WO2010132437A1 - Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof - Google Patents

Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof Download PDF

Info

Publication number
WO2010132437A1
WO2010132437A1 PCT/US2010/034373 US2010034373W WO2010132437A1 WO 2010132437 A1 WO2010132437 A1 WO 2010132437A1 US 2010034373 W US2010034373 W US 2010034373W WO 2010132437 A1 WO2010132437 A1 WO 2010132437A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
triazolo
pyridinyl
halogen
benzo
Prior art date
Application number
PCT/US2010/034373
Other languages
French (fr)
Inventor
Shuang Liu
Bruce F. Molino
Kassoum Nacro
Original Assignee
Albany Molecular Research, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Albany Molecular Research, Inc. filed Critical Albany Molecular Research, Inc.
Priority to EP20100775394 priority Critical patent/EP2429295B1/en
Priority to JP2012510930A priority patent/JP2012526823A/en
Priority to AU2010247849A priority patent/AU2010247849B2/en
Priority to MX2011011901A priority patent/MX2011011901A/en
Priority to ES10775394T priority patent/ES2446971T3/en
Priority to CN2010800316663A priority patent/CN102458123A/en
Publication of WO2010132437A1 publication Critical patent/WO2010132437A1/en

Links

Classifications

    • 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
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/10—Quaternary compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • 6,596,741 discloses the use of a NE, DA, or 5-HT inhibitor with either a neurokinin- 1 receptor antagonist or a serotonin- IA antagonist for the treatment of a wide variety of conditions.
  • a neurokinin- 1 receptor antagonist or a serotonin- IA antagonist for the treatment of a wide variety of conditions.
  • Also advantageous is the use of compounds that inhibit one or more of the neurotransmitters at the same time.
  • the antidepressant qualities of the dual NET and SERT reuptake inhibitor duloxetine is disclosed in European Patent No. EP 273658.
  • Venlafaxine is disclosed in U.S. Patent No. 4,535,186 as a reuptake inhibitor of both NE and 5-HT for the treatment of depressive disorders.
  • R 1 is H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, Ci-C 6 haloalkyl, or gem-dialkyl of which each alkyl is Ci-C 4 ;
  • R 8 is H, Ci-C 6 alkyl, halogen or OR 11 ;
  • R 14 is independently selected at each occurrence from a substituent selected from the group consisting of halogen, NO 2 , OR n , NR 11 R 12 , NR 11 C(O)R 12 , NR 11 C(O) 2 R 12 , NR 11 C(O)NR 12 R 13 , S(O) n R 12 , CN, C(O)R 12 , C(O)NR 11 R 12 , Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl where Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4- C 7 cydoalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of Ci
  • the present invention is directed to a compound of formula (T) :
  • R 9 and R 10 are each independently H, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, C(O)R 13 , phenyl, or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, Ci-C 4 alkyl, Ci-C 4 haloalkyl, and Ci-C 4 alkoxy; or R 9 and R 10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
  • heteroaryl means an aromatic monocyclic or multicyclic ring system of about S to about 14 ring atoms, preferably about S to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example, nitrogen, oxygen, or sulfur.
  • element(s) other than carbon for example, nitrogen, oxygen, or sulfur.
  • Preferred heteroaryls contain about S to 6 ring atoms.
  • aza, oxa, thia, or thio before heteroaryl means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom.
  • non-aromatic heterocycle means a non-aromatic monocyclic system containing 3 to 10 atoms, preferably 4 to about 7 carbon atoms, in which one or more of the atoms in the ring system is/are elements) other than carbon, for example, nitrogen, oxygen, or sulfur.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
  • a compound with a hydroxy group drawn next to a nitrogen on a heterocycle can exist as the keto form.
  • 3-(2-hydroxy-[l,2,4]triazolo[l,5- a]pyridin-6-yl)propanoic acid can exist as 3-(2-oxo-2,3-dihydro-[l,2,4]triazolo[l,5- a]pyridin-6-yl)propanoic acid.
  • cycloalkylalkyl means an cycloalkyl-alkyl-group in which the cycloalkyl and alkyl are as defined herein.
  • exemplary cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylmethyl.
  • Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed.
  • Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts. The sodium and potassium salts are preferred.
  • prodrugs as used herein means those prodrugs of the compounds useful according to the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug means compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention.
  • suspending agents examples include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agaragar and tragacanth, or mixtures of these substances.
  • Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosterate and gelatin.
  • R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, halogen, OR n , NR 11 R 12 , NR 11 C(O)R 12 , S(O) 2 R 12 ,
  • Another more preferred embodiment of the present invention is the compound of formula (T), wherein R 7 is H.
  • Another more preferred embodiment of the present invention is the compound of formula (T), wherein R 5 and R 6 are each independently selected from the group consisting of H, F, Cl, OH, OCH 3 , and CH 3 , more particularly, Cl.
  • R 3 is phenyl, pyridyl, 2-oxo-pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, ihiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4- oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzoihiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzo
  • R 4 is H, F, Cl, Me, CN, OR 11 , Q-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 4 -C 7 cycloalkylalkyl, and wherein each of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C 3 alkyl, halogen, CN, OR 9 , NR 9 R 10 , and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci -C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy, CN, OR 9
  • R 12 is H, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C 4 alkyl, Ci-C 4 haloalkyl, or Ci-C 4 alkoxy; or R 11 and R 12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring, with the proviso that only one of R 9 and R 10 or R 11 and R 12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine
  • n 0, 1, or 2;
  • R 1 is H, methyl, or gem-dimethyl
  • R 4 is H, F, Cl, CN, Me, CF 3 , CF 2 H, OMe, OCF 3 , OCF 2 H, or OH;
  • R 5 to R 7 are independently, H, F, Cl, CN, Me, CF 3 , CF 2 H, OMe, OCF 3 , OCF 2 H, or OH;
  • the compound of formula (I) is a (S)(+)-stereoisomer.
  • the method involves inhibiting synaptic dopamine and norepinephrine uptake by administering a therapeutically effective inhibitory amount of the compound of formula CD, which functions as both a dual acting dopamine and norepinephrine uptake inhibitor.
  • Another embodiment of the present invention relates to a method of treating a disorder referred to in the above-mentioned embodiments in a patient in need thereof.
  • the method involves inhibiting synaptic norepinephrine, dopamine, and serotonin uptake by administering a therapeutically effective inhibitory amount of the compound of formula (F), which functions as a triple acting norepinephrine, dopamine, and serotonin uptake inhibitor.
  • Another embodiment of the present invention relates to a method for inhibiting serotonin uptake in mammals.
  • the method involves administering to a mammal requiring increased neurotransmission of serotonin a pharmaceutically effective amount of the compound of formula (F).
  • Another embodiment of the present invention relates to a method of suppressing the desire of humans to consume alcohol.
  • the method involves administering to a human in need of such suppression an effective dose, to relieve the desire to consume alcohol, of the compound of formula (I).
  • Another embodiment of the present invention relates to a process for preparation of a product compound of Formula (T). This process comprises treating a first intermediate compound of Formula (II):
  • Suitable acids include, but are not limited to, sulfuric acid, methansulfonic acid, phorphoric acid, and L-tartaric acid.
  • a compound of formula (J) including a group containing one or more nitrogen ring atoms may be converted to the corresponding compound wherein one or more nitrogen ring atom of the group is oxidized to an N-oxide, preferably by reacting with a peracid, for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature.
  • a peracid for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane
  • V ⁇ i (R ⁇ H) Treatment of amines of Formula (H) with halides (bromides or chlorides) of Formula (ID) generates the alkylation products of Formula (IV).
  • the alkylation reactions may be run under a wide variety of conditions familiar to one skilled in the art of organic synthesis. Typical solvents include acetonitrile, toluene, diethyl ether, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, methylene chloride, and lower alkyl alcohols including ethanol.
  • the reactions may be successfully run at temperatures ranging from 0 0 C up to the boiling point of the solvent employed. Reaction progress is conventionally monitored by standard chromatographic and spectroscopic methods.
  • the alkylation reaction is optionally run with the addition of a non-nucleophilic organic base such as, but not limited to, pyridine, triethylamine, and diisopropyl ethylamine.
  • ketones of Formula (IX) are available from commercial sources or are conveniently obtained via several well known methods, including the treatment of the corresponding aromatic carboxylic acid intermediates with two stoichiometric equivalents of methyllithium (Jorgenson, Organic Reactions, 18:1 (1970), which is hereby incorporated by reference in its entirety.).
  • Cyclizations may also be effected by treatment of compounds of Formula (V) with strong Lewis acids, such as aluminum trichloride typically in halogenated solvents such as methylene chloride.
  • strong Lewis acids such as aluminum trichloride typically in halogenated solvents such as methylene chloride.
  • Inert solvents may include, but are not limited to acetonitrile, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylacetamides (preferably dimethylacetamide), N,N-dialkylformamides (preferably dimethylformamide), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes (preferably methylene chloride).
  • Preferred reaction temperatures range from room temperature up to the boiling point of the solvent employed. The reactions may be run in conventional glassware or in one of many commercially available parallel synthesizer units.
  • B(OR a )(OR b )) may be ⁇ -demethylated via aforementioned methods to yield compounds of formula (VIE), which then may be converted to compounds of formula (J) via aforementioned methods.
  • the protection of the nitrogen of the tetrahydroisoquinoline of formula (Vm) may be needed.
  • Examples of typical protecting groups are Boc, F-Moc, and 2-nitrobenzenesulfonyl.
  • Compounds of the present invention where a stable radioisotope, such as carbon- 14, tritium, iodine-121, or another radioisotope, has been introduced synthetically are useful diagnostic agents for identifying areas of the brain or central nervous system that may be affected by disorders where norepinephrine, dopamine, or serotonin transporters and their uptake mechanism are implicated.
  • excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used for preparing tablets.
  • lactose and high molecular weight polyethylene glycols When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
  • Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol, and chloroform or mixtures thereof may also be used.
  • the products according to the present invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day.
  • some compounds of formula (F) are useful in treating such a disorder at doses at which synaptic serotonin uptake may be substantially inhibited but at which synaptic norepinephrine or dopamine uptake is not substantially inhibited, or vice versa
  • Other compounds of formula (I) are useful in treating such a disorder at doses at which synaptic norepinephrine, dopamine, and serotonin uptake are substantially inhibited.
  • the present invention provides compounds where the inhibitory effects on serotonin and norepinephrine uptake occurs at similar or even the same concentrations of these compounds, while the effects on inhibition of dopamine uptake occurs at vastly different concentrations or doses.
  • the present invention provides compounds where the inhibitory effects on norepinephrine and dopamine uptake occurs at similar or even the same concentrations of these compounds while the effects on inhibition of dopamine uptake occurs at vastly different concentrations or doses. As a result, some compounds of formula (I) are useful in treating such a disorder at doses at which synaptic norepinephrine and dopamine uptake may be substantially inhibited but at which synaptic serotonin uptake is not substantially inhibited, or vice versa. [0139] The present invention provides compounds where the inhibitory effects on norepinephrine, dopamine, and serotonin uptake occur at similar or even the same concentration. As a result, some compounds of formula (I) are useful in treating such a disorder at doses at which synaptic norepinephrine, dopamine, and serotonin uptake may all be substantially inhibited.
  • Selected compounds ( triple action transporter reuptake inhibitors) of the present invention have potent binding affinity simultaneously for all three of the biogenic amine transporters, NET, DAT, or SERT.
  • selected compounds of this invention possess potent (NET, DAT, & SERT IC S0 /Ki values ⁇ 200 nM) binding affinity for NET, DAT, and SERT.
  • the in vivo affinity of the compounds to the three transporter proteins, SERT, DAT, and NET are demonstrated by means well known to those of ordinary skill in the art, including, without limitation, those described in the Examples section below.
  • Selected compounds of the present invention when administrated at a pharmaceutically feasible dose via means such as, but not limited to, oral, intravenous, subcutaneous, intraperitoneal and intramuscular, have statistically significant percent occupancy value(s) at one, two or all of the biogenic amine transporters NET, DAT, or SERT.
  • Step A To a mixture of (+)-7-bromo-4-(4-fluorophenyl)-2-methyl-l,2,3,4- tetrahydroisoquinoline (184 mg, 0.58 mmol, prepared following similar methods described in Step A to Step C of Example 1 starting from 2-bromo-l-(4- fluorophenyl)ethanone and l-(3-bromophenyl)-iV-methylmethanamine), and proton sponge (123 mg, 0.58 mmol) in 1,2-dichloroethane (3 mL) was added 1-chloroethyl chloroformate (0.50 mL, 4.60 mmol) at 0 0 C under a nitrogen atmosphere.
  • the reaction mixture was stirred at 0 0 C for 1 hour and then allowed to warm to ambient temperature overnight
  • the mixture was quenched with IN HCl in diethyl ether (10 mL), concentrated under reduced pressure to give the intermediate 2-chloroethylcarbamate.
  • the intermediate was dissolved in methanol and heated at 70 0 C for 3 hours before concentrating under reduced pressure to 4 mL volume.
  • the solution was treated with di- tert-butyl-dicarbonate (252 mg, 1.16 mmol) and 2N NaOH (3 mL) with stirring overnight then partitioned between ethyl acetate (20 mL) and brine.
  • Step B To a solution of tert-butyl 7-bromo-4-(4-fluorophenyl)-3,4- dihydroisoquinoline-2(lH)-carboxylate (110 mg, 0.27 mmol) in DMSO (2 mL) was added bis(pinacolato)diboron (76 mg, 0.30 mmol), potassium acetate (80 mg, 0.81 mmol) and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium( ⁇ ) (11 mg, 0.01 mmol). The reaction flask was purged with nitrogen and heated at 85 0 C for 4 hours.
  • the reaction mixture was cooled to ambient temperature and di-te/f-butyl 6-chloropyridazin- 3-yliminodicarbonate (116 mg, 0.35 mmol), cesium carbonate (265 mg, 0.81 mmol), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium( ⁇ ) (11 mg, 0.01 mmol), and water (0.3 mL) was added.
  • the reaction flask was purged with nitrogen and heated at 85 0 C for 2 hours.
  • the reaction mixture was cooled to ambient temperature then partitioned between ethyl acetate (SO mL) and water (30 mL).
  • Step C To a solution of (+)-6-(4-(4-fluorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine (38 mg, 0.12 mmol) in methanol (3.6 mL) was added L-tartaric acid (18 mg, 0.12 mmol). The mixture was sonicated for 2 minutes, diluted with water (20 mL), and lyophilized to give the correspondent tartrate salt (61 mg, 86%, AUC HPLC 97.9%) as a white solid.
  • Step A (+)-4-(4-Fluorophenyl)-2-methyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline was prepared following similar methods described in Step A to Step D of Example 1 starting from 2-bromo-l-(4- fluorophenyl)ethanone.
  • Step B To a mixture of the product from Step A (428 mg, 0.96 mmol) and proton sponge (102 mg, 0.50 mmol) in 1,2-dichloroethane (3 mL) was added 1- chloroethyl chloroformate (208 ⁇ L, 1.91 mmol) at 0 0 C under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature over a weekend and concentrated in vacuo. The intermediate 2-chloroethylcarbamate was purified by flash column chromatography (dichloromethane) and refluxed in methanol for 3 hours.
  • Step C To a solution of 6-(4-(4-fluorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine (64 mg, 0.19 mmol) in methanol (2 mL) and water (2 mL) was added L-tartaric acid (29 mg, 0.19 mmol). The mixture was sonicated, diluted with water (12 mL) and lyophilized to give the correspondent L- tartarate salt ((+)-enantiomer) (97 mg, 87%, AUC HPLC 97.9%) as a white solid.
  • L-tartaric acid 29 mg, 0.19 mmol
  • Step A (+)-4-(4- ⁇ orophenyl)-2-methyl-7-(6-(trifluoromethyl)pyridazin-
  • the resulting precipitate was collected by filtration and washed with water, dried at 60 0 C under vacuum to afford 3.1 g of white solid which contained a mixture of benzyl amine (desired product) and dibenzyl amine in 1:1.2 ratio.
  • the filtrate was adjusted to pH >10 with solid KOH and extracted with dichloromethane (3 x 100 mL).
  • Step D To an ice-cooled solution of the crude product from Step C (5.98 g, 16.9 mmol) in dichloromethane (70 mL) was added concentrated sulfuric acid (4.2 mL) dropwise. The reaction mixture was stirred at 0 0 C for 2 hours and the adjusted to pH > 8 by adding saturated sodium bicarbonate. The organic layer was separated and the aqueous was extracted with dichloromethane (2x). The combined extracts were washed with brine, dried over sodium sulfate, and concentrated.
  • Step E Bis(pinacolato)diboron (531 mg, 2.09 mmol) was added to a mixture of the product from Step D (640 mg, 1.90 mmol) and potassium acetate (559 mg, 5.70 mmol) in dimethyl sulfoxide (10 mL). The reaction mixture was degassed with argon. PdCl2(dppf)(CH 2 Cl2) (78 mg, 0.095 mmol) was added and the reaction mixture was stirred at 80 0 C for 1 hour, cooled, diluted with water, and extracted with ethyl acetate (2x).
  • Example 8 Preparation of 4-(4-Chloro-phenyl)-7-(6-methoxy-pyridazin-3-yl)-l- methyl -1,2,3,4-tetrahydro-isoquinoline. [0185] Step A: To a solution of the product from Step B of Example 6 (240 mg,
  • Step A Cerium(m) chloride heptahydrate (29.8 g, 80 mmol) was dried with magnetic stirring at 145 0 C under vacuum overnight Tetrahydrofuran (160 mL) was added and the white suspension was stirred at room temperature for 2 hours and then cooled with dry-ice/acetone bath. To this dry-ice/acetone bath cooled solution was added methyl lithium (1.6 M in ether, SO mL, 80 mmol). The reaction mixture was stirred for 30 minutes and then a solution of 3-bromobenzonitrile (3.68 g, 20 mmol) in tetrahydrofuran (10 mL) was added. The resulting reaction mixture was stirred at 70 to 60 0 C for 5 hours.
  • Step C To a solution of the ketone (1.37 g, 3.41 mmol) from Step B above in methanol (40 mL) at 0 0 C was added sodium borohydride (133 mg, 3.5 mmol). The reaction mixture was stirred at 0 0 C for 1 hour. The solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane. The resultant solution was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the desired alcohol (1.35 g, 98% crude). The crude product was used in the next step without further purification: ESI MS m/z 404 [M+H] + . [0189] Step D: To an ice-cooled solution of the alcohol (1.35 g, 3.35 mmol) from methanol (40 mL) at 0 0 C was added sodium borohydride (133 mg, 3.5 mmol). The reaction mixture was stirred at 0 0 C for 1 hour. The solvent was then removed under
  • Step E To a mixture of the product (113 mg, 0.293 mmol) from Step D above, bis(pinacolato)diboron (82 mg, 0.323 mmol), and potassium acetate (87 g, 0.88 mmol) was added dimethyl sulfoxide (4 mL). The resultant solution was purged with argon for 10 minutes, and then dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (24 mg, 0.029 mmol) was added to it. The reaction solution was degassed again with argon for 5 minutes and heated at 80 0 C for 1 hour.
  • Step F 3-Chloropyridazine (51 mg, 0.44 mmol) was added to a mixture of the boronate ester from Step E (0.293 mmol, crude) and cesium carbonate (287 mg, 0.88 mmol) in DMF (3 mL) and water (0.4 mL). The reaction mixture was degassed with argon.
  • Step G The product from Step F (28 mg) was resolved by preparative chiral HPLC (ChiralCel OD column, using 85:15:0.1 heptane/ethanol/diethylamine as the eluent) to give the (+)-enantiomer ([ ⁇ ] 25 D +33.0° (c 0.20, methanol)) and the 0- enantiomer ([ ⁇ ] 25 D 38.0° ( c 0.20, methanol)).
  • Step A To a solution of 2-bromo-l-(3,4-dichlorophenyl)ethanone (5.1 g,
  • Step B A solution of l,l-dimethyl-3-bromobenzyl amine (1.18 g, 5.51 mmol) which was prepared in Step A of Example 9, and the epoxide from Step A (0.95g, 5.02 mmol) in ethanol (10 mL) was heated at 90 0 C for 17 hours. The mixture was concentrated under reduced pressure.
  • Step C To an ice-cooled solution of the alcohol (920 mg, 2.49 mmol) from Step B above in dichloromethane (60 mL) was added concentrated sulfuric acid (6 mL) drop-wise. The reaction solution was stirred at 0 0 C for 5 hours, and then was added slowly to ice-cold saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2x). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • Step D To a solution of the product (535 mg, 1.39 mmol) from Step C in dimethyl sulfoxide (20 mL), was added bis(pinacolato)diboron (423 mg, 1.67 mmol) and potassium acetate (409 mg, 4.17 mmol). The resultant solution was purged with argon for 10 minutes, and then dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (114 mg, 0.14 mmol) was added. The reaction solution was further deoxygenated with argon for 5 minutes and heated at 80 0 C for 2 hours.
  • Step F The trifluoromethylpyridazinyl tetrahydro-isoquinoline (153 mg) from Step E was resolved by preparative chiral HPLC (Chiralcel OJ column, using 80:20:0.1 heptane/ethanol/diethylamine as the eluent) to give the 0-enantiomer ([ OC] 2S D 51.0° (c 0.10, methanol)) and the (+)-enantiomer ([ ⁇ ] 25 D +33.2° (c 0.10, methanol)).
  • Step A To a solution of 3-methoxybenzaldehyde (180 g, 1.32 mol) in methanol (1 L) was added a 40% aqueous solution of methylamine (113 ml, 1.31 mol) followed by 1 hour stirring at 0 0 C. Sodium borohydride (75 g, 1.98 mol) was added portionwise at 0 0 C and the reaction mixture was stirred for 1 hour. The solution was concentrated to a smaller volume then, was diluted with water (200 mL) and the resulting solution was extracted with methylene chloride (3 x 500 mL).
  • Step B To a solution of the above amine (6.2 g, 41.00 mmol) from Step A in methylene chloride (100 mL) was added 3,4-dichlorophenacyl bromide (10.0 g, 37.3 mmol) and the resulting mixture was stirred at 0 0 C for 1 hour prior to the addition of triethylamine (5.20 mL, 37.31 mmol), followed by 1 hour stirring at 0 0 C. The reaction mixture was diluted with water (100 mL) then the aqueous phase was extracted with additional methylene chloride (3 x 75 mL).
  • Step C To a solution of the ketone (-37 mmol) from Step B in methanol
  • Step E The racemic 4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-l,2,3,4- tetrahydroisoquinoline (7.0 g) from Step D above was resolved by preparative chiral HPLC (CHIRALPAK AD column, using 80:20:0.1 heptane/2-propanol/diethylamine as the eluent) to give the (+)-enantiomer ([ ⁇ ] 25 D +31.9° (c 0.49, methanol)) (3.68 g) as a colorless oil and the 0-enantiomer (3.99 g) as a colorless oil.
  • Step F A solution of (+)-4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-
  • 1,2,3,4-tetrahydroisoquinoline (3.68 g, 11.42 mmol) in a mixture of acetic acid (20 mL) and 48% aqueous hydrobromic acid solution (SO mL) was refluxed for 8 hours.
  • the ice- cold reaction mixture was basified with a concentrated aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium bicarbonate until reaching a pH of about 8-9 and was extracted with dichloromethane (3x).
  • the combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude alcohol (2.6 g) as a yellow solid.
  • Step G To a solution of the phenol from Step F above (2.1 g, 6.81 mmol) and pyridine (0.72 mL, 8.85 mmol) in dichloromethane (60 mL) was added trifluoromethanesulfonic anhydride (1.37 mL, 8.14 mmol) at 78 0 C. The reaction was allowed to warm to 0 0 C and stirred for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 x). The combined extracts were dried over sodium sulfate, filtered, and concentrated to give the crude triflate as a yellow oil.
  • Step H A mixture of the triflate from Step G above ( ⁇ 6.8 mmol), bis(pinacolato)diboron (2.07 g, 8.15 mmol), and potassium acetate (2.05 g, 20.8 mmol) in dimethyl sulfoxide (35 mL) was degassed with argon. To this mixture was added dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) (0.40 g, 0.55 mmol). The resulting mixture was degassed with argon and then heated at 85 0 C for 2 hours. The cold reaction mixture was diluted with ethyl acetate (150 mL).
  • Step I To a solution of the boronate ester (2.6 g, 6.22 mmol) from Step F and proton sponge (2.6 g, 12.1 mmol) in dichloroethane (80 mL) at 0 0 C was added 1- chloroethyl chloroformate (2.4 mL, 22.1 mmol). The mixture was stirred at 0 0 C for 15 minutes, then was refluxed for 40 minutes and was concentrated in vacuo. The residue was filtered through a short pad of silica gel (eluent, 1:1:1 dichloromethane/hexanes/ethyl acetate) and the filtrate was concentrated in vacuo.
  • Step J A solution of the product from Step I (-6.2 mmol), (Boc) 2 O (3.60 g, 16.4 mmol), triethylamine (1.5 mL, 10.7 mmol) and DMAP (0.26 g, 2.20 mmol) in dichloromethane (120 mL) was stirred at room temperature for 4 hours.
  • Step K A dry flask was loaded with the product from Step J above (0.3 g,
  • Step L A solution of the Boc-protected 4-(3,4-dichlorophenyl)-7-(6-
  • Step A A dry flask was loaded with the boronate ester (0.3 g, 0.59 mmol) from Step J in Example 11, 3-chloro-6-(difluoromeihoxy)pyridazine (0.16 g, 0.97 mmol), cesium carbonate (0.48 g, 1.47 mmol), and dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(ll) (43 mg, 0.058 mmol).
  • Step B A solution of the boc-protected 4-(3,4-dichlorophenyl)-7-(6-
  • Step C To a solution of the product above (97 mg, 0.23 mmol) from Step B in a mixture of methanol and water was added L-tartaric acid (34 mg, 0.23 mmol). The solution thus obtained was frozen and lyophilized overnight to give 4-(3,4- dicMorophenyl)-7-(6-(dMuoromethoxy)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoun, L- tarlrate (115 mg, 87%, AUC HPLC >99%) as a white solid.
  • Step A A mixture of 4-(3,4-dichlorophenyl)-2-methyl-l,2,3,4- tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (100 mg, 0.23 mmol) which was prepared in Step G of Example 11, 2-cyanophenylboronic acid (51 mg, 0.35 mmol) and cesium carbonate (225 mg, 0.69 mmol) in water (1 mL) and ⁇ f,W-dimemylformamide (2 mL) was degassed with argon and then [1,1- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (8 mg, 0.01 mmol) was added.
  • Step B To an ice-cold solution of 2-(4-(3,4-dichlorophenyl)-2-methyl- l,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile (57 mg, 0.14 mmol) and N 1 Jf 1 J ⁇ Jf- tetramethylnaphthalene-l,8-diamine (30 mg, 0.14 mmol) in 1,2-dichloroethane (3mL) was added 1-chlorethyl chloroforamte (0.03 mL, 0.28 mmol) drop wise. The mixture was stirred for 15 minutes and then warmed to room temperature overnight.
  • Example 15 Preparation of 3-(4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)benzoiiitrile, trifluoroacetate Salt [0218] Following the procedure in Steps A and B of Example 14, 4-(3,4- dicMorophenyl)-2-methyl-l,2,3,4-tetrahydroisoqumoUn-7-yl trifluoromethanesulfonate (100 mg, 0.23 mmol), 3-cyanophenylboronic acid (51 mg, 0.35 mmol), cesium carbonate (225 mg, 0.69 mmol), and dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (8 mg, 0.01 mmol) in N ⁇ V-dimethylformamide (2 mL) and water (1 mL) followed by iV-de-methylation with ⁇
  • 1,2,3,4-tetrahydroisoquinoline (500 mg, 1.35 mmol) which was prepared following similar method described in Steps A to C of Example 1 starting from 2-bromo-l-(3,4- dichlorophenyl)ethanone and l-(3-bromophenyl)-N-meihylniethanamine, pyridin-2-ol (154 mg, 1.62 mmol), N, N- dimethlethylene diamine (58 ⁇ l, 0.54 mmol), and potassium phosphate (572 mg, 2.69 mmol) in 1,4-dioxane (5 mL) was added copper(l) iodide (51 mg, 0.27 mmol).
  • the mixture was degassed with argon and then heated to 110 0 C for 17 hours.
  • the reaction mixture was diluted with water (20 mL) and extracted with methylene chloride (2 x 25 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo.
  • Step B A procedure similar to the one in Step B of Example 29 was used to demethylate l-(4-(3,4-dichlorophenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-7- yl)pyridin-2(lH)-one.
  • Step A A procedure similar to the one in Step A of Example 17 was used to couple 7-hromo-4-(3,4-dichlorophenyl)-2-methyl- 1 ,2,3,4-tetrahydroisoquinoline with pyridazin-3(2H)-one.
  • 2-(4-(3,4-Dichlorophenyl)-2-methyl- 1 ,2,3,4-tetrahydroisoquinolin- 7-yl)pyridazin-3(2H)-one was obtained in 23% yield as an off-white foam: ESI MS m/z 386 [M + H] + .
  • Step B A procedure similar to the one in Step B of Example 29 was used to demethylate 2-(4-(3,4-dichlorophenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-7- yl)pyridazin-3(2H)-one.
  • Step A A mixture of 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-
  • Step B To an ice-cold solution of 4-(3,4-dichlorophenyl)-6-fluoro-2- meihyl-7-(pyridin-2-yl)-l,2,3,4-tJetrahydroisoquinoline (282 mg, 0.73 mmol) and ⁇ XX-tetrameihylnaphihalene-l.S-diainine (313 mg, 1.46 mmol) in 1,2- dichloroethane (10 mL) was added 1-chlorethyl chloroforamte (0.32 mL, 1.46 mmol) drop wise. The mixture was stirred for IS minutes and then heated to reflux for 2 hours.
  • Step A To an ice-cold solution of 4-(3,4-dichlorophenyl)-2-methyl- l,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (1.0 g, 2.3 mmol) and ⁇ fWXX-tetrame ⁇ ymaphthalene-l,8-diamine (493 mg, 2.3 mmol) in 1,2- dichloroethane (25 mL) was added 1-chlorethyl chloroforamte (0.75 mL, 6.9 mmol) drop wise. The mixture was heated to reflux for 1 hour.
  • the mixture was cooled to room temperature, concentrated, and filtered through a pad of silica gel (1:1:1 hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated, the residue dissolved in methanol (50 mL), and then heated to reflux for 1 hour.
  • Step B A mixture of 4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl trifluoromethanes ⁇ lfonate (225 mg, 0.53 mmol), 4- carbamoylphenylboronic acid (132 mg, 0.8 mmol) and cesium carbonate (521 mg, 1.6 mmol) in water (2 mL) and N ⁇ V-dimethylformamide (4 mL) was degassed with argon and then [l,l-bis(diphenylphosphino)ferrocene]palladium(II) (22 mg, 0.03 mmol) was added.
  • Step A To a solution of l-(4-fluoro-3-methoxyphenyl)-iV- methylmethanamine (0.9 g, 5.39 mmol) in ethanol (8.0 mL) was added potassium carbonate (0.6 g, 4.48 mmol) and 2-bromo-l-(3,4-dichlorophenyl)ethanone (1.2 g, 4.48 mmol). The reaction solution was stirred for 2.5 hours at room temperature and then sodium borohydride (0.2 g, 5.83 mmol) was added to it portionwise at 0 0 C. The reaction mixture was stirred overnight while warming up to room temperature. The reaction solution was concentrated in vacuo.
  • Step B To a solution of the alcohol (1.1 g, 2.93 mmol) from Step A above in methylene chloride (10.0 mL) was added concentrated sulfuric acid (1.5 mL, 0.56 mmol). The reaction mixture was stirred at 0 0 C for 30 minutes and at room temperature for 2 hours. The reaction solution was quenched at 0 0 C by addition of an aqueous solution of sodium hydroxide (2N) and the aqueous phase was extracted with additional methylene chloride (3x). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo.
  • Step D To a solution of (+) 7-methoxytetrahydroisoquinoline from Step C above (3.4 g, 11.70 mmol) in hydrobromic acid (90 mL, 48% solution in water) was added acetic acid (48 mL). The reaction solution was stirred at 110 0 C overnight under nitrogen and then concentrated under reduced pressure.
  • Step E To a solution of the phenol (2.5 g, 7.79 mmol) from Step D above in dichloromethane (30 mL) at 0 0 C was added pyridine (0.8 mL, 10.12 mmol) followed by slow addition of trifluoromethanesulfonic anhydride (1.4 mL, 8.18 mmol) dropwise. The resultant reaction solution was stirred at 0 0 C for 1 hour, and then was quenched with aqueous saturated sodium bicarbonate. The organic extract was separated and the aqueous layer was extracted with dichloromethane (3x).
  • Step F To a mixture of triflate (3.5 g, 7.57 mmol) in Step E above bis(pinacolato)diboron (2.3 g, 9.09 mmol) and potassium acetate (2.2 g, 22.72mmol) were added in DMSO (100.0 mL). The reaction solution was purged with argon for 10 minutes, and then l,r-bis(diphenylphosphino)ferrocenedichloropalladium (0.5 g, 0.61 mmol) was added to it. The reaction solution was degassed again with argon for 5 minutes and heated at 80 0 C overnight.
  • Step G A mixture of 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-
  • Step A To an ice-cold solution of 4-(3,4-dichlorophenyl)-7-methoxy-2- methyl-l,2,3,4-tetrahydroisoquinoline (3.46 g, 10.7 mmol, prepared in Step D of Example 11) andiV ⁇ W ⁇ -tetramethylnaphthalene-l.S-diamine (2.3 g, 10.7 mmol) in 1,2- dichloroethane (70 mL) was added 1-chlorethyl chloroforamte (2.4 mL, 21.4 mmol) drop wise. The mixture was stirred for 15 minutes and then heated to reflux for 1 hour.
  • Step B To an ice-cold solution of 4-(3 ,4-dichlorophenyl)-7 -methoxy-
  • Step C To a 78 0 C solution of 4-(3,4-dichlorophenyl)-7-methoxy-2-(2- nitrophenylsulfonyl)-l,2,3,4-tetrahydroisoquinoline (3.39 g, 6.88 mmol) in dichloromethane (70 mL) was added boron tribromide (3.25 mL, 34.4 mmol) drop wise. The mixture was stirred for 5 minutes and then warmed to 0 0 C for 1 hour. The mixture was quenched with water slowly and then the aqueous layer was extracted with dichlormethane (2x).
  • Step D To a 20 0 C solution of 4-(3,4-dichlorophenyl)-2-(2- nitrophenylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-7-ol (2.0 g, 4.18 mmol) and pyridine (0.37 mL, 4.6 mmol) in dichloromethane (40 mL) was added trifluoromethanesulfonic acid anhydride (0.77 mL, 4.6 mmol) drop wise. The mixture was stirred for 3 hours and then quenched with saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • Step E A mixture of 4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)- l,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (2.0 g, 3.27 mmol), bis(pinacolato)diboron (914 mg, 3.6 mmol) and potassium acetate (963 mg, 9.81 mmol) in dimethyl sulfoxide (15 mL) was degassed with argon and then [1,1- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (131 mg, 0.16 mmol) was added.
  • Step F A mixture of 4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline (300 mg, 0.51 mmol), 5-bromopyrazin-2-amine (174 mg, 1.0 mmol) and cesium carbonate (490 mg, 1.5 mmol) in water (1.5 mL) and iV ⁇ V-dimethylformamide (5 mL) was degassed with argon and then [l,l-bis(diphenylphosphino)ferrocene]palladium( ⁇ ) dichloromethane adduct (24 mg, 0.03 mmol) was added.
  • the mixture was degassed again and then heated to 90 0 C for 3 hours.
  • the mixture was partitioned between water and ethyl acetate (3x) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated.
  • Step G 5-(4-(3,4-Dichlorophenyl)-2-(2-nitrophenylsulfonyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)pyrazin-2-amine (40 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL) and ethanol (2 mL). Thiophenol (0.04 mL, 0.35 mmol) and potassium carbonate (77 mg, 0.56 mmol) were added and the mixture stirred overnight at room temperature. The mixture was filtered and concentrated.
  • Example 28 Preparation of 6-(4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)pyrazin-2-amine, trifluoroacetate Salt.
  • the mixture was degassed again and then heated to 90 0 C for 2.5 hours.
  • the reaction mixture was diluted with ethyl acetate (30 mL), washed with water (2 x 10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
  • the reaction mixture was diluted with methylene chloride (30 mL) and washed with 1 N HCl (10 mL), water (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
  • methanol IS mL
  • the residue was taken up in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
  • Step A A mixture of 4-(4-chlorophenyl)-6-fluoro-2-methyl- 1,2,3,4- tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (695 mg, 1.64 mmol) which was prepared using similar methods described in Step A to Step E of Example 26 starting from 2-bromo-l-(4-chlorophenyl)ethanone, 4-carbamoylphenylboronic acid (406 mg, 2.46 mmol) and cesium carbonate (1.6 mg, 4.92 mmol) in water (5 mL) and NJf- dimethylformamide (20 mL) was degassed with argon and then [1,1- bis(diphenylphosphino)ferrocene]palladium(II) (59 mg, 0.08 mmol) was added.
  • the mixture was degassed again and then heated to 90 0 C for 2 hours.
  • the mixture was partitioned between water and ethyl acetate (3x) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • Step C To an ice-cold solution of bis-Boc protected 4-(4-(4- cUorophenyl)-6-fluoro-2-memyl-l,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (59 mg, 0.10 mmol) andN 1 ,N 1 ,-V 8 ,-V 8 -tetramemylnaphthalene-l,8-diamine (64 mg, 0.30 mmol) in 1,2-dichloroethane (2mL) was added 1-chlorethyl chloroforamte (0.03 mL, 0.30 mmol) drop wise.
  • the mixture was stirred for 15 minutes and then heated to 40 0 C for 1 hour.
  • the mixture was concentrated and filtered through a pad of silica gel (1 : 1 : 1 hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated, the residue dissolved in methanol (5 mL) and heated to reflux for 30 minutes and then concentrated.
  • Step A A procedure similar to the one in Step A of Example 29 was used to couple (+)-4-(3,4-dicUorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline with 3-chloro-6- (difluoromeihoxy)pyridazine.
  • Step B A procedure similar to the one in Step B of Example 29 was used to demethylate (+)-4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-6- fluoro-2-methyl-l,2,3,4-tetrahydroisoquinoline.
  • Example 33 Preparation of 4-(3,4-dicWorophenyl)-7-(pjridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline, tartrate salt.
  • Step A A mixture of tert-butyl 4-(3,4-dichlorophenyl)-7-(4,4,5,5- tetiamethyl-l.S ⁇ -dioxaborolan-l-y ⁇ -S ⁇ -dmydroisoquinoline- ⁇ lHJ-carboxylate CSSl mg, 0.66 mmol) from Step H in Example 11, 3,6-dichloropyridazine (149 mg, 0.90 mmol), cesium carbonate (860 mg, 2.64 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium( ⁇ ) (27 mg, 0.03 mmol) was taken up in DMF (2.5 mL) and water (0.5 mL).
  • Step C To a solution of 4-(3,4-dichlorophenyl)-7-(pyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline (135 mg, 0.38 mmol) in methanol (2.5 mL) was added L-tartaric acid (57 mg, 0.38 mmol). The mixture was sonicated for 5 minutes, diluted with water (15 mL), and lyophilized to give the correspondent, L-tartrate salt (96 mg, 45%, AUC HPLC 98.6%) as a white solid.
  • Step A 4-(4-CMorophenyl)-l,l-dimeihyl-7-(4,4,5,5-tBtramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline was prepared following similar methods described in Step A to Step E of Example 9 starting from 2-(3- bromophenyl)propan-2-amine and 2-bromo-l-(4-chlorophenyl)ethanone.
  • Step B The racemic 4-(4-chlorophenyl)-l,l-dimethyl-7-(6- (trMuoromethyl)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline (153 mg) from Step A was resolved by preparative chiral HPLC (ChiralPak AD column, using 80:20:0.1 heptane/isopropanol/diethylamine as the eluent) to give the 0-enantiomer ([ «] 25 D 41.4 0 (c 0.22, methanol)) and the (+)-enantiomer ([ ⁇ ] 25 D +41.4° (c 0.21, methanol)).
  • Step B To a solution of the above amine (6.2 g, 41.00 mmol) from Step A in methylene chloride (100 mL) was added 3,4-dichlorophenacyl bromide (10.0 g, 37.3 mmol) and the resulting mixture was stirred at 0 0 C for 1 hour prior to the addition of triethylamine (5.20 mL, 37.31 mmol), followed by 1 hour stirring at 0 0 C. The reaction mixture was diluted with water (100 mL) then the aqueous phase was extracted with additional methylene chloride (3 x 75 mL).
  • Step F A solution of (+)-4-(3,4-dichlorophenyl)-7-methoxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline (3.68 g, 11.42 mmol) in a mixture of acetic acid (20 mL) and 48% aqueous hydrobromic acid solution (50 mL) was refluxed for 8 hours.
  • the ice- cold reaction mixture was basified with a concentrated aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium bicarbonate until reaching a pH of about 8-9 and was extracted with dichloromethane (3x).
  • Step G To a solution of the phenol from Step F above (2.1 g, 6.81 mmol) and pyridine (0.72 mL, 8.85 mmol) in dichloromethane (60 mL) was added trifluoromethanesulfonic anhydride (1.37 mL, 8.14 mmol) at 78 0 C. The reaction was allowed to warm to 0 0 C and stirred for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 x). The combined extracts were dried over sodium sulfate, filtered, and concentrated to give the crude triflate as a yellow oil.
  • Step H A mixture of the triflate from Step G above ( ⁇ 6.8 mmol), bis(pinacolato)diboron (2.07 g, 8.15 mmol), and potassium acetate (2.05 g, 20.8 mmol) in dimethyl sulfoxide (35 mL) was degassed with argon. To this mixture was added dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) (0.40 g, 0.55 mmol). The resulting mixture was degassed with argon and then heated at 85 0 C for 2 hours. The cold reaction mixture was diluted with ethyl acetate (150 mL).
  • Step I To a solution of the boronate ester (2.6 g, 6.22 mmol) from Step F and proton sponge (2.6 g, 12.1 mmol) in dichloroethane (80 mL) at 0 0 C was added 1- chloroethyl chloroformate (2.4 mL, 22.1 mmol). The mixture was stirred at 0 0 C for 15 minutes, then was refluxed for 40 minutes and was concentrated in vacuo. The residue was filtered through a short pad of silica gel (eluent, 1:1:1 dichloromethane/hexanes/ethyl acetate) and the filtrate was concentrated in vacuo.
  • Step J A solution of the product from Step I (-6.2 mmol), (Boc) 2 O (3.60 g, 16.4 mmol), triethylamine (1.5 mL, 10.7 mmol) and DMAP (0.26 g, 2.20 mmol) in dichloromethane (120 mL) was stirred at room temperature for 4 hours. The reaction was quenched by the addition of water (SO mL) then, the aqueous phase was extracted with additional dichloromethane (2 x 100 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo.
  • Step K A dry flask was loaded with the boronate ester (0.8 g, 1.59 mmol) from Step J, 6-bromo-[l,2,4]triazolo[l,5- ⁇ ]pyridine (0.35 g, 1.78 mmol), cesium carbonate (0.97 g, 2.98 mmol), and dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (87 mg, 0.12 mmol). The flask was blanketed with argon then, DMF (20 mL) and water (4 mL) were added followed by a short sonication.
  • DMF 20 mL
  • water 4 mL
  • the syrup thus obtained was diluted with dichloromethane and treated with a saturated aqueous solution of sodium bicarbonate until pH 8-9.
  • the aqueous phase was extracted with additional dichloromethane (3x) and the organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to give7-([l,2,4]triazolo[l,5- ⁇ ]pyridin-6-yl)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline (0.59 g, 87%) as a white foam.
  • Step M To a solution of the product (0.59 g, 1.49 mmol) from Step B in ethanol was added L-tartaric acid (0.22 g, 1.49 mmol). The slurry was filtered. The cake was rinsed with ethanol and dried to give 7-([l,2,4]triazolo[l,5- ⁇ ]pyridin-6-yl)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline, L-tartrate salt (0.49 g, 59%, AUC HPLC >99%) as a white solid. [[ ⁇ ] 25 D +9.0° (c 0.11, methanol)].
  • Step A To a solution of the triflate (9.5 g, 21.6 mmol) from step G in
  • Step B To a solution of the 7-([l,2,4]triazolo[l,5- ⁇ ]pyridin-6-yl)-4-(3,4- dichlorophenyl)-2-methyl-l,2,3,4-tetrahydroisoquinoline (7.2 g, 17.6 mmol) from step A above in 1,2-dichloroethane (180 mL) at 0 0 C was added proton sponge (3.8 g, 17.6 mmol), followed by addition of 1-chloroethyl chloroformate (2.3 mL, 21.1 mmol). After the addition, the reaction solution was stirred at 0 0 C for 20 minutes and room temperature for 14 hours.
  • Step C To a solution of des-methyl tetrahydroisoquinoline (3.75 g, 9.48 mmol) from step B above in ethanol (80 mL) was added activated carbon (3.0 g) and stirred at room temperature for 30 minutes. The carbon was removed by filtration and the filtrate obtained was concentrated in vacuo. The resultant oil was dissolved in ethanol (60 mL) and a solution of L-tartaric acid (1.44 g, 9.5 mmol) in ethanol (20 mL) was added. Upon which, white precipitate formed immediately. The slurry was stirred at room temperature for 10 minutes and filtered. The cake obtained was stirred in hot ethanol (70 0 C) for 3 hours and filtered.
  • Step A To a 1 L round-bottom flask was added 2-amino-5-bromopvridine
  • Step B N-(5-bromopyridin-2-yl)-N'-hydroxyformimidamide was dissolved in THF (1 L). To the solution at 10 0 C was added trifluoroacetic anhydride (106 mL, 751 mmol) slowly to control the reaction temperature below 20 0 C. After the addition was complete, the mixture was warmed to room temperature and stirred for 2 h. After the reaction was finished, it was quenched with Na 2 COs aqueous solution to adjust pH >7.
  • Step C To a mixture of 3-formylphenylboronic acid (21.41 g, 143 mmol),
  • Step D A mixture of ⁇ -bromo-3,4-dichloroacetophenone (26.7 g, 100 mmol), hexamethylenetetramine (HMTA) (13.97 g, 100 mmol) and NaI (0.5 g) was stirred at room temperature overnight. HPLC analysis indicated consumption of starting materials. The ammonium intermediate was collected by filtration as a white solid, washed with acetone and dried (36 g, 89% yield). [0287] To a solution of the intermediate (36 g, 88 mmol) in EtOH (500 mL) was added 12 N HCl (75 mL, 0.9 mol). The mixture was stirred at 76 0 C overnight, and then cooled to room temperature.
  • HMTA hexamethylenetetramine
  • Step E To a solution of 2-amino-l-(3,4-dichlorophenyl)ethanone hydrochloride (50 g, 208 mmol) in MeOH (200 mL) was added sodium borohydride (7.86 g, 208 mmol) at 0 0 C slowly. HPLC indicated 100% conversion after 10 min. A solution of 3-([l,2,4]triazolo[l,5-a]pyridin-6-yl)benzaldehyde (46.4 g, 208 mmol) in DCM / MeOH (18OmL / 5OmL) was added to the previous solution in one portion at room temperature.
  • Step F A solution of concentrated sulfuric acid (500 g, 5.0 mol) in a 3 L round bottom flask was cooled to 0 0 C with an ice bath. To the flask was added dropwise a solution of 2-(3-([l,2,4]triazolo[l,5- ⁇ ]pyridin-6-yl)benzylamino)-l-(3,4- dichlorophenyl)ethanol (79 g, 0.191 mol) in DCM (250 mL). The addition was finished in 30 min and the reaction temperature was controlled in the range of 10-20 0 C. DCM was blown away with nitrogen gas during the addition. The evaporation of DCM helped to lower the reaction temperature.
  • Step G To a solution of 7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline (25.2 g, 63.8 mmol) in DMF (30 ml) was added di-tert-butyl dicarbonate (13.91 g, 63.8 mmol). The reaction mixture was stirred at RT for 1 h, then AcOEt (500 ml) was added. The solution was washed with brine and water. The organic layer was dried over Na 2 SO 4 .
  • Step I To a solution of the (+)-enantiomer from Step H (32.41 g, 65.43 mmol) in DCM (150 ml) was added hydrogen chloride-EtOH solution (2.5N, 250 mL) and EtOH 500 mL. The reaction mixture was stirred at 70 0 C for 2h. After removal of the solvent, the residue was refluxed in 1000 ml AcOEt for Ih.
  • Step A To a solution of l-(4-fluoro-3-methoxyphenyl)-iV- methylmethanamine (0.9 g, 5.39 mmol) in ethanol (8.0 mL) was added potassium carbonate (0.6 g, 4.48 mmol) and 2-bromo-l-(3,4-dichlorophenyl)ethanone (1.2 g, 4.48 mmol). The reaction solution was stirred for 2.5 hours at room temperature and then sodium borohydride (0.2 g, 5.83 mmol) was added to it portionwise at 0 0 C. The reaction mixture was stirred overnight while warming up to room temperature. The reaction solution was concentrated in vacuo.
  • Step B To a solution of the alcohol (1.1 g, 2.93 mmol) from Step A above in methylene chloride (10.0 mL) was added concentrated sulfuric acid (1.5 mL, 0.56 mmol). The reaction mixture was stirred at 0 0 C for 30 minutes and at room temperature for 2 hours. The reaction solution was quenched at 0 0 C by addition of an aqueous solution of sodium hydroxide (2N) and the aqueous phase was extracted with additional methylene chloride (3x). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo.
  • Step C The racemic 7-methoxy tetrahydroisoquinole from Step B above
  • Step D To a solution of (+) 7-methoxytetrahydroisoquinoline from Step C above (3.4 g, 11.70 mmol) in hydrobromic acid (90 mL, 48% solution in water) was added acetic acid (48 mL). The reaction solution was stirred at 110 0 C overnight under nitrogen and then concentrated under reduced pressure.
  • Step E To a solution of the phenol (2.5 g, 7.79 mmol) from Step D above in dichloromethane (30 mL) at 0 0 C was added pyridine (0.8 mL, 10.12 mmol) followed by slow addition of trifluoromethanesulfonic anhydride (1.4 mL, 8.18 mmol) dropwise. The resultant reaction solution was stirred at 0 0 C for 1 hour, and then was quenched with aqueous saturated sodium bicarbonate. The organic extract was separated and the aqueous layer was extracted with dichloromethane (3x).
  • Step F To a mixture of triflate (3.5 g, 7.57 mmol) in Step E above bis(pinacolato)diboron (2.3 g, 9.09 mmol) and potassium acetate (2.2 g, 22.72mmol) were added in DMSO (100.0 mL). The reaction solution was purged with argon for 10 minutes, and then l,r-bis(diphenylphosphino)ferrocenedichloropalladium (0.5 g, 0.61 mmol) was added to it. The reaction solution was degassed again with argon for 5 minutes and heated at 80 0 C overnight.
  • Step G A mixture of the boronate ester from Step F (350 mg, 0.80 mmol, prepared in Step F), 6-bromo-[l,2,4]triazolo[l,5- ⁇ ]pyridine (191 mg, 0.96 mmol) and cesium carbonate (786 mg, 2.41 mmol), in water (0.8 mL) and iV ⁇ V-dimethylformamide (4 mL) was degassed with argon and then [1,1- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (33 mg, 0.040 mmol) was added. The mixture was degassed again and then heated to 90 0 C for 2.5 hours.
  • Step H To (+)-7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4- dichlorophenyl)-6-fluoro-2-methyl-l,2,3,4-tetrahydroisoquinoline (160 mg, 0.37 mmol) and Nl,Nl,N8,N8-tetramethylnaphthalene-l,8-diamine (160 mg, 0.37 mmol) in 1,2- dichloroethane (5 mL) was added 1-chlorethyl chloroformate (0.082 mL, 0.75 mmol) dropwise. The mixture was heated to reflux for 3 hours and then cooled to ambient temperature.
  • reaction mixture was diluted with methylene chloride and washed with 1 N HCl, water, dried over sodium sulfate, filtered, and concentrated in vacuo.
  • methanol IS mL
  • the reaction mixture was heated to reflux. After 1 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure.
  • the residue was taken up in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
  • Step A Cerium(m) chloride heptahydrate (29.8 g, 80 mmol) was dried with magnetic stirring at 145 0 C under vacuum overnight Tetrahydrofuran (160 mL) was added and the white suspension was stirred at room temperature for 2 hours and then cooled with dry-ice/acetone bath. To this dry-ice/acetone bath cooled solution was added methyl lithium (1.6 M in ether, 50 mL, 80 mmol). The reaction mixture was stirred for 30 minutes and then a solution of 3-bromobenzonitrile (3.68 g, 20 mmol) in tetrahydrofuran (10 mL) was added. The resulting reaction mixture was stirred at 70 to 60 0 C for 5 hours.
  • Step B To a solution of 2-bromo-l-(3,4-dichlorophenyl)ethanone (5.1 g,
  • Step F 6-Bromo-[l,2,4]triazolo[l,5- ⁇ ]pyridine (600 mg, 3.03 mmol) was added to a mixture of the boronate ester from step E (873 mg, 1.68 mmol), cesium carbonate (1.97 g, 6.06 mmol) in DMF (60 mL) and water (12 mL). The reaction mixture was deoxygenated with argon.
  • the supernatant was decanted and the pellet resuspended and homogenized in 50 mM Tris-Cl, pH 7.5, 1 mM EDTA for 10 seconds. The suspension was then centrifuged again for 30 minutes at 32,000 x g, 4°C. The supernatant was decanted and the pellet resuspended in 50 mM Tris-Cl, pH 7.5, 1 mM EDTA and briefly homogenized. A Bradford assay (Bio-rad) was performed and the membrane preparation diluted to 2 mg/ml with 50 mM Tris-Cl, pH 7.5, 1 mM EDTA. Aliquots were prepared, and then frozen and stored at -80 0 C.
  • 0.4 ⁇ l/well of each solution was dispensed to a Nunc polypropylene, round bottom, 384- well plate. 100% inhibition is defined with 0.4 ⁇ l/well of 1 mM fluoxetine dissolved in DMSO. 20 ⁇ l/well of a 2x membrane preparation (15 ug/ml in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl) and 20 ⁇ l/well of a 2x radioligand solution (520 pM [ 125 I]RTI- 55 in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl) were added to each well and the reaction incubated for 1 hour at room temperature.
  • a 2x membrane preparation 15 ug/ml in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl
  • 2x radioligand solution 520 pM [ 125 I]RTI- 55
  • the contents of the assay plate were then transferred to a Millipore MultiscreenHTS GF/B filter plate which was pretreated with 0.5% PEI for at least one hour.
  • the plate was vacuum filtered and washed with 7 washes of 100 ⁇ l/well 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl chilled to 4°C. The filtration and washing were completed in less than 90 seconds.
  • the plates were air-dried overnight, 12 ⁇ l/well of MicroScint scintillation fluid added, and the plates counted in a Trilux.
  • the plate was vacuum-filtered and washed with 7 washes of 100 ⁇ l/well 50 mM Tris-Cl, pH 7.5, 120 mM NaQ, 5 mM KCl chilled to 4°C. The filtration and washing were completed in less than 90 seconds. The plates were air-dried overnight, 12 ⁇ l/well of MicroScint scintillation fluid added, and the plates counted in a Trilux.
  • 1.0 ⁇ l/well of each solution was dispensed to a Nunc polypropylene, round bottom, 384- well plate. 100% inhibition is defined with 1.0 ⁇ l/well of 10 mM desipramine dissolved in DMSO. 50 ⁇ l/well of a 2x membrane preparation (0.4 mg/ml in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl) and 50 ⁇ l/well of a 2x radioligand solution (4 nM [ 3 H]nisoxetine in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5 mM KCl) were added to the well and the reaction incubated for 1 hour at room temperature.
  • a 2x membrane preparation 0.4 mg/ml in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl
  • a 2x radioligand solution 4 nM [ 3 H]niso
  • the contents of the assay plate were then transferred to a Millipore Multiscreen H ⁇ s GF/B filter plate which was pretreated with 0.5% PEI for at least one hour.
  • the plate was vacuum filtered and washed with 7 washes of 100 ⁇ l/well 50 mM Tris-Cl, pH 7.5, 120 mM NaQ, 5 mM KCl chilled to 4°C. The filtration and washing were completed in less than 90 seconds.
  • the plates were air-dried overnight, 12 ⁇ l/well of MicroScint scintillation fluid added, and the plates counted in a Trilux.
  • the radioligand concentration chosen for each assay corresponds to the Kd concentration determined through saturation binding analysis for each assay.
  • mice were sacrificed by asphyxiation in CO 2 , rats by decapitation and dogs by IV injection of euthanasia solution.
  • the forebrain tissue was used for SERT, NET, and DAT occupancy assessment
  • the striatum was dissected for DAT occupancy and the remaining forebrain tissue (without the striatum, brainstem, and cerebellum) was used for SERT and NET occupancy assessment
  • the brain tissues were frozen in chilled isopentane and stored at -80°C until homogenization.
  • mice Male Swiss Webster mice were housed 3-4 per cage in rooms maintained at a constant temperature (21-23°C) and humidity (50 ⁇ 10%) on a 12-hour light/dark cycle. Animals had ad libitum access to water and food throughout studies. On the day of testing, they were brought into the testing room and allowed to acclimate for one hour. To begin testing, the tail was attached to a piece of tape which ias then attached to a hook on the ceiling of a sound-attenuated chamber. Immobility was automatically recorded using the Med Associates software. Compounds were administered acutely at a fixed pretreatment interval before session. [0319] The minimum effective dose of Example 36-(+)-enantiomer in the mouse tail suspension study was 10 mg/kg.
  • Compounds are administered at three time points in the next 24 hour (23.5, 5, and 1 hour), prior to a second test swim.
  • This swim test is 5 minutes in duration and the animals behavior is videotaped and active behaviors (immobility, swimming, climbing) are scored.
  • the rat's behavior is scored as one of the following: immobility (the rat remained floating in the water without struggling and made only those movements necessary to keep its head above water), swimming (the rat made active swimming motions, more than necessary to merely maintain its head above water, e.g., moving around in the cylinder), or climbing (the rat made active movements with its forepaws in and out of the water, usually directed against the cylinder wall).
  • Compounds are only identified by a predesignated code and the experimenter remains blinded throughout the experiment (including while scoring videotapes).
  • U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
  • U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
  • Unit cell dimensions a 7.1183(2)
  • a gamma 90 deg.
  • Atomic coordinates ( x 10 4 ) and equivalent isotropic displacement parameters (A 2 x 10 3 ) for Form N-2.
  • U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

Abstract

Novel aryl, heteroaryl, and non-aromatic heterocyle substituted tetrahydroisoquinolines are described in the present invention. These compounds are used in the treatment of various neurological and physiological disorders. Methods of making these compounds are also described in the present invention.

