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WO2008035356A2 - Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation - Google Patents

Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation Download PDF

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Publication number
WO2008035356A2
WO2008035356A2 PCT/IN2007/000119 IN2007000119W WO2008035356A2 WO 2008035356 A2 WO2008035356 A2 WO 2008035356A2 IN 2007000119 W IN2007000119 W IN 2007000119W WO 2008035356 A2 WO2008035356 A2 WO 2008035356A2
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WO
WIPO (PCT)
Prior art keywords
pyrazole
dihydrochromeno
dichlorophenyl
dimethyl
carboxamide hydrochloride
Prior art date
Application number
PCT/IN2007/000119
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French (fr)
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WO2008035356A3 (en
Inventor
Sachin S. Chaudhari
Abraham Thomas
Srinivas Gullapalli
Ashok Bhausaheb Kadam
Mangesh Jagannath Pawar
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Glenmark Pharmaceuticals Limited
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Publication of WO2008035356A2 publication Critical patent/WO2008035356A2/en
Publication of WO2008035356A3 publication Critical patent/WO2008035356A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—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 modulated by a cannabinoid receptor (such as pain, neurodegenerative disorders, eating disorders, weight loss or control, and obesity).
  • CBDl cannabinoid 1
  • CBD2 cannabinoid 2
  • 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., 5-19, 2005).
  • Anandamide which is produced postsynaptically, is the main fatty acid involved in the system. It gains access to the extra cellular space and activates CBl cannabinoid receptors located on presynaptic nerve terminals. This activation causes presynaptic inhibition of ⁇ - 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.
  • CBl agonists or antagonists increase or decrease the motivation to work for palatable ingesta (Gallate J E and McGregor I S, Psychopharmacology, 142, 302-308, 1999 and Gallate J E, Saharov T, Mallet P E and McGregor I S, 1999, Eur. J, Pharmacol, 370, 233-240, 1999).
  • Cannabinoids appear to directly stimulate eating by actions on appetitive processes, making food stimuli more salient and rapidly inducing eating even in satiated animals (Williams C M and Kirkham TC, Physiol. Behav., 76, 241-250, 2002).
  • 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, neuroinflarnmatory 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 receptor mediated syndromes diseases or disorders which include appetite, metabolism, diabetes, obesity, glaucoma associated intra-ocular pressure, mood disorders, seizures, substance abuse, learning disorders,
  • CB modulators have been characterized as agonists, inverse agonists or antagonists to CBl and/or CB2 receptors.
  • These modulators include naphthalen- l-yl-(4-pentyloxynaphthalen-l-yl) methanone (SAB-378), 4-(2,4-dichlorophenylamino)-N- (terahydropyran-4-yl)methyl-2-trifluoromethylbenzamide (GW-842166X), N-(l-piperidinyl)- 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3 -carboxamide (SRl 41716A), 3-(4-chlorophenyl-N'-(4-chlorophenyl)sulfonyl-N-methyl-4-phenyl-4,5-dihydro-l/i-pyrazole- 1 -carboxamide (SLV-319), and
  • 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.
  • U.S. Patent No. 6,906,080 discloses tricyclic derivatives of pyrazolecarboxylic acid of formula (A) (shown below), methods for preparing the compounds of formula (A) and pharmaceutical compositions containing them.
  • the compounds of formula (A) are active on cannabinoid CBl receptors.
  • X— Y— represents — CH 2 - S(O) P — or — S(O) P — CH 2 - ; and Ri represents an NR 2 R 3 group.
  • WO 97/29079 WO 98/37061, WO 99/02499, WO 00/10967, WO 00/10968, WO 01/58869, WO 01/70700, WO 02/076949, WO 03/026647, WO 03/026648, WO 03/027069, WO 03/027076, WO 03/027114, WO 03/077847, WO 03/088968, WO 04/13120, WO 04 /69837, WO 04/058145, WO 04/26301, WO 04/058744, and WO 04/096763.
  • the present invention relates to CBl receptor antagonists or inverse agonists of general formula (I):
  • Z is -O-, -S(O) m - or -NR e - ;
  • R and R are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a protecting group or R 1 and R 2 taken together with the nitrogen atom to which they are attached may be joined to form an optionally substituted 3 to
  • R 3 and R 4 are independently hydrogen or Ci -6 alkyl optionally substituted with halogen, or R 3 and R 4 taken together with the carbon atom to which they are attached may form a carbonyl
  • R 3 and R 4 taken together with the carbon atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least one heteroatoms selected from O, NR e or
  • Preferred is a compound of formula (I) where Z is O;
  • a compound of formula (I) where R 3 and R 4 taken together with the carbon atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least one heteroatoms selected from O, NR e or S(O) n ,; Further preferred is a compound of formula (I) where -CR 3 R 4 is cyclobutyl; Further preferred is a compound of formula (I) where -CR 3 R 4 is cyclopentyl; Further preferred is a compound of formula (I) where -CR 3 R 4 is cyclohexyl; Further preferred is a compound of formula (I) where R 1 is hydrogen Further preferred is a compound of formula (I) where R 2 is 2, 4-Difluorophenyl Further preferred is a compound of formula (I) where R 1 and R 2 taken together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic
  • R 5 is hydrogen, -0R a , halo or cyano.
  • Representative compounds of the present invention include those specified below and pharmaceutically acceptable salts thereof.
  • the present invention should not be construed to be limited to them.
  • 35 ⁇ G-Piperidino- 1 -(2,4-dichlorophenyl)-7-iodo- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3- carboxamide hydrochloride, 36. iV3-Azepanyl-l-(2,4-dichlorophenyl)-7-iodo-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the present invention and optionally together with one or more pharmaceutically acceptable excipients, diluents, carriers or mixture thereof.
  • the compounds and pharmaceutical compositions of the present invention are useful in the treatment of diseases, conditions and/or disorders modulated by cannabinoid receptors and in particular CBl and /or CB2 receptor modulators. These compounds are particularly useful in the treatment of appetite disorders, metabolism disorders, diabetes, obesity, glaucoma-associated intraocular pressure, social disorder, 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, pain or neurodegenerative related syndromes, disorders or diseases.
  • Yet another aspect of the invention provides a method of treating a disease, condition and/or disorder modulated by a cannabinoid (CB) receptor and in particular CBl and /or CB2 receptor modulators 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
  • cannabinoid (CB) receptor modulator is CBl or CB2 receptor modulator.
  • CB receptor modulator is agonist, antagonist, partial agonist or inverse agonist.
  • cannabinoid receptor mediated disease is obesity or dyslipidemia mediated by cannabinoid receptor 1 (CBl).
  • the disease, condition 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 syndrome, disorder and disease.
  • the present invention also discloses combination product or medicament comprising one or more compounds described herein and one or more of other therapeutic agents for treating disease, disorder or condition described in this invention.
  • the present invention preferably discloses combination product or medicament comprising one or more compounds described herein and one or more of antiobesity agent, ACAT inhibitor, PDE IV inhibitor, DPP IV inhibitor, antidiabetic agent, dyslipidemic agent, CETP inhibitor, HMG-CoA reductase inhibitor, fibrate, guggle lipid or other CBl or CB2 modulator for treating disease, disorder or condition described in this invention.
  • the present invention further provides intermediates of formula 2 useful for the preparation of compounds of formula I:
  • the present invention further provides intermediates of formula 5 useful for the preparation of compounds of formula I:
  • aryl refers to aromatic radicals having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydr ⁇ napthyl, 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 .
  • heterocyclic ring refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepanyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom from the alkyl group that results in the creation of a stable structure.
  • heterocyclyl refers to a heterocyclic ring radical as defined above.
  • the heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methyl ethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl ⁇ tert- butyl).
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, and 2-butenyl.
  • alkynyl refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH 3 and -OC 2 H 5 .
  • cycloalkyl denotes a 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 or sprirobicyclic groups, e.g., spiro(4.4) non-2 -yl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical, having 3 to about 8 carbon atoms, directly attached to an alkyl group.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • cycloalkylaryl refers to a cyclic ring-containing radical, having 3 to about 8 carbon atoms, directly attached to an aryl group.
  • Non-limiting examples of such groups include phenylcyclopropyl, phenylcylobutyl and phenyl cyclopentyl.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
  • the substituents in the aforementioned "substituted” groups cannot be further substituted.
  • substituent on “substituted alkyl” is "substituted aryl”
  • substituent on "substituted aryl” cannot be “substituted alkenyl”.
  • protecting group refers to a substituent that is employed to block or protect a particular functionality. Other functional groups on the compound may remain reactive.
  • 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, tert-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 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-f ⁇ >-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, and nitroethyl.
  • stereoisomer refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. These include enantiomers, diastereomers, geometrical isomers, atropisomer or conformational isomers. All the stereoisomers of 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, which are characterized by relatively easy interconversion of isomeric forms in equilibrium. These isomers are intended to be covered by this invention.
  • prodrug refers to compounds, which are an inactive precursor of a compound, converted into its active form in the body by normal metabolic processes.
  • ester refers to compounds, which are formed by reaction between an acid and an alcohol with elimination of water. Ester can be represented by the formula RCOOR'.
  • polymorph refers to a specific crystalline form of a compound.
  • cannabinoid receptor refers to any one of the known or heretofore unknown subtypes of the class of cannabinoid receptors, including CBl and/or CB2 receptors, that may be bound by a cannabinoid modulator compound of the present invention.
  • modulator further refers to the use of a compound of the invention as a CB (e.g., CBl and/or CB2) receptor agonist, partial agonist, antagonist or inverse-agonist.
  • treating or “treatment” of a state, disorder or condition includes:
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, 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-
  • salts include acid addition salts (where appropriate) such as sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartarates, maleates, citrates, fumarates, succinates, palmoates, methanesulfonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • acid addition salts such as sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartarates, maleates, citrates, fumarates, succinates, palmoates, methanesulfonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates
  • solvates includes hydrates and other solvents of crystallization (such as alcohols).
  • the compounds of the present invention may form solvates with standard 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 pharmaceutically acceptable carrier or diluent).
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention.
  • the compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone .
  • the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic 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, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampule, 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 can be adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • the oral route is preferred.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approximately 9 mg Mywacett 9-40 T and approximately 0.9 mg acylated monoglyceride
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment, amelioration, and/or prevention of diseases, conditions and/or disorders modulated by a cannabinoid (CB) receptor, especially those modulated by the CBl or CB2 receptor including those discussed below.
  • CBD cannabinoid
  • the present invention further provides a method of treating a disease, condition and/or disorder modulated by a cannabinoid receptor (CB), and in particular the CBl or CB2 receptor, in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • CBD cannabinoid receptor
  • Diseases, conditions, and/or disorders that are modulated by a CB receptor include, but are not limited to, appetite disorders, metabolism disorders, catabolism disorders, diabetes, obesity, social related disorders, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, pain (such as neuropathic pain) and neurodegenerative related syndromes, disorders and diseases.
  • Appetite related syndromes, disorders or diseases include, but are not limited to, obesity, overweight conditions, anorexia, bulimia, cachexia, dysregulated appetite and the like.
  • Obesity related syndromes, disorders or diseases include, but are not limited to, obesity as a result of genetics, diet, food intake volume, metabolic syndrome, disorder or disease, hypothalmic disorder or disease, age, abnormal adipose mass distribution, abnormal adipose compartment distribution, compulsive eating disorders, motivational disorders which include the desire to consume sugars, carbohydrates, alcohols or drugs or any ingredient with hedonic value and the like.
  • Symptoms associated with obesity related syndromes, disorders, and diseases include, but are not limited to, reduced activity.
  • Metabolism related syndromes, disorders or diseases include, but are not limited to, metabolic syndrome, dyslipidemia, elevated blood pressure, insulin sensitivity or resistance, hyperinsulinemia, hypercholesterolemia, hyperlipidemias, atherosclerosis, hypertriglyceridemias, arteriosclerosis, other cardiovascular diseases, osteoarthritis, dermatological diseases, sleep disorders (disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), cholelithiasis, hepatomegaly, steatosis, abnormal alanine aminotransferase levels, polycystic ovarian disease, inflammation, and the like.
  • Diabetes related syndromes, disorders or diseases include, but are not limited to, glucose dysregulation, insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity, hyperglycemia and the like.
  • Catabolism related syndromes, disorders or diseases include, but are not limited to, catabolism in connection with pulmonary dysfunction and ventilator dependency; cardiac dysfunction, e.g., associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure.
  • Ophthalmic diseases include, but are not limited to, glaucoma, glaucoma-associated intraocular pressure retinitis, retinopathies, uveitis, and acute injury to the eye tissue (e.g. conjunctivitis).
  • Social or mood related syndromes, disorders or diseases include, but are not limited to, depression (including, but not limited to, bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, cognitive disorders and the like).
  • depression including, but not limited to, bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, cognitive disorders and the like).
  • Substance abuse related syndromes, disorders or diseases include, but are not limited to, drug abuse and drug withdrawal.
  • Abused substances include, but are not limited to, alcohol, amphetamines (or amphetamine like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin abuse, barbiturates, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics, benzodiazepines, or combinations of any of the foregoing.
  • the compounds and pharmaceutical compositions can also be used to treat withdrawal symptoms and substance- induced anxiety or mood disorder.
  • the present invention further provides a method of treating nicotine dependency, addiction, withdrawal or aiding in the cessation or lessening of tobacco in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • 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, disorders or diseases include, but are not limited to, multiple sclerosis, cerebral palsy and the like.
  • Locomotor activity and movement syndromes, disorders or diseases include, but are not limited to, stroke, Parkinson's disease, multiple sclerosis, epilepsy and the like.
  • Respiratory related syndromes, disorders or diseases include, but are not limited to, diseases of the respiratory tract, chronic obstructive pulmonary disorder, emphysema, asthma, bronchitis and the like.
  • Kidney dysfunction nephritis which can be treated with the modulators of the present invention includes, but is not limited to, mesangial proliferative glomerulonephritis, nephritic syndrome, liver dysfunction (hepatitis, cirrhosis).
  • Autoimmune or inflammation related syndromes, disorders or diseases include, but are not limited to, psoriasis, lupus erythematosus, diseases of the connective tissue, Sjogren's syndrome, ankylosing spondylarthritis, rheumatoid arthritis, reactional arthritis, undifferentiated spondylarthritis, Behcet's disease, autoimmune hemolytic anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, graft rejection or diseases affecting the plasma cell line; allergic diseases: delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis or allergic conjunctivitis infectious parasitic, viral or bacterial diseases (such as AIDS and meningitis), inflammatory diseases (such as diseases of the joints including, but not limited to, arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease
  • Cell growth related syndromes, disorders or diseases include, but are not limited to, dysregulated mammalian cell proliferation, breast cancer cell proliferation, prostrate cancer cell proliferation and the like.
  • Pain related syndromes, disorders or diseases include, but are not limited to, central and peripheral pathway mediated pain, bone and joint pain, migraine headache associated pain, cancer pain, dental pain, menstrual cramps, labor pain, chronic pain of the inflammatory type, allergies, rheumatoid arthritis, dermatitis, immunodeficiency, chronic neuropathic pain, (e.g.
  • diabetic neuropathy sciatica, non specific lower back pain, fibromyalgia; HIV -related neuropathy; post herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions), hodgkin's disease, myasthenia gravis, nephrotic syndrome, scleroderma, thyroiditis and the like.
  • Neurodegenerative related syndromes, disorders or diseases include, but are not limited to, Parkinson's disease, multiple sclerosis, epilepsy, ischemia or secondary biochemical injury collateral to traumatic head or brain injury, brain inflammation, eye injury or stroke and the like.
  • Suitable pharmaceutical agents include, but are not limited to, anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, 11 ⁇ -hydroxy steroid dehydrogenase- 1 (1 I ⁇ -HSD type 1) inhibitors, peptide YY 3-36 or analogs thereof, MCR-4 agonists, cholecystol ⁇ nin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte-stimulating hormone receptor
  • anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, 11 ⁇ -hydroxy steroid dehydrogenase- 1 (1 I ⁇ -HSD
  • anorectic agents such as a bombesin agonist
  • neuropeptide- Y receptor antagonists such as a bombesin agonist
  • thyromimetic agents such as a bombesin agonist
  • dehydroepiandrosterone or an analog thereof glucocorticoid receptor agonists or antagonists, orexin receptor antagonists
  • glucagon-like peptide- 1 (GLP-I) receptor agonists GLP-I
  • DPP-IV dipeptidyl peptidase IV
  • ciliary neurotrophic factors such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, N. Y.
  • the present invention preferably provides a combination product or medicament comprising one or more compounds described herein and one or more of other therapeutic agents for treating disease, disorder or condition described in this invention.
  • the instant invention preferably discloses combination product or medicament comprising one or more compounds described herein and one or more of antiobesity agent, ACAT inhibitor, PDE IV inhibitor, DPP IV inhibitor, antidiabetic agent, dyslipidemic agent, CETP inhibitor, HMG-CoA reductase inhibitor, fibrate, guggle lipid or other CBl or CB2 modulator for treating disease, disorder or condition described in this invention.
  • anti-obesity agents such as orlistat, sibutramine, bromocriptine, ephedrine, leptin, peptide YY 3-36 or an analog thereof (including the complete peptide YY), and pseudoephedrine.
  • compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
  • Anti-obesity agents for use in the combinations, pharmaceutical compositions, and methods of the invention can be prepared using methods known to one of ordinary skill in the art, for example, sibutramine can be prepared as described in U.S. Pat. No. 4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888; orlistat can be prepared as described in U.S. Pat. Nos. 5,274,143, 5,420,305, 5,540,917, and 5,643,874; and PYY 3-36 (including analogs) can be prepared as described in U.S. Patent Publication No. 2002/0141985 and International Publication No. WO 03/027637. All of the above recited references are incorporated herein by reference.
  • agents for reducing alcohol withdrawal symptoms may also be co-administered, such as benzodiazepines, beta- blockers, clonidine, carbamazepine, pregabalin, and gabapentin (NeurontinTM).
  • Treatment for alcoholism is preferably administered in combination with behavioral therapy including such components as motivational enhancement therapy, cognitive behavioral therapy, and referral to self-help groups, including Alcohol Anonymous (AA).
  • AA Alcohol Anonymous
  • antihypertensive agents include antihypertensive agents; antidepressants (e.g., fluoxetine hydrochloride (ProzacTM); cognitive improvement agents (e.g., donepezil hydrochloride (AirceptTM.) and other acetylcholinesterase inhibitors); neuroprotective agents (e.g., memantine); antipsychotic medications (e.g., ziprasidone (GeodonTM), risperidone (RisperdalTM), and olanzapine (ZyprexaTM)); insulin and insulin analogs (e.g., LysPro insulin); GLP-I (7-37) (insulinotropin) and GLP-I (7-36)-NH 2 ; sulfonylureas and analogs thereof: chloropropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide ® , glimepiride, repaglinide, meglitinide
  • 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.
  • Pyrazole carboxylic acid of the formula 5 where R 5 is cyano group or heterocycle derived from cyano group may be prepared as shown in Scheme 4.
  • Aromatic cyanation of intermediate 4 where X is Br, I, or OSO 2 CF 3 with transition metal cyanides or trimethylsilyl cyanide (TMSCN) in presence of a suitable Pd(O) catalyst affords intermediate 12 (Chatani N. et al J. Org. Chem. 1986, 51(24), 4714-4716).
  • Selective ester hydrolysis of 12 affords pyrazole acid 5.
  • the cyano group can be transformed to a heterocycle, eg. tetrazole, prior to hydrolysis to pyrazole acid 4 (Koguro K. et al Synthesis, 1998, 6, 910).
  • the compound of formula 4 where X is protected hydroxyl group can be converted to free hydroxyl group by using a suitable reagent such as trimethylsilyl iodide boron tribromide or 48 % HBr in acetic acid.
  • a suitable reagent such as trimethylsilyl iodide boron tribromide or 48 % HBr in acetic acid.
  • X is a benzyloxy group
  • catalytic hydrogenolysis affords the phenolic derivative.
  • the phenolic hydroxyl group can be realkylated with a suitable alkyl or fluoroalkyl halide (eg. CHF 2 Cl) and subsequently hydrolysed to the pyrazole acid of the general formula 5.
  • [ 3 H]CP55940 was used as the radioligand to bind the CBl receptor present in a rat brain membrane preparation which can be displaced by unlabeled ligands having affinity to the CBl receptor.
  • the assay was performed according to the modified method of Thomas et ah, 1998 (J. Pharmacol. Exp. Ther. 285: 285-292).
  • the total reaction mixture 250 ⁇ l contains Tris-BSA buffer (50 mM 2-amino-2-(hydroxymethy I)- 1,3 -propanediol, pH 7.4 with 1.5 % bovine serum albumin) or unlabeled WIN55212-2 (1 ⁇ M) or test samples (1 ⁇ M), [ 3 H]CP55940 (0.8 nM) and 100 ⁇ g of rat brain membrane.
  • the non-specific binding was defined by 1 ⁇ M of WIN55212-2.
  • the assay mixture was incubated at 37 0 C for 1 hour. The reaction was then stopped by rapid filtration under vaccum using Whatman GF/B-96 micro filter plate. A scintillation cocktail was added and radioactive counts were measured using Topcount beta scintillation counter.
  • [ 3 H]CP55940 was used as the radioligand to bind human CBl receptors expressed on the membranes from CHO cells (the hCBl-CHO cell line was generated in- house) which can be displaced by unlabeled ligands having affinity to the CBl receptor.
  • the assay was performed according to the modified method of Ross et al., 1999 (Br. J. Pharmacol. 128, 735-743). The reaction was set up in a total volume of 200 ⁇ l in poly- ethyleneimine (PEI) (0.2 %) pre-coated Millipore GFB (Glass Fibre-B) filter plates. 1.0 mM 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 reaction mixture contained Tris-BSA buffer (50 mM Tris, 5 mM MgCl 2 , 1 mM EDTA, pH 7.4 with 0.1 % BSA), unlabeled CP-55,940 (0.5 ⁇ M) or test samples, [ 3 H]CP55940 (0.75 nM ) and 50 ⁇ g of human CBl receptor preparation.
  • Tris-BSA buffer 50 mM Tris, 5 mM MgCl 2 , 1 mM EDTA, pH 7.4 with 0.1 % BSA
  • unlabeled CP-55,940 0.5 ⁇ M
  • test samples [ 3 H]CP55940 (0.75 nM )
  • [ 3 H]CP55940 (0.75 nM )
  • the results of the assay are shown in the Tables 1 - 6.
  • Examples 1-98 represent preferred embodiments of the present invention. It should be understood that there may be other embodiments which fall within the scope and spirit of this invention.
  • Specific methods adopted for the coupling reaction of pyrazole carboxylic acids 5 with amines 6 have been given in Scheme 5-10. However, the coupling reaction can be performed using various other approaches known in the literature. For example, activation of carboxylic acid 5 with various activating reagents (thionyl chloride, oxalyl chloride, DCC 5 CDI and the like) followed by treatment with amines of the general formula 6 affords compounds of the general formula I.
  • activating reagents thionyl chloride, oxalyl chloride, DCC 5 CDI and the like
  • Step 1 Ethyl 2-oxo-2-(4-oxo-3,4-dihydro-2H-3-chromenyl)acetate: A solution of 2,3- dihydro-4i/-chromen-4-one (5.0 g, 33.8 mmol) in THF (50 niL) was added dropwise (30 min) to a stirred and cooled (-78 0 C) solution of 20 % lithium bis(trimethylsilyl)amide [LHMDS] (31.10 niL, 37,0 mmol) in THF under nitrogen atmosphere. This mixture was allowed to warm up to -40 0 C and maintained at -40 to -30 °C for 30 min.
  • LHMDS lithium bis(trimethylsilyl)amide
  • Step 2 Ethyl l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate: A solution of Step 1 intermediate (4.0 g, 16.1 mmol) in absolute ethanol (30 mL) was treated with 2,4-dichlorophenylhydrazine (2.35 g, 16.1 mmol) in one portion with stirring under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The yellow solid separated out was collected by filtration, rinsed with cold ethanol and dried to afford 6.0 g of the desired hydrazone.
  • Step 3 l-(2,4-Dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: To a solution of Step 2 intermediate (5.50 g, 14.0 mmol) in methanol (80 mL) was added IN potassium hydroxide (KOH) (30 mL) and the mixture was refluxed for 1.0 h under stirring. The methanol was evaporated under reduced pressure and the residue was diluted with water (100 mL) and the mixture was acidified with IN hydrochloric acid (HCl) to pH 2.0.
  • KOH potassium hydroxide
  • Step 4 N3-Piperidino-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride: The Step 3 intermediate (100 mg, 0.3 mmol) was dissolved in anhydrous THF (5 mL) under nitrogen atmosphere. 1-aminopiperidine (30 mg, 0.3 mmol), triethylamine (141 mg, 1.40 mmol), and benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate [BOP] (147 mg, 0.3 mmol) was added and the reaction mixture was allowed to stir at room temperature under nitrogen atmosphere for 3 h.
  • the reaction mixture was diluted with EtOAc (15 mL) and the layers were separated.
  • the aqueous layer was extracted with EtOAc (2 x 20 mL) and combined organic extracts were washed with IN sodium hydroxide (NaOH) (25 mL) and dried over anhydrous Na 2 SO 4 .
  • the residue obtained after evaporation of the solvent was purified on a silica gel column using 20 % EtOAc in hexane to afford 98 mg of the product as an off-white solid.
  • the free base 98 mg (0.221 mmol) was dissolved in EtOAc (1 mL), cooled to 0 0 C and 12 % HCl in EtOAc (3 mL) was added to result in a white solid.
  • Examples 2 to 6 were prepared from l-(2,4-Dichloropheny I)-1, 4-dihydrochromeno [4,3- c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 1 and the appropriate amines (Refer to Table 1) according to the procedure mentioned in Example 1, Step 4.
  • Step ⁇ 4 N3-Piperidino-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 2.56 mmol) with 1-aminopiperidine (28 mg, 0.28 mmol) using BOP reagent (136 mg, 0.31mmol) and triethylamine (130 mg, 1.28 mmol) as described in Example 1, Step 4 gave 67 mg of the product as a white solid; IR (KBr) 3393, 2932, 1690, 1509, 1382, 1360, 1140, 807, 747 cm “1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.60-1.78 (m, 2H), 1.77 (s, 3H) 5 1.84 (s, 3H), 1.90-2.02 (m, 4H), 3.42-3.61 (m, 4
  • Examples 8 to 11 were prepared using l-(2,4-Dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 7 and appropriate amines (Refer to Table 1) according to the coupling procedure described in Step 4, Example 1.
  • Example 12 iV3-Piperidino-6-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride
  • Step 1 Ethyl 2-(8-chloro-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate: 8- chloro-4-chromanone (3.1O g, 16.97 mmol) in T ⁇ F was reacted with diethyl oxalate (2.49 g, 16.97 mmol) in the presence of 20 % L ⁇ MDS in T ⁇ F (15.62 mL, 18.67 mmol) as described in Example 1, Step 1 to give 3.88 g of the compound as yellow liquid which solidifies on standing; IR (KBr) 3423, 2980, 1723, 1598, 1475, 1286, 1237, 1144, 1072, 1008 cm "1 ; 1 H N
  • Example 13 and 14 were prepared using 6-Chloro-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 12 and appropriate amines (Refer to Table 2) according to the procedure mentioned in Example 12, Step 4.
  • Step 4 ⁇ G-Piperidino- ⁇ -chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochro- meno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (62 mg, 0.146 mmol) with 1 -aminopiperidine (16 mg, 0.160 mmol) using BOP reagent (77 mg, 0.175 mmol) and triethylamine (74 mg, 0.73 mmol) as described in Example 1, Step 4 gave 40 mg of the product as a white solid; IR (KBr) 3436, 2919, 2850, 1680, 1509, 1452, 1244, 1111, 813 cm “1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.62-1.78 (m, 2H), 1.78 (s, 3H), 1.86 (s, 3H), 1.93-2.02 (m, 4H), 3.
  • Step 1 Ethyl 2-(6-bromo-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate: 6- bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (7.35 g, 28.81 mmol) was reacted with diethyl oxalate (4.21 g, 28.81 mmol) in the presence of 20 % LHMDS in THF (26.5 mL, 31.69 mmol) as described in Example 1, Step 1 to give 8.21 g of the compound as a dark yellow semi-solid; IR (neat) 3087, 2872, 1727, 1590, 1466, 1282 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.32-1.43 (m, 3H), 1.57 (s, 3H), 1.62 (s, 3H), 4.32-4.42 (m, 2H), 4.93 (s,
  • Step 2 Ethyl 8-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Step 1 intermediate (2.0 g, 5.64 mmol) was reacted with 2,4- dichlorophenylhydrazine (1.0 g, 5.64 mmol) in ethanol (50 mL) as described in Example 1, Step 2 to give 1.45 g of the product as a brown solid; IR (KBr) 3423, 2976, 1732, 1606, 1411, 1252 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.42-1.47 (m, 3H), 1.79 (s, 3H), 1.85 (s, 3H), 4.40- 4.48 (m, 2H) 5 6.49 (s, IH), 6.82-6.85 (m, IH) 3 7.24-7.27 (m, IH), 7.49-7.
  • Step 3 8-Bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 -c]pyrazole- 3-carboxylic acid:.
  • Step 4 7V3-Piperidino-8-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.21 mmol) with 1-aminopiperidine (24 mg, 0.24 mmol) using BOP reagent (113 mg, 0.25 mmol) and triethylamine (108 mg, 1.07 mmol) as described in Example 1, Step 4 gave 56 mg of the product as an off-white solid; IR (KBr) 3421, 2936, 2629, 1703, 1509, 1381, 1439, 1245 cm “1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.85 (br s, 2H), 1.68 (s, 3H), 1.76 (s, 3H), 1.87-1.93 (m 4H), 3.45 (br s
  • Examples 20 and 21 were prepared from Ethyl 2-(7-chloro-4-oxo-3,4-dihydro-2H-3- chromenyl)-2-oxoacetate and the appropriate hydrazines (Refer to Table 2) followed by hydrolysis and subsequent coupling of the acid obtained with 1-aminopiperidine according to the procedure described in Example 1, Steps 2, 3 and 4.
  • Step 4 N3-Piperidino-l-(2,4-difluorophenyl)-7-iodo-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (130 mg, 0.27 mmol) with 1-aminopiperidine (30 mg, 0.297 mmol) using BOP reagent (130 mg, 0.297 mmol) and triethylamine (136 mg, 1.35 mmol) as described in Example 1, Step 4 gave 80 mg of the product as an off-white solid; IR (KBr) 3422, 2940, 1698, 1603, 1520, 1441, 1382, 1263, 1197, 984, 828, cm '1 ; 1 H NMR (300 MHz, OMSO-d 6 ) ⁇ 1.32 (br m, 2H), 1.57 (br m, 4H), 1.66 (s, 3H), 1.75 (
  • Examples 23 to 28 were prepared from Ethyl 2-(7-iodo-2,2-dimethyl-4-oxo-3,4- dihydro-27J-3-chromenyl)-2-oxoacetate and the appropriate hydrazines (Refer to Table 2) followed by hydrolysis and coupling of subsequent acid with 1 -aminopiperidine according to the procedure described in Example 1, Steps 2, 3 and 4.
  • Examples 30 and 31 were prepared from 7-Chloro-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 29 and appropriate amines (Refer to Table 3) according to the coupling procedure described in Example 1, Step 4.
  • Examples 33 and 34 were prepared from 7-Bromo-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 32 and appropriate amines (Refer to Table 3) according to the coupling procedure described in Example 1, Step 4.
  • Step 3 l-(2,4-Dichlorophenyl)-7-fluoro-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (1.20 g, 4.64 mmol) using IN KOH (9.26 mL) in methanol (18 mL) as described in Example 1, Step 3 gave the 0.817 g of the acid as an off-white solid; IR (KBr) 3444, 2974 ⁇ 2851, 1719, 1586, 1490, 1382, 1279, 1068, 822 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.82 (br s, 3H), 1.85 (br s, 3H) 5 6.10 (br m, IH), 6.20-6.40 (m, 2H), 7.40-7.58 (m, 2H), 7.63 (br m, IH).
  • Step 4 N3-Piperidino-l-(2,4-dichlorophenyl)-7-fluoro-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (350 mg, 1.52 mmol) with 1-aminopiperidine (167 mg, 1.67 mmol) using triethylamine (770 mg, 7.60 mmol) and BOP reagent (642 mg, 1.52 mmol) as described in Example 1, Step 4 gave 127 mg of the product as an off-white solid; IR (KBr) 3421, 2945, 2550, 1705, 1621, 1515, 1453, 1384, 1210, 1138, 1064, 981, 816 cm “1 ; 1 H NMR (SOO MHZ, CD 3 OD) ⁇ 1.60-1.90 (m, 8H), 1.90-2.13 (m, 4H), 3.10-3.58 (m, 4
  • Examples 40 to 44 were prepared from 7-Chloro ⁇ l-(2,4-dichlorophenyl) ⁇ 4,4- dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 39 and the appropriate amines (Refer to Table 3) according to the coupling procedure described in Example 1 , Step 4.
  • Step 4 N3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.21 mmol) with 1-aminopiperidine (26 mg, 0.26 mmol) using BOP reagent (115 mg, 0.25 mmol) and triethylamine (106 mg, 1.05 mmol) as described in Example 1, Step 4 gave 70 mg of the product as a white solid; IR (KBr) 3428, 3084, 2950, 1645, 1500, 1380, 1400, 1230, 725 cm “1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.44-1.64 (m, 2H) 3 1.77 (s, 3H) 3 1.75-1.85 (m, 4H) 3 1.85 (s, 3H) 3 3.10-3.
  • Examples 46 to 49 were prepared from 7-Bromo-l-(2,4-dichlorophenyl)-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]-pyrazole-3-carboxylic acid, Step 3 intermediate, Example 45 and the appropriate amines (Refer to Table 3) according to the coupling procedure described in Example I 3 Step 4.
  • Step 4 N3-Piperidino-l-(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydiO- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.19 mmol) with 1-aminopiperidine (21 mg, 0.21 mmol) using BOP reagent (94 mg, 0.21 mmol) and triethylamine (98 mg, 0.97 mmol) as described in Example 1, Step 4 gave 102 mg of the product as an off-white solid; IR (KBr) 3368, 3060, 2935, 1690, 1600, 1504, 1381, 1234, 1063, 810 cm “1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.55-1.58 (m, 2H), 1.68 (s, 3H), 1.75 (s, 3H), 1.86-1.90 (m, 4H),
  • Examples 51 and 52 were prepared from l-(2,4-Dichlorophenyl)-7-iodo-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]-pyrazole-3-carboxylic acid, Step 3 intermediate, Example 50 and the appropriate amines (Refer to Table 3) according to the coupling procedure mentioned in Example 1, Step 4.
  • Example 55 iV3-Piperidino-l-(2,4-dichlorophenyI)-7-isopropyl-4,4-dimethyl ⁇ l,4 dihy drochromeno [4,3-c] py razole-3-carboxamide hydrochloride Step 1: Ethyl (7-isopropyl-2,2-diniethyl-4-oxo-3,4-dihydro-2H-chromen-3-yl)oxoacetate: 7- isopropyl-2,2-dimethyl-2,3-dmydro-4H-chromen-4-one (3.10 g, 14.20 mmol) was reacted with diethyl oxalate (2.07 g, 14.20 mmol) in the presence of 20 % LHMDS in THF (14.24 mL, 17.04 mmol) as described in Example 1, Step 1 to give 2.60 g of the compound as a brown oil; IR (neat) 2965,
  • Step 4 N3-Piperidino-7-(/ert-butyl)-l -(2,4-dichlorophenyl)-4,4-dimethyl-l ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride : Coupling reaction of Step 3 intermediate (270 mg, 0.61 mmol) with 1-aminopiperidine (67 mg, 0.67 mmol) using BOP reagent (0.30 g, 0.67 mmol) and triethylamine (0.31 g, 3.10 mmol) as described in Example 1, Step 4 gave 65 mg of the product as a white solid ; IR (KBr) 2964, 1698, 1618, 1455, 1215, 1099, 984, 756 cm '1 ; 1 H NMR (300 MHz, DMSO-fife) ⁇ 1.19 (s, 9H), 1.41 (br m, 2H), 1.73 (br s, 6H), 1.78
  • Step 1 Ethyl 7-cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: A stirred solution of Ethyl l-(2,4-dichlorophenyl)-7-iodo-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (600 mg, 1.10 mmol) and tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.022 mmol) in triethylamine (6 mL) was treated with trimethylsilyl cyanide (165 mg, 1.66 mmol) at room temperature followed by reflux for 2 h to afford 390 mg of the compound as a white solid; IR (KBr) 2985, 2228, 1733, 1581, 1412, 1259, 1188, 971, 8
  • Step 4 N3 -Piperidino- 1 -(2,4-dichlorophenyl)-7-methoxy- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.26 mmol) with 1-aminopiperidine (28 mg, 0.28 mmol) using BOP reagent (136 mg, 0.31 mmol) and triethylamine (130 mg, 1.28 mmol) as described in Example 1, Step 4 gave 70 mg of the product as a white solid; IR (KBr) 3434, 2929, 1701, 1625, 1484, 1299, 1268, 1165, 1108, 837, 801 cm '1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.66 (br s, 2H), 1.90-2.01 (m, 4H), 3.50 (br m, 4H), 3.74 (br s,
  • Examples 61 and 62 were prepared from l-(2,4-Dichlorophenyl)-7-methoxy-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 60 and the appropriate amines (Refer to Table 3) according to the coupling procedure mentioned in Example 1, Step 4.
  • Step 1 Ethyl 2-(7-methoxy-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate: 7-methoxy-2,2-dimethyl-2,3-dihydro-4/f-chromen-4-one (5.68 g, 27.54 mmol) was reacted with diethyl oxalate (4.02 g, 27.54 mmol) in the presence of 20 % LHMDS in THF (25.5 mL, 30.29 mmol) as described in Example 1, Step 1 to give 4.16 g of the compound as a pale yellow solid; IR (KBr) 2980, 1735, 1671, 1608, 1443, 1276 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.30-1.44 (m, 3H), 1.50-1.62 (m, 6H), 3.84 (s, 3H), 4.35-4.4.43 (m, 2H), 4.88 (
  • Step 3 l-(2,4-Dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (1.20 g, 2.68 mmol) using IiV KOH (6 mL) in methanol (20 mL) as described in Example 1, Step 3 gave the 1.02 g of the acid as a white solid; IR (KBr) 2939, 1695, 1615, 1434, 1201, 1071 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.82 (s, 3H), 1.86 (s, 3H), 3.76 (s, 3H), 6.26-6.38 (m. 2H), 6.25 (s, IH), 7.46- 7.53 (m, 2H), 7.64 (s, IH).
  • Step 4 iV3-Piperidino-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.23 mmol) with 1-aminopiperidine (26 mg, 0.26 mmol) using BOP reagent (126 mg, 0.28 mmol) and triethylamine (120 mg, 1.19 mmol) as described in Example 1, Step 4 gave 30 mg of the product as a white solid; IR (KBr) 3399, 2943, 1644, 1618, 1434, 1204, 1138 cm '1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.52-1.56 (m, 2H), 1.66 (s, 3H), 1.73 (s, 3H), 1.83-1.87 (m, 4H), 3.33 (br s, 4H), 3.
  • Examples 64 to 69 were prepared from l-(2,4-Dichlorophenyl)-7-methoxy-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]-pyrazole-3-carboxylic acid, Step 3 intermediate, Example 63 and the appropriate amines (Refer to Table 3) according to the coupling procedure described in Example 1, Step 4.
  • Step 1 Ethyl 2-(7-benzyloxy-2,2-dimethyl-4-oxo ⁇ 3,4-dihydro-2H-3-chromenyl)-2- oxoacetate: 7-Benzyloxy-2,2-dimethyl-4-chromanone (15.0 g, 53.12 mmol) (See Synth. Commun.
  • Step 4 N3-Piperidino-l-(2,4-dichlorophenyl)-7-benzyloxy-4,4-dimethyl-l ,A- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (200 mg, 0.40 mmol) with 1 -aminopiperidine (44 mg, 0.44 mmol) using BOP reagent (241 mg, 0.48 mmol) and triethylamine (204 mg, 2.02 mmol) as described in Example 1, Step 4 gave 215 mg of the product as a white solid; IR (KBr) 3420, 2932, 1707, 1621, 1452, 1360, 1271, 1137, 978, 734 cm “1 ; 1 H NMR (300 MHz, DMSO- ⁇ ) ⁇ 1.45 (br s, 2H), 1.72 (br s, 4H), 1.79 (br s, 6H), 3.26 (br
  • Step 1 Ethyl l-(2,4-dichlorophenyl)-7-hydroxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: A stirred solution of Ethyl 7-benzyloxy-l-(2,4-dichlorophenyl)- 4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate, Example 73, Step 2 (500 mg, 0.96 mmol) and sodium iodide (NaI) (157 mg, 1.05 mmol) was treated dropwise with trimethylsilyl chloride (114 mg, 1.05 mmol) in acetonitrile (5 mL) at room temperature and refluxed for 15 h.
  • NaI sodium iodide
  • Step 2 Ethyl l-(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: A stirred solution of Step 1 intermediate (500 mg, 1.15 mmol) and potassium carbonate (318 mg, 2.31 mmol) in dry DMF was purged with dichlorofiuoromethane gas at 80 0 C for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous Na 2 SO 4 and concentrated.
  • Step 4 iV3-Piperidino-l-(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4- dihydrochromeno[4 5 3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.22 mmol) with 1-aminopiperidine (24 mg,0.24 mmol) using BOP reagent (117 mg, 0.26 mmol) and triethylamine (111 mg, 1.10 mmol) as described in Example 1, Step 4 gave 48 mg of the product as a white solid; IR (KBr) 3410, 2939, 1687, 1535, 1457, 1382, 1274, 1181, 1049, 990, 816 cm “1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.48 (br m, 2H), 1.78 (br m, 7H), 1.85 (br s, 3H), 2.95
  • Examples 72 to 74 were prepared from l-(2,4-Dichlorophenyl)-7-difluoromethoxy- 4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 71 and the appropriate amines (Refer to Table 3) according to the coupling procedure mentioned in Example I 5 Step 4.
  • Step 1 Ethyl l-(2,4-dichlorophenyl)-7-(3-chlorophenyl)-l,4-dihydrochromeno-[4,3- c]pyrazole-3-carboxylate: A solution of Step 2 intermediate, Example 36 (200 mg, 0.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.01 rnmol) in dimethoxyethane (DME) (10 mL) was treated with 3-chlorophenylboronic acid (67 mg, 042 mmol) followed by solution of sodium carbonate (Na 2 CO 3 ) (45 mg, 0.42 mmol) in water (5 mL).
