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EP2029535A1 - Isoindole derivatives useful for treating pain, gastrointestinal diseases and cancer - Google Patents

Isoindole derivatives useful for treating pain, gastrointestinal diseases and cancer

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Publication number
EP2029535A1
EP2029535A1 EP07748167A EP07748167A EP2029535A1 EP 2029535 A1 EP2029535 A1 EP 2029535A1 EP 07748167 A EP07748167 A EP 07748167A EP 07748167 A EP07748167 A EP 07748167A EP 2029535 A1 EP2029535 A1 EP 2029535A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
alkoxy
oxo
amino
halogenated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07748167A
Other languages
German (de)
French (fr)
Inventor
Yun-Xing Cheng
Miroslaw Tomaszewski
Hua Yang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP2029535A1 publication Critical patent/EP2029535A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • 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
    • 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
    • A61P25/14—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
    • A61P25/28—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
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • Isoindole derivatives useful for treating pain, gastrointestinal diseases and cancer are useful for treating pain, gastrointestinal diseases and cancer.
  • the invention is related to therapeutic compounds, pharmaceutical compositions containing these compounds, manufacturing processes thereof and uses thereof. Particularly, the present invention is related to compounds that may be effective in treating pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and/or cardiovascular disorders. 2. Discussion of Relevant Technology
  • Pain management has been an important field of study for many years. It has been well known that cannabinoid receptor (e.g., CBi receptor, CB 2 receptor) ligands including agonists, antagonists and inverse agonists produce relief of pain in a variety of animal models by interacting with CBi and/or CB 2 receptors.
  • cannabinoid receptor e.g., CBi receptor, CB 2 receptor
  • CBi receptors are located predominately in the central nervous system
  • CB 2 receptors are located primarily in the periphery and are primarily restricted to the cells and tissues derived from the immune system.
  • CBi receptor agonists such as ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC) and anadamide
  • CNS side effects e.g., psychoactive side effects, the abuse potential, drug dependence and tolerance, etc.
  • CBi receptors located in CNS There are lines of evidence, however, suggesting that CBl agonists acting at peripheral sites or with limited CNS exposure can manage pain in humans or animals with much improved overall in vivo profile. Therefore, there is a need for new CBi receptor ligands such as agonists that may be useful in managing pain or treating other related symptoms or diseases with reduced or minimal undesirable CNS side effects.
  • the present invention provides CBi receptor ligands which may be useful in treating pain and/or other related symptoms or diseases.
  • C m-n or "C m-n group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • hydrocarbon used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.
  • hydrocarbon radical or “hydrocarbyl” used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon
  • alkyl used alone or as a suffix or prefix, refers to a saturated monovalent straight or branched chain hydrocarbon radical comprising 1 to about 12 carbon atoms.
  • alkyls include, but are not limited to, C 1-6 alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l- pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, such as
  • alkylene used alone or as suffix or prefix, refers to divalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together.
  • alkenyl used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 2 up to about 12 carbon atoms.
  • the double bond of an alkenyl can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkenyl groups include, but are not limited to C ⁇ - ⁇ alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3- butene)-pentenyl.
  • An alkenyl can be unsubstituted or substituted with one or two suitable substituents.
  • alkynyl used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond and comprising at least 2 up to about 12 carbon atoms.
  • the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkynyl groups include, but are not limited to, C 2 - 6 alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l -butynyl, 4-propyl-2-pentynyl, and 4-butyl- 2-hexynyl.
  • An alkynyl can be unsubstituted or substituted with one or two suitable substituents.
  • cycloalkyl refers to a saturated monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.
  • cycloalkyls include, but are not limited to, Cs ⁇ cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes.
  • a cycloalkyl can be unsubstituted or substituted by one or two suitable substituents.
  • the cycloalkyl is a monocyclic ring or bicyclic ring.
  • cycloalkenyl used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms.
  • cycloalkynyl used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon triple bond and comprising about 7 up to about 12 carbon atoms.
  • aryl used alone or as suffix or prefix, refers to a monovalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms.
  • arylene used alone or as suffix or prefix, refers to a divalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, ⁇ e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, which serves to link two structures together.
  • heterocycle used alone or as a suffix or prefix, refers to a ring-containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s).
  • Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or tmfused. Fused rings generally refer to at least two rings share two atoms therebetween. Heterocycle may have aromatic character or may not have aromatic character.
  • heteromatic used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s), wherein the ring-containing structure or molecule has an aromatic character (e.g., 4n + 2 delocalized electrons).
  • heterocyclic group refers to a radical derived from a heterocycle by removing one or more hydrogens thereftom.
  • heterocyclyl used alone or as a suffix or prefix, refers a monovalent radical derived from a heterocycle by removing one hydrogen therefrom.
  • heterocyclylene used alone or as a suffix or prefix, refers to a divalent radical derived from a heterocycle by removing two hydrogens therefrom, which serves to links two structures together.
  • five-membered used as prefix refers to a group having a ring that contains five ring atoms.
  • a five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms ⁇ wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.
  • Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl.
  • a six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.
  • heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • heteroaryl used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character.
  • heterocycloalkyl used alone or as a suffix or prefix, refers to a monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and having no unsaturation.
  • heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, and pyranyl.
  • a heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substituents.
  • the heterocycloalkyl group is a monocyclic or bicyclic ring, more preferably, a monocyclic ring, wherein the ring comprises from 3 to 6 carbon atoms and form 1 to 3 heteroatoms, referred to herein as C 3-6 heterocycloalkyl.
  • Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazol ne, dioxolane, sulfolane 2,3-dihydrofuran, 2,5-dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro-lH-azepine homopipe
  • heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazoIe, tetrazole, 1,2,3-thiadiazole, 1,2,3- oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-triazole, 1,3,4- thiadiazole, and 1,3,4- oxadiazole.
  • aromatic heterocycles for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole
  • heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazi ⁇ e, 1,2-benzisoxazole, benzothiophene, benzoxazo
  • heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.
  • Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyi, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomo ⁇ holinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4
  • heterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.
  • heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteri
  • heterocyclyl includes polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1]heptyl.
  • alkoxy used alone or as a suffix or prefix, refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical.
  • exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy.
  • amine or “amino” refers to -NH 2 .
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Halogenated used as a prefix of a group, means one or more hydrogens on the group are replaced with one or more halogens.
  • RT room temperature
  • DMF dimethyl formamide
  • DIPEA N,N-diisopropylethylamine
  • HATU refers to 2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate.
  • One aspect of the invention is a compound of formula I, a pharmaceutically acceptable salt thereof, a diastereomer, an enantiomer, or a mixture thereof:
  • R 2 is selected from
  • said group used in defining R ⁇ is optionally substituted by one or more groups selected from halogen, halogenated C 1-6 alkyl, C 1-6 alkyl, halogenated C 1-6 alkoxy, cyano, nitro, C 1-6 alkoxy, hydroxy, hydroxy-C 1-6 alkyl, amino, C 1-6 alkyl-C 6-10 aryl, C 1-6 alkoxy-Ci. ealkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylamino, di-C 1-6 alkylamino, di-Cj.
  • R 3 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C ⁇ cycloalkenyl, C 1 . ⁇ alkoxy, and C 2-5 heterocycloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 4- ecycloalkenyl, C 1-6 alkoxy, and C 2-5 heterocycloalkyl used in defining R 3 is optionally substituted by one or more groups selected from halogen, halogenated C h alky!, C 1-6 alkyl, halogenated C 1-6 alkoxy, cyano, nitro, C ⁇ galkoxy, hydroxy, hydroxy-C 1-6 alkyl, amino, Q.
  • alkyl-C ⁇ -ioaryl C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, Ci- 6alkylamino, di-Ci -e alkylamino, di-C 1-6 alkylammo-C 1-6 alkyL, amino-C 1-6 alkyl, d- ⁇ alkyl- arnino-carbonyl, C 2-5 heteroaryl-carbonyl, C 2-5 heterocycloalkyl-carbonyl, C ⁇ -ioarylcarbonyl, C 2-5 heterocycloalkyl, Cs ⁇ cycloalkyl, C3-6cycloalkyl-Ci -6 alkyl, C 2-5 heteroaryl, C 2- sheteroaryl-C 1-6 alkyl, C 6-10 aryl, and C 6 -ioaryl-C 1-6 alkyl;
  • R 4 is selected from Ci -6 alkyl, halogenated C 1-6 alkyl, hydroxy, hydroxy-Cj. ⁇ alkylamino, amino, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, hydroxyamino, Q. 6 alkoxyamino, benzylamino, C 2-5 heterocycloalkyl, C 2-5 heteroaryl, and C 2-5 heteroaryl-Q. ⁇ alkyl;
  • R 1 is selected from hydrogen, methoxy, 2- hydroxyethoxy, benzyloxy, acetoxy and acetylamino.
  • R 1 is selected from ethylsulfonyloxy, and 3- trifluoropropylsulfonyloxy.
  • R 4 is selected from hydroxy, methoxy, amino, methylamino, dimethylamino, hydroxyamino, methoxyamino, beirzylamino, morpholinyl, 2-hydroxyethylamino, and pyridinylmethyl.
  • certain compounds of the present invention are those of fo ⁇ nula I as defined above, wherein R 1 is independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkoxy, C 1 . ⁇ alkyl, halogenated C 1-6 alkoxy, halogenated Q.galkyl, amino, and C 1-6 alkylamino and di-Q. ⁇ alkylamino;
  • R 2 is selected from
  • R 2 wherein said group used in defining R 2 is optionally substituted by one or more groups selected from halogen, halogenated C h alky!, C h alky!, halogenated C 1-6 aUcoxy, cyano, nitro, C 1-6 alkoxy, hydroxy, hydroxy-C 1-6 alkyl, amino, C 1-6 alkyl-C 6-10 aryl, C 1-6 alkoxy-Ci. ⁇ alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylair ⁇ io, di-C 1-6 alkylamino, di-Ci.
  • R 3 is selected from C 1-6 alkyl, C 2-6 alkenyl, C3.6cycloalkyl, C ⁇ cycloalkenyl, Q. ⁇ alkoxy, and C 2-5 heterocycloalkyl; wherein said C 1-6 alkyl, C 2 - 6 alkenyl, C 3-6 cycloalkyl, C 4 .
  • ⁇ cycloalkenyl, C 1-6 alkoxy, and C 2-5 heterocycloalkyl used in defining R 3 is optionally substituted by one or more groups selected from halogen, halogenated C ⁇ aHcyl, C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkoxy, hydroxy, hydroxy-C 1-6 alkyl, amino, C 1-6 alkoxy-Ci. ealkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylamino, and di-C 1-6 alkylamino;
  • R 1 is hydrogen
  • R 2 is selected from
  • said group used in defining R is optionally substituted by one or more groups selected from halogen, halogenated C 1-6 alkyl, C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkoxy, hydroxy, hydroxy-C 1-6 alkyl, amino, C 1-6 alkoxy-C 1-6 alkyl, C 2- sheteroaryl-Ci-6alkyl, Ci- 6 alkylamino, di-C 1-6 alkylamino, di-C 1-6 alkylamino-Ci-salkyl;
  • R 3 is selected from C h alky!, C2. ⁇ alkenyl, Ca- ⁇ cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl and tetrahydropyranyl; wherein said C h alky!, C 2-6 alkenyl, C3.
  • 6 cycloalkyl ; piperdinyl, morpholinyl, and tetrahydropyranyl used in defining R 3 is optionally substituted by one or more groups selected from halogen, halogenated C h alky!, d- ⁇ alkyl, halogenated C 1-6 alkoxy, Ci -6 alkoxy, hydroxy, hydroxy-C 1-6 alkyI, amino, C 1-6 alkoxy-C 1-6 alkyl, Ci- galkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylamino, and di-C 1-6 alkylamino;
  • R 1 is hydrogen
  • R 2 is selected from
  • R 2 is optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
  • R 2 is selected from cyclohexyl, phenyl and naphtbyl, wherein said cyclohexyl, phenyl and naphthyl are optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
  • R 2 is selected from cyclohexyl, phenyl and 1- naphthyl, wherein said cyclohexyl, phenyl and 1 -naphthyl are optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
  • R 2 is selected from phenyl and 1 -naphthyl, wherein said phenyl and 1 -naphthyl are optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
  • R 3 is selected from C 1-6 alkyl, C 2-6 alkenyl, Cs-gcycloalkyl and C 2- 5heterocycIoalkyl, wherein said Q-ealkyl, C 2 - 6 alkenyl, C3- 6 cycloalkyl and C 2- 5 heterocycloalkyl are optionally substituted by one or more groups selected from halogen, halogenated Q.ealkyl, C h alky!, t-butoxycarbonyl, amino, C 1-6 alkoxy-C 1-6 alkyl, Ci. ⁇ alkylamino, and di-C 1-6 alkylamino with a proviso that R 3 is not an optionally substituted 2,6-dioxopiperidi ⁇ -3-yl.
  • R 3 is. selected from Q.ealkyl, C 2 - 6 alkenyl, Cs-gcycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl, wherein said C 1-6 alkyl, C 2- 6alkenyl, Ca- ⁇ cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl are optionally substituted by one or more groups selected from halogen, halogenated C 1-6 alkyl, C ⁇ aUcyl, t-butoxycarbonyl, amino, Cj- ⁇ alkoxy-C 1-6 alkyl, Ci -5 alkylamino, and di-C 1-6 alkylamino.
  • R 3 is selected from C 3-6 cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl, wherein said C 3 .. ⁇ cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl are optionally substituted by one or more groups selected from halogen, halogenated Q- ealkyl, C 1-6 alkyl, t-butoxycarbonyl, amino, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylamino, and di-Ci. galkylamino.
  • the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture.
  • the present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I.
  • the optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.
  • certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes.
  • the present invention includes any geometrical isomer of a compound of Formula I. It will further be understood that the present invention encompasses tautomers of the compounds of the formula I.
  • salts of the compounds of the formula I are also salts of the compounds of the formula I.
  • pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCI or acetic acid, to afford a physiologically acceptable anion.
  • a corresponding alkali metal such as sodium, potassium, or lithium
  • an alkaline earth metal such as a calcium
  • a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.
  • a suitably acidic proton such as a carboxylic acid or a phenol
  • an alkali metal or alkaline earth metal hydroxide or alkoxide such as the ethoxide or methoxide
  • a suitably basic organic amine such as choline or meglumine
  • the compound of formula I above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate.
  • the compounds of the invention exhibit activity as agonist of the CBi receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which dysfunction of CBi receptors is present or implicated. Furthermore, the compounds of the invention may be used to treat cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiavascular disorders.
  • Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.
  • Compounds of the invention are useful in disease states where degeneration or dysfunction of cannabinoid receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
  • PET positron emission tomography
  • Compounds of the invention are useful for the treatment of diarrhea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung edema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
  • stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung edema, various gastro-intestinal disorders, e
  • Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care.
  • Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.
  • Another aspect of the present invention is the use of a compound according to Formula I, for the inhibition of transient lower esophageal sphincter relaxations (TLESRs) and thus for treatment or prevention of gastroesophageal reflux disorder (GERD).
  • TLESRs transient lower esophageal sphincter relaxations
  • GERD gastroesophageal reflux disorder
  • the major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter.
  • TLESRs transient lower esophageal sphincter relaxations
  • the compound according to Formula I are useful for the prevention of reflux, treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive.
  • a further aspect of the present invention is the use of a compound according to Formula I, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations, for the treatment or prevention of GERD, for the prevention of reflux, for the treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive.
  • Still another aspect of the present invention is the use of a compound according to Formula I, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations, for the treatment or prevention of GERD, for the prevention of reflux, for the treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive.
  • Still another aspect of the present invention is the use of a compound according to Formula I, for the manufacture of a medicament for the inhibition of transient lower esophageal sphin
  • Formula I for the manufacture of a medicament for the treatment or prevention of functional gastrointestinal disorders such as functional dyspepsia (FD).
  • a compound according to Formula I for the manufacture of a medicament for the treatment or prevention of irritable bowel syndrome (IBS) such as constipation predominant IBS, diarrhea predominant IBS or alternating bowel movement predominant IBS.
  • IBS irritable bowel syndrome
  • FGD functional gastrointestinal disorders
  • a further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment.
  • the invention provides a compound of formula I, or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • therapy also includes “prophylaxis” unless there are specific indications to the contrary.
  • therapeutic and
  • terapéuticaally should be construed accordingly.
  • the term "therapy” within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition.
  • This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.
  • the compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
  • the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
  • the route of administration may be oral, intravenous or intramuscular.
  • the dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substance, which may also act as diluents, flavoring agents, sohibilizers, lubricants, suspending agents, binders, or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized molds and allowed to cool and solidify.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low- melting wax, cocoa butter, and the like.
  • composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
  • Liquid form compositions include solutions, suspensions, and emulsions.
  • sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical composition will preferably include from 0.05% to 99%w (percent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition.
  • a therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.
  • any compound according to Formula I for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
  • a further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such therapy.
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.
  • composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.
  • Another aspect of the invention is a method of preparing the compounds of the present invention.
  • the method of the invention is a method for preparing a compound of formula I,
  • R 2 -X-Y optionally in the presence of a base, such as diisopropylethylamine, a solvent such as dichloromethane, wherein Y is selected from Cl, Br, F, and OH; and X, R 1 , R 2 and R 3 are defined as above.
  • a base such as diisopropylethylamine
  • a solvent such as dichloromethane
  • Methyl-2-bromoethyl-6-nitro-benzoate (1 equiv.) and the corresponding primary amine (1.8 equiv.) are dissolved in a minimum amount of DMF.
  • Diisopropyl ethylamine (2 equiv.) is added and the mixture is heated at 80°C overnight. Volatiles are evaporated under vacuum, leaving 2-alkyl-7-nitroisoindolin-l-one as a yellow oil (used without further purification). Reactions are performed on 0.5 to 15 mmol scale.
  • 2-Alkyl-7-nitroisoindolin-l-one (-0.5 mmol) is dissolved in 20 ml of methanol. FeClj. ⁇ HaO (200 mg) is added and the mixture is heated to 65°C. Hydrazine hydrate (0.6 ml) is added dropwise. Heating is continued for 15h. After cooling to rt, the mixture is diluted with diethylether (80 ml) and filtered over Celite. Evaporation of solvents leaves an intermediate (2-(alkyl)isoindolin-4-amine) as white to yellow solids. The intermediate is used without further purification.
  • Human CBi receptor from Receptor Biology (hCBi) or human CB 2 receptor from BioSignal (I1CB2) membranes are thawed at 37 °C, passed 3 times through a 25-gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4) and aliquots containing the appropriate amount of protein are distributed into 96-well plates.
  • cannabinoid binding buffer 50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4
  • the IC 50 of the compounds of the invention at hCBi and I1CB 2 are evaluated from 10-point dose-response curves done with 3 H-CP55,940 at 20000 to 25000 dpm per well (0.17-0.21 nM) in a final volume of 300 ⁇ l.
  • the total and non-specific binding are determined in the absence and presence of 0.2 ⁇ M of HU210 respectively.
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered through Unifilters GFfB (presoaked in 0.1% polyethyleneimine) with the Tomtec or Packard harvester using 3 mL of wash buffer (50 mM Tris, 5 mM MgCl 2 , 0.5 mg BSA pH 7.0).
  • the filters are dried for 1 hour at 55 0 C.
