) 2978, 1715, 1678, 1490, 1202, 1085, 977 cm'1; 1H NMR (300 MHz, DMSO-J0) δ 1.34 (t, J= 7.2 Hz, 3H), 4.41 (q, J = 7.2 Hz, 2H), 7.34 (d, J= 8.1 Hz, 2H), 7.43 (d, J= 8.1 Hz, 2H), 7.50-7.61 (m, 3H), 7.78 (d, J = 6.9 Hz, IH), 10.31 (s, IH); ESI-MS (m/z) 389.57 [85%, (M+H)+].
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 (Na2SO4). The solvent was evaporated to give 11.5 g of the product as a yellow solid; IR (KBr) 3066, 2590, 1731, 1683, 1628, 1469, 1184, 1089 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 7.34 (d, J = 8.1 Hz, 2H), 7.43 (d, J= 8.1 Hz, 2H), 7.50-7.61 (m, 3H), 7.78 (d, J= 6.9 Hz, IH), 10.31 (s, IH); ESI-MS (m/z) 361 Al [80%, (M+H)+].
Step 5: 3-Amino-l-(2-chlorophenyl)-5-(4-chloroρhenyl)-lH-pyrazole-4-carbaldehyde: To a solution of Step 4 intermediate (18.8 g, 52.051 mmol) in tetrahydrofuran (300 ml) at 0 0C was added triethylamine (10 ml, 76.51 mmol). While maintaining the temperature at 0 0C, ethyl chloroformate (11.5 ml, 121.271 mmol) was added slowly. The mixture was stirred for 30 min at 0 0C followed by dropwise addition of a solution of sodium azide (8.9 g, 137.413 mmol) in water (50 ml). The resulting mixture was stirred at 0 0C for 1 h, the precipitate formed was filtered and the solvent was removed under reduced pressure at room temperature. The solid residue obtained was dissolved in diethyl ether (300 ml), filtered and evaporation of the solvent at room temperature afforded 18.5 g of l-(2-chlorophenyl)-5-(4- chlorophenyl)-4-formyl-lH-pyrazole-3-carbonyl azide as an off-white solid. The acyl azide was used as such in the next step. Acyl azide (18.5 g, 47.902 mmol) in 1,2-dimethoxy ethane (250 ml) and water (6 ml) was refluxed overnight. After cooling to room temperature, 1,2- dimethoxy ethane was evaporated under reduced pressure to dryness. The residue was dissolved in dichloromethane (300 ml), washed with brine (200 ml) and dried (Na2SO4). Removal of solvent under reduced pressure afforded 9.5 g of the product as a yellow solid; IR (KBr) 3327, 2858, 1649, 1616, 1479, 1088, 767 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 6.01 (s, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.29-7.50 (m, IH), 7.51-7.60 (m, 4H), 7.62 (d, J= 6.3 Hz, IH), 9.53 (s, IH); ESI-MS (m/z) 332.18 [80%, (M+H)+].
Intermediate 2
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-6-(trifluoromethyl)-2H-pyrazolo[3,4-5]pyridine-5- carboxylic acid:
Figure imgf000036_0001
Step 1: Ethyl 2-(2-chlorophenyl)-3 -(4-chlorophenyl)-6-(trifluoromethyl)-2JH-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. The solid obtained on cooling was filtered by suction and washed with cold ethanol (10 ml) to afford 0.305 g of the product as a yellow solid; IR (KBr) 3067, 2983, 1732, 1618, 1497, 1257 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.32 (t, J = 7.2 Hz, 3H), 4.36 (q, J= 6.6 Hz, 2H), 7.45 (d, J= 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.58-7.70 (m, 3H), 7.88 (d, J = 6.6 Hz, IH), 8.85 (s, IH); ESI-MS (m/z) 480.26 [88%, (M+H)+].
Step 2: 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-6-(trifluoromethyl)-2H"-ρyrazolo[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). Resulting mixture was acidified with 17V HCl to pH 2.0, extracted with ethyl acetate (2 x 50 ml), washed with brine (50 ml) and dried (Na2SO4). The solvent was evaporated under reduced pressure to give 0.3 g of the product as a yellow solid; IR (KBr) 3435, 2963, 1708, 1496, 1256, 1150, 1029, 831, 797 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 7.45 (d, J = 8.4 Hz5 2H), 7.53 (d, J= 8.4 Hz, 2H), 7.60-7.76 (m, 3H), 7.87 (d, J = 7.8 Hz, IH), 8.81 (s, IH); ESI-MS (m/z) 452.36 [100%,(M+H)+].
Intermediate 3
2,3-bis(4-Chlorophenyl)-6-(trifluoromethyl)-2H-pyrazolo[3,4-6]pyridine-5-carboxylic acid:
Figure imgf000037_0001
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. The organic layer was washed with water (200 ml) followed by brine (200 ml), dried (Na2SO4), filtered and concentrated under reduced pressure to give 11.2 g of the product as a brown solid; IR (Neat) 2070, 1714, 1634, 1496, 1262, 1093, 832 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.35 (t, J = 6.9 Hz, 3H), 4.38 (q, J = 7.2 Hz, 2H), 4.69 (s, 2H), 7.30-7.42 (m, 4H), 7.44-7.64 (m, 4H); ESI-MS (m/z) 455.27 [60%, (MH)+].
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 0C 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 (Na2SO4). The solvent was removed under reduced pressure to afford 9.5 g of the product as an off-white solid; IR (Neat) 3400, 2070, 1634, 1496, 1296, 1086, 833 cm"1; 1H NMR (300 MHz, DMSO-J5) δ 1.33 (t, J= 7.2 Hz, 3H), 4.34 (q, J= 7.2 Hz, 2H), 4.49 (s, 2H), 4.91 (br s, IH), 7.24-7.38 (m, 4H), 7.51 (dd, J = 6.0, 2.4 Hz, 4H); ESI-MS (m/z) 391.35 [100%, (M+H)+].
Step 3: Ethyl l,5-di(4-chlorophenyl)-4-formyl-lϋ/-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 NaHCO3 (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 0C, diluted with ethyl acetate (3 x 100 ml) and quenched at 0 °C by adding an aqueous solution OfNa2SO3 (250 ml). Layers were separated. Organic layer was washed with saturated aqueous KHCO3 (250 ml) followed by brine (250 ml) and dried (Na2SO4). Concentration under reduced pressure afforded 8.75 g of the product as a yellow solid; IR (KBr) 3094, 2982, 2887, 1725, 1685, 1495, 1195, 1076, 832 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.35 (t, J= 7.2 Hz, 3H), 4.41 (q, J= 7.2 Hz, 2H), 7.36 (t, J= 8.1 Hz, 4H), 7.40-7.56 (m, 4H), 10.28 (s, IH); ESI-MS (m/z) 389 [65%, (M+H)+].
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 (Na2SO4). The solvent was evaporated to give 7.3 g of the product as an off-white solid; IR (KBr) 3363, 2984, 2595, 1913, 1713, 1683, 1484, 1089, 833 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 7.30-7.44 (m, 4H), 7.46-7.60 (m, 4H), 10.33 (s, IH), 13.82 (br s, IH); ESI-MS (m/z) 361.56 [56%, (M+H)+].
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 0C was added triethylamine (1.12 ml, 8.102 mmol). While maintaining the temperature at 0 0C, ethyl chloroformate (1.25 ml, 12.903 mmol) was added slowly. The mixture was stirred for 30 min at 0 0C followed by dropwise addition of a solution of sodium azide (0.96 g, 14.762 mmol) in water (6 ml). The resulting mixture was stirred at 0 0C for 1 h, the precipitate formed was filtered and the solvent was removed under reduced pressure at room temperature. The solid residue obtained was dissolved in diethyl ether (50 ml), filtered and evaporation of the solvent at room temperature afforded 3.1 g of l,5-bis(4-chlorophenyl)-4-formyl-lH-3- pyrazolecarbonyl azide as an off-white solid. Acyl azide was used as such in the next step. Acyl azide intermediate (3 g, 7.832 mmol) in 1,2-dimethoxy ethane (30 ml) and water (0.5 ml) was refluxed overnight. After cooling to room temperature, 1,2-dimethoxy ethane was evaporated under reduced pressure to dryness. The residue was dissolved in dichloromethane (50 ml), washed with brine (50 ml) and dried (Na2SO4). Removal of solvent under reduced pressure afforded 1.5 g of the product as a yellow solid; IR (KBr) 3302, 2866, 1910, 1659, 1488, 1093, 789 cm4; 1H NMR (300 MHz, DMSO-J6) δ 6.04 (s, 2H)5 7.19 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 7.8 Hz, 4H), 7.50 (d, J = 8.1 Hz, 2H), 9.46 (s, IH); ESI-MS (m/z) 332.30 [100%, (M+H)+].
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. The solid obtained on cooling was filtered by suction and washed with cold ethanol (10 ml) to afford 0.51 g of the product as an off white solid; IR (KBr) 3101, 2983, 1732, 1618, 1496, 1257, 1147, 1094 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.32 (t, J= 7.2 Hz, 3H), 4.34 (q, J = 6.3 Hz, 2H), 7.45-7.65 (m, 8H), 8.76 (s, IH); ESI-MS (m/z) 480.23 [100%, (M+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; 1H ΝMR (300 MHz, DMSO-J6) δ 7.45-7.65 (m, 8H), 8.73 (s, IH), 12.43 (s, IH); ESI-MS (m/z) 452.19 [60%, (M+H)+].
Intermediate 4
3 -Amino-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)- 1 H-pyrazole-4-carbaldehyde:
Figure imgf000039_0001
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 AIBΝ (0.072 g, 0.438 mmol). The resulting mixture was refluxed overnight. After cooling to room temperature, diethyl ether (200 ml) was added to get a clear solution. The organic layer was washed with water (100 ml) followed by brine (100 ml) and dried (Na2SO4), filtered and concentrated under reduced pressure to give 8.75 g of the product as an off-white solid; IR (KBr) 3421, 3090, 2982, 1720, 1496, 1262, 1085, 836, 809, 725 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.46 (t, J= 6.9 Hz, 3H), 4.52 (q, J= 6.9 Hz, 2H), 4.68 (s, 2H), 7.20-7.45 (m, 7H).
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 0C 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 (Na2SO4). The solvent was removed under reduced pressure to afford 4.5 g of the product as an off-white solid; IR (KBr) 3445, 3086, 2980, 1698, 1495, 1268, 1105, 835 cm"1; 1H NMR (300 MHz, DMSO-*/*) δ 1.32 (t, J= 6.9 Hz, 3H), 4.34 (q, J= 6.9 Hz, 2H), 4.53 (br s, 2H), 4.96 (t, J = 4.5 Hz, IH), 7.32 (d, J= 8.1 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 7.55-7.65 (m, IH), 7.73 (d, J= 8.4 Hz, IH), 7.81 (brs, IH).
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 NaHCO3 (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 0C, diluted with ethyl acetate (50 ml) and quenched at 0 0C by adding an aqueous solution of sodium sulfite (50 ml). Layers were separated. Organic layer was washed with saturated aqueous KHCO3 (50 ml) followed by brine (50 ml) and dried (Na2SO4). Concentration under reduced pressure afforded 0.15 g of the product as a white solid; IR (KBr) 3349, 3087, 2762, 1714, 1685, 1492, 1240, 1086, 977, 829 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.35 (t, J= 6.6 Hz, 3H), 4.42 (q, J= 7.2 Hz, 2H), 7.35 (d, J= 8.4 Hz, 2H), 7.46 (d, J= 8.7 Hz, 2H), 7.60-7.66 (m, IH), 7.80-7.89 (m, 2H), 10.31 (s, IH).
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
mixture was acidified with INHCl to pH 2.0. The mixture was extracted with ethyl acetate (2 x 100 ml), washed with brine and dried (Na2SO4). The solvent was evaporated to give 1.5 g of the product as an off-white solid; IR (KBr) 3440, 2925, 2645, 1732, 1684, 1621, 1482, 1190, 1089, 822 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 7.35 (d, J= 7.8 Hz, 2H), 7.45 (d,,J= 8.7 Hz, 2H) 7.60-7.65 (m, IH), 7.80-7.87 (m, 2H)3 10.36 (s, IH), 13.00-13.82 (br s, IH).
Step 5: 3-Amino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-liϊ-pyrazole-4-carbaldehyde: To a solution of Step 4 intermediate (0.75 g, 1.898 mmol) in acetone (10 ml) at about 0 0C was added triethylamine (0.26 ml, 1.898 mmol). While maintaining the temperature at 0 0C, ethyl chloroformate (0.18 ml, 1.898 mmol) was added slowly. The mixture was stirred for 30 min at 00C followed by dropwise addition of a solution of sodium azide (0.123 g, 1.898 mmol) in water (0.5 ml). The resulting mixture was stirred at about 0 0C for about 1 h, the precipitate formed was filtered and the solvent was removed under reduced pressure at room temperature. The solid residue obtained was dissolved in diethyl ether (50 ml), filtered and evaporation of the solvent at room temperature afforded 0.775 g of 5-(4-chlorophenyl)-l- (2,4-dichlorophenyl)-4-formyl-lH-pyrazole-3-carbonyl azide as a white solid; IR (KBr) 3434, 3062, 2889, 2138, 1692, 1489, 1428, 1179, 971, 796 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.53 (s, 9H), 7.36 (d, J = 8.4 Hz, 2H), 7.48 (d, J= 8.4 Hz, 2H) 7.60-7.66 (m, IH), 7.80-7.87 (m, 2H), 10.36 (s, IH). Acyl azide was used as such for the next step. The acyl azide intermediate (1 g, 2.146 mmol) and glacial acetic acid (5 ml) was gently refluxed overnight. Reaction mixture was poured in ice-cold water (50 ml) and solid obtained was filtered. The solid was dissolved in ethyl acetate (2 x 50 ml) and washed with saturated sodium carbonate (100 ml) followed by brine (100 ml), and dried (Na2SO4). Removal of solvent under reduced pressure afforded 0.5 g of the product as an off-white solid; IR (KBr) 3434, 3297, 2844, 1652, 1479, 1090, 1010, 785 cm"1; 1H NMR (300 MHz, DMSO-J15) δ 6.05 (s, 2H), 7.38 (d, J= 8.4 Hz, 2H), 7.49 (d, J= 8.4 Hz, 2H), 7.50-7.59 (m, IH), 7.71 (d, J= 8.4 Hz, IH) 7.78 (br s, IH), 9.57 (s, IH).
Intermediate 5
3-(4-Chloroρhenyl)-2-(2,4-dichlorophenyl)-6-methyl-2H-ρyrazolo[3,4-b]pyridine-5- carboxylic acid:
Figure imgf000041_0001
Step 1: Ethyl 3-(4-chloroρhenyl)-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. The solid obtained on cooling was filtered by suction and washed with cold ethanol (2 ml) to afford 0.18 g of the product as a white solid; IR (KBr) 3436, 2979, 1721, 1618, 1498, 1255, 1071, 970, 828 cm'1; 1H NMR (300 MHz, DMSCM5) δ 1.34 (t, J= 6.9 Hz, 3H)5 2.84 (s, 3H), 4.34 (q, J= 7.5 Hz, 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.58 (d, J= 8.7 Hz, 2H), 7.68-7.73 (m, IH), 7.80-7.94 (m, 2H), 8.65 (s, IH).
Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-methyl-2H-pyrazolo[3,4-έ]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). Resulting mixture was acidified with IiV HCl to pH 2.0, extracted with ethyl acetate (2 x 30 ml), washed with brine (50 ml) and dried (Na2SO4). The solvent was evaporated under reduced pressure to give 0.155 g of the product as a white solid; IR (KBr) 3430, 2929, 1694, 1614, 1497, 1263, 1097, 836 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 2.83 (s, 3H), 7.41 (d, J= 8.1 Hz, 2H), 7.56 (d, J= 8.1 Hz, 2H), 7.60-7.73 (m, IH), 7.72-7.98 (m, 2H), 8.55 (s, IH).
Intermediate 6
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(trifluoromethyl)-2H-pyrazolo[3,4-6]pyridine- 5-carboxylic acid:
Figure imgf000042_0001
Step 1 : Ethyl 3-(4-chloroρhenyl)-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. The solid obtained on cooling was filtered by suction and washed with cold ethanol (5 ml) to afford 0.13 g of the product as a white solid; IR (KBr) 3446, 3080, 1734, 1618, 1497, 1257, 1150, 1035, 798 cm"1; 1H NMR (300 MHz, DMSO-J6) 3
δ 1.33 (t, J= 7.5 Hz, 3H), 4.37 (q, J= 6.9 Hz, 2H), 7.49 (d, J= 8.1 Hz, 2H), 7.60 (d, J= 8.4 Hz, 2H), 7.73-7.77 (m, IH), 7.95-8.00 (m, 2H), 8.89 (s, IH).
Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichloroρhenyl)-(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. The mixture was extracted with ethyl acetate (2 x 25 ml), washed with brine (50 ml) and dried (Na2SO4). The solvent was evaporated to give 0.105 g of the product as an off-white solid; IR (KBr) 3435, 2928, 1708, 1613, 1497, 1257, 1155, 1030, 833 cm"1; 1H NMR (300 MHz, DMSO-^) δ 7.49 (d, J= 8.1 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.73-7.77 (m, IH), 7.95-8.00 (m, 2H), 8.85 (s, IH), 13.80 (br s, IH).
Intermediate 7
Ethyl 2-(2-chlorophenyl)-3-(4-chlorophenyl)-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-6]pyridine- 5-carboxylate:
Figure imgf000043_0001
A solution of Intermediate 1 (0.1 g, 0.273 mmol), diethyl malonate (0.042 ml, 0.275 mmol) and piperidine (0.067 ml, 0.682 mmol) in ethanol (1 ml) was heated under reflux overnight. The solid obtained on cooling was collected by suction filtration and washed with cold ethanol (5 ml) to afford 0.07 g of the product as a white solid; 1H NMR (300 MHz, DMSO- d6) δ 1.26 (t, J= 7.2 Hz, 3H), 4.22 (q, J= 7.5 Hz, 2H), 7.38 (d, J= 8.4 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.64 (dd, J= 8.1, 1.2 Hz, IH), 7.82 (d, J= 9.0 Hz, IH), 7.86 (d, J= 1.5 Hz, IH), 8.21 (s, IH), 12.30 (s, IH); ESI-MS (m/z) 428.49 [100%, (M+H)+].
Intermediate 8 Ethyl 2,3-bis(4-chlorophenyl)-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-&]pyridine-5-carboxylate:
Figure imgf000043_0002
A solution of Intermediate 3, Step 5 (1 g, 3.010 tnmol), diethyl malonate (0.45 ml, 2.996 mmol) and piperidine (0.74 ml, 7.516 mmol) in ethanol (8 ml) were heated under reflux overnight. The solid obtained on cooling was collected by suction filtration and washed with cold ethanol (10 ml) to afford 0.85 g of the product as a yellow solid; IR (KBr) 3056, 2975, 1741, 1640, 1091, 830 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.25 (t, J= 7.5 Hz, 3H), 4.19 (q, J = 5.4 Hz, 2H), 7.30-7.40 (m, 4H), 7.42-7.50 (m, 4H), 8.10 (s, IH), 12.22 (s, IH); ESI- MS (m/z) 428.14 [69%, (MMH)+].
Intermediate 9
Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-b] pyridine-5-carboxylate:
Figure imgf000044_0001
A solution of Intermediate 4 (0.1 g, 0273 mmol), diethyl malonate (0.042 ml, 0.275 mmol) and piperidine (0.067 ml, 0.682 mmol) in ethanol (1 ml) were heated under reflux overnight. The solid obtained on cooling was collected by suction filtration and washed with cold ethanol (5 ml) to afford 0.07 g of the product as a white solid; IR (KBr) 3447, 3060, 1741, 1643, 1482, 1255, 1093, 824 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.26 (t, J- 7.2 Hz, 3H), 4.22 (q, J= 7.5 Hz, 2H), 7.38 (d, J= 8.4 Hz, 2H), 7.55 (d, J= 8.1 Hz, 2H), 7.64 (dd, J= 8.1, 1.2 Hz5 IH), 7.82 (d, J= 9.0 Hz, IH), 7.86 (d, J= 1.5 Hz, IH), 8.21 (s, IH), 12.30 (s, IH).
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. For example, 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 (Λ^N'-Dicyclohexylcarbodiimide), CDI (l,r-Carbonyldiimidazole) and the like followed by treatment with various amines.
Example 1
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-6-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine-5- carboxamide:
Figure imgf000045_0001
To a stirred solution of Intermediate 2 (0.04 g, 0.088 mmol) in dichloromethane (4 ml) was added EDCI.HC1 (0.02 g, 0.104 mmol), 1-hydroxybenzotriazole (HOBt) (0.014 g, 0.103 mmol) and the reaction mixture was allowed to stir at 0 0C for 15 min. Then 25% aqueous ammonia (0.025 ml) was added to the reaction mixture over 15 min and the reaction mixture was allowed to warm to room temperature and stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate (20 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with saturated aqueous NaHCO3 (25 ml) and dried (Na2SO4). The solvent was evaporated under reduced pressure to give 28 mg of the product as a white solid; IR (KBr) 3383, 1688, 1614, 1498, 1032, 835 cm"1; 1H NMR (300 MHz, DMSO-^6) δ 7.43 (d, J= 7.8 Hz, 2H), 7.52 (d, J= 8.4 Hz, 2H), 7.60-7.79 (m, 4H), 7.87 (d, J= 6.9 Hz, IH), 8.08 (s, IH), 8.53 (s, IH); ESI-MS (m/z) 451.36 [50%, (M+H)+].