  • DME dimethoxyethane
  • Step 3 N3 -Piperidino-7-(3 -chlorophenyl)- 1 -(2,4-dichlorophenyl)- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 2 intermediate (100 mg, 0.21 mmol) with 1-aminopiperidine (23 mg, 0.23 mmol) using BOP reagent (112 mg, 0.25 mmol and triethylamine (107 mg, 1.05 mmol) as described in Example 1, Step 4 gave 55 mg of the product as an off-white solid; IR (KBr) 3411, 2942, 2858, 1698, 1537, 1390, 1265, 1188, 1140, 1007, 977, 749 cm “1 ; 1 H NMR (300 MHz, OMSO-d 6 ) ⁇ 1.40 (br s, 2H), 1.70 (br s, 4H), 3.08 (br s,
  • Step 1 Ethyl l-(2,4-dichlorophenyl)-4,4-dimethyl-7-phenyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Coupling reaction of Step 2 intermediate, Example 50, (0.20 g, 0.37 mmol) with phenylboronic acid (65 mg, 0.42 mmol) using tetrakis(triphenyl- phosphine)palladium(O) (22 mg, 0.02 mmol) in DME (4 mL) followed by solution OfNa 2 CO 3 (45 mg, 0.42 mmol) in water (2 mL) according to the procedure described in Example 76, Step 1 afforded 155 mg of the compound as an off-white solid; IR (KBr) 3019, 2400, 1619, 1518, 1420, 1218, 772, 669 cm “1 ; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇
  • Step 3 N3 -Piperidino- 1 -(2,4-dichlorophenyl)-4,4-dimethyl-7-phenyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (90 mg, 0.19 mmol) with 1-aminopiperidine (21 mg, 0.21 mmol) using BOP reagent (93 mg, 0.21 mmol) and triethylamine (96 mg, 0.95 mmol) as described in Example 1, Step 4 gave 40 mg of the product as an off-white solid; IR (KBr) 3414, 2931, 2855, 1700, 1498, 1259, 1140, 1098, 982, 888, 817, 763 cm “1 ; 1 H NMR (300 MHz, DMSO-4) ⁇ 1.39 (br s, 2H), 1.67 (br s, 4H), 1.76 (s, 3H), 1.
  • Examples 78 to 82 were prepared from Step 2 intermediate, Example 51 and the appropriate phenylboronic acids (Refer to Table 4) followed by hydrolysis and subsequent coupling of the acid with 1-aminopiperidine according to the procedure described in Example 77, Steps 1, 2 and 3.
  • Step 2 iV3-Piperidino-l-(2 5 4-dichlorophenyl)-7-(3-pyridyl-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: A stirred solution of Step 1 intermediate (150 mg, 0.30 mmol) and 1-aminopiperidine (36 mg, 0.36 mmol) in anhydrous THF (2 mL) was treated with 20% LHMDS in THF (0.38 niL, 0.46 mmol). The resulting mixture was stirred at room temperature for 5 h.
  • Step 1 Ethyl (7-chloro-4-oxo-3,4-dihydrospiro[chromene-2,r-cyclobutan]-3- yl)oxoacetate: 7-chlorospiro[criromene-2,l'-cyclobutan]-4(3/J)-one (Kabbe H. J. et al Synthesis 1978, 886-887; Bergmann et al. J. Med Chem.
  • Step 4 iV3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,r- cyclobutane] - 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (70 mg, 0.16 mmol) with 1-aminopiperidine (180 mg, 0.18 mmol) using BOP reagent (79 mg, 0.18 mmol) and triethylamine (81 mg, 0.80 mmol) as described in Example I 5 Step 4 gave 28 mg of the product as an off-white solid; IR (KBr) 3400, 2925, 1636, 1409, 1216, 1044, 759, 669 cm “1 ; 1 H NMR (300 MHz, OMSO-d 6 ) ⁇ 1.39 (br s, IH), 1.68 (br s, 4H), 2.00-2.
  • Step 1 Ethyl (7-bromo-4-oxo-3 ,4-dihydrospiro [chromene-2, 1 '-cyclobutan] -3 -yl)oxoacetate : 7-Bromospiro[chromene-2,l'-cyclobutan]-4(3H)-one (Kabbe H. J. et al .Synthesis 1978, 886-887; Bergmann et al. J. Med. Chem.
  • Step 2 Ethyl 7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l-cyclobutane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (3.0 g, 8.17 mmol) was reacted with 2,4-dichlorophenylhydrazine (1.20 g, 8. 20 mmol) in ethanol (5 mL) as described in.
  • Step 4 iV3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r- cyclobutane]-l ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (200 mg, 0.445 mmol) with 1 -aminopiperidine (49 mg, 0.490 mmol) using BOP reagent (0.215 mg, 0.49 mmol) and triethylamine (225 mg, 2.22 mmol) as described in Example " 1, Step 4 gave 150 mg of the product as a white solid; IR (KBr) 3412, 2945, 2334, 1696, 1507, 1266, 1102, 978, 803 cm “1 ; 1 H NMR (300 MHz, DMSO- ⁇ ) ⁇ 1.42 (br s, 2H), 1.73 (br s, 4H), 2.06-2.
  • Step 1 Ethyl (7-iodo-4-oxo-3,4-dihydrospiro[chromene-2,l '-cyclobutan]-3-yl)oxoacetate: 7-iodospiro[chromene-2,r-cyclobutan]-4(3#)-one (Kabbe H. J. et al. Synthesis 1978, 886- 887; Bergmann et al. J. Med Chem.
  • Step 4 N3-Piperidino-l-(2,4-dichlorophenyl) 7-iodo-spiro[chromene-4,l '- cyclobutane]-l ⁇ -dihydrochromeno ⁇ S-cJpyrazole-S-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (200 mg, 0.342 mmol) with 1-aminopiperidine (349 mg, 0.376 mmol) using BOP reagent (182 mg, 0.410 mmol) and triethylamine (0.173 g, 1.71 mmol) as described in Example 1, Step 4 gave 168 mg of the product as a white solid; IR (KBr) 3410, 2944, 2297, 1694, 1505, 1401, 1266, 1192, 1065, 977, 803 cm “1 ; 1 H NMR (300 MHz, DMSO- ⁇ k) ⁇ 1.38 (br s, IH), 1.66 (br s, 4
  • Step 1 Ethyl (7-chloro-4-oxo-3,4-dihydrospiro[chromene-2,l '-cyclopentan]-3-yl)oxoacetate: 7-chlorospiro[chromene-2,l'-cyclopentan]-4(3//)-one (Kabbe H. J. et al .Synthesis 1978, 886- 887; Bergmann et al. J. Med Chem.
  • Step 4 N3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chiOmene-4,r-cyclopentane]- l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: This compound was prepared by the coupling reaction of Step 3 intermediate (0.154 mg, 0.34 mmol) with 1- aminopiperidine (38 mg, 0.37 mmol) using BOP reagent (0.166 g, 0.37 mmol) and triethylamine (0.17 g, 1.71 mmol) as described in Example 1, Step 4; IR (KBr) 3411, 2944, 2857, 1690, 1509, 1457, 1411, 1261, 1183, 981, 862, 815 cm “1 ; 1 H NMR (300 MHz, DMSO- d 6 ) ⁇ 1.37 (br s, 2H), 1.64 (br s, 4H),
  • Step 4 N3 -Piperidino-7-bromo- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cycl'o- pentane]-l ⁇ -dihydrochromeno ⁇ -cjpyrazole-S-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (93 mg, 0.19 mmol) with 1 -aminohomopiperidine (25 mg, 0. 21 mmol) using BOP reagent (92 mg, 0.
  • Step 1 Ethyl (7-difluoromethoxy-4-oxo-3,4-dihydrospiro[chromene-2,l'-cyclopentane]-3- yl)oxoacetate: 7-difluoromethoxy-spiro[chromene-2,r-cyclopentan]-4(3/i)-one (9.0 g, 33.5 mmol) was reacted with diethyl oxalate (5.4 g, 36.9 mmol) in the presence of 20 % LHMDS in THF (33.0 mL, 40.2 mmol) as described in Example 1, Step 1 to give 7.08 g of the compound; IR (neat) 3382, 2963, 1732, 1685, 1614, 1445, 1254, 1057, 857 cm '1 ; 1 H NMR (300 MHz, DMSO-40 ⁇ 1.26 (m, 3H), 1.75-1.91 (m, 8H), 4.35 (m, 2H),
  • Step 4 N3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,l '-cyclo- hexaneJ-l ⁇ -dihydrochromeno ⁇ -cJpyrazole-S-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (0.55 g, 1.18 mmol) with 1 -aminopiperidine (0.13 g, 1.3 mmol) using BOP reagent (0.57 g, 1.3 mmol) and triethylamine (0.60 g, 5.
  • Step 4 N3 -(Piperidino)-7-bromo- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' - cyclohexane]-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride Coupling reaction of Step 3 intermediate (200 mg, 0.39 mmol) with 1-aminopiperidine (49 mg, 0.43 mmol) using BOP reagent (208 mg, 0.47 mmol) and triethylamine (199 mg, 1.96 mmol) as described in Example 1, Step 4 gave 145 mg of the product as an off-white solid; IR (KBr) 3410, 2929, 1688, 15.05, 1227, 979, 838 cm “1 ; 1 H NMR (300 MHz, DMSO- ⁇ ) ⁇ 1.40 (br s, 2H), 1.57-1.94 (m, 13H), 2.26 (br s
  • Example 94 iV3-(l-Azepanyl)-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l'-cyclohexane]- 1 ,4-dihydrochromeno [4,3-c] py razole-3-carboxamide hydrochloride
  • This compound was prepared from Step 3 intermediate, Example 91 and 1- aminohomopiperidine according to the coupling procedure described in Example 1, Step 4;
  • 1 H NMR 300 MHz, DMSO- d 6 ) ⁇ 1.37 (br s, 2H), 1.58 (br s, 6H), 1.76 (br s, 6H), 1.91-1.95 (m, 2H), 2.21-2.29 (m, IH), 2.41-2.50 (m, IH), 3.31 (br
  • Step 1 Ethyl 2-[7-chloro-l-(4-methylphenylsulfonyl)-4-oxo-l,2,3,4-tetrahydro-3- quinolinyl]-2-oxoacetate: 7-chloro-l-(4-methylphenylsulfonyl)- 1,2,3, 4-tetrahydro-4- quinolinone (Johnson et al J. Am. Chem.

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Abstract

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 modulated by a cannabinoid receptor (such as pain, neurodegenerative disorders, eating disorders, weight loss or control, and obesity).

Description

NOVEL CANNABINOID RECEPTOR LIGANDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND PROCESS FOR THEIR
PREPARATION
This application claims the benefit of Indian Patent Application No. 1482/MUM/ 2006 filed on September 20, 2006, U.S. Provisional Patent Application No. 60/827,484, filed September 29, 2006, 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 modulated by a cannabinoid receptor (such as pain, neurodegenerative disorders, eating disorders, weight loss or control, and obesity).
Background of the Invention
The endogenous cannabinoid system comprises two main receptors, CBl and CB2, and a number of ligands including anandamide and virodhamine which demonstrate the greatest activity at the cannabinoid receptor (Jonathan A. W. & Louis J A, Obes Man., 5-19, 2005). Anandamide, which is produced postsynaptically, is the main fatty acid involved in the system. It gains access to the extra cellular space and activates CBl cannabinoid receptors located on presynaptic nerve terminals. This activation causes presynaptic inhibition of γ- aminobutyric acid or glutamate through inhibition of calcium channels, while simultaneously interfering with vesicle release and activating potassium channels.
However, anandamide is prone to rapid enzymatic hydrolysis. This represents a serious drawback in its use as a drug because, inter alia, substances which are susceptible to hydrolytic cleavage may undergo changes in the gastrointestinal tract.
CBl receptors are predominantly located in the brain and other neurons, while CB2 receptors are predominantly located in immune cells. Stimulation of these receptors is known to affect the central and peripheral action on lipid and glucose metabolism in adipose tissue and most notably, helps to regulate food intake, energy balance and nicotine dependence as well as regulate fear and anxiety.
There 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, 142, 302-308, 1999 and Gallate J E, Saharov T, Mallet P E and McGregor I S, 1999, Eur. J, Pharmacol, 370, 233-240, 1999). Cannabinoids appear to directly stimulate eating by actions on appetitive processes, making food stimuli more salient and rapidly inducing eating even in satiated animals (Williams C M and Kirkham TC, Physiol. Behav., 76, 241-250, 2002).
Current data reveals that cannabinoids mediate suppression of inflammation in vitro and in vivo through stimulation of CB2 receptors (Ehrhart J, et al. J. Neuroinflammation, 2, 29, 2005). The inflammatory mediators such as nitric oxide, cytokines, and chemokines play an important role in microglial cell-associated neuron cell damage. Activated microglial cells have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease, multiple sclerosis, HIV and dementia.
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, neuroinflarnmatory 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-pentyloxynaphthalen-l-yl) methanone (SAB-378), 4-(2,4-dichlorophenylamino)-N- (terahydropyran-4-yl)methyl-2-trifluoromethylbenzamide (GW-842166X), N-(l-piperidinyl)- 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3 -carboxamide (SRl 41716A), 3-(4-chlorophenyl-N'-(4-chlorophenyl)sulfonyl-N-methyl-4-phenyl-4,5-dihydro-l/i-pyrazole- 1 -carboxamide (SLV-319), and (R)-(+)-[2,3-dihydro-5-methyl-3-[4-morpholinylmethyl]- pyrrolo-[l ,2,3-de]-l ,4-benzoxazin-6-yl](l -naphthyl) methanone (WIN55212-2).
Figure imgf000004_0001
SAB-378 (CBl agonist) GW-842166X (CB2 agonist)
Figure imgf000004_0002
SR-141716A SLV-319 WIN-55212-2 (CBl inverse agonist) (CBl antagonist) (CB1/CB2 non-selective agonist)
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.
U.S. Patent Application Publication No 2003/0114432 discloses substituted pyrazolyl derivatives, compositions comprising them, methods of making the substituted pyrazolyl derivatives, and methods for treating cancer, inflammation, and inflammation-associated disorders, such as arthritis with the substituted pyrazolyl derivatives. In particular the patent discloses the pyrazole derivatives of the formula:
Figure imgf000004_0003
U.S. Patent No. 6,906,080 discloses tricyclic derivatives of pyrazolecarboxylic acid of formula (A) (shown below), methods for preparing the compounds of formula (A) and pharmaceutical compositions containing them. The compounds of formula (A) are active on cannabinoid CBl receptors.
Figure imgf000004_0004
(A) wherein
X— Y— represents — CH2- S(O)P— or — S(O)P— CH2- ; and Ri represents an NR2R3 group.
U.S. Patent Nos. 5,624,941, 6,028,084, and 6,509,367; PCT International Publication Nos. WO 98/31227, WO 98/41519, WO 98/43636 and WO 98/43635; and European Publication No. EP 0 658 546 disclose substituted pyrazoles having activity against the cannabinoid receptors.
U.S. Patent Nos. 6,355,631 and US 6,479,479 and PCT International Publication Nos. WO 01/64632, WO 01/64633, and WO 01/64634 are directed to azetidine derivatives as cannabinoid antagonists.
Other cannabinoid receptor modulating compounds are disclosed in U.S. Patent Nos. 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, and 5,532,237, and PCT International Publication Nos. WO 97/29079, WO 98/37061, WO 99/02499, WO 00/10967, WO 00/10968, WO 01/58869, WO 01/70700, WO 02/076949, WO 03/026647, WO 03/026648, WO 03/027069, WO 03/027076, WO 03/027114, WO 03/077847, WO 03/088968, WO 04/13120, WO 04 /69837, WO 04/058145, WO 04/26301, WO 04/058744, and WO 04/096763.
In addition to obesity, there also exists an unmet need for treatment of alcohol abuse. Health risks associated with alcoholism include impaired motor control and decision making, cancer, liver disease, birth defects, heart disease, drug/drug interactions, pancreatitis and interpersonal problems. Studies have suggested that endogenous cannabinoid tone plays a critical role in the control of ethanol intake. The endogenous CBl receptor antagonist SR- 141716A has been shown to block voluntary ethanol intake in rats and mice. (See, Arnone, M., et al, "Selective Inhibition of Sucrose and Ethanol Intake by SR141716, an Antagonist of Central Cannabinoid (CBl) Receptors," Psychopharmacol, 132,104-106 (1997)). For a review, see, Hungund, B. L and B. S. Basavarajappa, "Are Anadamide and Cannabinoid Receptors involved in Ethanol Tolerance? A Review of the Evidence," Alcohol & Alcoholism, 35(2) 126-133, 2000.
Current treatments for alcohol abuse or dependence are generally impeded by non- compliance or potential hepatotoxicity. There is an unmet need for more effective treatments of alcohol abuse or dependence.
There still exists a need for a more effective and safe therapeutic treatment of diseases conditions and/or disorders modulated by cannabinoid receptor antagonists. Summary of the Invention
The present invention relates to CBl receptor antagonists or inverse agonists of general formula (I):
Figure imgf000006_0001
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, N-oxides, stereoisomers, tautomers, prodrugs or polymorphs thereof, wherein:
Z is -O-, -S(O)m- or -NRe- ;
R and R are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a protecting group or R1 and R2 taken together with the nitrogen atom to which they are attached may be joined to form an optionally substituted 3 to
7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NRe or S(O)111;
R3 and R4 are independently hydrogen or Ci-6 alkyl optionally substituted with halogen, or R3 and R4 taken together with the carbon atom to which they are attached may form a carbonyl
(C=O) group, or R3 and R4 taken together with the carbon atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least one heteroatoms selected from O, NRe or
S(0)m; each occurrence of R5 and R6 are independently hydrogen, -0Ra, halo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NRaRb, -C(=L)-Ra, -C(O)O-R3, -C(0)NRaRb, -S(O)m-Ra or -S(0)m-NRaRb; each occurrence of m is independently 0, 1 or 2; each occurrence of p is independently 0, 1, 2, 3 or 4; each occurrence of q is independently 0, 1, 2, 3, 4 or 5; each occurrence of L is independently O, S, or NR?; each occurrence of Ra and Rb is independently hydrogen, -OR0, -SR0, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=L)-R°, - C(O)O-R0, -C(0)NR°Rd, -S(O)1n-R0, -S(O)m-NR°Rd, -NR°Rd, or a protecting group, or Ra and Rb taken together with the nitrogen atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NRe or S; each occurrence of Rc and Rd is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl or a protecting group, or R° and Rd taken together with the nitrogen atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NRe or S; each occurrence of Re is independently hydrogen or substituted or unsubstituted alkyl, N- protecting group or a prodrug thereof, pharmaceutically acceptable salt thereof, or hydrate or solvate thereof, with the provision that when Z is -S(O)m-, R3 and R4 are not both hydrogen.
Preferred is a compound of formula (I) where Z is O;
Further preferred is a compound of formula (I) where Z is S;
Further preferred is a compound of formula (I) where Z is NRe;
Further preferred is a compound of formula (I) where Re is N-protecting group;
Further preferred is a compound of formula (I) where R° is 4-methylbenzene sulfonyl; Further preferred is a compound of formula (I) where each of R3 and R4 is hydrogen. Further preferred is a compound of formula (I) where each of R3 and R4 is methyl. Further preferred is a compound of formula (I) where R3 and R4 taken together with the carbon atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least one heteroatoms selected from O, NRe or S(O)n,; Further preferred is a compound of formula (I) where -CR3R4 is cyclobutyl; Further preferred is a compound of formula (I) where -CR3R4 is cyclopentyl; Further preferred is a compound of formula (I) where -CR3R4 is cyclohexyl; Further preferred is a compound of formula (I) where R1 is hydrogen Further preferred is a compound of formula (I) where R2 is 2, 4-Difluorophenyl Further preferred is a compound of formula (I) where R1 and R2 taken together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NRe or S(O)1n. Further preferred is a compound of formula (I) where -NR1R2 is:
Figure imgf000008_0001
Further preferred is a compound of formula (I) where -NR1R2 is piperidin-1-yl.
Further preferred is a compound of formula (I) where -NR1R2 is 2,6-dimethyl piperidin-1-yl.
Further preferred is a compound of formula (I) where -NR1R2 is 4-methylpiperazin- i-yi.
Further preferred is a compound of formula (I) where -NR1R2 is morpholin-1-yl.
Further preferred is- a compound of formula (I) where -NR1R2 is azepan-lyl.
Further preferred is a compound of formula (I) where -NR1R2 is perhydrocyclopenta[c]azol-2-yl.
Further preferred is a compound of formula (I) where -NR1R2 is 4H- 1,2,4 triazol-4- yl.
Further preferred is a compound of formula (I) where R5 is hydrogen, -0Ra , halo or cyano.
Further preferred is a compound of formula (I) where R5 is hydrogen. Further preferred is a compound of formula (I) where R5 is -ORa wherein Ra is methyl.
Further preferred is a compound of formula (I) where R5 is -ORa wherein Ra is benzyl.
Further preferred is a compound of formula (I) where R5 is -ORa wherein Ra is difluoromethyl
Further preferred is a compound of formula (I) where R5 is methyl.
Further preferred is a compound of formula (I) where R5 is isopropyl.
Further preferred is a compound of formula (I) where R5 is tert-butyl.
Further preferred is a compound of formula (I) where R5 is chloro.
Further preferred is a compound of formula (I) where R5 is bromo.
Further preferred is a compound of formula (I) where R5 is iodo.
Further preferred is a compound of formula (I) where R5 is fluoro.
Further preferred is a compound of formula (I) where R5 is cyano.
Further preferred is a compound of formula (I) where R5 is phenyl.
Further preferred is a compound of formula (I) where R5 is 2-chlorophenyl.
Further preferred is a compound of formula (I) where R5 is 3-chlorophenyl.
Further preferred is a compound of formula (I) where R5 is 4-chlorophenyl.
Further preferred is a compound of formula (I) where R5 is 4-fluorophenyl.
Further preferred is a compound of formula (I) where R5 is lH-tetrazol-5-yl.
Further preferred is a compound of formula (I) where R5 is pyridin-3-yl.
Further preferred is a compound of formula (I) where R is halo or hydrogen.
Further preferred is a compound of formula (I) where R6 is chloro.
Further preferred is a compound of formula (I) where R6 is fluoro.
Further preferred is a compound of formula (I) where p=l.
Further preferred is a compound of formula (I) where q=2.
Representative compounds of the present invention include those specified below and pharmaceutically acceptable salts thereof. The present invention should not be construed to be limited to them.
1. ΛG-Piperidino-l -(2,4-dichlorophenyl)-l ,4-dihydrochromeno[4,3-c]pyrazole~3- carboxamide hydrochloride,
2. iV3-(256-Dimethylpiperidino)-l-(254-dichlorophenyl)-l54-dihydrochromeno[453- c]pyrazole-3 -carboxamide hydrochloride, 3. JV3-Morpholino-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
4. AG-(I -Azepanyl)- 1 -(2,4-dichloroρhenyl)- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 - carboxamide hydrochloride,
5. Λ/3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno-[4,3- c]pyrazole-3 -carboxamide hydrochloride,
6. N3-(4/i-l,2,4-Triazol-4-yl-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide,
7. Λ73-Piperidino-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
8. Λ3-(2,6-Dimethylpiperidino)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
9. ΛG-Morpholino- 1 -(2,4-dichlorophenyl)-4,4-dimethyl-l ,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxamide hydrochloride,
10. 7V3-(l-Azepanyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
11. Λ73-Perhydrocyclopenta[c]azol-2-yl- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
12. N3-Piperidino-6-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
13. N3-Azepanyl-6-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
14. Λ73-Perhydrocyclopenta[c]azol-2-yl-6-chloro- 1 -(2,4-dichlorophenyl)- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
15. ΛG-Piperidino-δ-chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno- [4,3-c]pyrazole-3-carboxamide hydrochloride,
16. iV3-Morpholino-8-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
17. iV3-Piperidino-8-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno- [4,3-c]pyrazole-3-carboxamide hydrochloride,
18. iV3 -Morpholino-8-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
19. iV3-Piperidino-7-chloro-l-(2,4-difluorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride, 20. JVS-Piperidino^-chloro- 1 -(4-chlorophenyl)- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
21. ΛG-Piperidino-7-chloro- 1 -(2-chlorophenyl)- 1 ,4-dihydrochromeno[4,3-<?]pyrazole-3- carboxamide hydrochloride,
22. ΛΗ-Piperidino-l -(2,4-difluorophenyl)-7-iodo-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
23. iV3 -Piperidino- 1 ~(4-fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 -c] pyrazole-3 -carboxamide hydrochloride,
24. iV3-Pipeπdino-l-(2-fluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c] pyrazole-3 -carboxamide hydrochloride,
25. N3 -Piperidino- 1 -(2-chloro-4-fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
26. iV3-Piperidino- 1 -(4-chloro-2-fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
27. ΛG-Piperidino-1 -(2-chlorophenyl)-7-iodo-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
28. N3 -Piperidino- 1 -(4-chlorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3 -carboxamide hydrochloride,
29. iV3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-cJpyrazole-3- carboxamide hydrochloride,
30. iV3-Azepanyl-7-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
31. iV3-Perhydrocyclopenta[c]azol-2-yl-7-chloro-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno [4,3 -c] -pyrazole-3 -carboxamide hydrochloride,
32. iV3-Piperidmo-7-bromo-l -(2,4-dichlorophenyl)-l ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
33. N3 - Azepanyl-7-bromό- 1 r(2;,4-dichlorophenyl)- 1 ,4-dihydrochromeno [4,3-c]ρyrazole-3- carboxamide hydrochloride,
34. iV3-Perhydrocyclopenta[c]azol-2-yl-7-bromo-l-(2,4-dichloiOphenyl)-l,4 dihydrochromeno [4, 3 -c]pyrazole-3 -carboxamide hydrochloride,
35. ΛG-Piperidino- 1 -(2,4-dichlorophenyl)-7-iodo- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3- carboxamide hydrochloride, 36. iV3-Azepanyl-l-(2,4-dichlorophenyl)-7-iodo-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
37. 7V3-Piperidino-1 -(2,4-dichlorophenyl)-7-fluoro-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
38. ΛG-Azepanyl-l-(2,4-dichlorophenyl)-7-fluoro-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
39. iV3-(2,6-Dimethylpiperidino)-7-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
40. ΛG-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
41. N3 -( 1 -Azepanyl)-7-chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxarnide hydrochloride,
42. iV3-Perhydrocyclopenta[c]azol-2-yl-7-chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
43. iV3-Morpholino-7-chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
44. N3-(4-Methylpiperazino)-7-chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide dihydrochloride,
45. iV3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno- [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
46. iV3-Azepanyl-7-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochro- meno[4,3-c]pyrazole-3-carboxamide hydrochloride,
47. N3 -Morpholino-7-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochro- meno[4,3-c]pyrazole-3-carboxamide hydrochloride,
48. iV3-Perhydrocycloρenta[c]azol-2-yl-7-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
49. iV5-(4-Methylpiperazino)-7-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide dihydrochloride,
50. ΛG-Piperidino-1 -(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l ,4-dihydrochromeno-[4,3- c]pyrazole-3 -carboxamide hydrochloride,
51. ΛG-(1 -Azepanyl)- 1 -(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydro- chromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
52. 7V3-Perhydrocyclopenta[c]azol-2-yl- 1 -(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride, 53. iV3-Morpholino-l-(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
54. iV3-Piperidino-l-(2,4-dichlorophenyl)-7-methyl-4,4-dimetliyl-l,4- dihydrochromeno [4,3-c]pyrazole-3-carboxamide hydrochloride
55. JV3 -Piperidino- 1 -(2,4-dichlorophenyl)-7-isopropyl-4,4-dimethyl- 1 ,4 dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
56. N3-Piperidino-7-(fert-butyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
57. iV3-Piperidino-7-cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride
58. 7V3-Azepanyl-7-cyano-l -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
59. iV3-Piperidino-l -(254-dichlorophenyl)-4,4-dimethyl-7-(lH-tetrazol-5-yl)-l ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
60. N3 -Piperidino- 1 -(2,4-dichlorophenyl)-7-methoxy-l ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
61. iV3-(l -Azepanyl)- 1 -(2,4-dichlorophenyl)-7-methoxy- 1 ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
62. iV3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-7-methoxy-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
63. N3 -Piperidino- 1 -(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl- 1 ,4-dihydro- chromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
64. iV3-(2,6-Dimethylpiperidino)-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
65. iV3-Morpholino-l -(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
66. N3 -(I -Azepanyl)- 1 -(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
67. iV3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl- 1 ^-dihydrochromeno^jS-cJpyrazole-S-cai-boxamide hydrochloride,
68. N3-(4H-l,354-Triazol-4-yl-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide,
69. iV3-(4-Methylpiperazino)-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4- dihydrochromeno [4, 3 -c] pyrazole-3 -carboxamide dihydrochloride, 70. ΛG-Piperidino- 1 -(2,4-dichlorophenyl)-7-benzyloxy-4,4-dimethyl- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
71. iV3-Piperidino- 1 -(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
72. 7V3-Azepanyl-l-(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
73. ΛG -Perhydrocyclopentafc] azol-2-yl- 1 -(2,4-dichlorophenyl)-7-difluoromethoxy-4,4- dimethyl- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
74. 1 -(2,4-Dichlorophenyl)-7-difluoromethoxy-N'-(2,4-difluorophenyl)-4,4-dimethyl-l ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carbohydrazide hydrochloride,
75. iV3-Piperidino-7-(3-chlorophenyl)-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride
76. iV3-Piperidino-7-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
77. ΛG-Piperidino- 1 -(2,4-dichlorophenyl)-4,4-dimethyl-7-phenyl-l ,4-dihydrochromeno- [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
78. iV3-Piperidino-l-(2,4-dichlorophenyl)-7-(4-fluorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
79. Λ/3-Piperidino-7-(2-chlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
80. N3-Piperidino-7-(3-chlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
81. N3-Piperidino-7-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
82. 7V3-Piρeridino-l-(2,4-dichlorophenyl)-4,4-dimethyl-7-(3-pyridyl)-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide dihydrochloride,
83. N2> -Piperidino-7-chloro- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cyclobutane] - 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
84. N3 -Piperidino-7-bromo- 1 -(2 ,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cyclobutane] -1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
85. N3-(l-Azepanyl)-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclobutane]- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride, 86. N3-Piρeridino-l-(2,4-dichlorophenyl)-7-iodo-spiro[chromene-4,l '-cyclobutane]-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
87. ΛG-Piperidino^-chloro- 1 -(2,4-dichlorophenyl)-spiro[chromene-4, 1 ' -cyclopentane]- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
88. AG-(I -Azepanyl)-7-bromo- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cyclopentane] - 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
89. N3-(l- Piperidino)-7-bromo-l-(2,4-dichlorophenyl)-spiro [chromene-4, 1 '- cyclopentane]-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
90. N3-Piperidino-l-(2,4-dichlorophenyl)-7-difluoromethoxy-l,4-dihydrochromeno[4,3-c] pyrazole-3 -carboxamide hydrochloride,
91. iV3-Perhydrocyclopenta[cJazol-2-yl- 1 -(2,4-dichlorophenyl)-7-difluoromethoxy- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
92. N3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclohexane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
93. iV3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclohexane]-l,4- dihydrochromeno [4, 3 -c]pyrazole-3 -carboxamide hydrochloride,
94. iV3-(l-Azepanyl)-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclohexane]- 1 ^-dihydrochromeno^jS-cJpyrazole-S-carboxamide hydrochloride,
95. iV3-Piperidino-8-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrothiochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
96. iV3-Perhydrocyclopenta[c]azol-2-yl-8-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrothio- chromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
97. ΛG-Piperidino-7-chloro- 1 -(2,4-dichlorophenyl)-5-(4-methylphenylsulfonyl)-4,5- dihydro-lϋT-pyrazolo[4,3-c]quinoline-3-carboxamide,
98. 7V3-(l-Azeρanyl)-7-chloro-l-(2,4-dichlorophenyl)-5-(4-methylphenylsulfonyl)-4,5- dihydro-lH-pyrazolo[4,3-c]quinoline-3-carboxamide.
Also provided herein ai"e specific compounds selected from, but are not limited to: 99. Ethyl 2-oxo-2-(4-oxo-3,4-dihydro-2H-3-chromenyl)acetate
100. Ethyl 2-(2,2-dimethyl-4-oxo-3,4-dihydro-2/J-3-chromenyl)-2-oxoacetate
101. Ethyl 2-(8-chloro-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate
102. Ethyl 2-(6-chloro-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate
103. Ethyl 2-(6-bromo-2,2-dimethyl-4-oxo-3,4-dihydro-2i7-3-chromenyl)-2-oxoacetate
104. Ethyl 2-(7-chloro-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate 105. Ethyl 2-(7-iodo-2,2-dimethyl-4-oxo-3 ,4-dihydro-2H-3 -chromenyl)-2-oxoacetate
106. Ethyl 2-(7-chloro-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate
107. Ethyl 2-(7-bromo-4-oxo-3 ,4-dihydro-2H-3 -chromenyl)-2-oxoacetate
108. Ethyl 2-(7-iodo-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate
109. Ethyl 2-(7-fluoro-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate
110. Ethyl 2-(7-chloro-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate
111. Ethyl 2-(7-bromo-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate
112. Ethyl 2-(74odo-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate
113. Ethyl 2-oxo-2-(2,2,7-trimethyl-4-oxo-3 ,4-dihydro-2H-3 -chromenyl)acetate
114. Ethyl (7-isopropyl-2,2-dimethyl-4-oxo-3,4-dihydro-2/J-chromen-3-yl)oxoacetate
115. Ethyl-2-[7-(tert-butyl)-2,2-dimethyl-4-oxo-3 ,4-dihydro-2H-3-chromenyl]-2-oxoacetate
116. Ethyl 2-(7-methoxy-4-oxo:3,4-dihydro-2H-3-chromenyl)-2-oxoacetate
117. Ethyl 2-(7-methoxy-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate
118. Ethyl 2-(7-benzyloxy-2,2-dimethyl-4-oxo-3 ,4-dihydro-2H-3 -chromenyl)-2-oxoacetate
119. Ethyl(7-chloro-4-oxo-3,4-dihydrospiro[cliromene-2,l '-cyclobutan]-3yl)oxoacetate
120. Ethyl (7-bromo-4-oxo-3,4-dihydrospiro[chromene-2,r-cyclobutan]-3-yl)oxoacetate
121. Ethyl (7-iodo-4-oxo-3 ,4-dihydrospiro [chromene-2, 1 ' -cyclobutan] -3 -yl)oxoacetate
122. Ethyl (7-chloro-4-oxo-3,4-dihydrospiro[chromene-2,r-cyclopentan]-3-yl)oxoacetate
123. Ethyl (7-bromo-4-oxo-3,4-dihydrospiro[chromene-2,r-cyclopentan]-3-yl)oxoacetate
124. Ethyl (7-difluoromethoxy-4-oxo-3 ,4-dihydrospiro [chromene-2, 1 '-cyclopentan]-3- yl)oxoacetate
125. Ethyl (7-chloro-4-oxo-3 ,4-dihydrospiro [chromene-2, 1 '-cyclohexan]-3-yl)oxoacetate
126. Ethyl (7-bromo-4-oxo-3,4-dihydrospiro[chromene-2,r-cyclohexan]-3-yl)oxoacetate
127. Ethyl 2-(6-chloro-4-oxo-3,4-dihydro-2H-3-thiochromenyl)-2-oxoacetate
128. Ethyl 2-[7-chloro-l-(4-methylphenylsulfonyl)-4-oxo-l,2,3,4-tetrahydro-3-quinolinyl]- 2-oxoacetate
129. Ethyl 7-chloro-l-(2-chlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate
130. Ethyl l-(2,4-dichlorophenyl)-7-hydroxy-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxylate 131. Ethyl 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno[4,3 -c]pyrazole-3 -carboxylate
132. Ethyl l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3- carboxylate
133. Ethyl 6-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate
134. Ethyl 6-bromo-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate
135. Ethyl 8-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxylate
136. Ethyl 8-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxylate
137. Ethyl 7-chloro-l -(2,4-difluorophenyl)-l ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate
138. Ethyl7-chloro- 1 -(4-chlorophenyl)- 1 ,4-dihydrochromeno [4,3 -c]ρyrazole-3-carboxylate
139. Ethyl 1 -(2,4-difluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno[4,3-c]pyrazole- 3 -carboxylate
140. Ethyl 7-chloro-l -(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxyl ate
141. Ethyll-(4-fluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate
142. Ethyll-(2-fluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate
143. Ethyl 1 -(2-chloro-4-fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3-c]pyrazole-3-carboxylate
144. Ethyl 1 -(4-chloro-2-fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxylate
145. Ethyl l-(2-chlorophenyl)-7-iodo-4,4-dimethyl-l ,4-dihydrochromeno[4,3-c]ρyrazole-3- carboxylate
146. Ethyl l-(4-chlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate
147. Ethyl 7-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate 148. Ethyl 7-bromo-l -(2,4-dichlorophenyl)-l ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate
149. Ethyl 7-iodo-l -(2,4-dichlorophenyl)-l,4-dihydrochromeno [4,3 -c]pyrazole-3- carboxylate
150. Ethyl- l-(2,4-dichlorophenyl)-7-fluoro-4,4-dimethyl-l,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxylate
151. Ethyl 7-chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno
[4,3 -c]pyrazole-3 -carboxylate
152. Ethyl 7-bromo-l -(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxylate
153. Ethyl l-(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate
154. Ethyl- l-(2,4-dichlorophenyl)-4,4,7-trimethyl-l ,4-dihydrochromeno [4,3 -c]pyrazole-3- carboxylate
155. Ethyl 7-isopropyl -l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate
156. Ethyl 7-(tert~buty\) -l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate
157. Ethyl-7-cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate
158. Ethyl l-(2,4-dichlorophenyl)-7-methoxy-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate
159. Ethyl l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate
160. Ethyl 7-benzyloxy-l -(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxylate
161. Ethyl 1 (2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl- 1 ,4dihydrochromeno [4,3 -c]pyrazole-3 -carboxylate
162. Ethyl l-(2,4-dichlorophenyl)-7-(3-chlorophenyl)-l,4-dihydrochromeno-[4,3- c]pyrazole-3 -carboxylate
163. Ethyl7-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate
164. Ethyl l-(2,4-dichlorophenyl)-4,4-dimethyl-7-phenyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate 165. Ethyl 1 -(2,4-dichlorophenyl)-7-(4-fluorophenyl)-4,4-dimethyl- 1 ,4-dihydro- chromeno [4,3 -c]pyrazole-3 -carboxylate
166. Ethyl 7-(2-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate
167. Ethyl 7-(3-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate
168. Ethyl 7-(4-chloroρhenyl)-l-(2,4-dichloroρhenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3~c]pyrazole-3-carboxylate
169. Ethyl 1 -(2,4-dichlorophenyl)-7-(3-pyridyl)-4,4-dimethyl- 1 ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate
170. Ethyl 7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclobutane]-l,4- dihydrochrorneno[4,3-c]pyrazole-3-carboxylate
171. Ethyl [7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclohexane]-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxylate
172. Ethyl 8-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrothiochromeno[4,3-c]pyrazole-3- carboxylate
173. Ethyl 7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclohexane]-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxylate
174. Ethyl 7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclobutane]-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxylate
175. Ethyl 7-iodo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclobutane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate
176. Ethyl 7-chloro-l-(2,4-dichlorophenyl)-spiro[chiOmene-4,l '-cyclopentane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate
177. Ethyl 7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclopentane]-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxylate
178. Ethyl 1 -(2,4-dichlorophenyl)-7-difluoromethoxy-spiro[chromene-4, 1 ' -cyclopentane]- l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate
179. Ethyl 7-chloro-l-(2,4-dichlorophenyl)-5-(4-methylphenylsulfonyl)-4,5-dihydro-lH- pyrazolo [4,3 -c]quinoline-3 -carboxylate
180. 7-Chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid 181. 1 -(2,4-Difluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 - carboxylic acid
182. l-(4-Fluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid,
183. l-(2-Fluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid
184. 1 -(2-Chloro-4-fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid
185. l-(2,4-Dichlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid
186. 7-Bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid
187. l-(2,4-Dichlorophenyl)-7-fluoro-4,4-dimethyl-l ,4-dihydrochromeno [4,3 -c]pyrazole-3- carboxylic acid
188. 7-Iodo- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxylic acid
189. 7-Bromo-l -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
190. 7-Chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
191. l-(4-Chlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid
192. 1 -(4-Chloro-2-fluorophenyl)-7-iodo-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid
193. 1 -(2-Chlorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3- carboxylic acid
194. 7-Chloro- l-(4-chloropheny I)- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxylic acid
195. 7-Cliloro-l-(2,4-difluorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
196. 8-Bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid
197. 8-Chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]-pyrazole-3- carboxylic acid
198. 6-Bromo-l -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid 199. 6-Chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
200. l-(2,4-Dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid
201. l-(2,4-Dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
202. 7-Chloro- l-(2-chlorophenyl)-l,4-dihydrochromeno [4,3 -c]pyrazole-3-carboxylic acid
203. 1 -(2,4-Dichlorophenyl)-4,4,7-trimethyl- 1 ,4-dihydrochromeno[4,3-φyrazole-3- carboxylic acid
204. 7-Isopropyl-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole- 3-carboxylic acid
205. 7-(tert-butyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid
206. 7-Cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid
207. l-(2,4-Dichlorophenyl)-7-methoxy-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
208. 1 -(2,4-Dichlorophenyl)-7-methoxy-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 -c]pyrazole- 3 -carboxylic acid
209. 7-Benzyloxy-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid
210. l-(2,4-Dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- . c]pyrazole-3 -carboxylic acid
211. l-(2,4-Dichlorophenyl)-7-(3-chlorophenyl)-l,4-dihydrochiOmeno[4,3-c]pyrazole-3- carboxylic acid
212. 7-(4-Chlorophenyl)-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid
213. l-(2,4-Dichlorophenyl)-4,4-dimethyl-7-phenyl-l,4-dihydiOchromeno[4,3-c]pyrazole-3- carboxylic acid
214. l-(2,4-Dichlorophenyl)-7-(4-fluorophenyl)-454-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid
215. 7-(2-Dichlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid 216. 7-(3-Chlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid
217. 7-(4-Chlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid
218.. 7-Chloro- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cyclobutane] - 1 ,4- dihydrochromeno [4, 3 -c]pyrazole-3 -carboxylic acid
219. 7-Chloro- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cyclohexane] - 1 ,4- dihydrochromeno [4, 3 -c]pyrazole-3 -carboxylic acid
220. 7-Bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclohexane]-l,4-dihydrochro meno [4,3 -c]pyrazole-3 -carboxylic acid
221. 7-Bromo- 1 -(2,4-dichlorophenyl)-spiro[chromene-4, 1 '-cyclobutane]- 1 ,4-dihydrochro meno [4,3 -c]pyrazole-3 -carboxylic acid
222. 7-Iodo- 1 -(2,4-dichlorophenyl)~spiro [chromene-4, 1 ' -cyclobutane] - 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxylic acid
223. 7-Chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclopentane]-l,4-dihydrochro meno [4,3 -c]pyrazole-3 -carboxylic acid
224. 7-Bromo- 1 -(2,4-dichlorophenyl)-spiro[chromene-4, 1 '-cyclopentane]- 1 ,4-dihydiOchro meno [4,3 -c]pyrazole-3 -carboxylic acid
225. 1 -(2,4-dichlorophenyl)-7-difluoromethoxy-spiro [chromene-4, 1 ' -cyclopentane] -1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
226. 8-Chloro-l-(2,4-dichlorophenyl)-l,4-dihydrothiochromeno[4,3-cJpyrazole-3-carboxylic acid
227. 7-chloro-l-(2,4-dichlorophenyl)-5-(4-methylphenylsulfonyl)-4,5-dihydro-l/7- pyrazolo[4,3-c]quinoline-3-carboxylic acid.