  • the radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • Human CBi receptor from Receptor Biology (hCBi) or human CB 2 receptor membranes (BioSignal) are thawed at 37 0 C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTP ⁇ S binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl 2 , pH 7.4, 0.1% BSA).
  • the EC 50 and E max of the compounds of the invention are evaluated from 10-point dose-response curves done in 300 ⁇ l with the appropriate amount of membrane protein and 100000-130000 dpm of GTPg 35 S per well (0.11 -0.14 nM).
  • the basal and maximal stimulated binding is determined in absence and presence of 1 ⁇ M (hCB 2 ) or 10 ⁇ M (hCBi) Win 55,212-2 respectively.
  • the membranes are pre-incubated for 5 minutes with 56.25 ⁇ M (hCB2) or 112.5 ⁇ M (hCBi) GDP prior to distribution in plates (15 ⁇ M (hCB 2 ) or 30 ⁇ M (hCBi) GDP final).
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unifilters GF/B (presoaked in water) with the Tomtec or Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0). The filters are dried for 1 hour at 55 0 C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • wash buffer 50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0.
  • Antagonist reversal studies are done in the same way except that (a) an agonist dose-response curve is done in the presence of a constant concentration of antagonist, or (b) an antagonist dose-response curve is done in the presence of a constant concentration of agonist.
  • Kd is the dissociation constant of the radioactive ligand towards the particular receptor.
  • Certain compounds of the invention's activities towards certain human CBl receptors are tested using the above-mentioned assays and are found to be active.
  • Step B The preparation of 7-amino-2-(cyclobutylmethyl)isoindolin-l-one
  • Step C The preparation of N-[2-(cyclobutylmethyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]- 1-naphthamide
  • Step A The preparation of 2-allyl-7-nitroisoindoIin- 1 -one
  • Step B 2-allyl-7-nitroisoindolin-l-one (206 mg, 0.944 mmol) was reduced with Zinc (300 mg) in HOAc (5 ml) and MeOH (5 ml). The crude product was used without purification.
  • Step C The preparation of N-(2-allyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide
  • Step A The preparation of 7-nitro-2-propylisoi ⁇ dolin-l-one
  • Step B The preparation of 2-propyl-7-aminoisoindoIi ⁇ -l-one
  • 2-Propyl-7-aminoisoindolin-l-one was prepared from 7-nitro-2-propylisoindolin-l-one following General Procedure B. MS (M+l):191, 78% purity (UV detection at 254 nm).
  • Step C The preparation of N-(2-propyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-l- naphthamide
  • N-(2-propyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide (25.6 mg, 74% yield in 3 steps) as white solid was prepared .from 2-propyl-7-aminoisoindolin-l-one and 1-naphthoyl chloride following General Procedure C. MS (M+l): 345.
  • Step A The preparation of 7-nitro-2-butyl-isoindolin-l-one
  • Step B The preparation of 2-butyl-7-aminoisoindoKn-l-one
  • Step C The preparation of N-(2-butyl-3-oxo-2,3-dihydro-lH-isoi ⁇ dol-4-yl)-l-naphthamide
  • N-(2-buryl-3-oxo-2 3 3-diliydro-lH-isoindol-4-yl)-l-naphthamide (18.1 mg, 50% yield in 3 steps) as white solid was prepared from 2-butyl-7-aminoisoindolin-l-one and 1-naphthoyl chloride following General Procedure C. MS (M+l): 359 (M+l).
  • Step A The preparation of 2-[2-(dirnethylarnino)ethyl]-7-mtroisoindolin-l-one
  • Step B The preparation of 7-amino-2-[2-(dimethylar ⁇ ino)ethyl]isoindolm-l-one
  • Step C The preparation ofN- ⁇ 2-[2-(dimethylamino)ethyl]-3-oxo-2 ; 3-dihydro-lH-isoindol- 4-yl ⁇ -1 -naphthamide
  • Step A The preparation of 2-(cyclohexylmethyl)-7-nitroisoindolin-l-one
  • Step B The preparation of 7-amino-2-(cyclohexylmethyl)isoindolin-l-one
  • Step C The preparation of N-[2-(cyclohexylmethyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]- 1- naphthamide
  • Step A The preparation of 2-(tetrahydro-2H-pyran-4-ylmethyl)-7-nitroisoindolin-l-one
  • Step B The preparation of 7-amino-2-(tetrahydro-2H-pyran-4-yhnethyl)isoindolin-l-one
  • Step C The preparation of N-[2-( tetrahydro-2H-pyran-4-ylmethyl)-3-oxo-2,3-dihydro-lH- isoindol-4-yl]-l- naphthamide
  • Step 2 The preparation of tert-butyl 3-(7-nitro-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-l -carboxylate
  • Step B The preparation of tert-butyl 3-(7-amino-l-oxo-l 3 3-dihydro-2H-isoindol-2- yl)piperidine-l -carboxylate
  • Step C The preparation of tert-butyl 3-[7-(l-naphthoylamino)-l-oxo-l,3-dihydro-2H- isoindol-2-yl]piperidine-l-carboxylate
  • Step D The preparation of N-(3-oxo-2-piperidin-3-yl-2,3-dihydro-lH-isoindol-4-yl)-l- naphthamide
  • Step A The preparation of tert-butyl 2-[(7-mtro-l-oxo-l,3-dlhydro-2H-isoindol-2- yl)methyl]piperidine-l -carboxylate
  • Step B The preparation of tert-butyl 2-[(7-amino-l-oxo-l,3-dihydro-2H-isoindol-2- yl)methyl]piperidine-l-carboxylate
  • Step C The preparation of tert-butyl 2- ⁇ [7-(l-naphthoylamino)-l-oxo-l,3-dihydro-2H- isoindol-2-yl]methyl ⁇ piperidine- 1 -carboxylate
  • Step D The preparation of N-[3-oxo-2-(piperidin-2-ylmethyl)-2,3-dihydro-lH-isoindol-4- yl]-l-naphthamide
  • Step A The preparation of tert-butyl 2-( ⁇ 7-[(4-methoxy-l-naphthoyl)amino]-l-oxo-l,3- dihydro-2H-isoindol-2-yl ⁇ methyl)piperidine-l-carboxylate
  • Step B The preparation of 4-methoxy-N-[3-oxo-2-( ⁇ iperidin-2-ylmethyl)-2,3-dihydro-lH- isoindol-4-yl]- 1-naphthamide
  • Step B Preparation of 7-amino-2-(2-mo ⁇ holin-4-ylethyl)isoindolin-l-one hydrate
  • Step A The preparation of 4-(bromomethy I)-I -naphthoic acid
  • Step B The preparation of 4-(methoxymethyl)-l-naphthoic acid
  • Step C The preparation of 4-(methoxymethyl)-N-[3-oxo-2-(tetrahydro-2H-pyran-4- ylmethyl)-2,3 -dihydro- 1 H-isoindol-4-yl]- 1 -naphthamide
  • Step A The preparation of 4-(lH-l,2,3-triazol-l-yhnethyl)-l-naphthoic acid
  • Step B The preparation of N-[3-oxo-2-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-lH- isoindol-4-yl]-4-(lH-l,2,3-triazol-l-yhnethyl)-l-naphthamide
  • N-(2-Allyl-3-oxo-2,3-dihydro-lH-isokidol-4-yl)-2,3-dichlorobenzamide (57 mg, 45% yield in 3 steps) as white solid was prepared from 2-allyl-7-aminoisoindolin-l-one and 2,3- dichlorolbenzoyl chloride following General Procedure C. MS (M+l): 361.1 (M+l).
  • Step A N-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl]naphthylcarboxamide
  • Step B 2-(Cyclohexylmethyl)-7-nitroisoindoli ⁇ -l-one
  • Step C 7-Ammo-2-(cyclohexyhnethyl)isomdolin-l-one
  • Step A N-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl](4-me1hylnaphthyl)carboxaniide
  • Step B 4-Methylnaphthalenecarbonyl chloride
  • Step A N-[2-(Cyclohexymiethyl)-3-oxoisoindolin-4-yl](4-methoxylnaphthyl)carboxamide
  • step A reaction of 7-amino-2- (cyclohexylmethyl) isoindolin-1-one (0.122 g, 0.500 mmol) with 4- methoxynaphthalenecarbonyl chloride (0.202 g, 1.00 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.21 mL, 1.5 mmol) in CHzCl 2 (10 mL), after purification by flash chromatography over silica gel, using EtO Ac/hexanes (1:10 to 1:5), gave the title compound as a white foam, which was crystallized from EtOAc to afford a white solid, 0.11 g (52%).
  • Step A N-[2-(Cyclohexybnethyl)-3-oxoisoindolin-4-yl](4-fluoronaphthyl)carboxamide
  • step A reaction of 7-amino-2- (cyclohexylmethyl)isoindolin-l-one (0.147 g, 0.600 mmol) with 4- fluoronaphthalenecarbonyl chloride (0.170 g, 0.900 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH 2 Cl 2 (10 mL), after purification by flash chromatography over silica gel, using EtO Ac/hexanes (1:10 to 1:5) gave the title compound, as a white foam.
  • step A reaction of 7-amino-2- (cyclohexylmethyl)isoindolm-l-one (0.147 g, 0.600 mmol) with 4,7- (dimethoxy) ⁇ aphthalenecarbonyl chloride (0.210 g, 0.900 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH 2 CI 2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:10 to 1:5), followed by preparative tic (CE ⁇ Gb/hexanes, 2: 1), gave the title compound as a pale yellow foam, which was crystallized from EtOAc/hexanes (1 :3) to afford a pale yellow solid, 0.2 g (73%).
  • Step A Naphthyl-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4-yhnethyl)isoindolin-4- yl)carboxamide
  • Step B 7-Nitro-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one
  • Step C 7-Ami ⁇ o-2-(2H-3,4,5,6-tetrah.ydropyran-4-ylmethyl)isoindolij ⁇ -l-one Compound 6
  • step B reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.148 g, 0.600 mmol) with 4- methylnaphthalenecarbonyl chloride (0.223 g, 1.20 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH 2 CI 2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a white foam, which was crystallized from EtOAc/hexanes (1:1) to afford a white solid, 0.18 g (72%).
  • 1 H NMR 400 MHz,
  • step B reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.123 g, 0.500 mmol) with 4- methoxynaphthalenecarbonyl chloride (0.202 g, 1.00 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.21 mL, 1.5 mmol) in CH 2 Cl 2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a white foam, which was crystallized from EtOAc/hexanes (1:1) to afford a white solid, 0.17 g (79%).
  • step A reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropy ⁇ an-4-ylmeth.yl)isoindolm-l-one (0.148 g, 0.600 mmol) with 4- fluoronaphthalenecarbonyl chloride (0.170 g, 0.900 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH 2 Cl 2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a white foam, which was crystallized from EtOAc to afford a white solid, 0.18 g (72%).
  • step A reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.148 g, 0.600 mmol) with 4,7- dimethoxynaphthalenecarbonyl chloride (0.210 g, 0.900 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH 2 CI 2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a white foam.
  • Step A N-[2-(Morpholin-4-ylethyl)-3-oxoisoindolin-4-yl]naphthylcarboxamide
  • Step B 2-(2-Morpholin-4-yIethyl)-7-nitroisoindolin-l-one
  • step B reaction of 7-amino-2-(2- morpholin-4-ylethyl)isoindolin-l-one (0.15 g, 0.57 mmol) with 4- methylnaphthalenecarbonyl chloride (0.40 g, 1.14 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.16 mL), 1.14 mmol) in CH 2 CI 2 (20 mL) gave the crude product, which was purified by crystallization from C ⁇ Cyhexanes. The title compound was an off-white solid 0.085 g (34%).
  • step B reaction of 7-amino-2-(2- morpholin-4-ylethyl)isomdolin-l-one (0.150 g, 0.57 mmol) with 4- methoxynaphthalenecarbonyl chloride (0.250 g, 1.14 mmol) (prepared according to the procedure of Step B in example 2) and triethylamine (0.16 mL, 1.14 mmol), in dry CH 2 CI 2 (20 mL), after chromatography over silica gel using EtOAc/hexanes (3:7), gave the title compound as a solid. Crystallization from CHaCb/hexanes gave a solid 0.095 g (38%).
  • Step A (4-Methoxynaphthyl)-iV-[3-oxo-2-(2-piperidylethyl)isoindolin-4- yl]carboxamide
  • step B reaction of 7-amino-2-(2- (piperidin-l-ylemyl)isoindolin-l-one (0.150 g, 0.58 mnaol) (for preparation, see the following steps B and C) with 4-methoxynaphthalenecarbonyl chloride (0.250 g, 1.14 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.16 mL, 1.14 mmol) in CH2CI 2 (20 mL), after purification by chromatography over silica gel using CH 2 Cl 2 MeOH (9:1) gave the title compound.
  • Step B 7-Nitro-2-(2-(piperidin-l-ylethyl)isoindolin-l-one
  • Step C 7-Amino-2-(2-(piperidin-l-ylethyl)isoindolm-l-one
  • step B reaction of 7-amino-2-(2- (piperidin-l-ylethyl)isoindolin-l-one (0.200 g, 0.77 mmol) with 4- fluoronaphthalenecarbonyl chloride (0.240 g, 1.15 mmol) (prepared according to the procedure of Step B in example 22.) in CH2CI2 (30 mL), after chromatography over silica gel using CH 2 Cl 2 ZMeOH (98:2 to 95:5) gave the title compound as a solid 0.195 g (57%).
  • Step B N-[2-(cyclohexylmethyl)-3-oxoisoindolin-4-yI][4- (phenylmethoxy)naphthyl] carboxamide
  • step A reaction of 7-amino-2 ⁇ (cyclohexyhnethyl)isoindolin-l-one (0.135 g, 0.550 mmol) with 4- (phenylmethoxy)naphthalenecarbonyl chloride (0.230 g, 0.827 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.24 mL, 1.7 mmol) in CH 2 Cl 2 (10 mL), after purification by flash chromatography over silica gel, using CH 2 Cl 2 /hexanes (1:3 to 1:1) gave the title compound , 0.26 g (94%) as a pale white solid.
  • Step A [4-(Hydroxy)naphthyl)]-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4- ylmethyl)isoindolm-4-yl]carboxamide
  • Step B N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindoIinyl] [4- (phenylmethoxy)naphthyl]carboxamide
  • step B reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.136 g, 0.550 mmol) with 4- (phenylmethoxy)naphthalenecarbonyl chloride (0.230 g, 0.827 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.24 mL, 1.6 mmol) in CH 2 Cl 2 (10 ⁇ iL), after purification by flash chromatography over silica gel, using EtOAc/CH 2 Cl 2 (1:10 to 1:5), gave the title compound, 0.26 g (94%) as a white solid.

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Abstract

Compounds of formula I or pharmaceutically acceptable salts thereof: [Chemical formula should be inserted here. Please see paper copy] I wherein X, R1, R2, R3, m and n are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

Description

Isoindole derivatives useful for treating pain, gastrointestinal diseases and cancer
BACKGROUND OFTHE INVENTION
1. Field of the invention. The invention is related to therapeutic compounds, pharmaceutical compositions containing these compounds, manufacturing processes thereof and uses thereof. Particularly, the present invention is related to compounds that may be effective in treating pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and/or cardiovascular disorders. 2. Discussion of Relevant Technology
Pain management has been an important field of study for many years. It has been well known that cannabinoid receptor (e.g., CBi receptor, CB2 receptor) ligands including agonists, antagonists and inverse agonists produce relief of pain in a variety of animal models by interacting with CBi and/or CB2 receptors. Generally, CBi receptors are located predominately in the central nervous system, whereas CB2 receptors are located primarily in the periphery and are primarily restricted to the cells and tissues derived from the immune system.
While CBi receptor agonists, such as Δ9-tetrahydrocannabinol (Δ9-THC) and anadamide, are useful in anti-nociception models in animals, they tend to exert undesired CNS side effects, e.g., psychoactive side effects, the abuse potential, drug dependence and tolerance, etc. These undesired side effects are known to be mediated by the CBi receptors located in CNS. There are lines of evidence, however, suggesting that CBl agonists acting at peripheral sites or with limited CNS exposure can manage pain in humans or animals with much improved overall in vivo profile. Therefore, there is a need for new CBi receptor ligands such as agonists that may be useful in managing pain or treating other related symptoms or diseases with reduced or minimal undesirable CNS side effects. DESCRIPTION OF THE EMBODIMENTS
The present invention provides CBi receptor ligands which may be useful in treating pain and/or other related symptoms or diseases.
Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by references herein for its exemplary chemical structure names and rales on naming chemical structures.
The term "Cm-n" or "Cm-n group" used alone or as a prefix, refers to any group having m to n carbon atoms.
The term "hydrocarbon" used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.
The term "hydrocarbon radical" or "hydrocarbyl" used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon, The term "alkyl" used alone or as a suffix or prefix, refers to a saturated monovalent straight or branched chain hydrocarbon radical comprising 1 to about 12 carbon atoms. Illustrative examples of alkyls include, but are not limited to, C1-6alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l- pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, such as heptyl, and octyl. An alkyl can be unsubstituted or substituted with one or two suitable substituents.
The term "alkylene" used alone or as suffix or prefix, refers to divalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together.
The term "alkenyl" used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 2 up to about 12 carbon atoms. The double bond of an alkenyl can be unconjugated or conjugated to another unsaturated group. Suitable alkenyl groups include, but are not limited to C∑-βalkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3- butene)-pentenyl. An alkenyl can be unsubstituted or substituted with one or two suitable substituents.
The term "alkynyl" used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond and comprising at least 2 up to about 12 carbon atoms. The triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group. Suitable alkynyl groups include, but are not limited to, C2-6alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l -butynyl, 4-propyl-2-pentynyl, and 4-butyl- 2-hexynyl. An alkynyl can be unsubstituted or substituted with one or two suitable substituents.
The term "cycloalkyl," used alone or as suffix or prefix, refers to a saturated monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms. Examples of cycloalkyls include, but are not limited to, Cs^cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes. A cycloalkyl can be unsubstituted or substituted by one or two suitable substituents. Preferably, the cycloalkyl is a monocyclic ring or bicyclic ring.
The term "cycloalkenyl" used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms.
The term "cycloalkynyl" used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon triple bond and comprising about 7 up to about 12 carbon atoms.
The term "aryl" used alone or as suffix or prefix, refers to a monovalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms.
The term "arylene" used alone or as suffix or prefix, refers to a divalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, {e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, which serves to link two structures together. The term "heterocycle" used alone or as a suffix or prefix, refers to a ring-containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s). Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or tmfused. Fused rings generally refer to at least two rings share two atoms therebetween. Heterocycle may have aromatic character or may not have aromatic character.
The term "heteroaromatic" used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s), wherein the ring-containing structure or molecule has an aromatic character (e.g., 4n + 2 delocalized electrons).
The term "heterocyclic group," "heterocyclic moiety," "heterocyclic," or "heterocyclo" used alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removing one or more hydrogens thereftom.
The term "heterocyclyl" used alone or as a suffix or prefix, refers a monovalent radical derived from a heterocycle by removing one hydrogen therefrom.
The term "heterocyclylene" used alone or as a suffix or prefix, refers to a divalent radical derived from a heterocycle by removing two hydrogens therefrom, which serves to links two structures together.
The term "six-membered" used as prefix refers to a group having a ring that contains six ring atoms.
The term "five-membered" used as prefix refers to a group having a ring that contains five ring atoms.
A five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms ■wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.
Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl. A six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.
Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. The term "heteroaryl" used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character.
