WO2010049366A1 - Tricyclic compounds as glutamate receptor modulators - Google Patents

Tricyclic compounds as glutamate receptor modulators Download PDF

Info

Publication number
WO2010049366A1
WO2010049366A1 PCT/EP2009/064015 EP2009064015W WO2010049366A1 WO 2010049366 A1 WO2010049366 A1 WO 2010049366A1 EP 2009064015 W EP2009064015 W EP 2009064015W WO 2010049366 A1 WO2010049366 A1 WO 2010049366A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
carboxamide
dihydro
pyrazole
methylpyridin
Prior art date
Application number
PCT/EP2009/064015
Other languages
French (fr)
Inventor
Peter Bertinato
Merav Fichman
Shomir Ghosh
Jian Lin
Dalia Segal
Zhaoda Zhang
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to US13/126,118 priority Critical patent/US20110263588A1/en
Priority to JP2011532652A priority patent/JP2012506848A/en
Priority to EP09740889A priority patent/EP2346832A1/en
Publication of WO2010049366A1 publication Critical patent/WO2010049366A1/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the amino acids glutamate and aspartate are known to function as excitator neurotransmitters, which activate a large series of receptors known as glutamate receptors.
  • Glutamate receptors comprise a large family of proteins with extensive heterogeneity at the molecular level.
  • At least three classes of glutamate receptors have been identified.
  • One of these, the NMDA class of receptors is specifically activated by the glutamate analog methyl- D-aspartate. When stimulated, NMDA receptors open ion channels and allow an influx of cations into a neuron.
  • the non-NMDA receptors comprise another group of ionotropic receptors which mediate cation flow into neurons.
  • mGluR metabotropic glutamate receptors
  • mGluR5 metabotropic glutamate receptor subtype 5
  • Modulators of mGluR5 may be also useful in the treatment of psychiatric and neurological disorders.
  • mGluR5 -selective compounds appear effective in animal models of mood disorders, including anxiety and depression.
  • Gene expression data from humans has appeared to indicate that modulation of mGluR5 may be useful for the treatment of schizophrenia.
  • Studies with mGluR5 knockout mice and MPEP also suggest that modulation of these receptors may be useful in the treatment of drug addiction, drug abuse and drug withdrawal.
  • compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier.
  • compositions comprising such compounds.
  • methods of treating disorders such as Alzheimer's disease, Fragile X syndrome, L-DOPA induced dyskinesia, depression, anxiety, migraine, pain, gastroesophageal reflux disease, and/or aiding smoking cessation comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula VII:
  • each W is independently N or CR 1 ;
  • V is N or CR 2 ;
  • X is selected from the group consisting of: O, S, SO 2 , N, NR 4 , CR 5 , CR 5 R 6 , and CO; each T is independently selected from the group consisting of: CO, CR 7 Rs, and NRg; U is selected from the group consisting of: C, CR 1 O, and N;
  • Y is selected from the group consisting of: NR 11 , O, and CR 12 ; Z is selected from the group consisting of: N, NR 13 , and O; A is selected from the group consisting of: -CONR 16 -, -NR 16 CO-, -CONR 16 -CR 14 R 15 -, -0-, -NRi 6 CONRi 6 -, -CRI 4 RI 5 -NRI 6 CO-, -CRI 4 RI 5 -O-, -CRi 4 Ri 5 -NRi 6 -, -0-CRi 4 Ri 5 -, -NRi 6 -
  • B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl; wherein B is optionally substituted by one, two, or three substituents each independently represented by R 3 ; n is O, 1 or 2; m is O, 1 or 2;
  • R 1 , R 2 , and R 3 are each independently selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • R 4 , R 9 , R 11 , Ri 3 , and Ri 6 are each independently selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
  • R 5 , R 6 , Ri 2 , Ri 4 , and Ri 5 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl;
  • R 7 and Rs are each independently selected from the group consisting of: alkoxy, alkyl, halogen, haloalkyl, hydrogen, and hydroxyl, or R 7 and Rs taken together are oxo; and
  • Rio is selected from the group consisting of: methyl, oxide, or hydrogen.
  • Another embodiment provides compounds represented by one or more of the following formulae: in;
  • compositions that include a compound represented by one of formulas I, II, III, IV, V, and VI and e.g., a pharmaceutically acceptable excipient.
  • the disclosure further provides methods of modulating activity of one or more metabotropic receptors-subtype 5 comprising, for example, exposing said receptor to a disclosed compound.
  • the modulator compound is a negative allosteric modulator.
  • Also provided herein are methods of treating a disease associated with expression or activity of one or more metabotropic receptors-subtype 5 in a patient comprising administering to the patient a therapeutically effective amount of a disclosed compound.
  • a disease associated with expression or activity of one or more metabotropic receptors-subtype 5 comprising administering to the patient a therapeutically effective amount of a disclosed compound.
  • method of treating Alzheimer's disease, Fragile X syndrome, dyskinesia such as 1-dopa induced dyskinesia, depression, anxiety, migraine, pain, gastroesophageal reflux disease, and/or aiding smoking cessation comprising administering a compound represented by I, II, III, VI, V, VI, and/or VII.
  • compound represented by Formula VII for use in therapy and/or for the manufacture of a medicament for the treatment of disease associated with negative metabotropic receptors- subtype 5.
  • Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
  • aldehyde or “formyl” as used herein refers to the radical -CHO.
  • alkanoyl refers to a radical -O-CO-alkyl.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C 2 -Ci 2 alkenyl, C 2 -Cioalkenyl, and C 2 -C 6 alkenyl, respectively.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, etc.
  • alkoxy refers to an alkyl group attached to an oxygen (-O-alkyl-).
  • Exemplary alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl or alkynyl group of 1-12, 1-8, or 1-6 carbon atoms, referred to herein as C 1 - C 12 alkoxy, CrCgalkoxy, and CrC ⁇ alkoxy, respectively.
  • Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, etc.
  • exemplary "alkenoxy” groups include, but are not limited to vinyloxy, allyloxy, butenoxy, etc.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as Ci-C 12 alkyl, Ci-Cioalkyl, and Ci-C ⁇ alkyl, respectively.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2 -methyl- 1 -propyl, 2- methyl-2-propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l- propyl, 2-methyl-l -pentyl, 3 -methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl -2 -pentyl, 2, 2 -dimethyl- 1 -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l- butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl
  • Alkyl, alkenyl and alkynyl groups can optionally be substituted with or interrupted by at least one group selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-12, 2-8, or 2-6 carbon atoms, referred to herein as C 2 -C 12 alkynyl, C 2 _Cgalkynyl, and C 2 _C 6 alkynyl, respectively.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl- 1-butynyl, A- propyl-2-pentynyl, and 4-butyl-2-hexynyl, etc.
  • amide or “amido” as used herein refers to a radical of the form
  • R a , R b and R c are each independently selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, and nitro.
  • the amide can be attached to another group through the carbon, the nitrogen, R b , R 0 , or R a .
  • the amide also may be cyclic, for example R b and R 0 , R a and Rb, or Ra and R c may be joined to form a 3- to 12-membered ring, such as a 3- to 10- membered ring or a 5- to 6-membered ring.
  • the term "carboxamido" refers to the structure -C(O)NRbRc.
  • R, R', and R" can each independently be selected from alkyl, alkenyl, alkynyl, amide, aryl, arylalkyl, cyano, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone and nitro.
  • amine or "amino” as used herein refers to a radical of the form
  • Rd, Rs, and Rf are independently selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, and nitro.
  • the amino can be attached to the parent molecular group through the nitrogen, Rj, R e or R f .
  • the amino also may be cyclic, for example any two of Rd, Re or Rf may be joined together or with the N to form a 3- to 12-membered ring, e.g., morpholino or piperidinyl.
  • the term amino also includes the corresponding quaternary ammonium salt of any amino group, e.g., -[N(Rd)(Re)(Rf)]+.
  • Exemplary amino groups include aminoalkyl groups, wherein at least one of R d , R s , or R f is an alkyl group.
  • aryl refers to refers to a mono-, bi-, or other multi- carbocyclic, aromatic ring system.
  • the aromatic ring may be substituted at one or more ring positions with substituents selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.
  • aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • arylalkyl refers to an aryl group having at least one alkyl substituent, e.g. -aryl-alkyl-.
  • Exemplary arylalkyl groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms.
  • phenylalkyl includes phenylC 4 alkyl, benzyl, 1 -phenylethyl, 2- phenylethyl, etc.
  • zido refers to the radical -N 3 .
  • R g? R h and R[ are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, sulfide, sulfonyl, and sulfonamide.
  • Exemplary carbamates include, but are not limited to, arylcarbamates or heteroaryl carbamates, e.g., wherein at least one of Rg Rf 1 and R[ are independently selected from aryl or heteroaryl, such as phenyl and pyridinyl.
  • carbonyl refers to the radical -C(O)-.
  • Carboxamido refers to the radical -C(O)NRR', where R and R' may be the same or different. R and R' may be selected from, for example, alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl and heterocyclyl.
  • carboxy refers to the radical -COOH or its corresponding salts, e.g. -COONa, etc.
  • cyano refers to the radical -CN.
  • cycloalkoxy refers to a cycloalkyl group attached to an oxygen.
  • cycloalkyl refers to a monovalent saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C4_8cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, cyclopentenes, cyclobutanes and cyclopropanes.
  • Cycloalkyl groups may be substituted with alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups.
  • ether refers to a radical having the structure -RiO-R m -, where Ri and R m can independently be alkyl, aryl, cycloalkyl, heterocyclyl, or ether.
  • the ether can be attached to the parent molecular group through Ri or R m .
  • Exemplary ethers include, but are not limited to, alkoxyalkyl and alkoxyaryl groups.
  • Ether also includes polyethers, e.g., where one or both of Ri and R m are ethers.
  • halo or "halogen” or "Hal” as used herein refer to F, Cl, Br, or I.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atoms.
  • heteroaryl refers to a 5-15 membered mono-, bi-, or other multi-cyclic, aromatic ring system containing one or more heteroatoms, for example one to four heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can also be fused to non-aromatic rings.
  • the heteroaryl ring may be substituted at one or more positions with such substituents as described above, as for example, alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
  • substituents as described above, as for example, alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl,
  • heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuryl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazo
  • heterocyclyl or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 3- to 10-membered ring structures, alternatively 3- to 7- membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur. Heterocycles may also be mono-, bi-, or other multi-cyclic ring systems. A heterocycle may be fused to one or more aryl, partially unsaturated, or saturated rings.
  • Heterocyclyl groups include, for example, biotinyl, chromenyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, thiazolidinyl, th
  • the heterocyclic ring may be substituted at one or more positions with substituents such as alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
  • substituents such as alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy
  • heterocycloalkyl is art-recognized and refers to a saturated heterocyclyl group as defined above.
  • heterocyclylalkoxy refers to a heterocyclyl attached to an alkoxy group.
  • heterocyclyloxyalkyl refers to a heterocyclyl attached to an oxygen (-O-), which is attached to an alkyl group.
  • hydroxy and "hydroxyl” as used herein refers to the radical -OH.
  • hydroxyalkyl refers to a hydroxy radical attached to an alkyl group.
  • nitro refers to the radical -NO2.
  • phenyl refers to a 6-membered carbocyclic aromatic ring.
  • the phenyl group can also be fused to a cyclohexane or cyclopentane ring.
  • Phenyl can be substituted with one or more substituents including alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
  • phosphate refers to the radical -OP(O)(OR aa )2 or its anions.
  • phosphanato refers to the radical - P(O)(OR aa )2 or its anions.
  • phosphinato refers to the radical -PR aa (O)(OR aa ) or its anion, where each R aa can be selected from, for example, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, hydrogen, haloalkyl, heteroaryl, and heterocyclyl.
  • sulfate refers to the radical -OS(O)(OR aa ) 2 or its anions, where R aa is defined above.
  • sulfonamide refers to a radical having the structure
  • R r , and R 8 can be, for example, hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl.
  • exemplary sulfonamides include alkylsulfonamides (e.g., where R 8 is alkyl), arylsulfonamides (e.g., where R 8 is aryl), cycloalkyl sulfonamides
  • R 8 is cycloalkyl
  • heterocyclyl sulfonamides e.g., where R 8 is heterocyclyl
  • sulfonyl refers to a radical having the structure
  • R u S ⁇ 2 where R u can be alkyl, aryl, cycloalkyl, and heterocyclyl, e.g., alkylsulfonyl.
  • alkylsulfonyl refers to an alkyl group attached to a sulfonyl group.
  • sulfide refers to the radical having the structure
  • R 2 can be alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, and ketone.
  • alkylsulf ⁇ de refers to an alkyl group attached to a sulfur atom.
  • Exemplary sulfides include "thio," which as used herein refers to an -SH radical.
  • thiocarbonyl or “thiocarboxy” as used herein refers to compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. "For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • “Individual,” “patient,” or “subject” are used interchangeably and include to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds of the invention can be administered to a mammal, such as a human, but can also be other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • the mammal treated in the methods of the invention is desirably a mammal in whom modulation of metabotropic receptors-subtype 5 is desired.
  • Modulation includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
  • the term "therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds of the invention are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the prevention of or a decrease in the symptoms associated with a disease associated with metabotropic receptors-subtype 5.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
  • compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate
  • Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
  • stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom.
  • Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated "( ⁇ )" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • Stereoisomeric mixtures can also be resolved into their component stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • Geometric isomers can also exist in the compounds of the present invention.
  • ⁇ r denotes a bond that may be a single, double or triple bond as described herein.
  • the present invention encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring.
  • Substituents around a carbon-carbon double bond are designated as being in the "Z” or "E” configuration wherein the terms “Z” and "E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E” and "Z” isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • the arrangement of substituents around a carbocyclic ring are designated as “cis” or “trans.”
  • the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated "cis/trans.”
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • the compound is amorphous.
  • the compound is a polymorph.
  • the compound is in a crystalline form.
  • the invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Certain isotopically-labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the e.g., Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C 2 -C 12 )alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1 -methyl- 1 -((C i -C 6 )alkanoyloxy)ethyl (C i -C 6 )alkoxycarbonyloxymethyl, N-(C 1 -C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-C6)alkanoyl, ⁇ -amino(C 1 -C4)alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C 1 -C 10 )alkyl 5 (C 3 -C 7 )cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ - aminoacyl or natural ⁇ -aminoacyl-natural ⁇ -aminoacyl, — C(OH)C(O)OY 1 wherein Y 1 is H, (Ci-C 6 )alkyl or benzyl, -C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (Ci-C 6 )alkyl, carboxy(Ci-C 6 )alkyl, amino(C 1 -C 4 )alkyl
  • compositions that include a compound represented by formula VII and e.g., a pharmaceutically acceptable carrier.
  • a method of treating Alzheimer's disease, Fragile X syndrome, L-DOPA induced dyskinesia, depression, anxiety, migraine, pain, gastroesophageal reflux disease, and/or aiding smoking cessation comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula VII:
  • each W is independently N or CR 1 ;
  • V is N or CR 2 ;
  • X is selected from the group consisting of: O, S, SO 2 , N, NR 4 , CR 5 , CR 5 R 6 , and CO; each T is independently selected from the group consisting of: CO, CR 7 Rs 1 and NR 9 ; U is selected from the group consisting of: C, CR 1O , and N;
  • Y is selected from the group consisting of: N, NR 11 , O, and CR 12 ;
  • Z is selected from the group consisting of: N, NR 13 , and O;
  • A is selected from the group consisting of: -CONR 16 -, -NR 16 CO-, -0-, -CONR 16 - CRi 4 R 15 -, -0-, -NRi 6 CONRi 6 -, -CRI 4 RI 5 -NRI 6 CO-, -CRI 4 RI 5 -O-, -CRi 4 Ri 5 -NRi 6 -, -O-
  • B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl; wherein B is optionally substituted by one, two, or three substituents each independently represented by R 3 ; n is O, 1 or 2; m is O, 1 or 2;
  • Ri, R 2 , and R 3 are each independently selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • R 4 , R 9 , R 11 , Ro, and R 16 are each independently selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
  • R 5 , R 6 , R 12 , R 14 , and R 1S are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl;
  • R 7 and R 8 are each independently selected from the group consisting of: alkoxy, alkyl, halogen, haloalkyl, hydrogen, and hydroxyl, or R 7 and R 8 taken together are oxo; or R 7 and R 8 taken together form a carbocycle or a heterocycle; and
  • R 1O is selected from the group consisting of: methyl, oxide, or hydrogen.
  • B can be selected from: or
  • one or two W are N, or each W and V are C.
  • R 1 and R 2 may be, in some embodiments, each independently selected from the group consisting of: alkyl, halogen, and hydrogen, for example, R 1 and R 2 may be each independently selected from the group consisting of: chloro, fluoro, hydrogen, and methyl.
  • R 11 is optionally substituted by one, two, three or more substituents selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, or alkoxy.
  • X in certain embodiments, may be selected from the group consisting of: O,
  • T may selected from the group consisting of: CO, CH 2 , CMe 2 , NH, and NMe.
  • the integer n in a specific embodiment, may be 1 or 2.
  • U, Y, and Z may be chosen from one of the following groups:
  • U is C, Y is N-alkyl or NH, and Z is N;
  • U is C, Y is N, and Z is N-alkyl;
  • C) U is N, Y is CH or C-alkyl, and Z is N;
  • U may be C
  • Y is NMe
  • Z is N.
  • A may be selected from the group consisting of: -CONH-,
  • R 1 , R 2 , and R 3 are each independently selected from the group consisting of: bromo, carboxamido, chloro, chlorophenyl, cyano, cyclopropyl, diethoxyphenyl, diethylaminoethoxycarbonyl, diethylaminosulfonyl, ethoxycarbonyl, ethoxyphenyl, ethyl, ethylpiperazinylmethylphenyl, fluoro, fluorophenyl, hydrogen, isopropyl, methoxy, methoxycarbonyl, methyl, methylcarbonyl, methylpiperadinylmethylphenyl, methylpiperazinyl, methylthio, nitro, phenyl, piperidinylsulfonyl, sulfonamido, and trifluoromethyl [0076]
  • One embodiment provides a compound represented by formula I:
  • V 1 , V 2 , V 3 , and V 4 are selected, independently for each occurrence, from the group consisting of: N and CR 2 ;
  • X is NR 4 or CR 7 R 8 ;
  • Y and Z are each independently selected from the group consisting of: NR 11 and N;
  • T is CO or CR 7 R 8 , wherein at least one T is CR 7 R 8; n is 0, 1 or 2; A is selected from the group consisting of: -CONR 16 -, -NR 16 CO-, -0-, -CONRi 6 -CRi 4 R 15 -, -NRi 6 CONRi 6 -, -CR I4 R I5 -NR I6 CO-, -CR I4 R I5 -O-, -CRi 4 Ri 5 -
  • NRi 6 -, -0-CRi 4 Ri 5 -, -NRi 6 -CRi 4 Ri 5 -, -NR i6 -, and m is O, 1 or 2;
  • R 2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl, wherein B is optionally substituted by one, two, or three substituents each independently represented by R 3 ;
  • R 3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • R 4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
  • R 7 and R 8 are each independently selected from the group consisting of: alkoxy, alkyl, halogen, haloalkyl, hydrogen and hydroxyl, or R 7 and R 8 taken together are oxo; or R 7 and R 8 taken together form a carbocycle or a heterocycle;
  • Rn is selected from the group consisting of: alkyl, cycloalkyl, or haloalkyl;
  • Ri 6 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and R 14 and R 15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl.
  • B can be selected from: or
  • each of V 1 , V 2 , V 3 , and V 4 can be CR 2 .
  • each OfV 1 , V 2 , and V 3 can be CR 2
  • V 4 can be N.
  • each OfV 1 , V 2 , and V 4 is CR 2
  • V3 is N.
  • R 11 is C ⁇ alkyl and/or R 4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen.
  • T in some embodiments, may be CH 2 or CF 2 .
  • R 11 is optionally substituted by one, two, three or more substituents selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, or alkoxy.
  • X in some embodiments, may be X is NR 4 or may be CR 7 Rs. In some embodiments, X is selected from the group consisting of: CH 2 , CHOH, and CO. T is CH 2 .
  • n may be, in some embodiments, 1 or 2.
  • A in some embodiments, may be for example -CONR 16 - or -CR 14 R 1 S-NR 16 -, wherein, in a specific embodiment, R 16 may be hydrogen or methyl.
  • Another embodiment provides a compound represented by formula II:
  • V 1 , V 2 , V 3 , and V 4 are selected, independently for each occurrence, from the group consisting of: N and CR 2 ;
  • T is CO or CR 7 Rg, wherein at least one T is CR 7 R 8; n is 0, 1 or 2; A is selected from the group consisting of: -CONR 16 -, -NR 16 CO-, -0-, -CONRi 6 -CRi 4 R 15 -, -NRi 6 CONRi 6 -, -CR I4 R I5 -NR I6 CO-, -CR I4 R I5 -O-, -CRi 4 Ri 5 -
  • NRi 6 -, -0-CRi 4 Ri 5 -, -NRi 6 -CRi 4 Ri 5 -, -NR i6 -, and m is O, 1 or 2;
  • R 2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl wherein B is optionally substituted by one, two, or three substituents each independently represented by R 3 ;
  • R 3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • R 4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
  • Rn is selected from the group consisting of: alkyl, cycloalkyl, alkanoyl, aryl, heteroaryl, or heterocyclyl;
  • Ri 6 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
  • Ri 4 and Ri 5 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl.
  • B can be selected from: or
  • each of V 1 , V 2 , V 3 , and V 4 can be CR 2 .
  • each OfV 1 , V 2 , and V 3 can be CR 2
  • V 4 can be N.
  • each OfV 1 , V 2 , and V 4 is CR 2
  • V3 is N.
  • R 11 is C ⁇ alkyl and/or R 4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen.
  • T in some embodiments, may be CH 2 or CF 2 .
  • R 11 is optionally substituted by one, two, three or more substituents selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, or alkoxy.
  • n may be, in some embodiments, 1 or 2.
  • A in some embodiments, may be for example -CONR 16 - or -CR 14 R 1S -NR 16 -, wherein, in a specific embodiment, R 16 may be hydrogen or methyl.
  • V 1 , V 2 , V 3 , and V 4 are selected, independently for each occurrence, from the group consisting of: N and CR 2 ;
  • T is CO or CR7R8, wherein at least one T is CR 7 Rs ; n is 0, 1 or 2;
  • A is selected from the group consisting of: -CONR 16 -, -NR 16 CO-, -O-, -CONRI 6 -CRI 4 RI 5 -, -NRI 6 CONRI 6 -, -CRI 4 RI 5 -NRI 6 CO-, -CRI 4 RI 5 -O-, -CRi 4 Ri 5 -
  • NRi 6 -, -0-CRi 4 Ri 5 -, -NRi 6 -CRi 4 Ri 5 -, -NRi 6 -, and m is 0, 1 or 2;
  • R 2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl wherein B is optionally substituted by one, two, or three substituents each independently represented by R 3 ;
  • R 3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • R 7 and R 8 are each independently selected from the group consisting of: alkyl, halogen, haloalkyl, and hydrogen; or R 7 and R 8 taken together form a carbocycle or a heterocycle;
  • R 11 is selected from the group consisting of: alkyl, cycloalkyl, alkanoyl, aryl, heteroaryl, or heterocyclyl;
  • R 16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
  • R 14 and R 1S are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl.
  • B can be selected from: or [0091]
  • each OfV 1 , V 2 , V 3 , and V 4 can be CR 2 .
  • each OfV 1 , V 2 , and V 3 can be CR 2 , and V 4 can be N.
  • each OfV 1 , V 2 , and V 4 is CR 2 , and V 3 is N.
  • R 11 is optionally substituted by one, two, three or more substituents selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, or alkoxy.
  • R 11 is C ⁇ alkyl and/or R 4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen.
  • T in some embodiments, may be CH 2 or CF 2 .
  • n may be, in some embodiments, 1 or 2.
  • A in some embodiments, may be for example -CONR 16 - or -CR 14 R 1 S-NR 16 -, wherein, in a specific embodiment, R 16 may be hydrogen or methyl.
  • V 1 , V 2 , V 3 , and V 4 are selected, independently for each occurrence, from the group consisting of: N and CR 2 ;
  • X is selected from the group consisting of: O, SO 2 , NR 4 and CR 7 R 8 ;
  • T is CO or CR 7 R 8 , wherein at least one T is CR 7 R 8; n is 0, 1 or 2;
  • A is selected from the group consisting of: -CONR 16 -, -NR 16 CO-, -O-, -CONR 16 -CR 14 R 15 -, -NR 16 CONR 16 -, -CR 14 R 15 -NR 16 CO-, -CR 14 R 15 -O-, -CR 14 R 15 -
  • NR 16 -, -0-CR 14 R 15 -, -NR 16 -CR 14 R 15 -, -NR 16 -, m is 0, 1 or 2;
  • R 2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl, wherein B is optionally substituted by one, two, or three substituents each independently represented by R 3 ;
  • R 3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • R 4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
  • R 7 and R 8 are each independently selected from the group consisting of: alkoxy, alkyl, halogen, haloalkyl, hydrogen and hydroxyl, or R 7 and R 8 taken together are oxo; or R 7 and R 8 taken together form a carbocycle or a heterocycle;
  • R 11 is selected from the group consisting of: alkyl, cycloalkyl, or haloalkyl;
  • R 16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
  • R 14 and R 1S are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl.
  • B can be selected from: or
  • each of V 1 , V 2 , V 3 , and V 4 can be CR 2 .
  • each OfV 1 , V 2 , and V 3 can be CR 2 , and V 4 can be N.
  • each OfV 1 , V 2 , and V 4 is CR 2 , and V 3 is N.
  • R 11 is C ⁇ aUcyl and/or R 4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen.
  • R 11 is optionally substituted by one, two, three or more substituents selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, or alkoxy.
  • T in some embodiments, may be CH 2 or CF 2 .
  • X in some embodiments, may be X is NR 4 or may be CR 7 Rs. In some embodiments, X is selected from the group consisting of: CH 2 , CHOH, and CO. T is CH 2 .
  • n may be, in some embodiments, 1 or 2.
  • A in some embodiments, may be for example -CONR 16 - or -CR 14 R 1 S-NR 16 -, wherein, in a specific embodiment, R 16 may be hydrogen or methyl.
  • V 1 , V 2 , V 3 , and V 4 are selected, independently for each occurrence, from the group consisting of: N and CR 2 ;
  • T is CO or CR 7 Re, wherein at least one T is CR 7 Rs ; n is 0, 1 or 2;
  • A is selected from the group consisting of: -CONR 16 -, -NR 16 CO-, -O-, -CONRi 6 -CRi 4 R 15 -, -NRi 6 CONRi 6 -, -CRI 4 RI 5 -NRI 6 CO-, -CRI 4 RI 5 -O-, -CRi 4 Ri 5 -
  • NRi 6 -, -0-CRi 4 Ri 5 -, -NRi 6 -CRi 4 Ri 5 -, -NRi 6 -, and m is 0, 1 or 2;
  • R 2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl, optionally substituted by one, two or three substituents each independently represented by R 3 ;
  • R 3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • R 4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
  • R 7 and R 8 are each independently selected from the group consisting of: alkyl, halogen, haloalkyl, and hydrogen; or R 7 and R 8 taken together are oxo; or R 7 and R 8 taken together form a carbocycle or a heterocycle;
  • R 16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
  • R 14 and R 15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl.
  • B can be selected from: or
  • each of V 1 , V 2 , V 3 , and V 4 can be CR 2 .
  • each OfV 1 , V 2 , and V 3 can be CR 2 , and V 4 can be N.
  • each OfV 1 , V 2 , and V 4 is CR 2 , and V 3 is N.
  • R 4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen.
  • T in some embodiments, may be CH 2 or CF 2 .
  • the integer n may be, in some embodiments, 1 or 2.
  • A in some embodiments, may be for example -CONR 16 - or -CR 14 RiS-NR 16 -, wherein, in a specific embodiment, R 16 may be hydrogen or methyl
  • Vi, V 2 , V 3 , and V 4 are selected, independently for each occurrence, from the group consisting of: N and CR 2 ;
  • X is selected from the group consisting of: NR 4 , S, SO 2 , and CR 7 R 8 ;
  • T is CO or CR 7 R 8 , wherein at least one T is CR 7 R 8; n is 0, 1 or 2;
  • A is selected from the group consisting of: -CONRi 6 -, -NRi 6 CO-, -O-, -CONR I6 -CR I4 R I5 -, -NR I6 CONR I6 - , -CR I4 R I5 -NR I6 CO-, -CR I4 R I5 -O-, -CRi 4 Ri 5 -
  • R 2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl, wherein B is optionally substituted by one, two or three substituents each selected from R 3 ;
  • R 3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
  • R 4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
  • R 7 and R 8 are each independently selected from the group consisting of: alkyl, halogen, haloalkyl, and hydrogen, or R 7 and R 8 taken together are oxo; or R 7 and R 8 taken together form a carbocycle or a heterocycle;
  • R 11 is alkyl
  • R 16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
  • R 14 and R 15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl.
  • B can be selected from: or
  • each of V 1 , V 2 , V 3 , and V 4 can be CR 2 .
  • each OfV 1 , V 2 , and V 3 can be CR 2 , and V 4 can be N.
  • each OfV 1 , V 2 , and V 4 is CR 2 , and V 3 is N.
  • R 11 is Ci_ 3 alkyl and/or R 4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen.
  • T in some embodiments, may be CH 2 or CF 2 .
  • X in some embodiments, may be X is NR 4 or may be CR 7 R 8 . In some embodiments, X is selected from the group consisting of: CH 2 , CHOH, and CO. The integer n may be, in some embodiments, 1 or 2.
  • A in some embodiments, may be for example -CONR 16 - or -CR 14 R 1 S-NR 16 -, wherein, in a specific embodiment, R 16 may be hydrogen or methyl.
  • Contemplated compounds, and pharmaceutical compositions,comprising at least one compound may be selected from the group consisting of: N-(3-chlorophenyl)-l- methyl-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide; 8-chloro-N-(3-chlorophenyl)-l- methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3-chlorophenyl)-8-fluoro-2- methyl-2,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(4-chloropyridin-2-yl)-l- methyl-l,4-di
  • compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • the invention further provides methods of modulating activity of one or more metabotropic receptors-subtype 5 comprising exposing said receptor to a compound of the invention.
  • the modulator compound is a negative allosteric modulator.
  • the invention further provides methods of treating a disease associated with expression or activity of one or more metabotropic receptors-subtype 5 in a patient comprising administering to the patient a therapeutically effective amount of a compound of the invention.
  • In one embodiment of the invention provides a method of treating Alzheimer's disease, Fragile X syndrome, L-DOPA induced dyskinesia, depression, anxiety, migraine, pain, gastroesophageal reflux disease, and/or aiding smoking cessation comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • diseases and disorders that may be treated by administration of a therapeutically effective amount of a compound of the invention include functional bowel disorders, post-operative ileus, urinary tract disorders (incontinence, BPH, prostatitis, OAB), Parkinson's disease, panic disorder, phobia, posttraumatic stress disorder, generalized anxiety disorder, acute stress disorder, depression, bipolar disorder, attention-deficit/hyperactivity disorder, cognitive impairment, Alzheimer's disease, dementia, delirium tremens, ischemia, and neuropathic pain.
  • Compounds of the invention may also be effective in the treatment of abuse or addition to alcohol, nicotine, cocaine, amphetamine, benzodiazepine, and opiates. Compounds of the invention may also be useful in treating or preventing substance tolerance or dependence to bulimia nervosa, anorexia nervosa, gambling dependence, smoking dependence, sex dependence, substance withdrawal, and obsessive compulsive disorders. [00121] The compounds of the invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
  • the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
  • the compound of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • compositions of this invention may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual nontoxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient may bemixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a non-toxic pharmaceutically acceptable salt thereof.
  • compositions of the invention when referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the liquid forms in which the compositions of the invention may be incorporated for administration orally or by injection include aqueous solution, suitably flavored syrups, aqueous or oil suspensions, and emulsions with acceptable oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, or with a solubilizing or emulsifying agent suitable for intravenous use, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation.
  • the instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like).
  • Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . " etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. More specifically, compounds of the invention may be prepared using the reactions and techniques described herein. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. [00128] Schemes 1-8 depict methods for making exemplary compounds of the invention as described below. Scheme 1
  • R 4 H, Me, Et & isopropyl
  • R 5 -R 6 -CH 2 CH 2 O-;
  • the title compound was prepared according to general procedure A described in Scheme 2.
  • the title compound was obtained as a yellow solid (1.76 g, 6.62 mmol, 66.2 % yield) by using 6-fluorochroman-4-one (1.66 g, 10.0 mmol), sodium ethoxide (21wt% in ethanol, 7.46 niL, 20.0 mmol), diethyl oxalate (1.36 ml, 10.0 mmol) in ethanol (100 mL).
  • the title compound was prepared according to general procedure D described in Scheme 2.
  • the title compound was obtained as a white solid with puritiy greater than 95 % (51.7 mg,.0.145 mmol, 15 % yield) by using 8-fluoro-l-methyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid (238 mg, 0.96 mmol), oxalyl chloride (0.53mL, 1.05 mmol), pyridine (0.23 ml, 2.9 mmol), 3-chloroaniline (147 mg, 1.15 mmol) and dichloromethane (20 mL).
  • the title compound was prepared according to general procedure D described in Scheme 2. The title compound was obtained as a white solid with puritiy greater than 95 % (38.6 mg,.0.108 mmol, 17 % yield) by using 8-fluoro-2-methyl-2,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid (160 mg, 0.65 mmol), oxalyl chloride (0.36mL, 0.71 mmol), pyridine (0.16 ml, 1.9 mmol), 3-chloroaniline (98 mg, 0.77 mmol) and dichloromethane (20 mL).
  • the title compound was prepared according to general procedure B described in Scheme 1.
  • the title compound was obtained as a pale-yellow solid (1.1 g,.4.3 mmol, 53 % yield) by using ethyl 2-oxo-2-(4-oxochroman-3-yl)acetate (2.0 g, 8.06 mmol), methyl hydrazine (0.47 ml, 8.86 mmol) and acetic acid (13 ml).
  • the title compound was shown at the retention time 4.4 min in LC-MS analysis (Kromasil 100-3.5 C4 column, 50 x 4.6 mm, 3.5 ⁇ m. Mobile phase A was 0.05% TFA in water; mobile phase B was 0.05% TFA in acetonitrile.
  • the title compound was prepared according to general procedure D described in Scheme 1.
  • the title compound was obtained as a white solid with puritiy greater than 95 % (25.4 mg,.0.07 mmol, 14 % yield) by using l-methyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid (119 mg, 0.52 mmol), oxalyl chloride (0.28 mL, 0.57 mmol), pyridine (0.13 ml, 1.6 mmol), 4-chloropyridin-2-amine (79.8 mg, 0.62 mmol) and dichloromethane (20 mL).
  • the title compound was prepared according to general procedure B described in Scheme 1.
  • the title compound was obtained as a orange solid (473 mg, 1.65 mmol, 33 % yield) by using ethyl 2-(2,2-dimethyl-4-oxochroman-3-yl)-2-oxoacetate (1.544 g, 5.0 mmol), methyl hydrazine (0.29 ml, 5.5 mmol) and acetic acid (10 ml).
  • the title compound was shown at the retention time 5.0 min in LC-MS analysis (Kromasil 100-3.5 C4 column, 50 x 4.6 mm, 3.5 ⁇ m. Mobile phase A was 0.05% TFA in water; mobile phase B was 0.05% TFA in acetonitrile.
  • the title compound was prepared according to general procedure D described in Scheme 1.
  • the title compound was obtained as a white solid with puritiy greater than 95 % (69.7 mg, 0.33 mmol, 39 % yield) by using l,4,4-trimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid (214 mg, 0.83 mmol), oxalyl chloride (0.46 mL, 0.91 mmol), pyridine (0.20 ml, 2.5 mmol), 3-chloroanaline (127 mg, 0.99 mmol) and dichloromethane (20 niL).
  • the solid was dissolved in methylene chloride (2 mL) and added dropwise to a solution of 2-amino-6-picoline (102 mg, 9.45 mmol) and triethylamine (263 uL, 1.9 mmol) in methylene chloride (3 mL). The resulting mixture was stirred at room temperature for 4h. The mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was dried (magnesium sulfate), filtered and concentrated. The solid was repulped in ethyl acetate to provide the desired compound in 90 % purity.
  • the title compound was prepared according to general procedure D described in Scheme 1.
  • the title compound was obtained as a white solid with puritiy greater than 95 % (1.6 mg, 0.005 mmol, 0.6 % yield) by using l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid (190 mg, 0.88 mmol), oxalyl chloride (0.48 mL, 0.97 mmol), pyridine (0.21 ml, 2.6 mmol), 6-methylpyridin-2-amine (114 mg, 1.06 mmol) and dichloromethane (20 mL).
  • the title compound was prepared according to general procedure D described in Scheme 1.
  • the title compound was obtained as a white solid with puritiy greater than 95 % (38.7 mg, 0.12 mmol, 13.5 % yield) by using l-methyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid (200 mg, 0.87 mmol), oxalyl chloride (0.48 mL, 0.95 mmol), pyridine (0.21 ml, 2.6 mmol), 2-amino-4-cyanopyridine (124 mg, 1.04 mmol) and dichloromethane (20 mL).
  • the title compound was prepared according to general procedure D described in Scheme 1.
  • the title compound was obtained as a pale-yellow solid with puritiy greater than 95 % (37.2 mg, 0.10 mmol, 15.7% yield) by using 1 -methyl- l,4-dihydrochromeno[4, 3- c]pyrazole-3-carboxylic acid (150 mg, 0.65 mmol), oxalyl chloride (0.36 mL, 0.72 mmol), pyridine (0.16 ml, 2.0 mmol), 3,4-ethylenedioxyaniline (118 mg, 0.78 mmol) and dichloromethane (15 mL).
  • the title compound was prepared according to general procedure D described in Scheme 1.
  • the title compound was obtained as a off-white solid with puritiy greater than 95 % (42.7 mg, 0.12 mmol, 18.9 % yield) by using l-methyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid (150 mg, 0.65 mmol), oxalyl chloride (0.36 mL, 0.72 mmol), pyridine (0.16 ml, 2.0 mmol), 3,4-dihydro-3H-l,4-benzoxazine (105 mg, 0.78 mmol) and dichloromethane (15 mL).
  • the reaction mixture was quenching at -78 0 C with a saturated solution OfNH 4 Cl (0.5 mL) as well as 2N HCl (1.0 mL). The mixture was stirred at room temperature for 30 min. The mixture was extracted with dichloromethane and the extracts were dried over anhydrous sodium sulfate. The solution was filtered and the solvent was removed under reduced pressure to give the crude product (229 mg, a mixture with the aldehyde). The title compound was shown at the retention time 3.3 min in LC-MS analysis (Kromasil 100-3.5 C4 column, 50 x 4.6 mm, 3.5 ⁇ m. Mobile phase A was 0.05% TFA in water; mobile phase B was 0.05% TFA in acetonitrile.
  • the solid was removed by filtration and the filtrate was concentrated to a dark oil under reduced pressure.
  • the oil was dissolved in acetic acid (12 mL) and the solution was treated with methyl hydrazine (390 uL, 7.4 mmol).
  • the solution was stirred 48h at room temperature.
  • the solid was removed by filtration.
  • the filtrate was dissolved in ethyl acetate and the mixture was washed with water (3 x 20 mL), aqueous sodium bicarbonate and brine.
  • the organic fraction was dried (MgSO 4 ), filtered and concentrated.
  • the acid chloride was dissolved in methylene chloride (2 mL) and added dropwise to a solution of 2-amino-6- picoline (142 mg, 1.32 mmol) and triethylamine (367 uL, 2.64 mmol) in methylene chloride (4 mL). The resulting mixture was stirred at room temperature for 5h. The mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was dried (magnesium sulfate), filtered and concentrated.
  • the title compound was prepared according to general procedure D described in Scheme 1.
  • the title compound was obtained as a white solid with puritiy greater than 95 % (88.0 mg, 0.25 mmol, 95 % yield) by using l-isopropyl-4,5-dihydro-lH-pyrazolo[4,3- /z]quinoline-3-carboxylic acid (68.0 mg, 0.26 mmol), oxalyl chloride (7.5 mL, 92 mol), pyridine (0.55 ml, 6.8 mmol), 6-methylpyridin-2-amine (65.0 mg, 0.6 mmol) in dichloromethane (15 mL).
  • the title compound was prepared according to general procedure D described in Scheme 1.
  • the title compound was obtained as a white solid with puritiy greater than 95 % (76 mg, 0.23 mmol, 89 % yield) by using l-ethyl-4,5-dihydro-lH-pyrazolo[4,3- /z]quinoline-3-carboxylic acid (62.0 mg, 0.25 mmol), oxalyl chloride (7.5 mL, 92 mmol), pyridine (0.45 ml, 5.6 mmol), 6-methylpyridin-2-amine (36.0 mg, 0.33 mmol) in dichloromethane (10 mL).
  • the title compound was prepared according to general procedure D described in Scheme 1.
  • the title compound was obtained as a white solid with puritiy greater than 90 % (10.3 mg, 0.032 mmol, 17 % yield) by using l-methyl-4,5-dihydro-lH-pyrazolo[4,3- /z]isoquinoline-3-carboxylic acid (60.0 mg, 0.22 mmol), oxalyl chloride (85.0 mg, 0.68 mmol), triethylamine (88.0 ml, 0.63 mmol), 6-methylpyridin-2-amine (27.0 mg, 0.025 mmol) in dichloromethane (6.0 mL).
  • Mobile phase A was 0.05 % TFA in water; mobile phase B was 0.05 % TFA in acetonitrile.
  • the gradient was initiated at 2 % B and ramp to 75 % B in 7 min, followed by a wash to 95 % B within 0.5 min and re-equilibration back to 2 % from 8.6 min.
  • the total analyzed time was 10 min.
  • Flow rate was 0.8 niL/min).
  • the title compound was prepared according to general procedure B as described in step 5 in Scheme 8.
  • a mixture of 2 regio-isomers were obtained by using 2-(l- (4-fluorobenzoyl)piperidine-3-carbonyl)-3,4-dihydronaphthalen-l(2 ⁇ )-one (100 mg, 0.26 mmol), methylhydrazine (15.3 ⁇ L, 0.29 mmol), acetic acid (0.5 ml) and dichloromethane (5 mL).
  • the title compound was isolated by prep-HP LC (1% TFA/acetonitril/water) to yield a TFA salt as a white solid (11.0 mg, 0.028 mmol, 10.9 % yield).
  • an inducible CHO cell line expressing the human mGlu5 recombinant receptor was used.
  • This cell line also stably expressed Aequorin (Euroscreen FAST), a photoprotein that spontaneously couples with coelenterazine h when added exogenously in the cell media.
  • the Aequorin-coelenterzine h complex undergoes a conformational change upon binding of calcium ions which results in the emission of blue light (wavelength 469 nm) that was measured using a Hamamatsu Functional Drug Screening System 6000.
  • mGluR5 expression was induced by a doxycycline responsive promoter by growing cells to mid-log phase for 18 hours in media without antibiotics and supplemented with doxycycline (600 ng/niL).
  • Cells were detached from the plate by gentle flushing using PBS-EDTA (5 rnM EDTA) and centrifuged for collection and resuspended in "assay buffer" (HBSS, 2.1 mM CaC12, 2 ug/mL glutamate-pyruvate transaminase, 4 mM MEM sodium pyruvate, and 0.1% protease free BSA).
  • HBSS "assay buffer”