Another aspect of the invention provides a pharmaceutical composition comprising at least one compound of the present invention and optionally together with one or more pharmaceutically acceptable excipients, diluents, carriers or mixture thereof.
The compounds and pharmaceutical compositions of the present invention are useful in the treatment of diseases, conditions and/or disorders modulated by cannabinoid receptors and in particular CBl and /or CB2 receptor modulators. These compounds are particularly useful in the treatment of appetite disorders, metabolism disorders, diabetes, obesity, glaucoma-associated intraocular pressure, social disorder, 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, pain or neurodegenerative related syndromes, disorders or diseases.
Yet another aspect of the invention provides a method of treating a disease, condition and/or disorder modulated by a cannabinoid (CB) receptor and in particular CBl and /or CB2 receptor modulators 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.
Methods may involve one or more of the following embodiments. For example, in one embodiment, cannabinoid (CB) receptor modulator is CBl or CB2 receptor modulator. In another embodiment, CB receptor modulator is agonist, antagonist, partial agonist or inverse agonist. In another embodiment, cannabinoid receptor mediated disease is obesity or dyslipidemia mediated by cannabinoid receptor 1 (CBl). In yet another embodiment, the disease, condition 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 syndrome, disorder and disease.
The present invention also discloses combination product or medicament comprising one or more compounds described herein and one or more of other therapeutic agents for treating disease, disorder or condition described in this invention. The present invention preferably discloses combination product or medicament comprising one or more compounds described herein and one or more of antiobesity agent, ACAT inhibitor, PDE IV inhibitor, DPP IV inhibitor, antidiabetic agent, dyslipidemic agent, CETP inhibitor, HMG-CoA reductase inhibitor, fibrate, guggle lipid or other CBl or CB2 modulator for treating disease, disorder or condition described in this invention.
Also provided herein are processes for preparing compounds described herein.
The present invention further provides intermediates of formula 2 useful for the preparation of compounds of formula I:
Figure imgf000024_0001
2 wherein Z5 R3, R4 and R5 are same as defined for formula I above. The present invention further provides intermediates of formula 4 useful for the preparation of compounds of formula I:
Figure imgf000024_0002
4 wherein Z, R3, R4 , R5 and R6 are same as defined for formula I above.
The present invention further provides intermediates of formula 5 useful for the preparation of compounds of formula I:
Figure imgf000024_0003
5 wherein Z, RJ, R4, R3 and R0 are same as defined for formula I above.
Detailed Description of the Invention Definitions
The term "aryl" refers to aromatic radicals having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydrόnapthyl, 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 "heterocyclic ring" refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepanyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepanyl, azepanyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heteroaryl" refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from the alkyl group that results in the creation of a stable structure.
The term "heterocyclyl" refers to a heterocyclic ring radical as defined above. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methyl ethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl {tert- butyl).
The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, and 2-butenyl.
The term "alkynyl" refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl.
The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH3 and -OC2H5.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., spiro(4.4) non-2 -yl.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical, having 3 to about 8 carbon atoms, directly attached to an alkyl group. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
The term "cycloalkylaryl" refers to a cyclic ring-containing radical, having 3 to about 8 carbon atoms, directly attached to an aryl group. Non-limiting examples of such groups include phenylcyclopropyl, phenylcylobutyl and phenyl cyclopentyl.
The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted guanidine, -COORx, -C(O)Rx, -C(S)Rx, -C(O)NRxRy, -C(O)ONRxRy, -NRxCONRyR2, - N(Rx)SORy, -N(Rx)SO2Ry, -(=N-N(Rx)Ry), -NRxC(O)ORy, -NRxRy, -NRxC(O)Ry, - NRxC(S)Ry, -NRxC(S)NRyR2, -SONRxRy, -SO2NRxRy, -ORx, -ORxC(O)NRyR2, - ORxC(O)ORy, -OC(O)Rx, -OC(O)NRxRy, -RxNRyC(O)R2, -RxORy, -RxC(O)ORy, - RxC(O)NRyR2, -RxC(O)Ry, -RxOC(O)Ry, -SRx, -SORx, -SO2Rx, and -ONO2, wherein Rx, Ry and R2 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. According to one embodiment, the substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl" the substituent on "substituted aryl" cannot be "substituted alkenyl".
The term "protecting group" or "PG" refers to a substituent that is employed to block or protect a particular functionality. Other functional groups on the compound may remain reactive. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-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 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-fø>-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 "stereoisomer" refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. These include enantiomers, diastereomers, geometrical isomers, atropisomer or conformational isomers. All the stereoisomers of 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, which are characterized by relatively easy interconversion of isomeric forms in equilibrium. These isomers are intended to be covered by this invention.The term "prodrug" refers to compounds, which are an inactive precursor of a compound, converted into its active form in the body by normal metabolic processes. The term "ester" refers to compounds, which are formed by reaction between an acid and an alcohol with elimination of water. Ester can be represented by the formula RCOOR'. The term "polymorph" refers to a specific crystalline form of a compound.
These prodrug, ester and polymorphs are intended to be covered within the scope of this invention.
The term "cannabinoid receptor" refers to any one of the known or heretofore unknown subtypes of the class of cannabinoid receptors, including CBl and/or CB2 receptors, that may be bound by a cannabinoid modulator compound of the present invention. The term "modulator" further refers to the use of a compound of the invention as a CB (e.g., CBl and/or CB2) receptor agonist, partial agonist, antagonist or inverse-agonist. The term "treating" or "treatment" of a state, disorder or condition includes:
(1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition;
(2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or
(3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
The benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician.
The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, 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 sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartarates, maleates, citrates, fumarates, succinates, palmoates, methanesulfonates, 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 sulfates (such as CH3I or (CH3)2SO4).
Pharmaceutically acceptable solvates includes hydrates and other solvents of crystallization (such as alcohols). The compounds of the present invention may form solvates with standard low molecular weight solvents by methods known in the art.
Pharmaceutical Compositions
The pharmaceutical composition of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone .
The carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic 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, 20th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.
The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is preferred.
Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
A typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approximately 9 mg Mywacett 9-40 T and approximately 0.9 mg acylated monoglyceride
Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Methods of Treatment and Combination Therapy
The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment, amelioration, and/or prevention of diseases, conditions and/or disorders modulated by a cannabinoid (CB) receptor, especially those modulated by the CBl or CB2 receptor including those discussed below.
The present invention further provides a method of treating a disease, condition and/or disorder modulated by a cannabinoid receptor (CB), and in particular the CBl or CB2 receptor, in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
Diseases, conditions, and/or disorders that are modulated by a CB receptor, include, but are not limited to, appetite disorders, metabolism disorders, catabolism disorders, diabetes, obesity, social related disorders, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, pain (such as neuropathic pain) and neurodegenerative related syndromes, disorders and diseases.
Appetite related syndromes, disorders or diseases include, but are not limited to, obesity, overweight conditions, anorexia, bulimia, cachexia, dysregulated appetite and the like. Obesity related syndromes, disorders or diseases include, but are not limited to, obesity as a result of genetics, diet, food intake volume, metabolic syndrome, disorder or disease, hypothalmic disorder or disease, age, abnormal adipose mass distribution, abnormal adipose compartment distribution, compulsive eating disorders, motivational disorders which include the desire to consume sugars, carbohydrates, alcohols or drugs or any ingredient with hedonic value and the like. Symptoms associated with obesity related syndromes, disorders, and diseases include, but are not limited to, reduced activity.
Metabolism related syndromes, disorders or diseases include, but are not limited to, metabolic syndrome, dyslipidemia, elevated blood pressure, insulin sensitivity or resistance, hyperinsulinemia, hypercholesterolemia, hyperlipidemias, atherosclerosis, hypertriglyceridemias, arteriosclerosis, other cardiovascular diseases, osteoarthritis, dermatological diseases, sleep disorders (disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), cholelithiasis, hepatomegaly, steatosis, abnormal alanine aminotransferase levels, polycystic ovarian disease, inflammation, and the like.
Diabetes related syndromes, disorders or diseases include, but are not limited to, glucose dysregulation, insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity, hyperglycemia and the like.
Catabolism related syndromes, disorders or diseases include, but are not limited to, catabolism in connection with pulmonary dysfunction and ventilator dependency; cardiac dysfunction, e.g., associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure.
Ophthalmic diseases include, but are not limited to, glaucoma, glaucoma-associated intraocular pressure retinitis, retinopathies, uveitis, and acute injury to the eye tissue (e.g. conjunctivitis).
Social or mood related syndromes, disorders or diseases include, but are not limited to, depression (including, but not limited to, bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, cognitive disorders and the like).
Substance abuse related syndromes, disorders or diseases include, but are not limited to, drug abuse and drug withdrawal. Abused substances include, but are not limited to, alcohol, amphetamines (or amphetamine like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin abuse, barbiturates, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics, benzodiazepines, or combinations of any of the foregoing. The compounds and pharmaceutical compositions can also be used to treat withdrawal symptoms and substance- induced anxiety or mood disorder.
The present invention further provides a method of treating nicotine dependency, addiction, withdrawal or aiding in the cessation or lessening of tobacco in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
Learning, cognition or memory related syndromes, disorders or diseases which can be treated with the compounds of the present invention include, but are not limited to, memory loss or impairment as a result of age, disease, side effects of medications (adverse events) or the like. Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld- Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline. Generally, dementias are diseases that include memory loss and additional intellectual impairment separate from memory. 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, disorders or diseases include, but are not limited to, multiple sclerosis, cerebral palsy and the like.
Locomotor activity and movement syndromes, disorders or diseases include, but are not limited to, stroke, Parkinson's disease, multiple sclerosis, epilepsy and the like.
Respiratory related syndromes, disorders or diseases include, but are not limited to, diseases of the respiratory tract, chronic obstructive pulmonary disorder, emphysema, asthma, bronchitis and the like.
Kidney dysfunction nephritis which can be treated with the modulators of the present invention includes, but is not limited to, mesangial proliferative glomerulonephritis, nephritic syndrome, liver dysfunction (hepatitis, cirrhosis).
Autoimmune or inflammation related syndromes, disorders or diseases include, but are not limited to, psoriasis, lupus erythematosus, diseases of the connective tissue, Sjogren's syndrome, ankylosing spondylarthritis, rheumatoid arthritis, reactional arthritis, undifferentiated spondylarthritis, Behcet's disease, autoimmune hemolytic anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, graft rejection or diseases affecting the plasma cell line; allergic diseases: delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis or allergic conjunctivitis infectious parasitic, viral or bacterial diseases (such as AIDS and meningitis), inflammatory diseases (such as diseases of the joints including, but not limited to, arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)) and osteoporosis.
Cell growth related syndromes, disorders or diseases include, but are not limited to, dysregulated mammalian cell proliferation, breast cancer cell proliferation, prostrate cancer cell proliferation and the like.
Pain related syndromes, disorders or diseases include, but are not limited to, central and peripheral pathway mediated pain, bone and joint pain, migraine headache associated pain, cancer pain, dental pain, menstrual cramps, labor pain, chronic pain of the inflammatory type, allergies, rheumatoid arthritis, dermatitis, immunodeficiency, chronic neuropathic pain, (e.g. pain associated with diabetic neuropathy, sciatica, non specific lower back pain, fibromyalgia; HIV -related neuropathy; post herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions), hodgkin's disease, myasthenia gravis, nephrotic syndrome, scleroderma, thyroiditis and the like.
Neurodegenerative related syndromes, disorders or diseases include, but are not limited to, Parkinson's disease, multiple sclerosis, epilepsy, ischemia or secondary biochemical injury collateral to traumatic head or brain injury, brain inflammation, eye injury or stroke and the like.
The compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases, conditions and/or disorders described herein. Therefore, methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided. Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include, but are not limited to, anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, 11 β-hydroxy steroid dehydrogenase- 1 (1 Iβ-HSD type 1) inhibitors, peptide YY3-36 or analogs thereof, MCR-4 agonists, cholecystolάnin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, β3 adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT20 receptor agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide- Y receptor antagonists, thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide- 1 (GLP-I) receptor agonists, Protein Tyrosine Phosphatase (PTP-IB) inhibitors, dipeptidyl peptidase IV (DPP-IV) inhibitors, ciliary neurotrophic factors (such as Axokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, N. Y. and Procter & Gamble Company, Cincinnati, Ohio), human agouti-related protein (AGRP) inhibitors, ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, and neuromedin U receptor agonists. Other anti-obesity agents, including the preferred agents set forth herein below, are well known, or will be readily apparent in light of the instant disclosure, to one of ordinary skill in the art. The present invention preferably provides a combination product or medicament comprising one or more compounds described herein and one or more of other therapeutic agents for treating disease, disorder or condition described in this invention. The instant invention preferably discloses combination product or medicament comprising one or more compounds described herein and one or more of antiobesity agent, ACAT inhibitor, PDE IV inhibitor, DPP IV inhibitor, antidiabetic agent, dyslipidemic agent, CETP inhibitor, HMG-CoA reductase inhibitor, fibrate, guggle lipid or other CBl or CB2 modulator for treating disease, disorder or condition described in this invention.
Especially preferred are anti-obesity agents such as orlistat, sibutramine, bromocriptine, ephedrine, leptin, peptide YY3-36 or an analog thereof (including the complete peptide YY), and pseudoephedrine. Preferably, compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
Anti-obesity agents for use in the combinations, pharmaceutical compositions, and methods of the invention can be prepared using methods known to one of ordinary skill in the art, for example, sibutramine can be prepared as described in U.S. Pat. No. 4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888; orlistat can be prepared as described in U.S. Pat. Nos. 5,274,143, 5,420,305, 5,540,917, and 5,643,874; and PYY3-36 (including analogs) can be prepared as described in U.S. Patent Publication No. 2002/0141985 and International Publication No. WO 03/027637. All of the above recited references are incorporated herein by reference.
Other suitable pharmaceutical agents that may be administered in combination with the compounds of the present invention include agents designed to treat tobacco abuse (e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename Zyban™) and nicotine replacement therapies), agents to treat erectile dysfunction (e.g., dopaminergic agents, such as apomorphine), ADD/ADHD agents (e.g., Ritalin (methylphenidate hydrochloride), Strattera™ (atomoxetine hydrochloride), Concerta™ (methylphenidate hydrochloride) and Adderall™ (amphetamine aspartate; amphetamine sulfate; dextroamphetamine saccharate; and dextroamphetamine sulfate)), and agents to treat alcoholism, such as opioid antagonists (e.g., naltrexone (also known under the tradename Re Via™) and nalmefene), disulfiram (also known under the tradename Antabuse ™), and acamprosate (also known under the tradename Campral™). In addition, agents for reducing alcohol withdrawal symptoms may also be co-administered, such as benzodiazepines, beta- blockers, clonidine, carbamazepine, pregabalin, and gabapentin (Neurontin™). Treatment for alcoholism is preferably administered in combination with behavioral therapy including such components as motivational enhancement therapy, cognitive behavioral therapy, and referral to self-help groups, including Alcohol Anonymous (AA).
Other pharmaceutical agents that may be useful include antihypertensive agents; antidepressants (e.g., fluoxetine hydrochloride (Prozac™); cognitive improvement agents (e.g., donepezil hydrochloride (Aircept™.) and other acetylcholinesterase inhibitors); neuroprotective agents (e.g., memantine); antipsychotic medications (e.g., ziprasidone (Geodon™), risperidone (Risperdal™), and olanzapine (Zyprexa™)); insulin and insulin analogs (e.g., LysPro insulin); GLP-I (7-37) (insulinotropin) and GLP-I (7-36)-NH2; sulfonylureas and analogs thereof: chloropropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide®, glimepiride, repaglinide, meglitinide; biguanides: metformin, phenformin, buformin; α2-antagonists and imidazolines: midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulin secretagogues: linogliride, A-4166; glitazones: ciglitazone, Actos® (pioglitazone), englitazone, troglitazone, darglitazone, Avandia® (BRL49653); fatty acid oxidation inhibitors: clomoxir, etomoxir; α-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; β- agonists: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL 316,243; phosphodiesterase inhibitors: L-386,398; lipid-lowering agents: benfluorex: fenfluramine; vanadate and vanadium complexes (e.g., Naglivan®) and peroxovanadium complexes; amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors; somatostatin analogs; antilipolytic agents: nicotinic acid, acipimox, WAG 994, pramlintide (SymlinrM), AC 2993, nateglinide, aldose reductase inhibitors (e.g., zopolrestat), glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, sodium-hydrogen exchanger type 1 (NHE-I) inhibitors and/or cholesterol biosynthesis inhibitors or cholesterol absorption inhibitors, especially a HMG- CoA reductase inhibitor, or a HMG-CoA synthase inhibitor, or a HMG-CoA reductase or synthase gene expression inhibitor, a CETP inhibitor, a bile acid sequesterant, a fibrate, an ACAT inhibitor, a squalene synthetase inhibitor, an anti-oxidant or niacin. The compounds of the present invention may also be administered in combination with a naturally occurring compound that acts to lower plasma cholesterol levels. Such naturally occurring compounds are commonly called nutraceuticals and include, for example, garlic extract, Hoodia plant extracts, and niacin.
The compounds of the present invention (including the pharmaceutical compositions and processes used therein) may be used alone or in combination with other pharmaceutical agents in the manufacture of a medicament for the therapeutic applications described herein.
General methods of preparation
Figure imgf000037_0001
Compounds of the general formula I, of the present invention, where Z is O, S, S(O)m or NR can be prepared as outlined in Scheme 1. Alkali metal enolate of active methylene ketones of the general formula 1 on reaction with diethyl oxalate gave the diketo ester 2. Diketo ester 2 on reaction with substituted phenyl hydrazines of the general formula 3 affords diaryl pyrazole ester 4 via its hydrazone derivative. Hydrolysis of the ester group of 4 followed by amidation with various ΛζiV-disubstituted hydrazines or its cyclic analogues of the general formula 6 affords compounds of the general formula I. Scheme 1
Figure imgf000037_0002
The starting ketones of the general formula 1 are commercially available or may be prepared by using various known approaches reported in the literature (Graffe, B. et al. J. Heterocyclic Chem. 1975, 12, 247-251; Ferreira J. Tercio, B. el. al. Synthesis 1987, 149-153). A few such approaches utilized for the synthesis of 1 are outlined in Scheme 2. Intermediate of the general formula 7 where Z is oxygen or sulfur and R5 is as defined in the general structure reacts with acrylonitrile 8 (R3 = R4 = H) in presence of a base to afford intermediate 9, which on hydrolysis and cyclization yields chormenone or thiochromenone of the general formula I. Alternatively, 7 can be reacted with acrylic acid ester 10 to give 11 which on hydrolysis and cyclization under acidic conditions affords 1. Scheme 2
1. hydrolysis
(R5)P- 2. cyclization
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000038_0003
Another approach for the synthesis of intermediate 1 where Z is oxygen and RJ and R4 are alkyl or R3 and R4 together constitute a carbocyclic ring may be prepared as shown in Scheme 3 using a known approach (Buell, B. G. et al. J. Am. Chem. Soc. 1949, 71 (1), 1901- 1905; Bergmann, R. et al. J. Med. Chem. 1990, 33, 492-504). Thus, reaction of substituted phenol of the general formula 7 (Z = O) on acylation with acetic anhydride in the presence of catalytic amounts of sulfuric acid affords 12 which on Lewis acid assisted Fries rearrangement afford 13. The hydroxyl acetophenone 13 on reaction with acyclic and cyclic ketones in the presence of pyrrolidine in acetonitrile affords intermediate 1. Scheme 3
Figure imgf000038_0004
Alternative approaches useful for the preparation of intermediate of the general formula 1 may be found in the following references: (a) Cox, B. et al. Synth. Commun. 1989, 709-711; (b) Gerlach, U. et al J. Med. Chem. 2001, 44, 3831-3837; (c) Holshouser, M. H. et al. J. Med. Chem. 1981, 24, 853-858; (d) Sacquet, M-C. et al. J. Heterocyclic Chem. 1985, 22, 713-718; (e) Jung, J-C. et al. Synth. Commun. 1999, 29 (20), 3587-3595; (f) Graffe, B. et al J. Heterocyclic Chem. 1985, 22, 713-718; (g) Kabbe, H. J. et al Angew. Chem. Int. Ed. Engl 1982, 21, 247.
Pyrazole carboxylic acid of the formula 5 where R5 is cyano group or heterocycle derived from cyano group (eg. tetrazole, oxazole, thiazole etc.) may be prepared as shown in Scheme 4. Aromatic cyanation of intermediate 4 where X is Br, I, or OSO2CF3 with transition metal cyanides or trimethylsilyl cyanide (TMSCN) in presence of a suitable Pd(O) catalyst affords intermediate 12 (Chatani N. et al J. Org. Chem. 1986, 51(24), 4714-4716). Selective ester hydrolysis of 12 affords pyrazole acid 5. Alternately, the cyano group can be transformed to a heterocycle, eg. tetrazole, prior to hydrolysis to pyrazole acid 4 (Koguro K. et al Synthesis, 1998, 6, 910). Scheme 4
Figure imgf000039_0001
The compound of formula 5 where R5 is aryl, substituted aryl, heteroaryl, substituted heteroaryl group are prepared as described in Scheme 5. Coupling reaction of a suitable boronic acid derivative with intermediate of the general formula 4 where X is Br, I, or OSO2CF3 under Suzuki coupling conditions affords compounds of the formula I. Scheme 5
The compound of formula 4 where X is protected hydroxyl group (eg. alkoxy) can be converted to free hydroxyl group by using a suitable reagent such as trimethylsilyl iodide boron tribromide or 48 % HBr in acetic acid. When X is a benzyloxy group, catalytic hydrogenolysis affords the phenolic derivative. The phenolic hydroxyl group can be realkylated with a suitable alkyl or fluoroalkyl halide (eg. CHF2Cl) and subsequently hydrolysed to the pyrazole acid of the general formula 5.
In-vitro assays
1. Protocol for rat CBl receptor binding assay using rat whole brain membrane
In this assay, [3H]CP55940 was used as the radioligand to bind the CBl receptor present in a rat brain membrane preparation which can be displaced by unlabeled ligands having affinity to the CBl receptor.
The assay was performed according to the modified method of Thomas et ah, 1998 (J. Pharmacol. Exp. Ther. 285: 285-292). The total reaction mixture (250 μl) contains Tris-BSA buffer (50 mM 2-amino-2-(hydroxymethy I)- 1,3 -propanediol, pH 7.4 with 1.5 % bovine serum albumin) or unlabeled WIN55212-2 (1 μM) or test samples (1 μM), [3H]CP55940 (0.8 nM) and 100 μg of rat brain membrane. The non-specific binding was defined by 1 μM of WIN55212-2. The assay mixture was incubated at 370C for 1 hour. The reaction was then stopped by rapid filtration under vaccum using Whatman GF/B-96 micro filter plate. A scintillation cocktail was added and radioactive counts were measured using Topcount beta scintillation counter.
The standard and test sample dilutions were made in the assay buffer containing either ethanol or dimethylsulfoxide (DMSO) at a final concentration of 1%. The percent displacement (% D) by a test ligand was calculated by comparing the specific bound values. The results of the assay are shown in Tables 1 - 6. H. Protocol for human CBl receptor binding assay using hCBl-CHO cell membrane
In this assay, [3H]CP55940 was used as the radioligand to bind human CBl receptors expressed on the membranes from CHO cells (the hCBl-CHO cell line was generated in- house) which can be displaced by unlabeled ligands having affinity to the CBl receptor.
The assay was performed according to the modified method of Ross et al., 1999 (Br. J. Pharmacol. 128, 735-743). The reaction was set up in a total volume of 200 μl in poly- ethyleneimine (PEI) (0.2 %) pre-coated Millipore GFB (Glass Fibre-B) filter plates. 1.0 mM 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 reaction mixture contained Tris-BSA buffer (50 mM Tris, 5 mM MgCl2, 1 mM EDTA, pH 7.4 with 0.1 % BSA), unlabeled CP-55,940 (0.5 μM) or test samples, [3H]CP55940 (0.75 nM ) and 50 μg of human CBl receptor preparation. The assay mixture 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 results of the assay are shown in the Tables 1 - 6.
Examples 1-98 (see Schemes 5-10 and Tables 1-6) represent preferred embodiments of the present invention. It should be understood that there may be other embodiments which fall within the scope and spirit of this invention. Specific methods adopted for the coupling reaction of pyrazole carboxylic acids 5 with amines 6 have been given in Scheme 5-10. However, the coupling reaction can be performed using various other approaches known in the literature. For example, activation of carboxylic acid 5 with various activating reagents (thionyl chloride, oxalyl chloride, DCC5 CDI and the like) followed by treatment with amines of the general formula 6 affords compounds of the general formula I.
Scheme 5 and Table 1 give detailed structural description of Examples 1-11. The percentage ddiissppllaacceemmeenntt vvaalluueess ((%% DD)) ooff [[33HH"]CP55940 by test molecules at 1.0 μM for rCBl and 300 nM for hCBl are given in Table 1.
Scheme 5
Figure imgf000041_0001
Figure imgf000041_0002
Figure imgf000042_0001
Example 1
Λ3-Piperidino-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride
Step 1: Ethyl 2-oxo-2-(4-oxo-3,4-dihydro-2H-3-chromenyl)acetate: A solution of 2,3- dihydro-4i/-chromen-4-one (5.0 g, 33.8 mmol) in THF (50 niL) was added dropwise (30 min) to a stirred and cooled (-78 0C) solution of 20 % lithium bis(trimethylsilyl)amide [LHMDS] (31.10 niL, 37,0 mmol) in THF under nitrogen atmosphere. This mixture was allowed to warm up to -40 0C and maintained at -40 to -30 °C for 30 min. Diethyl oxalate (4.6 mL, 33.8 mmol) was added dropwise over a period of 5 min. The solution was then allowed to warm to room temperature and further stirred at room temperature for 15 h. The mixture was diluted with water (100 mL) and the layers were separated. The aqueous layer was acidified with IN HCl to pH 2.0 and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water, brine and dried over anhydrous sodium sulfate (Na2SO4). The solvent was evaporated to give 7.20 g of the product as a yellow solid; IR (KBr) 3436, 2985, 1720, 1606, 1470, 1360, 1300, 1253, 725 cm'1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J= 7.0 Hz, 3H), 4.40 (q, J- 7.2 Hz, 2H), 5.35 (d, J= 20.0 Hz, 2H), 6.90 (d, J= 7.5 Hz, IH)5 7.10 (t, J = 2.0 Hz, IH), 7.50 (t, J = 1.8 Hz, IH), 7.90 (d, J= 7.5 Hz, IH), 15.50 (br s, IH).
Step 2: Ethyl l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate: A solution of Step 1 intermediate (4.0 g, 16.1 mmol) in absolute ethanol (30 mL) was treated with 2,4-dichlorophenylhydrazine (2.35 g, 16.1 mmol) in one portion with stirring under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The yellow solid separated out was collected by filtration, rinsed with cold ethanol and dried to afford 6.0 g of the desired hydrazone.
The hydrazone (6.0 g, 15.0 mmol) was suspended in glacial acetic acid (120 mL) and the mixture was refluxed for 24 h. The mixture was then poured into ice-cold water (500 mL) and the solid precipitated out was collected by filtration, washed with water and dried to 5.50 g of the product as a pale yellow solid; IR (KBr) 3080, 2950, 1730, 1500, 1380, 1260, 725 cm"1; 1H NMR (300 MHz, CDCl3,) δ 1.42 (t, J = 7.0 Hz, 3H), 4.44 (q, J= 7.2 Hz, 2H), 5.60 (d, J = 7.2 Hz, IH), 5.60 (d, J = 7.2 Hz, IH), 6.50 (d, J = 6.0 Hz, IH), 6.74 (t, J = 7.8 Hz, IH), 7.0 (d, J= 6.0 Hz, IH), 7.20 (t, J= 7.2 Hz, IH), 7.40-7.60 (m, 2H), 7.61 (d, J= 2.0 Hz, IH).
Step 3: l-(2,4-Dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: To a solution of Step 2 intermediate (5.50 g, 14.0 mmol) in methanol (80 mL) was added IN potassium hydroxide (KOH) (30 mL) and the mixture was refluxed for 1.0 h under stirring. The methanol was evaporated under reduced pressure and the residue was diluted with water (100 mL) and the mixture was acidified with IN hydrochloric acid (HCl) to pH 2.0. The mixture was extracted with ethyl acetate (EtOAc) (2 x 75 mL), washed with brine and dried (Na2SO4). The solvent was evaporated to give 5.0 g of the product as an off-white solid; IR (KBr) 3080, 2700, 1700, 1500, 1280, 725 cm"1; 1H NMR (300 MHz, DMSO-cfe) δ 5.52 (d, J= 7.2 Hz, IH), 5.52 (d, J= 7.2 Hz, IH) 6.42 (d, J= 7.0 Hz, IH), 6.80 (t, J= 7.8 Hz, IH), 7.0 (d, J= 7.8 Hz, IH), 7.24 (t, J= 7.8 Hz, IH).
Step 4: N3-Piperidino-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride: The Step 3 intermediate (100 mg, 0.3 mmol) was dissolved in anhydrous THF (5 mL) under nitrogen atmosphere. 1-aminopiperidine (30 mg, 0.3 mmol), triethylamine (141 mg, 1.40 mmol), and benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate [BOP] (147 mg, 0.3 mmol) was added and the reaction mixture was allowed to stir at room temperature under nitrogen atmosphere for 3 h. The reaction mixture was diluted with EtOAc (15 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 20 mL) and combined organic extracts were washed with IN sodium hydroxide (NaOH) (25 mL) and dried over anhydrous Na2SO4. The residue obtained after evaporation of the solvent was purified on a silica gel column using 20 % EtOAc in hexane to afford 98 mg of the product as an off-white solid. The free base 98 mg (0.221 mmol) was dissolved in EtOAc (1 mL), cooled to 0 0C and 12 % HCl in EtOAc (3 mL) was added to result in a white solid. The solvent was evaporated under reduced pressure and the residue was dried under vacuum to give 82 mg of the product as an off-white solid; IR (KBr) 3435, 2935, 1700, 1500, 1266, 725 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.56-1.60 (m, 2H), 1.85-1.92 (m, 4H), 3.38-3.42 (m, 4H), 5.60 (d, J = 14.1 Hz, IH), 5.60 (d, J= 14.1 Hz, IH) 6.50 (d, J= 9.0 Hz, IH), 6.67 (t, J= 7.8 Hz, IH), 6.98 (d, J = 9.0 Hz, IH), 7.20 (t, J= 8.4 Hz, IH)5 7.60-7.70 (m, 2H), 7.85 (d, J= 2.0 Hz, IH). Examples 2 to 6 were prepared from l-(2,4-Dichloropheny I)-1, 4-dihydrochromeno [4,3- c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 1 and the appropriate amines (Refer to Table 1) according to the procedure mentioned in Example 1, Step 4.
Example 2
Λr3-(2,6-Dimethylpiperidino)-l-(2,4-dichloro]3henyI)-l,4-dihydrochromeno[4,3- c] py razole-3-carboxamide hydrochloride
IR (KBr) 3121, 2923, 1665, 1500, 1380, 1276, 725 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.02 (d, J = 6.3 Hz, 6H), 1.15-1.67 (m, 6H), 2.78-2.82 (m, 2H) 5.60 (q, J = 12.0 Hz, 2H), 6.50 (d, J= 9.0 Hz, IH), 6.80 (t, J= 7.8 Hz, IH), 6.98 (d, J= 9.0 Hz, IH), 7.20 (t, J= 7.0 Hz, IH)3 7.60-7.70 (m, 2H), 7.85 (d, J= 2.0 Hz, IH).
Example 3
Λr3-Morpholino-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride
IR (KBr) 3436, 2934, 1682, 1500, 1280, 725 cm"1; 1H NMR (300 MHz, CD3OD) δ 2.98 (t, J = 4.8 Hz, 4H), 3.82 (t, J= 4.5 Hz, 4H), 5.60 (q, J = 12.0 Hz, 2H), 6.50 (d, J= 9.0 Hz, IH), 6.80 (t, J= 12 Hz, IH), 6.98 (d, J= 9.0 Hz, 1H),7.2O (t, J= 7.2 Hz, IH), 7.60-7.70 (m, 2H), ' 7.85 (d, J= 2.0 Hz, IH).
Example 4
A3-(l-Azepanyl)-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride
IR (KBr) 3434, 2929, 1683, 1500, 1265, 725 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.74-1.78 (m, 4H), 1.94-1.98 (m, 4H), 3.60 (t, J= 5.0 Hz, 4H), 5.60 (q, J= 12.0 Hz, 2H), 6.50 (d, J = 9.0 Hz, IH), 6.80 (t, J= 7.5 Hz, IH), 6.98 (d, J= 9.0 Hz, IH), 7.2 (t, J= 7.0 Hz, IH), 7.60- 7.70 (m, 2H), 7.85 (d, J= 2 Hz, IH).
Example 5
Λr3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno-[4,3- c] py razole-3-carboxamide hydrochloride
IR (KBr) 3435, 2940, 1665, 1500, 1230, 725 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.58-1.62 (m, 2H), 1.65-1.80 (m, 4H), 2.88-1.92 (m, 2H), 2.98-3.00 (m, 2H), 3.98-4.02 (m, 2H), 5.60 (q, J = 14.0 Hz, 2H), 6.50 (d, J = 9.0 Hz, IH), 6.80 (t, J = 7.2 Hz5 IH), 6.98 (d, J = 9.0 Hz, IH), 7.20 (t, J= 7.8 Hz, IH), 7.60-7.70 (m, 2H), 7.85 (d, J= 2.0 Hz, IH).
Example 6 iV3-(4jHr-l,2,4-TriazoI-4-yl-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazoIe- 3-carboxamide
IR (KBr) 3450, 2930, 1680, 1500, 1230, 725 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 5.60 (q, J = 12.0 Hz, 2H), 6.50 (d, J= 9.0 Hz9IH), 6.80 (t, J = 7.8 Hz, IH), 6.98 (d, J= 9.0 Hz, IH), 7.20 (t, J= 7.2 Hz, IH), 7.60-7.70 (m, 2H)5 7.85 (d, J= 2.0 Hz, IH), 8.40 (s, 2H).
Example 7
N3-Piperidino-l-(2,4-dichlorophenyl)-4,4-dimethyI-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 2-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate: 2,2- dimethyl-2,3-dihydro-4H-chromen-4-one (2.0 g, 11.36 mmol) was reacted with diethyl oxalate (1.66 g, 11.36 mmol) in the presence of 20 % LHMDS in THF (10.48 mL, 12.50 mmol) as described in Example 1, Step 1 to give 2.60 g of the compound as a yellowish semisolid; IR (neat) 3436, 2980, 1735, 1684, 1609, 1465, 1309, 1248, 1128, 763 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.40 (t, J= 7.5 Hz, 3H), 1.54 (s, 3H), 1.57 (s, 3H), 4.30-4.40 (m, 2H), 5.01 (s, IH), 6.88-7.10 (m, 2H), 7.50-7.60 (m, IH), 7.78-7.86 (m, IH). Step 2: Ethyl l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate: Step 1 intermediate (2.56 g, 9.26 mmol) was reacted with 2,4- dichlorophenylhydrazine (1.64 g, 9.26 mmol) in ethanol (50 mL) as described in Example 1, Step 2 to give 1.60 g of the product as a brown solid; IR (KBr) 3392, 2928, 1720, 1509, 1382, 1250, 1189, 1051, 756, 746 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.43 (t, J= 7.2 Hz, 3H), 1.81 (s, 3H), 1.86 (s, 3H), 4.45 (q, J= 6.9 Hz, 2H), 6.45 (d, J= 7.8 Hz, IH), 6.69 (t, J= 7.2 Hz, IH), 6.96 (d, J= 7.8 Hz, IH), 7.14-7.20 (m, IH), 7.40-7.58 (m, 2H), 7.61 (br s, IH). Step 3: l-(2,4-Dichlorophenyl)-4,4-dimethyl-l ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid: Hydrolysis of Step 2 intermediate (1.60 g, 3.83 mmol) using IiV KOH solution (10 mL) in methanol (40 mL) as described in Example 1, Step 3 gave the 0.90 g of the acid as a brown solid; IR (KBr) 3401, 2978, 1701, 1509, 1439, 1252, 1193, 1071, 982, 947, 755 cm'1; 1H NMR (300 MHz, CDCl3) δ 1.83 (s, 3H), 1.87 (s, 3H), 6.46 (d, J= 7.5 Hz, IH), 6.71 (t, J= 7.5 Hz, IH), 6.97 (d, J= 7.5 Hz, IH), 7.19 (t, J= 6.9 Hz, IH), 7.42-7.58 (m, 2H), 7.65 (br s, IH).
Step ■ 4: N3-Piperidino-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 2.56 mmol) with 1-aminopiperidine (28 mg, 0.28 mmol) using BOP reagent (136 mg, 0.31mmol) and triethylamine (130 mg, 1.28 mmol) as described in Example 1, Step 4 gave 67 mg of the product as a white solid; IR (KBr) 3393, 2932, 1690, 1509, 1382, 1360, 1140, 807, 747 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.60-1.78 (m, 2H), 1.77 (s, 3H)5 1.84 (s, 3H), 1.90-2.02 (m, 4H), 3.42-3.61 (m, 4H), 6.47 (dd, J= 8.1, 1.5 Hz, IH), 6.72 (t, J= 7.5 Hz, IH), 6.94 (d, J= 8.4 Hz, IH), 7.20 (t, J= 7.8 Hz, IH), 7.60-7.78 (m, 2H), 7.85 (d, J= 2.1 Hz, IH). Examples 8 to 11 were prepared using l-(2,4-Dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 7 and appropriate amines (Refer to Table 1) according to the coupling procedure described in Step 4, Example 1.
Example 8
Λ3-(2,6-DimethyIpiperidino)-l-(2,4-dichlorophenyI)-4,4-dimethyI-l,4-dihydro- chromeno[4,3-c]pyrazoIe-3-carboxamide hydrochloride
IR (KBr) 3411, 2935, 1690, 1509, 1384, 1248, 1109, 746 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.20-2.00 (m, 6H), L34 (d, J= 6.6 Hz, 6H), 1.76 (s, 3H), 1.84 (s, 3H), 3.08-3.40 (m, 2H), 6.48 (d, J= 6.3 Hz3 IH), 6.73 (t, J= 7.2 Hz, IH), 6.94 (d, J= 8.1 Hz, IH), 7.21 (t, J = 6.9 Hz, IH), 7.60-7.78 (m, 2H), 7.85 (d, J= 1.8 Hz, IH).
Example 9 iV3-MorphoIino-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride
IR (KBr) 3434, 3182, 2866, 1654, 1508, 1112, 880, 748 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.75 (s, 3H), 1.82 (s, 3H), 2.82-2.96 (m, 4H), 3.72-3.84 (m, 4 H), 6.45 (d, J= 7.8 Hz, IH), 6.70 (t, J= 7.8 Hz, IH), 6.92 (d, J= 8.1 Hz, IH), 7.17 (t, J= 7.8 Hz, IH), 7.60-7.70 (m, 2H), 7.82 (d, J=I.8 Hz, IH).
Example 10
A3-^(l-Azepanyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c] py razole-3-carboxamide hydrochloride
IR (KBr) 3422, 2935, 1690, 1508, 1250, 1130, 757, 749 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.20-2.10 (m, 8H), 1.76 (s, 3H), 1.84 (s, 3H), 3.60-3.78 (m, 4H), 6.47 (d, J = 8.1 Hz, IH), 6.72 (t, J= 7.5 Hz, IH), 6.94 (d, J= 8.1 Hz, IH), 7.21 (t, J= 7.8 Hz, IH), 7.62-7.76 (m, 2H), 7.85 (d, J=I.8 Hz, IH).
Example 11
Λ3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]py razole-3-carboxamide hydrochloride IR (KBr) 3445, 2957, 2868, 2310, 1682, 1505, 1244, 808, 760 cm'1; 1H NMR (300 MHz, CD3OD) δ 1.52-1.90 (m, 6H), 1.76 (s, 3H), 1.83 (s, 3H), 2.82-3.10 (m, 4H), 3.82-3.98 (m, 2H), 6.47 (d, J= 7.5 Hz, IH), 6.69 (t, J= 8.1 Hz, IH), 6.94 (d, J= 7.8 Hz, IH), 7.20 (t, J = 8.4 Hz, IH), 7.60-7.78 (m, 2H), 7.84 (d, J= 1.5 Hz, IH).
Scheme 6 and Table 2 give detailed structural description of Examples 12-28. The percentage displacement values (% D) of [3H]CP55940 by test molecules at 1.0 μM for rCBl and 300 nM for hCBl are given in Table 2.
Scheme 6
Figure imgf000047_0001
Figure imgf000047_0002
Example 12 iV3-Piperidino-6-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride Step 1: Ethyl 2-(8-chloro-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate: 8- chloro-4-chromanone (3.1O g, 16.97 mmol) in TΗF was reacted with diethyl oxalate (2.49 g, 16.97 mmol) in the presence of 20 % LΗMDS in TΗF (15.62 mL, 18.67 mmol) as described in Example 1, Step 1 to give 3.88 g of the compound as yellow liquid which solidifies on standing; IR (KBr) 3423, 2980, 1723, 1598, 1475, 1286, 1237, 1144, 1072, 1008 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J = 6.9 Hz, 3H), 4.40 (q, J = 6.9 Hz, 2H), 5.49 (s, 2H),
7.03 (t, J= 7.8 Hz, IH), 7.58 (dd, J= 7.8, 1.8 Hz, IH), 7.83, (dd, J= 7.8, 1.8 Hz, IH), 15.38 (br s, IH).
Step 2: Ethyl 6-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole- 3-carboxylate: Step 1 intermediate (2.60 g, 5.89 mmol) was reacted with 2,4- dichlorophenylhydrazine (2.10 g, 11.78 mmol) in ethanol (20 mL) as described in Example 1, Step 2 to give 2.60 g of the product as a pale yellow solid; IR (KBr) 3435, 2929, 1683, 1560, 1473, 1381, 1257, 1166, 1012, 864, 742 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.43 (t, J= 7.5 Hz, 3H), 4.45 (q, J= 7.5 Hz, 2H), 5.67 (d, J= 14.1 Hz, IH), 5.76 (d, J= 14.1 Hz, IH), 6.40 (dd, J= 7.8, 1.5 Hz, IH), 6.68 (t, J= 7.8 Hz, IH), 7.25 (dd, J= 7.8, 1.5 Hz, IH), 7.49 (dd, J = 8.7, 1.8 Hz, IH), 7.50 (d, J= 8.7 Hz, IH), 7.61 (d, J= 1.8 Hz, IH).
