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WO2008118141A2 - Use of cannabinoid modulating compounds in combination with other therapeutic compounds for adjunctive therapy - Google Patents

Use of cannabinoid modulating compounds in combination with other therapeutic compounds for adjunctive therapy Download PDF

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Publication number
WO2008118141A2
WO2008118141A2 PCT/US2007/022464 US2007022464W WO2008118141A2 WO 2008118141 A2 WO2008118141 A2 WO 2008118141A2 US 2007022464 W US2007022464 W US 2007022464W WO 2008118141 A2 WO2008118141 A2 WO 2008118141A2
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WIPO (PCT)
Prior art keywords
compound
group
formula
antipsychotic
disease
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PCT/US2007/022464
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French (fr)
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WO2008118141A3 (en
Inventor
Ethan S. Burstein
Luis R. Gardell
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Acadia Pharmaceuticals Inc.
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Publication of WO2008118141A2 publication Critical patent/WO2008118141A2/en
Publication of WO2008118141A3 publication Critical patent/WO2008118141A3/en

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • This invention relates to the fields of organic chemistry, pharmaceutical chemistry, biochemistry, molecular biology and medicine.
  • compositions that contain a compound that modulate the activity of a cannabinoid receptor in conjunction with another therapeutic compound and uses of compounds that modulate the activity of a cannabinoid receptor in conjunction with another therapeutic compound to treat various conditions (e.g., side effects).
  • the cannabinoids which are bioactive lipids, naturally found in the cannabis sativa (marijuana) plant, have been used recreational Iy and therapeutically for at least 5000 years. In addition to their well-documented effects on mood, cannabinoids (often in the form of marijuana) have been prescribed to treat nausea, pain, migraine, epilepsy, glaucoma, hypertension, cachexia and pain associated with childbirth.
  • Two cannabinoid receptors, CBl and CB2 have been identified. Both are members of the G protein-coupled receptor superfamily, and are negatively coupled through Gi protein. The CB2 receptor has 44% sequence similarity to the CBl receptor.
  • the CBl receptor unlike the CB2 receptor, is highly expressed in the central nervous system, mostly presynaptically. Indeed, the CBl receptor is present in the brain at higher levels than many other GPCRs. It is found in the cortex, cerebellum, hippocampus, and basal ganglia (reviewed in Brievogel and Childres, 1998). In addition, the CBl receptor has also been detected in sperm, the prostate gland, and other peripheral tissues (including structures of the eye). The CB2 receptor is present in the cells of the immune system (spleen, thymus), testis, and lung.
  • An embodiment described herein relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • compositions that can include a first compound and a second compound, wherein the first compound is a compound used to treat Parkinsons's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II), wherein the first compound is present in an amount less than the amount needed to elicit the same therapeutic effect compared to when the first compound is administered alone.
  • An embodiment described herein relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II), wherein the first compound is present in an amount less than the amount needed to elicit the same therapeutic effect compared to when the first compound is administered alone.
  • Another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to reduce an adverse side effect associated with an antipsychotic in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment described herein relate to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or treat a negative symptom of schizophrenia in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein relate to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to reduce an adverse side effect associated with a compound used to treat Parkinson's disease in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment relates described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or inhibit a loss of cognition or improves cognition in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or inhibit weight gain in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to shorten or prevent the need for a drug holiday in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described hereien relates to a method of ameliorating or inhibiting an adverse effect associated with an antipsychotic that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a method of inhibiting or preventing weight gain associated with the use of a therapeutic compound that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment described herein relates to a method of suppressing the appetite of a subject that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein releates to a method of ameliorating or inhibiting a negative symptom of schizophrenia that can inlcude administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described herein relates to a method of ameliorating or inhibiting a loss of cognition or improving cognition that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • hererin relates to a method of ameliorating or inhibiting an adverse effect associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another described herein relates to a method of ameliorating or inhibiting a propensity for gambling associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein relates to a method of ameliorating or inhibiting dyskinesia associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described herein relate to a method of ameliorating or inhibiting psychosis associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a method for shortening or preventing a need for a drug holiday that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described hererin relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of an antipsychotic in a subject taking the antipsychotic that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or treats at least one adverse effect associated with the administration of the antipsychotic, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described hererin relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of a compound used to treat Parkinson's disease in a subject taking the compound used to treat Parkinson's disease that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or treats at least one adverse effect associated with the administration of the compound used to treat Parkinson's disease, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat a negative symptom of schizophrenia in a subject taking an antipsychotic that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or inhibits at least one negative symptom of schizophrenia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a loss of cognition or improve cognition in a subject taking a therapeutic compound that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the therapeutic compound ameliorates or inhibits a loss of cognition or improves cognition, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a propensity for gambling in a subject taking a compound used to treat Parkinson's disease comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits the propensity for gambling, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit dyskinesia associated with a compound used to treat Parkinson's disease in a subject that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits dyskinesia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit psychosis associated with a compound used to treat Parkinson's disease in a subject that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits psychosis, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to shorten or prevent a need for a drug holiday that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with a compound used to treat Parkinson's disease shortens or prevents the need for a drug holiday, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to inhibit or prevent weight gain that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with an antipsychotic or a compound used to treat Parkinson's disease inhibits or prevents weight gain, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a method for lowering the amount of an antipsychotic needed to elicit the same therapeutic effect compared to when the first is administered alone that can include administering to a subject a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment described herein relates to a method for lowering the amount of a compound used to treat Parkinson's disease needed to elicit the same therapeutic effect compared to when the first compound is administered alone that can include administering to a subject a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Some embodiment described herein relate to a method of manufacturing a pharmaceutical composition, said method that can include the steps of: obtaining a first compound comprising an antipsychotic or a compound used to treat Parkinson's disease; obtaining a second compound selected from a compound of Formula (I) and a compound of Formula (II); and packaging together the first compound and the second compound.
  • the first compound and the second compound can be merged together, thereby forming a combined dosage form.
  • the compound of Formula (I) can be selected from any of the compounds disclosed herein, including the claims. In some embodiments described herein, the compound of Formula (II) can be selected from any of the compounds disclosed herein, including the claims.
  • antipsychotics compounds used to treat Parkinson's disease, therapeutic compounds, adverse side effects associated with antipschotics and/or compounds used to treat Parkinson's disease, and negative symptoms of schizophrenia are described herein.
  • Figure IA is a graph showing the percent response of the CB 1 receptor as the concentration of l l-Cyclohexyl-dibenzo[b,fj [1,4]thiazepine-8-carboxylic acid piperidin-1-ylamide (Compound I) increases.
  • Figure IB is a graph showing the percent response of the CB2 receptor as the concentration of Compound I increase.
  • Figure 2 is a bar graph showing the food intake in fasted rats 1 and 2 hours after being administered either 1, 3, or 10 mg/kg doses of Compound I. * Indicates p ⁇ 0.05 as compared to the vehicle-treated controls. ** Indicates p ⁇ 0.01 as compared to the vehicle-treated controls.
  • Figure 3 is bar graph showing the time course food intake in fasted rats after being administered 1 mg/kg of Compound I. * Indicates p ⁇ 0.05 as compared to the vehicle-treated controls. ** Indicates p ⁇ 0.01 as compared to the vehicle-treated controls.
  • Figure 4 is a bar graph showing cumulative food consumption at several points in time after the rats had been dosed with 10 mg/kg of Compound I. * Indicates p ⁇ 0.05 as compared to the vehicle-treated controls.
  • Figure 5 A is a line graph showing the attenuation of CBl agonist- mediated effects after administration of CP 55,940 (0.3 and 1.0 mg/kg).
  • Figure 5B is a line graph showing the attenuation of CB 1 agonist-mediated effects after administration of Compound I alone or in combination with CP55,940.
  • Figure 6 is a bar graph showing the body temperature of the rats at several points in time after the rats had been dosed with various doses of CP 55,950 or CP55,950 and Compound I.
  • Figure 7 is a bar graph showing the concentration of Compound I in the plasma and brain at several points in time.
  • Figures 8A and 8B are bar graphs showing the concentration of compound, N-(butyl)-l l-(4-chlorophenyl)-dibenzo[b,f,][1,4]thiazepine-8-carboxamide (Compound II) in tissue and brain at several points in time.
  • Figures 8C and 8D are line graphs showing the concentration of Compound II in the plasma and brain at several points in time.
  • Figure 9B is a line graph showing the effects of Compound II (1 and 3 mg/kg/day) on food intake and water intake.
  • Figure 9C line graph showing the effects of Compound II (10 mg/kg/day) on body weight.
  • Figure 9D is a line graph showing the effects of Compound II (10 mg/kg/day) on food intake and water intake.
  • Figures 1OA and 1OC are bar graphs showing the exploration ratio at 1 and 2 hours after the mice had been dosed with the vehicle, CP 55,940 (0.3 mg/kg, ip), or SR 141716A (1 mg/kg, ip).
  • Figures 1OB and 1OD are bar graphs showing the discrimination index at 1 and 2 hours after the mice had been dosed with the vehicle, CP 55,940 (0.3 mg/kg, ip), or SR 141716A (1 mg/kg, ip).
  • Figure 1 IA is a bar graph showing the exploration ratio 2 hours after the mice had been dosed with Compound II (3 mg/kg, ip).
  • Figure HB is a bar graph showing the discrimination index 2 hours after the mice had been dosed with Compound II (3 mg/kg, ip).
  • Figure 12 is a bar graph showing percentage of novel recognition of a familiar object 2 hours after the mice had been dosed with 1, 3, or 10 mg/kg of Compound II.
  • Figure 13 is a line graph showing the working memory errors of the mice after being dosed with the vehicle, tacrine (0.3 mg/kg), or Compound II (3 mg/kg).
  • Figure 14 is a line graph showing the contralateral rotations over time of the mice after being dosed with apomorphine (0.05, 0.16, and 0.5 mg/kg).
  • Figure 15 is a line graph showing the contralateral rotations over time of the mice after being dosed with apomorphine (0.05 mg/kg), Compound II (3.0 mg/kg), or apomorphine (0.05 mg/kg) and Compound II (3.0 mg/kg).
  • Figure 16 is a line graph showing the contralateral rotations over time of the mice after being dosed with apomorphine (0.16 mg/kg), Compound II (3.0 mg/kg), or apomorphine (0.16 mg/kg) and Compound II (3.0 mg/kg).
  • Cognitive function is markedly impaired in most patients with schizophrenia.
  • second generation drugs such as olanzapine treat the psychosis caused by schizophrenia, they do not have the ability to improve all cognitive functions impaired by the disease.
  • Typical antipsychotics like haloperidol not only are unable to improve cognitive functions affected by schizophrenia but have actually been shown to impair cognitive performance.
  • antiarrhythmic agents disopyramide, , quinidine, and tocainide
  • antibiotics such as cephalexin, cephalothin, metronidazole, ciprofloxacin, and ofloxacin
  • anticholinergic agents such as benztropine, homatropine, scopolamine, and trihexyphenidyl
  • antidepressants such as amitriptyline, imipramine, desipramine, and fluoxetine
  • anticonvulsants like phenyltoin, valproic acid, and carbamazepine
  • antiemetics including promethazine, hyroxyzine, metocloporamide, and prochloroperazine
  • antihypertensive agents like propranolol, metoprolol, atenolol, verapamil, methyldopa, prazosin, and nifedipine
  • antineoplastic agents like chloramb
  • Blockade of dopamine receptors is the key mechanistic feature of antipsychotic medications believed to mediate many of their therapeutic benefits, but it is also responsible for many of the debilitating side effects associated with these drugs, particularly the movement disorder, extrapyramidal side effects (EPS) and hyperprolactinemia EPS consists of involuntary movements that occur due to blockade of dopamine receptors in the nigrostriatal pathway of the basal ganglia. Antipsychotic medications also cause hyperprolactinemia, a condition marked by unusually high levels of the hormone prolactin in non-pregnant individuals that can lead to loss of sexual function and infertility.
  • EPS extrapyramidal side effects
  • hyperprolactinemia a condition marked by unusually high levels of the hormone prolactin in non-pregnant individuals that can lead to loss of sexual function and infertility.
  • Parkinson's occurs when there is a loss of cells in a part of the brain that produces dopamine.
  • the conventional medical response is to raise dopamine levels in the brain by using L-dopa, a drug that binds to cells that have the D3 receptor.
  • L-dopa initially reduces the tremor, slow movement, and muscular rigidity associated with Parkinson's, but in most patients, a jerky and writhing side effect called dyskinesia sets in after a number of years, possibly as a result of the cells' excess exposure to dopamine.
  • Dyskinesia is resistant to treatment and is often treated by having patients reducing or stopping treatment with the prescribed Parkinson's drug (often referred to as taking a "drug holiday").
  • Current Parkinson's agents are also limited by desensitization effects which limit their effectiveness for chronic use, also necessitating frequent "drug holidays.”
  • a reduction in the dosage of Parkinson's drugs needed to maintain efficacy would increase the length of time they could be used, and reduce the need for or extent of "drug holidays.”
  • dopamine agonist therapy for example pramipexone
  • pathological gambling This may relate to disproportionate stimulation of dopamine D3 receptors.
  • a reduction of domapine levels in the mesocorticolimbic system would be expected to suppress such drug-induced behaviors.
  • Weight gain is among side effects listed in official information sheets for many medications including selective serotonin reuptake inhibitors such as citalopram (Celexa®), fluoxetine (Prozac®), fluvoxamine (Luvox®), paroxetine (Paxil®), and sertraline (Zoloft®); tricyclic antidepressants such as amitriptyline (Elavil®), amoxapine (Asendin®), clomipramine (Anafranil®), desipramine (Norepramine®, Pertofrane®), doxepin (Adapin®, Sinequan®), imipramine (Janimine®, Tofranil®), nortriptyline (Aventyl®, Pamelor®), protriptyline (Vivactil®), and trimipramine (Rhotramine®, Surmontil®); monoamine oxidase inhibitors such as isocarboxazid (Marplan®), phenelzine (N
  • Pronounced weight gain, and associated deterioration of serum lipid, and metabolic profiles is associated with chronic use of certain antipsychotics, particularly olanzapine.
  • Second-generation antipsychotics such as risperidone, clozapine, olanzapine, and quetiapine were shown to directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement.
  • the medical and psychological consequences of drug-induced obesity are often so intolerable that patients may discontinue treatment even if it is effective. Therefore, there is an unmet need in the art to provide pharmaceutical compositions that can ameliorate the weight-gain induced by certain drugs.
  • the CBl receptor is believed to be responsible for the appetite stimulating properties and habituation associated with cannabinoid use.
  • the CBl receptor antagonist, SR 141716 (rimonabant, Acomplia; Sanofi-Aventis) has shown efficacy in late-stage clinical trials for obesity and nicotine dependence, with no psychotropic effects. The compound has been shown to reduce both food intake and adipose tissue (by a mechanism independent of food intake).
  • Use of SR 141716 in animal models suggests additional use of CBl receptor antagonists and inverse agonists for the treatment of alcohol addiction, opiate addiction, cocaine addiction, anxiety, and septic shock.
  • mice null for the CBl gene also display impaired cocaine self- administration, and less severe withdrawal from morphine addiction compared to wild- type mice.
  • CB 1 knockout mice also display increased bone mineral density, and both CBl knockout mice and mice treated with CB antagonists are resistant to bone loss in a model for osteoporosis.
  • Other animal models indicate a use for CBl receptor antagonists and inverse agonists for the prevention of premature spontaneous abortion.
  • Cannabinoid signaling is hyperactive in animal models of several diseases suggesting that cannabinoids either have a protective role (e.g., CB l agonists may be therapeutic) or are involved in the pathology of these diseases (e.g., CBl antagonists or inverse agonists may be therapeutic). These include Parkinson's disease, Alzheimer's disease, multiple sclerosis, epilepsy, and intestinal disorders. In addition, the levels of endogenous cannabinoids and CBl receptors are elevated in the liver and blood of patients with cirrhosis of the liver. Moreover, cannabinoid levels have been shown to be elevated in the cerebrospinal fluid of a patient with stroke, as well as in the brains of depressed suicide victims.
  • Endogenous cannabinoids have also been shown to be higher in the cerebrospinal fluid of drug-naive paranoid schizophrenics compared to normal patients; interestingly, schizophrenic patients treated with atypical but not typical antipsychotics also exhibit higher CSF levels of anandamide. Additionally, the CB l gene is located in a chromosomal region that has been linked to schizophrenia. Moreover, high levels of the endogenous cannabinoid, anandamide, are correlated with premature abortion and failure of in vitro fertilization. Finally, activation of CB receptors by an anandamide analogue has been shown to reduce sperm fertilizing capacity by 50%.
  • CBl receptors by agonists or partial agonists may also be used to treat a number of disorders.
  • THC tetrahydrocannabinol; active cannabinoid in Cannabis sativa
  • cannabinoids have been shown to improve mobility and alleviate pain in patients with multiple sclerosis.
  • Other promising results for cannabinoids have been shown in clinical trials for Tourette's syndrome, Parkinson's disease, glaucoma, and pain.
  • cannabinoids have been shown to inhibit cancer growth, angiogenesis, and metastasis in animal models.
  • any "R" group(s) such as, without limitation, R 1 , R 1a and R 1 b , represent substituents that can be attached to the indicated atom.
  • R groups include but are not limited to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl.
  • An R group may be substituted or unsubstituted.
  • R groups are covalently bonded to the same atom or to adjacent atoms, then they may be “taken together” as defined herein to form a cycloalkyl, aryl, heteroaryl or heteroalicyclyl group.
  • R 3 and R b of an NR 3 R b group are indicated to be “taken together”, it means that they are covalently bonded to one another at their terminal atoms to form a ring that includes the nitrogen:
  • IC 50 refers to an amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of GPCR, including cannabinoid receptor, activity an assay that measures such response.
  • the assay may be an R-S AT ® assay as described herein but is not limited to an RSAT assay.
  • EC 5 o refers to an amount, concentration or dosage of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound, in an assay that measures such response such as but not limited to R-SAT ® assay described herein.
  • substituent is a group that may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N
  • C m to C n in which "m” and “n” are integers refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or the number of carbon atoms in the ring of a cycloalkyl or cycloalkenyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl or ring of the cycloalkenyl can contain from “m” to "n", inclusive, carbon atoms.
  • a "C 1 to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CHb) 3 C-. If no "m” and "n” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group, the broadest range described in these definitions is to be assumed.
  • alkyl refers to a straight or branched hydrocarbon chain fully saturated (no double or triple bonds) hydrocarbon group.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 5 carbon atoms.
  • the alkyl group of the compounds may be designated as "C 1 -C 4 alkyl” or similar designations.
  • “C 1 -C 4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group(s) is(are) one or more group(s) individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • An alkenyl group of * this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • An alkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
  • aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system that has a fully delocalized pi-electron system throughout all the rings.
  • aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group of this invention may be substituted or unsubstituted.
  • substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, iso
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system throughout all the rings), one or two or more fused rings that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • heteroaryl rings include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine.
  • a heteroaryl group of this invention may be substituted or unsubstituted.
  • substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, iso
  • an "aralkyl” is an aryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, substituted benzyl, 2- phenylethyl, 3-phenylpropyl, and naphtylalkyl.
  • a “heteroaralkyl” is heteroaryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylmethyl, 3- thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl, and their substituted as well as benzo-fused analogs.
  • Lower alkylene groups are straight-chained tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (- CH 2 CH 2 CH 2 -), and butylene (-(CH2V) groups. A lower alkylene group may be substituted or unsubstituted.
  • arylalkylidene refers to an alkylidene group in which either R' and R" is an aryl group. An alkylidene group may be substituted or unsubstituted.
  • alkoxy refers to the formula -OR wherein R is an alkyl is defined as above, e.g. methoxy, ethoxy, n-propoxy, 1-methylethoxy (isoproppxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy and the like.
  • An alkoxy may be substituted or unsubstituted.
  • alkylthio refers to the formula -SR wherein R is an alkyl is defined as above, e.g. methylmercapto, ethylmercapto, n-propylmercapto, 1- methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec- butylmercapto, tert-butylmercapto, and the like.
  • An alkylthio may be substituted or unsubstituted.
  • aryloxy and arylthio refers to RO- and RS-, in which R is an aryl, such as but not limited to phenyl. Both an aryloxy and arylthio may be substituted or unsubstituted.
  • acyl refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted. An acyl may be substituted or unsubstituted.
  • cycloalkyl refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkyl groups of this invention may range from C 3 to C 10 , in other embodiments it may range from C 3 to C 6 . A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated.
  • cycloalkenyl refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be "aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro-connected fashion.
  • a cycloalkenyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
  • cycloalkynyl refers to a cycloalkyl group that contains one or more triple bonds in the ring. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion.
  • a cycloalkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
  • heteroalicyclic or “heteroalicyclyl” refers to a stable 3- to 18 membered ring which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, oxygen and sulfur.
  • the "heteroalicyclic” or “heteroalicyclyl” may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be joined together in a fused, bridged or spiro-connected fashion; and the nitrogen, carbon and sulfur atoms in the "heteroalicyclic” or “heteroalicyclyl” may be optionally oxidized; the nitrogen may be optionally quaternized; and the rings may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system throughout all the rings.
  • Heteroalicyclyl groups of this invention may be unsubstituted or substituted.
  • the substituent(s) may be one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, iso
  • heteroalicyclic or “heteroalicyclyl” include but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl N-Oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone unless the substituent groups are otherwise indicated.
  • a "(heteroalicyclyl)alkyl” is a heterocyclic or a heterocyclyl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heterocyclic or a heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited 4-methyltetrahydro-2H-pyran, substituted 4-methyltetrahydro-2H-pyran, 4-ethylpiperidine, 4-propylpiperidine, 4- methyltetrahydro-2H-thiopyran, and 4-methyl-1,3-thiazinane.
  • a "(cycloalkyl)alkyl” is a cycloalkyl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and cycloalkyl of a (cycloalkyl)alkyl may be substituted or unsubstituted.
  • Examples include but are not limited cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like.
  • a "(cycloalkenyl)alkyl” is a cycloalkenyl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and cycloalkenyl of a (cycloalkenyl)alkyl may be substituted or unsubstituted.
  • a "(cycloalkynyl)alkyl” is a cycloalkynyl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and cycloalkynyl of a (cycloalkynyl)alkyl may be substituted or unsubstituted.
  • halo or “halogen” refers to F (fluoro), Cl (chloro), Br (bromo) or I (iodo).
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and l-chloro-2- fluoromethyl, 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to RO-group in which R is a haloalkyl group.
  • groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and l-chloro-2-fluoromethoxy, 2- fluoroisobutyoxy.
  • a haloalkoxy may be substituted or unsubstituted.
  • An "O-carboxy” group refers to a "RC(O)O-" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein.
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein.
  • An O- carboxy may be substituted or unsubstituted.
  • a "C-carboxy” group refers to a "-C(O)R” group in which R can be the same as defined with respect to O-carboxy.
  • a C-carboxy may be substituted or unsubstituted.
  • a "trihalomethanesulfonyl” group refers to an "X 3 CSO 2 -" group wherein X is a halogen.
  • a "cyano” group refers to a "-CN” group.
  • a "thiocyanato" group refers to a "-CNS” group.
  • An "isothiocyanato" group refers to an " -NCS” group.
  • a “sulfinyl” group refers to an "-S(O)-R” group in which R can be the same as defined with respect to O-carboxy.
  • a sulfinyl may be substituted or unsubstituted.
  • a “sulfonyl” group refers to an “SO 2 R” group in which R can be the same as defined with respect to O-carboxy.
  • a sulfonyl may be' substituted or unsubstituted.
  • S-sulfonamido refers to a "-SO 2 NR A R B " group in which R A and R B can be the same as R defined with respect to O-carboxy.
  • An S-sulfonamido may be substituted or unsubstituted.
  • An "N-sulfonamido” group refers to a "RSO 2 N(R A )-” group in which R and R A can be the same as R defined with respect to O-carboxy.
  • a sulfonyl may be substituted or unsubstituted.
  • a "trihalomethanesulfonamido" group refers to an "X 3 CSO 2 N(R)-" group with X as halogen and R can be the same as defined with respect to O-carboxy.
  • a trihalomethanesulfonamido may be substituted or unsubstituted.
  • An O-carbamyl may be substituted or unsubstituted.
  • An N-carbamyl may be substituted or unsubstituted.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • a C-amido may be substituted or unsubstituted.
  • An N-amido may be substituted or unsubstituted.
  • An ester may be substituted or unsubstituted.
  • a lower aminoalkyl refers to an amino group connected via a lower alkylene group.
  • a lower aminoalkyl may be substituted or unsubstituted.
  • a lower alkoxyalkyl refers to an alkoxy group connected via a lower alkylene group.
  • a lower alkoxyalkyl may be substituted or unsubstituted.
  • Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well- known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999).
  • substituents there may be one or more substituents present.
  • haloalkyl may include one or more of the same or different halogens.
  • C 1 -C 3 alkoxyphenyl may include one or more of the same or different alkoxygroups containing one, two or three atoms.
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enatiomerically pure or be stereoisomeric mixtures.
  • each double bond may independently be E or Z a mixture thereof.
  • all tautomeric forms are also intended to be included.
  • salts refers to a salt of a compound that does not abrogate the biological activity and properties of the compound.
  • Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base.
  • Base-formed salts include, without limitation, ammonium salt (NH 4 + ); alkali metal, such as, without limitation, sodium or potassium, salts; alkaline earth, such as, without limitation, calcium or magnesium, salts; salts of organic bases such as, without limitation, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, without limitation, arginine and lysine.
  • NH 4 + ammonium salt
  • alkali metal such as, without limitation, sodium or potassium
  • alkaline earth such as, without limitation, calcium or magnesium
  • salts of organic bases such as, without limitation, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine
  • Useful acid-based salts include, without limitation, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, methanesulfonates, ethanesulfonates, p-toluenesulfonates and salicylates.
  • solvates and hydrates are complexes of a compound with one or more solvent of water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
  • a "prodrug” refers to a compound that may not be pharmaceutically active but that is converted into an active drug upon in vivo administration.
  • the prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have better solubility than the active parent drug in pharmaceutical compositions.
  • prodrug a compound disclosed herein, which is administered as an ester (the "prodrug") to facilitate absorption through a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to a carboxylic acid (the active entity) once inside the cell where water-solubility is beneficial.
  • a further example of a. prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized in vivo to release the active parent compound.
  • the term “complement” refers to a oligonucleotide or polynucleotide that hybridizes by base-pairing, adenine to tyrosine and guanine to cytosine, to another oligonucleotide.
  • to "modulate" the activity of CBl means either to activate it, i.e., to increase its cellular function over the base level measured in the particular environment in which it is found, or deactivate it, i.e., decrease its cellular function to less than the measured base level in the environment in which it is found and/or render it unable to perform its cellular function at all, even in the presence of a natural binding partner.
  • a natural binding partner is an endogenous molecule that is an agonist for the receptor.
  • to "detect" changes in the activity of CBl or of a CBl sub-type refers to the process of analyzing the result of an experiment using whatever analytical techniques are best suited to the particular situation. In some cases simple visual observation may suffice, in other cases the use of a microscope, visual or UV light analyzer or specific protein assays may be required. The proper selection of analytical tools and techniques to detect changes in the activity of CB 1 or a CB 1 sub-type are well- known to those skilled in the art.
  • An "agonist” is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor).
  • partial agonist refers to a compound that has an affinity for a receptor but, unlike an agonist, when bound to the receptor it elicits only a fractional degree of the pharmacological response normally associated with the receptor even if a large number of receptors are occupied by the compound.
  • An "inverse agonist” is defined as a compound, which reduces, or suppresses the basal activity of a receptor, such that the compound is not technically an antagonist but, rather, is an agonist with negative intrinsic activity.
  • antagonist refers to a compound that binds to a receptor to form a complex that does not give rise to any response, as if the receptor were unoccupied.
  • An antagonist attenuates the action of an agonist on a receptor.
  • An antagonist may bind reversibly or irreversibly, effectively eliminating the activity of the receptor permanently or at least until the antagonist is metabolized or dissociates or is otherwise removed by a physical or biological process.
  • a "subject” refers to an animal that is the object of treatment, observation or experiment.
  • Animal includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • a "patient” refers to a subject that is being treated in order to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.
  • treating do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment or therapy. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well-being or appearance.
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • a "diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
  • an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • a “diluent” is a type of excipient.
  • adjunctive therapy refers to the administration of two pharmaceutical compositions to achieve a beneficial therapeutic effect relative to the therapeutic effect obtained by administering either of the pharmaceutical compositions alone.
  • the administration of a cannabinoid antagonist or inverse agonist and another pharmaceutical composition may ameliorate or inhibit an adverse effect associated with an antipsychotic or other medication such as, preventing weight gain associated with the use of an antipsychotic, suppressing the appetite of a subject taking a therapeutic compound, ameliorate or inhibit a negative symptom of schizophrenia in a subject taking an antipsychotic, ameliorate or inhibit a loss of cognition or improve cognition in a subject taking a therapeutic compound, ameliorate or inhibit an adverse effect associated with a compound used to treat Parkinson's disease, ameliorate or inhibit the propensity for gambling associated with a compound used to treat Parkinson's disease, ameliorate or inhibit the dyskinesia associated with a compound used to treat Parkinson's disease, ameliorate or inhibit the psychosis associated with a compound used to
  • Y can be -N(R 2 ) — or -C(R 1 R 2 ) — ; the symbol — represents a single or double bond, where when — is a double bond, R 2 is absent;
  • Z can be O (oxygen) or S (sulfur);
  • R 1 a and R 1 b can be taken together to form an unsubstituted or substituted heteroalicyclyl having 2 to 9 carbon atoms or an unsubstituted or substituted carbocyclyl having 3 to 9 carbon atoms;
  • R 2 can be absent or is selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl, wherein any member of said group can be substituted or unsubstituted except for hydrogen;
  • R 3, R 3a , and R 3b can each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, and (heteroalicyclyl)alkyl, wherein any member of said group can be substituted or unsubstituted except for hydrogen;
  • A cannot be a substituted or unsubstituted piperazine.
  • H is not selected from -CF 3 , phenyl, -OS(O) 2 -
  • CF 3 methyl, -CN, halogen, and when A is a substituted or unsubstituted heteroalicyclyl containing at least one nitrogen, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or -NR 1 a R 1 b .
  • H cannot be halogen when A is substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, halogen, and substituted or unsubstituted sulfenyl;
  • X is -NR 1 , wherein R 1 is hydrogen; and
  • Y is -N(R 2 ) — , wherein — is a double bond and R 2 is absent.
  • Y is -N(R 2 ) — , wherein — is a double bond and R 2 is absent, and X is S then F cannot be -S(O) 2 NR ⁇ a R 1 b , wherein R 1 a and R 1 b are both hydrogen.
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist;
  • X can be S;
  • A can be selected from aryl (e.g., unsubstituted or substituted phenyl) or a heteroaryl (e.g., thiophene and pyridine);
  • X can be S;
  • A can be selected from cycloalkyl (e.g., cyclohexyl), a heteroalicyclyl (e.g., piperidine), or - NR 1 a R 1 b group;
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist;
  • the optionally substituted cycloalkyl, cycloalkenyl, or cycloalkynyl is selected from: and and in some of the embodiments, n can be 1 or 2.
  • X can be S;
  • X can be S;
  • Y can be - N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist;
  • A can be selected from aryl (e.g., unsubstituted or substituted phenyl) or a heteroaryl (e.g., thiophene and pyridine);
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist;
  • A can be selected from cycloalkyl (e.g., cyclohexyl), a heteroalicyclyl (e.g., piperidine), or -NR 1 a R 1 b group;
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist; and
  • substituted aryl or aralkyl can be selected from: ,wherein Q can be -N(R 4 )-, oxygen or sulfur; and R 4 can be hydrogen or C 1-4 alkyl, and in some of the embodiments, n can be 1 or 2.
  • X can be S;
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist;
  • A can be selected from aryl (e.g., unsubstituted or substituted phenyl) or a heteroaryl (e.g., thiophene and pyridine);
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist;
  • A can be selected from cycloalkyl (e.g., cyclohexyl), a heteroalicyclyl (e.g., piperidine), or - NR 1 a R 1 b group;
  • X can be S;
  • the optionally substituted heteroalicyclyl or (heteroalicyclyl)alkyl can be selected from:
  • n can be 1 or 2.
  • X can be S;
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist; and
  • A can be selected from aryl (e.g., unsubstituted or substituted phenyl) or a heteroaryl (e.g., thiophene and pyridine);
  • X can be S;
  • A can be selected from cycloalkyl (e.g., cyclohexyl), a heteroalicyclyl (e.g., piperidine), or -NR 1 a R 1 b group;
  • X can be S;
  • Y can be -N(R 2 ) ⁇ wherein the symbol :r ⁇ : represents a double bond and R 2 does not exist;
  • the optionally substituted heteroaralkyl is from the
  • n 1 or 2.
  • the optionally substituted heteroaralkyl can be , wherein Q can be oxygen or sulfur, and in some of the embodiments, n can be 1 or 2.
  • A can be an aryl or a heteroaryl group
  • X can be S
  • H can be -C(-Z)NR 1 a R 1b , wherein R 1 a is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heteroalicyclyl, heteroaralkyl, and (heteroalicyclyl)alkyl.
  • A can be an aryl or a heteroaryl group
  • X can be S
  • A can be an aryl or a heteroaryl group
  • X can be S
  • A can be an aryl or a heteroaryl group
  • X can be S
  • Y can be -N(R 2 ) ⁇ wherein the symbol ⁇ represents a double bond and R 2 does not exist
  • H can be wherein R ⁇ a is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heteroalicyclyl, heteroaralkyl, and (heteroalicyclyl)alkyl
  • R 1 and R ⁇ can be hydrogen.
  • D' can be part of Ar', and is selected from the group consisting of CR' 1 , NR' 2 , S, and O.
  • R' 2 can be absent or is selected from the group consisting of hydrogen; mono-substituted, poly-substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl, and alkynyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl.
  • R' 3j R' 3a , and R' 3b can be each independently selected from the group consisting of: hydrogen; mono-substituted, poly-substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, and (heteroalicycyl)alkyl; and mono-substituted, poly- substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heteroalicyclyl.
  • Z' can be O or S.
  • B' is not selected from -CF 3 , phenyl, -OS(O) 2 -
  • A' is a substituted or unsubstituted heteroalicyclyl containing at least one nitrogen, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or -NR 1 a -R 1 b --
  • B' is not halogen when A' is substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, halogen, or substituted or unsubstituted sulfenyl;
  • X' is -NH; and
  • X' when X' is CR ⁇ a R 1 b ' and A' is phenyl, then B' cannot be NH 2 .
  • X' when both Ar r and Ar 2 - are pyridinyl rings, then X' cannot be NRp in which R 1 ' is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, trihalomethyl and hydroxyalkyl.
  • X' when X' is S or NRp, wherein Rp is hydrogen or alkyl, then A' cannot be a phenyl ring substituted at the O 2 H or C ⁇ 2(alkyl).
  • Rp is hydrogen or alkyl
  • A' when X' is CR 1a R 1 b ' R 1a - and R 1 b - cannot be a cycloalkyl, cycloalkenyl or piperazine rin nnot be taken together to a form a cycloalkyl, cycloalkenyl or piperazine ring.
  • X' can be S; and A' can be selected from a mono-substituted, poly- substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl and alkynyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl.
  • A' can be selected from a mono-substituted, poly-substituted, or unsubstituted, straight or branched alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, aryl, heteroaryl and heteroalicyclyl.
  • A' can be a mono- substituted, poly-substituted, or unsubstituted, straight or branched alkyl; or mono- substituted, poly-substituted or unsubstituted aryl.
  • A' can be a mono- substituted, poly-substituted, or unsubstituted, straight or branched alkyl; or mono- substituted, poly-substituted or unsubstituted aryl;
  • B' can be -S(O) 2 NR 1 a -R 1 b --
  • Z' can be O (oxygen).
  • Rp 1 R 13 1 and R 1 b3 - can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl and (heteroalicyclyl)alkyl.
  • Rp and R 13 ' can be independently selected from alkyl, cycloalkyl, heteroaryl, heteroalicyclyl and heteroaralkyl; and Ru, 1 is hydrogen.
  • R 1a and R 1b are as defined above for Formula (I).
  • R 3 and R 4 can be selected from the same group of substituents as R 1a and R 1b as defined above for Formula (I).
  • R 13 , R 1b , and A are as defined above for Formula (I).
  • R 3 and R 4 can be selected from the same group of substituents as R 1 a and R 1 b as defined above for Formula (I).
  • R 1 a , R 1 b ,, and A are as defined above for Formula (I).
  • R 3 and R 4 can be selected from the same group of substituents as R 1 a and R 1 b as defined above for Formula (I).
  • R 1 a , R 1 b> and A are as defined above for Formula (I), and X is a halogen.
  • R 3 and R 4 can be selected from the same group of substituents as R 1 a and R ⁇ as defined above for Formula (I).
  • R 1a , R 1 b , and A are as defined above for Formula (I), and X is a halogen.
  • R 3 and R 4 can be selected from the same group of substituents as R 1 a and R 1 b as defined above for Formula (I).
  • R 1 a , R 1 b , and A are as defined above for Formula (I), and X is a halogen.
  • R 3 and R 4 can be selected from the same group of substituents as R 1a and R 1 b as defined above for Formula (I).
  • R 1 a , R 1 b , and A are as defined above for Formula (I), and X is a halogen.
  • R 3 and R 4 can be selected from the same group of substituents as R 1 a and R 1 b as defined above for Formula (I).
  • R' 1a and A' are as defined above for Formula (II).
  • R' 4) R' 5 , and R ⁇ are appropriate radicals selected to obtain the desired A' group.
  • R' 1 a , R'4, R's, and R' 6 compounds 2a, 5a, 6a, 10a, 16a, 26a, 28a - 31a, 40a, 44a, 46a, 48a, 51a, and 58a can be prepared according to Scheme 1 1.
  • compound 2a can be prepared by using «-butyl amine as H 2 N-R'
  • Suitable heterocyclic 2-mercaptosubstituted carboxylic acids can be prepared as described in Blank et al, J. Med. Chem. 1911 , 20, 572-576; Sen et al, Indian J Chem B Og, 1981, 2OB, 275-278, and Solomon et al, Heterocycles, 1987, 26, 651-674), all of which are incorporated herein by reference in their entirety.
  • R' ⁇ a and A' are as defined above for Formula (II).
  • R' 4 , R's, and R ⁇ are appropriate radicals selected to obtain the desired A' group.
  • R' 1a , R' 4 , R' 5 , and R' 6 compounds 13a-16a, 18a, 36a-42a, 54a, 55a, 57a-60a can be prepared according to Scheme 12.
  • compound 13 can be prepared by using cyclohexyl amine a H 2 N-R' 1a and p-Cl-phenyl zinc iodide as R' 6 ZnX.
  • heterocyclic 2-chloro carboxylic acids include commercially available 2-chloro nicotinic acid, 3-chloro-4-pyridine carboxylic acid, 4-chloronicotinic acid and 3-chloro-2-pyrazine carboxylic acid and those synthesised by methods described in Bredereck et al. Chem. Ber, 1962, 95, 956-963 and Krasovskiy et al, Angew. Chem. Int. Ed., 2006, 45, 2958-2961, both of which are incorporated herein by reference in their entirety.
  • Scheme 13 illustrates one method of obtaining compound 7a.
  • compounds Ia, 3a, 8a, 9a, 1 1a, 19a- 25a, 27a, 32a- 34a, 43a, 45a, 49a, 50a, 52a, 53a, 61a, 62a, 82a-84a can be obtained using a similar method.
  • Suitable iodo-or bromo benzoheterophenones can be obtained commercially, synthesised by the methods described in Reynolds et al., Tetrahedron, 2001, 57, 7765-7770, Liu et al., Org. Lett. 2006, 8, 617-619 or by generation of zinc reagents from dibromo- or diiodo heterocycles followed by reaction with the appropriately substituted benzoyl chloride (Knochel et al., Angew. Chem. 2006). AU of the foregoing references are incorporated herein by reference in their entirety.
  • R' 1a and A' are as defined above for Formula (II).
  • R' 4 , R' 5) and R' 6 are appropriate radicals selected to obtain the desired A' group.
  • R' 1a , R'4, R' 5 , and R' 6 compounds 4a, 12a, 17a, 47a, 56a, 63a, and 84a can be prepared according to Scheme 14 by using the appropriate heterocyclic 2- mercaptosubstituted carboxylic acids followed by the appropriate alkyl or aryl metal halide or amine and the desired amine in the last step.
  • R' ⁇ a and A' are as defined above for Formula (II).
  • R' 4 , R' 5 , and R' 6 are appropriate radicals selected to obtain the desired A' group.
  • R' 1a , R' 4 , R' 5 , and R' 6 compounds 64a, 68a, 72a, 78a, 88a, 92a, and 96a can be prepared by using the appropriate heterocycle, amine, metal reagent/amine and amine. Further relevant synthetic methods can be found in Thompson et al. , J. Org. Chem. 1988, 53, 2052-2055, which is incorporated herein by reference in its entirety.
  • a and A' are as defined above for Formula (II).
  • R' 4 , R' 5 , and R' 6 are appropriate radicals selected to obtain the desired A' group.
  • R' 1a , R'4, R' 5 , and R' 6 compounds 64a-74a, 85a 86a, 88a-91a, 93a- 95a, 97a -101a, and 104a can be prepared by using appropriate pyridines obtained either commercially or synthesized by magnesiation of heterocycles via selective deprotonation as described in Liu et al, Org. Lett.
  • Scheme 17 illustrates one method of obtaining compound 102a.
  • Other pyrazines such as compound 87a can be obtained in a similar fashion following the methods described in PIe et al, J. Org. Chem. 1995, 60, 3781-3786, which is incorporated herein by reference in its entirety.
  • Pyrazines containing an amide side chain instead of sulfonamide side chain can be obtained by reacting the metalated species with a variety of alky 1 isocyanates.
  • Ar' ⁇ , Ar ⁇ , B', and D' are as described above for Formula (II).
  • A' is an aryl or heteroaryl.
  • X is Br, Cl, F, OTf, or OTs.
  • Scheme 18 proceeds by dilithiation of arylthiols or heteroaryl thiols as described in Figuly et al, J Am. Chem. Soc, 1989, ///, 654, Block et al, J. Am. Chem. Soc, 1989, 111, 658, and Smith et al, J. Am. Chem. Soc, 1989, / / /, 665, which are incorporated herein by reference in their entirety.
  • the dilithioketimine intermediate is obtained.
  • This intermediate can be in turn treated with suitable ⁇ -dihaloaryls or o- dihaloheteroaryls to obtain the thiazepine product.
  • ⁇ - deficient o-dihaloazaarenes constitute outstanding substrates for the reactions with ketimines, providing the thiazepine products in high yield simply by adding 1 equiv of a neat ⁇ -deficient o-dihaloazaarene to a reaction mixture containing a premade ketimine.
  • Ar' 2 and D' are as described above for Formula (II).
  • A' is an aryl or heteroaryl.
  • X is Br, Cl, F, OTf, or OTs.
  • Ar' i is a ⁇ -deficient azaaryl.
  • E' is an electrophile including, but not limited to, isocyanates, acid chlorides, nitriles, tosyl cyanide or 1-cyanoimidazole, aldehydes or ketones, halogens or organic halides, carbon dioxide, Weinreb amides, tosyl azide, zinc chloride, tin chloride and trimethyl borate.
  • organometallic intermediates thus generated can be treated with convenient electrophiles to give substituted thiazepines.
  • substitution tactics afford a mixture of two or more regioisomeric products
  • the products can be easily separated from each other by one of the standard methods known in the art.
  • an electrophile can be added to a ⁇ - deficient ⁇ -dihaloazaryl by a similar method as described above.
  • the resulting heteroaryl can be in turn be reacted with a ketimine to produce the desired thiazepine product.
  • Convenient substituents that can be introduced on the azaryl include, but are not limited to, nitrile or ester moieties. Introduction of such electron withdrawing groups on the rings of azaryls improves their reactivity towards ketimines. Also, at a later stage, these groups can be easily converted to other pertinent functional groups.
  • Ar' i, Ar' 2 , B', and D' are as described above for Formula (II).
  • A' is an alkyl, aryl, heteroaryl, or amino.
  • X is Br, Cl, F, OTf, or OTs.
  • Scheme 20 provides alkyl and amino substituted thiazepines by addition of 2 equiv of alkyllithiums, aryllithiums, heteroaryllithiums or 2 equiv of lithium amides to 2- cyanoarene thiols, giving rise to a ketimine, which can be reacted with o-dihaloaryl (or heteroaryl) to produce the desired thiazepine product.
  • the requisite 2-cyanoaryl thiols can be prepared for example by heating a 2-cyanobromoaryl (or heteroaryl) with mercaptoacetic ethyl ester in the presence of potassium /-butoxide and liquid ammonia (Brugelmans et al, Tetrahedron, 1983, 39, 4153, which is incorporated herein by reference in its entirety).
  • Ar' ( , Ar' 2 , B', and D' are as described above for Formula (II).
  • A' is an alkyl, amino, aryl, or heteroaryl.
  • X is I, Br, or Cl.
  • Scheme 21 provides thiazepines by hydrolysis of ketimines followed by reacting the resulting ketoaryl thiol with a suitable o-aminohaloaryl (or heteroaryl). The cyclization to produce the thiazepines can be carried under copper catalysis (Bates et al, Org. Lett., 2002, 4, 2803, Kwong et al, Org.
  • ketones can also be prepared by other methods known in the art, for example by addition of organolithiums to mercaptoaryl(or heteroaryl)carboxylic acids (Bull. Chem. Soc.
  • Ar'i, Ar' 2 , B', and D' are as described above for Formula (II).
  • A' is an alkyl, amino, aryl, or heteroaryl.
  • X is I, Br, or Cl.
  • M is a main group metal.
  • Scheme 22 described the production of thiazepines by reacting a haloketones with an ⁇ -aryl(or heteroaryl) thiol. In particular, such cyclizations can be carried out very efficiently under copper catalysis (Kwong et al, Org. Lett., 2002, 4, 3517, incorporated herein by reference in its entirety) using iodoketones and o-aminoaryl(or heteroaryl) thiols.
  • the requisite iodoketones can be synthesized by one of the methods known in the art, for example by addition of organomagnesium reagents (Reynolds and Hermitage, Tetrahedron, 2001, 57, 7765, incorporated herein by reference in its entirety) to 2-iodo Weinreb amides (Brunette and Lipton, J Org. Chem., 2000, 65, 51 14, incorporated herein by reference in its entirety), by copper catalyzed aromatic Finkelstein reaction (Klapars and Buchwald, J. Am. Chem.
  • o-aminoaryl(or heteroaryl) thiol employed herein for the synthesis of thiazepines can be prepared by one of the methods known in the art, for example by reduction of o-nitroaryl(or heteroaryl) thiols (Foster and Reid, J. Am. Chem. Soc, 1924, 46, 1936, incorporated herein by reference in its entirety), by heating of 2- halonitroaryls(or heteroaryls) with sodium sulphide in water (Jain et al, Chem.
  • chloroketones can be reacted with o- aminoaryl(or heteroaryl) thiols to afford thiazepines. Presence of several strongly electron withdrawing groups (such as nitro or cyano groups) on the aromatic ring of the chloroketones (Jarret and Loudon, J. Chem. Soc, 1957, 3818, Gait and Loudon, J. Chem. Soc, 1959, 885, incorporated herein by reference in its entirety), or a ⁇ -deficient azaromatic chloroketone (Warmhof, Synthesis., 1972, 151, Shalaby, Phosphorus, Sulfur Relat. Elem., 2003, 178, 199, incorporated herein by reference in its entirety), is typically required.
  • strongly electron withdrawing groups such as nitro or cyano groups
  • compositions comprising at one compound of Formula (I) and/or Formula (II) as described above in combination with another therapeutic compound, and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
  • An embodiment described herein relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • the antipsychotic can act on a dopamine receptor such as a D2 receptor.
  • the antipsychotic can be selected from olanzapine, risperidone, haloperidol, aripirazole, quetiapine, ziprasidone, raclopride, clozapine, Molindone (Moban®), Thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®), Risperidone (Risperdal®), Sertindole (Serlect®) and Ziprasidone (Seldox®).
  • the first compound and second compound can be provided in dosages which reduce an adverse side effect associated with an antipsychotic. In other embodiments, the first compound and second compound can be provided in dosages which ameliorate or treat a negative symptom of schizophrenia.
  • the adverse side effect can be selected from weight gain, metabolic syndrome, an extra- pyramidal side effect, akathisia, dystonia, acute dystonia, Parkinsonism, dykensia, tardive dyskinesia, neuroleptic malignant syndrome, hyperprolactinemia, and catalepsy.
  • the negative symptom can be selected from affective flattening, poverty of speech, absence of volition, apathy, self-neglect, inappropriate emotion, inability to experience pleasure, inattentiveness, inability to show a facial expression, and inability to start or complete a task.
  • a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is a compound used to treat Parkinsons' s disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • the compound used to treat Parkinson' disease can be selected from L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride.
  • the first compound and second compound can be provided in dosages which reduce an adverse side effect associated with a compound used to treat Parkinson's disease.
  • the adverse side effect can be selected from increased propensity for gambling, dyskinesia, and psychosis.
  • the first compound and second compound can be provided in dosages which shortens or prevents the need for a drug holiday.
  • Still another embodiment relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • the first compound and second compound can be provided in dosages which ameliorates or inhibits a loss of cognition or improves cognition. In some embodiment, the first compound and second compound can . be provided in dosages which ameliorate or inhibits weight gain and/or suppresses the appetite of a subject.
  • the instruction set comprising dosage amounts and dosing schedules for ameliorating or inhibiting weight gain and/or suppressing the appetite of a subject.
  • the therapeutic compound can be selected from an antidepressant, an anticonvulsant, a mood stabilizer, an antipsychotic, an antiarrhythmic agent, an antibiotic, an anticholinergic agent, an antiemetic, an antihypertensive agent, an antineoplastic agent, an anti-Parkinson's agent, an antihistamine, an cardiotonic agent, a corticosteroid, a H 2 receptor antagonist, an immunosuppressive agent, a narcotic analgesic, a muscle relaxant, a non-steroids antiinflammatory agent, a radiocontrast agent, and a sedative.
  • antidepressants include, but are not limited to, Buproprion HCL (Wellbutrin®), Mitrazapine (Remeron®), Nefazadone (Serzone®), Trazadone (Desyrel®), and Venlafaxine (Effexor®), clovoxamine, amitriptyline and imipramine.
  • Additional antidepressants include selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants and monoamine oxidase inhibitors. Examples of selective serotonin reuptake inhibitors include, but are not limited to citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.
  • tricyclic antidepressants include, but are not limited to, Amitriptyline (Elavil®), Amoxapine (Asendin®), Clomipramine (Anafranil®), Desipramine (Norepramine®, Pertofrane®), Doxepin (Adapin®, Sinequan®), Imipramine (Janimine®, Tofranil®), Nortriptyline (Aventyl®, Pamelor®), Protriptyline (Vivactil®), Trimipramine (Rhotramine®, and Surmontil®).
  • An exemplary monoamine oxidase inhibitor is a nonselective, irreversible monoamine oxidase inhibitor such as Isocarboxazid (Marplan®), Phenelzine (Nardil®), and/or Tranylcypromine (Parnate®). Additional monoamine oxidase inhibitors include, but are not limited to, Moclobemide (Manerix®) and/or Toloxatone (Humoryl®).
  • Suitable anticonvulsants include, but are not limited to, valproic acid, phenobarbital, Carbamazepine (Tegretol®), Divalproex (Depakote®), Gabapentin (Neurontin®), Lamotrigine (Lamictal®), Topiramate (Topamax®), and phenyltoin.
  • Exemplary mood stabilizers include, but are not limited to, Lithium, Cibalith-S®, Duralith®, Ekalith®, Eskalith CR®, Lithane®, Lithobid®, Lithonate®, and Lithotabs®.
  • Suitable antipsychotics include, but are not limited to, phenothiazines, phenylbutylpiperdines, debenzapines, benzisoxidils, salt of lithiums, butyrophenones, substituted benzamides (sulpiride), and racloprides.
  • phenothiazines include chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), thioridazine (Mellaril), Fluphenazine (Prolixin®), Perpehnazine (Trilafon®), and Trifluoperazine (Stelazine®).
  • Examples of debenzapines include clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), and quetiapine (Seroquel®).
  • Examples of benzisoxidils include resperidone (Resperdal®), ziprasidone (Geodon®, Zeldox®)), 9-hydroxy- risperidone.
  • An example of a salt of lithium is lithium carbonate.
  • antipsychotics include, but are not limited to, Aripiprazole (Ability®), Etrafon®, Droperidol (Inapsine®), Thioridazine (Mellaril®), Thiothixene (Navane®), Promethazine (Phenergan®), Metoclopramide (Reglan®), Chlorprothixene (Taractan®), Triavil®, Molindone (Moban®), Sertindole (Serlect®), Droperidol, Amisulpride (Solian®), Melperone, Paliperidone (Invega®), Tetrabenazine, Thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®), and thioxanthine (Fluphenthixol).
  • Aripiprazole Ability®
  • Etrafon® Droperido
  • the antipsychotic can be a typical antipsychotic. In other embodiments, the antipsychotic can be an atypical antipsychotic. In an embodiment, theantipsychotic can act on a dopamine receptor such as a D2 receptor Suitable antiarrhythmics include, but are not limited to, disopyramide, quinidine, and tocainide. Exemplary antibiotics include, but are not limited to, cephalexin, cephalothin, metronidazole, ciprofloxacin, and ofloxacin. Examples of suitable anticholinergic agents include, but are not limited to, benztropine, homatropine, scopolamine and trihexyphenidyl. A suitable antiemetic is lithium.
  • antihypertensive agents include, but are not limited to, propranolol, metoprolol, atenolol, verapamil, methyldopa, prazosin, and nifedipine.
  • suitable antineoplastic agents include, but are not limited to, cytosine arabinoside, and interleukin-2.
  • Suitable anti-Parkinson's agents include, but are not limited to, L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride.
  • Exemplary antihistamines include, but are not limited to, phenylpropanolamine, diphenhydramine, chlorpheniramine brompheniramine, and pseudoephedrine.
  • An example of a suitable cardiotonic agent is digoxin.
  • Suitable corticosteroids include, but are not limited to, hydrocortisone and prednisone.
  • Exemplary H 2 receptor antagonists include, but are not limited to, cimetidine and ranitidine.
  • suitable immunosuppressive agents include, but are not limited to, cyclosporine and interferon.
  • Suitable narcotic analgesics include, but are not limited to, codeine, hydrocodone oxycodone, meperidine, and propoxyphene.
  • Exemplary muscle relaxants include, but are not limited to, baclofen, cyclobenzaprine, and methocarbimol.
  • suitable non-steroids anti-inflammatory agents include, but are not limited to, aspirin, ibuprofen, indomethacin, naproxen, and sulindac.
  • Suitable radiocontrast agents include, but are not limited to, metrizamide, iothalamate and iohexol.
  • Exemplary sedatives include, but are not limited to, benzodiazepine, alprazolam, diazepam, lorazepam, phenobarbital, butabarbital, and chloral hydrate.
  • the first compound and the second compound can be in the same container or each can be in separate containers.
  • compositions that can include a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II), wherein the first compound is present in an amount less than the amount needed to elicit the same therapeutic effect compared to when the first compound is administered alone.
  • the antipsychotic can act on a dopamine receptor such as a D2 receptor.
  • a dopamine receptor such as a D2 receptor.
  • Exemplary antipsychotics are described herein.
  • An embodiment described herein relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II), wherein the first compound is present in an amount less than the amount needed to elicit the same therapeutic effect compared to when the first compound is administered alone.
  • suitable compounds used to treat Parkinson' disease are described herein.
  • a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to reduce an adverse side effect associated with an antipsychotic in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with an antipsychotic so as to reduce an adverse side effect associated with the antipsychotic.
  • the adverse side effect can be selected from weight gain, metabolic syndrome, an extra-pyramidal side effect, akathisia, dystonia, acute dystonia, Parkinsonism, dykensia, tardive dyskinesia, neuroleptic malignant syndrome, hyperprolactinemia, and catalepsy.
  • Still another embodiment described herein relate to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or treat a negative symptom of schizophrenia
  • the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with an antipsychotic that causes a negative symptom of schizophrenia so as to ameliorate of treat a negative symptom of schizophrenia.
  • the negative symptom can be selected from affective flattening, poverty of speech, absence of volition, apathy, self-neglect, inappropriate emotion, inability to experience pleasure, inattentiveness, inability to show a facial expression, and inability to start or complete a task.
  • Yet still another embodiment described herein relate to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to reduce an adverse side effect associated with a compound used to treat Parkinson's disease
  • the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with a compound used to treat Parkinson's disease so as to reduce an adverse side effect associated with the compound used to treat Parkinson's disease.
  • the adverse side effect is selected from the group consisting of increased propensity for gambling, dyskinesia, and psychosis.
  • An embodiment relates described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or inhibit a loss of cognition or improves cognition in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with a therapeutic compound ameliorate or inhibit a loss of cognition or improves cognition associated with the therapeutic compound.
  • a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or inhibit weight gain in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with an antipsychotic and/or a compound used to treat Parkinson's disease ameliorate or inhibit weight gain associated with the antipsychotic and/or the compound used to treat Parkinson's disease.
  • Still another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to shorten or prevent the need for a drug holiday in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the instructions can include instructions for taking the catinabinoid antagonist or inverse agonist in combination with a compound used to treat Parkinson'sdisease shorten or prevent the need for a drug holiday associated with the compound used to treat Parkinson's disease.
  • Some embodiment described herein relate to a method of manufacturing a pharmaceutical composition, said method that can include the steps of: obtaining a first compound comprising an antipsychotic or a compound used to treat Parkinson's disease; obtaining a second compound selected from a compound of Formula (I) and a compound of Formula (II); and packaging together the first compound and the second compound.
  • the first compound and the second compound can be merged together, thereby forming a combined dosage form.
  • An embodiment described herein relates to a pharmaceutical composition manufactured by the method described in this paragraph.
  • the compound of Formula (I) can be selected from any of the compounds disclosed herein, including the claims. In some embodiments described herein, the compound of Formula (II) can be selected from any of the compounds disclosed herein, including the claims.
  • composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, intramuscular, intraocular, intranasal, intravenous, injection, aerosol, parenteral, and topical administration.
  • compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990, which is hereby incorporated by reference in its entirety.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, intraocular injections or as an aerosol inhalant.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
  • compositions for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., as disclosed in Remington's Pharmaceutical Sciences, cited above. [0227]
  • the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels', syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly, concentrated solutions. [0235] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An exemplary pharmaceutical carrier for the hydrophobic compounds disclosed herein is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • a common co-solvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • VPD co-solvent system which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol may be varied; and other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms.
  • compositions suitable for use in the methods disclosed herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Chapter 1, which is hereby incorporated by reference in its entirety).
  • the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Where no human dosage is established, a suitable human dosage can be inferred from ED 50 or ID 50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.
  • compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day.
  • the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • An embodiment described hereien relates to a method of ameliorating or inhibiting an adverse effect associated with an antipsychotic that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II). Examples of antipsychotics and side effects associated with antipsychotics have been described previously.
  • the antipsychotic can act a dopamine receptor such as a D2 receptor.
  • Another embodiment described herein relates to a method of inhibiting or preventing weight gain associated with the use of a therapeutic compound that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • exemplary therapeutic compounds that can cause weight gain have been described previously.
  • antidepressant that can cause weight gain can be selected from Buproprion HCL (Wellbutrin®), Mitrazapine (Remeron®), Nefazadone (Serzone®), Trazadone (Desyrel®), and Venlafaxine (Effexor®).
  • antidepressant that can cause weight gain can be selected from is selected from a selective serotonin reuptake inhibitor (SSRJ), a tricyclic antidepressant and a monoamine oxidase inhibitor,
  • Still another embodiment described herein relates to a method of suppressing the appetite of a subject that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein releates to a method of ameliorating or inhibiting a negative symptom of schizophrenia that can inlcude administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II). Examples of negative symptoms of schizophrenia have been described previously.
  • An embodiment described herein relates to a method of ameliorating or inhibiting a loss of cognition or improving cognition that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • hererin relates to a method of ameliorating or inhibiting an adverse effect associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another described herein relates to a method of ameliorating or inhibiting a propensity for gambling associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • the compound used to treat Parkinson's disease can be L-dopa.
  • Yet still another embodiment described herein relates to a method of ameliorating or inhibiting dyskinesia associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described herein relate to a method of ameliorating or inhibiting psychosis associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a method for shortening or preventing a need for a drug holiday that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II). Exemplary compounds used to treat Parkinson's disease are described herein.
  • An embodiment described hererin relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of an antipsychotic in a subject taking an antipsychotic that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates at least one adverse effect associated with the administration of the antipsychotic, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). Examples of antipsychotics and side effects associated with antipsychotics have been described previously.
  • the antipsychotic can act a dopamine receptor such as a D2 receptor.
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or treats at least one adverse effect associated with the administration of the antipsychotic.
  • An embodiment described hererin relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of a compound used to treat Parkinson's disease in a subject taking a compound used to treat Parkinson's disease that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or treats at least one adverse effect associated with the administration of the compound used to treat Parkinson's disease, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates at least one adverse effect associated with the administration of the compound used to treat Parkinson's disease.
  • Still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat a negative symptom of schizophrenia in a subject taking an antipsychotic that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or inhibits at least one negative symptom of schizophrenia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). Examples of negative symptoms of schizophrenia have been described previously.
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or inhibits at least one negative symptom of schizophrenia.
  • Yet still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a loss of cognition or improve cognition in a subject taking a therapeutic compound that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the therapeutic compound ameliorates or inhibits a loss of cognition or improves cognition, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Exemplary therapeutic compounds such as antidepressants, anticonvulsants, mood stabilizers, antipsychotics, antiarrhythmic agents, antibiotics, anticholinergic agents, antiemetics, antihypertensive agents, antineoplastic agents, anti-Parkinson's agents, antihistamines, cardiotonic agents, corticosteroids, H 2 receptor antagonists, immunosuppressive agents, narcotic analgesics, muscle relaxants, non-steroids anti-inflammatory agents, radiocontrast agents, and sedatives are described herein.
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the therapeutic compound ameliorates or inhibits a loss of cognition or improves cognition.
  • An embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a propensity for gambling in a subject taking a compound used to treat Parkinson's disease comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits the propensity for gambling, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits the propensity for gambling.
  • Another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit dyskinesia associated with a compound used to treat Parkinson's disease in a subject that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits dyskinesia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits dyskinesia associated with a compound used to treat Parkinson's disease.
  • Still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit psychosis associated with a compound used to treat Parkinson's disease in a subject that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits psychosis, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits psychosis associated with a compound used to treat Parkinson's disease.
  • Yet still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to shorten or prevent a need for a drug holiday that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with a compound used to treat Parkinson's disease shortens or prevents the need for a drug holiday, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the information of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease shortens or prevents the need for a drug holiday.
  • An embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to inhibit or prevent weight gain that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with an antipsychotic or a compound used to treat Parkinson's disease inhibits or prevents weight gain, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the information of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic or the compound used to treat Parkinson's disease inhibits or prevents weight gain.
  • the printed matter can be a label.
  • An embodiment described herein relates to a method for lowering the amount of an antipsychotic needed to elicit the same therapeutic effect compared to when the first is administered alone that can include administering to a subject a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a method for lowering the amount of a compound used to treat Parkinson's disease needed to elicit the same therapeutic effect compared to when the first compound is administered alone that can include administering to a subject a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • the compound selected from the compound of Formula (I) and the compound of Formula (II) can bind to CB-I receptors in human tissue with a higher pKi compared to N-piperidino-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide.
  • the compound of Formula (I) and/or the compound of Formula (II) can bind to CB-I receptors in human tissue with a pKi > 9.0.
  • the compound selected from the compound of Formula (I) and the compound of Formula (II) can supress food intake more effectively compared to N-piperidino-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide.
  • the first compound can be administered prior to the second compound. In any of the embodiments, the first compound can be administered subsequent to the second compound. In any of the embodiments, the first compound can be at the same time as the second compound.
  • Procedure 1 The analysis was performed on a combined prep/analytical Waters/Micromass system consisting of a ZMD single quadropole mass spectrometer equipped with electro-spray ionization interface.
  • the HPLC system consisted of a Waters 600 gradient pump with on-line degassing, a 2700 sample manager and a 996 PDA detector.
  • GC method 50 was used. Method 50 starts at 5O°C and has a gradient of 20 °C/min until 250 °C then holds the temperature for 5 minutes.
  • the analysis was performed on an Aglient 6850 series GC system with capillary S/SL inlet and FID with EPC installation.
  • the column was a 30 m X 0.32 mm x 0.25 ⁇ m HP5 column.
  • PaVC (10%, 200 mg) and PtO 2 were added to 4-(2-carboxy- phenylsulfanyl)-3-nitro-benzoic acid (2.9 g, 9.1 mmol) dissolved in 100 ml of MeOH.
  • the reaction flask were repeatedly evacuated and filled with H 2 .
  • a balloon containing H 2 was connected to the flask.
  • the reaction mixture was filtered through a pad of celite, which was then washed carefully with MeOH. Concentration of the filtrate at reduced pressure gave 2.5 g (96% yield, approximately 95% purity) of the titled compound as a white solid.
  • the purity could be increased to 97% by recrystallization from EtOAc/MeOH (2.3g, 88% yield).
  • CDI (4.53 g, 29 mmol, 4 eq) was added to 3-Amino-4-(2-carboxy- phenylsulfanyl)-benzoic acid (2.1 g, 7.3 mmol) dissolved in THF (30 ml). The reaction was stirred for 16h at room temperature. Water (200 ml) was then added to the mixture resulting in, after filtration and drying, l.78g (91%) of the titled compound as a off-white solid.