Description

ARYL, HETEROARYL, AND HETEROCYCLE SUBSTITUTED TETRAHYDROISOQUINOLINES AND USE THEREOF
[0001] This application claims the benefit of U.S. Provisional Patent Application
Serial No. 61/177,464, filed May 12, 2009, which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds, compositions, methods for the treatment of various neurological and psychological disorders, and the use of the compounds in combination therapy. In particular, the present invention relates to such compounds, compositions, and methods, where the compounds are novel aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinoline derivatives. Methods of making these compounds are also described in the present invention.
BACKGROUND OF THE INVENTION
[0003] Monoamine reuptake inhibitors elevate extracellular levels of serotonin (S-
HT), norepinephrine (NE) and/or dopamine (DA) in the brain by binding to one or more of the transporters responsible for reuptake, namely the serotonin transporter (SERT), the norepinephrine transporter (NET) and the dopamine transporter (DAT), thereby blocking reuptake of the neurotransmitter(s) from the synaptic cleft Monoamine reuptake inhibitors are an established drug class that has proven utility for the treatment of a number of CNS disorders especially major depressive disorder (MDD). [0004] Since the introduction of tricylic antidepressants (TCAs) almost SO years ago, monoamine reuptake inhibitors with greatly improved safety profiles have significantly enhanced the treatment of depression. Although TCAs are very effective antidepressants, cardiovascular, anticholinergic and sedative side effects are common due to the interaction of TCAs with muscarinic, histaminic and adrenergic receptors. The revolutionary introduction of selective serotonin reuptake inhibitors (SSRIs) in the 1980s allowed a much larger patient population to be treated because of the highly improved safety profile. Over the past decades, inhibitors that selectively block the reuptake of NE or DA, or two of the three neurotransmitters simultaneously, have become available for the treatment of CNS disorders including depression, anxiety, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), pain and urinary incontinence. Two representative recent reviews (Liu and Molino, Annual Reports in Medicinal Chemistry, 42:13 (2007); Walter, Drug Dev. Res., 65:97 (2005)) on monoamine reuptake inhibitors summarized the history and recent development in the monoamine reuptake inhibitor area. [0005] Currently, the major effort in the field of monoamine reuptake inhibitors is focused on improving antidepressant efficacy since 30-40% of patients do not respond to treatment with currently available antidepressants. An additional major objective is to enhance the onset of action. Current antidepressants typically require 2-6 weeks of treatment before clinical efficacy is seen. Clinical trials exploring augmentation strategies, in which a DA reuptake inhibitor or a dual NE/DA reuptake inhibitor is combined with an SSRL have resulted in improved efficacy in depressed patients refractory to SSRI treatment alone (Patkar et. al, /. Clin. Psychopharmacol., 26:653 (2006); Zisook et aL Biol Psycfdat., 59:203 (2006)). The improved results from clinical trials such as these serve to justify the considerable focus on the development of inhibitors that simultaneously block the reuptake of 5-HT, NE and DA. Because of the continued need for better drugs to treat depression and the opportunities for new clinical indications, efforts to discover novel monoamine reuptake inhibitors continue unabated. [0006] Methylphenidate, currently used for the treatment of attention deficit- hyperactivity disorder, is known to be selective for inhibition of the DAT. Also, U.S. Patent No.5,444,070 discloses selective inhibitors of dopamine reuptake as treatments for Parkinsons disease, drug addiction or abuse including cocaine and amphetamines. [0007] Selective norepinephrine reuptake inhibitors (NARI) have also been disclosed. U.S. Patent No.6,352,986 describes methods of treating attention deficit- hyperactivity disorder (ADHD), addictive disorders, and psychoactive substance use disorders with Reboxetine. Also, Atomoxetine (STRATTERA®) is currently marketed as a selective NET reuptake inhibitor for ADHD.
[0008] The use of selective serotonin reuptake inhibitors (SSRI) has been shown to be effective in treating depressive disorders. Sertraline, citalopram, escitalopram, paroxetine, fluoxetine and fluvoxamine are well known examples of SSRIs used to treat disorders such as depression, obsessive compulsive disorder, and panic attacks. There are several known difficulties with the SSRI class of therapeutics, including the slow onset of action, unwanted side effects, and the existence of a significant subset of the population that is not responsive to SSRI therapy. Recent effort in the clinical development of new SSRIs has focused on the treatment of premature ejaculation (PE) by taking advantage of the ejaculation-delaying side effects of SSRIs. Although SSRIs have been prescribed off- label to treat this condition, an SSRI with rapid onset of action and rapid clearance could be preferred for on-demand treatment of PE. Dapoxetine (LY210448, 6), an SSRI structurally related to fluoxetine with a shorter half-life, was reported to be an effective and generally well tolerated treatment for men with moderate-to-severe PE in clinical trials (Feret, Formulary, 40:227 (2005); Pryor et al, Lancet, 368:929 (2006)). [0009] Selective inhibitors of DAT, NET, and SERT reuptake may also be coadministered with each other or with other drugs. U.S. Patent No. 5,532,244 discloses the use of serotonin reuptake inhibitors in combination with a serotonin IA antagonist for the treatment of obsessive-compulsive disorder, depression, and obesity. The use of a serotonin or norepinephrine reuptake inhibitor in combination with a neurokinin- 1 receptor antagonist has been disclosed in U.S. Patent No. 6,121,261 for the treatment of ADHD. U.S. Patent No. 4,843,071 discloses the use of a norepinephrine reuptake inhibitor in combination with a norepinephrine precursor in the treatment of obesity, drug abuse, or narcolepsy. U.S. Patent No. 6,596,741 discloses the use of a NE, DA, or 5-HT inhibitor with either a neurokinin- 1 receptor antagonist or a serotonin- IA antagonist for the treatment of a wide variety of conditions. [0010] Also advantageous is the use of compounds that inhibit one or more of the neurotransmitters at the same time. The antidepressant qualities of the dual NET and SERT reuptake inhibitor duloxetine is disclosed in European Patent No. EP 273658. Venlafaxine is disclosed in U.S. Patent No. 4,535,186 as a reuptake inhibitor of both NE and 5-HT for the treatment of depressive disorders. U.S. Patent No. 6,635,675 discloses the use of the dual NE and 5-HT reuptake inhibitor milnacipran for the treatment of chronic fatigue syndrome and fibromyalgia syndrome. In addition, dual NE and 5-HT reuptake inhibitors are also disclosed in U.S. Patent No. 6,136,083 for the treatment of depression. It is also recognized that compounds which inhibit the reuptake of NE, DA, and 5-HT in varying ratios not specifically mentioned here would also be advantageous. [0011] As the first SNRI drug approved, venlafaxine has become one of the first- line choices for depression and anxiety disorder. An active metabolite, desvenlafaxine, is also under clinical development for the treatment of major depressive disorders. Preclinical studies also indicate that desvenlafaxine may be effective in relieving vasomotor symptoms associated with menopause (e.g., hot flashes and night sweats) (Sorbera, et al Drugs of Future., 31:304 (2006); Albertazzi, J. Br. Menopause Soc., 12:7 (2006)). Desvenlafaxine is reported to be in clinical development for the treatment of fibromyalgia and neuropathic pain, as well as vasomotor symptoms associated with menopause. [0012] In addition to treating major depressive disorder, duloxetine was approved as the first agent for the treatment of painful diabetic neuropathy in the U.S. It also has been used for stress urinary incontinence in women in Europe. In 2007, duloxetine was approved for the treatment of generalized anxiety disorder in the U.S. Most recently, it was approved by the FDA for the management of fibromyalgia [0013] Milnacipran is currently available for use as an antidepressant in several countries outside the U.S. It is also under clinical development to assess its potential role in the treatment of fibromyalgia syndrome.
[0014] After more than a decade of use, bupropion, is considered a safe and effective antidepressant, suitable for use as first-line treatment. In addition, it is approved for smoking cessation and seasonal affective disorder. It is also prescribed off-label to treat the sexual dysfunction induced by SSRIs. Bupropion is often referred to as an atypical antidepressant It has much lower affinity for the monoamine transporters compared with other monoamine reuptake inhibitors. The mechanism of action of bupropion is still uncertain but may be related to inhibition of dopamine and norepinephrine reuptake transporters as a result of active metabolites. In a recently reported clinical trial, bupropion extended release (XL) had a sexual tolerability profile significantly better than that of escitalopram with similar remission rates and Hospital Anxiety and Depression (HAD) total scores in patients with major despressive disorder (Clayton et aL J. CIm. Psychiatry, 67:736 (2006)). [0015] Treating illnesses by inhibiting the reuptake of all three of the monoamines either through combination therapy or triple inhibitors may have clinical benefit as well. Triple inhibitors are considered to be the next generation antidepressant (Liang and Richelson, Primary Psychiatry, 15(4):50 (2008)). Rationale for inclusion of a dopamine enhancing component in anti-depressant therapy includes observed deficits in dopaminergic function, the success of combination therapy with dopamine agonists and traditional anti-depressants, and an increased sensitivity in dopamine receptors due to chronic anti-depressant administration (Skolnick et al., Life Sciences, 73:3175-3179 (2003)). Combination therapy with an SSRI and a noradrenaline and dopamine reuptake inhibitor was shown to be more efficacious in patients with treatment-resistant depression (Lam et al, /. Clin. Psychiatry, 65(3):337-34O (2004)). Clinical studies using the combination of bupropion and an SSRI or SNRI have showed improved efficacy for the treatment of MDD in patients refractory to the treatment with SSRIs, SNRIs, or bupropion alone (Zisook et al, Biol. Psychiat., 59:203 (2006); Papkostas, Depression and Anxiety, 23:178-181 (2006); Trivedi et al, New Engl. J. Med., 354:1243 (2006)). Other studies using methylphenidate, both immediate release and extended release formula, have shown it to be effective as an augmenting agent in treatment-resistant depression (Patkar et al, J. Clin. Psychopharmacol., 26:653 (2006); Masand et al, Depression and Anxiety, 7:89 (1998)). In addition, the combination of bupropion-SR with either SSRIs or norepinephrine and dopamine reuptake inhibitors was found to induce less sexual dysfunction than monotherapy (Kennedy et al, J. Clin. Psychiatry, 63(3):181-186 (2002)). As such, inhibitory activity against DA reuptake, in addition to NE and 5-HT reuptake, is expected to provide a more rapid onset of anti-depressant effect than other mixed inhibitors which are selective for NET and SERT over DAT. PCT International
Publication Nos. WO 03/101453 and WO 97/30997 disclose a class of compounds which are active against all three monoamine transporters. Also, PCT International Patent Publication No. WO 03/049736 discloses a series of 4-substituted piperidines, each of which displays similar activity against DA, NE, and 5-HT transporters. Bicyclo[2.2.1]heptanes (Axford et al., Bioorg. Med Chem. Lett., 13:3277-3280 (2003)) and azabicyclo[3.1.0]hexanes (Skolnick et al., Eur. J. Pharm., 461:99-104 (2003)) are also described as triple inhibitors of the three monoamine transporters. l-(3,4- Dichlorophenyl)-3-azabicyclo[3.1.0]hexane has been shown to be efficacious in treating depression in clinical trials (Beer et al, J. Clin. Pharmacol., 44:1360-1367 (2004)). Current widely used anti-obesity drug sibutramine is believed to work through the inhibition of all three transporters DAT, SERT, and NET (Ryan, Pharmacotherapy of Obesity, 245-266 (2004)). [0016] Recent drug approvals with SNRIs for treatment of fibromyalgia and diabetic neuropathy reinforce the utility of this drug class in the treatment of neuropathic pain. Other largely untapped areas which remain to be exploited with this drug class include sexual dysfunction, such as premature ejaculation, irritable bowel syndrome, obesity, neurodegenerative diseases such as Parkinsons disease, restless leg syndrome, and substance abuse and addiction.
[0017] There is still a large need for compounds that block the reuptake of norepinephine, dopamine, and serotonin and treat various neurological and psychological disorders. [0018] The present invention is directed achieving this objective.
SUMMARY OF THE INVENTION
[0019] The present invention is directed to a compound of formula (T) :
Figure imgf000007_0001
wherein: the carbon atom designated * is in the R or S configuration; R1 is H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, Ci-C6 haloalkyl, or gem-dialkyl of which each alkyl is Ci-C4;
R2 is H, halogen, OR n, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1-3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy, CN, OR 9, orNR 9R10 ; R3 is an aryl selected from the group consisting of phenyl, naphihyl, indanyl, and indenyl, or a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-l-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, ihiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4- thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dthydro-benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6αH-tnieno[2,3- d]imidazolyl, l/-r-pyrrolo[2,3-&]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5- α]pyridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3- 6]furanyl, thieno[2,3-6]pyridinyl, thieno[3,2-6]pyridinyl, furo[2,3-&]pyridinyl, furo[3,2- &]pyridinyl, thieno[3,2-rf]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-6]pyrazinyl, furo[2,3--7]pyrazinyl , imidazo[l,2-α]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2- α]pyrazinyl, όJ-dmydro^H-pyrazoloβ.l-cΗl^oxazinyl, 2-oxo-2,3- dihydrobenzo[d]oxazolyl, 2-oxo-2,3-dihydro-lΗ-benzo[d]imidazole, 3,3-dimethyl-2- oxoindolinyl, 2-oxo-2,3-dihydro-lH-pyrrolo[2,3--7]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dihydro-2H- benzo[6][l,4]oxazinyl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-α]pyrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo-[l,2,4]triazolo[4,3-α]pyridinyl, or a non- aromatic heterocycle selected from the group consisting of pyπolidinyl, 2- oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2- oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1- dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl; wherein the aryl, heteroaryl, or non-aromatic heterocycle is optionally substituted from 1 to 4 times with substituents as defined below in R14;
R4 , R5 and R6 and R7 are each independently H or are selected from the group consisting of halogen, OR n, NR 11R12, NR 11C(O)R12, NR 11CXO)2R12, NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2- Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloaliyl, and C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1-3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, orNR 9R10;
R8 is H, Ci-C6 alkyl, halogen or OR11;
R9 and R10 are each independently H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 alkoxy;
or R9 and R10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R11 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
R12 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring, with the proviso that only one of R9 and R10 or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring; R13 is Ci-C4 alkyl, Ci-C4 haloalkyl, or phenyl;
n is 0, 1, or 2; and,
R14 is independently selected at each occurrence from a substituent selected from the group consisting of halogen, NO 2, OR n, NR 11R12, NR 11C(O)R12, NR 11C(O)2R12, NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl where Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cydoalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of Ci-C3 alkyl, halogen, Ar, CN, OR 9, and NR 9R10;
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] Figure 1 illustrates experimental and simulated powder X-Ray diffraction (PXRD) patterns (CuKa λ^l.54178 A at T = room temperature) of crystalline Form SA-
1.
[0021] Figure 2 illustrates the differential scanning calorimetry (DSC) pattern of
Form SA-I.
[0022] Figure 3 illustrates thermogravimetric analysis (TGA) of Form SA-I.
DETAILED DESCRIPTION OF THE INVENTION
[0023] The present invention is directed to a compound of formula (T) :
Figure imgf000011_0001
wherein: the carbon atom designated * is in the R or S configuration;
R1 is H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, Ci-C6 haloalkyl, or gem-dialkyl of which each alkyl is Ci-C4;
R2 is H, halogen, OR n, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, orNR 9R10;
R3 is an aryl selected from the group consisting of phenyl, naphthyl, indanyl, and indenyl, or a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-l-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4- thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzotbiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6αff-thieno[2,3- djimidazolyl, lH-pyrτolo[2,3-έ]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5- α]pyridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3- &]furanyl, thieno[2,3-&]pyridinyl, ihieno[3,2-6]pyridinyl, furo[2,3-&]pyridinyl, furo[3,2- 6]pyridinyl, thieno[3,2-rf]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-&]pyrazinyl, furo[2,3-&]pyrazinyl , imidazo[l,2-α]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2- α]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazinyl, 2-oxo-2,3- dihydrobenzo[d]oxazolyl, 2-oxo-2,3-dihydro-lH-benzo[d]imidazole, 3,3-dimethyl-2- oxoindolinyl, 2-oxo-2,3-dihydro-lH-pyrrolo[2,3-.7]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dihydro-2H- benzo[6][l,4]oxazinyl, 5,6,7,8-tJetrahydro-[l,2,4]triazolo[4,3-α]pyrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo-[l,2,4]triazolo[4,3-α]pyridinyl, or a non- aromatic heterocycle selected from the group consisting of pyπolidinyl, 2- oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2- oxooxazolidinyl, morpholino, 3-oxomorpholino, tbiomorpholino, 1,1- dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl; wherein the aryl, heteroaryl, or non-aromatic heterocycle is optionally substituted from 1 to 4 times with substituents as defined below in R14;
R4 , R5 and R6 and R7 are each independently H or are selected from the group consisting of halogen, OR n, NR 11R12, NR 11C(O)R12, NR 11CXO)2R12,
NR 11C(O)NR12 R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloaliyl, and C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of C1-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, orNR 9R10;
R8 is H, Ci-C6 alkyl, halogen or OR11;
R9 and R10 are each independently H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 alkoxy; or R9 and R10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
R12 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
or R1 J and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring, with the proviso that only one of R9 and R10 or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R13 is Ci-C4 alkyl, Ci-C4 haloalkyl, or phenyl;
n is 0, 1, or 2; and
R14 is independently selected at each occurrence from a substituent selected from the group consisting of halogen, NO 2, OR n, NR 11R12, NR 11C(O)R12, NR 11C(O)2R12, NR 11C(O)NR12 R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, where Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cydoalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of Ci-C3 alkyl, halogen, Ar, CN, OR 9, and NR 9R10; or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.
[0024] As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
[0025] The term "alkyl" means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n- butyl, t-butyl, n-pentyl, and 3-pentyl.
[0026] The term "alkenyl" means an aliphatic hydrocarbon group containing a carboncarbon double bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, and i-butenyl.
[0027] The term "alkynyl" means an aliphatic hydrocarbon group containing a carboncarbon triple bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkynyl chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. [0028] The term "aryl" means an aromatic monocyclic or multicyclic ring system of 6 to about 14 carbon atoms, preferably of 6 to about 10 carbon atoms. Representative aryl groups include phenyl and naphthyl.
[0029] The term "heteroaryl" means an aromatic monocyclic or multicyclic ring system of about S to about 14 ring atoms, preferably about S to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example, nitrogen, oxygen, or sulfur. In the case of multicyclic ring system, only one of the rings needs to be aromatic for the ring system to be defined as "Heteroaryl". Preferred heteroaryls contain about S to 6 ring atoms. The prefix aza, oxa, thia, or thio before heteroaryl means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Representative heteroaryls include pyridyl, 2-oxo-pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, 2- oxoindolinyl, dthydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6αH-thieno[2,3- djimidazolyl, lH-pyrτolo[2,3-έ]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5- α]pyridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3- &]furanyl, thieno[2,3-&]pyridinyl, ihieno[3,2-6]pyridinyl, furo[2,3-&]pyridinyl, furo[3,2- 6]pyridinyl, thieno[3,2-rf]pyrimidinyl, furo[3,2-_flpvrimidinyl, thieno[2,3-&]pyrazinyl, imidazo[l,2-α]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2-α]pyrazinyl, 6,7-dihydro-4H- pyrazolo[5,l-c][l,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[-floxazolyl, 3,3-dimeihyl-2- oxoindoUnyl, 2-oxo-23-dihydro-lH-pvrrolo[2,3-6]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dihydro-2Η-benzo[.7][l,4]oxazinyl, 5,6,7,8-tBtrahydro- [l,2,4]triazolo[4,3-α]pvrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, 3-oxo-[l,2,4]triazolo[4,3- α]pyridin-2(3H)-yl, and the like. [0030] The term non-aromatic heterocycle means a non-aromatic monocyclic system containing 3 to 10 atoms, preferably 4 to about 7 carbon atoms, in which one or more of the atoms in the ring system is/are elements) other than carbon, for example, nitrogen, oxygen, or sulfur. Representative non-aromatic heterocycle groups include pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomoφholino, 1,1- dioxothiomorpholino, piperazinyl, tetrohydro-2H-oxazinyl, and the like. [0031] The term "alkoxy" means an alkyl-O- group wherein the alkyl group is as herein described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy. [0032] A compound with a hydroxy group drawn next to a nitrogen on a heterocycle can exist as the keto form. For example, 3-(2-hydroxy-[l,2,4]triazolo[l,5- a]pyridin-6-yl)propanoic acid can exist as 3-(2-oxo-2,3-dihydro-[l,2,4]triazolo[l,5- a]pyridin-6-yl)propanoic acid. [0033] The term "compounds of the invention", and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits. [0034] The term "cycloalkyl" means a non-aromatic mono- or multicyclic ring system of about 3 to about 7 carbon atoms, preferably of about 5 to about 7 carbon atoms. Exemplary monocyclic cycloalkyls include cyclopentyl, cyclohexyl, cycloheptyl, and the like.
[0035] The term "cycloalkylalkyl" means an cycloalkyl-alkyl-group in which the cycloalkyl and alkyl are as defined herein. Exemplary cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylmethyl.
[0036] The term gem-dialkyl means two alkyl groups that substitute the two hydrogen atoms of a methylene group
[0037] The term gem-dimethyl means two methyl groups that substitute the two hydrogen atoms of a methylene group. [0038] The term "halo" or "halogen" means fluoro, chloro, bromo, or iodo.
[0039] The term "haloalkyl" means both branched and straight-chain alkyl substituted with one or more halogen, wherein the alkyl group is as herein described. [0040] The term "haloalkoxy" means a
Figure imgf000016_0001
alkoxy group substituted by at least one halogen atom, wherein the alkoxy group is as herein described. [0041] The term "substituted" or "substitution" of an atom means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded. [0042] "Unsubstituted" atoms bear all of the hydrogen atoms dictated by their valency. When a substituent is keto (i.e., =0), then two hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds; by "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent [0043] The term "pharmaceutically acceptable salts" means the relatively nontoxic, inorganic, and organic acid addition salts, and base addition salts, of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Exemplary acid addition salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulphamates, malonates, salicylates, propionates, methylene-bis-b- hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinateslaurylsulphonate salts, and the like (see, for example, Berge et al., "Pharmaceutical Salts," J. Pharm. ScL, 66:1-9 (1977) and Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Eastern, Pa, 1985, p. 1418, which are hereby incorporated by reference in their entirety). Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed. Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts. The sodium and potassium salts are preferred. Suitable inorganic base addition salts are prepared from metal bases which include, for example, sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, and zinc hydroxide. Suitable amine base addition salts are prepared from amines which have sufficient basicity to form a stable salt, and preferably include those amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use, such as ammonia, ethylenediamine, N- methyl-glucamine, lysine, arginine, ornithine, choline, N.N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylarnine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e.g., lysine and arginine, dicyclohexylamine, and the like.
[0044] The term "pharmaceutically acceptable prodrugs" as used herein means those prodrugs of the compounds useful according to the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" means compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention. They include, but are not limited to, such groups as alkanoyl (such as acetyl, propionyl, butyryl, and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as trimethyl- and triethysilyl), monoesters formed with dicarboxylic acids (such as succinyl), and the like. Because of the ease with which the metabolically cleavable groups of the compounds useful according to this invention are cleaved in vivo, the compounds bearing such groups act as pro-drugs. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985); Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p.309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; "Design and Applications of Prodrugs" p.l 13-191 (1991); Advanced Drug Delivery Reviews, H. Bundgard, 8, p.1-38 (1992); Journal of Pharmaceutical Sciences, 77:285 (1988); Nakeya et al, Chem. Pharm. Bull, 32:692 (1984); Higuchi et al., Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press (1987), which are incorporated herein by reference in their entirety. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention.
[0045] The term "therapeutically effective amounts" is meant to describe an amount of compound of the present invention effective in increasing the levels of serotonin, norepinephrine, or dopamine at the synapse and thus producing the desired therapeutic effect Such amounts generally vary according to a number of factors well within the purview of ordinarily skilled artisans given the description provided herein to determine and account for. These include, without limitation: the particular subject, as well as its age, weight, height, general physical condition, and medical history, the particular compound used, as well as the carrier in which it is formulated and the route of administration selected for it; and, the nature and severity of the condition being treated. [0046] The term "pharmaceutical composition" means a composition comprising a compound of formula (T) and at least one component comprising pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifingal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agaragar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosterate and gelatin. Examples of suitable carriers, diluents, solvents, or vehicles include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, and dicalcium phosphate. Examples of disintegrating agents include starch, alginic acids, and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols. [0047] The term "pharmaceutically acceptable" means it is, within the scope of sound medical judgement, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. [0048] The term "pharmaceutically acceptable dosage forms" means dosage forms of the compound of the invention, and includes, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalants tablets, lozenges, emulsions, solutions, granules, capsules, and suppositories, as well as liquid preparations for injections, including liposome preparations. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Eastern, Pa., latest edition.
[0049] One preferred embodiment of the present invention is the compound of formula (J), wherein R1 is H, Ci-C6 alkyl, or gem-dialkyl, preferably wherein R1 is H or gem-dimethyl. [0050] Another preferred embodiment of the invention is the compound of formula (J), wherein R2 is H, halogen, OR n, S(O) 2R12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, or substituted Ci-C6 alkyl, more preferably H or halogen. [0051] Another preferred embodiment of the present invention is the compound of formula (T), wherein R3 is optionally substituted aryl, heteroaryl, or non-aromatic heterocycle group.
[0052] Another more preferred embodiment of the present invention is the compound of formula (I), wherein R3 is phenyl, or heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-l-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4- triazinyl, 1,3,5-triazinyl, furanyl, pyπolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzoihiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro- benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6αΗ-thieno[2,3-d]imidazolyl, l/-r-pyrrolo[2,3-&]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5-α]pyridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3--?]furanyl, thieno[2,3--?]pyridinyl, thieno[3,2- 6]pyridinyl, furo[2,3-6]pyridinyl, furo[3,2-ft]pyridinyl, thieno[3,2-rf]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-&]pyrazinyl, furo[2,3-&]pyrazinyl , imidazo[l,2- α]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2-α]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,l- c][l,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[rf]oxazoryl, 2-oxo-2,3-dihydro-lH- benzo[d]imidazole, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-l/-r-pyrrolo[2,3- ύ]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dthydro-2H- benzo[6][l,4]oxazinyl, 5,6J,8-tBtrahydro-[l,2,4]triazolo[4,3-α]pyrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo-[l,2,4]triazolo[4,3-α]pyridinyl, or non- aromatic heterocycle selected from the group consisting of pyπolidinyl, 2- oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2- oxooxazolidinyl, morpholino, 3-oxomorpholino, tbiomorpholino, 1,1- dioxotbiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl; wherein the phenyl, heteroaryl or non-aromatic heterocycle is optionally substituted from 1 to 4 times with substituents as defined in R14;
[0053] A further more preferred embodiment of the present invention is the compound of formula (F), wherein R3 is l,2,4-oxadiazol-3-yl, 3,5-dimethylisoxazol-4-yl, lH-pyrazol-3-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3- (methanesulfonyl)phenyl, 4-(methanesulfonyl)phenyl, 3-carbamoylphenyl, 4- carbamoylphenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazin-3-yl, 6- methylpyridazin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6-(difluoromethyl)pyridazin-3- yl, 6-(difluoromethoxy)methyl)pyridazin-3-yl, 6-aminopyridazin-3-yl, (6- (hydroxymethyl)pyridazin-3-yl, 6-methoxypyridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-aminopyrazin-2-yl, 5-aminopyrazin-2-yl, 6-aminopyrazin- 2-yl, 2-oxopyridin-l(2H)-yl, 6-oxo-l,6-dihydropyridazin-3-yl, 6-oxopyridazin-l(6H)-yl, [l,2,4]triazolo[4,3-a]pyridin-6-yl, [l,2,4]triazolo[l,5-a]pyridin-6-yl, 3-oxo- [l,2,4]triazolo[4,3-α]pyridin-2(3H)-yl, 3-(trifluoromethyl)-5,6-dihydro- [l,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl, [l,2,4]triazolo[l,5-α]pyridin-6-yl, [l,2,4]triazolo[4,3-α]pyridin-6-yl, 3,3-dimethyl-2-oxoindolin-5-yl, 3,3-dimethyl-2- oxoindolin-6-yl, 3-methyl-[l,2,4]triazolo[4,3--7]-pyridazinyl, or [l,2,4]triazolo[4,3-6]- pyridazinyl, each of which is optionally substituted from 1 to 4 times with substituents as defined in R14. [0054] Another more preferred embodiment of the present invention is the compound of formula (T), wherein R4, R5, R6 and R7 are each independently selected from the group consisting of H, halogen, OR n, NR 11R12, NR 11C(O)R12, S(O) 2R12,
CN, C(O)R 12, C(O)NR 11R12, and optionally substituted Ci-C6 alkyl. [0055] Another more preferred embodiment of the present invention is the compound of formula (T), wherein R4 is H, Ci-C6 alkyl, OH, F, Cl, OH, or OCH3, more particularly H or F.
[0056] Another more preferred embodiment of the present invention is the compound of formula (T), wherein R7 is H. [0057] Another more preferred embodiment of the present invention is the compound of formula (T), wherein R5 and R6 are each independently selected from the group consisting of H, F, Cl, OH, OCH3, and CH3, more particularly, Cl.
[0058] Another more preferred embodiment of the present invention is the compound of formula (T), wherein R8 is H, OH, CH3, or F. [0059] Another more preferred embodiment of the present invention is the compound of formula (T) wherein:
R1 is H, Ci-C6 alkyl, or gem-dialkyl;
R2 is H, halogen, OR n, S(O) 2R12^i-C6 alkyl, or substituted Ci-C6 alkyl;
R3 is aryl, heteroaryl, or non-aromatic heterocycle;
R4 is H, F, or Cl; and
R5, R6 and R7 are each independently H, halogen, OR n, NR 11R12, S(O) 2R12, C(O)R 12, Ci-C6 alkyl, or substituted Ci-C6 alkyl.
[0060] Another more preferred embodiment of the present invention is the compound of formula (T) wherein:
R1 is H or gem-dimethyl; R2 is H;
R3 is phenyl, pyridyl, 2-oxo-pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, ihiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4- oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzoihiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzottiiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pfhalazinyl, quinoxalinyl, 2,3-dihydro- benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6αff-thieno[2,3-d]imidazolyl, lH-pyrrolo[2,3-&]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5-α]pyridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3--?]furanyl, thieno[2,3--?]pyridinyl, thieno[3,2- 6]pyridinyl, furo[2,3--7]pyridinyl, furo[3,2-ft]pyridinyl, ihieno[3,2-rf]pyrimidinyl, furo[3,2--flpyrimidinyl, thieno[2,3-.7]pyrazinyl, furo[2,3-6]pyrazinyl , imidazo[l,2- α]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2-α]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,l- c][l,4]oxazinyl, 2-oxo-2,3-diliydrobenzo[rf]oxazolyl, 2-oxo-2,3-dihydro-lΗ- benzo[d]imidazole, 3,3-dimeihyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-lH-pyrrolo[2,3- 6]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dihydro-2H- benzo[6][l,4]oxazinyl, 5,6,7,8-tBtrahydro-[l,2,4]triazolo[4,3-α]pyrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, or 3-oxo-[l,2,4]triazolo[4,3-α]pyridinyl, or non-aromatic heterocycle selected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1-dioxothiomorpholino, piperazinyl, and tetrohydro- 2H-oxazinyl, each of which is optionally and independently substituted 1 to 4 times with substituents as defined in R14;
R4 is H or F;
R5 and R6 are each independently H, F, Cl, OH, OCH3, or CH3;
R7 is H or F; and R8 is H, OH, or F.
[0061] Another more preferred embodiment of the present invention is the compound of formula (F) wherein:
R1 is H or gem-dimethyl;
R2 is H;
R3 is l,2,4-oxadiazol-3-yl, l,2,3-thiadiazol-4-yl, 3,5-dimethylisoxazol-4-yl, lH-pyrazol-
3-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-(methanesulfonyl)phenyl, 4- (methanesulfonyl)phenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, 2-aminopyridinyl, 3-aminopyridinyl, 4-aminopyridinyl, pyridazin-3-yl, 6-methylpyridazin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6- (difluoromethyl)pyridazin-3-yl, 6-(difluoromethoxy)methyl)pyridazin-3-yl, 6- aminopvridazin-3-yl, (6-(hydroxymethyl)pvridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-aminopyrazin-2-yl, 5-aminopyrazin-2-yl, 6-aminopyrazin- 2-yl, 2-oxopyridin-l(2H)-yl, 2-oxopyrrolidin-l-yl, 6-oxo-l,6-dihydropvridazin-3-yl, 6- oxopyridazin-l(6H)-yl, 3-oxo-[l,2,4]triazolo[4,3-α]pyridin-2(3H)-yl, 3-(trifluoromethyl)- 5,6-dihydro-[l,2,4]triazolo[4,3-α]pvrazin-7(8H)-yl, [l,2,4]triazolo[l,5-α]pyridin-6-yl, [l,2,4]triazolo[4,3-α]pvridin-6-yl, 3,3-dimethyl-2-oxoindolin-5-yl, 3-methyl- [l,2,4]triazolo[4,3--7]-pyridazinyl, [l,2,4]triazolo[4,3--7]-pyridazinyl, or oxooxazolidin-3- yi;
R4 is H or F;
R5 and R6 are each independently H, F, Cl, or CH3;
R7 is H; and
R8 is H. [0062] Another more preferred embodiment of the present invention is the compound of formula (F) wherein:
R1 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, Ci-C6 haloalkyl, or gem-dialkyl of which each alkyl is Ci-C4;
R2 is H, halogen, OR n, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, or NR 9R10;
R3 is an aryl selected from the group consisting of phenyl, naphthyl, indanyl, and indenyl, or a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-l-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4- thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzotbiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dthydro-benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-cbromenyl, indolizinyl, quinolizinyl, 6αff-thieno[2,3- d]imidazolyl, lH-pyrτolo[2,3-έ]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5- α]pyridinyl, [l,2,4]triazolo[4,3-α]pvridinyl, [l,2,4]triazolo[l,5-α]pvridinyl, thieno[2,3- 6]furanyl, thieno[2,3-&]pyridinyl, thieno[3,2-&]pyridinyl, furo[2,3--7]pvridinyl, furo[3,2- &]pyridinyl, thieno[3,2-rf]pvrimidinyl, furo[3,2-_flpvrimidinyl, thieno[2,3--7]pyrazinyl, furo[2,3-ύ]pyrazinyl , imidazo[l,2-α]pyrazinyl, S,6,7,8-tetrahydroimidazo[l,2- α]pyrazinyl, ό.V-dihydro^H-pyrazoloCS.l-clCl^oxazinyl, 2-oxo-2,3- dihydrobenzo[-floxazolyl, 2-oxo-2,3-dihydro-lΗ-benzo[d]imidazole, 3,3-dimethyl-2- oxoindolinyl, 2-oxo-2,3-dihydro-lH-pyrrolo[2,3--7]pvridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dihydro-2H- benzo[6][l,4]oxazinyl, 5,6,7,8-tJetrahydro-[l,2,4]triazolo[4,3-α]pyrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo-[l,2,4]triazolo[4,3-α]pyridinyl, or a non- aromatic heterocycle selected from the group consisting of pyπolidinyl, 2- oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2- oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1- dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl; wherein the aryl, heteroaryl, or non-aromatic heterocycle is optionally substituted from 1 to 4 times with substituents as defined below in R14;
R4 is selected from the group consisting of H, halogen, NR 11R12, NR 11CXO)R12, NR 11C(O)2R12, NR 11CXO)NR12R13, SOR 12, S(0) 2R12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, orNR 9R10;
R5 and R6 and R7 are each independently H or are selected from the group consisting of halogen, OR n, NR 11C(O)R12, NR 11C(O)2R^ NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting Of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci- C4 alkoxy, CN, OR 9, orNR 9R10;
R8 is H, halogen, or OR11; R9 and R10 are each independently H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 alkoxy;
or R9 and R10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R11 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
R12 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring, with the proviso that only one of R9 and R10 or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R13 is Ci-C4 alkyl, Ci-C4 haloalkyl, or phenyl;
n is 0, 1, or 2; and
R14 is independently selected at each occurrence from a substituent selected from the group consisting of halogen, NO 2, OR n, NR 11R12, NR 11C(O)R12, NR 11C(O)2R12, NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, where Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cydoalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of C1-C3 alkyl, halogen, Ar, CN, OR 9, and NR 9 R10, or
an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof; with the proviso that when R3 is phenyl or monocyclic aromatic heterocycle (pyridyl, 2- oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3- thiadiazolyl, 1,3,4-thiadiazolyl, or tetrazolyl), R14 cannot be Ci-C6 alkyl substituted with
NR9R10.
[0063] Another more preferred embodiment of the present invention is the compound of formula (F) wherein:
R1 is gem-dialkyl of which each alkyl is Ci-C4;
R2 is H, halogen, OR n, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Q-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, orNR 9R10;
R3 is an aryl selected from the group consisting of phenyl, naphthyl, indanyl, and indenyl, or a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-l-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, tniophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tniazolyl, isothiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4- thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6αH-ttiieno[2,3- d]imidazolyl, lH-pyrrolo[2,3-6]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5- α]pyridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3- 6]furanyl, thieno[2,3-&]pyridinyl, thieno[3,2-ft]pyridinyl, furo[2,3-6]pyridinyl, furo[3,2- 6]pyridinyl, thieno[3,2-rf]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-&]pyrazinyl, furo[2,3-6]pyrazinyl , imidazo[l,2-α]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2- α]pyrazinyl, 6,l-ϋhydm-4H-pyraz,olo[5,l-c][l,4]oxιaiayl, 2-oxo-2,3- dihydrobenzo[^oxazolyl, 2-oxo-2,3-dihydro-lΗ-benzo[d]imidazole, 3,3-dimethyl-2- oxoindolinyl, 2-oxo-2,3-dihydro-lH-pyrrolo[2,3-6]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dihydro-2H- benzo[6][l,4]oxazinyl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-α]pyrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo-[l,2,4]triazolo[4,3-α]pyridinyl, or a non- aromatic heterocycle selected from the group consisting of pyπolidinyl, 2- oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2- oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1- dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl; wherein the aryl, heteroaryl, or non-aromatic heterocycle is optionally substituted from 1 to 4 times with substituents as defined below in R14;
R4 , R5 and R6 and R7 are each independently H or are selected from the group consisting of halogen, OR n, NR 11R12, NR 11C(O)R12, NR 11CXO)2R12, NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2- Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloaliyl, and C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of C1-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, or NR 9R10;
R8 is H, halogen, or OR11; R9 and R10 are each independently H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 alkoxy;
or R9 and R10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R11 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
R12 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring, with the proviso that only one of R9 and R10 or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R13 is Ci-C4 alkyl, Ci-C4 haloalkyl, or phenyl;
n is 0, 1, or 2; and
R14 is independently selected at each occurrence from a substituent selected from the group consisting of halogen, NO 2, OR n, NR 11R12, NR 11C(O)R12, NR 11C(O)2R12, NR 11CXO)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, where Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cydoalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of Ci-C3 alkyl, halogen, Ar, CN, OR 9, and NR 9 R10, or
an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof. [0064] Another more preferred embodiment of the present invention is the compound of formula (F) wherein:
R1 is H, Ci-C4 alkyl, or gem-dialkyl of which each alkyl is Ci-C4;
R2 is H, halogen, OR n, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci -C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, or NR 9R10;
R3 is [l,2,4]triazolo[l,5-α]pyridine-2-yl, [l,2,4]triazolo[l,5-α]pyridine-5-yl, [l,2,4]triazolo[l,5-α]pyridine-6-yl, [l,2,4]triazolo[l,5-α]pyridine-7-yl, or [l,2,4]triazolo[l,5-α]pyridine-8-yl which is optionally substituted by R14;
R4 is H, F, Cl, Me, CN, OR11, Q-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci -C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, orNR 9R10; R5, R6, and R7 are each independently H or are selected from the group consisting of halogen, OR n, NR 11R12, NR 11CXO)R12, NR 11C(O)2R^ NR 11C(O)NR12 R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Q-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4 -C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3 -C6 cycloalkyl, and C4 -C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of C1-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, C1- C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, orNR 9 R10;
R8 is H, halogen, OR11 or C1^4 alkyl;
R9 and R10 are each independently H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 alkoxy;
or R9 and R10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R11 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
R12 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy; or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring, with the proviso that only one of R9 and R10 or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R13 is Ci-C4 alkyl, Ci-C4 haloalkyl, or phenyl;
n is 0, 1, or 2; and,
R14 is independently selected at each occurrence from a substituent selected from the group consisting of halogen, NO 2, OR n, NR 11R12, NR 11C(O)R12, NR 11C(O)2R12, NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, where Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of Ci-C3 alkyl, halogen, Ar, CN, OR 9, and NR 9R10, or
an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.
[0065] Another more preferred embodiment of the present invention is the compound of formula (F) wherein:
R1 is H, methyl, or gem-dimethyl;
R2 is H, F, Cl, CN, Me, CF3, CF2H, OMe, OCF3, OCF2H, or OH;
R3 is [l,2,4]triazolo[l,5-α]pyridinyl-6-yl which is optionally substituted by R14 ;
R4 is H, F, Cl, CN, Me, CF3, CF2H, OMe, OCF3, OCF2H, or OH; R5 to R7 are independently, H, F, Cl, CN, Me, CF3, CF2H, OMe, OCF3, OCF2H, or OH; and
R8 is H or methyl,
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
[0066] Another more preferred embodiment of the present invention is the compound of formula (I) with the proviso that R3 is not [l,2,4]triazolo[l,5-a]pyridin-6-yl. Yet another preferred embodiment of the present invention is the compound of formula
(T) with the proviso that when R1, R2, R4, R5, and R8 are H and R6 and R7 are Cl, R3 is not
[l,2,4]triazolo[l,5-a]pyridin-6-yl.
[0067] In another more preferred embodiment of the present invention, the compound of formula (F) is a (+)-stereoisomer. [0068] In another more preferred embodiment of the present invention, the compound of formula (I) is a (-)-stereoisomer.
[0069] Another more preferred embodiment of the present invention is the compound of formula (F) wherein the carbon atom designated * is in the R configuration.
[0070] Another more preferred embodiment of the present invention is the compound of formula (I) wherein the carbon atom designated * is in the S configuration.
[0071] In another preferred embodiment of the present invention, the compound of formula (I) is a (S)(+)-stereoisomer.
[0072] In yet another preferred embodiment of the present invention, the compound of formula (F) is a (R)(-)-stereoisomer. [0073] Another preferred embodiment of the present invention is a mixture of stereoisomeric compounds of formula (I) wherein * is in the S or R configuration.
[0074] Within these embodiments, the selection of a particular preferred substituent at any one of RJ-R8 does not affect the selection of a substituent at any of the others of R^R8. That is, preferred compounds provided herein have any of the preferred substituents at any of the positions. For example, as described hereinabove, R1 is preferably H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, Ci-C6 haloalkyl, or gem-dialkyl of which each alkyl is Ci-C4; the selection of R1 as any one of H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, Ci-C6 haloalkyl, or gem-dialkyl of which each alkyl is Ci-C4, does not limit the choice of R2 in particular to any one of H, halogen, OR n, S(O) nR12, CN, C(O)R 12, C(O)NR 1V2, Q-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, or C4-C7 cycloalkylalkyl. Rather, for R1 as any of H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, Ci-C6 haloalkyl, or gem-dialkyl of which each alkyl is Ci-C4, R2 is any of H, halogen, OR n, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl.
[0075] More preferred compounds of the present invention are described with the following substituents in Table 1, wherein the carbon atom designed * is in the R or S configuration.
TABLE 1
R1 R2 R3 R4 R5 R6 R7 R8 [Example
H H 6-methylpyridazin-3-yl H H Me H H 1
H H 6-aminopyιϊdazin-3-yl H H F H H 2
H H 6-(methylamino)pyridazin-3-yl H H H H 3
H H 6-(trifluoromethyl)pyridazin-3-yl H H Cl H H 4
H H 6-aminopyridazin-3-yl H H Cl H H 5
Me H 6-choropyridazin-3-yl H H Cl H H 6
Me H pyridazin-3-yl H H Cl H H 7
Me H 6-methoxypyridazin-3-yl H H Cl H H 8 gem-dimethyl H pyridazin-3-yl H Cl Cl H H 9 gem-dimethyl H 6-(trifluoromethyl)pyridazin-3-yl H Cl Cl H H 10
H H 6-(trifluoromethyl)pyridazin-3-yl H Cl Cl H H 11
H H 6-(difluoromethoxy)pyridazin-3-yl H Cl Cl H H 12 gem-dimethyl H 6-aminopyιϊdazin-3-yl H Cl Cl H H 13
H H 2-cyanophenyl H Cl Cl H H 14
H H 3-cyanophenyl H Cl Cl H H 15
H H 4-(methylsulfonyl)phenyl H Cl Cl H H 16
H H 2-oxopyridin-1 (2H)-yl H LL LL Cl Cl H H 17
H H 6-oxopyridazin-1 (6H)-yl H Cl Cl H H 18
H H pyridin-2-yl F Cl Cl H H 19
H H 6-methylpyridazin-3-yl F Cl Cl H H 20
H H 6-methoxypyridazin-3-yl F Cl C LLl H H 21
H H 6-0X0-1 ,6-dihydropyridazin-3-yl Cl Cl H H 22
H H 3-(methylsulfbnyl)phenyl F Cl Cl H H 23
H H 4-carbamoylphenyl H Cl Cl H H 24
H H 3,5-dimethylisoxazol-4-yl H Cl Cl H H 25
H H 4-carbamoylphenyl Cl Cl H H 26
H H 5-aminopyrazin-2-yl H Cl Cl H H 27
H H 6-aminopyrazin-2-yl H Cl Cl H H 28
H H 6-(trifluoromethyl)pyridazin-3-yl F Cl Cl H H 29
H H 4-carbamoylphenyl F H Cl H H 30
H H 6-(difluoromethoxy)pyridazin-3-yl F Cl Cl H H 31
H H pyrazin-2-yl F Cl Cl H H 32
H H pyridazin-3-yl H Cl Cl H H 33
H H 6-aminopyridazin-3-yl H Cl Cl H H 34 gem-dimethyl H 6-(trifluoromethyl)pyridazin-3-yl H H Cl H H 35
H H [1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl H Cl Cl H H 36
H H [1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl H Cl Cl H H 37
H H [1 ,2,4]triazolo(1 ,5-a]pyridiπ-6-yl H Cl Cl H H 38
H H [1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl F Cl Cl H H 39 gem-dimethyl H [1 ,2,4ltriazolof1 ,5-alpyridin-6-yl H Cl Cl H H 40
[0076] That is, specific preferred compounds provided herein include, but are not limited to: 4-(4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile;
7-(6-meihylpyridazin-3-yl)-4-p-tolyl-l,2,3,4-tetrahydroisoquinoline;
6-(4-(4-fluorophenyl)- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;
6-(4-(4-fluorophenyl)-l,23,4-tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine; 4-(4-chlorophenyl)-7-(6-(trifluoromeihyl)pyridazin-3-yl)- 1 ,2,3,4-tetrahydroisoquinoline;
6-(4-(4-chlorophenyl)-l,23,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;
4-(4-cUorophenyl)-7-(6-(Moropyridazin-3-yl)-l-methyl-l,23,4-tetrahydroisoquinoline;
4-(4-cUorophenyl)-l-meihyl-7-(pyridazin-3-yl)-l,23,4-tetrahydroisoquinoline;
4-(4-chlorophenyl)-7-(6-meihoxypyridazin-3-yl)-l-meihyl-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dichlσrophenyl)- 1 , 1 -dimethyl-7-(pyridazin-3-yl)- 1,2,3,4-tetrahydroisoquinoline;