Step 3: 6-Chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (1.1 g, 2.36 mmol) using IN KOH (4.72 mL) in methanol (20 mL) as described in Example 1, Step 3 gave 1.0 g of the acid as an off-white solid; IR (KBr) 3083, 2859, 1699, 1504, 1428, 1282, 1180, 999 cm"1; 1H NMR (300 MHz, CDCl3) δ 5.68 (d, J= 14.1 Hz, IH), 5.76 (d, J= 14.1 Hz, IH), 6,40 (d, J = 7.8 Hz, IH), 6.70 (t, J= 7.8 Hz, IH), 7.29 (d, J = 7.8 Hz, IH), 7.49 (dd, J= 8.4, 1.8 Hz, IH), 7.50 (d, J = 8.4 Hz, IH), 7.64 (s, IH)
Step 4: N3-Piperidino-6-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.25 mmol) with 1-aminopiperidine (28 mg, 0.29 mmol) using BOP reagent (134 mg, 0.30 mmol) and triethylamine (128 mg, 0.26 mmol) as described in Example 1, Step 4 gave 83 mg of the product as a white solid; IR (KBr) 3434, 2938, 1699, 1537, 1421, 1311, 1267, 993, 813, 729 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.69 (br s, 2H), 1.95-2.05 (m, 4H), 3.56 (br m, 4H), 5.63 (d, J= 14.1 Hz, IH), 5.73 (d, J= 14.1 Hz, IH), 6.45 (dd, J= 7.5, 1.5 Hz, IH), 6.76 (t, J= 7.5 Hz, IH), 7.32 (dd, J= 7.5, 1.5 Hz, IH), 7.66 (dd, J= 8.4, 2.4 Hz, IH), 7.71 (d, J =
8.4 Hz, IH), 7.85 (d, J= 2.4 Hz, IH). Example 13 and 14 were prepared using 6-Chloro-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 12 and appropriate amines (Refer to Table 2) according to the procedure mentioned in Example 12, Step 4.
Example 13 iV3-Azepanyl-6-chloro-l-(2,4-dichIoropheπyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride
IR (KBr) 3431, 2930, 1690, 1460, 1384, 1284, 1143, 1099, 983, 814 cm'1; 1H NMR (300 MHz, CD3OD) δ 1.77 (br s, 4H), 1.99 (br m, 4H), 3.60-3.80 (m, 4H), 5.63 (d, J = 14.1 Hz, IH), 5.74 (d, J= 14.1 Hz, IH), 6.45 (dd, J= 8.1, 1.5 Hz, IH), 6.76 (t, J= 8.1 Hz, IH), 7.31 (dd, J= 8.1, 1.5 Hz, IH), 7.66 (dd, J= 8.5, 1.8 Hz, IH), 7.68 (d, J= 8.7 Hz, IH)5 7.85 (d, J= 1.8 Hz5 IH).
Example 14
N3-Perhydrocyclopenta[c]azol-2-yl-6-chIoro-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride
IR (KBr) 3435, 2939, 2868, 1699, 1464, 1423, 1280, 1155, 1099, 1000, 811 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.64 (br s, 2H), 1.77 (br s, 4H), 3.10 (br m, 2H), 3.14 (t, J = 9.6 Hz, 2H), 4.00-4.20 (m, 2H), 5.63 (d, J = 14.1 Hz, IH), 5.93 (d, J = 14.1 Hz, IH), 6.45 (dd, J = 8.5, 1.5 Hz, IH), 6.76 (t, J = 8.1 Hz, IH), 7.31 (dd, J= 8.1, 1.5 Hz, IH), 7.66 (dd, J= 8.0, 1.8 Hz, IH), 7.70 (d, J= 8.0 Hz, IH), 7.85 (d, J= 1.8 Hz, IH).
Example 15
Λr3-Piperidino-8-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno-[4,3- c] pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 2-(6-chloro-2,2-dimethyl-4-oxo-3,4-dihydro-2/J-3-clτromenyl)-2-oxoacetate: 6- Chloro-2,2-dimethyl-2,3-dihydro-4#-chromen-4-one (0.50 g, 2.37 mmol) in THF was reacted with diethyl oxalate (0.35 g, 2.37 mmol in the presence of 20 % LHMDS in THF (2.18 mL, 2.61 mmol) as described in Example 1, Step 1 to give 0.617 g of the compound as a semi-solid; IR (neat) 2925, 1735, 1686, 1599, 1425, 1293, 1239, 1066, 951, 733 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.40 (t, J= 7.2 Hz, 3H), 1.53 (s, 3H), 1.63 (s, 3H), 4.30-4.44 (m, 2H), 4.94 (s, IH), 6.92 (d, J= 8.7 Hz, IH), 7.46 (dd, J= 9.0, 2.7 Hz, IH), 7.77 (d, J= 2.7 Hz, IH).
Step 2: Ethyl 8-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Step 1 intermediate (0.60 gs 1.93 mmol) was reacted with 2,4- dichlorophenylhydrazine (0.34 g, 1.93 mmol) in ethanol (15 mL) as described in Example 1, Step 2 to give 0.414 g of the product as a brown solid; IR (KBr) 2980, 1723, 1609, 1510, 1435, 1259, 1065, 980, 813, 757 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.43 (t, J = 7.2 Hz, 3H)5 1.80 (s, 3H), 1.86 (s, 3H), 4.44 (q, J= 6.9 Hz, 2H), 6.37 (d, J= 2.4 Hz, IH), 6.89 (d, J= 9.0 Hz, IH), 7.12 (dd, J= 6.3, 2.4 Hz, IH), 7.49-7.52 (m, 2H), 7.64 (d, J= 2.1 Hz, IH). Step 3: 8-Chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole- 3-carboxylic acid: Hydrolysis of Step 2 intermediate (0.41 g, 0.907 mmol) using IN KOH (2.5 mL) in methanol (8 mL) as described in Example 1, Step 3 gave the 0.36 g of the acid as a brown solid; IR (KBr) 2921, 2851, 1694, 1502, 1442, 1281, 1254, 1069, 787, 756 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.82 (s, 3H), 1.87 (s, 3H), 6.38 (d, J= 2.4 Hz, IH), 6.90 (d, J = 8.7 Hz, IH), 7.15 (dd, J= 9.0, 2.7 Hz, IH), 7.52 (s, 2H), 7.68 (s, IH).
Step 4: ΛG-Piperidino-δ-chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochro- meno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (62 mg, 0.146 mmol) with 1 -aminopiperidine (16 mg, 0.160 mmol) using BOP reagent (77 mg, 0.175 mmol) and triethylamine (74 mg, 0.73 mmol) as described in Example 1, Step 4 gave 40 mg of the product as a white solid; IR (KBr) 3436, 2919, 2850, 1680, 1509, 1452, 1244, 1111, 813 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.62-1.78 (m, 2H), 1.78 (s, 3H), 1.86 (s, 3H), 1.93-2.02 (m, 4H), 3.44 -3.58 (m, 4H), 6.37 (d, J= 2.4 Hz, IH), 6.95 (d, J= 8.7 Hz, IH), 7.21 (dd, J= 8.7, 2.4 Hz, IH), 7.12-7.75 (m, 2H), 7.91 (d, J= 1.5 Hz, IH).
Example 16
7V3-Morpholino-8-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazoIe-3-carboxamide hydrochloride
This compound was prepared from 8-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid and morpholine according to the coupling procedure described in Example 1, Step 4; IR (KBr) 3437, 2921, 2852, 1683, 1509, 1454, 1379, 1247, 1111, 754 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.77 (s, 3H), 1.85 (s, 3H), 3.13 (t, J= 4.8 Hz, 4H), 3.87 (t, J= 5.1 Hz, 4H), 6.37 (d, J= 2.4 Hz, IH), 6.94 (d, J= 9.0 Hz, IH) 7.19 (dd, J= 9.0, 2.4 Hz, IH), 7.65-7.75 (m, 2H), 7.89 (br s, IH).
Example 17
N3-Piperidino-8-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyI-l,4-dihydrochromeno-[4,3- c]pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 2-(6-bromo-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate: 6- bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (7.35 g, 28.81 mmol) was reacted with diethyl oxalate (4.21 g, 28.81 mmol) in the presence of 20 % LHMDS in THF (26.5 mL, 31.69 mmol) as described in Example 1, Step 1 to give 8.21 g of the compound as a dark yellow semi-solid; IR (neat) 3087, 2872, 1727, 1590, 1466, 1282 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.32-1.43 (m, 3H), 1.57 (s, 3H), 1.62 (s, 3H), 4.32-4.42 (m, 2H), 4.93 (s, IH), 6.86 (d, J= 8.7 Hz, IH), 7.58 (dd, J= 8.7, 2.7 Hz, IH), 7.92 (br s, IH).
Step 2: Ethyl 8-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Step 1 intermediate (2.0 g, 5.64 mmol) was reacted with 2,4- dichlorophenylhydrazine (1.0 g, 5.64 mmol) in ethanol (50 mL) as described in Example 1, Step 2 to give 1.45 g of the product as a brown solid; IR (KBr) 3423, 2976, 1732, 1606, 1411, 1252 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42-1.47 (m, 3H), 1.79 (s, 3H), 1.85 (s, 3H), 4.40- 4.48 (m, 2H)5 6.49 (s, IH), 6.82-6.85 (m, IH)3 7.24-7.27 (m, IH), 7.49-7.51 (m, 2H), 7.64 (s, IH).
Step 3 : 8-Bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 -c]pyrazole- 3-carboxylic acid:. Hydrolysis of Step 2 intermediate (1.45 g, 2.92 mmol) using IiV KOH (10 mL) in methanol (30 mL) as described in Example 1, Step 3 gave 1.10 g of the acid as an off- white solid; IR (KBr) 2980, 1734, 1605, 1402, 1274, 1064 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.81 (s, 3H), 1.87 (s, 3H), 6.50 (d, J= 2.4 Hz, IH), 6.84 (d, J- 8.7 Hz, IH), 7.28-7.29 (br s, IH), 7.52 (d, J- 9.0 Hz, 2H), 7.68 (s, IH).
Step 4: 7V3-Piperidino-8-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.21 mmol) with 1-aminopiperidine (24 mg, 0.24 mmol) using BOP reagent (113 mg, 0.25 mmol) and triethylamine (108 mg, 1.07 mmol) as described in Example 1, Step 4 gave 56 mg of the product as an off-white solid; IR (KBr) 3421, 2936, 2629, 1703, 1509, 1381, 1439, 1245 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.85 (br s, 2H), 1.68 (s, 3H), 1.76 (s, 3H), 1.87-1.93 (m 4H), 3.45 (br s, 4H), 6.42 (d, J= 2.4 Hz, IH), 6.78 (d, J= 8.7 Hz, IH), 7.24 (dd, J= 8.7, 2.1 Hz, IH), 7.59- 7.66 (m, 2H), 7.81 (d, J= 8.1 Hz, IH).
Example 18
N3-Morpholino-8-bromo-l-(2,4-dichIorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride
This compound was prepared from 8-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid and morpholine according to the coupling procedure described in Example 1, Step 4; IR (KBr) 3457, 3289, 2925, 2854, 1692, 1511, 1451, 1250 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.66 (s, 3H), 1.74 (s, 3H), 2.78 (t, J= 4.5 Hz, 4H), 3.69 (t, J= 4.5 Hz, 4H), 6.40 (d, J= 2.4 Hz, IH), 6.76 (d, J= 9.0 Hz, IH), 7.22 (dd, J= 8.7, 2.4 Hz, IH), 7.60 (br s, 2H), 7.78 (d, J=. 1.5 Hz, IH).
Example 19
Λr3-Piperidino-7-chIoro-l-(2,4-difluorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride
Step 1: Ethyl 2-(7-chloro-4-oxo-3,4-dihydro-2//-3-chromenyl)-2-oxoacetate: 7- chloro-4-chromanone (2.80 g, 15.33 mmol) was reacted with diethyl oxalate (2.24 g, 15.33 minol) in the presence of 20 % LHMDS in THF (14.10 mL, 16.86 mmol) as described in Example 1, Step 1 to give 2.40 g of the compound as a semi-solid; IR (neat) 3437, 2925, 1727, 1597, 1465, 1369, 1277, 1012, 896, 799 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J = 7.2 Hz, 3H), 4.40 (q, J= 7.2 Hz, 2H), 5.29 (s, IH), 5.40 (s, IH), 6.99 (d, J= 2.0 Hz, IH), 7.05 (dd, J= 8.4, 2.0 Hz, IH), 7.38 (d, J= 8.1 Hz, IH), 15.60 (s, IH). Step 2: Ethyl 7-chloro-l-(2,4-difluorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate: Step 1 intermediate (3.0 g, 10.61 mmol) was reacted with 2,4- difluorophenylhydrazine (1.53 g, 10.61 mmol) in ethanol (15 mL) as described in Example 1, Step 2 to give 0.912 g of the product as a yellow solid; IR (KBr) 3433, 3091, 2977, 2166, 1741, 1708, 1579, 1380, 1271, 1143, 982, 834, cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J = 7.2 Hz, 3H), 4.44 (q, J= 7.2 Hz, 2H), 5.55 (d, J= 13.8 Hz, IH), 5.64 (d, J= 13.8 Hz, IH), 6.53 (d, J = 8.4 Hz, IH), 6.74 (dd, J = 8.7, 2.0 Hz, IH), 7.01 (d, J= 1.8 Hz, IH), 7.03-7.14 (m, 2H), 7.50-7.62 (m, IH).
Step 3: 7-Chloro-l-(2,4-difluorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (0.90 g, 2,12 mmol) using IN KOH (4.60 mL) in methanol (18 mL) as described in Example 1, Step 3 gave the 0.71 g of the acid as a white solid; IR (KBr) 3444, 3080, 2889, 1695, 1525, 1446, 1274, 1183, 1067, 983, 857 cm"1; 1H NMR (300 MHz, DMSO-rf*) δ 5.54 (d, J= 13.5 Hz, IH), 5.59 (d, J= 13.5 Hz, IH), 6.56 (d, J = 8.4 Hz, IH), 6.94 (dd, J= 8.4, 2.1 Hz, IH), 7.15 (d, J= 1.8 Hz, IH), 7.42 (br t, J= 8.4 Hz, IH) 7.73 (br t, J= 8.4 Hz, IH), 7.80-7.95 (m, IH), 13.40 (br s, IH).
Step 4 : AG -Piperidino-7-chloro- 1 -(2,4-difluorophenyl)- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (300 mg, 0.83 mmol) with 1-aminopiperidine (91 mg, 0.91 mmol) using BOP reagent (349 mg, 0.83 mmol) and triethylamine (418 mg, 4.13 mmol) as described in Example 1, Step 4 gave 157 mg of the product as an off-white solid; IR (KBr) 3429, 2927, 1707, 1609, 1551, 1437, 1379, 1266, 1142, 983, 855 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.69 (m, 2H), 1.90-2.10 (m, 4H), 3.57 (s, 4H), 5.55 (d, J = 13.8 Hz5 IH), 5.64 (d, J = 13.8 Hz, IH), 6.61 (d, J = 8.4 Hz, IH), 6.83 (dd, J = 8.4, 2.1 Hz, IH), 7.05 (d, J = 2.1 Hz, IH), 7.25-7.33 (m, IH), 7.35-7.43 (m, IH), 7.70-7.80 (m, IH).
Examples 20 and 21 were prepared from Ethyl 2-(7-chloro-4-oxo-3,4-dihydro-2H-3- chromenyl)-2-oxoacetate and the appropriate hydrazines (Refer to Table 2) followed by hydrolysis and subsequent coupling of the acid obtained with 1-aminopiperidine according to the procedure described in Example 1, Steps 2, 3 and 4.
Example 20
Λr3-Piperidino-7-chloro-l-(4-chlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride
Step 1: Ethyl 7-chloro-l-(4-chlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate: IR (KBr) 3415, 3077, 2928, 1702, 1614, 1525, 1439, 1273, 1091, 840, cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J = 7.2 Hz, 3H), 4.44 (q, J = 7.2 Hz, 2H), 5.55 (d, J = 13.8, IH), 5.64 (d, J= 13.8 Hz, IH), 6.53 (d, J= 8.4 Hz, IH), 6.74 (dd, J= 8.7, 2.0 Hz, IH), 7.01 (d, J= 1.8 Hz, IH), 7.03-7.14 (m, 2H), 7.50-7.62 (m, IH). Step 2: 7-Chloro- l-(4-chloropheny I)-1 ,4-dihydrochromeno [4,3 -c]pyrazole-3- carboxylic acid: IR (KBr) 3400, 3020, 2401, 1701, 1686, 1537, 1489, 1288, 1092, 1011 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 5.55 (s, 2H), 6.66 (d, J = 8.5, 2.1 Hz, IH), 6.96 (dd, J = 8.5, 2.1 Hz, IH), 7.15 (d, J = 2.1 Hz, IH), 7.64 (d, J = 9.3, 2H), 7.70 (d, J = 9.3 Hz, 2H), 13.40 (br s, IH)
Step 3: 7V3-Piperidino-7-chloro-l -(4-chlorophenyl)-l ,4-dihydrochromeno[4,3- φyrazole-3-carboxamide hydrochloride: IR (KBr) 3434, 2922, 2434, 1692, 1552, 1437, 1376, 1266, 1125, 1095, 848 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.68 (br m, 2H), 1.99 (br m, 4H), 3.55 (br s, 4H), 5.56 (s, 2H), 6.72 (d, J= 8.4 Hz, IH), 6.84 (dd, J= 8.4, 1.8 Hz, IH), 7.06 (d, J= 1.8 Hz, IH), 7.57 (dd, J= 6.3, 1.8 Hz5 2H), 7.65 (dd, J= 6.3, 1.8 Hz, 2H).
Example 21 iV3-Piperidino-7-chloro-l-(2-chlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazoIe-3- carboxamide hydrochloride
Step 1: Ethyl 7-chloro-l-(2-chlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate: IR (KBr) 3429, 2980, 1724, 1621, 1518, 1494, 1382, 1258, 1141, 1097, 982, 835, cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J= 7.2 Hz, 3H), 4.45 (q, J = 7.2 Hz, 2H), 5.59 (d, J= 13.8 Hz, IH), 5.67 (d, J= 13.8 Hz, IH), 6.36 (d, J= 8.4, 2.0 Hz, IH), 6.68 (dd, J = 8.4, 2.0 Hz, IH), 6.99 (d, J= 2.0 Hz, IH), 7.42-7.65 (m, 4H). Step 2 : 7-Chloro- 1 -(2-chlorophenyl)- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 - carboxylic acid: IR (KBr) 3401, 3020, 1643, 1412, 1216, 757, 669 cm-1; 1H NMR (300 MHz, OMSO-d6) δ 5.54 (d, J = 13.8 Hz, IH), 5.62 (d, J= 13,8 Hz, IH), 6.32 (d, J= 8.1, Hz, IH), 6.90 (dd, J= 8.1, 1.8 Hz, IH), 7.14 (d, J= 1.8 Hz, IH), 7.61-7.85 (m, 4H). Step 3: ΛG-Piperidino-7-chloro-l -(2-chlorophenyl)- 1 ,4-dihydrochromeno [4,3- c]pyrazole-3-carboxamide hydrochloride: IR (KBr) 3434, 2962, 1687, 1609, 1542, 1453, 1266, 1210, 1011, 755 cm-1; 1H NMR (300 MHz, CD3OD) δ 1.69 (br m, 2H), 1.99 (pentet, J = 6.0 Hz, 4H), 3.56 (br s, 4H), 5.58 (d, J= 13.8 Hz, IH), 5.66 (d, J= 13.8 Hz, IH), 6.39 (d, J = 8.4 Hz, IH), 6.75 (dd, J= 8.4, 2.1 Hz, IH), 7,03 (d, J= 2.1 Hz, IH), 7.64 (dt, J = 7.8, 1.8 Hz, 2H), 7.73 (dt, J= 7.8, 1.8 Hz, 2H).
Example 22 iV3-Piperidino-l-(2,4-difluorophenyI)-7-iodo-4,4-dimethyI-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 2-(7-iodo-2,2-dimethyl-4-oxo-3,4-dihydro-2/f-3-chromenyl)-2-oxoacetate: 7- iodo-2,2-dimethyl-2,3-dihydiO-4if-chromen-4-one (8.85 g, 29.28 mmol) was reacted with diethyl oxalate (4.27 g, 29.28 mmol) in the presence of 20 % LHMDS in THF (27 mL, 32.20 mmol) as described in Example 1, Step 1 to give 8.0 g of the compound as a brown semisolid; IR (neat) 2979, 1735, 1685, 1589, 1413, 1232, 1133 757 cm'1; 1U NMR (300 MHz, CDCl3) δ 1.42 (t, J= 14.0 Hz, 3H), 1.52-1.61 (m, 6H), 4.31-4.39 (m, 2H), 4.93 (s, IH), 6.93- 7.05 (m, IH), 7.47-7.49(m, IH), 7.79-7.82 (m, IH).
Step 2: Ethyl l-(2,4-difluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Step 1 intermediate (2.00 g, 4.97 mmol) was reacted with 2,4- difluorophenylhydrazine (0.715 g, 4.96 mmol) in ethanol (15 mL) as described in Example 1, Step 2 to give 0.885 g of the product as a pale yellow solid; IR (KBr) 3020, 2401, 1723, 1604, 1523, 1435, 1261, 1147, 1078, 963, 857, cm"1 ; 1H NMR (300 MHz, DMSO-^) δ 1.31 (t, J= 7.2 Hz, 3H), 1.69 (s, 3H), 1.77 (s, 3H), 4.33 (q, J = 7.2 Hz, 2H), 6.31 (d, J = 8.4 Hz, IH),), 7.20 (d, J= 8.4 Hz, IH), 7.38 (s, IH), 7.41 (t, J= 8.0 Hz, IH), 7.71 (dt, J= 8.0, 2.4 Hz, IH), 7.82-7.95 (m, IH)
Step 3 : 1 -(2,4-Difluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3 -carboxylic acid: Hydrolysis of Step 2 intermediate (150 mg, 0.294 mmol) using IiV KOH (0.63 mL) in methanol (2 mL) as described in Example 1, Step 3 gave 135 mg of the acid as an off-white solid; IR (KBr) 3400, 2930, 1604, 1520, 1404, 1215, 757, 669 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.70 (s, 3H), 1.78 (s, 3H), 6.31 (d, J = 8.2 Hz, IH), 7.19 (dd, J = 8.2, 1.5 Hz, IH), 7.37 (d, J = 1.5 Hz, IH)3 7.40 (t, J = 10.2 Hz, IH), 7.71 (dt, J = 10.2, 2.4 Hz, IH), 7.84-7.94 (m, IH), 13.40 (br s, IH)
Step 4: N3-Piperidino-l-(2,4-difluorophenyl)-7-iodo-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (130 mg, 0.27 mmol) with 1-aminopiperidine (30 mg, 0.297 mmol) using BOP reagent (130 mg, 0.297 mmol) and triethylamine (136 mg, 1.35 mmol) as described in Example 1, Step 4 gave 80 mg of the product as an off-white solid; IR (KBr) 3422, 2940, 1698, 1603, 1520, 1441, 1382, 1263, 1197, 984, 828, cm'1; 1H NMR (300 MHz, OMSO-d6) δ 1.32 (br m, 2H), 1.57 (br m, 4H), 1.66 (s, 3H), 1.75 (s, 3H), 2.75 (t, J= 6.0 Hz, 4H), 6.32 (d, J= 8.1 Hz, IH), 7.19 (dd, J= 8.1, 1.5 Hz, IH), 7.35-7.42 (m, IH), 7.37 (br s, IH), 7.68 (dt, J = 9.0, 2.7 Hz, IH), 7.90-7.95 (m, IH), 9.42 (s, IH)
Examples 23 to 28 were prepared from Ethyl 2-(7-iodo-2,2-dimethyl-4-oxo-3,4- dihydro-27J-3-chromenyl)-2-oxoacetate and the appropriate hydrazines (Refer to Table 2) followed by hydrolysis and coupling of subsequent acid with 1 -aminopiperidine according to the procedure described in Example 1, Steps 2, 3 and 4.
Example 23
N3-Piperidino-l-(4-fluorophenyl)-7-iodo-4,4-dinoiethyl-l,4-dihydrochromeno[4,3- c] py razole-3-carboxamide hydrochloride
Step 1: Ethyl l-(4-fluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochiOmeno[4,3- c]pyrazole-3-carboxylate: IR (KBr) 3020, 1720, 1517, 1216, 1060, 981, 845, 758, 669 cm'1 ; 1H NMR (300 MHz, OMSO-d6) δ 1.30 (t, J= 7.2 Hz, 3H), 1,72 (s, 6H), 4.32 (q, J= 7.2 Hz, 2H), 6.30 (d, J= 8.4 Hz, IH)5), 7.17 (dd, J = 8.4, 1.5 Hz, IH), 7.37 (d, J= 1.5 Hz, IH), 7.47 (t, J= 8.7 Hz, 2H), 7.60-7.72 (m, 2H)
Step 2: l-(4-Fluorophenyl)-7-iodo-4,4-dimethyl-l ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid: IR (KBr) 3400, 2929, 1638, 1515, 1403, 1215, 758, 669 Cm-V1H NMR (300 MHz, DMSO-rff) δ 1.73 (br s, 6H), 6.32 (d, J = 8.4 Hz, IH), 7.17 (dd, J = 8.4, 1.5 Hz, IH), 7.36 (d, J= 1.5 Hz, IH), 7.46 (t, J= 8.7 Hz, 2H), 7.60-7.70 (m, 2H), 13.30 (br s, IH) Step 3: N3-Piperidino-l-(4-fluorophenyl)-7-iodo-4,4-dimethyl-l ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: IR (KBr) 3431, 2949, 1707, 1515, 1452, 1365, 1278, 1060, 982, 891 cm'1; 1H NMR (300 MHz,
Figure imgf000055_0001
δ 1.44 (br s, 2H)3 1.74 (br m, 10H), 3.18 (br s, 4H), 6.32 (br dd, J= 8.1, 1.5 Hz, IH), 7.19 (br dd, J= 8.4, 1.5 Hz3 IH)3 7.38 (br m, IH)3 7.42-7.54 (m, 2H), 7.66-7.76 (m, 2H), 11.0 (br s, IH)
Example 24 N3-Piperidino-l-(2-fluorophenyl)-7-iodo-4,4-dimethyI-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride
Step 1 : Ethyl 1 -(2-fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3-carboxylate: IR (KBr) 3401, 2981, 1724, 1602, 1515, 1432, 1366, 1262, 1189, 1080, 980, 758 cm'1 ; 1H NMR (300 MHz, DMSO-4) δ 1.31 (t, J= 7.2 Hz, 3H), 1.70 (s, 3H), 1.78 (s, 3H), 4.35 (q, J = 7.2 Hz, 2H), 6.26 (d, J= 8.4 Hz, IH),), 7.17 (dd, J = 8.4, 1.8 Hz, IH), 7.38 (br s, IH), 7.46-7.54 (m, IH), 7.56-7.62 (m, IH),' 7.70-7.83 (m, 2H) Step 2 : 1 -(2-Fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 - φyrazole-S-carboxylic acid: IR (KBr) 3020, 2401, 1516, 1430, 1216, 771, 669 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.70 (s, 3H), 1.79 (s, 3H), 6.26 (d, J= 7.8 Hz, IH), 7.16 (dd, J = 7.8, 1.8 Hz, IH), 7.37 (d, J= 1.8 Hz, IH), 7.49 (t, J= 8.5 Hz, IH), 7.58 (t, J= 8.5 Hz, IH), 7.75-7.80 (m, 2H), 13.40 (br s, IH)
Step 3: N3-Piperidino-l-(2-fluorophenyl)-7-iodo-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: IR (KBr) 3431, 3118, 2930, 1698, 1515, 1461, 1362, 1263, 1081, 981, 892, 862, 769 cm"1; 1H NMR (300 MHz, DMSO- d6) δ 1.42 (br s, 2H), 1.70 (br s, 4H), 1.80 (s, 6H), 3.12 (br s, 4H), 6.27 (d, J= 8.4 Hz, IH), 7.18 (dd, J= 8.4, 1.2 Hz, IH), 7.39 (d, J= 1.2 Hz, IH), 7.50 (t, J= 7.5 Hz, IH), 7.58 (t, J= 7.5 Hz, IH), 7.74 (br t, J= 7.5 Hz, IH), 7.82 (t, J= 7.5 Hz, IH), 10.74 (br s, IH)
Example 25 iV3-Piperidino-l-(2-chIoro-4-fluorophenyI)-7-iodo-4,4-dimethyl-l,4- dihy drochromeno [4,3-c] py razole-3-carboxamide hydrochloride
Step 1: Ethyl l-(2-chloro-4-fluorophenyl)-7-iodo-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: IR (KBr) 3392, 3018, 1724, 1603, 1509, 1435, 1384, 1215, 1072, 911, 757 cm"1; 1H NMR (300 MHz, DMSO-^6) δ 1.31 (t, J = 7.2 Hz, 3H), 1.71 (s, 3H), 1.77 (s, 3H), 4.32 (q, J= 7.2 Hz, 2H), 6.13 (d, J= 8.4 Hz, IH), 7.17 (dd, J= 8.4, 1.8 Hz, IH), 7.36 (d, J= 1.5 Hz, IH), 7.55 (dt, J= 8.7, 3.0 Hz, IH), 7.85-7.95 (m, 2H). Step 2: l-(2-Chloro-4-fluorophenyl)-7-iodo-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid: IR (KBr) 3421, 2932, 1694, 1545, 1484, 1389, 1276, 815, 794, 732 cm4; 1H NMR (300 MHz, DMSO-^) δ 1.72 (s, 3H), 1.77 (s, 3H), 6.13 (d, J = 8.1 Hz, IH),), 7.16 (dd, J= 8.1, 1.5 Hz, IH), 7.35 (d, J= 1.5 Hz, IH), 7.54 (dt, J= 8.4, 3.0 Hz, IH), 7.82-7.95 (m, 2H), 13.40 (br s, IH)
Step 3: N3-Piperidino-l-(2-chloro-4-fluorophenyl)-7-iodo-4,4-dimethyl-l,4- dihydrocnromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: IR (neat) 3020, 2929, 2401, 1686, 1511, 1451, 1259, 757, 670 cm"1; 1E NMR (300 MHz, DMSO-rf*) δ 1.35 (br m, 2H)3 1.61 (br m, 4H), 1.71 (s, 3H), 1.77 (s, 3H), 2.87 (br m, 4H), 6.14 (d, J- 8.1 Hz, IH), 7.17 (br d, J = 8.1 Hz, IH), 7.35 (d, J= 1.5 Hz, IH), 7.54 (br d, J= 8.1 Hz, IH), 7.85-7.95 (m, 2H), 9.81 (br s, IH).
Example 26 iV3-Piperidmo-l-(4-chloro-2-fluorophenyl)-7-iodo-4,4-dimethyl-l,4- dihydrochromeno [4,3-c] pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl l-(4-chloro-2-fluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno [4,3- φyrazole-3-carboxylate: IR (KBr) 3432, 2977, 1722, 1603, 1588, 1437, 1261, 1188, 1072, 950, 861 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J= 7.2 Hz, 3H), 1.77 (s, 3H), 1.85 (s, 3H), 4.44 (q, J= 7.2 Hz, 2H), 6.36 (br d, J= 8.4 Hz, IH), 7.06 (br d, J = 8.4 Hz, IH), 7.30- 7.40 (m, 3H), 7.52 (br t, J= 8.1 Hz, IH).
Step 2: l-(4-Chloro-2-fluorophenyl)-7-iodo-4,4-dimethyl-l ,4-dihydrochromeno[4,3- φyrazole-3-carboxylic acid: IR (KBr) 3442, 3066, 2927, 1693, 1604, 1510, 1412, 1280, 1191, 1069, 906 cm-1; 1H NMR (300 MHz, DMSO-J5) δ 1.69 (s, 3H), 1.78 (s, 3H), 6.36 (d, J = 8.1 Hz, IH), 7.21 (dd, J= 8.1, 1.5 Hz, IH), 7.37 (d, J= 1.5 Hz, IH), 7.59 (br d, J= 8.4 Hz, IH), 7.83 (d, J= 8.4 Hz, IH), 7.89 (dd, J= 8.4, 2.4 Hz, IH ), 13.4 (br s, IH). -Step 3 : N3 -Piperidino- 1 -(4-chloro-2-fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: IR (KBr) 2941, 2807, 1687, 1567, 1456, 1215, 970, 894, 756 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.34 (br m, 2H), 1.59 (br m, 4H), 1.66 (s; 3H), 1.76 (s, 3H), 2.80 (br m, 4H), 6.37 (d, J = 7.5 Hz, IH), 7.22 (dd, J = 8.1, 1.8 Hz, IH), 7.38 (d, J = 1.8 Hz, IH), 7.50-7.61 (m, IH), 7.80-7.90 (m, 2H), 9.61 (br s, IH).
Example 27
Λ3-Piperidino-l-(2-chlorophenyl)-7-iodo-4,4-dimethyϊ-l,4-dihydrochromeno[4,3- c] py razoIe-3-carboxamide hydrochloride
Step 1: Ethyl l-(2-chlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: IR (KBr) 3019, 2979, 1721, 1511, 1215, 1064, 929, 770, 669 cm'1; 1H NMR (300 MHz, DMSO-cfe) δ 1.31 (t, J= 7.2 Hz, 3H), 1.72 (s, 3H), 1.78 (s, 3H), 4.33 (q, J= 7.2 Hz, 2H), 6.07 (d, J= 8.1 Hz, IH), 7.14 (dd, J= 8.1, 2.0 Hz, IH), 7.37 (d, J= 2.0 Hz, IH), 7.65 (dt, J= 8.1, 1.8 Hz, IH), 7.74 (dt, J= 8.1, 1.8 Hz, IH), 7.81 (d, J= 8.7 Hz, 2H). Step 2: 1 -(2-Chlorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno[4,3- φyrazole-3-carboxylic acid: IR (KBr) 3019, 2400, 1602, 1516, 1215, 1048, 928, 759, 669 cm"1; 1H NMR (300 MHz5 OMSO-d6) δ 1.72 (s, 3H), 1.78 (s, 3H), 6.07 (d, J= 8.1 Hz, IH),), 7.13 (dd, J= 8.1, 1.8 Hz, IH), 7.35 (d, J= 1.8 Hz, IH), 7.64 (dt, J= 7.8, 1.8 Hz, IH), 7.73 (s, IH), 7.80 (m, 2H), 13.30 (br s, IH).
Step 3: N3-Piperidino- 1 -(2-chlorophenyl)-7-iodo-4,4-dimethyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride; IR (KBr) 3428, 2934, 1701, 1603, 1532, 1451, 1361, 1263, 1136, 1063, 980, 861 cm"1 : 1H NMR (300 MHz, DMSO-rftf) δ 1.32 (br m, 2H), 1.56 (br m, 4H), 1.70 (s, 3H), 1.77 (s, 3H), 2.76 (t, J= 5.1 Hz, 4H), 6.08 (d, J= 8.4 Hz, IH), 7.12 (dd, J= 8.4, 1.8 Hz, IH), 7.35 (d, J= 1.8 Hz, IH), 7.63 (dt, J= 7.8, 1.8 Hz, IH), 7.71 (dt, J= 7.8, 1.8 Hz, IH), 7.80 (m, 2H), 9.36 (br s, IH)
Example 28
Λr3-Piperidino-l-(4-chlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- c] py razole-3-carboxamide hydrochloride
Step 1: Ethyl l-(4-chlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: IR (KBr) 3400, 2932, 1719, 1506, 1216, 1060, 758, 670 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.31 (t, J= 7.2 Hz, 3H), 1.70 (s, 6H), 4.33 (q, J= 7.2 Hz, 2H), 6.38 (d, J= 8.4 Hz, IH), 7.20 (d, J= 8.4 Hz3 IH), 7.43 (s, IH), 7.64 (d, J= 8.7 Hz, 2H), 7.69 (d, J= 8.7 Hz, 2H)
Step 2 : 1 -(4-Chlorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihy drochromeno [4,3 - c]pyrazole-3-carboxylic acid: IR (KBr) 3401, 1684, 1403, 1263, 1219, 1155, 1085, 1058, 772 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.60 (s, 6H), 6.39 (d, J = 8.1 Hz, IH)3), 7.19 (d, J = 8.1 Hz, IH), 7.37 (s, IH), 7.64 (d, J= 8.7 Hz, 2H), 7.69 (d, J= 8.7 Hz, 2H)3 13.20 (br s, IH). Step 3: N3-Piperidino-l-(4-chlorophenyl)-7-iodo-4,4-dimethyl-l,4- dihydrochromeno[4,3-φyrazole-3-carboxamide hydrochloride: IR (KBr) 3421, 2948, 1709, 1597, 1453, 1365, 1257, 1187, 1084, 836 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.41 (br s, 2H), 1.72 (br m, 10H)3 3.05 (br s, 4H), 6.39 (d, J = 8.1 Hz, IH), 7.21 (dd, J = 8.1, 1.8 Hz, IH), 7.38 (d, J= 1.8 Hz, IH), 7.60-7.70 (m, 4H), 10.50 (br s, IH).
Scheme 7 and Table 3 gives detailed structural description of Examples 29-74. The percentage displacement values (% D) of [3H]CP55940 by test molecules at 1.0 μM for rCBl and 300 nM for hCBl are given in Table 3. Scheme 7
Figure imgf000059_0001
5 I
Table 3: Detailed description of Examples 29 - 74 and their in-vitro screenin data
Figure imgf000059_0002
Figure imgf000060_0001
Example 29
Λ3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride
Step 1: Ethyl 2-(7-chloro-4-oxo-3,4-dihydro-2//-3-chromenyl)-2-oxoacetate: 7- chloro-4-chromanone (2.80 g, 15.33 mmol) was reacted with diethyl oxalate (2.24 g, 15.33 mmol) in the presence of 20 % LHMDS in THF (14.10 mL, 16.86 mmol) as described in Example 1, Step 1 to give 2.40 g of the compound as a semi-solid; IR (neat) 3437, 2925, 1727, 1597, 1465, 1369, 1277, 1012, 896, 799 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J = 7.2 Hz, 3H), 4.40 (q, J- 7.2 Hz, 2H), 5.29 (s, IH), 5.40 (s, IH), 6.99 (d, J = 2.0 Hz, IH), 7.05 (dd, J= 8.4, 2.0 Hz, IH), 7.38 (d, J= 8.1 Hz, IH), 15.60 (s, IH).
Step 2: Ethyl 7-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate: Step 1 intermediate (2.30 g, 8.13 mmol) was reacted with 2,4- dichlorophenylhydrazine (1.44 g, 8.13 mmol) in ethanol (15 mL) as described in Example 1, Step 2 to give 0.912 g of the product as a brown solid; IR (KBr) 3437, 2925, 2854, 1740, 1715, 1437, 1377, 1268, 1106, 977, 864 cm'1; 1H NMR (300 MHz, CDCl3) δ 1.43 (t, J= 7.2 Hz, 3H), 4.44 (q, J= 7.2 Hz, 2H), 5.55 (d, J= 13.8 Hz, IH), 5.65 (d, J= 13.8 Hz, IH), 6.39 (d, J = 8.4 Hz, IH), 6.73 (dd, J = 8.4, 1.8 Hz, IH), 7.00 (d, J= 7.8 Hz, IH)5 7.40-7.50 (m, 2H), 7.02 (d, J= 2.4 Hz, IH).
Step 3: 7-Chloro-l -(2,4-dichlorophenyl)-l ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid: Hydrolysis of Step 2 intermediate (0.90 g, 2.12 mmol) using IN KOH (4.30 mL) in methanol (18 mL) as described in Example 1, Step 3 gave the 0.65 g of the acid as a white solid; IR (KBr) 3436, 3088, 2855, 2611, 1702, 1681, 1440, 1282, 1179, 1080, 865, cm" '; 1H NMR (300 MHz, CDCl3) δ 5.58 (d, J= 14.1 Hz, IH), 5.65 (d, J= 14.1 Hz, IH), 6.40 (d, J= 8.2 Hz, IH), 6.74 (dd, J= 8.2, 2.0 Hz, IH), 7.02 (d, J= 2,0 Hz, IH), 7.49 (s, 2H), 7.65 (d, J= 1..2 Hz, IH). Step 4: 7V3-Piperidino-7-chloro-l -(2,4-dichlorophenyl)-l ,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (200 mg, 0.51 mmol) with 1-aminopiperidine (56 mg, 0.56 mmol) using BOP reagent (210 mg, 0.51 mmol) and triethylamine (260 mg, 2.52 mmol) as described in Example I5 Step 4 gave 113 mg of the product as an off-white solid; IR (KBr) 3434, 1615, 1436, 1267, 1079, 1008, 802 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.54 (br s, 2H), 1.82 (br s, 4H), 3.25-3.00 (br m, 4H), 5.53 (d, J = 14.1 Hz, IH), 5.63 (d, J = 14.1 Hz, IH), 6.45 (d, J = 8.4 Hz, IH), 6.78 (dd, J = 8.4, 2.4 Hz, IH), 7.00 (d, J= 1.8 Hz, IH), 7.60-7.75 (m, 2H), 7.83 (d, J= 1.5 Hz, IH).
Examples 30 and 31 were prepared from 7-Chloro-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 29 and appropriate amines (Refer to Table 3) according to the coupling procedure described in Example 1, Step 4.
Example 30 iV3-Azepanyl-7-chIoro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride
IR (KBr) 3434, 2928, 1616, 1459, 1266, 1079, 1004, 805 cm'1; 1H NMR (300 MHz, CD3OD) δ 1.77 (br s, 4H), 1.98 (br s, 4H), 3.60-3.70 (m, 4H), 5.56 (d, J= 14.1 Hz, IH), 5.65 (d, J = 14.1 Hz, IH), 6.47 (d, J = 8.4 Hz, IH), 6.82 (dd, J = 8.4, 2.1 Hz, IH), 7.04 (d, J = 1.8 Hz, IH), 7.60-7.75 (m, 2H), 7.86 (d, J= 2.1 Hz, IH).
Example 31 iV3-Perhydrocyclopenta[c]azol-2-yl-7-chloro-l-(2,4-dichlorophenyl)-4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride
IR (KBr) 3434, 2953, 1694, 1612, 1543, 1436, 1281, 1079, 976, 804, cm"1; 1H NMR (300 MHz, CD3OD) δ 1.70-1.80 (br m, 6H), 2.94 (br s, 2H), 3.00-3.15 (br m, 2H), 4.03 (br m, 2H), 5.56 (d, J= 14.1 Hz, IH), 5.65 (d, J = 14.1 Hz, IH), 6.47 (d, J = 8.4 Hz, IH), 6.82 (dd, J = 8.4, 2.1 Hz, IH), 7.04 (d, J= 2.1 Hz, IH), 7.60-7.75 (m, 2H), 7.85 (d, J= 1.8 Hz, IH).