The term "heterocylcoalkyl" used alone or as a suffix or prefix, refers to a monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and having no unsaturation. Examples of heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, and pyranyl. A heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substituents. Preferably, the heterocycloalkyl group is a monocyclic or bicyclic ring, more preferably, a monocyclic ring, wherein the ring comprises from 3 to 6 carbon atoms and form 1 to 3 heteroatoms, referred to herein as C3-6heterocycloalkyl.
Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazol ne, dioxolane, sulfolane 2,3-dihydrofuran, 2,5-dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro-lH-azepine homopiperazine, 1,3-dioxepane, 4,7-dihydro-l,3-dioxepin> and hexamethylene oxide. In addition, heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazoIe, tetrazole, 1,2,3-thiadiazole, 1,2,3- oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-triazole, 1,3,4- thiadiazole, and 1,3,4- oxadiazole.
Additionally, heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxaziαe, 1,2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine.
In addition to the polycyclic heterocycles described above, heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.
Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyi, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomoφholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7- tetrahydro-lH-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-l,3-dioxepinyl? and hexamethylene oxidyl.
In addition, heterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.
Additionally, heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, 1,2-benzisoxazoIyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrolizidinyl, and quinolizidinyl.
In addition to the polycyclic heterocyclyls described above, heterocyclyl includes polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1]heptyl.
The term "alkoxy" used alone or as a suffix or prefix, refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical. Exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy.
The term "amine" or "amino" refers to -NH2.
Halogen includes fluorine, chlorine, bromine and iodine.
"Halogenated," used as a prefix of a group, means one or more hydrogens on the group are replaced with one or more halogens.
"RT", "r.t." or "rt" means room temperature.
"DMF" refers to dimethyl formamide.
"DIPEA" refers to N,N-diisopropylethylamine.
"HATU" refers to 2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate.
One aspect of the invention is a compound of formula I, a pharmaceutically acceptable salt thereof, a diastereomer, an enantiomer, or a mixture thereof:
wherein: R1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, acetoxy, hydroxyl, C1-6alkoxy, hydroxy-C1-6alkoxy, benzyloxy, -OCH2-C(=O)-R4, -OS(=O)2-R4, C1-6alkyl, halogenated C1-6alkoxy, C2-6alkylene, halogenated C1-6alkyl, halogenated C2-6alkenyl C1-6alkylamino, di-C1-6alkylamino and amino; R2 is selected from
wherein said group used in defining R^ is optionally substituted by one or more groups selected from halogen, halogenated C1-6alkyl, C1-6alkyl, halogenated C1-6alkoxy, cyano, nitro, C1-6alkoxy, hydroxy, hydroxy-C1-6alkyl, amino, C1-6alkyl-C6-10aryl, C1-6alkoxy-Ci. ealkyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylamino, di-C1-6alkylamino, di-Cj. salkylamino-C1-6alkyl, amino-C1-6alkyl, C1-6alkyl-amino-carbonyl, C2-5heteroaryl-carbonyl, C2-5heterocycloalkyl-carbonyl, C6-10arylcarbonyl, C2-5heterocycloalkyl, Cs-gcycloalkyl, C3_ ecycloalkyl-C1-6alkyl, C2-5heteroaryl, C2-5heteroaryl-C1-6alkyl, C6-10aryl, and C6-10aryl-Ci. βalkyl;
R3 is selected from C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, C^βcycloalkenyl, C1. βalkoxy, and C2-5heterocycloalkyl; wherein said C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, C4- ecycloalkenyl, C1-6alkoxy, and C2-5heterocycloalkyl used in defining R3 is optionally substituted by one or more groups selected from halogen, halogenated Chalky!, C1-6alkyl, halogenated C1-6alkoxy, cyano, nitro, Cμgalkoxy, hydroxy, hydroxy-C1-6alkyl, amino, Q. βalkyl-Cδ-ioaryl, C1-6alkoxy-C1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, Ci- 6alkylamino, di-Ci-ealkylamino, di-C1-6alkylammo-C1-6alkyL, amino-C1-6alkyl, d-βalkyl- arnino-carbonyl, C2-5heteroaryl-carbonyl, C2-5heterocycloalkyl-carbonyl, Cθ-ioarylcarbonyl, C2-5heterocycloalkyl, Cs^cycloalkyl, C3-6cycloalkyl-Ci-6alkyl, C2-5heteroaryl, C2- sheteroaryl-C1-6alkyl, C6-10aryl, and C6-ioaryl-C1-6alkyl;
R4 is selected from Ci-6alkyl, halogenated C1-6alkyl, hydroxy, hydroxy-Cj. θalkylamino, amino, C1-6alkoxy, C1-6alkylamino, di-C1-6alkylamino, hydroxyamino, Q. 6alkoxyamino, benzylamino, C2-5heterocycloalkyl, C2-5heteroaryl, and C2-5heteroaryl-Q. βalkyl;
X is selected from — C(=O)- and -CH2-; and m and n are independently selected from 0, 1, 2, 3, 4 and 5, with a proviso that R3 is not an optionally substituted 2,6-dioxopiperdin-3-yl. In a particular embodiment, R1 is selected from hydrogen, methoxy, 2- hydroxyethoxy, benzyloxy, acetoxy and acetylamino.
In another particular embodiment, R1 is selected from ethylsulfonyloxy, and 3- trifluoropropylsulfonyloxy.
In another particular embodiment, R4 is selected from hydroxy, methoxy, amino, methylamino, dimethylamino, hydroxyamino, methoxyamino, beirzylamino, morpholinyl, 2-hydroxyethylamino, and pyridinylmethyl.
In another embodiment, certain compounds of the present invention are those of foπnula I as defined above, wherein R1 is independently selected from hydrogen, halogen, hydroxyl, C1-6alkoxy, C1. βalkyl, halogenated C1-6alkoxy, halogenated Q.galkyl, amino, and C1-6alkylamino and di-Q. βalkylamino;
R2 is selected from
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated Chalky!, Chalky!, halogenated C1-6aUcoxy, cyano, nitro, C1-6alkoxy, hydroxy, hydroxy-C1-6alkyl, amino, C1-6alkyl-C6-10aryl, C1-6alkoxy-Ci. βalkyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylairώio, di-C1-6alkylamino, di-Ci. 6alkylamino-C1-6alkyl, amino-C1-6alkyl, C^alkyl-amino-carbonyl, C2-5heteroaryl-carbonyl, C2-5heterocycloalkyl-carbonyl, C6-10arylcarbonyl, C2-sheterocycloalkyl, C3-6cycloalkyl, C3. 6cycloalkyl-C1-6alkyl, C2-5heteroaryl, C2-5heteroaryl-C1-6alkyl, C6-10aryl, and C6-10aryl-Ci. ealkyl; R3 is selected from C1-6alkyl, C2-6alkenyl, C3.6cycloalkyl, C^βcycloalkenyl, Q. βalkoxy, and C2-5heterocycloalkyl; wherein said C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, C4. δcycloalkenyl, C1-6alkoxy, and C2-5heterocycloalkyl used in defining R3 is optionally substituted by one or more groups selected from halogen, halogenated C^aHcyl, C1-6alkyl, halogenated C1-6alkoxy, C1-6alkoxy, hydroxy, hydroxy-C1-6alkyl, amino, C1-6alkoxy-Ci. ealkyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylamino, and di-C1-6alkylamino;
X is selected from -C(=O)~ and -CH2-; and m and n are independently selected from 0, 1, and 2, with a proviso that R3 is not an optionally substituted 2,6-dioxopiperdin-3-yl.
In a further embodiment, certain compounds of the present invention are those of formula I, wherein
R1 is hydrogen;
R2 is selected from
wherein said group used in defining R is optionally substituted by one or more groups selected from halogen, halogenated C1-6alkyl, C1-6alkyl, halogenated C1-6alkoxy, C1-6alkoxy, hydroxy, hydroxy-C1-6alkyl, amino, C1-6alkoxy-C1-6alkyl, C2-sheteroaryl-Ci-6alkyl, Ci- 6alkylamino, di-C1-6alkylamino, di-C1-6alkylamino-Ci-salkyl;
R3 is selected from Chalky!, C2.βalkenyl, Ca-βcycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl and tetrahydropyranyl; wherein said Chalky!, C2-6alkenyl, C3.6cycloalkyl; piperdinyl, morpholinyl, and tetrahydropyranyl used in defining R3 is optionally substituted by one or more groups selected from halogen, halogenated Chalky!, d-βalkyl, halogenated C1-6alkoxy, Ci-6alkoxy, hydroxy, hydroxy-C1-6alkyI, amino, C1-6alkoxy-C1-6alkyl, Ci- galkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylamino, and di-C1-6alkylamino;
X is selected from -C(=O)- and -CR2-; and m and n are independently selected from 0, 1, and 2.
In a particular embodiment, R1 is hydrogen.
In another particular embodiment, R2 is selected from
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl. In another particular embodiment, R2 is selected from cyclohexyl, phenyl and naphtbyl, wherein said cyclohexyl, phenyl and naphthyl are optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl. In another particular embodiment, R2 is selected from cyclohexyl, phenyl and 1- naphthyl, wherein said cyclohexyl, phenyl and 1 -naphthyl are optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
In a further embodiment, R2 is selected from phenyl and 1 -naphthyl, wherein said phenyl and 1 -naphthyl are optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
In another embodiment, R3 is selected from C1-6alkyl, C2-6alkenyl, Cs-gcycloalkyl and C2-5heterocycIoalkyl, wherein said Q-ealkyl, C2-6alkenyl, C3-6cycloalkyl and C2- 5heterocycloalkyl are optionally substituted by one or more groups selected from halogen, halogenated Q.ealkyl, Chalky!, t-butoxycarbonyl, amino, C1-6alkoxy-C1-6alkyl, Ci. βalkylamino, and di-C1-6alkylamino with a proviso that R3 is not an optionally substituted 2,6-dioxopiperidiα-3-yl.
In another embodiment, R3 is. selected from Q.ealkyl, C2-6alkenyl, Cs-gcycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl, wherein said C1-6alkyl, C2-6alkenyl, Ca-βcycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl are optionally substituted by one or more groups selected from halogen, halogenated C1-6alkyl, C^aUcyl, t-butoxycarbonyl, amino, Cj- βalkoxy-C1-6alkyl, Ci-5alkylamino, and di-C1-6alkylamino. In a further embodiment, R3 is selected from C3-6cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl, wherein said C3.. βcycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl are optionally substituted by one or more groups selected from halogen, halogenated Q- ealkyl, C1-6alkyl, t-butoxycarbonyl, amino, C1-6alkoxy-C1-6alkyl, C1-6alkylamino, and di-Ci. galkylamino.
In another embodiment, n is 0. In a further embodiment, n is 1. In an even further embodiment, n is 2. In another embodiment, m is 0. In a further embodiment, m is 1. In another embodiment, X is -C(=O)-. In a further embodiment, X is methylene.
It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I. The optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.
It will also be appreciated that certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes. The present invention includes any geometrical isomer of a compound of Formula I. It will further be understood that the present invention encompasses tautomers of the compounds of the formula I.
It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of the formula I.
Within the scope of the invention are also salts of the compounds of the formula I. Generally, pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCI or acetic acid, to afford a physiologically acceptable anion. It may also be possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques. In one embodiment, the compound of formula I above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate. We have now found that the compounds of the invention have activity as pharmaceuticals, in particular as modulators or ligands such as agonists, partial agonists, inverse agonist or antagonists of CBi receptors. More particularly, the compounds of the invention exhibit activity as agonist of the CBi receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which dysfunction of CBi receptors is present or implicated. Furthermore, the compounds of the invention may be used to treat cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiavascular disorders.
Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents. Compounds of the invention are useful in disease states where degeneration or dysfunction of cannabinoid receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET). Compounds of the invention are useful for the treatment of diarrhea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung edema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.
Another aspect of the present invention is the use of a compound according to Formula I, for the inhibition of transient lower esophageal sphincter relaxations (TLESRs) and thus for treatment or prevention of gastroesophageal reflux disorder (GERD). The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, e.g. Holloway & Dent (1990) Gastroenterol. CHn. N. Amer. 19, pp. 517-535, has shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESRs), i.e. relaxations not triggered by swallows. In yet further embodiments of the present invention, the compound according to Formula I are useful for the prevention of reflux, treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive.
A further aspect of the present invention is the use of a compound according to Formula I, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations, for the treatment or prevention of GERD, for the prevention of reflux, for the treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive. Still another aspect of the present invention is the use of a compound according to
Formula I for the manufacture of a medicament for the treatment or prevention of functional gastrointestinal disorders, such as functional dyspepsia (FD). Yet another aspect of the present invention is the use of a compound according to Formula I for the manufacture of a medicament for the treatment or prevention of irritable bowel syndrome (IBS), such as constipation predominant IBS, diarrhea predominant IBS or alternating bowel movement predominant IBS. Exemplary irritable bowel syndrome (IBS) and functional gastrointestinal disorders (FGD), such as functional dyspepsia (FD), are illustrated in Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Mueller-Lissner SA. C. Functional- Bowel Disorders and Functional Abdominal Pain. In: Drossman DA, T alley NJ, Thompson WG, Whitehead WE, CoraziarriE, eds. Rome II: Functional Gastrointestinal Disorders: Diagnosis, Pathophysiology and Treatment. 2 ed. McLean, VA: Degnon Associates, Inc.; 2000:351-432 and Drossman DA, Corazziari E1 Talley NJ, Thompson WG and Whitehead WE. Rome II: A multinational consensus document on Functional Gastrointestinal Disorders. Gut 45(Suppl.2), II1-II81.9-1-1999.
' Also within the scope of the present invention is the use of any of the compounds according to the Formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment. Thus, the invention provides a compound of formula I, or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In a further aspect, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy. In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The term "therapeutic" and
"therapeutically" should be construed accordingly. The term "therapy" within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.
The compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
In use for therapy in a warm-blooded animal such as a human, the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
In one embodiment of the invention, the route of administration may be oral, intravenous or intramuscular. The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.
For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
A solid carrier can be one or more substance, which may also act as diluents, flavoring agents, sohibilizers, lubricants, suspending agents, binders, or tablet-disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized molds and allowed to cool and solidify.
Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low- melting wax, cocoa butter, and the like.
The term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
Depending on the mode of administration, the pharmaceutical composition will preferably include from 0.05% to 99%w (percent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition. A therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.
Within the scope of the invention is the use of any compound of formula I as defined above for the manufacture of a medicament.
Also within the scope of the invention is tiie use of any compound of formula I for the manufacture of a medicament for the therapy of pain.
Additionally provided is the use of any compound according to Formula I for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
A further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such therapy. Additionally, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. Particularly, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.
Further, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.
Another aspect of the invention is a method of preparing the compounds of the present invention.
In one embodiment, the method of the invention is a method for preparing a compound of formula I,
comprising the step of reacting a compound of formula II,
with a compound of R2-X-Y, optionally in the presence of a base, such as diisopropylethylamine, a solvent such as dichloromethane, wherein Y is selected from Cl, Br, F, and OH; and X, R1, R2 and R3 are defined as above.
Compounds of the present invention may be prepared according to the synthetic routes as depicted in Schemes 1-3 using one or more of the general procedures A-C. Scheme 1: Example 1-9; 14-15; 21-39
Scheme 2: Examples 11-13
Scheme 3: Example 10
Experimental Procedures General procedure A: The preparation of 2-alkyl-7-nitroisoindolin-l-one
Methyl-2-bromoethyl-6-nitro-benzoate (1 equiv.) and the corresponding primary amine (1.8 equiv.) are dissolved in a minimum amount of DMF. Diisopropyl ethylamine (2.5 equiv.) is added and the mixture is heated at 80°C overnight. Volatiles are evaporated under vacuum, leaving 2-alkyl-7-nitroisoindolin-l-one as a yellow oil (used without further purification). Reactions are performed on 0.5 to 15 mmol scale.
General Procedure B: The preparation of 2-(alkyl)isoindolin-4-amine
2-Alkyl-7-nitroisoindolin-l-one (-0.5 mmol) is dissolved in 20 ml of methanol. FeClj.όHaO (200 mg) is added and the mixture is heated to 65°C. Hydrazine hydrate (0.6 ml) is added dropwise. Heating is continued for 15h. After cooling to rt, the mixture is diluted with diethylether (80 ml) and filtered over Celite. Evaporation of solvents leaves an intermediate (2-(alkyl)isoindolin-4-amine) as white to yellow solids. The intermediate is used without further purification.
General Procedure C: N-[2-Alkyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]-Arylamide
2-(Alkyl)isoindolin-4-amine is dissolved in dry dichloromethane. Diisopropyl ethylamine (2 equiv.) and the corresponding acid chloride (2 equiv.) are added. The •mixture is stirred at rt for 45 min. Volatiles are evaporated under vacuum and the residue is purified by HPLC to give the desired product. Biological Evaluation
hCBi and I1CB2 receptor binding
Human CBi receptor from Receptor Biology (hCBi) or human CB2 receptor from BioSignal (I1CB2) membranes are thawed at 37 °C, passed 3 times through a 25-gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl2, and 0.5 mg/mL BSA fatty acid free, pH 7.4) and aliquots containing the appropriate amount of protein are distributed into 96-well plates. The IC50 of the compounds of the invention at hCBi and I1CB2 are evaluated from 10-point dose-response curves done with 3H-CP55,940 at 20000 to 25000 dpm per well (0.17-0.21 nM) in a final volume of 300 μl. The total and non-specific binding are determined in the absence and presence of 0.2 μM of HU210 respectively. The plates are vortexed and incubated for 60 minutes at room temperature, filtered through Unifilters GFfB (presoaked in 0.1% polyethyleneimine) with the Tomtec or Packard harvester using 3 mL of wash buffer (50 mM Tris, 5 mM MgCl2, 0.5 mg BSA pH 7.0). The filters are dried for 1 hour at 55 0C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 μl/well of MS-20 scintillation liquid. hCBi and hCB2 GTPγS binding
Human CBi receptor from Receptor Biology (hCBi) or human CB2 receptor membranes (BioSignal) are thawed at 370C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTPγS binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl2, pH 7.4, 0.1% BSA). The EC50 and Emax of the compounds of the invention are evaluated from 10-point dose-response curves done in 300μl with the appropriate amount of membrane protein and 100000-130000 dpm of GTPg35S per well (0.11 -0.14 nM). The basal and maximal stimulated binding is determined in absence and presence of 1 μM (hCB2) or 10 μM (hCBi) Win 55,212-2 respectively. The membranes are pre-incubated for 5 minutes with 56.25 μM (hCB2) or 112.5 μM (hCBi) GDP prior to distribution in plates (15 μM (hCB2) or 30 μM (hCBi) GDP final). The plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unifilters GF/B (presoaked in water) with the Tomtec or Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl2, 50 mM NaCl, pH 7.0). The filters are dried for 1 hour at 55 0C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 μl/well of MS-20 scintillation liquid. Antagonist reversal studies are done in the same way except that (a) an agonist dose-response curve is done in the presence of a constant concentration of antagonist, or (b) an antagonist dose-response curve is done in the presence of a constant concentration of agonist.
Based on the above assays, the dissociation constant (Ki) for a particular compound of the invention towards a particular receptor is determined using the following equation: Ki = IC50/(l+[rad]/Kd), Wherein IC5O is the concentration of the compound of the invention at which 50% displacement has been observed; [rad] is a standard or reference radioactive ligand concentration at that moment; and
Kd is the dissociation constant of the radioactive ligand towards the particular receptor.