4-(3,4-dicUorophenyl)-14-dimethyl-7-(6-(Mfluoromeihyl)pyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)- 1 ,2,3,4- tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-7-(6-(difluoromeihoxy)pyridazin-3-yl)-l,2,3,4- tetrahydroisoqυinoline; ό^-CS^-dichlorophenyO-lJ-dimethyl-l^.S^-tBtiahydroisoquinolin^-yl^yridazin-S- anαine; 2-(4-(3,4-di(Morophenyl)-l,2,3,4-tetraliydroisoquinolin-7-yl)benzonitrile;
3-(4-(3,4-di(Morophenyl)-l,2,3,4-tetraliydroisoquinolin-7-yl)benzonitrile;
4-(3,4-dicUorophenyl)-7-(4-(methylsulfonyl)phenyl)-l,2,3,4-tetrahydroisoquinoline; l-(4-(3,4-di(Morophenyl)-l,2,3,4-tetraliydroisoquinolin-7-yl)pyridin-2(lH)-one;
2-(4-(3,4-di(Morophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one; 4-(3,4-dichlorophenyl)-6-fluoro-7-(pyridin-2-yl)- 1 ,2,3,4-tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methylpyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methoxypyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline; 6-(4-(3,4-di(Morophenyl)-6-fluoro-l,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)- one;
4-(3,4-dichlorophenyl)-6-fluoro-7-(3-(methylsulfonyl)phenyl)-l,2,3,4- tetrahydroisoquinoline; 4-(4-(3,4-di(Morophenyl)-l,23,4-tetrahydroisoquinolin-7-yl)-3,5-diinethylisoxazole;
4-(4-(3,4-dichlorophenyl)-6-fluoro-l,23,4-tBtτahydroisoquinolin-7-yl)benzamide;
5-(4-(3,4-dichlorophenyl)-l,23,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine; ό^-ζS^-dicMoropheny^-l^^^-tetrahydroisoquinolin^-yl^yrazin^-amine; 4-(3,4-dicUorophenyl)-6-fluoro-7-(6-(trifluoromeihyl)pyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline;
4-(4-(4-(Morophenyl)-6-fluoro-l,23,4-tetτahydroisoquinolin-7-yl)benzamide;
4-(3,4-dichlorophenyl)-7-(6-(difluoromeihoxy)pyridazin-3-yl)-6-fluoro- 1 ,2,3,4- tetrahydroisoquinoline; 4-(3,4-dichlorophenyl)-6-fluoro-7-(pyrazin-2-yl)- 1 ,2,3,4-tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-7-(pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline;
6-(4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;
4-(4-cωorophenyl)-14-dimethyl-7-(6-(tτMuoromeihyl)pyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline; 7-([l,2,4]triazolo[l,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinoline;
7-( [l,2,4]triazolo[l,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-l,2,3,4- tetrahydroisoquinoline;
7-([l,2,4]Mazolo[l,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-l,l-dimethyl- 1 ,2,3,4-tetrahydroisoquinoline;
7-([l,2,4]Mazolo[l,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,l-dimethyl-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-7-(5-methyl-[l,2,4]triazolo[l,5-α]pyridin-6-yl)-l,2,3,4- tetrahydroisoquinoline; 4-(3,4-dichlorophenyl)-7-(7-methyl-[l,2,4]triazolo[l,5-α]pyridin-6-yl)-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-7-(8-methyl-[l,2,4]triazolo[l,5-α]pyridin-6-yl)-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-7-(2-methyl-[l,2,4]triazolo[l,5-α]pyridin-6-yl)-l,2,3,4- tetrahydroisoquinoline;
6-(4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)-[l,2,4]triazolo[l,5- a]pyridin-2(3H)-one; or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
[0077] Single enantiomers, any mixture of enantiomers, including racemic mixtures, or diastereomers (both separated and as any mixtures) of the compounds of the present invention are also included within the scope of the invention.
[0078] The scope of the present invention also encompasses active metabolites of the present compounds.
[0079] The present invention also includes compounds of formula (T), wherein one or more of the atoms, e.g., C or H, are replaced by the corresponding radioactive isotopes of that atom (e.g., C replaced by 14C and H replaced by 3H), or a stable isotope of that atom (e.g., C replaced by 13C or H replaced by 2H). Such compounds have a variety of potential uses, e.g., as standards and reagents in determining the ability of a potential pharmaceutical to bind to neurotransmitter proteins. In addition, in the case of stable isotopes, such compounds may have the potential to favorably modify the biological properties, e.g., pharmacological and/or pharmacokinetic properties, of compounds of formula (T). The details concerning selection of suitable sites for incorporating radioactive isotopes into the compounds are known to those skilled in the art. [0080] Another aspect of the present invention is a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (T) and a pharmaceutically acceptable carrier.
[0081] Another aspect of the present invention relates to a method of treating a disorder which is created by or is dependent upon decreased availability of serotonin, norepinephrine, or dopamine. The method involves administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (T), or a pharmaceutically acceptable salt thereof. The method of the present invention is capable of treating subjects afflicted with various neurological and psychiatric disorders including, without limitation: attention deficit hyperactivity disorder (ADHD), cognition impairment, anxiety disorders, generalized anxiety disorder (GAD), panic disorder, bipolar disorder or manic depression or manic-depressive disorder, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), acute stress disorder, social phobia, simple phobias, pre-menstrual dysphoric disorder (PMDD), social anxiety disorder (SAD), major depressive disorder (MDD), postnatal depression, dysthymia, depression associated with Alzheimers disease, Parkinsons disease, or psychosis, supranuclear palsy, eating disorders, obesity, anorexia nervosa, bulimia nervosa, binge eating disorder, diabetes, ischemic diseases, pain, substance abuse disorders, chemical dependencies, nicotine addiction, cocaine addiction, amphetamine addiction, alcohol addiction, Lesch-Nyhan syndrome, neurodegenerative diseases, Parkinsons disease, late luteal phase syndrome or narcolepsy, psychiatric symptoms, anger, rejection sensitivity, movement disorders, extrapyramidal syndrome, Tic disorders, restless leg syndrome (RLS), tardive dyskinesia, supranuclear palsy, sleep related eating disorder (SRED), night eating syndrome (NES), stress urinary incontinence (SUI), migraine, neuropathic pain, diabetic neuropathy, lower back pain, fibromyalgia syndrome (FS), osteoarthritis pain, arthritis pain, chronic fatigue syndrome (CFS), sexual dysfunction, premature ejaculation, male impotence, thermoregulatory disorders (e.g., hot flashes associated with menopause), and irritable bowel syndrome (IBS).
[0082] The compounds provided herein are particularly useful in the treatment of these and other disorders due, at least in part, to their ability to selectively bind to the transporter proteins for certain neurochemicals with a greater affinity than to the transporter proteins for other neurochemicals.
[0083] In another embodiment of the present invention, the above method further involves administering a therapeutically effective amount of a serotonin IA receptor antagonist or a pharmaceutically acceptable salt thereof. Suitable serotonin IA receptor antagonists include WAY 100135 and spiperone. WAY 100135 (N-(t-butyl)-3-[a-(2- methoxyphenyl)piperazin-l-yl]-2 phenylpropanamide) is disclosed as having an affinity for the serotonin IA receptor in U.S. Patent No. 4,988,814 to Abou-Gharbia et al., which is hereby incorporated by reference in its entirety. Also, Cliffe et al., J Med Chem 36:1509-10 (1993), which is hereby incorporated by reference in its entirety, showed that the compound is a serotonin IA antagonist. Spiperone (8-[4-(4-fluorophenyl)-4- oxobutyl]-l-phenyl-l,3,8-triazaspiro[4,5]decan-4-one) is a well-known compound and is disclosed in U.S. Patent Nos. 3,155,669 and 3,155,670, which are hereby incorporated by reference in their entirety. The activity of spiperone as a serotonin IA antagonist is described in Middlemiss et al., Neurosc and Biobehav Rev. 16:75-82 (1992), which is hereby incorporated by reference in its entirety.
[0084] In another embodiment of the present invention, the above method further involves administering a therapeutically effective amount of a selective neurokinin- 1 receptor antagonist or pharmaceutically acceptable salt thereof. Neurokinin- 1 receptor antagonists that can be used in combination with the compound of formula (F), in the present invention are fully described, for example, in U.S. Patent Nos. 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,162,339, 5,232,929, 5,242,930, 5,496,833, and 5,637,699; PCT International Patent Publication Nos. WO 90/05525, 90/05729, 94/02461, 94/02595, 94/03429,94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767,94/15903, 94/19320, 94/19323, 94/20500, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151,92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304,96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942, 97/21702, and 97/49710; and in U.K. Patent Application Nos. 2266529, 2268 931, 2 269 170, 2269590, 2271 774, 2292 144, 2293168, 2293 169, and 2302689; European Patent Publication Nos. EP 0360390, 0517 589, 0520555, 0522808, 0528 495, 0532 456, 0533 280, 0536 817, 0545 478, 0558 156, 0577 394, 0585 913, 0590 152, 0599 538, 0610793, 0634402, 0686629, 0693 489, 0694535, 0699655, 0394989, 0428 434, 0429 366, 0430771, 0436 334, 0443 132, 0482539, 0498 069, 0499 313, 0512901, 0512902, 0514273, 0514274, 0514275, 0514276, 0515 681, 0699674, 0707 006, 0708 101, 0709 375, 0709 376, 0714 891, 0723 959, 0733 632 and 0776 893, which are hereby incorporated by reference in their entirety. The preparations of such compounds are fully described in the aforementioned patents and publications. [0085] In another embodiment of the present invention, the above method further involves administering a therapeutically effective amount of a norepinephrine precursor or a pharmaceutically acceptable salt thereof. Suitable norepinephrine precursors include L-tyrosine and L-phenylalanine. [0086] Another embodiment of the present invention is a method of inhibiting synaptic norepinephrine uptake in a patient in need thereof. The method involves administering a therapeutically effective inhibitory amount of a compound of formula (I). [0087] Another embodiment of the present invention is a method of inhibiting synaptic serotonin uptake in a patient in need thereof. The method involves administering a therapeutically effective inhibitory amount of a compound of formula (F). [0088] Another embodiment of the present invention is a method of inhibiting synaptic dopamine uptake in a patient in need thereof. The method involves administering a therapeutically effective inhibitory amount of a compound of formula (I). [0089] Another embodiment of the present invention is a therapeutic method described herein, where the (+)-stereoisomer of the compound of formula CD is employed. [0090] Another embodiment of the present invention is a therapeutic method described herein, where the (-)-stereoisomer of the compound of formula (I) is employed. [0091] Another embodiment of the present invention is a kit comprising a compound of formula (F), and at least one compound selected from the group consisting of: a serotonin IA receptor antagonist compound, a selective neurokinin- 1 receptor antagonist compound, and a norepinephrine precursor compound. [0092] Another embodiment of the present invention relates to a method of treating a disorder referred to in the above-mentioned embodiments in a patient in need thereof. The method involves inhibiting synaptic serotonin and norepinephrine uptake by administering a therapeutically effective inhibitory amount of the compound of formula (T), which functions as both a dual acting serotonin and norepinephrine uptake inhibitor. [0093] Another embodiment of the present invention relates to a method of treating a disorder referred to in the above-mentioned embodiments in a patient in need thereof. The method involves inhibiting synaptic serotonin and dopamine uptake by administering a therapeutically effective inhibitory amount of the compound of formula (T), which functions as both a dual acting serotonin and dopamine uptake inhibitor. [0094] Another embodiment of the present invention relates to a method of treating a disorder referred to in the above-mentioned embodiments in a patient in need thereof. The method involves inhibiting synaptic dopamine and norepinephrine uptake by administering a therapeutically effective inhibitory amount of the compound of formula CD, which functions as both a dual acting dopamine and norepinephrine uptake inhibitor. [0095] Another embodiment of the present invention relates to a method of treating a disorder referred to in the above-mentioned embodiments in a patient in need thereof. The method involves inhibiting synaptic norepinephrine, dopamine, and serotonin uptake by administering a therapeutically effective inhibitory amount of the compound of formula (F), which functions as a triple acting norepinephrine, dopamine, and serotonin uptake inhibitor.
[0096] Another embodiment of the present invention relates to a method for inhibiting serotonin uptake in mammals. The method involves administering to a mammal requiring increased neurotransmission of serotonin a pharmaceutically effective amount of the compound of formula (F).
[0097] Another embodiment of the present invention relates to a method for inhibiting dopamine uptake in mammals. The method involves administering to a mammal requiring increased neurotransmission of dopamine a pharmaceutically effective amount of the compound of formula (I). [0098] Another embodiment of the present invention relates to a method for inhibiting norepinephrine uptake in mammals. The method involves administering to a mammal requiring increased neurotransmission of norepinephrine a pharmaceutically effective amount of the compound of formula (I). [0099] Another embodiment of the present invention relates to a method of suppressing the desire of humans to smoke. The method involves administering to a human in need of such suppression an effective dose, to relieve the desire to smoke, of the compound of formula (F).
[0100] Another embodiment of the present invention relates to a method of suppressing the desire of humans to consume alcohol. The method involves administering to a human in need of such suppression an effective dose, to relieve the desire to consume alcohol, of the compound of formula (I). [0101] Another embodiment of the present invention relates to a process for preparation of a product compound of Formula (T). This process comprises treating a first intermediate compound of Formula (II):
Figure imgf000044_0001
Formula II with an acid under conditions effective to produce the product compound. [0102] Suitable acids include, but are not limited to, sulfuric acid, methansulfonic acid, phorphoric acid, and L-tartaric acid.
[0103] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
[0104] Compounds according to the invention, for example, starting materials, intermediates, or products, are prepared as described herein or by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature. [0105] Compounds useful according to the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example, those described by Larock, Comprehensive Organic Transformations, Wiley- VCH publishers, New York (1989), which is hereby incorporated by reference in its entirety. [0106] A compound of formula (J) including a group containing one or more nitrogen ring atoms, may be converted to the corresponding compound wherein one or more nitrogen ring atom of the group is oxidized to an N-oxide, preferably by reacting with a peracid, for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature. [0107] In the reactions described hereinafter, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio, or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice (e.g., Wuts et al., Protective Groups in Organic Chemistry (4th Edition), Wiley (2006), and McOmie, Protective Groups in Organic Chemistry, Plenum Press (1973), which are hereby incorporated by reference in their entirety).
[0107] The novel tetrahydroisoquinoline reuptake inhibitors of Formula (J) of this invention can be prepared by the general scheme outlined below (Scheme 1). The methyl-substituted N-benzyl amines of Formula (II) may be purchased from commercial sources, or alternatively, obtained from a simple reductive amination protocol under a wide variety of conditions familiar to one skilled in the art of organic synthesis (Larock, Comprehensive Organic Transformations, Wiley- VCH publishers, New York, (1989), which is hereby incorporated by reference in its entirety). In addition, one skilled in the art will be familiar with other methods of benzylamine synthesis described in Larock, Comprehensive Organic Transformations, Wiley- VCH publishers, New York, (1989).
Scheme 1
Figure imgf000045_0001
Vπi (R^H) [0108] Treatment of amines of Formula (H) with halides (bromides or chlorides) of Formula (ID) generates the alkylation products of Formula (IV). The alkylation reactions may be run under a wide variety of conditions familiar to one skilled in the art of organic synthesis. Typical solvents include acetonitrile, toluene, diethyl ether, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, methylene chloride, and lower alkyl alcohols including ethanol. The reactions may be successfully run at temperatures ranging from 00C up to the boiling point of the solvent employed. Reaction progress is conventionally monitored by standard chromatographic and spectroscopic methods. The alkylation reaction is optionally run with the addition of a non-nucleophilic organic base such as, but not limited to, pyridine, triethylamine, and diisopropyl ethylamine.
[0109] The aforementioned intermediate of formula (HI) may be purchased from commercial sources or prepared via treatment of an optionally substituted ketone of Formula (IX)
Figure imgf000046_0001
with common brominating agents such as, but not limited to, bromine, NBS, or tetrabutylammonium tribromide which readily affords the desired bromoacetophenones of Formula (HI). These reactions are optimally conducted in acetic acid or methylene chloride with methanol used as a co-solvent for the tribromide reagent with reaction temperatures at or below room temperature. Another embodiment of this methodology would include the use of chloroacetophenone compounds of Formula (HI).
[0110] The ketones of Formula (IX) are available from commercial sources or are conveniently obtained via several well known methods, including the treatment of the corresponding aromatic carboxylic acid intermediates with two stoichiometric equivalents of methyllithium (Jorgenson, Organic Reactions, 18:1 (1970), which is hereby incorporated by reference in its entirety.). Alternatively, one may treat the corresponding aromatic aldehydes with an alkyl-Grignard (for example, MeMgBr) or alkyl-lithium (for example, MeIi) nucleophile followed by oxidation to the correspondent ketones under a wide variety of conditions familiar to one skilled in the art of organic synthesis (see, e.g., Larock, Comprehensive Organic Transformations, Wiley- VCH publishers (1989), which is hereby incorporated by reference in its entirety).
[0111] Reductions of compounds of Formula (IV) to the secondary alcohols of
Formula (V) proceeds with many reducing agents including, for example, sodium borohydride, lithium borohydride, borane, dϋsobutylaluminum hydride, and lithium aluminum hydride. The reductions are carried out for a period of time between 1 hour to 3 days at room temperature or elevated temperature up to the reflux point of the solvent employed. If borane is used, it may be employed as a complex for example, but not limited to, borane-methyl sulfide complex, borane-piperidine complex, or borane- tetrahydrofuran complex. One skilled in the art will understand the optimal combination of reducing agents and reaction conditions needed or may seek guidance from the text of Larock, Comprehensive Organic Transformations, Wiley- VCH publishers (1989), which is hereby incorporated by reference in its entirety. [0112] Compounds of Formula (V) may be cyclized to the tetrahydroisoquinoline compounds of Formula (VI) of this invention by the treatment with a strong acid.
Suitable acids include, but are not limited to, concentrated sulfuric acid, polyphosphoric acid, methanesulfonic acid, trifluoroacetic acid, and Eaton's reagent (Fhosphorpentoxid/methanesulfonic acid). The reactions are run neat or in the optional presence of a co-solvent such as, for example, methylene chloride or 1,2-dichloroethane. The cyclizations may be conducted at temperatures ranging from 00C up to the reflux point of the solvent employed. One skilled in the art of heterocyclic chemistry will readily understand these conditions or may consult the teachings of Mondeshka, // Farmaco, 49:475-480 (1994) and Venkov, Synthesis, 253-255 (1990), which are hereby incorporated by reference in their entirety. Cyclizations may also be effected by treatment of compounds of Formula (V) with strong Lewis acids, such as aluminum trichloride typically in halogenated solvents such as methylene chloride. One skilled in the art will be familiar with the precedent taught by Kaiser, J Med Chem, 27:28-35 (1984) and Wyrick, J Med Chem, 24:1013-1015 (1981), which are hereby incorporated by reference in their entirety. [0113] Compounds of Formula (VL Y = OMe) may be converted to compounds of Formula (VL Y = OH) by a demethylation procedure such as, but not limited to heating to reflux in aqueous HBr with or without an organic solvent such as acetic acid, or treatment with BBr3 in methylene chloride at low temperature. One skilled in the art will understand the optimal combination of demethylation agents and reaction conditions needed or may seek guidance from the text of Wuts et al., Protective Groups in Organic Chemistry (4th Edition), published by Wiley (2006), which is hereby incorporated by reference in its entirety. [0114] Compounds of Formula (VI, Y = OH) may be converted to compounds of formula (VI; OSO2CF3) by reacting with a triflating reagent such as trifluoromethanesulfonic anhydride in the presence of a base such as pyridine in a halogenated solvent such as methylene chloride. Compounds of formula (VII) of this invention may be prepared by treatment of compounds of Formula (VI; Y=Br, OSO2CF3) with aryl or heteroaryl boronic acids or aryl or heteroaryl boronic acid esters with formula ZrR3 where Z is equivalent to B(OH)2 or B^R'^OR1') (where Ra and Rb are lower alkyl, Le., Ci-C6 alkyl, or taken together, Ra and Rb are lower alkylene, i.e., C2 -Ci2 alkylene) in the presence of a metal catalyst with or without a base in an inert solvent to give tetrahydroisoquinoline compounds of Formula (VII). Metal catalysts include, but are not limited to, salts or phosphine complexes of Cu, Pd, or Ni (e.g., Cu(OAc)2, PdCl2 (PPh3)2, and NiCl2 (PPh3)2). Bases may include, but are not limited to, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably diisopropylethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to acetonitrile, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylacetamides (preferably dimethylacetamide), N,N-dialkylformamides (preferably dimethylformamide), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes (preferably methylene chloride). Preferred reaction temperatures range from room temperature up to the boiling point of the solvent employed. The reactions may be run in conventional glassware or in one of many commercially available parallel synthesizer units. Non-commercially available boronic acids or boronic acid esters may be obtained from the corresponding optionally substituted aryl halide as described by Gao, Tetrahedron, 50:979-988 (1994), which is hereby incorporated by reference in its entirety. It will also be appreciated by one skilled in the art that compounds of Formula (VI, Y = Br, OSO2CF3) may be converted to the corresponding boronic acids or boronate esters and subsequently treated with the aryl or heteroaryl halides or triflate R3-X (X = Cl, Br, I, OSO2CF3) in discreet steps or in tandem as taught by Baudoin, / Org Chem, 67:1199-1207 (2002), which is hereby incorporated in its entirety.
[0115] Compounds of formula (I) can be obtained by an N-demethylation procedure taught by Koreeda and Luengo, /. Org. Chem. 49: 2081-2082 (1984), which is hereby incorporated in its entirety. Thus compounds of formula (VII) may be treated with 1-chloroethyl chloroformate in the presence of a proton scavenger such as, but not limited to N'^V'^^-tetramethylnφhthalene-l.S-diamine (known as proton sponge) in a halogenated solvent such as 1,2-dichloroethane or methylene chloride at temperatures ranging from 00C up to the boiling point of the solvent employed. The resulting carbamate intermediate may be heated in a low alkyl alcohol solvent such as methanol to give the target compounds of formula (J).
[0116] Alternatively, compounds of formula (VI, Y = OMe, OSO2CF3, Br,
B(ORa)(ORb)) may be Ν-demethylated via aforementioned methods to yield compounds of formula (VIE), which then may be converted to compounds of formula (J) via aforementioned methods. The protection of the nitrogen of the tetrahydroisoquinoline of formula (Vm) may be needed. Examples of typical protecting groups are Boc, F-Moc, and 2-nitrobenzenesulfonyl.
[0117] An alternative synthesis of compounds of formula (I) is to start with the compounds of formula (X), below.
Figure imgf000049_0001
X Compounds of formula (X) may be purchased from commercial sources, or made following the teaching in Larock, Comprehensive Organic Transformations, Wiley- VCH publishers, New York, (1989), which is familiar to one skilled in the art of organic synthesis and is hereby incorporated by reference in its entirety. Compounds of formula (X) may be converted to compounds of formula (I) via methods similar to the ones described earlier for the transformation of compounds of formula (II) to compounds of formula (VΗ). Compounds of Formula (IV) may be treated with a Ci-C4 alkyl lithium reagent or a Ci-C4 alkyl Grignard reagent The resulting tertiary alcohols may then be converted to compounds of Formula (VI), wherein R8 is the corresponding Ci-C4 alkyl, then to compounds of Formula (I), wherein R8 is the corresponding Ci-C4 alkyl, using the aforementioned methods.
[0118] Another method of preparing compounds in this invention is exemplified by the alternative synthesis of Example 2, as depicted in Scheme 2.
Scheme 2
Figure imgf000050_0001
Suzuki coupling of 3-formylphenylboronic acid and 6-bromo-[l,2,4]triazolo[l,5- a]pyridine gave 3-([l,2,4]triazolo[l,5-a]pyridin-6-yl)benzaldehyde. This aldehyde underwent a reductive amination to gave 2-(3-([l,2,4]triazolo[l,S-a]pyridin-6- yl)benzylamino)-l-(3,4-dichlorophenyl)ethanol, which was then subjected to sulfuric acid mediated cyclization to provide 7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline. [0119] A synthetic route of preparing L-tartrate salts of the present invention is depicted in Scheme 3. Scheme 3
800C
Figure imgf000051_0001
L-tartrate
Figure imgf000051_0002
[0120] Compounds of formula (J) may be obtained in enantiomerically enriched
(R) and (S) form by crystallization with chiral salts as well known to one skilled in the S art, or alternatively, may be isolated through chiral HPLC employing commercially available chiral columns.
[0121] It will be appreciated that compounds according to the present invention may contain asymmetric centers. These asymmetric centers may independently be in either the R or S configuration and such compounds are able to rotate a plane of polarized0 light in a polarimeter. If said plane of polarized light is caused by the compound to rotate in a counterclockwise direction, the compound is said to be the (-) stereoisomer of the compound. If said plane of polarized light is caused by the compound to rotate in a clockwise direction, the compound is said to be the (+) stereoisomer of the compound. It will be apparent to those skilled in the art that certain compounds useful according to theS invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (J) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates. [0122] Radiolabelled compounds of the invention are synthesized by a number of techniques well known to those of ordinary skill in the art, e.g., by using starting materials incorporating therein one or more radioisotopes. Compounds of the present invention where a stable radioisotope, such as carbon- 14, tritium, iodine-121, or another radioisotope, has been introduced synthetically are useful diagnostic agents for identifying areas of the brain or central nervous system that may be affected by disorders where norepinephrine, dopamine, or serotonin transporters and their uptake mechanism are implicated.
[0123] The present invention provides compositions containing the compounds described herein, including, in particular, pharmaceutical compositions comprising therapeutically effective amounts of the compounds and pharmaceutically acceptable carriers.
[0124] It is a further object of the present invention to provide kits having a plurality of active ingredients (with or without carrier) which, together, may be effectively utilized for carrying out the novel combination therapies of the invention. [0125] It is another object of the invention to provide a novel pharmaceutical composition which is effective, in and of itself, for utilization in a beneficial combination therapy because it includes a plurality of active ingredients which may be utilized in accordance with the invention.
[0126] The present invention also provides kits or single packages combining two or more active ingredients useful in treating the disease. A kit may provide (alone or in combination with a pharmaceutically acceptable diluent or carrier) the compounds of formula (I) and the additional active ingredient (alone or in combination with diluent or carrier) selected from a serotonin IA receptor antagonist, a selective neurokinin- 1 receptor antagonist, and a norepinephrine precursor. [0127] In practice, the compounds of the present invention may generally be administered parenterally, intravenously, subcutaneously, intramuscularly, colonically, nasally, intraperitoneally, rectally, or orally.
[0128] The products according to the present invention may be presented in forms permitting administration by the most suitable route and the invention also relates to phaπnaceutical compositions containing at least one product according to the invention which are suitable for use in human or veterinary medicine. These compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media, and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavorings, colorings, or stabilizers in order to obtain pharmaceutically acceptable preparations. [0129] The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the product, the particular mode of administration and the provisions to be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol, and chloroform or mixtures thereof may also be used.
[0130] For parenteral administration, emulsions, suspensions, or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil, or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride, and that they are sterilized by heating, irradiation, or microfiltration.
[0131] Suitable compositions containing the compounds of the present invention may be prepared by conventional means. For example, compounds of the present invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
[0132] Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula (T).
[0133] The percentage of active ingredient in the compositions of the present invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient In the adult, the doses are generally from about 0.01 to about 100 mg/kg body weight, preferably about 0.01 to about 10 mg/kg body weight per day by inhalation, from about 0.01 to about 100 mg/kg body weight, preferably 0.1 to 70 mg/kg body weight, more especially 0.1 to 10 mg/kg body weight per day by oral administration, and from about 0.01 to about 50 mg/kg body weight, preferably 0.01 to 10 mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health, and other characteristics which can influence the efficacy of the medicinal product
[0134] The products according to the present invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day. [0135] The present invention provides compounds which inhibit synaptic norepinephrine, dopamine, and serotonin uptake and are, therefore, believed to be useful in treating a disorder which is created by or is dependent upon decreased availability of serotonin, norepinephrine, or dopamine. Although the compounds of formula (I) inhibit synaptic norepinephrine, dopamine, and serotonin uptake, in any individual compound, these inhibitory effects may be manifested at the same or vastly different concentrations or doses. As a result, some compounds of formula (I) are useful in treating such a disorder at doses at which synaptic norepinephrine uptake may be substantially inhibited but at which synaptic serotonin uptake or dopamine uptake is not substantially inhibited, or vice versa. Also, some compounds of formula (T) are useful in treating such a disorder at doses at which synaptic dopamine uptake may be substantially inhibited but at which synaptic norepinephrine or serotonin uptake is not substantially inhibited, or vice versa. And, conversely, some compounds of formula (F) are useful in treating such a disorder at doses at which synaptic serotonin uptake may be substantially inhibited but at which synaptic norepinephrine or dopamine uptake is not substantially inhibited, or vice versa Other compounds of formula (I) are useful in treating such a disorder at doses at which synaptic norepinephrine, dopamine, and serotonin uptake are substantially inhibited. [0136] The present invention provides compounds where the inhibitory effects on serotonin and norepinephrine uptake occurs at similar or even the same concentrations of these compounds, while the effects on inhibition of dopamine uptake occurs at vastly different concentrations or doses. As a result, some compounds of formula (T) are useful in treating such a disorder at doses at which synaptic serotonin and norepinephrine uptake may be substantially inhibited but at which synaptic dopamine uptake is not substantially inhibited, or vice versa. [0137] The present invention provides compounds where the inhibitory effects on serotonin and dopamine uptake occurs at similar or even the same concentrations of these compounds while the effects on inhibition of norepinephrine uptake occurs at vastly different concentrations or doses. As a result, some compounds of formula (T) are useful in treating such a disorder at doses at which synaptic serotonin and dopamine uptake may be substantially inhibited but at which synaptic norepinephrine uptake is not substantially inhibited, or vice versa.
[0138] The present invention provides compounds where the inhibitory effects on norepinephrine and dopamine uptake occurs at similar or even the same concentrations of these compounds while the effects on inhibition of dopamine uptake occurs at vastly different concentrations or doses. As a result, some compounds of formula (I) are useful in treating such a disorder at doses at which synaptic norepinephrine and dopamine uptake may be substantially inhibited but at which synaptic serotonin uptake is not substantially inhibited, or vice versa. [0139] The present invention provides compounds where the inhibitory effects on norepinephrine, dopamine, and serotonin uptake occur at similar or even the same concentration. As a result, some compounds of formula (I) are useful in treating such a disorder at doses at which synaptic norepinephrine, dopamine, and serotonin uptake may all be substantially inhibited.
[0140] The concentrations or doses at which a test compound inhibits synaptic norepinephrine, dopamine, and serotonin uptake is readily determined by the use of standard assay and techniques well known and appreciated by one of ordinary skill in the art. For example, the degree of inhibition at a particular dose in rats can be determined by the method of Dudley, J Pharmacol Exp Ther, 217:834-840 (1981), which is hereby incorporated by reference in its entirety.
[0141] The therapeutically effective inhibitory dose is one that is effective in substantially inhibiting synaptic norepinephrine uptake, synaptic dopamine uptake, or synaptic serotonin uptake or inhibiting the synaptic uptake of two or more of norepinephrine, dopamine, and serotonin uptake. The therapeutically effective inhibitory dose can be readily determined by those skilled in the art by using conventional range finding techniques and analogous results obtained in the test systems described above. [0142] Compounds of this invention provide a particularly beneficial therapeutic index relative to other compounds available for the treatment of similar disorders. Without intending to be limited by theory, it is believed that this is due, at least in part, to some of the compounds having higher binding affinities for one or two of the neurotransmitter transporters, e.g., selectivity towards the norepinephrine transporter protein ("NET") over the transporters for other neurochemicals, e.g., the dopamine transporter protein ("DAT") and the serotonin transporter protein ("SERT"). [0143] Other compounds of the present invention may demonstrate selectivity towards the SERT over the transporters for other neurochemicals, e.g., the DAT and the NET.
[0144] Still other compounds of the present invention may demonstrate selectivity towards the DAT over the transporters for other neurochemicals, e.g., the SERT and the NET.
[0145] Yet other compounds of the present invention may demonstrate selectivity towards the NET over the transporters for other neurochemicals, e.g., the SERT and the DAT. [0146] Other compounds of the present invention may demonstrate selectivity towards the SERT and the NET over the transporter for other neurochemical, e.g., the DAT.
[0147] Still other compounds of the present invention may demonstrate selectivity towards the SERT and the DAT over the transporter for other neurochemical, e.g., the NET.
[0148] Still other compounds of the present invention may demonstrate selectivity towards the NET and the DAT over the transporter for other neurochemical, e.g., the SERT. [0149] Finally other compounds possess nearly identical affinity towards the
NET, the DAT, and the SERT.
[0150] Binding affinities are demonstrated by a number of means well known to ordinarily skilled artisans, including, without limitation, those described in the Examples section hereinbelow. Briefly, for example, protein-containing extracts from cells, e.g., HEK293E cells, expressing the transporter proteins are incubated with radiolabelled ligands for the proteins. The binding of the radioligands to the proteins is reversible in the presence of other protein ligands, e.g., the compounds of the present invention; said reversibility, as described below, provides a means of measuring the compounds binding affinities for the proteins (IC50 or Ki). A higher ICso/Ki value for a compound is indicative that the compound has less binding affinity for a protein than is so for a compound with a lower ICso/Ki; conversely, lower ICso/Ki values are indicative of greater binding affinities.
[0151] Accordingly, the difference in compound selectivity for proteins is indicated by a lower ICso/Ki for the protein for which the compound is more selective, and a higher ICso/Ki for the protein for which the compound is less selective. Thus, the higher the ratio in ICso/Ki values of a compound for protein A over protein B, the greater is the compounds selectivity for the latter over the former (the former having a higher ICso/Ki and the latter a lower ICso/Ki for that compound). Compounds provided herein possess a wide range of selectivity profiles for the norepinephrine, dopamine, and serotonin transporters as reflected by the ratios of the experimentally determined ICso/Ki values.
[0152] Selected compounds ( mono action transporter reuptake inhibitors) of the present invention have potent binding affinity for each of the biogenic amine transporters NET, DAT, or SERT. For example, selected compounds of the present invention possess potent (NET IC50/Ki < 200 nM) and selective binding affinity for NET. Other selected compounds of the present invention possess potent (SERT ICso/Ki < 200 nM) and selective binding affinity for SERT. Other selected compounds of the present invention possess potent (DAT IC50/Ki < 200 nM) and selective binding affinity for DAT.
[0153] Selected compounds ( dual action transporter reuptake inhibitors) of the present invention have potent binding affinity for two of the biogenic amine transporters, NET, DAT or SERT. For example, selected compounds of the present invention possess potent (NET & SERT IC50/Ki values < 200 nM) and selective binding affinity for NET and SERT. Other selected compounds of the present invention possess potent (NET & DAT IC50/Ki values < 200 nM) and selective binding affinity for NET and DAT. Other selected compounds of this invention possess potent (DAT & SERT ICso/Ki values < 200 nM) and selective binding affinity for DAT and SERT. [0154] Selected compounds ( triple action transporter reuptake inhibitors) of the present invention have potent binding affinity simultaneously for all three of the biogenic amine transporters, NET, DAT, or SERT. For example, selected compounds of this invention possess potent (NET, DAT, & SERT ICS0/Ki values < 200 nM) binding affinity for NET, DAT, and SERT. [0155] The in vivo affinity of the compounds to the three transporter proteins, SERT, DAT, and NET are demonstrated by means well known to those of ordinary skill in the art, including, without limitation, those described in the Examples section below. [0156] Accordingly, the difference in compound selectivity in vivo for protein is indicated by a higher percent occupancy value (or percent inhibition of the [3H] ligand compound used in the Examples section) at the transporter protein for which the compound is more selective, and a lower percent occupancy (or percent inhibition of the 3 [H] ligand compound used in the Examples section) for the protein for which the compound is less selective. Compounds provided herein possess a wide range of selectivity profiles for the norepinephrine, dopamine, and serotonin transporters as reflected by experimentally determined percent occupancy values. [0157] Selected compounds of the present invention, when administrated at a pharmaceutically feasible dose via means such as, but not limited to, oral, intravenous, subcutaneous, intraperitoneal and intramuscular, have statistically significant percent occupancy value(s) at one, two or all of the biogenic amine transporters NET, DAT, or SERT.
[0158] Selected compounds of the present invention, when administrated at a pharmaceutically feasible dose via means such as, but not limited to, oral, intravenous, subcutaneous, intraperitoneal and intramuscular, have 10%- 100% occupancy value(s) at one, two or all of the biogenic amine transporters NET, DAT, or SERT. In a preferred embodiment, compounds of the present invention have 40%-100% occupancy value(s) at one, two, or all of the biogenic amine transporters NET, DAT, or SERT.
EXAMPLES
Example 1 - Preparation of 7-(6-methylpridazin-3-yl)-4-p-tolyl-l,2,3,4- tetrahydroquinoline, L-tartrate Salt
[0159] Step A: To a solution of (3-bromo-benzyl)-methyl-amine (3.0 g, 15.0 mmol) in methylene chloride (60 mL) was added diisopropylethylamine (5.2 mL, 30.0 mmol). The reaction mixture was cooled to 00C and treated with 2-bromo-l-p-tolyl- ethanone (3.19 g, 15.0 mmol) portionwise over a period of 10 minutes. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with water (3x), dried over sodium sulfate, filtered, and the solvent was evaporated to afford 2-((3-bromobenzyl)(methyl)amino)-l-p-tolylethanone (4.89 g, 98%) as a viscous, orange oil: 1H NMR (CDCl3, 500 MHz) δ 7.85 (d, J = 8.2 Hz, 2H), 7.51 (br s, IH), 7.38 (d, / = 7.9 Hz, IH), 7.287.23 (m, 3H), 7.17 (t, / = 7.8 Hz, IH), 3.78 (s, 2H), 3.63 (s, 2H), 2.41 (s, 3H), 2.35 (s, 3H). [0160] Step B: Sodium borohydride (646 mg, 17.1 mmol) was added over a period of 10 minutes to an ice-cooled solution of the product from Step A (4.89 g, 15.0 mmol) in methanol (85 mL). The reaction mixture was allowed to warm to room temperature and continued to stir for an additional 2 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted with methylene chloride (3x). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-((3-bromobenzyl)(methyl)amino)-l-p-tolylethanol (4.58 g, 93%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 7.45 (s, IH), 7.40 (d, / = 5.8 Hz, IH), 7.257.13 (m, 6H), 4.72 (dd, J = 10.0, 3.7 Hz, IH), 3.86 (br s, IH), 3.68 (d, J = 13.4 Hz, IH), 3.49 (d, J = 13.2 Hz, IH), 2.622.47 (m, 2H), 2.33 (s, 3H), 2.30 (s, 3H). [0161] Step C: Methane sulfonic acid (30 mL, 480 mmol) was added dropwise via addition funnel to a mixture of the product from Step B (4.58 g, 8.57 mmol) in 1,2- dichloroethane (80 mL) at 400C. After the addition was completed, the reaction mixture was heated at 400C for an additional hour. The cooled reaction mixture was poured over ice and made basic to pH 9 with concentrated ammonium hydroxide. The reaction mixture was extracted with ethyl acetate (4x). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (120 g silica; 90:10 hexane/ethyl acetate) provided 7-bromo-2-methyl-4- p-tolyl-l,2,3,4-tetrahydroisoquinoline (1.05 g, 40%). This product was resolved by cbrial HPLC (Chiralpak AD, 95:5 heptane/isopropanol with 0.1 % diethylamine). The
(+)enantiomer (430 mg, 41%) was obtained as a clear oil: [α]2^ +11.9° (0.2, methanol); 1H NMR (500 MHz, CDCl3) δ 7.22 (s, IH), 7.16 (d, J = 8.3 Hz, IH), 7.09 (d, / = 7.9 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 6.74 (d, J = 8.5 Hz, IH), 4.033.98 (m, IH), 3.70 (d, J = 15.0 Hz, IH), 3.56 (d, /= 15.0 Hz, IH), 3.012.98 (m, IH), 2.532.49 (m, IH), 2.40 (s, 3H), 2.32 (s, 3H).
[0162] Step D: A mixture of the product ((+)-enantiomer) from Step C (430 mg,
1.36 mmol), bis(pinacole)diborane (380 mg, 1.50 mmol), and KOAc (400 mg, 4.08 mmol) was degassed with argon. To this mixture was added PdCl2(dppf) (67 mg, 0.082 mmol). The resulting mixture was degassed with argon and then heated to reflux for 6 hours. After completion by thin-layer chromatography analysis the cooled material was diluted with water and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3x). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-methyl-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-4-p-tolyl-l,2,3,4-tetrahydroisoquinoline as a brown oiL which was used in Step E without further purification: 1H NMR (500 MHz, CDCl3) δ 7.54 (s, IH), 7.51 (d, J = 7.7 Hz, IH), 7.10 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.88 (d, J= 7.7 Hz, IH), 4.38 (br s, IH), 3.943.91 (m, IH), 3.753.72 (m, IH), 3.16 3.14 (m, IH), 2.61 (s, 3H), 2.52 (s, IH), 2.32 (s, 3H), 1.33 (s, 6H), 1.25 (s, 6H). [0163] Step E: A mixture of the crude product from Step D (490 mg, 1.35 mmol), 3-chloro-6-methyl-pyridazine (217 mg, 1.69 mmol), and cesium carbonate (1.32 g, 4.05 mmol) in DMF (15 mL) and water (3 mL) was degassed with argon. To this mixture was added PdCl2(dppf) (66 mg, 0.08 mmol). The resulting mixture was degassed with argon and then heated to reflux for 5 hours. After completion by thin-layer chromatography analysis the cooled material was filtered through a bed of diatomaceous earth and washed with water (3x). The organic layers were separated, dried over sodium sulfate, filtered, and concentrated in vacuo. After purification by semi-preparative HPLC (95:5 acetonitrile/water gradient over 40 minutes), the material was free-based with sodium bicarbonate to afford 2-methyl-7-(6-methylpyridazin-3-yl)-4-p-tolyl-l,2,3,4- tetrahydroisoquinoline (95 mg, 21%) as a light-yellow solid; 1H NMR (500 MHz, CDCl3) δ 7.86 (s, IH), 7.717.68, (m, 2H), 7.34 (d, J = 8.7 Hz, IH), 7.137.09 (m, 4H), 7.01 (d, J = 8.1 Hz, IH), 4.30 (t, J = 7.6 Hz, IH), 3.87 (d, J= 15.0 Hz, IH), 3.70 (d, J = 14.9 Hz, IH), 3.083.05 (m, IH), 2.74 (s, 3H), 2.59 (t, J = 9.4 Hz, IH), 2.46 (s, 3H), 2.33 (s, 3H).
[0164] Step F: To a solution of the product from Step E above (270 mg, 0.820 mmol) in 1,2-dichloroethane (20 mL) at 00C was added proton sponge (184 mg, 0.860 mmol) and 1-chloroethyl chloroformate (234 mg, 1.64 mmol) dropwise. The resultant mixture was heated at reflux for 20 hours, and the mixture was concentrated in vacuo. The crude product obtained was purified by flash column chromatography (100% methylene chloride to 100% methylene chloride:methanol:concentrated ammonium hydroxide 90:8:2) to give the desired intermediate which was taken up in methanol (5.0 mL), refluxed for 2 hours. The reaction mixture was partitioned with saturated sodium bicarbonate (50 mL) and methylene chloride (2 x 50 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product obtained was purified by flash column chromatography (100% methylene chloride to 100% methylene chloride:methanol:concentrated ammonium hydroxide 80:18:2) to give 7-(6- Methylpridazin-3-yl)-4-p-tolyl-l,2,3,4-tetrahydroquinoline (60 mg, 23%) as an orange liquid. To a solution of the newly obtained tetrahydroisoquinoline (35 mg, 0.11 mmol) in methanol (2 mL) was added L-tartaric acid (16.8 mg, 0.11 mmol) followed by slow addition of water (10 mL). The resultant solution was lyophilized overnight to give 7-(6- methylpridazin-3-yl)-4-p-tolyl-l,2,3,4-tetrahydroquinoline, L-tartrate salt (98.1% AUC HPLC) as a light brown solid: 1H NMR (D2O, 300 MHz) δ 8.14 (d, / = 9.5 Hz, IH), 7.86 (d, J= 9.5 Hz, 2H), 7.88 (dd, J= 8.5, 1.5 Hz, IH), 7.28 (d, J= 9.5 Hz, 2H), 7.147.20 (m, 3H), 4.564.77 (m, 4H), 4.54 (s, 2H), 3.86 (dd, J = 6.5, 4.5 Hz, IH), 3.54 (dd, / = 8.5, 1.5 Hz, IH), 2.74 (s, 3H), 2.34 (s, 3H); ESI MS m/z 316 [M+H]+; [α]23 D +6.9° (c 0.09, methanol)]. Example 2 - Preparation of (+)-6-(4-(4-fluorophenyl)-l^,3,4-tetrahydroisoquinolin- 7-yl)-N-methylpyridazin-3-amine, L-tartrate Salt [0165] Step A: To a mixture of (+)-7-bromo-4-(4-fluorophenyl)-2-methyl-l,2,3,4- tetrahydroisoquinoline (184 mg, 0.58 mmol, prepared following similar methods described in Step A to Step C of Example 1 starting from 2-bromo-l-(4- fluorophenyl)ethanone and l-(3-bromophenyl)-iV-methylmethanamine), and proton sponge (123 mg, 0.58 mmol) in 1,2-dichloroethane (3 mL) was added 1-chloroethyl chloroformate (0.50 mL, 4.60 mmol) at 00C under a nitrogen atmosphere. The reaction mixture was stirred at 00C for 1 hour and then allowed to warm to ambient temperature overnight The mixture was quenched with IN HCl in diethyl ether (10 mL), concentrated under reduced pressure to give the intermediate 2-chloroethylcarbamate. The intermediate was dissolved in methanol and heated at 700C for 3 hours before concentrating under reduced pressure to 4 mL volume. The solution was treated with di- tert-butyl-dicarbonate (252 mg, 1.16 mmol) and 2N NaOH (3 mL) with stirring overnight then partitioned between ethyl acetate (20 mL) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude material which was purified by flash column chromatography (90:5 to 80:20 hexanes/ethyl acetate) to give tert-butyl 7-bromo-4-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(lH)- carboxylate (112 mg, 48%) as a white semi-solid: 1H NMR (CDCl3, 300 MHz) δ 7.33 (s, IH), 7.25 (dd, J = 8.4 Hz, 1.2 Hz, IH), 6.986.93 (m, 4H), 6.81 (d, J = 8.4 Hz, IH), 4.95 4.44 (m, 2H), 4.094.07 (m, IH), 3.903.82 (m, IH), 3.87 (br s, IH), 3.64 (br d, J= 8.7 Hz, IH), 1.44 (br s, 3H), 1.25 (br s, 6H); ESI MS m/z 306 [MC 5H9O2+H]+. [0166] Step B: To a solution of tert-butyl 7-bromo-4-(4-fluorophenyl)-3,4- dihydroisoquinoline-2(lH)-carboxylate (110 mg, 0.27 mmol) in DMSO (2 mL) was added bis(pinacolato)diboron (76 mg, 0.30 mmol), potassium acetate (80 mg, 0.81 mmol) and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(π) (11 mg, 0.01 mmol). The reaction flask was purged with nitrogen and heated at 85 0C for 4 hours. The reaction mixture was cooled to ambient temperature and di-te/f-butyl 6-chloropyridazin- 3-yliminodicarbonate (116 mg, 0.35 mmol), cesium carbonate (265 mg, 0.81 mmol), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(π) (11 mg, 0.01 mmol), and water (0.3 mL) was added. The reaction flask was purged with nitrogen and heated at 85 0C for 2 hours. The reaction mixture was cooled to ambient temperature then partitioned between ethyl acetate (SO mL) and water (30 mL). The organic layer was washed with water and brine then dried over sodium sulfate. Concentration in vacuo and purification by flash column chromatography (80:20 to 50:50 hexanes/ethyl acetate) afforded tert-butyl 7-(6-(bis(tert-butoxycarbonyl)amino)pvridazin-3-yl)-4-(4- fluorophenyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate which was deprotected directly by treating with trifluoroacetic acid (2 mL) in dichloromethane (2 mL) for 1 hour. The residue was concentrated in vacuo, partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine then dried over sodium sulfate. Concentration in vacuo gave the crude material which was purified by flash column chromatography (90:9: 1 dichloromethane/methanol/ammonium hydroxide) to give 6-(4-(4-fluorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3- amine (38 mg, 44%): ESI MS m/z 321 [M+H]+.