Example 2
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4- 6]ρyridine-5-carboxamide:
Figure imgf000045_0002
To a magnetically stirred solution of Intermediate 2 (0.05 g, 0.110 mmol) in anhydrous THF
(10 ml) was added methylamine hydrochloride (0.006 g, 0.121 mmol), triethylamine (0.153 ml, 1.096 mmol) and benzotriazol-l-yloxytris(dimethylamino) phosphoniurnhexa- 009/000083
fluorophosphate (0.053 g, 0.121 mmol) at room temperature. The resulting mixture was allowed to stir at the same temperature under nitrogen overnight. The reaction mixture was diluted with ethyl acetate (50 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 ml) and the combined organic extracts were washed with saturated aqueous NaHCO3 and dried (Na2SO4). Solvent was evaporated under reduced pressure to give 0.033 g of the product as an off-white solid; IR (KBr) 2943, 2347, 1668, 1618, 1496, 1258, 1147, 839 cm'1; 1H NMR (300 MHz, DMSO-^5) δ 2.79 (d, J = 5.1 Hz, 3H), 7.42 (d, J= 8.1 Hz, 2H), 7.53 (d, J= 8.4 Hz, 2H), 7.60-7.71 (m, 3H), 7.88 (d, J= 9.0 Hz, IH), 8.54 (s, 2H); ESI-MS (m/z) 465.17 [100%, (M+H)+].
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.
Table 1: Detailed Structural description of Examples 3-14
Figure imgf000046_0001
3
Example 3
2-(2-Chlorophenyl)-3-(4-chloroρhenyl)-N-ethyl-6-(trifluoromethyl)-2H-ρyrazolo[3,4- b]pyridine-5-carboxamide:
Prepared from Intermediate 2 and ethylamine as described in Example 2 to give the product
(60%) as a white solid; IR (KBr) 3306, 3065, 2975, 2359, 1663, 1615, 1495, 1093, 833 cm"1; 1H ΝMR (300 MHz, DMSO-J5) δ 1.12 (t, J- 7.2 Hz, 3H)5 3.28 (q, J= 6.9 Hz5 2H), 7.42 (d, J = 7.8 Hz, 2H), 7.51-7.66 (m, 5H)5 7.88 (d, J= 6.9 Hz, IH), 8.50 (s, IH), 8.57 (br s, IH).
Example 4
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-propyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-b] pyridine-5-carboxamide:
Prepared from Intermediate 2 and propylamine as described in Example 2 to give the product (74%) as a white solid; IR (KBr) 3304, 2963, 1664, 1613, 1495, 1257, 1151, 836 cm"1; 1H ΝMR (300 MHz, DMSO-J6) δ 0.91 (s, 3H), 1.52 (d, J= 6.3 Hz, 2H), 3.18-3.26 (m, 2H), 7.43 (d, J= 7.2 Hz, 2H), 7.50-7.78 (m, 5H), 7.88 (d, J= 6.3 Hz, IH), 8.49 (s, IH), 8.58 (br s, IH).
Example 5
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-isoρropyl-6-(trifluoromethyl)-2/J-pyrazolo-[3,4-6] pyridine-5-carboxamide:
Prepared from Intermediate 2 and isopropylamine as described in Example 2 to give the product (58%) as a white solid; IR (KBr) 3298, 2974, 1648, 1496, 1256, 1183, 836 cm"1; 1H ΝMR (300 MHz, CDCl3) δ 1.16 (d, J= 6.9 Hz, 6H), 4.02 (q, J= 6.0 Hz, IH), 7.43 (d, J= 8.1 Hz, 2H), 7.50-7.70 (m, 5H), 7.88 (d, J= 8.7 Hz, IH), 8.46 (s, 2H).
Example 6
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7V-(isobutyl)-6-(trifluoromethyl)-2//-pyrazolo-[3,4-&] pyridine-5-carboxamide:
Prepared from Intermediate 2 and isobutylamine as described in Example 2 to give the product (90%) as a white solid; 1H ΝMR (300 MHz, DMSO-J6) δ 0.91 (d, J= 6.6 Hz, 6H), 1.80 (q, J = 6.0 Hz, IH), 3.09 (t, J = 1.2 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.50-7.78 (m, 5H)3 7.90 (d, J= 6.6 Hz, IH), 8.51 (s, IH), 8.62 (br s, IH).
Example 7 IB2009/000083
2-(2-CMorophenyl)-3-(4-chlorophenyl)-N-(5ec-butyl)-6-(trifluoromethyl)-2H-pyrazolo- [3 ,4-b]pyridine-5-carboxamide:
Prepared from Intermediate 2 and sec-butylamine as described in Example 2 to give the product (53%) as a white solid; IR (KBr) 3247, 3066, 2967, 1638, 1496, 1043, 763 cm4; 1H ΝMR (300 MHz, DMSO-J6) δ 0.90 (t, J= 7.2 Hz5 3H)5 1.14 (d, J= 6.0 Hz5 3H), 1.40-1.60 (m, 2H)5 3.80-3.87 (m, IH)5 7.44 (d, J= 7.8 Hz5 2H)5 7.53-7.68 (m, 5H), 7.88 (d, J= 6.9 Hz5 IH), 8.39-8.43 (m, 2H).
Example 8
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-(tert-butyl)-6-(trifluoromethyl)-2H'-pyi-azolo-[3,4- b]pyridine-5-carboxamide:
Prepared from Intermediate 2 and tert-butylamine as described in Example 2 to give the product (81%) as a white solid; IR (KBr) 3349, 2971, 2930, 1648, 1621, 1036, 773 cm"1; 1H ΝMR (300 MHz, DMSO-J6) δ 1.36 (s, 9H), 7.44 (d, J= 7.5 Hz, 2H), 7.55-7.70 (m, 5H), 7.88 (d, J= 6.9 Hz5 IH)5 8.20 (s, IH)5 8.41 (s, IH).
Example 9
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-6-(trifluoromethyl)-2/J-pyrazolo-[3,4- &]pyridine-5-carboxamide:
Prepared from Intermediate 2 and cyclopropylamine as described in Example 2 to give the product (79%) as a white solid; IR (KBr) 3099, 2970, 1764, 1586, 1496, 1214, 802 cm4; 1H ΝMR (300 MHz, DMSO-J6) δ 0.53 (s, 2H), 0.72 (d, J= 5.4 Hz, 2H)5 2.80 (br s, IH), 7.41 (d, J= 7.8 Hz, 2H)5 7.49-7.70 (m, 5H), 7.87 (d, J= 6.9 Hz, IH)5 8.50 (s, IH)5 8.61 (br s, IH).
Example 10
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7Y-cyclopropylmethyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-δ]pyridine-5-carboxamide:
Prepared from Intermediate 2 and cyclopropylmethylamine as described in Example 2 to give the product (78%) as a white solid; IR (KBr) 3318, 2923, 1661, 1614, 1495, 1049, 835 cm4; 1H ΝMR (300 MHz, DMSO-J6) δ 0.22 (d, J= 4.5 Hz, 2H), 0.44 (d, J= 8.1 Hz5 2H), 1.00 (br s, IH), 3.15 (d, J= 4.8 Hz5 2H), 7.45 (d, J= 8.7 Hz, 2H)5 7.50-7.80 (m, 5H), 7.91 (d, J= 6.9 Hz, IH), 8.51 (s, IH), 8.71 (br s, IH).
Example 11 IB2009/000083
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclobutyl-6-(trifluoromethyl)-2H-pyrazolo-[3,4- έ]pyridine-5-carboxamide:
Prepared from Intermediate 2 and cyclobutylamine as described in Example 2 to give the product (67%) as a white solid; IR (KBr) 3307, 2982, 2865, 1650, 1611, 1256, 833 cm"1; 1H NMR (300 MHz,
Figure imgf000049_0001
δ 1.68 (br s, 2H), 1.98-2.02 (m, 2H), 2.25 (br s, 2H), 4.32-4.35 (m, IH)5 7.42-7.44 (m, 2H), 7.52-7.67 (m, 5H), 7.88 (d, J= 8.1 Hz, IH), 8.50 (s, IH), 8.81 (d, J= 7.5 Hz, IH).
Example 12
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-(2-dimethylaminoethyl)-6-(trifluoromethyl)-2H- pyrazolo[3,4-6]pyridine-5-carboxamide:
Prepared from Intermediate 2 and AζiV-dimethylethylenediamine as described in Example 2 to give the product (76%) as a white solid; IR (KBr) 3066, 2957, 1670, 1620, 1497, 1259, 1186, 846 cm"1; 1H NMR (300 MHz, CDCl3) δ 2.58 (s, 6H), 2.97 (s, 2H), 3.07 (br s, 2H), 7.34 (s, 4H), 7.30-7.50 (m, 3H), 7.56 (d, J= 6.6 Hz, IH), 7.90 (br s, IH), 8.38 (s, IH).
Example 13
(2-Chlorophenyl)-3-(4-chlorophenyl)-iV-(2-methoxyethyl)-6-(trifluoromethyl)-2H-pyrazolo [3 ,4-&]pyridine-5-carboxamide:
Prepared from Intermediate 2 and 2-methoxyethylamine as described in Example 2 to give the product (79%) as a white solid; IR (KBr) 3293, 3065, 2929, 1666, 1615, 1496, 1092, 833 cm-1; 1H NMR (300 MHz,
Figure imgf000049_0002
J= 8.4 Hz, 2H), 7.50-7.78 (m, 5H), 7.91 (d, J= 6.9 Hz, IH), 8.51 (s, IH), 8.73 (br s, IH).
Example 14
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-(2-fluoroethyl)-6-(trifluoromethyl)-2H-pyrazolo [3,4-b]pyridine-5-carboxamide:
Prepared from Intermediate 2 and 2-fluoroethylamine hydrochloride as described in Example 2 to give the product (70%) as a white solid; IR (KBr) 3290, 3019, 2926, 1730, 1668, 1495, 1215, 760 cm"1; 1H NMR (300 MHz, DMSO-^5) δ 3.42-3.69 (m, 2H), 4.45 (s, IH), 4.61 (s, IH), 7.44 (br s, 2H), 7.49-7.70 (m, 5H), 7.87 (br s, IH)5 8.52 (s, IH)5 8.88 (br s, IH).
Example 15 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-6-(2-fluorophenyl)-N-metliyl-2H-pyrazolo[3,4-Z?] pyridine-5-carboxamide:
Figure imgf000050_0001
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. The solid obtained on cooling was filtered by suction and washed with cold ethanol (10 ml) to afford 0.295 g of the product as an off-white solid; IR (KBr) 2947, 1722, 1674, 1242, 1094, 833 cm"1; 1H NMR (300 MHz, DMSO-rfβ) δ 1.05 (t, J= 7.5 Hz, 3H), 4.11 (q, J= 7.2 Hz, 2H), 7.20-7.38 (m, 2H), 7.42-7.70 (m, 9H), 7.86 (d, J= 7.5 Hz, IH), 8.71 (s, IH); ESI-MS (m/z) 506.32 [100%, (M+H)+].
Step 2: 2-(2-Chlorophenyl)-3-(4-chloroρhenyl)-6-(2-fluoroρhenyl)-2H"-ρyrazolo[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; 1H NMR (300 MHz, OMSO-d6) δ 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-δ]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; 1H NMR (300 MHz, OMSOd6) δ 2.67 (br s, 3H), 7.18-7.35 (m, 2H), 7.40-7.70 (m, 9H), 7.84-7.90 (m, IH), 8.39 (br s, 2H); ESI-MS (m/z) 491.25 [100%, (M+H)+].
Example 16
2,3-bis(4-Chlorophenyl)-N-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-&]ρyridine-5- carboxamide:
Figure imgf000051_0001
Coupling reaction of Intermediate 3 (0.1 g, 0.221 mmol) using BOP reagent (0.107 g, 0.343 mmol), triethylamine (0.306 ml, 2.203 mmol) and methylamine hydrochloride (0.013 g, 0.227 mmol) in anhydrous DMF (5 ml) according to the procedure described in Example 2 afforded 0.05 g of the product as a white solid; IR (KBr) 3283, 2938, 1645, 1564, 1496, 1257, 841 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 2.77 (d, J = 4.5 Hz, 3H), 7.47 (d, J = 8.1 Hz, 2H), 7.30-7.65 (m, 6H), 8.46 (s, IH), 8.52 (d, J = 4.5 Hz, IH); ESI-MS (m/z) 465.29 [100%, (M+H)+].
Example 17
6-(4-Bromophenyl)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-ό]pyridine:
Figure imgf000051_0002
A mixture of Intermediate 4 (0.12 g, 0.328 mmol), 4-bromoacetophenone (0.065 g, 0.328 mmol) and 2% ethanolic potassium hydroxide solution (2 ml) was heated under reflux for 1 h. The mixture was then allowed to cool to room temperature and the resulting solid was collected by suction filtration and washed with cold ethanol (5 ml) to afford 0.083 g of the product as a white solid; IR (KBr) 3436, 2966, 1612, 1495, 1094, 787 cm'1; 1H NMR (300 MHz, OMSO-d6) δ 7.43 (d, J = 6.9 Hz, 2H), 7.56 (d, J = 6.0 Hz, 2H), 7.68-7.92 (m, 6H), 8.15-8.27 (m, 2H), 8.37 (d, J= 8.4 Hz, IH); ESI-MS (m/z) 530.32 [100%, (M+H)+].
Example 18
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-[3-(trifluoromethyl)phenyl]-2H-pyrazolo-[3,4- bjpyridine:
Figure imgf000051_0003
The title compound was prepared from Intermediate 4 (0.050 g, 0.136 mmol) and 3- trifluoromethylacetophenone (0.021 ml, 0.138 mmol) according to the procedure described in Example 17 to give 0.07 g of the product as a white solid; IR (KBr) 3436, 3084, 2924, 1610, 1496, 1344, 1261, 1121, 828, 785 cm'1; 1H NMR (300 MHz, OMSOd6) δ 7.45 (d, J = 8.4 Hz, 2H), 7.57 (d, J= 7.8 Hz, 2H), 7.65-8.10 (m, 6H), 8.42 (d, J- 8.7 Hz, IH), 8.55-8.62 (m, 2H); ESI-MS (m/z) 518.38 [100%, (MH-H)+].
Example 19
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine- 5-carboxamide:
Figure imgf000052_0001
To a magnetically stirred solution of Intermediate 6 (0.04 g, 0.082 mmol) in dichloromethane (1 ml) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.019 g, 0.099 mmol) and 1-hydroxybenzotriazole (0.014 g, 0.104 mmol) at 0 0C. The reaction mixture was stirred at 0 0C for 15 min followed by addition of a 30% solution of ammonia in water (0.019 ml). The resulting mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate (25 ml), washed successively with water (30 ml), brine (30 ml) and dried (Na2SO4). Concentration under reduced pressure afforded 0.028 g of the product as an off-white solid; IR (KBr) 3401, 3173, 1687, 1499, 1258, 1156, 1031, 836 cm"1; 1H NMR (300 MHz, DMSO-Jό) δ 7.48 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.75 (dd, J = 6.6, 2.1 Hz, 2H), 7.92-8.01 (m, 2H) 8.10 (s, IH), 8.58 (s, IH); ESI-MS (m/z) 485.25 [100%, (MH-H)+].
Example 20
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-(6-(trifluoromethyl))-2H-pyrazolo[3,4-&] pyridme-5-carbonitrile:
Figure imgf000052_0002
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 0C. 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 NaHCO3 solution (30 ml), brine (30 ml), and dried (Na2SO4). Concentration under reduced pressure afforded 0.012 g of the product as an off- white solid; IR (KBr) 3069, 2975, 2233, 1648, 1614, 1499, 1040, 830 cm"1; 1H NMR (300 MHz, DMSO-J*) δ 7.51 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.1 Hz5 IH), 7.90-8.00 (m, 2H), 9.47 (s, IH); ESI-MS (m/z) 467.56 [100%, (M+H)+].
Examples 21 to 41 were prepared by coupling reaction of Intermediate 5 and 6 as applicable with appropriate amine as described in Example 2.
Table 2: Structural details of Examples 21-41
Figure imgf000053_0001
009/000083
Figure imgf000054_0001
Example 21
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-isopropyl-6-methyl-2H-pyrazolo[3,4-b] pyridine-5-carboxamide:
The title compound was prepared using Intermediate 5 and isopropylamine according to the procedure described in Example 2 to give the product (70%) as an off-white solid; IR (KBr) 3408, 3277, 2971, 1638, 1498, 1289, 1097, 837 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 1.17 (d, J= 6.3 Hz, 6H), 2.65 (s, 3H)5 4.06 (m, IH), 7.42 (d, J= 8.4 Hz, 2H), 7.56 (d, J= 8.4 Hz, 2H)3 7.67-7.73 (m, IH), 7.87-7.93 (m, 2H), 8.10 (s, IH), 8.35 (d, J= 7.2 Hz, IH).
Example 22
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-methyl-iV-(tert-butyl)-2H-pyrazolo[3,4-&] pyridine-5-carboxamide:
The title compound was prepared using Intermediate 5 and tert-butylamine according to the procedure described in Example 2 to give the product (50%) as an off-white solid; IR (KBr) 3430, 3227, 2965, 1642, 1499, 1290, 1096, 831 cm'1; 1H NMR (300 MHz, DMSO-^6) δ 1.38 (s, 9H), 2.63 (s, 3H), 7.40 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.65-7.72 (m, IH), 7.85-7.92 (m, 2H), 8.02 (s, IH), 8.07 (s, IH).
Example 23 3-(4-Chlorophenyl)-2-(254-dichloroρhenyl)-N-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-6] pyridine-5-carboxamide:
The title compound was prepared using Intermediate 6 and 40% solution of methylamine in water according to the procedure described in Example 2 to give the product (50%) as an off-white solid; IR (KBr) 3297, 3090, 1666, 1497, 1258, 1147, 1064, 797 cm"1; 1H NMR (300 MHz, DMSO-^6) δ 2.80 (d, J = 3.9 Hz, 3H), 7.47 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.73-7.77 (m, IH), 7.96-8.00 (m, 2H), 8.58 ( br s, 2H).
Example 24
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-iV-ethyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-b] pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and ethylamine as described in Example 2 to get the product (68%) as a white solid; IR (KBr) 3253, 2980, 1645, 1495, 1256, 1189, 1093, 802 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J= 7.5 Hz, 3H), 3.51 (q, J= 6.9 Hz, 2H), 6.12 (br s, IH), 7.27 (d, J= 5.7 Hz, 2H), 7.38-7.60 (m, 5H), 8.31 (s, IH).
Example 25
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-isopropyl-6-(trifluoromethyl)-2i:/-ρyrazolo- [3,4-b]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and isopropylamine as described in Example 2 to get the product (80%) as a white solid; IR (KBr) 3435, 3261, 2970, 1641, 1496, 1256, 1155, 1039, 801 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.28 (d, J= 6.3 Hz, 6H), 4.30 (m, IH), 5.77 (br s, IH), 7.20-7.56 (m, 5H), 8.35 (s, IH).
Example 26
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-propyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-Z)] pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and propylamine as described in Example 2 to get the product (92%) as a white solid; IR (KBr) 3444, 3255, 2966, 1645, 1496, 1256, 1151, 1093, 830 cm"1; 1H NMR (300 MHz, DMSO-^) δ 0.91 (t, J= 6.9 Hz, 3H), 1.53 (m, 2H), 3.22 (q, J = 6.3 Hz, 2H), 7.46 (d, J= 7.5 Hz, 2H), 7.59 (d, J = 7.5 Hz5 2H), 7.72- 7.77 (m, IH), 7.95-8.00 (m, 2H), 8.53 (s, IH), 8.61 (br s, IH).
Example 27 3-(4-Chlorophenyl)-2-(254-dichlorophenyl)-N-isobutyl-6-(trifluoromethyl)-2H-pyrazolo[3,4- &]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and isobutylamine as described in Example 2 to give the product (72%) as a white solid; IR (KBr) 3270, 2959, 1644, 1497, 1256, 1189, 1094, 829 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 0.90 (d, J= 6.9 Hz, 6H), 1.78- 1.91 (m, IH), 3.12-3.20 (m, 2H), 7.44 (d, J= 8.4 Hz, 2H), 7.56 (d, J= 9.0 Hz, 2H), 7.71 (d, J = 9.1 Hz, IH), 7.90-8.00 (m, 2H), 8.49(s, IH), 8.59 (br s, IH).
Example 28
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(tert-butyl)-6-(trifluoromethyl)-2H-pyrazolo [3,4-&]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and tert-butylamine as described in Example 2 to get the product (27%) as a white solid; IR (KBr) 3435, 3299, 2928, 1650, 1497, 1256, 1190, 1094, 799 cm"1; 1H NMR (300 MHz, DMSO-J15) δ 1.37 (s, 9H), 7.46 (d, J= 8.7 Hz, 2H), 7.60 (d, J= 8.1 Hz, 2H), 7.72-7.77 (m, IH), 7.97-7.99 (m, 2H), 8.21 (s, IH), 8.43 (s, IH).