Example 32 iV3-Piperidino-7-bromo-l-(2,4-dichlorophenyI)-l,4-dihydrochromeno[4,3-c]pyrazoIe-3- carboxamide hydrochloride
Step 1: Ethyl 2-(7-bromo-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate: 7- Bromo-2,3-dihydro-4H-chromen-4-one (3.90 g, 17.18 mmol) was reacted with diethyl oxalate (2.69 g, 18.41 mmol) in the presence of 20 % LHMDS in THF (15.80 mL, 18.90 mmol) as described in Example 1, Step 1 to give 3.70 g of the compound as brown solid; IR (KBr) 3432, 2925, 1730, 1587, 1476, 1365, 1275, 1018, 898, 789 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.40 (t, J= 7.2 Hz, 3H), 4.42 (q, J= 7.2 Hz, 2H), 5.32 (s, IH), 5.41 (s, IH), 6.93 (d, J= 2.0 Hz, IH), 7.06 (dd, J= 8.4, 2.0 Hz, IH)5 7.36 (d, J= 8.1 Hz, IH), 15.58 (s, IH). Step 2: Ethyl 7-bromo-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate: Step 1 intermediate (3.70 g, 11.31 mmol) was reacted with 2,4- dichlorophenylhydrazine (2.20 g, 12.43 mmol) in ethanol (30 mL) as described in Example 1, Step 2 to give 1.70 g of the product as a white solid; IR (KBr) 3400, 2927, 1714, 1614, 1478, 1267, 1008, 806 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.32 (t, J= 7.2 Hz, 3H), 4.32 (q, J = 7.2 Hz, 2H), 5.54 (d, J = 13.8 Hz, IH), 5.62 (d, J = 13.8 Hz, IH), 6.36 (d, J = 8.4 Hz, IH), 7.08 (dd, J = 8.4, 1.8 Hz, IH), 7.28 (d, J= 1.8 Hz, IH), 7.76 (dd, J = 8.4, 2.7 Hz, IH), 7.86 (d, J= 8.4 Hz, IH), 8.07 (d, J = 2.7 Hz, IH).
Step 3: 7-Bromo-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid: Hydrolysis of Step 2 intermediate (0.40 g, 0.85 mmol) using IN KOH (1.80 mL) in methanol (5 mL) as described in Example 1, Step 3 gave the 0.38 g of the acid as a brown solid; IR (KBr) 3400, 3019, 2400, 1667, 1515, 1405, 1210, 1011, 769 cm"1; 1H NMR (300 MHz, DMSO-rftf) δ 5.52 (d, J= 13.8 Hz, IH)5 5.60 (d, J = 13.8 Hz5 IH)5 6.35 (d, J = 8.4 Hz, IH), 7.07 (dd, J = 8.4, 1.8 Hz, IH), 7.26 (d, J= 1.8 Hz, IH)5 7.75 (dd, J - 8.4, 1.8 Hz, IH), 7.85 (d, J= 8.4 Hz, IH), 8.06 (d, J = 1.8 Hz5 IH), 13.50 (br s, IH). Step 4: N3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-l ,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg5 0.23 mmol) with 1-aminopiperidine (25 mg, 0.25 mmol) using BOP reagent (MO mg, 0.25 mmol) and triethylamine (148 mg, 1.15 mmol) as described in Example 1, Step 4 gave 45 mg of the product as a white solid; IR (KBr) 3422, 2929, 2344, 1689, 161O5 1434, 1265, 1109, 1002, 827 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.41 (br s, 2H), 1.71 (br s, 4H), 3.10 (br s, 4H), 5.55 (d, J= 13.8 Hz, IH), 5.64 (d, J = 13.8 Hz, IH)5 6.37 (d, J = 8.4 Hz5 IH), 7.08 (br dd, J = 8.4, 2.0 Hz, IH), 7.28 (d, J= 2.0 Hz5 IH), 7.76 (dd5 J = 8.4, 2.0 Hz, IH), 7.90 (dd, J = 8.4, 2.0 Hz, IH), 8.07 (d, J = 1.8 Hz, IH), 10.70 (br s, IH).
Examples 33 and 34 were prepared from 7-Bromo-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 32 and appropriate amines (Refer to Table 3) according to the coupling procedure described in Example 1, Step 4.
Example 33 iV3-Azepanyl-7-bromo-l-(2,4-dichIorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride
IR (KBr) 3434, 2929, 2377, 1690, 1610, 1545, 1459, 1265, 1145, 976, 804 cm"1; 1H NMR (300 MHz, DMSO-rfβ) δ 1.58 (br s, 4H), 1.75 (br s, 4H), 3.30 (br s, 4H), 5.55 (d, J= 13.8 Hz, IH), 5.64 (d, J = 13.8 Hz, IH), 6.37 (d, J = 8.1 Hz, IH), 7.08 (dd, J = 8.4, 1.8 Hz, IH), 7.28 (d, J= 1.8 Hz, IH), 7.76 (dd, J = 8.4, 2.1 Hz, IH), 7.89 (d, J- 8.4 Hz, IH), 8.07 (d, J = 2.1 Hz, IH).
Example 34
Λ3-Perhydrocyclopenta[c]azol-2-yl-7-bromo-l-(2,4-dichlorophenyl)-l,4 dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride.
IR (KBr) 3423, 2957, 2867, 1694, 1512, 1450, 1339, 1142, 975 cm"1; 1H NMR'(300 MHz, DMSO-rfrf) δ 1.40-1.70 (m, 8H), 2.78 (br m, 2H), 3.38 (br s, 2H), 5.55 (d, J = 14.1 Hz, IH), 5.64 (d, J = 14.1 Hz, IH), 6.36 (d, J = 8.4 Hz, IH), 7.07 (dd, J = 8.4, 1.8 Hz, IH), 7,27 (d, J = 1.8 Hz, IH), 7.76 (dd, J = 8.4, 2.1 Hz, IH), 7.90 (d, J= 8.4 Hz, IH), 8.07 (d, J = 2.1 Hz, IH), 10.40 (br s, IH).
Example 35
Λ73-Piperidino-l-(2,4-dichIorophenyl)-7-iodo-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride
Step 1: Ethyl 2-(7-iodo-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate: 7-iodo-4- chromanone (5.88 g, 21.45 mmol) was reacted with diethyl oxalate (3.14 g, 21.45 mmol) in the presence of 20 % LHMDS in THF (21.52 mL, 25.74 mmol) as described in Example 1, Step 1 to give 7.65 g of the compound as a yellow oil; IR (neat) 3338, 2980, 1726, 1589, 1461, 1296, 1010, 854 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.41 (t, J = 7.5 Hz, 3H), 4.32- 4.43 (m, 2H), 5.37 (s, 2H), 6.97 (d, J= 8.4 Hz, IH), 7.05 (d, J= 7.8 Hz, IH), 7.40 (d, J= 3.0 Hz, IH), 15.31 (br s, IH).
Step 2: Ethyl 7-iodo-l-(2,4-dichlorophenyl)-l,4-dihydroclαromeno[4,3-c]pyrazole-3- carboxylate: Step 1 intermediate (4.10 g, 10.95 mmol) was reacted with 2,4- dichlorophenylhydrazine (1.94 g, 10.95 mmol) in ethanol (50 mL) as described in Example 1, Step 2 to give 1.0 g of the product as a pale yellow solid; IR (KBr) 3449, 2926, 1735, 1608, 1514, 1437, 1376, 1256, 1179, 994, 846 cm"1; 1H NMR (300 MHz, DMSO-cfe) δ 1.31 (t, J = 7.2 Hz, 3H), 4.30 (q, J= 6.0 Hz, 2H), 5.53 (d, J = 13.8 Hz, IH), 5.57 (d, J = 14.1 Hz, IH), 6.17 (d, J= 8.1 Hz, IH), 7.22 (dd, J= 8.4, 1.8 Hz, IH), 7.41 (d, J= 1.8 Hz, IH), 7.74 (dd, J= 9.0, 2.4 Hz, IH), 7.83 (d, J= 8.4 Hz, IH), 8.06 (d, J= 2.4 Hz, IH). Step 3: 7-Iodo-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid: Hydrolysis of Step 2 intermediate (541 mg, 1.05 mmol) using WKOH (2.08 mL) in methanol (20 mL) as described in Example 1, Step 3 gave the 508 mg of the acid as an off-white solid; IR (KBr) 3421, 2869, 2601, 1704, 1606, 1537, 1436, 1282, 1178, 977, 805 cm"1; 1H NMR (300 MHz, DMSO-^5) δ 5.52 (d, J= 14.1, IH), 5.60 (d, J= 13.8 Hz, IH), 6.17 (d, J= 8.1 Hz, IH), 7.21 (d, J= 7.5 Hz, IH), 7.40 (s, IH), 7.73 (d, J= 8.1 Hz, IH), 7.82 (d, J = 9.0 Hz, IH), 8.05 (s, IH), 13.40 ( br s, IH)
Step 4: N3-Piperidino-7-iodo-l-(2,4-dichlorophenyl)-l ,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (125 mg, 0.25 mmbl) with 1-aminopiperidine (28 mg, 0.28 mmol) using BOP reagent (136 mg, 0.30 mmol) and triethylamine(130 mg, 1.28 mmol) as described in Example 1, Step 4 gave 64 mg of the product as an off-white solid; IR (KBr) 3422, 2928, 1683, 1608, 1433, 1265, 1108, 997, 821 cm"1; 1H NMR (300 MHz, DMSO d6) δ 1.41 (br s, 2H), 1.71 (br s, 4H), 3.10 (br s, 4H), 5.54 (d, J= 13.8 Hz, IH), 5.58 (d, J= 13.8 Hz, IH), 6.18 (d, J= 8.1 Hz, IH), 7.24 (dd, J = 8.4, 1.5 Hz, IH), 7.41 (d, J = 1.5 Hz, IH), 7.74 (dd, J= 8.7, 2.1 Hz, IH), 7.87 (d, J = 8.4 Hz, IH), 8.05 (d, J= 2.1 Hz, IH), 10.79 ( br s, IH).
Example 36
Λ3-Piperidino-l-(2,4-dichlorophenyl)-7-iodo-l,4-dihydrochromeno[4,3-c]pyrazoIe-3- carboxamide hydrochloride
This compound was was prepared from Step 3 intermediate, Example 35 and 1- homopiperidine according to the coupling procedure described in Example 1, Step 4; IR (KBr) 3432, 2931, 2382, 1679, 1550, 1283, 1010, 974, 809, 725 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.58 (br s, 4H), 1.78 (br s, 4H), 3.37 (br s, 4H), 5.56 (d, J= 14.1 Hz, IH), 5.60 (d, J= 13.8 Hz, IH), 6.19 (d, J= 8.1 Hz, IH), 7.23 (dd, J= 8.1, 1.8 Hz, IH), 7.42 (d, J= 1.8 Hz, IH), 7.74 (dd, J = 8.7, 2.4 Hz, IH), 7.87 (d, J = 8.4 Hz, IH), 8.06 (d, J = 2.1 Hz, IH), 11.29 ( br s, IH).
Example 37 iV3-Piperidino -l-(2,4-dichlorophenyl)-7-fluoro-4,4-dimethyl-l ,4-dihy drochromeno [4,3- c] pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 2-(7-fluoro-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2- oxoacetate: 7-Fluoro-2,2-dimethyl-4-chromanone (4.82 g, 24.72 mmol) was reacted with diethyl oxalate (3.61 g, 24.72 mmol) in the presence of 20 % LHMDS in THF (22.80 mL, 27.30 mmol) as described in Example 1, Step 1 to give 4.01 g of the compound as semi-solid; IR (neat) 3935, 1727, 1599, 1465, 1370, 1278, 1078, 1011, 894 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J = 6.9 Hz, 3H), 1.77 (br s, 6H), 4.20-4.42 (m, 2H), 5.88 (d, J = 2.1 Hz, IH), 6.32 (dd, J= 9.1, 2.1 Hz, IH), 7.82 (d, J= 9.3 Hz, IH). Step 2: Ethyl- l-(2,4-dichlorophenyl)-7-fluoro-4,4-dimethyl- 1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (3.95 g, 13,42 mmol) was reacted with 2,4-dichlorophenylhydrazine (2.38 g, 13.42 mmol) in ethanol (20 mL) as described in Example 1, Step 2 to give 1.21 g of the product as a brown solid; IR (KBr) 3444, 2944, 2862, 1718, 1620, 1474, 1387, 1220, 1186, 1068, 843, 795 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J= 7.2 Hz, 3H), 1.81 (br s, 3H), 1.85 (br s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 6.34 (br m, 2H), 6.46 (br m, IH), 7.44 (dd, J= 8.4, 2.1 Hz, IH), 7.51 (d, J =8.4 Hz, IH), 7.60 (d, J= 2. I Hz, IH).
Step 3: l-(2,4-Dichlorophenyl)-7-fluoro-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (1.20 g, 4.64 mmol) using IN KOH (9.26 mL) in methanol (18 mL) as described in Example 1, Step 3 gave the 0.817 g of the acid as an off-white solid; IR (KBr) 3444, 2974^ 2851, 1719, 1586, 1490, 1382, 1279, 1068, 822 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.82 (br s, 3H), 1.85 (br s, 3H)5 6.10 (br m, IH), 6.20-6.40 (m, 2H), 7.40-7.58 (m, 2H), 7.63 (br m, IH). Step 4: N3-Piperidino-l-(2,4-dichlorophenyl)-7-fluoro-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (350 mg, 1.52 mmol) with 1-aminopiperidine (167 mg, 1.67 mmol) using triethylamine (770 mg, 7.60 mmol) and BOP reagent (642 mg, 1.52 mmol) as described in Example 1, Step 4 gave 127 mg of the product as an off-white solid; IR (KBr) 3421, 2945, 2550, 1705, 1621, 1515, 1453, 1384, 1210, 1138, 1064, 981, 816 cm"1; 1H NMR (SOO MHZ, CD3OD) δ 1.60-1.90 (m, 8H), 1.90-2.13 (m, 4H), 3.10-3.58 (m, 4H), 6.10-6.20 (m, 2H), 6.30- 6.40 (m, IH), 7.60-7.75 (m, 2H), 7.80-7.87 (m, IH).
Example 38
Λ3-Azepanyl-l-(2,4-dichlorophenyl)-7-fluoro-4,4-dimethyl-l,4-dihydrochromeno[4,3- c] pyrazole-3-carboxamide hydrochloride
This compound was prepared from Step 3 intermediate, Example 37 and 1-aminopiperidine according to the coupling procedure described in Example 1, Step 4; IR (KBr) 3434, 3019, 2976, 1620, 1534, 1456, 1385, 1215, 756, 669 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.50- 2.10 (m, 8H), 1.67 (s, 3H), 1.75 (s, 3H), 3.34 (br m, 2H), 3.63 (t, J= 5.4 Hz, 2H), 6.32 (br m, 2H), 6.51 (br m, IH), 7.50-7.62 (m, 2H), 7.76 (d, J= 2.1 Hz, IH). Example 39
Λ3-(2,6-Dimethylpiperidino)-7-chloro-l-(2,4-dichIorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3-c] pyrazoIe-3-carboxamide hydrochloride
Step 1: Ethyl 2-(7-chloro-2,2-dimethyl-4-oxo-3,4-dihydro-2/7-3-chromenyl)-2-oxoacetate: 7- chloro-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (4.0 g, 18.99 mmol) was reacted with diethyl oxalate (2.77 g, 18.99 mmol) in the presence of 20 % LHMDS in THF (17.45 niL, 20.89 mmol) as described in Example 1, Step 1 to give 3.10 g of the compound as a yellow semi-solid; IR (neat) 3445, 1733, 1687, 1600, 1425, 1277, 1238, 1076, 950, 772 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.40 (t, J = 6.6 Hz, 3H), 1.53 (s, 3H), 1.63 (s, 3H), 4.34-4.42 (m, 2H), 4.94 (s, IH), 6.91-7.00 (m, 2H), 7.73-7.77 (m, IH).
Step 2: Ethyl 7-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (3.05 g, 12.07 mmol) was reacted with 2,4-dichlorophenylhydrazine (2.14 g, 12.07 mmol) in ethanol (80 mL) as described in Example 1, Step 2 to give 2.05 g of the product as a brown solid; IR (KBr) 2979, 1723, 1610, 1509, 1435, 1259, 1212, 1065, 980, 813 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.43 (t, J= 6.9 Hz, 3H), 1.81 (s, 3H), 1.87 (s, 3H), 4.45 (q, J= 7.2 Hz, 2H), 6.36 (d, J = 8.4 Hz, IH), 6.69 (dd, J = 8.4, 1.8 Hz, IH), 6.98 (d, J= 1.8 Hz, IH) 7.45-7.54 (m, 2H), 7.62 (d, J = 2.4 Hz, IH).
Step 3 : 7-Chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 -cjpyrazole- 3-carboxylic acid: Hydrolysis of Step 2 intermediate (2.0 g, 4.43 mmol) using IiV KOH (12 mL) in methanol (40 mL) as described in Example 1, Step 3 gave the 1.50 g of the acid as a brown solid; IR (KBr) 3083, 2978, 2933, 1730, 1609, 1500, 1440, 1183, 958, 771 cm'1; 1H NMR (300 MHz, CDCl3) δ 1.83 (s, 3H), 1.88 (s, 3H), 6.38 (d, J= 8.4 Hz, IH), 6.70 (dd, J = 8.4, 2.1 Hz, IH), 7.00 (d, J= 2.1 Hz, IH ), 7.47-7.56 (m, 2H), 7.66 (d, J= 1.5 Hz, IH). Step 4: ΛG-(2,6-Dimethylpiperidino)-7-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4 -dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.24 mmol) with l-amino-2,6-dimethylpiperidine (33 mg, 0.26 mmol) using BOP reagent (125 mg, 0.28 mmol) and triethylamine (119 mg, 1.18 mmol) as described in Example 1, Step 4 gave 65 mg of the product as a white solid; IR (KBr) 3430, 2974, 2930, 1689, 1611, 1450, 1382, 1075, 981, 814 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.29 (d, J = 6.6 Hz, 6H), 1.20-2.00 (m, 6H), 1.77 (s, 3H), 1.83 (s, 3H), 3.16-3.24 (m, 2H), 6.46 (d, J= 8.4 Hz, IH), 6.78 (dd, J= 8.4, 2.1 Hz, IH), 6.99 (d, J= 1.5 Hz, IH), 7.60-7.76 (m, 2H), 7.85 (d, J= 1.8 Hz, IH). Examples 40 to 44 were prepared from 7-Chloro~l-(2,4-dichlorophenyl)~4,4- dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 39 and the appropriate amines (Refer to Table 3) according to the coupling procedure described in Example 1 , Step 4.
Example 40 iV3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-4,4-diinethyl-l,4-dihydrochromeno[4,3- c] pyrazole-3-carboxamide hydrochloride
IR (KBr) 3361, 2945, 2861, 1691, 1510, 1381, 1197, 1065, 982, 864 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.80 (s, 3H), 1.87 (s, 3H), 1.95 (br m, 6H), 3.45 (br s, 4H), 6.46 (d, J = 8.4 Hz, IH), 6.78 (dd, J= 8.4, 1.8 Hz, IH), 7.00 (d, J= 1.8 Hz, IH), 7.65-7.74 (m, 2H), 7.87 (s, IH).
Example 41
Λ3-(l-Azepanyl)-7-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride
IR (KBr) 3429, 2929, 1689, 1610, 1457, 1259, 1140, 1073, 961, 809 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.60-2.08 (m, 8H)5 1.78 (s, 3H), 1.86 (s, 3H), 3.60-3.78 (m, 4H), 6.45 (d, J = 8.4 Hz, IH), 6.77 (d, J= 8.4 Hz, IH), 6.99 (d, J= 1.8 Hz, IH), 6.60-6.76 (m, 2H), 7.86 (d, J= 1.8 Hz, IH).
Example 42
7V3-Perhydrocyclopenta[c]azol-2-yl-7-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3-c] pyrazole-3-carboxamide hydrochloride
IR (KBr) 3436, 2953, 2872,1706, 1611, 1267, 1080, 959, 809 cm'1; 1H NMR (300 MHz, CD3OD) δ 1.60-1.88 (m, 6H ), 1.78 (s, 3H), 1.86 (s, 3H), 2.94-3.16 (m, 4H), 3.98-4.10 (m, 2H), 6.45 (d, J= 8.4 Hz, IH), 6.77 (dd, J= 8.4, 1.8 Hz, IH), 6.99 (d, J= 1.8 Hz, IH), 7.62- 7.76 (m, 2H), 7.86 (d, J= 1.5 Hz, IH).
Example 43
Λ3-Morpholino-7-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride
IR (KBr) 3436, 2968, 1639, 1512, 1440, 1383, 1271, 1113, 1061, 958, 814 cm'1; 1H NMR (300 MHz, CD3OD) δ 1.68 (s, 3H), 1.72 (s, 3H), 3.68 (br s, 4H), 3.75-3.85 (m, 4H), 6.51 (d, J = 8.4 Hz, IH)5 6.80 (dd, J= 8.4, 1.8 Hz, IH), 7.02 (d, J = 1.8 Hz,' IH), 7.63 (dd, J= 8.4, 2.1 Hz, IH), 7.71 (d, J- 8.4 Hz, IH), 7.84 (d, J= 2.1 Hz, IH).
Example 44 iV3-(4-Methylpiperazmo)-7-chloro-l-(2,4-dichlorophenyI)-4,4-dimethyI-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide dihydrochIoride
IR (KBr) 3436, 2931, 1675, 1511, 1458, 1361, 1262, 1184, 1097, 981, 958 cm-1; 1H NMR (300 MHz5 CD3OD) δ 1.79 (br s, 3H), 1.86 (br s, 3H), 2.93 (br s, 3H), 3.22 (br s, 6H), 3.40- 3.52 (m, 2H), 6.45 (d, J = 8.4 Hz, IH), 6.77 (dd, J = 8.4, 1.8 Hz, IH), 6.99 (d, J = 1.8 Hz, IH), 7.60-7.76 (m, 2H), 7.85 (br s, IH).
Example 45 iV3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno-[4,3- c] pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 2-(7-bromo-2,2-dimethyl-4-oxo-3,4-dihydro-2//-3-chromenyl)-2-oxoacetate: 7- bromo-2,2-dimethyl-2,3-dihydro-4i/-chromen-4-one (2.70 g, 10.59 mmol) was reacted with diethyl oxalate (1.55 g, 10.59 mmol) in the presence of 20 % LHMDS in THF (9.75 mL, 11.65 mmol) as described in Example 1, Step 1 to give 1.20 g of the compound as a red oil; IR (neat) 3080, 2950, 1730, 1600, 1470, 1380, 1270, 1220, 725 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.40 (t, J= 7.0 Hz, 3H), 1.52 (s, 3H), 1.57 (s, 3H), 4.40 (q, J= 7.2 Hz, 2H), 7.00- 7.10 (m, 2H), 7.70 (d, J= 8.0 Hz, IH).
Step 2: Ethyl 7-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Step 1 intermediate (1.0 g, 2.82 mmol) was reacted with 2,4- dichlorophenylhydrazine (0.50 g, 2.82 mmol) in ethanol (15 mL) as described in Example 1, Step 2 to give 0.80 g of the product as a yellow solid; IR (KBr) 3090, 2977, 1725, 1500, 1400, 1380, 1260, 725 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J = 7.5 Hz, 3H), 1.80 (s, 3H), 1.86 (s, 3H), 4.44 (q, J= 7.0 Hz, 2H), 6.29 (d, J= 8.4 Hz, IH), 6.82 (dd, J= 8.4, 1.5 Hz, IH), 7.14 (d, J= 2.4 Hz, IH), 7.40-7.54 (m, 2H), 7.60 (d, J= 2.1 Hz, IH). Step 3 : 7-Bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 -cjpyrazole- 3-carboxylic acid: Hydrolysis of Step 2 intermediate (0.80 g, 1.61 mmol) using IiV KOH (6 mL) in methanol (20 mL) as described in Example 1, Step 3 gave the 650 mg of the acid as a pale brown solid; IR (KBr) 3080, 2700, 1720, 1540, 1400, 1380, 1280, 725 cm"1; 1H NMR (300 MHz5 CDCl3) δ 1.82 (s, 3H ), 1.87 (s, 3H ), 6.30 (d, J = 8.0 Hz5 IH ), 6.84 (dd, J= 6.0, 2.0 Hz, IH), 7.15 (d, J= 2.0 Hz, IH)5 7.45-7.55 (m, 2H), 7.64 (d, J= 2.0 Hz5 IH). Step 4: N3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.21 mmol) with 1-aminopiperidine (26 mg, 0.26 mmol) using BOP reagent (115 mg, 0.25 mmol) and triethylamine (106 mg, 1.05 mmol) as described in Example 1, Step 4 gave 70 mg of the product as a white solid; IR (KBr) 3428, 3084, 2950, 1645, 1500, 1380, 1400, 1230, 725 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.44-1.64 (m, 2H)3 1.77 (s, 3H)3 1.75-1.85 (m, 4H)3 1.85 (s, 3H)3 3.10-3.20 (m, 4H), 6.37 (d, J = 8.4 Hz, IH)3 6.90 (dd3 J = 9.0, 1.8 Hz, IH), 7.12 (d, J = 1.8 Hz3 IH) 7.60-7.80 (m, 2H), 7.84 (d, J = 2.0 Hz3 IH).
Examples 46 to 49 were prepared from 7-Bromo-l-(2,4-dichlorophenyl)-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]-pyrazole-3-carboxylic acid, Step 3 intermediate, Example 45 and the appropriate amines (Refer to Table 3) according to the coupling procedure described in Example I3 Step 4.
Example 46
Λ3-Azepanyl-7-bromo-l-(2,4-dichIorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride
IR (KBr) 3395, 2933, 1691, 1509, 1450, 1382, 1260, 1140, 980, 812 cm"1; 1H NMR (300 MHz, CD3OD) δl.76 (br s, 4H)3 1.78 (s, 3H), 1.86 (s, 3H), 1.98 (br s, 4H)3 3.64 (br m3 4H)3 6.38 (d, J= 8.4 Hz3 IH), 6.92 (dd, J= 8.4, 2.0 Hz, IH), 7.15 (d, J = 2.0 Hz, IH) 7.60-7.70 ( m3 2H)3 7.85 (br S3 2H).
Example 47
Λr3-Morpholino-7-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3-c] pyrazoIe-3-carboxamide hydrochloride
IR (KBr) 3435, 3076, 2966, 2854, 1662, 1500, 1363, 1270, 1240, 725 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.76 (s, 3H), 1.83 (s, 3H), 2.88 (t, J= 4.5 Hz3 4H), 3.8 (t, J= 4.5 Hz, 4H), 6.37 (d, J= 8.4 Hz, IH), 6.90 (dd, J= 9.0, 1.8 Hz, IH), 7.12 (d, J= 1.8 Hz3 IH) 7.60-7.80 ( m, 2H), 7.84 (d, J= 2.0 Hz3 IH).
Example 48
A3-Perhydrocyclopenta[c]azol-2-yl-7-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride
IR (KBr) 343O3 2945, 2867, 1660, 1500, 1380, 1400, 1230, 725 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.58-1.62 (m, 2H), 1.65-1.80 (m, 4H), 1.78 (s, 3H), 1.85 (s, 3H), 2.80-3.20 (m, 4H), 3.86-3.90 (m, 2H), 6.37 (d, J= 8.4 Hz, IH), 6.90 (dd, J= 9.0, 1.8 Hz3 IH), 7.12 (d, J = 1.8 Hz, IH) 7.60-7.80 ( m, 2H), 7.84 (d, J= 2.0 Hz, IH).
Example 49 iV3-(4-Methylpiperazino)-7-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3-c] pyrazole-3-carboxamide dihydrochloride IR (KBr) 3411, 2970, 2679, 1678, 1535, 1460, 1362, 1280, 1183, 1097, 954, 891, 741 cm"1; 1H NMR (300 MHz,
Figure imgf000070_0001
δ 1.70 (s, 3H), 1.78 (s, 3H), 2.45-2.57 (m, 2H), 2.74 (br s, 3H), 3.10 (br s, 6H), 6.35 (d, J= 8.4 Hz, IH), 7.04 (dd, J= 8.7, 2.1 Hz, IH), 7.22 (d, J= 2.1 Hz, IH), 7.75 (dd, J= 8.4, 2.1 Hz, IH), 7.90 (d, J= 9.0 Hz, IH), 8.05 (d, J= 2.1 Hz, IH), 9.90 (s, IH)
Example 50
Λ3-Piperidino-l-(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno-[4,3- c] pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 2-(7-iodo-2,2-dimethyl-4-oxo-3,4-dihydro-2#-3-chromenyl)-2- oxoacetate: 7-iodo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (8.85 g, 29.28 mmol) was reacted with diethyl oxalate (4.27 g, 29.28 mmol) in the presence of 20 % LHMDS in THF (27 mL, 32.20 mmol) as described in Example 1, Step 1 to give 8.0 g of the compound as a brown semi-solid; IR (neat) 2979, 1735, 1685, 1589, 1413, 1232, 1133 757 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J= 14.0 Hz, 3H), 1.52-1.61 (m, 6H), 4.31-4.39 (m, 2H), 4.93 (s, IH), 6.93-7.05 (m, IH), 7.47-7.49 (m, IH), 7.79-7.82 (m, IH).
Step 2: Ethyl l-(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Step 1 intermediate (6.00 g, 14.9 mmol) was reacted with 2,4- dichlorophenylhydrazine (2.64 g, 14.9 mmol) in ethanol (80 mL) as described in Example 1, Step 2 to give 4.58 g of the product as a pale yellow solid; IR (KBr) 3436, 2976, 1718, 1602, 1433, 1260, 1062, 977, 810 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J= 7.2 Hz, 3H), 1.79 (s, 3H), 1.85 (s, 3H), 4.44 (q, J= 7:2 Hz, 2H), 6.13 (d, J = 8.4 Hz, IH), 7.01-7.05 (m, IH), 7.32-7.36 (m, IH), 7.43-7.52 (m, 2H), 7.58-7.62 (m, IH).
Step 3: l-(2,4-Dichlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (2.00 g, 36.80 mmol) using IiV KOH (12 mL) in methanol (40 mL) as described in Example 1, Step 3 gave the 1.82 g of the acid as an off-white solid; IR (KBr) 3435, 2928, 1699, 1603, 1436, 1191, 981, 765 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.81 (s, 3H), 1.86 (s, 3H), 6.14 (d, J= 8.4 Hz, IH), 7.02-7.05 (m, IH), 7.35 (br s, IH), 7.49 (br s, 2H), 7.64 (br s, IH).
Step 4: N3-Piperidino-l-(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydiO- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.19 mmol) with 1-aminopiperidine (21 mg, 0.21 mmol) using BOP reagent (94 mg, 0.21 mmol) and triethylamine (98 mg, 0.97 mmol) as described in Example 1, Step 4 gave 102 mg of the product as an off-white solid; IR (KBr) 3368, 3060, 2935, 1690, 1600, 1504, 1381, 1234, 1063, 810 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.55-1.58 (m, 2H), 1.68 (s, 3H), 1.75 (s, 3H), 1.86-1.90 (m, 4H), 3.40-3.44 (m, 4H), 6.13 (d, J = 8.1 Hz, IH), 7.00-7.03 (m, IH), 7.23-7.27 (m, IH), 7.54-7.62 (m, 2H), 7.59-7.76 (m, IH).
Examples 51 and 52 were prepared from l-(2,4-Dichlorophenyl)-7-iodo-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]-pyrazole-3-carboxylic acid, Step 3 intermediate, Example 50 and the appropriate amines (Refer to Table 3) according to the coupling procedure mentioned in Example 1, Step 4.
Example 51 iV3-(l-Azepanyl)-l-(2,4-dichlorophenyI)-7-iodo-4,4-dimethyl-l,4-dihydro-chromeno[4,3- c] py razole-3-carboxamide hydrochloride
IR (KBr) 3312, 3087, 2926, 1690, 1600, 1505, 1261, 978, 802 cm'1; 1H NMR (300 MHz, CD3OD) δ 1.68-1.75 (m, 10 H), 1.89 (br s, 4H), 3.54-3.57 (m, 4H), 6.13 (d, J= 9.0 Hz, IH), 7.00-7.03 (m, IH), 122-126 (m, IH), 7.55-7.62 (m, 2H), 7.75-7.76 (m, IH).
Example 52
Λ3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-7~iodo-4,4-dimethyl-l,4- dihy drochromeno [4,3-c] pyrazole-3-carboxamide hydrochloride
IR (KBr) 3421, 2954, 1693, 1602, 1507, 1380, 1264 1055, 950, 811 cm'1; 1H NMR (300 MHz, CD3OD) δ 1.17-1.21 (m, 2H), 1.52-1.75 (m, 10H), 2.82-2.98 (m, 4H), 3.81-3.85 (m, 2H), 6.12 (d, J= 8.4 Hz, IH), 6.99-7.03 (m, IH), 7.24-7.25 (m, IH), 7.54-7.61 (m, 2H), 7.53- 7.78 (m, IH ).
Example 53
A3-Morpholino-l-(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride
IR (KBr) 3432, 2925, 2858, 1659, 1603, 1505, 1401, 1113, 889 cm'1; 1H NMR (300 MHz, DMSO-rftf) δ 1.70 (s, 3H), 1.77 (s, 3H), 2.82 (s, 4H), 3.63 (s, 4H), 6.18 (d, J = 8.0 Hz, IH), 7.18 (d, J= 8.0 Hz, IH), 7.35 (s, IH), 7.73 (d, J= 7.5 Hz, IH), 7.87 (d, J= 7.5 Hz, IH), 8.03 (s, IH), 9.59 (s, IH).
Example 54
A3-Piperidino-l-(2,4-dichlorophenyl)-7-methyl-4,4-dimethyI-l,4-dihydrochromeno[4,3- c] pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 2-oxo-2-(2,2,7-trimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)acetate: 2,2,7- trimethyl-4-chromanone (9.0 g, 47.31 mmol) was reacted with diethyl oxalate (6.91 g, 47.31 mmol) in the presence of 20 % LHMDS in THF (43.50 mL, 52.04 mmol) as described in Example 1, Step 1 to give 9.70 g of the compound as semi-solid; IR (neat) 2980, 1735, 1680, 1423, 1387, 1300, 1255, 1.135, 1066, 965, 773 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.40 (t, J = 7.5 Hz, 3H), 1.53 (br s, 3H), 1.55 (br s, 3H), 2.37 (br s, 3H), 4.30-4.40 (m, 2H), 6.60-7.00 (m, 2H), 7.70 (d, J = 8.1 Hz, IH).
Step 2: Ethyl l-(2,4-dichlorophenyl)-4,4,7-trimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Step 1 intermediate (9.50 g, 32.72 mmol) was reacted with 2,4- dichlorophenylhydrazine (5.80 g, 32.72 mmol) in ethanol (40 mL) as described in Example 1, Step 2 to give 3.20 g of the product as a brown solid; IR (KBr) 3444, 2980, 1725, 1622, 1513, 1494, 1362, 1275, 1211, 1068, 1048, 834 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.43 (t, J = 7.2 Hz, 3H), 1.80 (s, 3H), 1.85 (s, 3H), 2.26 (s, 3H)5 4.44 (q, J = 7.2 Hz, 2H), 6.32 (d, J = 7.8 Hz, IH), 6.51 (br d, J = 7.8 Hz, IH), 6.79 (s, IH), 7.44 (dd, J = 8.4, 2.4 Hz, IH) 7.51 (d, J = 8.4 Hz, IH), 7.60 (d, J = 2.4 Hz, IH).
Step 3: l-(2,4-Dichlorophenyl)-4,4,7-trimethyl-l ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid: Hydrolysis of Step 2 intermediate (1.60 g, 6.29 mmol) using IN KOH (12.65 mL) in methanol (25 mL) as described in Example 1 , Step 3 gave 1.10 g of the acid as white solid; IR (KBr) 3433, 2976, 1694, 1514, 1494, 1265, 1071, 965, 870, 818 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.82 (s, 3H), 1.86 (s, 3H), 2.27 (br s, 3H), 6.32 (d, J = 7.8 Hz, IH), 6.52 (d, J = 7.8 Hz, IH), 6.80 (br s, IH), 7.50 (dd, J = 8.4, 2.1 Hz, IH) 7.51 (d, J = 8.4 Hz, IH), 7.64 (d, J = 2.1 Hz, IH).
Step 4: N3-Piperidino-l-(2,4-dichlorophenyl)-7-methyl-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.44 mmol) with 1-aminopiperidine (49 mg, 0.49 mmol) using BOP reagent (186 mg, 0.44 mmol) and triethylamine (220 mg, 2.20 mmol) as described in Example 1, Step 4 gave 27 mg of the product as white solid; IR (KBr) 3435, 3056, 2939, 1625, 1521, 1448, 1256, 1155, 1075, 841 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.50-1.69 (m, 9H), 1.74 (br s, 3H), 2.27 (s, 3H), 3.56 (t, J = 5.4 Hz 2H), 3.60-3.80 (m, 2H), 6.39 (br d, J = 7.2 Hz, IH), 6.54 (br d, J = 7.2 Hz, IH), 6.81 (br s, IH), 7.45 (dd, J = 8.7, 2.1 Hz, IH), 7.52 (d, J = 8.7 Hz, IH), 7.60 (d, J = 2.1 Hz, IH).
Example 55 iV3-Piperidino-l-(2,4-dichlorophenyI)-7-isopropyl-4,4-dimethyl~l,4 dihy drochromeno [4,3-c] py razole-3-carboxamide hydrochloride Step 1: Ethyl (7-isopropyl-2,2-diniethyl-4-oxo-3,4-dihydro-2H-chromen-3-yl)oxoacetate: 7- isopropyl-2,2-dimethyl-2,3-dmydro-4H-chromen-4-one (3.10 g, 14.20 mmol) was reacted with diethyl oxalate (2.07 g, 14.20 mmol) in the presence of 20 % LHMDS in THF (14.24 mL, 17.04 mmol) as described in Example 1, Step 1 to give 2.60 g of the compound as a brown oil; IR (neat) 2965, 1733, 1682, 1614, 1433, 1066, 972, 762 cm"1; 1H NMR (300 MHz, DMSO-ck) δ 1.17 (d, J = 2.7 Hz, 3H), 1.19 (d, J= 3.3 Hz, 3H), 1,23-1.29 (m, 3H), 1.50 (s, 3H), 1.56 (s, 3H), 2.85-2.93 (m, IH), 4.20-4.30 (m, 2H), 5.03 (s, IH), 6.89-6.99 (m, 2H), 7.59-7.64 (m, IH).
Step 2: Ethyl 7-(isopropyl) -l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (2.50 g, 7.85 mmol) was reacted with 2,4-dichlorophenylhydrazine (1.13 g, 7.85 mmol) in ethanol (5 mL) as described in Example 1, Step 2 to give 540 mg of the product as a white solid; IR (KBr) 2938, 1726, 1617, 1420, 1259, 1186, 967, 710 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.11 (d, J = 6.9 Hz, 6H), 1.30 (t, J= 7.2 Hz, 3H), 1.72 (s, 3H), 1.75 (s, 3H), 2.72-2.79 (m, IH), 4.31 (q, J = 7.2 Hz, 2H), 6.28 (d, J= 7.8 Hz, IH), 6.67 (dd, J= 8.1, 1.8 Hz, IH), 6.84 (d, J= 1.5 Hz, IH), 7.73 (dd, J= 8.7, 2.4 Hz, IH) 7.84 (d, J= 8.4 Hz, IH), 8.05 (d, J= 2.1 Hz, IH). Step 3 : 7-(Isopropyl)- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno[4,3 - c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (500 mg, 1.08 mmol) using IiVKOH (2.15 mL) in methanol (5 mL) as described in Example 1, Step 3 gave the 450 mg of the acid as an off-white solid; IR (KBr) 3422, 2961, 1698, 1618, 1266, 1074, 781 cm"1; 1H NMR (300 MHz, DMSO-4) δ 1.11 (d, J= 6.9 Hz, 6H), 1.72 (s, 3H), 1.75 (s, 3H), 2.71-2.81 (m, IH), 6.27 (d, J= 8.1 Hz, IH), 6.66 (d, J= 8.1 Hz, IH), 6.83 (s, IH), 7.72 (dd, J= 8.7, 2.1 Hz, IH) 7.82 (d, J= 9.0 Hz, IH), 8.05 (d, J= 2.1 Hz, IH), 13.15 (br s, IH). Step 4: iV3-Piperidino-7-(isopropyl)-l -(2,4-dichlorophenyl)-4,4-dimethyl-l ,A- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (200 mg, 0.46 mmol) with 1-aminopiperidine (51 mg, 0.51 mmol) using BOP reagent (246 mg, 0.55 mmol) and triethylamine (234 mg, 2.31 mmol) as described in Example 1, Step 4 gave 126 mg of the product as a white solid; IR (KBr) 3400, 2961, 1707, 1618, 1492, 1298, 971, 816 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.11 (d, J= 6.9 Hz, 6H), 1.44 (br s, 2H), 1.73-1.78 (m, 10H), 2.72-2.81 (m, IH), 3.21 (br s, 4H), 6.29 (d, J= 7.8 Hz, IH), 6.67 (d, J= 8.1 Hz, IH), 6.85 (s, IH), 7.74 (dd, J= 8.4, 2.1 Hz, IH), 7.86 (d, J= 8.7 Hz, IH), 8.06 (d, J= 2.4 Hz, IH), 11.10 (br s, IH).
Example 56 A'3-Piperidino-7-(te^-butyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3-c] pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl-2-[7-(fert-butyl)-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl]-2- oxoacetate: 7-(tørt-butyl)-2,2-dimethyl-4-chromanone (1.60 g, 6.89 mmol) was reacted with diethyl oxalate (1.11 g, 7.58 mmol) in the presence of 20 % LHMDS in THF (6.33 mL, 7.57 mmol) as described in Example 1, Step 1 to give 1.01 g of the compound as a red oil; IR (neat) 3445, 2968, 1733, 1682, 1570, 1421, 1388, 1217, 1098, 966, 757, cm"1; 1H NMR (300 MHz, CDCl3) δ 1.30 (s, 9H), 1.40 (t, J = 7.2 Hz, 3H), 1.55 (s, 3H), 1.58 (s, 3H), 4.30-4.50 (m, 2H), 6.85-7.10 (m, 2H), 7.70-7.76 (m, IH).