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Urology & Nephrology (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Rheumatology (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Disclosed herein are compounds that may be negative allosteric modulators of metabotropic receptors-subtype 5, and methods of making and using same.

Description

TRICYCLIC COMPOUNDS AS GLUTAMATE RECEPTOR MODULATORS
BACKGROUND
[0001] The amino acids glutamate and aspartate are known to function as excitator neurotransmitters, which activate a large series of receptors known as glutamate receptors. Glutamate receptors comprise a large family of proteins with extensive heterogeneity at the molecular level. At least three classes of glutamate receptors have been identified. One of these, the NMDA class of receptors, is specifically activated by the glutamate analog methyl- D-aspartate. When stimulated, NMDA receptors open ion channels and allow an influx of cations into a neuron. The non-NMDA receptors comprise another group of ionotropic receptors which mediate cation flow into neurons.
[0002] A third class of glutamate receptors are known as the metabotropic glutamate receptors ("mGluR"). To date, eight subtypes of mGluR have been cloned and classified into three groups on the basis of sequence similarities and pharmacological properties. These receptors are referred to as "metabotropic" because their stimulation does not appear to result directly in the opening of an ion channel, as is the case with the NMDA and non-NMDA ionotropic glutamate receptors. Instead, the cellular effects caused by the stimulation of a metabotropic receptor are mediated by G-proteins.
[0003] Modulation of metabotropic glutamate receptor subtype 5 (mGluR5) appears to affect affect the nervous system. For example, recent evidence demonstrates the involvement of mGluR5 in nociceptive processes and therefore modulation of mGluR5 using mGluR5 -selective compounds is useful in the treatment of various pain states, including acute, persistent and chronic pain and neuropathic pain.
[0004] Modulators of mGluR5 may be also useful in the treatment of psychiatric and neurological disorders. For example, mGluR5 -selective compounds appear effective in animal models of mood disorders, including anxiety and depression. Gene expression data from humans has appeared to indicate that modulation of mGluR5 may be useful for the treatment of schizophrenia. Studies have also shown a role for mGluR5, and the potential utility of mGluR5 -modulatory compounds, in the treatment of movement disorders such as Parkinson's disease, and other research supports a role for mGluR5 modulation in the treatment of cognitive dysfunction, epilepsy, and neuroprotection. Studies with mGluR5 knockout mice and MPEP also suggest that modulation of these receptors may be useful in the treatment of drug addiction, drug abuse and drug withdrawal.
[0005] Accordingly, compounds and methods for modulating the activity of mGluR5 are needed to address the treatment of these and other diseases and conditions.
SUMMARY
[0006] This disclosure is generally directed to compounds which may be negative allosteric modulators of metabotropic receptors-subtype 5, and their use as, for example, medicinal agents. Also provided are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier.
[0007] In an embodiment, provided herein are compounds represented by formula
VII, and compositions comprising such compounds. Also provided herein are methods of treating disorders such as Alzheimer's disease, Fragile X syndrome, L-DOPA induced dyskinesia, depression, anxiety, migraine, pain, gastroesophageal reflux disease, and/or aiding smoking cessation comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula VII:
Figure imgf000003_0001
and pharmaceutically acceptable salts or N-oxides thereof, wherein: each W is independently N or CR1;
V is N or CR2;
X is selected from the group consisting of: O, S, SO2, N, NR4, CR5, CR5R6, and CO; each T is independently selected from the group consisting of: CO, CR7Rs, and NRg; U is selected from the group consisting of: C, CR1O, and N;
Y is selected from the group consisting of: NR11, O, and CR12; Z is selected from the group consisting of: N, NR13, and O; A is selected from the group consisting of: -CONR16-, -NR16CO-, -CONR16-CR14R15-, -0-, -NRi6CONRi6-, -CRI4RI5-NRI6CO-, -CRI4RI5-O-, -CRi4Ri5-NRi6-, -0-CRi4Ri5-, -NRi6-
Figure imgf000004_0001
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl; wherein B is optionally substituted by one, two, or three substituents each independently represented by R3; n is O, 1 or 2; m is O, 1 or 2;
R1, R2, and R3 are each independently selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R4, R9, R11, Ri3, and Ri6 are each independently selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
R5, R6, Ri2, Ri4, and Ri5 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl;
R7 and Rs are each independently selected from the group consisting of: alkoxy, alkyl, halogen, haloalkyl, hydrogen, and hydroxyl, or R7 and Rs taken together are oxo; and
Rio is selected from the group consisting of: methyl, oxide, or hydrogen.
[0008] Treatment of diseases such as Parkinson's disease and panic disorder are also contemplated as described herein.
[0009] Another embodiment provides compounds represented by one or more of the following formulae:
Figure imgf000005_0001
in;
Figure imgf000005_0002
and pharmaceutically acceptable salts or N-oxides thereof, and in some embodiments, the substituents are defined above. Also contemplated herein are compositions that include a compound represented by one of formulas I, II, III, IV, V, and VI and e.g., a pharmaceutically acceptable excipient. [0010] The disclosure further provides methods of modulating activity of one or more metabotropic receptors-subtype 5 comprising, for example, exposing said receptor to a disclosed compound. In one embodiment, the modulator compound is a negative allosteric modulator.
[0011] Also provided herein are methods of treating a disease associated with expression or activity of one or more metabotropic receptors-subtype 5 in a patient comprising administering to the patient a therapeutically effective amount of a disclosed compound. For example, provided herein are method of treating Alzheimer's disease, Fragile X syndrome, dyskinesia such as 1-dopa induced dyskinesia, depression, anxiety, migraine, pain, gastroesophageal reflux disease, and/or aiding smoking cessation comprising administering a compound represented by I, II, III, VI, V, VI, and/or VII. Also provided are compound represented by Formula VII for use in therapy and/or for the manufacture of a medicament for the treatment of disease associated with negative metabotropic receptors- subtype 5.
DETAILED DESCRIPTION
[0012] The features and other details of the disclosure will now be more particularly described. Before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. Definitions
[0013] "Treating" includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like. [0014] The term "aldehyde" or "formyl" as used herein refers to the radical -CHO.
[0015] The term "alkanoyl" as used herein refers to a radical -O-CO-alkyl.
[0016] The term "alkenyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-Ci2alkenyl, C2-Cioalkenyl, and C2-C6alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, etc. [0017] The term "alkoxy" as used herein refers to an alkyl group attached to an oxygen (-O-alkyl-). Exemplary alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl or alkynyl group of 1-12, 1-8, or 1-6 carbon atoms, referred to herein as C1- C12alkoxy, CrCgalkoxy, and CrCβalkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, etc. Similarly, exemplary "alkenoxy" groups include, but are not limited to vinyloxy, allyloxy, butenoxy, etc.
[0018] The term "alkyl" as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as Ci-C12alkyl, Ci-Cioalkyl, and Ci-Cβalkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2 -methyl- 1 -propyl, 2- methyl-2-propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l- propyl, 2-methyl-l -pentyl, 3 -methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl -2 -pentyl, 2, 2 -dimethyl- 1 -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l- butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc. [0019] Alkyl, alkenyl and alkynyl groups can optionally be substituted with or interrupted by at least one group selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
[0020] The term "alkynyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-12, 2-8, or 2-6 carbon atoms, referred to herein as C2-C12alkynyl, C2_Cgalkynyl, and C2_C6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl- 1-butynyl, A- propyl-2-pentynyl, and 4-butyl-2-hexynyl, etc.
[0021] The term "amide" or "amido" as used herein refers to a radical of the form
-RaC(O)N(Rb)-, -RaC(O)N(Rb)Rc-, or -C(O)NRbRc, wherein Ra, Rb and Rc are each independently selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, and nitro. The amide can be attached to another group through the carbon, the nitrogen, Rb, R0, or Ra. The amide also may be cyclic, for example Rb and R0, Ra and Rb, or Ra and Rc may be joined to form a 3- to 12-membered ring, such as a 3- to 10- membered ring or a 5- to 6-membered ring. The term "carboxamido" refers to the structure -C(O)NRbRc.
[0022] The term "amidino" as used herein refers to a radical of the form
-C(=NR)NR'R" where R, R', and R" can each independently be selected from alkyl, alkenyl, alkynyl, amide, aryl, arylalkyl, cyano, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone and nitro.
[0023] The term "amine" or "amino" as used herein refers to a radical of the form
-NRdRe, -N(Rd)Re-, or -R6N(Rd)Rr where Rd, Rs, and Rf are independently selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, and nitro. The amino can be attached to the parent molecular group through the nitrogen, Rj, Re or Rf. The amino also may be cyclic, for example any two of Rd, Re or Rf may be joined together or with the N to form a 3- to 12-membered ring, e.g., morpholino or piperidinyl. The term amino also includes the corresponding quaternary ammonium salt of any amino group, e.g., -[N(Rd)(Re)(Rf)]+. Exemplary amino groups include aminoalkyl groups, wherein at least one of Rd, Rs, or Rf is an alkyl group.
[0024] The term "aryl" as used herein refers to refers to a mono-, bi-, or other multi- carbocyclic, aromatic ring system. The aromatic ring may be substituted at one or more ring positions with substituents selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. [0025] The term "arylalkyl" as used herein refers to an aryl group having at least one alkyl substituent, e.g. -aryl-alkyl-. Exemplary arylalkyl groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms. For example, "phenylalkyl" includes phenylC4alkyl, benzyl, 1 -phenylethyl, 2- phenylethyl, etc. [0026] The term "azido" as used herein refers to the radical -N3.
[0027] The term "carbamate" as used herein refers to a radical of the form
-RgOC(O)N(Rh)-, -Rg0C(0)N(Rh)Ri_, or -0C(0)NRhRi, wherein Rg? Rh and R[ are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, sulfide, sulfonyl, and sulfonamide. Exemplary carbamates include, but are not limited to, arylcarbamates or heteroaryl carbamates, e.g., wherein at least one of Rg Rf1 and R[ are independently selected from aryl or heteroaryl, such as phenyl and pyridinyl.
[0028] The term "carbonyl" as used herein refers to the radical -C(O)-.
[0029] The term "carboxamido" as used herein refers to the radical -C(O)NRR', where R and R' may be the same or different. R and R' may be selected from, for example, alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl and heterocyclyl.
[0030] The term "carboxy" as used herein refers to the radical -COOH or its corresponding salts, e.g. -COONa, etc.
[0031] The term "cyano" as used herein refers to the radical -CN.
[0032] The term "cycloalkoxy" as used herein refers to a cycloalkyl group attached to an oxygen.
[0033] The term "cycloalkyl" as used herein refers to a monovalent saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C4_8cycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, cyclopentenes, cyclobutanes and cyclopropanes. Cycloalkyl groups may be substituted with alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups.
[0034] The term "ether" refers to a radical having the structure -RiO-Rm-, where Ri and Rm can independently be alkyl, aryl, cycloalkyl, heterocyclyl, or ether. The ether can be attached to the parent molecular group through Ri or Rm. Exemplary ethers include, but are not limited to, alkoxyalkyl and alkoxyaryl groups. Ether also includes polyethers, e.g., where one or both of Ri and Rm are ethers. [0035] The terms "halo" or "halogen" or "Hal" as used herein refer to F, Cl, Br, or I.
[0036] The term "haloalkyl" as used herein refers to an alkyl group substituted with one or more halogen atoms.
[0037] The terms "heteroaryl" as used herein refers to a 5-15 membered mono-, bi-, or other multi-cyclic, aromatic ring system containing one or more heteroatoms, for example one to four heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can also be fused to non-aromatic rings. The heteroaryl ring may be substituted at one or more positions with such substituents as described above, as for example, alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl. Illustrative examples of heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuryl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyrazyl, pyridazinyl, pyridinyl, pyrimidilyl, pyrimidyl, pyrrolyl, quinolinyl, quinolizinyl, quinoxalinyl, quinoxaloyl, quinazolinyl, tetrazolyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiophenyl, triazinyl, (1,2,3,)- and (l,2,4)-triazolyl, and the like. Exemplary heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms.
[0038] The terms "heterocyclyl" or "heterocyclic group" are art-recognized and refer to saturated or partially unsaturated 3- to 10-membered ring structures, alternatively 3- to 7- membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur. Heterocycles may also be mono-, bi-, or other multi-cyclic ring systems. A heterocycle may be fused to one or more aryl, partially unsaturated, or saturated rings. Heterocyclyl groups include, for example, biotinyl, chromenyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, thiazolidinyl, thiolanyl, thiomorpholinyl, thiopyranyl, xanthenyl, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with substituents such as alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
[0039] The term "heterocycloalkyl" is art-recognized and refers to a saturated heterocyclyl group as defined above.
[0040] The term "heterocyclylalkoxy" as used herein refers to a heterocyclyl attached to an alkoxy group.
[0041] The term "heterocyclyloxyalkyl" refers to a heterocyclyl attached to an oxygen (-O-), which is attached to an alkyl group.
[0042] The terms "hydroxy" and "hydroxyl" as used herein refers to the radical -OH.
[0043] The term "hydroxyalkyl" as used herein refers to a hydroxy radical attached to an alkyl group.
[0044] The term "imino" as used herein refers to the radical -C(=N)-R' ' , where R' ' can be, for example, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, heterocyclyl, and ketone.
[0045] The term "nitro" as used herein refers to the radical -NO2.
[0046] The term "phenyl" as used herein refers to a 6-membered carbocyclic aromatic ring. The phenyl group can also be fused to a cyclohexane or cyclopentane ring. Phenyl can be substituted with one or more substituents including alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
[0047] The term "phosphate" as used herein refers to the radical -OP(O)(ORaa)2 or its anions. The term "phosphanato" refers to the radical - P(O)(ORaa)2 or its anions. The term "phosphinato" refers to the radical -PRaa(O)(ORaa) or its anion, where each Raa can be selected from, for example, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, hydrogen, haloalkyl, heteroaryl, and heterocyclyl.
[0048] The term "sulfate" as used herein refers to the radical -OS(O)(ORaa)2 or its anions, where Raa is defined above. [0049] The term "sulfonamide" as used herein refers to a radical having the structure
-N(Rr)-S(O)2-Rs- or -S(O)2-N(Rr)Rs, where Rr, and R8 can be, for example, hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl. Exemplary sulfonamides include alkylsulfonamides (e.g., where R8 is alkyl), arylsulfonamides (e.g., where R8 is aryl), cycloalkyl sulfonamides
(e.g., where R8 is cycloalkyl), and heterocyclyl sulfonamides (e.g., where R8 is heterocyclyl), etc.
[0050] The term "sulfonyl" as used herein refers to a radical having the structure
RuSθ2", where Ru can be alkyl, aryl, cycloalkyl, and heterocyclyl, e.g., alkylsulfonyl. The term "alkylsulfonyl" as used herein refers to an alkyl group attached to a sulfonyl group. [0051] The term "sulfide" as used herein refers to the radical having the structure
R2S-, where R2 can be alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, and ketone. The term "alkylsulfϊde" as used herein refers to an alkyl group attached to a sulfur atom. Exemplary sulfides include "thio," which as used herein refers to an -SH radical. [0052] The term "thiocarbonyl" or "thiocarboxy" as used herein refers to compounds and moieties which contain a carbon connected with a double bond to a sulfur atom. [0053] "Pharmaceutically or pharmacologically acceptable" include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. "For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.
[0054] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
[0055] The term "pharmaceutical composition" as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
[0056] "Individual," "patient," or "subject" are used interchangeably and include to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the invention can be administered to a mammal, such as a human, but can also be other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). The mammal treated in the methods of the invention is desirably a mammal in whom modulation of metabotropic receptors-subtype 5 is desired. "Modulation" includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
[0057] In the present specification, the term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the invention are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the prevention of or a decrease in the symptoms associated with a disease associated with metabotropic receptors-subtype 5. [0058] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,/?-toluenesulfonate and pamoate (i.e., 1 , 1 '-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. [0059] The compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term "stereoisomers" when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols "R" or "S," depending on the configuration of substituents around the stereogenic carbon atom. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated "(±)" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. [0060] Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
[0061] Geometric isomers can also exist in the compounds of the present invention.
The symbol ^≡≡r denotes a bond that may be a single, double or triple bond as described herein. The present invention encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration wherein the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers. [0062] Substituents around a carbon-carbon double bond alternatively can be referred to as "cis" or "trans," where "cis" represents substituents on the same side of the double bond and "trans" represents substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring are designated as "cis" or "trans." The term "cis" represents substituents on the same side of the plane of the ring and the term "trans" represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated "cis/trans."
[0063] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a polymorph. In another embodiment, the compound is in a crystalline form.
[0064] The invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36Cl, respectively. [0065] Certain isotopically-labeled disclosed compounds (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon- 14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the e.g., Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. [0066] The term "prodrug" refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood. For example, if a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as
Figure imgf000015_0001
(C2-C 12)alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, (U-N5N-(C1- C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N5N- di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2- C3)alkyl.
[0067] Similarly, if a compound of the invention contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1 -methyl- 1 -((C i -C6)alkanoyloxy)ethyl (C i -C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-C6)alkanoyl, α-amino(C1-C4)alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(ci-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
[0068] If a compound of the invention incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C1-C10)alkyl5 (C3-C7)cycloalkyl, benzyl, or R-carbonyl is a natural α- aminoacyl or natural α-aminoacyl-natural α-aminoacyl, — C(OH)C(O)OY1 wherein Y1 is H, (Ci-C6)alkyl or benzyl, -C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (Ci-C6)alkyl, carboxy(Ci-C6)alkyl, amino(C1-C4)alkyl or mono-N — or (U-N5N — (C1-C6)alkylaminoalkyl, — C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N— or di-N,N— (C1-C6)alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.
[0069] The disclosure provides, at least in part, compounds represented by formula
VII, as depicted below. Also contemplated herein are compositions that include a compound represented by formula VII and e.g., a pharmaceutically acceptable carrier. In an embodiment, provided herein is a method of treating Alzheimer's disease, Fragile X syndrome, L-DOPA induced dyskinesia, depression, anxiety, migraine, pain, gastroesophageal reflux disease, and/or aiding smoking cessation comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula VII:
Figure imgf000017_0001
VII and pharmaceutically acceptable salts or N-oxides thereof, wherein: each W is independently N or CR1;
V is N or CR2;
X is selected from the group consisting of: O, S, SO2, N, NR4, CR5, CR5R6, and CO; each T is independently selected from the group consisting of: CO, CR7Rs1 and NR9; U is selected from the group consisting of: C, CR1O, and N;
Y is selected from the group consisting of: N, NR11, O, and CR12; Z is selected from the group consisting of: N, NR13, and O;
A is selected from the group consisting of: -CONR16-, -NR16CO-, -0-, -CONR16- CRi4R15-, -0-, -NRi6CONRi6-, -CRI4RI5-NRI6CO-, -CRI4RI5-O-, -CRi4Ri5-NRi6-, -O-
CRi4Ri5-, -NRi6-CRi4Ri5-, -NRi6-,
Figure imgf000017_0002
;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl; wherein B is optionally substituted by one, two, or three substituents each independently represented by R3; n is O, 1 or 2; m is O, 1 or 2;
Ri, R2, and R3 are each independently selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R4, R9, R11, Ro, and R16 are each independently selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
R5, R6, R12, R14, and R1S are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl;
R7 and R8 are each independently selected from the group consisting of: alkoxy, alkyl, halogen, haloalkyl, hydrogen, and hydroxyl, or R7 and R8 taken together are oxo; or R7 and R8 taken together form a carbocycle or a heterocycle; and
R1O is selected from the group consisting of: methyl, oxide, or hydrogen. [0070] In one embodiment, B can be selected from:
Figure imgf000018_0001
or
[0071] In some embodiments, one or two W are N, or each W and V are C. R1 and R2 may be, in some embodiments, each independently selected from the group consisting of: alkyl, halogen, and hydrogen, for example, R1 and R2 may be each independently selected from the group consisting of: chloro, fluoro, hydrogen, and methyl.
[0072] In some embodiments, R11 is optionally substituted by one, two, three or more substituents selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, or alkoxy.
[0073] X, in certain embodiments, may be selected from the group consisting of: O,
S, SO2, N-alkanoyl, NH, NMe, CH2, CF2, CMe2, CHOH, and CO. In another embodiment, T may selected from the group consisting of: CO, CH2, CMe2, NH, and NMe. The integer n, in a specific embodiment, may be 1 or 2. In an embodiment, U, Y, and Z may be chosen from one of the following groups:
A) U is C, Y is N-alkyl or NH, and Z is N;
B) U is C, Y is N, and Z is N-alkyl; C) U is N, Y is CH or C-alkyl, and Z is N;
D) U is C, Y is O, and Z is N; and
E) U is C, Y is N, and Z is O.
For example, U may be C, Y is NMe, and Z is N.
[0074] In an embodiment, A may be selected from the group consisting of: -CONH-,
-CONMe-, -CH2-NH-, -CH2-NEt-, -CMe2-NH-, -CMe2-O-, -CHMe-O-, -CHMe-NH-,
Figure imgf000019_0001
m is 0, -NH-CHMe-, -0-CHMe-, -NH-, and -CONH-CH2-, for example, A may be -CONH-.
[0075] In an embodiment, R1, R2, and R3 are each independently selected from the group consisting of: bromo, carboxamido, chloro, chlorophenyl, cyano, cyclopropyl, diethoxyphenyl, diethylaminoethoxycarbonyl, diethylaminosulfonyl, ethoxycarbonyl, ethoxyphenyl, ethyl, ethylpiperazinylmethylphenyl, fluoro, fluorophenyl, hydrogen, isopropyl, methoxy, methoxycarbonyl, methyl, methylcarbonyl, methylpiperadinylmethylphenyl, methylpiperazinyl, methylthio, nitro, phenyl, piperidinylsulfonyl, sulfonamido, and trifluoromethyl [0076] One embodiment provides a compound represented by formula I:
Figure imgf000019_0002
and pharmaceutically acceptable salts or N-oxides thereof; wherein
V1, V2, V3, and V4 are selected, independently for each occurrence, from the group consisting of: N and CR2;
X is NR4 or CR7R8;
Y and Z are each independently selected from the group consisting of: NR11 and N;
T is CO or CR7R8, wherein at least one T is CR7R8; n is 0, 1 or 2; A is selected from the group consisting of: -CONR16-, -NR16CO-, -0-, -CONRi6-CRi4R15-, -NRi6CONRi6-, -CRI4RI5-NRI6CO-, -CRI4RI5-O-, -CRi4Ri5-
NRi6-, -0-CRi4Ri5-, -NRi6-CRi4Ri5-, -NRi6-,
Figure imgf000020_0001
and
Figure imgf000020_0002
m is O, 1 or 2;
R2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl, wherein B is optionally substituted by one, two, or three substituents each independently represented by R3;
R3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
R7 and R8 are each independently selected from the group consisting of: alkoxy, alkyl, halogen, haloalkyl, hydrogen and hydroxyl, or R7 and R8 taken together are oxo; or R7 and R8 taken together form a carbocycle or a heterocycle;
Rn is selected from the group consisting of: alkyl, cycloalkyl, or haloalkyl;
Ri6 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and R14 and R15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl. [0077] In one embodiment, B can be selected from:
Figure imgf000021_0001
or
[0078] In one embodiment, each of V1, V2, V3, and V4 can be CR2. In another embodiment, each OfV1, V2, and V3 can be CR2, and V4 can be N. In another exemplary embodiment, each OfV1, V2, and V4 is CR2, and V3 is N.
[0079] In another embodiment, R11 is C^alkyl and/or R4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen. T, in some embodiments, may be CH2 or CF2. In some embodiments, R11 is optionally substituted by one, two, three or more substituents selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, or alkoxy. [0080] X, in some embodiments, may be X is NR4 or may be CR7Rs. In some embodiments, X is selected from the group consisting of: CH2, CHOH, and CO. T is CH2.
[0081] The integer n may be, in some embodiments, 1 or 2.
[0082] A, in some embodiments, may be for example -CONR16- or -CR14R1S-NR16-, wherein, in a specific embodiment, R16 may be hydrogen or methyl.
[0083] Another embodiment provides a compound represented by formula II:
Figure imgf000021_0002
and pharmaceutically acceptable salts or N-oxides thereof; wherein
V1, V2, V3, and V4 are selected, independently for each occurrence, from the group consisting of: N and CR2;
T is CO or CR7Rg, wherein at least one T is CR7R8; n is 0, 1 or 2; A is selected from the group consisting of: -CONR16-, -NR16CO-, -0-, -CONRi6-CRi4R15-, -NRi6CONRi6-, -CRI4RI5-NRI6CO-, -CRI4RI5-O-, -CRi4Ri5-
NRi6-, -0-CRi4Ri5-, -NRi6-CRi4Ri5-, -NRi6-,
Figure imgf000022_0001
and
Figure imgf000022_0002
m is O, 1 or 2;
R2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl wherein B is optionally substituted by one, two, or three substituents each independently represented by R3;
R3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
Rn is selected from the group consisting of: alkyl, cycloalkyl, alkanoyl, aryl, heteroaryl, or heterocyclyl;
Ri6 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and
Ri4 and Ri5 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl. In one embodiment, B can be selected from:
Figure imgf000023_0001
or
[0085] In one embodiment, each of V1, V2, V3, and V4 can be CR2. In another embodiment, each OfV1, V2, and V3 can be CR2, and V4 can be N. In another exemplary embodiment, each OfV1, V2, and V4 is CR2, and V3 is N.