Certain compounds of the invention's activities towards certain human CBl receptors are tested using the above-mentioned assays and are found to be active.
The following table shows certain biological activities for some of the exemplified compounds.
EXAMPLES
The invention will further be described in more detail by the following Examples which describe methods whereby compounds of the present invention may be prepared, purified, analyzed and biologically tested, and which are not to be construed as limiting the invention.
Example 1 N-[2-(cyclobutylmethyl)-3-oxo-2,3-dmydro-lH-isomdol-4-yl]-l-naphmamide
Step A. The preparation of 2-(cyclobutylmethyl)-7-nitroisoindolin-l-one
The mixture of methyl-2-bromoethyl-6-nitro-benzoate (150 mg, 0.547 mmol) and cyclobutylmethylamine (0.25 ml, 5 M in MeOH, 0.75 mmol), triethylamine (0.20 ml) in DMF (5 ml) was heated at 800C for 2 h. Removal of solvent gave the crude product (120 mg), which was used without purification. MS (M+l): 247.
Step B. The preparation of 7-amino-2-(cyclobutylmethyl)isoindolin-l-one
Crude 2-(cyclobutyknethyl)-7-nitroisoindolin-l-one (120 mg) was dissolved in MeOH and acetic acid (1:1, 6 ml), and Zinc (100 mg) was added at 00C. The mixture was stirred for 30 min, another 50 mg of zinc powder was added, and the mixture was stirred for another 30 min. EtOAc (30 ml) was added to the reaction mixture, and the solid was filtered off through Celite. Removal of solvent afforded the crude intermediate (110 mg). MS (M+l): 216.88.
Step C. The preparation of N-[2-(cyclobutylmethyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]- 1-naphthamide
1-NaphthoyI chloride (100 mg, 0.53 mmol) was added to a solution of crude 7-amino-2- (cyclobutylmethyl)isoindolin-l-one (50 mg, 0.23 mmol), diisopropylethylamine (0.10 ml) in dichloromethane (3 ml). The mixture was stirred at room temperature for 4 h. Usual acid- base workup gave a crude product, which was purified on silica gel to afford the title compound (32 mg). MS (M+l): 370.99. 1HNMR (400 MHz, CDCl3) δ: 11.11 (s, IH), 8.77 (d, J = 8.2 Hz, IH), 8.58 (d, J = 8.4 Hz, IH), 7.97 (d, J = 8.2 Hz, IH), 7.90 (m, 2H), 7.50- 7.60 (m, 4H), 7.15 (d, J = 7.5 Hz, IH), 4.35 (s, 2H), 3.58 (d, J = , IH), 2.60.2.70 (m, IH), 1.74-2.15 (m, 6H) ppm.
Example 2
N-(2-allyl-3-oxo-2,3-dihydro- lH-isoindol-4-yl)- 1 -naphthamide
Step A. The preparation of 2-allyl-7-nitroisoindoIin- 1 -one
Following the similar procedure of Example 1, Step A except that allylamine was used instead of cyclobutylmethylamiαe. The mixture of methyi-2-bromoethyl-6-nitro-benzoate (274 mg, 1.00 mmol) and allylamine (63 mg, 1.1 mmol), triethylamine (2 mmol) in DMF (6 ml) was heated at 80°C for 3 h. Removal of solvent gave the crude product (206 mg), which was used without purification. MS (M+l): 218.79.
Step B. The preparation of 2-allyl-7-aminoisomdolin-l-one
Following the similar procedure of Example 1, Step B.2-allyl-7-nitroisoindolin-l-one (206 mg, 0.944 mmol) was reduced with Zinc (300 mg) in HOAc (5 ml) and MeOH (5 ml). The crude product was used without purification.
Step C. The preparation of N-(2-allyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide
1-Naphthoyl chloride (0.15 ml) was added to a solution of crude 2-allyl-7-aminoisoindolin- 1-one from Step B, triethylamine (0.30 ml) in dichloromethane (5 ml). The mixture was stirred at room temperature for 2 h. Usual acid-base workup gave a crude product, which was purified on silica gel to afford the title compound (125 mg). MS (M+l): 343. 1HNMR (400 MHz, CDCl3) δ: 11.04 (s, IH, NH), 8.78 (d, J = 8.2 Hz, IH), 8.57 (d, J = 8.2 Hz, IH), 7.98 (d, J = 8.2 Hz, IH), 7.91 (d, J = 7.0 Hz, IH), 7.89 (d, J = 7.9 Hz, IH), 7.52-7.62 (m, 4H)y 7.18 (d, J = 7.6 Hz, IH), 5.80-5.88 (m, IH), 5.26 (s, IH), 5.23 (dd, J = 1.3, 7.8 Hz, IH), 4.39 (s, 2H), 4.18 (d, J = 5.8 Hz, 2H).
Example 3 N-(3-oxo-2-propyl-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide
Step A: The preparation of 7-nitro-2-propylisoiήdolin-l-one
7-nitro-2-propylisoindolin-l-one was prepared following General Procedure A where R is n-propyl and n-propylamine was used. MS (M+l): 221, 78% pure by HPLC.
Step B. The preparation of 2-propyl-7-aminoisoindoIiα-l-one
2-Propyl-7-aminoisoindolin-l-one was prepared from 7-nitro-2-propylisoindolin-l-one following General Procedure B. MS (M+l):191, 78% purity (UV detection at 254 nm).
Step C. The preparation of N-(2-propyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-l- naphthamide
N-(2-propyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide (25.6 mg, 74% yield in 3 steps) as white solid was prepared .from 2-propyl-7-aminoisoindolin-l-one and 1-naphthoyl chloride following General Procedure C. MS (M+l): 345. 1H-NMR (400 MHz, CDCl3)δ : 0.95 (t, J=7.32 Hz, 3 H); 1.69 (m, 2 H); 3.53 (t, J=7.42 Hz, 2 H); 4.40 (s, 2 H); 7.18 (d, J=7.62 Hz, 1 H); 7.50 - 7.63 (m, 4 H); 7.87 - 7.94 (m, 2 H); 7.97 (d, J=8.20 Hz, 1 H); 8.57 (d, J=8'.2O Hz5.1 H); 8.78 (d, J=8.20 Hz, 1 H); 11.10 (s, 1 H).
Example 4 N-(3-oxo-2-butyll-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide
Step A: The preparation of 7-nitro-2-butyl-isoindolin-l-one
7-Nitro-2-butylisoindolin-l-one was prepared following General Procedure A where R is n- propyl and n-propylamine was used. MS (M+l): 235, 89% purity (UV detection at 254 nm).
Step B. The preparation of 2-butyl-7-aminoisoindoKn-l-one
2-Butyl-7-arninoisoindolin-l-one was prepared from 7-nitro-2-butylisoindolin-l-one following General Procedure B. MS (M+l): 205, 100% purity (UV detection at 254 nm).
Step C. The preparation of N-(2-butyl-3-oxo-2,3-dihydro-lH-isoiαdol-4-yl)-l-naphthamide
N-(2-buryl-3-oxo-233-diliydro-lH-isoindol-4-yl)-l-naphthamide (18.1 mg, 50% yield in 3 steps) as white solid was prepared from 2-butyl-7-aminoisoindolin-l-one and 1-naphthoyl chloride following General Procedure C. MS (M+l): 359 (M+l). 1H-NMR (400 MHz, CDCl3) δ: 0.94 (t, J=7.32 Hz, 3 H); 1.37 (quintet, J=7.84, 2 H); 1.59 - 1.69 (m, 2 H); 3.56 (t, J=7.42 Hz, 2 H); 4.40 (s, 2 H); 7.18 (dd, J=7.62, 0.78 Hz, 1 H); 7.51 - 7.62 (m, 4 H); 7.90 (td, J=7.57, 1.46 Hz, 2 H); 7.97 (d, J=8.40 Hz, 1 H); 8.57 (dd, J=8.20, 0.98 Hz, 1 H); 8.77 (d, J=8.20 Hz, 1 H); 11.09 (broad s, 1 H).
Example 5
N-{2-[2-(dime1iiylamino)e1hyl]-3-oxo-2,3-dihydro-lH-isomdol-4-yl}-l-naph1liarriide
Step A: The preparation of 2-[2-(dirnethylarnino)ethyl]-7-mtroisoindolin-l-one
2-[2-(dimethylamino)ethyl]-7-αitroisoindolin-l-one was prepared following General Procedure A where R is 2-dimethylaminoethyl and 2-dimethylamiαoethylamine was used. MS (M+l): 249, 89% purity (UV detection at 254 nm).
Step B. The preparation of 7-amino-2-[2-(dimethylarαino)ethyl]isoindolm-l-one
7-Ammo-2-[2-(dirne1iiylarnino)ethyl]isoindolin-l-one was prepared from 2-[2-(dirαethylamino)ethyl]-7-nitroisoindolin-l-one following General Procedure B. MS (M+l): 220, 93% purity (UV detection at 254 nm).
Step C. The preparation ofN-{2-[2-(dimethylamino)ethyl]-3-oxo-2;3-dihydro-lH-isoindol- 4-yl} -1 -naphthamide
N-{2-[2-(dimethylarrώio)ethyl]-3-oxo-2,3-dihydro-lH-isoindol-4-yl}-l-naphtharnide (20.6 mg, 55% yield in 3 steps) as white solid was prepared from 7-amino-2-[2- (dimethylamino)ethyl]isoindolin-l-one and 1-naphthoyl chloride following General Procedure C. MS (M+l): 374 (M+l). 1H-NMR (400 MHz, CDCl3) δ: 2.90 (s, 6 H); 3.37 (broad t, J=5.36 Hz, 2 H); 3.96 (broad t, J=5.76 Hz, 2 H); 4.51 (s, 2 H); 7.19 (d, J=7.62 Hz, 1 H); 7.51 - 7.67 (m, 4 H); 7.85 - 7.93 (m, 2 H); 7.99 (d, J=8.20 Hz, 1 H); 8.54 (d, J=8.01 Hz, 1 H); 8.77 (d, J=8.20 Hz, 1 H); 10.73 (broad s, 1 H). Example 6 N-[2-(cyclohexylmeύiyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]-l- naphthamide
Step A: The preparation of 2-(cyclohexylmethyl)-7-nitroisoindolin-l-one
2-(Cyclohexylmethyl)-7-nitroisoindolin-l-one was prepared following General Procedure A where R is cyclohexylmethyl and cyclohexylmethylamine was used. MS (M+l): 275 (M+l), 84% purity (UV detection at 254 nm).
Step B. The preparation of 7-amino-2-(cyclohexylmethyl)isoindolin-l-one
7-arnino-2-(cyclohexylmethyl)isoindolin-l-one was prepared from 2-(cyclohexylmethyl)-7- nitroisoindolin-1-one following General Procedure B. MS (M+l): 245 (M+l), 100% purity (UV detection at 254 nm).
Step C. The preparation of N-[2-(cyclohexylmethyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]- 1- naphthamide
N-[2-(cycloliexylmethyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]-l- naphthamide (77 mg, 39% yield in 3 steps) as white solid was prepared from 7-amino-2- (cyclohexylmethyl)isoiQdolin-l-one and 1-naphthoyl chloride following General Procedure C. MS (M+l): 400. 1H-NMR (400 MHz, CDCl3): 0.92 - 1.07 (m, 2 H); 1.11 - 1.28 (m, 3 H); 1.61 - 1.78 (m, 6 H); 3.39 (d, J=7.22 Hz, 2 H); 4.40 (s, 2 H); 7.17 (dd, J=7.52, 0.68 Hz, 1 H); 7.50 - 7.62 (m, 4 H); 7.86 - 7.94 (m, 2 H); 7.97 (d, J=8.40 Hz, 1 H); 8.57 (d, J=8.40 Hz, 1 H); 8.78 (d, J=8.20 Hz, 1 H); 11.10 (s, 1 H).
Example 7
N-[3-oxo-2-(tetrahydro-2H-pyran-4-yImethyl)-2,3-dihydro-lH-isoindol-4-yl]-l- naphthamide
Step A: The preparation of 2-(tetrahydro-2H-pyran-4-ylmethyl)-7-nitroisoindolin-l-one
2-(Tetrahydro-2H-pyran-4-ylmethyl)-7-nitroisoindolin-l-one was prepared following General Procedure A where R is tetrahydro-2H-pyran-4-ylmethyl and tetrahydro-2H-pyran- 4-ylmethyl amine was used. (M+l): 277, 100% purity (UV detection at 254 nm).
Step B. The preparation of 7-amino-2-(tetrahydro-2H-pyran-4-yhnethyl)isoindolin-l-one
7-Amino-2-(tetrahydro-2H-pyran-4-ylmethyl)isoindoliri-l-one was prepared from 2-( tetrahydro-2H-pyran-4-ylmethyl)-7-nitroisoindolin-l-one following General Procedure B. MS (M+l): 247, 100% purity (UV detection at 254 nm).
Step C. The preparation of N-[2-( tetrahydro-2H-pyran-4-ylmethyl)-3-oxo-2,3-dihydro-lH- isoindol-4-yl]-l- naphthamide
N-[2-(tetrahydro-2H-pyran-4-yhnethyl)-3 -oxo-2,3 -dihy dro- 1 H-isoindol-4-yl]- 1 - naphthamide (17.5 mg, 44% yield in 3 steps) as white solid was prepared from 7-amino-2- (tetrahydro-2H-pyran-4-yhnethyl)isoindolin-l-one and 1-naphthoyl chloride following General Procedure C. MS (M+l): 401 (M+l). 1H-NMR (400 MHz, CDCl3) δ: 1.33 - 1.46 (m, 2 H); 1.59 (dd, J=12.79, 2.05 Hz, 2 H); 1.94 - 2.07 (m, 1 H); 3.35 (td, J=I 1.77, 2.05 Hz, 2 H); 3.45 (d, J=7.42 Hz, 2 H); 3.97 (dd, J=I 1.62, 2.64 Hz, 2 H); 4.44 (s, 2 H); 7.18 (d, J=7.62 Hz, 1 H); 7.51 - 7.64 (m, 4 H); 7.87 - 7.93 (m, 2 H); 7.98 (d, J=8.20 Hz, 1 H); 8.57 (dd, J=8.20, 0.98 Hz, 1 H); 8.79 (d, J=8.20 Hz, 1 H); 11.04 (s, 1 H). Example 8 N-(2-butyl-3-oxo-2,3-diliydro-lH-isoindol-4-yl)-2,3-dime11iylbenzamide
N-(2-butyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-2,3-dimeth.ylbenzainide (14.6 mg, 43% yield in 3 steps) as white solid was prepared from 2-butyl-7-aminoisoindolin-l-one and 2,3- dimethylbenzoyl chloride following General Procedure C. MS (M+l): 337 (M+l). 1H-NMR (400 MHz, CDCl3) δ: 0.95 (t, J=7.32 Hz, 3 H); 1.37 (quintet, J=7.49 Hz, 2 H); 1.59 - 1.68 (m, 2 H); 2.32 (s, 3 H); 2.42 (s, 3 H); 3.56 (t, J=7.42 Hz, 2 H); 4.38 (s, 2 H); 7.12 - 7.19 (m, 2 H); 7.23 (d, J=7.24 Hz, 1 H); 7.42 (d, J=7.03 Hz, 1 H); 7.54 (t, J=7.91 Hz, 1 H); 8.68 (d, J=8.20 Hz, 1 H); 10.74 (broad s, 1 H).
Example 9
2,3-Dimethyl-N-[3-oxo-2-(tetrahydro-2H-pyran-4-ylme1iiyl)-2,3-dihydro-lH-isoindol-4- yl]benzamide
2,3-Dimethyl-N-[3-oxo-2-(tetrahydro-2H-pyran-4-yknethyl)-2,3-dihydro-lH-isoindol-4- yl]benzamide (7.4 mg, 20% yield in 3 steps) as white solid was prepared from 7-amino-2- (tetrahydro-2H-pyran-4-yhnethyl)isoindolin-l-one and 2,3-dimthylbenzoyl chloride following General Procedure C. MS (M+l): 379. 1H-NMR (400 MHz, CDCl3) δ: 1.33 - 1.47 (m, 2 H); 1.59 (dd, J=12.79, 1.86 Hz, 2 H); 1.94- 2.07 (m, 1 H); 2.32 (s, 3 H); 2.42 (s, 3 H); 3.36 (td, J=ILSl. 2.15 Hz, 2 H); 3.45 (d, J=7.22 Hz, 2 H); 3.98 (dd, J=I 1.52, 2.73 Hz, 2 H); 4.42 (s, 2 H); 7.12 - 7.21 (m, 2 H); 7.24 (d, J=7.24 Hz, 1 H); 7.42 (d, J=7.42 Hz, 1 H); 7.56 (t, J=7.91 Hz, 1 H); 8.69 (d, J=8.40 Hz, 1 H); 10.68 (broad s, 1 H).
Example 10 N-(3-oxo-2-piperidin-3-yl-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide
Step 2: The preparation of tert-butyl 3-(7-nitro-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-l -carboxylate
Tert-butyl 3-(7-nitro-l-oxo-l,3-diliydro-2H-isoindol-2-yl)piperidirie-l-caxboxylate (180 mg, 50%) was prepared following General Procedure A where tert-butyl 3- aminopiperidine-1-carboxylate (1 mmol) was used and purified on silica gel. MS (M+l): 362.
Step B. The preparation of tert-butyl 3-(7-amino-l-oxo-l33-dihydro-2H-isoindol-2- yl)piperidine-l -carboxylate
Tert-butyl 3-(7-amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-l-carboxylate was prepared from tert-butyl 3-(7-nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-l- carboxylate following General Procedure B. MS (M+l): 332.
Step C. The preparation of tert-butyl 3-[7-(l-naphthoylamino)-l-oxo-l,3-dihydro-2H- isoindol-2-yl]piperidine-l-carboxylate
Tert-butyl 3-[7-(l -naphthoylamino)- 1 -oxo- 1 ?3-dihydf o-2H-isoindol-2-yl]piperidine-l - carboxylate (62 mg, 26% yield in 2 steps) was prepared from tert-butyl 3-(7-amino-l-oxo- l,3-dihydro-2H-isoindol-2-yl)piperidine-l -carboxylate and 1-naphthoyl chloride following General Procedure C and purified on silica gel. MS (M+I): 486.
Step D. The preparation of N-(3-oxo-2-piperidin-3-yl-2,3-dihydro-lH-isoindol-4-yl)-l- naphthamide
Tert-bu1yI 3-[7-(l-naphmoylamrrio)-l-oxo-l,3-dihydro-2H-isoindol-2-yl]piperidine-l- carboxylate (62 mg, 0.127 mmol) was dissolved in 4N HCl solution in dioxane and the reaction was stirred at room temperature for 1 h. Removal of solvent afforded the title compound (54 mg, quantitatively). MS (M+l): 385.95. 1H NMR (400 MHz5CD3OD) δ: 10.96 (s, IH), 8.59 (d, J = 8.2 Hz, IH), 8.40 (m, IH), 8.06 (d, J = 8.2 Hz, IH), 7.96 (m, IH), 7.87 (d, J = 7.0 Hz, IH), 7.64 (t, J = 7.8 Hz5 IH), 7.50-7.60 (m, 3H), 7.30 (d, J = 7.8 Hz, IH), 4.54 (s, 2H), 4.25-4.35 (m, IH), 3.75-3.5 (m, 2H), 3.24-3.45 (m, 4H), 1.80-2.10 (m, 4H).