Example 29
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-iV-5ec-butyl-6-(trifluoromethyl)-2H-pyrazolo- [3,4-έ]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and sec-butylamine as described in Example 2 to give the product (57%) as a white solid; IR (KBr) 3252, 2968, 1663, 1556, 1093, 829 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 0.89 (t, J= 6.9 Hz, 3H), 1.13 (d, J = 6.3 Hz, 3H), 1.42-1.60 (m, 2H), 3.80-3.88 (m, IH), 7.43 (d, J= 4.5 Hz, 2H), 7.57 (d, J= 7.5 Hz, 2H), 7.71 (d, J= 8.4 Hz, IH), 7.92-7.99 (m, 2H), 8.36-8.44 (m, 2H).
Example 30
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-isopentyl-6-(trifluoromethyl)-2H"-pyrazolo- [3 ,4-b]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and isopentylamine as described in Example 2 to give the product (61%) as a white solid; IR (KBr) 3435, 3296, 2927, 1644, 1497, 1256, 1186, 1094, 826 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.91 (d, J = 6.6 Hz, 6H), 1.42-1.50 (m, 2H)3 1.60-1.70 (m, IH)5 3.20-3.40 (m, 2H), 7.47 (d, J= 8.4 Hz, 2H), 7.60 (d, J= 8.1 Hz, 2H), 7.70-7.80 (m, IH), 7.90-8.10 (m, 2H), 8.53 (s, IH), 8.59 (br s, IH).
Example 31
3-(4-CWorophenyl)-2-(2,4-dichlorophenyl)-N-(l,2-dimethylproρyl)-6-(trifluoromethyl)-2H- pyrazolo [3 ,4-δ]pyridine- 5 -carboxamide:
The title compound was prepared from Intermediate 6 and (>S)-(+)-3-methyl-2-butylamine as described in Example 2 to give the product (61%) as a white solid; IR (KBr) 3247, 2968, 1638, 1495, 1256, 1093, 828 cm"1; 1H NMR (300 MHz, CDCl3) δ 0.89 (s, 6H), 1.08 (d, J = 6.9 Hz, 3H), 1.72 (br s, IH), 3.77 (br s, IH), 7.43 (d, J = 8.1 Hz, 2H), 7.56 (d, J= 8.1 Hz, 2H), 7.70 (d, J= 8.4 Hz, IH), 7.93 (s, 2H), 8.24-8.42 (m, 2H).
Example 32
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(l,l-dimethylpropyl)-6-(trifluoromethyl)-2H- pyrazolo[3,4-6]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and 1,1-dimethylpropylarnine as described in Example 2 to give the product (23%) as a white solid; IR (KBr) 3348, 3081, 2970, 1649, 1618, 1498, 1039, 801 cm'1; 1H NMR (300 MHz, CDCl3) δ 0.85 (br s, 3H), 1.30 (s, 6H), 1.73-1.80 (m, 2H), 7.43 (d, J= 8.1 Hz, 2H), 7.57 (d, J= 7.5 Hz, 2H), 7.70 (d, J= 9.0 Hz, IH), 7.88-7.95 (m, 2H), 8.03 (s, IH), 8.36 (s, IH).
Example 33
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-cyclopropyl-6-(trifluoromethyl)-2H-pyrazolo [3,4-b]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and cyclopropylamine as described in Example 2 to give the product (30%) as a white solid; IR (KBr) 3444, 3231, 1645, 1495, 1257, 1156, 1040, 828 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.54 (br s, 2H), 0.72 (br s, 2H), 2.80 (m, IH), 7.46 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.72-7.77 (m, IH), 7.95-8.00 (m, 2H), 8.55 (s, IH), 8.66 (br s, IH).
Example 34
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-cyclopropylmethyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-6]pyridine-5-carboxamide: The title compound was prepared from Intermediate 6 and cyclopropylmethylamine as described in Example 2 to give the product (45%) as a white solid; IR (KBr) 3273, 3081, 2926, 1643, 1496, 1092, 829 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.22 (br s, 3H), 0.44 (br s, 2H), 3.10-3.22 (m, 2H), 7.38-7.58 (m, 4H), 7.62-7.82 (m, IH), 7.84-8.01 (m, 2H), 8.44- 8.58 (m, IH), 8.61-8.70 (m, IH).
Example 35
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-cyclobutyl-6-(trifluoromethyl)-2H'-pyrazolo [3 ,4-&]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and cyclobutylamine as described in Example 2 to give the product (75%) as a white solid; IR (KBr) 3256, 2982, 1640, 1545, 1496, 1255, 1142, 1091, 831 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 1.68-1.70 (m, 2H), 1.95-2.01 (m, 2H), 2.25 (br s, 2H), 4.32-4.37 (m, IH), 7.45 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.71 (d, J= 8.1 Hz, IH), 7.95 (dd, J= 8.7, 2.1 Hz, 2H), 8.50 (s, IH), 8.81 (d, J = 7.2 Hz, IH).
Example 36
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-cyclopentyl-6-(trifluoromethyl)-2Hr-prazolo [3 ,4-&]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and cyclopentylamine as described in Example 2 to give the product (62%) as a white solid; IR (KBr) 3261, 2962, 1638, 1496, 1256, 1094, 828 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.21-1.25 (m, IH), 1.44-1.70 (m, 5H), 1.80-1.94 (m, 2H), 4.16 (br s, IH), 7.47 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.70 (d, J= 9.6 Hz, IH), 7.90-8.00 (m, 2H), 8.40-8.60 (m, 2H).
Example 37
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-cyanomethyl-6-(trifluoromethyl)-2H-pyrazolo [3 ,4-b]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and aminoacetonitrile hydrochloride as described in Example 2 to give the product (46%) as a white solid; IR (KBr) 3364, 2927, 2360, 1666, 1497, 1257, 1092, 840 cm"1; 1H ΝMR (300 MHz, DMSO-J6) δ 4.35 (d, J= 2.1 Hz, 2H), 7.44 (d, J = 93 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H)5 7.70 (d, J= 9.6 Hz, IH), 7.90- 7.98 (m, 2H), 8.64 (s, IH), 9.35 (br s, IH). Example 38
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methoxy-6-(trifluoromethyl)-2H-pyrazolo[3,4- &]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and methoxyamine as described in Example 2 to give the product (39%) as a white solid; IR (KBr) 3177, 2982, 1687, 1618, 1498, 1066, 836 cm"1; 1H ΝMR (300 MHz, DMSO-J6) δ 3.74 (s, 3H), 7.44 (d, J = 5.4 Hz, 2H)5 7.52 (d, J= 8.4 Hz, 2H), 7.72 (d, J= 8.7 Hz, IH), 7.90-8.00 (m, 2H), 8.65 (s, IH), 11.73 (s, IH).
Example 39
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(2-methoxyethyl)-6-(trifluoromethyl)-2i/- pyrazolo[3,4-&]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and 2-methoxyethylamine as described in Example 2 to give the product (44%) as a white solid; IR (KBr) 3271, 1645, 1619, 1495, 1255, 1148, 1094, 829 cm'1; 1H ΝMR (300 MHz, DMSO-J6) δ 3.37 (s, 3H), 3.51-3.60 (m, 2H), 3.60-3.78 (m, 2H), 6.35 (br s, IH), 7.24 (s, IH), 7.39 (d, J= 7.8 Hz, 3H), 7.45-7.57 (m, 3H), 8.34 (s, IH).
Example 40
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(2-dimethylaminoethyl)-6-(trifluoromethyl)- 2H-pyrazolo[3,4-6]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and N,Λ/-dimethylaminoethylamine as described in Example 2 to give the product (78%) as a white solid; 1H ΝMR (300 MHz, CDCl3) δ 2.27 (s, 6H), 2.56 (t, J= 6.0 Hz5 2H), 3.55 (q, J= 6.0 Hz, 2H), 6.81 (br s, IH), 7.20- 7.27 (m, 3H), 7.40-7.45 (m, 2H)5 7.50-7.58 (m, 2H), 8.38 (s, IH).
Example 41
3 -(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(2-pyrrolidin- 1 -ylethyl)-6-(trifluoromethyl)- 2H-pyrazolo[3,4-b]pyridine-5-carboxamide:
The title compound was prepared from Intermediate 6 and l-(2-aminoethyl)pyrrolidine as described in Example 2 to give the product (65%) as a white solid; IR (KBr) 3352, 2959, 2351, 1638, 1549, 1483, 1093, 829 cm"1; 1H ΝMR (300 MHz, CDCl3) δ 1.79 (br s, 4H), 2.62 (br s, 4H), 2.76 (s, 2H)5 3.59 (d, J= 6.0 Hz5 2H), 7.26 (s, 2H)5 7.30-7.42 (m, 3H), 7.44-7.55 (m, 2H), 8.04 (s, IH), 8.39 (s, IH).
Example 42
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-(pyrrolidin-l-ylcarbonyl)-6-(trifluoromethyl)- 2H-pyrazolo[3,4-b]pyridine:
Figure imgf000060_0001
The title compound was prepared from Intermediate 6 and pyrrolidine as described in Example 2 to give the product (77%) as a white solid; IR (KBr) 3437, 2978, 1639, 1497, 1441, 1257, 1191, 1099, 833 cm"1; 1H NMR (300 MHz5 CDCl3) δ 1.80-2.10 (m, 4H), 3.22 (br s, 2H), 3.69 (br s, 2H), 7.20-7.60 (m, 7H), 8.18 (s, IH); ESI-MS (m/z) 541.36 [100 %, (M+H)+].
Example 43
3 -(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-A/-pyrrolidin- 1 -yl-6-(trifluoromethyl)-2i7- pyrazolo[3,4-b]pyridine-5-carboxamide:
Figure imgf000060_0002
The title compound was prepared from Intermediate 6 and pyrrolidin-1 -amine as described in Example 2 to give the product (65%) as a white solid; 1H NMR (300 MHz, DMSO-J6) δ 1.55 (br s, IH), 1.77 (br s, 3H), 2.77 (br s, IH)5 2.92 (br s, 3H), 7.40-7.50 (m, 2H), 7.52-7.62 (m, 2H), 7.70-7.80 (m, IH), 7.90-8.00 (m, 2H), 8.54 (s, IH)5 9.49 (s, IH); ESI-MS (m/z) 544.40 (M+H)+.
Example 44 l-[3-(4-Chloroρhenyl)-2-(2,4-dichlorophenyl)-6-(trifluoromethyl)-2H-ρyrazolo[3,4-b] pyridin-5-yl]-3-rnethylurea:
Figure imgf000061_0001
To a magnetically stirred solution of Intermediate 6 (0.10 g, 0.205 mmol) in 1,2- dimethoxyethane (2 ml) was added triethylamine (0.14 ml, 1.028 mmol) followed by phenyl chloroformate (0.038 ml, 0.306 mmol) at 0 0C. The reaction mixture was stirred at 0 0C for 1 h. Sodium azide (0.015 g, 0.231 mmol) was added at 0 0C and stirred at the same temperature for 1 h. After this time, the reaction mixture was heated to 75 0C and methylamine hydrochloride (0.028 g, 0.414 mmol) was added and heating continued overnight. Reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 ml) and washed with water (10 ml) and dried (Na2SO4). Concentration under reduced pressure afforded 0.03 g of the product as an off-white solid; 1H NMR (300 MHz3 DMSO-J6) δ 2.65 (d, J- 4.2 Hz, 3H)5 6.70 (d, J= 3.9 Hz5 IH)5 7.38 (d, J= 8.7 Hz, 2H)5 7.57 (d, J= 8.4 Hz5 2H)5 7.72 (dd5 J= 2.4, 2.1 Hz, IH)5 7.80-8.12 (m5 3H)5 8.52 (s, IH); ESI-MS (m/z) 514.39 [100%, (M+H)+].
Example 45
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(3,353-trifluoropropyl)-657-dihydro-2H-pyrazolo [354-&]pyridin-6-one:
Figure imgf000061_0002
Step 1: Ethyl 2-(2-chloroρhenyl)-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,l5l-trifluoro-3-iodopropane (0.041 ml, 0.351 mmol) at room temperature. The reacton mixture was stirred overnight at 80 °C. The 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 (Na2SO4). The organic layer was concentrated to give 40 mg of the product as an off-white solid; IR (KBr) 3099, 2980, 2306, 1737, 1651, 1484, 1094, 828 cm'1; 1H NMR (300 MHz5 OUSOd6) δ 1.27 (t, J= 7.2 Hz5 3H)5 2.68-2.90 (m, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.30-4.44 (m, 2H), 7.38 (d, J= 8.4 Hz, 2H), 7.48-7.70 (m, 5H), 7.78 (d, J= 6.9 Hz, IH)5 8.26 (s, IH); ESI-MS (m/z) 524.51 [100%, (M+H)+].
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). The layers were separated, the aqueous layer was extracted with ethyl acetate (3 x 50 ml) and the organic layer was washed with brine, dried (Na2SO4) and concentrated to give 300 mg of the product as an off-white solid; IR (KBr) 2957, 1739, 1612, 1467, 1097 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 2.80-3.00 (m, 2H), 4.47 (br s, 2H), 7.43 (d, J= 8.1 Hz, 2H), 7.50-7.76 (m, 5H), 7.83 (d, J = 7.5 Hz, IH), 8.64 (s, IH), 13.98 (br s, IH); ESI-MS (m/z) 496.73 [100 %, (M+H)+].
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. After this time, the hot mixture was cooled and diluted with ethyl acetate (20 ml), washed with brine (20 ml), water (20 ml) and dried (Na2SO4) to afford 0.023 g of the product as a pale yellow solid; IR (KBr) 2932, 1651, 1620, 1526, 1094, 825 cm"1; 1H NMR (300 MHz, DMSO- d6) δ 2.62-2.84 (m, 2H), 4.33 (br s, 2H), 6.36 (d, J = 8.7 Hz, IH), 7.30 (d, J= 8.4 Hz, 3H), 7.42-7.64 (m, 4H), 7.66-7.80 (m, 2H); ESI-MS (m/z) 452.41 [70%, (M+H)+].
Example 46
2-(2-Chlorophenyl)-3 -(4-chlorophenyl)-6-oxo-7-(3 ,3 ,3 -trifluoropropyl)-6,7-dihydro-2H"- pyrazolo[3,4-έ]pyridine-5-carboxamide:
Figure imgf000062_0001
The title compound was prepared from Example 45, Step 2 intermediate (0.09 g, 0.169 mmol), N-ethyl-iV'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.046 g, 0.241 mmol), 1-hydroxybenzotriazole (0.032 g, 0.241 mmol) and 25% solution of ammonia in water (0.057 ml) in dichloromethane (5 ml) according to procedure described in Example 1 to afford 0.08 g of the product as a white solid; IR (KBr) 3349, 3133, 2924, 2342, 1682, 1614, 1515, 1483, 1095, cm'1; 1H NMR (300 MHz, DMSO-J6) δ 2.76-2.90 (m, 2H), 4.42 (br s, 2H), 7.20-7.30 (m, IH), 7.32-7.40 (m, 2H), 7.50-7.70 (m, 5H), 7.70-7.80 (m, IH), 8.61 (s, IH), 8.82 (br s, IH); ESI-MS (m/z) 496 [76%, (M+H)+].
Example 47
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-methyl-6-oxo-7-propyl-6,7-dihydro-2H-pyrazolo [3 ,4-δ]pyridine-5-carboxamide:
Figure imgf000063_0001
Step 1: Ethyl 2-(2-chlorophenyl)-3-(4-chlorophenyl)-6-oxo-7-propyl-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxylate: Prepared from Intermediate 7 (0.2 g, 0.466 mmol), 1- bromopropane (0.063 ml, 0.599 mmol) and cesium carbonate (0.38 g, 1.166 mmol) in anhydrous DMF (5 ml) according to the procedure described in Example 45, Step 1 to afford 0.23 g of the product as a white solid; IR (KBr) 2953, 1729, 1645, 1618, 1485, 1089 cm 1; 1H ΝMR (300 MHz, DMSO-J6) δ 0.91 (t, J = 6.9 Hz, 3H), 1.26 (t, J = 6.9 Hz, 3H), 1.64-1.80 (m, IH), 4.04 (s, 2H), 4.22 (d, J= 7.2 Hz, 2H), 7.36 (d, J= 8.1 Hz, 2H), 7.44-7.62 (m, 5H),
7.70-7.80 (m, 2H), 8.18 (s, IH); ESI-MS (m/z) 470.12 [100%, (M+H)+].
Step 2: 2-(2-Chlorophenyl)-3 -(4-chlorophenyl)-6-oxo-7-propyl-6,7-dihydro-2H-pyrazolo[3 ,4- b]pyridine-5-carboxylic acid: Hydrolysis of Step 1 intermediate (0.23 g, 0.488 mmol) using IN KOH (1 ml) in methanol (4 ml) according to procedure described in Intermediate 3, Step 4 to give 0.21 g of the product as an off- white solid; IR (KBr) 3359, 2959, 1726, 1619, 1482, 1119, 759 cm'1; 1H ΝMR (300 MHz, DMSO-40 δ 0.94 (t, J = 7.2 Hz, 3H), 1.78-1.90 (m, 2H), 4.16-4.28 (m, 2H), 7.42 (d, J= 7.8 Hz, 2H), 7.50-7.70 (m, 5H), 7.81 (d, J= 7.8 Hz, IH), 8.62 (s, IH), 14.32 (s, IH); ESI-MS (m/z) 440.18 [100%, (M-H)"].
Step 3: 2-(2-Chlorophenyl)-3-(4-chloroρhenyl)-N-methyl-6-oxo-7-ρropyl-6,7-dihydro-2H- pyrazolo[3,4-6]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate (0.07 g, 0.158 mmol) using BOP reagent (0.077 g, 0.173 mmol), triethylamine (0.22 ml, 1.581 mmol) and methylamine hydrochloride (0.012 g, 0.173 mmol) in DMF (5 ml) according to the procedure described in Example 2 afforded 0.058 g of the product as an off-white solid; IR (KBr) 3372, 2961, 1669, 1611, 1510, 1483, 1091, 798 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.93 (t, J= 7.5 Hz, 3H), 1.76 (q, J= 7.5 Hz, 2H), 2.84 (d, J= 4.8 Hz, 3H)5 4.14 (t, J= 7.8 Hz, 2H), 7.38 (d, J= 8.1 Hz, 2H), 7.50-7.70 (m, 5H), 7.78 (d, J= 6.9 Hz, IH), 8.57 (s, IH), 9.49 (d, J= 6.0 Hz, IH); ESI-MS (m/z) 455.36 [100%, (M+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.
Table 3: Structural details of Examples 48 - 66
Figure imgf000064_0001
Figure imgf000065_0001
Example 48
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-6-oxo-7-propyl-637-dihydro-2/i"- pyrazolo[3,4-Z>]pyridine-5-carboxamide:
The title compound was prepared from Example 47, Step 2 intermediate and cyclopropylamine according to the procedure described in Example 47, Step 3 to get the product (65%) as an off-white solid; IR (KBr) 3375, 2929, 1641, 1609, 1509, 1484, 1093, 838 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.55 (s, 2H), 0.75 (d, J= 5.7 Hz, 2H), 0.92 (t, J= 7.2 Hz, 3H), 1.03 (d, J= 6.0 Hz, 2H), 1.74 (q, J= 6.9 Hz, 2H), 2.87 (br s, IH), 7.38 (d, J = 8.4 Hz, 2H), 7.50-7.65 (m, 5H), 7.78 (d, J= 7.8 Hz, IH), 8.57 (s, IH), 9.59 (d, J= 3.9 Hz, IH).
Example 49
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-isobutyl-N-methyl-6-oxo-6,7-dihydro-2JH- pyrazolo[3,4-έ]pyridine-5-carboxamide:
Step 1: Ethyl 2-(2-chlorophenyl)-3 -(4-chlorophenyl)-7-isobutyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-Z?]pyridine-5-carboxylate: This compound was prepared from Intermediate 7 and l-bromo-2-methylpropane according to the procedure described in Example 47, Step 1 to get the product (75%) as an off-white solid; IR (KBr) 2959, 1737, 1624, 1483, 1236, 1095 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.90 (d, J = 6.6 Hz, 6H), 1.26 (t, J = 7.2 Hz, 3H), 2.22-2.36 (m, IH), 3.92 (d, J = 7.8 Hz, 2H), 4.22 (q, J = 6.9 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.44-7.64 (m, 5H), 7.74 (d, J= 7.5 Hz, IH), 8.19 (s, IH); ESI-MS (m/z) 484.31 [100%, (M+H)+].
Step 2: 2-(2-Chlorophenyl)-3-(4-chloroρhenyl)-7-isobutyl-6-oxo-6,7-dihydro-2H-pyrazolo [3,4-b]pyridine-5-carboxylic acid: Saponification of Step 1 intermediate afforded the acid as a solid; IR (KBr) 3096, 2960, 1727, 1615, 1455, 1095 cm"1; 1H NMR (300 MHz, DMSO-J15) δ 0.93 (d, J= 6.9 Hz, 6H), 2.30-2.50 (m, IH), 4.07 (d, J= 7.8 Hz, 2H), 7.41 (d, J= 8.4 Hz, 2H), 7.50-7.62 (m, 5H), 7.79 (d, J= 7.8 Hz, IH), 8.63 (s, IH), 14.32 (s, IH); ESI-MS (m/z) 456.23 [100%, (MR-H)+].