[0086] In another embodiment, R11 is C^alkyl and/or R4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen. T, in some embodiments, may be CH2 or CF2.
In some embodiments, R11 is optionally substituted by one, two, three or more substituents selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, or alkoxy.
[0087] The integer n may be, in some embodiments, 1 or 2.
[0088] A, in some embodiments, may be for example -CONR16- or -CR14R1S-NR16-, wherein, in a specific embodiment, R16 may be hydrogen or methyl.
[0089] Another embodiment provides a compound represented by formula III:
Figure imgf000023_0002
III and pharmaceutically acceptable salts or N-oxides thereof; wherein
V1, V2, V3, and V4 are selected, independently for each occurrence, from the group consisting of: N and CR2;
T is CO or CR7R8, wherein at least one T is CR7Rs; n is 0, 1 or 2;
A is selected from the group consisting of: -CONR16-, -NR16CO-, -O-, -CONRI6-CRI4RI5-, -NRI6CONRI6-, -CRI4RI5-NRI6CO-, -CRI4RI5-O-, -CRi4Ri5-
NRi6-, -0-CRi4Ri5-, -NRi6-CRi4Ri5-, -NRi6-,
Figure imgf000023_0003
and
Figure imgf000023_0004
m is 0, 1 or 2;
R2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl wherein B is optionally substituted by one, two, or three substituents each independently represented by R3;
R3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R7 and R8 are each independently selected from the group consisting of: alkyl, halogen, haloalkyl, and hydrogen; or R7 and R8 taken together form a carbocycle or a heterocycle;
R11 is selected from the group consisting of: alkyl, cycloalkyl, alkanoyl, aryl, heteroaryl, or heterocyclyl;
R16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and
R14 and R1S are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl. In one embodiment, B can be selected from:
Figure imgf000024_0001
or [0091] In one embodiment, each OfV1, V2, V3, and V4 can be CR2. In another embodiment, each OfV1, V2, and V3 can be CR2, and V4 can be N. In another exemplary embodiment, each OfV1, V2, and V4 is CR2, and V3 is N. In some embodiments, R11 is optionally substituted by one, two, three or more substituents selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, or alkoxy.
[0092] In another embodiment, R11 is C^alkyl and/or R4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen. T, in some embodiments, may be CH2 or CF2.
[0093] The integer n may be, in some embodiments, 1 or 2.
[0094] A, in some embodiments, may be for example -CONR16- or -CR14R1S-NR16-, wherein, in a specific embodiment, R16 may be hydrogen or methyl.
[0095] Another embodiment provides a represented by formula IV:
Figure imgf000025_0001
and pharmaceutically acceptable salts thereof; wherein
V1, V2, V3, and V4 are selected, independently for each occurrence, from the group consisting of: N and CR2;
X is selected from the group consisting of: O, SO2, NR4 and CR7R8;
T is CO or CR7R8, wherein at least one T is CR7R8; n is 0, 1 or 2;
A is selected from the group consisting of: -CONR16-, -NR16CO-, -O-, -CONR16-CR14R15-, -NR16CONR16-, -CR14R15-NR16CO-, -CR14R15-O-, -CR14R15-
NR16-, -0-CR14R15-, -NR16-CR14R15-, -NR16-,
Figure imgf000025_0002
m is 0, 1 or 2;
R2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl, wherein B is optionally substituted by one, two, or three substituents each independently represented by R3;
R3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
R7 and R8 are each independently selected from the group consisting of: alkoxy, alkyl, halogen, haloalkyl, hydrogen and hydroxyl, or R7 and R8 taken together are oxo; or R7 and R8 taken together form a carbocycle or a heterocycle;
R11 is selected from the group consisting of: alkyl, cycloalkyl, or haloalkyl;
R16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and
R14 and R1S are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl. [0096] In one embodiment, B can be selected from:
Figure imgf000026_0001
or
[0097] In one embodiment, each of V1, V2, V3, and V4 can be CR2. In another embodiment, each OfV1, V2, and V3 can be CR2, and V4 can be N. In another exemplary embodiment, each OfV1, V2, and V4 is CR2, and V3 is N. [0098] In another embodiment, R11 is C^aUcyl and/or R4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen. In some embodiments, R11 is optionally substituted by one, two, three or more substituents selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, or alkoxy. T, in some embodiments, may be CH2 or CF2.
[0099] X, in some embodiments, may be X is NR4 or may be CR7Rs. In some embodiments, X is selected from the group consisting of: CH2, CHOH, and CO. T is CH2.
[00100] The integer n may be, in some embodiments, 1 or 2.
[00101] A, in some embodiments, may be for example -CONR16- or -CR14R1S-NR16-, wherein, in a specific embodiment, R16 may be hydrogen or methyl.
[00102] Another embodiment provides a compound represented by formula V:
Figure imgf000027_0001
and pharmaceutically acceptable salts or N-oxides thereof; wherein
V1, V2, V3, and V4 are selected, independently for each occurrence, from the group consisting of: N and CR2;
T is CO or CR7Re, wherein at least one T is CR7Rs; n is 0, 1 or 2;
A is selected from the group consisting of: -CONR16-, -NR16CO-, -O-, -CONRi6-CRi4R15-, -NRi6CONRi6-, -CRI4RI5-NRI6CO-, -CRI4RI5-O-, -CRi4Ri5-
NRi6-, -0-CRi4Ri5-, -NRi6-CRi4Ri5-, -NRi6-,
Figure imgf000027_0002
and m is 0, 1 or 2;
R2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl, optionally substituted by one, two or three substituents each independently represented by R3;
R3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
R7 and R8 are each independently selected from the group consisting of: alkyl, halogen, haloalkyl, and hydrogen; or R7 and R8 taken together are oxo; or R7 and R8 taken together form a carbocycle or a heterocycle;
R16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and
R14 and R15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl. [00103] In one embodiment, B can be selected from:
Figure imgf000028_0001
or
[00104] In one embodiment, each of V1, V2, V3, and V4 can be CR2. In another embodiment, each OfV1, V2, and V3 can be CR2, and V4 can be N. In another exemplary embodiment, each OfV1, V2, and V4 is CR2, and V3 is N.
[00105] In another embodiment, R4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen. T, in some embodiments, may be CH2 or CF2. [00106] The integer n may be, in some embodiments, 1 or 2.
[00107] A, in some embodiments, may be for example -CONR16- or -CR14RiS-NR16-, wherein, in a specific embodiment, R16 may be hydrogen or methyl
[00108] Another claim embodiment provides a compound represented by formula VI:
Figure imgf000029_0001
and pharmaceutically acceptable salts or N-oxides thereof; wherein
Vi, V2, V3, and V4 are selected, independently for each occurrence, from the group consisting of: N and CR2;
X is selected from the group consisting of: NR4, S, SO2, and CR7R8;
T is CO or CR7R8, wherein at least one T is CR7R8; n is 0, 1 or 2;
A is selected from the group consisting of: -CONRi6-, -NRi6CO-, -O-, -CONRI6-CRI4RI5-, -NRI6CONRI6-, -CRI4RI5-NRI6CO-, -CRI4RI5-O-, -CRi4Ri5-
NRi6-, -0-CRi4Ri5-, -NRi6-CRi4Ri5-, -NRi6-,
Figure imgf000029_0002
and 'm ; m is 0, 1 or 2;
R2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl, wherein B is optionally substituted by one, two or three substituents each selected from R3; R3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
R7 and R8 are each independently selected from the group consisting of: alkyl, halogen, haloalkyl, and hydrogen, or R7 and R8 taken together are oxo; or R7 and R8 taken together form a carbocycle or a heterocycle;
R11 is alkyl;
R16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and
R14 and R15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl. [00109] In one embodiment, B can be selected from:
Figure imgf000030_0001
or
[00110] In one embodiment, each of V1, V2, V3, and V4 can be CR2. In another embodiment, each OfV1, V2, and V3 can be CR2, and V4 can be N. In another exemplary embodiment, each OfV1, V2, and V4 is CR2, and V3 is N.
[00111] In another embodiment, R11 is Ci_3alkyl and/or R4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen. T, in some embodiments, may be CH2 or CF2.
[00112] X, in some embodiments, may be X is NR4 or may be CR7R8. In some embodiments, X is selected from the group consisting of: CH2, CHOH, and CO. The integer n may be, in some embodiments, 1 or 2.
[00113] A, in some embodiments, may be for example -CONR16- or -CR14R1S-NR16-, wherein, in a specific embodiment, R16 may be hydrogen or methyl. [00114] Contemplated compounds, and pharmaceutical compositions,comprising at least one compound, may be selected from the group consisting of: N-(3-chlorophenyl)-l- methyl-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide; 8-chloro-N-(3-chlorophenyl)-l- methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3-chlorophenyl)-8-fluoro-2- methyl-2,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(4-chloropyridin-2-yl)-l- methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3-chlorophenyl)-8-fluoro-l- methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3-chlorophenyl)- 1,4,4- trimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; 7-fluoro-l-methyl-N-(6- methylpyridin-2-yl)- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; 3-chloro-N-((l - methyl-l,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methyl)aniline; l-methyl-N-(6- methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; N-(6- methylpyridin-2-yl)- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(4- cyanopyridin-2-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide; (2H-benzo[b][l,4]oxazin-4(3H)-yl)(l -methyl- l,4-dihydrochromeno[4, 3- c]pyrazol-3-yl)methanone; 5-acetyl-N-(3-chlorophenyl)-l-methyl-4,5-dihydro-lH- pyrazolo[4,3-c]quinoline-3-carboxamide; N-(3-chlorophenyl)-l-methyl-lH-pyrazolo[4,3- c]quinoline-3-carboxamide; N-(3-chlorophenyl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3- c] quinoline-3 -carboxamide; 5 -bromo-N-ethyl-N-(( 1 -methyl- 1 ,4-dihydrochromeno [4,3 - c]pyrazol-3-yl)methyl)furan-2-carboxamide; l-isopropyl-N-(6-methylpyridin-2-yl)-4,5- dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; 1 -ethyl -N-(6-methylpyridin-2-yl)-4,5- dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)- 1 ,4,5,6,7,8-hexahydro-7,8-(2-pyridino)cyclohepta[c]pyrazole-3-carboxamide; 1 ,8-dimethyl- N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; 1- methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]isoquinoline-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline- 3 -carboxamide; 1 ,5-dimethyl-N-(6-methylpyridin-2-yl)-l ,4,5,6-tetrahydropyrazolo[4,3- c]pyrido[2,3-e]azepine-3-carboxamide; 1 ,6-dimethyl-N-(6-methylpyridin-2-yl)-l ,4,5,6- tetrahydropyrazolo [3, 4-d]pyrido [3, 2-b]azepine-3 -carboxamide; 1 -methyl -N-(6- methylpyridin-2-yl)-6-oxo-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3-c]azepine-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-l,4,5,6-tetrahydrobenzo[b]pyrazolo[3,4-d]azepine- 3 -carboxamide; 5,5-difluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH- pyrazolo[4,3-h]quinoline-3-carboxamide; 5,5-difluoro-l-methyl-N-(6-methylpyridin-2-yl)- 4,5-dihydro-lH-benzo[g]indazole-3-carboxamide; l,6-dimethyl-N-(6-methylpyridin-2-yl)- 1 ,4,5,6-tetrahydrobenzo[b]pyrazolo[3,4-d]azepine-3-carboxamide; 1 ,5-dimethyl-N-(6- methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-c]quinoline-3-carboxamide; 8-fluoro-l,5- dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-c]quinoline-3-carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3-c]azepine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro-lH-pyrazolo[4,3- h]quinoline-3-carboxamide; 1 -methyl-N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1 ,5- d] [ 1 ,4]oxazine-3-carboxamide; 1 -methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro- IH- pyrazolo[4,3-h]quinoline-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4H- benzo[b]imidazo[l,5-d][l,4]oxazine-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5- oxo-4,5-dihydro-lH-pyrazolo[4,3-c]isoquinoline-3-carboxamide; l,5-dimethyl-N-(6- methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-c][l,5]naphthyridine-3-carboxamide; 9- fluoro-l-methyl-N-(6-methylpyridin-2-yl)-6-oxo-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3- c]azepine-3 -carboxamide; l,5,5-trimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH- pyrazolo[4,3-h]quinoline-3-carboxamide; l-methyl-N-(6-(trifluoromethyl)pyridin-2-yl)-4,5- dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)- 4,5-dihydro-lH-pyrazolo[3,4-f]quinoxaline-3-carboxamide; 9-fluoro-l-methyl-N-(6- methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline-3-carboxamide; 8-fluoro-l- methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline-3-carboxamide; 7-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; 6-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- h]quinoline-3 -carboxamide; N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1,5- d] [ 1 ,4]oxazine-3-carboxamide; N-(6-cyclopropylpyridin-2-yl)- 1 -methyl-4,5 -dihydro- 1 H- pyrazolo[4,3-h]quinoline-3-carboxamide; l-methyl-N-(l-methyl-5-phenyl-lH-pyrrol-2-yl)- 4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; 6-methyl-N-(2-(l -methyl-4,5 - dihydro-lH-pyrazolo[4,3-h]quinolin-3-yl)propan-2-yl)pyridin-2-amine; 3-(2-(3- chlorophenoxy)propan-2-yl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline; 6-methyl- N-(l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-yl)picolinamide; 3-(l-(3- chlorophenoxy)ethyl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline; 6-cyclopropyl-N- ( 1 -( 1 -methyl-4,5 -dihydro- 1 H-pyrazolo [4,3 -h] quinolin-3 -yl)ethyl)pyridin-2-amine; 1 -methyl- N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydro-6,7-(2-pyridino)cyclopenta[c]pyrazole-3- carboxamide; l-methyl-N-(2-methylpyrimidin-4-yl)-4,5-dihydro-lH-pyrazolo[4,3- h]quinoline-3 -carboxamide; l-methyl-N-(6-methylpyrazin-2-yl)-4,5-dihydro-lH- pyrazolo[4,3-h]quinoline-3-carboxamide; 9-fluoro-l -methyl -N-(6-methylpyridin-2-yl)-5-oxo- l,4,5,6-tetrahydrobenzo[b]pyrazolo[3,4-d]azepine-3-carboxamide; l-methyl-N-(6- methylpyridin-2-yl)-4,5,7,8-tetrahydrobenzo-lH-oxepino[4,5-c]pyrazole-3-carboxamide; 1- methyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3-c]azepine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5,7,8-tetrahydrobenzo-lH-thiepino[4,5- c]pyrazole-3-carboxamide; 1 -methyl -N-(6-methylpyridin-2-yl)-6-dioxo-4,5, 7, 8-tetrahydro- 7,8-(2-pyridino)-lH-thiepino[4,5-c]pyrazole-3-carboxamide; l-methyl-3-(l-(6- methylpyridin-2-yl)azetidin-3-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline; l-methyl-N-(6- methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-amine; l-methyl-N-(l-(6- methylpyridin-2-yl)ethyl)-4,5 -dihydro- 1 H-pyrazolo [4,3 -h] quinolin-3 -amine; 1 -methyl-3 -( 1 - (6-methylpyridin-2-yl)ethoxy)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline; l-methyl-N-(6- methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]isoquinoline-3-carboxamide; 5-hydroxy- l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide; 1- methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-6- hydroxybenzocyclohepta[c]pyrazole-3-carboxamide; 1 -methyl -N-(6-methylpyridin-2-yl)- 1,4,5,6, 7, 8-hexahydro-6,6-difluorobenzocyclohepta[c]pyrazole-3-carboxamide; 5-hydroxy-l- methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-6-hydroxy-7,8-(2- pyridino)cyclohepta[c]pyrazole-3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)- l,4,5,6,7,8-hexahydro-6,6-difluoro-7,8-(2-pyridino)cyclohepta[c]pyrazole-3-carboxamide; N- (3-chlorophenyl)-N-methyl-4H-chromeno[3,4-d]isoxazole-3-carboxamide; l-methyl-N-(3- (trifluoromethyl)phenyl)- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3- chlorophenyl)-N, 1 -dimethyl- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(2- chlorophenyl)- 1 -methyl- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(4- chlorophenyl)- 1 -methyl- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(4- chlorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide; N-(pyridin-3-yl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3-methoxyphenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(4-methoxyphenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3-chlorophenyl)- 1 ,8-dimethyl- 1 ,4- dihydrothiochromeno[4,3-c]pyrazole-3-carboxamide; N-(4-fluorophenyl)-l -methyl- 1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3-chloro-4-fluorophenyl)- 1 -methyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(5-chloro-2-methoxyphenyl)-l-methyl- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3-methoxyphenyl)- 1 -methyl- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(5-chloropyridin-2-yl)- 1 -methyl- 1 ,A- dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3-chlorophenyl)-l -methyl- 1,4- dihydrothiochromeno[4,3-c]pyrazole-3-carboxamide; N-(3-chlorobenzyl)-l -methyl- 1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3-chlorophenyl)- 1 -methyl-4,5-dihydro- lH-thieno[2,3-g]indazole-3-carboxamide; N-(3-chlorophenyl)-4H-thiochromeno[3,4- d]isoxazole-3-carboxamide; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 - methyl-N-(6-methyl-2-pyridinyl)-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4- dihydro- 1 -methyl -N-2-pyridinyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(3- fluorophenyl)-5-isoxazolyl]- 1 ,4-dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3- carboxamide, N-[3-(2-ethoxyphenyl)-5-isoxazolyl]- 1 ,4-dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-(5-methyl-2- pyridinyl)-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(4-ethoxyphenyl)-5- isoxazolyl]-l,4-dihydro-l -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(3- chlorophenyl)-5-isoxazo IyI] -1,4-dihydro-l -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3- carboxamide, l,4-dihydro-l-methyl-N-3-pyridinyl-; l-methyl-N-(5-methylisoxazol-3-yl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide; [l]Benzopyrano[4,3-c]pyrazole-3- carboxamide, N-(3,5-dimethylphenyl)-l,4-dihydro-l-methyl-; Benzoic acid, 4-[[(l,4- dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3-yl)carbonyl]amino]-, methyl ester; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(3,4-diethoxyphenyl)-5-isoxazolyl]- 1 ,4-dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[4-[(4-ethyl-l - piperazinyl)methyl]phenyl]-l ,4-dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3- carboxamide, l,4-dihydro-l-methyl-N-[4-[(4-methyl-l-piperidinyl)methyl]phenyl]-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-[4-(l - piperidinylsulfonyl)phenyl]-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[4- [(diethylamino)sulfonyl]phenyl]- 1,4-dihydro-l -methyl-; l,3-Benzodioxole-5-carboxylic acid, 6-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3-yl)carbonyl]amino]-, methyl ester; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-(4-methyl-2-oxo- 2H-l-benzopyran-7-yl)-; 2-Thiophenecarboxylic acid, 3-[[(l,4-dihydro-l- methyl[ 1 ]benzopyrano[4,3-c]pyrazol-3-yl)carbonyl]amino]-, methyl ester; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,5-difluorophenyl)-l,4-dihydro-l- methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-acetylphenyl)- 1,4-dihydro-l - methyl-; Benzoic acid, 4-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, ethyl ester; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[4- (aminosulfonyl)phenyl]- 1 ,4-dihydro-l -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3- carboxamide, N-(4-chlorophenyl)-l,4-dihydro-l -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3- carboxamide, N-(2-chlorophenyl)-l,4-dihydro-l -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3- carboxamide, N-(2-cyanophenyl)- 1 ,4-dihydro-l -methyl-; N-(2-carbamoylphenyl)- 1 -methyl- l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; [l]Benzopyrano[4,3-c]pyrazole-3- carboxamide, 1 ,4-dihydro-N-(4-methoxyphenyl)- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole- 3-carboxamide, N-(2-chloro-3-pyridinyl)-l,4-dihydro-l -methyl-; [l]Benzopyrano[4,3- c]pyrazole-3 -carboxamide, N-(4-acetylphenyl)- 1 ,4-dihydro-l -methyl-; 1,3- Benzenedicarboxylic acid, 5-[[(l ,4-dihydro- 1 -methyl[ 1 ]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, 1,3-dimethyl ester; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N- (2-ethylphenyl)-l,4-dihydro-l -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1,4- dihydro-1 -methyl -N-(2-methylphenyl)-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1,4- dihydro-l-methyl-N-[2-(4-methyl-l-piperazinyl)phenyl]-; Benzoic acid, 4-[[(l,4-dihydro-l- methyl[ 1 ]benzopyrano[4,3-c]pyrazol-3-yl)carbonyl]amino]-, 2-(diethylamino)ethyl ester; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(5-chloro-2-pyridinyl)-l ,4-dihydro- 1 - methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-[3- (methylthio)phenyl]-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-ethylphenyl)- 1 ,4- dihydro-l -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(9-ethyl-9H-carbazol- 3 -yl)-l,4-dihydro-l -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1- methyl-N-(2-methyl-3-nitrophenyl)-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2- chloro-4-methylphenyl)- 1 ,4-dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3- carboxamide, N-(4-chloro-2-methoxy-5-methylphenyl)- 1 ,4-dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-[4-(l - methylethyl)phenyl]-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-ethylphenyl)- 1 ,4-dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro-N-(2- methoxy-5-methylphenyl)-l -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2- ethoxyphenyl)-l,4-dihydro-l -methyl-; Benzoic acid, 2-[[(l,4-dihydro-l- methyl[ 1 ]benzopyrano[4,3-c]pyrazol-3-yl)carbonyl]amino]-, ethyl ester; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro-N-(2-methoxy-5-nitrophenyl)- 1 - methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,5-dimethoxyphenyl)-l,4- dihydro-1 -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-ethoxyphenyl)-l,4- dihydro-1 -methyl-; Benzoic acid, 2-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, methyl ester; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,3- dihydro-l,4-benzodioxin-6-yl)-l,4-dihydro-l -methyl; [l]Benzopyrano[4,3-c]pyrazole-3- carboxamide, N-(4-bromo-2-methylphenyl)-l,4-dihydro-l -methyl-; [l]Benzopyrano[4,3- c]pyrazole-3-carboxamide, N-(5-chloro-2,4-dimethoxyphenyl)-l,4-dihydro-l -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-(3 ,4,5- trimethoxyphenyl)-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, l,4-dihydro-N-(3- methoxyphenyl)-l -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2- fluorophenyl)-l ,4-dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(5- chloro-2-methoxyphenyl)-l,4-dihydro-l -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3- carboxamide, N-(2,4-difluorophenyl)- 1 ,4-dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3- c]pyrazole-3 -carboxamide, N-(2,4-dimethoxyphenyl)- 1 ,4-dihydro- 1 -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-chloro-4-methoxyphenyl)-l,4-dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-chloro-4-fluorophenyl)- 1 ,4- dihydro- 1 -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-bromo-4- methylphenyl)-l ,4-dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4- dihydro-1 -methyl -N-[3-(trifluoromethyl)phenyl]-; [l]Benzopyrano[4,3-c]pyrazole-3- carboxamide, N-(3 -chlorophenyl)- 1 ,4-dihydro- 1 -methyl-; [ 1 JBenzopyrano [4,3-c]pyrazole-3- carboxamide, N-(4-fluorophenyl)- 1 ,4-dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3- carboxamide, l,4-dihydro-N-(2-methoxyphenyl)-l -methyl-; and pharmaceutically acceptable salts or N-oxides thereof, and, in some embodiments, a pharmaceutically acceptable carrier. [00115] Also contemplated herein are compounds selected from the group consisting of: N-(3 -chlorophenyl)- 1 -methyl -4,5-dihydro-lH-benzo[g]indazole-3-carboxamide; 8-chloro- N-(3 -chlorophenyl)- 1 -methyl-1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3- chlorophenyl)-8-fluoro-2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(4- chloropyridin-2-yl)-l -methyl- l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3- chlorophenyl)-8-fluoro-l -methyl-1, 4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(3- chlorophenyl)-l,4,4-trimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; 7-fluoro- 1 -methyl-N-(6-methylpyridin-2-yl)- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; 3- chloro-N-((l -methyl- l,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methyl)aniline; 1-methyl-N- (6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; N-(6- methylpyridin-2-yl)- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(4- cyanopyridin-2-yl)-l -methyl-1, 4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l -methyl-1, 4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide; (2H-benzo[b][l,4]oxazin-4(3H)-yl)(l -methyl- l,4-dihydrochromeno[4, 3- c]pyrazol-3-yl)methanone; 5-acetyl-N-(3-chlorophenyl)-l-methyl-4,5-dihydro-lH- pyrazolo[4,3-c]quinoline-3-carboxamide; N-(3-chlorophenyl)-l-methyl-lH-pyrazolo[4,3- c]quinoline-3-carboxamide; N-(3-chlorophenyl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3- c] quinoline-3 -carboxamide; 5 -bromo-N-ethyl-N-(( 1 -methyl- 1 ,4-dihydrochromeno [4,3 - c]pyrazol-3-yl)methyl)furan-2-carboxamide; l-isopropyl-N-(6-methylpyridin-2-yl)-4,5- dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; 1 -ethyl -N-(6-methylpyridin-2-yl)-4,5- dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)- 1 ,4,5,6,7,8-hexahydro-7,8-(2-pyridino)cyclohepta[c]pyrazole-3-carboxamide; 1 ,8-dimethyl- N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; 1- methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]isoquinoline-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline- 3 -carboxamide; 1 ,5-dimethyl-N-(6-methylpyridin-2-yl)-l ,4,5,6-tetrahydropyrazolo[4,3- c]pyrido[2,3-e]azepine-3-carboxamide; 1 ,6-dimethyl-N-(6-methylpyridin-2-yl)-l ,4,5,6- tetrahydropyrazolo [3, 4-d]pyrido [3, 2-b]azepine-3 -carboxamide; 1 -methyl -N-(6- methylpyridin-2-yl)-6-oxo-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3-c]azepine-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-l,4,5,6-tetrahydrobenzo[b]pyrazolo[3,4-d]azepine- 3 -carboxamide; 5,5-difluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH- pyrazolo[4,3-h]quinoline-3-carboxamide; 5,5-difluoro-l-methyl-N-(6-methylpyridin-2-yl)- 4,5-dihydro-lH-benzo[g]indazole-3-carboxamide; l,6-dimethyl-N-(6-methylpyridin-2-yl)- 1 ,4,5,6-tetrahydrobenzo[b]pyrazolo[3,4-d]azepine-3-carboxamide; 1 ,5-dimethyl-N-(6- methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-c]quinoline-3-carboxamide; 8-fluoro-l,5- dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-c]quinoline-3-carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3-c]azepine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro-lH-pyrazolo[4,3- h] quinoline-3 -carboxamide; 1 -methyl-N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1 ,5- d] [ 1 ,4]oxazine-3-carboxamide; 1 -methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro- IH- pyrazolo[4,3-h]quinoline-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4H- benzo[b]imidazo[l,5-d][l,4]oxazine-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5- oxo-4,5-dihydro-lH-pyrazolo[4,3-c]isoquinoline-3-carboxamide; l,5-dimethyl-N-(6- methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-c][l,5]naphthyridine-3-carboxamide; 9- fluoro-l-methyl-N-(6-methylpyridin-2-yl)-6-oxo-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3- c]azepine-3 -carboxamide; l,5,5-trimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH- pyrazolo[4,3-h]quinoline-3-carboxamide; l-methyl-N-(6-(trifluoromethyl)pyridin-2-yl)-4,5- dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)- 4,5-dihydro-lH-pyrazolo[3,4-f]quinoxaline-3-carboxamide; 9-fluoro-l-methyl-N-(6- methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline-3-carboxamide; 8-fluoro-l- methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline-3-carboxamide; 7-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; 6-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- h]quinoline-3-carboxamide; N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1,5- d] [ 1 ,4]oxazine-3-carboxamide; N-(6-cyclopropylpyridin-2-yl)- 1 -methyl-4,5 -dihydro- 1 H- pyrazolo[4,3-h]quinoline-3-carboxamide; l-methyl-N-(l-methyl-5-phenyl-lH-pyrrol-2-yl)- 4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; 6-methyl-N-(2-(l -methyl-4,5 - dihydro-lH-pyrazolo[4,3-h]quinolin-3-yl)propan-2-yl)pyridin-2-amine; 3-(2-(3- chlorophenoxy)propan-2-yl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline; 6-methyl- N-(l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-yl)picolinamide; 3-(l-(3- chlorophenoxy)ethyl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline; 6-cyclopropyl-N- ( 1 -( 1 -methyl-4,5 -dihydro- 1 H-pyrazolo [4,3 -h] quinolin-3 -yl)ethyl)pyridin-2-amine; 1 -methyl- N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydro-6,7-(2-pyridino)cyclopenta[c]pyrazole-3- carboxamide; l-methyl-N-(2-methylpyrimidin-4-yl)-4,5-dihydro-lH-pyrazolo[4,3- h]quinoline-3 -carboxamide; l-methyl-N-(6-methylpyrazin-2-yl)-4,5-dihydro-lH- pyrazolo[4,3-h]quinoline-3-carboxamide; 9-fluoro-l -methyl -N-(6-methylpyridin-2-yl)-5-oxo- l,4,5,6-tetrahydrobenzo[b]pyrazolo[3,4-d]azepine-3-carboxamide; l-methyl-N-(6- methylpyridin-2-yl)-4,5,7,8-tetrahydrobenzo-lH-oxepino[4,5-c]pyrazole-3-carboxamide; 1- methyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3-c]azepine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5,7,8-tetrahydrobenzo-lH-thiepino[4,5- c]pyrazole-3 -carboxamide; 1 -methyl -N-(6-methylpyridin-2-yl)-6-dioxo-4,5, 7, 8-tetrahydro- 7,8-(2-pyridino)-lH-thiepino[4,5-c]pyrazole-3-carboxamide; l-methyl-3-(l-(6- methylpyridin-2-yl)azetidin-3-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline; l-methyl-N-(6- methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-amine; l-methyl-N-(l-(6- methylpyridin-2-yl)ethyl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-amine; l-methyl-3-(l- (6-methylpyridin-2-yl)ethoxy)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline; l-methyl-N-(6- methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]isoquinoline-3-carboxamide; 5-hydroxy- l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide; 1- methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-6- hydroxybenzocyclohepta[c]pyrazole-3-carboxamide; 1 -methyl -N-(6-methylpyridin-2-yl)- 1,4,5,6, 7, 8-hexahydro-6,6-difluorobenzocyclohepta[c]pyrazole-3-carboxamide; 5-hydroxy-l- methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-6-hydroxy-7,8-(2- pyridino)cyclohepta[c]pyrazole-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)- 1,4,5,6, 7, 8-hexahydro-6,6-difluoro-7,8-(2-pyridino)cyclohepta[c]pyrazole-3-carboxamide; and pharmaceutically acceptable salts or N-oxides thereof.