  • Example 7b Alternative synthesis of 1 1 -Chloro-dibenzo fb,f
  • Example 12 (l l-chloro-dibenzofb.f] [1,41thiazepin-8-yl)- f2,4-dimethyl-phenvD- piperazin-1 -yli-methanone.
  • Example 13 l l-chloro-dibenzo[b,f
  • Example 14 4-[(l l-chloro-dibenzorb,fl f1,41thiazepine-8-carbonyl)-amino]-piperidine-
  • Example 16 f4-(2,4-Dimethyl-phenyl)-piperazin-1-y I]-(I l-pentyl-dibenzo[b,f] [1 ,41thiazepin-8-yl)methanone.
  • Example 17 [4-(2,4-Dimethyl-phenyl)-piperazin-1-yll-(l l-isobutyl-dibenzorb,f
  • Example 18 d l-Cvclohexyl-dibenzo[b,f1 rK41thiazepin-8-ylV f4-(2,4-dimethyl- phenvD-piperazin- 1 -y 11 methanone.
  • Example 19 [l l-(4-chloro-phenylVdibenzorb,f] fL41thiazepin-8-ylY144-(2,4-dimethyl- phenyl)-piperzin- 1 -yl]-methanone.
  • Example 20 l l-Propyl-dibenzofb,f
  • Example 21 l l-Butyl-dibenzo[b,f] [1,41thiazepine-8-carboxylic acid piperidin-1- ylamide.
  • Example 22 l l-Pentyl-dibenzofb,f] ⁇ ,41thiazepine-8-carboxylic acid piperidin-1- ylamide.
  • Example 23 l l-Isobutyl-dibenzo[b,f
  • Example 24 11 -Cyclohexyl-dibenzof b,f
  • Example 25 4-
  • Example 27 4-f(l l-Pentyl-dibenzorb,f) fl ,41thiazepine-8-carbonyD-amino1-piperidine- 1-carboxylic acid ethyl ester.
  • Example 28 4-1Y1 l-Isobutyl-dibenzo[b,f] rU41thiazepine-8-carbonylVaminol- piperidine-1-carboxylic acid ethyl ester.
  • Example 29 4-[(l l-Cyclohexyl-dibenzofb,f) f1,41thiazepine-8-carbonyl)-aminol- piperidine-1-carboxylic acid ethyl ester.
  • Example 30 4-[(l l-(4-chloro-phenyl)-dibenzofb 1 fj [L4]thiazepine-8-carbonyl)-aminol- piperidine-1-carboxylic acid ethyl ester.
  • Example 30b Alternative synthesis of 4-[Yl l-(4-chloro-phenyl)-dibenzofb,f] ⁇ thiazepine-S-carbonyl)-aminol-piperidine-1-carboxylic acid ethyl ester.
  • Example 32 l l-(2-cyanophenyl)-dibenzo[b,f
  • Example 33 l l-(3-bromophenylVdibenzofb,f1 ⁇ ,4]thiazepin-8-carboxylic acid piperidin- 1 -ylamide
  • Example 35 1 l-piperidinyl-dibenzo[b,f] ri,41thiazepin-8-carboxylic acid piperidin-1- ylamide
  • Example 37 1 l-(propylaminyl)-dibenzo[b,f] [1,4]thiazepin-8-carboxylic acid piperidin- 1 -ylamide
  • Example 38 l l-(4-methylpiperazinyl>-dibenzo[b,fl ⁇ ,41thiazepin-8-carboxylic acid piperidin- 1 -ylamide
  • reaction mixture was concentrated in vacuo and purified by column chromatography using EtOAc (0-10%) in heptane as the eluent furnishing 338 mg of 4-(2-Methoxycarbonyl-benzyl)-3-nitro- benzoic acid ethyl ester as a colorless solid (1.13 mmol, 65%).
  • Example 53 1 l-(4-Fluorophenyl)-dibenzo[d,/1f1,4]oxazepine-8-carboxylic acid piperidin- 1 -ylamide
  • Example 54 1 l ⁇ -ChlorophenylVdibenzof ⁇ ./iri ⁇ ioxazepine-S-carboxylic acid piperidin- 1 -ylamide
  • Example 55 1 l-(3-Chlorophenyl)-dibenzo[ ⁇ ,/][L41oxazepine-8-carboxylic acid piperidin- 1 -ylamide
  • Example 61-66 are examples of compounds synthesised from 8-bromo-l l-chloro-dibenzo[6,/][l ,4]thiazepine according to the general procedure for palladium catalysed Negishi couplings and the procedures described by Pandya et al. J. Org. Chem. (2003), 68, 8274-8276 and Sezen and Sames et al., Org. Lett. (2003), 5, 3607-3610, which are both incorporated by reference in their entireties.
  • Example 62 1 l-(4-Chlorophenyl)-dibenzo[6,/][1,41thiazepine-8-sulfonic acid butylamide
  • Example 63 1 l-(4-Chlorophenyl)-dibenzo[b,f][1,4]thiazepine-8-sulfonic acid piperidin- 1 -ylamide
  • Example 70 2-Fluoro-l l-oxo-10,1 l-dihydro-dibenzo[6,/1[1,4]thiazepine-8-carboxylic acid
  • Example 73 l l-Chloro-2-fluoro-dibenzo[6,/][1,41thiazepme-8-carboxylic acid (3- chlorobenzyl)-amide
  • Example 74 1 l-(4-Chlorophenyl " )-2-fluoro-dibenzo ⁇ ,/i ⁇ ,41thiazepine-8-carboxylic acid (2-phen ⁇ lpropylVamide
  • Example 75 1 l-(3-Chlorophenyl)-2-fluoro-dibenzor ⁇ ,/iri 1 41thiazepine-8-carboxylic acid (2-phenylpropylVamide
  • Example 77 1 l-(3-Chlorophenyl)-2-fluoro-dibenzo[6,/1
  • Example 78 1 l-(4-Chlorophenyl)-2-fluoro-dibenzo[ ⁇ ,/][K4]thiazepine-8-carboxylic acid (3-chlorobenzylVamide
  • Trifluoroacetic acid (90 mL) was added to a solution of 4-tert- butylsulfanyl-3-nitrobenzoic acid ethyl ester (4.65 g; 16.4 mmol) in 20 mL dichloromethane. The mixture was stirred for 3 days at room temperature before evaporation of the solvent. The residue was partitioned between dichloromethane and 1 M aqueous sodium carbonate. After acidification of the aqueous phase using 4M HCl the desired compound was extracted from the aqueous layer with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The crude compound was used in the next step without purification (1.86 g, 50%).
  • Example 1 1 1 : l l-Chloro-3-chloro-dibenzoF6,/1[L4]thiazepine-8-carboxylic acid butyl amide
  • Example 1 13 N-(4-Fluorobenzyl)-l l-(4-chlorophenyl)-5-oxo-5H-5 ⁇ 4 - dibenzof ⁇ ,/UT,41thiazepine-8-carboxamide
  • Example 1 14 yV-(4-Fluorobenzyl)-l l-(4-chlorophenyl)-5,5-dioxo-5//-5 ⁇ 6 - dibenzof ⁇ ,/irU41thiazepine-8-carboxamide
  • Example 1 15 N-O-Chlorobenzyl)-l l-(4-fluorophenyl)-5-oxo-5H-5X 4 - dibenzo[ ⁇ ,/in,41thiazepine-8-carboxamide
  • Example 1 16 3-Chlorobenzyl)-l l-(4-fluorophenyl)-5,5-dioxo-5//-5 ⁇ 6 - dibenzof6JlfL41thiazepine-8-carboxamide
  • the desired compound was isolated from the crude mixture, which was obtained during the preparation of vV-(3-chlorobenzyl)-l l-(4-fluorophenyl)-5-oxo- 5H-5 ⁇ 4 -dibenzo[ ⁇ ,/][1,4]thiazepine-8-carboxamide. Purification by silica gel column chromatography eluting with a stepwise gradient of 20-50% ethyl acetate in heptane, afforded the desired compound (2.3 mg).
  • Example 117 iV-butyl-1 l-(4-chlorophenvn-5-oxo-5//-5 ⁇ 4 -dibenzor6./i ⁇ ,41thiazepine-8- carboxamide
  • N-Butyl-l l-(4-chlorophenyl)-dibenzo[ ⁇ ,/][1,4]thiazepine-8- carboxamide (86 mg; 0.2 mmol) was dissolved in acetic acid (20 mL) and methanol (15 mL). Hydrogen peroxide (-35% in water; 1 mL) was added. The reaction mixture was stirred at room temperature for 5 hours before it was neutralized by addition of saturated aqueous sodium bicarbonate. The aqueous solution was extracted with DCM (3 x 10 mL) and the combined organic phases were washed with water before drying over sodium sulphate, filtration and evaporation of the solvent in vacuo.
  • Example 118 iV-butyl-l l-(4-chlorophenyl)-5,5-dioxo-5H-5 ⁇ 6 - dibenzofft,fl ⁇ ,41thiazepine-8-carboxamide
  • N-Butyl-l l-(4-chlorophenyl)-dibenzo[6J][1,4]thiazepine-8- carboxamide (70 mg; 0.17 mmol) was dissolved in DCM (10 mL) and 3- chloroperbenzoic acid (225 mg; 1.0 mmol) was added. After 4 hours stirring at room temperature the mixture was diluted with DCM (20 mL) and washed with saturated aqueous sodium hydrogen carbonate (3 x 15 mL). The organic phase was dried over sodium sulphate, filtered and evaporated to dryness. Purification by preparative TLC eluting twice with 50% ethyl acetate in heptane afforded the title compound (7.9 mg; 10 %).
  • Example 119 l l-(l-Oxy-piperidin-1-ylVdibenzor6,/]rK41thiazepine-8-carboxylic acid 3- chlorobenzylamide (A) and 5-oxo-l l-piperidin-1-yl-5H-5 ⁇ 4 -dibenzol ⁇ , ⁇ -ri,41thiazepine- 8-carboxylic acid 3-chlorobenzylamide (B)
  • Example 120 5,5-Dioxo-l l-piperidin-1-yl-5H-5 ⁇ 4 -dibenzo[6,/irU4]thiazepine-8- carboxylic acid 3-chlorobenzylamide
  • Example 121 1 l-Cvclohexyl-5,5-dioxo-5//-5 ⁇ 4 -dibenzo[ ⁇ ,/][1,41thiazepine-8-carboxylic acid 4-fluorobenzylamide
  • Example 123 7V-(4-Fluorobenzyl)-l l-(4-fluorophenyr)-5H-dibenzo[6,e][1,4]diazepine-8- carboxamide
  • Example 125 1 l-(4-FluorophenyiyN-(l-phenylethyl)-5H-dibenzof6,el[l ,4]diazepine-8- carboxamide
  • Example 127 N-(4-Fluorobenzyl)-l l-(4-fluorophenyl)-5-methyl-5H- dibenzor6,eiri,41diazepine-8-carboxamide
  • Example 128 1 [8-Chloro-1 l-(4-fluorophenyl)-dibenzo
  • iV,N-Dimethyl amine 40 mg, 0.33 mmol was added to a solution of 8- chloro-l l-(4-fluorophenyl)-5H-dibenzo[6,e][1,4]diazepine (108 mg, 0.33 mmol) in dry T ⁇ F (2 mL) at room temperature, followed by addition of acetyl chloride (70 ⁇ L, 0.99 mmol). The reaction mixture was shaken overnight at 60°C, allowed to cool to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and evaporated to dryness.
  • amidoimidoyl chlorides (Examples 147 - 162) were synthesized according to the general procedure for amide formation at 0.5 mmol scale except that the reaction mixture was passed through a pad of acidic alumina oxide and eluted with a mixture of CH 2 Cl 2 and EtOAc. The eluents were concentrated at reduced pressure and the obtained crude products were directly used in the next reactions without further purifications or characterization.
  • Example 150 N-(butyO-l l-(chloro)-dibenzo[b,f
  • Example 151 N-(3-phenylpropyl)- 11 -(chloro " )-dibenzofb,fir 1 ,4]thiazepine-8- carboxamide
  • Example 154 N-(2,4-dichlorobenzyQ-l l-(chloroydibenzofb,f
  • Example 156 N-(2-(3-chlorophenyl)ethyl)-l l-(chloro)-dibenzo
  • Example 160 N-((N-ethyl-N-phenyl)aminoethylVl l-(chloro)- dibenzo[b,f
  • Example 162 N-(4-fluorobenzyl)-l l-(chloro)-dibenzorb, ,fi ⁇ ,41thiazepine-8- carboxamide
  • Example 163 1 l-(piperidinyl)-dibenzofb,f][1,4]thiazepin-8-yl-(piperidin-1-yl)- methanone
  • Example 170 N-(2,4-dichlorobenzyl)-l l-(piperidinyl)-dibenzofb,Fi ⁇ ,41thiazepine-8- carboxamide
  • Example 175 N-(2-phenyl-propyl)-l l-(piperidinyl)-dibenzo[b,f
  • Example 176 N-(Q ⁇ -ethyl-N-phenyl)aminoethyiyi l-(piperidiny ⁇ )- dibenzofb,fU1,4 ⁇ thiazepine-8-carboxam ⁇ de
  • Example 179 1 l-(cvclohexyl)-dibenzo[b,fl[1,4]thiazepin-8-yl-(piperidin-1-yl ' )- methanone
  • Example 190 N-CCN-ethyl-N-phenyHaminoethylVl l-CcyclohexylV dibenzofb,firi,41thiazepine-8-carboxamide
  • Example 191 l l-(cyclohexyl)-dibenzo
  • the arylzinc halide used for Examples 193 - 205 was 3- chlorophenylzinc iodide.
  • Example 193 1 l-(3-chlorophenyl)-dibenzo[b/
  • Example 200 N-(2-(4-chlorophenylkthylyi l-(3-chlorophenvn- dibenzo [b, f] [ 1 ,4] thiazepine -8 -carboxamide
  • Example 201 N-(3-chlorobenzv0-l l-(3-chlorophenylVdibenzo[b,f
  • Example 202 N-(2-phenyl-propyl)-l l-(3-chlorophen ⁇ l)-dibenzo[b,f
  • Example 204 1 l-(3-chlorophenylVdibenzo[b,f
  • Example 205 N-(4-fluorobenzyD-l l-(3-chlorophenyl)-dibenzo[b,f
  • the arylzinc halide used for Examples 206 - 217 was 4- fluorophenylzinc iodide.
  • Example 216 N-(2-phenyl-propyl)-l l-(4-fluorophenyl)-dibenzo[b,f
  • Example 217 N-(flS[-ethyl-N-phenyl)aminoethyl)-l 1 -(4-fluorophenyiy dibenzorb,fi ⁇ ,41thiazepine-8-carboxamide

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Abstract

The present invention relates to pharmaceutical compositions that contain a compound that modulate the activity of a cannabinoid receptor in conjunction with another therapeutic compound and uses of compounds that modulate the activity of a cannabinoid receptor in conjunction with another therapeutic compound to treat various conditions (e.g., side effects).

Description

USE OF CANNABINOID MODULATING COMPOUNDS IN COMBINATION WITH OTHER THERAPEUTIC COMPOUNDS FOR ADJUNCTIVE THERAPY
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 60/852,622, entitled "Use of Cannabinoid Modulating Compounds in Combination with Other Therapeutic Compounds for Adjunctive Therapy", filed October 17, 2006; which is incorporated by reference in its entirety including all drawings.
BACKGROUND OF THE INVENTION Field of the Invention
[0002] This invention relates to the fields of organic chemistry, pharmaceutical chemistry, biochemistry, molecular biology and medicine. In particular it relates to compositions that contain a compound that modulate the activity of a cannabinoid receptor in conjunction with another therapeutic compound and uses of compounds that modulate the activity of a cannabinoid receptor in conjunction with another therapeutic compound to treat various conditions (e.g., side effects).
Description of the Related Art
[0003] The cannabinoids, which are bioactive lipids, naturally found in the cannabis sativa (marijuana) plant, have been used recreational Iy and therapeutically for at least 5000 years. In addition to their well-documented effects on mood, cannabinoids (often in the form of marijuana) have been prescribed to treat nausea, pain, migraine, epilepsy, glaucoma, hypertension, cachexia and pain associated with childbirth. Two cannabinoid receptors, CBl and CB2, have been identified. Both are members of the G protein-coupled receptor superfamily, and are negatively coupled through Gi protein. The CB2 receptor has 44% sequence similarity to the CBl receptor.
[0004] The CBl receptor, unlike the CB2 receptor, is highly expressed in the central nervous system, mostly presynaptically. Indeed, the CBl receptor is present in the brain at higher levels than many other GPCRs. It is found in the cortex, cerebellum, hippocampus, and basal ganglia (reviewed in Brievogel and Childres, 1998). In addition, the CBl receptor has also been detected in sperm, the prostate gland, and other peripheral tissues (including structures of the eye). The CB2 receptor is present in the cells of the immune system (spleen, thymus), testis, and lung.
SUMMARY OF THE INVENTION
[0005] An embodiment described herein relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0006] Another embodiment described herein relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is a compound used to treat Parkinsons's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0007] Still another embodiment relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0008] Yet still another embodiment described herein relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II), wherein the first compound is present in an amount less than the amount needed to elicit the same therapeutic effect compared to when the first compound is administered alone.
[0009] An embodiment described herein relates to a pharmaceutical composition comprising a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II), wherein the first compound is present in an amount less than the amount needed to elicit the same therapeutic effect compared to when the first compound is administered alone.
[0010] Another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to reduce an adverse side effect associated with an antipsychotic in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0011] Still another embodiment described herein relate to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or treat a negative symptom of schizophrenia in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0012] Yet still another embodiment described herein relate to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to reduce an adverse side effect associated with a compound used to treat Parkinson's disease in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0013] An embodiment relates described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or inhibit a loss of cognition or improves cognition in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0014] Another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or inhibit weight gain in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0015] Still another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to shorten or prevent the need for a drug holiday in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0016] An embodiment described hereien relates to a method of ameliorating or inhibiting an adverse effect associated with an antipsychotic that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0017] Another embodiment described herein relates to a method of inhibiting or preventing weight gain associated with the use of a therapeutic compound that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0018] Still another embodiment described herein relates to a method of suppressing the appetite of a subject that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0019] Yet still another embodiment described herein releates to a method of ameliorating or inhibiting a negative symptom of schizophrenia that can inlcude administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0020] An embodiment described herein relates to a method of ameliorating or inhibiting a loss of cognition or improving cognition that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0021] Another embodiment described hererin relates to a method of ameliorating or inhibiting an adverse effect associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0022] Still another described herein relates to a method of ameliorating or inhibiting a propensity for gambling associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0023] Yet still another embodiment described herein relates to a method of ameliorating or inhibiting dyskinesia associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0024] An embodiment described herein relate to a method of ameliorating or inhibiting psychosis associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0025] Another embodiment described herein relates to a method for shortening or preventing a need for a drug holiday that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0026] An embodiment described hererin relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of an antipsychotic in a subject taking the antipsychotic that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or treats at least one adverse effect associated with the administration of the antipsychotic, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0027] Another embodiment described hererin relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of a compound used to treat Parkinson's disease in a subject taking the compound used to treat Parkinson's disease that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or treats at least one adverse effect associated with the administration of the compound used to treat Parkinson's disease, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0028] Still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat a negative symptom of schizophrenia in a subject taking an antipsychotic that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or inhibits at least one negative symptom of schizophrenia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0029] Yet still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a loss of cognition or improve cognition in a subject taking a therapeutic compound that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the therapeutic compound ameliorates or inhibits a loss of cognition or improves cognition, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0030] An embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a propensity for gambling in a subject taking a compound used to treat Parkinson's disease comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits the propensity for gambling, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0031] Another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit dyskinesia associated with a compound used to treat Parkinson's disease in a subject that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits dyskinesia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0032] Still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit psychosis associated with a compound used to treat Parkinson's disease in a subject that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits psychosis, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0033] Yet still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to shorten or prevent a need for a drug holiday that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with a compound used to treat Parkinson's disease shortens or prevents the need for a drug holiday, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0034] An embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to inhibit or prevent weight gain that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with an antipsychotic or a compound used to treat Parkinson's disease inhibits or prevents weight gain, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
[0035] Another embodiment described herein relates to a method for lowering the amount of an antipsychotic needed to elicit the same therapeutic effect compared to when the first is administered alone that can include administering to a subject a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0036] Still another embodiment described herein relates to a method for lowering the amount of a compound used to treat Parkinson's disease needed to elicit the same therapeutic effect compared to when the first compound is administered alone that can include administering to a subject a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0037] Some embodiment described herein relate to a method of manufacturing a pharmaceutical composition, said method that can include the steps of: obtaining a first compound comprising an antipsychotic or a compound used to treat Parkinson's disease; obtaining a second compound selected from a compound of Formula (I) and a compound of Formula (II); and packaging together the first compound and the second compound. In an embodiment, the first compound and the second compound can be merged together, thereby forming a combined dosage form.
[0038] In some embodiments described herein, the compound of Formula (I) can be selected from any of the compounds disclosed herein, including the claims. In some embodiments described herein, the compound of Formula (II) can be selected from any of the compounds disclosed herein, including the claims.
[0039] Exemplary antipsychotics, compounds used to treat Parkinson's disease, therapeutic compounds, adverse side effects associated with antipschotics and/or compounds used to treat Parkinson's disease, and negative symptoms of schizophrenia are described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] Figure IA is a graph showing the percent response of the CB 1 receptor as the concentration of l l-Cyclohexyl-dibenzo[b,fj [1,4]thiazepine-8-carboxylic acid piperidin-1-ylamide (Compound I) increases. Figure IB is a graph showing the percent response of the CB2 receptor as the concentration of Compound I increase.
[0041] Figure 2 is a bar graph showing the food intake in fasted rats 1 and 2 hours after being administered either 1, 3, or 10 mg/kg doses of Compound I. * Indicates p<0.05 as compared to the vehicle-treated controls. ** Indicates p<0.01 as compared to the vehicle-treated controls.
[0042] Figure 3 is bar graph showing the time course food intake in fasted rats after being administered 1 mg/kg of Compound I. * Indicates p<0.05 as compared to the vehicle-treated controls. ** Indicates p<0.01 as compared to the vehicle-treated controls.
[0043] Figure 4 is a bar graph showing cumulative food consumption at several points in time after the rats had been dosed with 10 mg/kg of Compound I. * Indicates p<0.05 as compared to the vehicle-treated controls.
[0044] Figure 5 A is a line graph showing the attenuation of CBl agonist- mediated effects after administration of CP 55,940 (0.3 and 1.0 mg/kg). Figure 5B is a line graph showing the attenuation of CB 1 agonist-mediated effects after administration of Compound I alone or in combination with CP55,940.
[0045] Figure 6 is a bar graph showing the body temperature of the rats at several points in time after the rats had been dosed with various doses of CP 55,950 or CP55,950 and Compound I. [0046] Figure 7 is a bar graph showing the concentration of Compound I in the plasma and brain at several points in time.
[0047] Figures 8A and 8B are bar graphs showing the concentration of compound, N-(butyl)-l l-(4-chlorophenyl)-dibenzo[b,f,][1,4]thiazepine-8-carboxamide (Compound II) in tissue and brain at several points in time. Figures 8C and 8D are line graphs showing the concentration of Compound II in the plasma and brain at several points in time.
[0048] Figure 9A in a line graph showing the effects of Compound II (1 and 3 mg/kg/day) on body weight Figure 9B is a line graph showing the effects of Compound II (1 and 3 mg/kg/day) on food intake and water intake. Figure 9C line graph showing the effects of Compound II (10 mg/kg/day) on body weight. Figure 9D is a line graph showing the effects of Compound II (10 mg/kg/day) on food intake and water intake.
[0049] Figures 1OA and 1OC are bar graphs showing the exploration ratio at 1 and 2 hours after the mice had been dosed with the vehicle, CP 55,940 (0.3 mg/kg, ip), or SR 141716A (1 mg/kg, ip). Figures 1OB and 1OD are bar graphs showing the discrimination index at 1 and 2 hours after the mice had been dosed with the vehicle, CP 55,940 (0.3 mg/kg, ip), or SR 141716A (1 mg/kg, ip).
[0050] Figure 1 IA is a bar graph showing the exploration ratio 2 hours after the mice had been dosed with Compound II (3 mg/kg, ip). Figure HB is a bar graph showing the discrimination index 2 hours after the mice had been dosed with Compound II (3 mg/kg, ip).
[0051] Figure 12 is a bar graph showing percentage of novel recognition of a familiar object 2 hours after the mice had been dosed with 1, 3, or 10 mg/kg of Compound II.
[0052] Figure 13 is a line graph showing the working memory errors of the mice after being dosed with the vehicle, tacrine (0.3 mg/kg), or Compound II (3 mg/kg).
[0053] Figure 14 is a line graph showing the contralateral rotations over time of the mice after being dosed with apomorphine (0.05, 0.16, and 0.5 mg/kg). [0054] Figure 15 is a line graph showing the contralateral rotations over time of the mice after being dosed with apomorphine (0.05 mg/kg), Compound II (3.0 mg/kg), or apomorphine (0.05 mg/kg) and Compound II (3.0 mg/kg).
[0055] Figure 16 is a line graph showing the contralateral rotations over time of the mice after being dosed with apomorphine (0.16 mg/kg), Compound II (3.0 mg/kg), or apomorphine (0.16 mg/kg) and Compound II (3.0 mg/kg).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT [0056] There are many known medications with adverse side effects and/or the inability to treat all symptoms of the conditions for which they are administered. For example, most antipsychotics have relatively poor efficacy against negative symptoms of schizophrenia and/or impair cognitive functioning. The use of many antipsychotic drugs leads to extrapyramidal side effects characterized by involuntary movements. Aside from the onset of extrapyramidal effects, drugs prescribed for Parkinson's disease also cause drug-induced psychosis, writhing, muscle rigidity, and compulsive gambling after sustained use. Weight gain is a side effect that mars some of the most frequently prescribed drugs. Thus there is a need for new drugs and therapies to alleviate the side effects caused by medicines prescribed for schizophrenia, Parkinson's disease and other aliments, including new drugs that can be used as an adjunctive therapy to alleviate the limitations and side effects presented by these drugs.
[0057] Cognitive function is markedly impaired in most patients with schizophrenia. Although second generation drugs such as olanzapine treat the psychosis caused by schizophrenia, they do not have the ability to improve all cognitive functions impaired by the disease. Typical antipsychotics like haloperidol not only are unable to improve cognitive functions affected by schizophrenia but have actually been shown to impair cognitive performance. Many other known drugs prescribed for a variety of indications cause cognitive impairment including the antiarrhythmic agents disopyramide, , quinidine, and tocainide; antibiotics such as cephalexin, cephalothin, metronidazole, ciprofloxacin, and ofloxacin; anticholinergic agents such as benztropine, homatropine, scopolamine, and trihexyphenidyl; antidepressants such as amitriptyline, imipramine, desipramine, and fluoxetine; anticonvulsants like phenyltoin, valproic acid, and carbamazepine; antiemetics including promethazine, hyroxyzine, metocloporamide, and prochloroperazine; antihypertensive agents like propranolol, metoprolol, atenolol, verapamil, methyldopa, prazosin, and nifedipine; antineoplastic agents like chlorambucil, cytosine arabinoside, and interleukin-2; antimanic agents like lithium; anti-parkinsonian agents like L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride; antihystamines/decongestants like phenylpropanolamine, diphenhydramine, chlorpheniramine, brompheniramine, and pseudoephedrine; cardiotonic agents such as digoxin; corticosteroids such as hydrocortisone, prednisone; H2 receptor antagonists like cimetidine and rantidine; immunosuppressive agents like cyclosporine and interferon; narcotics analgesics such as codeine, hydrocodone, oxycodone, meperidine, and propoxyphene; muscle relaxants such as baclofen, cyclobenzaprine, and methocarbimol; nonsteroidal anti-inflammatory agents such as aspirin, ibuprofen, indomethacin, naproxen, and sulindac; radiocontrast agents such as metrizamide, iothalamate, and iohexol; sedatives such as, alprazolam, diazepam, lorazepam, phenobarbital, butabarbital, and chloral hydrate. In addition, new medications may be approved that may also cause cognitive impairment. Impaired cognitive function adversely affects daily activities and social interactions and is therefore related to poor functional outcome. There is thus an unmet need in the art for adjunctive therapies that would offset the limitations presented by the administration of typical and second- generation antipsychotic drugs alone.
[0058] Blockade of dopamine receptors is the key mechanistic feature of antipsychotic medications believed to mediate many of their therapeutic benefits, but it is also responsible for many of the debilitating side effects associated with these drugs, particularly the movement disorder, extrapyramidal side effects (EPS) and hyperprolactinemia EPS consists of involuntary movements that occur due to blockade of dopamine receptors in the nigrostriatal pathway of the basal ganglia. Antipsychotic medications also cause hyperprolactinemia, a condition marked by unusually high levels of the hormone prolactin in non-pregnant individuals that can lead to loss of sexual function and infertility. These conditions are caused by antipsychotics that block the D2 dopamine receptors and therefore dopamine action. A reduction in the dosage of standard antipsychotics needed to maintain efficacy would raise dopamine levels in key brain regions responsible for these side effects and result in fewer side effects related to decreased dopamine production.
[0059] In addition to antipsychotics, drugs used to treat Parkinson's disease also have numerous side effects. Parkinson's occurs when there is a loss of cells in a part of the brain that produces dopamine. The conventional medical response is to raise dopamine levels in the brain by using L-dopa, a drug that binds to cells that have the D3 receptor. L-dopa initially reduces the tremor, slow movement, and muscular rigidity associated with Parkinson's, but in most patients, a jerky and writhing side effect called dyskinesia sets in after a number of years, possibly as a result of the cells' excess exposure to dopamine. Dyskinesia is resistant to treatment and is often treated by having patients reducing or stopping treatment with the prescribed Parkinson's drug (often referred to as taking a "drug holiday"). Current Parkinson's agents are also limited by desensitization effects which limit their effectiveness for chronic use, also necessitating frequent "drug holidays." A reduction in the dosage of Parkinson's drugs needed to maintain efficacy would increase the length of time they could be used, and reduce the need for or extent of "drug holidays."
[0060] Studies have implicated dopamine agonist therapy, for example pramipexone, with causing pathological gambling,. This may relate to disproportionate stimulation of dopamine D3 receptors. A reduction of domapine levels in the mesocorticolimbic system would be expected to suppress such drug-induced behaviors.
[0061] Weight gain is among side effects listed in official information sheets for many medications including selective serotonin reuptake inhibitors such as citalopram (Celexa®), fluoxetine (Prozac®), fluvoxamine (Luvox®), paroxetine (Paxil®), and sertraline (Zoloft®); tricyclic antidepressants such as amitriptyline (Elavil®), amoxapine (Asendin®), clomipramine (Anafranil®), desipramine (Norepramine®, Pertofrane®), doxepin (Adapin®, Sinequan®), imipramine (Janimine®, Tofranil®), nortriptyline (Aventyl®, Pamelor®), protriptyline (Vivactil®), and trimipramine (Rhotramine®, Surmontil®); monoamine oxidase inhibitors such as isocarboxazid (Marplan®), phenelzine (Nardil®), and tranylcypromine (Parnate®); selective reversible RJMAs including moclobemide (Manerix®) and toloxatone (Humoryl®); other antidepressants like buproprion HCL (Wellbutrin®), mitrazapine (Remeron®), nefazadone (Serzone®), trazadone (Desyrel®), venlafaxine (Effexor®); anticonvulsants/mood stabilizers like carbamazepine (Tegretol®), divalproex (Depakote®), gabapentin (Neurontin®), lamotrigine (Lamictal®), and topiramate (Topamax®); conventional mood stabilizers like lithium (Cibalith-S®, Duralith®, Ekalith®, Eskalith CR®, Lithane®, Lithobid®, Lithonate®, Lithotabs®); antipsychotics such as haloperidol (Haldol®, Peridol®), molindone (Moban®), thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®); newer antipsychotics, classified as atypical antipsychotics, including clozapine (Clozaril®), olanzapine (Zyprexa®), quetiapine (Seroquel®), risperidone (Risperdal®), sertindole (Serlect®), and ziprasidone (Seldox®); heartburn drugs such as Nexium® and Prevacid®; Clozaril and Zypexa, used to treat serious mental disorders; diabetes drugs like Glucotrol®, Diabeta®, and Diabinese®; and the high blood pressure drugs Minipress®, Cardura®, and Inderal®. Although the exact mechanisms through which these drugs cause weight gain is unknown, recent studies have shown that antipsychotic drugs, for example, can differentially affect insulin action and metabolism through direct cellular effects in adipocytes.
[0062] Pronounced weight gain, and associated deterioration of serum lipid, and metabolic profiles is associated with chronic use of certain antipsychotics, particularly olanzapine. Second-generation antipsychotics such as risperidone, clozapine, olanzapine, and quetiapine were shown to directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement. The medical and psychological consequences of drug-induced obesity are often so intolerable that patients may discontinue treatment even if it is effective. Therefore, there is an unmet need in the art to provide pharmaceutical compositions that can ameliorate the weight-gain induced by certain drugs.
[0063] The CBl receptor is believed to be responsible for the appetite stimulating properties and habituation associated with cannabinoid use. The CBl receptor antagonist, SR 141716 (rimonabant, Acomplia; Sanofi-Aventis) has shown efficacy in late-stage clinical trials for obesity and nicotine dependence, with no psychotropic effects. The compound has been shown to reduce both food intake and adipose tissue (by a mechanism independent of food intake). Use of SR 141716 in animal models suggests additional use of CBl receptor antagonists and inverse agonists for the treatment of alcohol addiction, opiate addiction, cocaine addiction, anxiety, and septic shock. Interestingly, mice null for the CBl gene also display impaired cocaine self- administration, and less severe withdrawal from morphine addiction compared to wild- type mice. In addition, CB 1 knockout mice also display increased bone mineral density, and both CBl knockout mice and mice treated with CB antagonists are resistant to bone loss in a model for osteoporosis. Other animal models indicate a use for CBl receptor antagonists and inverse agonists for the prevention of premature spontaneous abortion.
[0064] Cannabinoid signaling is hyperactive in animal models of several diseases suggesting that cannabinoids either have a protective role (e.g., CB l agonists may be therapeutic) or are involved in the pathology of these diseases (e.g., CBl antagonists or inverse agonists may be therapeutic). These include Parkinson's disease, Alzheimer's disease, multiple sclerosis, epilepsy, and intestinal disorders. In addition, the levels of endogenous cannabinoids and CBl receptors are elevated in the liver and blood of patients with cirrhosis of the liver. Moreover, cannabinoid levels have been shown to be elevated in the cerebrospinal fluid of a patient with stroke, as well as in the brains of depressed suicide victims. Endogenous cannabinoids have also been shown to be higher in the cerebrospinal fluid of drug-naive paranoid schizophrenics compared to normal patients; interestingly, schizophrenic patients treated with atypical but not typical antipsychotics also exhibit higher CSF levels of anandamide. Additionally, the CB l gene is located in a chromosomal region that has been linked to schizophrenia. Moreover, high levels of the endogenous cannabinoid, anandamide, are correlated with premature abortion and failure of in vitro fertilization. Finally, activation of CB receptors by an anandamide analogue has been shown to reduce sperm fertilizing capacity by 50%.
[0065] Selective activation of CBl receptors by agonists or partial agonists may also be used to treat a number of disorders. Some patients in clinical trials of the CB l antagonist, SR 141716A, have reported diarrhea and nausea, suggesting that an agonist would alleviate those symptoms. THC (tetrahydrocannabinol; active cannabinoid in Cannabis sativa) has been shown to improve mobility and alleviate pain in patients with multiple sclerosis. Other promising results for cannabinoids have been shown in clinical trials for Tourette's syndrome, Parkinson's disease, glaucoma, and pain. Finally cannabinoids have been shown to inhibit cancer growth, angiogenesis, and metastasis in animal models.
Definitions
[0066] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patent, applications, published applications and other publications referenced herein are incorporated by reference in their entirety. In the event that there are plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0067] As used herein, any "R" group(s) such as, without limitation, R1, R1a and R1 b, represent substituents that can be attached to the indicated atom. A non-limiting list of R groups include but are not limited to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl. An R group may be substituted or unsubstituted. If two "R" groups are covalently bonded to the same atom or to adjacent atoms, then they may be "taken together" as defined herein to form a cycloalkyl, aryl, heteroaryl or heteroalicyclyl group. For example, without limitation, if R3 and Rb of an NR3Rb group are indicated to be "taken together", it means that they are covalently bonded to one another at their terminal atoms to form a ring that includes the nitrogen:
Figure imgf000017_0001
[0068] As used herein, "IC50" refers to an amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of GPCR, including cannabinoid receptor, activity an assay that measures such response. The assay may be an R-S AT® assay as described herein but is not limited to an RSAT assay.
[0069] As used herein, "EC5o" refers to an amount, concentration or dosage of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound, in an assay that measures such response such as but not limited to R-SAT® assay described herein.
[0070] Whenever a group of this invention is described as being "optionally substituted" that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being "unsubstituted or substituted" if substituted, the substituent may be selected from one or more the indicated substituents.
[0071] Unless otherwise indicated, when a substituent is deemed to be "optionally substituted," or "substituted" it is meant that the substituent is a group that may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is hereby incorporated by reference in its entirety.
[0072] As used herein, "Cm to Cn" in which "m" and "n" are integers refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or the number of carbon atoms in the ring of a cycloalkyl or cycloalkenyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl or ring of the cycloalkenyl can contain from "m" to "n", inclusive, carbon atoms. Thus, for example, a "C1 to C4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CHb)3C-. If no "m" and "n" are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group, the broadest range described in these definitions is to be assumed.
[0073] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 5 carbon atoms. The alkyl group of the compounds may be designated as "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.
[0074] The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is(are) one or more group(s) individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfϊnyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. Wherever a substituent is described as being "optionally substituted" that substitutent may be substituted with one of the above substituents unless otherwise indicated.
[0075] As used herein, "alkenyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group of * this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
[0076] As used herein, "alkynyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
[0077] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system that has a fully delocalized pi-electron system throughout all the rings. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group of this invention may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof, unless the substituent groups are otherwise indicated. [0078] As used herein, "heteroaryl" refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system throughout all the rings), one or two or more fused rings that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine. A heteroaryl group of this invention may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, SiIyI1 sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
[0079] An "aralkyl" is an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, substituted benzyl, 2- phenylethyl, 3-phenylpropyl, and naphtylalkyl.
[0080] A "heteroaralkyl" is heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylmethyl, 3- thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl, and their substituted as well as benzo-fused analogs.
[0081] "Lower alkylene groups" are straight-chained tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-), and butylene (-(CH2V) groups. A lower alkylene group may be substituted or unsubstituted.
[0082] As used herein, "alkylidene" refers to a divalent group, such as =CR'R", which is attached to one carbon of another group, forming a double bond, Alkylidene groups include, but are not limited to, methylidene (=CH2) and ethylidene (=CHCH3). As used herein, "arylalkylidene" refers to an alkylidene group in which either R' and R" is an aryl group. An alkylidene group may be substituted or unsubstituted.
[0083] As used herein, "alkoxy" refers to the formula -OR wherein R is an alkyl is defined as above, e.g. methoxy, ethoxy, n-propoxy, 1-methylethoxy (isoproppxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy and the like. An alkoxy may be substituted or unsubstituted.
[0084] As used herein, "alkylthio" refers to the formula -SR wherein R is an alkyl is defined as above, e.g. methylmercapto, ethylmercapto, n-propylmercapto, 1- methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec- butylmercapto, tert-butylmercapto, and the like. An alkylthio may be substituted or unsubstituted.
[0085] As used herein, "aryloxy" and "arylthio" refers to RO- and RS-, in which R is an aryl, such as but not limited to phenyl. Both an aryloxy and arylthio may be substituted or unsubstituted.
[0086] As used herein, "acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted. An acyl may be substituted or unsubstituted.
[0087] As used herein, "cycloalkyl" refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkyl groups of this invention may range from C3 to C10, in other embodiments it may range from C3 to C6. A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated.
[0088] As used herein, "cycloalkenyl" refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be "aryl," as defined herein). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro-connected fashion. A cycloalkenyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
[0089] As used herein, "cycloalkynyl" refers to a cycloalkyl group that contains one or more triple bonds in the ring. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. A cycloalkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
[0090] As used herein, "heteroalicyclic" or "heteroalicyclyl" refers to a stable 3- to 18 membered ring which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, oxygen and sulfur. For the purpose of this invention, the "heteroalicyclic" or "heteroalicyclyl" may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be joined together in a fused, bridged or spiro-connected fashion; and the nitrogen, carbon and sulfur atoms in the "heteroalicyclic" or "heteroalicyclyl" may be optionally oxidized; the nitrogen may be optionally quaternized; and the rings may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system throughout all the rings. Heteroalicyclyl groups of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, , nitro, silyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. Examples of such "heteroalicyclic" or "heteroalicyclyl" include but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl N-Oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone unless the substituent groups are otherwise indicated.
[0091] A "(heteroalicyclyl)alkyl" is a heterocyclic or a heterocyclyl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclic or a heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited 4-methyltetrahydro-2H-pyran, substituted 4-methyltetrahydro-2H-pyran, 4-ethylpiperidine, 4-propylpiperidine, 4- methyltetrahydro-2H-thiopyran, and 4-methyl-1,3-thiazinane.
[0092] A "(cycloalkyl)alkyl" is a cycloalkyl group connected, as a substituent, via a lower alkylene group. The lower alkylene and cycloalkyl of a (cycloalkyl)alkyl may be substituted or unsubstituted. Examples include but are not limited cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like.
[0093] A "(cycloalkenyl)alkyl" is a cycloalkenyl group connected, as a substituent, via a lower alkylene group. The lower alkylene and cycloalkenyl of a (cycloalkenyl)alkyl may be substituted or unsubstituted.
[0094] A "(cycloalkynyl)alkyl" is a cycloalkynyl group connected, as a substituent, via a lower alkylene group. The lower alkylene and cycloalkynyl of a (cycloalkynyl)alkyl may be substituted or unsubstituted.
[0095] As used herein, "halo" or "halogen" refers to F (fluoro), Cl (chloro), Br (bromo) or I (iodo). [0096] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and l-chloro-2- fluoromethyl, 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.
[0097] As used herein, "haloalkoxy" refers to RO-group in which R is a haloalkyl group. Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and l-chloro-2-fluoromethoxy, 2- fluoroisobutyoxy. A haloalkoxy may be substituted or unsubstituted.
[0098] An "O-carboxy" group refers to a "RC(O)O-" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. An O- carboxy may be substituted or unsubstituted.
[0099] A "C-carboxy" group refers to a "-C(O)R" group in which R can be the same as defined with respect to O-carboxy. A C-carboxy may be substituted or unsubstituted.
[0100] A "trihalomethanesulfonyl" group refers to an "X3CSO2-" group wherein X is a halogen.
[0101] A "cyano" group refers to a "-CN" group.
[0102] An "isocyanato" group refers to a "-NCO" group.
[0103] A "thiocyanato" group refers to a "-CNS" group.
[0104] An "isothiocyanato" group refers to an " -NCS" group.
[0105] A "sulfinyl" group refers to an "-S(O)-R" group in which R can be the same as defined with respect to O-carboxy. A sulfinyl may be substituted or unsubstituted.
[0106] A "sulfonyl" group refers to an "SO2R" group in which R can be the same as defined with respect to O-carboxy. A sulfonyl may be' substituted or unsubstituted.
[0107] An "S-sulfonamido" group refers to a "-SO2NRARB" group in which RA and RB can be the same as R defined with respect to O-carboxy. An S-sulfonamido may be substituted or unsubstituted. [0108] An "N-sulfonamido" group refers to a "RSO2N(RA)-" group in which R and RA can be the same as R defined with respect to O-carboxy. A sulfonyl may be substituted or unsubstituted.
[0109] A "trihalomethanesulfonamido" group refers to an "X3CSO2N(R)-" group with X as halogen and R can be the same as defined with respect to O-carboxy. A trihalomethanesulfonamido may be substituted or unsubstituted.
[0110] An "O-carbamyl" group refers to a "-OC(=O)NRARB" group in which RA and RB can be the same as R defined with respect to O-carboxy. An O-carbamyl may be substituted or unsubstituted.
[0111] An "N-carbamyl" group refers to an "ROC(=O)NRA -" group in which R and RA can be the same as R defined with respect to O-carboxy. An N-carbamyl may be substituted or unsubstituted.
[0112] An "O-thiocarbamyl" group refers to a "-OC(=S)-NRARB" group in which RA and RB can be the same as R defined with respect to O-carboxy. An O-thiocarbamyl may be substituted or unsubstituted.
[0113] An "N-thiocarbamyl" group refers to an "ROC(=S)NRA-" group in which R and RA can be the same as R defined with respect to O-carboxy. An N-thiocarbamyl may be substituted or unsubstituted.
[0114] A "C-amido" group refers to a "-C(=O)NRARB" group in which RA and RB can be the same as R defined with respect to O-carboxy. A C-amido may be substituted or unsubstituted.
[0115] An "N-amido" group refers to a "RC(=O)NRA-" group in which R and RA can be the same as R defined with respect to O-carboxy. An N-amido may be substituted or unsubstituted.
[0116] An "ester" refers to a "-C(=O)OR" group in which R can be the same as defined with respect to O-carboxy. An ester may be substituted or unsubstituted.
[0117] A lower aminoalkyl refers to an amino group connected via a lower alkylene group. A lower aminoalkyl may be substituted or unsubstituted.
[0118] A lower alkoxyalkyl refers to an alkoxy group connected via a lower alkylene group. A lower alkoxyalkyl may be substituted or unsubstituted. [0119] Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well- known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999).
[0120] Where the numbers of substituents are not specified (e.g. haloalkyl), there may be one or more substituents present. For example "haloalkyl" may include one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" may include one or more of the same or different alkoxygroups containing one, two or three atoms.
[0121] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common Usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 1 1 :942-944 (1972)).
[0122] As employed herein, the following terms have their accepted meaning in the chemical literature.
AcOH acetic acid anhyd anhydrous aq aqueous
CDI 1 , 1 '-carbonyldiimidazole
DCM dichloromethane
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
Et2O diethyl ether
EtOAc ethyl acetate
EtOH ethanol
MeOH methanol
NH4OAc ammonium acetate
Pd/C palladium on activated carbon r.t. room temperature [0123] It is understood that, in any compound of this invention having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enatiomerically pure or be stereoisomeric mixtures. In addition it is understood that, in any compound of this invention having one or more double bond(s) generating geometrical isomers that can be defined as E or Z each double bond may independently be E or Z a mixture thereof. Likewise, all tautomeric forms are also intended to be included.
[0124] As used herein, "pharmaceutically acceptable salt" refers to a salt of a compound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Base-formed salts include, without limitation, ammonium salt (NH4 +); alkali metal, such as, without limitation, sodium or potassium, salts; alkaline earth, such as, without limitation, calcium or magnesium, salts; salts of organic bases such as, without limitation, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, without limitation, arginine and lysine. Useful acid-based salts include, without limitation, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, methanesulfonates, ethanesulfonates, p-toluenesulfonates and salicylates.
[0125] Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent of water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
[0126] As used herein, a "prodrug" refers to a compound that may not be pharmaceutically active but that is converted into an active drug upon in vivo administration. The prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have better solubility than the active parent drug in pharmaceutical compositions. An example, without limitation, of a prodrug would be a compound disclosed herein, which is administered as an ester (the "prodrug") to facilitate absorption through a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to a carboxylic acid (the active entity) once inside the cell where water-solubility is beneficial. A further example of a. prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized in vivo to release the active parent compound. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those skilled in the art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g. Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392)
[0127] As used herein, the term "complement" refers to a oligonucleotide or polynucleotide that hybridizes by base-pairing, adenine to tyrosine and guanine to cytosine, to another oligonucleotide.
[0128] As used herein, to "modulate" the activity of CBl means either to activate it, i.e., to increase its cellular function over the base level measured in the particular environment in which it is found, or deactivate it, i.e., decrease its cellular function to less than the measured base level in the environment in which it is found and/or render it unable to perform its cellular function at all, even in the presence of a natural binding partner. A natural binding partner is an endogenous molecule that is an agonist for the receptor.
[0129] As used herein, to "detect" changes in the activity of CBl or of a CBl sub-type refers to the process of analyzing the result of an experiment using whatever analytical techniques are best suited to the particular situation. In some cases simple visual observation may suffice, in other cases the use of a microscope, visual or UV light analyzer or specific protein assays may be required. The proper selection of analytical tools and techniques to detect changes in the activity of CB 1 or a CB 1 sub-type are well- known to those skilled in the art.
[0130] An "agonist" is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor). [0131] As used herein, "partial agonist" refers to a compound that has an affinity for a receptor but, unlike an agonist, when bound to the receptor it elicits only a fractional degree of the pharmacological response normally associated with the receptor even if a large number of receptors are occupied by the compound.
[0132] An "inverse agonist" is defined as a compound, which reduces, or suppresses the basal activity of a receptor, such that the compound is not technically an antagonist but, rather, is an agonist with negative intrinsic activity.
[0133] As used herein, "antagonist" refers to a compound that binds to a receptor to form a complex that does not give rise to any response, as if the receptor were unoccupied. An antagonist attenuates the action of an agonist on a receptor. An antagonist may bind reversibly or irreversibly, effectively eliminating the activity of the receptor permanently or at least until the antagonist is metabolized or dissociates or is otherwise removed by a physical or biological process.
[0134] As used herein, a "subject" refers to an animal that is the object of treatment, observation or experiment. "Animal" includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. "Mammal" includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
[0135] As used herein, a "patient" refers to a subject that is being treated in order to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.
[0136] As used herein, the terms "treating," "treatment," "therapeutic," or "therapy" do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment or therapy. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well-being or appearance.
[0137] As used herein, a "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.
[0138] As used herein, a "diluent" refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
[0139] As used herein, an "excipient" refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A "diluent" is a type of excipient.
[0140] As used herein "adjunctive therapy" refers to the administration of two pharmaceutical compositions to achieve a beneficial therapeutic effect relative to the therapeutic effect obtained by administering either of the pharmaceutical compositions alone. For example, without limitation, in some embodiments, the administration of a cannabinoid antagonist or inverse agonist and another pharmaceutical composition may ameliorate or inhibit an adverse effect associated with an antipsychotic or other medication such as, preventing weight gain associated with the use of an antipsychotic, suppressing the appetite of a subject taking a therapeutic compound, ameliorate or inhibit a negative symptom of schizophrenia in a subject taking an antipsychotic, ameliorate or inhibit a loss of cognition or improve cognition in a subject taking a therapeutic compound, ameliorate or inhibit an adverse effect associated with a compound used to treat Parkinson's disease, ameliorate or inhibit the propensity for gambling associated with a compound used to treat Parkinson's disease, ameliorate or inhibit the dyskinesia associated with a compound used to treat Parkinson's disease, ameliorate or inhibit the psychosis associated with a compound used to treat Parkinson's disease, or shorten or prevent the need for a drug holiday in a subject taking a compound used to treat Parkinson's disease. Compounds
[0141] One embodiment described herein relates to a compound of formula (I):
Figure imgf000032_0001
(I) as a single isomer, a mixture of isomers, a racemic mixture of isomers, pharmaceutically acceptable salt, a solvate, metabolite or polymorph thereof, wherein:
X can be selected from the group consisting of O, S, S=O, SO2, NR1, NC≡N, NC(=Z)R1, NC(=Z)NR,aR,b, CR,aR,b, C=O, C=CR1 aR,b, and SiR,aR1 b;
Y can be -N(R2) — or -C(R1 R2) — ; the symbol — represents a single or double bond, where when — is a double bond, R2 is absent;
A can be selected from the group consisting of C3-C12alkyl, C4-C12alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkynyl)alkyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, halogen, -NR1 aR1 b, -N=CR1 aR1b, sulfenyl, sulfinyl, sulfonyl, and - (CH2)0-4-C(=Z)-OR1 , wherein any member of said group can be substituted or unsubstituted;
B, C, D, E, F, G and I can be separately selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heteroalicyclyl, (heteroalicyclyl)alkyl, halogen, hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, -CN, -C(=Z)R1, -C(=Z)OR,, -C(=Z)NR,aR1 b, -C(=Z)N(R,)NR,aR1 b, -C(=Z)N(R,)N(R,)C(=Z)R,, -C(R1)=NR1 , - NR1 aR,b, -N=CR,aR1 b, -N(R,)-C(=Z)R,, -N(R,)-C(=Z)NR1 aR1 b, -S(O)NR1 aR1 b, - S(O)2NR1 aR,b, -N(R1)-S(=O)R1, -N(R,)-S(=O)2R1, -OR1, -SR1, and -OC(=Z)R1, wherein any member of said group can be substituted or unsubstituted except for hydrogen; H can be selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heteroalicyclyl; (heteroalicyclyl)alkyl, halogen, hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, -CN, -CC=Z)R1, -C(=Z)0R1, -C(=Z)NR,aR,b, -C(=Z)N(R1)NR,aR,b, -C(=Z)N(R,)N(R,)C(=Z)R,, -C(R1)=NR1, -NR18R1 b, -N=CR1 aR1 b, -N(R,)-C(=Z)R,, -N(R0-C(=Z)NR,.R1 b, -S(O)NR1aR1b, -S(O)2NR1aR1 b, -N(R1J-S(K))R1, -N(R1)-S(=O)2R1, -OR1 , -SR1, and -OC(=Z)R1, wherein any member of said group can be substituted or unsubstituted;
Z can be O (oxygen) or S (sulfur);
R]1 R1 a and R1 b can each independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalicyclyl, (heteroalicyclyl)alkyl, -(CH2)O-7-OR3, - (CH2)O-7-SR3, -(CH2)O-7-NR33R31,, haloalkyl, -C(=Z)R3, -C(=Z)OR3, and -C(=Z)NR3aR3b. wherein any member of said group can be substituted or unsubstituted except for hydrogen; or R1 a and R1 b can be taken together to form an unsubstituted or substituted heteroalicyclyl having 2 to 9 carbon atoms or an unsubstituted or substituted carbocyclyl having 3 to 9 carbon atoms;
R2 can be absent or is selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl, wherein any member of said group can be substituted or unsubstituted except for hydrogen;
R3, R3a, and R3b can each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, and (heteroalicyclyl)alkyl, wherein any member of said group can be substituted or unsubstituted except for hydrogen;
[0142] In some embodiments, A cannot be a substituted or unsubstituted piperazine.
[0143] In other embodiments, H is not selected from -CF3, phenyl, -OS(O)2-
CF3, methyl, -CN, halogen, and
Figure imgf000033_0001
when A is a substituted or unsubstituted heteroalicyclyl containing at least one nitrogen, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or -NR1 aR1 b.
[0144] In still other embodiments, H cannot be halogen when A is substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, halogen, and substituted or unsubstituted sulfenyl; X is -NR1 , wherein R1 is hydrogen; and Y is -N(R2) — , wherein — is a double bond and R2 is absent.
[0145] In yet still other embodiments, when X is O or -NR11 wherein R1 is methyl and Y is -N(R2) —, wherein — is a double bond and R2 is absent then H cannot be -C(=Z)OR1 , wherein R1 is hydrogen, methyl, or ethyl.
[0146] In one embodiments, when A is halogen, Y is -N(R2) — , wherein — is a double bond and R2 is absent, and X is S then F cannot be -S(O)2NR ιaR1 b, wherein R1 a and R1 b are both hydrogen.
[0147] In some embodiments, A can be selected from C3-C12alkyl, C4- C12alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclyl, halogen, -NR13RH,, and -(CH2)0-4- C(=Z)-ORι; X can be S; Y can be -N(R2) — wherein the symbol — represents a double bond and R2 does not exist; and B can be -C(=Z)NR1aR1 b, wherein R1a is an optionally substituted cycloalkyl, cycloalkenyl, or cycloalkynyl. In other embodiments, A can be selected from C3-C12alkyl, C4-C12alkyl, halogen, and -(CH2)0-4-C(=Z)-ORι; X can be S; Y can be -N(R2) — wherein the symbol = represents a double bond and R2 does not exist; and B can be -C(=Z)NR1 aR1 b, wherein R1 a is an optionally substituted cycloalkyl, cycloalkenyl, or cycloalkynyl. In still other embodiments, A can be selected from aryl (e.g., unsubstituted or substituted phenyl) or a heteroaryl (e.g., thiophene and pyridine); X can be S; Y can be -N(R2) — wherein the symbol = represents a double bond and R2 does not exist; and B can be -C(=Z)NR1 aR1 b, wherein R1 a is an optionally substituted cycloalkyl, cycloalkenyl, or cycloalkynyl. In yet still other embodiments, A can be selected from cycloalkyl (e.g., cyclohexyl), a heteroalicyclyl (e.g., piperidine), or - NR1 aR1 b group; X can be S; Y can be -N(R2) — wherein the symbol — represents a double bond and R2 does not exist; and B can be -C(=Z)NR1 aR1 b, wherein R1 a is an optionally substituted cycloalkyl, cycloalkenyl, or cycloalkynyl. In an embodiment, the optionally substituted cycloalkyl, cycloalkenyl, or cycloalkynyl is selected from: and and in some
Figure imgf000035_0002
Figure imgf000035_0003
of the embodiments, n can be 1 or 2.
[0148] In some embodiments, A can be selected from C3-C12alkyl, C4- C12alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclyl, halogen, -NR1 aR1 b, and -(CH2)0-4- C(=Z)-OR1 ; X can be S; Y can be -N(R2) — wherein the symbol ^= represents a double bond and R2 does not exist; and B can be -C(=Z)NR1aR1b, wherein R1a is an optionally substituted aryl or aralkyl. In other embodiments, A can be selected from C3- C12alkyl, C4-C12alkyl, halogen, and -(CH2)0-4-C(=Z)-OR!; X can be S; Y can be - N(R2) — wherein the symbol — represents a double bond and R2 does not exist; and B can be -C(=Z)NR1 aR1 b, wherein R1 a is an optionally substituted aryl or aralkyl. In still other embodiments, A can be selected from aryl (e.g., unsubstituted or substituted phenyl) or a heteroaryl (e.g., thiophene and pyridine); X can be S; Y can be -N(R2) — wherein the symbol — represents a double bond and R2 does not exist; and B can be -C(=Z)NR1 aR1 b, wherein R1 a is an optionally substituted aryl or aralkyl. In yet still other embodiments, A can be selected from cycloalkyl (e.g., cyclohexyl), a heteroalicyclyl (e.g., piperidine), or -NR1 aR1 b group; X can be S; Y can be -N(R2) — wherein the symbol — represents a double bond and R2 does not exist; and B can be -C(=Z)NR1aR1b, wherein R13 is an optionally substituted aryl or aralkyl. In an embodiment, the optionally
substituted aryl or aralkyl can be selected from:
Figure imgf000035_0004
Figure imgf000035_0001
,wherein Q can be -N(R4)-, oxygen or sulfur; and R4 can be hydrogen or C1-4alkyl, and in some of the embodiments, n can be 1 or 2. [0149] In some embodiments, A can be selected from C3-C12alkyl, C4- C12alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclyl, halogen, -NR13R1 b,, and -(CH2)0-4- C(=Z)-OR1 ; X can be S; Y can be -N(R2) — wherein the symbol ^= represents a double bond and R2 does not exist; and B can be -C(=Z)NR1 aR1 b, wherein R1 a is an optionally substituted heteroalicyclyl or (heteroalicyclyl)alkyl. In other embodiments, A can be selected from C3-C12alkyl, C4-C12alkyl, halogen, and -(CH2)0-4-C(=Z)-OR1 ; X can be S; Y can be -N(R2) — wherein the symbol — represents a double bond and R2 does not exist; and B can be -C(=Z)NR1 aR1 b, wherein R1 a is an optionally substituted heteroalicyclyl or (heteroalicyclyl)alkyl. In still other embodiments, A can be selected from aryl (e.g., unsubstituted or substituted phenyl) or a heteroaryl (e.g., thiophene and pyridine); X can be S; Y can be -N(R2) — wherein the symbol — represents a double bond and R2 does not exist; and B can be -C(=Z)NR1 aR1 b, wherein Rj3 is an optionally substituted heteroalicyclyl or (heteroalicyclyl)alkyl. In yet still other embodiments, A can be selected from cycloalkyl (e.g., cyclohexyl), a heteroalicyclyl (e.g., piperidine), or - NR1 aR1 b group; X can be S; Y can be -N(R2) — wherein the symbol = represents a double bond and R2 does not exist; and B can be -C(=Z)NR1 aR1 b, wherein R1 a is an optionally substituted heteroalicyclyl or (heteroalicyclyl)alkyl. In an embodiment, the optionally substituted heteroalicyclyl or (heteroalicyclyl)alkyl can be selected from:
Figure imgf000036_0001
, and in some of the embodiments, n can be 1 or 2.
[0150] In some embodiments, A can be selected from C3-C12alkyl, C4- C12alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclyl, halogen, -NR1 aR1 b,^ and -(CH2)0-4- C(=Z)-OR1; X can be S; Y can be -N(R2) — wherein the symbol ^= represents a double bond and R2 does not exist; and B can be -C(=Z)NR1 aR1 b, wherein R1 a is an optionally substituted heteroaryl or heteroaralkyl. In other embodiments, A can be selected from C3-C12alkyl, C4-C12alkyl, halogen, and -(CH2)0.4-C(=Z)-OR, ; X can be S; Y can be -N(R2) — wherein the symbol — represents a double bond and R2 does not exist; and B can be -C(=Z)NR1 aR1 b, wherein R1 a is an optionally substituted heteroaryl or heteroaralkyl. In still other embodiments, A can be selected from aryl (e.g., unsubstituted or substituted phenyl) or a heteroaryl (e.g., thiophene and pyridine); X can be S; Y can be -N(R2) ^= wherein the symbol =^= represents a double bond and R2 does not exist; and B can be -C(=Z)NRιaR1 b, wherein R1 a is an optionally substituted heteroaryl or heteroaralkyl. In yet still other embodiments, A can be selected from cycloalkyl (e.g., cyclohexyl), a heteroalicyclyl (e.g., piperidine), or -NR1 aR1 b group; X can be S; Y can be -N(R2) ^^ wherein the symbol :r^: represents a double bond and R2 does not exist; and B can be -C(=Z)NR1 aR1 b, wherein R13 is an optionally substituted heteroaryl or heteroaralkyl. In an embodiment, the optionally substituted heteroaralkyl is from the
group consisting of:
Figure imgf000037_0002
Figure imgf000037_0004
, and
Figure imgf000037_0003
, wherein Q can be oxygen or sulfur, and in some of the embodiments, n can be 1 or 2. In certain other embodiments,
the optionally substituted heteroaralkyl can be
Figure imgf000037_0001
, wherein Q can be oxygen or sulfur, and in some of the embodiments, n can be 1 or 2. [0151] In an embodiment, X can be S; Y can be -N(R2)^= wherein the symbol — represents a double bond and R2 does not exist; and H can be -C(=Z)NR1aR1 b, wherein R1 a is selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalicyclyl, (heteroalicyclyl)alkyl, and haloalkyl, wherein any member of said group can be substituted or unsubstituted, and R^ is hydrogen. In some embodiments, A can be an aryl or a heteroaryl group; X can be S; Y can be -N(R2) =-=^ wherein the symbol =-÷ represents a double bond and R2 does not exist; and H can be -C(-Z)NR1 aR1b, wherein R1 a is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heteroalicyclyl, heteroaralkyl, and (heteroalicyclyl)alkyl. In an embodiment, A can be an aryl or a heteroaryl group; X can be S; Y can be -N(R2) — wherein the symbol =-^= represents a double bond and R2 does not exist; H can be -C(=Z)NR1 aR1 b, wherein R1 a is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heteroalicyclyl, heteroaralkyl, and (heteroalicyclyl)alkyl; and R1b can be hydrogen. In some embodiments, A can be an aryl or a heteroaryl group; X can be S; Y can be -N(R2) =^~= wherein the symbol ^^ represents a double bond and R2 does not exist; and H can be -C(=Z)NR1NR1 aR1 b, wherein R1 a is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heteroalicyclyl, heteroaralkyl, and (heteroalicyclyl)alkyl. In some embodiments, A can be an aryl or a heteroaryl group; X can be S; Y can be -N(R2) ^^ wherein the symbol ^^ represents a double bond and R2 does not exist; H can be
Figure imgf000038_0001
wherein Rιa is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heteroalicyclyl, heteroaralkyl, and (heteroalicyclyl)alkyl; and R1 and R^ can be hydrogen.
[0152] Another embodiment described herein relates to a compound of Formula (II):
Figure imgf000038_0002
as a single isomer, a mixture of isomers, a racemic mixture of isomers, or a pharmaceutically acceptable salt, solvate, metabolite, prodrug, or polymorph thereof.
[0153] X' can be selected from the group consisting of O, S, S=O, SO2, NR' i, NC≡N, NC(=Z')R'1, NC(=Z')NR'1aR'1b, CR'1aR'1b, C=O, C=CR'1aR'1b, and SiR'1aR'1b. Y' can be -N(R'2) — or -C(R'1R'2) — where the symbol — represents a single or double bond, where when =-=-= is a double bond, R'2 is absent. A' can be selected from the group consisting of halogen, -NR'1aR'1b, and -N=CR'ιaR'1b; mono-substituted, poly- substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkynyl)alkyl, aralkyl, heteroaralkyl, and (heteroalicycyl)alkyl; and mono- substituted, poly-substituted or unsubstituted -variants of the following residues: cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, sulfenyl, sulfinyl, sulfonyl, and -(CH2)0-4-C(=Z')-OR'1; provided that A' cannot be a substituted or unsubstituted piperazine.