Step 2: Ethyl 7-(tert-buty\) -l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (1 ,00 g, 3.01 mmol) was reacted with 2,4-dichlorophenylhydrazine (0.53 g, 3.01 mmol) in ethanol (6 mL) as described in Example 1, Step 2 to give 353 mg of the product as a pale yellow solid; IR (KBr) 3422, 3020, 2969, 1722, 1619, 1439, 1263, 1215, 1066, 968, 756, 669 cm 1; 1H NMR ( 300 MHz, DMSO-40 δ 1.19 (s, 9H), 1.31 (t, J= 7.2 Hz, 3H), 1.73 (s, 3H), 1.76 (s, 3H), 4.32 (q, J= 7.2 Hz, 2H), 6.30 (d, J = 8.2 Hz, IH), 6.84 (dd, J = 8.2, 1.5 Hz, IH), 6.95 (dd, J = 8.1, 1.5 Hz, IH), 7.74 (dd, J= 8.4, 2.1 Hz, IH) 7.85 (d, J= 8.4 Hz, IH), 8.07 (d, J= 2.1 Hz, IH). Step 3: 7-(fer^butyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (0.314 g, 0.66 mmol) using INKOH (1.60 mL) in methanol (5 mL) as described in Example 1, Step 3 gave the 0.27 g of the acid; IR (KBr) 3087, 2959, 1728, 1618, 1500, 1446, 1256, 1047, 970, 770 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.19 (s, 9H), 1.74 (s, 3H), 1.76 (s, 3H), 6.30 (d, J = 8.1 Hz, IH), 6.82 (d, J= 8.1 Hz, IH), 6.93 (s, IH), 7.73 (dd, J = 8.4, 2.0 Hz, IH) 7.84 (d, J= 8.4 Hz, IH), 8.06 (d, J= 2.0 Hz, IH), 13.40 (br s, IH).
Step 4: N3-Piperidino-7-(/ert-butyl)-l -(2,4-dichlorophenyl)-4,4-dimethyl-l ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride : Coupling reaction of Step 3 intermediate (270 mg, 0.61 mmol) with 1-aminopiperidine (67 mg, 0.67 mmol) using BOP reagent (0.30 g, 0.67 mmol) and triethylamine (0.31 g, 3.10 mmol) as described in Example 1, Step 4 gave 65 mg of the product as a white solid ; IR (KBr) 2964, 1698, 1618, 1455, 1215, 1099, 984, 756 cm '1; 1H NMR (300 MHz, DMSO-fife) δ 1.19 (s, 9H), 1.41 (br m, 2H), 1.73 (br s, 6H), 1.78(br m, 4H), 3.12 (br m, 4H), 6.32 (d, J = 8.1 Hz, IH), 6.84 (dd, J= 8.1, 1.8 Hz, IH), 6.95 (d, J= 1.8 Hz, IH), 7.75 (dd, J= 9.0, 2.7 Hz, IH), 7.87 (d, J= 8.4 Hz, IH), 8.06 (d, J= 2.1 Hz, IH), 10.07 (br s, IH). Example 57
7V3-Piperidino-7-cyano-l-(2,4-dichlorophenyI)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c] pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 7-cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: A stirred solution of Ethyl l-(2,4-dichlorophenyl)-7-iodo-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (600 mg, 1.10 mmol) and tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.022 mmol) in triethylamine (6 mL) was treated with trimethylsilyl cyanide (165 mg, 1.66 mmol) at room temperature followed by reflux for 2 h to afford 390 mg of the compound as a white solid; IR (KBr) 2985, 2228, 1733, 1581, 1412, 1259, 1188, 971, 813 cm"1; 1H NMR (SOO MHz, DMSO-J6) δ 1.31 (t, J= 7.2 Hz, 3H), 1.75 (s, 3H), 1.81 (s, 3H), 4.34 (q, J =7.2 Hz, 2H), 6.56 (br m, IH), 7.28 (m, IH), 7.49 (s, IH), 7.78 (m, IH), 7.91 (m, IH), 8.08 (s, IH).
Step 2: 7-Cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l ,4-dihydrochromeno[4,3-c]pyrazole- 3-carboxylic acid: Hydrolysis of Step 1 intermediate (380 mg, 0.90 mmol) using 1 N LiOH (4.5 mL) in 50 % aqueous methanol (4 mL) using the procedure described in Example 1, Step 3 gave 0.35 g of the acid as an off-white solid; IR (KBr) 3423, 3082, 2975, 2228, 1729, 1490, 1267, 1189, 1067, 989, 820, 772 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.75 (s, 3H), 1.81 (s, 3 H), 6.55 (d, J= 7.5 Hz, IH), 7.27 (d, J = 7.5 Hz, IH), 7.47 (s, IH), 7.77 (d, J= 8.5 Hz, IH), 7.90 (d, J= 8.5 Hz, IH), 8.07 (s, IH), 13.4 (br s, IH) Step 3 : N3 -Piperidino-7-cyano- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 2 intermediate (100 mg, 0.24 mmol) with 1-aminopiperidine (26 mg, 0.27 mmol) using BOP reagent (128 mg, 0.29 mmol) and triethylamine (122 mg, 1 ,21 mmol) as described in Example 1, Step 4 gave 71 mg of the product as an off-white solid; IR (KBr) 3435, 2931, 2228, 1694, 1514, 1418, 1259, 1112, 990, 834 cm"1; 1H NMR (300 MHz, DMSO-^j δ 1.40 (br s, 2H), 1.69 (br m, 4H), 1.74 (s, 3H), 1.82 (s, 3H), 3.05 (s, 4H), 6.56 (br d, J= 7.1 Hz, IH), 7.28 (br d, J = 7.1 Hz, IH), 7.49 (s, IH), 7.78 (br d, J= 7.8 Hz, IH), 7.92 (m, IH), 8.07 (s, IH), 10.52 (br s, IH).
Example 58
Λ3-Azepanyl-7-cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c] pyrazole-3-carboxamide hydrochloride
This compound was prepared from Step 2 intermediate, Example 58, and 1-homopiperidine according to the coupling procedure described in Example 1, Step 3; IR (KBr) 3435, 2930, 2228, 1694, 1411, 1258, 1140, 1097, 989, 817 cm'1; 1H NMR (300 MHz, DMSO-^; δ 1.59 (br s, 8H), 1.75 (br s, 3 H), 1.83 (br s, 3H), 3.37 (br s, 4H), 6.57 (br d, J= 7.5 Hz, IH), 7.29 (br d, J = 7.5 Hz, IH), 7.49 (s, IH), 7.80 (br d, J= 7.8 Hz, IH), 7.93 (br d, J = 7.8 Hz, IH), 8.08 (s, lH), 11.38 (br s, IH).
Example 59 iV3-Piperidino-l-(2,4-dichlorophenyl)-4,4-dimethyl-7-(lHr-tetrazol-5-yl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride
A stirred solution of N3-Piperidino-7-cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide (400 mg, 0.80 mmol), NaN3 (135 mg, 2.41 mmol) and Et3N1HCl (332 mg, 2.41 mmol) in toluene was heated to 70 0C for 12 h The reaction mixture was cooled and treated with water. Concentrated HCl was then added dropwise to the aqueous layer. The separated solid was filtered and dried under reduced pressure to afford 210 mg of white product; IR (KBr) 3432, 2946, 2228, 166, 1511, 1244, 1140, 1049, 955, 822 cm'1; 1H NMR (300 MHz, OMSO-d6) δ 1.37 (br s, 2H), 1.64-1.68 (m, 4H), 1.76 (s, 3H), 1.83 (s, 3H), 2.92 (br s, 4H), 6.62 (d, J= 8.1 Hz, IH), 7.22 (m, IH), 7.47 (dd, J = 8.1, 1.8 Hz, IH), 7.61 (d, J= 1.5 Hz, IH), 7.77 (dd, J= 9.0, 2.1 Hz, IH), 7.91 (d, J = 9.0 Hz, IH), 8.05 (d, J= 2.1 Hz, IH), 10.0 (br s, IH).
Example 60
Λ3-Piperidino-l-(2,4-dichlorophenyl)-7-methoxy-l,4-dihydrochromeno[4,3-c]pyrazole- 3-carboxamide hydrochloride
Step 1: Ethyl 2-(7-methoxy-4-oxo-3,4-dihydro-2/J-3-chromenyl)-2-oxoacetate: 7- methoxy 4-chromanone (4.5 g, 25.25 mmol) was reacted with diethyl oxalate (3.69 g, 25.25 mmol) in the presence of 20 % LHMDS (23.23 mL, 27.78 mmol) in THF (200 mL) as described in Example 1, Step 1 to give 6.63 g of the compound as a yellow solid; IR (KBr) 3262, 2983, 2856, 1719, 1607, 1457, 1372, 1299, 1257, 1015, 839 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.41 (t, J= 7.2 Hz, 3H), 3.86 (br s, 3H), 4.39 (q, J= 7.2 Hz, 2H), 5.39 (br m, 2H), 6.40 (d, J= 2.1 Hz, IH), 6.63 (dd, J= 9.0, 2.1 Hz, IH), 7.84 (d, J= 9.0 Hz, IH), 15.80 (br s, IH).
Step 2: Ethyl l-(2,4-dichlorophenyl)-7-methoxy-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Step 1 intermediate (6.20 g, 22.28 mmol) was reacted with 2,4- dichlorophenylhydrazine (3.60 g, 20.05 mmol) in ethanol (31 mL) as described in Example 1, Step 2 to give 3.50 g of the product as an off-white solid; IR (KBr) 3077, 2983, 1715, 1627, 1589, 1435, 1377, 1264, 1134, 1011, 834, 797 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J = 7.2 Hz, 3H), 3.76 (s, 3H), 4.44 (q, J= 7.2 Hz, 2H), 5.55 (d, J= 14.1 Hz, IH), 5,61 (d, J = 14.1 Hz, IH), 6.31 (dd, J = 8.7, 2.5 Hz, IH), 6.40 (d, J = 8.7 Hz, IH), 6.55 (d, J = 2.5 Hz, IH), 7.45 (dd, J= 8.1, 2.1 Hz, IH), 7.50 (d, J= 8.1 Hz, IH), 7.61 (d, J= 2.1 Hz, IH). Step 3: l-(2,4-Dichlorophenyl)-7-methoxy-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid: Hydrolysis of Step 2 intermediate (1.50 g, 3.58 mmol) using W KOH (7.12 niL) in methanol (25 mL) as described in Example 1, Step 3 gave 1.40 g of the acid as an off- white solid; IR (KBr) 3414, 2957, 2857, 1670, 1589, 1488, 1385, 1297, 1167, 978, 835 cm'1; 1H NMR (300 MHz, DMSO-^) δ 3.70 (br s, 3H), 5.45 (d, J= 13.5 Hz, IH), 5.53 (d, J= 13.5 Hz, IH), 6.31 (d, J = 8.7 Hz, IH), 6.43 (dd, J = 8.7, 2.4 Hz, IH), 6.59 (d, J = 2.4 Hz, IH), 7.72 (dd, J= 8.4, 2.2 Hz, IH), 7.78 (d, J= 8.4 Hz, IH), 8.02 (d, J= 2.2 Hz, IH). Step 4 : N3 -Piperidino- 1 -(2,4-dichlorophenyl)-7-methoxy- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.26 mmol) with 1-aminopiperidine (28 mg, 0.28 mmol) using BOP reagent (136 mg, 0.31 mmol) and triethylamine (130 mg, 1.28 mmol) as described in Example 1, Step 4 gave 70 mg of the product as a white solid; IR (KBr) 3434, 2929, 1701, 1625, 1484, 1299, 1268, 1165, 1108, 837, 801 cm'1; 1H NMR (300 MHz, CD3OD) δ 1.66 (br s, 2H), 1.90-2.01 (m, 4H), 3.50 (br m, 4H), 3.74 (br s, 3H), 5.50 (d, J= 13.8 Hz, IH), 5.58 (d, J= 13.8 Hz, IH), 6.37 (dd, J= 9.0, 2.4 Hz, IH), 6.41 (d, J= 9.0 Hz, IH), 6.57 (d, J= 2.4 Hz, IH), 7.60-7.70 (m, 2H), 7.83- 7,85 (m, IH).
Examples 61 and 62 were prepared from l-(2,4-Dichlorophenyl)-7-methoxy-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 60 and the appropriate amines (Refer to Table 3) according to the coupling procedure mentioned in Example 1, Step 4.
Example 61
N3-(l-Azepanyl)-l-(2,4-dichlorophenyl)-7-methoxy-l,4-dihydrochromeno[4,3-c]- pyrazole-3-carboxamide hydrochloride
IR (KBr) 3434, 2926, 2854, 1682, 1618, 1595, 1459, 1238, 1134, 1033, 830 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.75 (br s, 4H), 1.95 (br s, 4H), 3.57 (br s, 4H), 3.74 (s, 3H), 5.50 (d, J = 14.1 Hz, IH), 5.58 (d, J= 14.1 Hz, IH), 6.36 (dd, J= 8.7, 2.4 Hz, IH), 6.41 (d, J= 8.7 Hz, IH), 6.57 (d, J= 2.4 Hz , IH), 7.65 (br s, 2H), 7.84 (s, IH).
Example 62 iV3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-7-methoxy-l,4- dihydrochromeno [4,3-c] py razole-3-carboxamide hydrochloride IR (KBr) 3434, 2938, 2867, 1621,1487, 1437, 1275, 1241, 1141, 1015, 799 cm-1; 1H NMR (300 MHz, CD3OD) δ 1.76 (br s, 6H), 2.94 (br s, 2H), 3.11 (br m, 2H), 3.74 (s, 3H), 4.01 (br m, 2H), 5.49 (d, J= 14.1 Hz, IH), 5.57 (d, J- 14.1 Hz, IH), 6.36 (dd, J= 8.4, 2.1 Hz, IH), 6.41 (d, J= 8.4 Hz, IH), 6.56 (d, J= 2.1 Hz, IH), 7.60-7.66 (m, 2H), 7.83 (br s, IH).
Example 63 iV3-Piperidino-l-(2,4-dichIorophenyl)-7-methoxy-4,4-dimethyI-l,4-dihydro- chromeno [4,3-c] pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 2-(7-methoxy-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate: 7-methoxy-2,2-dimethyl-2,3-dihydro-4/f-chromen-4-one (5.68 g, 27.54 mmol) was reacted with diethyl oxalate (4.02 g, 27.54 mmol) in the presence of 20 % LHMDS in THF (25.5 mL, 30.29 mmol) as described in Example 1, Step 1 to give 4.16 g of the compound as a pale yellow solid; IR (KBr) 2980, 1735, 1671, 1608, 1443, 1276 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.30-1.44 (m, 3H), 1.50-1.62 (m, 6H), 3.84 (s, 3H), 4.35-4.4.43 (m, 2H), 4.88 (s, IH), 6.36-6.40 (m, IH), 6.55-6.57 (m, IH), 7.69-7.77 (m, IH).
Step 2: Ethyl l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Step 1 intermediate (4.0 g, 13.05 mmol) was reacted with 2,4- dichlorophenylhydrazine (2.30 g, 13.05 mmol) in ethanol (60 mL) as described in Example 1, Step 2 to give 1.50 g of the product as a white solid; IR (KBr) 2978, 1717, 1624, 1519, 1434, 1260, 1049 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J= 7.5 Hz, 3H), 1.80 (s, 3H), 1.85 (s, 3H), 3.75 (s, 3H), 4.42 (q, J = 7.5 Hz, 2H), 6.24-6.36 (m, 2H), 6.52 (s, IH), 7.42-7.52 (m, 2H), 7.60 (s, IH).
Step 3: l-(2,4-Dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (1.20 g, 2.68 mmol) using IiV KOH (6 mL) in methanol (20 mL) as described in Example 1, Step 3 gave the 1.02 g of the acid as a white solid; IR (KBr) 2939, 1695, 1615, 1434, 1201, 1071 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.82 (s, 3H), 1.86 (s, 3H), 3.76 (s, 3H), 6.26-6.38 (m. 2H), 6.25 (s, IH), 7.46- 7.53 (m, 2H), 7.64 (s, IH).
Step 4: iV3-Piperidino-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.23 mmol) with 1-aminopiperidine (26 mg, 0.26 mmol) using BOP reagent (126 mg, 0.28 mmol) and triethylamine (120 mg, 1.19 mmol) as described in Example 1, Step 4 gave 30 mg of the product as a white solid; IR (KBr) 3399, 2943, 1644, 1618, 1434, 1204, 1138 cm'1; 1H NMR (300 MHz, CD3OD) δ 1.52-1.56 (m, 2H), 1.66 (s, 3H), 1.73 (s, 3H), 1.83-1.87 (m, 4H), 3.33 (br s, 4H), 3.64 (s, 3H), 6.20-6.29 (m, 2H), 6.42 (s, IH), 7.56 (br s, 2H), 7.74 (s, IH).
Examples 64 to 69 were prepared from l-(2,4-Dichlorophenyl)-7-methoxy-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]-pyrazole-3-carboxylic acid, Step 3 intermediate, Example 63 and the appropriate amines (Refer to Table 3) according to the coupling procedure described in Example 1, Step 4.
Example 64 iV3-(2,6-DimethyIpiperidino)-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyI-l,4- dihy drochromeno [4,3-c] py razole-3-carboxamide hydrochloride
IR (KBr) 3422, 2932, 1689, 1621, 1458, 1382, 1273, 1140 cm"1; 1H NMR (CD3OD, 300 MHz) δ 1.18-1.25 (m, 8H), 1.63-1.71 (m, 10H), 1.85-1.89 (m, 2H), 3.64 (s, 3H), 6.21-6.31 (m, 2H), 6.44 (s, IH), 7.54-7.61 (m, 2H), 7.74 (s, IH).
Example 65 iV3-Morpholino-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride
IR (KBr) 3445, 2957, 2834, 1644, 1618, 1434, 1111, 1035 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.65 <s, 3H), 1.71 (s, 3H), 2.78 (t, 7= 4.5 Hz, 4H), 3.64 (s, 3H), 3.69 (t, J= 4.5 Hz, 4H), 6.19-6.29 (m, 2H), 6.41 (s, IH), 7.50-7.57 (m, 2H), 7.71 (s, IH).
Example 66
A/3-(l-Azepanyl)-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4-dihydro- chromeno [4,3-c] pyrazole-3-carboxamide hydrochloride
IR (KBr) 3394, 2932, 1689, 1619, 1457, 1274, 1204, 1141 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.66-1.73 (br s, 10H), 1.88 (br s, 4H), 3.51-3.55 (m, 4H), 3.64 (s, 3H), 6.21-6.30 (m, 2H), 6.42 (s, IH), 7.53-7.60 (m, 2H), 7.74 (s, IH).
Example 67
Λ3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4- dihydrochromeno [4,3-c] pyrazole-3-carboxamide hydrochloride
IR (KBr) 3413, 2955, 2868, 1694, 1620, 1455, 1203, 1145 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.52-1.55 (m, 2H), 1.66-1.73 (m, 10H), 2.83 (br s, 2H), 2.95-3.01 (m, 2H), 3.20 (s, 3H), 3.85-3.88 (br s, 2H), 6.20-6.29 (m, 2H), 6.42 (s, IH), 7.53-7.56 (m, 2H), 7.74 (s, IH).
Example 68
Λ3-(4J£T-l,3,4-Triazol-4-yl-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4- dihydrochromeno [4,3-c] pyrazole-3-carboxamide IR (KBr) 3455, 2934, 1714, 1650, 1501, 1201, 1165, 846 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.66 (s, 3H), 1.71 (s, 3H), 3.65 (s, 3H), 6.21-6.31 (m, 2H), 6.44 (s, IH), 7.54-7.61 (m, 2H), 7.76 (s, IH), 9.09 (s, 2H).
Example 69
A3-(4-Methylpiperazino)-l-(2,4-dichIorophenyl)-7-methoxy-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide dihydrochloride
IR (KBr) 3429, 2966, 2680, 1676, 1469, 1382, 1292, 1184, 1031, 983, 847 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.76 (s, 3H), 1.82 (s, 3H), 2.65 (m, 4H), 2.93 (s, 3H), 3.10-3.20 (m, 2H), 3.54 (br m, 2H), 3.74 (s, 3H), 6.31 (d, J= 8.6 Hz, IH), 6.37 (d, J= 8.6 Hz, IH), 6.52 (s, IH), 7.65 (br s, 2H), 7.83 (s, IH).
Example 70
Λ3-Piperidino-l-(2,4-dichlorophenyl)-7-benzyloxy-4,4-dimethyl-l,4- dihydrochromeno [4,3-c] py razole-3-carboxamide hydrochloride
Step 1: Ethyl 2-(7-benzyloxy-2,2-dimethyl-4-oxo~3,4-dihydro-2H-3-chromenyl)-2- oxoacetate: 7-Benzyloxy-2,2-dimethyl-4-chromanone (15.0 g, 53.12 mmol) (See Synth. Commun. 1988, 18, 1379) was reacted with diethyl oxalate (5.10g, 79.69 mmol) in the presence of 20 % LHMDS (48.95 mL, 58.44 mmol) in diethyl ether (250 mL) as described in Example 1, Step 1 to give 15.30 g of the compound as an off-white solid; IR (KBr) 3208, 2980, 1733, 1672, 1607, 1442, 1268, 1025, 837 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J = 7.2 Hz, 3H), 1.81 (s, 3H), 1.85 (s, 3H), 4.44 (q, J= 7.2 Hz, 2H), 5.00 (s, 2H), 6.30-6.40 (m, 2H), 6.60-6.61 (m, IH), 7.30-7.40 (m, 5H), 7.44 (dd, J = 8.4, 1.8 Hz, IH), 7.51 (d, J = 8.4 Hz, IH), 7.60 (d, J= 1.8 Hz, IH)
Step 2: Ethyl 7-benzyloxy-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (15.20 g, 39.60 mmol) was reacted with 2,4-dichlorophenylhydrazine (6.30 g, 35.68 mmol) in ethanol (80 mL) as described in Example 1, Step 2 to give 10.20 g of the product as an off-white solid; IR (KBr) 3408, 2978, 1715, 1624, 1519, 1260, 1176, 1067, 971, 814, 736 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J= 7.2 Hz, 3H), 1.81 (br s, 3H), 1.85 (br s, 3H), 4.44 (q, J= 7.5 Hz, 2H), 5.01 (s, 2H), 6.30-6.40 (m, 2H), 6.60-6.61 (m, IH), 7.30-7.40 (m, 5H), 7.44 (dd, J= 8.4, 1.8 Hz, IH), 7.51 (d, J= 8.4 Hz, IH), 7.60 (d, J= 1.8 Hz, IH).
Step 3: 7-Benzyloxy-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (450 mg, 0.86 mmol) using IiVKOH (1.72 mL) and methanol (10 mL) as described in Example 1, Step 3 gave 420 mg of the acid as an off-white solid; IR (KBr) 3079, 1726, 1622, 1446, 1177, 985, 736 cm-1; 1H NMR (300 MHz, OMSO-d6) δ 1.71 (s, 3H), 1.76 (s, 3H), 5.06 (s, 2H), 6.29 (d, J = 8.4 Hz, IH), 6.46 (dd, J= 8.4, 2.1 Hz, IH), 6.64 (d, J= 2.7 Hz, IH), 7.33-7.41 (m, 5H), 7.22 (dd, J = 8.4, 2.1 Hz, IH), 7.86 (d, J= 8.4 Hz, IH), 8.04 (d, J= 2.4 Hz, IH), 13.20 (br s, IH). Step 4: N3-Piperidino-l-(2,4-dichlorophenyl)-7-benzyloxy-4,4-dimethyl-l ,A- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (200 mg, 0.40 mmol) with 1 -aminopiperidine (44 mg, 0.44 mmol) using BOP reagent (241 mg, 0.48 mmol) and triethylamine (204 mg, 2.02 mmol) as described in Example 1, Step 4 gave 215 mg of the product as a white solid; IR (KBr) 3420, 2932, 1707, 1621, 1452, 1360, 1271, 1137, 978, 734 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.45 (br s, 2H), 1.72 (br s, 4H), 1.79 (br s, 6H), 3.26 (br s, 4H), 5,07 (br s, 2H), 6.32 (d, J= 8.4 Hz, IH), 6.48 (d, J= 7.5 Hz, IH), 6.65 (br s, IH), 7.39 (br s, 5H), 7.48 (br d, J= 7.4 Hz, IH), 7.88 (br d, J= 7.40, IH), 8.05 (br s, IH), 11.20 (br s, IH).
Example 71 iV3-Piperidino-l-(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl l-(2,4-dichlorophenyl)-7-hydroxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: A stirred solution of Ethyl 7-benzyloxy-l-(2,4-dichlorophenyl)- 4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate, Example 73, Step 2 (500 mg, 0.96 mmol) and sodium iodide (NaI) (157 mg, 1.05 mmol) was treated dropwise with trimethylsilyl chloride (114 mg, 1.05 mmol) in acetonitrile (5 mL) at room temperature and refluxed for 15 h. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water, sodium thiosulfate solution, brine, dried over anhydrous Na2SO4 and concentrated. The residue obtained was purified by silica gel column chromatography to yield 285 mg of the compound as a white solid; IR (KBr) 3305, 2981, 1726, 1617, 1439, 1187, 1064, 979, 833, 780 cm'1; 1H NMR (300 MHz, CDCl3) δ 1.41 (t, J= 7.2 Hz, 3H), 1.80 (br s, 3H), 1.84 (br s, 3H), 4.43 (q, J = 7.2 Hz, 2H), 5.43 (s, IH), 6.17 (dd, J = 8.4, 2.1 Hz, IH), 6.30 (d, J= 8.4 Hz, IH), 6.44 (d, J= 2.1 Hz, IH), 7.43 (dd, J= 8.4, 2.1 Hz, IH), 7.50 (d, J= 8.4 Hz, IH), 7.59 (d, J= 2.1 Hz, IH).
Step 2: Ethyl l-(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: A stirred solution of Step 1 intermediate (500 mg, 1.15 mmol) and potassium carbonate (318 mg, 2.31 mmol) in dry DMF was purged with dichlorofiuoromethane gas at 80 0C for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to afford 270 mg of the compound as a white solid; IR (KBr) 3435, 2984, 1735, 1617, 1519, 1258, 1128, 1070, 978, 864, 810 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.31 (t, J = 6.9 Hz, 3H), 1.74 (s, 3H), 1.79 (s, 3H), 4.33 (q, J= 6.9 Hz, 2H), 6.42 (d, J= 9.0 Hz, IH), 6.64 (dd, J= 9.0, 2.4 Hz, IH), 6.81 (d, J = 2.4 Hz, IH), 7.25 (t, 7 = 73.8 Hz, IH), 7.75 (dd, J = 8.4, 2.1 Hz, IH), 7.88 (d, J = 8.4 Hz, IH), 8.06 (d, J= 2.1 Hz, IH).
Step 3: l-(2,4-Dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- e]pyrazole-3-carboxylic acid : Hydrolysis of Step 2 intermediate (1.50 g, 3.10 mmol) using IiV KOH (350 mg, 6.20 mmol) in water (5 mL) and methanol (25 mL) as described in Example 1, Step 3 gave 1.30 g of the acid as white solid; IR (KBr) 3415, 2984, 1699, 1520, 1445, 1385, 1271, 1123, 997, 778 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.74 (s, 3H), 1.79 (s, 3 H), 6.42 (d, J = 8.4 Hz, IH), 6.63 (dd, J = 8.4, 1.8 Hz, IH), 6.80 (d, J = 1.8 Hz, IH), 7.24 (t, J = 74.0 Hz, IH), 7.40 (dd, J= 8.4, 2.1 Hz, IH), 7.86 (d, J= 8.4 Hz, IH)5 8.05 (d, J= 2.1 Hz, IH).
Step 4: iV3-Piperidino-l-(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4- dihydrochromeno[453-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.22 mmol) with 1-aminopiperidine (24 mg,0.24 mmol) using BOP reagent (117 mg, 0.26 mmol) and triethylamine (111 mg, 1.10 mmol) as described in Example 1, Step 4 gave 48 mg of the product as a white solid; IR (KBr) 3410, 2939, 1687, 1535, 1457, 1382, 1274, 1181, 1049, 990, 816 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.48 (br m, 2H), 1.78 (br m, 7H), 1.85 (br s, 3H), 2.95 (br s, 4H), 6.47 (d, J= 8.4 Hz, IH), 6.52 (dd, J = 8.4, 1.8 Hz, IH), 6.73 (d, J= 1.8 Hz, IH), 6.82 (t, J= 73.5 Hz5 IH), 7.64 (dd, J= 8.4, 1.8 Hz, IH), 7.68 (d, J= 8.4 Hz5 IH), 7.83 (d, J= 1.8 Hz, IH).
Examples 72 to 74 were prepared from l-(2,4-Dichlorophenyl)-7-difluoromethoxy- 4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 71 and the appropriate amines (Refer to Table 3) according to the coupling procedure mentioned in Example I5 Step 4.
Example 72 iV3-Azepanyl-l-(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4- dihydrochromeno[4,3-^]pyrazole-3-carboxamide hydrochloride IR (KBr) 3422, 2932, 1690, 1621, 1518, 1382, 1271, 1181, 1051, 815 cm"1; 1H NMR (300 MHz, CD3OD) δ 1.75 (br s, 4H), 1.78 (s, 3H), 1.S5 (s, 3H), 1.95 (br s, 4H), 3.56 (br s, 4H), 6.40-6.57 (m, 2H), 6.73 (s, IH), 6.82 (t, J= 73.5 Hz, IH), 7.60-7.80 (m, 2H), 7.85 (s, IH).
Example 73
Λ/3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyI)-7-difluoromethoxy-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride IR (KBr) 3432, 2954, 1694, 1620, 1518, 1382, 1363, 1271, 1180, 1119, 1053 cm'1; 1H NMR (300 MHz, CD3OD) δ 1.55-1.75 (m, 6H), 1.79 (s, 3H), 1.86 (s, 3H), 2.87 (br m, 2H), 2.92- 3.00 (m, 2H), 3.70-3.90 (m, 2H)5 6.48 (d, J= 9.0 Hz, IH), 6.53 (dd, J = 9.0, 1.8 Hz, IH), 6.73 (s, IH), 6.83 (t, J = 73.8 Hz, IH), 7.66 (dd, J = 9.0, 1.8 Hz, IH), 7.69 (d, J = 9.0 Hz, IH), 7.85 (d, J= 1.8 Hz, IH).
Example 74 l-(2,4-Dichlorophenyl)-7-difluoromethoxy-ΛL(2,4-difluorophenyl)-4,4-dimethyI-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride
IR (KBr) 3419, 2930, 1694, 1664, 1516, 1379, 1283, 1189, 1096, 960, 827 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.70 (s, 3H), 1.75 (s, 3H), 6.44 (d, J= 8.4 Hz, IH), 6.63 (d, J= 6.6 Hz, IH), 6.73-6.81 (m5 2H), 6.88-6.94 (m, IH), 7.13-7.19 (m, IH), 7.25 (t, J= 74.1 Hz, IH), 7.75-7.77 (m, IH), 7.82 (s, IH), 7.90 (d, J= 8.7 Hz, IH), 8.06 (d, J= 1.8 Hz , IH), 10.42 (s, IH).
Scheme 8 and Table 4 gives detailed structural description of Examples 75-82. The percentage displacement values (% D) of [3H]CP55940 by test molecules at 300 nM for hCBl are given in Table 4. Scheme 8
Figure imgf000083_0001
Table 4: Detailed description of Examples 75 - 82 and their in-vitro screening data
Figure imgf000083_0002
Figure imgf000084_0001
Example 75
A3-Piperidino-7-(3-chlorophenyl)-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3- c] py razole-3-carboxamide hydrochloride
Step 1: Ethyl l-(2,4-dichlorophenyl)-7-(3-chlorophenyl)-l,4-dihydrochromeno-[4,3- c]pyrazole-3-carboxylate: A solution of Step 2 intermediate, Example 36 (200 mg, 0.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.01 rnmol) in dimethoxyethane (DME) (10 mL) was treated with 3-chlorophenylboronic acid (67 mg, 042 mmol) followed by solution of sodium carbonate (Na2CO3) (45 mg, 0.42 mmol) in water (5 mL). The resulting solution was refluxed for 1.5 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue obtained was purified by silica gel column chromatography in 10 % ethyl acetate in hexane to give 120 mg of the compound as an off-white solid; IR (KBr) 3431, 1718, 1617, 1495, 1389, 1269, 1130, 1001, 809 cm"1; 1H NMR (300 MHz, OM$O-d6) δ 1.32 (t, J= 7.2 Hz, 3H), 4.32 (q, J= 6.0 Hz, 2H), 5.58 (d, J= 13.5 Hz, IH), 5.61 (d, J= 14.4 Hz, IH), 6.48 (d, J= 8.4 Hz, IH), 7.21 (dd, J = 8.4, 1.8 Hz, IH), 7.37 (d, J = 1.5 Hz, IH), 7.43-7.48 (m, 2H), 7.60-7.63 (m, IH), 7.70 (s, IH), 7.77 (dd, J= 8.4, 2.1 Hz, IH), 7.88 (d, J= 8.4 Hz, IH), 8.10 (d, J= 2.1 Hz, IH)
Step 2: l-(2,4-Dichlorophenyl)-7-(3-chlorophenyl)-l ,4-dihydrochromeno[4,3-c] pyrazole-3-carboxylic acid: Hydrolysis of Step 1 intermediate (120 mg, 0.24 mmol) using IN KOH (0.5 mL) in methanol (4 mL) as described in Example 1, Step 3 gave the 115 mg of the acid as an off-white solid; IR (KBr) 3422, 2868, 1685, 1538, 1449, 1280, 1189, 1107, 1012, 787, 745 cm'1; 1H NMR (300 MHz, DMSO-^) δ 5.53 (d, J- 14.1 Hz, IH), 5.60 (d, J= 13.8 Hz, IH), 6.48 (d, J= 8.1 Hz, IH), 7.20 (dd, J= 8.1, 1.8 Hz, IH), 7.43-7.48 (m, 2H), 7.60 (d, J= 7.2 Hz, IH), 7.70 (s, 2H), 7.76 (dd, J= 8.4, 2.1 Hz, IH), 7.87 (d, J= 8.7 Hz, IH), 8.09 (d, J= 2.1 Hz, IH), 13.40 (br s, IH).
Step 3 : N3 -Piperidino-7-(3 -chlorophenyl)- 1 -(2,4-dichlorophenyl)- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 2 intermediate (100 mg, 0.21 mmol) with 1-aminopiperidine (23 mg, 0.23 mmol) using BOP reagent (112 mg, 0.25 mmol and triethylamine (107 mg, 1.05 mmol) as described in Example 1, Step 4 gave 55 mg of the product as an off-white solid; IR (KBr) 3411, 2942, 2858, 1698, 1537, 1390, 1265, 1188, 1140, 1007, 977, 749 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.40 (br s, 2H), 1.70 (br s, 4H), 3.08 (br s, 4H), 5.55 (d, J = 13.8 Hz, IH), 5.62 (d, J = 13.8 Hz, IH), 6.48 (d, J= 8.1 Hz, IH), 7.20 (d, J= 8.1 Hz, IH), 7.37 (s, IH), 7.43-7.48 (m, 2H), 7.60 (d, J= 7.5 Hz, 2H), 7.77 (dd, J = 8.4, 2.4 Hz, IH), 7.91 (d, J= 8.4 Hz, IH), 8.09 (d, J= 2.1 Hz, IH), 10.60 (br s, IH).
Example 76
Λ3-Piperidino-7-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3- cJpyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 7-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: This compound was prepared from Example 36, Step 2 intermediate and 4-chlorophenylboronic acid according to the procedure described in Example 76, Step 1; IR (KBr) 3431, 2929, 1718, 1617, 1495, 1302, 1269, 1177, 976, 784 cm'1; 1H NMR (300 MHz, DMSO-^) δ 1.32 (t, J = 7.2 Hz, 3H), 4.31 (q, J = 9.0 Hz, 2H), 5.57 (d, J= 14.1 Hz, IH), 5.60 (d, J= 14.1 Hz, IH), 6.48 (d, J= 8.1 Hz, IH), 7.18 (dd, J = 8.1, 1.8 Hz, IH), 7.34 (d, J= 1.8 Hz, IH), 7.47 (d, J= 8.4 Hz, 2H), 7.66 (d, J= 8.7 Hz, 2H), 7.76 (dd, J= 8.4, 2.4 Hz, IH), 7.87 (d, J= 8.4 Hz, IH), 8.09 (d, J= 2.4 Hz, IH). Step 2 : 7-(4-Chlorophenyl)- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno [4,3 - cJpyrazole-S-carboxylic acid: This compound was prepared by the hydrolysis of Step 1 intermediate according to the procedure mentioned in Example 75, Step 2; IR (KBr) 3422, 2923, 1701, 1617, 1537, 1445, 1276, 1191, 1002, 835, 807 cm"1; 1H NMR (300 MHz, DMSO-J5) 5.56 (d, J= 13.8 Hz, IH), 5.59 (d, J= 13.8 Hz, IH), 6.48 (d, J= 8.1 Hz, IH), 7.17 (dd, J= 8.1, 1.5 Hz, IH), 7.33 (d, J = 1.5 Hz, IH), 7.47 (d, J= 8.4 Hz, 2H), 7.66 (d, J= 8.4 Hz, 2H), 7.78 (dd, J = 8.1, 2.1 Hz, IH), 7.87 (d, J = 8.4 Hz, IH), 8.08 (d, J = 2.4 Hz, IH), 13.40 (br s, IH)
Step 3 : N3 -Piperidino-7-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno [4,3- c]pyrazole-3-carboxamide hydrochloride: This compound was prepared from Step 2 intermediate and 1 -aminopiperidine according to the coupling procedure described in Example 1, Step 4; IR (KBr) 3433, 2946, 2460, 1701, 1617, 1491, 1263, 1187, 1002, 838 813 cm'1; 1H NMR (300 MHz1 DMSO-Jtf) δ 1.42 (br s, 2H), 1.73 (br s, 4H), 3.15 (br s, 4H), 5.59 (d, J= 13.8 Hz, IH), 5.62 (d, J= 13.5 Hz, IH), 6.49 (d, J= 8.1 Hz, IH), 7.18 (d, J= 8.4 Hz, IH), 7.34 (s, IH), 7.47 (d, J= 8.4 Hz, IH), 7.66 (d, J= 8.4 Hz, 2H), 7.77 (dd, J = 8.4, 2.1 Hz, IH), 7.91 (d, J= 8.7 Hz, IH), 8.09 (d, J= 2.4 Hz, IH), 10.90 (br s, IH). Example 77
A'3-Piperidino-l-(2,4-dichlorophenyl)-4,4-dimethyI-7-phenyI-l,4-dihydrochromeno-[4,3- c] pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl l-(2,4-dichlorophenyl)-4,4-dimethyl-7-phenyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Coupling reaction of Step 2 intermediate, Example 50, (0.20 g, 0.37 mmol) with phenylboronic acid (65 mg, 0.42 mmol) using tetrakis(triphenyl- phosphine)palladium(O) (22 mg, 0.02 mmol) in DME (4 mL) followed by solution OfNa2CO3 (45 mg, 0.42 mmol) in water (2 mL) according to the procedure described in Example 76, Step 1 afforded 155 mg of the compound as an off-white solid; IR (KBr) 3019, 2400, 1619, 1518, 1420, 1218, 772, 669 cm"1; 1H NMR (300 MHz, DMSO-^6) δ 1.32 (t, J= 7.2 Hz, 3H), 1.76 (s, 3H), 1.81 (s, 3H), 4.33 (q, J= 7.2 Hz, 2H), 6.48 (d, J= 7.8 Hz, IH), 7.16 (dd, J= 7.8, 1.5 Hz, IH), 7.29 (d, J= 1.5 Hz, IH), 7.30-7.50 (m, 3H), 7.64 (br d, J- 7.2 Hz, 2H), 7.77 (dd, J= 8.4, 2.1 Hz, IH), 7.92 (d, J= 8.4 Hz, IH), 8.10 (d, J= 2.1 Hz, IH). Step 2: 1 -(2,4-Dichlorophenyl)-4,4-dimethyl-7-phenyl-l,4-dihydrochromeno[4,3-c]pyrazole- 3-carboxylic acid: Hydrolysis of Step 1 intermediate (0.1 g, 0.2 mmol) using IN KOH (0.40 ml) in methanol (5 mL) as described in Example 1, Step 3 gave the 95 mg of the acid as an off-white solid; IR (KBr) 3401, 3019, 2400, 1618, 1506, 1215, 1069, 757, 669 cm"1; 1H NMR (300 MHz, DMSO-40 δ 1.77 (s, 3H), 1.81 (s, 3H), 6.48 (d, J= 8.4 Hz, IH), 7.14 (dd, J= 8.4, 1.3 Hz, IH), 7.27 (d, J = 1.3 Hz, IH), 7.30-7.50 (m, 3H), 7.63 (d, J= 7.2 Hz, 2H), 7.76 (dd, J= 8.4, 2.0 Hz, IH), 7.90 (d, J= 8.7 Hz, IH), 8.08 (d, J= 1.8 Hz, IH), 13.30 (br s, IH). Step 3 : N3 -Piperidino- 1 -(2,4-dichlorophenyl)-4,4-dimethyl-7-phenyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (90 mg, 0.19 mmol) with 1-aminopiperidine (21 mg, 0.21 mmol) using BOP reagent (93 mg, 0.21 mmol) and triethylamine (96 mg, 0.95 mmol) as described in Example 1, Step 4 gave 40 mg of the product as an off-white solid; IR (KBr) 3414, 2931, 2855, 1700, 1498, 1259, 1140, 1098, 982, 888, 817, 763 cm"1; 1H NMR (300 MHz, DMSO-4) δ 1.39 (br s, 2H), 1.67 (br s, 4H), 1.76 (s, 3H), 1.82 (s, 3H), 2.98 (br s, 4H), 6.49 (d, J = 8.1 Hz, IH), 7.16 (dd, J= 8.4, 1.5 Hz, IH), 7.29 (d, J= 1.8 Hz, IH), 7.36-7.45 (m, 3H), 7.64 (br d, J= 7.5 Hz, 2H), 7.77 (dd, J = 8.7, 2.1 Hz, IH), 7.92 (d, J= 8.4 Hz, IH), 8.08 (d, J = 2.4 Hz, IH), 10.20 (br s, IH).
Examples 78 to 82 were prepared from Step 2 intermediate, Example 51 and the appropriate phenylboronic acids (Refer to Table 4) followed by hydrolysis and subsequent coupling of the acid with 1-aminopiperidine according to the procedure described in Example 77, Steps 1, 2 and 3.
Example 78 iV3-Piperidino-l-(2,4-dichIorophenyI)-7-(4-fluorophenyl)-4,4-dimethyI-l,4- dihydrochromeno [4,3-c] pyrazole-3-carboxamide hydrochloride Step 1 : Ethyl 1 -(2,4-dichlorophenyl)-7-(4-fluorophenyl)-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxylate: IR (KBr) 3401, 2981, 1723, 1506, 1383, 1262, 1189, 1069, 982, 814, 756 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.32 (t, J = 6.9 Hz, 3H),
1.76 (s, 3H), 1.81 (s, 3H), 4.34 (q, J= 6.9 Hz, 2H), 6.47 (d, J= 8.4 Hz, IH), 7.14 (dd, J= 8.1,
2.0 Hz, IH), 7.24 (d, J= 8.1 Hz, 2H), 7.28 (d, J= 2.0 Hz, IH), 7.66-7.74 (m, 2H), 7.77 (dd, J= 8.4, 2.1 Hz, IH), 7.92 (d, J= 8.4 Hz, IH), 8.09 (d, J= 2.4 Hz, IH).