[00116] The present disclosure also provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
[00117] The invention further provides methods of modulating activity of one or more metabotropic receptors-subtype 5 comprising exposing said receptor to a compound of the invention. In one embodiment, the modulator compound is a negative allosteric modulator. [00118] The invention further provides methods of treating a disease associated with expression or activity of one or more metabotropic receptors-subtype 5 in a patient comprising administering to the patient a therapeutically effective amount of a compound of the invention.
[00119] In one embodiment of the invention provides a method of treating Alzheimer's disease, Fragile X syndrome, L-DOPA induced dyskinesia, depression, anxiety, migraine, pain, gastroesophageal reflux disease, and/or aiding smoking cessation comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention. Other diseases and disorders that may be treated by administration of a therapeutically effective amount of a compound of the invention include functional bowel disorders, post-operative ileus, urinary tract disorders (incontinence, BPH, prostatitis, OAB), Parkinson's disease, panic disorder, phobia, posttraumatic stress disorder, generalized anxiety disorder, acute stress disorder, depression, bipolar disorder, attention-deficit/hyperactivity disorder, cognitive impairment, Alzheimer's disease, dementia, delirium tremens, ischemia, and neuropathic pain.
[00120] Compounds of the invention may also be effective in the treatment of abuse or addition to alcohol, nicotine, cocaine, amphetamine, benzodiazepine, and opiates. Compounds of the invention may also be useful in treating or preventing substance tolerance or dependence to bulimia nervosa, anorexia nervosa, gambling dependence, smoking dependence, sex dependence, substance withdrawal, and obsessive compulsive disorders. [00121] The compounds of the invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. For treating clinical conditions and diseases noted above, the compound of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. [00122] Exemplary pharmaceutical compositions of this invention may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual nontoxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease. [00123] For preparing solid compositions such as tablets, the principal active ingredient may bemixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [00124] The liquid forms in which the compositions of the invention may be incorporated for administration orally or by injection include aqueous solution, suitably flavored syrups, aqueous or oil suspensions, and emulsions with acceptable oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, or with a solubilizing or emulsifying agent suitable for intravenous use, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
[00125] Advantageously, the invention also provides kits for use by a consumer having, or at risk of having, a disease or condition associated with metabotropic receptors- subtype 5. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
[00126] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . " etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
EXAMPLES
[00127] The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. More specifically, compounds of the invention may be prepared using the reactions and techniques described herein. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. [00128] Schemes 1-8 depict methods for making exemplary compounds of the invention as described below. Scheme 1
Figure imgf000043_0001
R4 = H, Me, Et & isopropyl;
R5 = Me, CN, Cl, -OCH2CH2O-; Separate 2 regio-isomers Step 2
R6 = H;
R5-R6 = -CH2CH2O-;
X = O, CH2, CH3CO-N. KOH, MeOH Step 3
Figure imgf000043_0002
Scheme -2
Figure imgf000044_0001
1-3b
Separate 2 regio-isomers Step 2
KOH, MeOH Step 3
Figure imgf000044_0002
Step 4
Figure imgf000044_0003
Scheme 3
Figure imgf000045_0001
CH3CH2NH2 NaBCNH3
Coupling
Figure imgf000045_0002
Figure imgf000045_0004
Figure imgf000045_0003
r
Example 11
Scheme 4
DIBAL-H
Figure imgf000045_0005
Figure imgf000045_0006
Example 12
Scheme -5
O [H2C=N(CHs)2]Cl HO-NH3CI . reflux Ethanol
Figure imgf000046_0001
Figure imgf000046_0002
reflux
Figure imgf000046_0003
CH3NHNH2 AcOH
Figure imgf000046_0004
Scheme 6
Figure imgf000046_0005
Example 20 Example 21 Scheme 7
Oxalyl chloride DMSO
Figure imgf000047_0001
Figure imgf000047_0002
1 Oxalyl Chloride Separate 2
Figure imgf000047_0003
' N"N OH
Figure imgf000047_0006
regio-isomers
Figure imgf000047_0004
Figure imgf000047_0005
Figure imgf000047_0007
Example 23
Scheme 8
Figure imgf000047_0008
LDA THF
Figure imgf000047_0009
Figure imgf000047_0010
A: General procedure for synthesis of α, γ-diketoesters 1-2 (Step 1 of Scheme 1)
[00129] To a solution of appropriate chroman-4-one (or 3,4-dihydronaphthalen- l(2H)-one, or 2,3-dihydroquinolin-4(lH)-one) starting material (1.0 eq.) in ethanol was added a solution of sodium ethoxide (1.05 eq.). The mixture was stirred for 10 min at room temperature and then diethyl oxalate (1.0 eq.) was added. After the mixture was stirred overnight, IN HCl solution was added to adjust the pΗ to 4-5. The product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield α, γ-diketoester 1-2, which was used in step 2 without further purification.
B: General procedure for synthesis of tricyclic ester l-3a and b (Step 2 of Scheme 1)
[00130] To a solution of α, γ-diketoester 1-2 (1.0 eq.) in acetic acid was added the appropriate hydrazine (1.1 eq.) at room temperature. The mixture was stirred overnight. The solvent was removed under reduced pressure. The reaction mixture was purified by silica chromatography on an ISCO system (EtOAc/hexanes) to collect 2 regio-isomers l-3a and 1- 3b.
C: General procedure for synthesis of tricyclic acid (Step 3 of Scheme 1)
[00131] To a solution of α, γ-tricyclic ethyl ester l-3a or l-3b (1.0 eq.) in methanol was added a IM solution of potassium hydroxide in methanol (6 eq.) and water. The resulting mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature and then acidified with IN HCl to pH 4-5. The product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed to yield tricyclic acid l-4a or l-4b.
D: General procedure for synthesis of tricyclic carboxamides (Step 4 of Scheme 1)
[00132] To a solution of tricyclic acid l-4a or l-4b (1.0 eq.) and pyridine (3 eq.) in dichloromethane was added oxalyl chloride (1.1 eq.) at room temperature. The mixture was stirred for 2 h and then the appropriate aniline (1.2 eq.) was added. The mixture was stirred overnight. After the solvent was removed under reduced pressure, the reaction mixture was purified by silica chromatography on an ISCO system (EtOAc/hexanes) to yield tricyclic carboxamides; l-5a or l-5b.
Example 1
iV-(3-Chlorophenyl)-8-fluoro-l-methyl-l,4-dihvdrochromeno[4,3-clPyrazole-3- carboxamide
Ethyl 2-(6-fluoro-4-oxochroman-3-yl)-2-oxoacetate
Figure imgf000049_0001
[00133] The title compound was prepared according to general procedure A described in Scheme 2. The title compound was obtained as a yellow solid (1.76 g, 6.62 mmol, 66.2 % yield) by using 6-fluorochroman-4-one (1.66 g, 10.0 mmol), sodium ethoxide (21wt% in ethanol, 7.46 niL, 20.0 mmol), diethyl oxalate (1.36 ml, 10.0 mmol) in ethanol (100 mL).
Ethyl 8-fluoro-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate
Figure imgf000049_0002
[00134] The title compound was prepared according to general procedure B described in Scheme 2. A mixture of ethyl 2-(6-fluoro-4-oxochroman-3-yl)-2-oxoacetate (1.6 g, 6.0 mmol) and methyl hydrazine (0.36 mL, 6.9 mmol) in ethanol (40 mL).was refluxed for 6 h. The solvent was removed under reduced pressure. The reaction mixture was purified by silica chromatography on an ISCO system (EtOAc/hexanes) to collect 2 regio-isomers. The title compound was obtained as a white solid (421.5 mg,.1.53 mmol, 25.5 % yield) that was shown at retention time 4.6 min in LC-MS analysis (Kromasil 100-3.5 C4 column, 50 x 4.6 mm, 3.5 μm. Mobile phase A was 0.05% TFA in water; mobile phase B was 0.05% TFA in acetonitrile. The gradient was initiated at 2 % B and ramp to 75 % B in 7 min, followed by a wash to 95 % B within 0.5 min and re-equilibration back to 2 % from 8.6 min. The total analyzed time was 10 min. Flow rate was 0.8 niL/min). MS (ESI) m/z: Calculated for Ci4H13FN2O3: 276.1; found: 277.0 (M+H)+.
8-Fluoro- 1-methyl- 1 ,4-dihydrochromeno [4,3-c] pyrazole-3-carboxylic acid
Figure imgf000049_0003
[00135] The title compound was prepared according to general procedure C described in Scheme 2. The title compound was obtained as a white solid (238 mg,.0.96 mmol, 81 % yield) by using ethyl 8-fluoro-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (330 mg, 1.19 mmol), IN potassium hydroxide in methanol (7.2 mL, 7.2 mmol), methanol (60 ml) and water (1 mL). MS (ESI) m/z: Calculated for C12H9FN2O3: 248.1; found: 249.0 (M+H)+.
iV-(3-Chlorophenyl)-8-fluoro-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide
Figure imgf000050_0001
[00136] The title compound was prepared according to general procedure D described in Scheme 2. The title compound was obtained as a white solid with puritiy greater than 95 % (51.7 mg,.0.145 mmol, 15 % yield) by using 8-fluoro-l-methyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid (238 mg, 0.96 mmol), oxalyl chloride (0.53mL, 1.05 mmol), pyridine (0.23 ml, 2.9 mmol), 3-chloroaniline (147 mg, 1.15 mmol) and dichloromethane (20 mL). 1H NMR (282 MHz, CDCl3): δ 8.61 (s, IH), 7.81 (t, IH), 7.50(m, IH), 7.27 (t, IH), 7.21 (dd, IH), 7.10 (m, IH), 6.98 (m, 2H), 5.54 (s, 2H), 4.18(s, 3H); 19F NMR (376 MHz, CDCl3): δ -120.8; MS (ESI) m/z: Calculated for Ci8H13ClFN3O2: 357.1; found: 358.0 (M+H)+.
Example 2
iV-(3-Chlorophenyl)-8-fluoro-2-methyl-2,4-dihvdrochromeno[4,3-clpyrazole-3- carboxamide
Ethyl 8-fluoro-2-methyl-2,4-dihydrochromeno [4,3-c] pyrazole-3-carboxylate
Figure imgf000051_0001
[00137] The title compound was prepared according to general procedure B described in Scheme 2. A mixture of ethyl 2-(6-fluoro-4-oxochroman-3-yl)-2-oxoacetate (1.6 g, 6.0 mmol) and methyl hydrazine (0.36 mL, 6.9 mmol) in ethanol (40 mL).was refluxed for 6 h. The solvent was removed under reduced pressure. The reaction mixture was purified by silica chromatography on an ISCO system (EtOAc/hexanes) to collect 2 regio-isomers. The title compound was obtained as a white solid (597.8 mg, 2.16 mmol, 36.0 % yield) that was shown at the retention time 5.2 min in LC-MS analysis (Kromasil 100-3.5 C4 column, 50 x 4.6 mm, 3.5 μm. Mobile phase A was 0.05% TFA in water; mobile phase B was 0.05% TFA in acetonitrile. The gradient was initiated at 2% B and ramp to 75% B in 7 min, followed by a wash to 95% B within 0.5 min and re-equilibration back to 2% from 8.6 min. The total analyzed time was 10 min. Flow rate was 0.8 niL/min). MS (ESI) m/z: Calculated for C14Hi3FN2O3: 276.1; found: 277.0 (M+H)+.
8-Fluoro-2-methyl-2,4-dihydrochromeno [4,3-c] pyrazole-3-carboxylic acid
Figure imgf000051_0002
[00138] The title compound was prepared according to general procedure C described in Scheme 2. The title compound was obtained as a white solid (335 mg,.1.35 mmol, 85 % yield) by using ethyl 8-fluoro-2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (440 mg, 1.59 mmol), IN potassium hydroxide in methanol (9.6 mL, 9.6 mmol), methanol (80 ml) and water (2 mL). MS (ESI) m/z: Calculated for Ci2H9FN2O3: 248.1; found: 249.0 (M+H)+.
iV-(3-Chlorophenyl)-8-fluoro-2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide
Figure imgf000052_0001
[00139] The title compound was prepared according to general procedure D described in Scheme 2. The title compound was obtained as a white solid with puritiy greater than 95 % (38.6 mg,.0.108 mmol, 17 % yield) by using 8-fluoro-2-methyl-2,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid (160 mg, 0.65 mmol), oxalyl chloride (0.36mL, 0.71 mmol), pyridine (0.16 ml, 1.9 mmol), 3-chloroaniline (98 mg, 0.77 mmol) and dichloromethane (20 mL). 1H NMR (300 MHz, CDCl3): δ 7.69 (t, IH), 7.48-7.42 (m, IH), 7.41-7.36 (m, IH), 7.32 (t, IH), 7.22-7.15 (m, 2H), 6.94-6.90 (m, 2H), 5.39 (s, 2H), 4.18 (s, 3H); 19F NMR (376 MHz, CDCl3): δ -121.1; MS (ESI) m/z: Calculated for C18Hi3ClFN3O2: 357.1; found: 358.0 (M+H)+.
Example 3
iV-(4-Chloropyridin-2-yl)-l-methyl-l,4-dihvdrochromeno[4,3-clpyrazole-3-carboxamide
Ethyl 2-oxo-2-(4-oxochroman-3-yl)acetate
Figure imgf000052_0002
[00140] The title compound was prepared according to general procedure A described in Scheme 1. The title compound was obtained as a crude product by using 4-chromanone (5.0 g, 33.74 mmol), sodium ethoxide (21wt% in ethanol, 15.1 mL, 40.5 mmol), diethyl oxalate (7.77 ml, 33.74 mmol) in ethanol (40 mL). MS (ESI) m/z: Calculated for Ci3Hi2O5: 248.1; found: 249.0 (M+H)+.
Ethyl l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate
Figure imgf000053_0001
[00141] The title compound was prepared according to general procedure B described in Scheme 1. The title compound was obtained as a pale-yellow solid (1.1 g,.4.3 mmol, 53 % yield) by using ethyl 2-oxo-2-(4-oxochroman-3-yl)acetate (2.0 g, 8.06 mmol), methyl hydrazine (0.47 ml, 8.86 mmol) and acetic acid (13 ml). The title compound was shown at the retention time 4.4 min in LC-MS analysis (Kromasil 100-3.5 C4 column, 50 x 4.6 mm, 3.5 μm. Mobile phase A was 0.05% TFA in water; mobile phase B was 0.05% TFA in acetonitrile. The gradient was initiated at 2% B and ramp to 75% B in 7 min, followed by a wash to 95% B within 0.5 min and re-equilibration back to 2% from 8.6 min. The total analyzed time was 10 min. Flow rate was 0.8 niL/min). MS (ESI) m/z: Calculated for Ci4H14N2O3: 258.1; found: 259.0 (M+H)+.
l-Methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
Figure imgf000053_0002
[00142] The title compound was prepared according to general procedure C described in Scheme 1. The title compound was obtained as a white solid (161 mg, 0.70 mmol, 99 % yield) by using ethyl 1 -methyl- l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (183 mg, 0.71 mmol), IN potassium hydroxide in methanol (4.2 mL, 4.2 mmol), methanol (25 ml) and water (1 mL). MS (ESI) m/z: Calculated for Ci2Hi0N2O3: 230.1; found: 231.0 (M+H)+.
iV-(4-Chloropyridin-2-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide
Figure imgf000053_0003
[00143] The title compound was prepared according to general procedure D described in Scheme 1. The title compound was obtained as a white solid with puritiy greater than 95 % (25.4 mg,.0.07 mmol, 14 % yield) by using l-methyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid (119 mg, 0.52 mmol), oxalyl chloride (0.28 mL, 0.57 mmol), pyridine (0.13 ml, 1.6 mmol), 4-chloropyridin-2-amine (79.8 mg, 0.62 mmol) and dichloromethane (20 mL). 1H NMR (400 MHz, CDCl3): δ 9.32 (s, IH), 8.43 (d, IH), 8.23 (t, IH), 7.53 (m, IH), 7.25 (m, IH), 7.06 (m, 3H), 5.59 (d, 2H), 4.20(s, 3H); MS (ESI) m/z: Calculated for C17Hi3ClN4O2: 340.1; found: 341.0 (M+H)+.
Example 4
iy-(3-Chlorophenyl)-l.,4,4-trimethyl-l,4-(iihv(irochromeno[4,3-clpyrazole-3- carboxamide
Ethyl 2-(2,2-dimethyl-4-oxochroman-3-yl)-2-oxoacetate
Figure imgf000054_0001
[00144] The title compound was prepared according to general procedure A described in Scheme 1. The title compound was obtained as a crude product by using 2,2- dimethylchroman-4-one (910 mg, 5.16 mmol), sodium ethoxide (21wt % in ethanol, 2.02 mL, 5.42 mmol), diethyl oxalate (1.2 ml, 5.16 mmol) in ethanol (20 mL). MS (ESI) m/z: Calculated for Ci5Hi6O5: 276.1; found: 277.0 (M+H)+.
Ethyl 1 ,4,4-trimethyl- 1 ,4-dihydrochromeno [4,3-c] pyrazole-3-carboxylate
Figure imgf000054_0002
[00145] The title compound was prepared according to general procedure B described in Scheme 1. The title compound was obtained as a orange solid (473 mg, 1.65 mmol, 33 % yield) by using ethyl 2-(2,2-dimethyl-4-oxochroman-3-yl)-2-oxoacetate (1.544 g, 5.0 mmol), methyl hydrazine (0.29 ml, 5.5 mmol) and acetic acid (10 ml). The title compound was shown at the retention time 5.0 min in LC-MS analysis (Kromasil 100-3.5 C4 column, 50 x 4.6 mm, 3.5 μm. Mobile phase A was 0.05% TFA in water; mobile phase B was 0.05% TFA in acetonitrile. The gradient was initiated at 2 % B and ramp to 75% B in 7 min, followed by a wash to 95 % B within 0.5 min and re-equilibration back to 2% from 8.6 min. The total analyzed time was 10 min. Flow rate was 0.8 niL/min). MS (ESI) m/z: Calculated for C16Hi8N2O3: 286.1; found: 287.2 (M+H)+.
l,4,4-Trimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
Figure imgf000055_0001
[00146] The title compound was prepared according to general procedure C described in Scheme 1. The title compound was obtained as a white solid (368 mg, 1.42 mmol, 91 % yield) by using ethyl l,4,4-trimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (450 mg, 1.57 mmol), IN potassium hydroxide in methanol (9.5 mL, 9.5 mmol), methanol (80 ml) and water (2 mL). MS (ESI) m/z: Calculated for Ci4Hi4N2O3: 258.1; found: 259.1 (M+H)+.
iV-(3-Chlorophenyl)-l,4,4-trimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide
Figure imgf000055_0002
[00147] The title compound was prepared according to general procedure D described in Scheme 1. The title compound was obtained as a white solid with puritiy greater than 95 % (69.7 mg, 0.33 mmol, 39 % yield) by using l,4,4-trimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid (214 mg, 0.83 mmol), oxalyl chloride (0.46 mL, 0.91 mmol), pyridine (0.20 ml, 2.5 mmol), 3-chloroanaline (127 mg, 0.99 mmol) and dichloromethane (20 niL). 1H NMR (400 MHz, CDCl3): δ 8.84 (s, IH), 7.81 (m, IH), 7.51 (m, 2H), 7.25 (m, 2H), 7.08 (m, IH), 7.0 (m, 2H), 4.18 (d, 3H) 1.83 (d, 6H); MS (ESI) m/z: Calculated for C20H18ClN3O2: 367.1; found: 368.2 (M+H)+.
Example 5
iV-(3-Chlorophenyl)-8-chloro-l-methyl-l,4-dihvdrochromeno[4,3-clPyrazole-3- carboxamide
Ethyl 8-chloro-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate
Figure imgf000056_0001
[00148] The title compound was prepared according to general procedure B described in Scheme 1. The title compound was obtained as a white solid (367 mg,.1.26 mmol, 32 % yield) by using ethyl 2-(6-chloro-4-oxochroman-3-yl)-2-oxoacetate (1131 mg, 4 mmol), methyl hydrazine (242 uL, 4.6 mmol) and ethanol (28 ml). MS (ESI) m/z: Calculated for C14Hi3ClN2O3: 292.1; found: 293.0 (M+H)+.
8-Chloro-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
Figure imgf000056_0002
[00149] The title compound was prepared according to general procedure C described in Scheme 1. The title compound was obtained as a white solid (285 mg, 1.08 mmol, 86 % yield) by using ethyl 8-chloro-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (367 mg, 1.26 mmol), potassium hydroxide (141 mg, 2.51 mmol), methanol (15 ml). MS (ESI) m/z: Calculated for Ci2H9ClN2O3: 264.0; found: 265.0 (M+H)+. iV-(3-Chlorophenyl)-8-chloro-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide
Figure imgf000057_0001
[00150] The title compound was prepared according to general procedure D described in Scheme 1. To a suspension of 8-chloro-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid (106 mg, 0.4 mmol) in methylene chloride (4 mL) was added a 2M (methylene chloride) solution of oxalyl chloride (1 mL, 5 mmol) followed by 1 drop of DMF. The resulting mixture was stirred at room temperature for 2h. The mixture was concentrated under reduced pressure to provide a colorless solid. The solid was dissolved in methylene chloride (2 mL)and added dropwise to a solution of 3-chloroaniline (63 uL, 1.2 mM) and triethylamine (167 uL, 1.2 mmol) in methylene chloride (8 mL). The resulting mixture was stirred at room temperature for 18h. The mixture was diluted with ethyl acetate and washed with IN aq. HCl, water and brine. The organic fraction was dried (magnesium sulfate), filtered and concentrated. The residue was purified by recrystalization from ethyl acetate. Yield 48 mg of title compound (32 % yield): 1H NMR (300 MHz, CDCl3): 8.60 (s, IH), 7.82 (s, IH), 7.48-6.96 (m, 5H), 5.58 (d, 2H), 4.20 (d, 3H). MS (ESI) m/z calculated for C18Hi3Cl2N3O2: 373.0; found: 398.0 (M+Na+)+.
Example 6
ό-Methylpyridin-l-yl T-fluoro-l-methyl-l^-dihydrochromenoR^-clpyrazole-S- carboxylate
7-Fluoro- 1-methyl- 1 ,4-dihydrochromeno [4,3-c] pyrazole-3-carboxylic acid
Figure imgf000057_0002
[00151] The title compound was prepared according to general procedure A, B and C described in Scheme 1. To a solution of ethanol solution of sodium ethoxide (21 wt%, 4.1 mL, 10.92 mmol) at 0 0C was added 7-fluorochroman-4-one (1.72 g, 10.4 mmol) as a solution in ethanol (20 mL), The mixture was stirred at 0 0C for 10 minutes and then diethyl oxalate (1.14 mL, 10.4 mL) was added drpowise. The ice-bath was removed and the solution was heated to 40 0C for 2.5h. After cooling the mixture was concentrated to approx. 10 mL and diluted with water (30 mL). The pH of the solution was adjusted to 4.0 with IN HCl and the mixture was extracted with ethyl acetate. The ethyl acetate fraction was dried (magnesium sulfate), filtered and concentrated. The product, ethyl 2-(7-fluoro-4-oxochroman-3-yl)-2- oxoacetate (2.78 g) was used as is without further purification.
[00152] To a mixture of 2-(7-fluoro-4-oxochroman-3-yl)-2-oxoacetate (2.78 g, 10.4 mmol) in acetic acid (15 mL) was added methyl hydrazine (602 uL, 11.44 mmol) dropwise. The mixture was stirred at room temperature for 12h. The mixture was poured into water (150 mL). the aqueous mixture was extract 3 time with ethyl acetate (50 mL). The combined ethyl acetate fractions were washed with aqueous sodium bicarbonate, water, and brine. The organic fraction was dried (magnesium sulfate), filtered and concentrated. The product, ethyl 7-fluoro-l-methyl-l,4-dihydrochromene[4,3-c]pyrazole-3-carboxylate was purified on an ISCO system eluting with 5% ethyl acetate in methylene chloride. Yield 830 mg, 29%. [00153] To a suspension of ethyl 7-fluoro-l-methyl-l,4-dihydrochromene[4,3- c]pyrazole-3-carboxylate (830 mg, 3.0 mmol) in methanol was added freashly powdered potassium hydroxide (337 mg, 6.0 mmol). The mixture was heated to reflux for 18h. After cooling the mixture was diluted with water (30 mL) and cooled to 0 0C. The pH was made acidic with IN HCl. The solid, 7-fluoro-l-methyl-l,4-dihydrochromene[4,3-c]pyrazole-3- carboxylic acid was collected by filtration, washed with water and dried in a vacuum oven at 50 0C overnight. Yield 706 mg, 95% MS (ESI) m/z: Calculated for C12H9FN2O3: 248.1; found: 249.0 (M+l)+.
7-Fluoro-l-methyl-iV-(6-methylpyridin-2-yl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide
Figure imgf000058_0001
[00154] The title compound was prepared according to general procedure D described in Scheme 1. To a suspension of 7-fluoro-l-methyl-l,4-dihydrochromene[4,3-c]pyrazole-3- carboxylic acid (156 mg, 0.63 mmol) in methylene chloride (5 mL) was added a 2M (methylene chloride) solution of oxalyl chloride (1.6 mL, 3.15 mmol) followed by 1 drop of DMF. The resulting mixture was stirred at room temperature for Ih. The mixture was concentrated under reduced pressure to provide a colorless solid. The solid was dissolved in methylene chloride (2 mL) and added dropwise to a solution of 2-amino-6-picoline (102 mg, 9.45 mmol) and triethylamine (263 uL, 1.9 mmol) in methylene chloride (3 mL). The resulting mixture was stirred at room temperature for 4h. The mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was dried (magnesium sulfate), filtered and concentrated. The solid was repulped in ethyl acetate to provide the desired compound in 90 % purity. The solid was recrystalized from ethyl acetate to provide the title compound (94 mg, 4 5% yield) in greater then 95 % purity. 1H NMR (300 MHz, CDCl3): δ 9.19 (s, IH), 8.10 (d, IH), 7.61 (t, IH), 7.46 (m,lH), 6.90 (d, IH), 6.76 (m, IH), 5.60 (s, 2H) 4.16 (s, 3H), 2.49 (s, 3H); MS (ESI) m/z: calculated for C18Hi5FN4O2: 338.1; found: 339.2 (M+l)+.
Example 7
iV-fό-Methylpyridin-l-vD-l^-dihvdrochromenoR^-clPyrazole-S-carboxamide Ethyl 1 ,4-dihydrochromeno [4,3-c] pyrazole-3-carboxylate
Figure imgf000059_0001
[00155] The title compound was prepared according to general procedure B described in Scheme 1. The title compound was obtained as a off-white solid (2.4 g, 9.9 mmol, 41 % yield) by using ethyl 2-oxo-2-(4-oxochroman-3-yl)acetate (6.0 g, 24.17 mmol), hydrazine (0.83 ml, 26.59 mmol) and acetic acid (40 ml). MS (ESI) m/z: Calculated for Ci3Hi2N2O3: 244.1; found: 245.0 (M+H)+. 1 ,4-Dihydrochromeno [4,3-c] pyrazole-3-carboxylic acid
Figure imgf000060_0001
[00156] The title compound was prepared according to general procedure C described in Scheme 1. The title compound was obtained as a white solid (410 mg, 1.42 mmol, 81 % yield) by using ethyl l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (427 mg, 1.75 mmol), IN potassium hydroxide in methanol (10.5 mL, 10.5 mmol), methanol (60 ml) and water (1 mL). MS (ESI) m/z: Calculated for C11H8N2O3: 216.1; found: 217.0 (M+H)+.
^-(ό-Methylpyridin-l-ylJ-l^-dihydrochromeno^^-clpyrazole-S-carboxamide
Figure imgf000060_0002
[00157] The title compound was prepared according to general procedure D described in Scheme 1. The title compound was obtained as a white solid with puritiy greater than 95 % (1.6 mg, 0.005 mmol, 0.6 % yield) by using l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylic acid (190 mg, 0.88 mmol), oxalyl chloride (0.48 mL, 0.97 mmol), pyridine (0.21 ml, 2.6 mmol), 6-methylpyridin-2-amine (114 mg, 1.06 mmol) and dichloromethane (20 mL). 1H NMR (300 MHz, DMSO): δ 7.97 (d, IH), 7.74 (t, IH), 7.63 (d, IH), 7.26 (t, IH), 7.02 (m, 3H), 5.57 (s, 2H), 2.44 (s, 3H); MS (ESI) m/z: Calculated for C17H14N4O2: 306.1; found: 307.2 (M+H)+. Example 8
iV-(4-Cvanopyridin-2-yl)-l-methyl-l,4-dihvdrochromeno[4,3-clpyrazole-3-carboxamide
Figure imgf000061_0001
[00158] The title compound was prepared according to general procedure D described in Scheme 1. The title compound was obtained as a white solid with puritiy greater than 95 % (38.7 mg, 0.12 mmol, 13.5 % yield) by using l-methyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid (200 mg, 0.87 mmol), oxalyl chloride (0.48 mL, 0.95 mmol), pyridine (0.21 ml, 2.6 mmol), 2-amino-4-cyanopyridine (124 mg, 1.04 mmol) and dichloromethane (20 mL). 1H NMR (300 MHz, DMSO): δ 10.02 (br, IH), 8.63 (d, IH), 8.43 (s, IH), 7.77 (d, IH), 7.63 (d, IH), 7.33 (t, IH), 7.09 (m, 2H), 5.48 (s, 2H), 4.25 (s, 3H); MS (ESI) m/z: Calculated for C18Hi3N5O2: 331.1; found: 332.2 (M+H)+.
Example 9
iV-(2,3-Dihvdrobenzo [61 [ 1 ,41 dioxin-6-yl)- 1-methyl-l ,4-dihydrochromeno [4,3-cl pyrazole- 3-carboxamide
Figure imgf000061_0002
[00159] The title compound was prepared according to general procedure D described in Scheme 1. The title compound was obtained as a pale-yellow solid with puritiy greater than 95 % (37.2 mg, 0.10 mmol, 15.7% yield) by using 1 -methyl- l,4-dihydrochromeno[4, 3- c]pyrazole-3-carboxylic acid (150 mg, 0.65 mmol), oxalyl chloride (0.36 mL, 0.72 mmol), pyridine (0.16 ml, 2.0 mmol), 3,4-ethylenedioxyaniline (118 mg, 0.78 mmol) and dichloromethane (15 mL). 1H NMR (300 MHz, DMSO): δ 10.04 (s, IH), 7.75 (dd, IH), 7.42 (s, IH), 7.29 (m, 2H), 7.05 (m, 2H), 6.79 (d, IH), 5.45 (s, 2H), 4.22 (s, 7H); MS (ESI) m/z: Calculated for C20HnN3O4: 363.1; found: 364.2 (M+H)+. Example 10
^H-Benzor^iri^loxazin^O/D-vDd-methyl-l^-dihvdrochromenoR^-clpyrazol-S- vDmethanone
Figure imgf000062_0001
[00160] The title compound was prepared according to general procedure D described in Scheme 1. The title compound was obtained as a off-white solid with puritiy greater than 95 % (42.7 mg, 0.12 mmol, 18.9 % yield) by using l-methyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid (150 mg, 0.65 mmol), oxalyl chloride (0.36 mL, 0.72 mmol), pyridine (0.16 ml, 2.0 mmol), 3,4-dihydro-3H-l,4-benzoxazine (105 mg, 0.78 mmol) and dichloromethane (15 mL). 1H NMR (400 MHz, DMSO): δ 7.76 (d, IH), 7.61 (br, IH), 7.31 (dt, IH), 7.12-7.02 (m, 3H), 6.91 (d, IH), 6.84 (t, IH), 5.26 (s, 2H), 4.33 (s, 4H), 4.18 (s, 3H); MS (ESI) m/z: Calculated for C20Hi7N3O3: 347.1; found: 348.2 (M+H)+.