[0154] Ar' i and Ar'2 can be separately selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more radical selected from the group consisting of halogen, hydroxyl, nitro, -CN, -C(=Z')R'1, -C(=Z')OR' ι, -C(=Z')NR' laR'1b, -C(=Z')N(R' ,)NR'1 aR'1b, -C(=Z')N(R' ,)N(R'1)C(=Z')R' , , - C(R'1)=NR'1, -NR'1aR'1b, -N=CR'1aR'1b, -N(R'1)-C(=Z')R'1, -NCR'1)-C(=Z')NR' iaR' 1b - S(O)NR' laR'1b, -S(O)2NR' 1aR'.b, -N(R'1)-S(=O)R'1, -N(R'1)-S(=O)2R'1, -OR'1, -SR'1, and -OC(=Z')R'1; mono-substituted, poly-substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, (heteroalicycyl)alkyl, haloalkyl, and haloalkoxy; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, sulfenyl, sulfinyl, and sulfonyl; provided that at least one of Ar, and Ar2 is an optionally substituted heteroaryl.
[0155] D' can be part of Ar', and is selected from the group consisting of CR'1, NR'2, S, and O. B' can be attached to Ar' i on the carbon adjacent to D' and separated from Y' by three atoms, wherein one of the three atoms is D', and is selected from the group consisting of halogen, hydroxyl, nitro, -CN, -C(=Z')R'ι, -C(=Z')OR'1, -C(=Z')NR'ι.R'1b, -C(=Z')N(R'1)NR'laR'1b, -C(=Z')N(R'1)N(R'1)C(=Z')R'1, - C(R'1)=NR' 1 ; -NR'1aR'1b, -N=CR'1 aR' ib, -N(R'1)-C(=Z')R'1, -N(R'1)-C(=Z')NR'1aR'1b, - S(O)NR'laR'1b, -S(O)2NR'1 aR'lb, -N(R'1)-S(=O)R'1, -N(R'1)-S(O)2R'1, -OR'1, -SR'1, and -OC(=Z')R'1; mono-substituted, poly-substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, (heteroalicycyl)alkyl, haloalkyl, and haloalkoxy; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, sulfenyl, sulfinyl, and sulfonyl.
[0156] R'1, R'1a and R'1b can be each independently selected from the group consisting of hydrogen, halogen, -C(=Z')R'3, -C(=Z')OR'3, and -C(=Z')NR'3aR'3b; mono- substituted, poly-substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, (heteroalicycyl)alkyl, and haloalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, -(CH2)0-7-OR'3, -(CH2)0-7-SR'3, and -(CH2)0-7-NR'3aR'3b; or R'la and R'1b can be taken together to form an unsubstituted or substituted heteroalicyclyl having 2 to 9 carbon atoms or an unsubstituted or substituted carbocyclyl having 3 to 9 carbon atoms. R'2 can be absent or is selected from the group consisting of hydrogen; mono-substituted, poly-substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl, and alkynyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl. R'3j R'3a, and R'3b can be each independently selected from the group consisting of: hydrogen; mono-substituted, poly-substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, and (heteroalicycyl)alkyl; and mono-substituted, poly- substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heteroalicyclyl. Z' can be O or S. [0157] In some embodiments, B' is not selected from -CF3, phenyl, -OS(O)2-
CF3, methyl, -CN, halogen, and
Figure imgf000041_0001
o when A' is a substituted or unsubstituted heteroalicyclyl containing at least one nitrogen, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or -NR1 a-R1 b--
[0158] In an embodiment, B' is not halogen when A' is substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, halogen, or substituted or unsubstituted sulfenyl; X' is -NH; and Y' is -N=.
[0159] In some embodiments, when X' is O or -NCH3 and Y' is -N=, then B' cannot be -C(=Z')OH, -C(=Z')Me or -C(=Z')Et.
[0160] In an embodiment, when X' is CRιa R1 b' and A' is phenyl, then B' cannot be NH2. In some embodiments, when both Arr and Ar2- are pyridinyl rings, then X' cannot be NRp in which R1' is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, trihalomethyl and hydroxyalkyl.
[0161] In an embodiments, when X' is S or NRp, wherein Rp is hydrogen or alkyl, then A' cannot be a phenyl ring substituted at the O2H or Cθ2(alkyl). In some embodiments, when X' is CR1a R1 b' R1a- and R1 b- cannot be a cycloalkyl, cycloalkenyl or piperazine rin nnot be taken together to a form a cycloalkyl, cycloalkenyl or piperazine ring.
[0162] In an embodiment, when X' is NRr, wherein Ry is hydrogen, - C(=0)H or -C(=O)CF3, then A1 cannot be a phenyl ring substituted at the para-position with a nitro group. In some embodiments, when X' is NR1- and A' is aryl, then B' cannot be alkyl, alkoxy, hydroxy, or an acid salt thereof.
[0163] In an embodiment, when X' is NRr and Y' is -N(R2 ) r^:, wherein =÷ represents a single bond, then B' cannot be alkyl or alkoxy.
[0164] Some embodiments disclosed herein describe a compound of Formula (II) wherein X' can be S; and A' can be selected from a mono-substituted, poly- substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl and alkynyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl. In an embodiment, A' can be selected from a mono-substituted, poly-substituted, or unsubstituted, straight or branched alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, aryl, heteroaryl and heteroalicyclyl. In an embodiment, A' can be a mono- substituted, poly-substituted, or unsubstituted, straight or branched alkyl; or mono- substituted, poly-substituted or unsubstituted aryl. In an embodiment, A' can be a mono- substituted, poly-substituted, or unsubstituted, straight or branched alkyl; or mono- substituted, poly-substituted or unsubstituted aryl; X' can be S; and -N(R2 ) r^=, where =÷ is a double bond; and R2- is absent. In some embodiments, B' can be -C(=Z)NR1 a'R1 b\ In other embodiments, B' can be -C(=Z')R1-. In still other embodiments, B' can be -S(O)2NR1 a-R1 b-- In an embodiment, when B' is -C(=Z')NR1 a-R1 b- or -C(=Z')Rr, Z' can be O (oxygen). In some embodiments, Rp1 R13 1 and R1 b3- can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl and (heteroalicyclyl)alkyl. In an embodiment, Rp and R13' can be independently selected from alkyl, cycloalkyl, heteroaryl, heteroalicyclyl and heteroaralkyl; and Ru,1 is hydrogen. In some embodiments, Y' can be -N(R2-) =^÷, where — is a double bond; and R2- is absent. In an embodiment, A' can be selected from a mono-substituted, poly-substituted, or unsubstituted, straight or branched alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, aryl, heteroaryl and heteroalicyclyl; B' can be -C(=Z)NR1 a-R1 b-; R1a- can be independently selected from alkyl, cycloalkyl, heteroalicyclyl and heteroaralkyl; R1b' is hydrogen; Y' can be -N(R2-) =^, where ^= is a double bond; and R2- is absent. In an embodiment, A' can be selected from a mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, aryl, heteroaryl and heteroalicyclyl; B' can be -C(=Z')NR1 a-R1 b-; R1 a- can be independently selected from alkyl, cycloalkyl, heteroalicyclyl and heteroaralkyl; R^- is hydrogen; Y' can be -N(R2-) —. where ^= is a double bond; and R2- is absent. In still another embodiment, A' can be selected from a mono-substituted, poly-substituted, or unsubstituted, straight or branched alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, aryl, heteroaryl and heteroalicyclyl; B' can be -C(=Z')Rp; Rr can be alkyl; Y' can be -N(R2-)=^=, where ^=-= is a double bond; and R2- is absent. In yet still another embodiment, A' can be selected from a mono-substituted, poly-substituted, or unsubstituted, straight or branched alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, aryl, heteroaryl and heteroalicyclyl; B' can be -S(O)2NR18 R1 b'; R1 a' can be alkyl or heteroalicyclyl; R^- is hydrogen; Y' can be -N(R2-)—, where =^=-= is a double bond; and R2- is absent.
Synthesis
[0165] General synthetic routes to the compounds of this invention are shown in Schemes 1-22. The routes shown are illustrative only and are not intended, nor are they to be construed, to limit the scope of this invention in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed synthesis and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of this invention.
6 %
Figure imgf000044_0001
[0166] In Scheme 1, R!a, R1b, and A are as defined above for Formula (I).
Scheme 2
Figure imgf000044_0002
[0167] In Scheme 2, R1a and R1b are as defined above for Formula (I). R3 and R4 can be selected from the same group of substituents as R1a and R1b as defined above for Formula (I). Scheme 3
Figure imgf000045_0001
[0168] In Scheme 3, R13, R1b, and A are as defined above for Formula (I). R3 and R4 can be selected from the same group of substituents as R1 a and R1 b as defined above for Formula (I).
Scheme 4
Figure imgf000046_0001
[0169] In Scheme 4, R1 a, R1 b,, and A are as defined above for Formula (I). R3 and R4 can be selected from the same group of substituents as R1 a and R1 b as defined above for Formula (I).
Scheme 5
Figure imgf000046_0002
[0170] In Scheme 5, R1a, R1 b,, and A are as defined above for Formula (I). cheme 6:
Figure imgf000047_0001
DMF
Figure imgf000047_0002
Figure imgf000047_0003
Scheme 7a:
Figure imgf000047_0004
Scheme 7b:
THF
AfγNθ2 + Cs2CO3, DMF
Figure imgf000048_0001
quant
Figure imgf000048_0002
Figure imgf000048_0003
CDI1THF DCM
Figure imgf000048_0004
Figure imgf000048_0005
Figure imgf000048_0006
[0171] In Schemes 7a and 7b, R1 a, R1 b> and A are as defined above for Formula (I), and X is a halogen. R3 and R4 can be selected from the same group of substituents as R1 a and R^ as defined above for Formula (I).
Scheme 8a:
F
Figure imgf000049_0001
Scheme 8b:
Figure imgf000050_0001
[0172] In Schemes 8a and 8b, R1a, R1 b, and A are as defined above for Formula (I), and X is a halogen. R3 and R4 can be selected from the same group of substituents as R1 a and R1 b as defined above for Formula (I).
Scheme 9:
Figure imgf000051_0001
[0173] In Scheme 9, R1 a, R1 b, and A are as defined above for Formula (I), and X is a halogen. . R3 and R4 can be selected from the same group of substituents as R1a and R1 b as defined above for Formula (I).
Scheme 10:
THF
Figure imgf000052_0001
[0174] In Scheme 10, R1 a, R1 b, and A are as defined above for Formula (I), and X is a halogen. R3 and R4 can be selected from the same group of substituents as R1 a and R1 b as defined above for Formula (I).
Scheme 11
Figure imgf000052_0002
[0175] In Scheme 11, R'1a and A' are as defined above for Formula (II). R'4) R' 5, and R\ are appropriate radicals selected to obtain the desired A' group. By appropriate selection of R'1 a, R'4, R's, and R'6 compounds 2a, 5a, 6a, 10a, 16a, 26a, 28a - 31a, 40a, 44a, 46a, 48a, 51a, and 58a can be prepared according to Scheme 1 1. For example, compound 2a can be prepared by using «-butyl amine as H2N-R' |a and 2-pyridyl zinc bromide as R'6ZnX. Suitable heterocyclic 2-mercaptosubstituted carboxylic acids can be prepared as described in Blank et al, J. Med. Chem. 1911 , 20, 572-576; Sen et al, Indian J Chem B Og, 1981, 2OB, 275-278, and Solomon et al, Heterocycles, 1987, 26, 651-674), all of which are incorporated herein by reference in their entirety.
Scheme 12
Figure imgf000053_0001
[0176] In Scheme 12, R' ιa and A' are as defined above for Formula (II). R'4, R's, and R\ are appropriate radicals selected to obtain the desired A' group. By appropriate selection of R'1a, R'4, R'5, and R'6 compounds 13a-16a, 18a, 36a-42a, 54a, 55a, 57a-60a can be prepared according to Scheme 12. For example, compound 13 can be prepared by using cyclohexyl amine a H2N-R'1a and p-Cl-phenyl zinc iodide as R' 6ZnX. Other suitable heterocyclic 2-chloro carboxylic acids include commercially available 2-chloro nicotinic acid, 3-chloro-4-pyridine carboxylic acid, 4-chloronicotinic acid and 3-chloro-2-pyrazine carboxylic acid and those synthesised by methods described in Bredereck et al. Chem. Ber, 1962, 95, 956-963 and Krasovskiy et al, Angew. Chem. Int. Ed., 2006, 45, 2958-2961, both of which are incorporated herein by reference in their entirety. Scheme 13
Figure imgf000054_0001
[0177] Scheme 13 illustrates one method of obtaining compound 7a. By employing other optionally substituted iodo-or bromo benzoheterophenones followed by the appropriate amine in the amide coupling step, compounds Ia, 3a, 8a, 9a, 1 1a, 19a- 25a, 27a, 32a- 34a, 43a, 45a, 49a, 50a, 52a, 53a, 61a, 62a, 82a-84a can be obtained using a similar method. Suitable iodo-or bromo benzoheterophenones can be obtained commercially, synthesised by the methods described in Reynolds et al., Tetrahedron, 2001, 57, 7765-7770, Liu et al., Org. Lett. 2006, 8, 617-619 or by generation of zinc reagents from dibromo- or diiodo heterocycles followed by reaction with the appropriately substituted benzoyl chloride (Knochel et al., Angew. Chem. 2006). AU of the foregoing references are incorporated herein by reference in their entirety.
Scheme 14
Figure imgf000054_0002
[0178] In Scheme 14, R'1a and A' are as defined above for Formula (II). R'4, R'5) and R'6 are appropriate radicals selected to obtain the desired A' group. By appropriate selection of R'1a, R'4, R'5, and R'6 compounds 4a, 12a, 17a, 47a, 56a, 63a, and 84a can be prepared according to Scheme 14 by using the appropriate heterocyclic 2- mercaptosubstituted carboxylic acids followed by the appropriate alkyl or aryl metal halide or amine and the desired amine in the last step. Scheme 15
Figure imgf000055_0001
[0179] In Scheme 15, R'ιa and A' are as defined above for Formula (II). R'4, R'5, and R'6 are appropriate radicals selected to obtain the desired A' group. By appropriate selection of R'1a, R'4, R'5, and R'6 compounds 64a, 68a, 72a, 78a, 88a, 92a, and 96a can be prepared by using the appropriate heterocycle, amine, metal reagent/amine and amine. Further relevant synthetic methods can be found in Thompson et al. , J. Org. Chem. 1988, 53, 2052-2055, which is incorporated herein by reference in its entirety.
Scheme 16
Figure imgf000055_0002
[0180] In Scheme 16, R'|a and A' are as defined above for Formula (II). R'4, R'5, and R'6 are appropriate radicals selected to obtain the desired A' group. By appropriate selection of R'1a, R'4, R'5, and R'6 compounds 64a-74a, 85a 86a, 88a-91a, 93a- 95a, 97a -101a, and 104a can be prepared by using appropriate pyridines obtained either commercially or synthesized by magnesiation of heterocycles via selective deprotonation as described in Liu et al, Org. Lett. 2006, 8, 617-619, incorporated herein by reference in its entirety, combined with the above mentioned 2-mercaptosubstituted carboxylic acids/esters followed by the appropriate reagents in the reaction sequence. In addition, compounds 80a, 81a, 103a, and 105a can be prepared according to Scheme 16 using pyrimidines obtained as described in Krasovskiy et al., Angew. Chem. Int. Ed. 2006, 45, 2958-2961, which is incorporated herein by reference in its entirety.
Scheme 17
Figure imgf000056_0001
[0181] Scheme 17 illustrates one method of obtaining compound 102a. Other pyrazines such as compound 87a can be obtained in a similar fashion following the methods described in PIe et al, J. Org. Chem. 1995, 60, 3781-3786, which is incorporated herein by reference in its entirety. Pyrazines containing an amide side chain instead of sulfonamide side chain can be obtained by reacting the metalated species with a variety of alky 1 isocyanates.
Scheme 18 i. 2 equiv n-Buϋ, 2 equiv TMEDA, cyclohexane ii. 1 equiv ACN
Figure imgf000056_0003
Figure imgf000056_0002
[0182] In Scheme 18, Ar' \, Ar^, B', and D' are as described above for Formula (II). A' is an aryl or heteroaryl. X is Br, Cl, F, OTf, or OTs. Scheme 18 proceeds by dilithiation of arylthiols or heteroaryl thiols as described in Figuly et al, J Am. Chem. Soc, 1989, ///, 654, Block et al, J. Am. Chem. Soc, 1989, 111, 658, and Smith et al, J. Am. Chem. Soc, 1989, / / /, 665, which are incorporated herein by reference in their entirety. Upon addition of aromatic or a heteroaromatic nitriles as described in Brieaddy and Donaldson, J. Heterocyclic Chem., 1995, 32, 1683 and Katritzky et al, Chem. Heterocyclic Compd. Eng. Trans., 2002, 55, 156, which are incorporated herein by reference in their entirety, the dilithioketimine intermediate is obtained. This intermediate can be in turn treated with suitable ø-dihaloaryls or o- dihaloheteroaryls to obtain the thiazepine product. Specifically, but not exclusively, π- deficient o-dihaloazaarenes constitute outstanding substrates for the reactions with ketimines, providing the thiazepine products in high yield simply by adding 1 equiv of a neat π-deficient o-dihaloazaarene to a reaction mixture containing a premade ketimine.
Scheme 19
or or MgCI
Figure imgf000057_0001
Figure imgf000057_0002
[0183] In Scheme 19, Ar'2 and D' are as described above for Formula (II). A' is an aryl or heteroaryl. X is Br, Cl, F, OTf, or OTs. Ar' i is a π-deficient azaaryl. E' is an electrophile including, but not limited to, isocyanates, acid chlorides, nitriles, tosyl cyanide or 1-cyanoimidazole, aldehydes or ketones, halogens or organic halides, carbon dioxide, Weinreb amides, tosyl azide, zinc chloride, tin chloride and trimethyl borate.
[0184] On the left side of Scheme 19, an electrophile is added to a π-deficient- azaaryl-containing thiazepines by means of α-lithiation (Queguiner et al, Adv. Heterocycl. Chem. 1991, 52, 187, Gros et al, J. Org. Chem. 2002, 67, 234, Smith et al, Org. Lett.
2005, 7, 5457, incorporated by reference in its entirety), α-zincation (Kondo et al, J. Am. Chem. Soc. 1999, 121, 3539, Imahori et al, Chem. Commun. 2001, 2450, incorporated by reference in its entirety) or α-magnesiation (Krasovskiy et al, Angew. Chem Int. Ed,
2006, 45, 2958, incorporated by reference in its entirety). The organometallic intermediates thus generated can be treated with convenient electrophiles to give substituted thiazepines. In the cases where such substitution tactics afford a mixture of two or more regioisomeric products, the products can be easily separated from each other by one of the standard methods known in the art. [0185] On the right side of Scheme 19, an electrophile can be added to a π- deficient σ-dihaloazaryl by a similar method as described above. The resulting heteroaryl can be in turn be reacted with a ketimine to produce the desired thiazepine product. Convenient substituents that can be introduced on the azaryl include, but are not limited to, nitrile or ester moieties. Introduction of such electron withdrawing groups on the rings of azaryls improves their reactivity towards ketimines. Also, at a later stage, these groups can be easily converted to other pertinent functional groups.
Scheme 20
Figure imgf000058_0001
[0186] In Scheme 20, Ar' i, Ar'2, B', and D' are as described above for Formula (II). A' is an alkyl, aryl, heteroaryl, or amino. X is Br, Cl, F, OTf, or OTs. Scheme 20 provides alkyl and amino substituted thiazepines by addition of 2 equiv of alkyllithiums, aryllithiums, heteroaryllithiums or 2 equiv of lithium amides to 2- cyanoarene thiols, giving rise to a ketimine, which can be reacted with o-dihaloaryl (or heteroaryl) to produce the desired thiazepine product. The requisite 2-cyanoaryl thiols can be prepared for example by heating a 2-cyanobromoaryl (or heteroaryl) with mercaptoacetic ethyl ester in the presence of potassium /-butoxide and liquid ammonia (Brugelmans et al, Tetrahedron, 1983, 39, 4153, which is incorporated herein by reference in its entirety).
Scheme 21
Figure imgf000059_0001
[0187] In Scheme 21, Ar'(, Ar'2, B', and D' are as described above for Formula (II). A' is an alkyl, amino, aryl, or heteroaryl. X is I, Br, or Cl. Scheme 21 provides thiazepines by hydrolysis of ketimines followed by reacting the resulting ketoaryl thiol with a suitable o-aminohaloaryl (or heteroaryl). The cyclization to produce the thiazepines can be carried under copper catalysis (Bates et al, Org. Lett., 2002, 4, 2803, Kwong et al, Org. Lett., 2002, 4, 3517, which is incorporated herein by reference in its entirety) using a ketone and ø-aminoiodoaryl (or heteroaryl); or under palladium catalysis (Li, J. Org. Chem., 2001, 66, 8677, Li, Angew. Chem Int. Ed, 2001, 40, 1513, which is incorporated herein by reference in its entirety) using a ketone and o- aminobromo(chloro or bromo)aryl (or heteroaryl). The ketones can also be prepared by other methods known in the art, for example by addition of organolithiums to mercaptoaryl(or heteroaryl)carboxylic acids (Bull. Chem. Soc. Jpn. 2001, 77, 2095, which is incorporated herein by reference in its entirety) or by thermal rearrangement of thiocarbamate esters followed base hydrolysis (Tremont et al, J. Med. Chem., 2005, 18, 5837, which is incorporated herein by reference in its entirety). Scheme 22
Figure imgf000060_0001
[0188] In Scheme 22, Ar'i, Ar'2, B', and D' are as described above for Formula (II). A' is an alkyl, amino, aryl, or heteroaryl. X is I, Br, or Cl. M is a main group metal. Scheme 22 described the production of thiazepines by reacting a haloketones with an ø-aryl(or heteroaryl) thiol. In particular, such cyclizations can be carried out very efficiently under copper catalysis (Kwong et al, Org. Lett., 2002, 4, 3517, incorporated herein by reference in its entirety) using iodoketones and o-aminoaryl(or heteroaryl) thiols. The requisite iodoketones can be synthesized by one of the methods known in the art, for example by addition of organomagnesium reagents (Reynolds and Hermitage, Tetrahedron, 2001, 57, 7765, incorporated herein by reference in its entirety) to 2-iodo Weinreb amides (Brunette and Lipton, J Org. Chem., 2000, 65, 51 14, incorporated herein by reference in its entirety), by copper catalyzed aromatic Finkelstein reaction (Klapars and Buchwald, J. Am. Chem. Soc, 2002, 124, 14844, incorporated herein by reference in its entirety) using the more ubiquitous bromoketones (Krasovskiy and Knochel, Angew. Chem. 2004, 43, 3333, incorporated herein by reference in its entirety) or by diazotation/Sandmeyer-type iodination (J. Org. Chem., 1982, 47, 2441, incorporated herein by reference in its entirety) using the readily available aminoketones (Sternbach et al, J Am. Chem. Soc, 1961, 26, 4488, incorporated herein by reference in its entirety). Likewise, the o-aminoaryl(or heteroaryl) thiol employed herein for the synthesis of thiazepines can be prepared by one of the methods known in the art, for example by reduction of o-nitroaryl(or heteroaryl) thiols (Foster and Reid, J. Am. Chem. Soc, 1924, 46, 1936, incorporated herein by reference in its entirety), by heating of 2- halonitroaryls(or heteroaryls) with sodium sulphide in water (Jain et al, Chem. End., 1969, 989, incorporated herein by reference in its entirety) or by saponification of (het)arofused 2-substituted thiazoles (Hodson et al, J. Med. Chem., 2002, 45, 2229). Bromo(or chloro)ketones can also participate in reactions with o-aminoaryl(or heteroaryl) thiols using a palladium catalyst (Li, J. Org. Chem., 2002, 67, 3643, incorporated herein by reference in its entirety) to provide thiazepines.
[0189] Finally, under SNAΓ conditions, chloroketones can be reacted with o- aminoaryl(or heteroaryl) thiols to afford thiazepines. Presence of several strongly electron withdrawing groups (such as nitro or cyano groups) on the aromatic ring of the chloroketones (Jarret and Loudon, J. Chem. Soc, 1957, 3818, Gait and Loudon, J. Chem. Soc, 1959, 885, incorporated herein by reference in its entirety), or a π-deficient azaromatic chloroketone (Warmhof, Synthesis., 1972, 151, Shalaby, Phosphorus, Sulfur Relat. Elem., 2003, 178, 199, incorporated herein by reference in its entirety), is typically required.
Pharmaceutical Compositions
[0190] Some embodiments described herein relates to a pharmaceutical composition comprising at one compound of Formula (I) and/or Formula (II) as described above in combination with another therapeutic compound, and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
[0191] An embodiment described herein relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0192] In some embodiments, the antipsychotic can act on a dopamine receptor such as a D2 receptor. [0193] In an embodiment, the antipsychotic can be selected from olanzapine, risperidone, haloperidol, aripirazole, quetiapine, ziprasidone, raclopride, clozapine, Molindone (Moban®), Thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®), Risperidone (Risperdal®), Sertindole (Serlect®) and Ziprasidone (Seldox®).
[0194] In some embodiments, the first compound and second compound can be provided in dosages which reduce an adverse side effect associated with an antipsychotic. In other embodiments, the first compound and second compound can be provided in dosages which ameliorate or treat a negative symptom of schizophrenia.
[0195] In some embodiments, the adverse side effect can be selected from weight gain, metabolic syndrome, an extra- pyramidal side effect, akathisia, dystonia, acute dystonia, Parkinsonism, dykensia, tardive dyskinesia, neuroleptic malignant syndrome, hyperprolactinemia, and catalepsy. In an embodiment, the negative symptom can be selected from affective flattening, poverty of speech, absence of volition, apathy, self-neglect, inappropriate emotion, inability to experience pleasure, inattentiveness, inability to show a facial expression, and inability to start or complete a task.
[0196] In some embodiments, in addition to the dosages, there can be further an instruction set that includes directions for administering the first compound and the second compound, the instruction set comprising dosage amounts and dosing schedules for reducing an adverse side effect associated with the antipsychotic. In other embodiments, in addition to the dosages, there can be further an instruction set that includes directions for administering the first compound and the second compound, the instruction set comprising dosage amounts and dosing schedules for ameliorating or treating a negative symptom of schizophrenia.
[0197] Another embodiment described herein relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is a compound used to treat Parkinsons' s disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II). [0198] In an embodiment, the compound used to treat Parkinson' disease can be selected from L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride.
[0199] In some embodiment, the first compound and second compound can be provided in dosages which reduce an adverse side effect associated with a compound used to treat Parkinson's disease. In an embodiment, the adverse side effect can be selected from increased propensity for gambling, dyskinesia, and psychosis. In another embodiment, the first compound and second compound can be provided in dosages which shortens or prevents the need for a drug holiday.
[0200] In some embodiments, in addition to the dosages, there can be further an instruction set that includes directions for administering the first compound and the second compound, the instruction set comprising dosage amounts and dosing schedules for reducing an adverse side effect associated with a compound used to treat Parkinson's disease. In other embodiments, in addition to the dosages, there can be further an instruction set that includes directions for administering the first compound and the second compound, the instruction set comprising dosage amounts and dosing schedules for shortening or preventing the need for a drug holiday.
[0201] Still another embodiment relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0202] In an embodiment, the first compound and second compound can be provided in dosages which ameliorates or inhibits a loss of cognition or improves cognition. In some embodiment, the first compound and second compound can . be provided in dosages which ameliorate or inhibits weight gain and/or suppresses the appetite of a subject.
[0203] In an embodiment, in addition to the dosages, there can be further an instruction set that includes directions for administering the first compound and the second compound, the instruction set comprising dosage amounts and dosing schedules for ameliorating or inhibiting a loss of cognition or improves cognition. In another embodiment, in addition to the dosages, there can be further an instruction set that includes directions for administering the first compound and the second compound, the instruction set comprising dosage amounts and dosing schedules for ameliorating or inhibiting weight gain and/or suppressing the appetite of a subject.
[0204] In some embodiments, the therapeutic compound can be selected from an antidepressant, an anticonvulsant, a mood stabilizer, an antipsychotic, an antiarrhythmic agent, an antibiotic, an anticholinergic agent, an antiemetic, an antihypertensive agent, an antineoplastic agent, an anti-Parkinson's agent, an antihistamine, an cardiotonic agent, a corticosteroid, a H2 receptor antagonist, an immunosuppressive agent, a narcotic analgesic, a muscle relaxant, a non-steroids antiinflammatory agent, a radiocontrast agent, and a sedative. Exemplary antidepressants include, but are not limited to, Buproprion HCL (Wellbutrin®), Mitrazapine (Remeron®), Nefazadone (Serzone®), Trazadone (Desyrel®), and Venlafaxine (Effexor®), clovoxamine, amitriptyline and imipramine. Additional antidepressants, include selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants and monoamine oxidase inhibitors. Examples of selective serotonin reuptake inhibitors include, but are not limited to citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. Examples of tricyclic antidepressants include, but are not limited to, Amitriptyline (Elavil®), Amoxapine (Asendin®), Clomipramine (Anafranil®), Desipramine (Norepramine®, Pertofrane®), Doxepin (Adapin®, Sinequan®), Imipramine (Janimine®, Tofranil®), Nortriptyline (Aventyl®, Pamelor®), Protriptyline (Vivactil®), Trimipramine (Rhotramine®, and Surmontil®). An exemplary monoamine oxidase inhibitor is a nonselective, irreversible monoamine oxidase inhibitor such as Isocarboxazid (Marplan®), Phenelzine (Nardil®), and/or Tranylcypromine (Parnate®). Additional monoamine oxidase inhibitors include, but are not limited to, Moclobemide (Manerix®) and/or Toloxatone (Humoryl®). Suitable anticonvulsants include, but are not limited to, valproic acid, phenobarbital, Carbamazepine (Tegretol®), Divalproex (Depakote®), Gabapentin (Neurontin®), Lamotrigine (Lamictal®), Topiramate (Topamax®), and phenyltoin. Exemplary mood stabilizers include, but are not limited to, Lithium, Cibalith-S®, Duralith®, Ekalith®, Eskalith CR®, Lithane®, Lithobid®, Lithonate®, and Lithotabs®. Examples of suitable antipsychotics include, but are not limited to, phenothiazines, phenylbutylpiperdines, debenzapines, benzisoxidils, salt of lithiums, butyrophenones, substituted benzamides (sulpiride), and racloprides. Examples phenothiazines include chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), thioridazine (Mellaril), Fluphenazine (Prolixin®), Perpehnazine (Trilafon®), and Trifluoperazine (Stelazine®). Examples of phenylbutylpiperadines inlcude haloperidol (Haldol®) and pimozide (Orap®). Examples of debenzapines include clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), and quetiapine (Seroquel®). Examples of benzisoxidils include resperidone (Resperdal®), ziprasidone (Geodon®, Zeldox®)), 9-hydroxy- risperidone. An example of a salt of lithium is lithium carbonate. Additional examples of suitable antipsychotics include, but are not limited to, Aripiprazole (Ability®), Etrafon®, Droperidol (Inapsine®), Thioridazine (Mellaril®), Thiothixene (Navane®), Promethazine (Phenergan®), Metoclopramide (Reglan®), Chlorprothixene (Taractan®), Triavil®, Molindone (Moban®), Sertindole (Serlect®), Droperidol, Amisulpride (Solian®), Melperone, Paliperidone (Invega®), Tetrabenazine, Thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®), and thioxanthine (Fluphenthixol). In some embodiments, the antipsychotic can be a typical antipsychotic. In other embodiments, the antipsychotic can be an atypical antipsychotic. In an embodiment, theantipsychotic can act on a dopamine receptor such as a D2 receptor Suitable antiarrhythmics include, but are not limited to, disopyramide, quinidine, and tocainide. Exemplary antibiotics include, but are not limited to, cephalexin, cephalothin, metronidazole, ciprofloxacin, and ofloxacin. Examples of suitable anticholinergic agents include, but are not limited to, benztropine, homatropine, scopolamine and trihexyphenidyl. A suitable antiemetic is lithium. Exemplary antihypertensive agents include, but are not limited to, propranolol, metoprolol, atenolol, verapamil, methyldopa, prazosin, and nifedipine. Examples of suitable antineoplastic agents include, but are not limited to, cytosine arabinoside, and interleukin-2. Suitable anti-Parkinson's agents include, but are not limited to, L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride. Exemplary antihistamines include, but are not limited to, phenylpropanolamine, diphenhydramine, chlorpheniramine brompheniramine, and pseudoephedrine. An example of a suitable cardiotonic agent is digoxin. Suitable corticosteroids include, but are not limited to, hydrocortisone and prednisone. Exemplary H2 receptor antagonists include, but are not limited to, cimetidine and ranitidine. Examples of suitable immunosuppressive agents include, but are not limited to, cyclosporine and interferon. Suitable narcotic analgesics include, but are not limited to, codeine, hydrocodone oxycodone, meperidine, and propoxyphene. Exemplary muscle relaxants include, but are not limited to, baclofen, cyclobenzaprine, and methocarbimol. Examples of suitable non-steroids anti-inflammatory agents include, but are not limited to, aspirin, ibuprofen, indomethacin, naproxen, and sulindac. Suitable radiocontrast agents include, but are not limited to, metrizamide, iothalamate and iohexol. Exemplary sedatives include, but are not limited to, benzodiazepine, alprazolam, diazepam, lorazepam, phenobarbital, butabarbital, and chloral hydrate.
[0205] In any of the embodiments described herein, the first compound and the second compound can be in the same container or each can be in separate containers.
[0206] Yet still another embodiment described herein relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II), wherein the first compound is present in an amount less than the amount needed to elicit the same therapeutic effect compared to when the first compound is administered alone.
[0207] As described previously, the antipsychotic can act on a dopamine receptor such as a D2 receptor. Exemplary antipsychotics are described herein.
[0208] An embodiment described herein relates to a pharmaceutical composition comprising a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II), wherein the first compound is present in an amount less than the amount needed to elicit the same therapeutic effect compared to when the first compound is administered alone. Examples of suitable compounds used to treat Parkinson' disease are described herein. [0209] Another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to reduce an adverse side effect associated with an antipsychotic in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II). In an embodiment, the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with an antipsychotic so as to reduce an adverse side effect associated with the antipsychotic.
[0210] In an embodiment, the adverse side effect can be selected from weight gain, metabolic syndrome, an extra-pyramidal side effect, akathisia, dystonia, acute dystonia, Parkinsonism, dykensia, tardive dyskinesia, neuroleptic malignant syndrome, hyperprolactinemia, and catalepsy.
[0211] Still another embodiment described herein relate to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or treat a negative symptom of schizophrenia in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II). In an embodiment, the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with an antipsychotic that causes a negative symptom of schizophrenia so as to ameliorate of treat a negative symptom of schizophrenia.
[0212] In an embodiment, the negative symptom can be selected from affective flattening, poverty of speech, absence of volition, apathy, self-neglect, inappropriate emotion, inability to experience pleasure, inattentiveness, inability to show a facial expression, and inability to start or complete a task.
[0213] Yet still another embodiment described herein relate to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to reduce an adverse side effect associated with a compound used to treat Parkinson's disease in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II). In an embodiment, the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with a compound used to treat Parkinson's disease so as to reduce an adverse side effect associated with the compound used to treat Parkinson's disease.
[0214] In some embodiments, the adverse side effect is selected from the group consisting of increased propensity for gambling, dyskinesia, and psychosis.
[0215] An embodiment relates described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or inhibit a loss of cognition or improves cognition in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II). In an embodiment, the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with a therapeutic compound ameliorate or inhibit a loss of cognition or improves cognition associated with the therapeutic compound.
[0216] Another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or inhibit weight gain in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II). In an embodiment, the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with an antipsychotic and/or a compound used to treat Parkinson's disease ameliorate or inhibit weight gain associated with the antipsychotic and/or the compound used to treat Parkinson's disease.
[0217] Still another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to shorten or prevent the need for a drug holiday in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II). In an embodiment, the instructions can include instructions for taking the catinabinoid antagonist or inverse agonist in combination with a compound used to treat Parkinson'sdisease shorten or prevent the need for a drug holiday associated with the compound used to treat Parkinson's disease.
[0218] Some embodiment described herein relate to a method of manufacturing a pharmaceutical composition, said method that can include the steps of: obtaining a first compound comprising an antipsychotic or a compound used to treat Parkinson's disease; obtaining a second compound selected from a compound of Formula (I) and a compound of Formula (II); and packaging together the first compound and the second compound. In an embodiment, the first compound and the second compound can be merged together, thereby forming a combined dosage form. An embodiment described herein relates to a pharmaceutical composition manufactured by the method described in this paragraph.
[0219] In some embodiments described herein, the compound of Formula (I) can be selected from any of the compounds disclosed herein, including the claims. In some embodiments described herein, the compound of Formula (II) can be selected from any of the compounds disclosed herein, including the claims.
[0220] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, intramuscular, intraocular, intranasal, intravenous, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
[0221] The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound. [0222] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990, which is hereby incorporated by reference in its entirety.
[0223] Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, intraocular injections or as an aerosol inhalant.
[0224] Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the area of pain or inflammation, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.
[0225] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
[0226] Pharmaceutical compositions for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., as disclosed in Remington's Pharmaceutical Sciences, cited above. [0227] For injection, the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
[0228] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels', syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
[0229] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
[0230] Pharmaceutical preparations, which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
[0231] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
[0232] For administration by inhalation, the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[0233] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
[0234] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly, concentrated solutions. [0235] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0236] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
[0237] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0238] An exemplary pharmaceutical carrier for the hydrophobic compounds disclosed herein is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common co-solvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; and other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
[0239] - Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms.
[0240] Pharmaceutical compositions suitable for use in the methods disclosed herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
[0241] The exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Chapter 1, which is hereby incorporated by reference in its entirety). Typically, the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Where no human dosage is established, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
[0242] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day. Alternatively the compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day. Thus, the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
[0243] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
[0244] Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
[0245] In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
[0246] The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
[0247] The compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
Methods of Use
[0248] Also disclosed herein are methods of treating clinical manifestations in which a subject would benefit from antagonism of or inverse agonism of the CB-I receptor by a compound such a compound of Formula (I) and/or a compound of Formula
(H)
[0249] An embodiment described hereien relates to a method of ameliorating or inhibiting an adverse effect associated with an antipsychotic that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II). Examples of antipsychotics and side effects associated with antipsychotics have been described previously. In an embodiment, the antipsychotic can act a dopamine receptor such as a D2 receptor.
[0250] Another embodiment described herein relates to a method of inhibiting or preventing weight gain associated with the use of a therapeutic compound that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II). Exemplary therapeutic compounds that can cause weight gain have been described previously. In an embodiment, antidepressant that can cause weight gain can be selected from Buproprion HCL (Wellbutrin®), Mitrazapine (Remeron®), Nefazadone (Serzone®), Trazadone (Desyrel®), and Venlafaxine (Effexor®). In some embodiments, antidepressant that can cause weight gain can be selected from is selected from a selective serotonin reuptake inhibitor (SSRJ), a tricyclic antidepressant and a monoamine oxidase inhibitor,
[0251] Still another embodiment described herein relates to a method of suppressing the appetite of a subject that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0252] Yet still another embodiment described herein releates to a method of ameliorating or inhibiting a negative symptom of schizophrenia that can inlcude administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II). Examples of negative symptoms of schizophrenia have been described previously.
[0253] An embodiment described herein relates to a method of ameliorating or inhibiting a loss of cognition or improving cognition that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0254] Another embodiment described hererin relates to a method of ameliorating or inhibiting an adverse effect associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0255] Still another described herein relates to a method of ameliorating or inhibiting a propensity for gambling associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II). In an embodiment the compound used to treat Parkinson's disease can be L-dopa.
[0256] Yet still another embodiment described herein relates to a method of ameliorating or inhibiting dyskinesia associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0257] An embodiment described herein relate to a method of ameliorating or inhibiting psychosis associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0258] Another embodiment described herein relates to a method for shortening or preventing a need for a drug holiday that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II). Exemplary compounds used to treat Parkinson's disease are described herein.
[0259] An embodiment described hererin relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of an antipsychotic in a subject taking an antipsychotic that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates at least one adverse effect associated with the administration of the antipsychotic, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). Examples of antipsychotics and side effects associated with antipsychotics have been described previously. In an embodiment, the antipsychotic can act a dopamine receptor such as a D2 receptor. In some embodiments, the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or treats at least one adverse effect associated with the administration of the antipsychotic.
[0260] An embodiment described hererin relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of a compound used to treat Parkinson's disease in a subject taking a compound used to treat Parkinson's disease that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or treats at least one adverse effect associated with the administration of the compound used to treat Parkinson's disease, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). Examples of compounds used to treat Parkinson's diease and side effects associated with the compounds used to treat Parkinson's disease have been described herein. In some embodiments, the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates at least one adverse effect associated with the administration of the compound used to treat Parkinson's disease.
[0261] Still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat a negative symptom of schizophrenia in a subject taking an antipsychotic that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or inhibits at least one negative symptom of schizophrenia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). Examples of negative symptoms of schizophrenia have been described previously. In an embodiment, the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or inhibits at least one negative symptom of schizophrenia. [0262] Yet still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a loss of cognition or improve cognition in a subject taking a therapeutic compound that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the therapeutic compound ameliorates or inhibits a loss of cognition or improves cognition, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). Exemplary therapeutic compounds such as antidepressants, anticonvulsants, mood stabilizers, antipsychotics, antiarrhythmic agents, antibiotics, anticholinergic agents, antiemetics, antihypertensive agents, antineoplastic agents, anti-Parkinson's agents, antihistamines, cardiotonic agents, corticosteroids, H2 receptor antagonists, immunosuppressive agents, narcotic analgesics, muscle relaxants, non-steroids anti-inflammatory agents, radiocontrast agents, and sedatives are described herein. In an embodiment, the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the therapeutic compound ameliorates or inhibits a loss of cognition or improves cognition.
[0263] An embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a propensity for gambling in a subject taking a compound used to treat Parkinson's disease comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits the propensity for gambling, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). In some embodiments, the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits the propensity for gambling.
[0264] Another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit dyskinesia associated with a compound used to treat Parkinson's disease in a subject that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits dyskinesia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). In an embodiment, the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits dyskinesia associated with a compound used to treat Parkinson's disease.
[0265] Still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit psychosis associated with a compound used to treat Parkinson's disease in a subject that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits psychosis, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). In some embodiments, the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits psychosis associated with a compound used to treat Parkinson's disease.
[0266] Yet still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to shorten or prevent a need for a drug holiday that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with a compound used to treat Parkinson's disease shortens or prevents the need for a drug holiday, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). In an embodiment, the information of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease shortens or prevents the need for a drug holiday. [0267] An embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to inhibit or prevent weight gain that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with an antipsychotic or a compound used to treat Parkinson's disease inhibits or prevents weight gain, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). In some embodiments, the information of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic or the compound used to treat Parkinson's disease inhibits or prevents weight gain.
[0268] In any of the methods described herein, the printed matter can be a label.
[0269] An embodiment described herein relates to a method for lowering the amount of an antipsychotic needed to elicit the same therapeutic effect compared to when the first is administered alone that can include administering to a subject a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0270] Another embodiment described herein relates to a method for lowering the amount of a compound used to treat Parkinson's disease needed to elicit the same therapeutic effect compared to when the first compound is administered alone that can include administering to a subject a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
[0271] In any of the embodiments described herein, the compound selected from the compound of Formula (I) and the compound of Formula (II) can bind to CB-I receptors in human tissue with a higher pKi compared to N-piperidino-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide. For example, the compound of Formula (I) and/or the compound of Formula (II) can bind to CB-I receptors in human tissue with a pKi > 9.0. [0272] In any of the embodiments described herein, the compound selected from the compound of Formula (I) and the compound of Formula (II) can supress food intake more effectively compared to N-piperidino-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide.
[0273] In any of the embodiments, the first compound can be administered prior to the second compound. In any of the embodiments, the first compound can be administered subsequent to the second compound. In any of the embodiments, the first compound can be at the same time as the second compound.
[0274] It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure.
EXAMPLES
[0275] Embodiments of the present invention are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the invention.
Example 1 - General analytical LC-MS procedure
[0276] Procedure 1 (API): The analysis was performed on a combined prep/analytical Waters/Micromass system consisting of a ZMD single quadropole mass spectrometer equipped with electro-spray ionization interface. The HPLC system consisted of a Waters 600 gradient pump with on-line degassing, a 2700 sample manager and a 996 PDA detector.
[0277] Separation was performed on an X-Terra MS C 18, 5 μm 4.6x50mm column. Buffer A: 1OmM ammonium acetate in water, buffer B: 1OmM ammonium acetate in acetonitrile/water 95/5. A gradient was run from 30%B to 100%B in 10 min, dwelling at 100%B for 1 min, and re-equilibrating for 6 min. The system was operated at 1 ml/min. [0278] Procedure 2 (AP2): The analysis was performed on a combined prep/analytical Waters/Micromass system consisting of a ZMD single quadropole mass spectrometer equipped with electro-spray ionization interface. The HPLC system consisted of a Waters 600 gradient pump with on-line degassing, a 2700 sample manager and a 996 PDA detector.
[0279] Separation was performed on an X-Terra MS C 18, 5 μm 4.6x50rήm column. Buffer A: 1OmM ammonium acetate in water, buffer B: 1OmM ammonium acetate in acetonitrile/water 95/5. A gradient was run from 30%B to 100%B in 7 min, dwelling at 100%B for 1 min, and re-equilibrating for 5.5 min. The system was operated at 1 ml/min.
Example 2 - General gas chromatography (GC) procedure
[0280] GC method 50 was used. Method 50 starts at 5O°C and has a gradient of 20 °C/min until 250 °C then holds the temperature for 5 minutes. The analysis was performed on an Aglient 6850 series GC system with capillary S/SL inlet and FID with EPC installation. The column was a 30 m X 0.32 mm x 0.25 μm HP5 column.
Example 3: 4-(2-methoxycarbonyl-phenylsulfanyl)-3-nitro-benzoic acid ethyl ester
Figure imgf000084_0001
[0281] Methyl 2-mercaptobenzoate (4.67 ml, 34 mmol) was added during 30 min to a mixture of ethyl 4-flouro-3-nitrobenzoate (6.60 g, 30.9 mmol) and Cs2CO3 (10.06 g, 30.9 mol) in DMF (60 mL) at 40 °C. The reaction mixture was diluted with EtOAc, water after additional 15 min (full conversion according to TLC). The aqueous phase was extracted once with EtOAc and the combined organic phases were washed twice with water followed by brine and then dried (Na2SO4). Filtration and concentration of the organic phase at reduce pressure gave a yellow crystalline residue. Recrystallization from EtO Ac/heptane gave 10.3 g '(92%) of the titled compound as yellow crystals. 1H NMR (400 MHz, CDCl3) δ 8.82 (d, 1H, J = 1.9 Hz), 7.94 (m, 2H), 7.62-7.57 (m, 3H), 6.92 (d, 1H, J - 8.6 Hz), 4.38 (q, 2H, J = 7.2 Hz), 3.78 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3); δ 166.8, 164.6, 145.5, 144.1, 137.6, 136.3, 133.4, 133.0, 131.5, 131.3, 130.5, 129.8, 128.1, 126.9, 61.9, 52.7, 14.5.
Example 4: 4-(2-carboxy-phenylsulfanyl')-3-nitro-benzoic acid
Figure imgf000085_0001
[0282] 4-(2-methoxycarbonyl-phenylsulfanyl)-3-nitro-benzoic acid ethyl ester (9.56 g, 26.5 mmol) dissolved in THF (570 mL) and aqueous LiOH (264 ml, IM) was stirred at 60 °C for 2 h, then allowed to cool to room temperature. THF was removed at reduced pressure and the remaining aqueous mixture was extracted once with EtOAc. HCl (2M) was then added to the resulting aqueous solution until pH 2. The precipitation was filtred off, washed with water and finally dried, which afforded 8.7 g (99%) of the titled compound as yellow crystals. The crude product was sufficiently pure to be used in the next step without further purifications. 1H NMR (400 MHz, CD3OD) δ 8.71 (d, 1H, J = 1.8 Hz), 7.95 (m, 2H), 7.64-7.59 (m, 3H), 7.00 (d, 1H, J = 8.6 Hz); 13C NMR (100 MHz, CD3OD) δ 168.3, 166.1, 145.9, 143.3, 137.0, 136.5, 133.2, 132.6, 131.2, 131.1, 130.1, 130.0, 128.6, 126.3.
Example 5: 3-Amino-4-(2-carboxy-phenylsulfanyl)-benzoic acid
Figure imgf000085_0002
[0283] PaVC (10%, 200 mg) and PtO2 were added to 4-(2-carboxy- phenylsulfanyl)-3-nitro-benzoic acid (2.9 g, 9.1 mmol) dissolved in 100 ml of MeOH. The reaction flask were repeatedly evacuated and filled with H2. A balloon containing H2 was connected to the flask. After 16 h the reaction mixture was filtered through a pad of celite, which was then washed carefully with MeOH. Concentration of the filtrate at reduced pressure gave 2.5 g (96% yield, approximately 95% purity) of the titled compound as a white solid. The purity could be increased to 97% by recrystallization from EtOAc/MeOH (2.3g, 88% yield). 1H NMR (400 MHz, CD3OD) δ 8.01 (d, 1H, J = 7.6 Hz), 7.51 (s, 1H), 7.44 (d, 1H, J = 8.0 Hz), 7.31 (d, 1H, J = 8.0 Hz), 7.28 (t, 1H, J = 8.0 Hz), 7.16 (t, 1H, J - 7.2 Hz), 6.74 (d, 1H, J = 8.0 Hz); MS (ES+, M+l) = 290.
Example 6: 1 l-Oxo-10,11 -dihydro-dibenzo [b,f|[l Aj thiazepine-8-carboxylic acid
Figure imgf000086_0001
[0284] CDI (4.53 g, 29 mmol, 4 eq) was added to 3-Amino-4-(2-carboxy- phenylsulfanyl)-benzoic acid (2.1 g, 7.3 mmol) dissolved in THF (30 ml). The reaction was stirred for 16h at room temperature. Water (200 ml) was then added to the mixture resulting in, after filtration and drying, l.78g (91%) of the titled compound as a off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.78 (br s, 1H), 7.77 (s, 1H), 7.67 (m, 3H), 7.55-7.42 (m, 3H); 13C NMR (100 MHz, DMSO-d6); δ 168.9, 166.9, 140.3, 138.3, 136.0, 134.5, 133.5, 133.0, 132.9, 132.2, 132.1, 129.9, 126.5, 124.3.
Example 7: 11 -Chloro-dibenzo [b,f|[ 1 ,4] thiazepine-8-carbonyl chloride
Figure imgf000086_0002
[0285] A solution of 11-Oxo-l 0,11 -dihydro-dibenzo [b,fj[1,4] thiazepine-8- carboxylic acid. (200 mg, 0.74 mmol) and phosphorus pentachloride (756 mg, 3.68mmol) in 4 mL toluene was heated to 110 °C for 2 h. Toluene and excess of phosphorus pentachloride was removed at reduced pressure to give the title compound (193 mg, 85%) as an yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, 1H, J = 2.0 Hz), 7.87 (dd, 1H, J = 8.4, 2.2 Hz), 7.77 (m, 1H), 7.58 (d, 1H, J = 8.2 Hz), 7.47-7.44 (m, 2H), 7.44-7.39 (m, 1H); 13C NMR (100 MHz, CDCl3); δ 167.5, 157.1, 146.7, 137.8, 137.4, 136.3, 134.5, 133.4, 133.3, 132.6, 130.3, 129.5, 129.1, 128.8;
Example 7b: Alternative synthesis of 1 1 -Chloro-dibenzo fb,f|[1,41 thiazepine-8- carbonyl chloride
[0286] A solution of SOCl2 (25 ml), 1 1 -Oxo- 10,1 1 -dihydro-dibenzo [b,f][ 1 ,4] thiazepine-8-carboxylic acid (1.24 g, 4.6 mmol) and DMF (0.05 ml) in toluene (25 ml) was heated at 80 °C for 17h. Toluene and excess SOCl2 were removed at reduced pressure to give 1.18 g (84%) of the title compound5 as a yellow solid, which was used in the next step without further purifications. 1H NMR (400 MHz CDCl3) δ 8.01 (d, 1H, j = 2.0 Hz), 7.87 (dd, 1H, J = 8.4, 2.2 Hz), 7.77 (m, 1H), 7.58 (d, 1H, J = 8.2 Hz), 7.47-7.44 (m, 2H), 7.44-7.39 (m, 1H); 13C NMR (100 MHz, CDCl3); δ 167.5, 157.1 , 146.7, 137.8, 137.4, 136.3, 134.5, 133.4, 133.3, 130.3, 129.5, 129.1, 128.8.
Example 8: N-(butyl>l l-(chloro)-dibenzo[b,f,]f 1,41thiazepine-8-carboxamide
Figure imgf000087_0001
[0287] 11 -Chloro-dibenzo [b,f][l ,4] thiazepine-8-carbonyl chloride (616 mg; 2 mmol) dissolved in dry DCM (5mL) was added to a solution of butylamine (366 mg; 5 mmol) in dry DCM (1OmL) was added at 0 °C. The reaction was stirred for 30 min and then diluted with EtOAc. The organic phase was washed with NH4Cl (aq), brine and dried (Na2SO4). Filtration and evaporation at reduced pressure followed by purification by column chromatography (ethyl acetate/heptane 1 :1) gave the title compound (557 mg, 81%) as a yellow solid. MS (ES+, M+l) = 345.
Example 9: N-(butyl)-l l-(4-chlorophenyl)-dibenzo[b1f,][l14]thiazepine-8-carboxamide
Figure imgf000088_0001
[0288] 4-Chlorophenylzinc iodide (0.5M in THF, 35mL) was added to N- (butyl)-l l-(chloro)-dibenzo[b,f,][1,4]thiazepine-8-carboxamide (2.8 g; 8.1 mmol) and PdCl2(PPh3)2 (5 mol%, 275 mg) in dry THF (90 niL) at room temperature. After 3h saturated aqueous NH4Cl and EtOAc was added and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine and then dried (Na2SO4). Filtration, concentration at reduced pressure of the organic phase followed by purification by column chromatography (heptane/EtOAc 3:1 to 1:1) and recrystallization from toluene gave 2.86 g (84%) of the title compound as pale yellow crystals, m.p. 217- 219 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (m, 2H), 7.64 (d, 1H, J = 1.2 Hz), 7.55 (dd, 1H, J= 7.8, 1.2 Hz), 7.50 (m, 2H), 7.42 (m, 3H), 7.31 (dt, 1H, J = 7.6, 1.2 Hz), 7.16 (dd, 1H, J = 7.6, 1.4 Hz). 6.06 (br s, 1H), 3.44 (q, 2H, J = 7.2 Hz). 1.58 (m, 2H), 1.40 (m, 2H, J = 7.4 Hz), 0.95 (t, 3H, J = 7.2 Hz); MS (ES+, M+l) = 421.
Example 10: 1 l-Chloro-dibenzo[6,/r][1,4]thiazepine-8-carboxylic acid isobutylamide
Figure imgf000088_0002
[0289] A solution of 11 -chloro-dibenzo [b,f][1,4]thiazepine-8-carbonyl chloride (0.59 g; 1.92 mmol) in DCM (10 mL) was added to a solution of isobutylamine (0.38 mL; 3.84 mmol) in DCM (10 mL) at 0°C under argon. The mixture was stirred at room temperature for Vi hour. The reaction mixture was diluted with DCM and NH4Cl (sat). The aqueous phase was extracted twice with DCM and the combined organic phases dried over Na2SO4. After filtration and concentration by evaporation, the residue was purified by silica gel column chromatography eluting with 10-20 % EtOAc in n- heptane. 0.51 g (77%) of the title compound was obtained as a white powder. [0290] 1H NMR (400 MHz, CDCl3) δ 7.77 - 'J.IZ (m, 1H, ArH), 7.63 (dd, 1H,
J= 2.0, 8.0, ArH), 7.56 (d, 1H, J = 2.0, ArH), 7.51 (d, 1H, J = 8.0, ArH), 7.47 - 7.37 (m, 3H, ArH), 6.07 (br s, 1H, NH), 3.26 (dd, 2H, J= 6.1, 6.8, CH2,Bu), 1.86 (sept, I H5 J= 6.6, CH1Bu), 0.96 (d, 6H, J= 6.6, 2 x CH3).
Example 11 : l l-(5-Chlorothiophen-2-yl)-dibenzo[6J]p,41miazepine-8-carboxylic acid isobutylamide
Figure imgf000089_0001
[0291] 5-Chloro-2-thienyl zinc bromide (0.5 M in THF, 3.5 mL; 1.72 mmol) was added to a solution of l l-chloro-dibenzo[b,fj[1,4]thiazepine-8-carboxylic acid isobutylamide (0.15 g; 0.43 mmol) and bis(triphenylphosphine)palladiurn(II)chloride (30 mg; 0.043 mmol) in 4 mL dry THF at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned between EtOAc and NH4C1 (sat). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The mixture was purified by silica gel column chromatography (10-30% EtOAc in n-heptane) and repurified by prep HPLC to afford the title compound as a yellow solid (27 mg; 15 %).
[0292] 1H NMR (400 MHz, CDCl3) δ 7.60 - 7.34 (m, 7H, ArH), 6.94 (d, 1H,
J = 4.0, thiophenH), 6.89 (d, 1H, J = 4.0, thiopheneH), 6.15 (br m, 1H, NH), 3.26 (dd, 2H, J= 6.4, 7.2, CH21Bu), 1.87 (m, 1H, CHlBu), 0.96 (d, 6H, J = 6.8, 2 x CH3). 13C NMR (100 MHz, CDCl3) δ 166.8, 162.7, 148.5, 145.1, 140.5, 137.1, 136.2, 135.3, 133.0, 132.8, 132.1, 132.0, 131.9, 130.3, 128.4, 127.3, 124.7, 123.9, 47.6, 28.8, 20.4. MS (ES+, M+l) = 427.
General Procedure A - Amide Formation: [0293] A flame-dried flask was charged under argon with 1 1-Chloro-dibenzo [b,f)[1,4] thiazepine-8-carbonyl chloride (180 mg; 0.58 mmol) in 4 mL dry DCM and cooled to 0 C. The amine (1.45 mmol) was then slowly added and the reaction was allowed to reach room temperature and stirred for 30 min. The reaction was diluted with DCM and the organic phase was washed with NH4Cl (aq), brine and dried (Na2SO4). Filtration and evaporation at reduced pressure follwed by purification by column chromatography (ethyl acetate/heptane 1:1) gave the compounds listed as Examples 12 - 14 (72-88 %) as off-white solids.
Example 12: (l l-chloro-dibenzofb.f] [1,41thiazepin-8-yl)- f2,4-dimethyl-phenvD- piperazin-1 -yli-methanone.
[0294] The reaction was performed according to the general procedure A, which gave 220 mg (82%) of the titled compound. 1H NMR (400 MHz, CDCl3) δ 7.75 (m, 1H), 7.51 (d, 1H, J = 8.0 Hz), 7.47-7.44 (m, 2H), 7.44-7.39 (m, 1H), 7.31, (d, 1H, J = 1.8 Hz), 7.24 (dd, 1H, J = 7.8, 1.8 Hz), 7.02 (br s, 1H), 6.98 (br d, 1H, J = 8.0 Hz), 6.89 (d, 1H, J = 8.0 Hz), 3.88 (br s, 2H), 3.54 (br s, 2H), 2.85 (br s, 4H), 2.28 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 169.0, 156.2, 148.5, 146.4, 138.4, 137.9, 137.6, 133.6, 133.3, 133.1, 132.9, 132.3, 132.1, 130.2, 129.5, 129.1, 127.4, 126.1 , 124.3, 1 19.4, 31.1, 20.9, 17.8; MS (ES+, M) - 462.
Example 13: l l-chloro-dibenzo[b,f| [1,4]thiazepin-8-carboxylic acid piperidin-1- ylamide.
Figure imgf000090_0002
[0295] The reaction was performed according to the general procedure A, which gave 157 mg (72%) of the titled compound. 1H NMR (400 MHz, CDCl3) δ 7.74 (m, 1H), 7.59 (dd, I H, J = 8.0, 1.8 Hz), 7.54 (s, 1H), 7.50 (d, 1H, J = 8.2 Hz), 7.47-7.43 (m, 2H), 7.43-7.39 (m, 1H), 2.80 (br s, 4H), 1.74 (br s, 4H), 1.44 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ 164.3, 156.6, 146.5, 138.5, 138.1, 135.8, 133.5, 133.4, 132.7, 131.8, 130.4, 129.4, 126.7, 124.2, 57.7, 32.4, 25.8; MS (ES+, M+l) = 372.
Example 14: 4-[(l l-chloro-dibenzorb,fl f1,41thiazepine-8-carbonyl)-amino]-piperidine-
1-carboxylic acid ethyl ester.
Figure imgf000091_0001
[0296] The reaction was performed according to the general procedure A, which gave 189 mg (88%) of the titled compound. 1H NMR (400 MHz, CDCl3) δ 7.74 (m, 1H), 7.61 (dd, 1H, J - 8.2, 1.9 Hz), 7.56 (d, 1H, J = 1.6Hz), 7.51 (d, 1H, J = 8.2 Hz), 7.47-7.44 (m, 2H), 7.44-7.39 (m, 1H), 6.00 (d, 1H, J = 7.6 Hz), 4.12 (m, 5H), 2.94 (t, 2H, J = 1 1.9 Hz), 2.00 (m, 2H), 1.38 (m, 2H), 1.26 (dt, 3H, J = 7.2, 1.6 Hz); 13C NMR (100 MHz, CDCl3) δ 165.6, 156.3, 155.7, 146.3, 138.3, 137.8, 136.0, 133.2, 133.2, 132.4, 131.6, 130.2, 129.1, 126.2, 123.9, 61.7, 47.5, 43.0, 32.2, 14.9; MS (ES+, M+l) = 444.
General Procedure B- Iron-Catalyzed Alkyl-Iπu'doyl Chloride Cross-Coupling
[0297] A flame-dried flask was charged under argon with the imidoyl chloride (0.05 mmol), Fe(acac)3 (0.9 mg, 0.0025 mmol), THF (1 mL) and NMP (0.1 mL). A solution of alkylmagnesium halogen (2M in Et2O, 100 μL, 0.20 mmol) was slowly added to the resulting red solution, causing an immediate colour change to dark brown. The resulting mixture was stirred for 10 min, and the reaction was then carefully quenched with NH4Cl (aq) and diluted with Et2O. The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give the crude product. Purification by column chromatography (ethyl acetate/heptane/MeOH 1:1 :0.05) gave the product (60-90%). Example 15: (l l-Butyl-dibenzofb,fl fK41thiazepin-8-ylV [4-(2,4-Dimethyl-phenvlV piperazin-1-vH methanone.
Figure imgf000092_0001
[0298] The reaction was performed according to the general procedure B, which gave 18.7 mg (77%) of the titled compound. 1H NMR (400 MHz, CDCl3) δ 7.45 (m, 2H), 7.40-7.32 (m, 3H), 7.23 (d, 1H, J = 1.8 Hz), 7.08 (dd, 1H, J = 8.0, 1.8 Hz), 7.02 (br s, 1H), 6.98 (br d, 1H, J = 8.0 Hz), 6.89 (d, 1H, J = 8.0 Hz), 3.88 (br s, 2H), 3.58 (br s, 2H), 3.05-2.75 (m, 6H), 2.29 (s, 6H), 1.7 (m, 2H), 1.5 (m, 2H), 0.95 (t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 174.6, 169.7, 149.1, 148.6, 140.0, 139.0, 137.0, 133.5, 132.9, 132.8, 132.1, 130.8, 130.6, 128.8, 127.9, 127.4, 123.8, 123.8, 119.4, 42.3, 29.6, 22.7, 20.9, 17.8, 14.2; MS (ES+, M+l) = 484.
Example 16: f4-(2,4-Dimethyl-phenyl)-piperazin-1-y I]-(I l-pentyl-dibenzo[b,f] [1 ,41thiazepin-8-yl)methanone.
Figure imgf000092_0002
[0299] The reaction was performed according to the general procedure B, which gave 20.1 mg (81%) of the titled compound. 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 2H), 7.40-7.32 (m, 3H), 7.23 (d, I H, J = 1.6 Hz), 7.08 (dd, 1H, J = 8.0, 1.8 Hz), 7.02 (br s, 1H), 6.98 (br d, 1H, J = 8.0 Hz), 6.89 (d, 1H, J = 8.0 Hz), 3.88 (br s, 2H), 3.58 (br s, 2H), 3.05-2.75 (m, 6H), 2.29 (s, 6H), 1.7 (m, 2H), 1.5-1.2 (m, 4H), 0.95 (t, 3H, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) 6 174.9, 170.0, 149.3, 148.9, 140.3, 139.3, 137.3, 133.8, 133.1, 133.1, 132.4, 131.1 , 130.9, 129.0, 128.2, 127.6, 124.1, 119.7, 42.7, 32.0, 27.3, 22.9, 21.2, 18.1, 14.5; MS (ES+, M+l) = 498.
Example 17: [4-(2,4-Dimethyl-phenyl)-piperazin-1-yll-(l l-isobutyl-dibenzorb,f| rK41thiazepin-8-vQ methanone.
Figure imgf000093_0001
[0300] The reaction was performed according to the general procedure B, which gave 17.3 mg (72%) of the titled compound. MS (ES+, M-H) = 484.
Example 18: d l-Cvclohexyl-dibenzo[b,f1 rK41thiazepin-8-ylV f4-(2,4-dimethyl- phenvD-piperazin- 1 -y 11 methanone.
Figure imgf000093_0002
[0301] The reaction was performed according to the general procedure B, which gave 16.8 mg (66%) of the titled compound. MS (ES+, M+l) - 510
Example 19: [l l-(4-chloro-phenylVdibenzorb,f] fL41thiazepin-8-ylY144-(2,4-dimethyl- phenyl)-piperzin- 1 -yl]-methanone.
Figure imgf000093_0003
[0302] The reaction was performed according to the general procedure B, which gave 16.2 mg (60%) of the titled compound. MS (ES+, M) = 538.
Example 20: l l-Propyl-dibenzofb,f| [1,4]thiazepine-8-carboxylic acid piperidin-1- ylamide.