Step 3: 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-isobutyl-N-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-&]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate with methylamine hydrochloride according to the procedure described in Example 47, Step 3 afforded the resultant compound (70%) as a white solid; IR (KBr) 3280, 2959, 1669, 1611, 1510, 1483, 1092, 743 cm'1; 1H NMR (300 MHz, DMSO-^6) δ 0.91 (d, J= 6.3 Hz, 6H), 2.24- 2.40 (m, IH), 2.84 (d, J = 4.2 Hz, 3H)5 4.02 (d, J = 7.2 Hz, 2H), 7.38 (d, J= 8.4 Hz, 2H), 7.44-7.62 (m, 5H), 7.76 (d, J= 7.2 Hz, IH), 8.58 (s, IH), 9.48 (d, J- 5.1 Hz, IH).
Example 50
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-7-isobutyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-Z?]pyridine-5-carboxamide:
The title compound was prepared using Example 49, Step 2 intermediate and cyclopropylamine according to the coupling procedure described in Example 47, Step 3 to afford the resultant compound (62%) as a white solid; IR (KBr) 3352, 2929, 2349, 1670, 1610, 1508, 1094 cm"1; 1H NMR (300 MHz, OMSOd6) δ 0.56 (br s, 2H), 0.76 (d, J = 5.7 Hz, 2H), 0.91 (d, J= 6.9 Hz, 6H), 2.22-2.38 (m, IH), 2.82-2.96 (m, IH), 4.01 (d, J= 7.2 Hz, 2H), 7.39 (d, J= 8.1 Hz, 2H), 7.44-7.64 (m, 5H), 7.77 (d, J= 7.2 Hz, IH), 8.59 (s, IH), 9.59 (d, J= 4.5 Hz, IH).
Example 51
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-cyclopropylmethyl-N-methyl-6-oxo-6,7-dihydro- 2H-pyrazolo [3 ,4-6]pyridine-5 -carboxamide:
Step 1 : Ethyl 2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-cyclopropylmethyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-ό]pyridine-5-carboxylate: This compound was prepared from Intermediate 7 and (bromomethyl)cyclopropane according to the procedure described in Example 47, Step 1 to get the product as a white solid; IR (KBr) 2980, 1735, 1622, 1483, 1092, 833 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.45 (d, J = 6.0 Hz, 4H), 1.27 (t, J = 6.9 Hz, 3H), 1.30-1.40 (m, IH), 3.98 (br s, 2H), 4.20-4.30 (m, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.42-7.64 (m, 5H) 7.70-7.80 (m, IH), 8.19 (s, IH); ESI-MS (m/z) 483 [85%, (M+H)+].
Step 2: 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-cyclopropylmethyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-&]pyridine-5-carboxylic acid: Saponification of Step 1 intermediate afforded the acid as a white solid; IR (KBr) 3444, 3081, 1737, 1634, 1422, 804 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.51 (d, J= 6.6 Hz, 4H), 1.40 (br s, IH), 4.14 (br s, 2H), 7.43 (d, J= 6.3 Hz, 2H), 7.40-7.90 (m, 6H), 8.63 (s, IH), 14.30 (br s, IH); ESI-MS (w/z) 454.27 [100%, (M+H)+].
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; 1H ΝMR (300 MHz, DMSO-J6) δ 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).
Example 52
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-7-cyclopropylmethyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-Z?]pyridine-5-carboxamide:
The title compound was prepared from Example 51, Step 2 intermediate and cyclopropylamine according to the coupling procedure described in Example 47, Step 3 to afford the resultant compound (51%) as a white solid; IR (KBr) 3375, 2926, 2348, 1670, 1610, 1508, 832 cm"1; 1H ΝMR (300 MHz, OMSO-d6) δ 0.47 (d, J = 6.3 Hz, 4H), 0.55 (s, IH), 0.75 (d, J= 5.4 Hz, 2H), 1.03 (d, J= 6.3 Hz, IH), 1.30-1.42 (m, IH), 1.84-1.94 (m, IH), 4.04 (d, J= 6.6 Hz, 2H), 7.39 (d, J= 8.1 Hz, 2H), 7.44-7.64 (m, 4H), 7.70-7.80 (m, IH), 8.57 (s, IH), 9.59 (d, J= 4.5 Hz, 2H).
Example 53
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(isopentyl)-7V-methyl-6-oxo-6,7-dihydro-2H"- pyrazolo[3,4-ό]pyridine-5-carboxamide:
Step 1: Ethyl 2-(2-chlorophenyl)-3 -(4-chlorophenyl)-7-isopentyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-έ]pyridine-5-carboxylate: This compound was prepared from Intermediate 7 and l-bromo-3-methylbutane according to the procedure described in Example 47, Step 1 to afford the resultant compound as a white solid; IR (KBr) 3359, 2953, 1729, 1645, 1618, 1485, 1089, 833 cm"1; 1H ΝMR (300 MHz, DMSO-J6) δ 0.92 (d, J= 5.4 Hz, 6H), 1.26 (t, J= 6.9 Hz, 3H), 1.60 (s, 3H), 4.10 (br s, 2H), 4.23 (q, J= 7.8 Hz, 2H), 7.38 (d, J= 8.7 Hz, 2H), 7.45-7.70 (m, 5H), 7.75-7.90 (m, IH), 8.20 (s, IH); ESI-MS irn/z) 498.32 [43%, (M+H)+]. Step 2: 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-isopentyl-6-oxo-6,7-dihydro-2H-pyrazolo [3,4-b]pyridine-5-carboxylic acid: Saponification of Step 1 intermediate afforded the acid as a solid; IR (KBr) 3363, 2961, 2308, 1733, 1613, 1592, 1448, 1093, 741 cm"1; 1H NMR (300 MHz, DMSOtiβ) δ 0.94 (d, J= 6.0 Hz, 6H), 1.67 (s, 3H), 4.25 (br s, 2H), 7.43 (d, J- 7.8 Hz, 2H), 7.58-7.75 (m, 5H), 7.82 (d, J= 7.8 Hz, IH), 8.64 (s, IH), 14.36 (s, IH); ESI-MS (m/z) 470.65 [100%, (M+H)"1"].
Step 3: 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-isopentyl-N-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate with methylamine hydrochloride according to the procedure described in Example 47, Step 3 afforded the resultant compound (69%) as a white solid; IR (KBr) 3281, 2955, 1671, 1611, 1510, 1483, 1243, 1091, 833 cm"1; 1H NMR (300 MHz,
Figure imgf000068_0001
= 3.9 Hz, 6H), 1.63 (s, 3H), 2.84 (d, J= 4.2 Hz, 3H), 4.19 (s, 2H), 7.39 (d, J= 8.1 Hz, 2H), 7.50-7.70 (m, 5H), 7.80 (d, J= 5.7 Hz, IH), 8.59 (s, IH), 9.50 (s, IH).
Example 54
2-(2-Clilorophenyl)-3-(4-chlorophenyl)-N-methyl-7-neopentyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide:
Step 1: Ethyl 2-(2-chlorophenyl)-3 -(4-chlorophenyl)-7-neopentyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxylate: This compound was prepared from Intermediate 7 and l-bromo-2,2-dimethylpropane according to the procedure described in Example 47, Step 1 to afford the resultant compound as a white solid; IR (KBr) 3066, 2962, 1739, 1643, 1483, 1228, 1182, 1094, 824 cm 1; 1H NMR (300 MHz, DMSO-J6) δ 0.97 (s, 9H), 1.26 (t, J= 7.2 Hz, 3H), 4.00 (s, 2H), 4.22 (q, J= 6.9 Hz, 2H), 7.36 (d, J= 8.4 Hz, 2H), 7.42-7.64 (m, 5H), 7.70 (d, J= 6.9 Hz, IH), 8.16 (s, IH); ESI-MS (m/z) 499.44 [100%, (M+H)+].
Step 2: 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-neopentyl-6-oxo-6,7-dihydro-2H-pyrazolo [3,4-έ]pyridine-5-carboxylic acid: Saponification of Step 1 intermediate afforded the acid as an off-white solid; IR (KBr) 3344, 2966, 1731, 1611, 1451, 1089, 803 cm"1; 1H NMR (300 MHz, OM&O-d6) δ 1.01 (s, 9H), 4.14 (s, 2H), 7.41 (d, J= 8.4 Hz, 2H), 7.46-7.70 (m, 5H), 7.74 (d, J= 8.7 Hz, IH), 8.62 (s, IH), 14.35 (s, IH); ESI-MS (m/z) 471.35 [100 %, (M+H)+].
Step 3: 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-methyl-7-neopentyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-έ]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
1613, 1509, 1483, 1091, 798 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.99 (s, 9H), 2.84 (s, 3H), 4.09 (s, 2H), 7.30-7.42 (m, 2H), 7.44-7.64 (m, 5H), 7.64-7.80 (m, IH), 8.58 (s, IH), 9.46 (br s, IH).
Example 55
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-iV-methyl-6-oxo-7-(3,3,3-trifluoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide:
Coupling reaction of Example 45, Step 2 intermediate and methylamine hydrochloride according to the procedure described in Example 47, Step 3 afforded the desired compound (80%) as an off-white solid; IR (KBr) 3298, 2928, 1673, 1613, 1512, 1483, 1059, 797 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 2.78-2.95 (m, 5H), 4.38-4.56 (m, 2H), 7.39 (d, J= 8.1 Hz, 2H), 7.50-7.74 (m, 5H), 7.78-7.90 (m, IH), 8.61 (s, IH), 9.39 (br s, IH).
Example 56
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-ethyl-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro- 2H-pyrazolo[3,4-Z>]pyridine-5-carboxamide:
The title compound was prepared from Example 45, Step 2 intermediate and ethylamine hydrochloride according to the coupling procedure described in Example 47, Step 3 to afford the desired compound (66%) as a white solid; IR (KBr) 3286, 2932, 1671, 1610, 1510, 1481, 1095, 835 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.44 (t, J = 7.2 Hz, 3H), 2.70-2.90 (m, 2H), 3.40-3.56 (m, 2H), 4.43 (br s, 2H), 7.38 (d, J= 7.8 Hz, 2H), 7.44-7.70 (m, 5H), 7.79 (d, J= 7.2 Hz, IH), 8.60 (s, IH), 9.46 (br s, IH).
Example 57
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-iV-isopropyl-6-oxo-7-(3,3,3-trifluoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-6]pyridine-5-carboxamide:
The title compound was prepared from Example 45, Step 2 intermediate and isopropyl amine according to the coupling procedure described in Example 47, Step 3 to afford the desired compound (65%) as a white solid; IR (KBr) 3289, 2959, 1669, 1612, 1513, 1482, 1057, 837 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.19 (d, J= 6.3 Hz, 6H), 2.76-2.90 (m, 2H), 4.05 (d, J= 6.9 Hz, IH), 4.42 (t, J= 6.9 Hz, 2H), 7.38 (d, J= 8.1 Hz, 2H), 7.50-7.70 (m, 5H), 7.78 (d, J= 9.3 Hz, IH)5), 8.60 (s, IH), 9.39 (d, J= 7.8 Hz, IH).
Example 58 2-(2-Chloroρhenyl)-3 -(4-chlorophenyl)-N-cycloproρyl-6-oxo-7-(3 ,3 ,3 -trifmoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide:
The title compound was prepared from Example 45, Step 2 intermediate and cyclopropylamine according to the coupling procedure described in Example 47, Step 3 to afford the desired compound (62%) as a white solid; IR (KBr) 3277, 3065, 1682, 1613, 1511, 1095, 765 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 0.56 (s, 2H), 0.76 (d, J = 5.4 Hz, 2H), 2.62-2.94 (m, 3H), 4.41 (br s, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.50-7.68 (m, 5H), 7.78 (d, J = 6.6 Hz, IH), 8.58 (s, IH), 9.43 (d, J= 6.3 Hz, IH).
Example 58.1
3-(4-Chlorophenyl)-2-(2-chlorophenyl)-iV-cyclopropyl-6-(3,3,3-trifluoropropoxy)-2H- pyrazolo[3,4-έ»]pyridine-5-carboxamide:
Figure imgf000070_0001
This intermediate was obtained as a regiomer (72%) of Example 58 as a white solid; IR (KBr) 2986, 1698, 1622, 1275, 1155, 832 cm4; 1H NMR (300 MHz, DMSO-J6) δ 1.29 (t, J= 7.2 Hz, 3H), 2.80-2.98 (m, 2H), 4.26 (q, J= 8.4 Hz, 2H), 4.65 (t, J= 5.7 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.45-7.65 (m, 5H), 7.78 (d, J= 6.9 Hz, 2H), 8.51 (s, IH).
Example 59
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-(2-fluoroethyl)-6-oxo-7-(3,3,3-trifluoroproρyl)- 6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide:
The title compound was prepared from Example 45, Step 2 intermediate and 2- fluoroethylamine hydrochloride according to the coupling procedure described in Example 47, Step 3 to afford the desired compound (65%) as a white solid; IR (KBr) 3287, 3066, 2925, 1672, 1612, 1512, 1484, 1094, 834 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 2.70-2.90 (m, 2H), 3.64-3.76 (m, IH), 3.78-3.90 (m, IH), 4.40-4.60 (m, 3H), 4.60-4.76 (m, IH), 7.30- 7.44 (m, 2H), 7.45-7.70 (m, 5H), 7.70-7.90 (m, IH), 8.62 (br s, IH), 9.71 (br s, IH).
Example 60 3
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-iV-[2-(dimethylamino)ethyl]-6-oxo-7-(3,3,3- trifluoropropyl)-6,7-dihydro-2H-pyrazolo[3,4-&]ρyridine-5-carboxamide:
The title compound was prepared from Example 45, Step 2 intermediate and iV^/V-dimethyl ethylenediamine according to the coupling procedure described in Example 47, Step 3 (35%) as a white solid; IR (KBr) 3275, 2946, 2372, 1671, 1610, 1508, 1483, 1096, 794 cm'1; 1H NMR (300 MHz, DMSO-Je) δ 2.18 (s, 7H), 2.74-2.92 (m, 3H), 3.56 (d, J= 6.6 Hz, 2H), 4.43 (br s, 2H), 7.37 (d, J= 7.8 Hz, 2H), 7.44-7.70 (m, 5H), 7.74-7.86 (m, IH), 8.60 (s, IH), 9.55 (br s, IH).
Example 61
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-methoxyethyl)-A/-methyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-&]pyridine-5-carboxamide:
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: IR (KBr) 3368, 2926, 1736, 1622, 1644, 1483, 1090, 797 cm4; 1H NMR (300 MHz, DMSO-J6) δ 1.18-1.30 (m, 3H), 3.25 (s, 3H), 3.64-3.76 (m, 2H), 4.10-4.35 (m, 4H), 7.36 (d, J= 8.1 Hz, 2H), 7.45-7.68 (m, 5H), 7.74-7.84 (m, IH), 8.20 (s, IH); ESI-MS (m/z) 486.69 [100%, (IVH-H)+].
Step 2: 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-methoxyethyl)-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxylic acid: Saponification of Step 1 intermediate afforded the acid as a light yellow solid: IR (KBr) 3369, 2922, 1732, 1610, 1454, 1090, 800 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 3.25 (s, 3H), 3.64-3.80 (m, 2H), 4.36-4.50 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.50-7.70 (m, 5H), 7.80 (d, J = 7.2 Hz, IH), 8.62 (s, IH), 14.20 (br s, IH); ESI-MS (m/z) 458.30 [100%, (MH-H)+].
Step 3: 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-methoxyethyl)-iV-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-δ]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; 1H NMR (300 MHz, DMSO-J6) δ 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 s, IH). Example 62
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-7-(2-methoxyethyl)-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-δ]pyridine-5-carboxamide:
The title compound was prepared from Example 61, Step 2 intermediate and cyclopropylamine according to the coupling procedure described in Example 47, Step 3 to give the product (76%) as a white solid; IR (KBr) 3268, 2924, 1681, 1614, 1510, 1484, 1118, 835 cm'1; 1H ΝMR (300 MHz, DMSO-J6) δ 0.55 (s, 2H), 0.75 (d, J= 7.2 Hz, 2H), 2.87 (br s, IH), 3.24 (s, 3H), 3.71 (s, 2H), 4.35 (br s, 2H), 7.38 (d, J = 7.5 Hz, 2H), 7.44-7.64 (m, 5H), 7.78 (d, J= 7.5 Hz, IH), 8.57 (s, IH), 9.54 (s, IH).
Example 63
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-ethoxyethyl)-7V-methyl-6-oxo-6,7-dihydro-2H- pvrazolo[3,4-Z>]pyridine-5-carboxamide:
Step 1: Ethyl 2-(2-chlorophenyl)-3 -(4-chlorophenyl)-7-(2-ethoxyethyl)-6-oxo-6,7-dihydro- 2H"-pyrazolo[3,4-δ]pyridine-5-carboxylate: This compound was prepared from Intermediate 7 and 2-bromoethyl ethyl ether according to the procedure described in Example 47, Step 1 to afford the resultant compound as an off-white solid; IR (KBr) 2975, 1732, 1623, 1483, 1179, 1098 cm-1; 1H ΝMR (300 MHz, DMSO-J6) δ 1.04 (t, J = 7.5 Hz, 3H), 1.26 (t, J= 7.8 Hz, 3H), 3.45 (q, J = 5.7 Hz, 2H), 3.69 (br s, 2H), 4.20-4.30 (m, 4H), 7.36 (d, J = 8.1 Hz, 2H), 7.45-7.65 (m, IH), 7.70-7.80 (m, 5H), 8.19 (s, IH); ESI-MS (rø/z) 500.09 [5 %, (M+H)+].
Step 2: 2-(2-Chloroρhenyl)-3-(4-chlorophenyl)-7-(2-ethoxyethyl)-6-oxo-6,7-dihydro-2H'- pyrazolo[3,4-6]pyridine-5-carboxylic acid: Saponification of Step 1 intermediate afforded the acid as an off-white solid; IR (KBr) 3446, 3066, 1725, 1613, 1482, 1120, 1093, 837 cm"1; 1H ΝMR (300 MHz, DMSO-J6) δ 1.02 (t, J= 7.2 Hz, 3H), 3.20-3.58 (m, 3H), 3.78 (s, IH), 4.41 (s, 2H), 7.30-7.70 (m, 7H), 7.80 (d, J = 6.3 Hz, IH), 8.62 (s, IH), 14.22 (s, IH); ESI-MS (m/z) 470.30 [100 %, (M-H)"].
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; 1H ΝMR (300 MHz, DMSO-J15) δ 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), 9.43 (s, IH).
Example 64
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-ethoxyethyl)-N-isopropyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-&]pyridine-5-carboxamide:
The title compound was prepared from Example 63, Step 2 intermediate and isopropylamine according to the coupling procedure described in Example 47, Step 3 to afford the resultant compound (56%) as an off-white solid; IR (KBr) 3275, 2970, 1667, 1609, 1510, 1116, 1093, 742 cm"1; 1H NMR (300 MHz, DMSOd6) δ 1.03 (t, J= 6.9 Hz, 3H), 1.19 (d, J= 6.3 Hz, 6H), 3.46 (q, J= 6.9 Hz, 2H), 3.65-3.75 (m, 2H), 4.00-4.10 (m, IH), 4.34 (s, 2H), 7.38 (d, J= 8.7 Hz, 2H), 7.50-7.65 (m, 5H), 7.78 (d, J= 5.4 Hz, IH), 8.59 (s, IH), 9.50 (d, J= 7.2 Hz, IH).
Example 65
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-cyanoethyl)-N-methyl-6-oxo-6,7-dihydro-2H- pyrazolo [3 ,4-6]pyridine- 5 -carboxamide:
Step 1: Ethyl 2-(2-chlorophenyl)-3 -(4-chlorophenyl)-7-(2-cyanoethyl)-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-5]pyridine-5-carboxylate: This compound was prepared from Intermediate 7 and 3-bromopropionitrile according to the procedure described in Example 47, Step 1 to afford the resultant compound as an off-white solid; IR (KBr) 3067, 2978, 2250, 1735, 1621, 1483, 1243, 1092, 836 cm"1; 1H NMR (300 MHz, DMSC-d6) δ 1.20-1.30 (m, 3H)5 3.05 (t, J= 6.9 Hz, 2H), 4.16-4.30 (m, 2H), 4.35 (t, J= 6.6 Hz, 2H), 7.37 (d, J= 9.0 Hz, 3H), 7.44-7.64 (m, 4H), 7.76 (d, J= 6.9 Hz, IH), 8.26 (s, IH); ESI-MS (m/z) 481.26 [100 %, (M+H)+].
Step 2: 2-(2-Chlorophenyl)-3-(4-chloroρhenyl)-7-(2-cyanoethyl)-6-oxo-6,7-dihydro-2Hr- pyrazolo[3,4-δ]pyridine-5-carboxylic acid: Saponification of Step 1 intermediate afforded the acid as a white solid; IR (KBr) 3358, 2928, 2252, 1730, 1614, 1443, 1092, 741 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 3.13 (t, J = 6.3 Hz, 2H), 4.44-4.56 (m, 2H), 7.36-7.50 (m, 2H)5 7.54-7.70 (m, 5H), 7.81 (d, J= 6.9 Hz, IH), 8.62 (s, IH)5 13.29 (s, IH); ESI-MS (m/z) 453 [93 %, (M+H)+].
Step 3: 2-(2-Chloroρhenyl)-3-(4-chlorophenyl)-7-(2-cyanoethyl)-N-methyl-6-oxo-6,7- dihydro-2H-ρyrazolo[3,4-b]pyridme-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 (30%) as an off-white solid; IR (KBr) 3309, 2927, 2249, 1675, 1612, 1513, 1479, 1093, 843 cm"1; 1H NMR (300 MHz, DMSO-^6) δ 2.85 (d, J= 3.9 Hz, 3H), 3.08 (s, 2H), 4.44 (s, 2H), 7.39 (d, J= 7.2 Hz, 2H), 7.50-7.65 (m, 5H), 7.70-7.82 (m, IH), 8.60 (s, IH), 9.33 (s, IH).