Example 11
S-Bromo-iV-ethyl-iV-fd-methyl-l^-dihvdrochromenoR^-clPyrazol-S-vDmethvDfuran- 2-carboxamide
[00161] The title compound was synthesized according to procedures in Scheme 3.
(l-Methyl-l,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methanol
Figure imgf000062_0002
[00162] To a solution of ethyl 1 -methyl- l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxylate (300 mg, 1.16 mmol) in dichloromethane (20 mL) at -78 0C was added a solution of DIBAL (3.48 mL,lM in dichloromethane) dropwise. The mixture was stirred at -78 °C for 1 h and was warmed up to room temperature and stirred overnight. LC-MS analysis indicated that the ester was converted to a mixture of the alcohol and the aldehyde that was the designed product for the next step. The reaction mixture was quenching at -78 0C with a saturated solution OfNH4Cl (0.5 mL) as well as 2N HCl (1.0 mL). The mixture was stirred at room temperature for 30 min. The mixture was extracted with dichloromethane and the extracts were dried over anhydrous sodium sulfate. The solution was filtered and the solvent was removed under reduced pressure to give the crude product (229 mg, a mixture with the aldehyde). The title compound was shown at the retention time 3.3 min in LC-MS analysis (Kromasil 100-3.5 C4 column, 50 x 4.6 mm, 3.5 μm. Mobile phase A was 0.05% TFA in water; mobile phase B was 0.05% TFA in acetonitrile. The gradient was initiated at 2 % B and ramp to 75 % B in 7 min, followed by a wash to 95 % B within 0.5 min and re- equilibration back to 2 % from 8.6 min. The total analyzed time was 10 min. Flow rate was 0.8 niL/min). MS (ESI) m/z: Calculated for C12H12N2O2: 216.1; found: 217.0 (M+H)+. The aldehyde was shown at the retention time 3.9 min in the same LC-MS analysis. MS (ESI) m/z: Calculated for C12Hi0N2O2: 214.1; found: 215.0(M+H)+.
l-Methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carbaldehyde
Figure imgf000063_0001
[00163] To the mixture of (l-methyl-l,4-dihydrochromeno[4,3-c]pyrazol-3- yl)methanol and the title aldehyde (229 mg, 1.06 mmol), NMO (149 mg, 1.27 mmol) and activated 4 A molecular sieves (500 mg) in dichloromethane (50 mL) was added TPAP (37.2 mg, 0.11 mmol) at room temperature. After stirred overnight, the mixture was filtered and purified by silica gel column chromatography on an ISCO system (hexane/ethylacetate) to give a white solid (91 mg, 0.42 mmol, 40 % yield). MS (ESI) m/z: Calculated for Ci2Hi0N2O2: 214.1; found: 215.0(M+H)+. ^-((l-Methyl-l^-dihydrochromeno^^-clpyrazol-S-ylJmethylJethanamine
Figure imgf000064_0001
[00164] A mixture of 1 -methyl- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carbaldehyde
(91 mg, 0.42 mmol), acetic acid (40 μL) and ethylamine (0.84 mmol) in DCM/MeOH (5 mL/10 mL) was sonicated for 1 h. After the reaction mixture was cooled, sodium cyanoborohydride (26.7 mg, 0.425 mmol) was added and the reaction mixture was stirred at room temperature overnight. After the solvents were removed under reduced pressure, the crude product was obtained as a off-white solid. MS (ESI) m/z: Calculated for C14H17N3O: 243.1; found: 244.2(M+H)+.
S-Bromo-iV-ethyl-iV-^l-methyl-l^-dihydrochromeno^^-clpyrazol-S-yOmethylJfuran- 2-carboxamide
Figure imgf000064_0002
[00165] The title compound was obtained as a off-white gel with puritiy greater than
95 % (9.0 mg, 0.02 mmol, 5.1% yield) by using 5-bromofuran-2-carboxylic acid (96 mg, 0.50 mmol), oxalyl chloride (0.27 mL, 0.55 mmol), pyridine (0.10 ml, 1.3 mmol), 7V-((1 -methyl - l,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methyl)ethanamine (102 mg, 0.42 mmol) and dichloromethane (10 mL). 1H NMR (400 MHz, CDCl3): δ 7.50 (d, IH), 7.22 (t, IH), 7.06- 6.99 (m, 3H), 6.42 (d, IH), 5.24 (br, 2H), 4.64 (br, 2H), 4.10 (s, 3H), 3.65 (br, 2H), 1.29 (br, 3H); MS (ESI) m/z: Calculated for C19Hi8BrN3O3: 415.1; found: 416.0 (M+H)+. Example 12
S-Chloro-iV-fd-methyl-l^-dihvdrochromenoRJ-clpyrazol-S-vDmethvDaniline
Figure imgf000065_0001
[00166] The title compound was synthesized according to procedure in Scheme 4. To a solution of N-(3-chlorophenyl)-l -methyl- l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide (261 mg, 0.77 mM) in methylene chloride (5 mL) was added a IM solution of DIBAL in methylene chloride (2.7 mL, 2.7 mM). The mixture was stirred at room temperature for 3h. An additional 1.5 mL (1.5 mM) of DIBAL was added and the stirring was continued for 3h. The reaction was quenched with IN HCl (10 mL) and the mixture was stirred vigorously for 30 minutes. The organic fraction was separated, dried (sodium sulfate), filtered and concentrated. The residue was purified on an ISCO system eluting with 20 % ethylacetate in hexanes. The product was then further purified by preparative TLC on silica gel eluting with 30 % ethyl acetate in hexanes. Yield 20 mg, 8 %. 1H NMR (300 MHz, CDCl3): δ 7.5 (dd, IH), 7.21 (m, IH), 7.05 (m, 3H), 6.67 (m, 2H), 6.53 (m, IH), 5.09 (s, 2H), 4.27 (s, 2H), 4.11 (s, 3H); MS (ESI) m/z: calculated for Ci8H16ClN3O: 325.10; found 326.3 (M+ 1)+.
Example 13
l-Methyl-iV-(6-methylpyridin-2-yl)-4,5-dihvdro-lH-pyrazolo[4,3-MQuinoline-3- carboxamide.
Ethyl l-methyl-4,5-dihydro-lH-pyrazolo[4,3-/ι]quinoline-3-carboxylate
Figure imgf000065_0002
[00167] The title compound was prepared according to general procedures A and B described in Scheme 1. To a mixture of 6,7-dihydroquinolin-8(5H)-one (Ig, 6.71 mmol) in ethanol (3 mL) at 0 0C was added a solution of sodium ethoxide in ethanol (21 wt %, 2.75 mL, 7.38 mmol). The mixture was stirred 5 minutes at 0 0C and the treated with diethyl oxalate (909 uL, 6.781 mmol). The mixture was stirred at room temperature for Ih and then recooled to 0 0C. The reaction was quenched with IN HCl in ethanol (7.4 mL). The solid was removed by filtration and the filtrate was concentrated to a dark oil under reduced pressure. The oil was dissolved in acetic acid (12 mL) and the solution was treated with methyl hydrazine (390 uL, 7.4 mmol). The solution was stirred 48h at room temperature. The solid was removed by filtration. The filtrate was dissolved in ethyl acetate and the mixture was washed with water (3 x 20 mL), aqueous sodium bicarbonate and brine. The organic fraction was dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography on an ISCO system eluting with a linear gradient for 5 % ethyl acetate in metylene chloride to 30 % ethyl acetate in methylene chloride. The major less polar regioisomer was identified as the desired compound. Yield 951 mg, 55 %. 1H NMR (300 MHz, CDCl3): δ 8.45 (dd, IH), 7.55 (dt, IH), 7.13 (dd, IH) 4.45 (m, 5H), 3.10 (m, 2H), 2.99 (m, 2H), 1.41 (t, 3H). Minor, more polar regioisomer 354 mg, 20 % yield; 1H NMR (300 MHz, CDCl3): δ 8.51 (dd, IH), 7.51 (dt, IH), 7.12 (dd, IH), 4.39 (q, 2H), 4.25 (s, 3H), 3.05 (m, 4H), 1.45 (t, 3H).
l-Methyl-4,5-dihydro-lH-pyrazolo[4,3-Λ]quinoline-3-carboxylic acid
Figure imgf000066_0001
[00168] The title compound was prepared according to general procedure C described in Scheme 1. To ethyl l-methyl-4,5-dihydro-lH-pyrazolo[4,3-/z]quinoline-3-carboxylate (930 mg, 3.64 mmol) in tetrahydrofuran/methanol/water (20 mL, 3:1 :1) was added lithium hydroxide (762mg, 18.16 mmol). The mixture was heated to 50 0C for Ih. After cooling the pΗ was adjusted to 4.0 with IN HCl. The solid was collected by filtration and dried under high vacuum. Yield 666 mg, 80%. MS (ESI) m/z: calculated for C12H11N3O2: 229.1; found 230.00 (M+l)+. Methyl-iV-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-Λ]quinoline-3- carboxamide.
Figure imgf000067_0001
[00169] The title compound was prepared according to general procedure D described in Scheme 1. To a suspension of l-methyl-4,5-dihydro-lH-pyrazolo[4,3-/z]quinoline-3- carboxylic acid acid (200 mg, 0.88 mmol) in methylene chloride (6 mL) was added a 2M solution (methylene chloride) of oxalyl chloride (2.2 mL, 4.38 mmol) followed by 1 drop of DMF. The resulting mixture was stirred at room temperature for Ih. The mixture was concentrated under reduced pressure to provide the acid chloride. The acid chloride was dissolved in methylene chloride (2 mL) and added dropwise to a solution of 2-amino-6- picoline (142 mg, 1.32 mmol) and triethylamine (367 uL, 2.64 mmol) in methylene chloride (4 mL). The resulting mixture was stirred at room temperature for 5h. The mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was dried (magnesium sulfate), filtered and concentrated. The product was purified by silica gel chromatography on an ISCO system eluting with 10 % ethyl acetate in methylene chloride.Yield 70 mg, 25 %, 1H NMR (300 MHz, CDCl3): δ 11.8 (broad s, IH), 8.71(d, IH), 8.45 (dd, IH), 8.06 (m, IH), 7.56 (d, IH), 7.14 (m, 2H), 4.5 (s, 3H), 3.14 (m, 2H), 3.03 (m, 2H), 2.83 (s, 3H); MS (ESI) m/z: calculated for C18H17N5O: 319.1; found 320.2 (M+l)+.
Example 14
iV-(3-Chlorophenyl)-l-methyl-4,5-dihvdro-lH-benzo[glindazole-3-carboxamide
Figure imgf000067_0002
[00170] The title compound was prepared according to general procedure D described in Scheme 1. To a suspension of l-methyl-4,5-dihydro-lH-benzo[g]indazole-3-carboxylic acid (228 mg, 1 mmol) in methylene chloride was added a 2M (methylene chloride) solution of oxalyl chloride (2 mL, 4 mmol) followed by 1 drop of DMF. The resulting mixture was stirred at room temperature for 2h. The mixture was concentrated under reduced pressure to provide a colorless solid. The solid was dissolved in methylene chloride (2 mL) and added dropwise to a solution of 3-chloroaniline (153 mg, 1.2 mmol) and triethylamine (418 uL, 3 mmol) in methylene chloride (8 mL). The resulting mixture was stirred at room temperature for 4h. The mixture was diluted with ethyl acetate and washed with IN aq. HCl, water and brine. The organic fraction was dried (magnesium sulfate), filtered and concentrated. The residue was purified on an ISCO system eluting with 10 % ethyl acetate in hexanes. Yield 220 mg. 1H NMR (300 MHz, CDCl3): 8.73 (s, IH), 7.81 (s, IH), 7.60 (m, 2H), 7.31 (m, 3H), 7.1 (m, IH), 4.20 (s, 3H), 3.15 (m, 2H), 2.95 (m, 2H). MS (ESI) m/z calculated for C19H16ClN3O: 337.1; found: 338.2 (M+H)+.
Example 15
l-Isopropyl-iV-(6-methylpyridin-2-yl)-4,5-dihvdro-lH-pyrazolo[4,3-MQuinoline-3- carboxamide
Figure imgf000068_0001
[00171] The title compound was prepared according to general procedure D described in Scheme 1. The title compound was obtained as a white solid with puritiy greater than 95 % (88.0 mg, 0.25 mmol, 95 % yield) by using l-isopropyl-4,5-dihydro-lH-pyrazolo[4,3- /z]quinoline-3-carboxylic acid (68.0 mg, 0.26 mmol), oxalyl chloride (7.5 mL, 92 mol), pyridine (0.55 ml, 6.8 mmol), 6-methylpyridin-2-amine (65.0 mg, 0.6 mmol) in dichloromethane (15 mL). 1H NMR (400 MHz, CDCl3): δ 9.31 (s, IH), 8.44 (dd, IH), 8.19 (d, IH), 7.63 (d, IH), 7.56 (t, IH), 7.11 (q, IH), 6.90 (d, IH), 6.12 (m, IH), 3.20 (dt, 2H), 2.99 (t, 2H), 2.52 (s, 3H), 1.56 (d, 6H); MS (ESI) m/z: Calculated for C20H21N5O: 347.2; found: 348.2 (M+H)+ Example 16
l-Ethyl-iV-(6-methylpyridin-2-yl)-4,5-dihvdro-lH-pyrazolor4,3-Mquinoline-3- carboxamide
Figure imgf000069_0001
[00172] The title compound was prepared according to general procedure D described in Scheme 1. The title compound was obtained as a white solid with puritiy greater than 95 % (76 mg, 0.23 mmol, 89 % yield) by using l-ethyl-4,5-dihydro-lH-pyrazolo[4,3- /z]quinoline-3-carboxylic acid (62.0 mg, 0.25 mmol), oxalyl chloride (7.5 mL, 92 mmol), pyridine (0.45 ml, 5.6 mmol), 6-methylpyridin-2-amine (36.0 mg, 0.33 mmol) in dichloromethane (10 mL). 1H NMR (400 MHz, CDCl3): δ 9.34 (s, IH), 8.44 (dd, IH), 8.17 (d, IH), 7.62 (d, IH), 7.56 (t, IH), 7.12 (dd, IH), 6.90 (IH), 4.87 (q, 2H), 3.20 (dt, 2H), 3.01 (t, 2H), 2.50 (s, 3H), 1.52 (t, 3H); MS (ESI) m/z: Calculated for C19H19N5O: 333.2; found: 334.2 (M+H)+
Example 17
l-Methyl-iV-(6-methylpyridin-2-yl)-4,5-dihvdro-lH-pyrazolo[4,3-Misoαuinoline-3- carboxamide
Figure imgf000069_0002
[00173] The title compound was prepared according to general procedure D described in Scheme 1. The title compound was obtained as a white solid with puritiy greater than 90 % (10.3 mg, 0.032 mmol, 17 % yield) by using l-methyl-4,5-dihydro-lH-pyrazolo[4,3- /z]isoquinoline-3-carboxylic acid (60.0 mg, 0.22 mmol), oxalyl chloride (85.0 mg, 0.68 mmol), triethylamine (88.0 ml, 0.63 mmol), 6-methylpyridin-2-amine (27.0 mg, 0.025 mmol) in dichloromethane (6.0 mL). 1H NMR (400 MHz, CDCl3): δ 9.28 (s, IH), 8.65 (s, IH), 8.48 (d, IH), 8.14 (d, IH), 7.62 (t, IH), 6.91 (d, IH), 4.24 (s, 3H), 3.18 (dt 2H), 2.98 (t, 2H), 2.50 (s, 3H); MS (ESI) m/z: Calculated for C18Hi7N5O: 319.1; found: 320.2 (M+H)+
Example 18
l,8-Dimethyl-iV-(6-methylpyridin-2-yl)-4,5-dihvdro-lH-pyrazolo[4,3-/tlquinoline-3- carboxamide
Figure imgf000070_0001
[00174] The title compound was prepared according to procedures described in
Scheme 5. The title compound was obtained as a white solid with puritiy greater than 90 % : 1H NMR (400 MHz, CDCl3): δ 3.32 (s, IH), 8.15 (d, IH), 7.60 (t, IH), 7.43 (d, IH), 6.98 (d, IH), 6.89 (d, IH), 4.41 (s, 3H), 3.17 (t, 2H), 2.96 (t, 2H), 2.54 (s, 3H), 2.49 (s, 3H); MS (ESI) m/z: Calculated for Ci9Hi9N5O: 333.2; found: 334.1 (M+H)+.
Example 19
5-Acetyl-iV-(3-chlorophenyl)-l-methyl-4,5-dihvdro-lH-pyrazolo[4,3-clαuinoline-3- carboxamide
Figure imgf000070_0002
[00175] The title compound was prepared according to general procedures A-D described in Scheme 6 (20 mg, 13.2 % yield): 1H NMR (300 MHz, CD3OD): δ 8.57 (s, IH), 7.76 (t, IH), 7.57 (d, 2H), 7.47 (d, IH), 7.36-7.26 (m, 3H), 7.04 (dd, IH), 5.10 (s, 2H), 4.18 (s, 3H), 2.21 (s, 3H); MS (ESI) m/z: Calculated for C20Hi7ClN4O2: 380.8; found: 381.0 (M+H)+. . Example 20
JV-O-ChlorophenvD-l-methyl-lH-pyrazoloRJ-clαuinoline-S-carboxamide
Figure imgf000071_0001
[00176] The title compound was prepared as described in step 6 of Scheme 6: 5-acetyl-
Λ/-(3-chlorophenyl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-c]quinoline-3-carboxamide (60 mg, 0.16 mmol) was mixed with 6 NHCi (2 mL, 0.33 mmol) in a mixture of water (2 mL) and MeOH (5 mL). The mixture was heated at 120 0C for 30 min under microwave irradiation (Personal Chemistry Emrys™ Optimizer microwave reactor). Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase preparative ΗPLC to yield the title compound as trifluoroacetic salt with puritiy greater than 95 % (13 mg, 18 % yield): 1H NMR (400 MHz, DMSO-de): δ 10.81 (s, IH), 9.59 (s, IH), 8.61 (d, IH), 8.22 (d, IH), 8.11 (s, IH), 7.86 (m, 2H), 7.80 (t, IH), 7.39 (t, IH), 7.19 (d, IH), 4.62 (s, 3H); MS (ESI) m/z: Calculated for C18H13ClN4O: 336.1; found: 337.2 (M+H)+.
Example 21
iV-(3-Chlorophenyl)-l-methyl-4,5-dihvdro-lH-pyrazolo[4,3-clαuinoline-3-carboxamide
Figure imgf000071_0002
[00177] The title compound was prepared as described in step 7 of Scheme 6: N-(3- chlorophenyl)-l -methyl- lH-pyrazolo[4,3-c]quinoline-3-carboxamide (21 mg, 0.063 mmol) was treated with NaBH4 (24 mg, 0.63 mmol) in a mixture of THF (3 mL) and ethanol (0.8 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The crude product was purified by reverse phase preparative HPLC to yield the title compound as trifluoroacetic salt with puritiy greater than 95 % (2.2 mg, 10 % yield): 1H NMR (400 MHz, CD3OD): δ 7.88 (dd, IH), 7.56 (d, IH), 7.54 (d, IH), 7.32 (t, IH), 7.11 (d, IH), 7.06 (t, IH), 6.71 (m, 2H), 4.71 (s, 2H), 4.19 (s, 3H); MS (ESI) m/z: Calculated for C18H15ClN4O: 338.1; found: 339.0 (M+H)+.
Example 22
3-Methyl-iV-(6-methylpyridin-2-yl)-3,4,14- triazatricvclor8.4.0.0Λ{2,6}ltetradeca- l(14),2(6).,4,10,12-pentaene-5-carboxami(ie
[00178] The title compound was synthesized according to Scheme 7.
6,7,8,9-Tetrahydro-5H-cyclohepta[6]pyridine-l -oxide
Figure imgf000072_0001
[00179] To a solution of 6,7,8,9-tetrahydro-5H-cyclohepta[δ]pyridine (1Og) in DCM
(100 niL), was added 60 % mCPBA (20.2g) with ice cooling. After being stirred for 2h at room temperature, the reaction was washed with saturated NaHCO3, and brine. The organic layer was dried over Na2SO4, concentrated, and then purified by silica chromatography (5 to 10 % MeOH/DCM) to yield 7.3 g of the title compound in 66 % yield.
6,7,8,9-Tetrahydro-5H-cyclohepta [b] pyridin-9-ol
Figure imgf000072_0002
[00180] To a solution of 6,7,8,9-tetrahydro-5H-cyclohepta[δ]pyridine-l-oxide 2 (7.3 g) in DCM (40 mL), was added 20 ml of TFAA with ice cooling. The reaction was stirred for 4 h at room temperature. To this, was added of saturated K2CO3 until basic. After being stirred for 3h at rt, the reaction mixture was extracted DCM (x 2) and washed with brine. The combined organic layers were dried over Na2SO4, concentrated, and then purified by silica chromatography (30 % EtOAc in hexanes) to yield 3.0 g of the title compound in 38 % yield.
5,6,7,8-Tetrahydrocyclohepta [b] pyridin-9-one
Figure imgf000073_0001
[00181] To a solution of 6,7,8,9-tetrahydro-5H-cyclohepta[δ]pyridin-9-ol (3.Og) and
1.9 mL of DMSO in DCM (50 mL), was added dropwise 2.4 mL of oxalyl chloride at -78 0C. After Ih, 8.6 mL of triethylamine was added slowly and then stirred for an additional 30 min. The reaction was stirred at room temperature for 2 h, it was then extracted with DCM and washed with brine. The organic layer was dried over Na2SO4, concentrated, and then purified by silica chromatography to yield 2.6g of the title compound in 89 % yield.
2-(6,7,8,9-Tetrahydro-9-oxo-5H-cyclohepta [b] pyridin-8-yl)-2-oxoacetic acid
Figure imgf000073_0002
[00182] To a freshly prepared NaOEt solution (0.8g of Na in 40 mL of absolute EtOH) was added 2.7 mL of diethyl oxalate followed by a solution of 5,6, 7,8- tetrahydrocyclohepta[δ]pyridin-9-one (2.6 g in 6 mL of absolute EtOH) in a water bath. The reaction was stirred at room temperature for Ih and then quenched by addition of saturated citric acid solution until acidic (pΗ = 3-4). The mixture was extracted with EtOAc (x 2), washed with brine, dried over Na2SO4, and then concentrated to yield 2.0 g of the title compound (53%). 3-Methyl-3,4,14- triazatricyclo[8.4.0.0Λ{2,6}]tetradeca- l(14),2(6),4,10,12-pentaene- Scarboxylic acid
Figure imgf000074_0001
[00183] To a mixture of 2-(6,7,8,9-tetrahydro-9-oxo-5H-cyclohepta[6]pyridin-8-yl)-2- oxoacetic acid (1.1 g, 4.9 mmol) in 25 rnL of glacial acetic acid, was added 0.36 rnL of methylhydrazine at room temperature. The volatiles were removed in vacuo. To the resulting suspension, was added 30 mL of EtOAc and then it was stirred for Ih at room temperature. The resulting solids were collected by filtration, washed with EtOAc and then dried to yield 1.1 g of title compound (92 %) as a yellow solid; 1H NMR (400 MHz, CDCl3): δ 8.60 (dd, IH), 7.62 (m, IH), 7.24 (m, IH), 4.23 (s, 3H), 3.04 (m, 2H), 2.68 (m, 2H), 2.13 (m, 2H); MS (ESI) m/z: Calculated for C13H13N3O2: 243.1; found: 244.1 (M+H)+.
3-Methyl-iV-(6-methylpyridin-2-yl)-3,4,14- triazatricyclo[8.4.0.0Λ{2,6}]tetradeca- l(14),2(6),4,10,12-pentaene-5-carboxamide
Figure imgf000074_0002
[00184] A suspension of 3-methyl-3 ,4,14- triazatricyclo[8.4.0.0Λ{2,6}]tetradeca- l(14),2(6),4,10,12-pentaene-5carboxylic acid (130 mg, 0.53 mmol) and 10 μL of DMF in anhydrous DCM (5mL), was added 130 uL of oxalyl chloride at room temperature. After being stirred for Ih, ImL of triethylamine was added to the reaction mixture. To this was added a solution of 150 mg of 2-amino-6-methylpyridine in anhydrous DCM (3 mL). After stirring for 1 h the mixture was extracted with EtOAc (x 2), washed with IN NaOH followed by brine, dried over Na2SO4, and then purified by PTLC (40 % EtOAc/hexane) to yield 25 mg (14%) of the title compound as a brown solid. 1H NMR (400 MHz, CDCl3): δ 10.22 (s, IH), 8.62 (dd, IH), 8.09 (d, IH), 7.98 (t, IH), 7.83 (dd, IH), 7.39 (dd, IH), 7.20 (d, IH), 4.20 (s, 3H), 2.98 (dd, 2H), 2.65 (m, 2H), 2.52 (s, 3H), 2.06(m, 2H); MS (ESI) m/z: Calculated for C19Hi9N5O: 333.2; found: 334.2 (M+H)+.
Example 23
4-Methyl-iV-(6-methylpyridin-2-yl)-3,4,14- triazatricvclor8.4.0.0Λ{2,611tetradeca- l(14),2,5.l10.l12-pentaene-5-carboxamide
[00185] The title compound was synthesized according to Scheme 7.
4-Methyl-3,4,14- triazatricyclo[8.4.0.0Λ{2,6}]tetradeca- l(14),2,5,10,12-pentaene-5- carboxylic acid
Figure imgf000075_0001
[00186] The title compound was obtained as a white solid (11 mg, 3 % yield) by using
2-oxo-2-(9-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[δ]pyridin-8-yl)acetic acid (400 mg, 1.72 mmol), methyl hydrazine (87 mg, 1.89 mmol) and acetic acid (4 ml). Purification conditions were as follows (water/ acetonitrile (0.05 % TFA); 5-50 % acetonitrile over 45 min. The title compound was shown at the retention time 2.84 min in LC-MS analysis (Kromasil 100-3.5 C4 column, 50 x 4.6 mm, 3.5 μm. Mobile phase A was 0.05 % TFA in water; mobile phase B was 0.05 % TFA in acetonitrile. The gradient was initiated at 2 % B and ramp to 75 % B in 7 min, followed by a wash to 95 % B within 0.5 min and re-equilibration back to 2 % from 8.6 min. The total analyzed time was 10 min. Flow rate was 0.8 niL/min). 1H NMR (400 MHz, CDCl3): δ 8.87 (m, IH), 8.12 (m, IH), 7.65 (m, IH), 4.19 (s, 3H), 3.20 (m, 2H), 3.07 (m, 2H), 2.13 (m, 2H); Calculated for Ci3Hi3N3O2: 243.1; found: 244.3 (M+H)+.
4-Methyl-iV-(6-methylpyridin-2-yl)-3,4,14- triazatricyclo[8.4.0.0Λ{2,6}]tetradeca- l(14),2,5,10,12-pentaene-5-carboxamide
Figure imgf000076_0001
[00187] The title compound was obtained as a white solid with puritiy greater than 95
% (4.2 mg, 31% yield) by using 4-methyl-3 ,4,14- triazatricyclo[8.4.0.0Λ{2,6}]tetradeca- l(14),2(6),4,10,12-pentaene-5carboxylic acid (10 mg, 0.04 mmol), 6-methylpyridin-2-amine (8.9 mg, 0.08 mmol), diisopropylethylamine (0.044 ml, 0.24 mmol), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide (EDC, 22.9 mg, 0.12 mmol), HOBt (16.2 mg, 0.12 mmol) in dichloromethane (2 mL). MS (ESI) m/z: Calculated for C19H19N5O: 333.2; found: 334.4 (M+H)+.
Example 24
(4-Fluorophenyl)(3-(2-methyl-4,5-dihvdro-2H-benzo[glindazol-3-yl)piperidin-l- vDmethanone
[00188] The title compound was synthesized according to Scheme 8.
Ethyl l-(4-fluorobenzoyl)piperidine-3-carboxylate
Figure imgf000076_0002
[00189] To a solution of ethyl nipecotate (10 g, 63.6 mmol) and DIPEA (22.2 mL,
127.2 mmol) in dichloromethane (300 mL) was added 4-fluorobenzoyl chloride (8.01 mL, 66.8 mmol) slowly at room temperature. The mixture was stirred for 4 h and then the mixture was washed with IN NaOH and IN HCl. The organic phase was separated and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a pale yellow oil (17.1 g, 61.2 mmol, 97%). MS (ESI) m/z: Calculated for C15Hi8FNO3: 279.1; found: 280.2 (M+H)+. l-(4-Fluorobenzoyl)piperidine-3-carboxylic acid
Figure imgf000077_0001
[00190] The title compound was prepared according to general procedure C described in Scheme 8. The title compound was obtained as an off-white solid by using ethyl l-(4- fluorobenzoyl)piperidine-3-carboxylate (36.7 mmol), IN potassium hydroxide in methanol (200 mL, 200 mmol), methanol (200 ml) and water (5 mL). MS (ESI) m/z: Calculated for C13Hi4FNO3: 251.1; found: 252.0 (M+H)+.
2-(l-(4-Fluorobenzoyl)piperidine-3-carbonyl)-3,4-dihydronaphthalen-l(2H)-one
Figure imgf000077_0002
[00191] The title compound was prepared according to steps 3 and 4 described in
Scheme 8. To IM a solution of lithium hexamethyldisilazide in TΗF (12.5 mL, 12.5 mmol) was added α-tetralone (1.66g, 1.52 mL, 11.38 mmol) in TΗF (12 mL) at -78 0C under argon atmosphere, the resulting mixture was stirred for 30 min at the same temperature (solution A). A solution of 1,1 ' -carbonyldi-lH-imidazole (CDI, 1.88g, 11.38 mmol) and 1 -(4- fluorobenzoyl)piperidine-3-carboxylic acid (2.86 g, 11.38 mmol) in TΗF (35 mL) was stirred for 45 min at room temperature (solution B). The resulting solution B was added dropwise to solution A over 30 min at -78 0C. After removal of the cold bath, the reaction mixture was warmed to room temperature and stirred for 12 h. To this resulting mixture was added 10% aqueous citric acid (35 mL), and the resulting solution was taken up in ethylacetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography on an ISCO system to yield a pale yellow sticky oil (420 mg, 1.11 mmol, 9.7 % yield). MS (ESI) m/z: Calculated for C23H22FNO3: 379.2; found: 380.1 (M+H)+. Example 25
(4-Fluorophenyl)(3-(2-methyl-4,5-dihvdro-2H-benzo[glindazol-3-yl)piperidin-l- vDmethanone
Figure imgf000078_0001
[00192] The title compound was prepared according to general procedure B as described in step 5 in Scheme 8. A mixture of 2 regio-isomers were obtained by using 2-(l- (4-fluorobenzoyl)piperidine-3-carbonyl)-3,4-dihydronaphthalen-l(2Η)-one (100 mg, 0.26 mmol), methylhydrazine (15.3 μL, 0.29 mmol), acetic acid (0.5 ml) and dichloromethane (5 mL). The title compound was isolated by prep-HP LC (1% TFA/acetonitril/water) to yield a TFA salt as a white solid (11.0 mg, 0.028 mmol, 10.9 % yield). The title compound was shown at the retention time 16.2 min in LC-MS analysis (Phenomenex Luna C18 column, 100 x 2.0 mm, 5 μm. Mobile phase A was 0.0 5% TFA in water; mobile phase B was 0.05 % TFA in acetonitrile. The gradient was initiated at 5% B for 1 min and then ramp to 75 % B in 23 min, followed by a wash to 95% B within 1 min and re-equilibration back to 2 % from 27 min. The total analyzed time was 30 min. Flow rate was 0.8 mL/min). 1H NMR (400 MHz, CD3OD): δ 7.64 (br, IH), 7.48 (br, 2H), 7.38-7.1 (m & br, 5H), 4.70 (br, IH), 4.52 (br, IH), 4.07 (d, 3H), 3.75 (d, IH), 3.20-2.68 (m & br, 4H), 2.51 (br, IH), 2.30(br, IH), 2.10 (d, IH), 1.94 (br, IH), 1.80-1.60 (br, 2H); 19F NMR (376 MHz, CDCl3): δ -112.49; MS (ESI) m/z: Calculated for C24H24FN3O: 389.2; found: 390.2 (M+H)+.
Example 25
(4-Fluorophenyl)(3-(l-methyl-4,5-dihvdro-lH-benzo[glindazol-3-yl)piperidin-l- vDmethanone
Figure imgf000079_0001
[00193] The title compound was prepared according to general procedure B as described in step 5 in Scheme 8. A mixture of 2 regio-isomers were obtained by using 2-(l- (4-fluorobenzoyl)piperidine-3-carbonyl)-3,4-dihydronaphthalen-l(2H)-one (100 mg, 0.26 mmol), methylhydrazine (15.3 μL, 0.29 mmol), acetic acid (0.5 ml) and dichloromethane (5 mL). The title compound was isolated by prep-HP LC (1 %TFA/acetonitril/water) to yield a TFA salt as a white solid (8.1 mg, 0.028 mmol, 8.0 % yield). The title compound was shown at the retention time 15.2 min in LC-MS analysis (Phenomenex Luna C18 column, 100 x 2.0 mm, 5 μm. Mobile phase A was 0.05 % TFA in water; mobile phase B was 0.05 % TFA in acetonitrile. The gradient was initiated at 5 % B for 1 min and then ramp to 75 % B in 23 min, followed by a wash to 95 % B within 1 min and re-equilibration back to 2 % from 27 min. The total analyzed time was 30 min. Flow rate was 0.8 mL/min). 1H NMR (400 MHz, CD3OD): δ 7.68 (br, IH), 7.52 (m, 2H), 7.22 (t, 5H), 4.69 (br, IH), 3.94 (br, IH), 3.85-3.6 (br, 2H), 3.40-3.20 (br, IH), 3.10 (br, 2H), 2.90 (br, 5H), 2.08 (br, 2H), 1.80-1.6 (br, 2H); 19F NMR (376 MHz, CDCl3): δ -112.49; MS (ESI) m/z: Calculated for C24H24FN3O: 389.2; found: 390.2 (M+H)+.
Example 26 mGluRS calcium mobilization in inducible mGluRS CHO cells
[00194] To functionally measure mGluR5 calcium mobilization in response to agonists or antagonists, an inducible CHO cell line expressing the human mGlu5 recombinant receptor was used. This cell line also stably expressed Aequorin (Euroscreen FAST), a photoprotein that spontaneously couples with coelenterazine h when added exogenously in the cell media. The Aequorin-coelenterzine h complex undergoes a conformational change upon binding of calcium ions which results in the emission of blue light (wavelength 469 nm) that was measured using a Hamamatsu Functional Drug Screening System 6000.
[00195] mGluR5 expression was induced by a doxycycline responsive promoter by growing cells to mid-log phase for 18 hours in media without antibiotics and supplemented with doxycycline (600 ng/niL). Cells were detached from the plate by gentle flushing using PBS-EDTA (5 rnM EDTA) and centrifuged for collection and resuspended in "assay buffer" (HBSS, 2.1 mM CaC12, 2 ug/mL glutamate-pyruvate transaminase, 4 mM MEM sodium pyruvate, and 0.1% protease free BSA). Cells were incubated with coelenterazine h (Molecular Probes) at room temperature for 4 hours before testing.
[00196] To measure mGluR5 antagonist activity, cell suspensions containing test compound were mixed with EC80 glutamate and emission of light was recorded. Reference and test compounds were tested at several concentrations in duplicate to obtain dose response curves using the Prism GraphPad software (GraphPad Software Inc.). IC50 values were calculated from the dose response curves using the equation: Y=Bottom + (Top-Bottom)/(l+10Λ((LogEC50-X)*HillSlope)). The results are given in Tables 2 and 3.
Table 2.
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
a. when IC50 > 10 uM: designated as "+"; when 10 uM > IC50 > 1 uM; designated as "++"; when IC50 < 1 uM, designated as "+++".
Table 3.
Figure imgf000083_0002
Figure imgf000084_0001
a. when IC50 > 10 uM: designated as "+"; when 10 uM > IC50 > 1 uM; designated as "++"; when IC5O < 1 uM, designated as "+++".
References
[00197] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
Equivalents
[00198] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.
[00199] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