Figure imgf000094_0001
[0303] The reaction was performed according to the general procedure B, which gave 15.3 mg (81%) of the titled compound. MS (ES+, M+l) = 380.
Example 21 : l l-Butyl-dibenzo[b,f] [1,41thiazepine-8-carboxylic acid piperidin-1- ylamide.
Figure imgf000094_0002
[0304] The reaction was performed according to the general procedure B, which gave 15.8 mg (80%) of the titled compound. MS (ES+, M+l ) = 394.
Example 22: l l-Pentyl-dibenzofb,f] π,41thiazepine-8-carboxylic acid piperidin-1- ylamide.
Figure imgf000094_0003
[0305] The reaction was performed according to the general procedure B, which gave 16.1 mg (79%) of the titled compound. MS (ES+, M+l) = 408.
Example 23: l l-Isobutyl-dibenzo[b,f| [1 ,4]thiazepine-8-carboxylic acid piperidin-1- ylamide.
Figure imgf000095_0001
[0306] The reaction was performed according to the general procedure B, which gave 16.2 mg (82%) of the titled compound. MS (ES+, M+l) = 394.
Example 24: 11 -Cyclohexyl-dibenzof b,f| f1,41thiazepine-8-carboxylic acid piperidin-1- ylamide.
Figure imgf000095_0002
[0307] The reaction was performed according to the general procedure B, which gave 15.9 mg (76%) of the titled compound. MS (ES+, M+l) = 420.
Example 25: 4-|Yl l-Propyl-dibenzo|b,f| [1,41thiazepine-8-carbonyl)-aminol-piperidine-
1-carboxylic acid ethyl ester.
Figure imgf000095_0003
[0308] The reaction was performed according to the general procedure B, which gave 19.7 mg (87%) of the titled compound. MS (ES+, M+l) = 452. Example 26: 4-f(l l-Butyl-dibenzo[b,f| [1,41thiazepine-8-carbonylVamino]-piperidine- 1-carboxylic acid ethyl ester.
Figure imgf000096_0001
[0309] The reaction was performed according to the general procedure B, which gave 19.2 mg (83%) of the titled compound. 1H NMR (400 MHz, CD3OD) δ 7.45 (dd, 1H, J = 1.4, 0.8 Hz), 7.44-7.37 (m, 3H), 7.34-7.28 (m, 3H), 4.03 (q, 2H, J = 7.1 Hz), 4.03 (m, 2H), 3.92 (m, 1H), 3.00 (m, 1H), 2.84 (br t, 2H, J = 1 1.9), 2.78 (m, 1H), 1.80 (d, 2H, J = 12.5 Hz), 1.52 (m, 2H), 1.37 (m, 4H), 1.15 (t, 3H, J = 7.0 Hz), 0.83 (t, 3H, J = 7.4 Hz); MS (ES+, M+l) = 466.
Example 27: 4-f(l l-Pentyl-dibenzorb,f) fl ,41thiazepine-8-carbonyD-amino1-piperidine- 1-carboxylic acid ethyl ester.
Figure imgf000096_0002
[0310] The reaction was performed according to the general procedure B, which gave 20.1 mg (84%) of the titled compound. 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 4H), 7.39-7.32 (m, 3H), 5.89 (d, 1H, J = 7.6 Hz), 4.12 (q, 2H, J = 7.0 Hz), 4.10 (m, 3H), 2.92 (m, 4H), 1.98 (d, 2H, J = 1 1.9 Hz), 1.68 (m, 2H), 1.39 (m, 6H), 1.25 (t, 3H, J = 7.1 Hz), 0.90 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 174.6, 165.9, 155.4, 148.6, 139.6, 138.7, 135.3, 132.6, 132.0, 130.7, 128.6, 127.6, 123.9, 123.0, 61.4, 47.1, 42.7, 42.2, 32.0, 31.4, 26.8, 22.4, 14.6, 13.9; MS (ES+, M+l) = 480. Example 28: 4-1Y1 l-Isobutyl-dibenzo[b,f] rU41thiazepine-8-carbonylVaminol- piperidine-1-carboxylic acid ethyl ester.
Figure imgf000097_0001
[0311] The reaction was performed according to the general procedure B, which gave 17.3 mg (74%) of the titled compound. 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 4H), 7.39-7.31 (m, 3H), 5.98 (d, 1H, J = 7.8 Hz), 4.12 (q, 2H, J = 7.0 Hz), 4.10 (m, 3H), 3.03 (dd, 1H, J = 14.1, 5.5 Hz), 2.85 (t, 2H, J = 13.7 Hz), 2.63 (dd, I H, J = 14.1, 9.0 Hz), 1.98 (m, 3H), 1.35 (m, 2H), 1.25 (t, 3H, J = 7.1 Hz), 1.08 (d, 3H, J = 6.5Hz), 1.03 (d, 3H, J = 6.5 Hz); 13C NMR (100 MHz, CDCl3) δ 174.2, 166.2, 155.7, 148.8, 139.8, 139.0, 135.5, 132.9, 132.8, 132.4, 131.0, 128.9, 128.1, 124.3, 123.4, 61.6, 51.7, 47.4, 43.0, 42.2, 32.3, 27.3, 23.4, 22.4, 14.9; MS (ES+, M+l) = 466.
Example 29: 4-[(l l-Cyclohexyl-dibenzofb,f) f1,41thiazepine-8-carbonyl)-aminol- piperidine-1-carboxylic acid ethyl ester.
Figure imgf000097_0002
[0312] The reaction was performed according to the general procedure B, which gave 21.3 mg (87%) of the titled compound. MS (ES+, M+l) = 492.
Example 30: 4-[(l l-(4-chloro-phenyl)-dibenzofb1fj [L4]thiazepine-8-carbonyl)-aminol- piperidine-1-carboxylic acid ethyl ester.
Figure imgf000098_0001
[0313] The reaction was performed according to the general procedure B, which gave 18.2 mg (70%) of the titled compound. MS (ES+, M) = 520.
Example 30b: Alternative synthesis of 4-[Yl l-(4-chloro-phenyl)-dibenzofb,f] π^thiazepine-S-carbonyl)-aminol-piperidine-1-carboxylic acid ethyl ester.
[0314] 4- chlorophenylzinc iodide (0.5M in THF, 1 1.5 ml, 5.76 mmol) was added dropwise to 4-[(l l-chloro-dibenzo[b,f] [1,4]thiazepine-8-carbonyl)-amino]- piperidine-1-carboxylic acid ethyl ester (640 mg, 1.44 mmol), and PdCl2(PPhJ)2 (59 mg, 0.14 mmol, 0.1 eq) in dry THF (15 ml) at room temperature. After 30 min saturated aqueous NH4Cl and EtOAc was added and the aqueous phase was extracted once with EtOAc. The combined organic phases were washed with water, brine and then dried (Na2SO4). Filtration, concentration at reduced pressure of the organic phase followed by purification of the crude product by column chromatography (Heptane-EtOAc-MeOH 1:1:0.01) gave 730 mg (97 %) of the titled compound as yellow crystals. 1H NMR (400 MHz, acetone-d6) δ 7.82 (d, 2H, J - 8.8 Hz), 7.78 (d, 1H, J = 2.0 Hz), 7.62 (m, 3H), 7.58- 7.52 (m, 4H), 7.45 (dt, 1H, J- 8.8, 1.4 Hz), 7.29 (dd, 1H, J = 5.8, 1.6 Hz), 4.08 (m, 5H), 2.96 (m, 2H), 1.93 (m, 2H), 1.52 (m, 2H), 1.22 (t, 3H, 7.0 Hz); 13C NMR (100 MHz, acetone-d6) δ 167.8, 165.1, 155.1, 148.7, 140.4, 139.0, 136.9, 136.8, 136.6, 132.4, 132.0, 131.5, 131.3, 130.5, 128.9, 128.7, 124.9, 124.1, 60.8, 47.4, 42.9, 31.9, 14.3.
General Procedure C: Palladium catalyzed Negishi cross-coupling of imidoyl chlorides and arylzinc halides.
[0315] The arylzinc halide (3-5 eq) was added to the imidoyl chloride (10 mg) and PdCl2(PPh3)2 (10 mol%) in dry THF (1 ml) at room temperature. After 30 min saturated aqueous NH4Cl and EtOAc was added and the aqueous phase was extracted once with EtOAc. The combined organic phases were washed with water, brine and then dried (Na2SO4). Filtration, concentration at reduced pressure of the organic phase followed by purification of the crude product by column chromatography (Heptane- EtOAc 1 : 1) gave the product.
Example 31 : l l-phenyl-dibenzo[b,f| [1,41thiazepin-8-carboxylic acid piperidin-1- ylamide
Figure imgf000099_0001
[0316] The reaction was performed according to the general procedure C using l l-chloro-dibenzo[b,fj [1,4]thiazepin-8-carboxylic acid piperidin-1-ylamide and phenylzinc iodide, which gave 4.9 mg of the titled compound. MS (ES+, M+l) = 414.
Example 32: l l-(2-cyanophenyl)-dibenzo[b,f| rK41thiazepin-8-carboxylic acid piperidin- 1 -ylamide
Figure imgf000099_0002
[0317] The reaction was performed according to the general procedure C using 11 -chloro-dibenzo[b,fj [1,4]thiazepin-8-carboxylic acid piperidin-1-ylamide and 2- cyanophenylzinc iodide, which gave 5.4 mg of the titled compound. MS (ES+, M+l) = 439.
Example 33: l l-(3-bromophenylVdibenzofb,f1 π,4]thiazepin-8-carboxylic acid piperidin- 1 -ylamide
Figure imgf000100_0001
[0318] The reaction was performed according to the general procedure C using l l-chloro-dibenzo[b,f] [1,4]thiazepin-8-carboxylic acid piperidin-1-ylamide and 3- bromophenylzinc iodide, which gave 6.4 mg of the titled compound. MS (ES+, M+l) = 492.
Example 34: l l-(4-chlorophenylVdibenzo[b,f] fh4]thiazepin-8-carboxylic acid piperidin-1 -ylamide
Figure imgf000100_0002
[0319] The reaction was performed according, to the general procedure C using l l-chloro-dibenzo[b,fj [1,4]thiazepin-8-carboxylic acid piperidin-1-ylamide and 4- chlorophenylzinc iodide, which gave 5.4 mg of the titled compound. MS (ES+, M+l) = 439.
General Procedure D: Synthesis of Amidines
[0320] Imidoyl chloride 11 -chloro-dibenzo[b,fj [1,4]thiazepin-8-carboxylic acid piperidin-1-ylamide (5 mg, 0.013 mmol) was mixed with an excess of the appropriate amine in dry toluene. The reaction was shaken for 18 h at 80 degrees C. Concentration of the reaction mixture at reduced pressure gave a crude product, which was purified by column chromatography (ethyl acetate/heptane 1:1 to 3:1).
Example 35: 1 l-piperidinyl-dibenzo[b,f] ri,41thiazepin-8-carboxylic acid piperidin-1- ylamide
Figure imgf000101_0001
[0321] The reaction was performed according to the general procedure D using piperidine, which gave 2.8 mg of the titled compound. MS (ES+, M+l) = 421.
Figure imgf000101_0002
piperidin- 1 -ylamide
Figure imgf000101_0003
[0322] The reaction was performed according to the general procedure D using 7 mg (0.019 mmol) of the imidoyl chloride and morpholine, which gave 5.9 mg of the titled compound. MS (ES+, M+l) = 423.
Example 37: 1 l-(propylaminyl)-dibenzo[b,f] [1,4]thiazepin-8-carboxylic acid piperidin- 1 -ylamide
Figure imgf000101_0004
[0323] The reaction was performed according to the general procedure D using propyl amine except for applying lower reaction temperature (50 degrees), which gave 2.6 mg of the titled compound. MS (ES+, M+l) = 395.
Example 38: l l-(4-methylpiperazinyl>-dibenzo[b,fl π,41thiazepin-8-carboxylic acid piperidin- 1 -ylamide
Figure imgf000102_0001
[0324] The reaction was performed according to the general procedure D using 10 mg of the imidoyl chloride and methylpiperazine, which gave 7.6 mg of the titled compound. MS (ES+, M+l) = 436.
Example 39: l l-phenylaminyl-dibenzo[b,f| [Mlthiazepin-S-carboxylic acid piperidin- 1-ylamide
Figure imgf000102_0002
[0325] The reaction was performed according to the general procedure D using piperidine, which gave 2.6 mg of the titled compound. MS (ES+, M+l) = 429.
Synthesis of Carbon Analogs
Example 40: 4-(2-Methoxycarbonyl-benzvQ-3-nitro-benzoic acid ethyl ester
Figure imgf000102_0003
[0326] A solution of methyl 2-(bromomethyl)benzoate (261 mg, 1.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) in DME (2 mL) under argon was stirred at room temperature for lOmin. 4-Ethoxycarbonyl-2-nitrophenylboronic acid (308 mg, 1.29 mmol) dissolved in DME/EtOH 2:1 (3 mL) was added followed by 2M aq. Na2CO3 (2 mL) and stirring was continued for 2h. The reaction mixture was concentrated in vacuo and purified by column chromatography using EtOAc (0-10%) in heptane as the eluent furnishing 338 mg of 4-(2-Methoxycarbonyl-benzyl)-3-nitro- benzoic acid ethyl ester as a colorless solid (1.13 mmol, 65%).
[0327] 1H NMR (400MHz, CDCl3): 8.58 (d, 2H), 8.06 (dd, 1H), 8.02 (dd,
2H), 7.50 (dt, 1H), 7.38 (dt, 1H), 7.18 (d, 1H), 7.06 (d, 1H), 4.69 (s, 2H), 4.39 (q, 2H), 3.76 (s, 3H), 1.40 (t, 3H).
Example 41 : 4-(2-Carboxy-benzyl)-3-nitro-benzoic acid
Figure imgf000103_0001
[0328] A solution of 4-(2-Methoxycarbonyl-benzyl)-3-nitro-benzoic acid ethyl ester (159 mg, 0.46 mmol) in THF (14mL) and IM aq. LiOH (4.6 mL, 4.6 mmol) was stirred at 60 °C for 2h, then allowed to cool to room temperature. THF was removed at reduced pressure and the resulting aqueous mixture was treated with 2M HCl until the pH was about I. Filtration provided 93 mg (0.3 mmol, 67%) of 4-(2-Carboxy-benzyl)-3- nitro-benzoic acid as a yellow solid.
[0329] 1H NMR (400MHz, CD3OD): 8.49 (d, 1H), 8.06 (dd, 1H), 8.02 (dd,
1H), 7.53 (dt, 1H), 7.40 (dt, 1H), 7.26 (d, 1H), 7.12 (d, 1H), 4.69 (s, 2H).
Example 42: 3-Amino-4-(2-carboxy-benzyl*)-benzoic acid
Figure imgf000103_0002
[0330] A solution of 4-(2-Carboxy-benzyl)-3-nitro-benzoic acid (79mg, 0.26mmol) in MeOH (3mL) containing PtO2 (6mg) and Pd/C (7mg) was stirred under a hydrogen atmosphere for 2h at room temperature. Filtration and concentration in vacuo provided 71mg (0.267mmol, 100%) of 3-Amino-4-(2-carboxy-benzyl)-benzoic acid as yellow oil. [0331] 1H NMR (400MHz, CD3OD): 7.26 (dd, 1H), 7.44-7.38 (m, 2H), 7.32-
7.26 (m, 2H), 7.16 (d, 1H), 6.87 (d, 1H), 4.29 (s, 2H).
Example 43 : 6-0x0-6, 1 1 -dihydro-5H-dibenzo[b,e1azepine-3-carboxylic acid
Figure imgf000104_0001
[0332] To a stirred solution of 3-Amino-4-(2-carboxy-benzyl)-benzoic acid (70mg, 0.26mmol) in THF (3mL) at room temperature was added carbonyldiimidazole (167mg, 1.03mmol) in small portions and stirring was continued. After 4h, 4M HCl (3mL) was added followed by water. Filtration and drying provided 51mg (0.2mmol, 78%) of 6-Oxo-6,l l-dihydro-5H-dibenzo[b,e]azepine-3-carboxylic acid as a colourless solid. The product was further purified by crystallation from 2-propanol.
[0333] 1H NMR (400MHz, DMSO-d6): 10.58 (s, I H), 7.70-7.61 (m, 3H),
7.48-7.30 (m, 4H), 3.95 (s, 2H).
Example 44: 6-chloro- 1 1 H-dibenzo[b,elazepine-3-carboxylic acid piperidin- 1 -ylamide
Figure imgf000104_0002
[0334] A solution of 6-oxy-5,6-dihydro-l 1H-dibenzo[b,e]azepine-3- carboxylic acid (45 mg, 0.18 mmol) and phosphorus pentachloride (187 mg, 0.9 mmol) in 2 mL toluene was heated to 90 °C for 6 h. Toluene and excess of phosphorus pentachloride were removed at reduced pressure to give 60mg of 6-chloro- 11 H- dibenzo[£,e]azepine-3-carbonyl chloride. 1 -Aminopiperidine (0.078 ml, 0.7 mmol) dissolved in CH2Cl2 was added to the crude acid chloride dissolved in CH2Cl2 at room temperature. EtOAc and H2O were added to the reaction mixture after Ih. The H2O phase was extracted once with EtOAc and the combined organic phases were washed with saturated aqueous NaHCO3 and brine and dried (Na2SO4). Filtration and concentration at reduced pressure of the organic phase followed by purification of the crude product by column chromatography (heptane-EtOAc 1 :1) gave 25 mg (40%) of 6-chloro-l 1H- dibenzo[b,e]azepine-3-carboxylic acid piperidin-1-ylamide. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, 2H, J = 7.4 Hz), 7.68 (dd, 1H, J = 8.0, 1.8 Hz), 7.59 (s, 1H), 7.47 (dt, 1H, J = 7.4, 1.2 Hz), 7.33 (t, 1H, J= 7.6 Hz), 7.27 (t, 1H, J = 7.4 Hz), 3.74 (s, 2H), 2.83 (m, 4H), 1.72 (m, 4H), 1.42 (m, 2H); MS (ES+, M+l) = 354.
Example 45: 6-cyclohexyl-l 1H-dibenzorb,e]azepine-3-carboxylic acid piperidin-1- ylamide
Figure imgf000105_0001
[0335] The reaction was performed according to the general procedure for iron-catalyzed alkyl-imidoyl chloride cross coupling using 25 mg of 6-chloro-l 1H- dibenzo[b,e]azepine-3-carboxylic acid piperidin-1-ylamide and an excess (0.35 ml) of cyclohexylmagnesium chloride (2M). This gave 13.7 mg (49%) of 6-cyclohexyl-l 1H- dibenzo[b,e]azepine-3-carboxylic acid piperidin-1-ylamide. MS (ES+, M+l) = 402; UV/MS purity 100/100.
Synthesis of Oxygen Analogs
Example 46: 4-(2-Methoxycarbonyl-phenoxy)-3-nitro-benzoic acid ethyl ester
Figure imgf000105_0002
[0336] To a stirred solution of ethyl 4-fluoro-3-nitrobenzoate (2.53g, 11.87mmol) in DMF (4OmL) containing Cs2CO3 (4.26g, 13.06mmol) at 100 °C was added drop wise methyl salicylate (1.69mL, 13.06 mol) dissolved in DMF (40 mL) over 2h. After 15min the reaction mixture was allowed to reach room temperature and then diluted with EtOAc (10OmL) and washed with water (2xl00mL). The aqueous layer was extracted with DCM (10OmL). Drying (MgSO4) of the combined organic layers followed by filtration, concentration in vacuo and purification by CC using EtOAc (0-40%) in heptane provided 3.75g (10.85mmol, 91%) of 4-(2-Methoxycarbonyl-phenoxy)-3-nitro- benzoic acid ethyl ester as a yellow solid.
[0337] 1H NMR (400MHz, CDCl3): 8.60 (d, 1H), 8.04 (dt, 2H), 7.62 (dt, 1H),
7.38 (dt, 1H), 7.19 (dd, 1H), 6.73 (d, 1H), 4.37 (q, 2H), 3.71 (s, 3H), 1.38 (t, 3H).
Example 47: 4-(2-Carboxy-phenoxy)-3-nitro-benzoic acid
Figure imgf000106_0001
[0338] A solution of 4-(2-Methoxycarbonyl-phenoxy)-3-nitro-benzoic acid ethyl ester (3.68 mg, 10.65 mmol) in THF (200 mL) and I M aq. LiOH (100 mL, 100 mmol) was stirred at 60 °C for 2h, then allowed to cool to room temperature. THF was removed at reduced pressure and the resulting aqueous mixture was treated with 2 M HCl until the pH was about 1. Filtration provided 2.75g (9.08mmol, 85%) of 4-(2-Carboxy- phenoxy)-3-nitro-benzoic acid as a pale yellow solid.
[0339] 1H NMR (400MHz, CD3OD): 8.53 (d, 1H), 8.10 (dd, 1H), 8.04 (dd,
1H), 7.69 (dt, 1H), 7.42 (dt, 1H), 7.26 (dd, 1H), 6.82 (d, 1H).
Example 48: 3-Amino-4-(2-carboxγ-phenoxy)-benzoic acid
Figure imgf000106_0002
[0340] A solution of 4-(2-Carboxy-phenoxy)-3-nitro-benzoic acid (2.75 g, 9.08 mmol) in MeOH (80 mL) containing PtO2 (59 mg) and Pd/C (211 mg) was stirred for 2h under a hydrogen atmosphere at room temperature. Filtration and concentration in vacuo provided 2.47g (9.05 mmol, 100%) of 3-Amino-4-(2-carboxy-phenoxy)-benzoic acid as a pale yellow solid.
[0341] 1H NMR (400 MHz, CD3OD): 7.89 (dd, 1H), 7.54-7.47 (m, 2H), 7.31
(dt, 1H), 7.21 (dt, 1H), 6.97 (d, 1H), 6.68 (d, 1H).
Example 49: 1 l-Oxo-10,1 l-dihydro-dibenzo|"b,f]π,41oxazepine-8-carboxylic acid
Figure imgf000107_0001
[0342] To a stirred solution of 3-Amino-4-(2-carboxy-phenoxy)-benzoic acid (2.44 g, 0.26 mmol) in THF (100 mL) at room temperature was added carbonyldiimidazole (3.7 g, 22.8 mmol) in small portions and stirring was continued. After 4 h, 4 M HCl (100 mL) was added followed by cupious amounts of water. Filtration and drying followed by crystallization (2-propanol) provided 1.017 g (3.99 mmol, 45%) of 1 l-Oxo-10,1 l-dihydro-dibenzo[b,fj[1,4]oxazepine-8-carboxylic acid as white crystals.
[0343] 1H NMR (400 MHz, DMSO-d6): 10.61(s, 1H), 1.11 -1.1 A (m, 2H), 7.67
(dd, 1H), 7.60 (dt, 1H), 7.39 (d, 1H), 7.34 (d, 1H) 7.31 (dt, 1H).
Example 50: U-Chloro-dibenzollxfjπ^oxazepine-S-carboxylic acid piperidin-1- ylamide
Figure imgf000107_0002
[0344] To a stirred solution of 11-Oxo- 10,1 1 -dihydro- dibenzo[b,f][1,4]oxazepine-8-carboxylic acid (476 mg, 1.86 mmol) in toluene (20 mL) and thionyl chloride (20 mL) was added DMF (0.5 mL) and stirring was continued at 80 °C for 19 h. The reaction mixture was concentrated in vacuo and re-dissolved in anhydruos DCM (20 mL) and added to a solution of 1 -aminopiperidine (604 μL, 5.59 mmol) dissolved in DCM (20 mL) at 0 °C and stirring was continued for 2h. The resulting reaction mixture was concentrated in vacuo and purified by CC using EtOAc (0- 70%) in heptane affording 353 mg (0.99 mmol, 53%) of 11-Chloro- dibenzo[b,f][1,4]oxazepine-8-carboxylic acid piperidin-1-ylamide as a pale yellow solid.
[0345] 1H NMR (400 MHz, CDCl3): 7.77-7.72 (m, 2H), 7.63 (s, 1H), 7.53 (dt,
1 H), 7.22 (dt, 1 H), 7.18 (dd, 1 H), 2.92 (br s), 1.76 (br s), 1.43 (br s).
Example 51: l l-Cvclohexyl-dibenzo[b,flri,4]oxazepine-8-carboxylic acid piperidin-1- ylamide
Figure imgf000108_0001
[0346] To a flame dried flask loaded with Fe(acac)3 under argon was added sequentially l l-Chloro-dibenzofbjflfl^joxazepine-S-carboxylic acid piperidin-1-ylamide (79mg, 0.22mmol) dissolved in dry THF, NMP (0.5mL) and a 2M etheral solution of cyclohexylmagnesium chloride (440μL, 0.88mmol) at -78 °C and the reaction micture was allowed to slowly reach ambient temperature. After additionally 2h sat aq NH4Cl (5mL) was added followed by EtOAc (1OmL). After separation of the layers, the aq layer was extracted with EtOAc (2x1 OmL). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and purified by CC using EtOAc (0-50%) in heptane as the eluent affording 89mg (0.22mmol, 100%) of the 1 1-Cyclohexyl- dibenzo[b,f][1,4]oxazepine-8-carboxylic acid piperidin-1-ylamide as a grey solid.
[0347] 1H NMR (400MHz, CDCl3): 7.65 (br s, 1H), 7.63 (br s, 1H), 7.45-7.39
(m, 2H), 7.21 (dt, 1H), 7.15 (dd, 2H), 3.10 (br s), 2.91 (tt), 1.97 (d), 1.85 (br s), 1.74 (d), 1.61 (dd), 1.50 (br s), 1.42-1.29 (m), 1.25 (br s), 0.89-0.85 (m).
Example 52: l l-Phenyl-dibenzo[b,f]f1,41oxazepine-8-carboxylic acid piperidin-1- ylamide
Figure imgf000109_0001
[0348] The title compound was synthesised by the same procedure as for preparation of l l-cyclohexyl-dibenzo[6,/][1,4]oxazepine-8-carboxylic acid piperidin-1- ylamide using l l-chloro-dibenzotό./Jtl^Joxazepine-δ-carboxylic acid piperidin-1- ylamide (19 mg; 0.05 mmol), phenylmagnesium bromide (3M in diethyl ether; 100 μL; 0.3 mmol), Fe(acac)3 (3 mg) and NMP (50 μL) in 1 mL dry THF. The titled copound was purified by preparative HPLC. Yield: 5.3 mg. LCMS m/z 398 [M+H]+. HPLC /R = 7.76 min.
Example 53: 1 l-(4-Fluorophenyl)-dibenzo[d,/1f1,4]oxazepine-8-carboxylic acid piperidin- 1 -ylamide
Figure imgf000109_0002
[0349] The title compound was synthesised by the same procedure as for preparation of l l-cyclohexyl-dibenzo[6,/][1,4]oxazepine-8-carboxylic acid piperidin-1- ylamide using l l-chloro-dibenzo[ό,/J[1,4]oxazepine-8-carboxylic acid piperidin-1- ylamide (19 mg; 0.05 mmol), 4-fluorophenylmagnesium bromide (2M in diethyl ether; 150 μL; 0.3 mmol), Fe(acac)3 (3 mg) and NMP (50 μL) in 1 mL dry THF. The titled copound was purified by preparative HPLC. Yield: 3.9 mg. LCMS m/z 416 [M+H]+. HPLC tκ = 7.97 min.
Example 54: 1 l^-ChlorophenylVdibenzofά./iri^ioxazepine-S-carboxylic acid piperidin- 1 -ylamide
Figure imgf000110_0001
[0350] The title compound was synthesised by the same procedure as for preparation of l l-cyclohexyl-dibenzo[fr,/][l ,4]oxazepine-8-carboxylic acid piperidin-1- ylamide using l l-chloro-dibenzo[ό,/J[1,4]oxazepine-8-carboxylic acid piperidin-1- ylamide (19 mg; 0.05 mmol), 4-chlorophenylmagnesium bromide (IM in diethyl ether; 300 μL; 0.3 mmol), Fe(acac)3 (3 mg) and NMP (50 μL) in 1 mL dry THF. The titled copound was purified by preparative HPLC. Yield: 2.1 mg. LCMS m/z 432 [M+H]+, 434 [M+2+H]+. HPLC tR = 8.63 min.
Example 55: 1 l-(3-Chlorophenyl)-dibenzo[ά,/][L41oxazepine-8-carboxylic acid piperidin- 1 -ylamide
Figure imgf000110_0002
[0351] The title compound was synthesised by the same procedure as for preparation of 1 l-cyclohexyl-dibenzo[6,/][1,4]oxazepine-8-carboxylic acid piperidin-1- ylamide using l l-chloro-dibenzo[ό,/][1,4]oxazepine-8-carboxylic acid piperidin-1- ylamide (19 mg; 0.05 mmol), 3-chlorophenylzinc iodide (0.5M in THF; 600 μL; 0.3 mmol) and PdCl2(Ph3P)2 (3 mg) in 1 mL dry THF. The titled copound was purified by preparative HPLC. Yield: 8.7 mg. LCMS m/z 432 [M+H]+, 434 [M+2+H]+. HPLC /R = 8.63 min.
Synthesis of 8-bromo analogs:
Example 56: 2-(4-Bromo-2-nitrophenylsulfanyl) benzoic acid methyl ester
Figure imgf000111_0001
[0352] 5-Bromo-2-fluoronitrobenzene (1.23 mL; 10.0 mmol) and Cs2CO3 (3.58 g; 11.0 mmol) was mixed in 30 mL DMF and heated to 7O°C. A solution of methyl 2-mercaptobenzoate (1.5 mL mg; 10.9 mmol) in 30 mL DMF was added dropwise over 15 min. The heating was turned of and the mixture left stirring overnight at room temperature. Water and ethyl acetate was added and the aqueous layer extracted twice with ethyl acetate/heptane. After separation of the phases, the organic phase was washed twice with water, before drying over sodium sulphate, filtration and concentration in vacuo. Purification was done by silica gel column chromatography (0-30 % ethyl acetate in heptane) to afford the title compound as a yellow solid (3.61 g; 98%).
[0353] 1H NMR (400 MHz, CDCl3) δ 8.30 (d, 1H, J = 2.4), 7.95 - 7.92 (m,
1H), 7.54 - 7.45 (m, 4H), 6.86 (d, 1H, J- 8.4), 4.82 (s, 3H). HPLC tκ = 4.97 min.
Example 57: 2-(4-Bromo-2-nitrophenylsulfanyl) benzoic acid
Figure imgf000111_0002
[0354] Ester 2-(4-bromo-2-nitrophenylsulfanyl) benzoic acid methyl ester (3.57 g; 9.7 mmol) was dissolved in 120 mL THF and IM LiOH (aq, 60 mL) added. The solution was heated to 70 °C and stirred at that temperature for 2 hours. The temperature was allowed to cool to room temperature over 3 hours and THF was removed at reduced pressure. The remaining aqueous mixture was extracted once with EtO Ac/heptane (1 : 1, 75 mL). HCl (2M) was then added to the resulting aqueous solution until pH 2. The precipitates were collected by filtration, washed with water and finally dried, which afforded the title compound as a yellow solid (2.82 g; 82%) that was used without further purification. [0355] 1H NMR (400 MHz, CD3OD) δ 8.59 (d, 1H, J= 2.0), 8.02 (dd, 1H, J =
2.0, 8.8), 7.94-7.90 (m, 1H), 7.65-7.57 (m, 3H), 7.08 (d, 1H, J = 8.8).
Example 58: 2-(2-Amino-4-bromophenylsulfanyl) benzoic acid
Figure imgf000112_0001
[0356] 2-(4-Bromo-2-nitrophenylsulfanyl) benzoic acid (1.1 g; 3.1 mmol) was dissolved in 100 mL absolute ethanol and a catalytic amount of palladium on activated carbon was added. The reaction flask was evacuated and equipped with a balloon containing hydrogen. This procedure was repeated twice before the mixture was left stirring overnight at room temperature. The reaction mixture was filtered through a pad of celite and the solvent removed by evaporation to give the crude product (930 mg; 93 %) that was used without further purification. LCMS m/z 324 [M+H]+, 326 [M+2+H] , HPLC /R = 10.28 min.
Example 59: 8-Bromo-10//-dibenzo[6J]fL4]thiazepin-l l-one
Figure imgf000112_0002
[0357] 2-(2-Amino-4-bromophenylsulfanyl) benzoic acid (930 mg; 2.87 mmol) was dissolved in 25 mL dry THF and CDI was added (1.4 g mg; 8.61 mmol). The mixture was stirred at room temperature for 2'Λ days before addition of 4 M aqueous HCl and water. The title compound precipitates and was collected by filtration to afford the desired lactam as colourless crystals (4.45 g; 85 %). LCMS m/z 306 [M+H]+, 308 [M+2+H] , HPLC tR = 3.87 min.
Example 60: 8-Bromo-l l-chloro-dibenzo[6JirL4]thiazepine
Figure imgf000113_0001
[0358] Lactam 8-bromo-10H-dibenzo[6,/][1,4]thiazepin-l 1-one (748 mg; 2.44 mmol) was mixed with thionyl chloride (18 mL) in toluene (18 mL). DMF was added (200 μL) and the mixture stirred for 3 hours. After cooling the solvents were removed by evaporation under reduced pressure. Purification was done by silica gel column chromatography (0 - 20 % ethyl acetate in heptane) to afford the imidoyl chloride as a white powder. LCMS m/z 324 [M+H]+, 326 [M+2+H]\ 328 [M+4+H]+ , HPLC tR ='6.00 min.
[0359] The following compounds (Examples 61-66) are examples of compounds synthesised from 8-bromo-l l-chloro-dibenzo[6,/][l ,4]thiazepine according to the general procedure for palladium catalysed Negishi couplings and the procedures described by Pandya et al. J. Org. Chem. (2003), 68, 8274-8276 and Sezen and Sames et al., Org. Lett. (2003), 5, 3607-3610, which are both incorporated by reference in their entireties.
Example 61 : 8-Bromo-l l-(4-chlorophenyl)-dibenzo[ά,/)f 1,4]thiazepine
Figure imgf000113_0002
Example 62: 1 l-(4-Chlorophenyl)-dibenzo[6,/][1,41thiazepine-8-sulfonic acid butylamide
Figure imgf000114_0001
Example 63: 1 l-(4-Chlorophenyl)-dibenzo[b,f][1,4]thiazepine-8-sulfonic acid piperidin- 1 -ylamide
Figure imgf000114_0002
Example 64: 1 l-(4-Chlorophenyl)-8-oxazol-2-yl-diben2o[b,f][1,4]thiazepine
Figure imgf000114_0003
Example 65: 1 l-(4-Chlorophenyl)-8-thiazol-2-yl-dibenzo[b,f][1,4]thiazepine
Figure imgf000114_0004
Example 66: 11 -(4-Chlorophenyl)-8-imidazol-2-yl-dibenzof6,/]jl ,4]thiazepine
Figure imgf000115_0001
Synthesis of 2-fluoro analogs:
Example 67: 4-(4-Fluoro-2-ethoxycarbonylphenylsulfanylV3-nitrobenzoic acid ethyl ester
Figure imgf000115_0002
[0360] Ethyl 4-fluoro-3-nitrobenzoate (953 mg; 4.47 mmol) and Cs2CO3 (1.54 g; 4.72 mmol) were mixed in 20 mL DMF and heated to 8O°C. A solution of ethyl 5- fluoro-2-mercaptobenzoate (808 mg; 4.34 mmol) in 20 mL DMF was added dropwise over 15 min. The heating was turned of and the mixture left stirring overnight at room temperature. Water and ethyl acetate was added and the aqueous layer extracted twice with ethyl acetate/heptane. The combined organic phases were washed with water before drying over sodium sulphate, filtration and evaporation of the solvents. Purification was done by silica gel column chromatography (0-10 % THF in heptane) to afford the title compound as a yellow oil (1.55 g; 94%).
[0361] 1H NMR (400 MHz, CDCl3) δ 8.84 (d, 1H, J - 2.0), 7.96 (dd, 1H, J =
1.6, 8.4), 7.67 - 7.62 (m, 2H), 7.32 - 7.27 (m, 1H), 6.87 (d, 1H, J = 8.4), 4.38 (q, 2H, J = 7.2), 4.23 (q, 2H, J = 7.2), 1.38 (t, 3H, J = 7.2), 1.17 (t, 3H, J = 7.2). LCMS m/z 394 [M+H]+ , HPLC /R = 5.43 min. Example 68: 4-(4-Fluoro-2-carboxyphenylsulfanylV3-nitrobenzoic acid
Figure imgf000116_0001
[0362] Diester 4-(4-fluoro-2-ethoxycarbonylphenylsulfanyl)-3-nitrobenzoic acid ethyl ester (1.45 g; 3.8 mmol) was dissolved in 100 mL THF and IM LiOH (aq, 30 mL) added. The solution was heated to 70 °C and stirred at that temperature for 4 hours. The temperature was allowed to cool to room temperature and THF was removed at reduced pressure. The remaining aqueous mixture was extracted once with EtOAc. HCl (2M) was then added to the resulting aqueous solution until pH 2. The precipitates were filtered off, washed with water and finally dried, which afforded the title compound (1.22 g; 99%).
[0363] 1H NMR (400 MHz, CD3OD) 6 8.77 (d, 1H, J = 1.6), 8.00 (dd, 1H, J =
2.0, 8.4), 7.78 - 7.73 (m, 2H), 7.45 (dt, 1H, J= 3.2, 8.4), 7.01 (d, 1H, J= 8.8).
Example 69: 3-Amino-4-(4-fluoro-2-carboxyphenylsυlfanvπbenzoic acid
Figure imgf000116_0002
[0364] Diacid ,4-(4-fluoro-2-carboxyphenylsulfanyl)-3-nitrobenzoic acid (728 mg; 2.16 mmol), was dissolved in 50 mL absolute ethanol and stannous chloride, dihydrate (2.43 g; 10.8 mmol) was added. The temperature was raised to 70 °C and the temperature attained for 15 min. The heating was turned of and the flask slowly allowed to reach room temperature. Water was added and the aqueous phase extracted with ethyl acetate (3 times). The combined organic phases were washed extensively with brine, before drying over sodium sulphate, filtration and removal of the solvent by evaporation. The crude product was obtained as a pale yellow powder (320 mg; 48 %) that was used without further purification.
[0365] 1H NMR (400 MHz, CD3OD) δ 7.70 (dd, 1H, J = 2.8, 9.2), 7.50 (d,
1H, J - 2.0), 7.44 (d, 1H, J = 8.0), 7.33 - 7.29 (m, 1H), 7.12 - 7.05 (m, I H), 6.74 (dd, 1H, J= 4.8, 9.2).
Example 70: 2-Fluoro-l l-oxo-10,1 l-dihydro-dibenzo[6,/1[1,4]thiazepine-8-carboxylic acid
Figure imgf000117_0001
[0366] 3-Amino-4-(4-fluoro-2-carboxyphenylsulfanyl)benzoic acid (320 mg; 1.04 mmol) was dissolved in 10 mL dry THF and CDI was added (675 mg; 4.17 mmol). The mixture was stirred at room temperature for 2'Λ days before addition of 4 M aqueous HCl and water. The title compound precipitates and was collected by filtration to afford the desired lactam as colourless crystals (199 mg; 66 %).
[0367] 1H NMR (400 MHz, DMSO-J6) δ 7.82 - 7.75 (m, 1 H), 7.54 - 7.52 (m,
3H), 7.51 - 7.42 (m, 1H), 7.40 - 7.29 (m, 1H).
Example 71 : 1 l-Chloro-4-fluoro-dibenzori>,/]f 1 ,4]thiazepine-8-carbonyl chloride
Figure imgf000117_0002
[0368] The lactam 2-fluoro-l 1-oxo- 10,1 1 -dihydro- dibenzo[ό,/][1,4]thiazepine-8-carboxylic acid (199 mg; 0.69 mmol) was mixed with thionyl chloride (8 mL) in toluene (8 mL). DMF (100 μL) was added and the mixture stirred at 80°C overnight. After cooling the solvents were removed by evaporation under reduced pressure to afford the crude, yellow dichloride as a powder that was used immediately without further purification. Example 72: l l-Chloro-2-fluoro-dibenzor6,/)|'l ,4'|thiazepine-8-carboxylic acid (2- phenylpropyD-amide
Figure imgf000118_0001
[0369] The title compound was synthesized by the general procedure for amide formation using l l-chloro-4-fluoro-dibenzo[6,/][1,4]thiazepine-8-carbonyl chloride (~ 0.35 mmol), 8 mL dry dichloromethane and 2-phenylpropylamine (300 μL; 2.0 mmol). Yield: 87 mg (-30%).
[0370] LCMS m/z 425 [M+H]+, 427 [M+2+H]+ , HPLC tR = 5.40 min
Example 73: l l-Chloro-2-fluoro-dibenzo[6,/][1,41thiazepme-8-carboxylic acid (3- chlorobenzyl)-amide
Figure imgf000118_0002
[0371] The title compound was synthesized by the general procedure for amide formation using l l-chloro-4-fluoro-dibenzo[o,/][1,4]thiazepine-8-carbonyl chloride (~ 0.35 mmol), 8 mL dry dichloromethane and 3-chlorobenzylamine (252 μL; 2.0 mmol). Yield: 117 mg (-34%). LCMS m/z 431 [M+H]+, 433 [M+2+H]+ , 436 [M+4+H]+ . HPLC tκ = 5.40 min.
Example 74: 1 l-(4-Chlorophenyl")-2-fluoro-dibenzo^,/iπ,41thiazepine-8-carboxylic acid (2-phenγlpropylVamide
17
Figure imgf000119_0001
[0372] The title compound was synthesized by the general procedure for palladium catalyzed Negishi cross-coupling of amidoimidoyl chlorides and arylzinc halides using l l-chloro^-fluoro-dibenzofb./JtMlthiazepine-S-carboxylic acid (2- phenylpropyl)-amide (29 mg; 0.067 mmol) and 4-chlorophenylzinc iodide (0.5 M in THF). The compound was purified by preparative HPLC. Yield: 4.3 mg. LCMS m/z 501 [M+H]+, 503 [M+2+H]+. HPLC tR = 6.68 min.
Example 75: 1 l-(3-Chlorophenyl)-2-fluoro-dibenzorό,/iri 141thiazepine-8-carboxylic acid (2-phenylpropylVamide
Figure imgf000119_0002
[0373] The title compound was synthesised by the general procedure for palladium catalyzed Negishi cross-coupling of amidoimidoyl chlorides and arylzinc halides using l l-chloro-2-fluoro-dibenzo[6,/][1,4]thiazepine-8-carboxylic acid (2- phenylpropyl)-amide (29 mg; 0.067 mmol) and 3-chlorophenylzinc bromide (0.5 M in THF). The compound was purified by preparative HPLC. Yield: 5.3 mg. LCMS m/z 501 [M+H]+, 503 [M+2+H]+. HPLC /R = 6.65 min.
18 Example 76: 2-Fluoro-l l-piperidm4-yl-dibenzor6,/lfM1thiazepine-8-carboxylic acid (2-phenylpropyl)-amide
Figure imgf000120_0001
[0374] The title compound was synthesised by the general procedure for synthesis of amidines using l l-chloro^-fluoro-dibenzo^/Jfl^thiazepine-δ-carboxylic acid (2-phenylpropyl)-amide (29 mg; 0.067 mmol) and piperidine. The title compound was purified by preparative HPLC. Yield: 8.3 mg. LCMS m/z 474 [M+H]+. HPLC /R = 5.65 min.
Example 77: 1 l-(3-Chlorophenyl)-2-fluoro-dibenzo[6,/1|~L41thiazepine-8-carboxylic acid (3-chlorobenzvP-amide
Figure imgf000120_0002
[0375] The title compound was synthesised by the general procedure for palladium catalyzed Negishi cross-coupling of amidoimidoyl chlorides and arylzinc halides using 1 l-chloro-2-fluoro-dibenzo[ά,/J[1,4]thiazepine-8-carboxylic acid (3- chlorobenzyl)-amide (22 mg; 0.052 mmol) and 3-chlorophenylzinc bromide (0.5 M in THF). The compound was purified by preparative HPLC. Yield: 2.3 mg. LCMS m/z 507 [M+H]+, 509 [M+2+Hf. HPLC tκ = 6.73 min.
Example 78: 1 l-(4-Chlorophenyl)-2-fluoro-dibenzo[ά,/][K4]thiazepine-8-carboxylic acid (3-chlorobenzylVamide
Figure imgf000121_0001
[0376] The title compound was synthesised by the general procedure for palladium catalyzed Negishi cross-coupling of amidoimidoyl chlorides and arylzinc halides using l l-chloro^-fluoro-dibenzof^/Jfl^jthiazepine-δ-carboxylic acid (3- chlorobenzyl)-amide (22 mg; 0.052 mmol) and 4-chlorophenylzinc iodide (0.5 M in THF). The compound was purified by preparative HPLC. Yield: 5.6 mg. LCMS m/z 507 [M+H]+, 509 [M+2+H]+. HPLC (κ = 6.78 min.
Example 79: l l-Cyclohexyl-2-fluoro-dibenzo[ά,/]f1,41thiazepine-8-carboxylic acid (3- chlorobenzvD-amide
Figure imgf000121_0002
[0377] The title compound was synthesised by the general procedure for iron catalyzed cross-couplings using l l-chloro-2-fluoro-dibenzo[ό,/l[1,4]thiazepine-8- carboxylic acid (3-chlorobenzyl)-amide (22 mg; 0.052 mmol) and cyclohexylmagnesium chloride (2 M in diethyl ether). The compound was purified by preparative HPLC. Yield: 5.7 mg. LCMS m/z 479 [M+H]+, 481 [M+2+H]+. HPLC tR = 7.37 min. Example 80: 2-Fluoro-l l-pipqridin-1-yl-dibenzorά,/]π,41thiazepine-8-carboxylic acid (3-chlorobenzvD-amide
Figure imgf000122_0001
[0378] The title compound was synthesised by the general procedure for synthesis of amidines using l l-chloro^-fluoro-dibenzo^/jfl^Jthiazepine-δ-carboxylic acid (3-chlorobenzyl)-amide (22 mg; 0.052 mmol) and piperidine. The title compound was purified by preparative HPLC. Yield: 6.5 mg. LCMS m/z 480 [M+H]+. HPLC /R = 5.77 min.
Synthesis of 3-fluoro and 3-chloro analogs
Examples 81-104
[0379] The synthesis of 3-fluoro and 3-chloro analogs are synthesized using 4- fluoro-2-mercaptobenzoic acid and 3-chloro-2-mercaptobenzoic acid according to the procedures in Marciano et al., Bioorg. Med. Chem. Lett. (1997), 7, 1709-1714, which is incorporated by reference in its entirety.
[0380] The following compounds are examples several of 3-fluoro and 3- chloro analogs:
Figure imgf000123_0001
Figure imgf000123_0002
Figure imgf000123_0003
Figure imgf000124_0001
Figure imgf000124_0002
Figure imgf000124_0003
Alternative synthesis of 3-chloro analogs:
Scheme 23:
Figure imgf000125_0001
Example 105: 4-fer(-Butylsulfanyl-3-nitrobenzoic acid ethyl ester
Figure imgf000125_0002
[0381] As shown in Scheme 23, ethyl 4-fluoro-3-nitrobenzoate (3.86 g; 18.1 mmol) was dissolved in 90 mL dry DMF together with cesium carbonate (1 1.8 g; 36.2 mmol). ter/-Butylmercaptane (8.15 mL; 72.4 mmol) was added and the mixture was stirred at room temperature for 45 min. Water (50 mL) and ethyl acetate (50 mL) was added and the phases separated. The organic layer was washed with water (2 x 50 mL) followed by drying over magnesium sulfate. After filtration and evaporation 4.95 g (97 %) of a crude yellow oil was isolated that was used without further purification.
[0382] R/-= 0.25 (EtO Ac/heptane 30:70). 1H NMR (CDCl3, 400 MHz) δ 8.32 (d, 1H, J- 2.0, ArH6), 8.10 (dd, 1H, J= 2.0, 8.0, ArH2), 7.75 (d, 1H, J = 8.0, ArH5), 4.37 (q, 2H, J= 7.2, OCH2), 1.38 (t, 3H, J = 7.2, CH3), 1.35 (s, 9H, fBu). Example 106: 4-Mercapto-3-nitro benzoic acid ethyl ester
Figure imgf000126_0001
[0383] Trifluoroacetic acid (90 mL) was added to a solution of 4-tert- butylsulfanyl-3-nitrobenzoic acid ethyl ester (4.65 g; 16.4 mmol) in 20 mL dichloromethane. The mixture was stirred for 3 days at room temperature before evaporation of the solvent. The residue was partitioned between dichloromethane and 1 M aqueous sodium carbonate. After acidification of the aqueous phase using 4M HCl the desired compound was extracted from the aqueous layer with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The crude compound was used in the next step without purification (1.86 g, 50%).
Example 107: 2-(4-(EthoxycarbonylV2-nitrophenylsulfanyl)-4-chlorobenzoic acid
Figure imgf000126_0002
[0384] To a mixture of 4-chloro-2-iodobenzoic acid (1.02 g; 3.62 mmol), copper(I) iodide (72.2 mg; 0.17 mmol) and potassium carbonate (947 mg; 6.82 mmol) under argon was added 4-mercapto-3-nitrobenzoic acid ethyl ester (776 mg; 3.41 mmol), ethylene glycol (380 μL; 6.82 mmol) and 10 mL 2-propanol. The mixture was stirred at 80°C for 1 'Λh before cooling to room temperature where stirring was attained overnight. Water, 4M HCl and ethyl acetate were added. After separation of the phases the organic phase was washed several times with water, before drying over magnesium sulfate and concentration in vacuo. Purification was done by silica gel column chromatography (0- 8% methanol in dichloromethane) to afford the desired compound as yellow crystals (921 mg; 71%).
[0385] 1H NMR (CDCl3, 400 MHz) δ 8.80 (d, 1H, J = 2.0, ArH), 8.10 - 8.02
(m, 2H, ArH), 7.54 - 7.51 (m, 2H, ArH), 7.07 (d, 1H, J = 8.8, ArH), 4.41 (q, 2H, J = 7.2, OCH2), 1.41 (t, 3H, J = 7.2, CH3). LCMS m/z 399 [M+NH4]+, purity (UWMS) 94/84, rR= 7.86 min.
Example 108: 4-(3-Chloro-6-carboxyphenylsulfanyl>3-nitrobenzoic acid
Figure imgf000127_0001
[0386] 2-(4-(Ethoxycarbonyl)-2-nitrophenylsulfanyl)-4-chlorobenzoic acid (892 mg; 2.34 mmol) was dissolved in a mixture of IM LiOH (aq, 1 1 mL) and THF (35 mL). The reaction mixture was stirred at 70°C for 4 hours. Upon addition of 4M HCl a yellow oil precipitated from the aqueous layer which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness affording 1.25 g of which only the majority could be dissolved in ethyl acetate leaving a white solid. After filtration precipitates were accomplished with copious amounts of heptane to afford the title compound as a yellow solid (682 mg; 82%).
[0387] LCMS m/z 371 [M+NH4]+, ^R = 0.67 min.
Example 109: 3-Amino-4-(3-chloro-6-carboxyphenylsulfanyl)benzoic acid
Figure imgf000127_0002
[0388] A solution of 4-(3-chloro-6-carboxyphenylsulfanyl)-3-nitrobenzoic acid (680 mg; 1.92mmol) and potassium carbonate (1.32 g; 9.61 mmol) in 40 mL water was cooled to 0°C. Sodium dithionite (1.67 g; 9.61 mmol) was added portionwise over 5 min. When the shiny yellow colour had disappeared the reaction mixture was allowed to reach room temperature. Drops of 4M HCl were added until precipitates appeared. Ethyl acetate was added (10 mL) and after separation of the layers the organic phase was concentrated in vacuo to afford the title compound as a white crystalline solid. Used immediately without purification. Example 110: 3-Chloro-l l-oxo-10,1 l-dihvdro-dibenzo[fe,/1[1,41thiazepine-8-carboxylic acid
Figure imgf000128_0001
[0389] 3-Amino-4-(3-chloro-6-carboxyphenylsulfanyl)benzoic acid (~1.92 mmol) was dissolved in 20 mLdry THF at room temperature. 1,1-Carbonyldiimidazole (1.51 g; 1.52 mmol) was added portionwise and the mixture stirred at room temperature for 2 hours. 4 mL 4M HCl was added ensued by 10 mL of water. The colourless precipitate was collected by filtration to afford the desired compound as a white solid (159 mg; 27% over two steps).
[0390] LCMS m/z 306 [M+H]\ purity (UV/MS) 98/-, (R = 3.47 min.
Example 1 1 1 : l l-Chloro-3-chloro-dibenzoF6,/1[L4]thiazepine-8-carboxylic acid butyl amide
Figure imgf000128_0002
[0391] 3-Chloro-l l-oxo-10,1 l-dihydro-dibenzo[6,/][1,4]thiazepine-8- carboxylic acid (38.5 mg; 0.13 mmol), thionyl chloride (2 mL), iV,iV-dimethylformamide (100 μL) and toluene (2 mL) was heated to 100°C for 4 hours. The crude mixture was concentrated to dryness to leave the crude acid and imidoyl chloride. The trichloride was redissolved in 5 mL dry dichloromethane and cooled to 0°C. A solution of «-butyl amine (37 μL; 0.38 mmol) in 2 mL dry dichloromethane was added and the mixture stirred for 1 hour. After evaporation of the solvent the residue was purified by silica gel column chromatography (0-30% ethyl acetate in heptane) to afford 27.5 mg of a white solid (58 %).
[0392] LCMS m/z 379 [M+H]+, purity (UV/MS) 100/100, tR= 4.70 min. Example 112: 1 l-(4-Chlorophenyl)-3-chloro-dibenzofάJ|[lΛ]thiazepine-8-carboxylic acid butyl amide
Figure imgf000129_0001
[0393] A reaction flask was charged with l l-Chloro-3-chloro-dibenzo[&,/] [1,4]thiazepine-8-carboxylic acid butyl amide (27.5 mg; 0.073 mmol) and bis(triphenylphosphine) palladium(ΪI) chloride (3.3 mg; 0.047 mmol) under argon. 4 mL dry tetrahydrofuran was added and followed by addition of 4-chlorophenylzinc iodide (0.5 M in tetrahydrofuran, 290 μL; 0.145 mmol) at room temperature. The mixture was stirred for 1A hour before evaporation of the solvent. The crude residue was purified by silica gel column chromatography (0-10% ethyl acetate in heptane) to afford the title compound as a yellow oil (25.7 mg; 78 %).
[0394] 1H NMR (CDCl3, 400 MHz) δ 7.75 - 7.71 (m, 2H, ArH), 7.66 (t, 1H, J
= 1.2, ArH), 7.57 (d, 1H, J - 2.0, ArH), 7.51 (d, 2H, J = 1.2, ArH), 7.44 - 7.40 (m, 2H, ArH), 7.30 (dd, 1H, J = 2.0, 8.4, ArH), 7.10 (d, 1H, J = 8.0, ArH), 6.09 (br m, I H, NH), 3.47 - 3.41 (m, 2H, NCH2), 1.63 - 1.54 (m, 2H, CH2), 1.46 - 1.35 (m, 2H, CH2), 0.95 (t, 3H, J = 7.2, CH3). 13C NMR (CDCl3, 100 MHz) δ 167.3, 166.6, 148.8, 141.9, 138.3, 137.7, 136.4, 135.3, 133.0, 132.3, 131.5, 131.4, 131. T, 128.9*, 128.8, 124.6, 124.0, 40.1 , 31.9, 20.3, 14.0. 'Denotes double intensity. LCMS m/z 454 [M+H]+, purity (UV/MS) 100/77, rR= 6.88 min.
Synthesis of sulfoxide and sulfone analogs:
[0395] The sulfoxides and sulfones described below (Examples 1 13 - 121) were synthesized from compounds that have been described previously.
Example 1 13: N-(4-Fluorobenzyl)-l l-(4-chlorophenyl)-5-oxo-5H-5λ4- dibenzofά,/UT,41thiazepine-8-carboxamide
[0396] 7V-(4-Fluorobenzyl)-l l-(4-chlorophenyl)-dibenzo[ό,/][l ,4]thiazepine- 8-carboxamide (182 mg, 0.385 mmol) was suspended in acetic acid (25 mL). Hydrogen peroxide (35% aqueous solution: 1.65 mL) was added dropwise to the suspension at room temperature. After ~ 5 hours stirring at room temperature the reaction mixture became clear yellow solution. The stirring was continued overnight at room temperature. The reaction mixture was slowly poured into saturated aqueous sodium bicarbonate (150 mL) - vigorous gas liberation. The neutralized mixture (pH~7) was extracted with DCM. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulphate, filtered and evaporated to dryness. The residue was a mixture of the desired product and the corresponding 5,5-dioxo compound. Purification of the crude mixture by silica gel column chromatography, eluting with a stepwise gradient of 10-30% ethyl acetate in toluene, afforded the desired compound (54 mg, 29 %). R/ = 0.20 (EtOAc/Toluene 20:80).
[0397] 1H NMR (CDCl3, 300 MHz) δ 7.91-7.70 (m, 7H, Ar-H), 7.50-7.44 (m,
3H, Ar-H), 7.35-7.27 (m, 3H, Ar-H), 7.03 (m, 2H, Ar-H), 6.56 (m, I H, NH), 4.61 (m, 2H, CH2PhF). LCMS m/z 489 [M+H]+ HPLC /R= 5.1 min.
Example 1 14: yV-(4-Fluorobenzyl)-l l-(4-chlorophenyl)-5,5-dioxo-5//-5λ6- dibenzofά,/irU41thiazepine-8-carboxamide
Figure imgf000130_0002
[0398] The desired compound was isolated from the crude mixture, which was obtained during the preparation of N-(4-fluorobenzyl)-l l-(4-chlorophenyl)-5-oxo- 5H-5λ4-dibenzo[ό,/][1,4]thiazepine-8-carboxamide. Purification by silica gel column chromatography eluting with a stepwise gradient of 10-30% ethyl acetate in toluene, afforded the desired compound (46 mg, 23 %). R7= 0.41 (EtO Ac/Toluene 20:80).
[0399] 1H NMR (CDCl3, 300 MHz) δ 8.19-8.15 (m, 2H, Ar-H), 7.89-7.66 (m,
6H, Ar-H), 7.47 (m, 3H, Ar-H), 7.33 (m, 2H, Ar-H), 7.06 (m, 2H, Ar-H), 6.50 (m, 1H, NH), 4.63 (m, 2H, CH2PhF). LCMS m/z 505 [M+H]+ HPLC /R = 5.1 min.
Example 1 15: N-O-Chlorobenzyl)-l l-(4-fluorophenyl)-5-oxo-5H-5X4- dibenzo[ά,/in,41thiazepine-8-carboxamide
Figure imgf000131_0001
[0400] N-(3-Chlorobenzyl)-l l-(4-fluorophenyl)-dibenzo[ό,/J[1,4]thiazepine- 8-carboxamide (25 mg; 0.05 mmol) was dissolved in DCM (3 mL) and 3- chloroperbenzoic acid (26 mg; 0.15 mmol) was added. The mixture was stirred at room temperature for 1 hour. At this point TLC showed full conversion of the starting material and formation of 2 products. The reaction mixture was diluted with DCM and washed three times with saturated aqueous sodium bicarbonate to extract excess 3- chloroperbenzoic acid/The organic phase was dried over sodium sulphate, filtered and evaporated to dryness. Purification was done by silica gel column chromatography eluting with 20-50 % ethyl acetate in heptane to give the title compound (9.9 mg).
[0401] 1H NMR (acetone-^, 400 MHz) δ 8.42 (br s, 1H), 8.01-7.95 (m, 3H),
7.90-7.83 (m, 3H), 7.75 (d, 1H, J = 8.0), 7.61 (m, 1H), 7.44-7.40 (m, 2H), 7.34-7.25 (m, 4H), 4.61 (d, 2H, J= 6.0). LCMS m/z 489 [M+H]+, 491 [M+2+H]+ HPLC /R = 4.97 min.
Example 1 16: 3-Chlorobenzyl)-l l-(4-fluorophenyl)-5,5-dioxo-5//-5λ6- dibenzof6JlfL41thiazepine-8-carboxamide
Figure imgf000132_0001
[0402] The desired compound was isolated from the crude mixture, which was obtained during the preparation of vV-(3-chlorobenzyl)-l l-(4-fluorophenyl)-5-oxo- 5H-5λ4-dibenzo[ό,/][1,4]thiazepine-8-carboxamide. Purification by silica gel column chromatography eluting with a stepwise gradient of 20-50% ethyl acetate in heptane, afforded the desired compound (2.3 mg).
[0403] 1H NMR (acetone-^, 400 MHz) δ 8.18-8.06 (m, 3H), 7.98-7.85 (m,
5H), 7.65-7.62 (m, 1H), 7.44-7.42 (m, 1H), 7.36-7.26 (m, 5H), 4.66-4.61 (m, 2H), 3.44 (q, 2H, J= 7.2), 1.58 (m, 2H, J- 7.2), 1.39 (m, 2H, J= 7.2), 0.94 (t, 3H, J= 7.2). LCMS m/z 505 [M+H]+, 507 [M+2+H]+ HPLC tR = 5.08 min.
Example 117: iV-butyl-1 l-(4-chlorophenvn-5-oxo-5//-5λ4-dibenzor6./iπ,41thiazepine-8- carboxamide
Figure imgf000132_0002
[0404] N-Butyl-l l-(4-chlorophenyl)-dibenzo[^,/][1,4]thiazepine-8- carboxamide (86 mg; 0.2 mmol) was dissolved in acetic acid (20 mL) and methanol (15 mL). Hydrogen peroxide (-35% in water; 1 mL) was added. The reaction mixture was stirred at room temperature for 5 hours before it was neutralized by addition of saturated aqueous sodium bicarbonate. The aqueous solution was extracted with DCM (3 x 10 mL) and the combined organic phases were washed with water before drying over sodium sulphate, filtration and evaporation of the solvent in vacuo. The resulting residue was purified by silica gel column chromatography (20 - 50% ethyl acetate in heptane) followed by preparative TLC on silica eluting 4 times with 5% ethyl acetate in heptane to give the desired compound (20.1 mg; 23%). [0405] 1H NMR (CDCl3, 400 MHz) δ 7.92 - 7.89 (m, 1H), 7.80-7.76 (m, 3H),
7.74-7.68 (m, 3H), 7.49 - 7.42 (m, 3H), 7.26 (dd, 1H, J = 0.8, 7.6), 6.21 (m, 1H), 3.44 (q, 2H, J= 7.2), 1.58 (m, 2H, J= 7.2), 1.39 (m, 2H, J= 7.2), 0.94 (t, 3H, J= 7.2). LCMS m/z 437 [M+H]+, 439 [M+2+H]+ HPLC fc = 4.83 min.
Example 118: iV-butyl-l l-(4-chlorophenyl)-5,5-dioxo-5H-5λ6- dibenzofft,flπ,41thiazepine-8-carboxamide
Figure imgf000133_0001
[0406] N-Butyl-l l-(4-chlorophenyl)-dibenzo[6J][1,4]thiazepine-8- carboxamide (70 mg; 0.17 mmol) was dissolved in DCM (10 mL) and 3- chloroperbenzoic acid (225 mg; 1.0 mmol) was added. After 4 hours stirring at room temperature the mixture was diluted with DCM (20 mL) and washed with saturated aqueous sodium hydrogen carbonate (3 x 15 mL). The organic phase was dried over sodium sulphate, filtered and evaporated to dryness. Purification by preparative TLC eluting twice with 50% ethyl acetate in heptane afforded the title compound (7.9 mg; 10 %).
[0407] 1H NMR (acetone-*/*, 400 MHz) δ 8.18 - 8.13 (m, 1H), 8.08 (d, 1H1 J
= 8.0), 8.01 (d, 1H, J = 1.6), 7.94 - 7.86 (m, 5H), 7.67m - 7.58 (m, 3H), 3.42 (q, 2H, J = 7.4), 1.60 (qn, 2H, J = 7.4), 1.40 (m, 2H, J = 7.4), 0.93 (t, 3H, J = 7.4). LCMS m/z 453 [M+H]+, 455 [M+2+H]+ HPLC /R = 7.93 min.
Example 119: l l-(l-Oxy-piperidin-1-ylVdibenzor6,/]rK41thiazepine-8-carboxylic acid 3- chlorobenzylamide (A) and 5-oxo-l l-piperidin-1-yl-5H-5λ4-dibenzolά,ή-ri,41thiazepine- 8-carboxylic acid 3-chlorobenzylamide (B)
Figure imgf000134_0001
[0408] l l-Piperidinyl-dibenzo[ό,/J[1,4]thiazepine-8-carboxylic acid 3- chlorobenzyl-amide (280 mg; 0.61 mmol) was dissolved in acetic acid (20 mL) and hydrogen peroxide (-35% in water; 2 mL) added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was neutralized by addition of aqueous saturated NaHCO3. The aqueous solution was extracted with DCM (3 x 10 mL) and the combined organic phases were washed with water before drying over sodium sulphate, filtration and evaporation of the solvent in vacuo. Formation of two products was observed by TLC (A: R/ 0.06; B: R/ 0.25; 1 :1 EtO Ac/heptane). Both products were isolated by preparative TLC on aluminium oxide eluting twice with 50% ethyl acetate in heptane. Yield: A: 3.0 mg; B: 33 mg as a fine white powder.
[0409] A: LCMS m/z 478 [M+H]+, 480 [M+2+H]+. HPLC tκ = 4.13 min.
[0410] B: 1H NMR (400 MHz, CD3Cl) δ 7.83 (dd, 1H, J = 1.2, 7.6), 7.63 - 7.57 (m, 2H), 7.53 (dd, 1H, J - 2.0, 8.4), 7.44 (dt, 1H, J = 1.2, 7.6), 7.39 (d, 1H, J= 1.6), 7.31 (dd, 1 H, J = 1.2, 7.6), 7.29 - 7.15 (m, 4H), 6.64 (m, 1 H), 4.55 (d, 2H, J = 6.0), 3.85 - 3.30 (br s, 2H), 1.72 - 1.45 (m, 8H). LCMS m/z 478 [M+H]+, 480 [M+2+H]+. HPLC tR = 4.65 min.