[0167] Step C: To a solution of (+)-6-(4-(4-fluorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine (38 mg, 0.12 mmol) in methanol (3.6 mL) was added L-tartaric acid (18 mg, 0.12 mmol). The mixture was sonicated for 2 minutes, diluted with water (20 mL), and lyophilized to give the correspondent tartrate salt (61 mg, 86%, AUC HPLC 97.9%) as a white solid. 1H NMR (CD3OD, 300 MHz) δ 7.85 (s, IH), 7.82 (d, J = 9.3 Hz, IH), 7.75 (dd, J = 8.3 Hz, 1.5 Hz, IH), 7.30 (dd, J= 8.7 Hz, 5.4 Hz, 2H), 7.13 (t, J= 8.7 Hz, 2H), 7.04 (d, J = 9.3 Hz, IH), 6.99 (d, J= 8.1 Hz, IH), 4.654.49 (m, 3H), 4.42 (s, 2H), 3.78 (dd, J = 12.8 Hz, 6.0 Hz, IH), 3.45 (dd, / = 12.5 Hz, 11.1 Hz, IH); ESI MS m/z 321 [M+H]+. Anal, calcd.
C19H17FN4I.5C 4H5O62.7H 2O: C, 50.54; H, 5.33; N, 9.43. Found C, 50.50; H, 4.96; N, 9.23.
Example 3 - Preparation of (+)-6-(4-(4-fluorophenyl)-l^,3,4-tetrahydroisoquinolin- 7-yl)-N-methylpyridazin-3-amine, L-tartarate Salt.
[0168] Step A: (+)-4-(4-Fluorophenyl)-2-methyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline was prepared following similar methods described in Step A to Step D of Example 1 starting from 2-bromo-l-(4- fluorophenyl)ethanone.
[0169] To a mixture of 4-(4-fluorophenyl)-2-methyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline ( 1.13 g, 3.08 mmol), and tert-batyl 6- chloropyridazin-3-yl(methyl)carbamate (751 mg, 3.08 mmol) in DMF (15 mL) and water (3 mL) was added cesium carbonate ( 4.01 g, 12.3 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(π) (SO mg, 0.06 mmol). The reaction flask was evacuated and back filled with nitrogen. After heating the reaction mixture at 85 0C for 4 hours, it was cooled to ambient temperature then partitioned between ethyl acetate (300 mL) and water (150 mL). The organic layer was washed with water and brine then dried over sodium sulfate. Concentration in vacuo gave the crude material which was purified by flash column chromatography to give tert-batyl 6-(4-(4- fluorophenyl)-2-methyl-l,2,3,4-tetrahydroisoquinoUn-7-yl)pyridazin-3- yl(methyl)carbamate (1.24 g, 90%) as an orange/brown foam: 1H NMR (CDCl3, 500 MHz) δ 8.12 (d, / = 9.5 Hz, IH), 7.88 (d, /= 1.5 Hz, IH), 7.757.70 (m, 2H), 7.19 (dd, / = 8.8 Hz, 5.0 Hz, 2H), 7.016.97 (m, 3H), 4.30 ((brs, IH), 3.82 (d, J = 14.5 Hz, IH), 3.71 (d, J= 14.5 Hz, IH), 3.61 (s, 3H), 3.083.05 (m, IH), 2.59 (dd, /= 11.5 Hz, 8.0 Hz, IH), 2.46 (s, 3H), 1.56 (s, 9H); ESI MS m/z 449 [M+H]+. [0170] Step B: To a mixture of the product from Step A (428 mg, 0.96 mmol) and proton sponge (102 mg, 0.50 mmol) in 1,2-dichloroethane (3 mL) was added 1- chloroethyl chloroformate (208 μL, 1.91 mmol) at 00C under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature over a weekend and concentrated in vacuo. The intermediate 2-chloroethylcarbamate was purified by flash column chromatography (dichloromethane) and refluxed in methanol for 3 hours. The resulting solution was concentrated under reduced pressure and treated with trifluoroacetic acid (5 mL) in dichloromethane (5 mL) for 1 hour. After concentration in vacuo, the residue was partitioned between dichloromethane (30 mL) and 2N aqueous sodium hydroxide (10 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the crude material which was purified by flash column chromatography (90: 10 to 50:50 ethyl acetate/ethyl acetate: methanol: ammonium hydroxide) to give 6-(4-(4-fluorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)- iV-methylpyridazin-3-amine (65 mg, 20%) as a colorless oil: [α]D = + 18.0 ° (0.05, methanol): 1H NMR (CDCl3, 300 MHz) δ 7.76 (d, J = 1.2 Hz, IH), 7.66 (dd, J = 8.1 Hz, 1.8 Hz, IH), 7.58 (d, /= 9.6 Hz, IH), 7.127.06 (m, 2H), 7.036.95 (m, 2H), 6.99 (t, / = 8.4 Hz, IH), 6.72 (d, /= 9.3 Hz, IH), 4.95 (d, / = 5.1 Hz, IH), 4.264.09 (m, 2H), 3.42 (dd, J = 12.9 Hz, 5.1 Hz, IH), 3.113.05 (m, 4H), 1.96 (br s, 2H); ESI MS m/z 335 [M+H]+. [0171] Step C: To a solution of 6-(4-(4-fluorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine (64 mg, 0.19 mmol) in methanol (2 mL) and water (2 mL) was added L-tartaric acid (29 mg, 0.19 mmol). The mixture was sonicated, diluted with water (12 mL) and lyophilized to give the correspondent L- tartarate salt ((+)-enantiomer) (97 mg, 87%, AUC HPLC 97.9%) as a white solid. 1H ΝMR (CD3OD, 300 MHz) δ 7.87 (s, IH), 7.76 (d, J = 9.6 Hz, 2H), 7.337.28 (m, IH), 7.30 (dd, J = 8.7 Hz, 5.4 Hz, IH), 7.13 (t, /= 8.7 Hz, 2H), 6.99 (d, /= 8.1 Hz, IH), 6.97 (d, J = 9.3 Hz, IH), 4.654.54 (m, 3H), 4.42 (s, 2H), 3.78 (dd, J = 12.6 Hz, 5.7 Hz, IH), 3.45 (t, J = 11.1 Hz, IH), 3.01 (s, 3H); ESI MS m/z 335 [M+H]+. Anal, calcd. C20H19FΝ4I.4C 4H6O62H 2O: C, 52.96; H, 5.45; N, 9.65. Found C, 53.13; H, 5.47; N, 9.70.
Example 4 - Preparation of (+)-4-(4-chlorophenyl)-7-(6-(trifluoromethyl)pyridaziii- 3-yl)-l^,4-tetrahydroquinoline, L-tartrate Salt
[0172] Step A: (+)-4-(4-αύorophenyl)-2-methyl-7-(6-(trifluoromethyl)pyridazin-
3-yl)-l,2,3,4-tetrahydroisoquinoline was prepared following similar methods described in Step A to Step E of Example 1 starting from 2-bromo-l-(4-chlorophenyl)ethanone and 1- (3-bromophenyl)-iV-methylmethanamine. [0173] To a solution of 4-(4-chlorophenyl)-2-methyl-7-(6-
(trMuoromethyl)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline (69 mg, 0.17 mmol) in 1,2-dichloroethane (5 mL) at 00C was added proton sponge (37 mg, 0.17 mmol) and 1- chloroethyl chloroformate (56 μL, 0.51 mmol) dropwise. The resultant mixture was stirred at 00C for one hour and then heated at reflux for 1.5 hours. After concentrating the mixture in vacuo, the crude intermediate was taken up in methanol (5.0 mL) and heated at reflux for 1 hour. After concentrating in vacuo, the crude product obtained was purified by preparative thin layer chromatography using 90:9: 1 ethyl acetate/methanol/concentrated ammonium hydroxide as eluent to give 4-(4- cmorophenyl)-7-(6-(trMuoromethyl)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline (22 mg, 33%) as a light yellow oil: [α]23 D +7.5° (c 0.08, methanol). To a solution of the newly obtained tetrahydroisoquinoline (20 mg, 0.051 mmol) in acetonitrile (1 mL) was added L-tartaric acid (8 mg, 0.051 mmol) followed by slow addition of water (4 mL). The resultant solution was lyophilized for two days to give the correspondent L-tartrate salt (>99% AUC HPLC) as an off-white solid: 1H NMR (CD3OD, 500 MHz) δ 8.39 (d, J = 9.0 Hz, IH), 8.17 (d, J = 9.0 Hz, IH), 8.17 (s, IH), 8.03 (dd, J= 8.0, 2.0 Hz, IH), 7.41 (d, J= 8.5 Hz, 2H), 7.28 (d, /= 8.5 Hz, 2H), 7.11 (d, /= 8.5 Hz, IH), 4.654.53 (m, 3H), 4.42 (s, 2H), 3.803.76 (m, IH), 3.473.43 (m, IH); ESI MS m/z 390 [M+H]+.
Example 5 - Preparation of (+)-6-(4-(4-chlorophenyl)-l^^,4-tetrahydroisoquinolin- 7-yl)pyridaziii-3-amine, L-tartrate Salt.
[0174] Step A: To an ice-cold solution of the (+)-7-bromo-4-(4-chlorophenyl)-2- methyl-l,2,3,4-tetrahydroisoquinoline (400 mg, 1.2 mmol) which was prepared following similar methods described in Step A to Step C of Example 1 starting from 2-bromo-l-(4- chlorophenyl)ethanone and l-(3-bromophenyl)-N-meihylmethanamine, and proton sponge (Λf1,N1,-V8,-\ΛtetrameΛymaphthalene-l,8-diamine, 77 mg, 0.4 mmol) in 1,2- dichloroethane (6 mL) was added 1-chloroethyl chloroformate (0.16 mL, 1.4 mmol) drop wise. The mixture was stirred for 15 minutes and then heated to reflux for 3 hours. Additional 1-chloroethyl chloroformate (0.16 mL, 1.4 mmol) and proton sponge (77 mg, 0.4 mmol) were added. The mixture heated to reflux for 2 days, then cooled to room temperature and concentrated. The residue was dissolved in methanol (10 mL) and heated to reflux for 1.5 hours. The mixture was cooled to room temperature, concentrated and the residue dissolved in dichloromethane (10 mL). Di-te/t-butyl dicarbonate (314 mg, 1.4 mmol) was added and the mixture stirred overnight. The mixture was partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (hexanes to 1:1 hexanes/ethyl acetate) gave tert-butyl 7-bromo-4-(4-chlorophenyl)-3,4- dihydroisoquinoline-2(lH)-carboxylate (360 mg, 71%) as a tan solid (mixture of rotamers): 1H ΝMR (CDCl3, 500 MHz) δ 7.34 (br s, IH), 7.30-7.22 (m, 3H), 7.05-6.93 (m, 2H), 6.82-6.78 (m, IH), 5.00-4.38 (m, 2H), 4.08 (br s, IH), 3.98-3.50 (m, 2H), 1.49- 1.16 (m, 9H); ESI MS m/z 322 [M + H Boc] +.
[0175] Step B : A mixture of the protected bromotetrahydroisoquinoline (360 mg,
0.85 mmol), bis(pinacolato)diboron (239 mg, 0.94 mmol) and potassium acetate (255 mg, 2.6 mmol) in DMSO (5 mL) was degassed with argon, and then dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) (29 mg, 0.04 mmol) was added. The mixture was degassed again and then heated to 500C for 2 hours. The mixture was partitioned with water and ethyl acetate (3x) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to a brown oil used directly in the next reaction without purification.
[0176] A solution of the boronate ester (400 mg, 0.85 mmol) from above, cesium carbonate (1.2 g, 3.4 mmol) and bis-Boc protected 6-cMoro-N,N-pyridazine-3-amine (421 mg, 1.3 mmol) in DMF (S mL) and water (1 mL) was degassed with argon, bis(diphenylphosphino)ferrocene]palladium(II) (29 mg, 0.04 mmol) was added, the mixture degassed again, and then stirred at room temperature overnight. The mixture was partitioned with water and ethyl acetate (3x). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (hexanes to 1 : 1 hexanes/ethyl acetate) to give the coupled tetrahydroisoquinoline (225 mg, 41%) product as an off-white solid. To a solution of this tetrahydroisoquinoline (240 mg, 0.38 mmol) in dichloromethane (S mL) was added trifluoroacetic acid (S mL) and then the mixture stirred at room temperature for 3 hours. The mixture was concentrated and the residue partitioned with saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by semi-preparative HPLC to give the de-protected tetrahydroisoquinoline (82 mg, 64%) as a yellow oil. [0177] A suspension of the above tetrahydroisoquinoline (44 mg, 0.13 mmol) and
L-tartaric acid (18 mg, 0.13 mmol) in MeOH was sonicated for S minutes and then concentrated. The residue was dissolved in acetonitrile and water, and then lyophilized overnight to give (+)-6-(4-(4-chlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin- 3-amine, L-tartrate salt (34 mg, 23%, AUC HPLC >99%) as a white solid: 1H ΝMR (DMSOd6, 500 MHz) δ 7.85 (d, J = 1.5 Hz, IH), 7.77 (d, J = 9.0 Hz, IH), 7.73 (dd, J = 8.5, 2.0 Hz, IH), 7.43-7.41 (m, 2H), 7.30-7.28 (m, 2H), 6.85-6.83 (m, 2H), 6.49 (s, 2H), 4.38-4.35 (m, 2H), 4.29-4.26 (m, IH), 4.07 (s, 1.4H), 3.53 (dd, / = 12.5, 5.5 Hz, IH), 3.22 (dd, / = 12.0, 9.5 Hz, IH); ESI MS m/z 337 [M + H]+.
Example 6 - Preparation of 4-(4-Chloro-phenyl)-7-(6-chloro-pyridazin-3-yl)-l- methyl -1,2,3,4-tetrahydro-isoquinoline.
[0178] Step A: To a mixture of 3-bromoacetophenone (8.21 g, 40 mmol) and ammonium acetate (30.8 g, 0.4 mol) in methanol (100 mL) was added sodium cyanoborohydride (1.76 g, 28 mmol). The reaction mixture was stirred at room temperature for 3 days and then concentrated HQ was added until pH < 2. The resulting ammonium chloride precipitate was filtered off and washed with water. The filtrate was concentrated under reduced pressure. To the residue was added water (100 rαL). The resulting precipitate was collected by filtration and washed with water, dried at 600C under vacuum to afford 3.1 g of white solid which contained a mixture of benzyl amine (desired product) and dibenzyl amine in 1:1.2 ratio. The filtrate was adjusted to pH >10 with solid KOH and extracted with dichloromethane (3 x 100 mL). The combined extracts were dried over sodium sulfate and concentrated to provide l-(3- bromophenyl)ethanamine (4.65 g, 58%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.51 (t, J= 1.7 Hz, IH), 7.387.34 (m, IH), 7.287.25 (m, IH), 7.19 (t, /= 7.7 Hz, IH), 4.09 (q, J = 6.6 Hz, IH), 1.37 (d, J= 6.6 Hz, 3H). ESI MS m/z = 200 [M + H]+.
[0179] Step B: To an ice-cooled mixture of the product from Step A (4.6 g, 23 mmol) and diisopropylethylamine (4.46 g, 34.5 mmol) in dichloromethane (50 mL) was added 2-bromo-4-chloroacetophenone (5.48 g, 23 mmol). The reaction mixture was stirred at room temperature for 3 hours and then diluted with dichloromethane (100 mL). The mixture was washed with water and brine, dried over sodium sulfate, and concentrated. Flash chromatography (silica gel, 20 to 40% ethyl acetate/hexanes) purification provided the 2-(l-(3-bromophenyl)ethylamino)-l-(4-chlorophenyl)ethanone (6.0 g, 74%): 1H NMR (CDCl3, 300 MHz) δ 7.80 (dd, J = 6.7, 2.0 Hz, 2H), 7.52 (U J = 1.7 Hz, IH), 7.437.37 (m, 3H), 7.297.17 (m, 2H), 3.93 (d, J= 1.4 Hz, 2H), 3.80 (q, J= 6.6 Hz, IH), 1.42 (d, J= 6.6 Hz, 3H). ESI MS m/z = 352 [M + H]+.
[0180] Step C: To an ice-cooled solution of the product from Step B (5.97 g, 16.9 mmol) in methanol (90 mL) was added sodium borohydride (703 mg, 18.6 mmol). The reaction mixture was stirred at 00C for 1 hour. The solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and water. The aqueous was extracted with dichloromethane (2x). The combined extracts were washed with brine, dried over sodium sulfate, and concentrated to provide the desired alcohol (5.98 g, 99% crude yield): ESI MS m/z = 354 [M + H]+. This crude product was used in the next step without further purification. [0181] Step D: To an ice-cooled solution of the crude product from Step C (5.98 g, 16.9 mmol) in dichloromethane (70 mL) was added concentrated sulfuric acid (4.2 mL) dropwise. The reaction mixture was stirred at 00C for 2 hours and the adjusted to pH > 8 by adding saturated sodium bicarbonate. The organic layer was separated and the aqueous was extracted with dichloromethane (2x). The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. Purification by column chromatography (silica gel, 0 to 4% methanol/dichloromethane) provided 7-bromo-4-(4- chlorophenyl)-l -methyl- 1,2,3,4-tetrahydroisoquinoline as a single diastereomer (1.19 g, 21%): 1H NMR (CDCl3, 500 MHz) δ 7.34 (d, J = 1.8Hz, IH), 7.287.24 (m, 2H),
7.19 (dd, J = 8.3, 2.0 Hz, IH), 7.036.98 (m, 2H), 6.69 (d, / = 8.3Hz, IH), 4.19 (q, / = 6.6 Hz, IH), 4.03 (dd, /= 8.1, 5.7 Hz, IH), 3.42 (dd, /= 12.9, 5.5 Hz, IH), 2.94 (dd, / = 12.9, 8.4 Hz, IH), 1.49 (d, J= 6.7 Hz, 3H). ESI MS m/z = 336 [M + H]+. [0182] Step E: Bis(pinacolato)diboron (531 mg, 2.09 mmol) was added to a mixture of the product from Step D (640 mg, 1.90 mmol) and potassium acetate (559 mg, 5.70 mmol) in dimethyl sulfoxide (10 mL). The reaction mixture was degassed with argon. PdCl2(dppf)(CH2Cl2) (78 mg, 0.095 mmol) was added and the reaction mixture was stirred at 800C for 1 hour, cooled, diluted with water, and extracted with ethyl acetate (2x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the desired boronate (880 mg, >99% crude yield). ESI MS m/z = 384 [M + H]+. This crude product was used in the next step without further purification.
[0183] Step F: 3,6-Dichloropyridazine (350 mg, 2.28 mmol) was added to a mixture of the crude product from Step E (880 mg, 1.90 mmol) and sodium carbonate (604 mg, 5.70 mmol) in dimethylformamide (10 mL) and water (2.5 mL). The reaction mixture was degassed with argon. PdCl2(dppf)(CH2Cl2) (93 mg, 0.114 mmol) was added and the reaction mixture was stirred at 800C for 2 hours, cooled, diluted with water, and extracted with ethyl acetate (2x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (silica gel, 0% to 5% MeOHZCH2Q2 gave 4-(4-chloro-phenyl)-7-(6- chloro-pyridazin-3-yl)-l -methyl -1,2,3,4-tetrahydro-isoquinoline (490 mg, 70% for 3 steps): 1H NMR (CDCl3, 500 MHz) δ 8.00 (d, J = 1.1 Hz, IH), 7.80 (d, J = 9.0 Hz, IH), 7.66 (dd, J = 8.1, 1.8 Hz, IH), 7.55 (d, /= 8.9 Hz, IH), 7.307.26 (m, 2H), 7.087.05 (m, 2H), 6.98 (d, / = 8.1 Hz, IH), 4.33 (q, J = 6.6 Hz, IH), 4.204.17 (m, IH), 3.49 (dd, J = 12.8, 5.5 Hz, IH), 3.02 (dd, J = 12.8, 8.4 Hz, IH), 1.58 (d, / = 6.7 Hz, 3H). ESI MS m/z = 370 [M + H]+. Example 7 - Preparation of 4-(4-Chloro-phenyl)-7-(pyridazin-3-yl)-l-methyl -1,2,3,4- tetrahydro-isoquinoline.
[0184] Step A: To a solution of the product from Step F of Example 6, (190 mg, 0.51 mmol) in ethanol (IS mL) was added hydrazine (1 mL, 20.6 mmol) and 10% Pd/C (100 mg). The reaction mixture was heated at reflux for 1 hour. The mixture was then filtered through celite and the celite bed was washed with methanol. The filtrate was concentrated and purified by column chromatography (silica gel, 1% to 5% MeOHZCH2Cl2) to provide 4-(4-Chloro-phenyl)-7-(pyridazin-3-yl)-l -methyl -1,2,3,4- tetrahydro-isoquinoline (99 mg, 57%): 1H NMR (CDCl3, 500 MHz) δ 9.15 (dd, / = 4.9, 1.6 Hz, IH), 8.05 (d, J= 1.3 Hz, IH), 7.83 (dd, J = 8.6, 1.6 Hz, IH), 7.69 (dd, J= 8.1, 1.8 Hz, IH), 7.53 (dd, J = 8.6, 4.9 Hz, IH), 7.297.26 (m, 2H), 7.087.05 (m, 2H), 6.98 (d, J = 8.1 Hz, IH), 4.35 4.33 (m, IH), 4.19 (dd, / = 7.9, 5.8 Hz, IH), 3.49 (dd, /= 12.8, 5.5 Hz, IH), 3.02 ( dd, J = 12.8, 8.3 Hz, IH), 1.59 (d, J = 6.7 Hz, 3H). ESI MS m/z = 336 [M + H]+.
Example 8 - Preparation of 4-(4-Chloro-phenyl)-7-(6-methoxy-pyridazin-3-yl)-l- methyl -1,2,3,4-tetrahydro-isoquinoline. [0185] Step A: To a solution of the product from Step B of Example 6 (240 mg,
0.648 mmol) in methanol (5 mL) was added sodium methoxide (25 wt % in methanol, 2 mL). The reaction mixture was heated at reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (50 mL). The solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (silica gel, 0% to 5% MeOHZCH2Cl2) gave the 4- (4-chloro-phenyl)-7-(6-methoxy-pyridazin-3-yl)- 1 -methyl - 1,2,3,4-tetrahydro- isoquinoline (171 mg, 72%): 1H NMR (CDCl3, 500 MHz) δ 7.99 (s, IH), 7.76 (d, J = 9.2 Hz, IH), 7.62 (dd, y= 8.1, 1.7 Hz, IH), 7.297.26 (m, 2H), 7.087.03 (m, 3H), 6.94 (d, J = 8.1 Hz, IH), 4.32 (q, J = 6.7 Hz, IH), 4.19 (s, 3H), 4.194.15 (m, IH), 3.49 (dd, J = 12.8, 5.5 Hz, IH), 3.02 (dd, J = 12.8, 8.4 Hz, IH), 1.58 (d, J = 6.7 Hz, 3H). ESI MS m/z = 366 [M + H]+. Example 9 - Preparation of (+)- and 0-4-(3,4-dichlorophenyl)-7-(pyrazin-3-yl)-l,l- dimethyl-l£,3,4-tetrahydro-isoquinoline.
[0186] Step A: Cerium(m) chloride heptahydrate (29.8 g, 80 mmol) was dried with magnetic stirring at 145 0C under vacuum overnight Tetrahydrofuran (160 mL) was added and the white suspension was stirred at room temperature for 2 hours and then cooled with dry-ice/acetone bath. To this dry-ice/acetone bath cooled solution was added methyl lithium (1.6 M in ether, SO mL, 80 mmol). The reaction mixture was stirred for 30 minutes and then a solution of 3-bromobenzonitrile (3.68 g, 20 mmol) in tetrahydrofuran (10 mL) was added. The resulting reaction mixture was stirred at 70 to 600C for 5 hours. Concentrated ammonium hydroxide (SO mL) was added at 400C. The mixture was allowed to warm to room temperature and filtered through Celite. The Celite bed was washed with dichloromethane. The filtrate was extracted with dichloromethane (3x). The combined extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 1 , 1 -dimethyl-3-bromobenzyl amine (4.33 g, >99% crude) as a clear oil, which was used in the next step without further purification: ESI MS m/z 214 [M+H]+.
[0187] Step B: To an ice-cooled solution of l,l-dimethyl-3-bromobenzyl amine
(3.82 g, 17.8 mmol) from Step A above in dichloromethane (100 mL) was added diisopropylethylamine (3.45 g, 26.7 mmol) and 2-bromo-3,4-dchloroacetophenone (2.44 g, 8.92 mmol). The reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with dichloromethane (SO mL), and washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (10 to 30% ethyl acetate/hexanes) to give 2-(2-(3-bromophenyl)propan-2-ylamino)-l-(3,4-dichlorophenyl)ethanone (1.37 g, 38% over 2 steps): 1H NMR (CDCl3, 500 MHz) δ 7.92 (d, / = 2.0 Hz, 2H), 7.67 (dd, J = 8.4, 2.0 Hz, IH), 7.58 (t, /= 1.8 Hz, IH), 7.51 (d, /= 8.4Hz, IH), 7.377.35 (m, 2H), 7.20 (t, J = 7.9 Hz, IH), 3.83 (s, 2H), 1.51 (s, 6H). [0188] Step C: To a solution of the ketone (1.37 g, 3.41 mmol) from Step B above in methanol (40 mL) at 00C was added sodium borohydride (133 mg, 3.5 mmol). The reaction mixture was stirred at 00C for 1 hour. The solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane. The resultant solution was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the desired alcohol (1.35 g, 98% crude). The crude product was used in the next step without further purification: ESI MS m/z 404 [M+H]+. [0189] Step D: To an ice-cooled solution of the alcohol (1.35 g, 3.35 mmol) from
Step C above in dichloromethane (80 mL) was added concentrated sulfuric acid (8 mL) dropwise. The reaction solution was stirred at room temperature for 16 hours, and then was added slowly to ice-cold saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2x). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (20 to 50% ethyl acetate/hexanes) to give 7-bromo-4-(3,4-dichlorophenyl)-l,l-dimethyl- 1,2,3,4-tetrahydroisoquinoline (113 mg, 9%): 1H NMR (CDCl3, 500 MHz) δ 7.42 (d, J = 2.0 Hz, IH), 7.36 (d, /= 8.2 Hz, IH), 7.21 (dd, / = 8.3, 2.0 Hz, IH), 7.14 (d, /= 2.0 Hz, IH), 6.88 (dd, J = 8.3, 2.0 Hz, IH), 6.72 (d, J = 8.3 Hz, IH), 3.95 (t, J= 5.2 Hz, IH), 3.38 (dd, / = 13.5, 5.0 Hz, IH), 3.03 (dd, / = 13.5, 5.6 Hz, IH), 1.52 (s, 3H), 1.47 (s, 3H); ESI MS m/z 386 [M+H]+.
[0190] Step E: To a mixture of the product (113 mg, 0.293 mmol) from Step D above, bis(pinacolato)diboron (82 mg, 0.323 mmol), and potassium acetate (87 g, 0.88 mmol) was added dimethyl sulfoxide (4 mL). The resultant solution was purged with argon for 10 minutes, and then dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (24 mg, 0.029 mmol) was added to it. The reaction solution was degassed again with argon for 5 minutes and heated at 800C for 1 hour. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the desired boronate ester (190 mg, crude) which was used in the next step without further purification: ESI MS m/z 432 [M+H]+. [0191] Step F: 3-Chloropyridazine (51 mg, 0.44 mmol) was added to a mixture of the boronate ester from Step E (0.293 mmol, crude) and cesium carbonate (287 mg, 0.88 mmol) in DMF (3 mL) and water (0.4 mL). The reaction mixture was degassed with argon. Dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (24 mg, 0.029 mmol) was added and the reaction mixture was stirred at 900C for 2 hours, cooled, diluted with water and extracted with ethyl acetate (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (2 to 5% methanol/ dichloromethane) followed by preparative HPLC gave 4-(3,4-dichlorophenyl)-l,l- dimeihyl-7-(pyridazin-3-yl)-l,2,3,4-tetraliydroisoquinoline (37 mg, 33% over 2 steps): 1H NMR (CDCl3, 500 MHz) δ 9.16 (dd, J= 4.9, 1.5 Hz, IH), 8.16 (d, J = 1.7 Hz, IH), 7.85 (dd, /= 8.6, 1.5 Hz, IH), 7.70 (dd, / = 8.0, 1.8 Hz, IH), 7.54 (dd, /= 8.6, 4.9 Hz, IH), 7.38 (d, /= 8.2 Hz, IH), 7.20 (d, /= 2.0 Hz, IH), 7.01 (d, /= 8.1 Hz, IH), 6.95 (dd, / = 8.2, 2.0 Hz, IH), 4.10 (t, / = 5.2 Hz, IH), 3.46 (dd, /= 13.4, 5.0 Hz, IH), 3.10 (dd, /= 13.4, 5.6 Hz, IH), 1.63 (s, 3H), 1.58 (s, 3H); ESI MS m/z 384 [M + H]+. [0192] Step G: The product from Step F (28 mg) was resolved by preparative chiral HPLC (ChiralCel OD column, using 85:15:0.1 heptane/ethanol/diethylamine as the eluent) to give the (+)-enantiomer ([α]25 D +33.0° (c 0.20, methanol)) and the 0- enantiomer ([α]25 D 38.0° ( c 0.20, methanol)).
Example 10 Preparation of (+)- and 0-4-(3,4-dichlorophenyl)-7-(6- (trifluoromethyl)pyridazin-3-yl)-l,l-dimethyl-l,2,3,4- tetrahydroisoquinoline.
[0193] Step A: To a solution of 2-bromo-l-(3,4-dichlorophenyl)ethanone (5.1 g,
18.96 mmol) in methanol (50 mL) at 00C was added sodium borohydride (2.1 g, 56.98 mmol). The reaction mixture was stirred at 00C for 1 hour. The pH was adjusted to 12 using 2 M sodium hydroxide solution, the solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane. The resultant solution was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 2-(3,4-dichlorophenyl)oxirane (1.79 g, 50 % crude). The crude product was used in the next step without further purification: 1H NMR (CDCl3, 500 MHz) δ 7.41 (d, / = 8.5 Hz, IH), 7.36 (d, / = 2.0 Hz, IH), 7.12 (dd, / = 8.5, 2.0 Hz, IH), 3.81 (dd, / = 4.0, 2.5 Hz, IH), 3.14 (dd, J = 5.5, 4.0 Hz, IH), 2.73 (dd, J= 5.5, 2.5 Hz, IH); ESI MS m/z 189 [M]+. [0194] Step B: A solution of l,l-dimethyl-3-bromobenzyl amine (1.18 g, 5.51 mmol) which was prepared in Step A of Example 9, and the epoxide from Step A (0.95g, 5.02 mmol) in ethanol (10 mL) was heated at 900C for 17 hours. The mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (0 to 100% ethyl acetate in hexanes) to afford 2-(2-(3- bromophenyl)propan-2-ylamino)-l-(3,4-dichlorophenyl)ethanol (1.46 g, 72%): 1H NMR (CDCl3, 500 MHz) δ 7.51 (d, J = 2.0 Hz, IH), 7.457.34 (m, 4H), 7.20 (t, J = 8.0 Hz, IH), 7.12 (dd, J = 2.0, 8.5 Hz, IH), 4.54 (dd, J= 3.5, 8.5 Hz, IH), 3.49 (s, IH), 2.65 (dd, J = 12.5, 3.5 Hz, IH); 2.35 (dd, J = 12.5, 8.5 Hz, IH), 1.58 (s, IH), 1.47 (s, 3H), 1.46 (s, 3H); ESI MS m/z 404 [M+H]+.
[0195] Step C: To an ice-cooled solution of the alcohol (920 mg, 2.49 mmol) from Step B above in dichloromethane (60 mL) was added concentrated sulfuric acid (6 mL) drop-wise. The reaction solution was stirred at 00C for 5 hours, and then was added slowly to ice-cold saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2x). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (10 to 40% ethyl acetate in hexanes) to give 7-bromo-4-(3,4-dichlorophenyl)-l,l-dimethyl-l,2,3,4- tetrahydroisoquinoline (431 mg, 33%): 1H NMR (CDCl3, 500 MHz) δ 7.40 (d, J = 2.0 Hz, IH), 7.36 (d, / = 8.0 Hz, IH), 7.22 (dd, / = 8.0, 2.0 Hz, IH), 7.14 (d, / = 2.0 Hz, IH), 6.88 (dd, J= 8.5, 2.0 Hz, IH), 6.71 (d, J= 8.5 Hz, IH), 3.96 (t, J = 5.5 Hz, IH), 3.38 (dd, /= 13.5, 5.0 Hz, IH), 3.03 (dd, /= 13.5, 5.5 Hz, IH), 1.51 (s, 3H), 1.47 (s, 4H); ESI MS m/z 386 [M+H]+.
[0196] Step D: To a solution of the product (535 mg, 1.39 mmol) from Step C in dimethyl sulfoxide (20 mL), was added bis(pinacolato)diboron (423 mg, 1.67 mmol) and potassium acetate (409 mg, 4.17 mmol). The resultant solution was purged with argon for 10 minutes, and then dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (114 mg, 0.14 mmol) was added. The reaction solution was further deoxygenated with argon for 5 minutes and heated at 800C for 2 hours. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to afford the boronate ester (557 mg, crude) which was used in the next step without further purification: ESI MS m/z 433 [M+H]+.
[0197] Step E: S-Trifluoromethyl-ό-chloropyridazine (470 mg, 2.57 mmol) was added to a mixture of the boronate ester from Step D (557 mg, 1.28 mmol), cesium carbonate (1.26 g, 3.87 mmol) in DMF (20 mL), and water (4 mL). The reaction mixture was deoxygenated with argon. Dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (105 mg, 0.128 mmol) was added and the reaction mixture was stirred at 900C for 1.5 hours, cooled, diluted with water, and extracted with ethyl acetate (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (0 to 50% 90:9:ldichloromethane/methanol /concentrated ammonium hydroxide solution in dichloromethane) gave the desired tifluoromethylpyridazinyl tetrahydro-isoquinoline product (338 mg, 58% over 2 steps): 1H NMR (CDCl3, 300 MHz) 1H NMR (CDCl3, 500 MHz) δ 8.23 (d, / = 2.0 Hz, IH), 8.01 (d, J = 9.0 Hz, IH), 7.87 (dd, / = 9.0, 2.5 Hz, IH), 7.73 (dd, J = 8.0, 1.5 Hz, IH), 7.39 (dd, / = 8.5, 2.5 Hz, IH), 7.23 (dd, / = 8.5, 2.5 Hz, IH), 7.04 (d, / = 8.0, 2.5 Hz, IH), 6. 94 (d, J = 8.5, 2.0 Hz, IH), 4.13 (t, /= 5.5 Hz, IH), 3.45 (dd, /= 13.5, 5.0 Hz, IH), 3.10 (dd, J= 13.5, 5.5 Hz, IH), 1.66 (s, IH), 1.57 (s, 3H), 1.55 (s, 3H); ESI MS m/z 453 [M + H]+. [0198] Step F: The trifluoromethylpyridazinyl tetrahydro-isoquinoline (153 mg) from Step E was resolved by preparative chiral HPLC (Chiralcel OJ column, using 80:20:0.1 heptane/ethanol/diethylamine as the eluent) to give the 0-enantiomer ([ OC]2SD 51.0° (c 0.10, methanol)) and the (+)-enantiomer ([α]25 D +33.2° (c 0.10, methanol)).
Example 11 - Preparation of 4-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridaziii- 3-yl)-l,2^,4-tetrahydroisoquinoline, L-Tartrate Salt
[0199] Step A: To a solution of 3-methoxybenzaldehyde (180 g, 1.32 mol) in methanol (1 L) was added a 40% aqueous solution of methylamine (113 ml, 1.31 mol) followed by 1 hour stirring at 00C. Sodium borohydride (75 g, 1.98 mol) was added portionwise at 00C and the reaction mixture was stirred for 1 hour. The solution was concentrated to a smaller volume then, was diluted with water (200 mL) and the resulting solution was extracted with methylene chloride (3 x 500 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude N-methylbenzylamine (220 g, quantitative) as clear oil, which was used in the next step without further purification: 1H ΝMR (CDCl3, 500 MHz) δ.7.23 (t, J = 8.0 Hz, IH), 6.926.88 (m, 2H), 6.816.78 (m, IH), 3.80 (s, 3H), 3.73 (s, 2H), 2.45 (s, 3H), 2.07 (broad s, IH). [0200] Step B: To a solution of the above amine (6.2 g, 41.00 mmol) from Step A in methylene chloride (100 mL) was added 3,4-dichlorophenacyl bromide (10.0 g, 37.3 mmol) and the resulting mixture was stirred at 00C for 1 hour prior to the addition of triethylamine (5.20 mL, 37.31 mmol), followed by 1 hour stirring at 00C. The reaction mixture was diluted with water (100 mL) then the aqueous phase was extracted with additional methylene chloride (3 x 75 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated to afford l-(3,4-dichlorophenyl)-2-((3- methoxybenzyl)(methyl)amino)ethanone (15.08 g) as a light yellow oil, which was used in the next step without further purification: 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 2.0 Hz, IH), 7.78 (dd, /= 8.5; 2.0 Hz, IH), 7.50 (d, /= 8.5 Hz, IH), 7.25 (d, /= 8.5 Hz, IH), 6.90 (d, / = 7.5 Hz, IH), 6.87 (d, J= 2.5 Hz, IH), 6.82 (dd, / = 8.0; 2.5 Hz, IH), 3.79 (s, 3H), 3.66 (s, 2H), 3.60 (s, 2H), 2.33 (s, 3H).
[0201] Step C: To a solution of the ketone (-37 mmol) from Step B in methanol
(150 mL), was added sodium borohydride (2.11 g, 55.79 mmol) portionwise at 00C. The reaction mixture was first stirred for 2 hours then, was diluted with water (100 mL) and extracted with methylene chloride (3 x 300 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure to afford the crude alcohol (14.14 g) as a yellow oil, which was used without further purification in the next step: 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 2.0 Hz, IH), 7.38 (d, J= 8.0 Hz, IH), 7.287.23 (m, IH), 7.16 (dd, /= 8.0; 2.0 Hz, IH), 6.906.81 (m, 3H), 4.704.65 (m, IH), 3.81 (s, 3H), 3.70 (d, J = 13.0 Hz, IH), 3.50 (d, J = 13.0 Hz, IH), 2.542.49 (m, 2H), 2.32 (s, 3H).
[0202] Step D: To a solution of the alcohol (-37 mmol) from Step C in methylene chloride (200 mL) was added concentrated sulfuric acid (12 mL, 235 mol) and the mixture was stirred at 00C for 28 hours. The reaction was quenched by adding a 6N NaOH solution till pH~9. The aqueous phase was extracted with additional methylene chloride (3x). The combined organic extracts were washed with brine (3x), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (1:1:1: to 1:1:2 dichloromethane/hexanes/ethyl acetate) to afford 4-(3,4- dichlorophenyl)-7-methoxy-2-methyl-l,2,3,4-tetrahydroisoquinoline (7.0 g, 59% over 3 steps) as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, IH), 7.29 (d, J= 2.0 Hz, IH), 7.03 (dd, J= 8.5; 2.0 Hz, IH), 6.76 (d, J= 8.5 Hz, IH), 6.66 (dd, J = 8.5; 3.0hz, IH), 6.61 (d, /= 2.5 Hz, IH), 4.164.11 (m, IH), 3.77 (s, 3H), 3.673.59 (m, 2H), 2.92 (dd, / = 11.5; 5.5 Hz, IH), 2.55 (dd, / = 11.5; 7.0 Hz, IH), 2.39 (s, 3H). The undesired 5-methoxy isomer was also isolated (1.20 g, 10% over 3 steps). [0203] Step E: The racemic 4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-l,2,3,4- tetrahydroisoquinoline (7.0 g) from Step D above was resolved by preparative chiral HPLC (CHIRALPAK AD column, using 80:20:0.1 heptane/2-propanol/diethylamine as the eluent) to give the (+)-enantiomer ([α]25 D +31.9° (c 0.49, methanol)) (3.68 g) as a colorless oil and the 0-enantiomer (3.99 g) as a colorless oil. [0204] Step F: A solution of (+)-4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-
1,2,3,4-tetrahydroisoquinoline (3.68 g, 11.42 mmol) in a mixture of acetic acid (20 mL) and 48% aqueous hydrobromic acid solution (SO mL) was refluxed for 8 hours. The ice- cold reaction mixture was basified with a concentrated aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium bicarbonate until reaching a pH of about 8-9 and was extracted with dichloromethane (3x). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude alcohol (2.6 g) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 8.5 Hz, IH), 7.26 (d, J = 2.0 Hz, IH), 7.01 (dd, J = 8.0; 2.0 Hz, IH), 6.65 (d, J = 8.0 Hz, IH), 6.54 (d, J = 8.5 Hz, IH), 6.49 (broad s, IH), 4.154.10 (m, IH), 3.60 (d, /= 15.0 Hz, IH), 3.56 (d, / = 15.0 Hz, IH), 2.96 (dd, / = 11.5; 5.7 Hz, IH), 2.52 (dd, /= 11.5, 8.0 Hz, IH), 2.39 (s, 3H). [0205] Step G: To a solution of the phenol from Step F above (2.1 g, 6.81 mmol) and pyridine (0.72 mL, 8.85 mmol) in dichloromethane (60 mL) was added trifluoromethanesulfonic anhydride (1.37 mL, 8.14 mmol) at 78 0C. The reaction was allowed to warm to 00C and stirred for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 x). The combined extracts were dried over sodium sulfate, filtered, and concentrated to give the crude triflate as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 8.5 Hz, IH), 7.30 (d, J = 2.0 Hz, IH), 7.036.98 (m, 3H), 6.94 (d, /= 8.5 Hz, IH), 4.194.15 (m, IH), 3.68 (s, 2H), 2.96 (dd, / = 11.7; 5.5 Hz, IH), 2.60 (dd, J= 11.7, 7.5 Hz, IH), 2.42 (s, 3H). [0206] Step H: A mixture of the triflate from Step G above (~6.8 mmol), bis(pinacolato)diboron (2.07 g, 8.15 mmol), and potassium acetate (2.05 g, 20.8 mmol) in dimethyl sulfoxide (35 mL) was degassed with argon. To this mixture was added dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) (0.40 g, 0.55 mmol). The resulting mixture was degassed with argon and then heated at 85 0C for 2 hours. The cold reaction mixture was diluted with ethyl acetate (150 mL). The resulting solution was washed with water (2 x 40 mL), brine (1 x 40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. A Purification flash chromatography column (eluent, 1 : 1 : 1 to 1:1:2 dichloromethane/hexanes/ethyl acetate) gave the desired boronate ester (2.6 g, 91% over 2 steps) as a yellow solid. IH NMR (500 MHz, CDC13) D 7.55 (s, IH), 7.52 (d, J = 7.5 Hz, IH), 7.33 (d, J = 8.5 Hz, IH), 7.28 (d, J = 2.0 Hz, IH), 7.01 (dd, J = 8.0, 2.0 Hz, IH), 6.85 (d, J = 8.0 Hz, IH), 4.23 (t, J = 6.5 Hz, IH), 3.71 (d, J = 15.0 Hz, IH), 3.67 (d, J = 15.0 Hz, IH), 2.98 (dd, J = 11.4, 5.3 Hz, IH), 2.56 (dd, J = 11.4, 7.5 Hz, IH), 2.41 (s, 3H), 1.33 (s, 12H).
[0207] Step I: To a solution of the boronate ester (2.6 g, 6.22 mmol) from Step F and proton sponge (2.6 g, 12.1 mmol) in dichloroethane (80 mL) at 00C was added 1- chloroethyl chloroformate (2.4 mL, 22.1 mmol). The mixture was stirred at 00C for 15 minutes, then was refluxed for 40 minutes and was concentrated in vacuo. The residue was filtered through a short pad of silica gel (eluent, 1:1:1 dichloromethane/hexanes/ethyl acetate) and the filtrate was concentrated in vacuo. The residue was diluted with methanol (160 mL), heated to reflux for 1 hour and concentrated in vacuo to give the 4- (3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4- tetrahydroisoquinoline as a brown foam. [0208] Step J: A solution of the product from Step I (-6.2 mmol), (Boc)2O (3.60 g, 16.4 mmol), triethylamine (1.5 mL, 10.7 mmol) and DMAP (0.26 g, 2.20 mmol) in dichloromethane (120 mL) was stirred at room temperature for 4 hours. The reaction was quenched by the addition of water (50 mL) then, the aqueous phase was extracted with additional dichloromethane (2 x 100 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. A purification by flash column chromatography (eluent, 47.5:47.5:5 to 1:1:1 dichloromethane/hexanes/ethyl acetate) gave the boc-protected tetrahydroisoquinoline (1.82 g, 58% over 3 steps) as a white foam. 1H NMR (500 MHz, CDCl3) δ 7.65 (s, IH), 7.58 (d, J= 7.5 Hz, IH), 7.32 (d, J = 8.0 Hz, IH), 7.13 (s, IH), 6.95 (d, J= 7.0 Hz, IH), 6.976.93 and 6.836.78 (m, IH), 5.014.95 and 4.484.43 (m, IH), 4.564.52 (m, IH), 3.95 (s, IH), 3.833.44 (m, 2H), 1.43 and 1.26 (2s, 9H), 1.33 (s, 12H).
[0209] Step K: A dry flask was loaded with the product from Step J above (0.3 g,
0.59 mmol), 3-chloro-6-(trifluoromethyl)pyridazine (0.17 g, 0.97 mmol), cesium carbonate (0.48 g, 1.47 mmol) and dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (43 mg, 0.058 mmol). The flask was blanketed with argon then, DMF (10 mL) and water (2 mL) were added followed by a short sonication. The reaction mixture was heated to 800C for 2 hours. The cold reaction mixture was diluted with water (40 mL) and the aqueous layer was extracted with dichloromethane (3x). The combined organic phases were concentrated in vacuo. Purification by flash column chromatography (eluent, 47.5:47.5:5 to 45:45:10 dichloromethane/hexanes/ethyl acetate) gave the Boc-protected 4-(3,4- dicMoropheny^^-ζό-ζtrifluoromethyl^yridazin-S-yO-l^.S^-tetrahydroisoquinoline (0.30 g, 97%) as a tan solid.
[0210] Step L: A solution of the Boc-protected 4-(3,4-dichlorophenyl)-7-(6-
(trifluoromethyl)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline (0.29 g, 0.55 mmol) and concentrated hydrochloric acid (1.5 mL) in ethanol was stirred at room temperature for 2.5 hours. The precipitate was isolated by filtration, washed with cold ethanol and hexanes, then dried in a vacuum oven to afford the starting material as an HCl salt The solid and the filtrate were combined, concentrated in vacuo, and dissolved in a mixture of TFA (~ 10 mL) and dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 1 hour and was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL) and treated with a saturated aqueous solution of sodium bicarbonate till pH~9. The aqueous phase was extracted with dichloromethane (2 x 40 mL). The extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. A purification by flash column chromatography (eluent: 98:1.8:0.2 to 96:3.6:0.4 to 90:9:1 dichloromethane/methanol/ammonium chloride) gave 4-(3,4-dichlorophenyl)-7-(6- (trMuoromethyl)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline (192 mg, 82%) as a white solid, [[Cl]25D +35.3° (c 0.15, methanol)].
[0211] Step M: To a solution of 4-(3,4-dichlorophenyl)-7-(6-
(trifluoromethyl)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline (176 mg, 0.41 mmol) from Step L in a mixture of methanol and water was added L-taitaric acid (62 mg, 0.41 mmol). The solution thus obtained was frozen and lyophilized overnight to afford the correspondent L-tartrate salt (196 mg, 81%, AUC HPLC >99%) as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.39 (d, J= 9.0 Hz, IH), 8.16 (d, J = 9.0 Hz, IH), 8.16 (s, IH), 8.05 (dd, J = 8.5; 2.0 Hz, IH), 7.55 (d, J = 8.5 Hz, IH), 7.50 (d, J = 2.0 Hz, IH), 7.24 (dd, J= 8.5; 2.0 Hz, IH), 7.11 (d, J= 8.5 Hz, IH), 4.664.61 (m, 2H), 4.55 (d, J= 16.0 Hz, IH), 4.41 (s, 2H), 3.80 (dd, J= 12.5; 6.0 Hz, IH), 3.493.42 (m, IH). ESI MS m/z 424 [M+H]+. Anal. Calcd. For C20H14Q2F3N3C 4H5O6H 2O: C, 48.66; H, 3.74; N, 7.09. Found: C, 48.67; H, 3.7; N, 6.89. Example 12 - Preparation of 4-(3,4-dichlorophenyl)-7-(6-
(difluoromethoxy)pyridazin-3-yl)-l^,3,4-tetrahydroisoquinoline, L- Tartrate Salt [0212] Step A: A dry flask was loaded with the boronate ester (0.3 g, 0.59 mmol) from Step J in Example 11, 3-chloro-6-(difluoromeihoxy)pyridazine (0.16 g, 0.97 mmol), cesium carbonate (0.48 g, 1.47 mmol), and dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(ll) (43 mg, 0.058 mmol). The flask was blanketed with argon then, DMF (10 mL) and water (2 roL) were added followed by a short sonication. The reaction mixture was heated to 800C for 2 hours. The cold reaction mixture was diluted with water (40 mL) and the aqueous layer was extracted with dichloromethane (3x). The combined organic phases were concentrated in vacuo. Purification by flash column chromatography (eluent, 47.5:47.5:5 to 45:45:10 dichloromethane/hexanes/ethyl acetate) gave the boc-protected 4-(3,4-dichlorophenyl)-7- (6-(difluoromethoxy)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline (286 mg, 93%) as a white foam.
[0213] Step B: A solution of the boc-protected 4-(3,4-dichlorophenyl)-7-(6-
(difluoromethoxy)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline (286 mg, 0.54 mmol) and concentrated hydrochloric acid (1.5 mL) in ethanol (6 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to dryness in vacuo. The syrup thus obtained was diluted with dichloromethane (20 mL) and treated with a saturated aqueous solution of sodium bicarbonate (~20 mL) until pH 8-9. The aqueous phase was extracted with additional dichloromethane (3 x 40 mL) and the organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. A purification by flash column chromatography (eluent, 98: 1.8:0.2 to 95:4.5:0.5 to 90:9: 10 dichloromethane/methanol/ammonium hydroxide) and preparative HPLC gave 4-(3,4- dicMorophenyl)-7-(6-(dMuoromethoxy)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoUn
(129 mg, 56%) as a light yellow solid, [[α]25 D +7.8° (c 0.11, methanol)].
[0214] Step C: To a solution of the product above (97 mg, 0.23 mmol) from Step B in a mixture of methanol and water was added L-tartaric acid (34 mg, 0.23 mmol). The solution thus obtained was frozen and lyophilized overnight to give 4-(3,4- dicMorophenyl)-7-(6-(dMuoromethoxy)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoun, L- tarlrate (115 mg, 87%, AUC HPLC >99%) as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.23 (d, J = 9.5 Hz, IH), 7.99 (s, IH), 7.907.88 (m, IH), 7.75 (U J = 72.0 Hz, IH), 7.55 (d, J = 8.5 Hz, IH), 7.487.44 (m, 2H), 7.22 (dd, J = 8.0; 2.0 Hz, IH), 7.07 (d, / = 8.5 Hz, IH), 4.614.54 (m, 2H), 4.49 (d. / = 16.0 Hz, IH), 4.41 (s, 2H), 3.76 (dd, J = 12.5; 6.0 Hz, IH), 3.463.40 (m, IH). ESI MS m/z 422 [M+H]+. Anal. Calcd. for C20Hi5Cl2F2N3CX: 4H6O6: C, 50.37; H, 3.70; N, 7.34. Found: C, 50.66; H 3.88; N, 7.36
Example 13 Preparation of 4-(3,4-dichlorophenyl)-7-(6-aminopyrida-dn-3-yl)-l,l- dimethyl-l^,4-tetrahydroisoquinoline.
[0215] Step A: 3-amino-6-chloropyridazine (420 mg, 3.23 mmol) was added to a mixture of 4-(3,4-dichlorophenyl)- 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,l- dimethyl-l,2,3,4-tetrahydroisoquinoline (700 mg, 1.68 mmol) which was prepared in Step D of Example 10, cesium carbonate (1.58 g, 4.85 mmol) in DMF (50 mL) and water (10 mL). The reaction mixture was deoxygenated with argon. Dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (66 mg, 0.081 mmol) was added and the reaction mixture was stirred at 900C for 1 hour, cooled, diluted with water, and extracted with dichloromethane (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (0 to 100% 90:9:ldichloromethane/methanol /concentrated ammonium hydroxide solution in dichloromethane) gave 4-(3,4-dichlorophenyl)-7-(6-aminopyridazin-3-yl)-l,l-dimethyl- 1,2,3,4-tetrahydroisoquinoline (387 mg, 60% over 2 steps): 1H NMR (CDCl3, 500 MHz) 1H NMR (CDCl3, 500 MHz) δ 8.01 (d, J = 2.0 Hz, IH), 7.647.54 (m, 2H), 7.37 (d, J = 8.0 Hz, IH), 7.19 (d, / = 8.0 Hz, IH), 6.986.90 (m, 2H), 6. 82 (d, / = 9.0 Hz, IH), 4.74 (s, 2H),4.07 (t, / = 5.5 Hz, IH), 3.45 (dd, /= 13.0, 5.5 Hz, IH), 3.10 (dd, / = 13.0, 5.5 Hz, IH), 1.64 (s, 3H), 1.60 (s, 3H); ESI MS m/z 399 [M+H]+.
Example 14 - Preparation of 2-(4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)benzonitrile, trifluoroacetate Salt. [0216] Step A: A mixture of 4-(3,4-dichlorophenyl)-2-methyl-l,2,3,4- tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (100 mg, 0.23 mmol) which was prepared in Step G of Example 11, 2-cyanophenylboronic acid (51 mg, 0.35 mmol) and cesium carbonate (225 mg, 0.69 mmol) in water (1 mL) and Λf,W-dimemylformamide (2 mL) was degassed with argon and then [1,1- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (8 mg, 0.01 mmol) was added. The mixture was degassed again and then heated to 900C for 3 hours. The mixture was partitioned between water and ethyl acetate (3x) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by preparative thin-layer chromatography (1 :4 hexanes/ethyl acetate) to give 2-(4-(3,4-dichlorophenyl)-2-methyl- l,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile (57 mg, 63%) as a brown solid: ESI MS m/z 393, 395 [M + H]+.
[0217] Step B: To an ice-cold solution of 2-(4-(3,4-dichlorophenyl)-2-methyl- l,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile (57 mg, 0.14 mmol) and N1Jf1J^Jf- tetramethylnaphthalene-l,8-diamine (30 mg, 0.14 mmol) in 1,2-dichloroethane (3mL) was added 1-chlorethyl chloroforamte (0.03 mL, 0.28 mmol) drop wise. The mixture was stirred for 15 minutes and then warmed to room temperature overnight. Additional ΛfWX^-tetramethymaphthalene-l,8-diamine (30 mg, 0.14 mmol) and 1-chlorethyl chloroforamte (0.03 mL, 0.28 mmol) were added at 00C, the mixture stirred 15 minutes, and then heated to reflux for 2 hours. The mixture was cooled to room temperature, concentrated and filtered through a pad of silica gel (1 : 1 : 1 hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated, the residue dissolved in methanol (10 mL) and heated to reflux for 1 hour. The mixture was cooled, concentrated, and purified by semi-preparative HPLC followed by lyophilization to give 2-(4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile, trifluoroacetate salt (18 mg, 26%) as a brown solid: 1H NMR (CD3OD, 500 MHz) δ 7.85 (dd, J = 7.7, 0.7 Hz, IH), 7.777.73 (m, IH), 7.607.48 (m, 6H), 7.25 (dd, J = 8.3, 2.1 Hz, IH), 7.07 (d, J = 8.2 Hz, IH), 4.64 (d, /= 16.0 Hz, IH), 4.62 (dd, / = 10.7, 6.2 Hz, IH), 4.54 (d, /= 15.7 Hz, IH), 3.84 (dd, J= 12.7, 6.1 Hz, IH), 3.54 (dd, J = 12.6, 10.9 Hz, IH); ESI MS m/z 379 [M + H]+.
Example 15 - Preparation of 3-(4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)benzoiiitrile, trifluoroacetate Salt [0218] Following the procedure in Steps A and B of Example 14, 4-(3,4- dicMorophenyl)-2-methyl-l,2,3,4-tetrahydroisoqumoUn-7-yl trifluoromethanesulfonate (100 mg, 0.23 mmol), 3-cyanophenylboronic acid (51 mg, 0.35 mmol), cesium carbonate (225 mg, 0.69 mmol), and dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (8 mg, 0.01 mmol) in N^V-dimethylformamide (2 mL) and water (1 mL) followed by iV-de-methylation with ΛrW,-vW-tetrameΛylr-aphthalene-l,8- diamine (52 mg, 0.24 mmol) and 1-chlorethyl chloroforamte (0.08 mL, 0.72 mmol) gave 3-(4-(3,4-dichlorophenyl)-l,2,3,4-tetraliydroisoquinolin-7-yl)benzonitrile, trifLuoroacetate salt (38 mg, 33%, 2 steps) as an off-white solid: 1H NMR (CD3OD, 500 MHz) δ 8.01 (d, / = 1.5 Hz, IH), 7.977.95 (m, IH), 7.757.73 (m, IH), 7.667.63 (m, 2H), 7.60 (dd, / = 8.2, 1.7 Hz, IH), 7.49 (d, / = 2.0 Hz, IH), 7.49 (d, / = 2.0 Hz, IH), 7.23 (dd, / = 8.3, 2.1 Hz, IH), 7.04 (d, /= 8.2 Hz, IH), 4.654.52 (m, 3H), 3.83 (dd, / = 12.6, 6.1 Hz, IH), 3.51 (dd, J= 12.6, 10.8 Hz, IH); ESI MS m/z 379 [M + H]+.
Example 16 - Preparation of 4-(3,4-dichlorophenyl)-7-(4-(methylsulfonyl)phenyl)- 1,2,3,4-tetrahydroisoquinoline, trifluoroacetate Salt.
[0219] Step A: A mixture of 4-(3,4-dichlorophenyl)-2-methyl-l,2,3,4- tetrahydroisoquinolin-7-yl trifluoromethanesυlfonate (300 mg, 0.68 mmol) from Step G of Example 11, 4-(methylsulfonyl)phenylboronic acid (176 mg, 0.88 mmol), potassium bromide (243 mg, 2.04 mmol) and potassium hydroxide (114 mg, 2.04 mmol) in toluene (7 mL) was degassed with argon and then tetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) was added. The mixture was degassed again and then heated to 800C for 3 hours. The mixture was cooled to room temperature, diluted with dichloromethane/methanol (9: 1), and filtered through a plug of silica. The filtrate was concentrated and the residue partially purified by column chromatography (hexanes to ethyl acetate) to give 4-(3,4-dichlorophenyl)-2-methyl-7-(4-(methylsulfonyl)phenyl)- 1,2,3,4-tetrahydroisoquinoline (72 mg, 24%) as an off-white solid: ESI MS m/z 446 [M + H]+. [0220] Step B: To an ice-cold solution of 4-(3,4-dichlorophenyl)-2-methyl-7-(4-
(methylsulfonyl)phenyl)-l,2,3,4-tetrahydroisoquinoline (70 mg, 0.16 mmol) and NWXX-tetrametoymaphthalene-l,8-diamine (69 mg, 0.32 mmol) in 1,2- dichloroethane (3 mL) was added 1-chlorethyl chloroforamte (0.07 mL, 0.64 mmol) drop wise. The mixture was stirred for 15 minutes and then heated to reflux for 2 hours. The mixture was cooled to room temperature, concentrated, and filtered through a pad of silica gel (1:1:1 hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated, the residue dissolved in methanol (10 mL) and heated to reflux for 1 hour. The mixture was cooled, concentrated, and purified by semi-preparative HPLC followed by lyophilization to give 4-(3,4-dichlorophenyl)-7-(4-(methylsulfonyl)phenyl)-l,2,3,4- tetrahydroisoquinoline, trifluσroacetate salt (58 mg, 66%) as a white solid: 1H NMR (CD3OD, 500 MHz) δ 8.04 (dd, / = 8.5 Hz, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.68 (s, IH), 7.64 (dd, J = 8.2, 1.7 Hz, IH), 7.57 (d, J= 8.3 Hz, IH), 7.50 (d, J = 2.1 Hz, IH), 7.23 (dd, / = 8.3, 2.1 Hz, IH), 7.06 (dd, / = 8.2 Hz, IH), 4.684.53 (m, 3H), 3.83 (dd, / = 12.6, 6.1 Hz, IH), 3.52 (dd, /= 12.5, 10,8 Hz, IH), 3.15 (s, 3H); ESI MS m/z 432 [M + H]+.
Example 17 - Preparation of l-(4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinoliii-7-yl)pyridiii-2(l£0-one, L-tartrate Salt [0221] Step A: To a mixture of 7-bromo-4-(3,4-dicruorophenyl)-2-methyl-
1,2,3,4-tetrahydroisoquinoline (500 mg, 1.35 mmol) which was prepared following similar method described in Steps A to C of Example 1 starting from 2-bromo-l-(3,4- dichlorophenyl)ethanone and l-(3-bromophenyl)-N-meihylniethanamine, pyridin-2-ol (154 mg, 1.62 mmol), N, N- dimethlethylene diamine (58 μl, 0.54 mmol), and potassium phosphate (572 mg, 2.69 mmol) in 1,4-dioxane (5 mL) was added copper(l) iodide (51 mg, 0.27 mmol). The mixture was degassed with argon and then heated to 1100C for 17 hours. The reaction mixture was diluted with water (20 mL) and extracted with methylene chloride (2 x 25 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was partially purified by column chromatography (methylene chloride to 90:9: 1 methylene chloride/methanol/ammonium hydroxide) to give l-(4-(3,4-dichlorophenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-7- yl)pyridin-2(lH)-one (37 mg, 7%): ESI MS m/z 385 [M + H]+.
[0222] Step B: A procedure similar to the one in Step B of Example 29 was used to demethylate l-(4-(3,4-dichlorophenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-7- yl)pyridin-2(lH)-one. The desired free base was obtained and a procedure similar to the one in Step C of Example 2 (with the exception of CΗ3CΝ instead of MeOH was used as the solvent) was used to obtain l-(4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7- yl)pyridin-2(lH)-one, L-tartrate salt (18 mg, 50%) as a white powder: 1H NMR (CD3OD, 500 MHz) δ 7.647.59 (m, 2H), 7.55 (d, J = 8.0 Hz, IH), 7.48 (s, IH), 7.35 (s, IH), 7.28 7.23 (m, 2H), 7.07 (d, / = 8.0 Hz, IH), 7.07 (d, J= 9.0, IH), 6.506.48 (m, IH), 4.55 4.52 (m, 2H), 4.424.40 (m, 3.3H), 3.753.74 (m, IH), 3.443.41 (m, IH); ESI MS m/z 371 [M + H]+. Example 18 - Preparation of 2-(4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)pyridaziii-3(2fl)-one, L-tartrate Salt.
[0223] Step A: A procedure similar to the one in Step A of Example 17 was used to couple 7-hromo-4-(3,4-dichlorophenyl)-2-methyl- 1 ,2,3,4-tetrahydroisoquinoline with pyridazin-3(2H)-one. 2-(4-(3,4-Dichlorophenyl)-2-methyl- 1 ,2,3,4-tetrahydroisoquinolin- 7-yl)pyridazin-3(2H)-one was obtained in 23% yield as an off-white foam: ESI MS m/z 386 [M + H]+. [0224] Step B: A procedure similar to the one in Step B of Example 29 was used to demethylate 2-(4-(3,4-dichlorophenyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-7- yl)pyridazin-3(2H)-one. The desired free base was obtained and a procedure similar to the one in Step C of Example 2 (with the exception that CH3CN was used instead of MeOH as the solvent) was used to obtain 2-(4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one, L-tartrate salt (48 mg, 50%) as a white powder: 1H NMR (CD3OD, 500 MHz) δ 8.058.03 (m, IH), 7.567.54 (m, 2H), 7.50
7.44 (m, 3H), 7.23 (dd, /= 8.0, 2.0 Hz, IH), 7.10 (dd, /= 9.5, 1.5 Hz, IH), 7.03 (d, / = 8.5 Hz, IH), 4.564.53 (m, 2H), 4.444.41 (m, 3.1H), 3.773.73 (m, IH), 3.443.40 (m, IH); ESI MS m/z 372 [M + H]+.
Example 19 - Preparation of 4-(3,4-dichlorophenyl)-6-fluoro-7-(pyridin-2-yl)-l,2^,4- tetrahydroisoquinoline.
[0225] Step A: A mixture of 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-