Claims

WHAT IS CLAIMED IS:
1. A compound represented by formula I:
Figure imgf000087_0001
and pharmaceutically acceptable salts or N-oxides thereof; wherein
V1, V2, V3, and V4 are selected, independently for each occurrence, from the group consisting of: N and CR2;
X is NR4 or CR7R8;
Y and Z are each independently selected from the group consisting of: NR11 and N;
T is CO or CR7R8, wherein at least one T is CR7R8; n is 0, 1 or 2;
A is selected from the group consisting of: -CONR16-, -NR16CO-, -O-, -NRi6CONRi6-, -CRI4RI5-NRI6CO-, -CRI4RI5-O-, -CRi4Ri5-NRi6-, -0-CRi4Ri5-, -NRi6-
Figure imgf000087_0002
m is O, 1 or 2;
R2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl, wherein B is optionally substituted by one, two, or three substituents each independently represented by R3; R3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
R7 and Rs are each independently selected from the group consisting of: alkoxy, alkyl, halogen, haloalkyl, hydrogen and hydroxyl, or R7 and Rs taken together are oxo; or R7 and Rs taken together form a carbocycle or a heterocycle;
R11 is selected from the group consisting of: alkyl, cycloalkyl, or haloalkyl wherein R11 may optionally substituted by halogen, cyano, hydroxy, nitro, or alkoxy;
R16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and
R14 and R15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl.
2. The compound of claim 1, wherein B is selected from:
Figure imgf000088_0001
or
3. The compound of claim 1 or 2, wherein each OfV1, V2, V3, and V4 is CR2.
4. The compound of claim 1 or 2, wherein each OfV1, V2, and V3 is CR2, and V4 is N.
5. The compound of claim 1 or 2, wherein each OfV1, V2, and V4 is CR2, and V3 is N.
6. The compound of any one of claims 1-5, wherein R11 is Ci_3alkyl.
7. The compound of any one of claims 1 -6, wherein X is NR4.
8. The compound of claim 7, wherein R4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen.
9. The compound of any one of claims 1-6, wherein X is CR7Rs.
10. The compound of claim 9, wherein X is selected from the group consisting of: CH2,
CHOH, and CO.
11. The compound of any one of claims 1-10, wherein T is CH2.
12. The compound of any one of claims 1-11, wherein n is 1.
13. The compound of any one of claims 1-11, wherein n is 2.
14. The compound of any one of claims 1-13, wherein A is -CONR16- or -CR14R1S-NR16-
15. The compound of any one of claims 1-14, wherein R16 is hydrogen or methyl.
16. A compound represented by formula II:
Figure imgf000089_0001
and pharmaceutically acceptable salts or N-oxides thereof; wherein
V1, V2, V3, and V4 are selected, independently for each occurrence, from the group consisting of: N and CR2;
T is CO or CR7Rg, wherein at least one T is CR7Rs; n is 0, 1 or 2;
A is selected from the group consisting of: -CONR16-, -NR16CO-, -O-, -NR16CONR16-, -CR14R15-NR16CO-, -CR14R15-O-, -CR14R15-NR16-, -0-CR14R15-, -NR16-
Figure imgf000089_0002
m is 0, 1 or 2;
R2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl wherein B is optionally substituted by one, two, or three substituents each independently represented by R3;
R3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
R11 is selected from the group consisting of: alkyl, cycloalkyl, alkanoyl, aryl, heteroaryl, or heterocyclyl;
R16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and
R14 and R15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl.
17. The compound of claim 16, wherein B is selected from:
Figure imgf000090_0001
or
18. The compound of claim 16 or 17, wherein each OfV1, V2, V3, and V4 is CR2.
19. The compound of claim 16 or 17, wherein each OfV1, V2, and V3 is CR2, and V4 is N.
20. The compound of claim 16 or 17, wherein each OfV1, V2, and V4 is CR2, and V3 is N.
21. The compound of any one of claims 16-20, wherein R11 is C1-3 alkyl.
22. The compound of any one of claims 16-21 , wherein T is CH2.
23. The compound of any one of claims 16-22, wherein n is 1.
24. The compound of any one of claims 16-22, wherein n is 2.
25. The compound of any one of claims 16-24, wherein A is -CONR16- or -CR14R1S-NR16-.
26. The compound of any one of claims 16-25, wherein R16 is hydrogen or methyl.
27. A compound represented by formula III:
Figure imgf000091_0001
III and pharmaceutically acceptable salts or N-oxides thereof; wherein
V1, V2, V3, and V4 are selected, independently for each occurrence, from the group consisting of: N and CR2;
T is CO or CR7Rg, wherein at least one T is CR7Rs; n is 0, 1 or 2;
A is selected from the group consisting of: -CONR16-, -NR16CO-, -NR16CONR16-, -O-, -CRi4R15-NRi6CO-, -CRi4Ri5-O-, -CRi4Ri5-NRi6-, -0-CRi4Ri5-, -NRi6-CRi4Ri5-, -
Figure imgf000091_0002
m is O, 1 or 2;
R2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl wherein B is optionally substituted by one, two, or three substituents each independently represented by R3; R3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R7 and Rs are each independently selected from the group consisting of: alkyl, halogen, haloalkyl, and hydrogen; or R7 and Rs taken together form a carbocycle or a heterocycle;
R11 is selected from the group consisting of: alkyl, cycloalkyl, alkanoyl, aryl, heteroaryl, or heterocyclyl;
R16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and
R14 and R15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl.
28. The compound of claim 27, wherein B is selected from:
Figure imgf000092_0001
or
29. The compound of claim 27 or 28, wherein each OfV1, V2, V3, and V4 is CR2.
30. The compound of claim 27 or 28, wherein each OfV1, V2, and V3 is CR2, and V4 is N.
31. The compound of claim 27 or 28, wherein each OfV1, V2, and V4 is CR2, and V3 is N.
32. The compound of any one of claims 27-31 , wherein R11 is C1-3 alkyl.
33. The compound of any one of claims 27-32, wherein T is CH2.
34. The compound of any one of claims 27-33, wherein n is 1.
35. The compound of any one of claims 27-33, wherein n is 2.
36. The compound of any one of claims 27-35, wherein A is -CONR16- or -CR14R1S-NR16-
37. The compound of any one of claims 27-36, wherein R16 is hydrogen or methyl.
38. A compound represented by formula IV:
Figure imgf000093_0001
and pharmaceutically acceptable salts or N-oxides thereof; wherein
V1, V2, V3, and V4 are selected, independently for each occurrence, from the group consisting of: N and CR2;
X is selected from the group consisting of: O, SO2, NR4 and CR7R8;
T is CO or CR7R8, wherein at least one T is CR7R8; n is 0, 1 or 2;
A is selected from the group consisting of: -CONR16-, -NR16CO-, -O-, -NR16CONR16-, -CR14R15-NR16CO-, -CR14R15-O-, -CR14R15-NR16-, -0-CR14R15-, -NR16-
CR14R15-, -NR16-, 'm and 'm . m is O, 1 or 2;
R2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl, wherein B is optionally substituted by one, two, or three substituents each independently represented by R3;
R3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio; R4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
R7 and Rs are each independently selected from the group consisting of: alkoxy, alkyl, halogen, haloalkyl, hydrogen and hydroxyl, or R7 and Rs taken together are oxo; or R7 and Rs taken together form a carbocycle or a heterocycle;
R11 is selected from the group consisting of: alkyl, cycloalkyl, or haloalkyl;
R16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and
R14 and R15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl. 38. The compound of claim 37, wherein B is selected from:
Figure imgf000094_0001
or
39. The compound of claim 37 or 38, wherein each OfV1, V2, V3, and V4 is CR2.
40. The compound of claim 37 or 38, wherein each OfV1, V2, and V3 is CR2, and V4 is N.
41. The compound of claim 37 or 38, wherein each OfV1, V2, and V4 is CR2, and V3 is N.
42. The compound of any one of claims 37-41, wherein R11 is C1-3 alkyl.
43. The compound of any one of claims 37-42, wherein X is NR4.
44. The compound of claim 43, wherein R4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen.
45. The compound of any one of claims 37-42, wherein X is CR7Rs.
46. The compound of claim 45, wherein X is selected from the group consisting of: CH2, CHOH, and CO.
47. The compound of any one of claims 37-42, wherein X is O.
48. The compound of any one of claims 37-47, wherein T is CH2.
49. The compound of any one of claims 37-48, wherein n is 1.
50. The compound of any one of claims 37-48, wherein n is 2.
51. The compound of any one of claims 37-50, wherein A is -CONR16- or -CR14R1S-NR16-.
52. The compound of any one of claims 37-51 , wherein R16 is hydrogen or methyl.
53. A compound represented by formula V:
Figure imgf000095_0001
and pharmaceutically acceptable salts or N-oxides thereof; wherein
V1, V2, V3, and V4 are selected, independently for each occurrence, from the group consisting of: N and CR2;
T is CO or CR7Rg, wherein at least one T is CR7Rs; n is 0, 1 or 2;
A is selected from the group consisting of: -CONR16-, -NR16CO-, -O-, -NRi6CONRi6-, -CRI4RI5-NRI6CO-, -CRI4RI5-O-, -CRi4Ri5-NRi6-, -0-CRi4Ri5-, -NRi6-
Figure imgf000095_0002
m is 0, 1 or 2;
R2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl, optionally substituted by one, two or three substituents each independently represented by
R3; R3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
R7 and Rs are each independently selected from the group consisting of: alkyl, halogen, haloalkyl, and hydrogen; or R7 and Rs taken together are oxo; or R7 and Rs taken together form a carbocycle or a heterocycle;
R16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and
R14 and R15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl.
54. The compound of claim 53, wherein B is selected from:
Figure imgf000096_0001
or
55. The compound of claim 53 or 54, wherein each OfV1, V2, V3, and V4 is CR2.
56. The compound of claim 53 or 54, wherein each OfV1, V2, and V3 is CR2, and V4 is N.
57. The compound of claim 53 or 54, wherein each OfV1, V2, and V4 is CR2, and V3 is N.
58. The compound of any one of claims 53-57, wherein R4 is hydrogen or methyl.
59. The compound of any one of claims 53-58, wherein T is CH2.
60. The compound of any one of claims 53-59, wherein n is 1.
61. The compound of any one of claims 53-59, wherein n is 2.
62. The compound of any one of claims 53-61, wherein A is -CONR16- or -CR14R1S-NR16-
63. The compound of any one of claims 53-62, wherein R16 is H or methyl.
64. A compound represented by formula VI:
Figure imgf000097_0001
and pharmaceutically acceptable salts or N-oxides thereof; wherein
V1, V2, V3, and V4 are selected, independently for each occurrence, from the group consisting of: N and CR2;
X is selected from the group consisting of: NR4, S, SO2, and CR7R8;
T is CO or CR7R8, wherein at least one T is CR7R8; n is 0, 1 or 2;
A is selected from the group consisting of: -CONR16-, -NR16CO-, -O-, -NR16CONR16-, -CR14R15-NR16CO-, -CR14R15-O-, -CR14R15-NR16-, -0-CR14R15-, -NR16-
CR14R15-, -NR16-, 'm and 'm . m is O, 1 or 2;
R2 is independently selected for each occurrence from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl, wherein B is optionally substituted by one, two or three substituents each selected from
R3;
R3 is selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R4 is selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; R7 and Rs are each independently selected from the group consisting of: alkyl, halogen, haloalkyl, and hydrogen, or R7 and Rs taken together are oxo; or R7 and Rs taken together form a carbocycle or a heterocycle;
R11 is alkyl;
R16 is selected from the group consisting of: alkyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen; and
R14 and R15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl.
65. The compound of claim 64, wherein B is selected from:
Figure imgf000098_0001
or
66. The compound of claim 64 or 65, wherein each OfV1, V2, V3, and V4 is CR2.
67. The compound of claim 64 or 65, wherein each OfV1, V2, and V3 is CR2, and V4 is N.
68. The compound of claim 64 or 65, wherein each OfV1, V2, and V4 is CR2, and V3 is N.
69. The compound of any one of claims 64-68, wherein X is NR4.
70. The compound of claim 69, wherein R4 is selected from the group consisting of: alkyl, alkanoyl, and hydrogen.
71. The compound of any one of claims 64-68, wherein X is CR7Rs.
72. The compound of claim 71, wherein X is selected from the group consisting of: CH2, CHOH, and CO.
73. The compound of any one of claims 64-72, wherein T is CH2.
74. The compound of any one of claims 64-73, wherein A is -CONR16- or -CR14R1S-NR16-.
75. The compound of any one of claims 64-74, wherein R16 is hydrogen or methyl.
76. A pharmaceutical composition comprising at least one compound of any one of claims 1-
75 and a pharmaceutically acceptable carrier.
77. A method of treating Alzheimer's disease, Fragile X syndrome, L-DOPA induced dyskinesia, depression, anxiety, migraine, pain, gastroesophageal reflux disease, and/or aiding smoking cessation comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula VII:
Figure imgf000099_0001
VII and pharmaceutically acceptable salts or N-oxides thereof, wherein: each W is independently N or CR1;
V is N or CR2;
X is selected from the group consisting of: O, S, SO2, N, NR4, CR5, CR5R6, and CO; each T is independently selected from the group consisting of: CO, CR7Rs1 and NR9; U is selected from the group consisting of: C, CR1O, and N;
Y is selected from the group consisting of: N, NR11, O, and CR12; Z is selected from the group consisting of: N, NR13, and O;
A is selected from the group consisting of: -CONR16-, -NR16CO-, -0-, -CONR16- CRi4R15-, -NRi6CONRi6-, -CRI4RI5-NRI6CO-, -CRI4RI5-O-, -CRi4Ri5-NRi6-, -0-CRi4Ri5-, -
NRi6-CRi4Ri5-, -NRi6-,
Figure imgf000099_0002
;
B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl; wherein B is optionally substituted by one, two, or three substituents each independently represented by R3; n is O, 1 or 2; m is O, 1 or 2; R1, R2, and R3 are each independently selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;
R4, R9, R11, Ro, and R16 are each independently selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;
R5, R6, R12, R14, and R15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl;
R7 and Rs are each independently selected from the group consisting of: alkoxy, alkyl, halogen, haloalkyl, hydrogen, and hydroxyl, or R7 and Rs taken together are oxo; or R7 and Rs taken together form a carbocycle or a heterocycle; and
R1O is selected from the group consisting of: methyl, oxide, or hydrogen.
78. The method of claim 77, wherein one or two W are N.
79. The method of claim 77, wherein each W and V are C.
80. The method of any one of claims 77-79, wherein R1 and R2 are each independently selected from the group consisting of: alkyl, halogen, and hydrogen.
81. The method of claim 80, wherein R1 and R2 are each independently selected from the group consisting of: chloro, fluoro, hydrogen, and methyl.
82. The method of any one of claims 77-81 , wherein X is selected from the group consisting of: O, S, SO2, N-alkanoyl, NH, NMe, CH2, CF2, CMe2, CHOH, and CO.
83. The method of any one of claims 77-82, wherein T is selected from the group consisting of: CO, CH2, CMe2, NH, and NMe.
84. The method of claim 83, wherein n is 1 or 2.
85. The method of any one of claims 77-84, wherein U, Y, and Z are chosen from one of the following groups:
A) U is C, Y is N-alkyl or NH, and Z is N; B) U is C, Y is N, and Z is N-alkyl;
C) U is N, Y is CH or C-alkyl, and Z is N;
D) U is C, Y is O, and Z is N; and
E) U is C, Y is N, and Z is O.
86. The method of claim 85, wherein U is C, Y is NMe, and Z is N.
87. The method of any one of claims 77-86, wherein A is selected from the group consisting of: -CONH-, -CONMe-, -CH2-NH-, -CH2-NEt-, -CMe2-NH-, -CMe2-O-, -CHMe-O-, -CHMe-
NH-,
Figure imgf000101_0001
m is 0, -NH-CHMe-, -0-CHMe-, -NH-, and -CONH-CH2-.
88. The method of claim 87, wherein A is -CONH-.
89. The method of any one of claims 77-88, wherein B is selected from the group consisting
Figure imgf000101_0002
90. The method of any one of claims 77-89, wherein R1, R2, and R3 are each independently selected from the group consisting of: bromo, carboxamido, chloro, chlorophenyl, cyano, cyclopropyl, diethoxyphenyl, diethylaminoethoxycarbonyl, diethylaminosulfonyl, ethoxycarbonyl, ethoxyphenyl, ethyl, ethylpiperazinylmethylphenyl, fluoro, fluorophenyl, hydrogen, isopropyl, methoxy, methoxycarbonyl, methyl, methylcarbonyl, methylpiperadinylmethylphenyl, methylpiperazinyl, methylthio, nitro, phenyl, piperidinylsulfonyl, sulfonamido, and trifluoromethyl.
91. The method of any one of claims 77-90, wherein the compound of formula VII is selected from the group consisting of:
N-(3 -chlorophenyl)- 1 -methyl -4,5-dihydro-lH-benzo[g]indazole-3-carboxamide; 8-chloro-N-(3-chlorophenyl)-l -methyl- l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide; N-(3-chlorophenyl)-8-fluoro-2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(4-chloropyridin-2-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chlorophenyl)-8-fluoro-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(3-chlorophenyl)-l,4,4-trimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
7-fluoro- 1 -methyl-N-(6-methylpyridin-2-yl)- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
3 -chloro-N-((l -methyl- 1 ,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methyl)aniline; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
N-(6-methylpyridin-2-yl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(4-cyanopyridin-2-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l -methyl- l,4-dihydrochromeno[4,3-c]pyrazole- 3 -carboxamide;
(2H-benzo[b] [ 1 ,4]oxazin-4(3H)-yl)(l -methyl-1 ,4-dihydrochromeno[4,3-c]pyrazol-3- yl)methanone;
5-acetyl-N-(3-chlorophenyl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-c]quinoline-3- carboxamide;
N-(3-chlorophenyl)-l-methyl-lH-pyrazolo[4,3-c]quinoline-3-carboxamide;
N-(3-chlorophenyl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-c]quinoline-3-carboxamide;
5-bromo-N-ethyl-N-((l -methyl- l,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methyl)furan-2- carboxamide; l-isopropyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; 1 -ethyl -N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-7,8-(2- pyridino)cyclohepta[c]pyrazole-3-carboxamide; l,8-dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]isoquinoline-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline-3- carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydropyrazolo[4,3-c]pyrido[2,3- e]azepine-3 -carboxamide; l,6-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydropyrazolo[3,4-d]pyrido[3,2- b]azepine-3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-6-oxo-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3- c]azepine-3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-l,4,5,6-tetrahydrobenzo[b]pyrazolo[3,4- d]azepine-3 -carboxamide;
5,5-difluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- h]quinoline-3 -carboxamide;
5,5-difluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-benzo[g]indazole-3- carboxamide; l,6-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[b]pyrazolo[3,4- d]azepine-3 -carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-c]quinoline-3- carboxamide; 8-fluoro-l,5-dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- c] quinoline-3 -carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3- c]azepine-3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
1 -methyl-N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1 ,5-d] [ 1 ,4]oxazine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
1 -methyl-N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1 ,5-d] [ 1 ,4]oxazine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro-lH-pyrazolo[4,3-c]isoquinoline-3- carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- c] [ 1 ,5 ]naphthyridine-3 -carboxamide;
9-fluoro- 1 -methyl -N-(6-methylpyridin-2-yl)-6-oxo- 1 ,4,5,6- tetrahydrobenzo[e]pyrazolo[4,3-c]azepine-3-carboxamide; l,5,5-trimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(6-(trifluoromethyl)pyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline- 3 -carboxamide;
1 -methyl-N-(6-methylpyridin-2-yl)-4,5 -dihydro- 1 H-pyrazolo [3 ,4-f] quinoxaline-3 - carboxamide;
9-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline-3- carboxamide; 8-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline-3- carboxamide;
7-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
6-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1 ,5-d] [ 1 ,4]oxazine-3-carboxamide;
N-(6-cyclopropylpyridin-2-yl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(l-methyl-5-phenyl-lH-pyrrol-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- h]quinoline-3 -carboxamide;
6-methyl-N-(2-(l -methyl -4, 5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-yl)propan-2- yl)pyridin-2-amine;
3-(2-(3-chlorophenoxy)propan-2-yl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline;
6-methyl-N-(l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-yl)picolinamide;
3 -( 1 -(3 -chlorophenoxy)ethyl)- 1 -methyl -4, 5 -dihydro- 1 H-pyrazolo [4,3 -h] quinoline;
6-cyclopropyl-N-(l-(l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3- yl)ethyl)pyridin-2-amine;
1 -methyl-N-(6-methylpyridin-2-yl)- 1 ,4,5 ,6-tetrahydro-6,7-(2- pyridino)cyclopenta[c]pyrazole-3-carboxamide; l-methyl-N-(2-methylpyrimidin-4-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(6-methylpyrazin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
9-fluoro- 1 -methyl-N-(6-methylpyridin-2-yl)-5-oxo- 1 ,4,5 ,6- tetrahydrobenzo[b]pyrazolo[3,4-d]azepine-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5,7,8-tetrahydrobenzo-lH-oxepino[4,5-c]pyrazole-
3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3-c]azepine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5,7,8-tetrahydrobenzo-lH-thiepino[4,5-c]pyrazole- 3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-6-dioxo-4,5,7,8-tetrahydro-7,8-(2-pyridino)-lH- thiepino[4,5-c]pyrazole-3-carboxamide; l-methyl-3-(l-(6-methylpyridin-2-yl)azetidin-3-yl)-4,5-dihydro-lH-pyrazolo[4,3- h]quinoline; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-amine;
1 -methyl-N-( 1 -(6-methylpyridin-2-yl)ethyl)-4,5 -dihydro- 1 H-pyrazolo [4,3 -h] quinolin-3 - amine; l-methyl-3-(l-(6-methylpyridin-2-yl)ethoxy)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]isoquinoline-3- carboxamide;
5-hydroxy-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-benzo[g]indazole-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)- 1,4, 5,6,7, 8-hexahydro-6- hydroxybenzocyclohepta[c]pyrazole-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)- 1,4,5, 6,7,8-hexahydro-6,6- difluorobenzocyclohepta[c]pyrazole-3-carboxamide;
5-hydroxy-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline- 3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-6-hydroxy-7,8-(2- pyridino)cyclohepta[c]pyrazole-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-6,6-difluoro-7,8-(2- pyridino)cyclohepta[c]pyrazole-3-carboxamide;
N-(3-chlorophenyl)-N-methyl-4H-chromeno[3,4-d]isoxazole-3-carboxamide; l-methyl-N-(3-(trifluoromethyl)phenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(3-chlorophenyl)-N,l-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(2-chlorophenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(4-chlorophenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(4-chlorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide;
N-(pyridin-3-yl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-methoxyphenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(4-methoxyphenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chlorophenyl)-l,8-dimethyl-l,4-dihydrothiochromeno[4,3-c]pyrazole-3- carboxamide;
N-(4-fluorophenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chloro-4-fluorophenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(5-chloro-2-methoxyphenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(3-methoxyphenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(5-chloropyridin-2-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chlorophenyl)-l-methyl-l,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chlorobenzyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chlorophenyl)-l -methyl -4,5-dihydro-lH-thieno[2,3-g]indazole-3-carboxamide;
N-(3-chlorophenyl)-4H-thiochromeno[3,4-d]isoxazole-3-carboxamide; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-(6-methyl -2- pyridinyl)-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl -N-2-pyridinyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(3-fluorophenyl)-5-isoxazolyl]-l,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(2-ethoxyphenyl)-5-isoxazolyl]- 1 ,4-dihydro- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-(5-methyl-2- pyridinyl)-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(4-ethoxyphenyl)-5-isoxazolyl]- 1 ,4-dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(3-chlorophenyl)-5-isoxazolyl]-l,4- dihydro- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-3-pyridinyl-; l-methyl-N-(5-methylisoxazol-3-yl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3,5-dimethylphenyl)-l,4-dihydro-l- methyl-;
Benzoic acid, 4-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, methyl ester;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(3,4-diethoxyphenyl)-5- isoxazolyl]- 1 ,4-dihydro- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[4-[(4-ethyl- 1 - piperazinyl)methyl]phenyl] - 1 ,4-dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- l-methyl-N-[4-[(4-methyl- 1 -piperidinyl)methyl]phenyl]-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-[4-(l - piperidinylsulfonyl)phenyl]-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[4-[(diethylamino)sulfonyl]phenyl]- 1 ,4-dihydro- 1 -methyl-; l^-Benzodioxole-S-carboxylic acid, 6-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3- c]pyrazol-3-yl)carbonyl]amino]-, methyl ester;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-(4-methyl-2- oxo-2H-l-benzopyran-7-yl)-;