Example 120: 5,5-Dioxo-l l-piperidin-1-yl-5H-5λ4-dibenzo[6,/irU4]thiazepine-8- carboxylic acid 3-chlorobenzylamide
Figure imgf000134_0002
[0411] l l-Piperidinyl-dibenzo[ό,/)[1,4]thiazepine-8-carboxylic acid 3- chlorobenzyl-amide (259 mg; 0.56 mmol) was dissolved in DCM (15 mL) and 3- chloroperbenzoic acid (275 mg; 1.23 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with 20 mL DCM and washed with saturated aqueous NaHCO3 (3 x 15 mL) before drying over sodium sulphate, filtration and removal of the solvent by evaporation under reduced pressure. The crude product was purified by preparative TLC on silica eluting twice with 10% ethyl acetate in heptane to give the title compound (33 mg; 12%).
[0412] 1H NMR (400 MHz, CD3Cl) δ 8.00 (d, 1H, J = 8.0), 7.92 (d, 1H, J =
8.4), 7.64 (m, 2H), 7.52-7.45 (m, 2H), 7.41 (m, 1H), 7.30-7.17 (m, 4H), 6.46 (m, I H), 4.60-4.55 (m, 2H), 3.49 (br s, 2H), 1.92-1.44 (m, 8H). LCMS m/z 494 [M+H]+, 496 [M+2+H]+. HPLC tR = 4.93 min.
Example 121: 1 l-Cvclohexyl-5,5-dioxo-5//-5λ4-dibenzo[ά,/][1,41thiazepine-8-carboxylic acid 4-fluorobenzylamide
Figure imgf000135_0001
[0413] l l-Cyclohexyl-dibenzo[6,/]-[1,4]thiazepine-8-carboxylic acid (4- fluorobenzyl)amide (1 10 mg; 0.25 mmol) was dissolved in DCM (10 mL) and 3- chloroperbenzoic acid (84 mg; 0.37 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with 10 mL DCM and washed with saturated aqueous NaHCO3 (3 x 10 mL) before drying over sodium sulphate, filtration and removal of the solvent by evaporation under reduced pressure. The crude product was purified by preparative TLC on silica eluting 4 times with 5% EtOAc in heptane to give the title compound (2.2 mg). LCMS m/z All [M+H]+. HPLC /R = 5.25 min.
Synthesis of NitroRen Analogs:
Example 122: 8-Chloro-l l-(4-fluorophenyl)-5H-dibenzo|Λeiπ,4|diazepine
Figure imgf000135_0002
[0414] Bis(triphenylphosphine)palladium(II) chloride was added to a solution of 8,l l-dichloro-5H-dibenzo[6,e][1,4]diazepine (100 mg, 0.38 mmol) in anhydrous THF (10 mL) at room temperature under argon atmosphere, followed by addition of 4- fluorophenylzinc bromide (2.28 ml, 1.14 mmol). After 3 hours stirring at room temperature the reaction mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was dried over sodium sulphate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with 30% ethyl acetate in «-heptane, afforded the desired product (88 mg, 72%). R/= 0.38 (EtOAc/n-Heptane 30:70). LCMS m/z 323 [M+H]+ HPLC rR= 5.6 min.
Example 123: 7V-(4-Fluorobenzyl)-l l-(4-fluorophenyr)-5H-dibenzo[6,e][1,4]diazepine-8- carboxamide
Figure imgf000136_0001
[0415] The desired compound was synthesized using a literature procedure in Lagerlund et al., J. Comb. Chem. (2006), 8, 4-6, which is hereby incorporated by reference in its entirety. 8-Chloro-l l-(4-fluorophenyl)-5H-dibenzo[ό,e][l ,4]diazepine (40 mg, 0.12 mmol) was reacted with 4-fluorobenzylamine (46 mg, 0.37 mmol), molybdenum hexacarbonyl (32 mg, 0.12 mmol), trans-di-(μ-acetato)-bis[ø-(di-ø- tolylphosphino) benzyl]dipalladium(II) (2.3 mg, 0.025 mmol), tri-/er/-butylphosphine tetrafluoroborate (1.7 mg, 0.05 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (56 mg, 0.37 mmol) in anhydrous TΗF (0.5 mL). The reaction mixture was heated in a sealed flask for 20 minutes at 170° C under microwave irradiation. The reaction mixture was partitioned between DCM and weak acidic aqueous layer (10 mL water was acidified with 2-3 drops of concentrated HCl). The organic layer was dried over sodium sulphate, filtered and evaporated to dryness. Purification of the residue using a silica gel column chromatography, eluting with a stepwise gradient of 20 to 50% ethyl acetate in n-heptane, afforded the title compound (16 mg, 30%). R7= 0.19 (EtOAc/rc-Ηeptane 50:50). 104161 1H NMR (CDCl3, 300 MHz) 6 7.75-7.53 (m, 4H5 Ar-H), 7.40-7.26 (m,
3H, Ar-H), 7.18-6.92 (m, 6H, Ar-H), 6.87-6.76 (m, 2H, Ar-H), 6.69-6.54 (m, 1H, NH), 5.79-5.56 (m, 1H, NH), 4.59 (m, 2H, CH2PhF). LCMS m/z 440 [M+H]\ HPLC /R = 4.6 min.
Example 124: N-Butyl-1 l-(4-fluorophenyl)-5H-dibenzoffr,e][1,4|diazepine-8- carboxamide
Figure imgf000137_0001
[0417] The title compound was synthesized from 8-chloro-l l-(4- fluorophenyl)-5//-dibenzo[6,e][1,4]diazepine (25 mg, 0.077 mmol) and «-butylamine (17 mg, 0.23 mmol) using the same procedure as for synthesis of N-(4-fluorobenzyl)-l l-(4- fluorophenyl)-5H-dibenzo[b,e][1,4]diazepine-8-carboxamide. R/ = 0.32 (EtO AcIn- Ηeptane 50:50). LCMS m/z 388 [M+Η]\ HPLC tR = 4.4 min.
Example 125: 1 l-(4-FluorophenyiyN-(l-phenylethyl)-5H-dibenzof6,el[l ,4]diazepine-8- carboxamide
Figure imgf000137_0002
[0418] The title compound was synthesized from 8-chloro-l l-(4- fluorophenyl)-5H-dibenzo[6,e][1,4]diazepine (25 mg, 0.077 mmol) and DL-1-phenylethyl amine (28 mg, 0.23 mmol) using the same procedure as for synthesis of N-(4- fluorobenzyl)-l l-(4-fluorophenyl)-5//-dibenzo[ό,e][1,4]diazepine-8-carboxamide. R/ = 0.33 (EtOAc/«-Ηeptane 50:50). LCMS m/z 436 [M+H]+. HPLC tR= 4.7 min.
Example 126: 8-Chloro-l l-C4-fluorophenyl)-5-methyl-5H-dibenzor6,giri,41diazepine
Figure imgf000138_0001
[0419] Sodium hydride (60% suspension in an mineral oil: 18 mg, 0.38 mmol) was added to a solution of 8-chloro-l l-(4-fluorophenyl)-5H-dibenzo[ό,e][1,4]diazepine (60 mg, 0.19 mmol) in dry DMF (2 mL) at room temperature. After 10 minutes shaking at room temperature, the reaction mixture became green and iodomethane (25 μL, 0.38 mmol) was added. The reaction mixture was shaken for 2 hours at 50°C and then at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with 4% aqueous magnesium sulphate, dried over sodium sulphate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with 10% ethyl acetate in «-heptane, afforded the title compound (40 mg, 60%). R/ = 0.47 (EtOAc/rt-Heptane 30:70). LCMS m/z 337 [M+H]+. HPLC /R= 6.4 min.
Example 127: N-(4-Fluorobenzyl)-l l-(4-fluorophenyl)-5-methyl-5H- dibenzor6,eiri,41diazepine-8-carboxamide
Figure imgf000138_0002
[0420] The title compound was synthesized from 8-chloro-l l-(4- fluorophenyl)-5-methyl-5H-dibenzo[6,e][1,4]diazepine (20 mg, 0.060 mmol) and 4- fluorobenzyl amine (22 mg, 0.18 mmol) using the same procedure as for synthesis of N- (4-fluorobenzyl)-l l -(4-fluorophenyl)-5H-dibenzo[ό,e][1,4]diazepine-8-carboxamide. R/ - 0.32 (EtOAc/«-Ηeptane 50:50). LCMS m/z 454 [M+H]+. HPLC tR= 5.0 min.
Example 128: 1 [8-Chloro-1 l-(4-fluorophenyl)-dibenzo|Λe][M1diazepin-5-vπethanone
Figure imgf000139_0001
[0421] iV,N-Dimethyl amine (40 mg, 0.33 mmol) was added to a solution of 8- chloro-l l-(4-fluorophenyl)-5H-dibenzo[6,e][1,4]diazepine (108 mg, 0.33 mmol) in dry TΗF (2 mL) at room temperature, followed by addition of acetyl chloride (70 μL, 0.99 mmol). The reaction mixture was shaken overnight at 60°C, allowed to cool to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and evaporated to dryness. The crude mixture was passed over a short silica gel column using a mixture of ethyl acetate and ^-heptane (30:70) as the eluant. The isolated fractions were a mixture of the desired compound and a side product. The fractions were left on standing over the weekend. The desired compound was crystallized in the fractions and it was isolated by filtration (69 mg, 60%). Ry= 0.20 (EtOAc/rt-Ηeptane 50:50). LCMS m/z 365 [M+Η]+. HPLC /R = 5.0 min.
Examples 129-146
[0422] The following compounds are examples of nitrogen analogs synthesized from 8,1 l-dichloro-5H-dibenzo[Z?,e][1,4]diazepine according to the general procedure for palladium catalysed Negishi couplings followed by reductive amination and/or alkylation reactions:
Figure imgf000140_0001
Figure imgf000141_0001
140 Series A
Library synthesis; formation of amidoimidoyl chlorides
[0423] The amidoimidoyl chlorides (Examples 147 - 162) were synthesized according to the general procedure for amide formation at 0.5 mmol scale except that the reaction mixture was passed through a pad of acidic alumina oxide and eluted with a mixture of CH2Cl2 and EtOAc. The eluents were concentrated at reduced pressure and the obtained crude products were directly used in the next reactions without further purifications or characterization.
Example 147: 1 l-(chloro)-dibenzo[b,f][1,41thiazepin-8-yl-(piperidin-1-ylVmethanone
Figure imgf000142_0001
[0424] 173 mg
Example 148: N-benzyl-1 l-(chloro)-dibenzorb,fiπ,4]thiazepine-8-carboxamide
Figure imgf000142_0002
[0425] 148 mg
Example 149: N-d-phenylethylVl l-CchloroVdibenzofb^fiflΛithiazepine-S-carboxamide
Figure imgf000142_0003
[0426] 168 mg Example 150: N-(butyO-l l-(chloro)-dibenzo[b,f|[1,41thiazepine-8-carboxamide
Figure imgf000143_0001
[0427] 138 mg
Example 151 : N-(3-phenylpropyl)- 11 -(chloro")-dibenzofb,fir 1 ,4]thiazepine-8- carboxamide
Figure imgf000143_0002
[0428] 167 mg
Example 152: N-(2-phenylethylVl l-(chloroVdibenzorb,f|ri,41thiazepine-8-carboxamide
Figure imgf000143_0003
[0429] 160 mg
Example 153: N-(2-chlorobenzyl)-l l-(chloro)-dibenzo[b,firi,41thiazepine-8- carboxamide
Figure imgf000143_0004
[0430] 161 mg Example 154: N-(2,4-dichlorobenzyQ-l l-(chloroydibenzofb,f||"1,4]thiazepine-8- carboxamide
Figure imgf000144_0001
[0431] 120 mg
Example 155: N-(2-(4-chlorophenyr)ethyl)-l l-(chloro)-dibenzorb,fiπ,41thiazepine-8- carboxamide
Figure imgf000144_0002
[0432] 167 mg
Example 156: N-(2-(3-chlorophenyl)ethyl)-l l-(chloro)-dibenzo|b,f|ri ,41thiazepine-8- carboxamide
Figure imgf000144_0003
[0433] 171 mg
Example 157: N-(3-chlorobenzyl)-l l-(chloro)-dibenzo|b,f|[1,4]thiazepine-8- carboxamide
Figure imgf000145_0001
[0434] 176 mg
Example 158: N-(2-bromobenzyl)-l l-(chloro)-dibenzoPχf[π Althiazepine-8- carboxamide
Figure imgf000145_0002
[0435] 180 mg
Example 159: N-(2-phenyl-propyl)-l l-(chloro)-dibenzo[b,f|fh41thiazepine-8- carboxamide
Figure imgf000145_0003
[0436] 172 mg
Example 160: N-((N-ethyl-N-phenyl)aminoethylVl l-(chloro)- dibenzo[b,f|π,41thiazepine-8-carboxamide
Figure imgf000145_0004
[0437] 168 mg
Figure imgf000146_0001
amide
Figure imgf000146_0002
[0438] 160 mg
Example 162: N-(4-fluorobenzyl)-l l-(chloro)-dibenzorb, ,fiπ,41thiazepine-8- carboxamide
Figure imgf000146_0003
[0439] 120 mg
Series B
[0440] The following compounds were prepared according to the general procedure for the synthesis of amidines starting from the appropriate imidoylchloride (15 mg) and piperidine (excess).
Example 163: 1 l-(piperidinyl)-dibenzofb,f][1,4]thiazepin-8-yl-(piperidin-1-yl)- methanone
Figure imgf000146_0004
[0441] 2.8 mg, UV/MS purity 100/97
Example 164: N-benzyl-1 l-(piperidinyl)-dibenzo[b,f1[1,4]thiazepine-8-carboxamide
Figure imgf000147_0001
[0442] 15.9 mg, UV/MS purity 100/91
Example 165: N-(l-phenylethyl>-l l-(piperidinyiydibenzofb,f)fh4'|thiazepine-8- carboxamide
Figure imgf000147_0002
[0443] 6.2 mg, UV/MS purity 88/54
Example 166: N-(butylVl l-(piperidinylVdibenzorb,firK41thiazepine-8-carboxamide
Figure imgf000147_0003
[0444] 15.1 mg, UV/MS purity 98/80
Example 167: N-(3-phenylpropyl>l l-(piperidinylVdibenzo[b,fiπ,41thiazepine-8- carboxamide
Figure imgf000148_0001
[0445] 16.7 mg mg, UV/MS purity 100/77
Example 168: N-(2-phenylethyl)-l l-(piperidinyl)-dibenzorb,f)[l ,41thiazepine-8- carboxamide
Figure imgf000148_0002
[0446] 14.5 mg, UV/MS purity 99/76
Example 169: N-(2-chlorobenzyl)-l l-(piperidinylVdibenzo[b,f|[K4]thiazepine-8- carboxamide
Figure imgf000148_0003
[0447] 15.2 mg, UV/MS purity 99/73
Example 170: N-(2,4-dichlorobenzyl)-l l-(piperidinyl)-dibenzofb,Fiπ,41thiazepine-8- carboxamide
Figure imgf000148_0004
[0448] 13.2 mg, UV/MS purity 100/73
Example 171 : N-(2-(4-chlorophenyl)ethyl)-l l-(piperidinyl)-dibenzorb,f|[1,4]thiazepine- 8-carboxamide
Figure imgf000149_0001
[0449] 10.7 mg, UV/MS purity 100/79
Figure imgf000149_0002
8-carboxamide
Figure imgf000149_0003
[0450] 8.4 mg, UV/MS purity 99/67
Example 173: N-(3-chlorobenzyl)-l l-(piperidinylVdibenzo[b,f|[1,41thiazepine-8- carboxamide
Figure imgf000149_0004
[0451] 12.9 mg, UV/MS purity 98/72
Example 174: N-(2-bromobenzylV 1 l-(pipendinylVdibenzo[b,f|[1,4]thiazepine-8- carbpxarnide
Figure imgf000150_0001
[0452] 16.2 mg, UV/MS purity 100/76
Example 175: N-(2-phenyl-propyl)-l l-(piperidinyl)-dibenzo[b,f|[1,4]thiazepine-8- carboxamide
Figure imgf000150_0002
[0453] 14.2 mg, UV/MS purity 100/72
Example 176: N-(Q^-ethyl-N-phenyl)aminoethyiyi l-(piperidiny^)- dibenzofb,fU1,4^thiazepine-8-carboxam^de
Figure imgf000150_0003
[0454] 6.0 mg, UV/MS purity 82/60
Figure imgf000150_0004
4-yl amide
Figure imgf000150_0005
[0455] 5.9 mg, UV/MS purity 100/78
Example 178: N-(4-fluorobenzy1H l-(piperidinyiydibenzorb,fl|"h41thiazepine-8- carboxamide
Figure imgf000151_0001
[0456] 14.7 mg, UV/MS purity 95/53
Series C
[0457] The following compounds were prepared according to the general procedure for an iron-catalyzed alkyl-imidoyl chloride cross-coupling starting from the appropriate imidoylchloride (15 mg) and cyclohexylmagnesium chloride (6eq). When the reactions were completed saturated ammonium chloride (1 ml) and EtOAc (2 ml) were added to the reaction mixtures. The organic phases were passed through a short silica column (eluted with EtOAc). After concentration at reduced pressure, the obtained crude products were purified by preparative HPLC.
Example 179: 1 l-(cvclohexyl)-dibenzo[b,fl[1,4]thiazepin-8-yl-(piperidin-1-yl')- methanone
Figure imgf000151_0002
[0458] 0.6 mg, UV/MS purity 90/90
Example 180: N-benzyl-1 l-(cvclohexylVdibenzo[b,f|[1,4]thiazepine-8-carboxamide
Figure imgf000152_0001
[0459] 5.1 mg, UV/MS purity 98/83
Example 181: N-d-phenylethy1H l-('cvclohexyl)-dibenzo[b,f||'1,4]thiazepine-8- carboxamide
Figure imgf000152_0002
[0460] 2.2 mg, UV/MS purity 98/87
Example 182: N-Cbuty1H l-(cyclohexyl)-dibenzorb,firi,41thiazepine-8-carboxamide
Figure imgf000152_0003
[0461] 4.6 mg, UV/MS purity 98/91
Figure imgf000152_0004
carboxamide
Figure imgf000152_0005
[0462] 4.5 mg, UV/MS purity 99/85 Example 184: N-(2,4-dichlorobenzylVl l-CcyclohexylVdibenzorb^Mithiazepine-S- carboxamide
Figure imgf000153_0001
[0463] 1.8 mg, UV/MS purity 100/82
Example 185: N-(2-(4-chlorophenyl)ethylyi l-(cyclohexylVdibenzofb,f1f 1,4]thiazepine- 8-carboxamide
Figure imgf000153_0002
[0464] 5.9 mg, UV/MS purity 100/87
Figure imgf000153_0003
8-carboxamide
Figure imgf000153_0004
[0465] 6.6 mg, UV/MS purity 99/90
Example 187: N-(3-chlorobenzyl>l l-Ccyclohexyiydibenzoπ^fiπ^thiazepine-S- carboxamide
Figure imgf000154_0001
[0466] 4.8 mg, UV/MS purity 99/87
Example 188: N-(2-bromobenzylVl l-(cvclohexylVdibenzo[b,f|[1,4]thiazepine-8- carboxamide
Figure imgf000154_0002
[0467] 0.8 mg, UV/MS purity 100/83
Example 189: N-(2-phenyl-propyl)-l l-(cyclohexyI)-dibenzo[b1fl[1,4'|thiazepine-8- carboxamide
Figure imgf000154_0003
[0468] 5.3 mg, UV/MS purity 93/83
Example 190: N-CCN-ethyl-N-phenyHaminoethylVl l-CcyclohexylV dibenzofb,firi,41thiazepine-8-carboxamide
Figure imgf000155_0001
[0469] 3.2 mg, UV/MS purity 98/79
Example 191 : l l-(cyclohexyl)-dibenzo|"b,f|fK41thiazepin-8-carboxylic acid morpholin- 4-yl amide
Figure imgf000155_0002
[0470] 3.8 mg, UV/MS purity 96/75
Example 192: N-(4-fluorobenzyl)-l l-(cyclohexyl)-dibenzo[b,f][U41thiazepine-8- carboxamide
Figure imgf000155_0003
[0471] 3.6 mg, UV/MS purity 98/74
Series D-H
[0472] The following compounds were prepared according to the general procedure for Negishi cross coupling starting from the appropriate imidoylchloride (15 mg) and arylzinc halide (8eq). Ammonium chloride (0.02 ml) was added to the reaction mixtures, which were then passed through a short column (Na2SCVsUiCa) using EtOAc as eluent. The eluents were concentrated at reduced pressure and the crude products were purified by preparative HPLC or by column chromatography (Heptane-EtOAc 4:1-1:1).
Series D
[0473] The arylzinc halide used for Examples 193 - 205 was 3- chlorophenylzinc iodide.
Example 193: 1 l-(3-chlorophenyl)-dibenzo[b/|[1,41thiazepin-8-yl-(piperidin-1-yO- methanone
Figure imgf000156_0001
[0474] 9.9 mg, UV/MS purity 100/80
Example 194: N-benzyl-1 l-(3-chlorophenyl)-dibenzorb,fiπ,41thiazepine-8-carboxamide
Figure imgf000156_0002
[0475] 19.2 mg, UV/MS purity 100/60
Example 195: N-(l-phenylethyl>l l-(3-chlorophenyl)-dibenzo[b,f|[U41thiazepine-8- carboxamide
Figure imgf000156_0003
[0476] 16.7 mg, UV/MS purity 100/85 Example 196: N-CbutylVl l-O-chlorophenylVdibenzofb^firMithiazepine-S-carboxamide
Figure imgf000157_0001
[0477] 17.3 mg, UV/MS purity 100/79
Example 197: N-(3-phenylpropyl)-l l-(3-chlorophenylVdibenzofb,f|[K4]thiazepine-8- carboxamide
Figure imgf000157_0002
[0478] 9.0 mg mg, UV/MS purity 95/80
Example 198: N-(2-phenylethylVl l-(3-chlorophenyl)-dibenzorb,f|[1,4]thiazepine-8- carboxamide
Figure imgf000157_0003
[0479] 10.9 mg, UV/MS purity 100/80
Example 199: N-(2-chlorobenzyl)-l l-(3-chlorophenyl)-dibenzo[b,f][l ,41thiazepine-8- carboxamide
Figure imgf000158_0001
[0480] 9.7 mg, UV/MS purity 98/80
Example 200: N-(2-(4-chlorophenylkthylyi l-(3-chlorophenvn- dibenzo [b, f] [ 1 ,4] thiazepine -8 -carboxamide
Figure imgf000158_0002
[0481] 11.2 mg, UV/MS purity 99/76
Example 201 : N-(3-chlorobenzv0-l l-(3-chlorophenylVdibenzo[b,f|[1,41thiazepine-8- carboxamide
Figure imgf000158_0003
[0482] 12.2 mg, UV/MS purity 95/72
Example 202: N-(2-phenyl-propyl)-l l-(3-chlorophenγl)-dibenzo[b,f|[1,41thiazepine-8- carboxamide
Figure imgf000158_0004
[0483] 8.8 mg, UV/MS purity 99/59 Example 203: N-fCN-ethyl-N-phenyl^aminoethyl)-! l-O-chlorophenylV dibenzo[b,f|[1,4]thiazepine-8-carboxamide
Figure imgf000159_0001
[0484] 6.3 mg, UV/MS purity 97/80
Example 204: 1 l-(3-chlorophenylVdibenzo[b,f|[1,4]thiazepin-8-carboxylic acid morpholin-4-yl amide
Figure imgf000159_0002
[0485] 1 1.8 mg, UV/MS purity 97/56
Example 205: N-(4-fluorobenzyD-l l-(3-chlorophenyl)-dibenzo[b,f|f 1,41thiazepine-8- carboxamide
Figure imgf000159_0003
[0486] 8.1 mg, UV/MS purity 100/55
Series E
[0487] The arylzinc halide used for Examples 206 - 217 was 4- fluorophenylzinc iodide.
[58 Example 206: 1 l-(4-fluorophenyl)-dibenzorb,fl[1,4]thiazepin-8-yl-(piperidin-1-vπ- methanone
Figure imgf000160_0001
[0488] 9.9 mg, UV/MS purity 99/62
Example 207: N-benzyl-1 l-f4-fluorophenyl)-dibenzorb,firi,41thiazepine-8-carboxamide
Figure imgf000160_0002
[0489] 12.2 mg, UV/MS purity 96/41
Example 208: N-d-phenylethyP-l l-(4-fluorophenylVdibenzorb,fl[1,41thiazepine-8- carboxamide
Figure imgf000160_0003
[0490] 11.4 mg, UV/MS purity 100/91 Example 209: N-(butylVU-(4-fluorophenylVdibenzofb,flf 1,41thiazepine-8-carboxamide
Figure imgf000161_0001
[0491] 7.5 mg, UV/MS purity 98/93
Example 210: N-(2-phenylethylVl l-(4-fluorophenylVdibenzofb1f||'1,41thiazepine-8- carboxamide
Figure imgf000161_0002
[0492] 4.6 mg, UV/MS purity 98/62
Example 211 : N-(2-chlorobenzyl)-l l-(4-fluorophenyl)-dibenzo[b,fj[1,41thiazepine-8- carboxamide
Figure imgf000161_0003
[0493] 8.4 mg, UV/MS purity 100/52
Example 212: N-(2,4-dichlorobenzylVl l-(4-fluorophenylVdibenzo|"b,fl[1,41thiazepine-8- carboxamide
Figure imgf000162_0001
[0494] 4.0 mg, UV/MS purity 96/36
Example 213: N-(2-(4-chlorophenyl)ethyl)-l l-(4-fluorophenyl')- dibenzorb,fl[1,4]thiazepine-8-carboxamide
Figure imgf000162_0002
[0495] 5.6 mg, UV/MS purity 100/65
Example 214: N-(2-(3-chlorophenyl)ethyiyi l-(4-fluorophenyl)- dibenzorb,f][L41thiazepine-8-carboxamide
Figure imgf000162_0003
[0496] 1.4 mg, UV/MS purity 99/56 Example 215: N-(3-chlorobenzyl>l l-(4-fluorophenviydibenzo[b,f^U4]thiazepine-8- carboxamide
Figure imgf000163_0001
[0497] 5.4 mg, UV/MS purity 99/50
Example 216: N-(2-phenyl-propyl)-l l-(4-fluorophenyl)-dibenzo[b,f|[h4]thiazepine-8- carboxamide
Figure imgf000163_0002
[0498] 1.9 mg, UV/MS purity 85/44
Example 217: N-(flS[-ethyl-N-phenyl)aminoethyl)-l 1 -(4-fluorophenyiy dibenzorb,fiπ,41thiazepine-8-carboxamide
Figure imgf000163_0003
[0499] 1.3 mg, UV/MS purity 78/45
Series F
[0500] The arylzinc halide used for Examples 218 - 232 was 2- fluorophenylzinc iodide. Example 218: 1 l-(2-fluorophenyl)-dibenzo[b,fl[1,4]thiazepin-8-yl-(piperidin-1-ylV methanone
Figure imgf000164_0001
[0501] 12.5 mg, UV/MS purity 99/67
Example 219: N-benzyl-1 l-(2-fluorophenylVdibenzo[b1flf 1,41thiazepine-8-carboxamide
Figure imgf000164_0002
[0502] 13.7 mg, UV/MS purity 100/100
Example 220: N-d-phenylethylVl l-(2-fluorophenyl)-dibenzo(~b,f~iri,4]thiazepine-8- carboxamide
Figure imgf000164_0003
[0503] 10.1 mg, UV/MS purity 100/96
Example 221 : N-CbutyQ-l l-(2-fluorophenyl)-dibenzorb,firi,41thiazepine-8-carboxamide
Figure imgf000164_0004
[0504] 12.3 mg, UV/MS purity 100/94
Example 222: N-(3-phenylpropyl)-l l-(2-fluorophenyl>dibenzo[b,f|f1,4")thiazepine-8- carboxamide
Figure imgf000165_0001
[0505] 12.3 mg mg, UV/MS purity 100/100
Example 223: N-(2-phenylethylVll-(2-fluorophenylVdibenzorb,fl[K41thiazepine-8- carboxamide
Figure imgf000165_0002
[0506] 9.3 mg, UV/MS purity 100/100
Example 224: N-(2-chlorobenzvQ-l l-(2-fluorophenyl)-dibenzorb,f|f 1,41thiazepine-8- carboxamide
Figure imgf000165_0003
[0507] 12.7 mg, UV/MS purity 100/89 Example 225: N-(2,4-dichlorobenzy1H l-(2-fluorophenylVdibenzorb,fl[1,4]thiazepine-8- carboxamide
Figure imgf000166_0001
[0508] 10.6 mg, UV/MS purity 100/84
Example 226: N-(2-(4-chlorophenyl)ethy1H 1 -(2-fluorophenylV dibenzorb,fiπ,41thiazepine-8-carboxamide
Figure imgf000166_0002
[0509] 8.4 mg, UV/MS purity 100/92
Example 227: N-(2-(3-chloropheny0ethy1Hl-(2-fluorophenyr)- dibenzofb,firi,41thiazepine-8-carboxamide
Figure imgf000166_0003
[0510] 10.4 mg, UV/MS purity 100/91
Example 228: N-(3-chlorobenzylVl l-(2-fluorophenylVdibenzo[b,flf 1,4]thiazepine-8- carboxamide
Figure imgf000167_0001
[0511] 12.5 mg, UV/MS purity 100/95
Example 229: N-(2-bromobenzylVl l-(2-fluorophenylVdibenzorb,firi,4]thiazepine-8- carboxamide
Figure imgf000167_0002
[0512] 8.3 mg, UV/MS purity 100/96
Example 230: N-(2-phenyl-propyl)-l l-(2-fluorophenyl)-dibenzo[b,flP ,41thiazepine-8- carboxamide
Figure imgf000167_0003
[0513] 11.2 mg, UV/MS purity 100/90
Example 231: N-((N-ethyl-N-pheny Oaminoethy IV 11 -(2-fluoropheny IV dibenzorb,firK41thiazepine-8-carboxamide
Figure imgf000168_0001
[0514] 5.7 mg, UV/MS purity 100/91
Example 232: N-(4-fluorobenzyl)-l l-fl-fluorophenyQ-dibenzorb^fifl^ithiazepine-S- carboxamide
Figure imgf000168_0002
[0515] 12.4 mg, UV/MS purity 100/91
Series G
[0516] The arylzinc halide used for Examples 233 - 246 was phenylzinc iodide.
Example 233: N-benzyl-1 l-(phenyl)-dibenzofb,f|[1,41thiazepine-8-carboxamide
Figure imgf000168_0003
[0517] 10.2 mg, UV/MS purity 100/57 Example 234: N-d-phenylethy1H l-(phenyr)-dibenzorb,fUh41thiazepine-8-carboxamide
Figure imgf000169_0001
[0518] 8.2 mg, UV/MS purity 91/61
Example 235: N-(buty1H l-(phenyl)-dibenzorb,fiπ ,41thiazepine-8-carboxamide
Figure imgf000169_0002
[0519] 9.4 mg, UV/MS purity 94/62
Example 236: N-(3-phenylpropylVl l-(phenyl)-dibenzo[b,firU41thiazepine-8- carboxamide
Figure imgf000169_0003
[0520] 1 1.4 mg mg, UV/MS purity 100/ 100
Example 237: N-(2-phenylethyl)-l l-(phenyπ-dibenzo[b,firi,4]thiazepine-8-carboxamide
Figure imgf000169_0004
[0521] 9.0 mg, UV/MS purity 97/85 Example 238: N-(2-chlorobenzyl)-l l-CphenylVdibenzo^b[b,f][1,4th]iazepine-S- carboxamide
Figure imgf000170_0001
[0522] 8.8 mg, UV/MS purity 100/100
Example 239: N-(2,4-dichlorobenzyl)-l l-(phenvn-dibenzor[b,f][1,4]thiazepine-8- carboxamide
Figure imgf000170_0002
[0523] 6.1 mg, UV/MS purity 100/87
Example 240: N-(2-(4-chlorophenyl)ethyl)-l l-(phenvn-dibenzo[b,f][1,4]thiazepine-8- carboxamide
Figure imgf000170_0003
[0524] 9.3 mg, UV/MS purity 100/90 Example 241: N-(2-(3-chlorophenyr)ethyl>-l l-(phenyl>dibenzorKfiri,41thiazepine-8- carboxamide
Figure imgf000171_0001
[0525] 8.9 mg, UV/MS purity 100/80
Example 242: N-(3 -chloro benzyl)- 1 l-(phenyl)-dibenzo[b,fiπ,4]thiazepine-8- carboxamide
Figure imgf000171_0002
[0526] 10.1 mg, UV/MS purity 100/100
Example 243: N-(2-bromobenzyl)-l l-(phenyl)-dibenzo|"b,firK4]thiazepine-8- carboxamide
Figure imgf000171_0003
[0527] 10.2 mg, UV/MS purity 100/89
Example 244: N-(2-phenyl-propyl)-l l-(phenylVdibenzofb,f|[K4]thiazepine-8- carboxamide
Figure imgf000172_0001
[0528] 9.5 mg, UV/MS purity 100/87
Example 245: N-((N-ethyl-N-phenyl)aminoethylVl l-(phenyl)- dibenzorb,firi,41thiazepine-8-carboxamide
Figure imgf000172_0002
[0529] 10.0 mg, UV/MS purity 100/91
Example 246: N-(4-fluorobenzyl)-l l-(phenyl)-dibenzo[b,f|[1,41thiazepine-8- carboxamide
Figure imgf000172_0003
[0530] 12.8 mg, UV/MS purity 100/93
Series H
[0531] The arylzinc halide used for Examples 247 - 260 was 4- chlorophenylzinc iodide.
Example 247: 1 l-(4-chlorophenyl)-dibenzo[b,f|[1,4]thiazepin-8-yl-(piperidin-1-yl')- methanone
Figure imgf000173_0001
[0532] 2.2 mg, UV/MS purity 100/100
Example 248: N-benzyl-1 l-(4-chlorophenyl)-dibenzofb,f||"1,41thiazepine-8-carboxamide
Figure imgf000173_0002
[0533] 6.3 mg, UV/MS purity 100/100
Example 249: N-d-phenylethylVl l-(4-chlorophenylVdibenzo[b,fl[1,41thiazepine-8- carboxamide
Figure imgf000173_0003
[0534] 5.7 mg, UV/MS purity 100/83
Example 250: N-(butyl)-l l-(4-chlorophenylVdibenzo[b,f]f1,4]thiazepine-8-carboxamide
Figure imgf000173_0004
[0535] 13.7 mg, UV/MS purity 100/100
Example 251 : N-(3-phenylpropyl)-l 1 -(4-chlorophenyr)-dibenzorb,flfl ,41thiazepine-8- carboxamide
Figure imgf000174_0001
[0536] 12.5 mg, UV/MS purity 100/100
Example 252: N-(2-phenylethylVl l-("4-chlorophenylVdibenzofb.firi,41thiazepine-8- carboxamide
Figure imgf000174_0002
[0537] 8.7 mg, UV/MS purity 100/100
Example 253: N-(2-chlorobenzyl)-l l-(4-chlorophenyl)-dibenzo[b,f||'l141thiazepine-8- carboxamide
Figure imgf000174_0003
[0538] 8.4 mg, UV/MS purity 100/ 100 Example 254: N-(2,4-dichlorobenzylVl l-(4-chlorophenγlVdibenzo[b,f|[1,4]thiazepine- 8-carboxamide
Figure imgf000175_0001
[0539] 5.4 mg, UV/MS purity 100/73
Example 255: N-(2-(4-chlorophenyl)ethylVl l-(4-chlorophenyl')- dibenzofb,f|( 1 ^Ithiazepine-δ-carboxamide
Figure imgf000175_0002
[05401 10.2 mg, UV/MS purity 100/80
Example 256: N-(2-O-chlorophenyl)ethy1Hl-(4-chlorophenyl)- dibenzo[b,f|[1,4]thiazepine-8-carboxamide
Figure imgf000175_0003
[0541] 10.0 mg, UV/MS purity 100/100 Example 257: N-(3-chlorobenzylVl l-(4-chlorophenyiydibenzorb,fl[1,41thiazepine-8- carboxamide
Figure imgf000176_0001
[0542] 10.0 mg, UV/MS purity 100/100
Example 258: N-(2-bromobenzy0-l l-(4-chlorophenyl)-dibenzo[b,f1fl ,41thiazepine-8- carboxamide
Figure imgf000176_0002
[0543] 10.2 mg, UV/MS purity 100/67
Example 259: N-(2-phenyl-propyl)-l l-(4-chlorophenyl)-dibenzo[b,f|[K41thiazepine-8- carboxamide
Figure imgf000176_0003
[0544] 11.9 mg, UV/MS purity 100/100
Example 260: N-((N-ethyl-N-phenvQaminoethyly 1 l-(4-chlorophenvO- dibenzo[b,f|f1,4]thiazepine-8-carboxamide
Figure imgf000177_0001
[0545] 12.4 mg, UV/MS purity 100/88
Example 261: N-(4-fluorobenzyl)-l l-(4-chlorophenyl)-dibenzo[b,f1[1,41thiazepine-8- carboxamide
Figure imgf000177_0002
[0546] 12.8 mg, UV/MS purity 100/100
Series I
[0547] The amidoimidoyl chlorides (Examples 262 - 271) were synthesized according to the general procedure for amide formation using 1 1 -Chloro- dibenzo[6,/|[1,4]thiazepine-8-carbonyl chloride (300 mg, 1 mmol) and the proper amine (3 mmol) except that the reaction mixture was passed through a pad of acidic alumina oxide and eluted with a mixture of CH2Cl2 and EtOAc. The eluents were concentrated at reduced pressure and the obtained crude products were directly used in the next reactions without further purifications or characterization. Examples 262-271
Figure imgf000178_0001
Series J Examples 272-301
[0548] Examples 272-301 are prepared according to the general procedure for the synthesis of amidines starting from 15 mg of the appropriate amidoimidoyl chloride (represented by titled compounds in Examples 262 - 271) and the appropriate amine (excess), except that purification is performed by eluting (EtOAc) the products through a pad of silica. The eluents are concentrated at reduced pressure to give the crude products, which are purified by preparative HPLC/MS. Yield is determined by weighing and purity by analytical LC/MS).
Figure imgf000180_0001
Figure imgf000181_0001
180
Figure imgf000182_0001
181
Figure imgf000183_0001
Series K Examples 302- 391
[0549] Examples 302-391 are prepared according to the general procedure for Negishi cross-coupling starting from 10-15 mg of the appropriate amidoimidoyl chloride (represented by titled compounds in Examples 262 - 271) and the proper arylzinc halide (8eq) in THF. Ammonium chloride (0.02 ml) is added to the reaction mixtures, which are then passed through a short column (Na2SOVsUiCa) using EtOAc as eluent. The eluents are concentrated at reduced pressure and the crude products are purified by preparative LC/MS. Yields are determined by weighing and purities by analytical LC/MS.
Figure imgf000184_0001
ı83
Figure imgf000185_0001
Figure imgf000185_0002
Figure imgf000186_0001
ı85
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000188_0002
ı87
Figure imgf000189_0001
Figure imgf000189_0002
Figure imgf000189_0003
Figure imgf000190_0001
Figure imgf000190_0002
Figure imgf000191_0001
Figure imgf000191_0002
Figure imgf000192_0001
191
Figure imgf000193_0001
Figure imgf000193_0002
Figure imgf000194_0001
Figure imgf000194_0002
ı93
Figure imgf000195_0001
Figure imgf000195_0002
Figure imgf000195_0003
Figure imgf000196_0001
Figure imgf000196_0002
Figure imgf000197_0001
Figure imgf000197_0002
Figure imgf000198_0001
Figure imgf000198_0002
Figure imgf000199_0001
Figure imgf000199_0002
ı98
Figure imgf000200_0001
Figure imgf000200_0002
Figure imgf000201_0001
Figure imgf000201_0002
Series L
[0550] The amidoimidoyl chlorides (Examples 392-403) were synthesized according to the general procedure for amide formation using 11-chloro- dibenzo[b,/][1,4]thiazepine-8-carbonyl chloride (300 mg, 1 mmol) and the proper amine (2.5 mmol) except that the reaction mixture was passed through a pad of silica and eluted with a mixture of THF and EtOAc. The eluents were concentrated at reduced pressure and the obtained crude products were directly used in the next reactions without further purifications or characterization. Examples 392 - 403
Figure imgf000202_0001
Figure imgf000202_0002
Figure imgf000202_0003
Figure imgf000202_0004
Figure imgf000202_0005
Figure imgf000203_0001
Series M Examples 404 - 499
[0551] Examples 404-499 are prepared according to the general procedure for Negishi cross-coupling starting from 10-15 mg of the appropriate amidoimidoyl chloride (represented by title compounds in Examples 392-403) and the proper arylzinc halide (8eq) in THF.
Figure imgf000204_0001
Figure imgf000204_0003
Figure imgf000204_0002
203
Figure imgf000205_0001
204
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
207
Figure imgf000209_0001
208
Figure imgf000210_0001
209
Figure imgf000211_0001
Figure imgf000212_0001
211
Figure imgf000213_0001
212
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000215_0003
Figure imgf000215_0002
[0552] The following compounds (Examples 500 - 533) were synthesised from l l-chloro-dibenzo[ό,/l[1,4] thiazepine-8-carbonyl chloride according to the general procedure for amide formation using the proper amide followed by the general procedure for palladium catalyzed Negishi cross-coupling of amidoimidoyl chlorides and arylzinc halides or the general procedure for synthesis of amidines. Example 500: (E)-I l-(5-chlorothiophen-2-yπ-N-propyldibenzo[b,f|[1,41thiazepine-8- carboxamide
Figure imgf000216_0001
[0553] Amount isolated: 2.5 mg. LCMS m/z [M+H]+: 413, purity (UV/MS): 100/98, /R = 5.60 min.
Example 501: (Z)-I l-(4-chloro-2-fluorophenyl)-N-isobutyldibenzorb,flf 1,4)thiazepine-8- carboxamide
Figure imgf000216_0002
[0554] Amount isolated: 88 mg (28 %).
|0SSS| 1H NMR (400 MHz, CDCl3) δ 7.90 (t, IH, J= 8.4, ArH), 7.67 (t, IH, J
= 0.9, ArH), 7.55 - 7.51 (m, 2H, ArH), 7.41 (dt, 1H, J = 1.6, 7.6, ArH), 7.32 - 7.24 (m, 3H, ArH), 7.14 - 7.08 (m, 2H, ArH), 6.12 (br s, 1H, NH), 3.28 (t, 2H, J = 6.8, NCH2), 1.87 (sept, 1H, J = 6.8, CH,Bu), 0.97 (d, 6H, J = 6.8, 2 x CH3). LCMS m/z [M+l]+: 439, purity (UV/MS): 100/95, tR = 5.63 min.
Example 502: (EVl l-(5-chlorothiophen-2-ylVN-isobutyldibenzo[b,f|[L41thiazepine-8- carboxamide
Figure imgf000217_0001
[0556] Amount isolated: 27 mg (15 %).
[0557] 1H NMR (400 MHz, CDCl3) δ 7.60 - 7.34 (m, 7H, ArH), 6.94 (d, 1 H,
J = 4.0, thiophenH), 6.89 (d, 1H, J = 4.0, thiopheneH), 6.15 (br m, 1H, NH), 3.26 (dd, 2H, J - 6.4, 7.2, CH2JBu), 1.87 (m, 1H, CHiBu), 0.96 (d, 6H, J = 6.8, 2 x CH3). 13C NMR (100 MHz, CDCl3) δ 166.8, 162.7, 148.5, 145.1, 140.5, 137.1, 136.2, 135.3, 133.0, 132.8, 132.1 , 132.0, 131.9, 130.3, 128.4, 127.3, 124.7, 123.9, 47.6, 28.8, 20.4. LCMS m/z [M+l]+: 427, purity (UV/MS): 66/98, tR = 5.83 min.
Example 503: (EVN-butyl-1 l-(5-chlorothiophen-2-vndibenzorb,fiπ,41thiazepine-8- carboxamide
Figure imgf000217_0002
[0558] Amount isolated: 1.2 mg. LCMS m/z [M+H]+: 427, purity (UV/MS): 100/86, /R = 5.96 min.
Example 504: (E)-N-(3-chlorobenzylVl l-(4-fluoropiperidin-1- yl)dibenzofb,f)l"1,41thiazepine-8-carboxamide
Figure imgf000218_0001
[0559] Amount isolated: 8 mg. LCMS m/z [M+H]+: 480, /R = 5.23 min.
Example 505: (Z)-N-(azepan-1-yD-l l-(3-chlorophenyQdibenzo[b,f|[1,4]thiazepine-8- carboxamide
Figure imgf000218_0002
[0560] Amount isolated: 2.5 mg. LCMS m/z [M+H]+: 462, purity (UV/MS): 100/94, tR = 5.23 min.
Example 506: fZ)-N-(QS,6RV2,6-dimethylpiperidin-1-vn-l l-(3- fluorophenvπdibenzorb,firi,41thiazepine-8-carboxamide
Figure imgf000218_0003
[0561] Amount isolated: 4.1 mg. LCMS m/z [M+H]+: 460, purity (UV/MS): 100/61, tR - 4.89 min. Example 507: (ZVU-(3.4-dichlorophenyl>-N-((2S,6RV2,6-dimethvlpiperidin-1- yl)dibenzofb,flf1,4"|thiazepine-8-carboxamide
[0562] Amount isolated: 0.7 mg. LCMS m/z [M+H]+: 510, purity (UV/MS): 100/100, tR = 5.68 min.
Example 508: (E)-N-isobutyl-l l-(3-methylthiophen-2-yQdibenzofb,f)π,41thiazepine-8- carboxamide
Figure imgf000219_0002
[0563] Amount isolated: 9.1 mg. LCMS m/z [M+H]+: 407, purity (UV/MS): 100/98, /R = 9.55 min.
Example 509: (Z)-N-(3-chlorophenethyl)-l l-(3- chlorophenyl)dibenzo[b,f|[L4]thiazepine-8-carboxamide
Figure imgf000219_0003
[0564] Amount isolated: 10 mg. LCMS m/z [M+H]+ 587, /R = 6.28 min. Example 510: (ZVl l-(4-bromophenylVN-isobutyldibenzofb,f][1,4]thiazepine-8- carboxamide
Figure imgf000220_0001
[0565] Amount isolated: 1.1 mg. LCMS m/z [M+H]+: 465, purity (UV/MS): 100/65, tR= 5.97 min.
Example 51 1 : (Z)-N-isobutyl-l l-(4-methoxyphenyl)dibenzo[b,f|f1,4]thiazepine-8- carboxamide
Figure imgf000220_0002
[0566] Amount isolated: 3.5 mg. LCMS m/z [M+H]+: 417, purity (UV/MS): 100/98, tø= 5.35 min.
Example 512: (Z)-I l-(4-fluorophenylVN-(piperidin-1-yl)dibenzo[b,f|[1,41thiazepine-8- carboxamide
Figure imgf000220_0003
[0567] Amount isolated: 0.6 mg. LCMS m/z [M+H]+: 432, purity (UV/MS):98/93, /R = 4.41 min. Example 513: (ZVl l-(3-chlorophenviyN-((2S,6RV2,6-dimethylpiperidin-1- vQdibenzofb,f][1,41thiazepine-8-carboxamide
Figure imgf000221_0001
[0568] Amount isolated: 10.7 mg. LCMS m/z [M+H]+: 476, purity (UV/MS): 100/54, tκ= 5.24 min.
Example 514: (Z)-I l-(4-chloro-2-fluorophenyl)-N-propyldibenzofb,f|[1,41thiazepine-8- carboxamide
Figure imgf000221_0002
[0569] Amount isolated: 4.4 mg. LCMS m/z [M+H]+: 425, purity (UV/MS): 100/94, /R = 9.56 min.
Example 515: (EVN-butyl-1 l-(3-methylthiophen-2-vπdibenzo[b,firK41thiazepine-8- carboxamide
Figure imgf000221_0003
[0570] Amount isolated: 6.3 mg. LCMS m/z [M+H]+: 407, purity (UV/MS): 100/100, rR = 9.63 min. Example 516: (ZVN-(azepan-1-yl)-l l-(3-fluorophenyl)dibenzofb,f|[1,41thiazepine-8- carboxamide
Figure imgf000222_0001
[0571] Amount isolated: 2.3 mg. LCMS m/z [M+H]+: 446, purity (UV/MS): 97/64, /R = 4.85 min.
Example 517: (Z)-N-butyl-l l-(4-methoxyphenvDdibenzo[b,f][1,4]thiazepine-8- carboxamide
Figure imgf000222_0002
[0572] Amount isolated: 2.8 mg. LCMS m/z [M+H]+: 417, purity (UV/MS): 90/94, tR = 5.25 min.
Example 518: (Z)-11-(3-chlorophenyl)-N-(2-(pyridin-2- yl)ethyl)dibenzofb,fl[1,41thiazepine-8-carboxarnide
Figure imgf000222_0003
[0573[ Amount isolated: 2.6 mg. LCMS m/z [M+H]+: 470, purity (UV/MS): 100/97, tR = 4.67 min. Example 519: (E)-N -butyl- 1 l-(pyridin-2-yl)dibenzorb,fin,41thiazepine-8-carboxamide
Figure imgf000223_0001
[0574] Amount isolated: 4.1 mg. LCMS m/z [M+H]+: 388, purity (UV/MS): 100/92, /R= 4.08 min.
Example 520: (Z)-I l-(4-methoxyphenylVN-propyldibenzo[b,f|[1,41thiazepine-8- carboxamide
Figure imgf000223_0002
[0575] Amount isolated: 0.9 mg. LCMS m/z [M+H]+: 403, purity (UV/MS): 93/100, /R = 4.95 min.
Example 521 : (E)-I l-(3-methylthiophen-2-yl)-N-propyldibenzorb,f|f1,41thiazepine-8- carboxamide
Figure imgf000223_0003
[0576] Amount isolated: 5.7 mg. LCMS m/z [M+H]+: 393, purity (UV/MS): 100/93, /R = 9.01 min. Example 522: (Z*)-! l-(3-fluorophenylVN-(piperidin-1-yl)dibenzo[b,f]ri,41thiazepine-8- carboxamide
Figure imgf000224_0001
[0577] Amount isolated: 2.8 mg. LCMS m/z [M+H]+: 432, purity (UV/MS): 100/78, /R = 4.47 min.
Example 523: (Z)-N-((2S,6R)-2,6-dimethyrpiperidin-1-vI)-l l-(4- fluorophenyl)dibenzofb,firK4]thiazepine-8-carboxamide
Figure imgf000224_0002
[0578] Amount isolated: 0.6 mg. LCMS m/z [M+H]+: 460, purity (UV/MS): 98/91, tκ= 4.79 min.
Example 524: (EVN-isopentyl-1 l-(3-methylthiophen-2-yl)dibenzo[b,fl[1,41thiazepine-8- carbpxarnide
Figure imgf000224_0003
[0579] Amount isolated: 6.7 mg. LCMS m/z [M+H]+: 421, purity (UV/MS): 100/96, /R = 10.05 min. Example 525: (EVl l-(S-chIorothiophen-2-ylVN-(2-methoxyethvπdibenzo[b,fiπ ,41 thiazepine-8-carboxamide
Figure imgf000225_0001
[0580] Amount isolated: 5.8 mg. LCMS m/z [M+H]+: 429, purity (UV/MS): 100/93, fR= 5.01 min.
Example 526: (ZVN-isopentyl-1 l-(4-methoxyphenyl)dibenzo[b,f|[1,4]thiazepine-8- carboxamide
Figure imgf000225_0002
[0581] Amount isolated: 3.9 mg. LCMS m/z [M+H]+: 431, purity (UV/MS): 100/100, /R = 5.67 min.
Example 527: (E)-N-isopentyM l-(pyridin-2-yl)dibenzo[b,f|[1,41thiazepine-8- carboxamide
Figure imgf000225_0003
[0582] Amount isolated: 127 mg (52 %).
[0583] 1H NMR (400 MHz, CDCl3) δ 8.69 - 8.59 (m, 2H, ArH), 8.30 - 8.25
(m, 1H, ArH), 7.87 - 7.81 (m, 1H, ArH), 7.71 (m, 1H, ArH), 7.52 (m, 2H, ArH), 7.43 - 7.19 (m, 4H, ArH), 6.16 (br s, 1H, NH), 3.48 - 3.41 (m, 2H, NCH2), 1.66 (sept, 1H, J = 6.6, CH,pen), 1.48 (q, 2H, CH2, J = 6.6), 0.93 (d, 6H, J = 6.6, 2 x CH3). LCMS m/z [M+H]+ 402, purity (UV/MS): 100/94. tR = 4.47 min.
Example 528: (Z)- 11 -f 4-chlorophenyl)-N-(2-(pyridin-2- vPethy l)dibenzorb,f| [ 1 ,41thiazepine-8-carboxamide
Figure imgf000226_0001
[0584] Amount isolated: 2.3 mg. LCMS m/z [M+H]+: 470, purity (UV/MS): 100/88, tR = 4.68 min.
Example 529: (Z)-N-(azepan-1-y1H l-(4-fluorophenyl)dibenzo[b,f|rK41thiazepine-8- carboxamide
Figure imgf000226_0002
[0585] Amount isolated: 0.7 mg. LCMS m/z [M+H]+: 446, purity (UV/MS): 98/92, tR = 4.80 min.
Example 530: (E)-N-isobutyl-l l-(pyridin-2-yl)dibenzo[b,firL41thiazepine-8- carboxamide
Figure imgf000226_0003
[0586] Amount isolated: 77 mg (46 %). [0587] 1H NMR (400 MHz, CDCl3) δ 8.72 - 8.70 (m, 1H, ArH), 8.29 - 8.24
(m, 1H, ArH), 7.87 (dt, 1H, J = 1.6, 7.6, ArH), 7.75 (m, 1H, ArH), 7.57 - 7.52 (m, 3H, ArH), 7.44 - 7.38 (m, 2H, ArH), 7.32 (dt, 1H, J = 1.2, 7.6, ArH), 7.23 - 7.20 (m, 1H, ArH), 6.19 (br s, 1H, NH), 3.27 (t, 2H, J= 6.4, NHCH2), 1.88 (sept, 1H, J= 6.4, CH,Bu), 0.97 (d, 6H, J= 6.4, 2 x CH3). LCMS m/z [M+H]+ 388, purity (UV/MS): 94/60. tR = 4.00 min.
Example 531: (Z)-I l-(4-bromophenyl)-N-propyldibenzorb,firi,41thiazepine-8- carboxamide
Figure imgf000227_0001
[0588] Amount isolated: 0.6 mg. LCMS m/z [M+H]+: 451, purity (UV/MS): 100/61, /R= 5.65 min.
Example 532: (ZVl l-(3,4-dichlorophenvn-N-(2-(pyridin-2-yl)ethyl)dibenzo[b,f|[L41 thiazepine-8-carboxamide
Figure imgf000227_0002
[0589] Amount isolated: 2.1 mg. LCMS m/z [M+H]+: 504, purity (UV/MS): 100/96, /R = 5.15 min. Example 533: (ZVl l-(4-bromophenylVN-(2-methoxyethyl)dibenzo[b,f|[K41thiazeDine-8- carboxamide
Figure imgf000228_0001
[0590] Amount isolated: 3.7 mg. LCMS m/z [M+H]+: 467, purity (UV/MS): 100/78, tR= 5.09 min.
Example 534: l l-chloro-dibenzofb^π^thiazepine-S-carboxylic acid methyl ester
Figure imgf000228_0002
[0591] A mixture of the lactam (1 eq.) and PCl5 (5 eq.) in toluene was heated at 110 °C for 2 hours. The reaction mixture was then cooled to room temperature and excess of PCl5 and toluene was removed at reduced pressure using an oilpump to give crude product, which was used without further purification. The following reagents were employed: l l-oxo-10,1 l-dibenzo[b,f][1,4]thiazepine-8-carboxylic acid methyl ester (540 mg, 1.89 mmol), PCl5 (1.97 g, 9.47 mmol), toluene (15 mL). Purification by flash chromatography (ethyl acetate/heptane 1:4) afforded 410 mg (71 %) of the titled compound as an yellow solid.
[0592] 1H NMR (400 MHz, CDCl3): δ 7.86 (1H, dd, J = 2.0, 0.4Hz), 7.75
(1H, dd, J = 8.0, 1.6 Hz), 7.69-7.67 (1H, m), 7.45 (1H, dd, J = 8.4, 0.4Hz), 7.40-7.32 (3H, m), 3.82 (3H, s). 13C NMR (100 MHz, CDCl3): δ 166.2, 156.1, 146.3, 138.1, 137.9, 133.2, 133.1, 132.9, 132.4, 131.7, 130.2, 129.2, 128.1 , 127.1, 52.6. Example 535: 1 l-butyl-dibenzo|"b,f}[1,4]thiazepine-8-carboxylic acid methyl ester
Figure imgf000229_0001
[0593] A flame dried 10 mL flask was charged under argon with the imidoyl chloride (1 eq.), Fe(acac)3 (5 mol%) in dry THF and cooled to - 40 °C. Functionalized arylmagnesium halide (2 eq., 1 M in THF; prepared at -40 °C) was slowly added to the solution, keeping the temperature below - 40 °C. The reaction was stirred for 5 min. at - 40 °C, then quenched with NH4Cl (sat., aq.) and allowed to warm to room temperature. The resulting mixture was diluted with Et2O and the organic phase was washed with water, brine, dried (Na2SO3), filtered, and evaporated to give crude product. Purification by flash chromatography. The following reagents were employed: 1 1-chloro- dibenzo[b,fj[1,4]thiazepine-8-carboxylic acid methyl ester (151.5 mg, 0.50 mmol), Fe(acac)3 (8.85 mg, 0.05 mmol), THF (4 mL) and N-methylpyrrolidone (0.4 mL), nButyl magnesium chloride (2 M in Et2O, 0.50 mL, 1.0 mmol). Purification by flash chromatography (ethyl acetate/heptane 1:5) afforded 144 mg (89 %) of the titled compound as a yellow solid.
[0594] 1H NMR (400 MHz, CDCl3): δ 7.84 (1H, d, J = 1.6Hz), 7.68 (I H, dd, J
= 8.0, 1.6Hz), 7.74-7.43 (2H, m), 7.40-7.31 (3H, m), 3.87 (3H, s), 3.02-2.85 (2H, m), 1.74-1.58 (2H, m), 1.55-1.41 (2H, m), 0.93 (3H, t, J = 7.2Hz). 13C NMR (100 MHz, CDCt3): δ 174.5, 166.7, 148.8, 139.7, 139.0, 134.4, 132.5, 132.3, 131.1, 130.9, 128.9, 127.9, 126.6, 126.1, 52.4, 42.2, 29.5, 22.7, 14.2.
Example 536: l l-butyl-dibenzofb^fiπ^Jthiazepine-S-carboxylic acid methoxy-methyl- amide
Figure imgf000229_0002
[0595] A flame dried 10 mL flask was charged under argon with the imidoyl chloride (1 eq.), Fe(acac)3 (5 mol%) in dry THF and cooled to - 40 "C. Functionalized arylmagnesium halide (2 eq., 1 M in THF; prepared at -40 "C) was slowly added to the solution, keeping the temperature below - 40 "C. The reaction was stirred for 5 min. at - 40 °C, then quenched with NH4Cl (sat., aq.) and allowed to warm to room temperature. The resulting mixture was diluted with Et2O and the organic phase was washed with water, brine, dried (Na2SO3), filtered, and evaporated to give crude product. Purification by flash chromatography. The following reagents were employed: 11-chloro- dibenzo[b,fj[1,4]thiazepine-8-carboxylic acid methoxy-methyl-amide (61.5 mg, 0.19 mmol), Fe(acac)3 (3.53 mg, 0.001 mmol), THF (2 mL) and N-methylpyrrolidone (0.20 mL), rt-Butyl magnesium chloride (2 M in Et2O, 0.11 mL, 0.23 mmol). Purification by flash chromatography (ethyl acetate/heptane 1 :1) afforded 47 mg (70 %) of the titled compound as a yellow oil.
[0596] 1H NMR (400 MHz, CDCl3): δ 7.45-7.42 (3H, m), 7.39-7.29 (4H, m),
3.54 (3H,s), 3.32 (3H,s), 3.01-2.82 (2H, m), 1.69-1.59 (2H, m), 1.51-1.41 (2H, m), 0.92 (3H, t, J = 7.2Hz). 13C NMR (100 MHz, CDCl3): δ 174.4, 169.2, 148.7, 140.0, 139.0, 135.2, 132.2, 132.1, 131.6, 130.8, 128.7, 127.9, 125.1, 124.9, 61.4, 42.2, 34.1, 29.6, 22.7, 14.1.
Example 537: (1 l-butyl-dibenzo[b,f]f lΛithiazepine-8-yO-cvdohexyl-methanone
Figure imgf000230_0001
[0597] A flame dried 10 mL flask was charged under argon with 11-butyl- dibenzo[b,f][1,4]thiazepine-8-carboxylic acid methoxy-methyl-amide (29 mg, 0.08 mmol) in dry THF (2 mL) and cyclohexyl magnesium chloride (2 M in Et2O, 0.12 mL, 0.24 mmol) was then added. The resulting reaction mixture was stirred at room temperature for 1 hour and was then diluted with ether. The organic phase was washed with water, brine, dried (Na2SO3), filtered and evaporated to give crude product. Purification by prepatory TLC (ethyl acetate/heptane 1 : 10) afforded 5 mg (17 %) of the titled compound as a colorless oil.
[0598] 1H NMR (400 MHz, CDCl3): δ 7.70 (1H, d, J = 2Hz), 7.60 (1H, dd, J
= 8.0, 2.0Hz), 7.49-7.44 (2H, m), 7.41-7.33 (3H,m), 3.19 (1H, tt, J = 11.2, 3.2Hz), 3.04- 2.97 (1H, m), 2.92-2.84 (1H, m), 1.83-1.79 (3H, m), 1.72-1.62 (3H, m), 1.51-1.21 (8H, m), 0.93 (3H, t, J - 7.6Hz). 13C NMR (100 MHz, CDCl3): δ 203.4, 174.7, 148.9, 139.8, 138.9, 137.3, 134.2, 132.8, 132.3, 130.9, 128.9, 127.9, 125.3, 124.9, 45.8, 42.3, 29.6, 29.5, 26.1, 26.0, 22.7, 14.2.
Example 538: 1-(1 l-chloro-dibenzo[b,f}[1,4]thiazepine-8-ylVpentan-1-one
Figure imgf000231_0001
[0599] A flame dried 10 mL flask was charged under argon with 11-chloro- dibenzo[b,f][1,4]thiazepine-8-carboxylic acid methoxy-methyl-amide (34 mg, 0.10 mmol) in dry THF (2 mL) and πButyl magnesium chloride (2 M in Et2O, 0.10 mL, 0.2 mmol) was then added. The resulting reaction mixture was stirred at room temperature for 1 hour and was then diluted with ether. The organic phase was washed with water, brine, dried (Na2SO3), filtered and evaporated to give crude product. Purification by flash chromatography (ethyl acetate/heptane 1:5) afforded 26.0 mg (81 %) of the titled compound as a yellow oil.
[0600] 1H NMR (400 MHz, CDCl3): δ 7.82 (1H, d, J = 1.6Hz), 7.77-7.74 (2H, m), 7.53 (1H, d, J = 8.4Hz), 7.47-7.39 (3H, m), 2.90 (2H, t, J = 7.2Hz), 1.68 (2H, quintet, J = 7.2Hz), 1.37 (2H, sextet, J = 7.2Hz), 0.93 (3H, t, J = 7.2Hz). 13C NMR (100 MHz, CDCl3): δ 199.5, 156.2, 146.4, 138.3, 138.1, 137.8, 133.2, 133.1(2), 132,5, 1302, 129.2, 126.6, 125.8, 38.7, 26.5, 22.6, 14.1.
Example 539: 1-(1 1-cyclohexyl-dibenzo rb,f]f 1,41 thiazepine-8-vD-pentan-1-one
Figure imgf000232_0001
[0601] A flame dried 10 mL flask was charged under argon with the imidoyl chloride (1 eq.), Fe(acac)3 (5 mol%) in dry THF and cooled to - 40 "C. Functionalized arylmagnesium halide (2 eq., 1 M in THF; prepared at -40 °C) was slowly added to the solution, keeping the temperature below - 40 °C. The reaction was stirred for 5 min. at - 40 °C, then quenched with NH4Cl (sat., aq.) and allowed to warm to room temperature. The resulting mixture was diluted with Et2O and the organic phase was washed with water, brine, dried (Na2SO3), filtered, and evaporated to give crude product. Purification by flash chromatography. The following reagents were employed: 1-(1 1-chloro- dibenzo[b,f][1,4]thiazepine-8-yl)-pentan-1-one (26.0 mg, 0.08 mmol), Fe(acac)3 (1.41 mg, 0.004 mmol), THF (2 mL) and N-methylpyrrolidone (0.20 mL), cyclohexyl magnesium chloride (2 M in Et2O, 0.08 mL, 0.16 mmol). Purification by prep. TLC (ethyl acetate/heptane 1: 10) afforded 17.2 mg (57%) of the titled compound as an colorless oil.
[0602] 1H NMR (400 MHz, CDCl3): δ 7.71 (1H, d, J - 1.6Hz), 7.59 (1H, dd, J
= 8.0, 2.0Hz), 7.48-7.43 (2H, m), 7.40-7.29 (3H, m), 2.92-2.85 (3H, m), 2.21-2.17 (1H, m), 1.98-1.93 (1H, m), 1.82-1.63 (6H, m), 1.43-1.26 (6H, m), 0.92 (3H, t, J = 7.2Hz). 13C NMR (100 MHz, CDCl3): δ 200.1, 177.8, 149.0, 140.1, 139.2, 137.9, 134.3, 132.6, 132.0, 130.6, 128.9, 127.4, 125.2, 124.3, 49.1, 38.6, 32.6, 30.2, 30.0, 26.6, 26.4, 26.1, 22.6, 14.1.