(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline (500 mg, 1.1 mmol) which was prepared according to the procedure in Step F of Example 26, 5- bromopyridine (0.21 mL, 2.2 mmol) and cesium carbonate (1.08 mg, 3.3 mmol) in water (3 mL) and N^V-dimethylformamide (10 mL) was degassed with argon and then [1,1- bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06 mmol) was added. The mixture was degassed again and then heated to 900C for 2.5 hours. The mixture was partitioned between water and ethyl acetate (3x) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by column chromatography (9:1 hexanes/ethyl acetate to ethyl acetate, then 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to give 4- (3,4-dicMorophenyl)-6-fluoro-2-methyl-7-(pyridin-2-yl)-l,2,3,4-tetrahydroisoquinoline (282 mg, 65%) as a brown oil: ESI MS m/z 387, 389 [M + H]+. [0226] Step B: To an ice-cold solution of 4-(3,4-dichlorophenyl)-6-fluoro-2- meihyl-7-(pyridin-2-yl)-l,2,3,4-tJetrahydroisoquinoline (282 mg, 0.73 mmol) and ^^XX-tetrameihylnaphihalene-l.S-diainine (313 mg, 1.46 mmol) in 1,2- dichloroethane (10 mL) was added 1-chlorethyl chloroforamte (0.32 mL, 1.46 mmol) drop wise. The mixture was stirred for IS minutes and then heated to reflux for 2 hours. The mixture was cooled to room temperature, concentrated, and filtered through a pad of silica gel (1:1:1 hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated, the residue dissolved in methanol (10 mL), and heated to reflux for 1 hour. The mixture was cooled, concentrated, neutralized with aqueous saturated sodium bicarbonate and ethyl acetate, and then purified by column chromatography (methylene chloride to
90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to give 4-(3,4- dichlorophenyl)-6-fluoro-7-(pyridin-2-yl)-l,2,3,4-tetrahydroisoquinoline as yellow oil (13 mg, 5%): 1H NMR (CDCl3, 500 MHz) δ 8.72 (d, J = 4.7 Hz, IH), 7.777.75 (m, 3H), 7.39 (d, / = 8.3 Hz, IH), 7.277.24 (m, 2H), 6.99 (dd, / = 8.3, 2.0 Hz, IH), 6.68 (d, / = 11.9 Hz, IH), 4.214.07 (m, 3H), 3.41 (dd, / = 12.9, 5.3 Hz, IH), 3.05 (dd, / = 12.9, 6.4 Hz, IH); ESI MS m/z 373 [M + H]+.
Example 20 - Preparation of 4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methylpyridaziii- 3-yl)-l,2^,4-tetrahydroisoquinoline.
[0227] Following the procedure in Step A and Step B of Example 19, 4-(3,4- dicMorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,2,3,4-tetrahydroisoquinoline (500 mg, 1.1 mmol), 3-chloro-6-methylpyridazine (282 mg, 2.2 mmol), cesium carbonate (1.08 mg, 3.3 mmol), and dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06 mmol) in NJI- dimethylformamide (10 mL) and water (3 mL) followed by N-de-methylation with N^^X-tetramethylnaphthalene-l.S-diamine (471 mg, 2.2 mmol) and 1-chlorethyl chloroforamte (0.48 mL, 4.4 mmol) gave 4-(3,4-dichlorophenyl)-6-fluoro-7-(6- methylpyridazin-3-yl)- 1,2,3,4-tetrahydroisoquinoline (15 mg, 3%, 2 steps) as a green solid: 1H ΝMR (CDCl3, 500 MHz) δ 7.95 (d, J = 7.8 Hz, IH), 7.83 (dd, J = 8.8, 1.9 Hz, IH), 7.427.35 (m, 3H), 7.00 (dd, / = 8.3, 1.9 Hz, IH), 6.70 (d, J = 12.0 Hz, IH), 4.23 4.09 (m, 3H), 3.42 (dd, J = 12.9, 5.3 Hz, IH), 3.06 (dd, J = 12.9, 6.7 Hz, IH), 2.77 (s, 3H); ESI MS m/z 388, 390 [M + H]+. Example 21 - Preparation of 4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methoxypyridazin- 3-yl)-l,2^,4-tetrahydroisoquinoline, trifluoroacetate Salt
[0228] Following the procedure in Step A and Step B of Example 19, 4-(3,4- dicMorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-l,3.2-dioxaborolan-2-yl)- 1,2,3,4-tetrahydroisoquinoline (500 mg, 1.1 mmol), 3-chloro-6-methoxypyridazine (318 mg, 2.2 mmol), cesium carbonate (1.08 g, 3.3 mmol), and dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06 mmol) in N,N- dimethylformamide (10 mL) and water (3 mL) followed by iV-de-methylation with ΛfWX^-tetrameΛymaphthalene-l,8-diamine (26 mg, 0.12 mmol) and 1-chlorethyl chloroforamte (0.04 mL, 0.36 mmol) gave after purification by semi-preparative HPLC and lyopMlization 4-(3,4-dicMoropb.enyl)-6-fluoro-7-(6-methoxypyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline, trifluoroacetate salt (33 mg, 6%, 2 steps) as a white solid: 1H ΝMR (CD3OD, 500 MHz) δ 7.95 (dd, J = 9.3, 2.1 Hz, 1H),7.86 (d, J= 7.4 Hz, IH), 7.59 (d, J = 8.4 Hz, IH), 7.53 (d, / = 2.0 Hz, IH), 7.287.25 (m, 2H), 6.82 (d, / = 11.6 Hz, IH), 4.634.53 (m, 3H), 4.16 (s, 3H), 3.83 (dd, /= 12.5, 6.2 Hz, IH), 3.553.50 (m, IH); ESI MS m/z 404 [M + H]+.
Example 22 - Preparation of 46-(4-(3,4-dichlorophenyl)-6-fluoro-l,2,3,4- tetrahydroisoquinolin-7-yl)pyridazin-3(2£0-one, trifluoroacetate salt
[0229] A mixture of 4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methoxypyridazin-3- yl)-l,2,3,4-tetrahydroisoquinoline, trifluoroacetate salt (20 mg, 0.04 mmol, product of Step B in Example 21) and hydrobromic acid (aqueous, 48%) was heated to reflux for 1 hour. The mixture was cooled to room temperature and concentrated. The residue was purified by semi-preparative HPLC followed by lyophilization to give 46-(4-(3,4- dichlorophenyl)-6-fluoro- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one, trifluoroacetate salt (16 mg, 80%) as a white solid: 1H ΝMR (CD3OD, 500 MHz) δ 7.84 (dd, / = 9.9, 2.1 Hz, IH), 7.74 (d, / = 7.5 Hz, IH), 7.58 (d, /= 8.3 Hz, IH), 7.52 (d, /= 2.0 Hz, IH), 7.24 (dd, J= 8.3, 2.0 Hz, IH), 7.04 (d, J= 9.9 Hz, IH), 6.78 (d, J= 11.7 Hz, IH), 4.674.49 (m, 3H), 3.81 (dd, /= 12.6, 6.0 Hz, IH), 3.50 (dd, / = 11.3, 11.3 Hz, IH); ESI MS m/z 390 [M + H]+. Example 23 - Preparation of 4-(3,4-dichlorophenyl)-6-fluoro-7-(3-
(metfaylsulfonyl)phenyl)-l^^,4-tetrahydroisoquinoline.
[0230] Following the procedure of Step A and Step B of Example 19, 4-(3,4- dicMorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,2,3,4-tetrahydroisoquinoline (500 mg, 1.1 mmol), l-hromo-3-(methylsulfonyl)benzene (517 mg, 2.2 mmol), cesium carbonate (1.08 g, 3.3 mmol), and dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06 mmol) in N,N- dimethylformamide (10 mL) and water (3 mL) followed by iV-de-methylation with ΛfWXX-tetrameΛymaphthalene-l,8-diamine (240 mg, 1.12 mmol) and 1-chlorethyl chloroforamte (0.31 mL, 2.8 mmol) gave after purification by preparative HPLC followed by preparative thin layer chromatography (90:10:1 diethyl ether/methanol/concentrated ammonium hydroxide) 4-(3,4-dichlorophenyl)-6-fluoro-7-(3-(methylsulfonyl)phenyl)- 1,2,3,4-tetrahydroisoquinoline (38 mg, 15%) as a colorless oil: 1H ΝMR (CDCl3, 500 MHz) δ 8.10 (s, IH), 7.94 (d, J = 7.5 Hz, IH), 7.84 (d, J = 7.5 Hz, IH), 7.65 (dd, J = 8.0, 8.0 Hz, IH), 7.41 (d, /= 8.0 Hz, IH), 7.26 (s, IH), 7.20 (d, / = 7.5 Hz, IH), 7.01 (dd, /= 8.0, 2.0 Hz, IH), 6.71 (d, J = 11.0 Hz, IH), 4.204.09 (m, 3H), 3.43 (dd, J = 13.0, 5.5 Hz, IH), 3.10 (s, 3H), 3.07 (dd, /= 13.0, 6.5 Hz, IH), 2.04 (br s, IH); ESI MS m/z 450 [M + H]+.
Example 24 - Preparation of 4-(4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)benzamide.
[0231] Step A: To an ice-cold solution of 4-(3,4-dichlorophenyl)-2-methyl- l,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (1.0 g, 2.3 mmol) and ΛfWXX-tetrameΛymaphthalene-l,8-diamine (493 mg, 2.3 mmol) in 1,2- dichloroethane (25 mL) was added 1-chlorethyl chloroforamte (0.75 mL, 6.9 mmol) drop wise. The mixture was heated to reflux for 1 hour. The mixture was cooled to room temperature, concentrated, and filtered through a pad of silica gel (1:1:1 hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated, the residue dissolved in methanol (50 mL), and then heated to reflux for 1 hour. The mixture was cooled, concentrated, neutralized with aqueous saturated sodium bicarbonate and ethyl acetate, and then purified by column chromatography (hexanes to ethyl acetate) to give 4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (455 mg, 46%) as a brown oil: ESI MS m/z 426 [M + H]+. [0232] Step B: A mixture of 4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl trifluoromethanesυlfonate (225 mg, 0.53 mmol), 4- carbamoylphenylboronic acid (132 mg, 0.8 mmol) and cesium carbonate (521 mg, 1.6 mmol) in water (2 mL) and N^V-dimethylformamide (4 mL) was degassed with argon and then [l,l-bis(diphenylphosphino)ferrocene]palladium(II) (22 mg, 0.03 mmol) was added. The mixture was degassed again and then heated to 900C for 2 hours. The mixture was partitioned between water and ethyl acetate (3x) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by semi-preparative HPLC followed by lyophilization to give 4- (4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (19 mg, 7%) as a yellow oil: 1H ΝMR (CD3OD, 500 MHz) δ 7.96 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.64 (s, IH), 7.627.59 (m, IH), 7.56 (d, / = 8.3 Hz, IH), 7.49 (d, J = 2.0 Hz, IH), 7.23 (dd, J = 8.3, 2.0 Hz, IH), 7.02 (d, J = 8.2 Hz, IH), 4.674.53 (m, 3H), 3.82 (dd, J = 12.6, 6.1 Hz, IH), 3.51 (dd, / = 12.5, 10.9 Hz, IH); ESI MS m/z 397 [M + H]+.
Example 25 - Preparation of 4-(4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)-3,5-dimethylisoxazole.
[0233] Following the procedure in Example 24, 4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (225 mg, 0.53 mmol), 3,5- dimethylisoxazol-4-ylboronic acid (114 mg, 0.8 mmol), cesium carbonate (521 mg, 1.6 mmol) and dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) (22 mg, 0.03 mmol) in N^-dimethylformamide (4 mL) and water (2 mL) gave 4-(4-(3,4- dicMorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dimethylisoxazole (95 mg, 48%) as a brown oil: 1H ΝMR (CD3OD, 500 MHz) δ 7.46 (d, J = 8.3 Hz, IH), 7.34 (d, J = 2.0 Hz, IH), 7.137.08 (m, 3H), 6.92 (d, J = 8.0 Hz, IH), 4.244.05 (m, 3H), 3.39 (dd, J = 12.9, 5.7 Hz, IH), 3.01 (dd, J= 12.9, 8.3 Hz, IH), 2.39 (s, 3H), 2.24 (s, 3H); ESI MS m/z 373 [M + H]+.
Example 26 - Preparation of 4-(4-(3,4-dichlorophenyl)-6-fluoro-l,2^,4- tetrahydroisoquinolin-7-yl)benzamide, L-tartrate Salt
[0234] Step A: To a solution of l-(4-fluoro-3-methoxyphenyl)-iV- methylmethanamine (0.9 g, 5.39 mmol) in ethanol (8.0 mL) was added potassium carbonate (0.6 g, 4.48 mmol) and 2-bromo-l-(3,4-dichlorophenyl)ethanone (1.2 g, 4.48 mmol). The reaction solution was stirred for 2.5 hours at room temperature and then sodium borohydride (0.2 g, 5.83 mmol) was added to it portionwise at 00C. The reaction mixture was stirred overnight while warming up to room temperature. The reaction solution was concentrated in vacuo. The slurry obtained was quenched with water and extracted with methylene chloride. The combined organic extracts were washed with brine (2 x 200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (1:1 to 1:9 hexanes/ethyl acetate) to afford l-(3,4-dichlorophenyl)-2-((4-fluoro-3- methoxybenzyl)(methyl)amino)ethanol (1.9 g): 1H NMR (CDCl3, 300 MHz) δ 7.45 (d, J = 1.5 Hz, IH), 7.39 (d, J = 3.0 Hz, IH), 7.16 (dd, J = 8.0, 2.0 Hz, IH), 7.05 7.01 (m, IH), 6.91 (dd, J= 8.0, 2.0 Hz, IH), 6.81 6.78 (m, IH), 4.69 (t, J= 7.0 Hz, IH), 3.98 (br.s, IH), 3.90 (s, 3H), 3.67 (d, / = 13.5 Hz, IH), 3.47 (d, / = 13.0 Hz, IH), 2.50 (d, / = 7.0 Hz, 2H), 2.32 (s, 3H); ESI MS m/z 358 [M+H]+. [0235] Step B: To a solution of the alcohol (1.1 g, 2.93 mmol) from Step A above in methylene chloride (10.0 mL) was added concentrated sulfuric acid (1.5 mL, 0.56 mmol). The reaction mixture was stirred at 00C for 30 minutes and at room temperature for 2 hours. The reaction solution was quenched at 00C by addition of an aqueous solution of sodium hydroxide (2N) and the aqueous phase was extracted with additional methylene chloride (3x). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (7:3 to 1:9 hexanes/ethyl acetate) to afford 4-(3,4-dichlorophenyl)-6- fluoro-7-methoxy-2-methyl-l,2,3,4-tetrahydroisoquinoline (1.0 g, 98%): 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 8.0 Hz, IH), 7.28 (d, J = 2.5 Hz, IH), 7.03 (dd, J = 8.0, 2.0 Hz, IH), 6.65 (d, J = 9.0 Hz, IH), 6.55 (d, J = 12.0 Hz, IH), 4.09 (t, J = 7.5 Hz, IH), 3.87 (s, 3H), 3.60 (s, 2H), 2.92 (dd, / = 12.0, 5.5 Hz, IH), 2.53 (dd, /= 11.5, 7.5 Hz, IH), 2.41 (s, 3H); ESI MS m/z 340 [M+H]+.
[0236] Step C: The racemic 7-methoxy tetrahydroisoquinole from Step B above
(8.5 g) was resolved by preparative chiral HPLC (CHIRALPAK AD column, using 80:20:0.1 heptane/isopropanol/diethylamine as the eluent) to give (+) enantiomer (4.0 g) and 0 enantiomer (4.0 g).
[0237] Step D: To a solution of (+) 7-methoxytetrahydroisoquinoline from Step C above (3.4 g, 11.70 mmol) in hydrobromic acid (90 mL, 48% solution in water) was added acetic acid (48 mL). The reaction solution was stirred at 1100C overnight under nitrogen and then concentrated under reduced pressure. The resultant solution was quenched with sodium bicarbonate and extracted with dichloromethane, dried over aqueous sodium sulfate, and concentrated under reduced pressure to give the desired phenol (3.6 g, crude), which was used in the next step without further purification: 1H NMR (MeOD, 500 MHz) δ 7.44 (d, J = 7.0 Hz, IH), 7.33 (d, J = 1.5 Hz, IH), 7.11 (dd, J = 8.0, 2.0 Hz, IH), 6.69 (d, / = 8.5 Hz, IH), 6.46 (d, / = 12.0 Hz, IH), 4.19 (t, / = 7.0 Hz, IH), 3.67 3.53 (m, 2H), 3.01 (dd, / = 11.5, 5.5 Hz, IH), 2.52 (dd, / = 12.0, 9.0 Hz, IH), 2.40 (s, 3H); ESI MS m/z 326 [M+H]+. [0238] Step E: To a solution of the phenol (2.5 g, 7.79 mmol) from Step D above in dichloromethane (30 mL) at 00C was added pyridine (0.8 mL, 10.12 mmol) followed by slow addition of trifluoromethanesulfonic anhydride (1.4 mL, 8.18 mmol) dropwise. The resultant reaction solution was stirred at 00C for 1 hour, and then was quenched with aqueous saturated sodium bicarbonate. The organic extract was separated and the aqueous layer was extracted with dichloromethane (3x). The combined organic extract was washed with 1 : 1 water/brine, dried over sodium sulfate, and concentrated under reduced pressure to give the desired triflate (3.5 g) as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 7.39 (dd, / = 8.0, 2.5 Hz, IH), 7.31 (d, / = 2.0 Hz, IH), 7.07 (d, / = 7.5 Hz, IH), 7.02 (dd, J = 6.0, 2.0 Hz, IH), 6.75 (d, J = 10.0 Hz, IH), 4.14 (t, J = 6.5 Hz, IH), 3.61 (s, 2H), 2.95 (dd, J = 11.5, 5.5 Hz, IH), 2.58 (dd, J = 11.5, 7.0 Hz, IH), 2.43 (s, 3H). [0239] Step F: To a mixture of triflate (3.5 g, 7.57 mmol) in Step E above bis(pinacolato)diboron (2.3 g, 9.09 mmol) and potassium acetate (2.2 g, 22.72mmol) were added in DMSO (100.0 mL). The reaction solution was purged with argon for 10 minutes, and then l,r-bis(diphenylphosphino)ferrocenedichloropalladium (0.5 g, 0.61 mmol) was added to it. The reaction solution was degassed again with argon for 5 minutes and heated at 800C overnight. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (90:9:1 dichloromethane/methanol/concentrated ammonia) to give the desired boronate ester ( 0.1 g, 3%): 1H NMR (CDCl3, 500 MHz) δ 7.48 (d, J = 6.0 Hz, IH), 7.37 7.34 (m, IH), 7.27 (s, IH), 7.00 (dd, J = 8.0, 2.0 Hz, IH), 6.56 6.51 (m, IH), 4.19 (t, / = 6.5 Hz, IH), 3.69 3.53 (m, 2H), 2.96 (dd, J= I 1.5, 5.5 Hz, IH), 2.53 (dd, J = 11.5, 7.5 Hz, IH), 2.40 (s, 3H), 1.35 (s, 12H).
[0240] Step G: A mixture of 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-
(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoqυinoline (1.0 g mg, 2.3 mmol), 4-bromobenzamide (690 mg, 3.45 mmol) and cesium carbonate (2.25 g, 6.9 mmol) in water (6 mL) and N^V-dimethylformamide (20 mL) was degassed with argon and then [l,l-bis(diphenylphosphino)ferrocene]palladium(II) (88 mg, 0.12 mmol) was added. The mixture was degassed again and then heated to 900C for 2 hours. The mixture was partitioned between water and ethyl acetate (3x) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by column chromatography (7:3 hexanes/ethyl acetate to ethyl acetate, then ethyl acetate to 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to give 4-(4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-l,2,3,4- tetrahydroisoquinolin-7-yl)benzamide (423 mg, 43%) as a brown solid: ESI MS m/z 429 [M + H]+.
[0241] Step H: A mixture of 4-(4-(3,4-dichlorophenyl)-6-fluoro-2-methyl- l,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (490 mg, 1.1 mmol), di-te/f -butyl dicarbonate (1.2 g, 0.65 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol) in dichloromethane (5 mL) was stirred at room temperature overnight and then concentrated. Purification by column chromatography (hexanes to 1 : 1 hexanes/ethyl acetate) gave bis- Boc protected 4-(4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-l,2,3,4-tetrahydroisoquinolin- 7-yl)benzamide (59 mg, 76%) as a light yellow oil: ESI MS m/z 628 [M + H]+. [0242] Step I: To an ice-cold solution of bis-Boc protected 4-(4-(3,4- dicMorophenyl)-6-fluoro-2-memyl-l,2,3,4-tetrahydroisoqumolin-7-yl)benzamide (515 mg, 0.82 mmol) and N^^^-tetramethylnaphthalene-l.S-diamine (527 mg, 2.46 mmol) in 1,2-dichloroethane (15mL) was added 1-chlorethyl chloroformate (0.27 mL, 2.46 mmol) drop wise. The mixture was stirred for 15 minutes and then heated to 400C for 2 hours. The mixture was concentrated and filtered through a pad of silica gel (1 : 1 : 1 hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated, the residue dissolved in methanol (5 mL) and heated to reflux for 1 hour and then concentrated. The residue was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL), stirred for 2 hours, concentrated and purified by semi-preparative HPLC, and neutralized with saturated sodium bicarbonate and ethyl acetate to give 4-(4-(3,4-dichlorophenyl)-6- fluoro-l,2,3,4-tetrahydroisoquinolin-7-yl)benzamide as an off-white solid (95 mg, 28%). A mixture of 4-(4-(3,4-dicUorophenyl)-6-fluoro-l,2,3,4-tetrahydroisoquinolin-7- yl)benzamide (20 mg, 0.05 mmol) and L-tartaric acid (7 mg, 0.05 mmol) in acetonitrile and water was lyophilized to give 4-(4-(3,4-dichlorophenyl)-6-fluoro- 1,2,3,4- tetrahydroisoquinolin-7-yl)benzamide, L-tartrate salt (29 mg, 100%): 1H NMR (CD3OD, 500 MHz) δ 7.96 (dd, J = 6.5, 2.0 Hz, 2H), 7.677.65 (m, 2H), 7.57 (d, J = 8.0 Hz, IH), 7.51 (d, /= 2.0 Hz, IH), 7.49 (d, /= 7.5 Hz, IH), 7.24 (dd, / = 8.5, 2.5 Hz, IH), 6.73 (d, J = 11.5 Hz, IH), 4.584.44 (m, 3H), 4.43 (s, 2.6H), 3.803.75 (m, IH), 3.453.40 (m, IH); ESI MS m/z 415 [M + H]+.
Example 27 - Preparation of 5-(4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)pyrazin-2-aiiiine, trifluoroacetate Salt
[0243] Step A: To an ice-cold solution of 4-(3,4-dichlorophenyl)-7-methoxy-2- methyl-l,2,3,4-tetrahydroisoquinoline (3.46 g, 10.7 mmol, prepared in Step D of Example 11) andiV^W^-tetramethylnaphthalene-l.S-diamine (2.3 g, 10.7 mmol) in 1,2- dichloroethane (70 mL) was added 1-chlorethyl chloroforamte (2.4 mL, 21.4 mmol) drop wise. The mixture was stirred for 15 minutes and then heated to reflux for 1 hour. The mixture was cooled to room temperature, concentrated and then filtered through a pad of silica gel (1 : 1 : 1 hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated, the residue dissolved in methanol (100 mL) and heated to reflux for 1 hour. The mixture was cooled, concentrated, and the residue neutralized with ethyl acetate and saturated aqueous sodium bicarbonate to give 4-(3,4-dichlorophenyl)-7-methoxy-l,2,3,4- tetrahydroisoquinoline (2.65 g, 80%) as a brown oil: 1H NMR (DMSCW6, 500 MHz) δ 7.53 (d, J= 8.3 Hz, IH), 7.41 (d, / = 2 Hz, IH), 7.15 (dd, /= 8.3, 2 Hz, IH), 9.716.67 (m, 3H), 4.074.00 (m, 2H), 3.91 (m, IH), 3.72 (s, 3H), 3.22 (dd, J= 12.5, 5.3 Hz, IH), 2.92 (dd, J= 12.5, 6.5 Hz, IH).
[0244] Step B: To an ice-cold solution of 4-(3 ,4-dichlorophenyl)-7 -methoxy-
1,2,3,4-tetrahydroisoquinoline (2.65 g, 8.6 mmol) and N^-diisopropyleihylamine (1.8 mL, 10.3 mmol) in dichloromethane (80 mL) was slowly added a solution of 2- nitrobenzene-1-sulfonyl chloride (2.1 g, 9.5 mmol) in dichloromethane (10 mL). The mixture was stirred for 2 hours and then quenched with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (hexanes to ethyl acetate) to give 4-(3,4- dichlorophenyl)-7-methoxy-2-(2-nitrophenylsulfonyl)-l,2,3,4-tetrahydroisoquinoline (3.39 g, 80%) as a yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.80 (dd, /= 8, 1.3 Hz, IH), 7.677.63 (m, IH), 7.58 (dd, J = 7.9, 1.2 Hz, IH), 7.547.50 (m, IH), 7.15 (d, J = 8.3 Hz, IH), 7.02 (d, /= 2.0 Hz, IH), 6.87 (dd, /= 8.3, 2 Hz, IH), 6.81 (d, /= 8.3 Hz, IH), 6.75 (d, / = 2.6 Hz, IH), 6.73 (s, IH), 4.77 (d, / = 16.0 Hz, IH), 4.56 ((L / = 16.0 Hz, IH), 4.18 (dd, /= 4.9, 4.9 Hz, IH), 3.82 (dd, / = 13.2, 4.5 Hz, IH), 3.81 (s, 3H), 3.63 (dd, /= 13.1, 5.5 Hz, IH).
[0245] Step C: To a 78 0C solution of 4-(3,4-dichlorophenyl)-7-methoxy-2-(2- nitrophenylsulfonyl)-l,2,3,4-tetrahydroisoquinoline (3.39 g, 6.88 mmol) in dichloromethane (70 mL) was added boron tribromide (3.25 mL, 34.4 mmol) drop wise. The mixture was stirred for 5 minutes and then warmed to 00C for 1 hour. The mixture was quenched with water slowly and then the aqueous layer was extracted with dichlormethane (2x). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)- l,2,3,4-tetrahydroisoquinolin-7-ol (3.25 g, 98%) as a yellow solid: 1H NMR (CDCI3^OO MHz) δ 7.80 (dd, / = 8.0, 1.2 Hz, IH), 7.677.63 (m, IH), 7.58 (dd, /= 7.9, 1.2 Hz, IH), 7.547.50 (m, IH), 7.16 (d, /= 8.3 Hz, IH), 7.02 (d, / = 2 Hz, IH), 6.86 (dd, /= 8.3, 2 Hz, IH), 6.77 (d, J = 8.2 Hz, IH), 6.686.65 (m, 2H), 4.88 (s, IH), 4.74 (d, J = 16.2 Hz, IH), 4.53 (d, J= 16.1 Hz, IH), 4.16 (dd, J= 4.9, 4.9 Hz, IH), 3.83 (dd, J= 13.2, 4.5 Hz, IH), 3.62 (dd, 7= 13.1, 5.5 Hz, IH).
[0246] Step D: To a 200C solution of 4-(3,4-dichlorophenyl)-2-(2- nitrophenylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-7-ol (2.0 g, 4.18 mmol) and pyridine (0.37 mL, 4.6 mmol) in dichloromethane (40 mL) was added trifluoromethanesulfonic acid anhydride (0.77 mL, 4.6 mmol) drop wise. The mixture was stirred for 3 hours and then quenched with saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (hexanes to 1:1 hexanes/ethyl acetate) to give 4- (3,4-dichlorophenyl)-2-(2-nitrophenylsulf onyl)- 1 ,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (2.03 g, 80%) as an off-white solid: 1H NMR (CDCl3, 500 MHz) δ 7.86 (dd, / = 8.0, 1.3 Hz, IH), 7.717.67 (m, IH), 7.637.56 (m, 2H), 7.23 (d, / = 8.5 Hz, IH), 7.16 (d, /= 2.5 Hz, IH), 7.10 (dd, / = 8.6, 2.6 Hz, IH), 7.05 (d, /= 2.1 Hz, IH), 7.00 (d, / = 8.6 Hz, IH), 6.86 (dd, / = 8.3, 2.2 Hz, IH), 4.80 (d, / = 16.5 Hz, IH), 4.64 (d, J = 16.5 Hz, IH), 4.27 (dd, J= 5.2, 5.2 Hz, IH), 3.90 (dd, J= 13.3, 4.7 Hz, IH), 3.62 (dd J = 13.4, 6.2 Hz, IH).
[0247] Step E: A mixture of 4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)- l,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (2.0 g, 3.27 mmol), bis(pinacolato)diboron (914 mg, 3.6 mmol) and potassium acetate (963 mg, 9.81 mmol) in dimethyl sulfoxide (15 mL) was degassed with argon and then [1,1- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (131 mg, 0.16 mmol) was added. The mixture was degassed again and then heated to 800C for 2.5 hours. The mixture was partitioned between water and ethyl acetate (3x) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-7-(4,4,5,5- tetramemyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline as a brown oil that was used without purification: ESI MS m/z 589 [M + H]+. [0248] Step F: A mixture of 4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline (300 mg, 0.51 mmol), 5-bromopyrazin-2-amine (174 mg, 1.0 mmol) and cesium carbonate (490 mg, 1.5 mmol) in water (1.5 mL) and iV^V-dimethylformamide (5 mL) was degassed with argon and then [l,l-bis(diphenylphosphino)ferrocene]palladium(π) dichloromethane adduct (24 mg, 0.03 mmol) was added. The mixture was degassed again and then heated to 900C for 3 hours. The mixture was partitioned between water and ethyl acetate (3x) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was partially purified by column chromatography (9:1 hexanes/ethyl acetate to ethyl acetate) to give 5-(4-(3,4-dichlorophenyl)-2-(2- nitrophenylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (40 mg, 14%) as a yellow oil: ESI MS m/z 556 [M + H]+.
[0249] Step G: 5-(4-(3,4-Dichlorophenyl)-2-(2-nitrophenylsulfonyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)pyrazin-2-amine (40 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL) and ethanol (2 mL). Thiophenol (0.04 mL, 0.35 mmol) and potassium carbonate (77 mg, 0.56 mmol) were added and the mixture stirred overnight at room temperature. The mixture was filtered and concentrated. The residue was purified by semi-preparative HPLC twice followed by lyophilization to give 5-(4-(3,4- dicMorophenyl)-l,2,3,4-tetι^ydroisoqumolm-7-yl)pyrazm-2-amine, trifluoroacetate salt (14 mg, 40%) as a yellow solid: 1H NMR (CD3OD, 500 MHz) δ 8.36 (s, IH), 8.16 (s, IH), 7.84 (s, IH), 7.78 (d, J= 7.8 Hz, IH), 7.56 (d, J = 8.2 Hz, IH), 7.48 (s, IH), 7.23 7.21 (m, IH), 6.99 (d, / = 8.0 Hz, IH), 4.644.50 (m, 3H), 3.81 (dd, / = 12.5, 6.0 Hz, IH), 3.523.47 (m, IH); ESI MS m/z 371 [M + H]+.
Example 28 - Preparation of 6-(4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)pyrazin-2-amine, trifluoroacetate Salt.
[0250] Following the procedure in Step F and Step G in Example 27, 4-(3,4- dicMorophenyl)-2-(2-nitrophenylsulfonyl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l,2,3,4-tetrahydroisoquinoline (300 mg, 0.51 mmol), 6-chloropyrazin-2-amine (129 mg, 1.0 mmol), cesium carbonate (490 mg, 1.5 mmol) and dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (24 mg, 0.03 mmol) in N^-dimeihylformamide (5 mL) and water (1.5 mL) followed by deprotection with thiophenol (0.02 mL, 0.2 mmol) and potassium carbonate (44 mg, 0.32 mmol) gave 6-(4-(3,4-dicMorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine, trifluoroacetate salt (9 mg, 5%, 2 steps) as a yellow solid: 1H ΝMR (CD3OD, 500 MHz) δ 8.22 (br s, IH), 7.95 (s, IH), 7.907.88 (m, 2H), 7.56 (d, / = 8.3 Hz, IH), 7.49 (d, / = 2.0 Hz, IH), 7.23 (dd, J= 8.3, 2.0 Hz, IH), 7.01 (d, J= 8.2 Hz, IH), 4.664.51 (m, 3H), 3.82 (dd, J = 12.7, 6.3 Hz, IH), 3.543.49 (m, IH); ESI MS m/z 371, 373 [M + H]+.
Example 29 - Preparation of (+)-4-(3,4-dichlorophenyl)-6-fluoro-7-(6-
(trifluoromethyl)pyridazin-3-yl)-l^,3,4-tetrahydroisoquinoline, L- tartrate Salt [0251] Step A: A mixture of (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-
(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline (350 mg, 0.80 mmol, prepared in Step F in Example 26), 3-chloro-6-(trifluoromethyl)pyridazine (176 mg, 0.96 mmol) and cesium carbonate (786 mg, 2.41 mmol), in water (0.8 mL) and N^V-dimethylformamide (4 mL) was degassed with argon and then [1,1- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (33 mg, 0.04 mmol) was added. The mixture was degassed again and then heated to 900C for 2.5 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (2 x 10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was partially purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to give (+)-4-(3,4- dicMoropheny^-ό-fluoro^-methyl-V-ζό-ζtrifluoromethylJpyridazin-S-yl)- 1 ,2,3,4- tetrahydroisoquinoline (373 mg, 28%) as a brown oil: ESI MS m/z 456 [M + H]+. [0252] Step B: To (+)-4-(3,4-dicWorophenyl)-6-fluoro-2-methyl-7-(6-
(trifluoromeihyl)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline (320 mg, 0.70 mmol) and N^^^-tetrameihylnaphihalene-l.S-diamine (299 mg, 0.70 mmol) in 1,2- dichloroethane (S mL) was added 1-chlorethyl chloroformate (0.15 mL, 1.4 mmol) drop wise. The mixture was heated to reflux for 3 hours and then cooled to ambient temperature. The reaction mixture was diluted with methylene chloride (30 mL) and washed with 1 N HCl (10 mL), water (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. To the residue was added methanol (IS mL) and the mixture was heated to reflux. After 1 hour, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9: 1 methylene chloride/methanol/ammonium hydroxide) and preparative TLC (90:9:1 methylene chloride/methanol/ammonium hydroxide). To the obtained material in acetonitrile (1.5 mL) was added L-taitaric acid (9.2 mg, 0.06 mmol) in water (5 mL). The resultant solution was lyophilized to give (+)-4-(3,4-dichlorophenyl)-6-fluoro-7-(6- (trifluoromethyl)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline, L-tartrate salt (47 mg, 11%) as a white powder: 1H NMR (CD3OD, 500 MHz) δ 8.32 (d, J = 8.5 Hz, IH), 8.19 (d, J= 9.0 Hz, IH), 8.07 (d, J = 7.0 Hz, IH), 7.57 (d, J= 8.0 Hz, IH), 7.51 (d, J= 1.5 Hz, IH), 7.24 (dd, / = 8.5, 2.0 Hz, IH), 6.85 (d, /= 11.5 Hz, IH), 4.594.48 (m, 3H), 4.41 (s, 1.8H), 3.773.71 (m, IH), 3.403.38 (m, IH); ESI MS m/z 442 [M + H]+.
Example 30 Preparation of 4-(4-(4-chlorophenyl)-6-fluoro-l,2,3,4- tetrahydroisoquinolin-7-yl)benzamide, trifluoroacetate Salt.
[0253] Step A: A mixture of 4-(4-chlorophenyl)-6-fluoro-2-methyl- 1,2,3,4- tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (695 mg, 1.64 mmol) which was prepared using similar methods described in Step A to Step E of Example 26 starting from 2-bromo-l-(4-chlorophenyl)ethanone, 4-carbamoylphenylboronic acid (406 mg, 2.46 mmol) and cesium carbonate (1.6 mg, 4.92 mmol) in water (5 mL) and NJf- dimethylformamide (20 mL) was degassed with argon and then [1,1- bis(diphenylphosphino)ferrocene]palladium(II) (59 mg, 0.08 mmol) was added. The mixture was degassed again and then heated to 900C for 2 hours. The mixture was partitioned between water and ethyl acetate (3x) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC followed by preparative thin-layer chromatography (90:10:1 diethyl ether/methanol/concentrated ammonium hydroxide) to give 4-(4-(4- cUorophenyl)-6-fluoro-2-memyl-l,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (204 mg, 32%) as an off-white solid: : ESI MS m/z 395 [M + H]+. [0254] Step B: A mixture of 4-(4-(4-cMorophenyl)-6-fluoro-2-methyl-l,2,3,4- tetrahydroisoquinolin-7-yl)benzamide (50 mg, 0.13 mmol), di-te/f-butyl dicarbonate (142 mg, 0.65 mmol) and 4-dimethylaminopyridine (1 mg, 0.01 mmol) in dichloromethane (1 mL) was stirred at room temperature overnight and then concentrated. Purification by preparative thin-layer chromatography (1:1 hexanes/ethyl acetate) gave bis-Boc protected 4-(4-(4-cMorophenyl)-6-fluoro-2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (59 mg, 76%) as a light yellow oil: ESI MS m/z 596 [M + H]+.
[0255] Step C: To an ice-cold solution of bis-Boc protected 4-(4-(4- cUorophenyl)-6-fluoro-2-memyl-l,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (59 mg, 0.10 mmol) andN1,N1,-V8,-V8-tetramemylnaphthalene-l,8-diamine (64 mg, 0.30 mmol) in 1,2-dichloroethane (2mL) was added 1-chlorethyl chloroforamte (0.03 mL, 0.30 mmol) drop wise. The mixture was stirred for 15 minutes and then heated to 400C for 1 hour. The mixture was concentrated and filtered through a pad of silica gel (1 : 1 : 1 hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated, the residue dissolved in methanol (5 mL) and heated to reflux for 30 minutes and then concentrated. The residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL), stirred for 2 hours, concentrated, and purified by semi-preparative HPLC followed by lyophilization to give 4-(4-(4-cMorophenyl)-6-fluoro-l,2,3,4-tetrahydroisoquinolin-7-yl)benzamide, trifluoroacetate salt (12 mg, 24%) as an off-white solid: 1H NMR (CD3OD, 500 MHz) δ 7.96 (dd, / = 6.5, 1.5 Hz, 2H), 7.65 (dd, /= 8.0, 1.5 Hz, 2H), 7.51 (d, / = 8.0 Hz, IH), 7.45 (dd, J = 6.5, 2.0 Hz, 2H), 7.30 (dd, J = 7.0, 2.0 Hz, 2H), 6.73 (d, J = 11.5 Hz, IH), 4.614.50 (m, 3H), 3.833.79 (m, IH), 3.513.46 (m, IH); ESI MS m/z 381[M + H]+. Example 31 - Preparation of (+)-4-(3,4-dichlorophenyl)-7-(6-
(difluoromethoxy)pyridazin-3-yl)-6-fluoro-l,2,3,4- tetrahydroisoquinoline, L-tartrate salt. [0256] Step A: A procedure similar to the one in Step A of Example 29 was used to couple (+)-4-(3,4-dicUorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline with 3-chloro-6- (difluoromeihoxy)pyridazine. (+)-4-(3,4-Dichlorophenyl)-7-(6- (difluoromeihoxy)pyridazin-3-yl)-6-fluoro-2-methyl-l,2,3,4-tetrahydroisoqιiinoline was obtained in 66% yield as a brown oil: ESI MS m/z 454 [M + H]+.
[0257] Step B: A procedure similar to the one in Step B of Example 29 was used to demethylate (+)-4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-6- fluoro-2-methyl-l,2,3,4-tetrahydroisoquinoline. The desired free base was obtained and a procedure similar to the one in Step C of Example 2 was used to obtain (+)-4-(3,4- dichloropheny^^-Cό-Cdifluoromethoxy^yridazin-S-yO-ό-fluoro- 1 ,2,3,4- tetrahydroisoquinoline, L-tartrate (70 mg, 24%) as a white powder: 1H NMR (CD3OD, 500 MHz) δ 8.13 (dd, J = 9.5, 1.5 Hz, IH), 7.89 (d/ = 7.5 Hz, IH), 7.77 (X, J = 12 Hz, IH), 7.57 (d, J = 8.0 Hz, IH), 7.52 (d, J= 1.5 Hz, IH), 7.47 (d, J = 9.5 Hz, IH), 7.25 (dd, J= 8.5, 2.0 Hz, IH), 6.80 (d, J= 11.5 Hz, IH), 4.624.51 (m, 3H), 4.43 (s, 2.25H), 3.80 3.76 (m, IH), 3.453.41 (m, IH); ESI MS m/z 440 [M + H]+.
Example 32 - Preparation of (+)-4-(3,4-dichlorophenyl)-6-fluoro-7-(pyrazin-2-yl)- 1,2,3,4-tetrahydroisoquinoliiie. [0258] Step A: A procedure similar to the one in Step A of Example 29 was used to couple (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline with 2-chloropyrazine. (+)-4-(3,4- DicMorophenyl)-6-fluoro-2-memyl-7-φyrazin-2-yl)-l,2,3,4-tetrahydroisoquinoline was obtained in 47% yield as a brown oil: ESI MS m/z 388 [M + H]+. [0259] Step B: A procedure similar to the one in Step B of Example 29 was used to demethylate (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(pyrazin-2-yl)-l,2,3,4- tetrahydroisoquinoline to obtain (+)-4-(3,4-dichlorophenyl)-6-fluoro-7-(pyrazin-2-yl)- 1,2,3,4-tetrahydroisoquinoline (15 mg, 7%) as a yellow residue: 1H NMR (CDCl3, 500 MHz) δ 9.07 (s, IH), 8.67 (d, / = 2.0 Hz, IH), 8.54 (d, / = 2.0 Hz, IH), 7.82 (d, /= 7.5 Hz, IH), 7.42 (d, J = 8.5 Hz, IH), 7.287.27 (m, 2H), 7.02 (dd, J = 8.5, 2.0 Hz, IH), 6.72 (d, J= 11.5 Hz, IH), 4.304.28 (m, 3H), 3.563.53 (m, IH), 3.133.08 (m, IH); ESI MS m/z 374 [M + H]+.
Example 33 - Preparation of 4-(3,4-dicWorophenyl)-7-(pjridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline, tartrate salt.
[0260] Step A: A mixture of tert-butyl 4-(3,4-dichlorophenyl)-7-(4,4,5,5- tetiamethyl-l.S^-dioxaborolan-l-y^-S^-dmydroisoquinoline-^lHJ-carboxylate CSSl mg, 0.66 mmol) from Step H in Example 11, 3,6-dichloropyridazine (149 mg, 0.90 mmol), cesium carbonate (860 mg, 2.64 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(π) (27 mg, 0.03 mmol) was taken up in DMF (2.5 mL) and water (0.5 mL). The reaction flask was purged with nitrogen and heated at 800C for 6 hours. The reaction mixture was cooled to ambient temperature then partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with water and brine then dried over sodium sulfate. Concentration in vacuo and purification by flash column chromatography (80:20 to 20:80 hexanes/ethyl acetate) gave tert-butyl 7-(6-chloropyridazin-3-yl)-4-(3,4-dichlorophenyl)-3,4- dihydroisoquinoline-2(lH)-carboxylate (259 mg, 79%) as abrown solid: 1H NMR (CDCl3, 300 MHz) δ 7.957.70 (m, IH), 7.81 (d, 2H), 7.58 (d, IH), 7.36 (d, IH), 7.19 (s, IH), 7.12 (d, IH), 7.026.85 (m, IH), 5.124.55 (m, 2H), 4.204.15 (m, IH), 4.073.85 (m, IH), 3.783.66 (m, IH), 1.45 (s, 3H), 1.24 (s, 6H); ESI MS m/z 490 [M+H]+. [0261] Step B: To a solution of tert-butyl 7-(6-chloropyridazin-3-yl)-4-(3,4- dichlorophenyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate (259 mg, 0.52 mmol) in ethanol (15 mL) was added 10% palladium on carbon (80 mg) and hydrazine hydrate (128 mL, 2.60 mmol). The reaction mixture was heated at 75 0C for 1 hour under a nitrogen atmosphere. An additional quantity of hydrazine hydrate (128 mL, 2.60 mmol) was added and the reaction mixture heated at 75 0C for 3 hours 10% palladium on carbon (80 mg) was additionally added and the heating continued for another 2 hours. The reaction mixture was filtered through a celite pad and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (10 mL) at ambient temperature for 1 hour. After concentration in vacuo the residue was partitioned between dichloromethane (50 mL) and 2N sodium hydroxide solution. The organic layer was washed with brine then dried over sodium sulfate. Concentration in vacuo gave the crude material which was purified by flash column chromatography ((95:5 to 50:50 ethyl acetate/ethyl acetate: methanol: ammonium hydroxide, 80:18:2 v/v) to give 4-(3,4-dicUorophenyl)-7-(pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline (144 mg, 77%): [α]D = + 19.2 ° (0.06, methanol): 1H NMR (CDCl3, 300 MHz) δ 9.15 (dd, J= 5.0 Hz, 1.5 Hz, IH), 7.90 (d, /= 1.0 Hz, IH), 7.85 (dd, / = 8.5 Hz, 1.5 Hz, IH), 7.77 (dd, /= 8.3 Hz, 2.0 Hz, IH), 7.54 (d, J= 8.5 Hz, IH), 7.37 (d, / = 8.5 Hz, IH), 7.24 (d, / = 2.0 Hz, IH), 7.04 (d, / = 8.0 Hz, IH), 6.99 (dd, / = 8.3 Hz, 2.0 Hz, IH), 4.154.11 (m, 3H), 3.44 (dd, / = 12.8 Hz, 5.5 Hz, IH), 3.10 (dd, /= 13.0 Hz, 6.0 Hz, IH), 1.95 (br s, IH); ESI MS m/z 356 [M+H]+. [0262] Step C: To a solution of 4-(3,4-dichlorophenyl)-7-(pyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline (135 mg, 0.38 mmol) in methanol (2.5 mL) was added L-tartaric acid (57 mg, 0.38 mmol). The mixture was sonicated for 5 minutes, diluted with water (15 mL), and lyophilized to give the correspondent, L-tartrate salt (96 mg, 45%, AUC HPLC 98.6%) as a white solid. 1H NMR (CD3OD, 500 MHz) δ 9.16 (dd, J = 5.0 Hz, 1.5 Hz, IH), 8.19 (dd, /= 8.8 Hz, 1.0 Hz, IH), 8.06 (s, IH), 7.95 (dd, /= 8.0 Hz, 1.5 Hz, IH), 7.80 (dd, J = 9.0 Hz, 5.0 Hz, IH), 7.56 (d, / = 8.0 Hz, IH), 7.51 (d, J = 2.0 Hz, IH), 7.25 (dd, J = 8.5 Hz, 2.0 Hz, IH), 7.08 (d, J= 8.0 Hz, IH), 4.654.54 (m, 3H), 4.434.41 (m, 2H), 3.81 (dd, /= 12.3 Hz, 5.5 Hz, IH), 3.47 (t, /= 12.5 Hz, IH); ESI MS m/z 356 [M+H]+. Anal, calcd.
Figure imgf000101_0001
4H6O6LSH 2O: C, 50.74; H, 4.51; N, 7.46. Found C 50.64, H, 4.36; N 7.47.
Example 34 - Preparation of 6-(4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinolin-7-yl)pyridaziii-3-amine, tartrate Salt
[0263] 6-(4-(3,4-DicUorophenyl)-L2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3- amine (64 mg, 0.19 mmol) in methanol (3 mL) was prepared using similar methods described in Step K to Step L in Example 11 starting with tert-batyl 4-(3,4- dicMorophenyl)-7-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline- 2(lH)-carboxylate and 6-chloropyridazin-3-amine. The L-tartrate salt was prepared as a white solid. 1H NMR (CD3CO2D, 300 MHz) δ 7.87 (s, IH), 7.76 (d, J = 9.6 Hz, 2H), 7.337.28 (m, IH), 7.30 (dd, /= 8.7 Hz, 5.4 Hz, IH), 7.13 (t, /= 8.7 Hz, 2H), 6.99 (d, /= 8.1 Hz, IH), 6.97 (d, /= 9.3 Hz, IH), 4.654.54 (m, 3H), 4.42 (s, 2H), 3.78 (dd, /= 12.6 Hz, 5.7 Hz, IH), 3.45 (t, J = 11.1 Hz, IH), 3.01 (s, 3H); ESI MS m/z 371 [M+H]+. Anal, calcd. Ci9Hi6Cl2N4I.^ 4H6O6USH 2O: C, 49.04; H, 4.62; N, 9.61; found C 49.07, H, 4.65; N 9.45. Example 35 - Preparation of (+)- and 0-4-(4-chlorophenyl)-7-(6-trifluoromethyl- pyrazin-3-yl)-l,l-dimethyl-l^,3,4-tetrahydro-isoquinoline. [0264] Step A: 4-(4-CMorophenyl)-l,l-dimeihyl-7-(4,4,5,5-tBtramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline was prepared following similar methods described in Step A to Step E of Example 9 starting from 2-(3- bromophenyl)propan-2-amine and 2-bromo-l-(4-chlorophenyl)ethanone. 3-Trifluoromethyl-6-chloropyridazine (95 mg, 0.52 mmol) was added to a mixture of the aforementioned boronate ester (285 mg, 0.43 mmol) and cesium carbonate (423 mg, 1.30 mmol) in DMF (5 mL) and water (0.65 mL). The reaction mixture was degassed with argon. Dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (35 mg, 0.043 mmol) was added and the reaction mixture was stirred at 900C for 1.5 hours, cooled, diluted with water, and extracted with ethyl acetate (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography [3% methanol (containing 10% concentrated ammonium hydroxide)/ dichloromethane] gave 4-(4- cUorophenyl)-l,l-dimemyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline (140 mg, 78% over 2 steps): 1H NMR (CDCl3, 300 MHz) 1H NMR (CDCl3, 500 MHz) δ 8.23 (d, /= 1.7 Hz, IH), 8.01 (d, /= 8.9 Hz, IH), 7.87 (d, /= 8.9 Hz, IH), 7.73 (dd, /= 8.1, 1.8 Hz, IH), 7.317.26 (m, 2H), 7.077.02 (m, 3H), 4.13 (t, J = 5.3 Hz, IH), 3.45 (dd, J= 13.5, 5.0 Hz, IH), 3.12 (dd, J= 13.5, 5.8 Hz, IH), 1.62 (s, 3H), 1.58 (s, 3H); ESI MS m/z 418 [M + H]+. [0265] Step B: The racemic 4-(4-chlorophenyl)-l,l-dimethyl-7-(6- (trMuoromethyl)pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline (153 mg) from Step A was resolved by preparative chiral HPLC (ChiralPak AD column, using 80:20:0.1 heptane/isopropanol/diethylamine as the eluent) to give the 0-enantiomer ([ «]25 D 41.40 (c 0.22, methanol)) and the (+)-enantiomer ([α]25 D +41.4° (c 0.21, methanol)).
Example 36 - Preparation of 7-([l^,4]triazolo[l,5-α]pvridin-6-yl)-4-(3,4- dichlorophenyl)-l^,3,4-tetrahydroisoquinoline, L-Tartrate Salt
[0266] Step A: To a solution of 3-methoxybenzaldehyde (180 g, 1.32 mol) in methanol (1 L) was added a 40% aqueous solution of methylamine (113 ml, 1.31 mol) followed by 1 hour stirring at O 0C. Sodium borohydride (75 g, 1.98 mol) was added portionwise at 00C and the reaction mixture was stirred for 1 hour. The solution was concentrated to a smaller volume then, was diluted with water (200 mL) and the resulting solution was extracted with methylene chloride (3 x SOO mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude N-methylbenzylamine (220 g, quantitative) as clear oil, which was used in the next step without further purification: 1H ΝMR (CDCl3, 500 MHz) δ.7.23 (t, J = 8.0 Hz, IH), 6.926.88 (m, 2H), 6.816.78 (m, IH), 3.80 (s, 3H), 3.73 (s, 2H), 2.45 (s, 3H), 2.07 (broad s, IH). [0267] Step B: To a solution of the above amine (6.2 g, 41.00 mmol) from Step A in methylene chloride (100 mL) was added 3,4-dichlorophenacyl bromide (10.0 g, 37.3 mmol) and the resulting mixture was stirred at 00C for 1 hour prior to the addition of triethylamine (5.20 mL, 37.31 mmol), followed by 1 hour stirring at 00C. The reaction mixture was diluted with water (100 mL) then the aqueous phase was extracted with additional methylene chloride (3 x 75 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated to afford l-(3,4-dichlorophenyl)-2-((3- methoxybenzyl)(methyl)amino)ethanone (15.08 g) as a light yellow oil, which was used in the next step without further purification: 1H ΝMR (500 MHz, CDCl3) δ 8.08 (d, J = 2.0 Hz, IH), 7.78 (dd, /= 8.5; 2.0 Hz, IH), 7.50 (d, /= 8.5 Hz, IH), 7.25 (d, /= 8.5 Hz, IH), 6.90 (d, / = 7.5 Hz, IH), 6.87 (d, J= 2.5 Hz, IH), 6.82 (dd, / = 8.0; 2.5 Hz, IH), 3.79 (s, 3H), 3.66 (s, 2H), 3.60 (s, 2H), 2.33 (s, 3H).
[0268] Step C: To a solution of the ketone (-37 mmol) from Step B in methanol
(150 mL), was added sodium borohydride (2.11 g, 55.79 mmol) portionwise at 00C. The reaction mixture was first stirred for 2 hours then, was diluted with water (100 mL) and extracted with methylene chloride (3 x 300 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure to afford the crude alcohol (14.14 g) as a yellow oil, which was used without further purification in the next step: 1H ΝMR (500 MHz, CDCl3) δ 7.45 (d, J = 2.0 Hz, IH), 7.38 (d, J= 8.0 Hz, IH), 7.287.23 (m, IH), 7.16 (dd, J = 8.0; 2.0 Hz, IH), 6.906.81 (m, 3H), 4.704.65 (m, IH), 3.81 (s, 3H), 3.70 (d, / = 13.0 Hz, IH), 3.50 (d, / = 13.0 Hz, IH), 2.542.49 (m, 2H), 2.32 (s, 3H). [0269] Step D: To a solution of the alcohol (-37 mmol) from Step C in methylene chloride (200 mL) was added concentrated sulfuric acid (12 mL, 235 mol) and the mixture was stirred at 00C for 28 hours. The reaction was quenched by adding a 6N NaOH solution till pH~9. The aqueous phase was extracted with additional methylene chloride (3x). The combined organic extracts were washed with brine (3x), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (1:1:1: to 1:1:2 dichloromethane/hexanes/ethyl acetate) to afford 4-(3,4- dichlorophenyl)-7-methoxy-2-methyl-l,2,3,4-tetrahydroisoquinoline (7.0 g, 59% over 3 steps) as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, IH), 7.29 (d, J = 2.0 Hz, IH), 7.03 (dd, J = 8.5; 2.0 Hz, IH), 6.76 (d, J = 8.5 Hz, IH), 6.66 (dd, J = 8.5; 3.0hz, IH), 6.61 (d, J= 2.5 Hz, IH), 4.164.11 (m, IH), 3.77 (s, 3H), 3.673.59 (m, 2H), 2.92 (dd, / = 11.5; 5.5 Hz, IH), 2.55 (dd, / = 11.5; 7.0 Hz, IH), 2.39 (s, 3H). The undesired 5-methoxy isomer was also isolated (1.20 g, 10% over 3 steps). [0270] Step E: The racemic 4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-l,2,3,4- tetrahydroisoquinoline (7.0 g) from Step D above was resolved by preparative chiral HPLC (CHIRALPAK AD column, using 80:20:0.1 heptane/2-propanol/diethylamine as the eluent) to give the (+)-enantiomer ([α]25 D +31.9° (c 0.49, methanol)) (3.68 g) as a colorless oil and the 0-enantiomer (3.99 g) as a colorless oil. [0271] Step F: A solution of (+)-4-(3,4-dichlorophenyl)-7-methoxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline (3.68 g, 11.42 mmol) in a mixture of acetic acid (20 mL) and 48% aqueous hydrobromic acid solution (50 mL) was refluxed for 8 hours. The ice- cold reaction mixture was basified with a concentrated aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium bicarbonate until reaching a pH of about 8-9 and was extracted with dichloromethane (3x). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude alcohol (2.6 g) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 8.5 Hz, IH), 7.26 (d, J = 2.0 Hz, IH), 7.01 (dd, J = 8.0; 2.0 Hz, IH), 6.65 (d, J = 8.0 Hz, IH), 6.54 (d, J = 8.5 Hz, IH), 6.49 (broad s, IH), 4.154.10 (m, IH), 3.60 (d, /= 15.0 Hz, IH), 3.56 (d, / = 15.0 Hz, IH), 2.96 (dd, J = 11.5; 5.7 Hz, IH), 2.52 (dd, J= 11.5, 8.0 Hz, IH), 2.39 (s, 3H).
[0272] Step G: To a solution of the phenol from Step F above (2.1 g, 6.81 mmol) and pyridine (0.72 mL, 8.85 mmol) in dichloromethane (60 mL) was added trifluoromethanesulfonic anhydride (1.37 mL, 8.14 mmol) at 78 0C. The reaction was allowed to warm to 00C and stirred for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 x). The combined extracts were dried over sodium sulfate, filtered, and concentrated to give the crude triflate as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 8.5 Hz, IH), 7.30 (d, J = 2.0 Hz, IH), 7.036.98 (m, 3H), 6.94 (d, /= 8.5 Hz, IH), 4.194.15 (m, IH), 3.68 (s, 2H), 2.96 (dd, / = 11.7; 5.5 Hz, IH), 2.60 (dd, /= 11.7, 7.5 Hz, IH), 2.42 (s, 3H). [0273] Step H: A mixture of the triflate from Step G above (~6.8 mmol), bis(pinacolato)diboron (2.07 g, 8.15 mmol), and potassium acetate (2.05 g, 20.8 mmol) in dimethyl sulfoxide (35 mL) was degassed with argon. To this mixture was added dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) (0.40 g, 0.55 mmol). The resulting mixture was degassed with argon and then heated at 85 0C for 2 hours. The cold reaction mixture was diluted with ethyl acetate (150 mL). The resulting solution was washed with water (2 x 40 mL), brine (1 x 40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. A Purification flash chromatography column (eluent, 1 : 1 : 1 to 1:1:2 dichloromethane/hexanes/ethyl acetate) gave the desired boronate ester (2.6 g, 91% over 2 steps) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.55 (s, IH), 7.52 (d, J = 7.5 Hz, IH), 7.33 (d, J= 8.5 Hz, IH), 7.28 (d, J = 2.0 Hz, IH), 7.01 (dd, J= 8.0, 2.0 Hz, IH), 6.85 (d, J= 8.0 Hz, IH), 4.23 (t, J = 6.5 Hz, IH), 3.71 (d, J= 15.0 Hz, IH), 3.67 (d, / = 15.0 Hz, IH), 2.98 (dd, / = 11.4, 5.3 Hz, IH), 2.56 (dd, / = 11.4, 7.5 Hz, IH), 2.41 (s, 3H), 1.33 (s, 12H).
[0274] Step I: To a solution of the boronate ester (2.6 g, 6.22 mmol) from Step F and proton sponge (2.6 g, 12.1 mmol) in dichloroethane (80 mL) at 00C was added 1- chloroethyl chloroformate (2.4 mL, 22.1 mmol). The mixture was stirred at 00C for 15 minutes, then was refluxed for 40 minutes and was concentrated in vacuo. The residue was filtered through a short pad of silica gel (eluent, 1:1:1 dichloromethane/hexanes/ethyl acetate) and the filtrate was concentrated in vacuo. The residue was diluted with methanol (160 mL), heated to reflux for 1 hour and concentrated in vacuo to give the 4- (3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4- tetrahydroisoquinoline as a brown foam.
[0275] Step J: A solution of the product from Step I (-6.2 mmol), (Boc)2O (3.60 g, 16.4 mmol), triethylamine (1.5 mL, 10.7 mmol) and DMAP (0.26 g, 2.20 mmol) in dichloromethane (120 mL) was stirred at room temperature for 4 hours. The reaction was quenched by the addition of water (SO mL) then, the aqueous phase was extracted with additional dichloromethane (2 x 100 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. A purification by flash column chromatography (eluent, 47.5:47.5:5 to 1:1:1 dichloromethane/hexanes/ethyl acetate) gave the boc-protected tetrahydroisoquinoline (1.82 g, 58% over 3 steps) as a white foam. 1H NMR (500 MHz, CDCl3) δ 7.65 (s, IH), 7.58 (d, J= 7.5 Hz, IH), 7.32 (d, J = 8.0 Hz, IH), 7.13 (s, IH), 6.95 (d, /= 7.0 Hz, IH), 6.976.93 and 6.836.78 (m, IH), 5.014.95 and 4.484.43 (m, IH), 4.564.52 (m, IH), 3.95 (s, IH), 3.833.44 (m, 2H), 1.43 and 1.26 (2s, 9H), 1.33 (s, 12H). [0276] Step K: A dry flask was loaded with the boronate ester (0.8 g, 1.59 mmol) from Step J, 6-bromo-[l,2,4]triazolo[l,5-α]pyridine (0.35 g, 1.78 mmol), cesium carbonate (0.97 g, 2.98 mmol), and dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (87 mg, 0.12 mmol). The flask was blanketed with argon then, DMF (20 mL) and water (4 mL) were added followed by a short sonication. The reaction mixture was heated to 800C for 1 hour. The cold reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane (3 x 60 mL). The combined organic phases were concentrated in vacuo. Purification by flash column chromatography (eluent, 1 : 1 : 1 to 1:1:2 dichloromethane/hexanes/ethyl acetate) gave the Boc-protected 7- ([l,2,4]triazolo[l,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline (0.86 g, quantitative) as a white foam.
[0277] Step L: A solution of the Boc-protected 7-([l,2,4]triazolo[l,5-α]pyridin-6- yl)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline (0.85 g, 1.72 mmol) and concentrated hydrochloric acid (4.0 mL) in ethanol (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness in vacuo. The residue was dissolved in a mixture of dichloromethane (14 mL) and TFA (10 mL), stirred at room temperature for 1 hour then concentrated in vacuo. The syrup thus obtained was diluted with dichloromethane and treated with a saturated aqueous solution of sodium bicarbonate until pH 8-9. The aqueous phase was extracted with additional dichloromethane (3x) and the organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to give7-([l,2,4]triazolo[l,5-α]pyridin-6-yl)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline (0.59 g, 87%) as a white foam. [0278] Step M: To a solution of the product (0.59 g, 1.49 mmol) from Step B in ethanol was added L-tartaric acid (0.22 g, 1.49 mmol). The slurry was filtered. The cake was rinsed with ethanol and dried to give 7-([l,2,4]triazolo[l,5-α]pyridin-6-yl)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline, L-tartrate salt (0.49 g, 59%, AUC HPLC >99%) as a white solid. [[α]25 D +9.0° (c 0.11, methanol)]. 1H NMR (SOO MH^ CD3OD) δ 9.09 (s, IH), 8.53 (s, IH), 8.02 (dd, /= 9.0, 2.0 Hz, IH), 7.86 (d, /= 9.0 Hz, IH), 7.68 (s, IH), 7.647.61 (m, IH), 7.55 (d, / = 8.0 Hz, IH), 7.48 (d, J = 2.0 Hz, IH), 7.24 (dd, J = 8.0, 2.0 Hz, IH), 7.04 (d, J = 8.0 Hz, IH), 4.654.57 (m, 2H), 4.52 (d, J = 16.0 Hz, IH), 4.41 (s, 2H), 3.79 (dd, J = 12.5, 6.0 Hz, IH), 3.44 (t, J = 12.5 Hz, IH). ESI MS m/z 395 [M+H]+. Anal. Calcd. for C2IHi6Q2N4C 4H6O60.5H 2O: C, 54.16; H, 4.18; N, 10.11. Found: C, 54.07; H 3.92; N, 9.97.
[0279] The L-tartrate of the (-)-7-([l,2,4]triazolo[l,5-α]pyridin-6-yl)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline was prepared using (-)-4-(3,4- dichlorophenyl)-7-methoxy-2-methyl-l,2,3,4-tetrahydroisoquinoline following similar steps described for the synthesis of the (+)-7-([l,2,4]triazolo[l,5-α]pyridin-6-yl)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline, L-tartrate salt ([O]24 D -6.0° (c 0.10, methanol)).
Example 37 Alternate Synthesis of Example 36
[0280] Step A: To a solution of the triflate (9.5 g, 21.6 mmol) from step G in
Example 36 and bis(pinacolato)diboron (6.6 g, 25.9 mmol) in dimethyl sulfoxide (200 mL) was added potassium acetate (6.4 g, 64.8 mmol). The solution was degassed with argon for 5 minutes and then dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) (1.6 g, 2.2 mmol) was added to it. The reaction mixture was degassed with argon for 5 minutes, heated at 800C for 1 hour, and then cooled to room temperature. To this solution were added 6-bromo- [l,2,4]triazolo[l,5-α]pyridine (4.8 g, 23.8 mmol) and an aqueous solution of cesium carbonate (21.1 g, 64.8 mmol in 87 mL of water). The resultant solution was degassed with argon and then dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) (0.8 g, 1.1 mmol) was added to it. The reaction mixture was degassed with argon and heated at 800C for 1 hour. A dark sticky oil formed during the reaction. The dark supernatant solution was poured out, diluted with water, and extracted with ethyl acetate (3x), which was dried over sodium sulfate and concentrated in vacuo. The oil left was dissolved in dichloromethane and the resultant solution was washed with water, dried over sodium sulfate, and concentrated in vacuo. The combined crude product was purified by flash column chromatography (100% ethyl acetate to 92:7.2:0.8 ethyl acetate/methanol/ammonium hydroxide) to give 7-([l,2,4]triazolo[l,S-α]pyridin-6-yl)-4- (3,4-dichlorophenyl)-2-methyl-l,2,3,4-tetrahydroisoquinoline (7.7 g, 87%, AUC HPLC 97.6%) as a brown foam: 1H NMR (500 MHz, CDCl3) δ 8.77 (s, IH), 8.37 (s, IH), 7.82 (d, J = 9.0 Hz, IH), 7.76 (d, J = 9.0 Hz, IH), 7.397.32 (m, 4H), 7.09 (d, J = 8.0 Hz, IH), 7.01 (d, J = 8.5 Hz, IH), 4.26 (t, J = 6.5 Hz, IH), 3.75 (app s, 2H), 3.01 (dd, J= 11.5, 5.5 Hz, IH), 2.64 (dd, J= 11.5, 6.5 Hz, IH), 2.46 (s, 3H).