Example 66
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-cyanoethyl)-N-cyclopropyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-b]pyridine-5-carboxamide:
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; 1H NMR (300 MHz, DMSO-J6) δ 0.55 (tar s, 2H), 0.76 (d, J = 2.4 Hz, 2H), 2.88 (tar s, IH), 3.07 (s, 2H), 4.43 (s, 2H), 7.36-7.70 (m, 7H), 7.77 (br s, IH), 8.60 (s, IH), 9.43 (s, IH).
Example 67
2-(2-Chlorophenyl)-3 -(4-chlorophenyl)-N,7V-dimethyl-6-oxo-7-(3 ,3 ,3 -trifluoropropyl)-6,7- dihydro-27i-pyrazolo[3,4-Z?]pyridine-5-carboxamide:
Figure imgf000074_0001
The title compound was prepared from Example 45, Step 2 intermediate and dimethylamine hydrochloride according to the coupling procedure described in Example 47, Step 3 to afford the resultant compound (54%) as an off-white solid; IR (KBr) 2929, 1641, 1484, 1399, 1245, 1149, 1093, 838 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 2.70-2.86 (m, 6H), 2.86-3.00 (m, 3H), 4.36 (br s, 2H), 7.32 (br s, 2H), 7.40-7.64 (m, 4H), 7.68-7.80 (m, 2H); ESI-MS (m/z) 523.42 [100 %, (M+H)+].
Example 68
2,3-bis(4-Chlorophenyl)-6-oxo-7-(3 ,3 ,3 -trifluoroρropyl)-6,7-dihydro-2H-pyrazolo[3 t4-b] pyridine-5-carboxamide:
Figure imgf000075_0001
Step 1 : Ethyl 2,3-bis(4-chlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxylate: Prepared from Intermediate 8 (0.85 g, 1.984 mmol), l,l,l-trifluoro-2-iodoethane (0.34 ml, 2.946 mmol) and Cs2CO3 (1.61 g, 4.962 mmol) in anhydrous DMF (10 ml) according to the procedure described in Example 45, Step 1 to afford 0.725 g of the product as a light yellow solid; IR (KBr) 3075, 2983, 1742, 1625, 1492, 1094, 829 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.26 (t, J = 7.2 Hz, 3H), 2.78-2.90 (m, 2H), 4.22 (q, J = 6.6 Hz, 2H), 4.30-4.42 (m, 2H), 7.42 (br s, 4H), 7.55 (t, J = 8.4 Hz, 4H), 8.17 (s, IH); ESI-MS (m/z) 524.15 [55 %, (M-H)"].
Step 2: 2,3-bis(4-Chlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro-2/J-pyrazolo [3,4-&]pyridine-5-carboxylic acid: Hydrolysis of Step 1 intermediate (0.7 g, 1.335 mmol) using 1 NKOH (2.5 ml) in methanol (7 ml) according to procedure described in Intermediate 3, Step 4 to give 0.61 g of the product as an off-white solid; IR (KBr) 3070, 2580, 1726, 1618, 1456, 1159, 836 cm"1; 1H ΝMR (300 MHz5 DMSO-J6) δ 2.80-3.00 (m, 2H), 4.40-4.48 (m, 2H), 7.45 (d, J= 8.4 Hz, 4H), 7.59 (t, J= 6.6 Hz, 4H), 8.54 (s, IH), 13.96 (br s, IH); ESI- MS (m/z) 496 [93 %, (M+H)+].
Step 3: 2,3-bis(4-Chlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro-2H-pyrazolo [3,4-b]pyridme-5-carboxamide: Coupling reaction of Step 2 intermediate (0.1 g, 0.201 mmol) using EDCI hydrochloride (0.046 g, 0.241 mmol), HOBt (0.032 g, 0.241 mmol) and 25% aqueous ammonia (0.057 ml) in DCM (5 ml) according to the procedure described in Example 1 afforded 0.04 g of the product as an off-white solid; IR (KBr) 3339, 3100, 1684, 1491, 1252, 837 cm"1; 1H ΝMR (300 MHz, DMSO-J15) δ 2.80-2.96 (m, 2H), 4.40-4.56 (m, 2H), 7.42 (d, J= 8.4 Hz, 4H), 7.50-7.65 (m, 4H), 7.75 (s, IH), 8.53 (s, IH), 8.83 (s, IH); ESI- MS (m/z) 495 [73 %, (M+H)+].
Example 69
2,3-bis(4-Chloroρhenyl)-N-cyclopropyl-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide:
Figure imgf000076_0001
The title compound was prepared from Example 68, Step 2 intermediate and cyclopropyl amine according to the procedure described in Example 47, Step 3 to afford the resultant compound (70%) as an off-white solid; IR (KBr) 3270, 3057, 2923, 1674, 1612, 1511, 1095, 836 cm"1; 1H NMR (300 MHz, DMSO-^) δ 0.56 (s, 2H), 0.76 (d, J= 6.9 Hz, 2H), 2.86 (s, 3H), 7.38-7.50 (m, 2H)5 7.42 (d, J= 7.2 Hz, 4H), 7.50-7.65 (m, 4H), 8.50 (s, IH), 9.45 (s, IH); ESI-MS (m/z) 535.18 [100 %, (M+H)+].
Example 70
N-tert-Butyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro-2H-pyrazolo[3,4- b]pyridine-5 -carboxamide:
Figure imgf000076_0002
Step 1: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-έ] 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). Resulting precipitated solid was filtered and dissolved in ethyl acetate (50 ml) and washed with water (30 ml), brine (30 ml) and dried (Na2SO4). Concentration under reduced pressure afforded 0.47 g of the product as a white solid; IR (KBr) 3187, 2966, 1739, 1634, 1481, 1257, 1142, 1095, 830 cm"1; 1H NMR (300 MHz, DMSO-^5) δ 7.43 (d, J= 8.4 Hz, 3H), 7.58 (d, J= 8.4 Hz, IH), 7.68 (dd, J= 1.8, 1.8 Hz, IH), 7.81-7.95 (m, 2H), 8.65 (s, IH), 13.54 (s, IH), 14.53 (s, IH); ESI-MS (m/z) 436.54 [100%, (MH-H)+].
Step 2: N-(tert-Butyl)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro-2H- ρyrazolo[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
at room temperature. The resulting mixture was refluxed under nitrogen atmosphere for 4 h. After this time, the reaction mixture was cooled to room temperature and solvent was evaporated under reduced pressure to get 0.09 g of 3-(4-chlorphenyl)-2-(2,4-dichlorophenyl)- 6-oxo-6,7-dihydro-2H-pyrazolo[3,4-b]pvridine-5-carbonylchloride as a white solid. A suspension of 3-(4-chlorphenyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro-2H"-pyrazolo[3 ,4- b]pyridine-5-carbonylchloride (0.09 g, 0.198 mmol) in dichloromethane (20 ml) was added dropwise to a solution of tert-butyl amine (0.031 ml, 0.032 mmol) and triethylamine (0.098 ml, 0.692 mmol) in anhydrous dichloromethane (20 ml) at 0 0C. Reaction mixture was allowed to stir at room temperature overnight under nitrogen atmosphere. After this time, reaction mixture was diluted with dichloromethane (10 ml) and washed with water (20 ml), brine (20 ml) and dried (Na2SO4). Concentration under reduced pressure afforded 0.035 g of the product as an off-white solid; IR (KBr) 3308, 2967, 1678, 1629, 1481, 1226, 1094, 830 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 1.37 (s, 9H), 7.39 (d, J= 8.4 Hz, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, IH), 7.80-7.91 (m, 2H), 8.60 (s, IH), 9.70 (s, IH), 12.73 (s, IH); ESI-MS (m/z) 438.26 [100 %, M+H)+].
Example 71
3-(4-Chloroρhenyl)-2-(2,4-dichlorophenyl)-N-(2-hydroxy- 1 , 1 -dimethylethyl)-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-&]pyridine-5-carboxamide:
Figure imgf000077_0001
The title compound was prepared from Example 70, Step 1 intermediate and 2-amino-2- methylpropan-1-ol according to the procedure described in Example 70, Step 2 to give the product (34%) as an off-white solid; IR (KBr) 3292, 2966, 1672, 1615, 1563, 1480, 1266, 1094, 832 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.30 (s, 6H), 3.46 (d, J= 5.4 Hz, 2H), 5.01 (br s, IH), 7.39 (d, J= 8.1 Hz, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.66 (d, J= 9.0 Hz, IH), 7.80- 7.89 (m, 2H), 8.59 (s, IH), 9.75 (s, IH), 12.69 (s, IH); ESI-MS (m/z) 505.59 [100%, (M+H)+].
Example 72
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoroproρyl)-6,7-dihydro-2H- pyrazolo[3,4-&]pyridine-5-carbonitrile:
Figure imgf000078_0001
Step 1 : Ethyl 3-(4-chloroρhenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoroproρyl)-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. The resulting suspension was stirred at 80 °C overnight. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (25 ml) and the layers were separated. The organic layer was washed with water (50 ml), brine (50 ml) and dried Na2SO4 to afford 0.107 g of major product, ethyl 3-(4- chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(2,2,2-trifiuoropropyl)-6,7-dihydro-2H- pyrazolo[3,4-Z>]pyridine-5-carboxylate as a white solid; IR (KBr) 3453, 2982, 1738, 1652, 1483, 1253, 1148, 1096, 828 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 1.27 (t, J= 7.2 Hz, 3H), 2.70-2.90 (m, 2H), 4.25 (q, J= 6.9 Hz, 2H), 4.35 (t, J= 5.4 Hz, 2H), 7.40 (d, J= 8.1 Hz, 2H), 7.57 (d, J= 7.8 Hz, 2H), 7.60-7.70 (m, IH), 7.80-7.90 (m, 2H), 8.27 (s, IH); along with 0.014 g of other regiomer ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-(2,2,2- trifluoropropoxy)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate as an off-white solid; IR (KBr) 3454, 2960, 1722, 1626, 1483, 1504, 1330, 1250, 1152, 1078, 830 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.30 (t, J= 6.9 Hz, 3H), 2.80-3.00 (m, 2H), 4.29 (q, J= 6.9 Hz, 2H), 4.67 (t, J= 5.4 Hz, 2H), 7.42 (d, J= 8.4 Hz, 2H), 7.56 (d, J= 8.1 Hz, 2H), 7.62-7.72 (m, IH), 7.82-7.95 (m, 2H), 8.54 (s, IH); ESI-MS (m/z) 559.70 [100%, (M+H)+].
Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-&]pyridine-5-carboxyric acid: Hydrolysis of Step 1 major intermediate (0.105 g, 0.188 mmol) using INKOH (0.5 ml) in methanol (2 ml) according to procedure described in Intermediate 3, Step 4 to give 0.097 g of the product as a white solid; IR (KBr) 3437, 3096, 1732, 1618, 1483, 1151, 1097, 804 cm'1; 1H NMR (300 MHz, DMSO- d6) δ 2.80-3.00 (m, 2H), 4.48 (t, J= 5.7 Hz, 2H), 7.46 (d, J= 9.0 Hz, 2H), 7.60 (d, J= 8.4 Hz, 2H), 7.60-7.80 (m, IH), 7.82-8.00 (m, 2H), 8.64 (s, IH), 13.95 (s, IH); ESI-MS (m/z) 529.12 [100%, (M-H)-]. 009/000083
Step 3: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoroproρyl)-6,7- dihydro-2H-pyrazolo[3,4-δ]pyridine-5-carboxamide: Coupling of Step 2 intermediate (0.045 g, 0.085 mmol) using EDCI hydrochloride (0.019 g, 0.099 mmol), HOBt (0.014 g, 0.104 mmol) with 25% solution of ammonia in water (0.019 ml) in dichloromethane according to procedure described in Example 1 gave 0.027 g of the product as a white solid; 1H NMR (300 MHz, DMS(We) δ 2.70-2.90 (m, 2H), 4.44 (t, J= 7.2 Hz, 2H), 7.42 (d, J= 8.7 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.68 (dd, J= 9.0, 2.4 Hz, IH), 7.75-7.85 (m, 2H), 7.90 (d, J= 2.4 Hz, IH), 8.64 (s, IH), 8.84 (br s, IH); ESI-MS Qn/z) 530.12 [100%, (M+H)+].
Step 4: 3-(4-Chloroρhenyl)-2-(2,4-dichloroρhenyl)-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; IR (KBr) 3435, 3092, 2230, 1659, 1619, 1483, 1147, 1095, 801 cm"1; 1H NMR (300 MHz, DMSO-^6) δ 2.70-2.90 (m, 2H), 4.34 (t, J= 6.3 Hz, 2H), 7.42 (d, J= 8.4 Hz, 2H), 7.56 (d, J= 8.4 Hz, 2H), 7.69 (dd, J= 9.0 Hz, 2.1 Hz, IH), 7.87 (d, J= 8.7 Hz, IH), 7.90 (d, J= 2.1 Hz, IH), 8.75 (s, IH); ESI-MS (m/z) 512.73 [100%, (M+H)+],
Example 73
3-(4-Chlorophenyl)-2-(2,4-dichloroρhenyl)-N,7-dimethyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-&]pyridine-5-carboxamide:
Figure imgf000079_0001
Step 1: Ethyl 3 -(4-chloroρhenyl)-2-(2,4-dichlorophenyl)-7-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-6]pyridine-5-carboxylate: Prepared from Intermediate 9 (0.1 g, 0.216 mmol), iodomethane (0.027 ml, 0.429 mmol) and cesium carbonate (0.21 g, 0.644 mmol) in anhydrous dimethylformamide (3 ml) according to the procedure described in Example 45, Step 1 to afford 0.07 g of the product as an off-white solid; IR (KBr) 2960, 1733, 1651, 1485, 1098, 817 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 1.30 (t, J= 3.0 Hz, 3H), 3.50 (s, 3H), 4.23 (q, J= 6.6 Hz, 2H), 7.39 (d, J= 8.7 Hz, 2H), 7.55 (d, J= 8.1 Hz, 2H), 7.65 (d, J= 9.3 Hz, IH), 7.86 (br s, 2H), 8.22 (s, IH); ESI-MS (m/z) 478.70 [46%, (M+H)+]. Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-methyl-6,7-dihydro-2H-pyrazolo [3,4-6]pyridine-5-carboxylic acid: Hydrolysis of Step 1 intermediate (0.06 g, 0.126 mmol) using INKOH (0.25 ml) in methanol (2 ml) according to procedure described in Intermediate 3, Step 4 to give 0.053 g of the product as an off-white solid; IR (KBr) 3091, 2924, 1724, 1614, 1482, 1096, 803 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 3.65 (s, 3H), 7.42 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.67 (d, J= 9.0 Hz, IH), 7.86 (d, J= 3.0 Hz, 2H), 8.61 (s, IH), 13.43 (s, IH); ESI-MS (m/z) 462.15 [100 %, (M+H)+j.
Step 3: 3-(4-Chloroρhenyl)-2-(2,4-dichloroρhenyl)-N,7-dimethyl-6-oxo-6,7-dihydro-2JH- pyrazolo[3,4-έ]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate (0.045 g, 0.101 mmol) using BOP reagent (0.049 g, 0.112 mmol), triethylamine (0.14 ml, 0.988 mmol) and methylamine hydrochloride (0.0075 g, 0.111 mmol) in DMF (3 ml) according to the procedure described in Example 2 afforded 0.038 g of the product as an off-white solid; IR (KBr) 3341, 2932, 1666, 1609, 1093, 815 cm"1; 1H ΝMR (300 MHz, DMSO-^) δ 2.85 (d, J = 4.5 Hz, 3H), 3.59 (s, 3H), 7.41 (d, J= 8.4 Hz, 2H), 7.59 (d, J= 8.1 Hz, 2H), 7.66 (d, J= 9.0 Hz, IH), 7.86-7.95 (m, 2H), 8.59 (s, IH), 9.48 (d, J = 4.2 Hz, IH); ESI-MS (m/z) 461.37 [80%, (M+H)+].
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.
Table 4: Structural details of Examples 74-89
Figure imgf000080_0001
Figure imgf000081_0001
Example 74
3-(4-Chlorophenyl)-7-cyclopropylmethyl-2-(2,4-dichlorophenyl)-iV-methyl-6-oxo-6,7- dihydro-2ϋT-pyrazolo[3,4-ό]pyridine-5-carboxamide:
Step 1 : Ethyl 3 -(4-chlorophenyl)-7-cyclopropylmethyl-2-(2,4-dichlorophenyl)-6-oxo-6,7- dihydro-2//-pyrazolo[3,4-Zj]pyridine-5-carboxylate: This compound was prepared from Intermediate 9 and (bromomethyl)cyclopropane in presence of cesium carbonate according to the procedure described in Example 45, Step 1 to afford the resultant compound as an off- white solid; 1H NMR (300 MHz, DMSO-J6) δ 0.46 (d, J= 4.8 Hz, 4H), 1.28 (t, J= 6.6 Hz, 3H), 1.30-1.40 (m, IH), 3.98 (d, J= 6.9 Hz, 2H), 4.25 (q, J= 7.5 Hz, 2H), 7.41 (d, J= 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.65 (dd, J = 8.7, 2.4 Hz, IH), 7.83 (d, J= 8.4 Hz, IH), 7.88 (d, J= 2.1 Hz, IH), 8.22 (s, IH); ESI-MS (m/z) 524.32 [100%, (M+H)+].
Step 2: 3-(4-Chlorophenyl)-7-cyclopropylmethyl-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-δ]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; IR (KBr) 2924, 1727, 1622, 1482, 1095, 803 cm"1; 1H NMR (300 MHz, DMSO- d6) δ 0.51 (d, J= 6.0 Hz, 4H), 1.35-1.45 (m, IH), 4.14 (d, J= 7.2 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.61 (d, J= 8.1 Hz, 2H), 7.69 (dd, J = 9.0, 1.5 Hz, IH), 7.88 (d, J = 8.4 Hz, IH), 7.92 (d, J= 1.8 Hz, IH), 8.66 (s, IH), 14.30 (s, IH); ESI-MS (m/z) 489.46 [100%, (M+H)+].
Step 3: 3-(4-Chlorophenyl)-7-cyclopropylmethyl-2-(2,4-dichlorophenyl)-iV;-methyl-6-oxo- 6,7-dihydro-2/f-pyrazolo[3,4-b]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate and methylamine hydrochloride according to the procedure described in Example 2 afforded the desired compound (20%) as a white solid; 1H NMR (300 MHz, DMSO-J6) δ 0.48 (d, J= 6.3 Hz, 4H), 1.25-1.35 (m, IH), 2.87 (d, J= 4.5 Hz, 3H), 4.08 (d, J = 6.9 Hz5 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.60 (d, J= 8.1 Hz, 2H), 7.62-7.70 (m, IH), 7.85 (d, J = 8.7 Hz, IH), 7.89 (d, J = 1.8 Hz, IH), 8.61 (s, IH), 9.50 (q, J = 5.1 Hz, IH); ESI-MS (m/z) 502.59 [100%, (M+H)+].
Example 75
7-Butyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-&]pyridme-5-carboxamide:
Step 1 : Ethyl 7-butyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro-2i7- pyrazolo[3,4-δ]pyridine-5-carboxylate: This compound was prepared from Intermediate 9 and 1-bromobutane according to the procedure described in Example 45, Step 1 to afford the resultant compound as an off-white solid; IR (KBr) 3080, 2959, 1733, 1644, 1482, 1092, 828 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.90 (t, J= 7.5 Hz, 3H), 1.26 (t, J= 7.5 Hz, 3H), 1.33 (q, J= 10.2 Hz, 2H), 1.69 (t, J= 7.8 Hz, 2H), 4.08 (t, J= 9.0 Hz, 2H), 4.23 (q, J= 7.5 Hz, 2H), 7.39 (d, J= 8.7 Hz, 2H), 7.55 (d, J= 8.4 Hz, 2H), 7.64 (dd, J= 1.5, 1.5 Hz, IH), 7.80- 7.90 (m, 2H), 8.20 (s, IH); ESI-MS (m/z) 518.54 [100%, (MH-H)+].
Step 2: 7-Butyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro-2H-pyrazolo [3,4-&]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: IR (KBr) 3090, 2926, 1724, 1620, 1482, 1090, 804 cm4; 1H NMR (300 MHz, DMSO-J6) δ 0.92 (t, J= 7.2 Hz, 3H), 1.36 (d, J= 7.2 Hz, 2H), 1.62-1.82 (m, 2H), 4.18-4.35 (m, 2H), 7.45 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.68 (d, J= 8.4 Hz, IH), 7.88 (d, J = 8.1 Hz, 2H), 8.63 (s, IH), 14.32 (s, IH); ESI-MS (m/z) 492.60 [100%, (M+H)+].
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: IR (KBr) 3293, 2934, 1664, 1609, 1519, 1092, 837 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.91 (t, J = 7.8 Hz, 3H), 1.33 (q, J= 7.2 Hz, 2H), 1.73 (t, J= 7.2 Hz, 2H), 2.85 (d, J= 4.8 Hz, 3H), 4.18 (t, J = 6.9 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.58 (d, J= 8.4 Hz, 2H)5 7.66 (dd, J= 2.4, 1.8 Hz, IH), 7.84-7.90 (m, 2H), 8.58 (s, IH), 9.49 (d, J= 5.1 Hz, IH).