Example 540: 1 l-(4-fluorophenyl)-N-(thiophen-2-ylmethyl)dibenzofb,f]π,41thiazepine-
8-carboxamide
Figure imgf000232_0002
[0603] Amount isolated: 0.8 mg. LCMS m/z [M+H]+: 444, purity (UV/MS): 100/62, ^ = 4.97 min. Example 541 : 1 l-(5-chlorothiophen-2-ylVN-(thiophen-2-ylmethyl*)dibenzo[b,fiπ ,4] thiazepine-8-carboxamide
Figure imgf000233_0001
[0604] Amount isolated: 1.1 mg. LCMS m/z [M+H]+: 466, purity (UV/MS): 99/3 UR = 3.00 min.
Example 542: 1 l-O-chlorophenylVN-fthiophen^-ylmethvDdibenzofb^fl^lthiazepine- 8-carboxamide
Figure imgf000233_0002
[0605] Amount isolated: 4.0 mg. LCMS m/z [M+H]+: 460, purity (UV/MS): 99/34, tR = 5.35 min.
Example 543: 1 l-(4-chlorophenyl)-N-(thiophen-2-ylmethγl)dibenzo[b,f|[L41thiazepine- 8-carboxamide
Figure imgf000233_0003
[0606] Amount isolated: 0.9 mg. LCMS m/z [M+H]+: 460, purity (UV/MS): 100/43, /R = 5.35 min.
Example 544: 1 l-(3-methylthiophen-2-yl)-N-(thiophen-2-ylmethyl)dibenzo[b,fiπ ,41 thiazepine-8-carboxamide
Figure imgf000234_0001
[0607] Amount isolated: 3.6 nig. LCMS m/z [M+H]+: 446, purity (UV/MS): 100/49, /R = 4.93 min.
Example 545: l l-(3,4-dichlorophenyl)-N-(pyridin-3- ylmethyl)dibenzofb,f|f1,4]thiazepine-8-carboxamide
Figure imgf000234_0002
[0608] Amount isolated: 1.5 mg. LCMS m/z [M+H]+: 489, purity (UV/MS): 96/25, /R = 4.93 min.
Example 546: 1 l-(4-chlorophenylVN-(furan-2-ylmethyl)dibenzo[b,fl[K4]thiazepine-8- carboxamide
Figure imgf000234_0003
[0609] Amount isolated: 4.7 mg. LCMS m/z [M+H]+: 444, purity (UV/MS): 100/58, /R = 5.19 min.
Example 547: 1 l-(4-fluorophenyl)-N-(furan-2-ylmethyl)dibenzofb,f|[K41thiazepine-8- carboxamide
Figure imgf000235_0001
[0610] Amount isolated: 1.7 mg. LCMS m/z [M+H]+: 428, purity (UV/MS): 99/48, /R = 4.73 min.
Example 548: 1 l-(5-chlorothiophen-2-ylVN-(furan-2- ylmethyl)dibenzofb,fiπ,41thiazepine-8-carboxamide
Figure imgf000235_0002
[0611] Amount isolated: 6.3 mg. LCMS m/z [M+H]+: 450, purity (UV/MS): 100/37, /R = 5.21 min.
Example 549: 1 l-(3-fluorophenyl)-N-(thiophen-2-ylmethyl)dibenzo[b,f|[1,41thiazepine-
8-carboxamide
Figure imgf000235_0003
[0612] Amount isolated: 3.7 mg. LCMS m/z [M+H]+: 444, purity (UV/MS): 100/47, /R = 5.07 min.
Example 550: 1 l-CSΛ-dichlorophenylVN-ffuran^-ylmethyl)dibenzol'b^πΛlthiazepinc- 8-carboxamide
Figure imgf000236_0001
[0613] Amount isolated: 9.4 mg. LCMS m/z [M+H]+: 478, purity (UV/MS): 100/62, fR = 5.55 min.
Example 551 : 11 -f 3,4-dichlorophenvD-N-(2-(pyridin-3- y0ethy0dibenzorb,firh41thiazepine-8-carboxami
Figure imgf000236_0002
[0614] Amount isolated: 4.8 mg. LCMS m/z [M+H]+: 503, purity (UV/MS): 100/34, tR = 4.93 min.
Example 552: 1 l-(3-chlorophenylVN-(furan-2-ylmethyl)dibenzo[b,f|f 1 ,4]thiazepine-8- carboxamid
Figure imgf000236_0003
[0615] Amount isolated: 7.2 mg. LCMS m/z [M+H]+: 444, purity (UV/MS): 100/70, tR = 5.13 min.
Example 553: 1 l-(5-chlorothiophen-2-ylVN-(2-(pyridin-3-vnethyl)dibenzorb,firK41 thiazepine-8-carboxamide
Figure imgf000237_0001
[0616] Amount isolated: 5.9 mg. LCMS m/z [M+H]+: 475, purity (UV/MS): 97/17, tR = 4.52 min.
Example 554: l l-(3,4-dichlorophenyl)-N-(2-(pyridin-4- yl)ethyOdibenzofb,fiπ,41thiazepine-8-carboxamide
Figure imgf000237_0002
[0617] Amount isolated: 0.8 mg. LCMS m/z [M+H]+: 504, purity (UV/MS): 97/44, tR = 4.90 min.
Example 555: 1 l-(5-chlorothiophen-2-vn-N-(2-(pyridin-4-vnethyl)dibenzo[b,firi,41 thiazepine-8-carboxamide
Figure imgf000237_0003
[0618] Amount isolated: 1.8 mg. LCMS m/z [M+H]+: 475, purity (UV/MS): 100/70, /R = 4.52 min.
Example 556: 1 l-(4-fluorophenyl)-N-(pyridin-3-ylmethyl)dibenzo[b,firi ,41thiazepine-8- carboxamide
Figure imgf000238_0001
[0619] Amount isolated: 1.3 mg. LCMS m/z [M+H]+: 439, purity (UV/MS): 99/47, ?R = 4.05 min.
Example 557: 1 l-(4-fluorophenylVN-(2-(pyridin-3-yl')ethvπdibenzo[b,f|f K4]thiazepine- 8-carboxamide
Figure imgf000238_0002
[0620] Amount isolated: 1.3 mg. LCMS m/z [M+H]+: 453, purity (UV/MS): 98/38, /R = 4.07 min.
Example 558: 1 l-(3-fluorophenylVN-(pyridin-3-ylmethyl)dibenzo[b,f|[L41thiazepine-8- carboxamide
Figure imgf000238_0003
[0621] Amount isolated: 3.0 mg. LCMS m/z [M+H]+: 439, purity (UV/MS): 99/40, /R = 4.10 min.
Example 559: 11 -(4-fluoropheny l)-N-("2-(pyridin-4-yl)ethyQdibenzo[b,flf 1 ,4]thiazepine- 8-carboxamide
Figure imgf000239_0001
[0622] Amount isolated: 0.9 mg. LCMS m/z [M+H]+: 453, purity (UWMS): 89/34, /R = 4.07 min.
Example 560: 1 l-(2-fluorophenyl)-N-(thiophen-2-ylmethyl)dibenzo[b,f|[1,4]thiazepine- 8-carboxamide
Figure imgf000239_0002
[0623] Amount isolated: 3.9 mg. LCMS m/z [M+H]+: 444, purity (UWMS): 100/41, fR = 4.67 min.
Example 561 : U-(3-fluorophenylVN-(furan-2-ylmethyl)dibenzo[b,f||'1,4]thiazepine-8- carboxamide
Figure imgf000239_0003
[0624] Amount isolated: 5.5 mg. LCMS m/z [M+H]+: 428, purity (UWMS): 100/47, tR = 4.75 min.
Example 562: N-(furan-2-ylmethy1Hl-(3-methylthiophen-2- yl)dibenzo["b,fin,41thiazepine-8-carboxamide
Figure imgf000240_0001
[0625] Amount isolated: 7.9 mg. LCMS m/z [M+H]+: 430, purity (UV/MS): 95/55, /R = 4.70 min.
Example 563: 1 l-(3-chlorophenyl)-N-(2-(pyridin-3-yl)ethyl)dibenzo[b1f][1,4]thiazepine- 8-carboxamide
Figure imgf000240_0002
[0626] Amount isolated: 6.2 mg. LCMS m/z [M+H]+: 469, purity (UV/MS): 100/64, /R = 4.50 min.
Example 564: 1 l-(2-fluorophenyl)-N-(pyridin-3-ylmethyl)dibenzo[b,fiπ,41thiazepine-8- carboxamide
Figure imgf000240_0003
[0627] Amount isolated: 4.0 mg. LCMS m/z [M+H]+: 439, purity (UV/MS): 99/39, tR = 3.75 min.
Example 565: 1 l-(4-chlorophenyl)-N-(2-(pyridin-3-yl)ethyl)dibenzo[b1f][1,41thiazepine- 8-carboxamide
Figure imgf000241_0001
[0628] Amount isolated: 5.6 mg. LCMS m/z [M+H]+: 469, purity (UV/MS): 88/19, /R = 4.50 min.
Example 566: 1 l-(3-fluorophenylVN-(2-(pyridin-3-yl)ethyl)dibenzofb,f|[1,41thiazepine- 8-carboxamide
Figure imgf000241_0002
[0629] Amount isolated: 4.4 mg. LCMS m/z [M+H]+: 453, purity (UV/MS): 100/39, /R = 4.12 min.
Example 567: 1 l-(4-Chlorophenyl')-N-(2-(pyridine-4- yl)ethyl)dibenzo Tb^f]T 1,41thiazepine-8-carboxamide
Figure imgf000241_0003
[0630] Amount isolated: 2.5 mg. LCMS m/z [M+H]+: 469, purity (UV/MS): 97/37, /R = 4.47 min. Example 568: 1 l-(pyridin-2-yl)-N-(thiophen-2-γlmethyl)dibenzo[b,fl[K41thiazepine-8- carboxamide
Figure imgf000242_0001
[0631] Amount isolated: 2.1 mg. LCMS m/z [M+H]+: 427, purity (UV/MS): 100/68, /R = 3.88 min.
Example 569: 1 l-("3-Fluorophenyl)-N-(2-(pyridin-4-yl)ethyl)dibenzo[b,f1[1,4]thiazepine-
8-carboxamide
Figure imgf000242_0002
[0632] Amount isolated: 3.7 mg. LCMS m/z [M+H]+: 453, purity (UV/MS): 94/35, tR = 4.08 min.
Example 570: 1 l-(2-FluorophenylVN-(furan-2-ylmethyl)dibenzofb,f][K4]thiazepine-8- carboxamide
Figure imgf000242_0003
[0633] Amount isolated: 5.7 mg. LCMS m/z [M+H]+: 428, purity (UV/MS): 94/34, tκ = 4.45 min.
Example 571 : 1 l-(3-methylthiophen-2-yl)-N-(2-(pyridin-3-yl)ethyl)dibenzo[b,fiπ ,41 thiazepi ne- 8-carboxamide
Figure imgf000243_0001
[0634] Amount isolated: 3.3 mg. LCMS m/z [M+H]+: 455, purity (UV/MS): 100/42, /R = 4.02 min.
Example 572: 1 l-(2-fluorophenyl)-N-(2-(pyridin-3-yl)ethyl)dibenzo[b,f|[1,4]thiazepine- 8-carboxamide
Figure imgf000243_0002
[0635] Amount isolated: 6.3 mg. LCMS m/z [M+H]+: 453, purity (UV/MS): 95/34, tR = 3.78 min.
Example 573: N-(furan-2-ylmethyl)-l l-(pyridin-2-yl)dibenzorb,f][U4]thiazepine-8- carboxamide
Figure imgf000243_0003
[0636] Amount isolated: 3.1 mg. LCMS m/z [M+H]+: 411, purity (UV/MS): 100/58, /R = 3.62 min.
Example 574: 1 l-fS-methylthiophen^-yl)-N-fpyridin-S-ylmethyπdibenzofb^fiπ^] thiazepine-8-carboxamide
Figure imgf000244_0001
[0637] Amount isolated: 2.2 mg. LCMS m/z [M+H]+: 441, purity (UV/MS):100/35, tR = 3.98 min.
Example 575: 1 l-(3-methylpyridin-2-ylVN-(thiophen-2-ylmethyl')dibenzo["b,f|[1,4] thiazepine-8-carboxamide
Figure imgf000244_0002
[0638] Amount isolated: 1.6 mg. LCMS m/z [M+H]+: 441, purity (UV/MS): 100/54, /R = 3.85 min.
Example 576: 1 l-(3-methylthiophen-2-yl)-N-(2-(pyπdin-4-yl)ethyl)dibenzo[b,fiπ.41 thiazepine-8-carboxamide
Figure imgf000244_0003
[0639] Amount isolated: 1.8 mg. LCMS m/z [M+H]+: 455, purity (UV/MS): 98/22, /R = 4.00 min.
Example 577: 1 l-(3-fluorophenyl)-N-(pyndin-4-ylmethyl)dibenzo[b,fl[1,4]thiazepine-8- carboxamide
Figure imgf000244_0004
[0640] Amount isolated: 2.4 mg. LCMS m/z [M+H]+: 439, purity (UV/MS): 98/35, tκ = 4.03 min.
Example 578: l l-(2,4-dichlorophenvn-N-(2-(pyπdin-3- yl)ethyl)dibenzorb,firL41thiazepine-8-carboxamide
Figure imgf000245_0001
[0641] Amount isolated: 3.9 mg. LCMS m/z [M+H]+: 503, purity (UV/MS): 96/24, tκ = 4.58 min.
Example 579: 1 l-(2-fluorophenyl)-N-(pyridin-4-ylmethyl)dibenzorb,flπ,41thiazepine-8- carboxamide
Figure imgf000245_0002
[0642] Amount isolated: 2.5 mg. LCMS m/z [M+H]+: 439, purity (UV/MS): 100/50, /R = 3.72 min.
Example 580: 1 l-(2-chlorophenvπ-N-(thiophen-2-ylmethyπdibenzorb,f|[K41thiazepine- 8-carboxamide
Figure imgf000245_0003
[0643] Amount isolated: 1.4 mg. LCMS m/z [M+H]+: 460, purity (UV/MS): 99/51, rR = 4.88 min. Example 581: 1 l-(2-chlorophenylVN-(furan-2-ylmethyl)dibenzo[b,f|[1,4]thiazepine-8- carboxamide
Figure imgf000246_0001
[0644] Amount isolated: 6.2 mg. LCMS m/z [M+H]+: 444, purity (UV/MS): 100/34, /R = 4.65 min.
Example 582: 1 l-π-methylthiophen-Σ-vn-N-Cpyridin^-ylmethvndibenzorb.firiΛl thiazepine-8-carboxamide
Figure imgf000246_0002
[0645] Amount isolated: 1.6 mg. LCMS m/z [M+H]+: 441, purity (UV/MS): 99/41, fo = 3.97 min.
Example 583: 1 l-(2-chlorophenyl)-N-('2-(pyridin-3-v0ethyl)dibenzo[b,f|[1,4]thiazepine- 8-carboxamide
Figure imgf000246_0003
[0646] Amount isolated: 4.5 mg. LCMS m/z [M+H]+: 470, purity (UV/MS): 100/40, /R = 3.97 min.
Example 584: 1 l-(pyridin-2-yl)-N-(2-(pyridin-4-yl)ethyl)dibenzorb,firK41thiazepine-8- carboxamide
Figure imgf000247_0001
[0647] Amount isolated: 3.0 mg. LCMS m/z [M+H]+: 436, purity (UV/MS): 98/60, tR = 2.90 min.
Example 585: l l-(2,4-dichlorophenyl)-N-(2-(pyridin-4- yl)ethy0dibenzorb,firi,41thiazepine-8-carboxamide
Figure imgf000247_0002
[0648] Amount isolated: 1.2 mg. LCMS m/z [M+H]+: 503, purity (UV/MS): 96/30, tκ = 4.58 min.
Example 586: 1 l-C∑-chlorophenyπ-N-fΣ-fpyridin^-yl)ethyπdibenzofb^f lΛithiazepine- 8-carboxamide
Figure imgf000247_0003
[0649] Amount isolated: 2.4 mg. LCMS m/z [M+H]+: 469, purity (UV/MS): 93/36, tR = 3.95 min.
Example 587: l l-(3-methylpyridin-2-yl)-N-(pyridin-3- y Imethyl)dibenzorb,f1 [ 1 ,41thiazepine-8-carboxamide
Figure imgf000248_0001
[0650] Amount isolated: 3.5 mg. LCMS m/z [M+H]+: 436, purity (UV/MS): 92/71, /R = .93 min.
Example 588: 1 l-(3-fluorophenyl)-N-(5-methyIisoxazol-3- yl)dibenzo[b,f|fU41thiazepine-8-carboxamide
Figure imgf000248_0002
[0651] Amount isolated: 0.6 mg. LCMS m/z [M+H]+: 430, purity (UV/MS): 100/36, tR = 4.92 min.
Example 589: 1 l-(3-methylpyridin-2-vn-N-f2-(pyridin-3-vnethvndibenzorb,fiπ,41 thiazepine-8-carboxamide
Figure imgf000248_0003
[0652] Amount isolated: 2.2 mg. LCMS m/z [M+H]+: 450, purity (UV/MS): 93/80, tR = 2.93 min.
Example 590: 1 l-(4-chlorobenzylamino)-N'-(2-phenylacetvπdibenzo[b,f][1,4]thiazepine- 8-carbohydrazide
Figure imgf000249_0001
[0653] Amount isolated: 5.1 mg. LCMS m/z [M]: 527, purity (UV/MS): 97/67, tR = 11.92 min.
Example 591 : N-(5-methyhsoxazol-3-yO-l l-(pyridin-2-yl)dibenzo[b,f][1,4]thiazepine-8- carboxamide
Figure imgf000249_0002
[0654] Amount isolated: 0.6 mg. LCMS m/z [M+H]+: 412, purity (UV/MS): 97/72, tR = 3.68 min.
Example 592: l l-(2-fluorophenyl)-N-(5-methylisoxazol-3- yπdibenzo[b,f|f 1,41thiazepine-8-carboxamide
Figure imgf000249_0003
[0655] Amount isolated: 0.7 mg. LCMS m/z [M+H]+: 429, purity (UV/MS): 100/54, tø = 4.59 min.
Example 593: 1 l-(4-chlorobenzylamino)-N-(pyridin-2- ylmethyl)dibenzorb,firi,41thiazepine-8-carboxarnide
Figure imgf000250_0001
[0656] Amount isolated: 8.6 mg. LCMS m/z [M+H]+: 485, purity (UV/MS): 95/77, tκ - 10.02 min.
Example 594: N-(5-methylisoxazol-3-yl)-l l-(3-methylpyridin-2-yl)dibenzorb,firi ,4] thiazepine-8-carboxamide
Figure imgf000250_0002
[0657] Amount isolated: 0.8 mg. LCMS m/z [M+H]+: 426, purity (UV/MS): 99/60, tκ = 3.72 min.
Example 595: 1 l-(4-chlorobenzylaminoVN-(2-oxoazepan-3- vπdibenzorb,fiπ,41thiazepine-8-carboxamide
Figure imgf000250_0003
[0658] Amount isolated: 4.7 mg. LCMS m/z [M+H]+: 505, purity (UV/MS): 88/40, tR = 1 1.36 min.
Example 596: N'-benzoyl-l l-(4-chlorobenzylamino)dibenzofb,f|[1,41thiazepine-8- carbohydrazide
Figure imgf000251_0001
[0659] Amount isolated: 7.1 mg. LCMS m/z [M+H]+: 513, purity (UV/MS): 97/73, ^R = 1 1.66 min.
Example 597: 1 l-(3-methylpyridin-2-vn-N-(2-(pyridin-4-yl)ethvndibenzorb,f|π,41 thiazepine-8-carboxamide
Figure imgf000251_0002
[0660] Amount isolated: 1.0 mg. LCMS m/z [M+H]+: 450, purity (UV/MS): 88/68, tR = 2.92 miri.
Example 598: 1 l-(4-chlorobenzγlamino)-N-memoxydibenzo[b,f|π ,41thiazepine-8- carboxamide
Figure imgf000251_0003
[0661] Amount isolated: 5.0 mg. LCMS m/z [M+H]+: 424, purity (UV/MS): 92/57, ^R = 10.82 min.
Example 599: 1 l-(2-chlorophenyl)-N-(pyridin-3-ylmethyl)dibenzo[b,f|[1,41thiazepine-8- carboxamide
Figure imgf000252_0001
[0662] Amount isolated: 1.7 mg. LCMS m/z [M+H]+: 455, purity (UV/MS): 99/35, /R = 3.95 min.
Example 600: N-(furan-2-ylmethylVl l-(3-methylpyridin-2- yl)dibenzoOxfiπ^ithiazepine-S-carboxamide
Figure imgf000252_0002
[0663] Amount isolated: 2.1 mg. LCMS m/z [M+H]+: 425, purity (UV/MS): 86/40, /R = 3.65 min.
Example 601 : 1 l-("pyridin-2-yl)-N-('2-(pyridin-3-yπethyl)dibenzorb,f|[1,41thiazepine-8- carboxamide
Figure imgf000252_0003
[0664] Amount isolated: 3.6 mg. LCMS m/z [M+H]+: 436, purity (UV/MS): 96/61, /R = 2.90 min.
Example 602: 1 l-(4-chlorobenzylamino)-N-(pyridin-3- ylmethyl)dibenzo[b,firi,41thiazepine-8-carboxamide
Figure imgf000253_0001
[0665] Amount isolated: 8.9 mg. LCMS m/z [M+H]+: 485, purity (UV/MS): 99/100, /R = 9.87 min.
Example 603: 1 l-(2-chlorophenyiyN-(pyridin-4-ylmethyl)dibenzo[b,f|[K41thiazepine-8- carboxamide
Figure imgf000253_0002
[0666] Amount isolated: 1.8 mg. LCMS m/z [M+H]+: 455, purity (UV/MS): 97/39, tR = 3.92 min.
Example 604: 1 l-(4-chlorobenzylamino)-N-(pyridin-4- ylmethyl)dibenzo[b,fl[l ,41thiazepine-8-carboxamide
Figure imgf000253_0003
[0667] Amount isolated: 4.7 mg. LCMS m/z [M+H]+: 485, purity (UV/MS): 93/95, tR = 9.88 min.
Example 605: 1 l-(4-chlorobenzylamino)-N-(4- sulfamoylbenzylMibenzorb,firh41thiazepine-8-carboxamide
Figure imgf000254_0001
[0668] Amount isolated: 6.1 mg. LCMS m/z [M+H]+: 563, purity (UV/MS): 77/43, /R = 1 1.56 min.
Example 606: 1 l-(5-Bromopyridin-2-ylVdibenzo[b,fl[1.4]thiazepine-8-carboxylic acid butylamide.
Figure imgf000254_0002
Preparation of the zinc reagent:
[0669] A dry flask equipped with a magnetic bar was charged with zinc dust. The reaction flask was flushed with argon and a solution of 1 ,2-dibromoethane (100 mg, 0.53 mmol) in ./V,./V-dimethylacetamide (1.5 mL) was added. The zinc suspension was shortly heated with a heat gun until evolution of ethylene occurred (repeated twice).
[0670] The reaction mixture was allowed to cool to room temperature. Trimethylsilyl chloride (0.30 mL, 2.3 mmol) was added in two portions. After 15 minutes stirring at room temperature a solution of 5-bromo-2-iodopyridine (1.42 g, 5.0 mmol) in N,iV-dimethylacetamide (3.0 mL) was added to the zinc suspension at 50°C. The reaction mixture was stirred at 7O°C for 3 hours. Conversion of the starting material was followed by GC using decane as the internal standard. After 3 hours at 7O°C, 60% of the starting material was converted to the desired zinc reagent. Stirring was continued overnight at 7O°C, which gave full conversion. The reaction mixture was allowed to cool to room temperature and diluted with dry THF (3.0 mL). The remaining zinc was allowed to settle. The obtained solution of 5-bromo-2-pyridylzinc iodide was used immediately in the next step. [0671] Bis(dibenzylideneacetone)palladium (18 mg, 0.031mmol) and tri-2- furylphosphine (15 mg, 0.065 mmol) were dissolved in dry THF (1.0 mL) in a dry flask, under argon atmosphere. A solution of l l-chloro-dibenzo[i,/J[l ,4]thiazepine-carboxylic . acid butylamide (prepared as previously described, 200 mg, 0.63 mmol) in dry THF (2.0 mL) was added to the flask. A solution of the freshly prepared 5-bromo-2-pyridylzinc iodide (3 mL, 2.0 mmol) was added dropwise to the reaction mixture at room temperature. After 20 hours stirring at room temperature the reaction mixture was partitioned between aqueous NH4CI (sat) and EtOAc. The organic layer was dried over Na2SO4, filtered end evaporated to dryness. The residue was purified by silica gel column chromatography, eluting with a stepwise gradient of 15-30% EtOAc in toluene. The isolated product was repurified using an acidic exchange cartridge eluting with NH3 in MeOH. Yield: 5.8 mg, 2%.
[0672] LCMS m/z 467 [M+H]+ HPLC /R = 4.3 min. 1H NMR (CDCl3, 400 MHz) δ 8.72 (m, 1H, Ar-H), 8.24 (m, 1H, Ar-H), 8.01-7.98 (m, I H, Ar-H), 7.71 (m, 1H, Ar-H), 7.66-7.52 (m, 3H, Ar-H), 7.43 (m, 1H, Ar-H), 7.32 (m, I H, Ar-H), 7.21 (m, I H, Ar-H), 6.12-6.03 (broad s, 1H, NH), 3.45 (q, 2H, J = 7.2 Hz, CH2Bu), 1 -58 (pentet, 2H, J = 7.2 Hz, CH2Bu), 2.80 (m, 2H, J= 7.2 Hz, CH2Bu), 0.95 (t, 3H, J= 7.2 Hz, CH3Bu).
Example 607: General procedure for the synthesis of the zinc reagents from bromopyridines:
1PrMgCl ZnBr
Figure imgf000255_0003
Figure imgf000255_0001
Figure imgf000255_0002
[0673] 2-Bromo-5-halopyridine (3 mmol) was dissolved in THF (5.5 mL) and isopropylmagnesium chloride (2 M in THF; 1.5 mL; 3.0 mmol) was added at room temperature. After 2hours, zinc bromide (1 M in THF; 3.0 mL; 3.0 mmol) was added and the mixture was stirred at room temperature under argon over night. The crude mixture was used immediately in the next step. Example 608: U-fS-Fluoropyπdin-Z-ylVdibenzofό./ifl^lthiazepine-carboxylic acid butylamide
Figure imgf000256_0001
[0674] A reaction flask was charged with 1 1-chloro- dibenzo[ό,/][1,4]thiazepine-carboxylic acid butylamide (0.17 g; 0.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (36.0 mg; 0.050 mmol) under argon. THF (5 mL) was added followed by the addition of 5-fluoro-2-pyridylzinc bromide (0.15 M in THF; 12.5 mL; 1.8 mmol) at room temperature. After 5 hours, aqueous NH4Cl (sat) was added to the mixture and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography (0-20% EtOAc in toluene) followed by ion exchange column chromatography (eluting with 2% NH3 in MeOH) and recrystallization from MeOH to yield the title compound as a yellow solid (54.4 mg; 27%).
[0675] LCMS m/z 406 [M+H]+, purity (UV/MS) 99/95, /R - 8.38 min. 1H NMR (CDCl3, 400 MHz) δ 8.50 (d, 1H, J= 2.8 Hz, ArH), 8.38 - 8.42 (m, 1H, ArH), 7.68 (d, 1H, J = 0.4 Hz, ArH), 7.50 - 7.58 (m, 4H, ArH), 7.40 - 7.44 (m, 1H, ArH), 7.30 - 7.34 (m, 1H, ArH), 7.20 - 7.25 (m, 1H, ArH), 6.03 (br m, 1H, NH), 3.44 (q, 2H, J = 6.8 Hz, CH2), 1.54 - 1.62 (m, 2H, CH2), 1.36 - 1.45 (m, 2H, CH2), 0.95 (t, 3H, J = 7.2 Hz, CH3).
Example 609: l l-(5-Chloropyridin-2-yl)-dibenzo[fc,/1[l ,4]thiazepine-carboxylic acid butylamide
Figure imgf000256_0002
[0676] A reaction flask was charged with 1 1 -chloro- dibenzo[ό,/][1,4]thiazepine-carboxylic acid butylamide (0.17 g; 0.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (36.0 mg; 0.050 mmol) under argon. THF (5 mL) was added followed by the addition of 5-chloro-2-pyridylzinc bromide (0.15 M in THF; 12.5 mL; 1.8 mmol) at room temperature. After 5 hours, aqueous NH4Cl (sat) was added to the mixture and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography (0-20% EtOAc in toluene) followed by ion exchange column chromatography (eluting with 2% NH3 in MeOH) and recrystallization from MeOH to yield the title compound as a yellow solid (69.5 mg; 33%).
[0677] LCMS m/z 422 [M+H]+, purity (UV/MS) 98/88, /R = 6.43 min. 1H NMR (CDCl3, 400 MHz) δ 8.60 (d, 1H, J= 1.6 Hz, ArH), 8.31 (d, 1H, J= 8.8 Hz, ArH), 7.82 - 7.85 (m, 1H, ArH), 7.69 (d, 1H, J= 0.4 Hz, ArH), 7.51 - 7.55 (m, 3H, ArH), 7.40 - 7.44 (m, 1H, ArH), 7.32 - 7.34 (m, 1H, ArH), 7.20 - 7.25 (m, 1H, ArH), 6.03 (br m, 1H, NH), 3.44 (q, 2H, J = 7.2 Hz, CH2), 1.54 - 1.62 (m, 2H, CH2), 1.37 - 1.47 (m, 2H, CH2), 0.95 (t, 3H, J= 7.6 Hz, CH3).
Example 610: l l-(5-Fluoropyridin-2-ylVdibenzo[a,/1[1,4]thiazepine-carboxylic acid piperidin- 1 -ylamide
Figure imgf000257_0001
[0678] A reaction flask was charged with 1 1-chloro- dibenzo[έ,/)[1,4]thiazepine-carboxylic acid piperidin- 1 -ylamide (80.0 mg; 0.22 mmol) and bis(triphenylphosphine) palladium(ll)chloride (15.1 mg; 0.022 mmol) under argon. THF (3 mL) was added followed by the addition of 5-fluoro-2-pyridylzinc bromide (0.15 M in THF; 5.0 mL; 0.75 mmol) at room temperature. After 3 hours, aqueous NH4Cl (sat) was added to the mixture and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography (0-30% EtOAc in toluene), ion exchange column chromatography (eluting with 2% NH3 in MeOH) and recrystallization from EtOAc to yield the title compound as a yellow solid (9.8 mg; 10%).
[0679] LCMS m/z 433 [M+H]+, purity (UV/MS) 97/92, /R = 3.80 min. 1H NMR (CDCl3, 400 MHz) δ 8.50 (d, 1H, J= 2.8 Hz, ArH), 8.38 - 8.40 (m, 1H, ArH), 7.67 (d, 1H, J = 0.4 Hz, ArH), 7.51 - 7.56 (m, 4H, ArH), 7.40 - 7.44 (m, 1H, ArH), 7.30 - 7.34 (m, 1H, ArH), 7.20 - 7.24 (m, 1H, ArH), 6.69 (br m, 1H, NH), 2.82 - 2.86 (m, 4H, CH2), 1.73 - 1.79 (m, 4H, CH2), 1.44 - 1.48 (m, 2H, CH2).
Example 611 : 1 HS-Chloropyridin^-yiydibenzoffrJlf lΛithiazepine-carboxylic acid piperidin- 1 -ylamide
Figure imgf000258_0001
[0680] A reaction flask was charged with 1 1 -chloro- dibenzo[&,/][l ,4]thiazepine-carboxylic acid piperidin- 1 -ylamide (80.0 mg; 0.22 mmol) and bis(triphenylphosphine) palladium(Il)chloride (15.1 mg; 0.022 mmol) under argon. THF (3 mL) was added followed by the addition of 5-chloro-2-pyridylzinc bromide (0.15 M in THF; 5.0 mL; 0.75 mmol) at room temperature. After 3 hours, aqueous NH4Cl (sat) was added to the mixture and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography (0-30% EtOAc in toluene) and recrystallization from EtOAc to yield the title compound as a yellow solid (13.8 mg; 14%).
[0681] LCMS m/z 449 [M+H]+, purity (UV/MS) 99/87, /R = 7.94 min. 1H NMR (CDCl3, 400 MHz) δ 8.60 (d, 1H, J = 1.6 Hz, ArH), 8.301 (d, I H, J = 8.0 Hz, ArH), 7.82 - 7.84 (m, 1H, ArH), 7.67 (d, 1H, J = 0.4 Hz, ArH), 7.51 - 7.55 (m, 3H, ArH), 7.40 - 7.44 (m, 1H, ArH), 7.30 - 7.34 (m, 1H, ArH), 7.20 - 7.22 (m, 1H, ArH), 6.68 (br m, 1H, NH), 2.81 - 2.83 (m, 4H, CH2), 1.74 - 1.78 (m, 4H, CH2), 1.42 - 1.48 (m, 2H5 CH2). Example 612: (£1-11 -Chloro-Λf-((tetrahydrofuran-2- yl)methyl)dibenzo[6,/U1,41thiazepine-8-carboxarnide
Figure imgf000259_0001
[0682] Yield: (619.8 mg; 1.67 mmol; 64%). 1H NMR (CDCl3, 400 MHz) δ 7.75-7.74 (m, 1H, ArH), 760-7.58 (m, 2H, ArH), 7.77 - 7.47 (m, 4H, ArH), 6.54 (br m, 1H, NH), 4.02-3.88 (m, 1H, OCH), 3.85-3.83 (m, 1H, CH2), 3.73-3.69 (m, 2H, CH2), 3.32-3.25 (m, 1H, CH2), 2.01-1.95 (m, 1Η, CH2), 1.93-1.86 (m, 2Η, CH2), 1.58-1.54 (m, 1H, CH2). LCMS m/z 373 [M+Η]+, purity (UV/MS) 97/85, /R = 3.92 min.
Example 613: (E)A l-Chloro-N-(4,4,4-trifluorobutyl)dibenzo|"6,/l[1,41thiazepine-8- carboxamide
Figure imgf000259_0002
[0683] Yield: (954.4 mg; 2.40 mmol; 92%). 1H NMR (CDCl3, 400 MHz) δ 7.74-7.72 (m, 1H, ArH), 7.59-7.55 (m, 2H, ArH), 7.50-7.38 (m, 4H, ArH), 6.29 (br m, 1H, NH), 3.52-3.47 (m, 2H, CH2), 2.18-2.12 (m, 2H, CH2), 1.83-1.89 (m, 2H, CH2). LCMS m/z 399 [M+H]+, purity (UV/MS) 100/100, /R = 4.40 min.
Example 614: (E)A l-Chloro-N-(2-fluoroethylMibenzor6./]π,4]thiazepine-8- carboxamide
Figure imgf000259_0003
[0684] The title compound was synthesized by the general procedure for amide formation using (£)-l l-chlorodibenzo[6,y][l ,4]thiazepine-8-carbonyl chloride (1.71 mmol), triethylamine (5.2 mmol), 5 mL dry dichloromethane and 2-fluoroethyl amine (2.0 mmol). Yield: 82 mg (14%). LCMS m/z 335 [M+H]+, HPLC tκ = 3.81 min Example 615: (E)-I l-Chloro-N-ff4-methylthiophen-2-yl)methyl)dibenzorά,/iπ .41 thiazepine-8-carboxamide
Figure imgf000260_0001
[0685] The title compound was synthesized by the general procedure for amide formation using (£)-l l-chlorodibenzo[έ,y][1,4]thiazepine-8-carbonyl chloride (1.71 mmol), triethylamine (5.2 mmol), 5 mL dry dichloromethane and 4-methyl-2- (aminomethyl)thiophene (2.0 mmol). Yield: 448 mg (66%). LCMS m/z 399 [M+H]+, HPLC tR = 9.04 min
Example 616: (E)-I l-Chloro-N-(3,33-trifluoropropyl)dibenzo[6,/][l ,4]thiazepine-8- carboxamide
Figure imgf000260_0002
[0686] The title compound was synthesized by the general procedure for amide formation using (E)-I l-chlorodibenzo[ό,/J[l ,4]thiazepine-8-carbonyl chloride (1.71 mmol), triethylamine (5.2 mmol), 5 mL dry dichloromethane and 3,3,3- trifluoropropan-1 -amine (2.0 mmol). Yield: 345 mg (53%). LCMS m/z 385 [M+H]+, HPLC tR = 8.40 min.
Example 617: (F)-I l-Chloro-N-^Λ-difluorocyclohexyOdibenzoffe./iπΛithiazepine-δ- carboxamide
Figure imgf000261_0001
[0687] The title compound was synthesized by the general procedure for amide formation using (F)-I l-chlorodibenzo[ό,/l[l ,4]thiazepine-8-carbonyl chloride (1.71 mmol), triethylamine (5.2 mmol), 5 mL dry dichloromethane and 4,4- difluorocyclohexyl amine (2.0 mmol). Yield: 330 mg (48%). LCMS m/z 407 [M+H]+, HPLC /R = 8.79 min.
Example 618: (F)-11 -Chloro-iV-((5-methylfuran-2- yr)methy0dibenzo[fr,/1[1,41thiazepine-8-carboxamide
Figure imgf000261_0002
[0688] The title compound was synthesized by the general procedure for amide formation using (F)-I l-chlorodibenzo[6,/][l ,4]thiazepine-8-carbonyl chloride (1.71 mmol), triethylamine (5.2 mmol), 5 mL dry dichloromethane and (5-methylfuran-2- yl)methyl amine (2.0 mmol). Yield: 400 mg (61%). LCMS m/z 382 [M+H]+, HPLC /R = 4.79 min.
Example 619: (F)-I l-Chloro-N'-(2.2.2-trifluoroethyl)dibenzofά,/irK41thiazepine-8- carbohydrazide
Figure imgf000261_0003
[0689] The title compound was synthesized by the general procedure for amide formation using (F)-I l-chlorodibenzo[b,/][1,4]thiazepine-8-carbonyl chloride (1.71 mmol), triethylamine (5.2 mmol), 5 mL dry dichloromethane and (2,2,2- trifluoro)hydrazine (2.0 mmol). Yield: 85 mg (13%). LCMS m/z 386 [M+H]+, HPLC rR 2.83 min.
Example 620: (Z)-11 -(4-ChlorophenylViV-((tetrahvdrofuran-2- vπmethyπdibenzo[6,/][l ,4] thiazepine-8-carboxamide
Figure imgf000262_0001
[0690] Yield: (95.4 mg; 0.21 mmol; 52%). 1H NMR (CDCl3, 400 MHz) δ 7.75-7.69 (m, 3H, ArH), 7.55-7.47 (m, 3H, ArH), 7.43-7.39 (m, 3H, ArH), 7.31-7.26 (m, 1H, ArH), 7.16-7.14 (m, 1H, ArH), 6.65 (br m, 1H, NH), 4.07-3.95 (m, I H, OCH), 3.86- 3.80 (m, 1H, CH2), 3.76-3.72 (m, 2H, CH2), 3.35-3.25 (m, 1H, CH2), 2.03-1.90 (m, I H, CH2), 1.91-1.87 (m, 2H, CH2), 1.60-1.55 (m, 1H, CH2). LCMS m/z 449 [M+Η]+, purity (UV/MS) 94/52, /R= 4.83 min.
Example 621 : (E)- 11 -(6-Memoxypyridin-2-viyΛ^(tetrahvdrofuran-2-v0methvQdibenzo fά./lfl ,41 thiazepine-8-carboxamide
Figure imgf000262_0002
[0691] Yield: (50.0 mg; 0.11 mmol; 27%). 1H NMR (CDCl3, 400 MHz) δ 7.97-7.95 (m, 1H, ArH), 7.74-7.70 (m, 2H, ArH), 7.53-7.49 (m, 3H, ArH), 7.39-7.35 (m, 3H, ArH), 6.84-6.82 (m, 1H, ArH), 6.55 (br m, 1H, NH), 4.04-4.00 (m, 1H, OCH), 3.90- 3.80 (m, 1H, CH2), 3.78-3.72 (m, 5Η, CH2), 3.35-3.30 (m, 1H, CH2), 2.05-1.95 (m, 1Η, CH2), 1.91-1.86 (m, 2Η, CH2), 1.61-1.50 (m, 1H, CH2). LCMS m/z 446 [M+Η]+, purity (UV/MS) 92/74, rR = 4.15 min. Example 622: (Z)-I l-(3,4-DichlorophenylViV-(4,4,4-trifluorobutvndibenzo|"6,/iπ,41 thiazepine-8-carboxamide
Figure imgf000263_0001
[0692] Yield: (198.1 mg; 0.39 mmol; 98%). 1H NMR (CDCl3, 400 MHz) δ 7.89-7.88 (m, 1H, ArH), 7.61-7.38 (m, 7H, ArH), 7.28-7.19 (m, 1H, ArH), 7.1 1-7.09 (m, 1H, ArH), 6.15 (br m, 1H, NH), 3.47-3.40 (m, 2H, CH2), 1.85-1.79 (m, 2H, CH2), 1.60- 1.50 (m, 2H, CH2). LCMS m/z 509 [M+H]+, purity (UV/MS) 96/35, /R = 5.74 min.
Example 623: (Z)-11 -(4-Chloro-2-fluorophenyiyiV-(4A4- trifluorobutyl)dibenzo|7j,/iri,41 thiazepine-8-carboxamide
Figure imgf000263_0002
[0693] Yield: (197.4 mg; 0.40 mmol; 100%). 1H NMR (CDCl3, 400 MHz) δ 7.92-7.88 (m, 1H, ArH), 7.69-7.68 (m, 1H, ArH), 7.55-7.52 (m, 3H, ArH), 7.45-7.40 (m, 1H, ArH), 7.30-7.24 (m, 2H, ArH), 7.15-7.09 (m, 2H, ArH), 6.22 (br m, 1H, NH), 3.53- 3.51 (m, 2H, CH2), 1.90-1.85 (m, 2H, CH2), 1.70-1.65 (m, 2H, CH2). LCMS m/z 493 [M+H]+, purity (UV/MS) 97/73, tκ= 5.22 min.
Example 624: 1 l-QΛ-DichlorophenylMibenzoffcJifMlthiazepine-S-carboxylic acid butyl amide
Figure imgf000264_0001
[0694] Purification was done by silica gel column chromatography (0-5% ethyl acetate in toluene) to afford the desired compound as yellow crystalline solid (0.12 g, 94%). mp 1 15.0 - 1 15.4 °C. 1H NMR (CDCl3, 400 MHz) δ 7.96 (d, 1H, J = 2.0 Hz, ArH), 7.63 (d, 1H, J= 1.1 Hz, ArH), 7.60 (dd, 1H, J= 2.0, 8.4 Hz, ArH), 7.56 (d, 1H, J = 7.8 Hz, ArH), 7.51 (m, 3H, ArH), 7.44 (ddd, 1H, J = 1.2, 7.5, 7.7 Hz, ArH), 7.32 (ddd, 1H, J = 1.2, 7.5, 7.7 Hz, ArH), 7.15 (dd, 1H5 J= 1.3, 7.7 Hz, ArH), 6.04 (br m, I H, NH), 3.46 - 3.41 (m, 2H, NCH2), 1.62 - 1.53 (m, 2H, CH2), 1 -45 - 1.36 (m, 2H, CH2), 0.95 (t, 3H, J= 7.4 Hz, CH3). LCMS m/z 455 [M+H]+, purity (UV/MS) 100/83, /R = 5.80 min.
Example 625: 1 l-(4-Chloro-3-fluorophenyl)dibenzo[6,/iπ,41thiazepine-8-carboxylic acid butyl amide
Figure imgf000264_0002
[0695] Purification was done by silica gel column chromatography (0-5% ethyl acetate in toluene) to afford the desired compound as yellow crystalline solid (0.12 g, 94%). mp 154.5 - 156.6 °C. LCMS m/z 439 [M+H]+, purity (UV/MS) 100/85, tk = 5.47 min. Example 626: 1 l-(3-Chloro-4-fluorophenyl)dibenzo[6,/1[K4]thiazepine-8-carboxylic acid butyl amide
Figure imgf000265_0001
[0696] Purification was done by silica gel column chromatography (0-5% ethyl acetate in toluene) to afford the desired compound as yellow crystalline solid (0.12 g, 94%). mp 124.4 - 125.9 °C. 1H NMR (CDCl3, 400 MHz) δ 7.94 (dd, 1H, J = 2.2, 7.2 Hz, ArH), 7.67 - 7.63 (m, 1H, ArH), 7.63 - 7.62 (m, 1H, ArH), 7.55 (dd, 1H, J= 0.9, 7.8 Hz, ArH), 7.51- 7.50 (m, 2H, ArH), 7.43 (ddd, 1H, J = 1.5, 7.4, 7.8 Hz, ArH), 7.33 (ddd, 1H, J = 1.3, 7.5, 7.7 Hz, ArH), 7.21 - 7.15 (m, 2H, ArH), 6.03 (br m, 1H, NH), 3.46 - 3.41 (m, 2H, NCH2), 1.62 - 1.55 (m, 2H, CH2), 1.45 - 1.36 (m, 2H, CH2), 0.95 (t, 3H, J = 7.3 Hz, CH3). LCMS m/z 439 [M+H]+, purity (UV/MS) 99/93, fR= 5.42 min.
Example 627: 1 l-(3,4-Difluorophenyl)dibenzo[ά,/|π,4]thiazepine-8-carboxylic acid butyl amide
Figure imgf000265_0002
[0697] Purification was done by silica gel column chromatography (0-5% ethyl acetate in toluene) to afford the desired compound as yellow crystalline solid (74 mg, 80%). mp 125.3 - 128.1 "C. 1H NMR (CDCl3, 400 MHz) δ 7.79 - 7.72 (m, 1H, ArH), 7.63 (d, J = 0.8 Hz, 1H, ArH), 7.56 (dd, 1H, J = 0.8, 7.6 Hz, ArH), 7.53- 7.48 (m, 3H, ArH), 7.44 (ddd, 1H, J = 1.2, 7.2, 8.0 Hz, ArH), 7.33 (ddd, 1H, J = 1.2, 7.6, 7.6 Hz, ArH), 7.24 - 7.16 (m, 2H, ArH), 6.05 (br m, 1H, NH), 3.47 - 3.42 (m, 2H, NCH2), 1.62 - 1.55 (m, 2H, CH2), 1.45 - 1.36 (m, 2H, CH2), 0.95 (t, 3H, J = 7.6 Hz, CH3). LCMS m/z 423 [M+H]+, purity (UV/MS) 99/74, tR = 5.10 min. Example 628: 1 l-(3,5-Dichlorophenyl)dibenzo[6,/][l ,4|thiazepine-8-carboxylic acid butyl amide
Figure imgf000266_0001
[0698] Purification was done by silica gel column chromatography (0-5% ethyl acetate in toluene) to afford the desired compound as yellow crystalline solid (97 mg, 89%). mp 169.7 - 171.2 °C. 1H NMR (CDCl3, 400 MHz) δ 7.67 (d, J = 1.6 Hz, 2H, ArH), 7.63 (d, J= 1.6 Hz, 1H, ArH), 7.55 (dd, 1H, J = 1.2, 8.0 Hz, ArH), 7.51 (d, J = 1.6 Hz, 1H, ArH), 7.50 (s, 1H, ArH), 7.47 (dd, 1H, J = 2.0, 2.0 Hz, ArH), 7.43 (dd, 1H, J = 1.2, 7.6 Hz, ArH), 7.33 (ddd, 1H, J = 1.6, 8.0, 7.2 Hz, ArH), 7.15 (dd, I H, J = 1.2, 7.6 Hz, ArH), 6.14 (br m, 1H, NH), 3.46 - 3.41 (m, 2H, NCH2), 1.60 - 1.54 (m, 2H, CH2), 1.44 _ 1.35 (m, 2H, CH2), 0.94 (t, 3H, J = 7.2 Hz, CH3). LCMS m/z 455 [M+H]+, purity (UV/MS) 98/93, tR= 5.97 min.
Example 629: 1 l-(4-Chloro-3-fluorophenyl)dibenzor^,/1[U4]thiazepine-8-carboxylic acid isobutyl amide
Figure imgf000266_0002
[0699] Purification was done by silica gel column chromatography (0-5% ethyl acetate in toluene) to afford the desired compound as yellow crystalline solid (0.15 g, 87%). 1H NMR (CDCl3, 400 MHz) δ 7.67 (dd, 1H, J = 2.0, 10.4 Hz, ArH), 7.64 (dd, 1H, J = 1.2, 1.2 Hz, ArH), 7.55 (dd, 1H, J = 1.2, 7.6 Hz, ArH), 7.51 (d, 2H, J = 1.2 Hz, ArH), 7.51 - 7.41 (m, 3H, ArH), 7.32 (ddd, 1H, J= 1.2, 7.6, 7.6 Hz, ArH), 7.16 (dd, 1H, J = 1.2, 8.0 Hz, ArH), 6.18 (br m, 1H, NH), 3.26 (t, 2H, J = 6.4 Hz, NCH2), 1.91 - 1.84 (m, 1H, CH), 0.97 (s, 3H, CH3), 0.96 (s, 3H, CH3). LCMS m/z 439 [M+H]+, purity (UV/MS) 99/82, tR = 5.50 min.
Example 630: 1 l-P-Chloro^-fluorophenyDdibenzolVj./II'M'lthiazepine-S-carboxylic acid isobutyl amide
Figure imgf000267_0001
[0700] Purification was done by silica gel column chromatography (0-5% ethyl acetate in toluene) to afford the desired compound as yellow crystalline solid (0.16 g, 93%). 1H NMR (CDCl3, 400 MHz) δ 7.95 (dd, 1H, J = 2.4, 7.2 Hz, ArH), 7.66 - 7.62 (m, 2H, ArH), 7.55 (dd, 1H, J = 1.2, 7.6 Hz, ArH), 7.51 (d, 2H, J = 1.2 Hz, ArH), 7.43 (ddd, 1H, J = 1.2, 7.2, 8.0 Hz, ArH), 7.32 (ddd, 1H, J = 1.2, 7.2, 8.0 Hz, ArH), 7.18 - 7.15 (m, 2H, ArH), 6.23 (br m, 1H, NH), 3.26 (t, 2H, J = 6.8 Hz, NCH2), 2.04 - 1.83 (m, 1H, CH), 0.97 (s, 3H, CH3), 0.95 (s, 3H, CH3). LCMS m/z 439 [M+H]+, purity (UV/MS) 99/96, /R= 5.38 min.
Example 631 : l l-(3,4-Dichlorophenyl)dibenzor^,/iπ ,41thiazepine-8-carboxylic acid N- aminopiperidyl amide
Figure imgf000267_0002
[0701] Purification was done by silica gel column chromatography (5-20% ethyl acetate in toluene) to afford the desired compound as yellow crystalline solid (0.12 g, 75%). mp 187.6 - 190.1 °C. 1H NMR (CDCl3, 400 MHz) δ 7.90 (d, 1H, J = 2.0 Hz, ArH), 7.68 (br m, 1H, NH), 7.56 - 7.43 (m, 7H, ArH), 7.33 (ddd, 1H, J = 1.2, 7.6, 7.6 Hz, ArH), 7.13 (dd, 1H, J = 1.2, 7.6 Hz, ArH), 2.91 (br m, 4H, CH2), 1.76 (br m, 4H, CH2), 1.43 (br m, 2H, CH2). LCMS m/z 482 [M+H]+, purity (UV/MS) 93/64, /R = 5.25 min. Example 632: 1 l-f4-Chloro-3-fluorophenyl)dibenzo[ά,/1[1,41thiazepine-8-carboxylic acid yV-aminopiperidyl amide
Figure imgf000268_0001
[0702] Purification was done by silica gel column chromatography (5-20% ethyl acetate in toluene) to afford the desired compound as yellow crystalline solid (0.13 g, 84%). mp 175.5 - 179.5 °C. 1H NMR (CDCl3, 400 MHz) δ 7.69 (br m, 1H, NH), 7.62 (d, 1H, J = 10.0 Hz, ArH), 7.56 - 7.42 (m, 6H, ArH), 7.33 (dd, I H, J= 7.6, 7.6 Hz, ArH), 7.17 - 7.14 (m, 1H, ArH), 2.91 (br m, 4H, CH2), 1.79 (br m, 4H, CH2), 1.44 (br m, 2H, CH2). LCMS m/z 466 [M+H]+, purity (UV/MS) 92/81 , fR = 4.93 min.
Example 633: 1 l-(3-Chloro-4-fluorophenyl)dibenzo[6./][l ,41thiazepine-8-carboxylic acid iV-aminopiperidyl amide
Figure imgf000268_0002
[0703] Purification was done by silica gel column chromatography (5-20% ethyl acetate in toluene) to afford the desired compound as yellow crystalline solid (0.13 g, 84%). mp 168.3 - 171.8 °C. 1H NMR (CDCl3, 400 MHz) δ 7.87 (dd, 1H, J = 1.6, 6.8 Hz, ArH), 7.71 (br m, 1H, NH), 7.60 - 7.52 (m, 4H, ArH), 7.48 (s, 1H, ArH), 7.44 (ddd, 1H, J = 1.6, 7.6, 7.6 Hz, ArH), 7.33 (ddd, 1H, J = 1.2, 7.6, 7.6 Hz, ArH), 7.15 - 7.1 1 (m, 2H, ArH), 2.95 (br m, 4H, CH2), 1.74 (br m, 4H, CH2), 1.43 (br m, 2H, CH2). LCMS m/z 466 [M+H]+, purity (UV/MS) 95/77, tR= 4.87 min. Example 634: l l-(3,4-DifluorophenylMibenzo[6J][l ,4]thiazepme-8-carboxylic acid N- aminopiperidyl amide
Figure imgf000269_0001
[0704] Purification was done by silica gel column chromatography (5-20% ethyl acetate in toluene) to afford the desired compound as yellow crystalline solid (21.3 mg, 19%). mp 135.6 - 137.4 °C. 1H NMR (CDCl3, 400 MHz) δ 7.71 - 7.65 (m, 1H, ArH), 7.54 (br s, 1H, ArH), 7.48 (dd, 1H, J = 1.2, 8.0 Hz, ArH), 7.45 - 7.41 (m, 3H, ArH), 7.37 (ddd, 1H, J= 1.6, 7.6, 7.6 Hz, ArH), 7.26 (ddd, 1H5 J= 1.2, 7.6, 7.6 Hz, ArH), 7.15 - 7.10 (m, 2H, ArH), 6.63 (br m, 1H, NH), 2.76 (br m, 4H, CH2), 1.69 (br m, 4H, CH2), 1.38 (br m, 2H, CH2). LCMS m/z 450 [M+H]+, purity (UV/MS) 100/91, /R = 4.60 min.
Example 635: (Z)-I l-(4-Chloro-2-fluorophenyl)-7vτ-(2-fluoroethyl)dibenzo[ά,/1f 1 ,4] thiazepine-8-carboxamide
Figure imgf000269_0002
[0705] Amount made: 0.6 mg. LCMS m/z 429 [M+H]+, purity (UV/MS) 71/50, tκ = 3.78 min. Example 636: (£)-.V-(2-FluoroethylVl l-(6-methylpyridin-2- yr)dibenzol77,/]ri,41thiazepine-8-carboxamide
Figure imgf000270_0001
[0706] Amount made: 1.5 mg. LCMS m/z 392 [M+H]+, purity (UV/MS) 83/50, fR = 3.41 min.
Example 637: (Z)-N-(2-Fluoroethyl)- 1 l-(thiophen-3-vπdibenzor6./iπ .41thiazepine-8- carboxamide
Figure imgf000270_0002
[0707] Amount made: 1.0 mg. LCMS m/z 383 [M+H]+, purity (UV/MS) 84/50, tκ = 4.02 min.
Example 638: (£D-N-(2-FluoroethylVl l-(6-methoxypyridin-2-vπdibenzor6./]f 1,41 thiazepine-8-carboxamide
Figure imgf000270_0003
[0708] Amount made: 1.5 mg. LCMS m/z 408 [M+H]+, purity (UV/MS) 98/80, tR = 4.07 min. Example 639: (Z)-I l-(4-Fluorophenyl)-Λ/-((4-methylthiophen-2- vQmethy Qdibenzofά, f\ \ 1 „41 thiazepine-8-carboxamide
Figure imgf000271_0001
[0709] Amount made: 0.3 mg. LCMS m/z 459 [M+H]+, purity (UV/MS) 99/40, tR = 4.92 min.
Example 640: (Z)- 1 1 -(3-FluorophenviyN-((4-methylthiophen-2- yl)methyl)dibenzo \b,f\\\ ,41 thiazepine-8-carboxamide
Figure imgf000271_0002
[0710] Amount made: 8.3 mg. LCMS m/z 459 [M+H]+, purity (UV/MS) 100/30, tR = 5.26 min.
Example 641 : (E)-11 -(3-Methylthiophen-2-ylVN-((4-methylthiophen-2- yl)methyl)dibenzo \b,f]\\ ,41 thiazepine-8-carboxamide
Figure imgf000271_0003
[0711] Amount made: 6.5 mg. LCMS m/z 461 [M+H]\ purity (UV/MS) 100/60, /R = 5.21 min. Example 642: (E)-I l-(5-Chlorothiophen-2-yl)-N-((4-methylthiophen-2- vDmethvDdibenzo [6. /U 1,41 thiazepine-8-carboxamide
Figure imgf000272_0001
[0712] Amount made: 0.9 mg. LCMS m/z 482 [M+H]+, purity (UV/MS) 96/50, fR = 5.62 min.
Example 643 : (E)- 11 -(6-Methylpyridin-2-yl)-iV-((4-methylthiophen-2-yl)methyl)dibenzo 1"6./UlAl thiazepine-8-carboxamide
Figure imgf000272_0002
[0713] Amount made: 5.8 mg. LCMS m/z 456 [M+H]+, purity (UV/MS) 100/70, tR = 4.52 min.
Example 644: (Z)-N-((4-Methylthiophen-2-yl)methviyi l-(thiophen-3- vDdibenzo \b, f\ [1 ,41 thiazepine-8-carboxamide
Figure imgf000272_0003
[0714] Amount made: 8.2 mg. LCMS m/z 447 [M+H]+, purity (UV/MS) 100/30, tR = 5.03 min. Example 645: (Z)-I l-(3-Chlorophenvn-N-(3,3,3-trifluoropropyl)dibenzol6,/iπ .41 thi azepine- 8-carboxamide
Figure imgf000273_0001
[0715] Amount made: 6.4 mg. LCMS m/z 461 [M+H]+, purity (UV/MS) 100/70, /R = 5.26 min.
Example 646: (E)-X l-fPyridin-2-ylWV-(3.3 J- trifluoropropyl)dibenzor6,/m,4]thiazepine-8-carboxamide
Figure imgf000273_0002
[0716] Amount made: 3.6 mg. LCMS m/z 428 [M+H]\ purity (UV/MS) 100/90, fR = 3.74 min.
Example 647: (Z)-I l-(4-FluorophenylWV-(3,3,3- trifluoropropyπdibenzo[ό,/irL41thiazepine-8-carboxamide
Figure imgf000273_0003
[0717] Amount made: 3.1 mg. LCMS m/z 445 [M+H]+, purity (UV/MS) 100/90, /R = 4.87 min. Example 648: (Z)-U-(3-T\uoγop\ieny\)-N-(333- trifluoropropyl)dibenzorfe,/iπ,41thiazepine-8-carboxamide
Figure imgf000274_0001
[0718] Amount made: 5.6 mg. LCMS m/z 445 [M+H]+, purity (UV/MS) 100/70, ?R = 4.91 min.
Example 649: (Z)-X l-(4-ChlorophenvD-./V-(333-trifluoropropyπdibenzo[b,f][1,4] thiazepine-8-carboxamide
Figure imgf000274_0002
[0719] Amount made: 6.4 mg. LCMS m/z 461 [M+H]+, purity (UV/MS) 100/40, tR = 5.26 min.
Example 650: (Z)-1 1 -(4-Chloro-2-fluorophenylV.V-(3.3,3- trifluoropropyl)dibenzofό,/1f 1 ,41 thiazepine-8-carboxamide
Figure imgf000275_0001
[0720] Amount made: 5.7 mg. LCMS m/z 479 [M+H]+, purity (UV/MS) 100/70, /R = 5.13 min.
Example 651: (E)-I l-(3-Methylthiophen-2-ylVN-(3,3.3-trifluoropropyl)dibenzor6,/iπ.41 thiazepine-8-carboxamide
Figure imgf000275_0002
[0721] Amount made: 7.3 mg. LCMS m/z 447 [M+H]+, purity (UV/MS) 100/90, /R = 4.84 min.
Example 652: (£)-! l-(5-Chlorothiophen-2-yl)-N-(3,3,3-trifluoropropyl)dibenzorά,/iπ.41 thiazepine-8-carboxamide
Figure imgf000275_0003
[0722] Amount made: 4.8 mg. LCMS m/z 467 [M+H]+, purity (UV/MS) 100/70, /R = 5.30 min. Example 653: (JT)-I l-(6-Methylpyridin-2-yl)-N-(3,3,3-lrifluoropropyl)dibenzo[fc,/][K4] thiazepine-8-carboxamide
Figure imgf000276_0001
[0723] Amount made: 4.3 mg. LCMS m/z 442 [M+H]+, purity (UV/MS) 100/80, /R = 4.1 1 min.
Example 654: (Z)-I l-(Thiophen-3-vn-N-(3,33- trifluoropropyl)dibenzor6,/iπ,41thiazepine-8-carboxamide
Figure imgf000276_0002
[0724] Amount made: 7.2 mg. LCMS m/z 433 [M+H]+, purity (UV/MS) 100/70, /R = 4.62 min.
Example 655: (E)-I l-(6-Methoxypyridin-2-ylVN-(3,3.3- trifluoropropyl)dibenzo[6,/1[L41 thiazepine-8-carboxamide
Figure imgf000276_0003
[0725] Amount made: 6.8 mg. LCMS m/z 458 [M+H]+, purity (UV/MS) 100/90, tκ = 4.66 min. Example 656: (E)-I l-(Pyridin-2-yl)-//-(4,4,4-trifluorobutvπdibenzor6,/iri,41thiazepine- 8-carboxamide
Figure imgf000277_0001
[0726] Amount made: 2.7 mg. LCMS m/z 442 [M+H]+, purity (UV/MS) 100/90, /R = 3.93 min.
Example 657: (Z)-I l-(3-Fluorophenyl)-JV-(4A4- trifluorobutvπdibenzor^,/]π,41thiazepine-8-carboxamide
Figure imgf000277_0002
[0727] Amount made: 7.4 mg. LCMS m/z 459 [M+H]+, purity (UV/MS) 100/70, tR = 5.03 min.
Example 658: (Z)-I l-(4-ChlorophenylWV-(4A4- trifluorobutyl)dibenzorά,/iπ,41thiazepine-8-carboxamide
Figure imgf000278_0001
[0728] Amount made: 4.1 mg. LCMS m/z 475 [M+H]+, purity (UV/MS) 100/70, tR = 5.38 min.
Example 659: (Z)-1 1 -(4-Chloro-2-fluorophenyl)-N-(4,4,4- trifluorobutyl)dibenzor^,/iπ,41 thiazepine-8-carboxamide
Figure imgf000278_0002
[0729] Amount made: 8.3 mg. LCMS m/z 493 [M+H]+, purity (UV/MS) 100/70, rR = 5.23 min.
Example 660: (E)-11 -(3-Methylthiophen-2-ylV-V-(4,4,4-trifluorobutyl)dibenzof6./]π .4] thiazepine-8-carboxamide
Figure imgf000279_0001
[0730] Amount made: 9.7 mg. LCMS m/z 461 [M+H]+, purity (UV/MS) 100/90, fR = 4.98 min.
Example 661 : (E)- 11 -(5-Chlorothiophen-2-yl VN-(4,4,4-trifluorobutvπdibenzo \b.i\\\ A) thiazepine-8-carboxamide
Figure imgf000279_0002
τ +
[0731] Amount made: 4.7 mg. LCMS m/z 481 [M+H] , purity (UV/MS) 100/70, tR = 5.41 min.
Example 662: (EVl l-(6-Methylpyridin-2-vn-N-(4A4-trifluorobutyl)dibenzotø,/U 1,4] thiazepine-8-carboxamide
Figure imgf000280_0001
[0732] Amount made: 5.3 mg. LCMS m/z 456 [M+H]+, purity (UV/MS) 100/80, /R = 4.28 min.
Example 663: (Z)A l-(Thiophen-3-yl>N-(4A4- trifluorobutvQdibenzo[6, f] \ 1 ,41thiazepine-8-carboxamide
Figure imgf000280_0002
[0733] Amount made: 8.2 mg. LCMS m/z 447 [M+H]+, purity (UV/MS) 100/70, tR = 4.76 min.
Example 664: (E)A l-(6-Methoxypyridiiv-2-ylViV-(4,4.4-lrifluorobutvndiben2o[6.^iri .4] thiazepine-8-carboxamide
Figure imgf000281_0001
[0734] Amount made: 5.2 mg. LCMS m/z 472 [M+H]+, purity (UV/MS) 97/60, /R = 4.82 min.
Example 665: (Z)-I l-(3-Chlorophenyl)-yV-(4,4-difluorocvclohexyndibenzorά,/] [1,41 thiazepine-8-carboxamide
Figure imgf000281_0002
[0735] Amount made: 1 1.5 mg. LCMS m/z 483 [M+H]+, purity (UV/MS) 100/60, /R = 5.43 min.