2-Thiophenecarboxylic acid, 3-[[(l ,4-dihydro- 1 -methyl[ 1 ]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, methyl ester;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,5-difluorophenyl)-l,4-dihydro-l- methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-acetylphenyl)- 1 ,4-dihydro- 1 - methyl-;
Benzoic acid, 4-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, ethyl ester;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[4-(aminosulfonyl)phenyl]- 1 ,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-chlorophenyl)-l,4-dihydro-l- methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-chlorophenyl)-l,4-dihydro-l- methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-cyanophenyl)- 1 ,4-dihydro- 1- methyl-;
N-(2-carbamoylphenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, l,4-dihydro-N-(4-methoxyphenyl)-l- methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-chloro-3-pyridinyl)- 1 ,4-dihydro- 1 - methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-acetylphenyl)- 1 ,4-dihydro- 1 - methyl-;
1 ,3-Benzenedicarboxylic acid, 5-[[(l ,4-dihydro- 1 -methyl[ 1 ]benzopyrano[4,3-c]pyrazol- 3-yl)carbonyl]amino]-, 1,3-dimethyl ester;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-ethylphenyl)- 1 ,4-dihydro-l - methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- l-methyl-N-(2- methylphenyl)-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- l-methyl-N-[2-(4-methyl-l- piperazinyl)phenyl]-;
Benzoic acid, 4-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, 2-(diethylamino)ethyl ester;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(5-chloro-2-pyridinyl)- 1 ,4-dihydro-l - methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, l,4-dihydro-l-methyl-N-[3- (methylthio)phenyl] -;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-ethylphenyl)- 1 ,4-dihydro-l - methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(9-ethyl-9H-carbazol-3-yl)-l,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, l,4-dihydro-l-methyl-N-(2-methyl-3- nitrophenyl)-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-chloro-4-methylphenyl)-l,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-chloro-2-methoxy-5- methylphenyl)- 1 ,4-dihydro- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-[4-(l - methylethyl)phenyl] - ;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-ethylphenyl)- 1 ,4-dihydro-l - methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro-N-(2-methoxy-5- methylphenyl)- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-ethoxyphenyl)- 1 ,4-dihydro-l - methyl-;
Benzoic acid, 2-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, ethyl ester;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro-N-(2-methoxy-5- nitrophenyl)- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,5-dimethoxyphenyl)- 1 ,4-dihydro-l - methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-ethoxyphenyl)- 1 ,4-dihydro-l - methyl-;
Benzoic acid, 2-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, methyl ester;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,3-dihydro- 1 ,4-benzodioxin-6-yl)- 1 ,4-dihydro-l -methyl;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-bromo-2-methylphenyl)-l,4- dihydro- 1 -methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(5-chloro-2,4-dimethoxyphenyl)-l,4- dihydro- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-(3 ,4,5- trimethoxyphenyl)-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, l,4-dihydro-N-(3-methoxyphenyl)-l- methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-fluorophenyl)- 1 ,4-dihydro- 1 - methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(5-chloro-2-methoxyphenyl)-l,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,4-difluorophenyl)-l,4-dihydro-l- methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,4-dimethoxyphenyl)- 1 ,4-dihydro-l - methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-chloro-4-methoxyphenyl)-l,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-chloro-4-fluorophenyl)-l,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-bromo-4-methylphenyl)-l,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, l,4-dihydro-l-methyl-N-[3- (trifluoromethyl)phenyl] -;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-chlorophenyl)-l ,4-dihydro- 1 - methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-fluorophenyl)- 1 ,4-dihydro-l - methyl-; and [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, l,4-dihydro-N-(2-methoxyphenyl)-l- methyl- or pharmaceutically acceptable salts or N-oxides thereof.
92. A pharmaceutical composition comprising at least one compound selected from the group consisting of:
N-(3-chlorophenyl)-l-methyl-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide;
8-chloro-N-(3-chlorophenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(3-chlorophenyl)-8-fluoro-2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(4-chloropyridin-2-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chlorophenyl)-8-fluoro-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(3-chlorophenyl)-l,4,4-trimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
7-fluoro- 1 -methyl-N-(6-methylpyridin-2-yl)- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
3 -chloro-N-((l -methyl- 1 ,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methyl)aniline; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
N-(6-methylpyridin-2-yl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(4-cyanopyridin-2-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole- 3-carboxamide;
(2H-benzo[b] [ 1 ,4]oxazin-4(3H)-yl)(l -methyl-1 ,4-dihydrochromeno[4,3-c]pyrazol-3- yl)methanone;
5-acetyl-N-(3-chlorophenyl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-c]quinoline-3- carboxamide; N-(3-chlorophenyl)-l-methyl-lH-pyrazolo[4,3-c]quinoline-3-carboxamide;
N-(3-chlorophenyl)-l -methyl -4,5-dihydro-lH-pyrazolo[4,3-c]quinoline-3-carboxamide;
5-bromo-N-ethyl-N-((l-methyl-l,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methyl)flιran-2- carboxamide; l-isopropyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-ethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-7,8-(2- pyridino)cyclohepta[c]pyrazole-3-carboxamide; l,8-dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]isoquinoline-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline-3- carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydropyrazolo[4,3-c]pyrido[2,3- e]azepine-3 -carboxamide; l,6-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydropyrazolo[3,4-d]pyrido[3,2- b]azepine-3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-6-oxo-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3- c]azepine-3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-l,4,5,6-tetrahydrobenzo[b]pyrazolo[3,4- d]azepine-3 -carboxamide;
5,5-difluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- h]quinoline-3 -carboxamide; 5,5-difluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-benzo[g]indazole-3- carboxamide; l,6-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[b]pyrazolo[3,4- d]azepine-3 -carboxamide;
1 ,5 -dimethyl-N-(6-methylpyridin-2-yl)-4,5 -dihydro- 1 H-pyrazolo [4,3 -c] quinoline-3 - carboxamide;
8-fluoro-l,5-dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- c] quinoline-3 -carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3- c]azepine-3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
1 -methyl-N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1 ,5-d] [ 1 ,4]oxazine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
1 -methyl-N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1 ,5-d] [ 1 ,4]oxazine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro-lH-pyrazolo[4,3-c]isoquinoline-3- carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- c] [ 1 ,5]naphthyridine-3-carboxamide;
9-fluoro- 1 -methyl -N-(6-methylpyridin-2-yl)-6-oxo- 1 ,4,5,6- tetrahydrobenzo[e]pyrazolo[4,3-c]azepine-3-carboxamide; l,5,5-trimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(6-(trifluoromethyl)pyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-
3-carboxamide;
1 -methyl-N-(6-methylpyridin-2-yl)-4,5 -dihydro- 1 H-pyrazolo [3 ,4-f] quinoxaline-3 - carboxamide;
9-fluoro- 1 -methyl -N-(6-methylpyridin-2-yl)-4,5 -dihydro- 1 H-pyrazolo [3 ,4-f] quinoline-3 - carboxamide;
8-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline-3- carboxamide;
7-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
6-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1 ,5-d] [ 1 ,4]oxazine-3-carboxamide;
N-(6-cyclopropylpyridin-2-yl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(l-methyl-5-phenyl-lH-pyrrol-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- h] quinoline-3 -carboxamide;
6-methyl-N-(2-(l -methyl -4, 5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-yl)propan-2- yl)pyridin-2-amine;
3-(2-(3-chlorophenoxy)propan-2-yl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline;
6-methyl-N-(l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-yl)picolinamide;
3 -( 1 -(3 -chlorophenoxy)ethyl)- 1 -methyl -4, 5 -dihydro- 1 H-pyrazolo [4,3 -h] quinoline;
6-cyclopropyl-N-(l-(l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3- yl)ethyl)pyridin-2-amine;
1 -methyl-N-(6-methylpyridin-2-yl)- 1 ,4,5 ,6-tetrahydro-6,7-(2- pyridino)cyclopenta[c]pyrazole-3-carboxamide; l-methyl-N-(2-methylpyrimidin-4-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(6-methylpyrazin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
9-fluoro- 1 -methyl -N-(6-methylpyridin-2-yl)-5-oxo- 1 ,4,5,6- tetrahydrobenzo[b]pyrazolo[3,4-d]azepine-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5,7,8-tetrahydrobenzo-lH-oxepino[4,5-c]pyrazole- 3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3-c]azepine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5,7,8-tetrahydrobenzo-lH-thiepino[4,5-c]pyrazole- 3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-6-dioxo-4,5,7,8-tetrahydro-7,8-(2-pyridino)-lH- thiepino[4,5-c]pyrazole-3-carboxamide; l-methyl-3-(l-(6-methylpyridin-2-yl)azetidin-3-yl)-4,5-dihydro-lH-pyrazolo[4,3- h]quinoline; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-amine;
1 -methyl-N-( 1 -(6-methylpyridin-2-yl)ethyl)-4,5 -dihydro- 1 H-pyrazolo [4,3 -h] quinolin-3 - amine; l-methyl-3-(l-(6-methylpyridin-2-yl)ethoxy)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]isoquinoline-3- carboxamide;
5-hydroxy-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-benzo[g]indazole-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)- 1,4, 5,6,7, 8-hexahydro-6- hydroxybenzocyclohepta[c]pyrazole-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)- 1,4,5, 6,7,8-hexahydro-6,6- difluorobenzocyclohepta[c]pyrazole-3-carboxamide;
5-hydroxy-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline- 3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-6-hydroxy-7,8-(2- pyridino)cyclohepta[c]pyrazole-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-6,6-difluoro-7,8-(2- pyridino)cyclohepta[c]pyrazole-3-carboxamide;
N-(3-chlorophenyl)-N-methyl-4H-chromeno[3,4-d]isoxazole-3-carboxamide;
1 -methyl-N-(3 -(trifluoromethyl)phenyl)- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 - carboxamide;
N-(3-chlorophenyl)-N, 1 -dimethyl- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(2-chlorophenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(4-chlorophenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(4-chlorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide;
N-(pyridin-3-yl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-methoxyphenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(4-methoxyphenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chlorophenyl)-l,8-dimethyl-l,4-dihydrothiochromeno[4,3-c]pyrazole-3- carboxamide;
N-(4-fluorophenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chloro-4-fluorophenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(5-chloro-2-methoxyphenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(3-methoxyphenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(5-chloropyridin-2-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chlorophenyl)-l-methyl-l,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chlorobenzyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chlorophenyl)-l -methyl -4,5-dihydro-lH-thieno[2,3-g]indazole-3-carboxamide;
N-(3-chlorophenyl)-4H-thiochromeno[3,4-d]isoxazole-3-carboxamide;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-(6-methyl -2- pyridinyl)-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl -N-2-pyridinyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(3-fluorophenyl)-5-isoxazolyl]-l,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(2-ethoxyphenyl)-5-isoxazolyl]- 1 ,4-dihydro- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-(5-methyl-2- pyridinyl)-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(4-ethoxyphenyl)-5-isoxazolyl]- 1 ,4-dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(3-chlorophenyl)-5-isoxazolyl]-l,4- dihydro- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-3-pyridinyl-; l-methyl-N-(5-methylisoxazol-3-yl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3,5-dimethylphenyl)-l,4-dihydro-l- methyl-;
Benzoic acid, 4-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, methyl ester; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[3-(3,4-diethoxyphenyl)-5- isoxazolyl]- 1 ,4-dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[4-[(4-ethyl-l- piperazinyl)methyl]phenyl] - 1 ,4-dihydro- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-[4-[(4-methyl- 1 -piperidinyl)methyl]phenyl]-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-[4-(l - piperidinylsulfonyl)phenyl]-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[4-[(diethylamino)sulfonyl]phenyl]- 1 ,4-dihydro- 1 -methyl-; l,3-Benzodioxole-5-carboxylic acid, 6-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3- c]pyrazol-3-yl)carbonyl]amino]-, methyl ester;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-(4-methyl-2- oxo-2H-l-benzopyran-7-yl)-;
2-Thiophenecarboxylic acid, 3-[[(l ,4-dihydro- 1 -methyl[ 1 ]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, methyl ester;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,5-difluorophenyl)-l,4-dihydro-l- methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-acetylphenyl)- 1 ,4-dihydro- 1 - methyl-;
Benzoic acid, 4-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, ethyl ester;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-[4-(aminosulfonyl)phenyl]- 1 ,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-chlorophenyl)-l,4-dihydro-l- methyl-; [l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-chlorophenyl)-l,4-dihydro-l- methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-cyanophenyl)- 1 ,4-dihydro-l - methyl-;
N-(2-carbamoylphenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, l,4-dihydro-N-(4-methoxyphenyl)-l- methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-chloro-3-pyridinyl)- 1 ,4-dihydro- 1 - methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-acetylphenyl)- 1 ,4-dihydro- 1 - methyl-;
1 ,3-Benzenedicarboxylic acid, 5-[[(l ,4-dihydro- 1 -methyl[ 1 ]benzopyrano[4,3-c]pyrazol- 3-yl)carbonyl]amino]-, 1,3-dimethyl ester;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-ethylphenyl)- 1 ,4-dihydro-l - methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- l-methyl-N-(2- methylphenyl)-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- l-methyl-N-[2-(4-methyl-l- piperazinyl)phenyl]-;
Benzoic acid, 4-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, 2-(diethylamino)ethyl ester;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(5-chloro-2-pyridinyl)- 1 ,4-dihydro-l - methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro-l -methyl-N-[3- (methylthio)phenyl] -; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-ethylphenyl)- 1 ,4-dihydro-l - methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(9-ethyl-9H-carbazol-3-yl)-l,4- dihydro- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-(2-methyl-3- nitrophenyl)-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-chloro-4-methylphenyl)-l,4- dihydro- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-chloro-2-methoxy-5- methylphenyl)- 1 ,4-dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- l-methyl-N-[4-(l- methylethyl)phenyl] - ;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-ethylphenyl)- 1 ,4-dihydro-l - methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro-N-(2-methoxy-5- methylphenyl)- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-ethoxyphenyl)- 1 ,4-dihydro-l - methyl-;
Benzoic acid, 2-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, ethyl ester;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro-N-(2-methoxy-5- nitrophenyl)- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,5-dimethoxyphenyl)- 1 ,4-dihydro-l - methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-ethoxyphenyl)- 1 ,4-dihydro-l - methyl-; Benzoic acid, 2-[[(l,4-dihydro-l-methyl[l]benzopyrano[4,3-c]pyrazol-3- yl)carbonyl]amino]-, methyl ester;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,3-dihydro-l,4-benzodioxin-6-yl)- 1 ,4-dihydro- 1 -methyl;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-bromo-2-methylphenyl)-l,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(5-chloro-2,4-dimethoxyphenyl)-l,4- dihydro- 1 -methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-(3 ,4,5- trimethoxyphenyl)-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, l,4-dihydro-N-(3-methoxyphenyl)-l- methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-fluorophenyl)- 1 ,4-dihydro-l - methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(5-chloro-2-methoxyphenyl)-l,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,4-difluorophenyl)-l,4-dihydro-l- methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2,4-dimethoxyphenyl)- 1 ,4-dihydro-l - methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-chloro-4-methoxyphenyl)-l,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-chloro-4-fluorophenyl)-l,4- dihydro- 1 -methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(2-bromo-4-methylphenyl)-l,4- dihydro- 1 -methyl-; [ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, 1 ,4-dihydro- 1 -methyl-N-[3-
(trifluoromethyl)phenyl] -;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(3-chlorophenyl)-l,4-dihydro-l- methyl-;
[ 1 ]Benzopyrano[4,3-c]pyrazole-3-carboxamide, N-(4-fluorophenyl)- 1 ,4-dihydro- 1 - methyl-;
[l]Benzopyrano[4,3-c]pyrazole-3-carboxamide, l,4-dihydro-N-(2-methoxyphenyl)-l- methyl-; and pharmaceutically acceptable salts or N-oxides thereof, and a pharmaceutically acceptable carrier.
93. A compound selected from the group consisting of:
N-(3-chlorophenyl)-l -methyl -4, 5-dihydro-lH-benzo[g]indazole-3-carboxamide;
8-chloro-N-(3-chlorophenyl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(3-chlorophenyl)-8-fluoro-2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(4-chloropyridin-2-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(3-chlorophenyl)-8-fluoro-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
N-(3-chlorophenyl)-l,4,4-trimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
7-fluoro- 1 -methyl-N-(6-methylpyridin-2-yl)- 1 ,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide;
3 -chloro-N-((l -methyl- 1 ,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methyl)aniline; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
N-(6-methylpyridin-2-yl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
N-(4-cyanopyridin-2-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide; N-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole-
3-carboxamide;
(2H-benzo[b] [ 1 ,4]oxazin-4(3H)-yl)(l -methyl-1 ,4-dihydrochromeno[4,3-c]pyrazol-3- yl)methanone;
5 -acetyl-N-(3 -chlorophenyl)- 1 -methyl-4,5 -dihydro- 1 H-pyrazolo [4,3 -c] quinoline-3 - carboxamide;
N-(3-chlorophenyl)-l-methyl-lH-pyrazolo[4,3-c]quinoline-3-carboxamide;
N-(3 -chlorophenyl)- 1 -methyl -4, 5-dihydro-lH-pyrazolo[4,3-c]quinoline-3-carboxamide;
5-bromo-N-ethyl-N-((l-methyl-l,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methyl)flιran-2- carboxamide; l-isopropyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-ethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-7,8-(2- pyridino)cyclohepta[c]pyrazole-3-carboxamide; l,8-dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]isoquinoline-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline-3- carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydropyrazolo[4,3-c]pyrido[2,3- e]azepine-3 -carboxamide; l,6-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydropyrazolo[3,4-d]pyrido[3,2- b]azepine-3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-6-oxo-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3- c]azepine-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-l,4,5,6-tetrahydrobenzo[b]pyrazolo[3,4- d]azepine-3-carboxamide;
5,5-difluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- h] quinoline-3 -carboxamide;
5,5-difluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-benzo[g]indazole-3- carboxamide; l,6-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[b]pyrazolo[3,4- d]azepine-3 -carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-c]quinoline-3- carboxamide;
8-fluoro-l,5-dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- c] quinoline-3 -carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3- c]azepine-3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
1 -methyl-N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1 ,5-d] [ 1 ,4]oxazine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
1 -methyl-N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1 ,5-d] [ 1 ,4]oxazine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-5-oxo-4,5-dihydro-lH-pyrazolo[4,3-c]isoquinoline-3- carboxamide; l,5-dimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- c] [ 1 ,5]naphthyridine-3-carboxamide;
9-fluoro- 1 -methyl-N-(6-methylpyridin-2-yl)-6-oxo- 1 ,4,5 ,6- tetrahydrobenzo[e]pyrazolo[4,3-c]azepine-3-carboxamide; l,5,5-trimethyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(6-(trifluoromethyl)pyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline- 3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoxaline-3- carboxamide;
9-fluoro- 1 -methyl-N-(6-methylpyridin-2-yl)-4,5 -dihydro- 1 H-pyrazolo [3 ,4-f] quinoline-3 - carboxamide;
8-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]quinoline-3- carboxamide;
7-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
6-fluoro-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
N-(6-methylpyridin-2-yl)-4H-benzo[b]imidazo[ 1 ,5-d] [ 1 ,4]oxazine-3-carboxamide;
N-(6-cyclopropylpyridin-2-yl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(l-methyl-5-phenyl-lH-pyrrol-2-yl)-4,5-dihydro-lH-pyrazolo[4,3- h] quinoline-3 -carboxamide;
6-methyl-N-(2-(l -methyl -4, 5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-yl)propan-2- yl)pyridin-2-amine;
3-(2-(3-chlorophenoxy)propan-2-yl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline; 6-methyl-N-(l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-yl)picolinamide;
3-(l-(3-chlorophenoxy)ethyl)-l -methyl -4, 5-dihydro-lH-pyrazolo[4,3-h]quinoline;
6-cyclopropyl-N-(l-(l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3- yl)ethyl)pyridin-2-amine;
1 -methyl-N-(6-methylpyridin-2-yl)- 1 ,4,5 ,6-tetrahydro-6,7-(2- pyridino)cyclopenta[c]pyrazole-3-carboxamide; l-methyl-N-(2-methylpyrimidin-4-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide; l-methyl-N-(6-methylpyrazin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide;
9-fluoro- 1 -methyl-N-(6-methylpyridin-2-yl)-5-oxo- 1 ,4,5,6- tetrahydrobenzo[b]pyrazolo[3,4-d]azepine-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5,7,8-tetrahydrobenzo-lH-oxepino[4,5-c]pyrazole- 3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6-tetrahydrobenzo[e]pyrazolo[4,3-c]azepine-3- carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-4,5,7,8-tetrahydrobenzo-lH-thiepino[4,5-c]pyrazole- 3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-6-dioxo-4,5,7,8-tetrahydro-7,8-(2-pyridino)-lH- thiepino[4,5-c]pyrazole-3-carboxamide; l-methyl-3-(l-(6-methylpyridin-2-yl)azetidin-3-yl)-4,5-dihydro-lH-pyrazolo[4,3- h]quinoline; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinolin-3-amine;
1 -methyl-N-( 1 -(6-methylpyridin-2-yl)ethyl)-4,5 -dihydro- 1 H-pyrazolo [4,3 -h] quinolin-3 - amine; l-methyl-3-(l-(6-methylpyridin-2-yl)ethoxy)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline; l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[3,4-f]isoquinoline-3- carboxamide;
5-hydroxy-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-benzo[g]indazole-3- carboxamide;
1 -methyl-N-(6-methylpyridin-2-yl)- 1 ,4,5 ,6,7,8-hexahydro-6- hydroxybenzocyclohepta[c]pyrazole-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)- 1,4,5, 6,7,8-hexahydro-6,6- difluorobenzocyclohepta[c]pyrazole-3-carboxamide;
5-hydroxy-l-methyl-N-(6-methylpyridin-2-yl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline- 3 -carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-6-hydroxy-7,8-(2- pyridino)cyclohepta[c]pyrazole-3-carboxamide; l-methyl-N-(6-methylpyridin-2-yl)-l,4,5,6,7,8-hexahydro-6,6-difluoro-7,8-(2- pyridino)cyclohepta[c]pyrazole-3-carboxamide; and pharmaceutically acceptable salts or N-oxides thereof.
PCT/EP2009/064015 2008-10-27 2009-10-23 Tricyclic compounds as glutamate receptor modulators WO2010049366A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US13/126,118 US20110263588A1 (en) 2008-10-27 2009-10-23 Tricyclic compounds as glutamate receptor modulators
JP2011532652A JP2012506848A (en) 2008-10-27 2009-10-23 Tricyclic compounds as glutamate receptor modulators
EP09740889A EP2346832A1 (en) 2008-10-27 2009-10-23 Tricyclic compounds as glutamate receptor modulators