[0281] Step B: To a solution of the 7-([l,2,4]triazolo[l,5-α]pyridin-6-yl)-4-(3,4- dichlorophenyl)-2-methyl-l,2,3,4-tetrahydroisoquinoline (7.2 g, 17.6 mmol) from step A above in 1,2-dichloroethane (180 mL) at 00C was added proton sponge (3.8 g, 17.6 mmol), followed by addition of 1-chloroethyl chloroformate (2.3 mL, 21.1 mmol). After the addition, the reaction solution was stirred at 00C for 20 minutes and room temperature for 14 hours. Additional 1-chloroethyl chloroformate (0.5 mL, 4.6 mmol) was added to the reaction solution. The reaction solution was stirred for another 3 hours and then it was cooled to 00C, washed with aqueous hydrochloric acid (IN). Precipitate formed during the acid wash. The organic extract was separated, dried over sodium sulfate, and concentrated in vacuo. The residue obtained was purified by flash column chromatography (dichloromethane to 95:4.5:0.5 dichloromethane/methanol/ammonium hydroxide) to give two batches of partially purified carbamate intermediates, which were dissolved in methanol and refluxed for 1 hour. The reaction solutions were concentrated in vacuo and the crude product obtained was purified by a combination of flash column chromatography (ethyl acetate to 88:10.2:0.8 ethyl acetate/methanol/ammonium hydroxide) and preparative thin layer chromatography (ethyl acetate/methanol/ammonium hydroxide 90:9:1) to give the desired des-methyl tetrahydroisoquinoline (3.8 g, 54%; AUC HPLC 98.7%) as a light pink foam: 1H NMR (500 MHz, CDCl3) δ 8.788.77 (m, IH), 8.37 (s, IH), 7.83 (dd, J = 9.5, 1.0 Hz, IH), 7.77 (dd, J = 9.0, 1.5 Hz, IH), 7.39 (d, J= 8.5 Hz, IH), 7.367.26 (m, 3H), 7.057.00 (m, 2H), 4.24 (d, J = 16.5 Hz, IH), 4.17 (d, J = 16.5 Hz, IH), 4.134.11 (m, IH), 3.44 (dd, J= 12.5, 5.0 Hz, IH), 3.11 (dd, / = 13.0, 6.0 Hz, IH).
[0282] Step C: To a solution of des-methyl tetrahydroisoquinoline (3.75 g, 9.48 mmol) from step B above in ethanol (80 mL) was added activated carbon (3.0 g) and stirred at room temperature for 30 minutes. The carbon was removed by filtration and the filtrate obtained was concentrated in vacuo. The resultant oil was dissolved in ethanol (60 mL) and a solution of L-tartaric acid (1.44 g, 9.5 mmol) in ethanol (20 mL) was added. Upon which, white precipitate formed immediately. The slurry was stirred at room temperature for 10 minutes and filtered. The cake obtained was stirred in hot ethanol (700C) for 3 hours and filtered. The cake obtained was dried in vacuo at 50-60 0C for 40 hours to give the (+)-7-([l,2,4]triazolo[l,5-α]pyridin-6-yl)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline L-tartrate (3.7 g, 73%; AUC HPLC 99.4% at 250 nm) as an off-white solid [α]23 D +16.8° (c 0.13, methanol): 1H NMR (500 MHz, CD3OD) δ 9.09 (s, IH), 8.53 (s, IH), 8.02 (dd, /= 9.0; 2.0 Hz, IH), 7.86 (d, / = 9.0 Hz, IH), 7.68 (s, IH), 7.647.61 (m, IH), 7.55 (d, J = 8.0 Hz, IH), 7.48 (d, J = 2.0 Hz, IH), 7.24 (dd, J = 8.0; 2.0 Hz, IH), 7.04 (d, J = 8.0 Hz, IH), 4.654.57 (m, 2H), 4.52 (d, J = 16.0 Hz, IH), 4.41 (s, 2H), 3.79 (dd, /= 12.5; 6.0 Hz, IH), 3.44 (t, /= 12.5 Hz. IH). ESI MS m/z 395 [M+H]+ Anal. Calcd. for C2IHi6Q2N4C 4I6O6O-SH 2O: C, 54.16; H, 4.18; N, 10.11. Found: C, 53.96; H 3.98; N, 9.94.
Example 38 - Alternative Synthesis of Example 36 (Hydrochloride)
[0283] Step A: To a 1 L round-bottom flask was added 2-amino-5-bromopvridine
(100 g, 578 mmol), DMF-DMA (101 mL, 751 mmol) and 2-propanol (200 mL). The mixture was heated to reflux for 3 h to give a clear dark solution. It was then cooled to 50 0C and hydroxylamine hydrochloride (52.2 g, 751 mmol) was added. The mixture was stirred at 500C overnight to give a yellow suspension. The precipitate was collected by filtration. The black filtrate was concentrated and the residue was stirred in EtOH (20 mL) for 20 min. The solid was collected by filtration. The combined solids were dried in an oven to give N-β-bromopyridin^-yφ-N'-hydroxyformiiridamide as a sandy solid (94 g, 75% yield). [0284] Step B: N-(5-bromopyridin-2-yl)-N'-hydroxyformimidamide was dissolved in THF (1 L). To the solution at 100C was added trifluoroacetic anhydride (106 mL, 751 mmol) slowly to control the reaction temperature below 200C. After the addition was complete, the mixture was warmed to room temperature and stirred for 2 h. After the reaction was finished, it was quenched with Na2COs aqueous solution to adjust pH >7. The organic solvent was removed under reduced pressure, and the product was then extracted with DCM (4 x 300 mL). The combined organic layers were dried over Na2SO4 and concentrated to dryness. The residue was stirred in ethyl ether (100 mL) and the product 6-bromo-[l,2,4]triazolo[l,5-a]pyridine was collected by filtration as an off- white solid (50 g, 58% yield).
[0285] Step C: To a mixture of 3-formylphenylboronic acid (21.41 g, 143 mmol),
6-bromo-[l,2,4]triazolo[l,5-a]pyridine (28.27 g, 143 mmol) in DMSO (600 mL) and water (50 mL) was added Pd(dppf)Cl2 (5.83 g, 7.14 mmol) and Cs2CO3 (116 g, 357 mmol). The reaction temperature reached 45 0C after the addition. HPLC showed that starting materials were consumed after 15 min. The reaction was diluted with water (400 mL). The black precipitate was collected by filtration and dissolved in DCM (300 mL), and washed with brine (200 mL). The aqueous layer was back extracted with DCM (100 mL). The combined organic layers were filtered through a Celite pad and the filtrate was concentrated to give a black solid mixture. The product was recrystallized in methanol to give 3-([l,2,4]triazolo[l,5-a]pyridin-6-yl)benzaldehyde (27.4 g, 123 mmol, 86 % yield) as a pale grey solid: m/z = 224.0 [M+l]; 1H NMR (400 MHz, DMSO-D6) δ ppm 7.74 (t, 7=7.68 Hz, 1 H), 7.91 - 8.02 (m, 2 H), 8.11 (dd, 7=9.19, 1.89 Hz, 1 H), 8.17 (d, 7=7.81 Hz, 1 H), 8.36 (s, 1 H), 8.57 (s, 1 H), 9.45 (s, 1 H), 10.11 (s, 1 H). [0286] Step D: A mixture of α-bromo-3,4-dichloroacetophenone (26.7 g, 100 mmol), hexamethylenetetramine (HMTA) (13.97 g, 100 mmol) and NaI (0.5 g) was stirred at room temperature overnight. HPLC analysis indicated consumption of starting materials. The ammonium intermediate was collected by filtration as a white solid, washed with acetone and dried (36 g, 89% yield). [0287] To a solution of the intermediate (36 g, 88 mmol) in EtOH (500 mL) was added 12 N HCl (75 mL, 0.9 mol). The mixture was stirred at 760C overnight, and then cooled to room temperature. The product 2-amino-l-(3,4-dichlorophenyl)ethanone hydrochloride was obtained as a crystal solid by filtration (20.2 g, 95% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 4.62 (s, 2 H), 7.79 - 7.94 (m, 1 H), 7.98 (dd, /=8.56, 2.01 Hz, 1 H), 8.26 (d, 7=2.01 Hz, 1 H), 8.48 (s, 3 H).
[0288] Step E: To a solution of 2-amino-l-(3,4-dichlorophenyl)ethanone hydrochloride (50 g, 208 mmol) in MeOH (200 mL) was added sodium borohydride (7.86 g, 208 mmol) at 00C slowly. HPLC indicated 100% conversion after 10 min. A solution of 3-([l,2,4]triazolo[l,5-a]pyridin-6-yl)benzaldehyde (46.4 g, 208 mmol) in DCM / MeOH (18OmL / 5OmL) was added to the previous solution in one portion at room temperature. The mixed solution was stirred at RT for 2 h, then sodium borohydride (7.86 g, 208 mmol) was added. HPLC indicated 100% conversion after 10 min. Most of the solvent was removed and the residual was dissolved in DCM / NH4OH (4N) (1 L / 1 L). The organic layer was washed with brine, dried over Na2SO4, and concentrated to ~250 mL. The product 2-(3-([l,2,4]triazolo[l,5-α]pyridin-6-yl)benzylamino)-l-(3,4- dichlorophenyl)ethanol in DCM solution was used in the next step without further purification (HPLC area 92%): m/z =413.1 [M+l]; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.72 (dd, /=12.21, 8.69 Hz, 1 H), 2.96 (dd, /=12.34, 3.53 Hz, 1 H), 3.85 - 3.98 (m, 2 H), 4.69 (dd, /=8.56, 3.53 Hz, 1 H), 7.18 (dd, /=8.31, 1.76 Hz, 1 H), 7.34-7.42 (m, 2 H), 7.43-7.56 (m, 4 H), 7.72-7.88 (m, 2 H), 8.36 (s, 1 H), 8.78 (s, 1 H). [0289] Step F: A solution of concentrated sulfuric acid (500 g, 5.0 mol) in a 3 L round bottom flask was cooled to 00C with an ice bath. To the flask was added dropwise a solution of 2-(3-([l,2,4]triazolo[l,5-α]pyridin-6-yl)benzylamino)-l-(3,4- dichlorophenyl)ethanol (79 g, 0.191 mol) in DCM (250 mL). The addition was finished in 30 min and the reaction temperature was controlled in the range of 10-200C. DCM was blown away with nitrogen gas during the addition. The evaporation of DCM helped to lower the reaction temperature. The mixture solution was stirred at RT overnight. HPLC indicated no remaining starting material. The HPLC area ratio of 7-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline and 5- ([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline was 75:25. The reaction mixture was cooled to 0 0C. Isopropanol (2 L) was added to the solution slowly, maintaining temperature < 00C. The solid (desired isomer 92% purity) was obtained by filtration. The solid was then dissolved in AcOEt (IL) and the pH adjusted to 10 with NH4OH. The water layer was extracted with EtOAc twice. The - Ill -
combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue was dissolved in EtOH (250 mL) and then 1.1 eq of methanesulfonic acid (20.20 g, 0.21 mol) was added and the solution stirred overnight The resulting precipitate methanesulfonic acid salt (98% purity) was filtered. This was dissolved in water and the pH adjusted with NH4OH to 10, then extracted with AcOEt twice. The combined extracts were washed with water and dried over Na2SO4. After removal of solvent, 7- ([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline 7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinoline was obtained in an amorphous state (40.8g, 54% yield): m/z = 395.0 [M+l]; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.05 (dd, 7=12.00, 8.00 Hz, 1 H), 3.40 (dd, 7=12.00, 4.00 Hz, 1 H), 4.05-4.25 (m, 3 H), 6.96 (m, 2 H), 7.25-7.35 (m, 4 H), 7.70-7.80 (m, 2 H), 8.32 (s, IH), 8.74(s, 1 H).
[0290] Step G: To a solution of 7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline (25.2 g, 63.8 mmol) in DMF (30 ml) was added di-tert-butyl dicarbonate (13.91 g, 63.8 mmol). The reaction mixture was stirred at RT for 1 h, then AcOEt (500 ml) was added. The solution was washed with brine and water. The organic layer was dried over Na2SO4. After removal of solvent, solid rac- tert-butyl 7-([ l,2,4]triazolo[ l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4- dihydroisoquinoline-2(lH)-carboxylate (30.6 g, 61.8 mmol, 97% yield) was obtained by recrystallization from MeOH; m/z = 495.1 [M+l]; 1H NMR (400 MHz,
CHLOROFORM-D) δ ppm 1.30 (s, 9H), 3.60-4.15 (m, 3 H), 4.40-5.10 (m, 2H), 6.84- 7.05 (m, 2H), 7.13 (d, J = 1.51 Hz, IH), 7.35 (m, 3H), 7.78 (dd, J=8.31, 1.77 Hz, 2 H), 8.31 (s, IH), 8.72 (s, IH). [0291] Step H: Chiral SFC separation on a Chiralpak AS-H column (3x25cm, 5μm; eluent: CO2/(MeOH/TEA=100/0.2(v/v))= 75/25; 220 ran) yielded f+J-tert-butyl 7- ([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline- 2(lH)-carboxylate (99.7% ee).
[0292] Step I: To a solution of the (+)-enantiomer from Step H (32.41 g, 65.43 mmol) in DCM (150 ml) was added hydrogen chloride-EtOH solution (2.5N, 250 mL) and EtOH 500 mL. The reaction mixture was stirred at 700C for 2h. After removal of the solvent, the residue was refluxed in 1000 ml AcOEt for Ih. The product (+)-7- ([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride (27.4 g, 97 % yield) was obtained after filtration and drying, m/z = 395.1 [M+l]; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.70 (m, 2 H), 4.40-4.65 (m, 3H), 6.90 (d, 7.80 Hz, IH), 7.35 (dd, J = 7.8, 2 Hz, IH), 7.68 (m, 4H), 8.58 (s, IH), 9.38 (s, IH), 9.8 (bs, 2H).
Example 39 - Preparation of (+)-7-([l^,4]triazolo[l^-α]pyridin-6-yl)-4-(3,4- dichlorophenyl)-6-fluoro-l^,3,4-tetrahydroisoquinoline, L-tartrate Salt
[0293] Step A: To a solution of l-(4-fluoro-3-methoxyphenyl)-iV- methylmethanamine (0.9 g, 5.39 mmol) in ethanol (8.0 mL) was added potassium carbonate (0.6 g, 4.48 mmol) and 2-bromo-l-(3,4-dichlorophenyl)ethanone (1.2 g, 4.48 mmol). The reaction solution was stirred for 2.5 hours at room temperature and then sodium borohydride (0.2 g, 5.83 mmol) was added to it portionwise at 00C. The reaction mixture was stirred overnight while warming up to room temperature. The reaction solution was concentrated in vacuo. The slurry obtained was quenched with water and extracted with methylene chloride. The combined organic extracts were washed with brine (2 x 200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (1:1 to 1:9 hexanes/ethyl acetate) to afford l-(3,4-dichlorophenyl)-2-((4-fluoro-3- methoxybenzyl)(methyl)amino)ethanol (1.9 g): 1H NMR (CDCl3, 300 MHz) δ 7.45 (d, J = 1.5 Hz, IH), 7.39 (d, J = 3.0 Hz, IH), 7.16 (dd, J = 8.0, 2.0 Hz, IH), 7.05 7.01 (m, IH), 6.91 (dd, J= 8.0, 2.0 Hz, IH), 6.81 6.78 (m, IH), 4.69 (t, J= 7.0 Hz, IH), 3.98 (br.s, IH), 3.90 (s, 3H), 3.67 (d, J= 13.5 Hz, IH), 3.47 (d, J= 13.0 Hz, IH), 2.50 (d, J = 7.0 Hz, 2H), 2.32 (s, 3H); ESI MS m/z 358 [M+H]+.
[0294] Step B: To a solution of the alcohol (1.1 g, 2.93 mmol) from Step A above in methylene chloride (10.0 mL) was added concentrated sulfuric acid (1.5 mL, 0.56 mmol). The reaction mixture was stirred at 00C for 30 minutes and at room temperature for 2 hours. The reaction solution was quenched at 00C by addition of an aqueous solution of sodium hydroxide (2N) and the aqueous phase was extracted with additional methylene chloride (3x). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (7:3 to 1 :9 hexanes/ethyl acetate) to afford 4-(3,4-dichlorophenyl)-6- fluoro-7-meihoxy-2-meihyl-l,2,3,4-tetrahydroisoquinoline (1.0 g, 98%): 1H NMR (500 MHz, CDCl3) δ 7.35 (d, / = 8.0 Hz, IH), 7.28 (d, J = 2.5 Hz, IH), 7.03 (dd, / = 8.0, 2.0 Hz, IH), 6.65 (d, J = 9.0 Hz, IH), 6.55 (d, J = 12.0 Hz, IH), 4.09 (t, J = 7.5 Hz, IH), 3.87 (s, 3H), 3.60 (s, 2H), 2.92 (dd, / = 12.0, 5.5 Hz, IH), 2.53 (dd, / = 11.5, 7.5 Hz, IH), 2.41 (s, 3H); ESI MS m/z 340 [M+H]+.
[0295] Step C: The racemic 7-methoxy tetrahydroisoquinole from Step B above
(8.5 g) was resolved by preparative chiral HPLC (CHIRALPAK AD column, using 80:20:0.1 heptane/isopropanol/diethylamine as the eluent) to give (+) enantiomer (4.0 g) and 0 enantiomer (4.0 g). [0296] Step D: To a solution of (+) 7-methoxytetrahydroisoquinoline from Step C above (3.4 g, 11.70 mmol) in hydrobromic acid (90 mL, 48% solution in water) was added acetic acid (48 mL). The reaction solution was stirred at 1100C overnight under nitrogen and then concentrated under reduced pressure. The resultant solution was quenched with sodium bicarbonate and extracted with dichloromethane, dried over aqueous sodium sulfate, and concentrated under reduced pressure to give the desired phenol (3.6 g, crude), which was used in the next step without further purification: 1H NMR (MeOD, 500 MHz) δ 7.44 (d, / = 7.0 Hz, IH), 7.33 (d, / = 1.5 Hz, IH), 7.11 (dd, J = 8.0, 2.0 Hz, IH), 6.69 (d, J = 8.5 Hz, IH), 6.46 (d, J = 12.0 Hz, IH), 4.19 (t, J = 7.0 Hz, IH), 3.67 3.53 (m, 2H), 3.01 (dd, J = 11.5, 5.5 Hz, IH), 2.52 (dd, J = 12.0, 9.0 Hz, IH), 2.40 (s, 3H); ESI MS m/z 326 [M+H]+.
[0297] Step E: To a solution of the phenol (2.5 g, 7.79 mmol) from Step D above in dichloromethane (30 mL) at 00C was added pyridine (0.8 mL, 10.12 mmol) followed by slow addition of trifluoromethanesulfonic anhydride (1.4 mL, 8.18 mmol) dropwise. The resultant reaction solution was stirred at 00C for 1 hour, and then was quenched with aqueous saturated sodium bicarbonate. The organic extract was separated and the aqueous layer was extracted with dichloromethane (3x). The combined organic extract was washed with 1:1 water/brine, dried over sodium sulfate, and concentrated under reduced pressure to give the desired triflate (3.5 g) as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 7.39 (dd, J = 8.0, 2.5 Hz, IH), 7.31 (d, J = 2.0 Hz, IH), 7.07 (d, J = 7.5 Hz, IH), 7.02 (dd, J = 6.0, 2.0 Hz, IH), 6.75 (d, / = 10.0 Hz, IH), 4.14 (t, / = 6.5 Hz, IH), 3.61 (s, 2H), 2.95 (dd, / = 11.5, 5.5 Hz, IH), 2.58 (dd, / = 11.5, 7.0 Hz, IH), 2.43 (s, 3H). [0298] Step F: To a mixture of triflate (3.5 g, 7.57 mmol) in Step E above bis(pinacolato)diboron (2.3 g, 9.09 mmol) and potassium acetate (2.2 g, 22.72mmol) were added in DMSO (100.0 mL). The reaction solution was purged with argon for 10 minutes, and then l,r-bis(diphenylphosphino)ferrocenedichloropalladium (0.5 g, 0.61 mmol) was added to it. The reaction solution was degassed again with argon for 5 minutes and heated at 800C overnight. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (90:9:1 dichloromethane/methanol/concentrated ammonia) to give 4-(3,4-dichlorophenyl)-6- fluoro-2-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4- tetrahydroisoquinoline ( 0.1 g, 3%): 1H NMR (CDCl3, 500 MHz) δ 7.48 (d, / = 6.0 Hz, IH), 7.37 7.34 (m, IH), 7.27 (s, IH), 7.00 (dd, J = 8.0, 2.0 Hz, IH), 6.56 6.51 (m, IH), 4.19 (t, J= 6.5 Hz, IH), 3.69 3.53 (m, 2H), 2.96 (dd, / = 11.5, 5.5 Hz, IH), 2.53 (dd, /= 11.5, 7.5 Hz, IH), 2.40 (s, 3H), 1.35 (s, 12H).
[0299] Step G: A mixture of the boronate ester from Step F (350 mg, 0.80 mmol, prepared in Step F), 6-bromo-[l,2,4]triazolo[l,5-α]pyridine (191 mg, 0.96 mmol) and cesium carbonate (786 mg, 2.41 mmol), in water (0.8 mL) and iV^V-dimethylformamide (4 mL) was degassed with argon and then [1,1- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (33 mg, 0.040 mmol) was added. The mixture was degassed again and then heated to 900C for 2.5 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (2x), brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was partially purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to give (+)-7-([l,2,4]triazolo[l,5- α]pyridin-6-yl)-4-(3,4-dicMorophenyl)-6-fluoro-2-memyl-l,2,3,4-tetι^ydroisoquinoline was obtained in 54% yield as a brown oil: ESI MS m/z 428 [M + H]+. [0300] Step H: To (+)-7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4- dichlorophenyl)-6-fluoro-2-methyl-l,2,3,4-tetrahydroisoquinoline (160 mg, 0.37 mmol) and Nl,Nl,N8,N8-tetramethylnaphthalene-l,8-diamine (160 mg, 0.37 mmol) in 1,2- dichloroethane (5 mL) was added 1-chlorethyl chloroformate (0.082 mL, 0.75 mmol) dropwise. The mixture was heated to reflux for 3 hours and then cooled to ambient temperature. The reaction mixture was diluted with methylene chloride and washed with 1 N HCl, water, dried over sodium sulfate, filtered, and concentrated in vacuo. To the residue was added methanol (IS mL) and the mixture was heated to reflux. After 1 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) and preparative TLC (90:9:1 methylene chloride/methanol/ammonium hydroxide). To the obtained material (10 mg, 0.024 mmol) in acetonitrile (1.5 mL) was added L-tartaric acid (3.6 mg, 0.024 mmol) in water (2 mL). The resultant solution was lyophilized to give (+)-7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6- fluoro-l,2,3,4-tetrahydroisoquinoUne, L-tartrate salt (19 mg, 9%, AUC HPLC >99%) as a white powder: IH NMR (CD3OD, 500 MHz) D9.03 (s, IH), 8.47 (s, IH), 7.93 (d, J = 9.0 Hz, IH), 7.87 (d, J = 9.5 Hz, IH), 7.607.56 (m, 2H), 7.50 (d, J = 2.0 Hz, IH), 7.24 (dd, J = 8.0, 1.5 Hz, IH), 6.80 (d, J = 11.5 Hz, IH), 4.564.46 (m, 3H), 4.43 (s, 2.3H), 3.783.73 (m, IH), 3.413.38 (m, IH); ESI MS m/z 413 [M + H]+; [ D]24D +21.2 ° (c 0.11, methanol).
Example 40 Preparation of 4-(3,4-dicWorophenyl)-7-([l,2,4]triazolo[l,5- α]pyridin- 6-yl)-l,l-dimetfayl-l,2^,4-tetrahydroisoquinoliiie.
[0301] Step A: Cerium(m) chloride heptahydrate (29.8 g, 80 mmol) was dried with magnetic stirring at 145 0C under vacuum overnight Tetrahydrofuran (160 mL) was added and the white suspension was stirred at room temperature for 2 hours and then cooled with dry-ice/acetone bath. To this dry-ice/acetone bath cooled solution was added methyl lithium (1.6 M in ether, 50 mL, 80 mmol). The reaction mixture was stirred for 30 minutes and then a solution of 3-bromobenzonitrile (3.68 g, 20 mmol) in tetrahydrofuran (10 mL) was added. The resulting reaction mixture was stirred at 70 to 600C for 5 hours. Concentrated ammonium hydroxide (50 mL) was added at 400C. The mixture was allowed to warm to room temperature and filtered through Celite. The Celite bed was washed with dichloromethane. The filtrate was extracted with dichloromethane (3x). The combined extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give l,l-dimethyl-3-bromobenzyl amine (4.33 g, >99% crude) as a clear oil, which was used in the next step without further purification: ESI MS m/z 214 [M+H]+.
[0302] Step B: To a solution of 2-bromo-l-(3,4-dichlorophenyl)ethanone (5.1 g,
18.96 mmol) in methanol (SO mL) at 00C was added sodium borohydride (2.1 g, 56.98 mmol). The reaction mixture was stirred at 00C for 1 hour. The pH was adjusted to 12 using 2 M sodium hydroxide solution, the solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane. The resultant solution was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 2-(3,4-dichlorophenyl)oxirane (1.79 g, 50 % crude). The crude product was used in the next step without further purification: IH NMR (CDC13, 500 MHz) D7.41 (d, J = 8.5 Hz, IH), 7.36 (d, J = 2.0 Hz, IH), 7.12 (dd, J = 8.5, 2.0 Hz, IH), 3.81 (dd, J = 4.0, 2.5 Hz, IH), 3.14 (dd, J = 5.5, 4.0 Hz, IH), 2.73 (dd, J = 5.5, 2.5 Hz, IH); ESI MS m/z 189 [M]+. [0303] Step C: A solution of l,l-dimethyl-3-bromobenzyl amine (1.18 g, 5.51 mmol) which was prepared in Step A, and the epoxide from Step B (0.95g, 5.02 mmol) in ethanol (10 mL) was heated at 900C for 17 hours. The mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (0 to 100% ethyl acetate in hexanes) to afford 2-(2-(3-bromophenyl)propan-2-ylamino)-l-(3,4- dichlorophenyl)ethanol (1.46 g, 72%): 1H NMR (CDCl3, 500 MHz) δ 7.51 (d, /= 2.0 Hz, IH), 7.457.34 (m, 4H), 7.20 (t, J = 8.0 Hz, IH), 7.12 (dd, J= 2.0, 8.5 Hz, IH), 4.54 (dd, / = 3.5, 8.5 Hz, IH), 3.49 (s, IH), 2.65 (dd, J = 12.5, 3.5 Hz, IH); 2.35 (dd, / = 12.5, 8.5 Hz, IH), 1.58 (s, IH), 1.47 (s, 3H), 1.46 (s, 3H); ESI MS m/z 404 [M+H]+. [0304] Step D: To an ice-cooled solution of the alcohol (920 mg, 2.49 mmol) from Step C above in dichloromethane (60 mL) was added concentrated sulfuric acid (6 mL) drop-wise. The reaction solution was stirred at 00C for 5 hours, and then was added slowly to ice-cold saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2x). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (10 to 40% ethyl acetate in hexanes) to give 7-bromo-4-(3,4-dichlorophenyl)-l,l-dimethyl-l,2,3,4- tetrahydroisoquinoline (431 mg, 33%): 1H NMR (CDCl3, 500 MHz) δ 7.40 (d, / = 2.0 Hz, IH), 7.36 (d, / = 8.0 Hz, IH), 7.22 (dd, / = 8.0, 2.0 Hz, IH), 7.14 (d, / = 2.0 Hz, IH), 6.88 (dd, J = 8.5, 2.0 Hz, IH), 6.71 (d, /= 8.5 Hz, IH), 3.96 (t, / = 5.5 Hz, IH), 3.38 (dd, J = 13.5, 5.0 Hz, IH), 3.03 (dd, J= 13.5, 5.5 Hz, IH), 1.51 (s, 3H), 1.47 (s, 4H); ESI MS m/z 386 [M+H]+.
[0305] Step E: To a solution of the product (535 mg, 1.39 mmol) from Step D in dimethyl sulfoxide (20 mL), was added bis(pinacolato)diboron (423 mg, 1.67 mmol) and potassium acetate (409 mg, 4.17 mmol). The resultant solution was purged with argon for 10 minutes, and then dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (114 mg, 0.14 mmol) was added. The reaction solution was further deoxygenated with argon for 5 minutes and heated at 800C for 2 hours. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to afford 4-(3,4-dicmorophenyl)- 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,l-dimethyl- 1,2,3,4-tetrahydroisoquinoline (557 mg, crude) which was used in the next step without further purification: ESI MS m/z 433 [M+H]+. [0306] Step F: 6-Bromo-[l,2,4]triazolo[l,5-α]pyridine (600 mg, 3.03 mmol) was added to a mixture of the boronate ester from step E (873 mg, 1.68 mmol), cesium carbonate (1.97 g, 6.06 mmol) in DMF (60 mL) and water (12 mL). The reaction mixture was deoxygenated with argon. Dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (82 mg, 0.10 mmol) was added and the reaction mixture was stirred at 900C for 1 hour, cooled, diluted with water, and extracted with dichloromethane (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (0 to 100% 90:9:ldichloromethane/methanol /concentrated ammonium hydroxide solution in dichloromethane) gave the desired 4-(3,4-dichlorophenyl)-7-([l,2,4]triazolo[l,5- α]pyridin-6-yl)-l,l-dimethyl-l,2,3,4-tetrahydroisoquinoline (431 mg, 50% over 2 steps): 1H NMR (CDCl3, 500 MHz) 1H NMR (CDCl3, 500 MHz) δ 8.79 (s, IH), 8.38 (s, IH), 7.84 (d, J= 9.0 Hz, IH), 7.77 (dd, J= 8.0, 1.5 Hz, IH), 7.48 (s, IH), 7.39 (d, J= 8.5 Hz, IH), 7.31 (dd, J = 8.0, 1.5 Hz, IH), ), 7.21 (d, /= 1.5 Hz, 1H),6.996.92 (m, 2H), 4.08 (t, J = 5.5 Hz, IH), 3.45 (dd, J= 13.5, 5.5 Hz, IH), 3.10 (dd, J= 13.5, 5.5 Hz, IH), 1.68 (s, 3H), 1.60 (s, IH), 1.57 (s, 3H); ESI MS m/z 423 [M+H]+. Example 41 Primary Binding Assay
Preparation of Membranes
[0307] Recombinant HEK-293 cells expressing either the hSERT, hDAT, or hNET proteins were harvested from T- 175 flasks as follows. The medium was removed from the flasks and the cells rinsed with HBSS without Ca and without Mg. The cells were then incubated for 5-10 minutes in 10 mM Tris-Cl, pH 7.5, 5 mM EDTA before the cells were lifted with a combination of pipetting and scraping, as needed. The cell suspension was collected into centrifuge bottles and homogenized for 30 seconds with a Polytron homogenizer. The suspension was centrifuged for 30 minutes at 32,000 x g, 4°C. The supernatant was decanted and the pellet resuspended and homogenized in 50 mM Tris-Cl, pH 7.5, 1 mM EDTA for 10 seconds. The suspension was then centrifuged again for 30 minutes at 32,000 x g, 4°C. The supernatant was decanted and the pellet resuspended in 50 mM Tris-Cl, pH 7.5, 1 mM EDTA and briefly homogenized. A Bradford assay (Bio-rad) was performed and the membrane preparation diluted to 2 mg/ml with 50 mM Tris-Cl, pH 7.5, 1 mM EDTA. Aliquots were prepared, and then frozen and stored at -800C.
SERT Radioligand Binding Assay
[0308] Compounds were dissolved in 100% DMSO at a concentration 100 times the desired highest assay concentration, serially diluted 1:3 in 100% DMSO, and
0.4 μl/well of each solution was dispensed to a Nunc polypropylene, round bottom, 384- well plate. 100% inhibition is defined with 0.4 μl/well of 1 mM fluoxetine dissolved in DMSO. 20 μl/well of a 2x membrane preparation (15 ug/ml in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl) and 20 μl/well of a 2x radioligand solution (520 pM [125I]RTI- 55 in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl) were added to each well and the reaction incubated for 1 hour at room temperature. The contents of the assay plate were then transferred to a Millipore MultiscreenHTS GF/B filter plate which was pretreated with 0.5% PEI for at least one hour. The plate was vacuum filtered and washed with 7 washes of 100 μl/well 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl chilled to 4°C. The filtration and washing were completed in less than 90 seconds. The plates were air-dried overnight, 12 μl/well of MicroScint scintillation fluid added, and the plates counted in a Trilux. DAT Radioligand Binding Assay
[0309] Compounds were dissolved in 100% DMSO at a concentration 100 times the desired highest assay concentration, serially diluted 1:3 in 100% DMSO, and 0.4 μl/well of each solution was dispensed to a Nunc polypropylene, round bottom, 384- well plate. 100% inhibition is defined with 0.4 μl/well of 1 mM GBR-1293S dissolved in DMSO. 20 ul/well of a 2x membrane preparation (12.5 μg/ml in 30 mM sodium phosphate buffer, pH 7.9 at 4°C) and 20 μl/well of a 2x radioligand solution (250 pM [125I]RΗ-55 in 30 mM sodium phosphate buffer, pH 7.9 at 4°C) were added to the well and the reaction incubated for 1 hour at room temperature. The contents of the assay plate were then transferred to a Millipore Multiscreenurs GF/B filter plate which was pretreated with 0.5% PEI for at least one hour. The plate was vacuum-filtered and washed with 7 washes of 100 μl/well 50 mM Tris-Cl, pH 7.5, 120 mM NaQ, 5 mM KCl chilled to 4°C. The filtration and washing were completed in less than 90 seconds. The plates were air-dried overnight, 12 μl/well of MicroScint scintillation fluid added, and the plates counted in a Trilux.
NET Radioligand Binding Assay
[0310] Compounds were dissolved in 100% DMSO at a concentration 100 times the desired highest assay concentration, serially diluted 1:3 in 100% DMSO, and
1.0 μl/well of each solution was dispensed to a Nunc polypropylene, round bottom, 384- well plate. 100% inhibition is defined with 1.0 μl/well of 10 mM desipramine dissolved in DMSO. 50 μl/well of a 2x membrane preparation (0.4 mg/ml in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl) and 50 μl/well of a 2x radioligand solution (4 nM [3H]nisoxetine in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5 mM KCl) were added to the well and the reaction incubated for 1 hour at room temperature. The contents of the assay plate were then transferred to a Millipore MultiscreenHτs GF/B filter plate which was pretreated with 0.5% PEI for at least one hour. The plate was vacuum filtered and washed with 7 washes of 100 μl/well 50 mM Tris-Cl, pH 7.5, 120 mM NaQ, 5 mM KCl chilled to 4°C. The filtration and washing were completed in less than 90 seconds. The plates were air-dried overnight, 12 μl/well of MicroScint scintillation fluid added, and the plates counted in a Trilux.
Data Analysis [0311] The raw data was normalized to percent inhibition using control wells defining 0% (DMSO only) and 100% (selective inhibitor) inhibition which were run on each plate. Each plate was run in triplicate, and the concentration response curve thus generated was fit using the four-parameter dose response equation, Y=Bottom + (Top- Bottom)/(l+10Λ((LogIC5o-X)*HillSlope)) in order to determine the IC50 value for each compound. The radioligand concentration chosen for each assay corresponds to the Kd concentration determined through saturation binding analysis for each assay.
Example 42 Occupancy Assay
[0312] The general procedure for brain tissue collection and transporter occupancy assessment is briefly described as follows. Mice were sacrificed by asphyxiation in CO2, rats by decapitation and dogs by IV injection of euthanasia solution. For mice and rats, after the brains were removed from the skull, the forebrain tissue (removal of the brainstem and cerebellum) was used for SERT, NET, and DAT occupancy assessment In dogs, the striatum was dissected for DAT occupancy and the remaining forebrain tissue (without the striatum, brainstem, and cerebellum) was used for SERT and NET occupancy assessment The brain tissues were frozen in chilled isopentane and stored at -80°C until homogenization.
[0313] The brain tissues were thawed and then homogenized using a polytron homogenizer (Kinematica). Sample aliquots were frozen immediately and stored at -800C. Protein content was measured for each sample using a Coomassie protein assay kit (Pierce).
[0314] On the day of ex vivo binding for occupancy assessment, frozen sample aliquots were thawed and needle homogenized, and 100 μg of the tissue was incubated for SERT, NET, and DAT binding under assay conditions summarized in Table 2. After incubation, the reactions were terminated by the addition of ice-cold assay buffer and rapid filtration through a Brandel Cell Harvester using FPXLR- 196 filters. The filters were washed twice with ice-cold incubation buffer, punched into a clear plate prior to the addition of 200ul scintillation fluid per well. Radioligand was measured using a Wallac Microbeta liquid scintillation counter.
Table 2. Ex Vivo Binding Assay Conditions for Serotonin, Norepinephrine and Dopamine Transporter Occupancy.
Figure imgf000122_0001
[0315] The specific binding was calculated by subtracting the value of the nonspecific binding from that of the total binding in each sample. The percent occupancy was calculated as (1- specific binding in drug treated/specific binding in vehicle treated) x 100%. For estimation of in vivo occupancy ECso (total plasma concentration of compound producing 50% occupancy), plots of occupancy values versus plasma concentrations were fitted to a one-site binding model using nonlinear regression according to the following equation: %Occupancy = Emax * CV(ECsO + C) where Emax is the maximal specific binding, C is the drug concentration, and ECso is the total plasma concentration required for 50% binding site occupancy. Nonlinear regression was performed using GraphPad Prism version 3.00 (GraphPad Software, San Diego, Calif.). [0316] The results are shown in Table 3, below:
Table 3. IC50 and Occupancy Data
Figure imgf000123_0001
Example 43 In vivo Behavioral Assays
For All Tests
[0317] All animals were maintained in accordance with the guidelines of the
Committee on Animals of the Bristol-Myers Squibb Company and Guide for Care and Use of Laboratory Animals, Institute of Animal Laboratory Resources, 1996, which are hereby incorporated by reference in their entirety. Research protocols were approved by the Bristol-Myers Squibb Company Institutional Animal Care and Use Committee. Mouse Tail Suspension Assay
[0318] Male Swiss Webster mice were housed 3-4 per cage in rooms maintained at a constant temperature (21-23°C) and humidity (50 ± 10%) on a 12-hour light/dark cycle. Animals had ad libitum access to water and food throughout studies. On the day of testing, they were brought into the testing room and allowed to acclimate for one hour. To begin testing, the tail was attached to a piece of tape which ias then attached to a hook on the ceiling of a sound-attenuated chamber. Immobility was automatically recorded using the Med Associates software. Compounds were administered acutely at a fixed pretreatment interval before session. [0319] The minimum effective dose of Example 36-(+)-enantiomer in the mouse tail suspension study was 10 mg/kg.
Rat Forced Swim Assay
[0320] Male Sprague Dawley rats are housed in pairs in rooms maintained at a constant temperature (21-23°C) and humidity (SO ± 10%) on a 12-hour light/dark cycle. Animals have ad libitum access to water and food throughout studies. Animals are handled for two minutes each on the two days prior to the start of the experiment. On the first day of testing, rats are placed in the swim tank (a Pyrex cylinder 46 cm tall x 21 cm in diameter, filled with 30 cm of water ranging between 24-26°C) for 15 minutes (the pre- swim session). At the end of the 15-minute session, rats are dried and replaced in their home cage. Compounds are administered at three time points in the next 24 hour (23.5, 5, and 1 hour), prior to a second test swim. This swim test is 5 minutes in duration and the animals behavior is videotaped and active behaviors (immobility, swimming, climbing) are scored. At the end of each 5-second period during the 5-minute test session the rat's behavior is scored as one of the following: immobility (the rat remained floating in the water without struggling and made only those movements necessary to keep its head above water), swimming (the rat made active swimming motions, more than necessary to merely maintain its head above water, e.g., moving around in the cylinder), or climbing (the rat made active movements with its forepaws in and out of the water, usually directed against the cylinder wall). Compounds are only identified by a predesignated code and the experimenter remains blinded throughout the experiment (including while scoring videotapes). RcU and Mouse Locomotor Activity
[0321] Animals are housed according to conditions described above for the two species. The testing apparatus consisted of Plexiglas chambers equipped with Digiscan activity monitors (Omnitech Electronics, Columbus, Ohio) that detect interruptions of eight photobeams. Horizontal activity was recorded in 5-minute bins for a total of 60 minutes and expressed as total distance covered (in cm). Compounds were administered acutely at a fixed pretreatment interval prior to testing.
Example 44 Preparation of single crystals of (S)-7-([l,2,4]triazolo[l,5-a]pyridiii-6- yl)-4-(3,4-dichlorophenyl)-l^,3,4-tetrahydroisoquinoline L-tartrate
(L-tartrate salt)
[0322] (SH-Ctl.^ltriazolotl.S-alpyridin-ό-ylH-CS^-dichlorophenyl)-!^^^- tetrahydroisoquinoline L-tartrate salt (20mg) was dissolved in methanol (8 mL) under heating in a vial. Distilled water (2mL) was then added to the above clear solution. The resulting solution was capped and placed at room temperature. Needle-like crystals of (SH-ζtl^^ltriazolotl.S-alpyridin-ό-ylH-ζS^-dichlorophenyl)-!^^^- tetrahydroisoquinoline L-tartrate salt were obtained after slow evaporation in air within days.
Example 45 Preparation of single crystals of (S)-7-([l£,4]triazolo[l,5-a]pyridin-6- yl)-4-(3,4-dichlorophenyl)-l^,3,4-tetrahydroisoquinoline monohydrochloride monoisopropanolate monohydrate (HCl salt; Form SA-I)
[0323] (SH-Ctl.^ltriazolotl.S-alpyridin-ό-ylH-CS^-dichlorophenyl)-!^^^- tetrahydroisoquinoline mono-HCl salt (20 mg) was dissolved in isopropanol (10 mL) under heating in a vial. Distilled water (2 mL) was then added to the above clear solution. The resulting solution was capped and placed at room temperature. Long needle crystals of (S)-7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydroisoquinoline mono-HCl monoisopropanolate monohydrate salt were obtained after slow evaporation in air within days. Example 46 Preparation of single crystals of (S)-7-([l,2,4]triazolo[l,5-a]pyridiii-6- yl)-4-(3,4-dichlorophenyl)-l^,3,4-tetrahydroisoquinoline monohydrochloride (HCl salt; Form N-2)
[0324] (SH-Ctl.^ltriazolotl.S-alpyridin-ό-ylH-CS^-dichlorophenyl)-!^^^- tetrahydroisoquinoline mono-HCl salt (20 mg) was dissolved in methanol (8 mL) under heating in a vial. Distilled water (2 mL) was then added to the above clear solution. The resulting solution was capped and placed at room temperature. Needle like single crystals of (S)-7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinoline mono-HCl salt were obtained after slow evaporation in air within days.
Example 47 Single Crystal Analysis by X-Ray Crystallography [0325] The data of (S)-7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline L-tartrate (L-tartrate salt) and (S)-7- ([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dicMorophenyl)-l,2,3,4-tetrahydroisoquinoline monohydrochloride (HCl salt; Form N-2) crystals were collected on a SMART CCD diffractometer equipped with graphite-monochromated Cu Ka radiation (λ = 1.54178 A) at 225K and the room temperature, respectively. The data of (S)-7-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline monohydrochloride monoisopropanolate monohydrate (HCl salt; Form SA-I) were collected on an X8-ApexH diffractometer equipped with graphite-monochromated Cu Ka radiation (λ = 1.54178 A) at room temperature (APEX-II 1.0-28, Data Collection Software for Bruker CCD devices. Bruker AXS Inc., Madison, Wisconsin, US. SAINT PLUS, Processing Software for BrukerCCD devices, Bruker AXS Inc., Madison, Wisconsin, US). The final unit cell parameters were determined using the entire data set
[0326] All structures were solved by direct methods and refined by the full-matrix least-squares techniques, using the SHELXTL software package (Sheldrick, GM. 1997, SHELXTL. Structure Determination Programs. Version 5.10, Bruker AXS, Madison,
2
Wisconsin, USA.). The function minimized in the refinements was Zw(IF0I - IFCI) . R is defined as Σ HF0I - IFCII/Σ IF0I while Rw = [
Figure imgf000126_0001
Σ^ IF0I - IF0U m, where w is an appropriate weighting function based on errors in the observed intensities. Difference Fourier maps were examined at all stages of refinement In L-tartrate form, one of chloro atoms on pendant phenyl ring is disordered over two positions with 50% occupancy ratio each. The tartaric acid molecule is also disordered, which could not be modeled well. The numbers of methanol molecules could not be identified due to disorder. All non- hydrogen atoms were refined with anisotropic thermal displacement parameters. The hydrogen atoms associated with hydrogen bonding were located in the final difference Fourier maps while the positions of the other hydrogen atoms were calculated from an idealized geometry with standard bond lengths and angles. They were assigned isotropic temperature factors and included in structure factor calculations with fixed parameters. [0327] The crystal data of the L-tartrate salt form is shown in Table 4 and the fractional atomic coordinates are listed in Table S. The crystal data of Form SA-I is shown in Table 6 and the fractional atomic coordinates are listed in Table 7. The crystal data of Form N-2 is shown in Table 8 and the fractional atomic coordinates are listed in Table 9. It should be understood by one of ordinary skills in the art that slight variations in the coordinates are possible and are considered to be within the scope the present disclosure.
Table 4. Crystal Data of L-tartrate Form
Empirical formula C40 H40 C12 N8 08
Formula weight 831.70
Temperature 225(1) K
Wavelength 1.54178 A
Crystal system, space group Qrthorhombic, C222i
Unit cell dimensions a = 7.6264(10) A alpha = 90 deg. b = 38.942(5) A beta = 90 deg. c = 24.449(3) A gamma = 90 deg.
Volume 7261.1(16) A3
Z, Calculated density 8, 1.522 Mg/m3
Absorption coefficient 2.195 mm 1
F(OOO) 3472
Theta range for data collection 2.27 to 66.20 deg. Limiting indices -8<=h^8, -45<=k<=42, -22<=1<=28
Reflections collected / unique 24815 / 6156 [R(int) = 0.1027] Refinement method Full-matrix least-squares on FΛ2
Data /restraints /parameters 6156 / 2/ 323 Goodness-of-fit on FΛ2 2.340
Final R indices [I>2sigma(I)] Rl = 0.2345, wR2 = 0.4418
R indices (all data) Rl = 0.3127, wR2 = 0.4595 Absolute structure parameter 0.00(11) Extinction coefficient 0.0075(9) Largest diff . peak and hole 0.991 and -0.773 e. A"3 Table 5. Atomic Coordinates of L-tartrate Form
Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (A2 x 103) for L-tartrate Form. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
X y Z U(eq)
Cl(I) 8174(9) 94(1) 4057(2) 171(2) α(2-) 5256(12) -323(2) 4561(3) 137(3)
Cl(2) 11696(16) -83(2) 4303(4) 201(6)
C(I) 8480(30) -296(3) 4374(6) 109(5)
C(2) 10110(40) -377(4) 4452(8) 149(8)
C(3) 10610(20) -698(5) 4682(7) 136(6)
C(4) 9280(20) -919(2) 4902(4) 78(3)
C(5) 7540(20) -803(3) 4839(5) 107(4)
C(6) 7210(20) -477(3) 4556(5) 109(5)
C(7) 9651(19) -1252(2) 5194(5) 97(4)
C(8) 8790(20) -1532(3) 4886(5) 122(5)
C(9) 7840(20) -1835(2) 5751(6) 111(5)
C(IO) 8275(16) -1504(3) 6055(6) 87(3)
C(Il) 9041(16) -1238(2) 5781(5) 83(3)
C(12) 9409(14) -941(2) 6125(5) 71(3)
C(13) 8887(15) -937(3) 6658(6) 82(3)
C(14) 8050(16) -1194(3) 6915(5) 75(3)
C(15) 7808(18) -1500(2) 6586(6) 90(4)
C(16) 7563(15) -1182(2) 7472(6) 79(3)
C(17) 6993(17) -875(4) 7699(6) 96(4)
C(18) 6487(18) -1113(4) 8577(8) 100(4)
C(19) 7058(19) -1442(5) 8390(5) 112(5)
C(20) 7492(19) -1472(3) 7861(7) 118(5)
C(21) 5610(30) -748(9) 8994(6) 194(13)
C(22) 7820(20) -2663(4) 4481(6) 124(4)
0(3) 10030(30) -2275(4) 4338(6) 225(7)
C(23) 9000(20) -2557(4) 4090(6) 119(4)
0(2) 7170(20) -2487(3) 4903(5) 170(4)
0(1) 7230(20) -2972(3) 4484(5) 186(5)
N(I) 8830(20) -1870(2) 5245(6) 138(5)
N(2) 6491(14) -849(3) 8247(6) 109(4)
N(3) 5890(20) -1046(4) 9099(9) 150(7)
N(4) 5882(18) -566(3) 8552(6) 119(4)
0(8) -840(20) 53(4) 2431(8) 235(7)
0(1W) 9327(17) -3528(3) 4909(5) 175(4)
C(74) 450(50) -1233(9) 3340(13) 272(14)
0(9) -2350(140) -964(16) 3320(30) 630(40)
0(4) 7600(60) -2153(9) 3690(14) 400(15) 0(6) 10620(40) -2645(6) 3106(9) 291(9)
C(72) -2920(80) -1321(14) 3380(20) 400(30)
0(7) -160(50) -761(8) 3131(12) 351(13)
C(70) -300(120) -361(12) 2710(20) 420(30)
C(25) 9840(80) -2305(16) 3320(20) 440(30)
0(5) 8080(40) -2558(7) 2969(9) 312(11)
C(24) 8360(40) -2552(8) 3522(10) 241(11)
H(3A) 11778 -764 4690 164
H(5A) 6612 -931 4976 128
H(7A) 10920 -1291 5191 116
H(8A) 9408 -1570 4544 146
H(8B) 7592 -1469 4803 146
H(9A) 8097 -2030 5986 133
H(9B) 6598 -1839 5669 133
H(12A) 10003 -753 5980 85
H(13A) 9130 -740 6861 99
H(15A) 7325 -1695 6744 108
H(17A) 6943 -680 7479 115
H(19A) 7126 -1628 8627 134
H(20A) 7766 -1689 7730 142
H(21A) 5111 -624 9280 233
H(IA) 8376 -2045 5049 166
H(IB) 9947 -1923 5325 166
Table 6. Crystal Data of HCl salt: Form SA-I
Empirical formula C24 H26 C13 N402
Formula weight 508.84
Temperature 298(2) K
Wavelength 1.54178 A
Crystal system, space group Monoclinic, P2i
Unit cell dimensions a = 11.0668(9) A alpha = 90 deg. b = 7.3750(6) A beta = 100.594(7) deg. c = 15.3927(14) A gamma = 90 deg.
Volume 1234.90(18) A3
Z, Calculated density 2, 1.363 Mg/m3
Absorption coefficient 3.595 mm 1
F(OOO) 530
Theta range for data collection 4.06 to 61.98 deg. Limiting indices -12<=h^l2, -7<=k<=6, -17^1^15
Reflections collected / unique 3911 / 2687 [R(int) = 0.0253] Completeness to theta = 61.98 89.5 % Refinement method Full-matrix least-squares on FΛ2
Data / restraints / parameters 2687 / 1 / 306 Goodness-of-fit on FΛ2 1.035
Final R indices [I>2sigma(I)] Rl = 0.0382, wR2 = 0.0994
R indices (all data) Rl = 0.0423, wR2 = 0.1027 Absolute structure parameter 0.02(2) Largest diff . peak and hole 0.270 and -0.201 e. A"3 Table 7. Atomic Coordinates of HCl salt: Form SA-I
Atomic coordinates ( x 104) and equivalent isotropic displacement parameters A2 x 103) for Form SA-I. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
X y Z U(eq)
α 12265(1) 6142(1) 1683(1) 49(1)
Cl(I) 7875(1) 12955(2) 4765(1) 82(1)
Cl(2) 8143(1) 9869(2) 6212(1) 87(1)
N(I) 2603(2) 8917(4) -585(2) 34(1)
N(2) 10328(2) 9284(4) 1422(2) 39(1)
C(3) 7992(3) 8350(5) 1854(2) 31(1)
C(4) 6974(3) 8951(5) 360(2) 32(1)
N(5) 1421(3) 9376(5) -494(2) 47(1)
C(6) 5842(3) 8414(5) 549(2) 32(1)
C(7) 4724(3) 8458(5) -145(2) 32(1)
C(8) 8036(3) 8902(5) 998(2) 31(1)
C(9) 3613(3) 8927(5) 63(2) 36(1)
C(IO) 9143(3) 8296(5) 2564(2) 35(1)
N(Il) 1476(3) 8685(5) -1929(2) 51(1)
C(12) 5807(3) 7820(6) 1405(2) 37(1)
C(13) 8878(3) 8695(5) 3475(2) 37(1)
C(14) 6859(3) 7787(6) 2035(2) 38(1)
C(15) 4772(3) 8039(5) -1033(2) 41(1)
C(16) 10107(3) 9607(5) 2333(2) 38(1)
C(17) 2614(3) 8532(5) -1448(3) 39(1)
C(18) 9221(3) 9458(6) 715(2) 42(1)
C(19) 8304(4) 10787(6) 4526(3) 47(1)
C(20) 8550(3) 10430(5) 3699(3) 42(1)
C(21) 3747(4) 8064(6) -1674(2) 46(1)
C(22) 821(3) 9193(6) -1314(3) 50(1)
C(23) 8957(4) 7332(6) 4108(3) 48(1)
C(24) 8714(4) 7701(7) 4937(3) 55(1)
C(25) 8399(4) 9426(8) 5162(3) 58(1)
OWl 12197(4) 11835(6) 1559(3) 63(1)
0(01) 13401(5) 9513(6) 2783(4) 138(2)
C(Ol) 14893(7) 7959(17) 3801(5) 166(5)
C(02) 14430(8) 9598(14) 3370(6) 139(3)
C(03) 14517(9) 11360(20) 3818(8) 221(8)
H(2A) 10639 8162 1397 46
H(2B) 10900 10076 1311 46
H(4A) 7017 9351 -207 38
H(9A) 3554 9248 638 43
H(IOA) 9484 7068 2573 42
H(12A) 5066 7445 1549 44 H(14A) 6817 7377 2600 46
H(15A) 5524 7738 -1183 49
H(16A) 9829 10844 2381 45
H(16B) 10871 9453 2750 45
H(18A) 9335 8717 216 50
H(18B) 9148 10709 518 50
H(20A) 8495 11359 3285 50
H(21A) 3795 me -2255 55
H(22A) -20 9407 -1461 60
H(23A) 9175 6163 3970 58
H(24A) 8763 6773 5351 66
HWl 12650(50) 11440(80) 1990(40) 67(19)
HW2 12190(50) 12930(110) 1710(40) 90(20)
H(OlD) 13362 8533 2528 207
H(OlA) 14782 6981 3382 249
H(OlB) 14456 7696 4270 249
H(OlC) 15752 8098 4041 249
H(02A) 15024 9777 2977 167
H(03A) 14198 12289 3401 331
H(03B) 15361 11617 4062 331
H(03C) 14047 11331 4284 331
Table 8. Crystal Data of HCl salt: Form N-2
Empirical formula C21 H17 C13 N4 Formula weight 431.74
Temperature 298(2) K
Wavelength 1.54178 A
Crystal system, space group Qrthorhombic, P2i2i2i
Unit cell dimensions a = 7.1183(2) A alpha = 90 deg. b = 21.2160(7) A beta = 90 deg. c = 26.3602(9) A gamma = 90 deg.
Volume 3981.0(2) A3
Z, Calculated density 8, 1.441 Mg/m3
Absorption coefficient 4.283 mm"1
F(OOO) 1776 Crystal size 0.16 x 0.07 x 0.06 mm
Theta range for data collection 2.67 to 44.53 deg.
Limiting indices -6<=h<=5, -19<=k<=18, -23<=1<=23
Reflections collected / unique 9626 / 2985 [R(int) = 0.0700]
Completeness to theta = 44.53 95.3 % Data / restraints / parameters 2985 / 0/ 505
Goodness-of-fit on FΛ2 1.031 Final R indices [I>2sigma(I)] Rl = 0.0580, wR2 = 0.1446 R indices (all data) Rl = 0.0780, wR2 = 0.1669 Absolute structure parameter 0.10(4)
Largest diff . peak and hole 0.260 and -0.278 e. A"3 Table 9. Atomic Coordinates of HCl salt: Form N-2
Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (A2 x 103) for Form N-2. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
X y Z U(eq)
Cl(I) 4498(5) 2054(2) 5726(1) 84(1)
Cl(2) 8606(6) 2604(2) 5897(1) 98(1)
Cl(3) 13423(5) 8143(1) 1794(1) 75(1)
Cl(4) 9097(4) 8448(1) 1988(1) 73(1)
Cl(5) -2074(4) 5119(1) 4228(1) 71(1)
Cl(6) 3031(4) 5078(1) 2983(1) 66(1)
N(I) 2223(11) 4893(4) 4125(3) 52(2)
N(2) 61(15) 7409(6) 6214(5) 64(3)
N(3) -573(13) 7985(6) 6078(5) 65(3)
N(4) -306(16) 7936(6) 6927(5) 75(4)
N(5) 7228(10) 5382(4) 3091(3) 47(2)
N(6) 9780(14) 2724(5) 1073(5) 56(3)
N(7) 10462(14) 2158(6) 1235(4) 62(3)
N(8) 10074(16) 2166(6) 367(4) 70(3)
C(I) 3750(20) 3157(6) 5294(4) 67(4)
C(2) 5220(20) 2801(5) 5526(4) 62(4)
C(3) 6990(20) 3065(8) 5577(5) 75(4)
C(4) 7330(20) 3646(7) 5390(5) 75(5)
C(5) 5980(20) 3987(6) 5149(5) 67(4)
C(6) 4180(20) 3750(6) 5092(4) 57(4)
C(7) 2634(17) 4168(5) 4848(4) 53(3)
C(8) 3267(15) 4321(5) 4307(4) 54(3)
C(9) 2762(18) 5465(5) 4424(5) 63(4)
C(IO) 2298(13) 5348(6) 4977(5) 44(3)
C(Il) 2294(14) 4749(5) 5175(5) 42(3)
C(12) 1796(17) 4667(5) 5682(5) 57(3)
C(13) 1424(16) 5177(6) 5975(5) 57(3)
C(14) 1510(15) 5791(5) 5785(5) 45(3)
C(15) 1928(14) 5865(5) 5284(5) 44(3)
C(16) 1095(14) 6353(6) 6107(5) 44(3)
C(17) 466(16) 6920(7) 5908(5) 52(3)
C(18) -747(19) 8258(7) 6533(8) 79(5)
C(19) 230(20) 7382(8) 6719(8) 79(4)
C(20) 856(16) 6812(7) 6955(5) 61(3)
C(21) 1241(15) 6307(6) 6639(6) 58(4)
C(31) 11260(20) 6456(5) 2095(5) 68(4)
C(32) 12471(16) 6939(6) 1978(4) 63(4)
C(33) 11878(19) 7564(6) 1953(4) 61(3)
C(34) 9939(18) 7684(5) 2033(4) 55(3)
C(35) 8744(17) 7205(5) 2162(4) 51(3) C(36) 9370(18) 6600(5) 2199(4) 52(3)
C(37) 8002(17) 6074(5) 2356(4) 49(3)
C(38) 8399(14) 5938(5) 2920(4) 51(3)
C(39) 7870(18) 4792(5) 2834(5) 60(4)
C(40) 8081(17) 4873(6) 2263(5) 53(3)
C(41) 8178(17) 5465(5) 2060(5) 52(3)
C(42) 8419(18) 5507(5) 1536(6) 66(4)
C(43) 8611(16) 4964(7) 1238(4) 59(3)
C(44) 8532(16) 4370(6) 1459(5) 54(3)
C(45) 8220(17) 4337(5) 1978(5) 57(3)
C(46) 8796(17) 3796(6) 1143(5) 54(3)
C(47) 9454(16) 3252(7) 1367(5) 56(3)
C(48) 10601(16) 1851(6) 794(7) 67(4)
C(49) 9511(17) 2725(6) 563(7) 55(4)
C(50) 8909(16) 3292(7) 321(5) 62(4)
C(51) 8534(16) 3805(6) 614(6) 53(3)
H(IA) 2481 4958 3795 62
H(IC) 979 4827 4155 62
H(5A) 7327 5336 3429 56
H(5C) 6012 5453 3016 56
H(IB) 2535 2999 5277 81
H(4B) 8526 3818 5427 90
H(5B) 6262 4384 5021 80
H(7B) 1466 3924 4831 63
H(8B) 4609 4401 4302 65
H(8C) 3009 3966 4086 65
H(9A) 2075 5829 4301 76
H(9B) 4095 5547 4386 76
H(12A) 1718 4264 5818 68
H(13A) 1102 5116 6313 69
H(15A) 1967 6267 5145 52
H(17A) 322 6962 5559 62
H(18A) -1175 8671 6562 94
H(20A) 998 6783 7305 73
H(21A) 1607 5926 6783 70
H(31A) 11679 6042 2104 81
H(32A) 13726 6845 1914 76
H(35A) 7486 7294 2226 62
H(37A) 6713 6232 2322 59
H(38A) 9722 5846 2967 61
H(38B) 8090 6306 3123 61
H(39A) 6970 4458 2901 71
H(39B) 9067 4664 2976 71
H(42A) 8454 5901 1382 79
H(43A) 8793 5002 890 71
H(45A) 8104 3945 2133 69
H(47A) 9678 3241 1714 67
H(48A) 11041 1439 779 80
H(50A) 8777 3311 -30 74 H(51A) 8094 4171 460 63
Example 48 Powder X-Ray Diffraction for Forms SA-I and N-2 [0328] X-ray powder diffraction (PXRD) data were obtained using a Bruker C2
GADDS. The radiation was Cu Ka (40KV, 40MA). The sample-detector distance was IS cm. Powder samples were placed in sealed glass capillaries of 1mm or less in diameter; the capillary was rotated during data colletion. Data were collected for 3<20<35° with a sample exposure time of at least 1000 seconds. The resulting two- dimensional diffraction arcs were integrated to create a traditional 1 -dimensional PXRD. The results of the PXRD pattern and a simulated pattern calculated from the single crystal data are shown in Figure 1.
[0329] Table 10 lists the characteristic PXRD peaks that describe Form SA-I
((S)-7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinoline monohydrochloride monoisopropanolate monohydrate) and Form N-2 ((S)-7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)^-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinoline monohydrochloride). In particular, Table 10 shows characteristic diffraction peak positions (degrees 20 + 0.1) at room temperature, based on a high quality pattern collected with a diffractometer (cuKα) with a spinning capillary with 2Θ calibrated with a NIST or other suitable standard.
Table 10
Figure imgf000137_0001
Example 49 Differential Scanning Calorimetry for Form SA-I [0330] Differential scanning calorimetry (DSC) experiments were performed in a
TA Instruments model QlOOO or 2920. The sample (about 2-6 mg) was weighed in a pinpricked hermetically sealed aluminum pan and accurately recorded to a hundredth of a milligram, and transferred to the DSC. The instrument was purged with nitrogen gas at 50mL/min. Data were collected between room temperature and 3000C at 10°C.min. heating rate. The plot was made with the endothermic peaks pointing down. The results are shown in Figure 2.
Example 50 Thermogravimetric Analysis for Form SA-I [0331] The results are shown in Figure 3.
[0332] Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow.