Example 666: (E)-N-(4.4-Difluorocyclohexyl)- 1 1 -(pyridin-2- yl)dibenzo[ά,/l[1,41thiazepine-8-carboxamide
Figure imgf000281_0003
[0736] Amount made: 3.9 mg. LCMS m/z 450 [M+H]+, purity (UV/MS) 100/90, /R = 3.98 min. Example 667: (Z)-./V-(4,4-Difluorocyclohexyl)-l l-(4-fluoropheny0dibenzo[6,/]|'l ,4] thiazepine-8-carboxamide
Figure imgf000282_0001
[0737] Amount made: 5.4 mg. LCMS m/z 467 [M+H]+, purity (UV/MS) 100/80, /R = 5.04 min.
Example 668: (ZWV-(4,4-Difluorocvclohexyiyi l-(3-fluorophenvndibenzo|'6,/iπ,41 thiazepine-8-carboxamide
Figure imgf000282_0002
[0738] Amount made: 7.0 mg. LCMS m/z 467 [M+H]+, purity (UV/MS) 100/70, tR = 5.10 min.
Example 669: (Z)-I l-(4-ChlorophenylViV-(4,4-difluorocvclohexyndibenzof6,/1[l .4] thiazepine-8-carboxamide
Figure imgf000283_0001
[0739] Amount made: 4.8 mg. LCMS m/z 483 [M+H]+, purity (UV/MS) 100/60, tR = 5.46 min.
Example 670: (Z)-I l-(4-Chloro-2-fluorophenyl)-N-(4,4-difluorocvclohexyπdibenzo \b, f] \ 1 ,41thiazepine-8-carboxamide
Figure imgf000283_0002
[0740] Amount made: 8.2 mg. LCMS m/z 501 [M+H]+, purity (UV/MS) 100/50, tR = 5.29 min.
Example 671 : (£)-iV-(4,4-Difluorocvclohexyl)-l l-(3-methylthiophen-2- vOdibenzora./iri ,4] thiazepine-8-carboxamide
Figure imgf000283_0003
[0741] Amount made: 7.3 mg. LCMS m/z 469 [M+H]+, purity (UV/MS) 100/80, tR = 5.00 min. Example 672: (E)A l-( S-Chlorothiophen-2-yl)-N-(4,4- difluorocyclohexyπdibenzor6,/1[l ,41 thiazepine-8-carboxamide
Figure imgf000284_0001
[0742] Amount made: 1.7 mg. LCMS m/z 490 [M+H]+, purity (UV/MS) 100/60, /R = 5.47 min.
Example 673 : (£>./V-(4,4-Difluorocvclohexy I)- 11 -(6-methylpyridin-2- yπdibenzofά,/iπ,41 thiazepine-8-carboxamide
Figure imgf000284_0002
[0743] Amount made: 5.2 mg. LCMS m/z 464 [M+H]+, purity (UV/MS) 100/80, /R = 4.35 min.
Example 674: f2)--V-(4.4-DifluorocyclohexylVl l-fthiophen-3-vπdibenzo^./iπ.41 thiazepine-8-carboxamide
Figure imgf000284_0003
[0744] Amount made: 7.1 mg. LCMS m/z 455 [M+H]+, purity (UV/MS) 100/50, /R = 4.82 min. Example 675 : (F)-N-(4,4-Difluorocyclohexyl)- 11 -(6-methoxypyridin-2- vDdibenzorά, /1 [ 1 ,41 thiazepine-8-carboxamide
Figure imgf000285_0001
[0745] Amount made: 5.6 mg. LCMS m/z 480 [M+H]+, purity (UV/MS) 100/70, fR = 4.87 min.
Example 676: (Z)-I l-O-Chlorophenvn-N-^S-methylfuran-Σ-vnmethvndibenzorά./iπΛl thiazepine-8-carboxamide
Figure imgf000285_0002
[0746] Amount made: 10.2 mg. LCMS m/z 459 [M+H]+, purity (UV/MS) 100/50, /R = 5.41 min.
Example 677: (■g)--V-((5-MethvIfiiran-2-v»methylVl Hpyridin-2-yl)dibenzorø./iri.41 thiazepine-8-carboxamide
Figure imgf000285_0003
[0747] Amount made: 3.6 mg. LCMS m/z 426 [M+H]+, purity (UV/MS) 98/90, tR = 3.90 min. Example 678: (Z)-I l-(4-FluorophenylVN-((5-methylfuran-2-vnmethyl)dibenzo^,/irK41 thiazepine-8-carboxamide
Figure imgf000286_0001
[0748] Amount made: 5.2 mg. LCMS m/z 443 [M+H]+, purity (UV/MS) 100/80, /R = 5.00 min.
Example 679: (Z)-I l-(3-Fluorophenyl)-N-('(5-methylfuran-2-vnmethvndibenzorb,/iri,41 thiazepine-8-carboxamide
Figure imgf000286_0002
[0749] Amount made: 9.5 mg. LCMS m/z 443 [M+H]+, purity (UV/MS) 100/40, tR = 5.04 min.
Example 680: (Z)-I l-(4-Chlorophenyl)-N-((5-methylfuran-2-vnmethvndibenzor6,/][K41 thiazepine-8-carboxamide
Figure imgf000287_0001
[0750] Amount made: 7.0 mg. LCMS m/z 459 [M+H]+, purity (UV/MS) 100/40, rR = 5.51 min.
Example 681: (Z)-I l-(3,4-Dichlorophenyl)-N-((5-methylfuran-2- yl)methyl)dibenzo["ά,/1f1,4] thiazepine-8-carboxamide
Figure imgf000287_0002
[0751] Amount made: 1.7 mg. LCMS m/z 493 [M+H]+, purity (UV/MS) 100/13, tR = 10.90 min.
Example 682: (Z)-I l-(4-Chloro-2-fluorophenyl)-N-((5-methylfuran-2-yl)methyl)dibenzo \b,f][l A] thiazepine-8-carboxamide
Figure imgf000287_0003
[0752] Amount made: 2.2 mg. LCMS m/z 477 [M+H]+, purity (UV/MS) 100/70, tR = 5.25 min. Example 683: (£VΛMT5-Methylfuran-2-yl)methyl)-l l-(3-methylthiophen-2- yl)dibenzof6,/UL41thiazepine-8-carboxamide
Figure imgf000288_0001
[0753] Amount made: 10.0 mg. LCMS m/z 445 [M+H]+, purity (UV/MS) 100/80, tø = 4.95 min.
Example 684: (E)-I l-(5-Chlorothiophen-2-yl)-yV-((5-methylfuran-2-yl)methvndibenzo[b,f][1,4]thiazepine-8-carboxamide
Figure imgf000288_0002
[0754] Amount made: 7.8 mg.- LCMS m/z 465 [M+H]+, purity (UV/MS) 100/50, /R = 5.46 min.
Example 685 : (£yN-(Y5-Methylfuran-2-yl)methyly 1 1 -(6-methylpyridin-2-yl)dibenzo[b,f][1,4] thiazepine-8-carboxamide
Figure imgf000288_0003
[0755] Amount made: 4.6 mg. LCMS m/z 440 [M+H]+, purity (UV/MS) 100/90, tR = 4.25 min. Example 686: (Z)-N-((5-Methyliuran-2-yl)methyl>l l-(thiophen-3-vndibenzorά,/iπ.41 thiazep ine- 8 -carboxamide
Figure imgf000289_0001
[0756] Amount made: 8.4 mg. LCMS m/z 431 [M+H]+, purity (UV/MS) 100/50, fR = 4.78 min.
Example 687: (E)-11-(6-Methoxypyridin-2-yl)-N-((5-methylfuran-2-yl)methyl)dibenzo \b,f]\l ,41 thiazepine-8-carboxamide
Figure imgf000289_0002
[0757] Amount made: 1.9 mg. LCMS m/z 456 [M+H]+, purity (UV/MS) 87/60, (R = 4.82 min.
Example 688: (E)-/V-Isobutyl-1 l-(6-methylpyridin-2-yl)dibenzorά,/iri.41thiazepine-8- carboxamide
Figure imgf000289_0003
[0758] Amount made: 2.0 mg. LCMS m/z 402 [M+H]+, purity (UV/MS) 100/80, tR = 4.17 min. Example 689: (ZV-V-Isobutyl-l Hthiophen-3-yl)dibenzol7>,/iri ,41thiazepine-8- carboxamide
Figure imgf000290_0001
[0759] Amount made: 4.6 mg. LCMS m/z 393 [M+H]+, purity (UV/MS) 100/70, tκ = 4.7 l min.
Example 690: (Z)A l-(3-Chlorophenyl)-N'(2,2,2- trifluoroethyl)dibenzo[b ,f][1,4] ,4]thiazepine-8-carbohydrazide
Figure imgf000290_0002
[0760] Amount made: 1.1 mg. LCMS m/z 462 [M+H]+, purity (UV/MS) 100/50, tR = 5.06 min.
Example 691 : (Z)-I l-(3-FluorophenylViV-(2.2,2- trtfluoroethyl)dibenzo[b,f][1,4]thiazepine-8-carbohydrazide
Figure imgf000290_0003
[0761] Amount made: 1.2 mg. LCMS m/z 446 [M+H]+, purity (UV/MS) 100/70, tR = 4.7 l min. Example 692 : (Z)- 1 1 -(4-Chlorophenyl)-N'-(2,212- trifluoroethvπdibenzotø, flfl ,41thiazepine-8-carbohydrazide
Figure imgf000291_0001
[0762] Amount made: 1.7 mg. LCMS m/z 462 [M+H]+, purity (UV/MS) 100/60, /R = SJO mIn.
Example 693: (E)-\ l-(6-Methoxypyridin-2-ylVN'-('2,2.2-trifluoroethvndibenzorά,/irK41 thiazepine-8-carbohydrazide
Figure imgf000291_0002
[0763] Amount made: 0.8 mg. LCMS m/z 458 [M+H]+, purity (UV/MS) 100/70, tκ = 4.64 min.
Example 694: l l-Chloro^-fluorodibenzofά./iflΛJthiazepine-S-carboxylic acid butyl amide
Figure imgf000291_0003
[0764] The title compound was prepared as described herein (0.40 g, 53%). 1H NMR (CDCl3, 400 MHz) δ 7.63 (dd, 1H, J = 2.0, 8.0 Hz, ArH), 7.56 (d, 1H, J = 1.6 Hz, ArH), 7.50 (dd, 1 H, J = 0.4, 8.0 Hz, ArH), 7.46 - 7.42 (m, 2H, ArH), 7.19 - 7.14 (m, 1H, ArH), 5.99 (br, 1H, NH), 3.45 - 3.40 (m, 2H, CH2), 1.61 - 1.52 (m, 2H, CH2), 1.44 - 1.35 (m, 2H, CH2), 0.95 (t, 3H, J = 7.2 Hz, CH3). LCMS m/z 363 [M+H]+, purity (UV/MS) 99/86, /R = 3.82 min.
Example 695: 1 l-(4-Chlorophenyl)-2-fluorodibenzo[6,/irL41thiazepine-8-carboxylic acid butyl amide
Figure imgf000292_0001
[0765] The title compound was prepared as described herein (45.8 mg, 37%). 1H NMR (CDCl3, 400 MHz) δ 7.77 - 7.75 (m, 2H, ArH), 7.63 (d, 1H, J= 0.8, ArH), 7.54 - 7.50 (m, 3H, ArH), 7.44 - 7.42 (m, 2H, ArH), 7.14 (ddd, 1H, J= 2.4, 8.4, 8.4 Hz ArH), 6.87 (dd, 1H, J = 2.8, 8.8 Hz, ArH), 6.04 (br m, 1H, NH), 3.47 - 3.42 (m, 2H, NCH2), 1.62 - 1.55 (m, 2H, CH2), 1.43 - 1.38 (m, 2H, CH2), 0.95 (t, 3H, J = 7.2 Hz, CH3). LCMS m/z 439 [M+H]+, purity (UV/MS) 99/87, /R = 5.86 min.
Example 696: 1 l-(3-Chlorophenyl)-2-fluorodibenzor6,/iπ ,41thiazepine-8-carboxylic acid butyl amide
Figure imgf000292_0002
[0766] The title compound was prepared as described herein (52.2 mg, 42%). 1H NMR (CDCl3, 400 MHz) δ 7.88 (dd, 1H, J = 2.0, 2.0 Hz, ArH), 7.64 - 7.61 (m, 2H, ArH), 7.55 - 7.47 (m, 4H, ArH), 7.39 (dd, 1H, J= 8.0, 8.0 Hz, ArH), 7.18 - 7.12 (m, 2H, ArH), 6.88 (dd, 1H, J = 2.8, 8.8 Hz, ArH), 6.04 (br m, 1H, NH), 3.47 - 3.42 (m, 2H, NCH2), 1.61 - 1.56 (m, 2H, CH2), 1.44 - 1.38 (m, 2H, CH2), 0.96 (t, 3H, J = 7.2 Hz, CH3). LCMS m/z 439 [M+H]+, purity (UV/MS) 100/92, /R = 5.86 min. Example 697: 1 HS-Chloro^-thieny^-fluorodibenzoffrJlfl^miazepine-δ-carboxylic acid butyl amide
Figure imgf000293_0001
[0767] The title compound was prepared as described herein (9.1 mg, 7%). 1H NMR (CDCl3, 400 MHz) δ 7.56 - 7.47 (m, 4H, ArH), 7.20 - 7.13 (m, 2H, ArH), 6.98 (dd, 1H, J = 0.4, 4.4 Hz, ArH), 6.92 (dd, 1H, J = 0.8, 4.0 Hz, ArH), 6.02 (br m, I H, NH), 3.46 - 3.41 (m, 2H, NCH2), 1.60 - 1.56 (m, 2H, CH2), 1.43 - 1.37 (m, 2H, CH2), 0.95 (t, 3H, J= 7.2 Hz, CH3). LCMS m/z 445 [M+H]+, purity (UV/MS) 96/82, fR = 10.42 min.
Example 698: 1 l-(5-Chloro-2-pyridyl)-2-fluorodibenzoffe,/iri ,4]thiazepine-8-carboxylic acid butyl amide
Figure imgf000293_0002
[0768] The title compound was prepared as described herein (18.8 mg, 15%). 1H NMR (CDCl3, 400 MHz) δ 8.61 (dd, 1H, J= 0.8, 2.4 Hz, ArH), 8.36 (dd, 1H, J= 0.8, 8.4 Hz, ArH), 7.85 (dd, 1H, J= 2.4, 8.4 Hz, ArH), 7.68 (d, 1H, J = 0.8 Hz, ArH), 7.54 - 7.53 (m, 2H, ArH), 7.50 (dd, 1H, J = 5.2, 8.8 Hz, ArH), 7.11 (ddd, 1H, J = 2.4, 8.4, 8.4 Hz, ArH), 6.95 (dd, 1H, J= 2.4, 8.8 Hz, ArH), 6.03 (br m, 1H, NH), 3.48 - 3.42 (m, 2H, NCH2), 1.60 - 1.52 (m, 2H, CH2), 1.43 - 1.40 (m, 2H, CH2), 0.95 (t, 3H, J = 7.2 Hz, CH3). LCMS m/z 440 [M+H]+, purity (UV/MS) 97/90, fR= 4.45 min. Example 699: S-Chloro^-mercaptobenzoic acid
Figure imgf000294_0001
[0769] A solution of 2-amino-5-chlorobenzoic acid (4.0 g; 23.3 mmol), sodium hydroxide (940 mg; 23.5 mmol) and sodium nitrite (1.6 g; 23.3 mmol) in 30 mL water was added slowly to a mixture of 6 mL concentrated HCl and 10 g of ice cooled with an ice bath. The temperature was maintained a O°C and stirring continued for 1Ah. In another beaker, potassium ethylxanthate (20.8 g; 65.2 mmol) was dissolved in 40 mL water and heated to 65°C. The cold diazonium salt solution was added slowly to the hot xanthate solution. Evolution of gas was observed. After the addition, the mixture was cooled to room temperature and acidified to pH~3 using 4M aqueous HCl. The aqueous phase was decanted from the resulting semi-solid and the sludge was dissolved in 20 mL 10% aqueous sodium hydroxide and heated for 2h at 100°C before addition of 2 g sodium hydrosulfite. Stirring and heating was continued for another 10 min before cooling to room temperature. After filtration the filtrate was acidified to pH~4 using concentrated HCl. The resulting solid was collected by filtration and washed with water. To avoid disulfide formation, the white solid was dissolved in 5 mL methanol and 65 mL diisopropyl ether and dried over sodium sulfate. After filtration and evaporation, the title compound was isolated as a light yellow solid (2.37 g; 54%). 1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 1H, J = 2.4 Hz), 7.35 (dd, 1H, J = 2.4 Hz, 8.4 Hz), 7.27 - 7.25 (m, 1H), 4.69 (s, 1H). 13C NMR (CDCl3, 100 MHz) δ 170.2, 138.0, 133.5, 132.4, 132.3, 130.7, 126.0.
Example 700: 5-Chloro-2-(4-ethoxycarbonyl-2-nitrophenylthio)benzoic acid
Figure imgf000295_0001
[0770] Ethyl 4-fluoro-3-nitrobenzoate (2.86 g; 13.4 mmol) was dissolved in 40 mL dry DMF and cesium carbonate (4.79 g; 14.7 mmol) was added. The mixture was heated to 70°C before dropwise addition of a solution of 5-chloro-2-mercaptobenzoic acid (2.3 g; 12.2 mmol) in 30 mL dry DMF. The mixture was stirred at 70°C for l 'Λh before cooling to room temperature. TLC (10% methanol in DCM) showed full conversion of the thiophenol and formation of the desired product (yellow spot, Rf = 0.48). Water was added and the solution acidified with 4M aqueous HCl before extraction using ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent removed by evaporation to give the crude product as an orange oil. Purification was performed using silica gel column chromatography (5% methanol in DCM) and the desired product isolated as a yellow solid (3.98 g; 85%). 1H NMR (CDCl3, 400 MHz) δ 8.68 (d, 1H, J = 2.0 Hz), 7.93 - 7.89 (m, 2H), 7.48 - 7.45 (m, 2H), 6.95 (d, 1H, J = 8.0 Hz), 4.33 (q, 2H, J= 7.2 Hz), 1.33 (t, 3H, J= 7.2 Hz). 13C NMR (CDCl3, 100 MHz) δ 166.0, 163.6, 145.2, 142.5, 137.4, 137.3, 135.6, 132.7, 131.8, 130.8, 129.6, 129.2, 127.6, 125.9, 61.1, 13.7. LCMS m/z 399 [M+NH4]+, purity (UV/MS) 96/-, TR = 4.27 min.
Example 701 : 2-(4-Carboxy-2-nitrophenylthio)-5-chlorobenzoic acid
Figure imgf000296_0001
[0771] 5-Chloro-2-(4-ethoxycarbonyl-2-nitrophenylthio)benzoic acid (3.9 g; 10.2 mmol) was dissolved in 80 mL THF and 65 mL IM aqueous lithium hydroxide. The solution was heated to 7O°C for !/_h. TLC (10% methanol in DCM) showed full conversion of the starting material and only formation of a baseline spot. The mixture was cooled to room temperature and the THF removed by evaporation. The basic aqueous phase was washed twice with ethyl acetate before acidification using 4M aqueous HCl. Acidification resulted in precipitation of a yellow solid that was collected by filtration and used without further purification and drying. 1H NMR (DMSOd6, 400 MHz) δ 8.58 (d, 1H, J= 2.0 Hz), 8.02 (dd, 1H, J= 1.6 Hz, 8.4 Hz), 7.91 (d, 1H, J= 2.0 Hz), 7.68 (dd, 1H, J= 2.4 Hz, 8.4 Hz), 7.58 (d, 1H, J= 8.4 Hz), 7.12 (d, 1H, J= 8.4 Hz).
Example 702: 2-(2-Amino-4-carboxyphenylthioV5-chlorobenzoic acid
Figure imgf000296_0002
[0772] 2-(4-Carboxy-2-nitrophenylthio)-5-chlorobenzoic acid (-10.2 mmol) was dissolved in 150 mL ethanol. A solution of potassium carbonate (6.5 g, 47 mmol) and sodium hydrosulfite (9.6 g; 47 mmol) in 100 mL water was added slowly. A color change was observed changing from strong yellow to light yellow/white. The solution was acidified using 4M HCl and extraction performed with ethyl acetate. The combined organic phases were washed with water followed by drying over sodium sulfate. Filtration and evaporation yielded an unpure crude yellow product that was purified by dissolving in IM aqueous sodium hydroxide. Upon acidification with 4M aqueous HCl, precipitates were formed. The solid was collected by filtration (1.03 g; 31% over two steps). 1H NMR (DMSCM6, 400 MHz) δ 8.87 (d, 1H, J= 2.4 Hz), 7.45 - 7.34 (m, 3H), 7.13 (dd, 1H, J = 1.6 Hz, 8.0 Hz), 6.59 (d, 1H, J = 8.4 Hz). 13C NMR (DMSCW6, 100 MHz) δ 168.0, 166.9, 151.3, 139.6, 138.0, 134.3, 132.7, 131.1, 129.8, 129.7, 128.0, 1 17.8, 1 16.7, 1 16.3.
Example 703: 2-Chloro-l 1-oxo-lOJ l-dihydrodibenzo[6,/|[h4]thiazepine-8-carboxylic acid
Figure imgf000297_0001
[0773] 2-(2-Amino-4-carboxyphenylthio)-5-chlorobenzoic acid (1.0 g; 3.1 mmol) was dissolved in 20 mL dry THF. 1,1-Carbonyldiimidazole (90%, 1.62 g; 9 mmol) was added portionwise and the mixture stirred at room temperature for 4h. The reaction was quenched by addition of 100 mL water and acidified with 4M aqueous HCl. Acidification resulted in formation of light yellow precipitates that were collected by filtration and washed with ethyl acetate and heptane to become almost white (720 mg; 76%). 1H NMR (DMSO-4, 400MHz) δ 10.9 (s, 1H), 7.76 (br s, 1H), 7.66 - 7.64 (m, 3H), 7.53 (d, 1H, J= 1.6 Hz).
Example 704: (E)-2Λ l-Dichlorodibenzorfr,/iπ,41thiazepine-8-carbonyl chloride
Figure imgf000297_0002
[0774] 2-Chloro-l 1-oxo- 10,1 l-dihydrodibenzo[ά,/][l ,4]thiazepine-8- carboxylic acid (700 mg; 2.3 mmol) was dissolved in a mixture of thionyl chloride (10 mL), DMF (35 μL) and toluene (20 mL). The mixture was heated to 80°C overnight. After cooling the solvents were removed by evaporation followed by co-evaporation (two times 30 mL) with toluene to give a light yellow solid that was used without further purification.
Example 705: (E)-N-Buty\-2,\ l-dichlorodibenzorά,/][l ,4]thiazepine-8-carboxamide
Figure imgf000298_0001
[0775] /7-Butyl amine (570 μL; 5.8 mmol) was dissolved in 15 mL DCM and cooled to 0°C. A solution of (E)-2,\ l-dichlorodibenzo[i,/J[1,4]thiazepine-8-carbonyl chloride (-2.3 mmol) in 20 mL DCM was added slowly. The mixture was stirred at room temperature for 4h. The mixture was diluted with 15 mL DCM and washed with saturated aqueous ammonium chloride. The organic phase was dried over sodium sulfate, filtered and the solvent removed by evaporation. The crude product was purified by silica gel column chromatography (5-25% ethyl acetate in heptane) to give 300 mg (34%) of the desired compound along with a large mixed fraction. 1H NMR (CDCl3, 400 MHz) δ 7.67 (d, 1H, J = 2.0 Hz), 7.60 (dd, 1H, J= 2.0 Hz, 8.0 Hz), 7.55 (d, 1H, J= 2.0 Hz), 7.44 (dd, 1H, J = 8.0 Hz), 7.39 (dd, 1H, J = 2.0 Hz, 8.4 Hz), 7.36 (d, 1H, J = 8.4 Hz), 6.33 (br s, 1H), 3.40 (m, 2H)5 1.59 - 1.50 (m, 2H), 1.41 - 1.31 (m, 2H), 0.91 (t, 3H, J= 7.4 Hz). 13C NMR (CDCl3, 100 MHz) δ 166.1, 154.2, 145.9, 138.7, 136.6, 136.5, 135.3, 133.4, 133.0, 132.9, 130.4, 129.8, 126.4, 123.9, 40.0, 31.7, 20.2, 13.8. LCMS m/z 379 [M+H]+, purity (UV/MS) 100/92, ?R = 4.67 min.
Example 706: (ZK/V-Butyl-2-chloro-l l-(4-chlorophenylMibenzor6.flri.41thiazepine-8- carboxamide
Figure imgf000298_0002
[0776] The title compound was synthesized according to the General Procedure C using (E)-N-bu\yl-2,\ l-dichlorodibenzo[6,/j[1,4]thiazepine-8-carboxarnide (75 mg; 0.2 mmol), bis(triphenylphosphine)palladium(ll) chloride (14 mg; 0.02 mmol) and 4-chlorophenylzinc iodide (0.5M in THF). The title compound was purified by silica gel column chromatography (0-10% ethyl acetate in toluene) followed by recrystalisation from ethyl acetate to give 59 mg of a yellow solid (65%). Rf = 0.45 (10% ethyl acetate in toluene). 1H NMR (CDCl3, 400 MHz) δ 7.77 - 7.73 (m, 2H), 7.63 (m, I H), 7.52 - 7.41 (m, 5H), 7.14 (d, 1H, J - 2.4 Hz), 6.06 (br s, 1H), 3.47 - 3.41 (m, 2H), 1.63 - 1.54 (m, 2H), 1.46 - 1.35 (m, 2H), 0.95 (t, 3H5 J = 7.6 Hz). 13C NMR (CDCl3, 100 MHz) δ 166.7, 166.6, 148.6, 138.8, 138.1, 138.0, 137.8, 136.3, 134.8, 133.7, 132.8, 131.7, 131.6, 131.0, 130.1, 128.9, 124.6, 123.8, 40.0, 31.9, 20.3, 13.9. LCMS m/z 455 [M+H]+, purity (UV/MS) 100/100, tκ= 6.75 min.
Example 707: (Z)-N-Butyl-2-chloro-l l-(3-chlorophenyl)dibenzo[ά,/1[1,41thiazepine-8- carboxamide
Figure imgf000299_0001
[0777] The title compound was synthesized according to the General Procedure C using (£)-N-butyl-2,l l-dichlorodibenzo[ά,/|[1,4]thiazepine-8-carboxamide (75 mg; 0.2 mmol), bis(triphenylphosphine)palladium(II) chloride (14 mg; 0.02 mmol) and 3-chlorophenylzinc iodide (0.5M in THF). The title compound was purified by silica gel column chromatography (0-10% ethyl acetate in toluene) followed by recrystalization from ethyl acetate to give 74 mg of a yellow solid (81%). Rf = 0.29 (10% ethyl acetate in heptane). 1H NMR (CDCl3, 400 MHz) δ 7.89 (t, 1H, J - 1.6 Hz), 7.64 (d, 1H, J = 2.0 Hz), 7.60 - 7.57 (m, 1H), 7.54 (dd, 1H, J = 1.6 Hz, 8.8 Hz), 7.52 - 7.47 (m, 3H), 7.40 - 7.36 (m, 2H), 7.15 (d, 1H, J = 2.4 Hz), 6.09 (br s, 1H), 3.48 - 3.42 (m, 2H), 1.64 - 1.55 (m, 2H), 1.46 - 1.36 (m, 2H), 0.96 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 100 MHz) δ 166.5, 148.4, 141.4, 138.8, 138.1, 136.3, 134.9, 134.8, 133.7, 132.9, 131.8, 131.3, 130.0, 129.8, 129.4, 128.1, 124.9, 123.8, 40.0, 31.9, 20.3, 13.9. LCMS m/z 455 [M+H]+, purity (UV/MS) 100/92, /R = 6.70 min. Example 708: (F)-N-Butyl-2-chloro-l H5-chlorothiophen-2- yl)dibenzo|~6,/1|T,41thiazepine-8-carboxamide
Figure imgf000300_0001
[0778] The title compound was synthesized according to the General Procedure C using (^-Λ^-butyl^^ l-dichlorodibenzof/j./lfl^jthiazepine-S-carboxamide (75 mg; 0.2 mmol), bis(triphenylphosphine)palladium(II) chloride (14 mg; 0.02 mmol) and 5-chloro-2-thienylzinc bromide (0.5M in THF). The title compound was purified by silica gel column chromatography (0-10% ethyl acetate in toluene) followed by recrystalization from ethyl acetate to give 77 mg of a yellow solid (84%). Rf = 0.39 (10% ethyl acetate in heptane). 1H NMR (CDCl3, 400 MHz) δ 7.56 - 7.39 (m, 6H), 6.97 (d, 1H, J = 4.0 Hz), 6.93 (d, 1H, J = 4.0 Hz), 6.05 (br s, 1H), 3.47 - 3.40 (m, 2H), 1.62 (m, 2H), 1.45 - 1.35 (m, 2H), 0.95 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 100 MHz) δ 166.5, 161.1, 148.2, 144.5, 138.8, 137.5, 136.4, 136.4, 134.8, 133.9, 132.9, 132.0, 131.9, 131.4, 129.9, 127.5, 124.9, 123.9, 40.0, 31.9, 20.3, 13.9. LCMS m/z 461 [M+H]+, purity (UV/MS) 97/-, ?R= 6.83 min.
Example 709: 4-Fluoro-2-mercaptobenzoic acid
Figure imgf000300_0002
[0779] A solution of 2-amino-4-fluorobenzoic acid (1.9 g; 12.3 mmol), sodium hydroxide (500 mg; 12.4 mmol) and sodium nitrite (850 mg; 12.3 mmol) in 15 mL water was added slowly to a mixture of 3 mL concentrated HCl and 5 g of ice cooled with an ice bath. The temperature was maintained a O°C and stirring continued for 'Λh. In another beaker, potassium ethylxanthate (2.95 g; 18.4 mmol) was dissolved in 20 mL water and heated to 65°C. The cold diazonium salt solution was added slowly to the hot xanthate solution. After the addition, the mixture was cooled to room temperature and acidified to pH~3 using 4M aqueous HCl. The mixture was filtered and the solid dissolved in 10 mL 10% aqueous sodium hydroxide and heated for l 'Λh at 100°C before addition of 1 g sodium hydrosulfite. Stirring and heating was continued for another 10 min before cooling to room temperature. After filtration the filtrate was acidified to pH~4 using concentrated HCl. The resulting solid was collected by filtration and washed with water. To avoid disulfide formation the white solid was dissolved in 5 mL methanol and 65 mL diisopropyl ether and dried over sodium sulfate. After filtration and evaporation, the title compound was isolated as a light yellow solid (1.45 g; 69%). 1H NMR (CDCl3 + DMSO-^6, 400 MHz) δ 7.95 (dd, 1H, J = 6.4 Hz, 8.8 Hz), 6.89 (dd, 1H, J = 2.4 Hz, 9.2 Hz), 6.69 (ddd, 1H, J = 2.4 Hz, 7.6 Hz, 8.8 Hz), 5.37 (s, I H). 13C NMR (CDCl3 + DMSO-4, 100 MHz) δ 168.3, 164.2 (d, J = 253 Hz), 141.6 (d, J = 10 Hz), 134.6 (d, J = 10 Hz), 122.6 (d, J = 3 Hz), 117.0 (d, J = 24 Hz), 11 1.9 (d, J = 22 Hz).
Example 710: 2-(4-Ethoxycarbonyl-2-nitrophenylthioV4-fluorobenzoic acid
Figure imgf000301_0001
[0780] Ethyl 4-fluoro-3-nitrobenzoate (1.64 g; 7.7 mmol) was dissolved in 25 mL dry DMF and cesium carbonate (2.96 g; 9.1 mmol) was added. The mixture was heated to 7O°C before dropwise addition of a solution of 4-fluoro-2-mercaptobenzoic acid (1.3 g; 7.6 mmol) in 15 mL dry DMF. The mixture was stirred at 7O°C for l 'Λh before cooling to room temperature. Water was added and the solution acidified with 4M aqueous HCl before extraction using ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent removed by evaporation to give the crude product as an orange oil. Purification was performed using silica gel column chromatography (5% methanol in DCM) and the desired product isolated as a yellow solid (2.79 g; 100%). 1H NMR (DMSO-^6, 400 MHz) δ 8.56 (d, 1H, J = 2.0 Hz), 8.06 (dd, 1H, J= 2.0 Hz, 8.4 Hz), 8.00 (dd, 1H, J= 6.0 Hz, 8.8 Hz), 7.40 (dt, 1H, J= 2.8 Hz, 8.4 Hz), 7.33 (dd, 1H, J = 2.8 Hz, 9.2 Hz), 7.28 (d, 1H, J = 8.4 Hz), 4.33 (q, 2H, J = 6.8 Hz), 1.30 (t, 3H, J= 7.2 Hz).
Example 71 1 : 2-(4-Carboxy-2-nitrophenylthioV4-fluorobenzoic acid
Figure imgf000302_0001
[0781] 2-(4-Ethoxycarbonyl-2-nitrophenylthio)-4-fluorobenzoic acid (2.7 g; 7.4 mmol) was dissolved in 60 mL THF and 50 mL IM aqueous lithium hydroxide. The solution was heated to 7O°C for 1 'Λh. The mixture was cooled to room temperature and the THF removed by evaporation. The basic aqueous phase was washed twice with ethyl acetate before acidification using 4M aqueous HCl. Acidification resulted in precipitation of a yellow solid that was collected by filtration and used without further purification and drying. 1H NMR (DMSO-Cf6, 400 MHz) 8.55 (d, 1H, J = 1.6 Hz), 8.04 (dd, 1H, J = 1.6 Hz, 8.4 Hz), 8.00 (dd, 1H, J= 6.0 Hz, 8.8 Hz), 7.40 (dt, 1H, J= 2.4 Hz, 8.4 Hz), 7.30 (dd, 1H, J= 2.4 Hz, 8.8 Hz), 7.26 (d, 1H, J= 8.0 Hz).
Example 712: 2-(2-Amino-4-carboxyphenylthio)-4-fluorobenzoic acid
Figure imgf000302_0002
[0782] 2-(4-Carboxy-2-nitrophenylthio)-4-fluorobenzoic acid (-7.4 mmol) was dissolved in 100 mL ethanol. A solution of potassium carbonate (2.1 g, 15 mmol) and sodium hydrosulfite (3.1 g; 15 mmol) in 75 mL water was added slowly. A color change was observed changing from strong yellow to light yellow/white. The solution was stirred for 15 min before evaporation of the ethanol. The resulting aqueous solution was acidified using 4M HCl and light yellow precipitates were formed. The solid was collected by filtration to give the title compound (815 mg; 36% over two steps). 1H NMR (DMSO-^6, 400 MHz) δ 8.01 (dd, 1H, J= 6.4 Hz, 8.4 Hz), 7.43 (d, 1H, J = 1.6 Hz), 7.38 (d, 1H, J = 7.6 Hz), 7.14 (dd, 1H, J = 1.6 Hz, 7.6 Hz), 7.01 (dt, 1H, J = 2.4 Hz, 8.0 Hz), 6.22 (dd, 1H, J = 2.4 Hz, 10.4 Hz), 5.64 (br s, 2H).
Example 713: 3-Fluoro-l l-oxo-10,1 l-dihvdrodibenzo[fr,/][~I,4]thiazepine-8-carboxylic acid
Figure imgf000303_0001
[0783] 2-(2-Amino-4-carboxyphenylthio)-4-fluorobenzoic acid (800 mg; 2.4 mmol) was dissolved in 15 mL dry THF. 1 ,1-Carbonyldiimidazole (90%, 1.33 g; 7.4 mmol) was added portionwise and the mixture stirred at room temperature for 4h. The reaction was quenched by addition of 75 mL water and acidified with 4M aqueous HCl. Acidification resulted in formation of light yellow precipitates that were collected by filtration and washed with ethyl acetate and heptane to become almost white (500 mg; 72%). 1H NMR (DMSCM6, 400MHz) δ 10.8 (s, 1H), 7.76 (s, 1H), 7.74 (dd, 1H, J = 6.4 Hz, 8.8 Hz), 7.65 (s, 2H), 7.42 (dd, 1H, J = 2.4 Hz, 8.4 Hz), 7.30 (dt, 1H, J = 2.4 Hz, 8.4 Hz).
Example 714: (F)-I l-Chloro-3-fluorodibenzorά,/iπ,41thiazepine-8-carbonyl chloride
Figure imgf000303_0002
[0784] 3-Fluoro-l l-oxo-10,1 l-dihydrodibenzo[6,y][1,4]thiazepine-8- carboxylic acid (500 mg; 1.7 mmol) was dissolved in a mixture of thionyl chloride (7.5 mL), DMF (30 μL) and toluene (15 mL). The mixture was heated to 80°C overnight. After cooling the solvents were removed by evaporation followed by co-evaporation (two times 15 niL) with toluene to give a light yellow solid that was used without further purification.
Example 715: (E)-N-BuXyI-I l-chloro-3-fluorodibenzo[77,/][L41thiazepine-8- carboxamide
Figure imgf000304_0001
[0785] π-Butyl amine (220 μL; 2.2 mmol) was dissolved in 5 mL DCM and cooled to O°C. A solution of (E)-\ l-chloro-3-fluorodibenzo[&,/][l ,4]thiazepine-8- carbonyl chloride (-0.86 mmol) in 15 mL DCM was added slowly. The mixture was stirred at room temperature for 3h. The mixture was diluted with 15 mL DCM and washed with saturated aqueous ammonium chloride. The organic phase was dried over sodium sulfate, filtered and the solvent removed by evaporation. The crude product was purified by silica gel column chromatography (10% ethyl acetate in toluene) to give 240 mg (77%). LCMS m/z 363 [M+H]+, purity (UV/MS) 100/100, /R = 4.57 min.
Example 716: (E)-NA l-Chloro-3-fluoro-N-isobutyldibenzo[fe,/1[1,41thiazepine-8- carboxamide
Figure imgf000304_0002
[0786] The title compound was synthesized according to the same procedure as for synthesis of (E)-N-butyl-\ l-chloro-3-fluorodibenzo[6,/][l ,4]thiazepine-8- carboxamide using isobutylamine (220 μL; 2.2 mmol) to afford 256 mg of the desired product (82%). 1H NMR (CDCl3, 400 MHz) δ 7.74 (dd, 1H, J = 6.0 Hz, 9.2 Hz), 7.62 (dd, 1H, J = 2.0 Hz, 8.4 Hz), 7.56 (d, 1H, J = 2.0 Hz), 7.48 (d, 1H, J = 8.0 Hz), 7.18 (dd, 1H, J = 2.4 Hz, 7.6 Hz), 7.13 - 7.07 (m, 1H), 6.20 (br s, 1H), 3.25 (t, 2H, J = 6.4 Hz), 1.86 (m, 1H, J = 6.8 Hz), 0.95 (d, 6H, J = 6.8 Hz). LCMS m/z 363 [M+H]+, purity (UV/MS) 100/100, /R = 4.47 min.
Example 717: (E)-./V-Butyl-l l-(5-pyridin-2-yl)-3-fluorodibenzotø,/iπ,41thiazepine-8- carboxamide
Figure imgf000305_0001
[0787] Zinc reagent preparation: 2-Bromo-5-chloropyridine (962 mg; 5 mmol) was dissolved in THF (10 mL) and isopropylmagnesium chloride (1.2 M in THF; 4.1 mL; 5.0 mmol) was added at room temperature. After 2h, zinc bromide (1 M in THF; 3.0 mL; 3.0 mmol) was added and the mixture was stirred at room temperature under argon over night. The crude mixture was used immediately.
[0788] The title compound was synthesized according to the General Procedure C using (^-N-butyl-l l-chloro-S-fluorodibenzot^/Jf l ^jthiazepine-δ- carboxamide (80 mg; 0.22 mmol), bis(triphenylphosphine)palladium(II) chloride (15 mg; 0.02 mmol) and a large excess of the freshly prepared zinc reagent (5-chloro-2- pyridylzinc bromide, -10 eq). The title compound was purified by silica gel column chromatography (0-30% ethyl acetate in toluene) followed by followed by preparative TLC eluting with 10 % ethyl acetate in toluene twice. 4.9 mg of the title compound was isolated as a yellow solid (5%). 1H NMR (CDCl3, 400 MHz) δ 8.59 (d, 1H, J= 2.0 Hz), 8.36 (d, 1H, J = 8.8 Hz), 7.84 (dd, 1H, J = 2.4 Hz, 8.0 Hz), 7.69 (s, 1H), 7.53 (s, 1H), 7.53 (s, 1H), 7.28 - 7.20 (m, 2H), 7.03 (dt, 1H, J = 2.4 Hz, 8.4 Hz), 6.03 (br s, 1H), 3.48 (m, 2H), 1.63 - 1.51 (m, 2H), 1.45 - 1.35 (m, 1H), 0.95 (t, 3H, J = 7.2 Hz). LCMS m/z 440 [M+H]+, purity (UV/MS) 96/65, tR = 4.85 min. Example 718: (Z)-iV-Butyl-l l-(4-chlorophenylV3-fluorodibenzo[6,/1[K4]thiazepine-8- carboxamide
Figure imgf000306_0001
[0789] The title compound was synthesized according to the General Procedure C using (£)-N-butyl-l l-chloro-3-fluorodibenzo[6,/J[1,4]thiazepine-8- carboxamide (50 mg; 0.14 mmol), bis(triphenylphosphine)palladium(II) chloride (15 mg; 0.02 mmol) and 4-chlorophenylzinc iodide (0.5M in THF, 0.5 mL; 0.25 mmol). The title compound was purified by silica gel column chromatography (5-10% ethyl acetate in toluene) to give 43 mg of a yellow solid (73%). Rf = 0.65 (30% ethyl acetate in toluene). 1H NMR (CDCl3, 400 MHz) δ 7.74 - 7.69 (m, 2H), 7.65 (s, 1H), 7.49 (s, 2H), 7.43 - 7.38 (m, 2H), 7.28 (dd, 1H, J = 2.4 Hz, 8.4 Hz), 7.15 (dd, 1H, J = 5.6 Hz, 8.8 Hz), 7.01 (dt, 1H, J = 2.8 Hz, 8.8 Hz), 6.13 (br s, 1H), 3.43 (q, 2H, J = 6.8 Hz), 1.62 - 1.53 (m, 2H), 1.45 - 1.34 (m, 2H), 0.94 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 100 MHz) δ 167.2, 166.8, 164.2 (d, J= 254 Hz), 148.9, 142.5 (d, J= 8 Hz), 138.7, 137.6, 136.4, 133.3 (d, J = 4 Hz), 133.0, 132.2 (d, J = 10 Hz), 131.4, 131.1, 128.8, 124.5, 124.0, 1 19.5 (d, J = 22 Hz), 115.8 (d, J = 21 Hz), 40.1, 31.9, 20.3, 14.0. LCMS m/z 439 [M+H]+, purity (UY/MS) 100/100, rR= 5.53 min.
Example 719: (£VN-Butyl-1 l-(5-chlorothiopheή-2-ylV3-
Figure imgf000307_0001
[0790] The title compound was synthesized according to the General Procedure C using (E)-N-buty\-\ l-chloro-3-fluorodibenzo[6,/][l ,4]thiazepine-8- carboxamide (50 mg; 0.14 mmol), bis(triphenylphosphine)palladium(II) chloride (15 mg; 0.02 mmol) and 5-chloro-2-thienylzinc bromide (0.5M in THF, 0.5 mL; 0.25 mmol). The title compound was purified by silica gel column chromatography (5-10% ethyl acetate in toluene) followed by preparative HPLC to give 10 mg of a yellow solid (16%). Rf = 0.69 (30% ethyl acetate in toluene). 1H NMR (CDCl3, 400 MHz) δ 7.56 (d, 1H, J = 2.0 Hz), 7.51 (dd, 1H, J= 2.0 Hz, 8.0 Hz), 7.49 (d, 1H, J = 8.0 Hz), 7.45 (dd, 1H, J = 5.6 Hz, 8.4 Hz), 7.28 (dd, 1H, J = 2.4 Hz, 8.4 Hz), 7.08 (dt, 1H, J = 2.4 Hz, 8.4 Hz), 6.90 (s, 2H), 6.06 (br s, 1H), 3.45 - 3.41 (m, 2H), 1.61 - 1.54 (m, 2H), 1.44 - 1.34 (m, 2H), 0.94 (t, 3H, J= 7.6 Hz). LCMS m/z 445 [M+H]+, purity (UV/MS) 100/90, /R = 5.62 min.
Example 720: (E)-I l-(5-Chlorothiophen-2-yl)-3-fluoro-ΛMsobutyldibenzorά./iπ,41 thiazepine-8-carboxylic acid
Figure imgf000307_0002
[0791] The title compound was synthesized according to the General Procedure C using (i^-N-l l-chloro-3-fluoro-ΛMsobutyldibenzo[έ>,/][1,4] thiazepine-8- carboxamide (55 mg; 0.15 mmol), bis(triphenylphosphine)palladium(ll) chloride (11 mg;
0.015 mmol) and 5-chloro-2-thienylzinc bromide (0.5M in THF, 0.76 mL; 0.38 mmol). i . The title compound was purified by silica gel column chromatography (0-10% ethyl acetate in toluene) followed by preparative TLC eluting six times with 2% ethyl acetate in toluene to give 10 mg of a yellow solid (15%). 1H NMR (CDCl3, 400 MHz) 5 7.58 - 7.43 (m, 4H), 7.28 (dd, 1H, J = 2.4 Hz, 8.0 Hz), 7.09 (dt, 1H, J- 2.4 Hz, 8.4 Hz), 6.91 (s, 2H), 6.10 (br s, 1H), 3.28 (t, 2H, J = 6.4 Hz), 1.88 (m, 1H, J = 6.8 Hz), 0.98 (d, 6H, J = 6.8 Hz). LCMS m/z 445 [M+H]+, purity (UV/MS) 100/94, /R = 5.50 min.
Example 721 : (Z)-X l-(4-ChlorophenylV3-fluoro-Λ^-isobutyldibenzo[ά,/]fL4]thiazepine- 8-carboxamide
Figure imgf000308_0001
[0792] The title compound was synthesized according to the General Procedure C using (£)-N-l l-chloro-3-fluoro-N-isobutyldibenzo[b,/)[1,4] thiazepine-8- carboxamide (55 mg; 0.15 mmol), bis(triphenylphosphine)palladium(ll) chloride (11 mg; 0.015 mmol) and 4-chlorophenylzinc iodide (0.5M in THF, 0.76 mL; 0.38 mmol). The title compound was purified by silica gel column chromatography (0-10% ethyl acetate in toluene) to give 55 mg of a yellow solid (84%). Rf = 0.33 (10% ethyl acetate in toluene). 1H NMR (CDCl3, 400 MHz) δ 7.76 - 7.64 (m, 3H), 7.55 - 7.36 (m, 4H), 7.30 - 7.22 (m, 1H), 7.20 - 7.11 (m, 1H), 7.04 - 6.96 (m, 1H), 6.31 (br s, 1H), 3.29 (m, 2H), 1.96 - 1.80 (m, 1H), 0.96 (t, 6H, J= 6.0 Hz). 13C NMR (CDCl3, 100 MHz) δ 167.2, 166.8, 164.2 (d, J= 253 Hz), 148.9, 142.4 (d, J = 9 Hz), 137.6, 136.4, 133.2 (d, J= 3 Hz), 133.0, 132.2 (J = 10 Hz), 131.4, 131.1, 128.8, 124.5, 124.0, 119.5 (d, J = 22 Hz), 115.8 (d, J = 22 Hz), 47.7, 28.8, 20.4. LCMS m/z 439 [M+H]+, purity (UV/MS) 100/30, /R = 5.50 min. Example 722: (E)A l-(5-Chloropyridin-2-ylV3-fluoro--V-isobutyldibenzo[6.f]π .41 thiazepine-8-carboxamide
Figure imgf000309_0001
[0793] Zinc reagent preparation: 2-bromo-5-chloropyridine (962 mg; 5 mmol) was dissolved in THF (10 mL) and isopropylmagnesium chloride (1.2 M in THF; 4.1 mL; 5.0 mmol) was added at room temperature. After 2h, zinc bromide (1 M in THF; 3.0 mL; 3.0 mmol) was added and the mixture was stirred at room temperature under argon over night. The crude mixture was used immediately.
[0794] The title compound was synthesized according to the General Procedure C using (£)-iV-l l-chloro-3-fluoro-Λ^-isobutyldibenzo[ά,/l[1,4] thiazepine-8- carboxamide (85 mg; 0.23 mmol), bis(triphenylphosphine)palladium(II) chloride (15 mg; 0.02 mmol) and a large excess of the freshly prepared zinc reagent (5-chloro-2- pyridylzinc bromide, -10 eq). The title compound was purified by silica gel column chromatography (10-30% ethyl acetate in toluene) followed by followed by ion exchange chromatography (SCX column eluting with 2% NH3 in MeOH) and preparative TLC eluting with 10 % ethyl acetate in toluene twice. 5.5 mg of the title compound was isolated as a yellow solid (5%). 1H NMR (CDCl3, 400 MHz) δ 8.59 (d, 1H, J = 2.0 Hz), 8.36 (d, 1H, J = 8.8 Hz), 7.83 (dd, 1H, J = 2.4 Hz, 8.4 Hz), 7.69 (s, 1H), 7.54 (s, 2H), 7.28 - 7.20 (m, 2H), 7.03 (dt, 1H, J= 2.4 Hz, 8.4 Hz), 6.10 (br s, 1H), 3.28 (t, 2H, J= 6.0 Hz), 1.88 (m, 1H, J = 6.8 Hz), 0.97 (d, 6H, J = 6.4 Hz). LCMS m/z 440 [M+H]+, purity (UV/MS) 97/85, tR = 9.26 min. Example 723: 1 l-(5-Chloro-2-thienylV3-chlorodibenzo[ά,/][K41thiazepine-8-carboxylic acid butyl amide
Figure imgf000310_0001
[0795] The title compound was prepared as described herein. The crude mixture was purified by silica gel column chromatography (0-20% ethyl acetate in toluene) followed by preparative TLC (2% EtOAc in toluene) to yield the title compound as a yellow solid (3.4 mg, 4%). 1H NMR (CDCl3, 400 MHz) δ 7.56 (d, 2H, J = 1.6 Hz, ArH), 7.53 - 7.48 (m, 2H, ArH), 7.41 - 7.34 (m, 2H, ArH), 6.91 (s, 2H, ArH), 6.02 (br m, 1H, NH), 3.48 - 3.43 (m, 2H, NCH2), 1.60 - 1.53 (m, 2H, CH2), 1.43 - 1.37 (m, 2H, CH2), 0.95 (t, 3H, J = 7.2 Hz, CH3). LCMS m/z 461 [M+H]+, purity (UV/MS) 100/confirmed, JR = 5.96 min.
Example 724: 1 l-(4-Chlorophenyl)-3-chlorodibenzo[ά,/][1,4]thiazepine-8-carboxylic acid /so-butyl amide
Figure imgf000310_0002
[0796] The title compound was prepared as described herein (4.0 mg, 8%). 1H
NMR (CDCl3, 400 MHz) δ 7.75 - 7.72 (m, 2H, ArH), 7.65 (dd, 1H, J = 1.6, 1.6, ArH), 7.57 (d, 1H, J = 2.0, ArH), 7.513 (s, 1H, ArH), 7.51 1 (s, 1H, ArH), 7.43 - 7.39 (m, 2H, ArH), 7.30 (dd, 1H, J = 2.4, 8.0 Hz ArH), 7.10 (d, 1H, J = 8.0 Hz, ArH), 6.09 (br m, 1H, NH), 3.28 (t, 2H, J = 6.4 Hz, CH2), 1.91 - 1.86 (m, 1H, CH), 0.98 (s, 3H, CH3), 0.97 (s, 3H, CH3). LCMS m/z 455 [M+H]+, purity (UV/MS) 98/confirmed, fR = 5.89 min. Example 725: 1 l-(5-Chloro-2-thienyl>3-chlorodibenzo[6,/]f 1 ,41thiazepine-8-carboxylic acid iso-butyl amide
Figure imgf000311_0001
[0797] The title compound was prepared as described herein. The crude mixture was purified by silica gel column chromatography (0-20% ethyl acetate in toluene) followed by preparative TLC (2% EtOAc in toluene) to yield the title compound as a yellow solid (0.8 mg, 2%). LCMS m/z 461 [M+H]\ purity (UWMS) 99/confirmed, /R = 5.92 min.
Example 726: 4-(2-Carboxy-5-chloro-phenylsulfanylV5-nitrobenzoic acid ethyl ester
Figure imgf000311_0002
[0798] 4-Fluoro-3-nitrobenzoic acid ethyl ester (1.1 g, 5.3 mmol) and Cs2CO3 (1.7 g, 5.3 mmol) were dissolved in DMF (10 mL) and heated to 80 °C. 4-chloro- thiosalicylic acid was prepared according to the procedure by Katz, et al, which is hereby incorporated by reference in its entirety. Karger, L. S. et al. J. Org. Chem., 1953, 18, 1380-1402. A solution of 4-chloro-thiosalicylic acid in DMF (20 mL) was added and the mixture was stirred at 80 °C for 30 min and then allowed to reach room temperature over night. HCl (2M) was added followed by EtOAc, and the layers were separated. The organic layer was washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography (0-4% methanol and 1% triethylamine in dichloromethane) to yield the title compound as a yellow solid (0.49 g, 32%). 1H NMR (CDCl3, 400 MHz) δ 8.48 (d, 1H, J = 2.0 Hz, ArH), 7.88 (dd, 1H, J = 2.0, 8.4 Hz, ArH), 7.57 (d, 1H, J - 8.4 Hz, ArH), 7.1 1 - 7.02 (m, 3H, ArH), 4.32 (q, 2H, J= 6.8 Hz, OCH2), 1.35 (t, 3H, J= 6.8 Hz, CH3).
Example 727: 1 l-(5-Chloro-2-pyridyl)-3-chlorodibenzorά,/][l 141thiazepine-8-carboxylic acid butyl amide
Figure imgf000312_0001
[0799] The title compound was prepared as described herein. The crude mixture was purified by silica gel column chromatography (0-5% ethyl acetate in toluene) followed by ion exchange chromatography (2M NH3 in MeOH) and preparative TLC (5% EtOAc in toluene) to yield the title compound as a yellow solid (4.1 mg, 4%). 1H NMR (CDCl3, 400 MHz) δ 8.52 (d, 1H, J = 2.0 Hz, ArH), 8.30 (dd, 1H, J = 0.8, 8.4 Hz, ArH), 7.78 (dd, 1H, J = 2.4, 8.4 Hz, ArH), 7.63 (dd, 1H, J = 1.2, 1.2 Hz, ArH), 7.48 (d, 1H, J = 2.0 Hz, ArH), 7.47 (s, 1H, ArH), 7.467 (s, 1H, ArH), 7.24 (dd, 1H, J= 2.0, 8.4 Hz, ArH), 7.10 (d, 1H, J = 8.4 Hz, ArH), 5.98 (br m, 1H, NH), 3.40 - 3.35 (m, 2H, NCH2), 1.55 - 1.48 (m, 2H, CH2), 1.39 - 1.29 (m, 2H, CH2), 0.89 (t, 3H, J = 7.2 Hz, CH3). LCMS m/z 456 [M+H]+, purity (UV/MS) 96/73, fR= 10.07 min.
Example 728: 1 l-(5-Chloro-2-pyridyl>-3-chlorodibenzo[ά,/][U4]thiazepine-8-carboxylic acid Λ?o-butyl amide
Figure imgf000312_0002
[0800] The title compound was prepared as described herein. The crude mixture was purified by silica gel column chromatography (0-5% ethyl acetate in toluene) followed by ion exchange chromatography (2M NH3 in MeOH) and preparative TLC (5% EtOAc in toluene) and finally HPLC (Cl 8 column, 5 mM NH4HCO3 pH 9.5 in MeCN) to yield the title compound as a yellow solid (1.6 mg, 2%). 1H NMR (CDCl3, 400 MHz) δ 8.59 (dd, 1H, J = 0.8, 1.2 Hz, ArH), 8.37 (dd, 1H, J = 0.4, 9.6 Hz, ArH), 7.84 (ddd, 1H, J = 1.2, 2.4, 8.0 Hz, ArH), 7.69 (d, 1H, J = 1.2 Hz ArH), 7.55 - 7.54 (m, 3H, ArH), 7.32 - 7.29 (m, 1H, ArH), 7.17 (dd, 1H, J- 0.8, 8.4 Hz, ArH), 6.10 (br m, I H, NH), 3.28 (t, 2H, J = 6.0 Hz, CH2), 1.91 - 1.85 (m, 1H, CH), 0.98 (d, 3H, J = 1.2 Hz, CH3), 0.97 (d, 3H, J = 1.2 Hz, CH3). LCMS m/z 456 [M+H]+, purity (UV/MS) 100/100, fR = 5.30 min.
Example 729: 10-Phenyl-5-thia- 1,4,1 l-triazadibenzo[a,d1cycloheptene
Figure imgf000313_0001
[0801] Thiophenol (5.0 g, 45.0 mmol) was added dropwise to π-BuLi in hexanes (42.8 mmol, 90 mmol) and tetramethylenediamine (13.6 mL, 90 mmol) in 4A mol sieves dried cyclohexane (50 mL), under Argon atmosphere at 0 °C. The resulting mixture was allowed to stir to rt overnight, then neat benzonitrile (4.59 mL, 45 mmol) was added dropwise at rt and the resulting brown suspension was stirred vigorously for 3 hours before adding neat 2,3-dichloropyrazine (6.8 g, 45 mmol) over ca. 1 min, causing a substantially exothermic reaction. After the heat evolution had ceased the crude reaction mixure was poured into 2M HCl (500 mL), extracted with toluene (3 x 250 mL), evaporated to dryness and passed through a pad of silica using EtOAc/w-heptane (1 : 2) as eluent to give 5.2 g (40 %) of the title compound as a brown solid.
[0802] LCMS m/z 290 [M+H]+. GCMS m/z 289 [M]+. 1H NMR (CDCl3) δ 7.28-7.56 (m, 6H), 7.67 (m, 1H), 7.88 (m, 2H), 8.24 (d, 1H, J = 2.3), 8.41 (d, 1H, J = 2.3). HPLC tR = 3.9 min (method B). GC tR = 9.7 min. Example 730: 3-Hydroxy-2-methoxycarbonylthiophene
Figure imgf000314_0001
[0803] The title compound was synthesised according to a procedure published by Huddleston and Barker, Synth. Commun., 1979, 9, 8, 731-734, which is hereby incorporated by reference in its entirety. To a solution of 15 mL dry MeOH was added sodium (700 mg; 30 mmol) to give a 2M solution of NaOMe. Methyl thioglycolate (1.9 g; 18 mmol) was added. The solution was cooled to O°C and methyl 2-chloroacrylate (2.1 g; 17.4 mmol) was added drop wise. Stirring was continued overnight raising the temperature to room temperature. The mixture was recooled to O°C and the quenched by addition of HCl (4M aq, ~5mL). Water was added and extraction done with 2 times EtOAc. The combined organic phases were dried over Na2SO4, filtered and the solvent removed in vacuo to give 2.0 g (70 %) of a brown oil that solidified upon drying. Used without further purification.
[0804] LCMS m/z -, tκ = 4.12 min, purity (UV/MS) 98/20. GCMS m/z 158 (M), tR = 4.52 min. 1H NMR (CDCl3, 400 MHz) δ 9.56 (br s, 1H, OH), 7.37 (d, 1H, J = 5.2 Hz, thiopheneH), 6.74 (d, 1H, J= 5.2 Hz, thiopheneH), 3.89 (s, 3H, OMe).
Example 731 : O-(2-Methoxycarbonyl-3-thienyl)- MiV-diethylthiocarbamate
Figure imgf000314_0002
[0805] 3-Hydroxy-2-methoxycarbonylthiophene (2.0 g; 12.6 mmol) was dissolved in 10 mL dry DMF and sodium hydride (-60% in mineral oil, 610 mg; ~15.2 mmol) was added portion wise. After hydrogen evolution had ceased the mixture was cooled to 5 °C and diethylthiocarbamoyl chloride (2.48 g; 16.4 mmol) was added in one portion and the temperature was raised to 80 °C for 1 hour. After cooling to room temperature the mixture was poured into a 1% aqueous potassium hydroxide solution (25 mL). The aqueous phase was extracted with toluene (3 times 15 mL). The combined organic phases were washed with 5% aqueous HCl (10 mL), water (10 mL) before drying over Na2SO4. After filtration the solvent was removed by evaporation to give a crude brown oil that was purified by silica gel column chromatography (20 % EtOAc in heptane, R/= 0.45) to give the title compound as a brown oil (1.74 g; 51 %)
[0806] LCMS m/z 274 [M+l]\ /R = 3.98 min, purity (UV/MS): 80/70. GCMS m/z 273, tR = 7.54 min. 1H NMR (CDCl3, 400 MHz) δ 7.44 d, 1H, J = 5.6 Hz, thiopheneH), 6.93 (d, 1H, J = 5.6 Hz, thiopheneH), 3.88 (q, 2H, J = 7.2 Hz, CH2), 3.82 (s, 3H, OMe), 3.74 (q, 2H, J = 7.2 Hz, CH2), 1.35 (t, 3H, J = 7.2 Hz, Me), 1.33 (t, 3H, J = 7.2 Hz, Me).
Example 732: S-(2-Methoxycarbonyl-3-thienyl>N,N-diethylcarbamate
Figure imgf000315_0001
[0807] O-(2-Methoxycarbonyl-3-thienyl)-N,iV-diethylcarbamate (1.74 g; 6.4 mmol) was stirred at 22O°C for 30 min. After cooling to room temperature the title compound was obtained as a brown oil. Used without further purification.
[0808] GCMS m/z 273, /R = 7.71 min.
[0809] 1H NMR (CDCl3, 400 MHz) δ 7.49 (d, 1H, J = 5.2 Hz, thiopheneH4),
7.37 (d, 1H, J= 5.2 Hz, thiopheneH5), 3.86 (s, 3H, OMe), 3.55 - 3.39 (m, 4H, 2 x CH2), 1.40 - 1.12 (m, 6H, 2 x CH3).
Example 733: 3-Mercaptothiophene-2-carboxylic acid
Figure imgf000315_0002
[0810] For a published procedure on synthesis of 3-mercaptothiophene-2- carboxylic acid see Corral et al , Synthesis, 1984, 172, which is hereby incorporated by reference in its entirety. 5'-(2-Methoxycarbonyl-3-thienyl)-N,N-diethylcarbamate (-6.4 mmol) was refluxed in a mixture of 10% aqueous NaOH (8 mL) and MeOH (4 mL) for 1 hour. After cooling to room temperature MeOH was removed under reduced pressure and the aqueous phase was acidified with 4M HCl. The title compound was isolated by filtration as a light brown solid (670 mg; 65 % over two steps). Used without further purification.
[0811] 1H NMR (DMS0-rf6, 400 MHz) δ 7.75 (d, 1H, J = 5.2 Hz, thiopheneH), 7.07 (d, 2H, J = 5.2 Hz, thiopheneH), 2.48 (s, 1H, SH).
Example 734: 3-(4-Ethoxycarboxy-2-nitro-phenylsulfanyl)thiophene-2-carboxylic acid
Figure imgf000316_0001
[0812] Ethyl 4-fluoro-3-nitrobenzoate (440 mg; 2.07 mmol) was dissolved in dry DMF (5 mL) and heated to 7O°C with cesium carbonate (715 mg; 2.2 mmol). A solution of 3-mercaptothiophene-2-carboxylic acid (300 mg; 1.88 mmol) in dry DMF (5 ml) was added slowly. The mixture was kept at 70 °C for 1 hour before cooling to room temperature overnight. Water was added and the aqueous phase was acidified with 4M HCl before extraction with EtOAc (2 times 10 mL). The combined organic phases were washed thoroughly with water and dried over Na2SO4. After filtration the crude yellow compound was obtained by evaporation of the solvent. Purification was done by silica gel column chromatography (5 % MeOH in DCM, R/= 0.42 in 10 % MeOH in DCM) to give 572 mg (86 %) of a yellow foam.
[0813] LCMS m/z 354 [M+H]+, 371 [M+NH4]+, fR = 7.83 min, purity (UV/MS): 97/30. 1H NMR (CD3OD, 400 MHz) δ 8.59 (s, 1H, ArH), 7.98 - 7.66 (m, 2H, ArH), 7.20 - 6.95 (m, 2H, ArH), 4.33 (q, 2H, J = 6.8 Hz, OCH2), 1.34 (t, 3H, J = 6.8 Hz, Me). 13C NMR (CD3OD, 100 MHz) δ 165.1, 164.4, 162.8, 146.3, 143.6, 136.3, 135.0, 133.8, 132.8, 130.1, 128.8, 126.9, 62.5, 14.1.
Example 735: 3-(4-Carboxy-2-nitrophenylsulfanyl)thiophene-2-carboxylic acid
Figure imgf000317_0001
3-(4-Ethoxycarboxy-2-nitro-phenylsulfanyl)thiophene-2-carboxylic acid (565 mg; 1.6 mmol) was dissolved in 15 mL THF and 10 mL IM aqueous LiOH was added. The solution was heated to 70 °C for 1 hour before cooling to room temperature. Tie (10 % MeOH in DCM) shows no more starting material and only a large orange spot on the baseline. THF was removed by evaporation and after acidification of the aqueous solution using 4M HCl the title compound precipitates as a yellow solid. 435 mg was isolated by filtration (84 %).
[0814] 1H NMR (CD3OD, 400 MHz) δ 8.73 (d, 1H, J = 2.0 Hz, ArH), 8.02
(dd, 1H, J= 2.0, 8.4 Hz, ArH), 7.85 (d, 1H5 J= 5.0 Hz, thiopheneH), 7.17 (d, 1H, J= 5.0 Hz, thiopheneH), 7.13 (d, 1H, J= 8.4 Hz, ArH).