Example 76 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-isobutyl-iV-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-δ]pyridine-5-carboxamide:
Step l: Ethyl 3 -(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-isobutyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-&]pyridine-5-carboxylate: This compound was prepared from Intermediate 9 and l-bromo-2-methylpropane according to the procedure described in Example 45, Step 1 to afford the resultant compound as an off-white solid; IR (KBr) 2926, 1732, 1639, 1485, 1182, 1093, 837 cm"1; 1H NMR (300 MHz, DMS(MJ) δ 0.90 (d, J= 6.6 Hz, 6H), 1.27 (t, J= 6.9 Hz, 3H), 2.20-2.35 (m, IH), 3.94 (d, J = 6.9 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.56 (d, J= 8.7 Hz, 2H), 7.60-7.70 (m, IH), 7.83 (d, J= 8.7 Hz, IH), 7.86 (d, J = 1.8 Hz, IH), 8.22 (s, IH); ESI-MS (m/z) 520.35 [100%, (M+H)+].
Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-isobutyl-6-oxo-6,7-dihydro-2/f- pyrazolo[3,4-Z>]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; IR (KBr) 3092, 2927, 1733, 1623, 1481, 1094, 834 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.92 (d, J = 6.6 Hz, 6H), 2.25-2.40 (m, IH), 4.10 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.60 (d, J= 8.4 Hz, 2H), 7.68 (dd, J= 9.0, 2.1 Hz, IH), 7.88 (d, J= 8.4 Hz, IH), 7.90 (d, J= 2.1 Hz, IH), 8.66 (s, IH), 14.33 (s, IH); ESI-MS (m/z) 492.25 [100%, (M+H)+].
Step 3: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-isobutyl-iV-methyl-6-oxo-6,7-dihydro- 2if-pyrazolo[3,4-έ]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate and methylamine hydrochloride according to the procedure described in Example 2 afforded the desired compound (50%) as a white solid; IR (KBr) 3278, 2962, 1670, 1616, 1510, 1093, 832 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.94 (d, J= 6.6 Hz, 6H), 2.20-2.40 (m, IH), 2.86 (d, J= 4.2 Hz, 3H), 7.42 (d, J = 8.4 Hz, 2H), 7.60 (d, J= 8.4 Hz, 2H), 7.60 (d, J= 8.4 Hz, 2H), 7.66 (dd, J= 9.0, 2.1 Hz, IH), 7.86 (d, J= 8.7 Hz, IH), 7.88 (d, J= 2.1 Hz, IH), 8.61 (s, IH), 9.50 (q, J= 4.5 Hz, IH).
Example 77
3-(4-Chlorophenyl)-2-(2,4-dichloroρhenyl)-7-isopentyl-N-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-δ]pyridine-5-carboxamide:
Step 1 : Ethyl 3-(4-chloroρhenyl)-2-(2,4-dichloroρhenyl)-7-isoρentyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-6]ρyridine-5-carboxylate: This compound was prepared from Intermediate 9 and l-bromo-3-methylbutane in presence of cesium carbonate according to the procedure described in Example 45, Step 1 to afford the resultant compound as an off-white solid; IR (KBr) 3089, 2926, 1732, 1639, 1485, 1182, 1093, 837 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.92 (d, J= 4.2 Hz, 6H), 1.26 (t, J= 6.9 Hz, 3H), 1.59 (br s, 3H), 4.10 (br s, 2H), 4.23 (q, J = 6.9 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 7.8 Hz, IH), 7.84 (d, J= 12.0 Hz, 2H), 8.20 (s, IH); ESI-MS (m/z) 532.49 [100%, (M+H)+].
Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-isopentyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-&]pyridine-5-carboxyric acid: Saponification of Step 1 intermediate according to the procedure described in Intermediate 3, Step 4 afforded the acid as an off-white solid; IR (KBr) 2927, 1733, 1623, 1481, 1384, 1094, 834 cm'1; 1H NMR (300 MHz, DMSOd6) δ 0.94 (d, J= 5.7 Hz, 6H), 1.58-1.79 (m, 4H), 4.19-4.30 (m, IH), 7.42 (d, J= 8.7 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.80-7.96 (m, IH), 7.86 (d, J= 10.8 Hz, 2H), 8.61 (s, IH), 14.26 (br s, IH); ESI-MS (m/z) 506.20 [100%, (M+H)+].
Step 3: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-isopentyl-7V-methyl-6-oxo-6,7-dihydro- 2/J-pyrazolo[3,4-δ]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate and methylamine hydrochloride according to the procedure described in Example 2 afforded the desired compound (85%) as a white solid; IR (KBr) 3322, 2931, 1676, 1613, 1524, 1257, 1095, 835 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.93 (d, J= 4.2 Hz, 6H), 1.63 (br s, 3H), 2.84 (d, J= 3.9 Hz, 3H), 4.19 (br s, 2H), 7.41 (d, J= 7.8 Hz, 2H), 7.58 (d, J= 7.8 Hz, 2H), 7.66 (d, J= 7.8 Hz, IH), 7.86 (d, J= 9.6 Hz, 2H), 8.58 (s, IH), 9.49 (br s, IH).
Example 78
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7Y-methyl-7-neopentyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-έ]pyridme-5-carboxamide:
Step 1 : Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-neopentyl-6-oxo-6,7-dihydro-2/J- pyrazolo[3,4-Z?]pyridine-5-carboxylate: Prepared from Intermediate 9 and l-bromo-2,2- dimethyl propane in presence of cesium carbonate according to the procedure described in Example 45, Step 1 to afford the resultant compound as an off-white solid; IR (KBr) 3089, 2926, 1735, 1625, 1483, 1095, 824 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 0.98 (s, 9H), 1.27 (t, J= 7.2 Hz, 3H), 4.01 (s, 2H), 4.24 (q, J= 7.5 Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.60-7.70 (m, IH), 7.80 (d, J= 9.0 Hz, IH), 7.85-7.90 (m, IH), 8.19 (s, IH); ESI-MS (m/z) 532.23 [100%, (M+H)+].
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
the procedure described in Intermediate 3, Step 4 afforded the acid as an off-white solid; IR (KBr) 2924, 1727, 1622, 1482, 1095, 803 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 0.90 (d, J = 6.6 Hz, 9H), 2.24-2.45 (m, IH), 4.12 (d, J= 7.8 Hz, IH), 7.48 (d, J= 8.4 Hz, 2H), 7.62 (d, J= 8.4 Hz, 2H), 7.68 (dd, J= 9.0, 2.1 Hz, IH), 7.88 (d, J= 8.4 Hz, IH), 7.90 (d, J= 2.1 Hz, IH), 8.62 (s, IH), 14.30 (s, IH); ESI-MS (m/z) 506.57 [100%, (M+H)+].
Step 3: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-7-neopentyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-&]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate and methylamine hydrochloride according to the procedure described in Example 2 afforded the desired compound (71%) as a white solid; 1H NMR (300 MHz, DMSO-^5) δ 1.00 (s, 9H), 2.86 (d, J= 4.2 Hz, 3H), 4.11 (s, 2H), 7.42 (d, J= 8.1 Hz, 2H)5 7.60 (d, J= 8.4 Hz, 2H), 7.65- 7.70 (m, IH), 7.81 (d, J= 9.0 Hz, IH), 7.85-7.95 (m, IH), 8.60 (s, IH), 9.45-9.55 (m, IH).
Example 79
3-(4-Chlorophenyl)-7-cyclohexylmethyl-2-(2,4-dichlorophenyl)-A/'-methyl-6-oxo-6,7- dihydro-2iJ-pyrazolo[3,4-ό]pyridine-5-carboxamide:
Step 1 : Ethyl 3 -(4-chlorophenyl)-7-cyclohexylmethyl-2-(2,4-dichlorophenyl)-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-&]pyridine-5-carboxylate: Prepared from Intermediate 9 and bromomethylcyclohexane in presence of cesium carbonate according to the procedure described in Example 45, Step 1 to afford the resultant compound as an off-white solid: IR (KBr) 3089, 2926, 1735, 1625, 1483, 1095, 824 cm"1; 1H NMR (300 MHz, DMSO-^) δ 0.98-1.20 (m, 6H), 1.21-1.30 (m, 4H), 1.51-1.70 (m, 3H), 1.89-2.00 (m, IH), 3.90-3.98 (m, 2H), 4.22 (d, J = 6.9 Hz, 2H), 7.38 (d, J = 7.8 Hz, 2H), 7.52 (d, J= 8.7 Hz, 2H), 7.59-7.64 (m, IH), 7.78-7.89 (m, 2H), 8.18 (s, IH); ESI-MS (m/z) 560.19 [100%, (M+H)+].
Step 2: 3-(4-Chlorophenyl)-7-cyclohexylmethyl-2-(2,4-dichlorophenyl)-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; IR (KBr) 2924, 1727, 1622, 1482, 1095, 803 cm"1; 1H NMR (300 MHz, DMSO- d6) δ 1.01-1.20 (m, 6H), 1.58-1.72 (m, 4H), 1.96-2.08 (m, IH), 4.12 (d, J= 6.6 Hz, 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.57 (d, J= 8.7 Hz, 2H), 7.66 (d, J= 10.2 Hz, IH), 7.80-7.92 (m, 2H), 8.61 (s, IH), 14.29 (s, IH); ESI-MS (m/z) 532.21 [100%, (M+H)+].
Step 3: 3-(4-Chlorophenyl)-7-cyclohexylmethyl-2-(2,4-dichlorophenyl)-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 2 afforded the desired compound (97%) as a white solid; IR (KBr) 3093, 2924, 1671, 1612, 1482, 1094, 813 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.10-1.24 (m, 5H), 1.57-1.76 (m, 5H), 1.89-2.10 (m, IH), 2.84 (d, J= 4.8 Hz, 3H)5 4.04 (d, J= 6.9 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 1.8 Hz, IH), 7.80-7.90 (m, 2H), 8.59 (s, IH), 9.50 (d, J= 4.2 Hz, IH).
Example 80
3-(4-Chlorophenyl)-2-(2,4-dichloroρhenyl)-N-methyl-6-oxo-7-(2,2,2-trifluoroethyl)-6,7- dihydro-2H-pyrazolo[3,4-&]pyridme-5-carboxamide:
Step 1: Ethyl 3 -(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(2,2,2-trifluoroethyl)-6,7- dihydro-2if-pyrazolo[3,4-&]pyridme-5-carboxylate: This compound was prepared from Intermediate 9 and l,l,l-trifluoro-2-iodoethane in presence of cesium carbonate according to the procedure described in Example 45, Step 1 to afford the resultant compound as an off- white solid; IR (KBr) 3460, 1746, 1625, 1483, 1262, 1184, 1032, 826 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.27 (t, J= 7.2 Hz, 3H), 4.25 (q, J= 7.2 Hz, 2H), 4.93 (q, J = 8.4 Hz, 2H), 7.45 (d, J= 6.9 Hz, 2H), 7.57 (d, J= 8.1 Hz, 2H), 7.62-7.72 (m, IH), 7.80-7.90 (m, 2H), 8.33 (s, IH); ESI-MS (m/z) 545.54 [100%, (IvH-H)+].
Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(2,2,2-trifluoroethyl)-6,7- dihydro-2H"-pyrazolo[3,4-δ]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: IR (KBr) 3441, 2734, 1736, 1610, 1483, 1259, 1155, 1098, 836 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 5.04 (q, J= 8.4 Hz, 2H), 7.46 (d, J= 7.5 Hz, 2H), 7.59 (d, J= 7.5 Hz, 2H), 7.60-7.75 (m, IH), 7.80-7.95 (m, 2H), 8.58 (s, IH), 13.43 (s, IH); ESI-MS (m/z) 531.54 [100%, (MH-H)+].
Step 3: 3-(4-Chloroρhenyl)-2-(2,4-dichloroρhenyl)-N-methyl-6-oxo-7-(2,2,2-trifluoroethyl)- 6,7-dihydro-2H-pyrazolo[3,4-δ]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate and methylamine hydrochloride according to the procedure described in Example 2 afforded the desired compound (40%) as a white solid; IR (KBr) 3322, 2931, 1676, 1613, 1524, 1257, 1155, 1095, 965, 835 cm"1; 1H ΝMR (300 MHz, DMSO-J6) δ 2.85 (br s, 3H), 5.01 (q, J= 8.4 Hz, 2H), 7.46 (d, J= 7.5 Hz, 2H), 7.60-7.80 (m, 5H), 8.65 (s, IH), 9.18 (s, IH).
Example 81 009/000083
3 -(4-Chloroρhenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3 ,3 ,3 -trifluoroρropyl)-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide:
Coupling reaction of Example 72, Step 2 intermediate (0.05 g, 0.094 mmol) using EDCI hydrochloride (0.022 g, 0.115 mmol), HOBt (0.015 g, 0.111 mmol) and 25% aqueous ammonia (0.021 ml) in dichloromethane (1 ml) according to the procedure described in Example 1 afforded 0.040 g of the product (60%) as an off-white solid; IR (KBr) 3435, 1683, 1620, 1515, 1484, 1257, 1149, 1057 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 2.75-2.84 (m, 2H), 4.43 (br s, 2H), 7.38-7.44 (m, 2H), 7.51-7.70 (m, 4H), 7.80-7.95 (m, 2H), 8.63 (s, IH), 8.85 (br s, IH).
Example 82
3 -(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-iV-methyl-6-oxo-7-(3 ,3 ,3 -trifluoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide:
Step 1: Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-637- dihydro-2H-pyrazolo[3,4-έ]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. The resulting suspension was stirred at 80 °C overnight. The reaction mixture was diluted with ethyl acetate (25 ml), the layers were separated. The organic layer was washed with water (50 ml), brine (50 ml) and dried Na2SO4 to afford 0.107 g of major product, ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7- (2,2,2-trifluoropropyl)-6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate as a white solid; IR (KBr) 3453, 2982, 1738, 1652, 1483, 1253, 1148, 1096, 828 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.27 (t, J= 7.2 Hz, 3H), 2.70-2.90 (m, 2H), 4.25 (q, J = 6.9 Hz, 2H), 4.35 (t, J = 5.4 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.60-7.70 (m, IH), 7.80-7.90 (m, 2H)5 8.27 (s, IH); ESI-MS (m/z) 544.54 [100%, (M+H)+] along with 0.014 g of other regiomer ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-(2,2,2-trifluoropropoxy)- 2H-pyrazolo[3,4-Z>]pyridine-5-carboxylate as an off-white solid; IR (KBr) 3454, 2960, 1722, 1626, 1483, 1504, 1330, 1250, 1152, 1078, 830 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.30 (t, J= 6.9 Hz, 3H), 2.80-3.00 (m, 2H), 4.29 (q, J= 6.9 Hz, 2H), 4.67 (t, J= 5.4 Hz, 2H), 7.42 (d, J= 8.4 Hz, 2H), 7.56 (d, J= 8.1 Hz, 2H), 7.62-7.72 (m, IH), 7.82-7.95 (m, 2H), 8.54 (s, IH). Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-Z>]pyridine-5-carboxylic acid: Hydrolysis of Step 1 intermediate (0.105 g, 0.188 mmol) using IN KOH (0.5 ml) in methanol (2 ml) according to procedure described in Intermediate 3, Step 4 to give 0.097 g of the product as a white solid; IR (KBr) 3437, 3096, 1732, 1618, 1483, 1151, 1097, 804 cm'1; 1H NMR (300 MHz, DMSO-dtf) δ 2.80- 3.00 (m, 2H), 4.48 (t, J = 5.7 Hz, 2H), 7.46 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.60-7.80 (m, IH), 7.82-8.00 (m, 2H), 8.64 (s, IH), 13.95 (s, IH); ESI-MS (m/z) 515.96 [100%, (M-H)"].
Step 3: 3-(4-Chloroρhenyl)-2-(2,4-dichloroρhenyl)-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), ΗOBt (0.027 g, 0.199 mmol) in dichloromethane (5 ml) at 0 0C 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; 1H NMR (300 MHz, OMSO-ds) δ 2.85 (br s, 5H), 4.44 (br s, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.60 (d, J= 6.6 Hz, 2H), 7.62-7.72 (m, IH), 7.80-7.90 (m3 2H), 8.61 (s, IH), 9.38 (br s, IH).
Example 83
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(3,3-difiuoropropyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide:
Step 1: Ethyl 3-(4-chloroρhenyl)-2-(2,4-dichloroρhenyl)-7-(3,3-difluoroρroρyl)-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: IR (KBr) 3456, 1740, 1626, 1483, 1253, 1149, 1049 cm"1; 1H ΝMR (300 MHz, DMSO- d6) δ 1.27 (t, J= 6.9 Hz, 3H), 2.20-2.42 (m, 2H), 4.24 (d, J= 6.6 Hz, 4H), 6.22 (br s, IH), 7.39 (d, J= 8.1Hz, 2H), 7.56 (d, J= 8.1 Hz, 2H), 7.66 (d, J= 8.7 Hz, IH), 7.85 (d, J= 10.5 Hz, 2H), 8.24 (s, IH); ESI-MS (m/z) 540.77 [55 %, (M+H)+].
Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(3,3-difiuoroρropyl)-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 3: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(3,3-difluoropropyl)-N-methyl-6-oxo- 6,7-dihydro-2H-pyrazolo[3,4-δ]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate with methylamine hydrochloride according to the procedure described in Example 2 afforded the desired compound (75%) as an off-white solid; IR (KBr) 3392, 2927, 2345, 1743, 1637, 1453, 1026, 701 cm"1; 1H NMR (300 MHz, DMSOi6) δ 2.21-2.30 (m, 2H), 2.85 (d, J= 4.5 Hz, 3H), 4.35 (br s, 2H), 6.24 (br s, IH), 7.40 (d, J= 8.4 Hz, 2H), 7.59 (d, J= 8.7 Hz, 2H), 7.66 (d, J= 9.0 Hz, IH), 7.87 (d, J= 9.0 Hz, 2H), 8.59 (s, IH)5 9.42 (d, J = 4.8 Hz, IH).
Example 84
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(4-fluorobutyl)-iV-methyl-6-oxo-6,7-dihydro- 2if-pyrazolo[3,4-b]pyridine-5-carboxamide:
Step 1: Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-(4-fluorobutyl)-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-ό]pyridine-5-carboxylate: This compound was prepared from Intermediate 9 and l-bromo-4-fluorobutane in presence of cesium carbonate according to the procedure described in Example 45, Step 1 to afford the compound as an off-white solid; IR (KBr) 3090, 2960, 1732, 1645, 1620, 1482, 1222, 1093, 825 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.26 (t, J= 7.2 Hz, 3H), 1.60-1.84 (m, 4H), 4.15-4.19 (m, 2H), 4.23 (q, J= 6.9 Hz, 2H), 4.38 (t, J= 5.4 Hz, IH), 4.54 (t, J= 5.7 Hz, IH), 7.39 (d, J= 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.64 (d, J= 8.1 Hz, IH), 7.84 (d, J= 9.9 Hz, 2H), 8.21 (s, IH); ESI-MS (m/z) 536.68 [100%, (MH-H)+].
Step 2: 3-(4-Chloroρhenyl)-2-(2,4-dichloroρhenyl)-7-(4-fluorobutyl)-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-£]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: IR (KBr) 3091, 2960, 1728, 1620, 1482, 1094, 804 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.82-2.00 (m, 4H), 4.20-4.25 (m, 2H), 4.26-4.35 (m, IH), 4.50-4.60 (m, IH), 7.43 (d, J= 8.4 Hz, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.60-7.75 (m, IH), 7.86 (d, J= 9.3 Hz, 2H), 8.61 (s, IH), 14.25 (s, IH); ESI-MS (m/z) 508.68 [60 %, (M+H)+].
Step 3: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(4-fluorobutyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate with methylamine hydrochloride according to the procedure described in Example 2 afforded the desired compound (70%) as an off-white solid; IR (KBr) 3279, 2927, 1668, 1613, 1522, 1094, 836 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.62-2.96 (m, 4H), 2.84 (d, J= 3.6 Hz, 3H), 4.18-4.30 (m, 2H), 4.34-4.44 (m, IH), 4.50-4.60 (m, IH), 7.41 (d, J= 8.1 Hz, 2H), 7.58 (d, J= 7.8 Hz, 2H), 7.66 (d, J= 8.4 Hz, IH), 7.86 (d, J= 9.0 Hz5 2H), 8.59 (s, IH), 9.47 (d, J= 4.8 Hz, IH).
Example 85
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-methoxyethyl)-N-methyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-έ]pyridine-5-carboxamide:
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; 1H NMR (300 MHz, DMSO-J5) δ 1.27 (t, J= 7.2 Hz, 3H), 3.26 (s, 3H), 3.70 (t, J= 6.0 Hz, 2H), 4.20-4.35 (m, 4H), 7.41 (d, J= 8.4 Hz, 2H), 7.56 (d, J= 8.7 Hz, 2H), 7.60-7.70 (m, IH), 7.84 (d, J = 8.4 Hz, IH), 7.87 (d, J = 2.1 Hz, IH), 8.22 (s, IH); ESI-MS (m/z) 507.40 [100%, (M+H)+].
Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-methoxyethyl)-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-&]pyridine-5-carboxylic acid: Saponification of Step 1 intermediate according to the procedure described in Intermediate 3, Step 4 afforded the acid as a white solid; 1H NMR (300 MHz, DMSO-J6) δ 3.27 (s, 3H), 3.78 (t, J= 6.0 Hz, 2H), 4.44 (t, J= 6.0 Hz, 2H), 7.47 (d, J= 8.4 Hz, 2H), 7.61 (d, J= 8.4 Hz, 2H), 7.62-7.72 (m, IH), 7.82-7.92 (m, 2H), 8.65 (s, IH), 14.20 (s, IH); ESI-MS (m/z) 492.34 [100%, (M+H)+].
Step 3: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-methoxyethyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-έ]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate with methylamine hydrochloride according to the procedure described in Example 2 afforded the desired compound (38%) as a white solid; 1H NMR (300 MHz, OMSO-d6) δ 2.86 (d, J= 4.2 Hz, 3H), 3.27 (s, 3H), 3.74 (br s, 2H), 4.38 (br s, 2H), 7.42 (d, J = 9.0 Hz, 2H), 7.60 (d, J= 8.1 Hz, 2H), 7.65-7.75 (m, IH), 7.85-7.95 (m, 2H), 8.60 (s, IH), 9.45 (q, J= 4.8 Hz, IH).
Example 86
3-(4-Chlorophenyl)-2-(2,4-dichloroρhenyl)-7-(2-ethoxyethyl)-N-methyl-6-oxo-6,7-dihydro- 2/J-pyrazolo[3,4-b]pyridine-5-carboxamide: Step 1: Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-ethoxyethyl)-6-oxo-6,7- dihydro-2H-pyrazolo[3,4~b]pyridine-5-carboxylate: This compound was prepared from Intermediate 9 and 2-bromoethyl ethyl ether in presence of cesium carbonate according to the procedure described in Example 45, Step 1 to afford the compound as an off-white solid; IR (KBr) 3091, 2974, 1732, 1650, 1483, 1178, 1098, 798 cm"1; 1H NMR (300 MHz, DMSO-Jβ) δ 1.04 (t, J= 6.9 Hz, 3H), 1.26 (t, J= 7.5 Hz, 3H), 3.46 (q, J= 6.9 Hz, 2H), 3.70 (t, J = 6.0 Hz, 2H), 4.18-4.30 (m, 4H), 7.40 (d, J = 8.4 Hz, 2H), 7.55 (d, J= 8.4 Hz, 2H), 7.64 (d, J = 8.7 Hz, IH), 7.80-7.90 (m, 2H), 8.22 (s, IH); ESI-MS (m/z) 534.55 [100%, (MH-H)+].
Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-ethoxyethyl)-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: IR (KBr) 3090, 2925, 1725, 1620, 1482, 1091, 804 cm"1; 1H NMR (300 MHz, OMSOd6) δ 1.02 (t, J= 7.2 Hz, 3H), 3.47 (q, J= 6.9 Hz, 2H), 3.78 (s, 2H), 4.41 (s, 2H), 7.45 (d, J= 8.4 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.4 Hz, IH), 7.88 (d, J = 10.5 Hz, 2H), 8.64 (s, IH), 14.22 (s, IH); ESI-MS (m/z) 508.83 [100%, (MH-H)+].
Step 3: 3-(4-Chloroρhenyl)-2-(2,4-dichlorophenyl)-7-(2-ethoxyethyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-&]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate with methylamine hydrochloride according to the procedure described in Example 2 afforded the desired compound (67%) as an off-white solid; IR (KBr) 3088, 2925, 1670, 1612, 1482, 813 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.03 (t, J= 7.2 Hz, 3H), 2.85 (d, J= 4.5 Hz, 3H), 3.46 (q, J= 6.9 Hz, 2H), 3.75 (t, J= 5.7 Hz, 2H), 4.35 (s, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.58 (d, J= 8.1 Hz, 2H), 7.66 (d, J= 8.1 Hz, IH), 7.85 (d, J= 9.0 Hz, 2H), 8.59 (s, IH), 9.44 (d, J= 4.2 Hz, IH).
Example 87
3-(4-Chlorophenyl)-7-(2-cyanoethyl)-2-(2,4-dichlorophenyl)-/vr-methyl-6-oxo-6,7-dihydro- 2if-pyrazolo[3,4-b]pyridine-5-carboxamide:
Step 1: Ethyl 3-(4-chlorophenyl)-7-(2-cyanoethyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate: This compound was prepared from Intermediate 9 and 3-bromopropionitrile in presence of cesium carbonate according to the procedure described in Example 45, Step 1 to afford the compound as a white solid; 1H NMR (300 MHz, OMSOd6) δ 1.28 (t, J= 7.2 Hz, 3H), 3.06 (t, J= 6.6 Hz, 2H), 4.26 (q, J= 7.2 Hz, 2H), 4.37 (t, J= 6.0 Hz, 2H), 7.42 (d, J= 8.4 Hz, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.67 (dd, J= 9.0 Hz, 2.1 Hz, IH), 7.85 (d, J= 8.7 Hz, IH), 7.88 (d, J= 1.8 Hz, IH), 8.29 (s, IH); ESI-MS (m/z) 515.39 [100%, (M+H)+].
Step 2: 3-(4-Chlorophenyl)-7-(2-cyanoethyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-&]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; 1H NMR (300 MHz, DMSO-^) δ 3.13 (t, J = 63 Hz, 2H), 4.50 (t, J= 6.3 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H), 7.65-7.75 (m, IH), 7.85-7.95 (m, IH), 8.65 (s, IH), 13.90 (s, IH); ESI-MS {m/z) 489.22 [100%, (M+H)+].
Step 3: 3-(4-Chloroρhenyl)-7-(2-cyanoethyl)-2-(2,4-dichlorophenyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-&]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate with methylamine hydrochloride according to the procedure described in Example 2 afforded the desired compound (40%) as a white solid; IR (KBr) 3434, 2931, 2253, 1675, 1613, 1484, 1081, 796 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 2.87 (d, J = 7.5 Hz, 3H), 3.10 (t, J= 6.0 Hz, 2H), 4.46 (t, J= 6.0 Hz, 2H), 7.43 (d, J= 9.0 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.65-7.75 (m, 2H), 7.85-7.90 (m, IH), 8.63 (s, IH), 9.35 (q, J= 4.8 Hz5 IH).
Example 88
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(3-cyanopropyl)-Λ/-methyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-b]pyridine-5-carboxarnide:
Step 1 : Ethyl 3 -(4-chlorophenyl)-7-(3 -cyanopropyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-5]pyridine-5-carboxylate: Prepared from Intermediate 9 and 4- bromobutyronitrile according to the procedure described in Example 45, Step 1 to afford the compound as an off-white solid; IR (KBr) 3080, 2926, 2246, 1732, 1646, 1484, 1095, 963 cm"1; 1H NMR (300 MHz, DMSO-J15) δ 1.27 (t, J= 6.9 Hz, 3H), 2.02 (t, J= 6.9 Hz, 2H), 2.60 (t, J= 7.2 Hz, 2H), 4.16-4.30 (m, 4H), 7.39 (d, J= 8.1 Hz, 2H), 7.55 (d, J= 8.7 Hz, 2H), 7.65 (d, J= 8.4 Hz, IH), 7.84 (d, J= 9.9 Hz, 2H), 8.23 (s, IH); ESI-MS (m/z) 531.73 [100 %, (M+H)+].
Step 2: 3 -(4-Chloroρhenyl)-7-(3 -cyanoρroρyl)-2-(2,4-dichloroρhenyl)-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxylic acid: Saponification of Step 1 intermediate as described in Intermediate 3, Step 4 afforded the acid as an off-white solid; IR (KBr) 3091, 2925, 2247, 1722, 1598, 1437, 1087, 837 cm"1; 1H NMR (300 MHz, DMSO-^) δ 2.04-2.19 (m, 2H), 2.60-2.70 (m, 2H), 4.25-4.40 (m, 2H), 7.41 (d, J= 8.1 Hz, 2H), 7.57 (d, J= 9.3 Hz, 2H), 7.56 (d, J = 8.7 Hz, IH), 7.86 (d, J = 8.7 Hz, 2H), 8.61 (s, IH), 14.13 (s, IH); ESI-MS (m/z) 501.72 [64 %, (M+H)+].
Step 3: 3-(4-Chlorophenyl)-7-(3-cyanopropyl)-2-(2,4-dichlorophenyl)-N-methyl-6-oxo-6,7- dmydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate with methylamine hydrochloride according to the procedure described in Example 2 afforded the desired compound (60%) as an off-white solid; IR (KBr) 3279, 2938, 2250, 1667, 1615, 1511, 1090, 843 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 2.06 (t, J = 7.2 Hz, 2H), 2.62 (t, J= 6.9 Hz, 2H), 2.85 (d, J= 4.2 Hz, 3H), 4.28 (t, J= 6.3 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.59 (d, J= 7.8 Hz, 2H), 7.65 (d, J= 2.1 Hz, IH), 7.68 (d, J= 1.8 Hz, 2H), 8.59 (s, IH), 9.43 (d, J= 4.8 Hz, IH).
Example 89
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-dimethylaminoethyl)-7V-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide:
Step 1: Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-dimethylaminoethyl)-6-oxo- 6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate: Prepared from Intermediate 9 and N,iV-dimethylethylenediamine according to the procedure described in Example 45, Step 1 to afford the compound as an off-white solid; IR (KBr) 3088, 2977, 1735, 1650, 1621, 1483, 1096, 818 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 1.38 (t, J= 7.5 Hz, 4H), 2.34 (s, 6H), 2.76 (br s, 2H), 4.24-4.42 (m, 3H), 7.18 (d, J= 8.4 Hz, 2H), 7.21-7.50 (m, 5H), 8.31 (s, IH); ESI- MS (m/z) 533.57 [100%, (M+H)+].
Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-dimethylaminoethyl)-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; IR (KBr) 3014, 2926, 1734, 1621, 1482, 1459, 1092, 833 cm4; 1H NMR (300 MHz, DMSO-J6) δ 2.23 (s, 6H), 2.73 (br s, 2H), 4.34 (br s, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.60-7.75 (m, IH), 7.80-7.95 (m, 2H), 8.61 (s, IH), 13.43 (s, IH); ESI-MS (m/z) 507.17 [100 %, (M+H)+].
Step 3: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-dimethylaminoethyl)-Λ/-methyl 6- oxo-6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide: Coupling reaction of Step 2 intermediate with methylamine hydrochloride according to the procedure described in Example 2 afforded the desired compound as an off-white solid; IR (KBr) 3285, 3070, 2942, 1671, 1612, 1511, 1094, 812 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 2.20 (s, 6H), 2.65 (br s, 2H), 2.84 (br s, 3H), 4.28 (br s, 2H), 7.41 (d, J = 8.1 Hz5 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.66 (d, J= 7.8 Hz, IH), 7.81-7.90 (m, 2H), 8.59 (s, IH), 9.46 (br s, IH).
Example 90
1 -[3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3 ,3 ,3-trifluoropropyl)-6,7-dihydro- 2H-pyrazolo[3,4-b]pyridin-5-yl]-3-methylurea:
Figure imgf000094_0001
Prepared from Example 72, Step 2 intermediate (0.1 g, 0.188 mmol), phenyl chloroformate (0.028 ml, 0.223 mmol), sodium azide (0.014 g, 0.215 mmol) and methylamine hydrochloride (0.025 g, 0.371 mmol) in 1,2-dimethoxyethane (3 ml) according to the procedure described in Example 44 to afford 0.015 g of the product (14%) as a white solid; IR (KBr) 2924, 1734, 1631, 1542, 1096, 817 cm"1; 1H NMR (300 MHz, DMSO-J15) δ 2.61 (d, J= 3.3 Hz, 3H), 2.76-2.90 (m, 2H), 4.43 (br s, 2H), 7.03 (br s, IH), 7.28 (d, J= 8.1 Hz, 2H), 7.50-7.70 (m, 3H), 7.76-7.90 (m, 2H), 8.28 (s, IH), 8.47 (s, IH); ESI-MS (m/z) 558.76 [70 %, (M+H)+].
Example 91
Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-2H-pyrazolo[3,4- b]pyridine-5-carboxylate:
Figure imgf000094_0002
To a magnetically stirred solution of Intermediate 9 (0.15 g, 0.324 mmol) in anhydrous dimethyl formamide (2 ml) was added cesium carbonate (0.265 g, 0.814 mmol) followed by 3,4-difluorobenzyl bromide (0.062 ml, 0.483 mmol) at room temperature. Resulting suspension was stirred at room temperature overnight under nitrogen atmosphere. The 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. IR (KBr) 3446, 2964, 1732, 1643, 1515, 1482, 1226, 1094, 815 cm"1; 1H NMR (300 MHz5 CDCl3) δ 1.38 (t, J = 7.2 Hz, 3H),
4.39 (q, J= 6.9 Hz, 2H), 5.33 (s, 2H), 7.00-7.60 (m, 10H), 8.33 (s, IH), along with 0.020 g of other regiomer ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,4-difluoro benzyl)-6,7-dihydro-2H-pyrazolo[3,4-&]pyridine-5-carboxylate as a white solid; IR (KBr) 3440, 3069, 1753, 1650, 1480, 1250, 1089, 836 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.34-
1.40 (m, 3H), 4.25-4.50 (m, 2H), 5.00-5.15 (m, 2H), 7.00-7.40 (m, 10H), 7.50 (s, IH); ESI- MS (m/z) 588.24 [100%, (M+H)+j.
Example 92
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-2H-pyrazolo[3,4- 6]pyridine-5-carbonitrile:
Figure imgf000095_0001
Step 1 : 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-2H-pyrazolo [3,4-δ]pyridine-5-carboxylic acid: Saponification of Example 91 (0.12 g, 0.203 mmol) in methanol (5 ml) and water (1 ml) with KOΗ (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; 1H NMR (300 MHz, DMSO-J6) δ 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)+j.
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), ΗOBt (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 0C according to the procedure described in Example 1 to afford 0.063 g of the product as an off- white solid; 1H NMR (300 MHz, DMSO-^) δ 5.35 (br s, 2H), 7.20-7.30 (m, IH), 7.35-7.52 (m, 4H), 7.55-7.70 (m, 3H), 7.80-7.90 (m, 3H), 8.65 (s, IH), 8.83 (br s, IH); ESI-MS (m/z) 561.28 [100%, (M+H)+]. Step 3: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-2iy-pyrazolo [3,4-έ]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; 1H NMR (300 MHz, DMSO-Jd) δ 5.28 (s, 2H), 7.22-7.30 (m, IH), 7.36-7.60 (br m, 6H), 7.67 (dd, J = 7.5 Hz, 2.1 Hz, IH), 7.83 (d, J= 8.7 Hz, IH), 7.90 (d, J= 2.4 Hz, IH), 8.75 (s, IH); ESI-MS (m/z) 541.37 [100%, (M+H)+].
Example 93
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difiuorobenzyloxy)-N-methyl-2H- pyrazolo[3,4-&]pyridine-5-carboxarnide:
Figure imgf000096_0001
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 1NKOΗ (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; 1H NMR (300 MHz, DMSO-J5) δ 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-Chloroρhenyl)-2-(2,4-dichloroρhenyl)-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; 1H NMR (300 MHz, DMSO-J6) δ 2.84 (br s, 3H), 5.35 (s, 2H), 7.20-8.00 (m, 10H), 8.62 (s, IH), 9.35 (br s, IH); ESI-MS (m/z) 573.27 [100%, (M+H)+].
Example 94 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(4-fluorobenzyloxy)-N-methyl-2H"-pyrazolo [3 ,4-Z?]pyridine-5-carboxamide:
Figure imgf000097_0001
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, 1626, 1509, 1223, 1097, 821 cm"1; 1H ΝMR (300 MHz, DMSO-J6) δ 1.27 (t, J = 6.9 Hz, 3H), 4.24 (q, J = 6.9 Hz, 2H), 5.26 (s, 2H), 7.16 (t, J= 8.7 Hz, 2H), 7.30-7.90 (m, 9H), 8.26 (s, IH); ESI-MS (m/z) 570.27 [100%, (M+H)+].
Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(4-fluorobenzyloxy)-2H-pyrazolo[3,4- Z>]pyridine-5-carboxylic acid: Step 1 intermediate (0.13 g, 0.228 mmol) was hydrolysed using IN KOΗ (0.5 ml) in methanol (2 ml) according to procedure described in Intermediate 3, Step 4 to afford 0.095 g of the product as an off-white solid; IR (KBr) 3443, 3081, 1722, 1615, 1448, 1218, 1096, 834 cm'1; 1H ΝMR (300 MHz, DMSO-J6) δ 5.40 (s, 2H), 7.17 (t, J= 8.4 Hz, 2H), 7.40-8.00 (m, 9H), 8.64 (s, IH), 14.00 (s, IH); ESI-MS (m/z) 543.27 [100%, (M+H)+].
Step 3: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(4-fluorobenzyloxy)-N-methyl-2i/- pyrazolo[3,4-δ]pyridine-5-carboxamide: Prepared from Step 2 intermediate (0.095 g, 0.175 mmol), EDCI hydrochloride (0.04 g, 0.208 mmol), HOBt (0.028 g, 0.207 mmol) in dichloromethane followed by addition of 40% solution of methylamine in water (0.041 ml, 0.515 mmol) at 0 0C according to the procedure described in Example 1 to afford 0.021 g of the product as a white solid; IR (KBr) 3436, 2928, 1671, 1611, 1515, 1286, 1095, 761 cm'1; 1H ΝMR (300 MHz, DMSO-^6) δ 2.85 (d, J = 4.5 Hz, 3H), 5.35 (s, 2H), 7.16 (t, J= 8.4 Hz, 2H), 7.35-8.00 (m, 9H), 8.62 (s, IH), 9.40 (d, J= 4.5 Hz, IH); ESI-MS (m/z) 557.37 [100%, (M+H)+]. Example 95
Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-(l-pyrrolidmyl)-2H-ρyrazolo[3,4- b]pyridine-5-carboxylate:
Figure imgf000098_0001
To a magnetically stirred solution of Intermediate 9 (0.1 g, 0.216 mmol) in anhydrous tetrahydrofuran (3 ml) was added l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.048 ml, 0.321 mmol) and BOP reagent (0.125 g, 0.282 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 min. After this time, pyrrolidine (0.027 ml, 0.323 mmol) was added and reaction mixture was stirred at room temperature overnight. Reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). Organic layer was washed successively with water (30 ml), brine (30 ml), dried (Na2SO4) and concentrated under reduced pressure to afford 0.16 g of the product as a white solid; 1H NMR (300 MHz, DMSO-J15) δ 1.90 (br s, 4H), 3.41 (br s, 4H), 3.84 (s, 3H), 7.35 (d, J = 7.5 Hz, 2H), 7.53 (d, J = 6.9 Hz, 2H), 7.60-7.70 (m, IH), 7.75-7.90 (m, 2H), 8.22 (s, IH); ESI-MS (rø/z) 535.27 [100%, (M+H)+].
Example 96
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-6-pyrrolidin-l-yl-2H-pyrazolo[3,4- b]pyridine-5-carboxamide:
Figure imgf000098_0002
Step 1: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-iV-methyl-6-oxo-6,7-dihydro-2H-pyrazolo [3,4-b]pyridine-5-carboxamide: Coupling reaction of Example 70, Step 1 intermediate (0.26 g, 0.598 mmol) using BOP reagent (0.291 g, 0.657 mmol), triethylamine (0.83 ml, 5.981 mmol) and methylamine hydrochloride (0.038 g, 0.657 mmol) in anhydrous dimethylformamide (5 ml) according to the procedure described in Example 2 to afford 0.245 g of the product as an off-white solid; IR (KBr) 3271, 2942, 1734, 1667, 1482, 1095 cm'1; 1H NMR (300 MHz, DMSO-J6) δ 2.83 (s, 3H), 7.36 (d, J = 8.1 Hz, 2H), 7.50-7.70 (m, 3H), 7.78-7.90 (m, 2H), 8.55 (s, IH), 9.46 (br s, IH), 12.67 (s, IH); ESI-MS (m/z) 447.39 [100%, (M+H)+].
Step 2: 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-6-pyrrolidm-l-yl-2H-pyrazolo [3,4-b]pyridine-5-carboxamide: To a magnetically stirred solution of Step 1 intermediate (0.075 g, 0.167 mmol) in anhydrous tetrahydrofuran (2 ml) was added BOP reagent (0.096 g, 0.217 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.037 ml, 0.251 mmol) at room temperature and stirred for 15 min. Pyrrolidine (0.021 ml, 0.251 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. After this time, the reaction mixture was diluted with ethyl acetate (20 ml) and washed with saturated aqueous NaHCO3 (25 ml), water (25 ml), brine (25 ml) and dried (Na2SO4). Concentration under reduced pressure afforded 0.078 g of the product as an off-white solid; IR (KBr) 3374, 3074, 2928, 1650, 1626, 1477, 1092, 844 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.87 (br s, 4H), 2.74 (s, 3H), 3.45 (br s, 4H), 7.29 (d, J- 8.7 Hz, 2H), 7.49 (d, J= 8.7 Hz, 2H), 7.63 (d, J= 8.7 Hz, IH), 7.66-7.82 (m, 3H), 8.37 (br s, IH); ESI-MS (m/z) 500.23 [100%, (M+H)+].