Example 11 N-[3-oxo-2-(piperidin-2-ylmethyl)-2,3-dihydro-lH-isoindol-4-yl]-l-naphthaπiide
Step A: The preparation of tert-butyl 2-[(7-mtro-l-oxo-l,3-dlhydro-2H-isoindol-2- yl)methyl]piperidine-l -carboxylate
The mixture of methyl-2-bromoethyl-6-nitro-benzoate (330 mg, 1.20 mmol) and tert-butyl 2-(aminomethyl)piperidine-l-carboxylate (403 mg, 1.83 mmol), triethylamine (0.50 ml, 3.50 mmol) in DMF (6 ml) was heated at 1400C for 6.5 h. Removal of solvent and purification on silica gel (eluent: 0-40% MeOH in dichloromethane) afforded the intermediate (250 mg, 55%). MS (M+l): 376.
Step B: The preparation of tert-butyl 2-[(7-amino-l-oxo-l,3-dihydro-2H-isoindol-2- yl)methyl]piperidine-l-carboxylate
Tert-butyl 2-[(7-amino-l-oxo-l,3-diliydro-2H-isoiαdoI-2-yl)methyl]piperidine-l- caxboxylate (180 mg, 78% yield) was prepared from tert-butyl 2-[(7-nitro-l-oxo-l,3- dmydro-2H-isoindol-2-yl)memyl]piperidme-l -carboxylate (250 mg, 0.667 mmol) following General Procedure B and purified on silica gel. MS (M+l): 346
Step C: The preparation of tert-butyl 2-{[7-(l-naphthoylamino)-l-oxo-l,3-dihydro-2H- isoindol-2-yl]methyl} piperidine- 1 -carboxylate
Tert-butyl 2- { [7-(l -naphthoylamino)-l -oxo-1 ,3-dihydro-2H-isoindol-2- yl]methyl}piperidine-l-carboxylate (160 mg, 60% yield) was prepared from tert-butyl 2- [(7-amino- 1 -oxo- 1 ,3 -dihydro-2H-isoindol-2-yl)methyl]piperidine- 1 -carboxylate (180 mg, 0.52 mg) and 1-naphthoyl chloride (0.1 mL) following General Procedure C and purified on silica gel. MS (M+l): 500.
Step D. The preparation of N-[3-oxo-2-(piperidin-2-ylmethyl)-2,3-dihydro-lH-isoindol-4- yl]-l-naphthamide
Tert-butyl 2- {[7-(l -naphthoylamino)- 1 -oxo- 1 ,3-dihydro-2H-isoindol-2- yl]methyl}piperidine-l-carboxylate (160 mg, 0.32 mmol) was dissolved in 4N HCl solution in dioxane (5 mL) and the reaction was stirred at room temperature for overnight. Removal of solvent afforded the title compound (149 mg) as its HCl salt. MS (M+l): 400.
Example 12 N-{2-[(l-methylpiperidin-2-yl)methyl]-3-oxo-2,3-dihydro-lH-isoindol-4-yl}-l- naphthamide
N-[3-oxo-2-(piperidin-2-ylmethyl)-2,3-dihydro- lH-isoindol-4-yl]-l -naphthamide HCl salt (60 mg, 0.137 mmol) was dissolved in 30% formaldehyde and 98% formic acid (4 ml, 1:1). The mixture was heated at 1100C overnight Removal of solvent in vacuo gave the crude product. The crude product was dissolved in water and basified with 1 N NaOH to pH ~10 and extracted with dichloromethane. Removal of dichloromethane afforded the title compound as the free base, which was converted to its HCl salt (42 mg, 68% yield). MS (M+l): 414. 1H NMR (free base, 400 MHz, CDCl3) δ: 8.77 (d, J = 8.2 Hz, IH), 8.55 (d, J = 8.4 Hz, IH), 7.97 (d, J = 8.2 Hz, IH), 7.90 (d, J = 5.9 Hz, IH), 7.90 (s, IH), 7.88 (br, IH), 7.50-7.65 (m, 4H), 7.17 (d, J = 7.6 Hz, IH), 4.72 (d, J = 17.4 Hz, IH), 4.44 (d, J = 17.4 Hz, IH), 3.88 (dd, J = 3.9, 14.3 Hz, IH), 3.76 (t, J = 5.3 Hz, IH), 3.60-3.68 (m, IH), 3.53 (dd, J = 6.4, 14.3 Hz, IH), 2.88 (m, IH), 2.40 (s, 3H), 2.29 (m, IH,), 2.13 (m, IH), 1.20-1.75 (m, 6H)..
Example 13
4-Me1iioxy-N-[3-oxo-2-(piρeridin-2-yhnethyl)-2,3-dihydro-lH-isokidol-4-yl]-l- naphthamide
Step A. The preparation of tert-butyl 2-({7-[(4-methoxy-l-naphthoyl)amino]-l-oxo-l,3- dihydro-2H-isoindol-2-yl}methyl)piperidine-l-carboxylate
Tert-butyl 2-({7-[(4-me1hoxy-l-naphthoyl)atnmo]-l-oxo-l,3-dihydro-2H-isoindol-2- yl}methyl)piperidine-l-carboxylate (20 mg) was prepared from tert-butyl 2-[(7-amino-l- oxo-l,3-dihydro-2H-isoindol-2-yl)methyl]piperidine-l-carboxylate (34 mg) and 4-methoxy- 1-naphthoyl chloride (38 mg) following General Procedure C and purified by prep-TLC. MS (M+l): 530.
Step B. The preparation of 4-methoxy-N-[3-oxo-2-(ρiperidin-2-ylmethyl)-2,3-dihydro-lH- isoindol-4-yl]- 1-naphthamide
Tert-butyl 2-({7-[(4-methoxy-l-naphthoyl)arnino]-l-oxo-l,3-dihydro-2H-isoindol-2- yl}methyl)piperidine-l-carboxylate (20 mg) was dissolved in 20% trifluoric acetic in dichloroethane (3 ml), and the reaction mixture was kept at room temperature for Ih. Removal of solvent and excess TFA gave the crude product, which was purified on prep HPLC to afford the title compound as its TFA salt. MS (M+l): 430. 1H NMR (400 MHz, METHANOL-D4) δ: 1.03 - 1.44 (m, 2 H), 1.46 - 1.72 (m, 3 H), 1.79 - 2.07 (m, 3 H), 2.86
2.96 (m, 1 H), 3.32 - 3.38 (m, J=2.15 Hz, 1 H), 3.39 - 3.52 (m, 1 H), 3.57 - 3.68 (m, 1 H), 3.82 - 3.99 (m, 1 H), 4.08 (d, 3 H), 4.53 (d, J=17.38 Hz, 1 H), 4.65 (d, J=17.38 Hz, 1 H),
6.97 (d, J=8.00 Hz, 1 H), 7.50 - 7.70 (m, 3 H), 7.90 (d, J=8.20 Hz, 1 H), 8.30 - 8.35 (m, 1 H), 8.42 - 8.51 (m, 1 H), 8.59 (d, J=8.20 Hz, 1 H) ppm.
Example 14 N-[2-(2-moφholm-4-ylethyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]-l-naphthamide
Step A. Preparation of 2-(2-morpholin-4-ylethyl)-7-nitroisoindolin-l-one
To a solution of methyl 2-(bromomethyl)-6-nitrobenzoate (137 mg, 0.5 mmol) in DMF (3 mL) was added morpholine-N-ethylene amine (0.5 mmol) followed by DIPEA (1.5 mmol). The reaction mixture was stirred at 850C for 3 h, concentrated and the residue was taken up into DCM (30 mL), extracted with water (20 mL) and brine (10 mL), dried over Na2SO4, the crude product was used with out further purification. MS: 291.92.
Step B. Preparation of 7-amino-2-(2-moφholin-4-ylethyl)isoindolin-l-one hydrate
To a solution of crude 2-(2-morpholin-4-ylethyl)-7-nitroisoindolin-l-one (0.5 mmol) in MeOH (10 mL) was added NH4C1 (2.5 mmol) and Zn powder (10 mmol), the mixture was stirred at reflux for 1 h. Cooled to room temperature, filtered through Celite and diluted with DCM (20 mL), extracted with water (20 mL) and brine (10 mL), dried over Na2SO4, the crude product was used with out further purification. MS: 261.90.
Step C. Preparation of N-[2-(2-morpholin-4-yIethyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]- 1-naphthamide
To a solution of crude 7-animo-2-(2-morpholin-4-ylethyl)isoindolin-l~one hydrate (0.25 mmol) in dry DCM (5 mL) was added 1-naphthoyl chloride (0.25 mmol) followed by Et3N (0.5 mmol), the reaction mixture was stirred at room temperature for overnight. Diluted with DCM (20 mL), extracted with water (20 mL) and brine (10 mL), dried over Na2SO4, the crude product was purified with reverse phase HPLC to yield TFA salt 23 mg (18% in 3 steps). MS: 415.98. IHNMR (CD3OD, 400 MHz) δ: 8.59(d, J=8.3Hz, IH), 8.45-8.38(m, IH), 8.06(d, J=8.3Hz, IH), 8.00-7.93(m, IH), 7.88(d, J=6.6Hz, IH), 7.65(t, J=8.0Hz, IH), 7.62-7.52(m, 3H), 7.30(d, J=7.6Hz, IH), 4.45(s, 2H), 4.02-3.95(m, 4H), 3.72-3.58(m, 4H), 3.52-3.46(m, 2H); 3.22-3.08(m, 2H).
Example 15
4-(Methoxymethyl)-N-[3-oxo-2-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-lH- isoindol-4-yl] - 1 -naphthamide
Step A. The preparation of 4-(bromomethy I)-I -naphthoic acid
4-MethyInaphthoic acid (1.05 g, 5.66 mmol), N-bromosuccinimide (1.01 g) and 1,1'- azobis(cyclohexane-carbonitrile) (50 mg, catalytic amount) were placed in a round- bottomed flask. 1,2-Dichloroethane (40 ml) was added and the mixture heated at 8O0C for 4 h. Volatiles were evaporated tinder vacuum. The residue was dissolved in a mixture of ethyl acetate and water, phases were separated and the organic phase dried over calcium chloride. After evaporation of solvent, the product was obtained as a white solid (1.07 g, 71%). 1H- NMR (400 MHz, CD3OD) δ: 5:08 (s, 2 H); 7.51 - 7.81 (m, 3 H); 8.10 (d, J=7.42 Hz, 1 H); 8.18 - 8.39 (m, 1 H); 8.85 - 9.09 (m, 1 H).
Step B. The preparation of 4-(methoxymethyl)-l-naphthoic acid
4-Bromomethylnaphthoic acid (250 mg, 0.94 mmol) was suspended in 5 ml of a 25% solution of sodium methoxide in methanol. The mixture was stirred at room temperature for 2 h. Excess sodium methoxide was quenched by addition of water. Volatiles were evaporated under vacuum, the residue was dissolved in water, the pH was adjusted to 6-7 by addition of HCl solution and 4-(methoxymethyl)-l -naphthoic acid was obtained as a white precipitate (166 mg, 82%). MS (M+l): 217.
Step C. The preparation of 4-(methoxymethyl)-N-[3-oxo-2-(tetrahydro-2H-pyran-4- ylmethyl)-2,3 -dihydro- 1 H-isoindol-4-yl]- 1 -naphthamide
4-(Methoxymethyl)-l -naphthoic acid (113 mg, 0.52 mmol) was suspended in 10 ml of dry dichloromethane. Oxalyl chloride (2 equiv.) was added and the mixture stirred at room temperature for 30 min. Volatiles were removed under vacuum. The white solid residue was dissolved in 5 ml of dry dichloromethane and 7-amino-2-(tetrahydro-2H-pyran-4- ylmethyl)isoindolin-l-one (1 equiv.) was added. The mixture was stirred overnight at room temperature. Volatiles were evaporated and part of the residue was purified by HPLC to afford the title compound (29 mg) as white solid. MS (M+l) 445. 1H-NMR (400 MHz, CDCl3) δ: 1.33 - 1.46 (m, 2 H); 1.59 (dd, J=12.89, 1.95 Hz, 2 H); 1.93 - 2.07 (m, 1 H); 3.36 (td, J=I 1.77, 2.05 Hz, 2 H); 3.45 (d, J=8.20 Hz, 2 H); 3.46 (s, 3 H); 3.97 (dd, J=I 1.62, 2.64 Hz, 2 H); 4.43 (s, 2 H); 4.95 (s, 2 H); 7.18 (d, J=7.62 Hz, 1 H); 7.55 - 7.64 (m, 4 H); 7.86 (d, J=7.22 Hz, 1 H); 8.11 - 8.19 (m, 1 H); 8.54 - 8.61 (m, 1 H); 8.78 (d, J=8.20 Hz, 1 H); 11.02 (S5 I H).
Example 16
N-[3-oxo-2-(teteahydro-2H-ρyran-4-ylmethyl)-253-dihydro-lH-isoindol-4-yl]-4-(lH-l;2,3- triazol- 1 -ylmethyl)- 1 -naphthamide
Step A. The preparation of 4-(lH-l,2,3-triazol-l-yhnethyl)-l-naphthoic acid
4-BromomethyInaphthoic acid (250 mg, 0.94 mmol) was dissolved in 5 ml of DMF. 1,2,3- Triazole (195 mgj 3 equiv.) was added and the mixture was stirred at room temperature overnight and then at 600C for 4 h. DMF was removed under vacuum. The residue was dissolved in water, and pH was adjusted to 6-7 by addition of HCi aqueous solution and A- (lH-l,2,3-triazol-l-ylmethyl)-l-naphthoic acid was obtained as a white precipitate (202 mg, 85%). MS (M+l): 254.
Step B. The preparation of N-[3-oxo-2-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-lH- isoindol-4-yl]-4-(lH-l,2,3-triazol-l-yhnethyl)-l-naphthamide
4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoic acid (202 mg, 0.80 mmol) was suspended in 10 ml of dry dichloromethane. Oxalyl chloride (2 equiv.) was added and the mixture stirred at room temperature for 30 min. Volatiles were removed under vacuum. The white solid residue was dissolved in 5 ml of dry dichloromethane and 7-amino-2-(tetrahydro-2H-pyran- 4-ylmethyl)isoindolin-l-one (1 equiv.) was added. The mixture was stirred overnight at room temperature. Volatiles were evaporated and part of the residue was purified by HPLC to afford the title compound as white solid (48 mg); MS (M+l): 482. 1H-TStMR (400 MHz, CDCl3) δ: 1.32 - 1.45 (m, 2 H); 1.59 (dd, J=12.79, 1.86 Hz, 2 H); 1.93 - 2.07 (m, 1 H); 3.35 (m, 2 H); 3.45 (d, J=7.42 Hz, 2 H); 3.97 (dd, J=I 1.62, 2.64 Hz, 2 H); 4.44 (s, 2 H); 6.07 (s, 2 H); 7.20 (dd, J=7.52, 0.49 Hz, 1 H); 7.39 (d, J=0.78 Hz, 1 H); 7.44 (d, J=7.23 Hz, 1 H); 7.56 - 7.65 (m, 3 H); 7.69 (d, J=0.78 Hz, 1 H); 7.86 (d, J=7.23 Hz, 1 H); 7.99 - 8.04 (m, 1 H); 8.56 - 8.60 (m, 1 H); 8.76 (d, J=8.40 Hz, 1 H); 11.06 (s, 1 H).
Example 17 7-{[(2-Memyl-l-naphmyl)me1hyl]amino}-2--(2-morpholin-4-ylethyl)isoindolin-l-one
To a solution of 7-amino-2-(2-morpholin-4-ylethyl)isoindolin-l-one (200mg, 0.766 mmol) in DMA (6 mL), iPr2NEt (0.41 mL, 0.30 g, 2.30 mmol) was added followed by 1- (chloromethyl)-2-methylnaphthalene (0.22g, 1.15 mmol) atrt. The reaction mixture was heated to 1000C for 18 hours. After being cooled, evaporated to dryness, the crude compound was purified by flash chromatographie (100% EtOAc) then by Prep-LCMS to afford 7-{[(2-methyl-l-naphthyl)methyl]amino}-2-(2-morpholin-4-ylethyl)isoindolin-l-one (45.1 mg, 14% yield). MS (M+l): 416.2 (M+l). 1HNMR (400 MHz3 DMSO-D6) 52.53 (s, 3 H) 3.05 (m, 2 H) 3.39 (m, 6 H) 3.73 (t, J=5.86 Hz, 2 H) 3.89 (m, 2 H) 4.40 (s, 2 H) 4.76 (m, 2 H) 6.81 (d, J=7.42 Hz, 1 H) 6.98 (d, J=8.20 Hz, 1 H) 7.49 (m, 4 H) 7.86 (d, J=8.40 Hz, 1 H) 7.93 (m, 1 H) 8.01 (d, J=8.20 Hz, 1 H)
Example 18 N-(2-allyI-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-2,3-dichlorobenzamide
N-(2-Allyl-3-oxo-2,3-dihydro-lH-isokidol-4-yl)-2,3-dichlorobenzamide (57 mg, 45% yield in 3 steps) as white solid was prepared from 2-allyl-7-aminoisoindolin-l-one and 2,3- dichlorolbenzoyl chloride following General Procedure C. MS (M+l): 361.1 (M+l). 1H NMR (400 MHz, CHLOROFORM-D) 5:4.16 (dt, J=5.86, 1.37 Hz, 2 H) 4.37 (m, 2 H) 5.21 (m, 1 H) 5.25 (m, 1 H) 5.82 (m, 1 H) 7.17 (dd, J=6.83, 0.59 Hz, 1 H) 7.29 (t, J=7.8I Hz, 2 H) 7.54 (m, 2 H) 8.62 (d, J=8.20 Hz, 1 H) 10.83 (br. s., 1 H)
Example 19 N-(2-Allyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide
N-(2-Allyl-3-oxo-2J3-dihydro-lH-isoindol-4-yl)-l-naphthamide (15.1 mg, 35% yield in 3 steps) as white solid was prepared from 2-allyl-7-aminoisoindolin-l-one and 1- naphthylbenzoyl chloride following General Procedure C. MS (M+l): 343.1 (M+l). IH NMR (400 MHz, CHLOROFORM-D) 8: 4.18 (d, J = 5.8 Hz, 2H) 4.39 (s, 2H) 5.23 (dd, J = 1.3, 7.8 Hz, IH) 5.80-5.88 (m, IH), 5.26 (s, IH) 7.18 (d; J = 7.6 Hz, IH) 7.52-7.62 (m, 4H) 7.89 (d, J = 7.9 Hz, IH) 7.91 (d, J = 7.0 Hz, IH) 7.98 (d, J = 8.2 Hz, IH) 8.57 (d, J = 8.2 Hz, IH) 8.78 (d, J = 8.2 Hz, IH) 11.04 (s, IH, NH)
Example 20
N-(2-Allyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-2-(trifluoromethyl)benzamide
N-(2-Allyl-3-oχo-2,3-dihydro-lH-isoindol-4-yl)-2-(trifluorometliyl)benzamide (45.1 mg, 46% yield in 3 steps) as white solid was prepared from 2-allyl-7-aminoisoindolin-l-one and 2-trifluoromethylbeozoyl chloride following General Procedure C. MS (M+l): 361.1 (M+l). IH NMR (400 MHz, CHLOROFORM-D) δ: 4.16 (dt, J=6.05, 1.17 Hz, 2 H) 4.37 (m, 2 H) 5.21 (m, 1 H) 5.25 (t, J=1.37 Hz, 1 H) 5.82 (m, 1 H) 7.16 (dd, J=6.83, 0.78 Hz, 1 H) 7.65 (m, 5 H) 8.62 (d, £=8.20 Hz, 1 H) 10.76 (br. s., 1 H)
Example 21 N-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl]naphthylcarboxamide
Step A: N-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl]naphthylcarboxamide
1-Naphthoyl chloride (0.114 mL, 0.753 mmol), followed by triethylamine (0.210 mL, 1.51 mmol) were added to a stirred solution of 7-amino-2-(cyclohexylmethyl)isoindolin-l-one (0.185 g, 0.753 mmol) (for preparation, see the following steps B and C) in CH2CI2 (10 mL). The reaction mixture was stirred at room temperature overnight, diluted with CH2CI2 (20 mL), washed with saturated NaHCθ3 solution (20 mL), brine (20 mL), and dried over Na2SO4. The solvent was removed under reduced pressure. Flash chromatography of the residue over silica gel, using EtOAc/hexanes (1:10 to 1:5) gave the title compound, as a white foam, which was crystallized from EtOAc to afford a white solid, 0.15 g (50%). 1H NMR (400 MHz, CHLOROFORM-D) δ 0.92 - 1.06 (m, 2 H), 1.10 - 1.30 (m, 3 H), 1.58 - 1.80 (m, 6 H), 3.39 (d, 2 H), 4.39 (s, 2 H), 7.16 (d, 1 H), 7.49 - 7.62 (m, 4 H), 7.90 (dd, 2 H), 7.96 (d, 1 H), 8.56 (d, 1 H), 8.78 (d, 1 H), 11.10 (s, 1 H); MS (ESI) (M+H)+ = 398.93; Anal. Calcd for C26H26N2O2: C, 78.36; H, 6.58; N, 7.03 Found: C, 78.48; H, 6.64; N, 7.18.