Step 2: 1 -(2,4-Dichlorophenyl)-7-(4-fluorophenyl)-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid: IR (KBr) 3401, 2932, 1704, 1508, 1446, 1384, 1265, 1098, 757 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.76 (s, 3H), 1.80 (s, 3H), 6.47 (d, J = 8.1 Hz, IH), 7.13 (dd, J = 8.1, 1.5 Hz, IH), 7.20-7.30 (m, 3H), 7.65-7.73 (m, 2H), 7.77 (dd, J = 8.4, 2.1 Hz, IH), 7.90 (d, J= 8.4 Hz, IH), 8.08 (d, J= 2.1 Hz, IH), 13.40 (br s, IH). Step 3: N3-Piperidino-l-(2,4-dichlorophenyl)-7-(4-fluorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: IR (KBr) 3432, 2933, 1706, 1617, 1536, 1454, 1384, 1300, 1215, 1098, 983, 813 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.40 (br s, 2H), 1.69 (br m, 4H), 1.76 (s, 3H), 1.82 (s, 3H), 3.05 (br s, 4H), 6.48 (d, J = 8.1 Hz, IH), 7.14 (dd, J= 8.1, 1.8 Hz, IH), 7.23 (d, J= 8.1 Hz, 2H), 7.28 (s, IH), 7.65-7.74 (m, 2H),
7.77 (dd, J= 8.4, 2.1 Hz, IH), 7.93 (d, J= 8.7 Hz, IH), 8.08 (d, J= 2.4 Hz, IH), 10.40 (br s, IH).
Example 79
Λ3-Piperidino-7-(2-chlorophenyl)-l-(2,4-dichIorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3-c] pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 7-(2-chlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: IR (KBr) 3400, 2931, 1724, 1619, 1406, 1260, 1066, 982, 756 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.32 (t, J - 7.2 Hz, 3H), 1.77 (s, 3H), 1.80 (s, 3H), 4.34 (q, J= 7.2 Hz, 2H), 6.49 (d, J= 8.1 Hz, IH), 6.87 (dd, J= 8.1, 1.8 Hz, IH), 7.02 (d, J = 1.8 Hz, IH), 7.34-7.41 (m, 3H), 7.50-7.60 (m, IH), 7.77 (dd, J = 8.4,
2.1 Hz, IH), 7.92 (d, J= 8.4 Hz, IH), 8.09 (d, J= 2.1 Hz, IH). Step 2 : 7-(2-Dichlorophenyl)- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: IR (KBr) 3067, 2979, 1618, 1488, 1440, 1256, 1067, 819, 756 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.77 (s, 3H), 1.80 (s, 3H), 6.48 (br d, J= 8.1 Hz, IH), 6.87 (br d, J= 7.8 Hz, IH), 7.01 (s, IH), 7.36-7.44 (br m, 3H), 7.50- 7.60 (br m, IH), 7.76 (dd, J= 8.4, 2.1 Hz, IH), 7.90 (d, J= 8.7 Hz, IH), 8.08 (d, J= 2.4 Hz, IH), 13.40 (br s, IH).
Step 3: iV3-Piperidino-7-(2-chlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: IR (KBr) 3435, 2932, 2865, 1617, 1449, 1253, 1097, 982, 954, 888, 816, 756 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.33 (br m, 2H), 1.57 (br m, 4H), 1.75 (s, 3H), 1.79 (s, 3H), 2.76 (t, J= 5.1 Hz, 4H), 6.49 (d, J = 8.1 Hz, IH), 6.87 (dd, J= 7.8, 1.8 Hz, IH), 7.01 (d, J= 1.8 Hz, IH), 7.35-7.42 (m, 3H), 7.50-7.60 (m, IH), 7.75 (dd, J = 8.4, 2.1 Hz, IH), 7.90 (d, J= 8.4 Hz, IH), 8.06 (d, J= 2.1 Hz, IH), 9.38 (s, IH).
Example 80
Λ3-Piperidino-7-(3-chlorophenyl)-l-(2,4-dichIorophenyl)-4,4-dimethyI-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl 7-(3-chlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: IR (KBr) 3401, 3019, 1732, 1430, 1215, 1068, 757 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.32 (t, J= 7.2 Hz, 3H), 1.76 (s, 3H), 1.81 (s, 3H), 4.34 (q, J= 7.2 Hz, 2H), 6.47 (d, J= 8.1 Hz, IH), 7.19 (dd, J= 7.8, 1.8 Hz, IH), 7.35 (d, J= 1.8 Hz, IH), 7.38-7.50 (m, 2H), 7.63 (dt, J= 7.2, 2.1 Hz, IH), 7.72 (br s, IH), 7.78 (dd, J= 8.4, 2.4 Hz, IH), 7.92 (d, J= 8.4 Hz, IH), 8.10 (d, J= 8.4 Hz, IH). Step 2: 7-(3-Chloropheny I)-I -(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno [4,3- c]pyrazole-3-carboxylic acid: IR (KBr) 3436, 3019, 2400, 1704, 1519, 149, 115, 1042, 759 cm"1; 1H NMR (300 MHz, DMSO-cfe) δ 1.77 (s, 3H), 1.81 (s, 3H), 6.47 (d, J = 8.4 Hz, IH), 7.17 (br d, J= 7.8 Hz, IH), 7.33 (s, IH), 7.36-7.50 (m, 2H), 7.63 (br d, J= 7.2, IH), 7.72 (br s, IH), 7.77 (dd, J = 8.4, 2.4 Hz, IH), 7.91 (d, J = 8.4 Hz, IH), 8.09 (d, J = 2.4 Hz, IH), 13.40 (br s, IH).
Step 3: N3-Piperidino-7-(3-chlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l ,4-dihydro- chromeno[4,3-φyrazole-3-carboxamide hydrochloride: IR (KBr) 3435, 2931, 1707, 1617, 1491, 1382, 1265, 1214, 1139, 1098, 983, 834, 783 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.38 (br m, 2H), 1.57 (br m, 4H), 1.74 (s, 3H), 1.80 (s, 3H), 2.77 (t, J= 5.1 Hz, 4H), 6.48 (d, J = 8.1 Hz, IH), 7.17 (br d, J = 9.0 Hz, IH), 7.33 (s, IH), 7.'35-7.5O (m, 2H), 7.62 (s, IH), 7.71 (s, IH), 7.76 (dd, J = 8.4, 2.1. Hz, IH), 7.90 (d, J = 8.4 Hz, IH), 8.07 (d, J = 2.4 Hz, IH), 9.39 (s, IH).
Example 81 iV3-Piperidino-7-(4-chlorophenyl)-l-(2,4-dichloropheήyI)-4,4-dimethyI-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride Step 1 : Ethyl 7-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno[4,3-c]ρyrazole-3-carboxylate: IR (KBr) 3400, 2931, 2400, 1719, 1517, 1216, 759, 669 cm-1; 1H NMR (300 MHz, DMSO-^y) δ 1.32 (t, J= 7.2 Hz, 3H), 1.76 (s, 3H), 1.81 (s, 3H), 4.34 (q, J= 7.2 Hz, 2H), 6.48 (br d, J= 8.4 Hz, IH), 7.16 (br d, J= 8.4 Hz, IH), '7.31 (br s, IH), 7.48 (br d, J= 8.1 Hz, 2H), 7.68 (br d, J= 8.1, 2H), 7.77 (br m, IH), 7.92 (br m, IH), 8.09 (br s, IH).
Step 2 : 7-(4-Chlorophenyl)- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 - φyrazole-3-carboxylic acid: IR (KBr) 3020, 2401, 1704, 1496, 1215, 757, 670 cm"1; 1H NMR (300 MHz, DMSO-J6) δ 1.76 (s, 3H), 1,81 (s, 3H), 6.47 (d, J= 8.7 Hz, IH), 7.16 (d, J = 8.7 Hz, IH), 7.29 (s, IH), 7.47 (d, J= 8.7 Hz, 2H), 7.68 (d, J= 8.7 Hz, 2H), 7.77 (dd, J = 8.4, 2.1 Hz, IH), 7.90 (d, J= 8.4 Hz, IH), 8.08 (d, J= 2.1 Hz, IH), 13.40 (br s, IH). Step 3: ΛG-Piperidino-7-(4-chlorophenyl)-l -(2,4-dichlorophenyl)-4,4-dimethyl-l ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: IR (KBr) 3433, 2931, 1700, 1458, 1265, 1210, 1140, 1093, 982, 864, 810 cm"1; 1H NMR (SOO MHz, DMSO-^) δ 1.33 (br m, 2H), 1.57 (br m, 4H), 1.74 (s, 3H), 1.80 (s, 3H), 2.77 (br m, 4H), 6.48 (d, J= 8.1 Hz, IH), 7.15 (dd, J= 8.4, 1.5 Hz, IH), 7.30 (s, IH), 7.47 (d, J= 8.7 Hz, 2H), 7.68 (d, J= 8.7 Hz, 2H), 7.75 (dd, J = 8.4, 2.4 Hz, IH), 7.90 (d, J = 8.7 Hz, IH), 8.06 (d, J = 2.1 Hz, IH), 9.38 (s, IH).
Example 82 iV3-Piperidino-l-(2,4-dichlorophenyl)-4,4-dimethyI-7-(3-pyridyl)-l,4- dihydrochromeno [4,3-c] pyrazole-3-carboxamide dihydrochloride Step 1: Ethyl l-(2,4-dichlorophenyl)-7-(3-pyridyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-φyrazole-3-carboxylate: IR (KBr) 3020, 1723, 1494, 1430, 1265, 1216, 1070, 759, 669 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.32 (t, J = 7.2 Hz, 3H), 1.77 (s, 3H), 1.82 (s, 3H), 4.34 (q, J= 7.2 Hz, 2H), 6.52 (d, J= 8.1 Hz, IH), 7.23 (dd, J= 8.1, 1.5 Hz, IH), 7.39 (d, J= 1.5 Hz, IH), 7.46 (dd, J= 8.1 Hz, IH), 7.78 (dd, J= 8.4, 2.0 Hz, IH), 7.93 (d, J= 8.4 Hz, IH), 8.06 (br d, J= 8.1 Hz, IH), 8.10 (d, J= 2.0 Hz, IH), 8.55 (dd, J = 7.8, 1.2 Hz, IH), 8.86 (d, J= 2.1 Hz, IH). Step 2: iV3-Piperidino-l-(254-dichlorophenyl)-7-(3-pyridyl-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: A stirred solution of Step 1 intermediate (150 mg, 0.30 mmol) and 1-aminopiperidine (36 mg, 0.36 mmol) in anhydrous THF (2 mL) was treated with 20% LHMDS in THF (0.38 niL, 0.46 mmol). The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (NH4Cl) and extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were washed with water (40 mL) followed by brine (40 mL) and dried over anhydrous Na2SO4. Removal of volatiles afforded crude residue which was purified by flash column chromatography on silica gel using 40 % ethyl acetate in hexane as eluent to afford 78 mg of the free base. Desired hydrochloride salt was prepared according to the procedure described in Example 1, Step 4 to afford 75 mg of the compound as an off- white solid; IR (KBr) 3413, 2932, 1700, 1537, 1266, 1224, 1098, 1068, 982, 957, 863, 814 cm-1; 1H NMR (300 MHz, OMSO-d6) δ 1.42 (br s, 2H), 1.71 (br s, 4H), 1.78 (s, 3H), 1.85 (s, 3H), 3.09 (br s, 4H), 6.54 (d, J- 8.1 Hz, IH), 7.33 (d, J= 8.1 Hz, IH), 7.55 (s, IH), 7.79 (br d, J = 8.4 Hz, IH), 7.96 (br d, J = 8.7 Hz, 2H),), 8.10 (s, IH), 8.64 (br m, IH), 8.78 (br m, IH), 9.14 (s, IH), 10.50 (br s, IH).
Scheme 9 and Table 5 gives detailed structural description of Examples 83-94. The percentage displacement values (% D) of [3H]CP55940 by test molecules at 300 nM for hCBl are given in Table 5. Scheme 9
Figure imgf000090_0001
Table 5: Detailed description of Examples 83 - 94 and their in-vitro screening data
Figure imgf000090_0002
Figure imgf000091_0001
Example 83
Λ3-Piperidino-7-chloro-l-(2,4-dichlorophenyI)-spiro[chromene-4,l'-cyclobutane]-l,4- dihy drochromeno [4,3-c] pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl (7-chloro-4-oxo-3,4-dihydrospiro[chromene-2,r-cyclobutan]-3- yl)oxoacetate: 7-chlorospiro[criromene-2,l'-cyclobutan]-4(3/J)-one (Kabbe H. J. et al Synthesis 1978, 886-887; Bergmann et al. J. Med Chem. 1990, 33, 492-504) (0.63 g, 2.80 mmol) was reacted with diethyl oxalate (0.45 g, 3.08 mmol) in the presence of 20 % LHMDS in THF (2.58 mL, 3.10 mmol) as described in Example 1, Step 1 to give 0.21 g of the compound as a yellow oil; IR (neat) 3400, 2926, 1732, 1640, 1601, 1428, 1217, 1075, 759 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.38 (t, J = 7.5 Hz, 3H), 2.27-2.40 (m, 3H), 2.71 (br m, 3H), 435 (q, J = 7.8 Hz, 2H), 7.02 (dd, J = 8.4, 1.8 Hz , IH), 7.06 (d, J = 1.8 Hz, IH), 7.76 (d, J= 8.4 Hz, IH).
Step 2: Ethyl 7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,l '-cyclobutane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (0.21 g, 0.65 mmol) was reacted with 2,4-dichlorophenylhydrazine (0.115 g, 0.65 mmol) in ethanol (9 mL) as described in Example 1 , Step 2 to give 102 mg of the product as a pale yellow solid; IR (KBr) 3421, 2952, 1721, 1614, 1579, 1492, 1386, 1263, 1175, 1109, 927, 804 cm"1; 1H NMR (300 MHz, DMSO-<4) δ 1.33 (t, J= 6.9 Hz, 3H), 2.00-2.30 (m, 3H), 2.80-3.10 (m, 3H), 4.37 (q, J = 7.2 Hz, 2H), 6.39 (d, J= 8.4 Hz, IH), 6.93 (dd, J= 8.4, 2.1 Hz, IH), 7.22 (dd, J= 1.8 Hz, IH), 7.76 (dd, J= 8.4, 2.1 Hz, IH) 7.88 (d, J= 8.4 Hz, IH), 8.06 (d, J= 2.1 Hz, IH). Step 3: 7-Chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,l '-cyclobutane]-l,4- dihy drochromeno [4,3 -c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (90 mg, 0.19 mmol) using IN KOH (0.50 mL) in methanol (5 mL) as described in Example 1, Step 3 gave the 70 mg of the acid as an off-white solid; IR (KBr) 3367, 3084, 2926, 1734, 1611, 1574, 1498, 1246, 1197, 1164, 1068, 983, 947, 843 cm"1; 1H NMR (300 MHz, DMSO- d6) δ 2.00-2.20 (m, 3H), 2.80-3.20 (m, 3H), 6.40 (d, J = 8.4 Hz, IH), 6.93 (dd, J = 8.4, 2.0 Hz, IH), 7.21 (d, J = 2.0 Hz, IH), 7.74 (dd, J = 8.4, 2.1 Hz, IH) 7.87 (d, J = 8.4 Hz, IH), 8.05 (d, J= 2.1 Hz, IH), 13.40 (br s, IH).
Step 4: iV3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,r- cyclobutane] - 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (70 mg, 0.16 mmol) with 1-aminopiperidine (180 mg, 0.18 mmol) using BOP reagent (79 mg, 0.18 mmol) and triethylamine (81 mg, 0.80 mmol) as described in Example I5 Step 4 gave 28 mg of the product as an off-white solid; IR (KBr) 3400, 2925, 1636, 1409, 1216, 1044, 759, 669 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.39 (br s, IH), 1.68 (br s, 4H), 2.00-2.30 (m, 3H), 3.03 (br m, 6H)5 6.41 (d, J= 8.7 Hz5 IH), 6.93 (dd, J= 8.7, 2.1 Hz, IH), 7.21 (d, J= 2.1 Hz5 IH)5 7.54 (dd, J= 8.4, 2.1 Hz5 IH) 7.89 (d, J = 8.4 Hz, IH), 8.04 (d, J= 2.1 Hz, IH)5 10.40 (br s, IH).
Example 84 iV3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l'-cyclobutane]-l,4- dihy drochromeno [4,3-c] pyrazoIe-3-carboxamide hydrochloride
Step 1 : Ethyl (7-bromo-4-oxo-3 ,4-dihydrospiro [chromene-2, 1 '-cyclobutan] -3 -yl)oxoacetate : 7-Bromospiro[chromene-2,l'-cyclobutan]-4(3H)-one (Kabbe H. J. et al .Synthesis 1978, 886-887; Bergmann et al. J. Med. Chem. 1990, 33, 492-504) (3.40 g, 12.73 mmol) was reacted with diethyl oxalate (1.94 g, 13.25 mmol) in the presence of 20 % LHMDS in THF (13.10 mL, 14.00 mmol) as described in Example 1, Step 1 to give 3.0 g of the compound as a brown liquid; IR (neat) 3445, 2958, 1731, 1594, 1418, 1288, 1034, 937, 862, 758 cm4; 1H NMR (300 MHz5 OMSO-d6) δ 1.25 (t5 J = 7.2 Hz, 3H), 1.61-2.40 (m, 6H), 4.24 (q, J = 7.8 Hz, 2H)5 7.23-7.44 (m, 2H)5 7.60-7.74 (m, IH).
Step 2: Ethyl 7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l-cyclobutane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (3.0 g, 8.17 mmol) was reacted with 2,4-dichlorophenylhydrazine (1.20 g, 8. 20 mmol) in ethanol (5 mL) as described in. Example 1, Step 2 to give 2.12 g of the product as a white solid; IR (KBr) 3421, 2951, 1722, 1609, 1509, 1406, 1252, 1187, 1048, 947, 802 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.34 (t, J= 7.2 Hz, 3H), 2.02-2.30 (m, 3H), 2.77-3.17 (m, 3H), 4.38 (q, J= 7.5 Hz, 2H), 6.34 (d, J = 8.4 Hz, IH), 7.07 (dd, J = 8.2, 2.1 Hz, IH), 7.35 (d, J = 2.4 Hz, IH), 7.75 (dd, J= 9.0, 2.1 Hz5 IH) 7.88 (d, J= 8.4 Hz, IH), 8.05 (d, J= 2.4 Hz, IH). Step 3: 7-Bromo-l-(2,4-dichlorophenyl)-spiro[chromeno-4,r-cyclobutane]-l,4- dihy drochromeno [4,3 -c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (1.00 g, 2.10 mmol) using IiV KOH (4.12 mL) in methanol (15 mL) as described in Example 1, Step 3 gave the 0.850 g of the acid as a white solid; IR (KBr) 3348, 2950, 1733, 1606, 1498, 1196, 1104, 1066, 981, 808 cm"1; 1H NMR (300 MHz5 DMSO- d6) δ 1.99-2.20 (m, 3H)5 2.80- 3.11 (m, 3H), 6.32 (d, J = 8.4 Hz, IH), 7.06 (dd, J = 8.4, 1.8 Hz, IH), 7.33 (d, J = 1.8 Hz5 IH), 7.74 (dd, J= 9.0, 3.0 Hz, IH) 7.87 (d, J= 9.0 Hz, IH), 8.05 (d, J= 2.4 Hz, IH), 13.40 (br s, IH).
Step 4: iV3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r- cyclobutane]-l ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (200 mg, 0.445 mmol) with 1 -aminopiperidine (49 mg, 0.490 mmol) using BOP reagent (0.215 mg, 0.49 mmol) and triethylamine (225 mg, 2.22 mmol) as described in Example "1, Step 4 gave 150 mg of the product as a white solid; IR (KBr) 3412, 2945, 2334, 1696, 1507, 1266, 1102, 978, 803 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.42 (br s, 2H), 1.73 (br s, 4H), 2.06-2.30 (m, 3H), 3.11 (br s, 4H), 6.35 (d, J= 8.4 Hz, IH), 7.07 (dd, J= 8.4, 1.8 Hz, IH), 7.35 (d, J= 1.8 Hz, IH), 7.75 (dd, J= 8.4, 2.4 Hz, IH) 7.90 (d, J = 8.4 Hz, IH), 8.05 (d, J= 2.1 Hz, IH), 10.60 (br S5 IH).
Example 85
Λr3-(l-AzepanyI)-7-bromo-l-(2,4-dichlorophenyI)-spiro[chromene-4,l'-cyclobutane]-l,4- dihy drochromeno [4,3-c] py razoIe-3-carboxamide hydrochloride
This compound was prepared from 7-Bromo-l-(2,4-dichlorophenyl)-spiro[chromeno-4,l '- cyclobutane]-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid and 1-homopiperidine according to the coupling procedure described in Example 1, Step 4; IR (KBr) 3411, 2933, 1698, 1509, 1406, 1286, 1106, 979, 809 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.59 (br s, 4H), 1.78 (br s, 4H), 2.00-2.30 (m, 3H), 2.70-3.25 (m, 3H), 3.34 (br s, 4H), 6.35 (d, J = 8.4 Hz, IH), 7.07 (dd, J= 8.41, 1.8 Hz, IH), 7.35 (d, J= 1.8 Hz, IH), 7.75 (dd, J= 9.0, 2.4 Hz, IH) 7.90 (d, J= 8.4 Hz, IH), 8.05 (d', J= 2.1 Hz, IH), 11.00 (br s, IH).
Example 86
N3-Piperidino-l-(2,4-dichlorophenyl)-7-iodo-spiro[chromene-4,l'-cyclobutane]-l,4- dihydrochromeno [4,3-c] py razole-3-carboxamide hydrochloride
Step 1: Ethyl (7-iodo-4-oxo-3,4-dihydrospiro[chromene-2,l '-cyclobutan]-3-yl)oxoacetate: 7-iodospiro[chromene-2,r-cyclobutan]-4(3#)-one (Kabbe H. J. et al. Synthesis 1978, 886- 887; Bergmann et al. J. Med Chem. 1990, 33, 492-504) (1.0 g, 3.18 mmol) was reacted with diethyl oxalate (0.40 g, 3.18 mmol) in the presence of 20 % LHMDS in THF (2.84 mL, 3.49 mmol) as described in Example 1, Step 1 to give 0.60 g of the compound as a dark brown oil; IR (neat) 3091, 2958, 1731, 1689, 1595, 1469, 1288, 1064, 815 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.37 (t, J= 6.0 Hz, 3H), 1.73-2.11 (m, 4H), 2.29 (t, J= 6.0 Hz, 2H), 4.35 (q, J= 6.9 Hz, 2H), 4.80 (s, IH), 7.16-7.19 (m, IH), 7.67-7.69 (m, 2H). Step 2: Ethyl 7-iodo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclobutane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (0.60 g, 1.44 mmol) was reacted with 2,4-dichlorophenylhydrazine (0.218 g, 1.44 mmol) in ethanol (4 mL) as described in Example 1, Step 2 to give 460 mg of the product as a pale yellow solid; IR (KBr) 3420, 2979, 1724, 1606, 1571, 1492, 1263, 1186, 976, 801 cm'1; 1H NMR (300 MHz, DMSO-rftf) δ 1.33 (t, J = 6.0 Hz, 3H), 2.01-2.22 (m, 4H), 2.76-2.86 (m, IH), 2.97-3.07 (m, IH)3 4.37 (q, J= 9.0 Hz, 2H), 6.16 (d, J= 9.0 Hz, IH), 7.22 (dd, J= 8.1, 1.8 Hz, IH), 7.48 (d, J= 1.5 Hz, IH), 7.73 (dd, J= 7.5, 2.0 Hz, IH) 7.87 (d, J= 6.0 Hz, IH), 8.06 (d, J= 3.0 Hz, IH).
Step 3: 7-Iodo-l-(2,4-dichloropheήyl)-spiro[chromene-4,r-cyclobutane]-l ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (0.220 g, 0.396 mmol) using IiV KOH (0.80 mL) in methanol (5 mL) as described in Example 1, Step 3 gave 0.20 g of the acid; IR (KBr) 3083, 2948, 1733, 1602, 1569, 1403, 1282, 1195, 1104, 1063, 979, 805, 760 cm"1; 1H NMR (300 MHz, DMSO-J5) δ 1.99-2.19 (m, 3H), 2.79- 3.16 (m, 3H), 6.16 (d, J = 6.0 Hz, IH), 7.21 (dd, J = 8.4, 1.5 Hz, IH), 7.47 (d, J = 3.0 Hz, IH), 7.74 (dd, J = 8.7, 2.7 Hz, IH) 7.86 (d, J= 9.0 Hz, IH), 8.04 (d, J= 2.1 Hz5 IH), 13.39 (br s, IH).
Step 4: N3-Piperidino-l-(2,4-dichlorophenyl) 7-iodo-spiro[chromene-4,l '- cyclobutane]-l ^-dihydrochromeno^S-cJpyrazole-S-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (200 mg, 0.342 mmol) with 1-aminopiperidine (349 mg, 0.376 mmol) using BOP reagent (182 mg, 0.410 mmol) and triethylamine (0.173 g, 1.71 mmol) as described in Example 1, Step 4 gave 168 mg of the product as a white solid; IR (KBr) 3410, 2944, 2297, 1694, 1505, 1401, 1266, 1192, 1065, 977, 803 cm"1; 1H NMR (300 MHz, DMSO-ύk) δ 1.38 (br s, IH), 1.66 (br s, 4H), 2.06-2.43 (br m, 5H), 2.72-3.07 (br m, 6H), 6.17 (d, J = 9.0 Hz, IH), 7.21 (dd, J - 8.1, 1.5 Hz, IH), 7.47 (d, J= 3.0 Hz, IH), 7.73 (dd, J= 8.4, 2.1 Hz, IH) 7.86 (d, J= 9.0 Hz, IH), 8.02 (d, J= 2.1 Hz, IH), 10.14 (br s, IH).
Example 87 iV3-Piperidino-7-chIoro-l-(2,4-dichlorophenyl)-spiro[chromene-4,l'-cyclopentane]-l,4- dihydrochromeno^S-cJpyrazole-S-carboxamide hydrochloride
Step 1: Ethyl (7-chloro-4-oxo-3,4-dihydrospiro[chromene-2,l '-cyclopentan]-3-yl)oxoacetate: 7-chlorospiro[chromene-2,l'-cyclopentan]-4(3//)-one (Kabbe H. J. et al .Synthesis 1978, 886- 887; Bergmann et al. J. Med Chem. 1990, 33, 492-504) (1.10 g, 4.65 mmol) was reacted with diethyl oxalate (0.75 g, 5.1 mmol) using 20 % LHMDS in THF (4.30 mL, 5.12 mmol) as described in Example 1, Step 1 to give 0.59 g of the compound as a red oil; IR (neat) 3400, 2928, 2852, 2255, 1732, 1600, 1466, 908, 734, 651 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J= 6.9 Hz, 3H), 1.60-3.00 (m, 8H), 4.30-4.45 (m, 2H), 6.95-7.02 (m, 2H), 7.76 (br d, J = 6.9 Hz, IH).
Step 2: Ethyl 7-chloro-l-(2,4-dichlorophenyl)-spiro[chromeno-4,l'-cyclopentane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (0.591 g, 1.75 mmol) was reacted with 2,4-dichlorophenylhydrazine (0.310 g, 1.75 mmol) in ethanol (9 mL) as described in Example 1, Step 2; IR (KBr) 3429, 2961, 1724, 1607, 1510, 1435, 1238, 1193, 1076, 979, 866, 741 cm"1; 1H NMR (300 MHz, DMSO^) δ 1.30 (t, J = 7.2 Hz, 3H), 1.70- 2.45 (m, 8H), 4.32 (q, J = 7.2 Hz, 2H), 6.40 (d, J= 8.4 Hz, IH), 6.91 (br d, J= 8.4 Hz, IH), 7.08 (s, IH), 7.76 (br d, J= 8.4 Hz, IH), 7.90 (d, J= 8.4 Hz, IH), 8.06 (s, IH). Step 3 : 7-Chloro- 1 -(2,4-dichlorophenyl)-spiro [chromeno-4, 1 ' -cyclopentane] - 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate using IiV KOH (0.5 mL) in methanol (5 mL) as described in Example 1, Step 3; IR (KBr) 3078, 2962, 1729, 1606, 1577, 1439, 1237, 1185, 1078, 981, 845 cm"1; 1H NMR (300 MHz, DMSO-fifc) δ 1.70-2.24 (m, 8H), 6.40 (d, J= 8.4 Hz, IH), 6.90 (dd, J= 8.4, 1.5 Hz, IH), 7.07 (d, J= 1.5 Hz, IH), 7.74 (dd, J= 8.4, 1.5 Hz, IH), 7.88 (d, J= 8.4 Hz, IH), 8.05 (d, J = 1.5 Hz, IH), 13.40 (br s, IH).
Step 4: N3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chiOmene-4,r-cyclopentane]- l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: This compound was prepared by the coupling reaction of Step 3 intermediate (0.154 mg, 0.34 mmol) with 1- aminopiperidine (38 mg, 0.37 mmol) using BOP reagent (0.166 g, 0.37 mmol) and triethylamine (0.17 g, 1.71 mmol) as described in Example 1, Step 4; IR (KBr) 3411, 2944, 2857, 1690, 1509, 1457, 1411, 1261, 1183, 981, 862, 815 cm"1; 1H NMR (300 MHz, DMSO- d6) δ 1.37 (br s, 2H), 1.64 (br s, 4H), 1.87 (br s, 4H), 2.00-2.40 (m, 4H), 2.93 (br s, 4H), 6.41 (d, J= 8.4 Hz, IH), 6.90 (d, J= 8.4 Hz, IH), 7.07 (s, IH), 7.74 (d, J= 8.4 Hz, IH), 7.91 (d, J = 8.4 Hz, IH), 8.04 (s, IH), 10.10 (br s, IH).
Example 88 iV3-(l-Azepanyl)-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l'-cyclopentane]- 1 ,4-dihy drochromeno [4,3-c] py razole-3-carboxamide hydrochloride Step 1: Ethyl (7-bromo-4-oxo-3,4-dihydrospiro[chromene-2,l'-cyclopentane]-3- yl)oxoacetate: 7-Bromospiro[chromene-2,r-cyclopentan]-4(3H)-one (Kabbe H. J. et al. Synthesis 1978, 886-887; Bergmann et al. J. Med Chem. 1990, 33, 492-504) (1.25 g, 4.40 mmol) was reacted with diethyl oxalate (0.72 g, 4.90 mmol) in the presence of 20 % LHMDS in THF (4.10 mL, 4.90 mmol) as described in Example 1, Step 1 to give 0.890 g of the compound as a yellow oil; IR (neat) 2963, 2874, 1730, 1695, 1563, 1418, 981, 814 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.38 (t, J= 7.2 Hz, 3H), 1.62-2.09 (m, 8H), 4.35 (q, J= 6.9 Hz, 2H), 4.94 (s, IH), 7.12 (dd, J= 8.4, 1.8 Hz, IH), 7.16 (s, IH), 7.68 (d, J= 8.4 Hz, IH). Step 2: Ethyl 7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l '-cyclopentane]- l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (0.350 g, 0.92 mmol) was reacted with 2,4-dichlorophenylhydrazine (0.17 g, 0,92 mmol) in ethanol (2 mL) as described in Example 1 , Step 2 to give 110 mg of the product as an off-white solid; IR (KBr) 2961, 2869, 1723, 1434, 1231, 1192, 978, 778 cm"1; 1H NMR (300 MHz5 OMSO-d6) δ 1.30 (t, J= 7.5 Hz, 3H), 1.86-2.43 (m, 8H), 4.32 (q, J= 7.5 Hz, 2H), 6.35 (d, J= 8.4 Hz, IH), 7.05 (dd, J= 8.1, 1.8 Hz, IH)5 7. 21 (d, J= 1.8 Hz5 IH), 7.76 (dd, J= 8.4, 2.4 Hz, IH) 7.90 (d, J= 8.4 Hz, IH), 8.06 (d, J= 1.8 Hz, IH).
Step 3: 7-Bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l '-cyclopentane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (94 mg g, 0.18 mmol) using IN KOH (0.40 mL) in methanol (5 mL) as described in Example 1, Step 3 gave the 96 mg of the acid as an off-white solid; IR (KBr) 3078, 2961, 1730, 1604, 1436, 1260, 1104, 979, 806, 763 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.84-2.45 (m, 8H), 6.34 (d, J= 8.4 Hz, IH), 7.03 (dd, J= 8.4, 1.8 Hz, IH), 7.20 (d, J= 2.1 Hz, IH), 7.75 (dd, J= 8.7, 2.1 Hz, IH) 7.89 (d, J= 8.4 Hz, IH), 8.05 (d, J= 1.8 Hz, IH), 13.30 (br s, IH). Step 4 : N3 -Piperidino-7-bromo- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cycl'o- pentane]-l ^-dihydrochromeno^^-cjpyrazole-S-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (93 mg, 0.19 mmol) with 1 -aminohomopiperidine (25 mg, 0. 21 mmol) using BOP reagent (92 mg, 0. 21 mmol) and triethylamine (95 mg, 0,94 mmol) as described in Example 1, Step 4 gave 52 mg of the product as an off-white solid; IR (KBr) 3410, 2929, 1688, 1605, 1454, 1406, 1258, 978, 814 cm"1; 1H NMR (300 MHz, DMSO-<&) δ 1.57 (br s, 4H), 1.71 (br s, 4H), 1.60-1.80 (m, 4H), 2.05-2.73 (m, 4H), 3.18 (br s, 4H), 6.35 (d, J= 7.8 Hz, IH), 7.04 (dd, J= 8.1, 2.1 Hz, IH), 7. 21 (d, J= 1.8 Hz, IH), 7.76 (dd, J= 8.4, 2.4 Hz, IH) 7.90 (d, J= 8.4 Hz, IH), 8.05 (d, J= 2.4 Hz, IH), 10.60 (br s, IH).
Example 89
Λ^3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l'-cyclopentane]-l,4- dihydrochromeno [4,3-c]pyrazole-3-carboxamide hydrochloride This compound was prepared from Step 3 intermediate, Example 88 and 1-aminopiperidine using the coupling procedure described in Example 1 , Step 4 to afford the product as a white solid; IR (KBr) 3412, 2946, 1690, 1506, 1260, 1193, 979, 861 on 1; 1H NMR (300 MHz, DMSO-dβ) δ 1.41 (br s, 2H), 1.70 (br s, 4H), 1.88 (br s, 5H), 2.09-2.25 (m, 3H), 3.09 (br s, 4H), 6.35 (d, J= 8.1 Hz, IH), 7.04 (d, J= 8.1 Hz, IH)3 7. 21 (s, IH), 7.76 (d, J= 8.4 Hz, IH)5 7.91 (d, J= 8.7 Hz, IH), 8.05 (s, IH), 10.60 (br s, IH).
Example 90 iV3-Piperidino-l-(2,4-dichlorophenyI)-7-difluoromethoxy-l,4-dihydrochromeno[4,3-c]- pyrazole-3-carboxamide hydrochloride
Step 1: Ethyl (7-difluoromethoxy-4-oxo-3,4-dihydrospiro[chromene-2,l'-cyclopentane]-3- yl)oxoacetate: 7-difluoromethoxy-spiro[chromene-2,r-cyclopentan]-4(3/i)-one (9.0 g, 33.5 mmol) was reacted with diethyl oxalate (5.4 g, 36.9 mmol) in the presence of 20 % LHMDS in THF (33.0 mL, 40.2 mmol) as described in Example 1, Step 1 to give 7.08 g of the compound; IR (neat) 3382, 2963, 1732, 1685, 1614, 1445, 1254, 1057, 857 cm'1; 1H NMR (300 MHz, DMSO-40 δ 1.26 (m, 3H), 1.75-1.91 (m, 8H), 4.35 (m, 2H), 5.00 (s, IH), 6.83- 6.88 (m, IH), 7.15-7.21 (m, IH), 7.39-7,45 (m, IH), 7.69-7.80 (m, IH). Step 2: Ethyl l-(2,4-dichlorophenyl)-7-difluoromethoxy-spiro[chromene-4,r- cyclopentane]-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (7.0 g, 19.0 mmol) was reacted with 2,4-dichlorophenylhydrazine (3.37 g, 19.0 mmol) in ethanol (21 mL) as described in Example 1, Step 2 to give 6.36 g of the product as an off-white solid; IR (KBr) 3439, 2962, 1719, 1617, 1519, 1389, 1260, 1124, 845 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.30 (t, J= 6.9 Hz, 3H), 1.89 (br m, 4H), 2.12 (br m, 3H), 2.20 (br m, IH), 4.32 (q, J= 7.2 Hz, 2H), 6.42 (d, J= 9.0 Hz5 IH), 6.64 (d, J= 6.3 Hz5 IH), 6.79 (s, IH), 7.24 (t, J = 73.5 Hz5 IH), 7.75 (dd, J= 8.4, 2.4 Hz, IH)5 7.89 (d, J= 8.4 Hz5 IH)5 8.06 (d, J= 1.8 Hz, IH).
Step 3: l-(2,4-dichlorophenyl)-7-difluoromethoxy-spiro[chromene-4,l '-cyclopent- ane]-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (3.5 g, 6.87 mmol) using IN KOH (14.0 mL) in methanol (50 mL) as described in Example 1, Step 3 gave the 3.2 g of the acid as an off-white solid; IR (KBr) 2954, 1694, 1518, 1283, 1113, 994, 855, 678 cm"1; 1H NMR (300 MHz, OMSO-d6) 1.87 (br m, 4H), 1.90- 2.45 (m, 4H), 6.42 (d, J= 8.7 Hz, IH), 6.64 (d, J= 8.4 Hz, IH), 6.79 (d, J= 2.4 Hz, IH), 7.24 (t, J= 73.8 Hz, IH), 7.75 (dd, J= 8.4, 2.4 Hz, IH), 7.87 (d, J= 9.0 Hz, IH), 8.05 (d, J= 2.1 Hz5 IH)5 13.30 (br s, IH) Step 4: N3-Piperidino-l-(2,4-dichlorophenyl)-7-difluoromethoxy-spiro[chromene- 4,1 '-cyclopentane]-l ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride:
Coupling reaction of Step 3 intermediate (250 mg, 0.52 mmol) with 1-aminopiperidine (57 mg, 0.57 mmol) using BOP reagent (253 mg, 0.57 mmol) and triethylamine (263 mg, 2.59 mmol) as described in Example 1, Step 4 gave 120 mg of the product as a white solid; IR (KBr) 3414, 2949, 1693, 1518, 1262, 1130, 988, 860 cmf1; 1H NMR (300 MHz, OMSO-d6) δ 1.39 (br s, 2H), 1.68 (br m, 4H), 1.89 (br m, 4H), 2.09-2.27 (m, 4H), 3.03 (br m, 4H), 6.43 (d, J= 8.1 Hz, IH), 6.64 (d, J= 8.1 Hz, IH), 6.79 (s, IH), 7.24 (t, J= 74.4 Hz, IH), 7.75 (d, J= 8.7 Hz, IH), 7.90 (d, J= 8.1 Hz, IH), 8.04 (s, IH), 10.39 (br s, IH).
Example 91
Λ/3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-7-difluoromethoxy-l,4- dihydrochromeno [4,3-c] py razole-3-carboxamide hydrochloride
This compound was prepared from Step 3 intermediate, Example 90 according to the coupling procedure described in Example 1, Step 4 to afford 150 mg of the product as a white solid; IR (KBr) 3414, 2955, 1695, 1517, 1383, 1262, 1130, 1049, 988, 813 cm'1 ; 1H NMR (300 MHz, OMSO-d6) δ 1.46-1.61 (m, 7H), 1.89 (br s, 4H), 2.10-2.27 (br s, 4H), 2.65-2.84 (br s, 5H), 6.44 (d, J= 8.1 Hz, IH), 6.64 (d, J= 6.9 Hz, IH), 6.80 (s, IH), 7.25 (t, J= 73.5 Hz, IH), 7.76 (d, J= 6.6 Hz, IH), 7.91 (d, J= 8.4 Hz), 8.05 (s, IH), 10.06 (br s, IH).
Example 92
Λr3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,l'-cyclohexane]-l,4- dihydrochromeno[4,3-c]py razole-3-carboxamide hydrochloride
Step 1: Ethyl (7-chloro-4-oxo-3,4-dihydrospiro[chromene-2,l'-cyclohexan]-3-yl)oxoacetate: 7-chlorospiro[chromene-2,r-cyclohexan]-4(3/J)-one (3.28 g, 13.11 mmol) was reacted with diethyl oxalate (2.11 g, 14.43mmol) in the presence of 20 % LHMDS in THF (12.06 mL, 14.43 mmol) as described in Example 1, Step 1 to give 1.24 g of the compound as a red oil; IR (neat) 3400, 2926, 1732, 1640, 1601, 1428, 1217, 1075, 759 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.38 (t, J= 6.9 Hz, 3H), 1.56-1.73 (m, 10H), 4.36 (q, J= 7.1 Hz, 2H), 4.83 (s, IH), 6.99 (dd, J= 8.4, 1.8 Hz, IH), 7.05-7.07 (m, IH), 7.75 (d, J= 8.4 Hz, IH). Step 2: Ethyl [7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,l '-cyclohexane]- l^-dihydrochromeno^-cJpyrazole-S-carboxylate: Step 1 intermediate (1.24 g, 3.54 mmol) was reacted with 2,4-dichlorophenylhydrazine (0.63 g, 3.54 mmol) in ethanol (8 mL) as described in Example 1, Step 2 to give 0.71O g of the product as a pale yellow solid; IR (KBr) 3421, 2932, 1723, 1608, 1508, 1434, 1257, 1157, 1078, 953, 756 cnϊ1; 1H NMR (300 MHz, OMSO-d6) δ 1.23 (m, IH), 1.32 (t, J= 7.2 Hz, 3H), 1.58 (m, 2H), 1.74-1.97 (m, 5H), 2.15-2.39 (m, 2H), 4.34 (q, J = 6.9 Hz, 2H), 6.41 (d, J= 8.4 Hz, IH), 6.91 (dd, J = 8.4, 2.1 Hz, IH), 7.19-7.20 (m, IH), 7.75 (dd, J= 8.4, 2.1 Hz, IH) 7.89 (d, J= 8.4 Hz, IH), 8.06 (d, J = 1.8 Hz, IH).
Step 3: 7-Chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclohexane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (0.62 g, 1.26 mmol) using INKOH (3.0 mL) in methanol (5 mL) as described in Example 1, Step 3 gave 0.60 g of the acid as a white solid; IR (KBr) 3082, 2936, 1729, 1606, 1327, 1228, 954, 811 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.23-1.31 (m, IH), 1.57-1.99 (m, 7H), 2.21-2.40 (m, 2H), 6.40 (d, J = 8.7 Hz, IH), 6.90 (dd, J = 8.4, 2.1 Hz, IH), 7.17 (d, J = 2.1 Hz, IH), 7.74 (dd, J= 8.4, 2.1 Hz, IH), 7.87 (d, J= 9.0 Hz, IH), 8.0 4 (d, J= 2.1 Hz, IH), 13.40 (br s, IH).