Claims

WHAT IS CLAIMED:
1. A compound of formula (I):
Figure imgf000139_0001
wherein:
the carbon atom designated * is in the R or S configuration;
R1 is H, Ci-Cealkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, Ci-C6 haloalkyl, or gem-dialkyl of which each alkyl is Ci-C4;
R2 is H, halogen, OR n, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, or NR 9R10;
R3 is an aryl selected from the group consisting of phenyl, naphthyl, indanyl, and indenyl, or a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-l-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, ihiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4- thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dthydro-benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6αH-thieno[2,3- d]imidazolyl, lH-pyrrolo[2,3-6]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5- α]pyridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3- 6]furanyl, thieno[2,3-&]pyridinyl, thieno[3,2-ft]pyridinyl, furo[2,3-6]pyridinyl, furo[3,2- 6]pyridinyl, thieno[3,2-rf]pyrimidinyl, furo[3,2-rf]pyrimidinyl, thieno[2,3-&]pyrazinyl, furo[2,3-£>]pyrazinyl , imidazo[l,2-α]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2- α]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazinyl, 2-oxo-2,3- dihydrobenzo[d]oxazolyl, 2-oxo-2,3-dihydro-lH-benzo[d]imidazole, 3,3-dimethyl-2- oxoindolinyl, 2-oxo-2,3-dihydro-lH-pyrrolo[2,3--7]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]ibiadiazolyl, 3,4-dihydro-2H- benzo[6][l,4]oxazinyl, 5,6,7,8-tetrab.ydro-[l,2,4]triazolo[4,3-α]pyrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo-[l,2,4]triazolo[4,3-α]pyridinyl, or a non- aromatic heterocycle selected from the group consisting of pyπolidinyl, 2- oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2- oxooxazolidinyl, morpholino, 3-oxomorpholino, tbiomorpholino, 1,1- dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl; wherein the aryl, heteroaryl, or non-aromatic heterocycle is optionally substituted from 1 to 4 times with substituents as defined below in R14;
R4 , R5 and R6 and R7 are each independently H or are selected from the group consisting of halogen, OR n, NR 11R12, NR 11C(O)R12, NR 11CXO)2R12, NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2- Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of C1-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloa]kyl, Ci-C4 alkoxy, CN, OR 9, orNR 9R10;
R8 is H, Ci-C6 alkyl, halogen, or OR11; R9 and R10 are each independently H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 alkoxy;
or R9 and R10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R11 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
R12 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring, with the proviso that only one of R9 and R10 or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R13 is Ci-C4 alkyl, Ci-C4 haloalkyl, or phenyl;
n is 0, 1, or 2; and
R14 is independently selected at each occurrence from a substituent selected from the group consisting of halogen, NO 2, OR n, NR 11R12, NR 11C(O)R12, NR 11C(O)2R12, NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, where Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cydoalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of C1-C3 alkyl, halogen, Ar, CN, OR 9, and NR 9 R10, or
an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.
2. The compound of claim 1, wherein R1 is H, Ci-C6 alkyl, or gem- dialkyl of which each alkyl is C1-C4.
3. The compound of claim 2, wherein R1 is H or gem-dimethyl.
4. The compound of claim 1, wherein R2 is H, halogen, OR ' ' , S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, or substituted Ci-C6 alkyl.
5. The compound of claim 4, wherein R2 is H or F.
6. The compound of claim 1, wherein R3 is phenyl optionally substituted from 1 to 4 times with substituents as defined in R14.
7. The compound of claim 1, wherein R3 is a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-l-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2, 3- oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzoihiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro- benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6αΗ-thieno[2,3-d]imidazolyl, lH-pyrrolo[2,3-&]pyridinyl, imidazo[l,2-α]pvridinyl, pyrazolo[l,5-α]pvridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3--?]furanyl, thieno[2,3--?]pyridinyl, thieno[3,2- 6]pyridinyl, furo[2,3-6]pyridinyl, furo[3,2-ft]pyridinyl, thieno[3,2-rf]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-&]pyrazinyl, furo[2,3-&]pyrazinyl , imidazo[l,2- α]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2-α]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,l- c][l,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[rf]oxazoryl, 2-oxo-2,3-dihydro-lH- benzo[d]imidazole, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-l/-r-pyrrolo[2,3- ύ]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dthydro-2H- benzo[6][l,4]oxazinyl, 5,6J,8-tBtrahydro-[l,2,4]triazolo[4,3-α]pyrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo-[l,2,4]triazolo[4,3-α]pyridinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R14.
8. The compound of claim 7, wherein R3 is l,2,4-oxadiazol-3-yl, 3,5- dimethylisoxazol-4-yl, lH-pyrazol-3-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-(methanesulfonyl)phenyl, 4-(methanesulfonyl)phenyl, 3-carbamoylphenyl, 4- carbamoylphenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazin-3-yl, 6- methylpyridazin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6-(difluoromethyl)pyridazin-3- yl, 6-(difluoromethoxy)methyl)pyridazin-3-yl, 6-aminopyridazin-3-yl, (6- (hydroxymethyl)pyridazin-3-yl, 6-methoxypyridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-aminopyrazin-2-yl, 5-aminopyrazin-2-yl, 6-aminopyrazin- 2-yl, 2-oxopyridin-l(2H)-yl, 6-oxo-l,6-dihydropyridazin-3-yl, 6-oxopyridazin-l(6H)-yl, [l,2,4]triazolo[4,3-a]pyridin-6-yl, [l,2,4]triazolo[l,5-a]pyridin-6-yl, 3-oxo- [l,2,4]triazolo[4,3-α]pyridin-2(3H)-yl, 3-(trifluoromethyl)-5,6-dihydro- [l,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl, [l,2,4]triazolo[l,5-α]pyridin-6-yl, [l,2,4]triazolo[4,3-α]pyridin-6-yl, 3,3-dimethyl-2-oxoindolin-5-yl, 3,3-dimethyl-2- oxoindolin-6-yl, 3-methyl-[l,2,4]triazolo[4,3-.7]-pyridazinyl, or [l,2,4]triazolo[4,3-6]- pyridazinyl.
9. The compound of claim 1, wherein R3 is a non-aromatic heterocycle selected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1-dioxothiomorpholino, piperazinyl, and tetrohydro- 2H-oxazinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R14.
10. The compound of claim 1, wherein R4 is H, Cl, F, CH3, OH, or OCH3.
11. The compound of claim 1, wherein R4 is H or F.
12. The compound of claim 1, wherein R5, R6, and R7 are each independently selected from the group consisting of H, halogen, OR n, NR 11R12, NR 11C(O)R12, S(O)nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, and substituted Ci-C6 alkyl.
13. The compound of claim 12, wherein R7 is H.
14. The compound of claim 13, wherein R5 and R6 are each H, F, Cl, OH, OCH3, or CH3.
15. The compound of claim 14, wherein R5 and R6 are each Cl.
16. The compound of claim 1, wherein R8 is H, OH, CH3, or F.
17. The compound of claim 1, wherein:
R1 is H, Ci-C6 alkyl, or gem-dialkyl of which each alkyl is Ci-C4;
R2 is H, halogen, OR n, S(O) 2R12, Ci-C6 alkyl, or substituted Ci-C6 alkyl;
R3 is aryl, heteroaryl, or non-aromatic heterocycle;
R4 is H, F, or Cl; and
R5, R6, and R7 are each independently H, halogen, OR n, NR 11R12, S(O) 2R12, C(O)R 12, Ci-C6 alkyl, or substituted Ci-C6 alkyl.
18. The compound of claim 1, wherein:
R1 is H or gem-dimethyl;
R2 is H;
R3 is phenyl, or heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-l- yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, ihiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4- thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dthydro-benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-cbromenyl, indolizinyl, quinolizinyl, 6αff-thieno[2,3- d]imidazolyl, l/-r-pyrrolo[2,3-&]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5- α]pyridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3- 6]furanyl, thieno[2,3-&]pyridinyl, thieno[3,2-6]pyridinyl, furo[2,3-&]pyridinyl, furo[3,2- &]pyridinyl, thieno[3,2-rf]pyrimidinyl, furo[3,2--flpyrimidinyl, thieno[2,3-6]pyrazinyl, furo[2,3-ύ]pyrazinyl , imidazo[l,2-α]pyrazinyl, S,6,7,8-tetrahydroimidazo[l,2- α]pyrazinyl, 6,7-dϋydro-4H-pyrazolo[5,l-c][l,4]oxazinyl, 2-oxo-2,3- dihydrobenzo[d]oxazolyl, 2-oxo-2,3-dihydro-lH-benzo[d]imidazole, 3,3-dimethyl-2- oxoindolinyl, 2-oxo-2,3-dihydro-lH-pyrrolo[2,3--7]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dihydro-2H- benzo[6][l,4]oxazinyl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-α]pyrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo-[l,2,4]triazolo[4,3-α]pyridinyl, or non- aromatic heterocycle selected from the group consisting of pyrrolidinyl, 2- oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxo-azepanyl, 2- oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1- dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl; wherein the phenyl, heteroaryl, or non-aromatic heterocycle is optionally substituted from 1 to 4 times with substituents as defined below in R14;
R4 is H or F;
R5 and R6 are each independently H, F, Cl, OH, OMe, or Me;
R7 is H or F; and
R8 is H, OH, or F.
19. The compound of claim 1, wherein: R1 is H or gem-dimethyl;
R2 is H;
R3 is l,2,4-oxadiazol-3-yl, l,2,3-thiadiazol-4-yl, 3,5-dimethylisoxazol-4-yl, lH-pyrazol- 3-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-(methanesulfonyl)phenyl, 4- (methanesulfonyl)phenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, 2-aminopyridinyl, 3-aminopyridinyl, 4-aminopyridinyl, pyridazin-3-yl, 6-methylpyridazin-3-yl, 6-(trffluoromethyl)pyridazin-3-yl, 6- (difluoromethyl)pyridazin-3-yl, 6-(difluoromethoxy)methyl)pyridazin-3-yl, 6- aminopyridazin-3-yl, (6-(hydroxymethyl)pyridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-aminopyrazin-2-yl, 5-aminopyrazin-2-yl, 6-aminopyrazin- 2-yl, 2-oxopyridin-l(2H)-yl, 2-oxopyrrolidin-l-yl, 6-oxo-l,6-dihydropyridazin-3-yl, 6- oxopyridazin-l(6H)-yl, 3-oxo-[l,2,4]triazolo[4,3-α]pyridin-2(3H)-yl, 3-(trifluoromethyl)- 5,6-dihydro-[l,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl, [l,2,4]triazolo[l,5-α]pyridin-6-yl, [l,2,4]triazolo[4,3-α]pyridin-6-yl, 3,3-dimethyl-2-oxoindolin-5-yl, 3-methyl- [l,2,4]triazolo[4,3--7]-pyridazinyl, [l,2,4]triazolo[4,3--7]-pyridazinyl, or oxooxazolidin-3- yl;
R4 is H or F; R5 and R6 are each independently H, F, Cl, or CH3;
R7 is H; and
R8 is H.
20. A compound according to claim 1, selected from the group consisting of:
4-(4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile;
7-(6-methylpyridazin-3-yl)-4-p-tolyl-l,2,3,4-tetrahydroisoquinoline;
6-(4-(4-fluorophenyl)- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;
6-(4-(4-fluorophenyl)-l,2,3,4-tetrahydroisoquinolm-7-yl)-N-memylpyridazin-3-amine;
4-(4-chlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)- 1 ,2,3,4-tetrahydroisoquinoline; 6-(4-(4-cMorophenyl)-l,23,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;
4-(4-cmorophenyl)-7-(6-cMoropyridazin-3-yl)-l-methyl-l,2,3,4-tetraliydroisoquinoline;
4-(4-chlorophenyl)-l-methyl-7-(pyridazin-3-yl)-l,2,3,4-tetraliydroisoquinoline;
4-(4-chlorophenyl)-7-(6-methoxypyridazin-3-yl)-l-methyl-l,2,3,4- tetrahydroisoquinoline; 4-(3,4-dichlorophenyl)- 1 , 1 -dimethyl-7-(pyridazin-3-yl)- 1,2,3,4-tetrahydroisoquinoline;
4-(3,4-dicmorophenyl)-14-dimethyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)- 1 ,2,3,4- tetrahydroisoquinoline; 4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline;
2-(4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile;
3-(4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile;
4-(3,4-dicUorophenyl)-7-(4-(memylsulfonyl)phenyl)-l,2,3,4-tetrahydroisoquinoline; l-(4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-2(lH)-one;
2-(4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one;
4-(3,4-dichlorophenyl)-6-fluoro-7-(pyridin-2-yl)- 1 ,2,3,4-tetrahydroisoquinoline; 4-(3,4-dichlorophenyl)-6-fluoro-7-(6-meihylpyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-6-fluoro-7-(6-meihoxypyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline; ό^-CS^-dichlorophenyO-ό-fluoro-l.l^^-tBtTahydroisoquinoUn^-yl^yridazin-SClH)- one;
4-(3,4-dicUorophenyl)-6-fluoro-7-(3-(methylsulfonyl)phenyl)-l,2,3,4- tetrahydroisoquinoline;
4-(4-(3,4-dichlorophenyl)-l,23,4-tetτahydroisoquinolin-7-yl)-3,5-dimeihylisoxazole; 4-(4-(3,4-di(Morophenyl)-6-fluoro-l,23,4-tBtτahydroisoquinolin-7-yl)benzamide;
S^-ζS^-dicMoropheny^-l^^^-tetrahydroisoquinolin^-yl^yrazin^-amine;
6-(4-(3,4-dichlorophenyl)-l,23,4-tetrahydroisoquinoUn-7-yl)pyrazin-2-amine;
4-(3,4-dicUorophenyl)-6-fluoro-7-(6-(trMuoromeihyl)pyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline; 7-([l,2,4]triazolo[l,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-7-(6-(difluoromeihoxy)pyridazin-3-yl)-6-fluoro- 1 ,2,3,4- tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-6-fluoro-7-(pyrazin-2-yl)- 1 ,2,3,4-tetrahydroisoquinoline; 4-(3,4-dicUorophenyl)-7-(pyridazin-3-yl)-l,2,3,4-tetrahydroisoquinoline;
6-(4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-amine;
4-(4-chlorophenyl)- 1 , 1 -dimethyl^-ζό-ζtrifluoromeihyl^yridazin-S-yl)- 1 ,2,3,4- tetrahydroisoquinoline;
4-(4-(4-chlorophenyl)-6-fluoro-l,2,3,4-tetrahydroisoquinolin-7-yl)benzamide; ό^-CS^-dicMoropheny^-l.l-dimethyl-l^.S^-tetiahydroisoquinolin^-yl^yridazin-S- amine;
7-([l,2,4]Mazolo[l,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,l-dimeihyl-l,2,3,4- tetrahydroisoquinoline;
7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-6-fluoro- 1 ,2,3,4- tetrahydroisoquinoline; and an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 1.
22. A method of treating a disorder which is created by or is dependent upon decreased availability of norepinephrine, dopamine, or serotonin, said method comprising: administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
23. A compound of formula (I):
Figure imgf000149_0001
wherein:
the carbon atom designated * is in the R or S configuration;
R1 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, Ci-C6 haloalkyl, or gem-dialkyl of which each alkyl is Ci-C4;
R2 is H, halogen, OR n, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, or NR 9R10;
R3 is an aryl selected from the group consisting of phenyl, naphthyl, indanyl, and indenyl, or a heteroaryl selected from the group consisting of monocyclic aromatic heterocycles selected from the group consisting of pyridyl, 2-oxo-pyridin-l-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, ihiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, and tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-cbromenyl, indolizinyl, quinolizinyl, 6αH-thieno[2,3- d]imidazolyl, l/-r-pyrrolo[2,3-&]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5- α]pyridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3- 6]furanyl, thieno[2,3-&]pyridinyl, thieno[3,2-&]pyridinyl, furo[2,3--7]pyridinyl, furo[3,2- &]pyridinyl, thieno[3,2-rf]pyrimidinyl, furo[3,2--flpyrimidinyl, thieno[2,3-6]pyrazinyl, furo[2,3-ύ]pyrazinyl , imidazo[l,2-α]pyrazinyl, S,6,7,8-tetrahydroimidazo[l,2- α]pyrazinyl, ό.V-dihydro^H-pyrazoloCS.l-clCl^oxazinyl, 2-oxo-2,3- dihydrobenzo[-floxazolyl, 2-oxo-2,3-dihydro-lH-benzo[d]imidazole, 3,3-dimethyl-2- oxoindolinyl, 2-oxo-2,3-dihydro-lH-pyrrolo[2,3--7]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]tbiadiazolyl, 3,4-dihydro-2H- benzo[6][l,4]oxazinyl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-α]pyrazinyl,
[l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo-[l,2,4]triazolo[4,3-α]pyridinyl, or a non- aromatic heterocycle selected from the group consisting of pyrrolidinyl, 2- oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2- oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1- dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl; wherein the aryl, heteroaryl, or non-aromatic heterocycle is optionally substituted from 1 to 4 times with substituents as defined below in R14; R4 is selected from the group consisting of H, halogen, NR 11R12, NR 11CXO)R12, NR 11C(O)2R12, NR 11CXO)NR12R13, SOR 12, S(O) 2R12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, orNR 9R10;
R5 and R6 and R7 are each independently H or are selected from the group consisting of halogen, OR n, NR 11C(O)R12, NR 11C(O)2R^ NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting Of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci- C4 alkoxy, CN, OR 9, orNR 9R10;
R8 is H, Ci-C6 alkyl, halogen, or OR11;
R9 and R10 are each independently H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 alkoxy;
or R9 and R10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R11 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
R12 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring, with the proviso that only one of R9 and R10 or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R13 is Ci-C4 alkyl, Ci-C4 haloalkyl, or phenyl;
n is 0, 1, or 2; and
R14 is independently selected at each occurrence from a substituent selected from the group consisting of halogen, NO 2, OR n, NR 11R12, NR 11C(O)R12,
NR 11C(O)2R12, NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, where Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cydoalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of Ci-C3 alkyl, halogen, Ar, CN, OR 9, and NR 9 R10, or
an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof ; with the proviso that when R3 is phenyl or monocyclic aromatic heterocycle, R14 cannot be Ci-C6 alkyl substituted with NR 9R10.
24. The compound of claim 23, wherein R1 is Q-C6 alkyl or gem- dialkyl.
25. The compound of claim 24, wherein R1 is gem-dimethyl.
26. The compound of claim 23, wherein R2 is H, halogen, OR 11 , S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, or substituted Ci-C6 alkyl.
27. The compound of claim 26, wherein R2 is H or F.
28. The compound of claim 23, wherein R3 is phenyl optionally substituted from 1 to 4 times with substituents as defined in R14.
29. The compound of claim 23, wherein R3 is a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-l-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzotbiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dthydro-benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6αH-tnieno[2,3- d]imidazolyl, lH-pyrrolo[2,3--7]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5- α]pyridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3- 6]furanyl, thieno[2,3-&]pyridinyl, thieno[3,2-&]pyridinyl, furo[2,3--7]pyridinyl, furo[3,2- 6]pyridinyl, thieno[3,2-rf]pyrimidinyl, furo[3,2-rf]pyrimidinyl, thieno[2,3-.7]pyrazinyl, furo[2,3--7]pyrazinyl , imidazo[l,2-α]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2- α]pyrazinyl, ό.V-dihydro^H-pyrazoloCS.l-clCl^oxazinyl, 2-oxo-2,3- dihydrobenzo[έf]oxazolyl, 2-oxo-2,3-dihydro-lΗ-benzo[d]imidazole, 3,3-dimethyl-2- oxoindoUnyl, 2-oxo-2,3-dmydro-lH-pyrrolo[2,3--7]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[-7][l,4]oxazinyl, 5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-α]pyrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo- [l,2,4]triazolo[4,3-α]pyridinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R14.
30. The compound of claim 29, wherein R3 is l,2,4-oxadiazol-3-yl,
3,5-dimethylisoxazol-4-yl, lH-pyrazol-3-yl, 2-cyanophenyl, 3-cyanophenyl, 4- cyanophenyl, 3-(methanesulfonyl)phenyl, 4-(methanesulfonyl)phenyl, 3- carbamoylphenyl, 4-carbamoylphenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazin-3-yl, 6-methylpyridazin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6- (difluoromethyl)pyridazin-3-yl, 6-(difluoromethoxy)methyl)pyridazin-3-yl, 6- aminopyridazin-3-yl, (6-(hydroxymethyl)pyridazin-3-yl, 6-methoxypyridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-aminopyrazin-2-yl, 5- aminopyrazin-2-yl, 6-aminopyrazin-2-yl, 2-oxopyridin-l(2H)-yl, 6-oxo-l,6- dihydropyridazin-3-yl, 6-oxopyridazin-l(6H)-yl, [l,2,4]triazolo[4,3-a]pyridin-6-yl, [l,2,4]triazolo[l,5-a]pyridin-6-yl, 3-oxo-[l,2,4]triazolo[4,3-α]pyridin-2(3H)-yl, 3-
(trmuoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl, [l,2,4]triazolo[l,5- α]pyridin-6-yl, [l,2,4]triazolo[4,3-α]pyridin-6-yl, 3,3-dimethyl-2-oxoindolin-5-yl, 3,3- dimethyl-2-oxoindolin-6-yl, 3-methyl-[l,2,4]triazolo[4,3-6]-pyridazinyl, or [l,2,4]triazolo[4,3--7]-pyridazinyl.
31. The compound of claim 23, wherein R3 is a non-aromatic heterocycle selected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1-dioxothiomorpholino, piperazinyl, and tetrohydro- 2H-oxazinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R14.
32. The compound of claim 23, wherein R4 is H, Cl, F, or CH3.
33. The compound of claim 32, wherein R4 is H or F.
34. The compound of claim 23, wherein R5, R6, and R7 are each independently selected from the group consisting of H, halogen, OR 11 , NR 11C(O)R12, S(O)nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, and substituted Ci-C6 alkyl.
35. The compound of claim 34, wherein R7 is H.
36. The compound of claim 35, wherein R5 and R6 are each H, F, Cl, OH, OCH3, or CH3.
37. The compound of claim 36, wherein R5 and R6 are each Cl.
38. The compound of claim 23, wherein R8 is H, OH, CH3, or F.
39. The compound of claim 23, wherein:
R1 is Ci-C6 alkyl or gem-dialkyl of which each alkyl is Ci-C4;
R2 is H, halogen, OR n, S(O) 2R12, Ci-C6 alkyl, or substituted Ci-C6 alkyl;
R3 is aryl, heteroaryl, or non-aromatic heterocycle;
R4 is H, F, or Cl; and
R5, R6, and R7 are each independently H, halogen, OR n,S(0) 2R12, C(O)R 12, Ci-C6 alkyl, or substituted Ci-C6 alkyl.
40. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 23.
41. A method of treating a disorder which is created by or is dependent upon decreased availability of norepinephrine, dopamine, or serotonin, said method comprising: administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 23 or a pharmaceutically acceptable salt thereof.
42. A compound of formula (T):
Figure imgf000156_0001
wherein:
the carbon atom designated * is in the R or S configuration;
R1 is gem-dialkyl of which each alkyl is Ci-C4;
R2 is H, halogen, OR n, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of C1-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, or NR 9R10;
R3 is an aryl selected from the group consisting of phenyl, naphthyl, indanyl, and indenyl, or a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-l-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, ihiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4- thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dthydro-benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6αH-thieno[2,3- d]imidazolyl, lH-pyrrolo[2,3-6]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5- α]pyridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3- 6]furanyl, thieno[2,3-&]pyridinyl, thieno[3,2-ft]pyridinyl, furo[2,3-6]pyridinyl, furo[3,2- 6]pyridinyl, thieno[3,2-rf]pyrimidinyl, furo[3,2-rf]pyrimidinyl, thieno[2,3-&]pyrazinyl, furo[2,3-£>]pyrazinyl , imidazo[l,2-α]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2- α]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazinyl, 2-oxo-2,3- dihydrobenzo[d]oxazolyl, 2-oxo-2,3-dihydro-lH-benzo[d]imidazole, 3,3-dimethyl-2- oxoindolinyl, 2-oxo-2,3-dihydro-lH-pyrrolo[2,3--7]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]ibiadiazolyl, 3,4-dihydro-2H- benzo[6][l,4]oxazinyl, 5,6,7,8-tetrab.ydro-[l,2,4]triazolo[4,3-α]pyrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo-[l,2,4]triazolo[4,3-α]pyridinyl, or a non- aromatic heterocycle selected from the group consisting of pyπolidinyl, 2- oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2- oxooxazolidinyl, morpholino, 3-oxomorpholino, tbiomorpholino, 1,1- dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl; wherein the aryl, heteroaryl, or non-aromatic heterocycle is optionally substituted from 1 to 4 times with substituents as defined below in R14;
R4 , R5 and R6 and R7 are each independently H or are selected from the group consisting of halogen, OR n, NR 11R12, NR 11C(O)R12, NR 11CXO)2R12, NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2- Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of C1-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloa]kyl, Ci-C4 alkoxy, CN, OR 9, orNR 9R10;
R8 is H, Ci-C6 alkyl, halogen, or OR11; R9 and R10 are each independently H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 alkoxy;
or R9 and R10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R11 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
R12 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring, with the proviso that only one of R9 and R10 or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R13 is Ci-C4 alkyl, Ci-C4 haloalkyl, or phenyl;
n is 0, 1, or 2; and
R14 is independently selected at each occurrence from a substituent selected from the group consisting of halogen, NO 2, OR n, NR 11R12, NR 11C(O)R12, NR 11C(O)2R12, NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, where Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cydoalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of C1-C3 alkyl, halogen, Ar, CN, OR 9, and NR 9 R10, or
an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.
43. The compound of claim 42, wherein R1 is gem-dimethyl.
44. The compound of claim 42, wherein R2 is H, halogen, OR 11 , S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, or substituted Ci-C6 alkyl.
45. The compound of claim 44, wherein R2 is H or F.
46. The compound of claim 42, wherein R3 is phenyl optionally substituted from 1 to 4 times with substituents as defined in R14.
47. The compound of claim 42, wherein R3 is a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-l-yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzotbiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-cbromenyl, indolizinyl, quinolizinyl, 6αff-thieno[2,3- d]imidazolyl, lH-pvrrolo[2,3-&]pvridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5- α]pyridinyl, [l,2,4]triazolo[4,3-α]pvridinyl, [l,2,4]triazolo[l,5-α]pvridinyl, thieno[2,3- 6]furanyl, thieno[2,3-&]pyridinyl, thieno[3,2-6]pyridinyl, furo[2,3--7]pvridinyl, furo[3,2- 2>]pvridinyl, tnieno[3,2-rf]pyrimidinyl, furo[3,2-d]pvrimidinyl, thieno[2,3-ύ]pyrazinyl, furo[2,3-&]pyrazinyl , imidazo[l,2-α]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2- α]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazinyl, 2-oxo-2,3- dihydrobenzo[-floxazolyl, 2-oxo-2,3-dihydro-lH-benzo[d]imidazole, 3,3-dimethyl-2- oxoindolinyl, 2-oxo-2,3-dihydro-lH-pyrrolo[2,3--7]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[-7][l,4]oxazinyl, 5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-α]pyrazinyl, [l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo- [l,2,4]triazolo[4,3-α]pyridinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R14.
48. The compound of claim 47, wherein R3 is l,2,4-oxadiazol-3-yl,
3,5-dimethylisoxazol-4-yl, lH-pyrazol-3-yl, 2-cyanophenyl, 3-cyanophenyl, 4- cyanophenyl, 3-(methanesulfonyl)phenyl, 4-(methanesulfonyl)phenyl, 3- carbamoylphenyl, 4-carbamoylphenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazin-3-yl, 6-methylpyridazin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6- (difluoromethyl)pyridazin-3-yl, 6-(difluoromethoxy)methyl)pyridazin-3-yl, 6- aminopyridazin-3-yl, (6-(hydroxymethyl)pyridazin-3-yl, 6-methoxypyridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-aminopyrazin-2-yl, 5- aminopyrazin-2-yl, 6-aminopyrazin-2-yl, 2-oxopyridin-l(2H)-yl, 6-oxo-l,6- dihydropyridazin-3-yl, 6-oxopyridazin-l(6H)-yl, [l,2,4]triazolo[4,3-a]pyridin-6-yl, [l,2,4]triazolo[l,5-a]pyridin-6-yl, 3-oxo-[l,2,4]triazolo[4,3-α]pyridin-2(3H)-yl, 3-
(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl, [l,2,4]triazolo[l,5- α]pyridin-6-yl, [l,2,4]triazolo[4,3-α]pyridin-6-yl, 3,3-dimethyl-2-oxoindolin-5-yl, 3,3- dimethyl-2-oxoindolin-6-yl, 3-methyl-[l,2,4]triazolo[4,3-.7]-pyridazinyl, or [l,2,4]triazolo[4,3--7]-pyridazinyl.
49. The compound of claim 42, wherein R3 is a non-aromatic heterocycle selected from the group consisting of pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxoazepanyl, 2-oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1-dioxothiomorpholino, piperazinyl, and tetrohydro- 2H-oxazinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R14.
50. The compound of claim 42, wherein R4 is H, Cl, F, CH3, OH, or
OCH3
51. The compound of claim SO, wherein R4 is H or F.
52. The compound of claim 42, wherein R5, R6, and R7 are each independently selected from the group consisting of H, halogen, OR 11 , NR 11R12, NR11C(O)R12, S(O)nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, and substituted Ci-C6 alkyl.
53. The compound of claim 52, wherein R7 is H.
54. The compound of claim 53, wherein R5 and R6 are each H, F, Cl, OH, OCH3, or CH3.
55. The compound of claim 54, wherein R5 and R6 are each Cl.
56. The compound of claim 42, wherein R8 is H, OH, CH3, or F.
57. The compound of claim 42, wherein:
R1 is gem-dialkyl of which each alkyl is Ci-C4;
R2 is H, halogen, OR n, S(O) 2R12, Ci-C6 alkyl, or substituted Ci-C6 alkyl;
R3 is aryl, heteroaryl, or non-aromatic heterocycle;
R4 is H, F, or Cl; and
R5, R6, and R7 are each independently H, halogen, OR n, NR 11R12, S(O) 2R12, C(O)R12, Ci-C6 alkyl, or substituted Ci-C6 alkyl.
58. The compound of claim 42, wherein: R1 is gem-dimethyl;
R2 is H;
R3 is phenyl, or heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-l- yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4- thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dthydro-benzo[l,4]dioxinyl, benzo[l,2,3]triazinyl, benzo[l,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6αff-thieno[2,3- d]imidazolyl, l/-r-pyrrolo[2,3-&]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[l,5- α]pyridinyl, [l,2,4]triazolo[4,3-α]pyridinyl, [l,2,4]triazolo[l,5-α]pyridinyl, thieno[2,3- 6]furanyl, thieno[2,3-6]pyridinyl, thieno[3,2-ft]pyridinyl, furo[2,3--7]pyridinyl, furo[3,2- 6]pyridinyl, thieno[3,2-rf]pyrimidinyl, furo[3,2-.flpyrimidinyl, thieno[2,3-.7]pyrazinyl, furo[2,3-ύ]pyrazinyl , imidazo[l,2-α]pyrazinyl, S,6,7,8-tetrahydroimidazo[l,2- α]pyrazinyl, 6,7-dϋydro-4H-pyrazolo[5,l-c][l,4]oxazinyl, 2-oxo-2,3- dihydrobenzo[-floxazolyl, 2-oxo-2,3-dihydro-lH-benzo[d]imidazole, 3,3-dimethyl-2- oxoindolinyl, 2-oxo-2,3-dihydro-lH-pyrrolo[2,3--7]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dihydro-2H- benzo[6][l,4]oxazinyl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-α]pyrazinyl,
[l,2,4]triazolo[4,3-α]pyrazinyl, and 3-oxo-[l,2,4]triazolo[4,3-α]pyridinyl, or non- aromatic heterocycle selected from the group consisting of pyrrolidinyl, 2- oxopyrrolidinyl, piperidinyl, 2-oxopiperidinyl, azepanyl, 2-oxo-azepanyl, 2- oxooxazolidinyl, morpholino, 3-oxomorpholino, thiomorpholino, 1,1- dioxothiomorpholino, piperazinyl, and tetrohydro-2H-oxazinyl; wherein the phenyl, heteroaryl, or non-aromatic heterocycle is optionally substituted from 1 to 4 times with substituents as defined below in R14; R4 is H or F;
R5 and R6 are each independently H, F, Cl, OH, OMe, or Me;
R7 is H or F; and
R8 is H, OH, or F.
59. The compound of claim 42, wherein: R1 is gem-dimethyl;
R2 is H;
R3 is l,2,4-oxadiazol-3-yl, l,2,3-thiadiazol-4-yl, 3,5-dimethylisoxazol-4-yl, lH-pyrazol- 3-yl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-(methanesulfonyl)phenyl, 4- (methanesulfonyl)phenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, 2-aminopyridinyl, 3-aminopyridinyl, 4-aminopyridinyl, pyridazin-3-yl, 6-methylpyridazin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6- (difluoromethyl)pyridazin-3-yl, 6-(difluoromethoxy)methyl)pyridazin-3-yl, 6- aminopyridazin-3-yl, (6-(hydroxymethyl)pyridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-aminopyrazin-2-yl, 5-aminopyrazin-2-yl, 6-aminopyrazin- 2-yl, 2-oxopyridin-l(2H)-yl, 2-oxopyrrolidin-l-yl, 6-oxo-l,6-dihydropyridazin-3-yl, 6- oxopyridazin-l(6H)-yl, 3-oxo-[l,2,4]triazolo[4,3-α]pyridin-2(3H)-yl, 3-(trifluoromethyl)- 5,6-dihydro-[l,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl, [l,2,4]triazolo[l,5-α]pyridin-6-yl, [l,2,4]triazolo[4,3-α]pyridin-6-yl, 3,3-dimethyl-2-oxoindolin-5-yl, 3-methyl-
[l,2,4]triazolo[4,3--7]-pyridazinyl, [l,2,4]triazolo[4,3--7]-pyridazinyl, or oxooxazolidin-3- yi;
R4 is H or F;
R5 and R6 are each independently H, F, Cl, or CH3;
R7 is H; and R8 is H.
60. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 42.
61. A method of treating a disorder which is created by or is dependent upon decreased availability of norepinephrine, dopamine, or serotonin, said method comprising: administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 42 or a pharmaceutically acceptable salt thereof.
62. A compound of formula (T):
Figure imgf000164_0001
Formula I
wherein:
the carbon atom designated * is in the R or S configuration;
R1 is H, C1-C4 alkyl, or gem-dialkyl of which each alkyl is Ci-C4;
R2 is H, halogen, OR 1 \ S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci -C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, or NR 9R10;
R3 is [l,2,4]triazolo[l,5-α]pyridine-2-yl, [l,2,4]triazolo[l,5-α]pyridine-5-yl, [l,2,4]triazolo[l,5-α]pyridine-6-yl, [l,2,4]triazolo[l,5-α]pyridine-7-yl, or [l,2,4]triazolo[l,5-α]pyridine-8-yl which is optionally substituted by R14;
R4 is H, F, Cl, Me, CN, OR11, Ci-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, Ci -C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, CN, OR 9, orNR 9R10;
R5, R6, and R7 are each independently H or are selected from the group consisting of halogen, OR n, NR 11R12, NR 11C(O)R12, NR 11C(O)2R^ NR 11C(O)NR12 R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4 -C7 cycloalkylalkyl, and wherein each of Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3 -C6 cycloalkyl, and C4 -C7 cycloalkylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of Ci-C3 alkyl, halogen, CN, OR 9, NR 9R10, and phenyl which is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, Ci- C4 haloalkyl, Ci-C4 alkoxy, CN, OR 9, orNR 9 R10;
R8 is H, halogen, OR11 or CJ-C4 alkyl;
R9 and R10 are each independently H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 alkoxy;
or R9 and R10 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R11 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C(O)R 13, phenyl, or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
R12 is H, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl or benzyl, where phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, or Ci-C4 alkoxy;
or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring, with the proviso that only one of R9 and R10 or R11 and R12 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine ring;
R13 is Ci-C4 alkyl, Ci-C4 haloalkyl, or phenyl;
n is 0, 1, or 2; and,
R14 is independently selected at each occurrence from a substituent selected from the group consisting of halogen, NO 2, OR n, NR 11R12, NR 11C(O)R12, NR 11C(O)2R12, NR 11C(O)NR12R13, S(O) nR12, CN, C(O)R 12, C(O)NR 11R12, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl, where Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C7 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of C1-C3 alkyl, halogen, Ar, CN, OR 9, and NR 9R10, or
an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.
63. The compound according to claim 62, wherein R1 is H, methyl, or gem-dimethyl.
64. The compound according to claim 62, wherein R2 is H, F, Cl, CN,
Me, CF3, CF2H, OMe, OCF3, OCF2H, or OH.
65. The compound according to claim 62, wherein R3 is [l,2,4]triazolo[l,S-α]pyridinyl-6-yl which is optionally substituted by R14.
66. The compound according to claim 62, wherein R4 is H, F, Cl, CN, Me, CF3, CF2H, OMe, OCF3, OCF2H, or OH.
67. The compound according to claim 62, wherein R5 to R7 is independently, H, F, Cl, CN, Me, CF3, CF2H, OMe, OCF3, OCF2H, or OH.
68. The compound according to claim 62, wherein R8 is H.
69. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 62.
70. A method of treating a disorder which is created by or is dependent upon decreased availability of norepinephrine, dopamine, or serotonin, said method comprising: administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 62 or a pharmaceutically acceptable salt thereof.
71. A compound of formula (T):
Figure imgf000168_0001
Formula I
wherein:
the carbon atom designated * is in the R or S configuration;
R1 is H, methyl, or gem-dimethyl;
R2 is H, F, Cl, CN, Me, CF3, CF2H, OMe, OCF3, OCF2H, or OH;
R3 is [l,2,4]triazolo[l,5-α]pyridinyl-6-yl which is optionally substituted by R14 ;
R4 is H, F, Cl, CN, Me, CF3, CF2H, OMe, OCF3, OCF2H, or OH;
R5 to R7 is independently, H, F, Cl, CN, Me, CF3, CF2H, OMe, OCF3, OCF2H, or OH; and
R8 is H or methyl,
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
72. The compound according to claim 71, selected from the group consisting of: 7-( [l,2,4]triazolo[l,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-l,2,3,4- tetrahydroisoquinoline;
T-ζCl^^lMazolotl.S-αlpyridin-ό-yO^-ζS^-dichlorophenyO-ό-fluoro-l.l-dimethyl-
1 ,2,3,4-tetrahydroisoquinoline; T-Ctl^^ltriazolotl.S-αlpyridin-ό-yO^-CS^-dichlorophenyO-l.l-dimeihyl-lAS^- tetrahydroisoquinoline;
4-(3,4-dichlorophenyl)-7-(5-methyl-[l,2,4]triazolo[l,5-α]pyridin-6-yl)-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dicWorophenyl)-7-(7-methyl-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dicωorophenyl)-7-(8-methyl-[l,2,4]triazolo[l,5-α]pyridin-6-yl)-l,2,3,4- tetrahydroisoquinoline;
4-(3,4-dicWorophenyl)-7-(2-methyl-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-l,2,3,4- tetrahydroisoquinoline; ό^-CS^-dichlorophenyO-l^.S^-tetrahydroisoquinolin^-y^-tl^^ltriazolotl.S- a]pyridin-2(3H)-one; and an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
73. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 71.
74. A method of treating a disorder which is created by or is dependent upon decreased availability of norepinephrine, dopamine, or serotonin, said method comprising: administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 71 or a pharmaceutically acceptable salt thereof.
PCT/US2010/034373 2009-05-12 2010-05-11 Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof WO2010132437A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP20100775394 EP2429295B1 (en) 2009-05-12 2010-05-11 Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
JP2012510930A JP2012526823A (en) 2009-05-12 2010-05-11 Aryl, heteroaryl, and heterocyclic substituted tetrahydroisoquinolines and uses thereof
AU2010247849A AU2010247849B2 (en) 2009-05-12 2010-05-11 Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
MX2011011901A MX2011011901A (en) 2009-05-12 2010-05-11 Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof.
ES10775394T ES2446971T3 (en) 2009-05-12 2010-05-11 Tetrahydroisoquinolines substituted with aryl, heteroaryl, and heterocycle and their use
CN2010800316663A CN102458123A (en) 2009-05-12 2010-05-11 Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17746409P 2009-05-12 2009-05-12
US61/177,464 2009-05-12