Step B: 2-(Cyclohexylmethyl)-7-nitroisoindoliα-l-one
Cyclohexylmethylamine (1.63 mL, 12.5 mmol), followed by DIPEA (4.4 mL, 25 mmol) were added to a stirred solution of methyl-2-bromomethyl-6-nitro-benzoate (3.43 g, 12.5 mmol) in DMF (50 mL). The mixture was stirred at 80 0C for 3 h, concentrated in vacuo, diluted with CH2Cl2 (150 mL), washed with saturated NaHCC>3 solution (2x50 mL), brine (50 mL), dried over Na2SO4, filtered and evaporated. Flash chromatography of the residue over silica gel, using EtOAc/hexanes (1:5 to 1:2) gave the title compound, 2.6 g (75%) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-D) δ 0.94 - 1.12 (m, 2 H), 1.13 - 1.30 (m, 3 H), 1.62 - 1.82 (m, 6 H), 3.44 (d, 2 H), 4.42 (s, 2 H), 7.60 - 7.71 (m, 3 H).
Step C: 7-Ammo-2-(cyclohexyhnethyl)isomdolin-l-one
Ammonium chloride (2.66 g, 49.7 mmol), followed by zinc dust (6.50 g, 99.5 mmol) were added to a stirred solution of 2-(cyclohexylmethyl)-7-nitroisoindolin-l-one (2.73 g, 9.95 mmol) in MeOH (100 mL). The mixture was stirred at 68 0C for 1 h, cooled to room temperature, filtered through celite, and washed with MeOH (2x30 mL). The filtrate was evaporated, diluted with CH2Cl2 (150 mL), washed with saturated NaHCOs solution (2x50 mL), brine (50 mL), and dried over Na2SO4. Evaporation of the solvent gave the title compound, 2.38 g (98%) as a pale yellow solid, which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-D) δ 0.94 - 1.10 (m, 2 H), 1.12 - 1.30 (m, 3 H), 1.61 - 1.77 (m, 6 H), 3.36 (d, 2 H), 4.25 (s, 2 H), 5.19 (brs, 2 H), 6.56 (d, 1 H), 6.68 (d, I H), 7.22 (dd, 1 H).
Example 22
N-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl](4-methylnaphthyl)carboxamide
Step A: N-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl](4-me1hylnaphthyl)carboxaniide
7-Ammo-2-(cydohexylmethyl)isoindolin-l-one (0.151 g, 0.610 mmol), followed by triethylamine (0.260 mL, 1.86 mmol) was added to a stirred solution of A- methylnaphthalene-1-carboήyl chloride (0.227 g, 1.22 mmol) (see the following step B for preparation) in CH2CI2 (10 mL). The reaction mixture was stirred at room temperature overnight, diluted with CH2CI2 (20 mL), washed with saturated NaHCCb solution (20 mL), brine (20 mL), dried over Na2SC>4. The solvent was removed under reduce pressure. Flash chromatography of the residue over silica gel using EtOAc/hexanes (1 : 10 to 1 :5) gave the title compound as a white foam, which was crystallized from EtOAc to afford a white solid, 0.2 g (79%). 1H NMR (400 MHz, CHLOROFORM-D) δ 0.90 - 1.08 (m, 2 H), 1.10 - 1.32 (m, 3 H), 1.60 - 1.79 (m, 6 H), 2.73 (s, 3 H), 3.38 (d, 2 H), 4.40 (s, 2 H), 7.15 (d, 1 H), 7.37 (d, 1 H), 7.52 - 7.62 (m, 3 H), 7.81 (d, 1 H), 8.01 - 8.08 (m, 1 H), 8.57 - 8.64 (m, 1 H), 8.77 (d, 1 H), 11.02 (s, 1 H). ; MS (ESI) (M+H)+ = 412.99; Anal. Calcd for C27H28N2O2: C, 78.6.1; H, 6.84; N3 6.79 Found: C, 78.21; H, 7.05; N3 6.86.
Step B: 4-Methylnaphthalenecarbonyl chloride
.
Oxalyl chloride (0.53 niL, 6.1 mmol), followed by anhydrous DMF (2-3 drops) was added to a stirred solution of 4-methylnaphthalenecarboxylic acid (0.227 g, 1.22 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 2 h, evaporated and dried under vacuum for 0.5 h. to give the title acid chloride , which was used without further purification in step A.
Example 23 N-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl](4-methoxylnaphthyl)carboxamide
Step A: N-[2-(Cyclohexymiethyl)-3-oxoisoindolin-4-yl](4-methoxylnaphthyl)carboxamide
Following the same general procedure as in example 22, step A, reaction of 7-amino-2- (cyclohexylmethyl) isoindolin-1-one (0.122 g, 0.500 mmol) with 4- methoxynaphthalenecarbonyl chloride (0.202 g, 1.00 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.21 mL, 1.5 mmol) in CHzCl2 (10 mL), after purification by flash chromatography over silica gel, using EtO Ac/hexanes (1:10 to 1:5), gave the title compound as a white foam, which was crystallized from EtOAc to afford a white solid, 0.11 g (52%). 1H NMR (400 MHz, CHLOROFORM-D) δ 0.94 - 1.08 (m, 2 H), 1.12 - 1.28 (m, 3 H), 1.60 - 1.78 (m, 6 H), 3.40 (d, 2 H), 4.04 (s, 3 H), 4.40 (s, 2 H), 6.86 (d, 1 H), 7.14 (d, 1 H), 7.50 - 7.62 (m, 3 H), 7.92 (d, 1 H), 8.32 (d, 1 H), 8.68 (d, 1 H), 8.76 (d, 1 H), 11.08 (s, 1 H); MS (ESI) (M+H)+ = 428.98; Anal. Calcd for C27H28N2O3: C, 75.68; H, 6.59; N, 6.54 Found: C, 75.44; H, 6.71; N, 6.60.
Example 24 N-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl](4-fluoronaphthyl)carboxamide
Step A: N-[2-(Cyclohexybnethyl)-3-oxoisoindolin-4-yl](4-fluoronaphthyl)carboxamide
Following the same general procedure as in example 22, step A, reaction of 7-amino-2- (cyclohexylmethyl)isoindolin-l-one (0.147 g, 0.600 mmol) with 4- fluoronaphthalenecarbonyl chloride (0.170 g, 0.900 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH2Cl2 (10 mL), after purification by flash chromatography over silica gel, using EtO Ac/hexanes (1:10 to 1:5) gave the title compound, as a white foam. The product was crystallized from EtOAc/hexanes (1:3) to afford a white solid, 0.18 g (72%). 1HNMR (400 MHz, CHLOROFORM-D) δ 0.92 - LOS (m, 2 H), 1.10 - 1.29 (m, 3 H), 1.60 - 1.80 (m, 6 H), 3.39 (d, 2 H)5 4.38 (s, 2 H), 7.12 - 7.23 (m, 2 H), 7.54 - 7.68 (m, 3 H), 7.89 (dd, 1 H), 8.16 (dd, 1 H), 8.63 (dd, 1 H), 8.74 (d, 1 H), 11.09 (s, 1 H); MS (ESI) (M+H)+ = 416.97; Anal. Calcd for C26H25FN2O2: C, 74.98; H, 6.05; N, 6.73 Found: C, 74.90; H, 6.04; N,.6.84.
Example 25 [4-(Dimethylamino)naphthyl)]-N-[2-(cyclohexylmethyl)-3-oxoisoindolin-4-yl]carboxamide
A solution of 4-(dimethylarmno)naphthalenecarbonyl chloride (0.275 g, 1.18 mmol)
(prepared according to the procedure of Step B in example 22) in CH2CI2/CICH2CH2CI (10 mL/10 mL) was added dropwise over 7 h, via a syringe pump, to a stirred solution of 7- amino-2-(cyclohexyhτaethyl)isoiαdolin-l-one (0.17 g, 0.70 mmol), pyridine (0.40 mL, 5.0 mmol) in ClGBbCTaCr(OO mL) at 45 0C. After the addition, the reaction mixture was stirred for 8 h, cooled to room temperature, diluted with CH2CI2 (40 mL), washed with saturated NaHCO3 solution (50 mL), water (50 mL), brine (50 mL), dried over Na2SO4, filtered and evaporated. Flash chromatography of the residue over silica gel using EtOAc/hexanes (1:10 to 1:5), followed by preparative tic (CH2Cl2/hexanes, 1:1), gave the title compound. This was crystallized from EtOAc/hexanes (1 :3) to afford pure compound as a pale yellow solid, 0.14 g (45%). 1H NMR (400 MHz, CHLOROFORM-D) δ 0.92 - 1.30 (m, 5 H), 1.58 - 1.80 (m, 6 H), 2.92 (s, 6 H), 3.38 (d, 2 H), 4.38 (s, 2 H), 7.05 (d, 1 H), 7.16 (d, 1 H), 7.42 - 7.62 (m, 3 H), 7.84 (dd, 1 H), 8.12 (dd, 1 H), 8.63 (d, 1 H), 8.76 (d, 1 H), 11.06 (s, 1 H); MS (ESI) (M+H)+ = 442.02; Anal. Calcd for C28H3IN3O2: C, 76.16; H, 7.08; N, 9.52 Found: C, 75.96; H, 7.45; N, 9.29.
Example 26 [4,7-(Dime1ioxy)naphthyl)]-N-[2-(cyclohexylmethyl)-3-oxoisoindolin--4-yl]carboxarnide
Following the same general procedure as in example 22, step A, reaction of 7-amino-2- (cyclohexylmethyl)isoindolm-l-one (0.147 g, 0.600 mmol) with 4,7- (dimethoxy)αaphthalenecarbonyl chloride (0.210 g, 0.900 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH2CI2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:10 to 1:5), followed by preparative tic (CE^Gb/hexanes, 2: 1), gave the title compound as a pale yellow foam, which was crystallized from EtOAc/hexanes (1 :3) to afford a pale yellow solid, 0.2 g (73%). 1H NMR (400 MHz, CHLOROFORM-D) δ 0.94 - 1.08 (m, 2 H), 1.12 - 1.28 (m, 3 H), 1.60 - 1.80 (m, 6 H), 3.41 (d, 2 H), 3.94 (s, 3 H), 4.02 (s, 3 H), 4.40 (s, 2 H), 6.74 (d, 1 H), 7.10 - 7.18 (m, 2 H), 7.56 (dd, 1 H), 7.93 (d, 1 H), 8.14 (d, 1 H), 8.22 (d, 1 H), 8.74 (d, 1 H), 11.09 (s, 1 H); MS (ESI) (M+H)+ = 459.02; Anal. Calcd for C28H30N2O4: C, 73.34; H, 6.59; N, 6.11 Found: C, 73.52; H, 6.48; N, 6.03.
Example 27 Naphtliyl-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyrau-4-ylmethyl)isoindolin-4-yl)carboxamide
Step A: Naphthyl-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4-yhnethyl)isoindolin-4- yl)carboxamide
1-Naphthoyl chloride (0.18 mL, 1.2 mmol), followed by triethylamine (0.26 mL, LS mmol) was added to a stirred solution of 7-amiαo-2-(2H-3,4,5,6-tetrahydropyran-4- ylmethyl)isoindolin-l-one (0.14S g, 0.600 mmol) (for preparation, see the following steps B and C) in CH2CI2 (10 mL). The reaction mixture was stirred at room temperature overnight, diluted with CH2Cl2 (20 mL), washed with saturated NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4, filtered and evaporated. Flash chromatography of the residue over silica gel, using EtOAc/hexanes (1:2 to 1:1) gave the title compound, as a white foam, which was crystallized from EtOAc to afford a white solid, 0.15 g (62%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.30 - 1.62 (m, 4 H), 1.92 - 2.08 (m, 1 H)5 3.32 (dd, 2 H), 3.42 (d, 2 H), 3.84 (dd, 2 H)5 4.40 (s, 2 H), 7.16 (d, 1 H), 7.48 - 7.64 (m, 4 H), 7.80 - 7.90 (m, 2 H), 7.94 (d, 1 H), 8.54 (d, 1 H), 8.76 (d, 1 H)5 11.02 (s, 1 H); MS (ESI) (M+H)+ = 400.88; Anal. Calcd for C25H24N2O3: C, 74.98; H, 6.04; N, 6.99 Found: C, 74.82; H, 5.99; N, 7.15.
Step B: 7-Nitro-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one
4-Aminomethyltetrahydropyran (2.00 g, 17.4 mmol), followed by DIPEA (6.0 mL, 34 mmol) were added to a stirred solution of methyl-2-bromomethyl-6-nitro-benzoate (4.76 g, 17.4 mmol) in anhydrous DMF (80 mL). The mixture was stirred at 80 0C for 3 h, concentrated in vacuo, diluted with CH2Cl2 (150 mL), washed with saturated NaHCO3 (2x50 mL), brine (50 mL), and dried over Na2SO4, filtered and evaporated. Flash chromatography of the residue over silica gel, using EtOAc/hexanes (1:1 to 2:1) gave the title compound (compound 5), 3.42 g (71%) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-D) δ 1.36 - 1.50 (m, 2 H), 1.54 - 1.65 (m, 2 H), 1.98 - 2.12 (m, 1 H), 3.36 (dd, 2 H), 3.50 (d, 2 H), 3.98 (dd, 2 H), 4.49 (s, 2 H), 7.60 - 7.76 (m, 3 H).
Step C: 7-Amiαo-2-(2H-3,4,5,6-tetrah.ydropyran-4-ylmethyl)isoindolijα-l-one Compound 6
Ammonium chloride (3.37 g, 61.9 mmol), followed by zinc dust (8.11 g, 124 mmol) were added to a stirred solution of 7-nitro-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindoliα- 1-one (3.42 g, 12.4 mmol) in MeOH (100 mL). The mixture was stirred at 68 0C for 1 h, cooled to room temperature and filtered through celite, washed with MeOH (2x30 mL). The filtrate was evaporated, diluted with CH2CI2 (150 mL), washed with saturated NaHCOs (2x50 mL), brine (50 mL), and dried over Na2SO4. Evaporation of the solvent gave the title compound (compound 6), 2.9 g (95%) as a pale yellow solid, which was used without further purification. 1HNMR (400MHz, CHLOROFORM-D) δ 1.36 - 1.48 (m, 2 H), 1.57 - 1.66 (m, 2 H), 1.92 - 2.06 (m, 1 H), 3.36 (dd, 2 H), 3.42 (d, 2 H), 3.98 (dd, 2 H), 4.32 (s, 2 H), 5.20 (brs, 2 H), 6.57 (d, 1 H), 6.68 (d, 1 H), 7.24 (dd, 1 H).
Example 28
(4-Methyhiaphthyl)-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4-yhnethyl)isoindolin-4- yl)carboxamide
Following the same general procedure as in example 22, step B, reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.148 g, 0.600 mmol) with 4- methylnaphthalenecarbonyl chloride (0.223 g, 1.20 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH2CI2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a white foam, which was crystallized from EtOAc/hexanes (1:1) to afford a white solid, 0.18 g (72%). 1H NMR (400 MHz,
CHLOROFORM-D) δ 1.32 - 1.44 (m, 2 H), 1.46 - 1.62 (m, 2 H), 1.92 - 2.08 (m, 1 H), 2.74 (s, 3 H), 3.34 (dd, 2 H), 3.42 (d, 2 H), 3.92 (dd, 2 H), 4.42 (s, 2 H), 7.16 (d, 1 H), 7.36 (d, 1 H), 7.52 - 7.62 (m, 3 H), 7.78 (d, 1 H), 8.06 (dd, 1 H), 8.58 (dd, 1 H), 8.76 (d, 1 H), 10.98 (s, 1 H); MS (ESI) (M+H)+ = 414.93; Anal. Calcd for C26H26N2O3: C, 75.34; H, 6.32; N, 6.76 Found: C, 75.51; H, 6.30; N, 6.90.
Example 29
(4-Memoxynaphthyl)-N-[3-oxo-2-(2H-3,435J6-tetrahydropyran-4-yhnethyl)isoindolin-4- yl)carboxamide
Following the same general procedure as in example 22, step B, reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.123 g, 0.500 mmol) with 4- methoxynaphthalenecarbonyl chloride (0.202 g, 1.00 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.21 mL, 1.5 mmol) in CH2Cl2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a white foam, which was crystallized from EtOAc/hexanes (1:1) to afford a white solid, 0.17 g (79%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.36 - 1.47 (m, 2 H), 1.54 - 1.64 (m, 2 H), 1.92 - 2.08 (m, 1 H), 3.36 (dd, 2 H), 3.46 (d, 2 H), 3.92 - 4.02 (m, 2 H), 4.05 (s, 3 H), 4.42 (s, 2 H), 6.86 (d, 1 H), 7.15 (d, 1 H), 7.50 - 7.62 (m, 3 H)5 7.92 (d, 1 H), 8.32 (d, 1 H), 8.67 (d, 1 H), 8.76 (d, 1 H), 11.01 (s, 1 H); MS (ESI) (M+H)+ = 430.99; Anal. Calcd for C26H26N2O4: C, 72.54; H, 6.09; N, 6.51 Found: C, 72.61; H, 6.07; N, 6.59.