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10866608P 2008-10-27 2008-10-27
US61/108,666 2008-10-27

Publications (1)

Publication Number Publication Date
WO2010049366A1 true WO2010049366A1 (en) 2010-05-06

Family

ID=41401883

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/064015 WO2010049366A1 (en) 2008-10-27 2009-10-23 Tricyclic compounds as glutamate receptor modulators

Country Status (4)

Country Link
US (1) US20110263588A1 (en)
EP (1) EP2346832A1 (en)
JP (1) JP2012506848A (en)
WO (1) WO2010049366A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011151361A1 (en) * 2010-06-03 2011-12-08 Glaxo Group Limited Novel compounds
WO2014209980A1 (en) * 2013-06-24 2014-12-31 Merck Patent Gmbh Pyrazole compounds as modulators of fshr and uses thereof
WO2016174616A1 (en) * 2015-04-30 2016-11-03 Novartis Ag Fused tricyclic pyrazole derivatives useful for modulating farnesoid x receptors
WO2017033019A1 (en) 2015-08-26 2017-03-02 Fundación Centro Nacional De Investigaciones Oncológicas Carlos Iii (Cnio) Condensed tricyclic compounds as protein kinase inhibitors
CN109789149A (en) * 2016-05-25 2019-05-21 阿卡纳治疗学有限公司 For treating the fused bicyclic compound of disease
US11530218B2 (en) 2020-01-20 2022-12-20 Incyte Corporation Spiro compounds as inhibitors of KRAS
US11739102B2 (en) 2020-05-13 2023-08-29 Incyte Corporation Fused pyrimidine compounds as KRAS inhibitors
US11767320B2 (en) 2020-10-02 2023-09-26 Incyte Corporation Bicyclic dione compounds as inhibitors of KRAS
US11939328B2 (en) 2021-10-14 2024-03-26 Incyte Corporation Quinoline compounds as inhibitors of KRAS
WO2024044778A3 (en) * 2022-08-26 2024-04-04 Celmatix Inc. Novel modulators of fshr and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007262A1 (en) * 1993-09-09 1995-03-16 Merck Sharp & Dohme Limited Fused tricyclic heteroaromatic derivatives as dopamine receptor subtype ligands
US20030114432A1 (en) * 2001-09-19 2003-06-19 Michael Clare Substituted pyrazolyl compounds for the treatment of inflammation
WO2005030128A2 (en) * 2003-09-23 2005-04-07 Merck & Co., Inc. Pyrazole modulators of metabotropic glutamate receptors
WO2008035356A2 (en) * 2006-09-20 2008-03-27 Glenmark Pharmaceuticals Limited Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
WO2009010824A1 (en) * 2007-07-13 2009-01-22 Glenmark Pharmaceuticals, S.A. Dihydrochromenopyrazole derivatives as vanilloid receptor ligands

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007262A1 (en) * 1993-09-09 1995-03-16 Merck Sharp & Dohme Limited Fused tricyclic heteroaromatic derivatives as dopamine receptor subtype ligands
US20030114432A1 (en) * 2001-09-19 2003-06-19 Michael Clare Substituted pyrazolyl compounds for the treatment of inflammation
WO2005030128A2 (en) * 2003-09-23 2005-04-07 Merck & Co., Inc. Pyrazole modulators of metabotropic glutamate receptors
WO2008035356A2 (en) * 2006-09-20 2008-03-27 Glenmark Pharmaceuticals Limited Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
WO2009010824A1 (en) * 2007-07-13 2009-01-22 Glenmark Pharmaceuticals, S.A. Dihydrochromenopyrazole derivatives as vanilloid receptor ligands

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
G. MURINEDDU ET. AL.: "Tricyclic Pyrazoles. 3. Synthesis, Biological Evaluation and Molecular Modelling of Analogues of the Cannabinoid Antagonist 8-Chloro-1-(2'-4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, no. 23, 19 October 2005 (2005-10-19), pages 7351 - 7362, XP002560419 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011151361A1 (en) * 2010-06-03 2011-12-08 Glaxo Group Limited Novel compounds
WO2014209980A1 (en) * 2013-06-24 2014-12-31 Merck Patent Gmbh Pyrazole compounds as modulators of fshr and uses thereof
CN105473596A (en) * 2013-06-24 2016-04-06 默克专利有限公司 Pyrazole compounds as modulators of FSHR and uses thereof
US10081637B2 (en) 2013-06-24 2018-09-25 Merck Patent Gmbh Pyrazole compounds as modulators of FSHR and uses thereof
CN105473596B (en) * 2013-06-24 2019-04-30 默克专利有限公司 Pyrazole compound and application thereof as follicle-stimulating hormone receptor regulator
US11365199B2 (en) 2013-06-24 2022-06-21 Merck Patent Gmbh Pyrazole compounds as modulators of FSHR and uses thereof
CN107531721B (en) * 2015-04-30 2020-07-17 诺华股份有限公司 Fused tricyclic pyrazole derivatives for modulating farnesoid X receptors
WO2016174616A1 (en) * 2015-04-30 2016-11-03 Novartis Ag Fused tricyclic pyrazole derivatives useful for modulating farnesoid x receptors
CN107531721A (en) * 2015-04-30 2018-01-02 诺华股份有限公司 For the tricyclic pyrazole derivatives for the fusion for adjusting farnesoid X receptor
US10351576B2 (en) 2015-04-30 2019-07-16 Novartis Ag Fused tricyclic pyrazole derivatives useful for farnesoid X receptors
WO2017033019A1 (en) 2015-08-26 2017-03-02 Fundación Centro Nacional De Investigaciones Oncológicas Carlos Iii (Cnio) Condensed tricyclic compounds as protein kinase inhibitors
EP3463372A4 (en) * 2016-05-25 2019-11-13 Akarna Therapeutics, Ltd. Fused bicyclic compounds for the treatment of disease
CN109789149A (en) * 2016-05-25 2019-05-21 阿卡纳治疗学有限公司 For treating the fused bicyclic compound of disease
US11530218B2 (en) 2020-01-20 2022-12-20 Incyte Corporation Spiro compounds as inhibitors of KRAS
US11739102B2 (en) 2020-05-13 2023-08-29 Incyte Corporation Fused pyrimidine compounds as KRAS inhibitors
US11767320B2 (en) 2020-10-02 2023-09-26 Incyte Corporation Bicyclic dione compounds as inhibitors of KRAS
US11939328B2 (en) 2021-10-14 2024-03-26 Incyte Corporation Quinoline compounds as inhibitors of KRAS
WO2024044778A3 (en) * 2022-08-26 2024-04-04 Celmatix Inc. Novel modulators of fshr and uses thereof

Also Published As

Publication number Publication date
US20110263588A1 (en) 2011-10-27
EP2346832A1 (en) 2011-07-27
JP2012506848A (en) 2012-03-22

Similar Documents

Publication Publication Date Title
WO2010049366A1 (en) Tricyclic compounds as glutamate receptor modulators
CN103038229B (en) Heteroaryl compound and using method thereof
ES2364046T3 (en) GAMMA-SUBSTITUTED TRICYCLIC CARBOLINES USED AS AGONISTS AND ANTAGONISTS OF SEROTONINE RECEPTORS.
JP7191826B2 (en) tricyclic RHO kinase inhibitor
US6048868A (en) Melatonin-antagonist β-carboline derivatives and analogues thereof containing naphthalenic structure, process for their preparation and their use as medicinal products
ES2734735T3 (en) 4-Oxo-3,4-dihydro-1,2,3, -benzotriazine derivatives as modulators of GPR139
WO2005103039A1 (en) 2- (3-aminopyrrolidin-1-yl) pyridines as melanin-concentrating hormone receptor an tagonists
KR20100039339A (en) Fused quinoline derivatives useful as gaba modulators
JP2002510695A (en) Thiazolo [4,5-d] pyrimidines and pyridines as corticotropin releasing factor (CRF) antagonists
WO2005044822A1 (en) Bicyclic pyrazolyl and imidazolyl compounds and uses thereof
EP2445877B1 (en) Bicyclic compounds and methods of making and using same
HU205354B (en) Process for producing new tricyclic benzimidazoles and pharmaceutical compositions comprising same
WO2009030952A2 (en) Phenylcarboxamide derivatives as inhibitors and effectors of the hedgehog pathway
WO2012114252A1 (en) Novel indole and pyrrolopyridine amides
KR100760072B1 (en) Ring fused pyrazole derivatives
JP2018150349A (en) Heteroaryl compounds and methods of use thereof
EP3534888B1 (en) Substituted bicyclic heteroaryl allosteric modulators of nicotinic acetylcholine receptors
WO2012052451A1 (en) Metabotropic glutamate receptor modulators
WO2021237038A1 (en) Competitive and noncompetitive inhibitors of the muscarinic acetylcholine receptor m5
WO2012085166A1 (en) Metabotropic glutamate receptor modulators
NZ200218A (en) Imidazo(1,2-a)quinoline derivatives
WO2023150526A1 (en) Competitive and noncompetitive octahydrocyclopenta[c]pyrrole inhibitors of the muscarinic acetylcholine receptor m5
JP2022037120A (en) 2-Heteroarylaminoquinazolinone derivative

Legal Events

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

Ref document number: 09740889

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2009740889

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2011532652

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 13126118

Country of ref document: US