Publications (1)

Publication Number Publication Date
WO2010132437A1 true WO2010132437A1 (en) 2010-11-18

Family

ID=43069017

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/034373 WO2010132437A1 (en) 2009-05-12 2010-05-11 Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof

Country Status (11)

Country Link
US (2) US9034899B2 (en)
EP (1) EP2429295B1 (en)
JP (2) JP2012526823A (en)
KR (1) KR20120034644A (en)
CN (1) CN102458123A (en)
AR (1) AR076866A1 (en)
AU (1) AU2010247849B2 (en)
ES (1) ES2446971T3 (en)
MX (1) MX2011011901A (en)
TW (1) TWI478920B (en)
WO (1) WO2010132437A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8741901B2 (en) 2004-07-15 2014-06-03 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8802696B2 (en) 2009-05-12 2014-08-12 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof
US8815894B2 (en) 2009-05-12 2014-08-26 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US9498476B2 (en) 2008-06-04 2016-11-22 Albany Molecular Research, Inc. Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9045468B2 (en) 2010-08-17 2015-06-02 Albany Molecular Research, Inc. 2,5-methano- and 2,5-ethano-tetrahydrobenzazepine derivatives and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US10653904B2 (en) 2017-12-02 2020-05-19 M-Fire Holdings, Llc Methods of suppressing wild fires raging across regions of land in the direction of prevailing winds by forming anti-fire (AF) chemical fire-breaking systems using environmentally clean anti-fire (AF) liquid spray applied using GPS-tracking techniques
US11865390B2 (en) 2017-12-03 2024-01-09 Mighty Fire Breaker Llc Environmentally-clean water-based fire inhibiting biochemical compositions, and methods of and apparatus for applying the same to protect property against wildfire
US11865394B2 (en) 2017-12-03 2024-01-09 Mighty Fire Breaker Llc Environmentally-clean biodegradable water-based concentrates for producing fire inhibiting and fire extinguishing liquids for fighting class A and class B fires
US11826592B2 (en) 2018-01-09 2023-11-28 Mighty Fire Breaker Llc Process of forming strategic chemical-type wildfire breaks on ground surfaces to proactively prevent fire ignition and flame spread, and reduce the production of smoke in the presence of a wild fire
CN109123908B (en) * 2018-09-07 2020-09-11 山东沃烯新材料科技有限公司 Graphene bacteriostatic insole and preparation method and application thereof
EP4076527A4 (en) * 2020-01-10 2024-05-15 Consynance Therapeutics Inc Therapeutic combinations of drugs and methods of using them
CN111362854B (en) * 2020-04-30 2021-04-27 安徽德信佳生物医药有限公司 Preparation method of ralotinib intermediate
US11911643B2 (en) 2021-02-04 2024-02-27 Mighty Fire Breaker Llc Environmentally-clean fire inhibiting and extinguishing compositions and products for sorbing flammable liquids while inhibiting ignition and extinguishing fire

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060111396A1 (en) * 2004-11-22 2006-05-25 Amr Technology, Inc. 4-Phenyl substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin
US20090099158A1 (en) * 2007-03-01 2009-04-16 Grice Cheryl A Tetrahydroisoquinoline compounds as modulators of the histamine h3 receptor

Family Cites Families (301)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947456A (en) 1970-01-06 1976-03-30 Hoffman-La Roche Inc. Substituted 4-phenyl isoquinolines
US3666763A (en) 1970-01-06 1972-05-30 Hoffmann La Roche 4-phenyl isoquinolines and process for preparing same
CH538477A (en) 1970-01-06 1973-06-30 Hoffmann La Roche Antidepressant 4-phenyl-tetrahydroquino- - lines
GB1504424A (en) 1975-08-09 1978-03-22 Beecham Group Ltd Isoquinoline-derived aminoethers
US4340600A (en) 1980-05-22 1982-07-20 Smithkline Corporation Renal dilating methods and compositions using 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines
DE3333994A1 (en) 1983-09-21 1985-04-04 Troponwerke GmbH & Co KG, 5000 Köln NEW PYRIDOINDOL DERIVATIVES, METHOD FOR THEIR PRODUCTION AND THEIR USE
US4843071A (en) 1986-12-05 1989-06-27 Serotonin Industries Of Charleston Method and composition for treating obesity, drug abuse, and narcolepsy
ZA885824B (en) 1987-08-14 1989-04-26 Merrell Dow Pharma Novel antidepressants
EP0360390A1 (en) 1988-07-25 1990-03-28 Glaxo Group Limited Spirolactam derivatives
WO1990005525A1 (en) 1988-11-23 1990-05-31 Pfizer Inc. Quinuclidine derivatives as substance p antagonists
FI895821A0 (en) 1988-12-07 1989-12-05 Wellcome Found PHARMACEUTICAL ACTIVE CNS FOERENINGAR.
US4902710A (en) 1988-12-14 1990-02-20 Eli Lilly And Company Serotonin and norepinephrine uptake inhibitors
US5114976A (en) 1989-01-06 1992-05-19 Norden Michael J Method for treating certain psychiatric disorders and certain psychiatric symptoms
EP0380223A1 (en) 1989-01-17 1990-08-01 Konica Corporation Colour filter and process for producing the same
JPH02281203A (en) 1989-04-21 1990-11-16 Konica Corp Color filter
BG49761A1 (en) 1989-04-24 1992-02-14 Vissh Khim T I 4- (4'- chalophenyl)- 2- methyl- 1, 2, 3, 4- tetrahydroisohinolines and method for its preparation
US5164372A (en) 1989-04-28 1992-11-17 Fujisawa Pharmaceutical Company, Ltd. Peptide compounds having substance p antagonism, processes for preparation thereof and pharmaceutical composition comprising the same
AU6368090A (en) 1989-10-03 1991-04-11 Warner-Lambert Company Substituted carboxytetrahydroisoquinolines and derivatives thereof having pharmaceutical activity
IE903957A1 (en) 1989-11-06 1991-05-08 Sanofi Sa Aromatic amine compounds, their method of preparation and¹pharmaceutical compositions in which they are present
FR2654726B1 (en) 1989-11-23 1992-02-14 Rhone Poulenc Sante NEW ISOINDOLONE DERIVATIVES AND THEIR PREPARATION.
FR2654725B1 (en) 1989-11-23 1992-02-14 Rhone Poulenc Sante NEW ISOINDOLONE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
GB8929070D0 (en) 1989-12-22 1990-02-28 Fujisawa Pharmaceutical Co Peptide compounds,processes for preparation thereof and pharmaceutical composition comprising the same
US5232929A (en) 1990-11-28 1993-08-03 Pfizer Inc. 3-aminopiperidine derivatives and related nitrogen containing heterocycles and pharmaceutical compositions and use
WO1991009844A1 (en) 1990-01-04 1991-07-11 Pfizer Inc. Substance p antagonists
WO1991012266A1 (en) 1990-02-15 1991-08-22 Fujisawa Pharmaceutical Co., Ltd. Peptide compound
US5447947A (en) 1990-02-26 1995-09-05 Arc 1 Compositions and methods of treatment of sympathetically maintained pain
ATE113947T1 (en) 1990-06-01 1994-11-15 Pfizer 3-AMINO-2-ARYLQUINUCLIDINES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM.
DE69106365T2 (en) 1990-07-23 1995-05-04 Pfizer CHINUCLIDINE DERIVATIVES.
DK0550635T3 (en) 1990-09-28 1995-09-04 Pfizer Cyclic compounds with condensed rings analogous to nitrogenous non-aromatic hot erocyclic compounds
GB9023116D0 (en) 1990-10-24 1990-12-05 Fujisawa Pharmaceutical Co Peptide compounds,processes for preparation thereof and pharmaceutical composition comprising the same
JPH04193867A (en) 1990-11-23 1992-07-13 Nippon Shinyaku Co Ltd Isoquinolinol derivative and medicine
DE69114117T2 (en) 1990-12-21 1996-03-21 Fujisawa Pharmaceutical Co New use of peptide derivative.
WO1992012151A1 (en) 1991-01-10 1992-07-23 Pfizer Inc. N-alkyl quinuclidinium salts as substance p antagonists
ATE154354T1 (en) 1991-02-11 1997-06-15 Merck Sharp & Dohme AZABICYCLIC COMPOUNDS, PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND THERAPEUTIC USE
ATE115581T1 (en) 1991-03-01 1994-12-15 Pfizer 1-AZABICYCLO(3.2.2>NONAN-3-AMINE DERIVATIVES.
WO1992017449A1 (en) 1991-03-26 1992-10-15 Pfizer Inc. Stereoselective preparation of substituted piperidines
FR2677361A1 (en) 1991-06-04 1992-12-11 Adir NOVEL PEPTIDES AND PSEUDOPEPTIDES, TACHYKININ DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR2676053B1 (en) 1991-05-03 1993-08-27 Sanofi Elf NOVEL DIALKYLENEPIPERIDINO COMPOUNDS AND THEIR ENANTIOMERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR2676055B1 (en) 1991-05-03 1993-09-03 Sanofi Elf AMINO POLYCYCLIC COMPOUNDS AND THEIR ENANTIOMERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR2676446B1 (en) 1991-05-17 1993-08-06 Rhone Poulenc Rorer Sa NOVEL THIOPYRANOPYRROLE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR2676447B1 (en) 1991-05-17 1993-08-06 Rhone Poulenc Rorer Sa NOVEL THIOPYRANOPYRROLE DERIVATIVES AND THEIR PREPARATION.
FR2676443B1 (en) 1991-05-17 1993-08-06 Rhone Poulenc Rorer Sa NOVEL PERHYDROISOINDOLE DERIVATIVES AND THEIR PREPARATION.
FR2676442B1 (en) 1991-05-17 1993-08-06 Rhone Poulenc Rorer Sa NEW PERHYDROISOINDOLE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
US5292726A (en) 1991-05-22 1994-03-08 Merck & Co., Inc. N,N-diacylpiperazines
DE9290057U1 (en) 1991-05-22 1994-01-05 Pfizer Substituted 3-aminoquinuclidines
KR100214905B1 (en) 1991-05-31 1999-08-02 디. 제이. 우드, 스피겔 알렌 제이 Quinuclidine derivatives
GB9113219D0 (en) 1991-06-19 1991-08-07 Fujisawa Pharmaceutical Co Peptide compound,processes for preparation thereof and pharmaceutical composition comprising the same
ES2092113T3 (en) 1991-06-20 1996-11-16 Pfizer FLUOROALCOXYBENCILAMINE DERIVATIVES OF HETEROCICLES CONTAINING NITROGEN.
TW202432B (en) 1991-06-21 1993-03-21 Pfizer
US5288730A (en) 1991-06-24 1994-02-22 Merck Sharp & Dohme Limited Azabicyclic compounds, pharmaceutical compositions containing them and their use in therapy
EP0536817A1 (en) 1991-07-05 1993-04-14 MERCK SHARP &amp; DOHME LTD. Azabicyclic compounds as tachykinin antagonists
US5472978A (en) 1991-07-05 1995-12-05 Merck Sharp & Dohme Ltd. Aromatic compounds, pharmaceutical compositions containing them and their use in therapy
IE72090B1 (en) 1991-07-05 1997-03-12 Merck Sharp & Dohme Aromatic compounds pharmaceutical compositions containing them and their use in therapy
US5495047A (en) 1991-07-10 1996-02-27 Merck, Sharp & Dohme (Ltd.) Fused tricyclic compounds, pharmaceutical compositions containing them and their use in therapy
JPH06509090A (en) 1991-07-10 1994-10-13 メルク　シヤープ　エンド　ドーム　リミテツド Aromatic compounds, compositions containing them and their use in therapy
MY110227A (en) 1991-08-12 1998-03-31 Ciba Geigy Ag 1-acylpiperindine compounds.
EP0600952B1 (en) 1991-08-20 1996-04-17 MERCK SHARP &amp; DOHME LTD. Azacyclic compounds, processes for their preparation and pharmaceutical compositions containing them
ES2149767T5 (en) 1991-09-20 2005-06-16 Glaxo Group Limited NEW MEDICAL USE FOR TAQUIQUININE ANTAGONISTS.
CA2118704C (en) 1991-09-26 1997-01-21 John A. Lowe, Iii Fused tricyclic nitrogen containing heterocycles as substance p receptor antagonists
WO1993009116A1 (en) 1991-11-07 1993-05-13 Yoshitomi Pharmaceutical Industries, Ltd. Quinuclidine compound and medicinal use thereof
CA2324959C (en) 1991-11-12 2002-11-12 Pfizer Limited Phthalimido compounds as intermediates for producing substance p receptor antagonists
EP0545478A1 (en) 1991-12-03 1993-06-09 MERCK SHARP &amp; DOHME LTD. Heterocyclic compounds as tachykinin antagonists
GB9200535D0 (en) 1992-01-10 1992-02-26 Fujisawa Pharmaceutical Co New compound
GB9201179D0 (en) 1992-01-21 1992-03-11 Glaxo Group Ltd Chemical compounds
US5241065A (en) 1992-02-25 1993-08-31 Schering Corporation 2,3,4,5-tetrahydro-1h-3-benzazepines having anti-psychotic activity
US5328927A (en) 1992-03-03 1994-07-12 Merck Sharpe & Dohme, Ltd. Hetercyclic compounds, processes for their preparation and pharmaceutical compositions containing them
US5595872A (en) 1992-03-06 1997-01-21 Bristol-Myers Squibb Company Nucleic acids encoding microsomal trigyceride transfer protein
JP2656702B2 (en) 1992-03-23 1997-09-24 ファイザー製薬株式会社 Peptide quinuclidine
FR2689888B1 (en) 1992-04-10 1994-06-10 Rhone Poulenc Rorer Sa NOVEL PERHYDROISOINDOLE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
WO1993021181A1 (en) 1992-04-15 1993-10-28 Merck Sharp & Dohme Limited Azacyclic compounds
GB2266529A (en) 1992-05-01 1993-11-03 Merck Sharp & Dohme Tetrahydroisoquinoline derivatives
CA2134964C (en) 1992-05-18 1997-12-30 Manoj C. Desai Bridged aza-bicyclic derivatives as substance p antagonists
GB9211193D0 (en) 1992-05-27 1992-07-08 Merck Sharp & Dohme Therapeutic agents
IL106142A (en) 1992-06-29 1997-03-18 Merck & Co Inc Morpholine and thiomorpholine tachykinin receptor antagonists, their preparation and pharmaceutical compositions containing them
US5612336A (en) 1992-07-13 1997-03-18 Merck, Sharp & Dohme Ltd. Heterocyclic amide derivatives as tachykinin antagonists
WO1994002595A1 (en) 1992-07-17 1994-02-03 Ribozyme Pharmaceuticals, Inc. Method and reagent for treatment of animal diseases
GB2268931A (en) 1992-07-22 1994-01-26 Merck Sharp & Dohme Azabicyclic tachykinin-receptor antagonists
US5561130A (en) 1992-07-28 1996-10-01 Merck Sharp & Dohme Limited Azacyclic compounds
GB2269170A (en) 1992-07-29 1994-02-02 Merck Sharp & Dohme Azatricyclic tachykinin antagonists
WO1994003429A1 (en) 1992-07-31 1994-02-17 Merck Sharp & Dohme Limited Substituted amines as tachykinin receptor antagonists
CA2141051A1 (en) 1992-08-04 1994-02-17 Terry J. Rosen Substituted nitrogen-containing heterocycles
GB9216911D0 (en) 1992-08-10 1992-09-23 Merck Sharp & Dohme Therapeutic agents
PT655055E (en) 1992-08-13 2001-03-30 Warner Lambert Co ANTAGONISTS OF TAQUIQUININ
US5212185A (en) 1992-08-14 1993-05-18 G. D. Searle & Co. Piperidinyl-terminated alkylamino ethynyl alanine amino diol compounds for treatment of hypertension
DK0655996T3 (en) 1992-08-19 2001-12-27 Pfizer Substituted benzylamino nitrogen-containing, non-aromatic heterocyclic compounds
US5482967A (en) 1992-09-04 1996-01-09 Takeda Chemical Industries, Ltd. Condensed heterocyclic compounds, their production and use
US5563161A (en) 1992-09-10 1996-10-08 Merck Sharp & Dohme Ltd. Alcohols and ethers with aromatic substituents as tachykinin-antagonists
GB9220286D0 (en) 1992-09-25 1992-11-11 Merck Sharp & Dohme Therapeutic agents
GB2271566A (en) 1992-10-14 1994-04-20 Merck & Co Inc HIV integrase inhibitors
JP2656699B2 (en) 1992-10-21 1997-09-24 ファイザー製薬株式会社 Substituted benzylaminoquinuclidine
GB9222262D0 (en) 1992-10-23 1992-12-09 Merck Sharp & Dohme Therapeutic agents
GB9222486D0 (en) 1992-10-26 1992-12-09 Merck Sharp & Dohme Therapeutic agents
AU678409B2 (en) 1992-10-28 1997-05-29 Merck Sharp & Dohme Limited 4-arylmethyloxymethyl piperidines as tachykinin antagonists
JP2656700B2 (en) 1992-10-28 1997-09-24 ファイザー製薬株式会社 Substituted quinuclidine derivatives
WO1994010167A1 (en) 1992-10-30 1994-05-11 Merck Sharp & Dohme Limited Tachykinin antagonists
EP0668863B1 (en) 1992-11-12 1997-01-08 Pfizer Inc. Quinuclidine derivative as substance p antagonist
US5261188A (en) 1992-11-23 1993-11-16 The Standard Products Company Belt weatherstrip with bulb
JPH06153997A (en) 1992-11-27 1994-06-03 Canon Inc Method for detecting target nucleic acid by amplification of detected signal
CA2150123C (en) 1992-12-10 2004-12-07 Harry R. Howard Aminomethylene substituted non-aromatic heterocycles
AU682838B2 (en) 1992-12-14 1997-10-23 Merck Sharp & Dohme Limited 4-aminomethyl/thiomethyl/sulfonylmethyl-4-phenylpiperidines as tachykinin receptor antagonists
GB9226581D0 (en) 1992-12-21 1993-02-17 Merck Sharp & Dohme Therapeutic agents
DK154192D0 (en) 1992-12-23 1992-12-23 Neurosearch As HETEROCYCLIC COMPOUNDS
GB9300051D0 (en) 1993-01-04 1993-03-03 Merck Sharp & Dohme Therapeutic agents
EP0610793A1 (en) 1993-02-08 1994-08-17 Takeda Chemical Industries, Ltd. Tetracyclic morpholine derivatives and their use or analgesics
US5633266A (en) 1993-02-18 1997-05-27 Merck Sharp & Dohme Ltd. Azacyclic compounds compositions containing them and their use as tachykinin antagonists
AU6140694A (en) 1993-02-22 1994-09-14 Merck Sharp & Dohme Limited Aromatic compounds, compositions containing them and their use in therapy
US5688806A (en) 1993-03-04 1997-11-18 Pfizer Inc. Spiroazacyclic derivatives as substance P antagonists
US5656642A (en) 1993-04-07 1997-08-12 Otsuka Pharmaceutical Co., Ltd. Peripheral vasodilating agent containing piperidine derivative as active ingredient
CA2160462C (en) 1993-05-06 1998-12-15 Timothy P. Burkholder Substituted pyrrolidin-3-yl-alkyl-piperidines useful as tachykinin antagonists
IL109646A0 (en) 1993-05-19 1994-08-26 Pfizer Heteroatom substituted alkyl benzylamino-quinuclidines
CA2163995A1 (en) 1993-06-07 1994-12-22 Malcolm Maccoss Spiro-substituted azacycles as neurokinin antagonists
EP0634402A1 (en) 1993-07-14 1995-01-18 Takeda Chemical Industries, Ltd. Isochinolinone derivatives, their production and use
DK0708771T3 (en) 1993-07-15 1999-06-21 Pfizer Benzyloxyquinuclidines as substance P antagonists
GB9315808D0 (en) 1993-07-30 1993-09-15 Merck Sharp & Dohme Therapeutic agents
TW365603B (en) 1993-07-30 1999-08-01 Rhone Poulenc Rorer Sa Novel perhydroisoindole derivatives, their preparation and pharmaceutical compositions which contain them
GB9317987D0 (en) 1993-08-26 1993-10-13 Glaxo Group Ltd Chemical compounds
WO1995007908A1 (en) 1993-09-17 1995-03-23 Pfizer Inc. Heteroarylamino and heteroarylsulfonamido substituted 3-benzylaminomethyl piperidines and related compounds
DK0719253T3 (en) 1993-09-17 2004-07-26 Pfizer 3-amino-5-carboxy-substituted piperidines and 3-amino-4-carboxy-substituted pyrrolidines as tachykinin antagonists
IL111002A (en) 1993-09-22 1998-09-24 Glaxo Group Ltd Piperidine derivatives their preparation and pharmaceutical compositions containing them
AU7947594A (en) 1993-10-27 1995-05-22 Merck Sharp & Dohme Limited Substituted amides as tachykinin antagonists
US6403577B1 (en) 1993-11-17 2002-06-11 Eli Lilly And Company Hexamethyleneiminyl tachykinin receptor antagonists
IT1271462B (en) 1993-12-03 1997-05-28 Menarini Farma Ind TACHYCHININ ANTAGONISTS, PROCEDURE FOR THEIR PREPARATION AND THEIR USE IN PHARMACEUTICAL FORMULATIONS.
IL111960A (en) 1993-12-17 1999-12-22 Merck & Co Inc Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them
CA2176130A1 (en) 1993-12-21 1995-06-29 Thomas Alan Crowell Non-peptide tachykinin receptor antagonists
EP0737194B1 (en) 1993-12-29 1999-03-03 Pfizer Inc. Diazabicyclic neurokinin antagonists
SK283070B6 (en) 1993-12-29 2003-02-04 Merck Sharp & Dohme Limited Substituted morpholine derivatives and their use as therapeutic agents
EP0741704A1 (en) 1994-01-28 1996-11-13 MERCK SHARP &amp; DOHME LTD. Aralkylamino substituted azacyclic therapeutic agents
GB9402688D0 (en) 1994-02-11 1994-04-06 Merck Sharp & Dohme Therapeutic agents
US5610165A (en) 1994-02-17 1997-03-11 Merck & Co., Inc. N-acylpiperidine tachykinin antagonists
TW385308B (en) 1994-03-04 2000-03-21 Merck & Co Inc Prodrugs of morpholine tachykinin receptor antagonists
FR2718136B1 (en) 1994-03-29 1996-06-21 Sanofi Sa Amino aromatic compounds, process for their preparation and pharmaceutical compositions containing them.
US5610145A (en) 1994-04-15 1997-03-11 Warner-Lambert Company Tachykinin antagonists
US5607939A (en) 1994-04-28 1997-03-04 Takeda Chemical Industries, Ltd. Condensed heterocyclic compounds, their production and use
EP0694535A1 (en) 1994-04-29 1996-01-31 Eli Lilly And Company Non-peptidyl tachykinin receptor antagonists
JPH10500944A (en) 1994-05-05 1998-01-27 メルク シヤープ エンド ドーム リミテツド Morpholine derivatives and their use as antagonists of tachykinins
EP0804463A1 (en) 1994-05-07 1997-11-05 Boehringer Ingelheim Kg Neurokinine (tachykinine) antagonists
PT764163E (en) 1994-06-06 2002-03-28 Warner Lambert Co TACHYCININ RECEPTOR ANTAGONISTS (NK1)
CA2150992A1 (en) 1994-06-10 1995-12-11 Philip Arthur Hipskind Cyclohexyl tachykinin receptor antagonists
CA2134038C (en) 1994-06-16 1997-06-03 David Taiwai Wong Potentiation of drug response
BR9508375A (en) 1994-07-12 1997-10-28 Lilly Co Eli Heterocyclic tachykinin receptor antagonist
NZ290422A (en) 1994-07-20 1999-02-25 Byk Gulden Lomberg Chem Fab Pyridyl or pyrimidinyl substituted thiopyridine derivatives and medicaments
DE4425612A1 (en) 1994-07-20 1996-04-04 Bayer Ag 6-membered nitrogen-containing heteroaryl oxazolidinones
CA2154116A1 (en) 1994-07-22 1996-01-23 Philip Arthur Hipskind 1-aryl-2-acetamidopentanone derivatives for use as tachykinin receptor antagonists
GB9415997D0 (en) 1994-08-08 1994-09-28 Merck Sharp & Dohme Therapeutic agents
GB9415996D0 (en) 1994-08-08 1994-09-28 Merck Sharp & Dohme Therapeutic agents
TW432061B (en) 1994-08-09 2001-05-01 Pfizer Res & Dev Lactams
DK0777659T3 (en) 1994-08-15 2001-09-03 Merck Sharp & Dohme Morpholine derivatives and their use as therapeutic agents
MX9701305A (en) 1994-08-25 1998-05-31 Merrell Pharma Inc Novel substituted piperidines useful for the treatment of allergic diseases.
ES2107118T3 (en) 1994-08-29 1997-11-16 Akzo Nobel Nv PROCEDURE FOR THE PREPARATION OF QUATERNARY DIESTERS.
GB9417956D0 (en) 1994-09-02 1994-10-26 Merck Sharp & Dohme Therapeutic agents
GB9418545D0 (en) 1994-09-15 1994-11-02 Merck Sharp & Dohme Therapeutic agents
US5457107A (en) 1994-09-16 1995-10-10 Merck & Co., Inc. Polymorphic form of a tachykinin receptor antagonist
JPH10506399A (en) 1994-09-30 1998-06-23 ノバルティス アクチェンゲゼルシャフト 1-acyl-4-marifatylaminopiperidine compound
TW397825B (en) 1994-10-14 2000-07-11 Novartis Ag Aroyl-piperidine derivatives
FR2725986B1 (en) 1994-10-21 1996-11-29 Adir NOVEL PIPERIDINE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
DE69534213T2 (en) 1994-10-25 2006-01-12 Astrazeneca Ab Therapeutically effective heterocycles
GB9421709D0 (en) 1994-10-27 1994-12-14 Zeneca Ltd Therapeutic compounds
CA2162786A1 (en) 1994-11-22 1996-05-23 Philip Arthur Hipskind Heterocyclic tachykinin receptor antagonists
FR2727411B1 (en) 1994-11-30 1997-01-03 Rhone Poulenc Rorer Sa NOVEL PERHYDROISOINDOLE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
IL116323A0 (en) 1994-12-13 1996-03-31 Sandoz Ag Tachykinin antagonists their preparation and pharmaceutical compositions containing them
GB9426103D0 (en) 1994-12-23 1995-02-22 Merck Sharp & Dohme Therapeutic agents
US6020346A (en) 1995-01-12 2000-02-01 Glaxo Wellcome Inc. Piperidine derivatives having tachykinin antagonist activity
FR2729951B1 (en) 1995-01-30 1997-04-18 Sanofi Sa NOVEL HETEROCYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
GB9505491D0 (en) 1995-03-18 1995-05-03 Merck Sharp & Dohme Therapeutic agents
GB9505492D0 (en) 1995-03-18 1995-05-03 Merck Sharp & Dohme Therapeutic agents
US5554641A (en) 1995-03-20 1996-09-10 Horwell; David C. Nonpeptides as tachykinin antagonists
GB9505692D0 (en) 1995-03-21 1995-05-10 Glaxo Group Ltd Chemical compounds
ATE242243T1 (en) 1995-03-24 2003-06-15 Takeda Chemical Industries Ltd CYCLIC COMPOUNDS, THEIR PREPARATION AND THEIR USE AS TACHYKINE RECEPTOR ANTAGONISTS
US5565568A (en) 1995-04-06 1996-10-15 Eli Lilly And Company 2-acylaminopropanamides as tachykinin receptor antagonists
KR100414321B1 (en) 1995-04-13 2004-02-18 아벤티스 파마슈티칼스 인크. Novel Substituted Piperazine Derivatives Having Tachykinin Receptor Antagonists Activity
AU706021B2 (en) 1995-05-25 1999-06-03 Fujisawa Pharmaceutical Co., Ltd. Piperazine derivatives
US5654316A (en) 1995-06-06 1997-08-05 Schering Corporation Piperidine derivatives as neurokinin antagonists
US5817832A (en) 1995-06-22 1998-10-06 Ciba Specialty Chemicals Corporation Blue diketopyrrolopyrrole pigments
GB9513118D0 (en) 1995-06-28 1995-08-30 Merck Sharp & Dohme Therapeutic agents
GB9513121D0 (en) 1995-06-28 1995-08-30 Merck Sharp & Dohme Therapeutic agents
GB9513117D0 (en) 1995-06-28 1995-08-30 Merck Sharp & Dohme Therapeutic agents
ATE199552T1 (en) 1995-07-07 2001-03-15 Pfizer SUBSTITUTED BENZOLACTAM COMPOUNDS AS SUBSTANCE P ANTAGONISTS
TW340842B (en) 1995-08-24 1998-09-21 Pfizer Substituted benzylaminopiperidine compounds
JP2002534955A (en) 1995-10-18 2002-10-15 メルク エンド カンパニー インコーポレーテッド Cyclopentyl tachykinin receptor antagonist
DE19541283A1 (en) 1995-11-06 1997-05-07 Boehringer Ingelheim Kg Novel amino acid derivatives, processes for their preparation and pharmaceutical compositions containing these compounds
GB9523244D0 (en) 1995-11-14 1996-01-17 Merck Sharp & Dohme Therapeutic agents
WO1997019084A1 (en) 1995-11-23 1997-05-29 Merck Sharp & Dohme Limited Spiro-piperidine derivatives and their use as tachykinin antagonists
GB9524157D0 (en) 1995-11-25 1996-01-24 Pfizer Ltd Therapeutic agents
HU224225B1 (en) 1995-12-01 2005-06-28 Sankyo Co. Ltd. Heterocyclic compounds having tachykinin receptor antagonist activity, their preparation, and their use for the preparation of pharmaceutical compositions
GB9525296D0 (en) 1995-12-11 1996-02-07 Merck Sharp & Dohme Therapeutic agents
ZA9610738B (en) 1995-12-22 1997-06-24 Warner Lambert Co Subtype selective nmda receptor ligands and the use thereof
US6025355A (en) 1997-05-19 2000-02-15 Cambridge Neuroscience, Inc. Pharmaceutically active compounds and methods of use
EP0891334A1 (en) 1996-04-03 1999-01-20 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5885983A (en) 1996-05-10 1999-03-23 Bristol-Myers Squibb Company Inhibitors of microsomal triglyceride transfer protein and method
US5827875A (en) 1996-05-10 1998-10-27 Bristol-Myers Squibb Company Inhibitors of microsomal triglyceride transfer protein and method
JP2000510153A (en) 1996-06-21 2000-08-08 メルク シヤープ エンド ドーム リミテツド Spiro-piperidine derivatives and their use as therapeutics
DE19638486A1 (en) 1996-09-20 1998-03-26 Basf Ag Hetaroyl derivatives
DE19638484A1 (en) 1996-09-20 1998-03-26 Basf Ag Hetaroyl derivatives
WO1998035939A1 (en) 1997-02-18 1998-08-20 Sanwa Kagaku Kenkyusho Co., Ltd. Malonic diamide derivatives and use thereof
US5907041A (en) 1997-03-12 1999-05-25 Rhone-Poulenc Inc. Process for preparing pyrazole derivatives
JPH10292008A (en) 1997-04-21 1998-11-04 Grand Polymer:Kk Process for producing alpha-olefin
WO1999018071A1 (en) 1997-10-07 1999-04-15 Boehringer Ingelheim (Canada) Ltd. Azetidinone derivatives for the treatment of hcmv infections
WO1999018073A1 (en) 1997-10-07 1999-04-15 Boehringer Ingelheim (Canada) Ltd. Azetidinone derivatives for the treatment of hcmv infections
US7041702B1 (en) 1997-10-21 2006-05-09 Scion Pharmaceuticals, Inc. Pharmaceutically active compounds and methods of use
US6121261A (en) 1997-11-19 2000-09-19 Merck & Co., Inc. Method for treating attention deficit disorder
US6943159B1 (en) 1998-02-18 2005-09-13 Neurosearch A/S Compounds and their use as positive AMPA receptor modulators
US6043253A (en) 1998-03-03 2000-03-28 Merck & Co., Inc. Fused piperidine substituted arylsulfonamides as β3-agonists
AU5907399A (en) 1998-09-04 2000-03-27 Ciba Specialty Chemicals Holding Inc. Process for making 2,4-dihydroxyphenyl and 2-hydroxy-4-alkoxyphenyl substituted triazine compounds
JP2000186110A (en) 1998-12-21 2000-07-04 Ube Ind Ltd Production of ethylene copolymer
ES2207485T3 (en) 1999-01-12 2004-06-01 Clariant Finance (Bvi) Limited BENZOPHENONAS AND ITS USE AS PHOTOINIATORS.
US6664293B2 (en) 1999-02-26 2003-12-16 Fujiwawa Pharmaceutical Co., Ltd. Amide compounds for the potentiation of cholinergic activity
US6586447B1 (en) 1999-04-01 2003-07-01 Pfizer Inc 3,3-disubstituted-oxindole derivatives useful as anticancer agents
JP2001026580A (en) 1999-05-10 2001-01-30 Sumitomo Chem Co Ltd Production of optically active 1-aryl-1,2,3,4- tetrahydroquinoline
US6562836B1 (en) 1999-05-24 2003-05-13 Queen's University Of Kingston Methods and compounds for inhibiting amyloid deposits
US6642228B1 (en) 1999-06-24 2003-11-04 Toray Industries, Inc. α1b-adrenergic receptor antagonists
AU5994900A (en) 1999-07-09 2001-01-30 Isis Innovation Limited Compounds for inhibiting diseases and preparing cells for transplantation
US6340681B1 (en) 1999-07-16 2002-01-22 Pfizer Inc 2-benzimidazolylamine compounds as ORL-1-receptor agonists
US7163949B1 (en) 1999-11-03 2007-01-16 Amr Technology, Inc. 4-phenyl substituted tetrahydroisoquinolines and use thereof
KR100878855B1 (en) 1999-11-03 2009-01-15 에이엠알 테크놀로지, 인크. 4-phenyl-substituted therahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin
ATE387429T1 (en) 1999-11-03 2008-03-15 Amr Technology Inc ARLY- AND HETEROARYL-SUBSTITUTED TETRAHYDROISOQUINOLINES AND THEIR USE AS NOREPINEPHRINE, DOPAMINE AND SEROTONIN REUPPOST INHIBITORS
CZ20022332A3 (en) 2000-01-07 2003-01-15 Transform Pharmaceuticals, Inc. Sample assembly
AU2001262150A1 (en) 2000-03-23 2001-10-03 Mitsubishi Pharma Corporation 2-(nitrogen-heterocyclic)pyrimidone derivatives
JP2003533513A (en) 2000-05-15 2003-11-11 ダーウィン・ディスカバリー・リミテッド Hydroxamic acid and carboxylic acid derivatives having MMP and TNF inhibitory activity
US6664256B1 (en) 2000-07-10 2003-12-16 Kowa Co., Ltd. Phenylpyridazine compounds and medicines containing the same
BR0112350A (en) 2000-07-11 2003-06-24 Albany Molecular Res Inc Compound, pharmaceutical composition, and method of treating an animal afflicted with a neurological or psychological disorder
WO2002046164A1 (en) 2000-12-07 2002-06-13 Astrazeneca Ab Therapeutic compounds
US6506772B1 (en) 2000-12-15 2003-01-14 Hoffmann-La Roche Inc. Substituted [1,2,4]triazolo[1,5a]pyridine derivatives with activity as adenosine receptor ligands
US6900220B2 (en) 2001-01-02 2005-05-31 Syntex (U.S.A.) Llc Quinazolone derivatives as alpha 1A/B adrenergic receptor antagonists
US6911453B2 (en) 2001-12-05 2005-06-28 Aventis Pharma Deutschland Gmbh Substituted 4-phenyltetrahydroisoquinolinium, process for their preparation, their use as a medicament, and medicament containing them
MXPA04005343A (en) 2001-12-05 2004-09-27 Aventis Pharma Gmbh Substituted 4-phenyltetrahydroisoquinolines, method for the production thereof, the use thereof as medicaments, in addition to a medicament containing same.
US6974803B2 (en) 2001-12-06 2005-12-13 Pfizer Inc Pharmaceutical combination
US6703405B2 (en) 2001-12-22 2004-03-09 Aventis Pharma Deutschland Gmbh Substituted 4-phenyltetrahydroisoquinolinium salts, process for their preparation, their use as a medicament, and medicament containing them
US20050261298A1 (en) 2002-01-18 2005-11-24 David Solow-Cordero Methods of treating conditions associated with an Edg-7 receptor
US20050113283A1 (en) 2002-01-18 2005-05-26 David Solow-Cordero Methods of treating conditions associated with an EDG-4 receptor
EP1676844A1 (en) 2004-12-28 2006-07-05 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
AU2003230665B2 (en) 2002-03-13 2010-02-18 University Of Tennessee Research Foundation Substituted tetrahydroisoquinoline compounds, methods of making, and their use
SI1539673T1 (en) 2002-07-09 2008-02-29 Lonza Ag Process for the preparation of n -monosubstituted beta-amino alcohols
BR0313727A (en) 2002-08-13 2005-07-12 Warner Lambert Co Isoquinoline derivatives as matrix metalloproteinase inhibitors
AU2003249531A1 (en) 2002-08-13 2004-02-25 Warner-Lambert Company Llc Azaisoquinoline derivatives as matrix metalloproteinase inhibitors
CA2499523C (en) 2002-09-20 2011-04-19 Medisyn Technologies, Inc. Therapeutic agents and corresponding treatments
EP2156830A1 (en) 2002-10-16 2010-02-24 Isis Innovation Limited Modulators of asparaginyl hydoxylase activity of FIH
GB0224557D0 (en) 2002-10-22 2002-11-27 Glaxo Group Ltd Novel compounds
BR0316919A (en) 2002-12-02 2005-10-18 Pharmacia & Upjohn Co Llc Use of 4-phenyl substituted tetrahydroisoquinolines in the treatment of pain, migraine headaches and urinary incontinence
AU2003283646A1 (en) 2002-12-02 2004-06-23 Pharmacia & Upjohn Company Llc The use of aryl- and heteroaryl-substituted tetrahydroisoquinolines in the treatment of chronic and neuropathic pain, migraine headaches, and urge, stress and mixed urinary incontinence
DE10303254B3 (en) 2003-01-28 2004-09-23 Johannes-Gutenberg-Universität Mainz 3,3-Dimethyl-8-oxoisoquinolines, process for their preparation, pharmaceutical compositions containing them and their use
WO2004069162A2 (en) 2003-01-31 2004-08-19 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US7241775B2 (en) 2003-03-24 2007-07-10 Sanofi-Aventis Deutschland Gmbh Composition, process of making, and medical use of substituted 4-phenyltetrahydroisoquinolines
WO2004096774A1 (en) 2003-05-01 2004-11-11 Glaxo Group Limited Acyl isoindoline derivatives and acyl isoquinoline derivatives as anti-viral agents
US7459460B2 (en) 2003-05-28 2008-12-02 Bristol-Myers Squibb Company Trisubstituted heteroaromatic compounds as calcium sensing receptor modulators
CA2529510A1 (en) 2003-07-01 2005-01-13 President And Fellows Of Harvard College Compositions for manipulating the lifespan and stress response of cells and organisms
WO2005014534A1 (en) 2003-08-08 2005-02-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use
SG133603A1 (en) 2003-09-17 2007-07-30 Us Gov Health & Human Serv Thalidomide analogs as tnf-alpha modulators
US7491794B2 (en) 2003-10-14 2009-02-17 Intermune, Inc. Macrocyclic compounds as inhibitors of viral replication
JP2007008816A (en) 2003-10-15 2007-01-18 Ube Ind Ltd New isoquinoline derivative
ES2299906T3 (en) 2003-11-25 2008-06-01 Eli Lilly And Company RECEIVER MODULATORS ACTIVATED BY PEROXISOM PROLIFERATORS.
EP1708689A2 (en) 2003-12-29 2006-10-11 The President and Fellows of Harvard College Compositions for treating or preventing obesity and insulin resistance disorders
CA2556413A1 (en) 2004-02-18 2005-09-09 Pfizer Products Inc. Tetrahydroisoquinolinyl derivatives of quinazoline and isoquinoline
CN1942186B (en) 2004-03-09 2010-10-06 国家卫生研究院 Pyrrolidine compounds
BRPI0509467A (en) 2004-03-30 2007-09-11 Intermune Inc macrocyclic compounds as viral replication inhibitors
ES2604197T3 (en) 2004-06-01 2017-03-03 University Of Virginia Patent Foundation Double small molecule inhibitors of cancer and angiogenesis
US20060014705A1 (en) 2004-06-30 2006-01-19 Howitz Konrad T Compositions and methods for selectively activating human sirtuins
ZA200701232B (en) 2004-07-15 2008-08-27 Amr Technology Inc Aryl-and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin
US20090054358A1 (en) 2004-07-19 2009-02-26 The John Hopkins University Flt3 inhibitors for immune suppression
US7211585B2 (en) 2004-08-18 2007-05-01 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US7211584B2 (en) 2004-08-18 2007-05-01 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor ligands
DE102004046492A1 (en) 2004-09-23 2006-03-30 Sanofi-Aventis Deutschland Gmbh Substituted 4-phenyltetrahydroisoquinolines, process for their preparation, their use as medicament, and medicament containing them
US20060111385A1 (en) 2004-11-22 2006-05-25 Molino Bruce F Novel 4-phenyl substituted tetrahydroisoquinolines and therapeutic use thereof
US20060111394A1 (en) * 2004-11-22 2006-05-25 Molino Bruce F Aryl-and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin
DE602005026169D1 (en) * 2004-12-17 2011-03-10 Janssen Pharmaceutica Nv TETRAHYDROISOCHINOLIN COMPOUNDS FOR THE TREATMENT OF CNS DISEASES
US20070060589A1 (en) 2004-12-21 2007-03-15 Purandare Ashok V Inhibitors of protein arginine methyl transferases
CA2595486A1 (en) 2005-01-20 2006-07-27 Sirtris Pharmaceuticals, Inc. Use of sirtuin-activating compounds for treating flushing and drug induced weight gain
JP2008530174A (en) 2005-02-15 2008-08-07 ノボ ノルディスク アクティーゼルスカブ 3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 5-aminopyridin-2-yl ester
US20060229265A1 (en) 2005-03-30 2006-10-12 Sirtris Pharmaceuticals, Inc. Nicotinamide riboside and analogues thereof
DE102005025625A1 (en) 2005-06-01 2006-12-07 Friedrich-Schiller-Universität Jena New benzazecine derivatives are dopamine receptor antagonists useful to treat schizophrenia
US7541347B2 (en) 2007-04-02 2009-06-02 Medicis Pharmaceutical Coropration Minocycline oral dosage forms for the treatment of acne
US7956050B2 (en) 2005-07-15 2011-06-07 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US7425633B2 (en) 2005-08-26 2008-09-16 National Health Research Institutes Pyrrolidine compounds
EP1924546A1 (en) 2005-09-14 2008-05-28 Amgen, Inc Conformationally constrained 3- (4-hydroxy-phenyl) - substituted-propanoic acids useful for treating metabolic disorders
JP2009510073A (en) 2005-09-27 2009-03-12 ノバルティス アクチエンゲゼルシャフト Carboxyamine compounds and methods of use thereof
CA2623879C (en) 2005-10-26 2014-03-25 Laboratoires Serono S.A. Sulfonamide derivatives and use thereof for the modulation of metalloproteinases
AU2006311101A1 (en) 2005-11-11 2007-05-18 F. Hoffmann-La Roche Ag Carbocyclic fused cyclic amines as inhibitors of the coagulation factor Xa
US8232399B2 (en) 2006-03-02 2012-07-31 Chao-Jun Li Chiral ligands, their preparation and uses thereof in asymmetric reactions
CN101410389A (en) 2006-03-29 2009-04-15 诺瓦提斯公司 Organic compounds
US7919598B2 (en) 2006-06-28 2011-04-05 Bristol-Myers Squibb Company Crystal structures of SGLT2 inhibitors and processes for preparing same
US20080076924A1 (en) 2006-06-30 2008-03-27 Patrick Betschmann Piperazines as P2X7 antagonists
MX2009000149A (en) 2006-07-04 2009-01-23 Janssen Pharmaceutica Nv Benzimidazole cannabinoid agonists bearing a substituted heterocyclic group.
EP2061763B1 (en) 2006-08-07 2016-03-16 Janssen Pharmaceutica NV Process for the preparation of substituted-1,2,3,4-tetrahydroisoquinoline derivates
US8993593B2 (en) 2006-08-23 2015-03-31 Valeant Pharmaceuticals International N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide as potassium channel modulators
CN101563085A (en) 2006-08-23 2009-10-21 威朗国际制药公司 Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators
DE102006046922B3 (en) 2006-09-27 2007-11-15 Julius-Maximilians-Universität Würzburg New anti-infective and organic film inhibiting isoquinoline compound useful e.g. as surface coating or washing solution, and to treat and prevent infectious diseases such as malaria
KR101546493B1 (en) 2006-11-06 2015-08-21 톨레로 파마수티컬스, 인크. [12-] [15-] Imidazo[12-B]pyridazine and pyrazolo[15-A]pyrimidine derivatives and their use as protein kinase inhibitors
US7321064B1 (en) 2007-03-08 2008-01-22 Cedarburg Pharmaceuticals, Inc. Preparation of amides of retinoic acid via mixed anhydride and mixed carbonate intermediates
JP2010526825A (en) 2007-05-10 2010-08-05 エーエムアール テクノロジー インコーポレイテッド Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and their use to block reuptake of norepinephrine, dopamine and serotonin
EP2146720A4 (en) 2007-05-10 2012-01-18 Amr Technology Inc Aryloxy-and heteroaryloxy-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US7846930B2 (en) 2007-05-18 2010-12-07 Janssen Pharmaceutica Nv Diaryl-substituted tetrahydroisoquinolines as histamine H3 receptor and serotonin transporter modulators
US20090069374A1 (en) 2007-06-06 2009-03-12 Phil Skolnick Novel 1-Heteroaryl-3-Azabicyclo[3.1.0]Hexanes, Methods For Their Preparation And Their Use As Medicaments
AR071997A1 (en) 2008-06-04 2010-07-28 Bristol Myers Squibb Co CRYSTAL FORM OF 6 - ((4S) -2-METHYL-4- (2-NAFTIL) -1,2,3,4-TETRAHYDROISOQUINOLIN-7-IL) PIRIDAZIN-3-AMINA
US9156812B2 (en) 2008-06-04 2015-10-13 Bristol-Myers Squibb Company Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
JP5595389B2 (en) 2008-06-20 2014-09-24 ジェネンテック， インコーポレイテッド Triazolopyridine JAK inhibitor compounds and methods
TWI453207B (en) 2008-09-08 2014-09-21 Signal Pharm Llc Aminotriazolopyridines, compositions thereof, and methods of treatment therewith
JP5739415B2 (en) 2009-05-12 2015-06-24 ブリストル−マイヤーズ スクウィブ カンパニー (S) -7-([1,2,4] triazolo [1,5-a] pyridin-6-yl) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydroisoquinoline Crystal forms and uses thereof
CA2760837C (en) 2009-05-12 2018-04-03 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-.alpha.]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
WO2010132437A1 (en) 2009-05-12 2010-11-18 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
EP2569316B1 (en) 2010-05-12 2014-04-23 Abbvie Inc. Pyrrolopyridine and pyrrolopyrimidine inhibitors of kinases
US9045468B2 (en) 2010-08-17 2015-06-02 Albany Molecular Research, Inc. 2,5-methano- and 2,5-ethano-tetrahydrobenzazepine derivatives and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US20160022675A1 (en) 2013-03-14 2016-01-28 Bristol-Myers Squibb Company Processes for preparing tetrahydroisoquinolines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060111396A1 (en) * 2004-11-22 2006-05-25 Amr Technology, Inc. 4-Phenyl substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin
US20090099158A1 (en) * 2007-03-01 2009-04-16 Grice Cheryl A Tetrahydroisoquinoline compounds as modulators of the histamine h3 receptor

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8741901B2 (en) 2004-07-15 2014-06-03 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9085531B2 (en) 2004-07-15 2015-07-21 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9499531B2 (en) 2004-07-15 2016-11-22 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9498476B2 (en) 2008-06-04 2016-11-22 Albany Molecular Research, Inc. Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
US8802696B2 (en) 2009-05-12 2014-08-12 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof
US8815894B2 (en) 2009-05-12 2014-08-26 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US9173879B2 (en) 2009-05-12 2015-11-03 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a ]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9604960B2 (en) 2009-05-12 2017-03-28 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof

Also Published As

Publication number Publication date
KR20120034644A (en) 2012-04-12
AU2010247849B2 (en) 2015-11-19
JP2016034963A (en) 2016-03-17
JP2012526823A (en) 2012-11-01
US20100292242A1 (en) 2010-11-18
MX2011011901A (en) 2012-01-20
TWI478920B (en) 2015-04-01
US20150126517A1 (en) 2015-05-07
AU2010247849A1 (en) 2011-12-01
TW201043625A (en) 2010-12-16
EP2429295A4 (en) 2012-12-05
ES2446971T3 (en) 2014-03-11
AR076866A1 (en) 2011-07-13
EP2429295A1 (en) 2012-03-21
CN102458123A (en) 2012-05-16
US9604960B2 (en) 2017-03-28
US9034899B2 (en) 2015-05-19
EP2429295B1 (en) 2013-12-25

Similar Documents

Publication Publication Date Title
EP2429295B1 (en) Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
AU2006270071B2 (en) Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
AU2005274927B2 (en) Aryl-and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
AU2008251558B2 (en) Aryloxy-and heteroaryloxy-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
CA2685860A1 (en) Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9045468B2 (en) 2,5-methano- and 2,5-ethano-tetrahydrobenzazepine derivatives and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
WO2010132487A1 (en) CRYSTALLINE FORMS OF (S)-7-([1,2,4]TRIAZOLO[1,5-a]PYRIDIN-6-YL)-4-(3,4-DICHLOROHPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF
SG175420A1 (en) 7-([1,2,4,]triazolo[1,5,-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydroisoquinoline and use thereof
AU2012202570B2 (en) Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201080031666.3

Country of ref document: CN

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

Ref document number: 10775394

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 8208/CHENP/2011

Country of ref document: IN

Ref document number: MX/A/2011/011901

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2010247849

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2012510930

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2010775394

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2010247849

Country of ref document: AU

Date of ref document: 20100511

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20117029425

Country of ref document: KR

Kind code of ref document: A