Example 30 (4-Fluoroynaphthyl)-N-[3-oxo-2-(2H-3,4,5J6-tetrahydropyran-4-ylmethyl)isoindolin-4- yi)carboxamide
Following the same general procedure as in example 22, step A, reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyτan-4-ylmeth.yl)isoindolm-l-one (0.148 g, 0.600 mmol) with 4- fluoronaphthalenecarbonyl chloride (0.170 g, 0.900 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH2Cl2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a white foam, which was crystallized from EtOAc to afford a white solid, 0.18 g (72%). 1HNMR (400 MHz, CHLOROFORM-D) δ 1.32 - 1.48 (m, 2 H), 1.54 - 1.64 (m, 2 H), 1.92 - 2.08 (m, 1 H), 3.36 (dd, 2 H), 3.45 (d, 2 H), 3.97 (dd, 2 H), 4.43 (s, 2 H), 7.14 - 7.24 (m, 2 H), 7.56 - 7.66 (m, 3 H), 7.89 (dd, 1 H), 8.17 (dd, 1 H), 8.63 (dd, 1 H), 8.74 (d, 1 H), 11.04 (s, 1 H); MS (ESI) (M+H)+ = 418.96; Anal. Calcd for C25H23FN2O3: C, 71.76; H, 5.54; N, 6.69 Found: C, 71.73; H, 5.50; N, 6.82.
Example 31
[4-(Dimethylamino)naphthyl)]-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4- ylmethyl)isoindolin-4-yl] carboxamide
Following the same procedure as in example 6, reaction of 7-amino-2-(2H-3 ,4,5,6- tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.172 g, 0.700 mmol) with the 4- (dimethylamino)naphthalenecarbonyl chloride (0.301 g, 1.40 mmol) (prepared according to the procedure of Step B in example 22) and pyridine (0.50 mL, 6.2 mmol) in
CICH2CH2CI/CH2CI2 (60 mL/10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a pale yellow solid, which was crystallized from EtO Ac/hexanes (1 : 1) to afford a pale yellow solid, 0.25 g (80%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.32 - 1.46 (m, 2 H), 1.54 - 1.66 (m, 2 H), 1.92 - 2.07 (m, 1 H), 2.94 (s, 6 H), 3.36 (dd, 2 H), 3.46 (d, 2 H), 3.97 (dd, 2 H), 4.42 (s, 2 H), 7.04 (d, 1 H), 7.14 (d, 1 H), 7.46 - 7.64 (m, 3 H), 7.82 (d, 1 H), 8.22 (dd, 1 H), 8.62 (dd, 1 H), 8.76 (d, 1 H), 10.98 (s, 1 H); MS (ESI) (M+H)+ = 444.01; Anal. Calcd for C27H29N3O3: C, 73.11; H, 6.59; N, 9.47 Found: C, 73.02; H, 6.40; N, 9.43.
Example 32 [4,7-(Dimethoxy)naphthyl)]-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4- ylmethyl)isoindolin-4-yl]carboxamide
Following the same general procedure as in example 22, step A, reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.148 g, 0.600 mmol) with 4,7- dimethoxynaphthalenecarbonyl chloride (0.210 g, 0.900 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH2CI2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a white foam. Crystallization from EtOAc/hexanes (1:1) afforded a white solid, 0.2 g (72%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.34 - 1.48 (m, 2 H), 1.55 - 1.64 (m, 2 H), 1.90 - 2.18 (m, 1 H), 3.36 (dd, 2 H), 3.46 (d, 2 H), 3.94 (s, 3 H), 3.97 (dd, 2 H), 4.04 (s, 3 H), 4.43 (s, 2 H), 6.75 (d, 1 H), 7.10 - 7.20 (m, 2 H), 7.58 (dd, 1 H), 7.94 (d, 1 H), 8.15 (d, 1 H), 8.22 (d, 1 H), 8.75 (d, 1 H), 11.01 (s, 1 H); MS (ESI) (M+H)+ = 460.98; Anal. Calcd for C27H28N2O5: C, 70.42; H, 6.13; N, 6.08 Found: C, 71.11; H, 6.24; N, 6.15.
Example 33 . N-[2-(Moφholin-4-ylethyl)-3-oxoisoindolin-4-yl]naphthylcarboxamide
Step A: N-[2-(Morpholin-4-ylethyl)-3-oxoisoindolin-4-yl]naphthylcarboxamide
Following the same general procedure as in example 22, reaction of 7-amino-2-(2- morpholin-4-ylethyl) isoindolin-1-one (150 mg, 0.57 mmol) (prepared according to the following steps B and C) with 1-naphthoyl chloride (0.086 mL, 0.57 mmol) in dry CH2Cl2 (15 mL) and triethylamine (0.16 mL, 1.14 mmol), gave the crude product.. The product was purified by chromatography using EtOAc/hexane (3:7) on a column of silica gel, followed by crystallization from CH2Cl2/hexanes, provided the title compound as a solid 0.090 g (37%). 1H NMR (400 MHz, METHANOL-D4) δ 2.64 (t, 2 H); 3.3 (brs, 3 H), 3.65 (t, 4 H), •3.7 (t, 2 H), 4.6 (s, 2 H)54.85 (s, 2 H), 7.30 (d,l H), 7.62 - 7.52 (m, 4 H), 7.84 (d, 1 H), 7.98 (d, 1 H), 8.10 (d, 1 H)5 8.45 (d, 1 H)5 8.58 (d, 1 H); MS (ESI) (M+H)+= 416.01; Anal. Calcd for C25H25N3O3: C, 72.27; H, 6.06; N5 10.11 Found: C, 71.94; H, 5.98; N, 9.91.
Step B: 2-(2-Morpholin-4-yIethyl)-7-nitroisoindolin-l-one
To a solution of methyl 2-(bromoethyl)-6-nitrobenzoate (1.37 g, 5 mmol) in DMF (30 mL) were added 2-morpholύα-4-ylethanamine (0.65 mL, 5.04 mmol) followed by DIPEA (1.73 mL, 14.25 mmol), the solution was stirred at 85 0C for 3 h. The reaction mixture was concentrated in vacuo, the residue was taken up in CH2CI2 (300 mL), and washed with saturated NaHCO3 solution (2x100 mL), brine (1x100 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to provide the crude compound as a brown solid. Purification by crystallization from EtOAc/hexanes gave the title compound as a yellow brown solid 0.93 g (32%). 1HNMR (400 MHz, CHLOROFORM-D) δ 2.5 (s, br, 4 H)5 2.66 (t, 2 H), 3.69 (t, 4H), 3.75 (t, 2 H), 4.58 (s, 2 H)5 7.64 - 7.68 (m, 2H), 7.68 - 7.25 (q, 1 H); MS (ESI) (M+H) += 291.94.
Step C: 7-Amino-2-(2-morpholin-4-ylethyl)isoindolin-l-one
To a solution of 2-(2-Mθφholin-4-ylethyl)-7-nitroisoindolin-l-one (0.330 g, 1.13 mmol) in anhydrous MeOH (23 mL), was added NH4Cl (0.3 g, 5.66 mmol) followed by zinc dust (7.39 g, 113 mmol) and the reaction mixture was stirred at 70 0C for 1 h. The mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and the product was dissolved in CH2Cl2 (50 mL), washed with sat. NaHCC>3 solution (2x25 mL), , brine (1x25 mL), dried over Na2SO4. The solvent was removed under reduced pressure to provide the title compound as a yellow brown solid 0.276 g (94%). This material was used without further purification in the next step. 1H NMR (400 MHz, CHLOROFOM-D) δ 2.5 (brs, 4 H), 2.6 (t, 2 H), 3.68 - 3.60 (m, 7 H,), 4.40 (s, 2 H), 5.20 (s, br, 2 H), 6.58 (d, 1 H), 6.65 (d, 1 H), 7.22 (m, 1 H); MS (ESI) ( M+H)+= 261.94.
Example 34 4-Methyl-iV-[2-(2-morpholinoethyl)-l-oxoisoindolin-7-yl]naphthalene-l-carboxainide
Following the same general procedure as in example 22, step B, reaction of 7-amino-2-(2- morpholin-4-ylethyl)isoindolin-l-one (0.15 g, 0.57 mmol) with 4- methylnaphthalenecarbonyl chloride (0.40 g, 1.14 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.16 mL), 1.14 mmol) in CH2CI2 (20 mL) gave the crude product, which was purified by crystallization from C^Cyhexanes. The title compound was an off-white solid 0.085 g (34%). 1H NMR (400 MHz, CHLOROFORM-D) δ 2.5 (brs, 4 H), 2.6 (t, 2 H), 2.75 (s, 3 H), 3.75 - 3.65 (m, 6 H), 4.52 (s, 2 H), 7.18 (d, 1 H), 7.38 (d,l H), 7.60 - 7.55 (m, 3 H), 7.8 (d, 1 H)5 8.08 - 8.02 (m, 1 H), 8.64 - 8.56 (m, 1 H), 8.75 (d, 1 H); MS (ESI) (M+H)+= 430.03; HPLC: 97.67; Anal. Calcd for C26H27N3O3: C, 72.71; H, 6.34; N, 9.78 Found: C, 72.57; H, 6.23; N, 9.72.
Example 35 (4-Methoxynaphthyl)-iV-[2-(2-morpholin-4-yIethyl)-3-oxoisoindoIin-4-yl]carboxainide
Following the same general procedure as in example 22, step B, reaction of 7-amino-2-(2- morpholin-4-ylethyl)isomdolin-l-one (0.150 g, 0.57 mmol) with 4- methoxynaphthalenecarbonyl chloride (0.250 g, 1.14 mmol) (prepared according to the procedure of Step B in example 2) and triethylamine (0.16 mL, 1.14 mmol), in dry CH2CI2 (20 mL), after chromatography over silica gel using EtOAc/hexanes (3:7), gave the title compound as a solid. Crystallization from CHaCb/hexanes gave a solid 0.095 g (38%). 1H NMR (400 MHz, CHLOROFORM-D) δ 2.5 (bra, 4 H), 2.65-2.58 (m, 2 H), 3.68 (brs, 6 H), 4.15 (s, 3 H), 4.5 (s, 2 H), 6.88 (d, 1 H), 7.18 (d,l H), 7.62 - 7.50 (m, 3 H), 7.9 (d, 1 H), 8.32 (d, 1 H), 8.65 (d, 1 H), 8.75 (d, 1 H); MS (ESI) (M+H)+= 445.93 HPLC: 97.36; Anal. Calcd for C26H27N3O4: C 70.10, H 6.11, N 9.43 Found: C 69.56, H 5.93, N 9.19.
Example 36 (4-Methoxynaphthyl)-Λr-[3-oxo-2-(2-piperidylethyl)isoindolin-4-yl]carboxamide
Step A: (4-Methoxynaphthyl)-iV-[3-oxo-2-(2-piperidylethyl)isoindolin-4- yl]carboxamide
Following the same general procedure as in example 22, step B, reaction of 7-amino-2-(2- (piperidin-l-ylemyl)isoindolin-l-one (0.150 g, 0.58 mnaol) (for preparation, see the following steps B and C) with 4-methoxynaphthalenecarbonyl chloride (0.250 g, 1.14 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.16 mL, 1.14 mmol) in CH2CI2 (20 mL), after purification by chromatography over silica gel using CH2Cl2MeOH (9:1) gave the title compound. Crystallization from CH2Cl2/hexanes gave a solid 0.160 g (62%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.45 (brs, 2 H), 1.55 (brs, 6 H), 2.49 - 2.38 (brs, 4 H), 3.72 - 3.65 (m, 2 H), 4.05 (s, 3 H), 4.55 (s, 2 H), 6.86 (d, 1 H), 7.15 (d, 1 H), 7.62 -7.48 (m, 3 H), 7.92 (d, 1 H), 8.32 (d, 1 H), 8.65 (d, 1 H), 8.75 (d, 1 H); MS (ESI) (M+H)+= 444.01; Anal. Calcd for C27H29N3O3: C 73.11, H 6.59, N 9.47 Found: C 73.41, H 6.65, N 9.24.
Step B: 7-Nitro-2-(2-(piperidin-l-ylethyl)isoindolin-l-one
To a solution of methyl 2-(bromoethyl)-6-nitrobenzoate (4.0 g, 14.6 mmol) in anhydrous DMF (88 mL), were added 2-(piperidin-l-yl)ethanamine (2.1 mL, 14.6 mmol) and DIPEA (7.23 mL, 41.61 mmol) and the mixture was stirred at 85 0C for 3 h. The reaction mixture was concentrated in vacuo, the residue was taken up in CH2CI2 (880 mL), and washed with cone. NaHCO3 solution (2x450 mL), brine (1x450 mL), dried over Na2SO4 and concentrated to provide the title compound as brown solid. Crystallization from CH2Cl2/hexanes gave the title compound as a yellow brown solid 3.2 g (76%).1H NMR (400 MHz, CHLOROFORM-D) δ 1.40 - 1.50 (m, 2 H), 1.50 - 1.64 (m, 4 H), 2.44 (brs, 4 H), 2.60 (t, 2 H), 3.70 (t, 2 H), 4.60 (s, 2 H), 7.60 -7.70 (m, 2 H), 7.69 - 7.78 (d, 1 H).
Step C: 7-Amino-2-(2-(piperidin-l-ylethyl)isoindolm-l-one
To a solution of 7-nitro-2-(2-(piperidin-l-ylethyl)isoindolin-l-one (3.2 g, 11.07 mmol) in anhydrous MeOH (240 mL) was added NH4Cl (2.93 g, 55.35 mmol) followed by zinc dust (72 g, 1107 mmol) and the reaction mixture was stirred at 70 0C for 1 h. The mixture was cooled to room temperature and filtered through celite. The solid was washed with MeOH (2x250 mL), the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (500 mL), the undissolved part was filtered off and the filtrate was washed with sat. NaHCOa solution (2x250 mL), brine (lx250mL), dried OVCrNa2SO4. The solvent was removed under reduced pressure to provide the title compound (compound 11) as a light yellow solid 2.76 g (96%), which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-D) 5 1.50-1.40 (m, 2 H), 1.65-1.54 (m, 5 H), 2.45 (brs, 4 H,), 2.55(t, 2 H), 3.65 (t, 2 H), 4.4 (s, 2 H), 6.56 (d, 1 H), 6.7 (d, 1 H), 7.2 (d, 1 H); MS (ESI) ( M+H)+= 259.95
Example 37 (4-Fluoronaphthyl)-Λr-[3-oxo-2-(2-piperidylethyl)isoindolin-4-yI]carboxamide
Following the general procedure as in example 22, step B, reaction of 7-amino-2-(2- (piperidin-l-ylethyl)isoindolin-l-one (0.200 g, 0.77 mmol) with 4- fluoronaphthalenecarbonyl chloride (0.240 g, 1.15 mmol) (prepared according to the procedure of Step B in example 22.) in CH2CI2 (30 mL), after chromatography over silica gel using CH2Cl2ZMeOH (98:2 to 95:5) gave the title compound as a solid 0.195 g (57%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.20 (s, 2 H), 1.40 (brs, 4 H), 2.40 (brs, 3 H), 2.60 (s, 2 H), 3.65 (s, 2 H), 4.45 (s, 2 H), 7.20 - 7.15 (m, 2 H), 7.65 - 7.50 (m, 3 H), 7.85 (d, ' 1 H), 8.2 (d, 1 H), 8.6 (d, 1 H), 8.7 (d, 1 H); Anal. Calcd for C26H26FN3O2: C 7237, H 6.07, N 9.74 Found: C 71.40, H 5.74, N 9.25; MS (ESI) (M+H)+= 432.03.
Scheme for 4-Hydroxynaphthalene Compounds
Example 38 N-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl](4-hydroxynaphthιyI)carboxamide
Steρ A: N-[2-(Cyclohexylmethyl)-3-oxoisomdolin-4-yl](4-hydroxynaphthyl)carboxamide
10% Palladium on carbon (0.050 g) was added to a stirred solution of N-[2- (cyclohexylmethyl)-3-oxoisoindol]bi-4-yl][4-(phenylmethoxy)naphthyl]carboxainide (0.14 g, 0.28 mmol) (for preparation, see the following step B) in MeOH/THF (10 roL/20 mL). The mixture was stirred under a hydrogen atmosphere for 2.5 h, filtered through celite, and washed with THF (2x15 mL). The filtrate was evaporated to give the title compound, which was washed with CH2CI2 to afford the title compound as a white solid, 0.090 g (78%). 1H NMR (400 MHz, DIMETHYLSULFOXIDE-De) δ 0.84 - 1.00 (m, 2 H), 1.04 - 1.26 (m, 3 H), 1.54 - 1.80 (m, 6 H), 3.33 (s, 2 H), 4.50 (s, 2 H), 6.98 (d, 1 H), 7.28 (d, 1 H), 7.50 - 7.68 (m, 3 H), 7.82 (d, 1 H), 8.26 (d, 1 H), 8.52 (d, 1 H), 10.98 (brs, 1 H), 11.02 (s,l H); MS (ESI) (M+H)+ = 414.97; Anal. Calcd for C26H26N2O3: C, 75.34; H, 6.32; N, 6.76 Found: C, 75.55; H, 6.29; N, 6.92.
Step B: N-[2-(cyclohexylmethyl)-3-oxoisoindolin-4-yI][4- (phenylmethoxy)naphthyl] carboxamide
Following the same general procedure as in example 22, step A, reaction of 7-amino-2~ (cyclohexyhnethyl)isoindolin-l-one (0.135 g, 0.550 mmol) with 4- (phenylmethoxy)naphthalenecarbonyl chloride (0.230 g, 0.827 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.24 mL, 1.7 mmol) in CH2Cl2 (10 mL), after purification by flash chromatography over silica gel, using CH2Cl2/hexanes (1:3 to 1:1) gave the title compound , 0.26 g (94%) as a pale white solid. 1H NMR (400 MHz, CHLOROFORM-D) δ 0.92 - 1.30 (m, 5 H), 1.60 - 1.80 (m, 6 H), 3.38 (d, 2 H), 4.38 (s, 2 H), 5.30 (s, 2 H), 6.92 (d, 1 H), 7.16 (d, 1 H), 7.30 - 7.64 (m, 8 H), 7.89 (d, 1 H), 8.38 (d, 1 H), 8.72 (dd, 1 H), 8.84 (d, 1 H), 11.05 (s, 1 H).
Example 39
[4-(Hydroxy)naphthyl)]-N-[3-oxo-2-(2H-354,5,6-tetrahydropyran-4- yImethyl)isoindolin-4-yl]carboxamide
Step A: [4-(Hydroxy)naphthyl)]-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4- ylmethyl)isoindolm-4-yl]carboxamide
10% Palladium on carbon (0.050 g) was added to a stirred solution of N-[3-oxo-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolinyl][4-(phenylmethoxy)naphthyl]carbox- amide (0.14 g, 0.28 mmol) (for preparation, see the following step B) in MeOH/THF (10 mL/20 mL). The mixture was stirred under a hydrogen atmosphere for 2.5 h, filtered through celite, and washed with THF (2x15 mL). The filtrate was evaporated to give the title compound, which was washed with CH2CI2 to afford the title compound as a white solid, 0.090 g (78%). 1H NMR (400 MHz, DIMETHYLSULFOXIDE-Dβ) δ 1.12 - 1.28 (m, 2 H), 1.46 - 1.56 (m, 2 H), 1.90 - 2.04 (m, 1 H), 3.24 (dd, 2 H), 3.38 (d, 2 H), 3.82 (dd, 2 H), 4.54 (s, 2 H), 6.98 (d, 1 H), 7.29 (d, 1 H), 7.51 - 7.66 (m, 3 H), 7.81 (d, 1 H), 8.25 (d, 1 H), 8.52 (d, 2 H), 10,96 (s, 1 H), 11.03 (s, 1 H); MS (ESI) (M+H)+ = 416.94; Anal. Calcd for C25H24N2O4: C, 72.10; H, 5.81; N, 6.73 Found: C, 70.63; H, 5.94; N, 6.69.