Example 97 Receptor binding assay protocol using hCBl and hCB2-CHO cell membranes:
In this assay, [3H]-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 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 and [3H]-CP-55,940 (0.75 nM ). For CBl assay 25-50 μg and for CB2 assay 0.25-0.50 μg of receptor preparation was used. 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. The percent (%) displacement by test ligand was calculated by comparing with the specific bound values.
The percentage displacement values (% D) of [3H]-CP-55940 by test molecules at 300 nM concentration for hCBl and hCB2 are given in Table 5.
The IC5O (nM) values of the compounds are set forth in Table 5 wherein "A" refers to an IC50 value of less than 50 nM, "B" refers to IC50 value of 50.01 to 100 nM, and "C" refers to an IC50 value of more than 100 nM.
Table 5: In- vitro screening results of Examples 1-96
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

000083WE CLAIM:
1. A compound of Formula (I):
Figure imgf000104_0001
Formula (I) and pharmaceutically acceptable salt thereof, an iV-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 NR1 and R2 represents an oxo group (=O); when dotted line [ — ] in the ring represents a bond, then X is N and R2 is as defined beolw; each occurance of X is N or NR1 each occurance of R1 is hydrogen, substituted or unsubstituted alkyl, haloalkyl, acyl, alkoxyalkyl, cyanoalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkynylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl or -(CRaRb)tNRaRb; each occurrence of R2 is hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, -ORa, -NRcRd, -S(O)qNHRa, -NHS(O)qRa; each occurrence of R3 is hydrogen, nitro, cyano, alkyl, haloalkyl, alkoxy, acyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, - NRaC(O)NRaRb, -NRaRb, N-acyl, -C(O)NRaRb, -C(O)OR3 or -NRaS(O)qRb, -S(O)qNRaRb; each occurrence of R is hydrogen, halogen, alkyl, alkoxy, -NRaRb, -NRaC(=B)Rb, -C(O)ORa, -C(O)NRaRb, - NRaS(O)qRb, or -S(O)qNRaRb; each occurrence of B is O, S or NRa; each occurrence of Ra and Rb are independently hydrogen, halogen, formyl, acyl, cyanoalkyl, -(CH2)2N(CH3)2, -(CH2)2OCH3, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -S(O)qRc, - S(O)qNRcRd, -NRcRd, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl or a protecting group, or Ra and Rb when bound to a common atom, are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated ring, which optionally includes one or more heteroatoms selected from O, NRd and S(O)q; each occurrence of Rc, Rd and Re is independently hydiOgen, halogen, cyano, formyl, azide, acetyl, oxo, thio, a protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylakyl, cycloalkenyl, cycloalkenylalkyl, heterocyclic ring, heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or Rc and Rd, 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, NRe 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.
2. A compound according to claim 1, wherein dotted line [ — ] in the ring is absent, X is NR1 and R is an oxo group (=0).
3. A compound according to claim 1, wherein dotted line [ — ] in the ring represents a bond, and X is N.
4. A compound according to claim 1, wherein R1 is hydrogen, substituted or unsubstituted alkyl, haloalkyl, alkoxyalkyl, cyanoalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, or alkylarninoalkyl.
5. A compound according to claim 1, wherein R2 is hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl.
6. A compound according to claim 1, wherein R3 is hydrogen, cyano, alkyl, haloalkyl, alkoxy, acyl, -NRaC(O)NRaRb, -NRaRb, N-acyl, -C(O)NRaRb, or -C(O)ORa; wherein each occurrence of Ra and Rb are independently hydrogen, cyanoalkyl, - (CH2)2N(CH3)2, -(CH2)2OCH3; substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl or a protecting group, or Ra and Rb together can form an optionally substituted 3 to 7 membered saturated or unsaturated ring.
7. A compound according to claim 1, wherein at each at occurrence R is hydrogen or halogen.
8. A compound of claim 1, comprising the structural formula (Ia):
Figure imgf000106_0001
Formula (Ia) and pharmaceutically acceptable salt thereof, an iV-oxide thereof, an analog thereof, a tautomer thereof, a regioisomer thereof, and stereoisomer thereof, wherein, R2, R3 and R are as defined in claim 1.
9. A compound of claim 1, comprising the structural formula (Ib):
Figure imgf000107_0001
Formula (Ib) and pharmaceutically acceptable salt thereof, an N-oxide thereof, an analog thereof, a tautomer thereof, a regioisomer thereof, and stereoisomer thereof, wherein, R1, R3 and R are as defined in claim 1.
10. A compound according to claim 1-18, the compound is selected from:
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-6-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine-5- carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4- &]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-ethyl-6-(trifluoromethyl)-2H-pyrazolo[3,4- &]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7V-propyl-6-(trifluoromethyl)-2H-pyrazolo[3,4- 6]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-isopropyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-(isobutyl)-6-(trifluoromethyl)-2H"- pyrazolo [3 ,4-&]pyridine-5 -carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-(5ec-butyl)-6-(trifluoromethyl)-2H-pyrazolo[3,4- ό]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-(tert-butyl)-6-(trifluoromethyl)-2H-pyrazolo[3,4- b]pyridine-5-carboxamide,
2-(2-Chloroρhenyl)-3-(4-chloroρhenyl)-N-cyclopropyl-6-(trifluoromethyl)-2H-pyrazolo[3,4- έ]pyridine-5-carboxamide, 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropylmethyl-6-(trifluoromethyl)-2H"- pyrazolo [3 ,4-b]pyridine- 5 -carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclobutyl-6-(trifluoromethyl)-2H-pyrazolo[3,4- b]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-(2-dimethylaminoethyl)-6-(trifluoromethyl)-2H'- pyrazolo[3,4-έ]pyridine-5-carboxamide,
(2-Chlorophenyl)-3-(4-chlorophenyl)-N-(2-methoxyethyl)-6-(trifluoromethyl)-2H'- pyrazolo[3,4-έ]pyridine-5-carboxamide,
2-(2-Chloroρhenyl)-3-(4-chlorophenyl)-N-(2-fluoroethyl)-6-(trifluoromethyl)-2Hr- pyrazolo[3,4-b]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-6-(2-fluorophenyl)-N-methyl-2H'-pyrazolo[3,4- Z?]pyridine-5-carboxamide,
2,3-Bis(4-chlorophenyl)-Λ/-methyl-6-(trifluoromethyl)-2H'-pyrazolo[3,4-6]pyridine-5- carboxamide,
6-(4-Bromophenyl)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo [3 ,4-b] pyridine,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-[3-(trifluorometliyl)phenyl]-2H-pyrazolo [3,4- έjpyridine,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(trifluoromethyl)-2Η-pyrazolo[3,4-b] pyridine- 5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(trifluoromethyl)-2H"-pyrazolo[3,4-b] pyridine- 5-carbonitrile ,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7V-isopropyl-6-methyl-2H-pyrazolo[3,4-6] pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-methyl-N-(tert-butyl)-2H-pyrazolo[3,4-b] pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-6-(trifluoromethyl)-2H-pyrazolo [3,4- έ]pyridine-5-carboxamide,
3-(4-Chloroρhenyl)-2-(2,4-dichloroρhenyl)-N-ethyl-6-(trifluoromethyl)-2H-pyrazolo[3,4- b]ρyridine-5-carboxamide, 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-isopropyl-6-(trifluoromethyl)-2H'-pyrazolo [3,4-b]pyridine-5-carboxamide ,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-propyl-6-(trifluoromethyl)-2H-pyrazolo [3,4- έ]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-iV-isobutyl-6-(trifluorometliyl)-2H-pyrazolo [3,4- έ]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(tert-butyl)-6-(trifluoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-5ec-butyl-6-(trifluoromethyl)-2//-pyrazolo [3 ,4-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7V-isopentyl-6-(trifluoromethyl)-2Jf/-pyrazolo [334-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(l,2-dimetliylpropyl)-6-(trifluorometliyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(l,l-dimethylpropyl)-6-(trifluoromethyl)-2H- pyrazolo [3 ,4-Z?]pyridine- 5 -carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-cyclopropyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-iV-cyclopropylmethyl-6-(trifluorometb.yl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-cyclobutyl-6-(trifluoromethyl)-2//- pyrazolo[3,4-6]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-cyclopentyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-cyanomethyl-6-(triflιιoromethyl)-2H- pyrazolo[3,4-ό]ρyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methoxy-6-(trifluoromethyl)-2H-pyrazolo [3 ,4-b]pyridine-5 -carboxamide, 3-(4-CUorophenyl)-2-(2,4-dichlorophenyl)-N-(2-methoxyethyl)-6-(trifluoro-methyl)-2H- pyrazolo [3 ,4-&]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(254-dichlorophenyl)-7V-(2-dimethylaminoethyl)-6-(trifluoro methyl)- 2H-pyrazolo[3,4-&]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(2-pyrrolidin- 1 -ylethyl)-6-(trifluoro methyl)- 2H-ρyrazolo[3,4-&]pyridine-5-carboxamide,
3 -(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-(pyrrolidin- 1 -ylcarbonyl)-6-(trifluoro methyl)- 2JH-pyrazolo[3,4-£]pyridine,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-pyrrolidin-l-yl-6-(trifluoromethyl)-2H- pyrazolo[3,4-δ]pyridme-5-carboxamide,
1 -[3 -(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(trifluoromethyl)-2H-pyrazolo[3 ,4-b] pyridin-5 -yl] -3 -methylurea,
2-(2-Chlorophenyl)-3-(4-chloroρhenyl)-7-(3,3,3-trifluoropropyl)-6,7-dihydro-2H- pyrazolo[3 ,4-6]pyridin-6-one,
2-(2-Chloroρhenyl)-3 -(4-chloroρhenyl)-6-oxo-7-(3 ,3 ,3 -trifluoroρropyl)-6,7-dihydro-2H- pyrazolo [3 ,4-&]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-methyl-6-oxo-7-propyl-6,7-dihydro-2H- pyrazolo[3,4-δ]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-6-oxo-7-propyl-6,7-dihydro-2H- pyrazolo[334-ό]pyridine-5-carboxaπiide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-isobutyl-7V-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-έ]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-7-isobutyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chloroρhenyl)-7-cyclopropylmethyl-N-methyl-6-oxo-6,7-dihydro- 2//-pyrazolo[3,4-δ]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-7-cycloproρylmethyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-&]pyridine-5-carboxamide, 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(isopentyl)-N-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-&]pyridine-5-carboxamide,
2-(2-Chloroρhenyl)-3-(4-chlorophenyl)-iV-methyl-7-neopentyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-methyl-6-oxo-7-(3,3,3-trifluoropropyl)-6,7- dihydro-2H-pyrazolo[3,4-έ]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-ethyl-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro- 2H-pyrazolo[3,4-b]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3 -(4-chlorophenyl)-N-isopropyl-6-oxo-7-(3 ,3 ,3 -trifluoro-propyl)-6,7- dihydro-2H-pyrazolo[3,4-5]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3 -(4-chlorophenyl)-N-cyclopropyl-6-oxo-7-(3 ,3 ,3 -trifluoro-propyl)-6,7- dihydro-2H-pyrazolo[3,4-&]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2-chlorophenyl)-iV-cyclopropyl-6-(3,3,3-trifluoropropoxy)-2H- pyrazolo[3,4-6]pyridine-5-carboxamide,
2-(2-Chloroρhenyl)-3-(4-chlorophenyl)-N-(2-fluoroethyl)-6-oxo-7-(3 ,3 ,3-trifluoro propyl)- 6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-[2-(dimethylamino)ethyl]-6-oxo-7-(3,3,3- trifluoropropyl)-6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-methoxyethyl)-Λ/-methyl-6-oxo-6,7-diliydro- 2H-pyrazolo[3,4-b]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-cyclopropyl-7-(2-methoxyethyl)-6-oxo-6,7- dihydro-2Hr-pyrazolo[3,4-6]pyridine-5-carboxamide,
2-(2-Chloroρhenyl)-3-(4-chloroρhenyl)-7-(2-ethoxyethyl)-N-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-&]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chloroρhenyl)-7-(2-ethoxyethyl)-7V-isopropyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-b]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chloroρhenyl)-7-(2-cyanoethyl)-N-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-&]pyridine-5-carboxainide, 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2-cyanoethyl)-iV-cycloρropyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-b]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-iV,N-dimethyl-6-oxo-7-(3,3,3-trifluoro-propyl)-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxatnide,
2,3-Bis(4-chloroρhenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro-2H-pyrazolo[3,4-b] pyridine-5 -carboxamide,
2,3 -Bis(4-chlorophenyl)-N-cyclopropyl-6-oxo-7-(3 ,3 ,3 -trifluoropropyl)-6,7-dihydro-2H"- pyrazolo[3,4-6]pyridine-5-carboxamide,
N"-/ert-Butyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-6,7-dihydro-2H-pyrazolo [3,4- b]pyridine-5-carboxamide,
3 -(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(2-hydroxy- 1 , 1 -dimethylethyl)-6-oxo-6,7- dib.ydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carbonitrile,
3-(4-Chloroρhenyl)-2-(2,4-dichlorophenyl)-N,7-dimethyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-ό]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-7-cyclopropylmethyl-2-(2,4-dichlorophenyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-Z?]pyridine-5-carboxamide,
7-Butyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-έ]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-isobutyl-N-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-isopentyl-iV-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-7-neoρentyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-7-cyclohexylmethyl-2-(2,4-dichlorophenyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide, 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-6-oxo-7-(2,2,2-trifluoro-ethyl)-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine~5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxamide,
3 -(4-Chlorophenyl)-2-(2,4-dichloroρhenyl)-N-methyl-6-oxo-7-(3 ,3 ,3 -trifluoro-propyl)-6,7- dihydro-2H-pyrazolo[3,4-&]pyridine-5-carboxamide,
3 -(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(3 ,3 -difluoropropyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-ύ]pyridine-5-carboxaniide,
3-(4-Chloroρhenyl)-2-(2,4-dichlorophenyl)-7-(4-fluorobutyl)-N-methyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-methoxyethyl)-N-methyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-Z?]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-ethoxyethyl)-N-methyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-έ]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-7-(2-cyanoethyl)-2-(2,4-dichlorophenyl)-N-methyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-έ>]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(3-cyanopropyl)-N-methyl-6-oxo-6,7-dihydro- 2H-pyrazolo[3,4-6]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-(2-dimethylaminoethyl)-N-methyl-6-oxo-6,7- dihydro-2H-pyrazolo[3,4-Zj]pyridine-5-carboxamide, l-[3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro- 2H-pyrazolo[3,4-b]pyridin-5-yl]-3-methylurea,
Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-2H-pyrazolo [3 ,4-b]pyridine-5-carboxylate,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-2H-pyrazolo[3,4- b]pyridine-5-carbonitrile,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(3,4-difluorobenzyloxy)-iVr-methyl-2H- pyrazolo[3,4-b]pyridine-5-carboxamide5 3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-6-(4-fluorobenzyloxy)-iV-methyl-2H- pyrazolo[3,4-ό]pyridine-5-carboxamide,
Ethyl 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-(l-pyrrolidinyl)-2H-pyrazolo [3,4-b] pyridine-5 -carboxylate,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7V-methyl-6-pyrrolidin-l-yl-2H-ρyrazolo[3,4- &]pyridine-5-carboxamide and pharmaceutically acceptable salt thereof, an iV-oxide thereof, an analog thereof, a tautomer thereof, a regioisomer thereof, and stereoisomer thereof.
11. A compound that is selected from:
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-iV-(5ec-butyl)-6-(trifluoromethyl)-2H-pyrazolo [3,4- έ>]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3 -(4-chlorophenyl)-N-(5ec-butyl)-6-(trifluoromethyl)-2H'-pyrazolo [3 ,4- έ]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3-(4-chlorophenyl)-N-ethyl-6-oxo-7-(3,3,3-trifluoropropyl)-6,7-dihydro-
2H-pyrazolo[3,4-έ]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3 -(4-chlorophenyl)-N-isopropyl-6-oxo-7-(3 ,3 ,3 -trifluoro-propyl)-6,7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide,
2-(2-Chlorophenyl)-3 -(4-chlorophenyl)-7V-(2-fluoroethyl)-6-oxo-7-(3 ,3 ,3 -trifluoro propyl)-
6,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxamide,
3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-7-isopentyl-iV-methyl-6-oxo-6,7-dihydro-2H- pyrazolo[3,4-ό]pyridine-5-carboxamide.
12. A process for the preparation of compounds of formula (Ia)
Figure imgf000114_0001
Formula (Ia)
and pharmaceutically acceptable salt thereof, an N-oxide thereof, an analog thereof, a tautomer thereof, a regioisomer thereof, and stereoisomer thereof, wherein, R2, R3 and R are defined as in claim 1, the process comprising of: (a) reacting compound of formula (1) with R2COCH2R3 to obtain compound of formula (Ia- 1),
Figure imgf000115_0001
(b) reacting compound of formula (1) with R2COCH2CO2R6 (wherein R6 is alkyl) followed by hydrolysis to obtain compound of formula (6),
Figure imgf000115_0002
(c) coupling compound of formula (6) with compound of formula RaRbNH in presence of a coupling agent to obtain compound of formula (Ia-2),
Figure imgf000115_0003
(d) reacting compound of formula (6) with NH4OH in presence of a coupling agent followed by dehydration with tiifluoroacetic anhydride to obtain compound of formula (Ia-3),
Figure imgf000115_0004
(Ia-3)
(e) decarboxylating compound of formula (6) in presence of copper to obtain compound of formula (Ia-4),
Figure imgf000116_0001
(f) rearrangement of compound of formula (6) followed by reaction with compound of formula R3R13NH to obtain compound of formula (Ia-5).
Figure imgf000116_0002
(Ia-5)
13. A process for the preparation of compounds of formula (Ia)
Figure imgf000116_0003
Formula (Ia)
and pharmaceutically acceptable salt thereof, an iV-oxide thereof, an analog thereof, a tautomer thereof, a regioisomer thereof, and stereoisomer thereof, wherein, R2, R3 and R are defined as in claim 1, the process comprising of:
(a) reacting compound of formula (1) with CH2(CO2Ra) to obtain compound of formula (7),
Figure imgf000116_0004
(b) benzylating compound of formula (7) with benzyl halide (RaX) to obtain compound of formula (8),
Figure imgf000117_0001
(8)
(c) hydrolyzing compound of formula (8) followed by coupling with compound of formula R8R13NH in presence of suitable coupling agent to obtain compound of formula (Ia-6),
Figure imgf000117_0002
(Ia-6)
(d) reacting compound of formula (7) with POCl3 followed by reaction with compound of formula RcRdNH to obtain compound of formula (9),
Figure imgf000117_0003
(9)
(e) hydrolyzing compound of formula (9) followed by coupling with compound of formula RaR NH in presence of suitable coupling agent to obtain compound of formula (Ia-7),
Figure imgf000117_0004
(Ia-7) (f) hydrolyzing compound of formula (7) followed by coupling with compound of formula R4R15NH to obtain compound of formula (9'),
Figure imgf000118_0001
(91)
(g) reacting compound of formula (9') with POCl3 followed by reaction with compound of formula RcRdNH, or reaction with benzotriazol-l-yloxytris(dimethylamino) phosphoniumhexafiuorophosphate (BOP) reagent and compound of formula RcRdNH to obtain compound of formula (Ia-7).
Figure imgf000118_0002
(Ia-7)
14. A process for the preparation of compounds of formula (Ib)
Figure imgf000118_0003
Formula (Ib) and pharmaceutically acceptable salt thereof, an JV-oxide thereof, an analog thereof, a tautomer thereof, a regioisomer thereof, and stereoisomer thereof, wherein, R1 , R3 and R are defined as in claim 1, the process comprising of:
(a) hydrolyzing compound of formula (7) followed by coupling with compound of formula R^15NH in presence of suitable coupling agent, to obtain compound of formula (Ib-I),
Figure imgf000119_0001
(b) alkylating compound of formula (7) with an alkyl halide of formula R1X to obtain compound of formula (10) as major regiomer and compound of formula (11) as minor regiomer,
Figure imgf000119_0002
(10) [major regiomer] (11) [minor regiomer]
(c) hydrolyzing compound of formula (10) and (11) independently, followed by coupling with compound of formula RaRbNH to obtain compound of formula (Ib-3) and compound of formula (Ia- 8) respectively,
Figure imgf000119_0003
(d) hydrolyzing compound of formula (10) followed by reacting with sodium azide and compound of formula R8R1TSTH to obtain compound of formula (Ib-2).
Figure imgf000119_0004
15. A pharmaceutical composition comprising a compound according to any of claims 1-14 either as a free base or in pharmaceutically acceptable salt form and a pharmaceutically acceptable excipient.
16. 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 1-14.
17. The method of claim 16 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.
18. The method of claim 16, 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.
PCT/IB2009/000083 2008-01-29 2009-01-20 Fused pyrazole derivatives as cannabinoid receptor modulators WO2009095752A1 (en)

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CN102603637A (en) * 2012-01-18 2012-07-25 中国药科大学 Pyrazol compound and purpose of pyrazol compound used as receptor tyrosine kinases (RTK) and phosphatidyl inositol 3-kinase (PI3K) dual inhibitors
JP2013544277A (en) * 2010-12-01 2013-12-12 ファイザー・インク KATII inhibitor
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WO2011153588A1 (en) * 2010-06-10 2011-12-15 Biota Scientific Management Pty Ltd Viral polymerase inhibitors
JP2013544277A (en) * 2010-12-01 2013-12-12 ファイザー・インク KATII inhibitor
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