Step 4: N3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,l '-cyclo- hexaneJ-l^-dihydrochromeno^^-cJpyrazole-S-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (0.55 g, 1.18 mmol) with 1 -aminopiperidine (0.13 g, 1.3 mmol) using BOP reagent (0.57 g, 1.3 mmol) and triethylamine (0.60 g, 5. 91 mmol) as described in Example 1, Step 4 gave 0.315 g of the product as a white solid; IR (KBr) 3410, 3086, 2934, 2346, 1698, 1508, 1257, 980, 812 cm"1; 1H NMR (SOO MHz, OMSO-d6) δ 1.24- 1.39 (m, 3H), 1.57-1.93 (m, 11 H), 2.26-2.45 (m, 2H), 2.97 (br m, 4H), 6.42 (d, J = 8.4 Hz, IH), 6.91 (dd, J= 8.4, 2.1 Hz, IH), 7.18 (d, J= 2.1 Hz, IH), 7.74 (dd, J= 9.0, 2.7 Hz, IH) 7.97 (d, J= 8.7 Hz, IH), 8.03 (d, J= 2.4 Hz, IH), 10.20 (br s, IH).
Example 93 iV3-Piperidino-7-bromo-l-(2,4-dichlorophenyI)-spiro[chromene-4,l'-cyclohexane]-l,4- dihydrochromeno [4,3-c] py razole-3-carboxamide hydrochloride
Step 1: Ethyl (7-bromo-4-oxo-3,4-dihydrospiro[chromene-2,r-cyclohexan]-3- yl)oxoacetate : 7-bromospiro[chromene-2,r-cyclohexan]-4(3//)-one (5.89 g, 19.64 mmol) was reacted with diethyl oxalate (2.8 g, 19.64 mmol) in the presence of 20 % LHMDS in THF (18.4 mL, 21.61 mmol) as described in Example 1, Step 1 to give 3.77 g of the compound as a dark brown liquid; IR (neat) 3372, 2935, 1731, 1685, 1594, 1419, 1221, 1055, 921 cm"1; 1H NMR (300 MHz, DMSO-J5) δ 1.25 (t, J = 6.9 Hz, 3H), 1.50-2.07 (m, 10H), 4.25 (m, 2H), 4.92(s, IH), 7.23-7.30 (m, IH), 7.43 (s, IH), 7.56-7.65 (m, IH). Step 2: Ethyl 7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclohexane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (3.7 g, 9.36 mmol) was reacted with 2,4-dichlorophenylhydrazine (2.0 g, 9.36 mmol) in ethanol (10 mL) as described in Example 1, Step 2 to give 2.66 g of the product as a pale yellow solid; IR (KBr) 3407, 2934, 1716, 1505, 1249, 1159, 1052, 978, 804 cm"1; 1H NMR (300 MHz, DMSO-d*) δ 1.31 (t, J= 7.5 Hz, 3H), 1.58-1.77 (m, 5H), 1.92-1.98 (m, 2H), 2.14-2.43 (m, 3H), 4.33 (q, J = 6.9 Hz, 2H), 6.34 (d, J = 8.4 Hz, IH), 7.04 (dd, J= 8.4, 1.8 Hz, IH), 7.32 (d, J= 1.8 Hz, IH), 7.75 (dd, J= 8.4, 2.4 Hz, IH) 7.88 (d, J= 8.4 Hz, IH), 8.05 (d, J= 2.4 Hz, IH) Step 3: 7-Bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l '-cyclohexane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (1.1 g, 2.05 mmol) using IN KOH (4.1 mL) in methanol (20 mL) as described in Example 1, Step 3 gave 1.0 g of the acid as a white solid; IR (KBr) 3081, 2933, 1729, 1603, 1505, 1434, 1263, 1157, 947, 780 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.23-1.31 (m, IH), 1.57-1.99 (m, 7H), 2.20-2.44 (m, 2H), 6.34 (d, J= 8.1 Hz, IH), 7.03 (dd, J= 8.1, 1.5 Hz, IH), 7.30 (d, J = 1.5 Hz, IH), 7.75 (dd, J= 8.4, 2.1 Hz, IH) 7.87 (d, J= 8.4 Hz, IH), 8.04 (d, J= 1.8 Hz, IH), 13.34 (br s, IH).
Step 4 : N3 -(Piperidino)-7-bromo- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' - cyclohexane]-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride Coupling reaction of Step 3 intermediate (200 mg, 0.39 mmol) with 1-aminopiperidine (49 mg, 0.43 mmol) using BOP reagent (208 mg, 0.47 mmol) and triethylamine (199 mg, 1.96 mmol) as described in Example 1, Step 4 gave 145 mg of the product as an off-white solid; IR (KBr) 3410, 2929, 1688, 15.05, 1227, 979, 838 cm"1; 1H NMR (300 MHz, DMSO-^) δ 1.40 (br s, 2H), 1.57-1.94 (m, 13H), 2.26 (br s, IH), 3.03 (br s, 4H), 6.35 (d, J= 8.4 Hz, IH), 7.04 (d, J= 7.8, IH), 7.30 (br s, IH), 7.75 (br s, IH), 7.89 (d, J= 8.7 Hz, IH), 8.03 (br s, IH), 10.47 (br s, IH).
Example 94 iV3-(l-Azepanyl)-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l'-cyclohexane]- 1 ,4-dihydrochromeno [4,3-c] py razole-3-carboxamide hydrochloride This compound was prepared from Step 3 intermediate, Example 91 and 1- aminohomopiperidine according to the coupling procedure described in Example 1, Step 4; IR (KBr) 3400, 2925, 1636, 1409, 1216, 1044, 759, 669 cm"1; 1H NMR (300 MHz, DMSO- d6) δ 1.37 (br s, 2H), 1.58 (br s, 6H), 1.76 (br s, 6H), 1.91-1.95 (m, 2H), 2.21-2.29 (m, IH), 2.41-2.50 (m, IH), 3.31 (br s, 4H), 6.35 (d, J = 8.4 Hz, IH), 7.05 (dd, J = 8.4, 1.5 Hz, IH), 7.31 (d, J = 1.5 Hz, IH), 7.76 (dd, J= 8.4, 1.8 Hz, IH), 7.89 (d, J = 8.4 Hz, IH), 8.05 (d, J = 2.4 Hz, IH), 11.02 (br s, IH).
Scheme 10 and Table 6 gives detailed structural description of Examples 95-98. The percentage displacement values (% D) of [3H]CP55940 by test molecules at 300 nM for hCBl are given in Table 7. Scheme 10
Figure imgf000101_0001
Table 7: Detailed description of Examples 95 — 98 and their in vitro screening data
Figure imgf000101_0002
Example 95
Λ3-Piperidino-8-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrothiochromeno[4,3- c] py razole-3-carboxamide hydrochloride
Step 1: Ethyl 2-(6-chloro-4-oxo-3,4-dihydro-2H-3-thiochromenyl)-2-oxoacetate: 6- choloro- 4-thiochromanone (1.0 g, 5.0 mmol) was reacted with diethyl oxalate (0.772 g, 5.29 mmol) in the presence of 20 % LHMDS in THF (4.60 mL, 5.50 mmol) as described in Example 1, Step 1 to give 1.40 g of the compound as a brown solid; IR (KBr) 3437, 2925, 1727, 1597, 1465, 1369, 1277, 1012, 896, 799 cm"1; 1YL NMR (300 MHz, CDCl3) δ 1.42 (t, J = 7.2 Hz, 3H), 4.40 (q, J= 7.2 Hz, 2H), 5.29 (s, IH), 5.40 (s, IH), 6.99 (d, J= 2.0 Hz, IH), 7.05 (dd, J = 8.4, 2.0 Hz, IH), 7.38 (d, J= 8.1 Hz, IH), 15.60 (s, IH).
Step 2: Ethyl 8-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrothiochromeno[4,3-c]pyrazole-3- carboxylate: Step 1 intermediate (1.40 g, 4.69 mmol) was reacted with 2,4- dichlorophenylhydrazine (0.685 g, 4.92 mmol) in ethanol (4 mL) as described in Example 1, Step 2 to give 0.25 g of the product as a yellow solid; IR (KBr) 3090, 2977, 1725, 1500, 1400, 1380, 1260, 725 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 1.33 (t, J= 7.5 Hz, 3H), 4.30- 4.40 (m, 4H), 6.50 (d, J = 2.1 Hz, IH), 7.32 (dd, J = 8.5, 2.4 Hz, IH), 7.53 (d, J = 8.7 Hz, IH), 7.80 (dd, J= 9.7, 2.1 Hz, IH), 7.89 (d, J= 8.4 Hz, IH), 8.07 (d, J= 2.4 Hz, IH). Step 3: 8-ChloiO-l-(2,4-dichlorophenyl)-l,4-dihydrothiochromeno[4,3-c]pyrazole-3- carboxylic acid: Hydrolysis of Step 2 intermediate (0.25 g, 0.61 mmol) using IN KOH (1.25 mL) in methanol (3.0 mL) as described in Example 1, Step 3 gave 0.21 g of the acid as a white solid; IR (KBr) 3080, 2700, 1730, 1560, 1400, 1380, 1280, 725 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 4.25 (d', J= 15.3 Hz, IH), 4.35 (d, J= 15.6 Hz, IH), 6.50 (br s, IH), 7.20- 7.33 (br m, IH), 7.52 (d, J= 8.4 Hz, IH), 7.70-7.81 (br m, IH), 7.87 (d, J= 8.4 Hz, IH), 8.06 (br s, IH), 13.43 (br s, IH).
Step 4: N3-Piperidino-8-chloro-l -(2,4-dichlorophenyl)-l ,4-dihydrothiochromeno[4,3- c]pyrazole~3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.27 mmol) with 1-aminopiperidine (30 mg, 0.297 mmol) using BOP reagent (135 mg, 0.297 mmol and triethylamine (140 mg, 1.35 mmol) as described in Example 1, Step 4 gave 80 mg of the product as a white solid; IR (KBr) 3428, 3084, 2950, 1645, 1500, 1400, 1230, 725 cm-1; 1H NMR (300 MHz, OMSO-d6) δ 1.34-1.50 (m, 2H), 1.62-1.80 (m, 4H), 2.80-3.20 (m, 4H), 4.28 (d, J = 15.0 Hz, IH), 4.37 (d, J = 14.7 Hz, IH), 6.50 (br s, IH), 7.30-7.40 (br m, IH), 7.53 (d, J= 9.0 Hz, IH), 7.70-7.90 (br m, IH), 7.93 (d, J= 8.7 Hz, IH), 8.07 (br s, IH), 10.63 (br s, IH).
Example 96 iV3-Perhydrocyclopenta[c]azol-2-yl-8-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrothio- chromeno [4,3-c] py razole-3-carboxamide hydrochloride
This compound was prepared from Step 3 intermediate, Example 95 and 3-amino-3- azabicyclo [3.3.0] octane using the procedure mentioned in Example 95, Step 4; IR (KBr) 3428, 3084, 2950, 1645, 1500, 1380, 1400, 1230, 725 cm"1; 1H NMR (300 MHz, DMSO- d6) δ 1.40-1.72 (br m, 7H), 2.60-2.90 (br m, 4H), 3.40-3.60 (br m, IH), 4.28 (d, J- 15.0 Hz, IH), 4.37 (d, J = 14.7 Hz, IH), 6.51 (br s, IH), 7.30-7.40 (br m, IH), 7.53 (d, J = 8.7 Hz, IH), 7.80-7.90 (br m, IH), 7.93 (d, J= 9.0 Hz, IH), 8.07 (br s, IH), 10.66 (br s, IH).
Example 97
7V3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-5-(4-methylphenylsulfonyl)-4,5-dihydro- LH-pyrazolo [4,3-c] quinoline-3-carboxamide
Step 1: Ethyl 2-[7-chloro-l-(4-methylphenylsulfonyl)-4-oxo-l,2,3,4-tetrahydro-3- quinolinyl]-2-oxoacetate: 7-chloro-l-(4-methylphenylsulfonyl)- 1,2,3, 4-tetrahydro-4- quinolinone (Johnson et al J. Am. Chem. Soc, 1949, 71 (6), 1901-1905) (2.0 g, 6.0 mmol) was reacted with diethyl oxalate (0.965 g, 6.6 mmol) in the presence of 20 % LHMDS in THF (6.0 mL, 7.2 mmol) as described in Example 1, Step 1 to give 0.63 g of the compound as a yellow solid; IR (KBr) 3421, 2922, 1720, 1592, 1355, 1273, 1166, 1059, 909, 708 cm"1; 1H NMR (300 MHz, CDCl3) δ 1.48 (t, J= 6.9 Hz, 3H), 2.35 (s, 3H), 4.45 (m, 2H), 4.99 (s, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.28 (d, J= 8.4 Hz, 2H), 7.37 (dd, J= 8.4, 1.8 Hz, IH), 7.77 (d, J = 8.4 Hz, IH), 7.82 (d, J= 2.4 Hz, 1H),14.9O (br s, IH).
Step 2: Ethyl 7-chloro-l-(2,4-dichlorophenyl)-5-(4-methylphenylsulfonyl)-4,5- dihydro-lif-pyrazolo[4,3-c]quinoline-3-carboxylate: Step 1 intermediate (0.587 g, 1.35 mmol) was reacted with 2,4-dichlorophenylhydrazine (0.240 g, 1.35 mrnol) in ethanol (30 rnL) as described in Example 1, Step 2 to give 0.328 g of the prodμct as a pale yellow solid; IR (KBr) 3075, 2984, 1734, 1596, 1433, 1353, 1249, 1167, 1083, 889 cm"1; 1H NMR (300 MHz, DMSO-ώfc) δ 1.33 (t, J= 6.6 Hz, 3H), 2.26 (s, IH), 4.41 (q, J = 6.9 Hz, 2H), 5.23 (d, J = 17.7 Hz, 2H), 6.48 (d, J = 8.7 Hz, IH), 7.16-7.25 (m, 5H), 7.34 (d, J= 6.6 Hz, IH), 7.73 (d, J =8.7 Hz, IH), 7.76 (s, IH), 7.99 (s, IH).
Step 3: 7-chloro-l-(2,4-dichlorophenyl)-5-(4-methylphenylsulfonyl)-4,5-dihydro-l/f- pyrazolo[4,3-c]quinoline-3-carboxylic acid: Hydrolysis of Step 2 intermediate (0.20 g, 0.35 mmol) using 1 N KOH (0.9 mL) in methanol (5 mL) as described in Example 1, Step 3 gave 0.180 g of the acid as a yellow solid; IR (KBr) 3438, 2964, 1713, 1596, 1440, 1358, 1262, 1167, 1086, 979, 804, 680 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 3.35 (s, 3H), 5.24 (q, J = 18.6 Hz, 2H), 6.47 (d, J = 8.4 Hz, IH), 7.11-7.21 (m, 5H), 7.34 (d, J= 6.3 Hz, IH), 7.73 (d, J = 8.7 Hz, IH), 7.76-7.77 (s, IH), 7.99 (d, J = 2.1 Hz, IH), 13.53 (br s, IH) Step 4: N3-piperidino-7-chloro- 1 -(2,4-dichlorophenyl)-5-(4-methylphenylsulfo-nyl)- 4,5-dihydro-l//-pyrazolo[4,3-c]quinoline-3-carboxamide: Coupling reaction of Step 3 intermediate (0.150 mg, 0.27 mmol) with 1-aminopiperidine (0.030 mg, 0.30 mmol) using triethylamine (137 mg, 1.35 mmol) and BOP reagent (133 mg, 0.30 mmol according to the procedure described in Example 83, Step 2 gave 90 mg of the product as an off-white solid; IR (KBr) 3401, 2936, 1679, 1359, 1167, 1091, 978, 893, 678 cm"1; 1H NMR (300 MHz, DMSO-J15) δ 1.35 (br s, 2H), 1.60 (br s, 4H), 2.26 (s, 3H), 2.81 (br s, 4H), 5.24 (q, J = 21.6 Hz, 2H)5 6.46 (d, J = 8.4 Hz, IH), 7.13-7.25 (br m, 4H), 7.33 (d, J= 7.2 Hz, IH), 7.72 (br m, 2H), 7.95 (s, IH), 9.31 (br s, IH).
Example 98 iV3-(l-AzepanyI)-7-chloro-l-(2,4-dichlorophenyI)-5-(4-methylphenylsulfonyl)-4,5- dihydro-l//-py razolo [4,3-c] quinoIine-3-carboxamide
This compound was prepared from Step 3 intermediate, Example 97 and 1- aminohomopiperidine according to the procedure described in Example 97, Step 3 to afford 38 mg of the compound as an off-white solid; IR (KBr) 3400, 925,1677, 1460, 1359, 1167, 1051, 978, 814, cm"1; 1H NMR (300 MHz, DMSO-4) δ 1.58-1.67 (br m, 8H), 2.26 (s, 3H), 3.01-3.04 (br m, 4H), 5.24 (q, J= 20.4 Hz5 2H), 6.46 (d, J = 8:7 Hz, IH), 7.13-7.34 (m, 6H), 7.71 (d, J= 8.7 Hz, IH), 7.74 (s, IH), 7.96 (s, IH), 9.55 (br s, IH)
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.
AU publications and patent applications cited in this application are - herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

We Claim:
1. A compound having the structure of formula I,
Figure imgf000105_0001
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, N- oxides, tautomers, stereoisomers, prodrugs or polymorph thereof, wherein:
Z is -O-, -S(O)n,- or -NRe- ;
R and R" are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a protecting group or R1 and R2 taken together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which optionally include at least two heteroatoms selected from O, NRe or
S(O)01;
R3 and R4 are independently hydrogen or Ci-6 alkyl optionally substituted with halogen, further, R3 and R4 taken together with the carbon atom to which they are attached form a carbonyl (C=O) group, or R3 and R4 taken together with the carbon atom to which they are attached form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which optionally include at least one heteroatoms selected from O, NReor S(0)m; each occurrence of R5 and R6 are independently hydrogen, -0Ra, halo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NRaRb, -C(=L)-Ra, -C(O)O-R3, - C(0)NRaRb 5 -S(O)m-Ra or -S(O)m-NRaRb; each occurrence of m is independently O, 1 or 2; each occurrence of p is independently 0, 1, 2, 3 or 4; each occurrence of q is independently 0, 1, 2, 3, 4 or 5; each occurrence of L is independently O, S, or NRe; each occurrence of Ra and Rb is independently hydrogen, -ORC, -SRC, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=L)-RC, -C(O)O-RC, -C(O)NRcRd, -S(O)m-Rc, - S(O)m-NRcRd, -NRcRd, or a protecting group, or Ra and Rb taken together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which optionally include at least two heteroatoms selected from O, NReor S; each occurrence of Rc and Rd is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl or a protecting group, or Rc and Rd taken together with the nitrogen atom to which they are attached form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which optionally include at least two heteroatoms selected from O, NRe or S; each occurrence of Re is independently hydrogen or substituted or unsubstituted alkyl, N-protecting group or hydrate or solvate thereof, with the proviso that when Z is - S(O)m-, R3 and R4 are not both hydrogen.
2. The compound according to claim 1 wherein: Z is -0-, -S(O)m- or ~NRe-, wherein Re is N-protecting group;R3 and R4 are hydrogen, methyl or R3 and R4 taken together with the carbon atom to which they are attached form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring; R1 is hydrogen; R2 is substituted or unsubstituted aryl; R1 and R2 taken together with the nitrogen atom to which they are attached form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which optionally include at least two heteroatoms selected from O, NRe or S(O)m, wherein -NR1R2 is piperidin-1-yl, 2,6-dimethyl piperidin-1- yl, 4-methyl piperazin-1-yl, morpholin-1-yl, azepanyl-lyl, perhydrocyclopenta[c]azol-2-yl, AH- 1,2,4 triazol-4-yl; R5 is -ORa , halo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, wherein Ra is substituted or unsubstituted alkyl or substituted or unsubstituted aryl; R6 is halo; p is 1; q is 2. 3. A compound selected from: iV3 -Piperidino- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 - carboxamide hydrochloride, iV3-(2,6-Dimethylpiperidino)- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxamide hydrochloride, iV3-Moφholino-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[433-c]pyrazole-3- carboxamide hydrochloride, iV3-(l-Azepanyl)-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
N3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno- [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
N3> -(4H- 1 ,2,4-Triazol-4-yl- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3 -carboxamide,
N3 -Piperidino- l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxamide hydrochloride,
7V3-(2,6-Dimethylpiperidino)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
N3 -Morpholino- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3 -carboxamide hydrochloride,
AG-(I -Azepanyl)- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3 -carboxamide hydrochloride, iV3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
N2 -Piperidino-6-chloro- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno [4,3 -c]pyrazole- 3 -carboxamide hydrochloride, iV3-Azepanyl-6-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole- 3-carboxamide hydrochloride,
ΛG-Perhydrocyclopenta[c]azol-2-yl-6-chloro-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
Aβ-Piperidmo-δ-chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno- [4,3-c]pyrazole-3-carboxamide hydrochloride,
ΛG-Morpholino-8-chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
ΛG-Piperidino-8-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno- [4,3 -c]pyrazole-3 -carboxamide hydrochloride, iV3-Morpholino-8-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
N3-Piperidino-7-chloro-l-(2,4-difluorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole- 3 -carboxamide hydrochloride, iV3-Piperidino-7-chloro-l-(4-chlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
N3-Piperidino-7-chloro-l-(2-chlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
N3-Piperidino-l-(2,4-difluoroρhenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
N3-Piperidino-l-(4-fluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c] pyrazole-3 -carboxamide hydrochloride,
N3-Piρeridino-l-(2-fluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c] pyrazole-3-carboxamide hydrochloride,
N3-Piperidino-l-(2-chloro-4-fluorophenyl)-7-iodo-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]ρyrazole-3 -carboxamide hydrochloride, iV3-Piperidino-l-(4-chloro-2-fluorophenyl)-7-iodo-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
N3-Piperidino-l-(2-chlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride, N3 -Piperidino- 1 -(4-chlorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3 -carboxamide hydrochloride,
JV3 -Piperidino-7-chloro- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno [4,3-c]pyrazole- 3 -carboxamide hydrochloride, iV3-Azepanyl-7-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole- 3 -carboxamide hydrochloride, iV3-Perhydrocyclopenta[c]azol-2-yl-7-chloro-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
N3 -Piperidino-7-bromo- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno [4,3 -cjpyrazole- 3 -carboxamide hydrochloride,
N3-Azepanyl-7-bromo-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole- 3 -carboxamide hydrochloride, iV3-Perhydrocyclopenta[c]azol-2-yl-7-bromo-l-(2,4-dichlorophenyl)-l,4 dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
iV3 -Piperidino- 1 -(2,4-dichlorophenyl)-7-iodo- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 - carboxamide hydrochloride, iV3-Azepanyl-l-(2,4-dichlorophenyl)-7-iodo-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
ΛG -Piperidino- 1 -(2,4-dichlorophenyl)-7-fluoro-4,4-dimethyl- 1 ,4- dihydrochromeno [4, 3 -e]pyrazole-3 -carboxamide hydrochloride,
ΛG-Azepanyl-l-(2,4-dichlorophenyl)-7-fluoro-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
iV3-(2,6-Dimethylpiperidino)-7-chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl-l ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride, iV3-Piperidino-7-chloro-l-(2,4-dichloroρhenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
N3-(l -Azepanyl)-7-chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl~ 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride, iV3-Perhydrocyclopenta[c]azol-2-yl-7-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl- 1 ^-dihydrochromeno^^-cjpyrazole-S-carboxamide hydrochloride, iV3-Morpholino-7-chloro-l-(2,4-dichlorophenyl)-4,4~dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride, JV3-(4-Methylpiperazino)-7-chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboχamide dihydrochloride,
JV3-Piperidino-7-bromo- l-(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno- [4,3-c]pyrazole-3-carboxamide hydrochloride, iV3-Azepanyl-7-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochro- meno[4,3-c]pyrazole-3-carboxamide hydrochloride,
JV3-Morpholino-7-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochro- meno[4,3-c]pyrazole-3-carboxamide hydrochloride, iV3-Perhydrocycloρenta[c]azol-2-yl-7-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride, iV3-(4-Methylpiperazmo)-7-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide dihydrochloride, yV3-Piperidino- 1 -(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno- [4,3 -c]pyrazole-3-carboxamide hydrochloride,
ΛG-(l-Azepanyl)-l-(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
N3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
N3-Morpholino-l-(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
N3-Piperidino-l-(2,4-dichlorophenyl)-7-methyl-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
N3-Piperidino-l-(2,4-dichlorophenyl)-7-isopropyl-4,4-dimethyl-l,4 dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride, iV3-Piperidino-7-(rert-butyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l54- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride, iV3-Piperidino-7-cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride, jV3-Azepanyl-7-cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
N3-Piperidino-1 -(2,4-dichlorophenyl)-4,4-dimethyl-7-(l H-tetrazol-5-yl)-l ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
7V3-Piperidino-l-(2,4-dichlorophenyl)-7-methoxy-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride, iV3-( 1 -Azepanyl)- 1 -(2,4-dichlorophenyl)-7-methoxy- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3 -carboxamide hydrochloride,
ΛG-Perhydrocyclopentafcjazol^-yl- 1 -(2,4-dichloroρhenyl)-7-methoxy- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride, iV3-Piperidino- 1 -(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
ΛG-(2,6-Dimethylpiperidino)- 1 -(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
N3 -Morpholino- 1 -(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
N3 -( 1 -Azepanyl)- 1 -(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
N3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride, iV3-(4H-l,3,4-Triazol-4-yl-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4- dihydrochromeno [4, 3 -c]pyr azole-3 -carboxamide, iV3-(4-Methylpiperazino)-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l-,4- dihydrochromeno [4,3-c]pyrazole-3-carboxamide dihydrochloride,
Λβ-Piperidino-l-(2,4-dichlorophenyl)-7-benzyloxy-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyr azole-3 -carboxamide hydrochloride,
N3-Piperidino-l-(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]-ρyrazole-3-carboxamide hydrochloride, iV3-Azepanyl- 1 -(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dirnethyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
N3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichloroρhenyl)-7-di£luoromethoxy-4,4- dimethyl-l^-dihydrochromeno^^-cjpyrazole-S-carboxamide hydrochloride, l-(2,4-Dichlorophenyl)-7-difluoromethoxy-N)-(2,4-difluoroρhenyl)-4,4-dimethyl-l,4- dihydro chromeno[4,3-c]pyrazole-3-carbohydrazide hydrochloride,
7V3-Piperidino-7-(3-chlorophenyl)-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride, jV3-Piperidino-7-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride, N3-Piperidino-l-(2,4-dichlorophenyl)-4,4-dimethyl-7-phenyl-l,4-dihydrochromeno- [4,3-c]pyrazole-3-carboxamide hydrochloride,
ΛG-Piperidino- 1 -(2,4-dichlorophenyl)-7-(4-fluorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
7V3-Piperidino-7-(2-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride, iV3-Piperidino-7-(3 -chlorophenyl)- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride, iV3-Piperidino-7-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
N3-Piperidino-l-(2,4-dichlorophenyl)-4,4-dimethyl-7-(3-pyridyl)-l,4- dihy drochromeno [4,3 -c]pyrazole-3 -carboxamide dihydrochloride,
N3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclobutane]- 1, 4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride,
N3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-spiro[cliromene-4,r-cyclobutane]- l^-dihydrochromeno^^-clpyrazole-S-carboxamide hydrochloride,
7V3 -( 1 -Azepanyl)-7-bromo- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cyclobutane] - l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
7V3-Piperidino- 1 -(2,4-dichlorophenyl)-7-iodo-spiro[chromene-4, 1' -cyclobutane]- 1 , 4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride, iV3-Piperidino-7-chloiO-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclopentane]- l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
N3-(l-Azepanyl)-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l-cyclo- pentane]-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride, iV3-(l- Piperidino)-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r- cyclopentane]-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride, iV3-Piρeridino-l-(2,4-dichlorophenyl)-7-difluoromethoxy-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxamide hydrochloride,
N3-Perhydrocyclopenta[c]azol-2-yl-l-(2,4-dichlorophenyl)-7-difluoromethoxy-l,4- dihydrochromeno [4, 3 -c]pyrazole-3 -carboxamide hydrochloride,
N3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclohexane]- l^-dihydrochromeno^jS-cjpyrazole-S-carboxamide hydrochloride,
N3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclohexane]- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride, iV3-(l-Azepanyl)-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4;,r- cyclohexane]-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
ΛG-Piperidino-8-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrothiochromeno[4,3-c]- pyrazole-3 -carboxamide hydrochloride, iV3-Perhydrocyclopenta[c]azol-2-yl-8-chloro- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrothio- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride,
N3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-5-(4-methylphenylsulfonyl)-4,5- dihy dro- 1 /i-pyrazolo [4,3 -c] quinoline-3 -carboxamide,
N3-(l-Azepanyl)-7-chloro-l-(2,4-dichlorophenyl)-5-(4-methylphenylsulfonyl)-4,5- dihydro-lH-pyrazolo[4,
3-c]quinoline-3-carboxamide, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, N- oxides, tautomers, stereoisomers, prodrugs or polymorph thereof.
4. A compound selected from:
Ethyl 2-oxo-2-(4-oxo-3 ,4-dihydro-2H-3 -chromenyl)acetate,
Ethyl 2-(2,2-dimethyl-4-oxo-3,4-dihydro-2f/-3-chromenyl)-2-oxoacetate,
Ethyl 2-(8-chloro-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate,
Ethyl2-(6-chloro-2,2-dimethyl-4-oxo-3,4-dihydro-2//-3-chromenyl)-2-oxoacetate,
Ethyl2-(6-bromo-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate,
Ethyl 2-(7-chloro-4-oxo-3 ,4-dihydro-2H-3 -chromenyl)-2-oxoacetate,
Ethyl 2-(7-iodo-2,2-dimethyl-4-oxo-3 ,4~dihydro-2#-3 -chromenyl)-2-oxoacetate,
Ethyl 2-(7-chloro-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate,
Ethyl 2-(7-bromo-4-oxo-3 ,4-dihydro-2H-3 -chromenyl)-2-oxoacetate,
Ethyl 2-(7-iodo-4-oxo-3 ,4-dihydro-2H-3 -chromenyl)-2-oxoacetate,
Ethyl 2-(7-fluoro-2,2-dimethyl-4-oxo-3,4-dihydro-2//-3-chromenyl)-2-oxoacetate,
Ethyl 2-(7-chloro-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate,
Ethyl 2-(7-bromo-2,2-dimethyl-4-oxo-3s4-dihydro-2H-3-chromenyl)-2-oxoacetate,
Ethyl 2-(7-iodo-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate,
Ethyl 2-oxo-2-(2,2,7-trimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)acetate!
Ethyl (7-isopropyl-2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-3-yl)oxoacetate,
Ethyl-2-[7-(rert-butyl)-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl]-2- oxoacetate,
Ethyl 2-(7-methoxy-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate, Ethyl 2-(7-methoxy-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate,
Ethyl 2-(7-benzyloxy-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2- oxoacetate,
Ethyl (7-chloro-4-oxo-3,4-dihydrospiro[chromene-2, 1 '-cyclobutan]-3-yl)oxoacetate, Ethyl (7-bromo-4-oxo-3,4-dihydrospiro[chromene-2,r-cyclobutan]-3-yl)oxoacetate, Ethyl (7-iodo-4-oxo-3,4-dihydrospiro[chromene-2, 1 '-cyclobutan]-3-yl)oxoacetate, Ethyl (7-chloro-4-oxo-3,4-dihydrospiro[chromene-2, 1 '-cyclopentan]-3-yl)oxoacetate, Ethyl (7-bromo-4-oxo-3,4-dihydrospiro[chromene-2, 1 '-cyclopentan]-3-yl)oxoacetate,
Ethyl (7-difluoromethoxy-4-oxo-3,4-dihydrospiro[chromene-2, 1 '-cyclopentan]-3- yl)oxoacetate,
Ethyl (7-chloro-4-oxo-3,4-dihydrospiro[chromene-2,r-cyclohexan]-3-yl)oxoacetate, Ethyl (7-bromo-4-oxo-3,4-dihydrospiro[chromene-2,l'-cyclohexan]-3-yl)oxoacetate, Ethyl 2-(6-chloro-4-oxo-3 ,4-dihydro-2//-3 -thiochromenyl)-2-oxoacetate,
Ethyl 2-[7-chloro-l -(4-methylphenylsulfonyl)-4-oxo-l ,2,3,4-tetraliydro-3-quinolinyl]- 2-oxoacetate,
Ethyl 7-chloro-l -(2-chlorophenyl)-l ,4-dihydrochromeno [4,3 -c]pyrazole-3- carboxylate,
Ethyl 1 -(2,4-dichlorophenyl)-7-hydroxy-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate,
Ethyl 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxylate,
Ethyl l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate,
Ethyl 6-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate,
Ethyl 6-bromo-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate,
Ethyl 8-chloro-l -(2,4-dichlorophenyl)-4,4-dimethyl-l ,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxylate,
Ethyl 8-bromo-l -(2,4-dichlorophenyl)-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate,
Ethyl 7-chloro-l -(2,4-difluorophenyl)-l ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate,
Ethyl7-chloro-l-(4-chlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate, Ethyll-(2,4-difluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydroclτromeno[4,3- c]pyrazole-3 -carboxylate,
Ethyl 7-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate,
Ethyll-(4-fluoroρhenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate,
Ethyl 1 -(2-fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3-c]pyrazole-3 - carboxylate,
Ethyl 1 -(2-chloro-4-fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3 -carboxylate,
Ethyll -(4-chloro-2-fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxylate,
Ethyl l-(2-chlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole- 3 -carboxylate,
Ethyl l-(4-chlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole- 3 -carboxylate,
Ethyl 7-chloro-l -(2,4-dichlorophenyl)-l,4-dihydrochromeno [4,3 -c]pyrazole-3- carboxylate,
Ethyl 7-bromo-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate,
Ethyl 7-iodo- 1 -(2,4-dichlorophenyl)- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 - carboxylate,
Ethyl-l-(2,4-dichlorophenyl)-7-fluoro-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate,
Ethyl7-chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate,
Ethyl 7-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4:,3- c]pyrazole-3-carboxylate,
Ethyl l-(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- e]pyrazole-3 -carboxylate,
Ethyl-l-(2,4-dichlorophenyl)-4,4,7-trimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate, Ethyl 7-(isopropyl) -l-(2,4-dichlorophenyl)-4,4-dimethyl-l ,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxylate,
Ethyl 7-(tert-bvΛyϊ) - 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3 -carboxylate,
Ethyl-7-cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate,
Ethyl 1 -(2,4-dichlorophenyl)-7-methoxy- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate,
Ethyl l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate,
Ethyl 7-benzyloxy-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate,
Ethyl 1 -(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxylate,
Ethyl l-(2,4-dichlorophenyl)-7-(3-chlorophenyl)-l,4-dihydrochromeno-[4,3- c]pyrazole-3 -carboxylate,
Ethyl7-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate,
Ethyl 1 -(2,4-dichlorophenyl)-4,4-dimethyl-7-phenyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylate,
Ethyl 1 -(2,4-dichlorophenyl)-7-(4-fluorophenyl)-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxylate,
Ethyl 7-(2-chlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxylate,
Ethyl 7-(3-chlorophenyl)-l -(2,4-dichlorophenyl)-4,4-dimethyl-l ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate,
Ethyl 7-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate,
Ethyl l-(2,4-dichlorophenyl)-7-(3-pyridyl)-4,4-dimethyl-l,4-dihydiOchronieno[4,3- c]pyrazole-3 -carboxylate,
Ethyl 7-chloro- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cyclobutane] - 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxylate,
Ethyl [7-chloro- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 '-cyclohexane]-l ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate, Ethyl 8-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrothiochromeno[4,3-c]pyrazole-3- carboxylate,
Ethyl 7-bromo-l -(2,4-dichlorophenyl)-spiro[chromene-4, 1 '-cyclohexane]-l ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate,
Ethyl 7-bromo- 1 -(2,4-dichloropb.enyl)-spiro[chromene-4, 1 ' -cy clobutane] - 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate,
Ethyl 7-iodo- 1 -(2,4-dichlorophenyl)-spiro [cliromene-4, 1 ' -cyclobutane] - 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate,
Ethyl 7-chloro- 1 -(2,4-dichlorophenyl)-spiro[chromene-4, 1 ' -cyclopentane]- 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxylate,
Ethyl 7-bromo-l-(2,4-dichlorophenyl)-spiro[chroraene-4,l ' -cyclopentane] -1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate,
Ethyl 1 -(2,4-dichlorophenyl)-7-difluoromethoxy-spiro[chromene-4, 1 '-cyclopentanej- l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate,
Ethyl 7-chloro-l-(2,4-dichlorophenyl)-5-(4-methylphenylsulfonyl)-4,5-dihydro-lHr- pyrazolo[4,3-c]quinoline-3-carboxylate,
7-Chloro-l'(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-ciρyrazole- 3-carboxylic acid,
1 -(2,4-Difluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid,
l-(4-Fluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid,
1 -(2-Fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4 ,3 -c]pyrazole-3 - carboxylic acid,
1 -(2-Chloro-4-fluorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3- c]pyrazole-3 -carboxylic acid,
1 -(2,4-Dichlorophenyl)-7-iodo-4,4-dimethyl- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid,
7-Bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole- 3 -carboxylic acid, l-(2,4-Dichlorophenyl)-7-fluoro-4,4-dimethyl-l,4-dihydiOchromeno[4,3-c]pyrazole- 3 -carboxylic acid, 7-Iodo-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid,
7-Bromo-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid,
7-Chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, l-(4-Chlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid, l-(4-Chloro-2-fluorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid, l-(2-Chlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid,
7-Chloro-l -(4-chloroρhenyl)-l ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid,
7-Cb.loro- 1 -(2,4-difluorophenyl)- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxylic acid,
8-Bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole- 3 -carboxylic acid,
8-Chloro-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochiOmeno[4,3-c]-pyrazole- 3 -carboxylic acid,
6-Bromo-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid,
6-Chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, l-(2,4-Dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid,
1 -(2,4-Dichlorophenyl)-l,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxylic acid, 7-Chloro-l-(2-chlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxyfic acid, l-(2,4-Dichlorophenyl)-4,4,7-trimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid,
7-Isopropyl-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid,
7-(fert-butyl)-l-(254-dichlorophenyl)-4,4-dirnethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid, 7-Cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydiOchromeno[4,3-c]pyrazole- 3-carboxylic acid,
1 -(2,4-Dichlorophenyl)-7-methoxy- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxylic acid, l-(2,4-Dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- ■ c]pyrazole-3 -carboxylic acid,
7-Benzyloxy-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid,
l-(2,4-Dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid,
l-(2,4-Dichlorophenyl)-7-(3-chlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid,
7-(4-Chlorophenyl)-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid,
1 -(2,4-Dichlorophenyl)-4,4-dimethyl-7-phenyl- 1 ,4-dihydrochromeno[4,3-c]pyrazole- 3 -carboxylic acid, l-(2,4-Dichlorophenyl)-7-(4-fluorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid,
7-(2-Dichlorophenyl)-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3 -carboxylic acid,
7-(3-Chlorophenyl)- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3 -carboxylic acid,
7-(4-Chlorophenyl)- 1 -(2,4-dichlorophenyl)r4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3 -carboxylic acid,
7-Chloro- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cyclobutane] - 1 ,4-dihy drochro meno[4,3-c]pyrazole-3-carboxylic acid,
7-Chloro- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cyclohexane] - 1 ,4- dihydrochromeno [4,3 -c]pyrazole-3 -carboxylic acid,
7-Bromo- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cyclohexane] - 1 ,4-dihydrochro meno [4,3 -c]pyrazole-3 -carboxylic acid,
7-Bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l'-cyclobutane]-l,4-dihydrochro meno[4,3-c]pyrazole-3-carboxylic acid,
7-Iodo- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cyclobutane] - 1 ,4- dihydrochromeno [4, 3 -c]pyrazole-3 -carboxylic acid, 7-Chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,r-cyclopentane]-l,4-dihydrochro meno[4,3-c]pyrazole-3-carboxylic acid,
7-Bromo- 1 -(2,4-dichlorophenyl)-spiro [chi-omene-4, 1 ' -cyclopentane]- 1 ,4-dihydrochro meno [4,3 -c]pyrazole-3 -carboxylic acid,
1 -(2,4-dichlorophenyl)-7-difluoromethoxy-spiro[chromene-4, 1 ' -cyclopentane] - 1 ,4- dihy drochromeno [4,3 -c]pyrazole-3 -carboxylic acid,
8-Chloro- 1 -(2,4-dichloroplienyl)- 1 ,4-dihydrothiochromeno [4,3 -c]pyrazole-3 - carboxylic acid,
7-chloro-l-(2,4-dichlorophenyl)-5-(4-methylphenylsulfonyl)-4,5-dihydro-lH- pyrazolo[4,3-c]quinoline-3-carboxylic acid, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, N- oxides, tautomers, stereoisomers, prodrugs or polymorphs thereof.
5. A pharmaceutical composition comprising one or more compounds of claim 1 and optionally together with one or more pharmaceutically acceptable exceipients, carriers, diluents or mixture thereof.
6. A method for preventing, ameliorating or treating a cannabinoid receptor mediated diseases, disorders or syndromes comprising administering to the subject in need thereof effective amounts of one or more compounds of claim 1 or a pharmaceutical composition of claim 5.
7. The method of claim 6 wherein 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, disorders and diseases, locomotor activity disorders, movement disorders, immune disorders, inflammation, cell growth , pain or neurodegenerative related syndromes.
8. A method for treating obesity and/or dyslipidemia in a subject in need thereof comprising administering to the subject therapeutically effective amounts of one or more compounds according to claim 1 or a pharmaceutical composition according to claim 5.
9. A process for preparing a compound of formula I,
Figure imgf000121_0001
wherein Z, R1 -R6 are same as defined in claim 1, which process comprises the steps of:
(a) reacting alkali metal enolate of active methylene ketone of Formula 1
Figure imgf000121_0002
1 with diethyl oxalate to form a compound of Formula 2
Figure imgf000121_0003
2 b) reacting the compound of Formula 2 with phenylhydrazines of Formula 3
NHNH2 ^(R6)q
3 to form a compound of Formula 4:
Figure imgf000121_0004
4 c) hydrolyzing the compound of Formula (4) to form a compound of Formula 5
Figure imgf000121_0005
5 d) reacting compound of Formula 5 with a compound of Formula 6
H2N→^RD
6 to form a compound of Formula I.
PCT/IN2007/000119 2006-09-20 2007-03-21 Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation WO2008035356A2 (en)

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