Step B: N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindoIinyl] [4- (phenylmethoxy)naphthyl]carboxamide
Following the same general procedure as in example 22, step B, reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.136 g, 0.550 mmol) with 4- (phenylmethoxy)naphthalenecarbonyl chloride (0.230 g, 0.827 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.24 mL, 1.6 mmol) in CH2Cl2 (10 πiL), after purification by flash chromatography over silica gel, using EtOAc/CH2Cl2 (1:10 to 1:5), gave the title compound, 0.26 g (94%) as a white solid. 1H NMR (400 MHz, CHLOROFORM -D) δ 1.32 - 1.62 (m, 4 H)5 1.92 - 2.08 (m, 1 H), 3.34 (dd, 2 H), 3.44 (d, 2 H), 3.96 (dd, 2 H), 4.04 (s, 2 H), 5.28 (s, 2 H), 6.92 (d, 1 H), 7.14 (d, 1 H), 7.32 - 7.64 (m, 8 H), 7.88 (d, 1 H), 8.38 (d, 1 H), 8.68 (d, 2 H), 8.74 (s, 1 H), 10.98 (s, 1 H).

Claims

What is claimed is:
1. A compound of formula I, a pharmaceutically acceptable salt thereof, a diastereomer, an enantiomer, or a mixture thereof:
wherein:
R1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, acetoxy, hydroxyl, C1-6alkoxy, hydroxy-C1-6alkoxy, benzyloxy, -OCH2-C(=O)-R4, -OS(=O)2-R4, C1-6alkyl, halogenated C1-6alkoxy, C2-6alkylene, halogenated C1-6alkyl, halogenated C2-6alkenyl C1-6alkylamino, di-Ci-salkylamiαo and amino; R2 is selected from
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated C1-6alkyl, C1-6alkyl, halogenated C1-6alkoxy, cyano, nitro, C1-6alkoxy, hydroxy, hydroxy-C1-6alkyl, amino, C1-6alkyl-C6-10aryl, C1-6alkoxy-Ci. βalkyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylamino, di-C1-6alkylamino, di-Ci. 6alkylamino-C1-6alkyl, amino-C1-6alkyl, C1-6alkyl-amino-carbonyl, C2-5heteroaryl-carbonyl, C2-5heterocycloalkyl-carbonyl, C6-10arylcarbonyl, C2-5heterocycloalkyl, C3-6cycloalkyl, C3.. βcycloalkyl-C1-6alkyl, C2-5heteroaryl, C2-5heteroaryl-Ci-6alkyl, C6-10aryl, and Cg-ioaryl-Ci. βalkyl;
R3 is selected from Q-ealkyl, C2-6alkenyl, C3-6cycloalkyl, C/t-βcycloalkenyl, Ci- βalkoxy, and C2-5heterocycloalkyl; wherein said C^aHcyl, C2-6alkenyl, C3-6cycloalkyl, C4- βcycloalkenyl, C1-6alkoxy, and C2-5heterocycloalkyl used in defining R3 is optionally substituted by one or more groups selected from halogen, halogenated C1-6alkyl, C1-6alkyl, halogenated Q.galkoxy, cyano, nitro, C1-6alkoxy, hydroxy, hydroxy-Cμδalkyl, amino, Q- 6alkyl-C6-ioaryl, C1-6alkoxy-C1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, Ci- 6alkylamino, di-Ci-salkylamino, di-Ci-salkylamino-C1-6alkyl, amino-C1-6alkyl, C1-6alkyl- amino-carbonyl, C2-5heteroaryl-carbonyl, C2-5heterocycloalkyl-carbonyl, C6-10arylcarbonyl, C2-5heterocycloalkyl, C3.6cycloall.yl, Cs-gcycIoalkyl-Gi-ealkyl, C2-5heteroaryl, C2- 5heteroaryl~C1.6alkyl, C6-10aryl, and C6-10aryl-C1-6alkyl;
R4 is selected from C^alkyl, halogenated C^aUcyl, hydroxy, hydroxy-Ci- 6alkylamino, amino, C1-6alkoxy, C1-6alkylamino, di-C1-6alkylamino, hydroxyamino, Ci- βalkoxyamino, benzylamino, C2-5heterocycloalkyl, C2-sheteroaryl, and C2-5heteroaryl-Ci. • 6alkyl;
X is selected from -C(=O)- and -CH2-; and m and n are independently selected from 0, 1, 2, 3, 4 and 5, with, a proviso that R3 is not an optionally substituted 2,6-dioxopiperdin-3-yl.
2. A compound as claimed in claim 1, wherein
R1 is selected from hydrogen, methoxy, 2-hydroxyethoxy,- benzyloxy, acetoxy and acetylamino.
3. A compound as claimed in claim 1, wherein
R1 is selected from ethylsulfonyloxy, and 3-trifluoropropylsulfonyloxy.
4. A compound as claimed in claim 1, wherein
R4 is selected from hydroxy, methoxy, amino, methylamino, dimethylamino, hydroxyamino, methoxyamino, benzylamino, morpholinyl, 2-hydroxyethylamino, and pyridinylmethyl.
5. A compound as claimed in claim 1, wherein
R1 is independently selected from hydrogen, halogen, hydroxyl, Ci-6alkoxy, Cj- βalkyl, halogenated C1-6alkoxy, halogenated C^aUcyl, amino, and Ci.θalkylamino and di-Q. 6alkylamino;
R2 is selected from
wherein said group used in defining R2 is optionally substituted by one or more groups selected from Halogen, halogenated C^aUcyl, d-βalkyl, halogenated C1-6alkoxy, cyano, nitro, C1-6alkoxy, hydroxy, hydroxy-C^galkyl, amino, C1-6alkyl-C6-10aryl, C1-6alkoxy-Ci. 6alkyl, C^alkylcarbonyl, Ci-6alkoxycarbonyl, C1-6alkylamino, di-C^alkylamino, di-Ci. galkylamino-Ci-salkyl, amino-C1-6alkyl, C1-6alkyl-amino-carbonyl, C2-5heteroaryl-carbonyl, C2-5heterocycloalkyl-carbonyl, C6-10arylcarbonyl, C2-5heterocycloalkyl, C3-6cycloalkyl, C^. βcycloalkyl-C1-6alkyl, C2-5heteroaryl, C2-5heteroaryl-C1-6alkyl, C6-10aryl, and C6-10aryl-Ci- ealkyl;
R3 is selected from C^alkyl, C2-6alkenyl, C3-6cycloalkyl, C4-6cycloalkenyl, Cj- βalkoxy, and C2-5heterocycloalkyl; wherein said C^aUcyl, C2-6alkenyl, C3-6cycloalkyl, C4- βcycloalkenyl, C1-6alkoxy, and C2-5heterocycloalkyl used in defining R3 is optionally substituted by one or more groups selected from halogen, halogenated Chalky!, C1-6alkyl, halogenated Cμβalkoxy, C1-6alkoxy, hydroxy, hydroxy-C1-6alkyl, amino, C1-6alkoxy-Ci. 6alkyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylamino, and di-Ci-6alkylamino;
X is selected from -C(=O)- and -CH2-; and m and n are independently selected from 0, 1, and 2, with a proviso that R3 is not an optionally substituted 2,6-dioxopiperdin-3-yl.
6. A compound as claimed in claim 1, wherein R1 is hydrogen; R2 is selected from
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated C1-6alkyl, C1-6alkyl, halogenated C1-6alkoxy, C1-6alkoxy, hydroxy, hydroxy-C^galkyl, amino, C1-6alkoxy-Q-ealkyl, C2-5heteroaryl-Ci-6alkyly C1. galkylamino, di-C1-6alkylamino, di-C1-6alkylamino-C1-6alkyl;
R3 is selected from Chalky!, C2-6alkenyl, C3.6cycloalkyl, piperdinyl, morpholinyl, tetrahydrofuranyl and tetrahydropyranyl; wherein said C^aUcyl, C2-6alkenyl, C3-6cycloalkyl, piperdinyl, morpholinyl, and tetrahydropyranyl used in defining R3 is optionally substituted by one or more groups selected from halogen, halogenated C1-6alkyl, C1-6alkyl, halogenated C1-6alkoxy, C1-6alkoxy, hydroxy, hydroxy-Ci-salkyl, amino, Ci-δalkoxy-Ci-δalkyl, Ci. βalkylcarbonyl, C1-6alkoxycarbonyl, Ci.ealkylamino, and di-C1-6alkylamino;
X is selected from-C(=O)- and-CH2-; and m and n are independently selected from 0, 1, and 2.
7. A compound as claimed in any one of claims 1-5, wherein R1 is hydrogen.
A compound as claimed in any one of claims 1-7, wherein R2 is selected from
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
9. A compound as claimed in any one of claims 1-7, wherein
R2 is selected from cyclohexyl, phenyl and naphthyl, wherein said cyclohexyl, phenyl and naphthyl are optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
10. A compound as claimed in any one of claims 1-7, wherein
R2 is selected from cyclohexyl, phenyl and 1 -naphthyl, wherein said cyclohexyl, phenyl and 1 -naphthyl are optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
11. A compound as claimed in any one of claims 1 -7, wherein
R2 is 1 -naphthyl optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
12. A compound as claimed in any one of claims 1-11, wherein
R3 is selected from C^aUcyl, C2-6alkenyl, C3-6cycloalkyl and C2-5heterocycloalkyl, wherein said C^aUcyl, C2_6alkenyl, C3_6cycloalkyl and C2-5heterocycloalkyl are optionally substituted by one or more groups selected from halogen, halogenated C1-6alkyl, C1-6alkyl, t-butoxycarbonyl, amino, C1-6alkoxy-C1-6alkyl, C1-6alkylammo, and di-C1-6alkylamino with a proviso that R3 is not an optionally substituted 2,6-dioxopiperidin-3~yl.
13. A compound as claimed in any one of claims 1-11, wherein R3 is selected from Ci- βalkyl, C2-6alkenyl, Cs-δcycloalkyl, piperidmyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl and pyrrolidinyl, wherein said Chalky!, C2-6alkenyl, C3. 6cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl are optionally substituted by one or more groups selected from halogen, halogenated Cj- βalkyl, C1-6alkyl, t-butoxycarbonyl, amino, C1-6alkoxy-C1-6alkyl, C1-6alkylamino, and di-Q. ealkylamino.
14. A compound as claimed in any one of claims 1-11, wherein R3 is selected from C3-6cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl, wherein said Cs^cycloalkyl, piperidinyl, morpholinyl, tetrahydropyranyl and pyrrolidinyl are optionally substituted by one or more groups selected from halogen, halogenated C1-6alkyl, C1-6alkyl, t-butoxycarbonyl, amino, C1. 6alkoxy-C1-6alkyl, C1-6alkylamino, and di-C1-6alkylamino.
15. A compound as claimed in any one of claims 1-14, wherein n is 0.
16. A compound as claimed in any one of claims 1-14, wherein n is 1.
17. A compound as claimed in any one of claims 1-14, wherein n is 2.
18. A compound as claimed in any one of claims 1-14, wherein m is 0.
19. A compound as claimed in any one of claims 1-14, wherein m is 1.
20. A compound as claimed in any one of claims 1-14, wherein X is -C(=O)-.
21. A compound as claimed in any one of claims 1-14, wherein X is methylene.
22. A compound selected from:
N-[2-(cyclobutylmethyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]-l-naphthamide
N-(2-allyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide
N-(3-oxo-2-propyl-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide
N-(3-oxo-2-butyll-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide N-{2-[2-(dimethylarQmo)emyl]-3-oxo-2,3-dmydro-lH-isoindol-4-yl}-l-naphthamide
N-[2-(cyclohexyhτaethyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]-l- naphthamide N-[3-oxo-2-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-diliydro-lH-isoindol-4-yl]-l- naphthamide
N-(2-butyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-2,3-dimethylbenzamide 2,3-dime%l-N-[3-oxo-2-(tetrahydτo-2H-pyran-4-ylmethyl)-2,3-dihydro-lH-isoindol-4- yljbenzamide
N-(3-oxo-2-piperidin-3-yl-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide N-[3-oxo-2-(piperidin-2-ylmethyl)-2,3-diliydro-lH-isoindol-4-yl]-l-naphthamide N-{2-[(l-methylpiperidin-2-yl)methyl]-3-oxo-2,3-diliydro-lH-isomdol-4-yl}-l- naphthamide 4-metlioxy-N-[3-oxo-2-(piperidin-2-ylmethyl)-2,3-dihydro- lH-isoindol-4-yl]- 1 - naphthamide
N-[2-(2-morpholin-4-ylethyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]-l-naphthamide 4-(methoxymethyl)-N-[3-oxo-2-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-lH- isoindol-4-yl]- 1 -naphthamide N-[3-oxo-2-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-lH-isoindol-4-yl]-4-(lH-l,2,3- triazol- 1 -ylmethyl)- 1 -naphthamide
7- { [(2-methyl- 1 -naphthyl)metliyl] amino} -2-(2-moψholin-4-ylethyl)isoindolin- 1 -one N-(2-allyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-2,3-dichlorobenzamide N-(2-allyl-3 -oxo-2,3 -dihydro- 1 H-isoindol-4-yl)- 1 -naphthamide N-(2-allyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-2-(trifluoromethyl)benzamide N-[2- (Cyclohexyhnethyl)-3-oxoisoindolin-4-yl]naphthylcarboxamide N-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl](4-methylnaphthyl)carboxamide N-[2-(CycIohexyhnethyl)-3-oxoisoindolin-4-yl](4-methoxylnaphthyl)carboxamide N-[2-(Cyclohexyhnethyl)-3-oxoisoindolin-4-yl](4-fluoronaphthyl)carboxamide [4-(Dimethylamino)naphthyl)]-N-[2-(cyclohexyhnethyl)-3-oxoisoindolin-4-yl]carboxamide [4,7-(Dimethoxy)naph1iiyl)]-N-[2-(cyclohexyknethyl)-3-oxoisoindolin-4-yl]carboxamide Naphthyl-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4-yhnethyl)isoindolin-4-yl)carboxamide (4-Methytoaphthyl)-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-4- yl)carboxamide (4-Methoxynaphthyl)-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-4- yl)carboxamide (4-Fluoroynaphthyl)-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindoliα-4- yl)carboxamide
[4-(Dimethylainino)naphthyl)]-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4- ylmethyl)isoindolm-4-yl]carboxamide [4,7-(Dimethoxy)naphthyl)]-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4- ylmethyl)isoindolin-4-yl]carboxamide
N-[2-(Morpholin-4-ylethyl)-3-oxoisoindolin-4-yl]naplithylcarboxainide 4-Methyl-N-[2-(2-moipholinoethyl)-l-oxoisoindolm-7-yl]naphthalene-l-carboxainide (4-Me1iioxynaphthyl)-N-[2-(2-moφholin-4-ylethyl)-3-oxoisoindolin-4-yl]carboxainide (4-Me1hoxynaphthyl)-N-[3-oxo-2-(2-piperidylethyl)isoindolin-4-yl]carboxainide (4-Fluoronaphthyl)-N-[3-oxo-2-(2-piperidyletiiyl)isoindolin-4-yl]carboxamide Ν-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl](4-hydroxynaphthyl)carboxainide [4-(Hydroxy)naphthyl)]-N- [3 -oxo-2-(2H-3 ,4,5,6-tetrahy dropyran-4-ylmethyl)isoindolin-4- yl]carboxamide and pharmaceutically acceptable salts thereof.
23. A compound according to any one of claims 1 -22 for use as a medicament.
24. The use of a compound according to any one of claims 1-22 in the manufacture of a medicament for the therapy of pain.
25. The use of a compound according to any one of claims 1-22 in the manufacture of a medicament for the therapy of functional gastrointestinal disorders.
26. The use of a compound according to any one of claims 1 -22 in the manufacture of a medicament for the treatment of irritable bowel syndrome.
27. The use of a compound according to any one of claims 1-22 in the manufacture of a medicament for the treatment of anxiety, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, and cardiavascular disorders.
28. A pharmaceutical composition comprising a compound according to any one of claims 1-22 and a pharmaceutically acceptable carrier.
29. A method for the therapy of functional gastrointestinal disorders in a warm-blooded animal, comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of a compound according to any one of claims 1-22.
30. A method for the therapy of irritable bowel syndrome in a warm-blooded animal, comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of a compound according to any one of claims 1-22.
31. A method for preparing a compound of formula I,
comprising the step of reacting a compound of formula II,
with a compound of R2-X-Y, wherein Y is selected from Cl, Br, F, and OH; R1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, acetoxy, hydroxyl, C^alkoxy, hydroxy-C1-6alkoxy, benzyloxy, -OCH2-C(=O)-R4, -OS(=O)2-R4, C1-6alkyl, halogenated C1-6alkoxy, C2-6alkylene, halogenated C1-6alkyl, halogenated C2-6alkenyl C1-6alkylamino, di-C1-6alkylamino and amino,- R2 is selected from wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated C1-6alkyl, C1-6alkyl, halogenated C1-6alkoxy, cyano, nitro, C1-6alkoxy, hydroxy, hydroxy-C1-6alkyl, amino, C1-6alkyl-C6-10aryl, Ci-salkoxy-Ci. βalkyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylamino, di-C1-6alkylamino, di-Ci. 6alkylamino-C1-6alkyl, amino-C1-6alkyl, C1-6alkyl-amino-carboayl, C2-5heteroaryl-carbonyl, C2-5heterocycloalkyl-carbonyl, C6-10arylcarbonyl, C2-5heterocycloalkyl, C3.6cycloalkyl, C3. 6cycloalkyl-Ci_6alkyl, C2-5heteroaryl, C2-5heteroaryl-Ci-δalkyl, C6-10aryl, and C6-10aryl-Ci. βalkyl;
R3 is selected from C1-6alkyl, C2-6alkenyl, Ca-gcycloalkyl, C^cycloalkenyl, Ci- βalkoxy, and C2-5heterocycloalkyl; wherein said C^aHcyl, C2-6alkenyI, C3-6cycloalkyl, C4. scycloalkenyl, C1-6alkoxy, and C2-5heterocycloalkyl used in defining R3 is optionally substituted by one or more groups selected from halogen, halogenated C^aUcyl, Chalky!, halogenated C1-6alkoxy, cyano, nitro, C1-6alkoxy, hydroxy, hydroxy-C1-6alkyl, amino, C1. 6alkyl-C6-ioaryl, Ci,6alkoxy-C1-6alkyl, C1-6alkylcarbonyl, Q.βalkoxycarbonyl, Ci- βalkylamino, di-C1-6alkylamino, di-C1-6alkylamino-C1-6alkyl, amino-C1-6alkyl, C1-6alkyl- amino-carbonyl, C2-5heteroaryl-carbonyl, C2-5heterocycloalkyl-carbonyl, C6-ioarylcarbonyl, C2-5heterocycloalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C2-5heteroaryl, C2-
5heteroaryI-C1-6aIkyl, C6-10aryl, and C6-10aryl-C1-6alkyl;
R4 is selected from C1-6alkyl, halogenated C1-6alltyl, hydroxy, hydroxy-C1-
6alkylamino, amino, C1-6alkoxy, C1-6alkylamino, di-C1-6alkylamino, hydroxyamino, Ci- βalkoxyamino, benzylamino, C2-5heterocycloalkyl, C2-5heteroaryl, and C2-5heteroaryl-Ci. βalkyl;
X is selected from -C(=O)- and -CH2-; and m and n are independently selected from 0, 1, 2, 3, 4 and 5, with a proviso that R3 is not an optionally substituted 2,6-dioxopiperdin-3-yl.
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