Example 736: 3-(2-Amino-4-carboxyphenylsulfanyl)thiophene-2-carboxylic acid
Figure imgf000317_0002
[0815] 3-(4-Carboxy-2-nitrophenylsulfanyl)thiophene-2-carboxylic acid (435 mg; 1.34 mmol) was dissolved in 15 mL EtOH. A solution Of K2CO3 (926 mg; 6.7 mmol) and Na2S2O4 (1.37 g; 6.7 mmol) in 10 mL water was added slowly. 5 minutes after ended addition the color changed from orange to light yellow indicating that the nitro compound was reduced to the desired amino compound. After another 15 minutes stirring EtOH was removed by evaporation. The resulting aqueous phase was acidified using 4M HCl before extraction with EtOAc (4 times 20 mL). The combined organic phases were washed with water, dried over Na2SO4, filtered and the solvent removed by evaporation to give 340 mg (86 %) of the title compound. The product was used without further purification.
[0816] 1H NMR (CD3OD, 400 MHz) δ 7.56 (d, 1H, J = 2 Hz, ArH), 7.50 -
7.48 (m, 2H, J= 5.6, 8.0 Hz, ArH, thiopheneH), 7.36 (dd, 1H, J= 2.0, 8.0 Hz, ArH), 6.33 (d, 1H, J= 5.6 Hz, thiopheneH).
Example 737: 10-Oxo-9,10-dihvdro-L4-dithia-9-azabenz[/]azulene-7-carboxylic acid
Figure imgf000318_0001
3-(2-Amino-4-carboxyphenylsulfanyl)thiophene-2-carboxylic acid (340 mg; 1.15 mmol) was dissolved in 5 mL THF. 1,1-Carbonyldiimidazole (630 mg; 3.5 mmol) was added portionwise and stirring was continued at room temperature overnight. Water and 4M HCl was added and the resulting white precipitate isolated by filtration (121 mg; 38 %).
[0817] 1H NMR (OMSO-d6, 400 MHz) δ 10.6 (s, 1H, NH), 7.93 (d, 1H, J =
5.6 Hz, thiopheneH), 7.81 (d, 1H, J = 2.0 Hz, ArH), 7.67 (dd, 1H, J = 2.0, 8.0 Hz, ArH), 7.56 (d, 1H, J= 8.0 Hz, ArH), 7.11 (d, 1H, J= 5.6 Hz, thiopheneH).
Example 738: 10-Chloro-K4-dithia-9-azabenzr/1azulene-7-carboxylic acid butylamide
Figure imgf000318_0002
[0818] 10-Oxo-9,10-dihydro-l ,4-dithia-9-azabenz[/]azulene-7-carboxylic acid (115 mg; 0.42 mmol) was dissolved in 5 mL dry toluene. DMF (50 μL) and thionyl chloride (5 mL) was added and the mixture stirred at 70 °C overnight. After cooling the solvent were removed by evaporation. Co-evaporation with three times toluene gave the crude dichloride as a light yellow solid that was used immediately without further purification. [0819] A solution of the crude dichloride in 5 mL dry DCM was added to a solution of π-butylamine (100 μL; 1 mmol) in 5 mL DCM at O°C. The temperature was allowed to rise to room temperature over 2 hours before addition of aqueous NH4CI (sat, 10 mL). The aqueous phase was extracted with EtOAc (3 times 5 mL) and the combined organic phases dried over Na2SO4 before removal of the solvent in vacuo. The title compound was purified by silica gel column chromatography (10 - 30% EtOAc in heptane, R/= 0.34 in 30% EtO Ac/heptane) to give 57 mg (41 %) of a yellow solid.
[0820] LCMS m/z 351 [M+H]+, tκ = 3.33 min, purity (UV/MS): 99/95.
Example 739: 10-(4-Chlorophenvπ-1,4-dithia-9-azabenzr/1azulene-7-carboxylic acid butylamide
Figure imgf000319_0001
[0821] Bis(triphenylphosphine)palladium(II) chloride (5.7 mg; 0.008 mmol) and 10-chloro-1,4-dithia-9-azabenz[/]azulene-7-carboxylic acid butylamide (27 mg; 0.077 mmol) was mixed in 2 mL THF. 4-Chlorophenylzinc iodide (0.5M in THF, 0.4 mL; 0.2 mmol) was added dropwise and the mixture stirred overnight. The reaction mixture turned green upon reaction overnight. Aqueous NH4Cl (sat) was added and extraction performed with EtOAc. The combined organic phases were dried over Na2SO4, filtered and the solvent removed by evaporation. The crude product was purified by silica gel column chromatography (5-15 % EtOAc in toluene, R/ = 0.67 in 30 % EtOAc in toluene) giving a green solid that was pure on tic but not according to LCMS. Therefore purification was attempted by preparative LCMS to give 1.5 mg of the desired compound.
[0822] LCMS m/z 427 [M+H]+, 429 [M+H+2]+, /R = 5.50 min, purity (UV/MS): 100/90. 1H NMR (CDCl3, 400 MHz) δ 7.91 - 7.87 (m, 2H, ArH), 7.63 (d, I H, J = 2.0 Hz, ArH), 7.57 (dd, 1H, J = 2.0, 8.0 Hz, ArH), 7.54 (d, 1H, J - 5.6 Hz, thiopheneH), 7.46 - 7.42 (m, 2H, ArH), 7.40 (d, 1H, J = 8.0 Hz, ArH), 7.00 (d, 1H, J = 5.6 Hz, thiopheneH), 6.06 (br s, 1H, NH), 3.49 - 3.43 (m, 2H, NCH2), 1.64 - 1.54 (m, 2H, CH2), 1.47 - 1.36 (m, 2H, CH2), 0.96 (t, 3H, J = 7.2 Hz, CH3).
Example 740: lO-Phenyl-5-thia- 1,4,1 l-triazadibenzorfl,fiπcycloheptene-2,3-dicarboxylic acid bis-butylamide
Figure imgf000320_0001
[0823] 2,2,6,6-Tetramethylpiperidine (675 μL; 4 mmol) was dissolved in 20 mL dry THF and the solution cooled to -30°C before addition of «-butyl lithium (1.1 M in hexane; 3,64 mL; 4 mmol). The mixture was stirred at -30°C for 1A hour before raising the temperature to 0°C for 1 hour. The mixture was cooled to -78°C and a solution of 10- phenyl-5-thia- 1,4,1 l-triazadibenzo[α,cf]cycloheptene (290 mg; 1 mmol) in VA mL THF was added. Stirring was continued for 10 min. before addition of n-butyl isocyanate (340 μL; 3 mmol). The mixture was stirred at -78°C for 2 hours and then quenched by addition of a mixture of 4M HCl (200 μL), water (5 mL) and EtOH (5 mL) and the temperature raised to room temperature. The mixture was neutralized by addition of NaHCO3 (sat) and extraction performed with DCM. The title compound was purified first by silica gel column chromatography (1 :1 EtOAc(heptane, Ry= 0.28) followed by recrystallisation of the combined fractions from EtOAc to give yellow crystals (25 mg). LCMS m/z 488 [M+H]+. 1H NMR (CDCl3, 400 MHz) δ 7.89-7.84 (m, 2H), 7.66-7.44 (m, 5H), 7.41 (dt, 1H, J= 1.2, 7.5 Hz), 7.31 (dd, 1H, J= 1.6, 7.6 Hz), 7.13 (br t, 1H, J- 5.4 Hz), 6.94 (br t, 1H, J= 5.4 Hz), 3.51-3.44 (m, 4H), 1.68-1.58 (m, 4H), 1.49-1.37 (m, 4H), 0.95 (dt, 6H, J = 1.2, 7.2 Hz). HPLC /R = 4.84 min. Example 741 : Receptor Selection and Amplification Technology Assay
[0824] The functional receptor assay, Receptor Selection and Amplification Technology (R-SAT®), was used to investigate the pharmacological properties of known and novel CBl compounds. R-SAT is disclosed in U.S. Patent Nos. 5,707,798, 5,912,132, and 5,955,281, all of which are hereby incorporated herein by reference in their entirety, including any drawings.
[0825] Briefly, N1H3T3 cells were grown in 96 well tissue culture plates to 70-80% confluence. Cells were transfected for 16-20 h with plasmid DNAs using Polyfect (Qiagen Inc.) using the manufacturer's protocols. R-SATs were generally performed with 10 ng/well of receptor, 10 ng/well of Gqi5 (Conklin et al, Nature 1993 363:274-6) and 20 ng/well of β-galactosidase plasmid DNA. All receptor constructs used were in the pSI-derived mammalian expression vector (Promega Inc). The CB 1 receptor gene was amplified by PCR from genomic DNA using oligodeoxynucleotide primers based on the published sequence (GenBank Accession # X54937) SEQ ID NO: 1 encodes a CBl receptor truncated after amino acid 417 (SEQ ID NO: 2). The CB2 gene was cloned by performing a PCR reaction on mRNA from spleen. The PCR product containing the entire coding sequence of the CB2 gene was cloned into an expression vector such that the CB2 gene was operably linked to an SV40 promoter. The sequence of the CB2 gene (GenBank Accession #NM_001841) is provided as. SEQ ID NO: 3 and the sequence of the encoded CB2 polypeptide is provided as SEQ ID NO: 4. For large- scale transfections, cells were transfected for 16-20 h, then trypsinized and frozen in DMSO. Frozen cells were later thawed, plated at -10,000 cells per well of a 96 half-area well plate that contained drug. With both methods, cells were then grown in a humidified atmosphere with 5% ambient CO2 for five days. Media was then removed from the plates and marker gene activity was measured by the addition of the β-galactosidase substrate o- nitrophenyl β-D-galactopyranoside (ONPG) in PBS with 0.5% NP-40. The resulting colorimetric reaction was measured using a spectrophotometric plate reader (Titertek Inc.) at 420 nm. All data was analyzed using the XLFit (IDBSm) computer program. PIC50 represents the negative logarithm of the concentration of ligand that caused 50% inhibition of the constitutive receptor response. Percent inhibition was calculated as the difference between the absorbance measurements in the absence of added ligand compared with that in the presence of saturating concentrations of ligand normalized to the absorbance difference for the reference ligand (SR 141716), which was assigned a value of 100%.
[0826] These experiments provide a molecular profile, or fingerprint, for each of these agents at the human CBl receptor. As can be seen in Table 1, the compounds are inverse agonists at the CBl receptor. Additional data is presented in Appendix A.
TABLE 1
Figure imgf000322_0001
% Inhibition is relative to the ligand SR 141716.
[0827] It will be appreciated that the foregoing assay may be used to identify compounds which are agonists, inverse agonists or antagonists of a cannabinoid receptor. In some embodiments, the cannabinoid receptor used in the assay may be a CBl receptor. In other embodiments, the cannabinoid receptor used in the assay may consist essentially of SEQ ID NO: 2. In further embodiments, the cannabinoid receptor used in the assay may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length CBl receptor or a truncated CB l receptor of SEQ ID NO: 2. [0828] Using the following methods, the compounds disclosed herein were evaluated for their ability to bind to a CBl receptor. The compounds were tested using a receptor binding assay and then determining of any change in GTPgamma S binding of transfected cells.
Example 742: CBl Receptor Binding Assays
[0829] To show that CBl antagonists can block binding of selective CBl ligands to native CB 1 receptors the ability of compounds of Formula I to block binding of the highly CB 1 -selective ligand SR 141716 was examined in rat brain membrane preparations as follows.
[0830] Membrane preparations - Whole brains were harvested from Harlan Sprague Dawley rats and placed in 50 ml Falcon Tubes on ice. The volume was made up to 30 ml with ice-cold membrane buffer (20 mM HEPES, 6 mM MgCl2, 1 mM EDTA, pH 7.2). The Brains were homogenized with a Brinkmann Polytron PT3000 at 20,000 rpm for 40 s. The homogenate was spun at 1,000 x g for 10 min at 4°C to remove nuclei and cellular debris. The supernatant was collected and re-centrifuged as previously before membranes were precipitated at 45,000 x g for 20 min at 4°C, resuspended in membrane buffer to a final concentration of 1 mg/ml, snap frozen as aliquots in liquid nitrogen and stored at -8O°C.
[0831] Membrane Binding - 10 μg of membranes were incubated in binding buffer (Ix DMEM with 0.1%BSA) in the presence of 3 nM radioligand ([3H]SR 141716A, Amersham Biosciences, Piscataway, NJ) and varying concentrations of ligands (total volume 100 μl in a 96 well plate). Cells were filtered onto a 96 well GF/B filterplate (Packard Bioscience, Shelton, CT) and washed with 300 ml wash buffer (25mM HEPES, 1 mM CaCl2, 5 mM MgCl2, 0.25M NaCL) using a Filtermate 196 Harvester (Packard Instruments, Downers Grove, IL). The filter plates were dried under a heat lamp before addition of 50 μl of scintillation fluid to each well (Microscint 20, Packard, Shelton, CT). Plates were counted on a Topcount NXT (Packard, Shelton, CT). [0832] Data Analysis - Graphs were plotted and KD values were determined by nonlinear regression analysis using Prism software (GraphPad version 4.0, San Diego, CA, USA).
Table 2. Binding of CBl antagonists to native CBl receptors
[0833] These results demonstrate that the compounds described herein bind with high affinity to native CBl receptors. Additional results for compounds described herein are shown in Appendix B.
Figure imgf000324_0001
[0834] 10-(4-Chlorophenyl)-l ,4-dithia-9-azabenz[/]azulene-7-carboxylic acid butylamide has a pKi 9.0.
[0835] It will be appreciated that the CBl receptor binding assay of Example 624 may be used to identify compounds which are agonists, inverse agonists or antogonists of a cannabinoid receptor. In some embodiments, the cannabinoid receptor used in the assay may be a CB 1 receptor. In other embodiments, the cannabinoid receptor used in the assay may consist essentially of SEQ ID NO: 2. In further embodiments, the cannabinoid receptor used in the assay may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length CBl receptor or a truncated CBl receptor of SEQ ID NO: 2. Example 743: Sequences for truncated CBl receptors
[0836] Below are sequences encoding a truncated CBl receptor.
SEQ ID NO:! :
ATGAAGTCGATCCTAGATGGCCTTGCAGATACCACCTTCCGCACCATCACCAC
TGACCTCCTGTACGTGGGCTCAAATGACATTCAGTACGAAGACATCAAAGGT
GACATGGCATCCAAATTAGGGTACTTCCCACAGAAATTCCCTTTAACTTCCTT
TAGGGGAAGTCCCTTCCAAGAGAAGATGACTGCGGGAGACAACCCCCAGCTA
GTCCCAGCAGACCAGGTGAACATTACAGAATTTTACAACAAGTCTCTCTCGTC
CTTCAAGGAGAATGAGGAGAACATCCAGTGTGGGGAGAACTTCATGGACATA
GAGTGTTTCATGGTCCTGAACCCCAGCCAGCAGCTGGCCATTGCAGTCCTGTC
CCTCACGCTGGGCACCTTCACGGTCCTGGAGAACCTCCTGGTGCTGTGCGTCA
TCCTCCACTCCCGCAGCCTCCGCTGCAGGCCTTCCTACCACTTCATCGGCAGC
CTGGCGGTGGCAGACCTCCTGGGGAGTGTCATTTTTGTCTACAGCTTCATTGA
CTTCCACGTGTTCCACCGCAAAGATAGCCGCAACGTGTTTCTGTTCAAACTGG
GTGGGGTCACGGCCTCCTTCACTGCCTCCGTGGGCAGCCTGTTCCTCACAGCC
ATCGACAGGTACATATCCATTCACAGGCCCCTGGCCTATAAGAGGATTGTCA
CCAGGCCCAAGGCCGTGGTGGCGTTTTGCCTGATGTGGACCATAGCCATTGT
GATCGCCGTGCTGCCTCTCCTGGGCTGGAACTGCGAGAAACTGCAATCTGTTT
GCTCAGACATTTTCCCACACATTGATGAAACCTACCTGATGTTCTGGATCGGG
GTCACCAGCGTACTGCTTCTGTTCATCGTGTATGCGTACATGTATATTCTCTG
GAAGGCTCACAGCCACGCCGTCCGCATGATTCAGCGTGGCACCCAGAAGAGC
ATCATCATCCACACGTCTGAGGATGGGAAGGTACAGGTGACCCGGCCAGACC
AAGCCCGCATGGACATTAGGTTAGCCAAGACCCTGGTCCTGATCCTGGTGGT
GTTGATCATCTGCTGGGGCCCTCTGCTTGCAATCATGGTGTATGATGTCTTTG
GGAAGATGAACAAGCTCATTAAGACGGTGTTTGCATTCTGCAGTATGCTCTG
CCTGCTGAACTCCACCGTGAACCCCATCATCTATGCTCTGAGGAGTAAGGAC
CTGCGACACGCTTTCCGGAGCATGTTTCCCTCTTGTGAAGGCTAG SEQ ID NO:2
MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTSFRGS PFQEKMTAGDNPQLVPADQVNITEFYNKSLSSFKENEENIQCGENFMDIECFMVL NPSQQLAIAVLSLTLGTFTVLENLLVLCVILHSRSLRCRPSYHFIGSLA VADLLGSVI FVYSFIDFHVFHRKDSRNVFLFKLGGVTASFTASVGSLFLTAIDRYIS1HRPLAYKRI VTRPKA VVAFCLMWTIAIVIAVLPLLGWNCEKLQSVCSDIFPHIDETYLMFWIGVT SVLLLFIVYAYMYILWKAHSHAVRMIQRGTQKSII1HTSEDGKVQVTRPDQARMD IRLAKTLVLILVVLIICWGPLLAIMVYD VFGKMNKLIKTVFAFCSMLCLLNSTVNPI IYALRSKDLRHAFRSMFPSCEG*
Example 744: CBl Receptor Human Binding Assays
[0837] To show that CBl antagonists can block binding of selective CBl ligands to native CBl receptors the ability of compounds of Formula I to block binding of the highly CBl -selective ligand SR 141716 was examined in human membranes as follows.
[0838] Membrane preparation - HEK-293T cells were cultured according to ATCC (Manassas, VA) guidelines and transfected with human CBRl cDNA (Genbank X54937) using Polyfect (Qiagen, Valencia, CA) or Fugene (Roche, Nutley, N.J.) according to manufacturer's instructions. 48 h after transfection cells were harvested in ice cold membrane buffer (20 mM HEPES, 6 mM MgCl2, 1 mM EDTA, pH 7.2) using a cell scraper. Cells were transferred to a nitrogen cavitation chamber and a pressure of 900 bar was applied for 30 min. The pressure was released and the cell debris was collected and centrifuged at 1000 g at 4°C for 10 min. The supernatant was collected and the spin was repeated until the supernatant was free of precipitate. Membranes were then pelleted by centrifugation at 12.000 g at 4°C for 20 min. Membranes were resuspended in an appropriate amount of membrane buffer. The membrane concentration was determined using a BioRad (Hercules, CA) protein assay dye reagent according to manufacturer's instructions. Membranes were diluted to 1 mg/ml and aliquots snap-frozen in liquid nitrogen and store at -8O°C. [0839] Binding assay - 10 μg of membranes were incubated in binding buffer (50 mM Tris, 0.5 mM EDTA, 0.1% BSA, pH 7.4) in the presence of 3 nM radioligand ([3H]SR 141716A, Amersham Biosciences, Piscataway, NJ) and varying concentrations of ligands (total volume 100 μl in a 96 well plate). Membranes were filtered onto a 96 well GF/B filterplate (Packard Bioscience, Shelton, CT) and washed with 500 ml wash buffer (25mM HEPES, 1 mM CaCl2, 5 mM MgCl2, 0.25M NaCl) using a Filtermate 196 Harvester (Packard Instruments, Downers Grove, IL). The filter plates were dried under a heat lamp before addition of 50 μl of scintillation fluid to each well (Microscint 20, Packard, Shelton, CT). Plates were counted on a Topcount NXT (Packard, Shelton, CT).
[0840] The results for compounds described herein are shown in Appendix B, and demonstrate that the compounds described herein bind with high affinity to native CBl receptors. Rimibonant has a pKi of 8.0, and an inhibition of 100 in humans, and a pKi of. 8.7and an inhibition of 97% in rats.
Example 745: Tail Flick Study
[0841] Male, NSA mice (15-20 g) served as subjects for these studies. Baseline nociceptive thresholds were assessed using the warm water tail flick test. Briefly, the distal 1/3 to '/_ of the tail was immersed in a 52°C water bath and the time (to the nearest 0.1 sec) until the mouse removed its tail (i.e., "flicks") from the water was recorded (i.e., tail flick latency). Mice were then injected ip with either vehicle or with various doses of the CBl agonist CP 55,940 and tail flick latencies were recorded for a period of up to 3 hr. A maximum latency of 10 sec was employed in order to prevent tissue damage. In order to determine if a CBl inverse agonists could block the antinociceptive actions of CP 55,940, mice were pretreated with either vehicle or with a test compound 30 min prior to CP55,940. CP55,940 (1 mg/kg) was administered subcutaneously, and Compound I was administered intraperitoneal Iy. Tail flick latencies were then obtained at various time points for a period of up to 2 hr. The vehicle for both compounds was 1 :1 : 18 cremphor:ethanol:saline.
[0842] Figure 5 A is a line graph showing the attenuation of CBl agonist- mediated effects after administration of CP 55,940 (0.3 and 1.0 mg/kg). Figure 5B is a line graph showing the attenuation of CB 1 agonist-mediated effects after administration of Compound I alone or in combination with CP55,940. As indicated by Figures 5A and 5B, Compound I attenuates the antinociceptive actions of CP55,940.
Example 746: Hypothermia Study
[0843] Male, NSA mice (15-20 g) served as subjects for these studies. In order to determine if the test compound could block hypothermia elicited by CP 55,940 (1 mg/kg, ip), mice were pretreated with either vehicle or with test compound 30 min prior to CP55,940. Core body temperatures were then obtained at various time points following CP 55,940 administration. Core body temperature (to the nearest 0.1°C) was obtained by rectal probe.
[0844] Figure 6 is a bar graph showing the body temperature of the mice at several points in time after the mice had been dosed with various doses of CP 55,950 or CP55,950 and Compound I. As shown by Figure 6, Compound I attenuates CP 55,940- induced hypothermia. In addition, the attenuation of the CP55,940 induced hypothermia was dose-dependent. A number of compounds of Formulae (I) and (II) were tested and a number of compounds attenuates CP 55,940-induced hypothermia. Measured values ranged from -16°C to 94°C (Compound dosage of 3 mg/kg).. Rimonabant has an ID50 0.2.
Example 747: Acute Feeding Study
[0845] Male, Sprague-Dawley rats (90-120 g) served as subjects for these studies. Rats were fasted for a period of 16 hrs (water was always available). After the fasting period, test compounds were administered either intraperitoneally (ip) or orally (po). Immediately following compound administration, the rats were returned to their home cage. Following 30 min after compound administration, the rats were removed from their home cages and placed individually into clean cages with a pre-measured amount of food. Food weights were obtained (to the nearest 0.1 g) at various time points. Food consumption was monitored for a period of up to 2 hrs (i.e., 2.5 hr after test compound administration). [0846] Figure 2 is a bar graph showing the food intake in fasted rats 1 and 2 hours after being administered either 1, 3, or 10 mg/kg doses of Compound I. * Indicates p<0.05 as compared to the vehicle-treated controls. ** Indicates p<0.01 as compared to the vehicle-treated controls. Figure 3 is bar graph showing the time course food intake in fasted rats after being administered 1 mg/kg of Compound I. * Indicates p<0.05 as compared to the vehicle-treated controls. ** Indicates pO.Ol as compared to the vehicle- treated controls. Figure 4 is a bar graph showing cumulative food consumption at several points in time after the rats had been dosed with 10 mg/kg of Compound I. * Indicates p<0.05 as compared to the vehicle-treated controls. As shown by Figures 2-4, Compound I suppresses the cumulative food intake in fasted rats. Figure 2 also shows that suppression of food take is dose-dependent.
Example 748: Chronic Feeding Study
[0847] Male, obese Zucker rats (400-500 g) served as subjects for these studies. Rats were housed individually and had access to food and water ad libitum. Rats were allowed to acclimate to the vivarium for a period of 3 days, during which body weight and consumption of food and water was monitored. Rats were weighed daily at 1500 hr and then injected with either vehicle or with various doses of the test compound. Daily food and water intakes were also monitored. Food and water bottles were weighed at the time body weights were recorded (i.e., 1350 hr). Vehicle or compound was administered daily for a period of up to 15 days.
[0848] Figure 9A in a line graph showing the effects of Compound II (1 and 3 mg/kg/day) on body weight Figure 9B is a line graph showing the effects of Compound II (1 and 3 mg/kg/day) on food intake and water intake. Figure 9C line graph showing the effects of Compound II (10 mg/kg/day) on body weight. Figure 9D is a line graph showing the effects of Compound II (10 mg/kg/day) on food intake and water intake. As shown by Figures 9A-9D, Compound II attenuated the food and water intake of the rats. Moreover, the attenuation of the food and water intake was dose-dependent. TABLE 3 - FEEDING DATA Compound F Feeeeddiinngg Comopound Feeding ID50 ID50
Figure imgf000330_0001
[0849] Rimonabant has an ID50 of 4.5 Example 749: Novel Object Recognition Study
[0850] Subjects: Subjects were male, C57 BK76 mice purchased from Harlan Laboratories, weighing 15-2Og upon arrival. Animals were housed 8 per cage with food and water available ad libidum. Animals were housed on a 12 hr light cycle (lights on 6 am) for 4-7 days prior to behavioral testing.
[0851] Equipment: Novel object recognition (NOR) was conducted in a novel environment consisting of a white plastic tub measuring 45.7 x 33.7 x 19 cm. Prior to each trial the bottom of the tub was covered with a piece of plastic lined bench top paper. There were two sets of identical objects chosen so that when given a opportunity to explore, mice would evenly divide exploration time between the objects. "A" objects were yellow, ceramic, 12-sided ramekins measuring 4 cm high x 7 cm diameter. "B" objects were 8 X 8 x 4 cm stainless steel, 4-sided ramekins.
[0852] Procedure: At the beginning of each test day, animals were placed in groups of 6 into clean cages. Testing was conducted in three phases: acclimation, sample and test. For acclimation, each group of six mice was- placed collectively into the NOR chamber and allowed to explore freely for 30 min. After acclimation animals were injected (dose and pretreatment time varied by test drug) and placed back into the cages to wait the pre-treatment interval. After the pre-treatment time elapsed, each mouse was placed, one at a time into the NOR chamber, into which two identical objects had been placed ("A" or "B" objects described above). Objects were placed on diagonal corners of the long axis of the arena approximately 5 cm from the walls, while subjects were placed into one of the neutral corners (alternating across subjects). Each mouse was allowed to explore the chamber and the objects for 3 min., and the time spent exploring at each position was recorded. Directly sniffing or touching the object was recorded as exploration. After 3 min., each mouse was removed from the arena and placed back into its cage. The test phase was conducted 1 or 2 hours after the sample phase. During test, one familiar object (seen during sample) and one novel object were placed into the chamber in the same positions used during the sample phase, and each mouse was allowed 3 min to explore. The test sessions were recorded on video and scored by an observer blind to each subject's treatment condition. Any time spent directly sniffing or touching an object was counted as exploration. The object serving as the novel object and the position where the novel object was placed were counterbalanced across subjects. Prior to each trial (acclimation, sample and test), all equipment was wiped with a Clorox wipe and bench paper (cut to fit) was placed in the bottom of the chamber. The procedure is shown below in Scheme 24.
[0853] Measures: In addition to time spent exploring each object (TN = time spent exploring novel object, Tp = time spent exploring familiar object), two measures were determined for each subject: exploration ratio (% of time spent exploring at novel object) ER - TN* 100/(TN + Tp) and discrimination index (preference for novel) Dl = (TN- TFV(TN + TF). Scheme 24
Group Acclimation - 30 min. (6 mice/ Group)
-treatm en t tim e
Figure imgf000332_0001
Sample
Figure imgf000332_0002
Test Phase - 3 min.
[0854] Figures 1OA and 1OC are bar graphs showing the exploration ratio at 1 and 2 hours after the mice had been dosed with the vehicle, CP 55,940 (0.3 mg/kg, ip), or SR 141716A (1 mg/kg, ip). Figures 1OB and 1OD are bar graphs showing the discrimination index at 1 and 2 hours after the mice had been dosed with the vehicle, CP 55,940 (0.3 mg/kg, ip), or SR 141716 A (1 mg/kg, ip). Figure HA is a bar graph showing the exploration ratio 2 hours after the mice had been dosed with Compound II (3 mg/kg, ip). Figure 1 IB is a bar graph showing the discrimination index 2 hours after the mice had been dosed with Compound II (3 mg/kg, ip).
[0855] As shown by Figures 10A-D and Figures 1 IA-B, mice treated with SR 141716A and Compound II showed a preference for the novel object (indicating the mice recognized the familiar object) up to two hours after being dosed with the test compound. Mice treated with the vehicle or CP 55,940 showed a preference for the novel object after 1 hour of being dosed with the test compound but then returned back to baseline exploration rates after 2 hours.
Example 750: Radial Arm Maze Study
[0856] Subjects: Subjects for the radial arm maze experiments were male, Sprague-Dawley rats purchased Charles Rivers Laboratories, weighing 225-250 g upon arrival, housed two per cage. All subjects had free access to food and water available for the duration of the study. Animals were housed on a 12 hr light cycle (lights on 7 am), and were acclimated to vivarium conditions for a minimum of two days prior to behavioral training. All experiments were conducted in accordance with N1H Guidelines or the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee at ACADIA Pharmaceuticals, Inc.
[0857] Radial Arm Maze Procedure: Radial arm maze (RAM) testing was conducted in a watertight maze (61.0 cm high) made of black ABS plastic, consisting of a central, round chamber (57.1 cm in diameter) with 8 (38.1 cm X 16.6 cm) equally spaced arms radiating from the center. The testing room had salient environmental cues that remained constant throughout testing, including a door, a table, a shelving unit, a solid black panel one wall, a black and white striped panel on the opposite wall, and the experimenter seated behind the start arm. Prior to each session, escape platforms were placed in the ends of 6 arms. Escape platforms were made of black ABS plastic (10.1 cm X 15.2 cm) covered with Velcro fitted 16 cm from the top of the maze. Each day the maze was filled with water (25°C) until the platforms were hidden with 1 cm of water covering the platforms. Additionally, non-toxic black paint was dissolved in the water to help visually obscure the platforms and ensure animals could not depend on visual cues to solve the task. For each subject, reference arms (arms without platforms) remained constant across training and testing. During a trial, a subject was released from the start arm, facing the center, and allowed 3 min to locate a platform. If the maximum time elapsed, the animal was guided to the nearest platform. Once a platform was found, animals remained on it for 15 sec before being removed from the maze and placed in a warmed holding tub for 30 sec. During the interval, the chosen platform was removed from the maze. The animal was then returned to the maze for another trial. This continued until all platforms were located. Training was conducted 5 days per week for 10 days. After training, animals began the test phase. During testing, animals received multiple test sessions. In order to ensure adequate time for drug clearance between treatments, subjects received only one test compound and one vehicle treatment per week. In all other respects, test sessions were conducted using the same method described for training.
[0858] Figure 12 is a bar graph showing percentage of novel recognition of a familiar object 2 hours after the mice had been dosed with 1, 3, or 10 mg/kg of Compound II. Figure 13 is a line graph showing the working memory errors of the mice after being dosed with the vehicle, tacrine (0.3 mg/kg), or Compound II (3 mg/kg).
[0859] As shown by Figures 12 and 13, mice treated with Compound II showed a preference for the novel object (indicating the mice recognized the familiar object) up to two hours after being dosed with the test compound.
Example 751 : Rotation Study
[0860] Subjects: Subjects were male, Sprague-Dawley rats purchased from Harlan Laboratories, weighing 250-275 g upon arrival. Prior to surgery animals were housed two per cage. All subjects had free access to food and water available for the duration of the study. Animals were housed on a 12 hr light cycle (lights on 6 am), and were acclimated to vivarium conditions for a minimum of one week prior to surgery. All experiments were conducted in accordance with N1H Guidelines for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee at ACADIA Pharmaceuticals, Inc.
[0861] Surgery. One week after arrival, subjects underwent stereotaxic surgery to unilaterally lesion dopamine terminals within the substantia nigra, a common model of Parkinson's disease. In order to protect noradrenergixc terminals, subjects were administered desipramine (20 mg/kg ip) approximately 20 min prior to surgery. Surgery was conducted under ketamine (80 mg/kg ip) and xylazine (12 mg/kg ip) anesthesia. Animals were placed in the stereotaxic instrument with the incisor bar at -3.2 mm and a hole was drilled in the skull over the substantia nigra according to the atlas of Paxinos and Watson (1997): A/P -5.2 mm, M/L - 2.1 mm. A computer-controlled microsyringe was lowered to -8.2 mm from bregma. 8 μg of 6-hydroxy-dopamine in 4 μl of saline with 0.2% ascorbic acid was infused over 5 min, and 1 min was allowed for diffusion before the syringe was removed and the incision closed. Animals were given a minimum of 15 days after surgery before any behavioral assessment.
[0862] Rotational Behavior. All animals were assessed for rotational behavior in rotometers purchased from San Diego Instruments, Inc. For each behavioral session, subjects were placed in the rotometers and allowed thirty minutes for acclimation. After 30 min., subjects were injected with either the dopamine agonist apomorphine (0.05, 0.16 or 0.5 mg/kg ip in saline with 0.2% ascorbic acid) or the cannabinoid 1 receptor inverse agonist Compound II, N-(butyl)-l l-(4-chlorophenyl)- dibenzo[b,f,][1,4]thiazepine-8-carboxamide, (3 mg/kg in sesame oil). When subjects received combinations of the two treatments, Compound II was injected 30 minutes prior to apomorphine. After treatment, rotations were measured for 60 min. Subjects were then removed from the rotometers and returned to their home cages. All animals received all three doses of apomorphine, and the combination of Compound II with both 0.05 mg/kg and 0.16 mg/kg apomorphine. A minimum of 2 days separated test days.
[0863] Figure 14 is a line showing the contralateral rotations over time of the mice after being dosed with apomorphine (0.05, 0.16, and 0.5 mg/kg). Figure 15 is a line showing the contralateral rotations over time of the mice after being dosed with apomorphine (0.05 mg/kg), Compound II (3.0 mg/kg), or apomorphine (0.05 mg/kg) and Compound II (3.0 mg/kg). Figure 16 is a line showing the contralateral rotations over time of the mice after being dosed with apomorphine (0.16 mg/kg), Compound II (3.0 mg/kg), or apomorphine (0.16 mg/kg) and Compound II (3.0 mg/kg).
[0864] As shown by Figure 14, apomorphine dose-dependently elicits contralateral rotations in rats with unilateral 6-OH dopamine lesions. Figures 15 and 16 show that Compound II augments dopaminergic functions. Example 752: Weight Gain Study
[0865] Animals and drug administration: Adult male Speague-Dawleys rats (Harlan, Indianapolis, IN) are used in all experiments described herein. Prior to any drug treatment, all rats are handled for 5 days to minimize non-specific stress. Rats are randomly assigned to the various experimental groups. Animals are individually housed under a 12 hr light:dark cycle (light on 0700) and allowed ad libitum access to food and water. Rats are injected intraperitoneally (IP) either with a vehicle (oil) and a drug that causes weight gain (e.g., olanazapine), or a CB-I compound of Formula (I) or (II) and a drug that causes weight gain.
[0866] Experimental procedures: Rats are injected for 14 consecutive days and body weights are recorded before (day 0) and daily during drug treatment. To determine average food intake over a 24 hr period, control-vehicle and experimental rats are given pre-measured food pellets (350 mg/rat) on day 0 and subsequent consumption is recorded on the next day. A similar procedure is instituted to assess average water intake over a 24 hr period: both groups are given pre-measured tap water (400 mL/rat) on day 0 and subsequent consumption is recorded on the next day.
[0867] Data analysis: Statistical comparisons in body weight are carried out using one-way ANOVA or two-tailed / tests where appropriate.
[0868] Rats injected with the CB-I compound of Formula (I) or (II) are expected to gain less weight than those rats injected with the vehicle and the drug that causes weight gain.
Example 753: Clearance Study
[0869] The test compounds were incubated at 1 μM in the presence of liver microsomes (0.5 mg protein/mL), using a Tecan liquid handling robot (LHR). A Tris buffer (100 mM, pH 7.4 at 37°C) was used as incubation media. The test compound was mixed with microsomes and a five-minute pre-incubation period was allowed. The enzymatic reaction was initiated by addition of NADPH (2.0 mM) and samples were drawn at 0, 5, 10, and 30 minutes. The reaction was stopped by protein precipitation by dispensing samples into a deep-well plate containing acetonitrile. This plate was then centrifuged offline from the LHR. The plate was again moved to the robotic worktable and the supernatants were transferred to a second deep-well plate for analysis. A reference compound, Midazolam, was included in the analysis. A number of compounds of Formulae (I) and (II) were tested and a number of compounds had clearance 3 to 546 in liver of a human, 5 to 846 of the liver of a rat, and 12 to 852 in the liver of a mouse. Rimonabant has a clearance of 41 in human, 159 in rat, 176 in mouse.
Example 754: HERG Safety Study
[0759] The HERG assay, Huma Ether-a-go-go, was used to investigate the cardiac safety of the compounds described herein. The assay was conducted by Aviva Biosciences.
Cells: Aviva' s CHO cell line stably expressing HERG channels was used for the study. Cells were cultured in DMEM/F12 containing 10% FBS, 1% penicillin/streptomycin and 500 μg/ml G418. Before testing cells were harvested using Accumax (Innovative Cell Technologies).
[0870] Solutions: For electrophysiological recordings the following solutions were used. The External Solution (in mM): 1.8 CaCl2; 1.0 MgCl2; 4 KCl; 137 NaCl; 10 Glucose; 10 HEPES;( pH 7.4 with IM NaOH, osmolarity -310 mOsm). The Internal Solution contained (in mM): . 13O KCl, 1 MgC12, 5 EGTA, 10 HEPES, 5 ATP (pH adjusted to 7.25 with KOH; osmolarity -295 mOsm).
[0871] Electrophysiology: Whole cell recordings were performed using PX 7000A (Axon Instruments) with AVTVA's SealChip™ technology. Cells were voltage clamped at a holding potential -80 mV and HERG current was activated by a depolarizing step first to -50 mV for 300 msec, a step to +20 mV for 5 sec to activate the channels, then finally back to -50 mV for 5 sec to remove the inactivation and observe the deactivating tail current. The first step at -50 mV was used as baseline for measuring the tail current peak amplitude. ,
[0872] Compound handling and dilutions: All compounds were prepared as 10 mM DMSO stocks in glass vials. Stock solutions were mixed by vigorous vortexing and sonication for about 2 minute at room temperature. For testing, compounds were diluted in glass vials using an intermediate dilution step in pure DMSO and then further diluted to working concentrations in External Solution; dilutions were prepared no longer than 20 minutes before use.
[0873] Electrophysiology procedures: After achieving whole cell configuration, the cells were monitored for 90s to assess stability and washed with external solution for 66s. The voltage protocol described above was then applied to the cells every 12 s and throughout the whole procedure. Only cells with recording parameters above threshold (see Quality control section) and stable were allowed to enter the drug addition procedure. External solution containing 0.1% DMSO (vehicle) (or 0.3% DMSO, depending on which maximal concentration is reached in the assay) was applied to the cells to establish the baseline. After allowing the current to stabilize for a 3 to 5 minutes test compounds were applied. Compound solution was added in 4 steps and cells were kept in test solution until compound's effect reached steady state or for a maximum of 12 mins. Subsequently, the positive control (1 μM Cisapride) was added. Washout with External Solution was performed until the recovery of the current reach a steady state.
[0874] Data Analysis: Data were analyzed using DataXpress, Clampfit (both by Axon Instruments) and Origin 7(Originlab Corporation).
[0875] Quality Control: Data included in the report originated from experiments which satisfied all of the following criteria:
[0876] Recording parameters: membrane resistance -Rm > 200MΩ; access resistance (R3) < 15MΩ; tail current amplitude >150pA; rundown < 1% per minute current stability, difference between tail current peak amplitude of 8 sweeps and the average of these sweeps, which should not exceed 0.2%
[0877] Pharmacological parameters: 1 μM Cisapride blocked >95%.
[0878] A number of compounds of Formulae (I) and (II) were tested and found 13 to 97. Rimonabant has a value of 50. Example 755: Oral Bioavailability Study
[0879] The compounds disclosed herein were evaluated for their oral bioavailbility. Using ACD/Labs' logP algorithm (Advanced Chemistry Development), the partition coefficient between n-octanol and water, clogP, was deteremined for several compounds of Formula I. A number of compounds of Formulae (I) and (II) were tested had cLogP values between about 3.0 to 7.6.
Example 756: PET Imaging
[0880] A compound of Formula I which includes a label detectable by a PET scanner is administerd to a subject. Imaging commencing after administration is complete. The duration of acquisition for data should be in accordance with the manufacturer's recommendations and the data must be corrected for scatter, random events, and dead-time losses using manufacturer's software.
[0881] Additional compounds, their synthesis and methods of use are described in the following U.S. and PCT applications, which are hereby incorporated by reference in their entireties including all drawings: U.S. Application No. 11/583,141, filed October 17, 2006; U.S. Application No. 11/737,120, filed April 18, 2007; PCT Application No. PCT/US2006/040662, filed October 17, 2006; and U.S. Provisional Application No. 60/852,579, filed October 17, 2006.
[0882] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.
References:
[0883] The following references are incorporated by reference herein in their entirety: 1. Le Foil B, Goldberg SR. Cannabinoid CB l receptor antagonists as promising new medications for drug dependence. J Pharmacol Exp Ther. 2005 Mar; 312(3):875-83.
2. Boyd ST, Fremming BA. Rimonabant--a selective CBl antagonist. Ann Pharmacother. 2005 Apr; 39(4):684-90.
3. Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004; 47 Suppl 1 :345-58.
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Claims

WHAT IS CLAIMED IS:
1. A method of ameliorating or inhibiting an adverse effect associated with an antipsychotic comprising administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from the group consisiting of a compound of Formula (I) and a compound of Formula (II).
2. The method of Claim 1, wherein the antipsychotic acts on a dopamine receptor.
3. The method of Claim 2, wherein the dopamine receptor is a D2 receptor.
4. The method of Claim 1, wherein the adverse side effect is selected from one or more of the group consisting of weight gain, metabolic syndrome, an extrapyramidal side effect, akathisia, dystonia, acute dystonia, Parkinsonism, dykensia, tardive dyskinesia, neuroleptic malignant syndrome, hyperprolactinemia, and catalepsy.
5. The method of Claim 1, wherein the antipsychotic is selected from the group consisting of phenothiazine, a phenylbutylpiperdine, a debenzapine, a benzisoxidil, a salt of lithium, a butyrophenone, a substituted benzamide (sulpiride), and a raclopride.
6. The method of Claim 5, wherein the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), thioridazine (Mellaril), Fluphenazine (Prolixin®), Perpehnazine (Trilafon®), and Trifluoperazine (Stelazine®).
7. The method of Claim 5, wherein the phenylbutylpiperadine is selected from the group consisting of haloperidol (Haldol®) and pimozide (Orap®).
8. The method of Claim 5, wherein the debenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), and quetiapine (Seroquel®).
9. The method of Claim 5, wherein the benzisoxidil is selected from the group consisting of resperidone (Risperdal®), ziprasidone (Geodon®, Zeldox®)), 9- hydroxy- risperidone.
10. The method of Claim 5, wherein the salt of lithium is lithium carbonate.
1 1. The method of Claim 1 , wherein the antipsychotic is selected from the group consisting of Aripiprazole (Abilify®), Etrafon®, Droperidol (Inapsine®), Thioridazine (Mellaril®), Thiothixene (Navane®), Promethazine (Phenergan®), Metoclopramide (Reglan®), Chlorprothixene (Taractan®), Triavil®, Molindone (Moban®), Sertindole (Serlect®), Droperidol, Amisulpride (Solian®), Melperone, Paliperidone (Invega®), Tetrabenazine, Thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®) and thioxanthine (Fluphenthixol).
12. The method of Claim 1 , wherein the antipsychotic is a typical antipsychotic.
13. The method of Claim 1, wherein the antipsychotic is an atypical antipsychotic.
14. A method of preventing weight gain associated with the use of a therapeutic compound comprising administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from the group consisiting of a compound of Formula (I) and a compound of Formula (II).
15. A method of suppressing the appetite comprising administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from the group consisiting of a compound of Formula (I) and a compound of Formula (II).
16. The method of any one of Claims 14 to 15, wherein the first compound is selected from the group consisting of an antidepressant, an anticonvulsant, a mood stabilizer, and an antipsychotic.
17. The method of Claim 16, wherein the antidepressant is selected from the group consisting of Buproprion HCL (Wellbutrin®), Mitrazapine (Remeron®), Nefazadone (Serzone®), Trazadone (Desyrel®), and Venlafaxine (Effexor®).
18. The method of Claim 16, wherein the antidepressant is selected form the group consisting of a selective serotonin reuptake inhibitor (SSRI), a tricyclic antidepressant and a monoamine oxidase inhibitor,
19. The method of Claim 18, wherein the selective serotonin reuptake inhibitor is selected from the group consisting of citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.
20. The method of Claim 18, wherein the tricyclic antidepressant is selected form the group consisting of Amitriptyline (Elavil®), Amoxapine (Asendin®), Clomipramine (Anafranil®), Desipramine (Norepramine®, Pertofrane®), Doxepin (Adapin®, Sinequan®), Imipramine (Janimine®, Tofranil®), Nortriptyline (Aventyl®, Pamelor®), Protriptyline (Vivactil®), Trimipramine (Rhotramine®, and Surmontil®).
21. The method of Claim 18, wherein the monoamine oxidase inhibitor is a nonselective, irreversible monoamine oxidase inhibitor.
22. The method of Claim 21, wherein the nonselective, irreversible monoamine oxidase inhibitor is selected from the group consisting of Isocarboxazid (Marplan®), Phenelzine (Nardil®), and Tranylcypromine (Parnate®),
23. The method of Claim 18, wherein the monoamine oxidase inhibitor is Moclobemide (Manerix®) or Toloxatone (Humoryl®).
24. The method of Claim 16, wherein the anticonvulsant is selected from the group consisting of valproic acid, phenobarbital, Carbamazepine (Tegretol®), Divalproex (Depakote®), Gabapentin (Neurontin®), Lamotrigine (Lamictal®), and Topiramate (Topamax®) and phenyltoin.
25. The method of Claim 16, wherein the mood stabilizer is selected from group consisting of Lithium, Cibalith-S®, Duralith®, Ekalith®, Eskalith CR®, Lithane®, Lithobid®, Lithonate®, and Lithotabs®.
26. The method of Claim 16, wherein the antipsychotic is selected from the group consisting of phenothiazine, a phenylbutylpiperdine, a debenzapine, a benzisoxidil, a salt of lithium, a butyrophenone, a substituted benzamide (sulpiride), and a raclopride.
27. The method of Claim 26, wherein the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), thioridazine (Mellaril), Fluphenazine (Prolixin®), Perpehnazine (Trilafon®), and Trifluoperazine (Stelazine®).
28. The method of Claim 26, wherein the phenylbutylpiperadine is selected from the group consisting of haloperidol (Haldol®) and pimozide (Orap®).
29. The method of Claim 26, wherein the debenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), and quetiapine (Seroquel®).
30. The method of Claim 26, wherein the benzisoxidil is selected from the group consisting of risperidone (Resperidal®), ziprasidone (Geodon®, Zeldox®)), 9- hydroxy- risperidone.
31. The method of Claim 26, wherein the salt of lithium is lithium carbonate.
32. The method of Claim 16, wherein the antipsychotic is selected from the group consisting of Aripiprazole (Abilify®), Etrafon®, Droperidol (Inapsine®), Thioridazine (Mellaril®), Thiothixene (Navane®), Promethazine (Phenergan®), Metoclopramide (Reglan®), Chlorprothixene (Taractan®), Triavil®, Molindone (Moban®), Sertindole (Serlect®), Droperidol, Amisulpride (Solian®), Melperone, Paliperidone (Invega®), Tetrabenazine, aripirazole, Thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®), thioxanthing (Fluphenthixol).
33. The method of Claim 16, wherein the antipsychotic is a typical antipsychotic.
34. The method of Claim 16, wherein the antipsychotic is an atypical antipsychotic.
35. A method of ameliorating or inhibiting a negative symptom of schizophrenia comprising administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from the group consisiting of a compound of Formula (I) and a compound of Formula (II).
36. The method of Claim 35, wherein the antipsychotic is selected from the group consisting of phenothiazine, a phenylbutylpiperdine, a debenzapine, a benzisoxidil, a salt of lithium, a butyrophenone, a substituted benzamide (sulpiride), and a raclopride.
37. The method of Claim 36, wherein the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), thioridazine (Mellaril), Fluphenazine (Prolixin®), Perpehnazine (Trilafon®), and Trifluoperazine (Stelazine®).
38. The method of Claim 36, wherein the phenylbutylpiperadine is selected from the group consisting of haloperidol (Haldol®) and pimozide (Orap®).
39. The method of Claim 36, wherein the debenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), and quetiapine (Seroquel®).
40. The method of Claim 36, wherein the benzisoxidil is selected from the group consisting of risperidone (Resperidal®), ziprasidone (Geodon®, Zeldox®)), 9- hydroxy- risperidone.
41. The method of Claim 36, wherein the salt of lithium is lithium carbonate.
42. The method of Claim 35, wherein the antipsychotic is selected from the group consisting of Aripiprazole (Abilify®), Etrafon®, Droperidol (Inapsine®), Thioridazine (Mellaril®), Thiothixene (Navane®), Promethazine (Phenergan®), Metoclopramide (Reglan®), Chlorprothixene (Taractan®), Triavil®, Molindone (Moban®), Sertindole (Serlect®), Droperidol, Amisulpride (Solian®), Melperone, Paliperidone (Invega®), Tetrabenazine, aripirazole, Thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®), and thioxanthine (Fluphenthixol).
43. The method of Claim 35, wherein the antipsychotic is a typical antipsychotic.
44. The method of Claim 35, wherein the antipsychotic is an atypical antipsychotic.
45. The method of Claim 35, wherein the negative symptom is selected from the group consisting of affective flattening, poverty of speech, absence of volition, apathy, self-neglect, inappropriate emotion, inability to experience pleasure, inattentiveness, inability to show a facial expression, and inability to start or complete a task.
46. A method of ameliorating or inhibiting a loss of cognition or improving cognition comprising administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from the group consisiting of a compound of Formula (I) and a compound of Formula (II).
47. The method of Claim 46, wherein the first compound is selected from the group consisting of an antidepressant, an anticonvulsant, a mood stabilizer, an antipsychotic, an antiarrhythmic agent, an antibiotic, an anticholinergic agent, an antiemetic, an antihypertensive agent, an antineoplastic agent, an anti-Parkinson's agent, an antihistamine, an cardiotonic agent, a corticosteroid, a H2 receptor antagonist, an immunosuppressive agent, a narcotic analgesic, a muscle relaxant, a non-steroids antiinflammatory agent, a radiocontrast agent, a sedative.
48. The method of Claim 47, wherein the antidepressant agent is selected from the group consisting of amitriptyline, imipramine, desipramine, fluoxetine and clovoxamine.
49. The method of Claim 47, wherein the anticonvulsant agent is selected from the group consisting of phenyltoin, valproic acid, and carbamazepine.
50. The method of Claim 47, wherein the mood stabilizer is selected from group consisting of Lithium, Cibalith-S®, Duralith®, Ekalith®, Eskalith CR®, Lithane®, Lithobid®, Lithonate®, and Lithotabs®.
51. The method of Claim 47, wherein the antipsychotic is selected from the group consisting of phenothiazine, a phenylbutylpiperdine, a debenzapine, a benzisoxidil, a salt of lithium, a butyrophenone, a substituted benzamide (sulpiride), and a raclopride.
52. The method of Claim 51, wherein the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), thioridazine (Mellaril), Fluphenazine (Prolixin®), Perpehnazine (Trilafon®), and Trifluoperazine (Stelazine®).
53. The method of Claim 51 , wherein the phenylbutylpiperadine is selected from the group consisting of haloperidol (Haldol®) and pimozide (Orap®).
54. The method of Claim 51 , wherein the debenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), and quetiapine (Seroquel®).
55. The method of Claim 51 , wherein the benzisoxidil is selected from the group consisting of risperidone (Resperidal®), ziprasidone (Geodon®, Zeldox®)), 9- hydroxy- risperidone.
56. The method of Claim 51 , wherein the salt of lithium is lithium carbonate.
57. The method of Claim 47, wherein the antipsychotic is selected from the group consisting of Aripiprazole (Abilify®), Etrafon®, Droperidol (Inapsine®), Thioridazine (Mellaril®), Thiothixene (Navane®), Promethazine (Phenergan®), Metoclopramide (Reglan®), Chlorprothixene (Taractan®), Triavil®, Molindone (Moban®), Sertindole (Serlect®), Droperidol, Amisulpride (Solian®), Melperone, Paliperidone (Invega®), Tetrabenazine, aripirazole, Thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®), and thioxanthine (Fluphenthixol).
58. The method of Claim 47, wherein the antipsychotic is a typical antipsychotic.
59. The method of Claim 47, wherein the antipsychotic is an atypical antipsychotic.
60. The method of Claim 47, wherein the antiarrhythmic agent is selected from the group consisting of disopyramide, quinidine, and tocainide.
61. The method of Claim 47, wherein the antibiotic is selected from the group consisting of cephalexin, cephalothin, metronidazole, ciprofloxacin, and ofloxacin.
62. The method of Claim 47, wherein the anticholinergic agent is selected from the group consisting of benztropine, homatropine, scopolamine and trihexyphenidyl.
63. The method of Claim 47, wherein the antiemetic is lithium.
64. The method of Claim 47, wherein the antihypertensive agent is selected from the group consisting of propranolol, metoprolol, atenolol, verapamil, methyldopa, prazosin, and nifedipine.
65. The method of Claim 47, wherein the antineoplastic agent is selected from the group consisting of cytosine arabinoside, and interleukin-2.
66. The method of Claim 47, wherein the anti-Parkinson's agent is selected from the group consisting of L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride.
67. The method of Claim 47, wherein the antihistamine is selected from the group consisting of phenylpropanolamine, diphenhydramine, chlorpheniramine brompheniramine, and pseudoephedrine.
68. The method of Claim 47, wherein the cardiotonic agent is digoxin.
69. The method of Claim 47, wherein the corticosteroid is selected from the group consisting of hydrocortisone and prednisone.
70. The method of Claim 47, wherein the H2 receptor antagonist is selected from the group consisting of cimetidine and ranitidine.
71. The method of Claim 47, wherein the immunosuppressive agent is selected from the group consisting of cyclosporine and interferon.
72. The method of Claim 47, wherein the narcotic analgesic is selected from the group consisting of codeine, hydrocodone oxycodone, meperidine, and propoxyphene.
73. The method of Claim 47, wherein the muscle relaxant is selected from the group consisting of baclofen, cyclobenzaprine, and methocarbimol.
74. The method of Claim 47, wherein the non-steroids anti-inflammatory agent is selected from the group consisting of aspirin, ibuprofen, indomethacin, naproxen, and sulindac.
75. The method of Claim 47, wherein the radiocontrast agent is selected from the group consisting of metrizamide, iothalamate and iohexol.
76. The method of Claim 47, wherein the sedative is selected from the group consisting of benzodiazepine, alprazolam, diazepam, lorazepam, phenobarbital, butabarbital, and chloral hydrate.
77. A method of ameliorating or inhibiting an adverse effect associated with a compound used to treat Parkinson's disease comprising administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from the group consisiting of a compound of Formula (I) and a compound of Formula (II).
78. The method of Claim 77, wherein the compound used to treat Parkinson's disease is selected from group consisting of L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride.
79. The method of Claim 77, wherein the adverse side effect is selected from the group consisting of increased propensity for gambling, dyskinesia, and psychosis.
80. A method of ameliorating or inhibiting a propensity for gambling associated with a compound used to treat Parkinson's disease comprising administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from the group consisiting of a compound of Formula (I) and a compound of Formula (II).
81. The method of Claim 80, wherein the compound used to treat Parkinson's disease is selected from group consisting of L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride.
82. The method of Claim 80, wherein the compound used to treat Parkinson's disease is pramipexole.
83. A method of ameliorating or inhibiting dyskinesia associated with a compound used to treat Parkinson's disease comprising administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from the group consisiting of a compound of Formula (I) and a compound of Formula (II).
84. A method of ameliorating or inhibiting psychosis associated with a compound used to treat Parkinson's disease comprising administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from the group consisiting of a compound of Formula (I) and a compound of Formula (II).
85. The method of any one of Claims 83 to 84, wherein the compound used to treat Parkinson's disease is selected from group consisting of L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride.
86. The method of any one of Claims 83 to 84, wherein the compound used to treat Parkinson's disease is L-dopa.
87. A method for shortening or preventing a need for a drug holiday comprising administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease the second compound is selected from the group consisiting of a compound of Formula (I) and a compound of Formula (II).
88. The method of Claim 87, wherein the compound used to treat Parkinson's disease is selected from group consisting of L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride.
89. The method of any one of Claims 1 to 88, wherein the compound selected from the compound of Formula (I) and the compound of Formula (II) binds to CB- 1 receptors in human tissue with a higher pKi compared to N-piperidino-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide.
90. The method of Claim 89, wherein the pKi of the compound selected from the compound of Formula (I) and the compound of Formula (II) is (> 9.0).
91. The method of any one of Claims 1 to 89, wherein the compound selected from the compound of Formula (I) and the compound of Formula (II) suppresses food intake more effectively compared to N-piperidino-5-(4-chlorophenyl)-l -(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide.
92. The method of any one of Claims 1 to 91 , wherein the first compound is administered prior to the second compound.
93. The method of any one of Claims 1 to 91, wherein the first compound is administered subsequent to the second compound.
94. The method of any one of Claims 1 to' 91 , wherein the first compound is administered at the same time as the second compound.
95. A method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of an antipsychotic in a subject taking the antipsychotic comprising informing the subject that coadministering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates at least one adverse effect associated with the administration of the antipsychotic, wherein the cannabinoid antagonist or inverse agonist is a compound selected from the group consisting of a compound of Formula (I) and a compound of Formula (II).
96. The method of Claim 95, wherein the adverse side effect is selected from the group consisting of weight gain, metabolic syndrome, an extra-pyramidal side effect, akathisia, dystonia, acute dystonia, Parkinsonism, dykensia, tardive dyskinesia, neuroleptic malignant syndrome, hyperprolactinemia, and catalepsy.
97. The method of Claim 95, wherein the adverse side effect is selected from the group consisting of increased propensity for gambling, dyskinesia, and psychosis.
98. The method of Claim 95, wherein the antipsychotic acts a dopamine receptor.
99. The method of Claim 98, wherein the dopamine receptor is a D2 receptor.
100. The method of Claim 95, wherein the antipsychotic is selected from the group consisting of phenothiazine, a phenylbutylpiperdine, a debenzapine, a benzisoxidil, a salt of lithium, a butyrophenone, a substituted benzamide (sulpiride), and a raclopride.
101. The method of Claim 100, wherein the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), thioridazine (Mellaril), Fluphenazine (Prolixin®), Perpehnazine (Trilafon®), and Trifluoperazine (Stelazine®).
102. The method of Claim 100, wherein the phenylbutylpiperadine is selected from the group consisting of haloperidol (Haldol®) and pimozide (Orap®).
103. The method of Claim 100, wherein the debenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), and quetiapine (Seroquel®).
104. The method of Claim 100, wherein the benzisoxidil is selected from the group consisting of risperidone (Resperidal®), ziprasidone (Geodon®, Zeldox®)), 9- hydroxy- risperidone.
105. The method of Claim 100, wherein the salt of lithium is lithium carbonate.
106. The method of Claim 95, wherein the antipsychotic is selected from the group consisting of Aripiprazole (Abilify®), Etrafon®, Droperidol (Inapsine®), Thioridazine (Mellaril®), Thiothixene (Navane®), Promethazine (Phenergan®), Metoclopramide (Reglan®), Chlorprothixene (Taractan®), Triavil®, Molindone (Moban®), Sertindole (Serlect®), Droperidol, Amisulpride (Solian®), Melperone, Paliperidone (Invega®), Tetrabenazine, aripirazole, Thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®), and thioxanthine (Fluphenthixol).
107. The method of Claim 95, wherein the antipsychotic is a typical antipsychotic.
108. The method of Claim 95, wherein the antipsychotic is an atypical antipsychotic.
109. The method of Claim 95, wherein informing the subject comprises providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or treats at least one adverse effect associated with the administration of the antipsychotic.
1 10. A method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of a compound used to treat Parkinson's disease in a subject taking the compound used to treat Parkinson's disease comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates at least one adverse effect associated with the administration of the compound used to treat Parkinson's disease, wherein the cannabinoid antagonist or inverse agonist is a compound selected from the group consisting of a compound of Formula (I) and a compound of Formula (II).
1 1 1. The method of Claim 1 10, wherein the compound used to treat Parkinson's disease is selected from group consisting of L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride.
112. The method of Claim 110, wherein informing the subject comprises providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or treats at least one adverse effect associated with the administration of the compound used to treat Parkinson's disease.
1 13. A method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a negative symptom of schizophrenia in a subject taking an antipsychotic comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or inhibits at least one negative symptom of schizophrenia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from the group consisting of a compound of Formula (I) and a compound of Formula (II).
1 14. The method of Claim 1 13, wherein the negative symptom is selected from the group consisting of affective flattening, poverty of speech, absence of volition, apathy, self-neglect, inappropriate emotion, inability to experience pleasure, inattentiveness, inability to show a facial expression, and inability to start or complete a task.
1 15. The method of Claim 1 13, wherein informing the subject comprises providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or inhibits at least one negative symptom of schizophrenia.
1 16. A method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a loss of cognition or improve cognition in a subject taking a therapeutic compound comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the therapeutic compound ameliorates or inhibits a loss of cognition or improves cognition, wherein the cannabinoid antagonist or inverse agonist is a compound selected from the group consisting of a compound of Formula (I) and a compound of Formula (II).
117. The method of Claim 116, wherein the therapeutic compound is selected from the group consisting of an antidepressant, an anticonvulsant, a mood stabilizer, an antipsychotic, an antiarrhythmic agent, an antibiotic, an anticholinergic agent, an antiemetic, an antihypertensive agent, an antineoplastic agent, an anti-Parkinson's agent, an antihistamine, an cardiotonic agent, a corticosteroid, a H2 receptor antagonist, an immunosuppressive agent, a narcotic analgesic, a muscle relaxant, a non-steroids antiinflammatory agent, a radiocontrast agent, and a sedative
1 18. The method of Claim 1 17, wherein the antidepressant agent is selected from the group consisting of amitriptyline, imipramine, desipramine, fluoxetine and clovoxamine. i.
1 19. The method of Claim 1 17, wherein the anticonvulsant agent is selected from the group consisting of phenyltoin, valproic acid, and carbamazepine.
120. n The method of Claim 1 17, wherein the mood stabilizer is selected from group consisting of Lithium, Cibalith-S®, Duralith®, Ekalith®, Eskalith CR®, Lithane®, Lithobid®, Lithonate®, and Lithotabs®.
121. The method of Claim 117, wherein the antipsychotic is selected from the group consisting of phenothiazine, a phenylbutylpiperdine, a debenzapine, a benzisoxidil, a salt of lithium, a butyrophenone, a substituted benzamide (sulpiride), and a raclopride.
122. The method of Claim 121, wherein the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), thioridazine (Mellaril), Fluphenazine (Prolixin®), Perpehnazine (Trilafon®), and Trifluoperazine (Stelazine®).
123. The method of Claim 121 , wherein the phenylbutylpiperadine is selected from the group consisting of haloperidol (Haldol®) and pimozide (Orap®).
124. The method of Claim 121, wherein the debenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), and quetiapine (Seroquel®).
125. The method of Claim 121 , wherein the benzisoxidil is selected from the group consisting of risperidone (Resperidal®), ziprasidone (Geodon®, Zeldox®)), 9- hydroxy- risperidone.
126. The method of Claim 121, wherein the salt of lithium is lithium carbonate.
127. The method of Claim 117, wherein the antipsychotic is selected from the group consisting of Aripiprazole (Abilify®), Etrafon®, Droperidol (Inapsine®), Thioridazine (Mellaril®), Thiothixene (Navane®), Promethazine (Phenergan®), Metoclopramide (Reglan®), Chlorprothixene (Taractan®), Triavil®, Molindone (Moban®), Sertindole (Serlect®), Droperidol, Amisulpride (Solian®), Melperone, Paliperidone (Invega®), Tetrabenazine, aripirazole, Thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®), and thioxanthine (Fluphenthixol).
128. The method of Claim 1 17, wherein the antipsychotic is a typical antipsychotic.
129. The method of Claim 117, wherein the antipsychotic is an atypical antipsychotic.
130. The method of Claim 117, wherein the antiarrhythmic agent is selected from the group consisting of disopyramide, quinidine, and tocainide.
131. The method of Claim 117, wherein the antibiotic is selected from the group consisting of cephalexin, cephalothin, metronidazole, ciprofloxacin, and ofloxacin.
132. The method of Claim 1 17, wherein the anticholinergic agent is selected from the group consisting of benztropine, homatropine, scopolamine and trihexyphenidyl.
133. The method of Claim 117, wherein the antiemetic is lithium.
134. The method of Claim 1 17, wherein the antihypertensive agent is selected from the group consisting of propranolol, metoprolol, atenolol, verapamil, methyldopa, prazosin, and nifedipine.
135. The method of Claim 1 17, wherein the antineoplastic agent is selected from the group consisting of cytosine arabinoside, and interleukin-2.
136. The method of Claim 1 17, wherein the anti-Parkinson's agent is selected from the group consisting of L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride.
137. The method of Claim 1 17, wherein the antihistamine is selected from the group consisting of phenylpropanolamine, diphenhydramine, chlorpheniramine brompheniramine, and pseudoephedrine.
138. The method of Claim 1 17, wherein the cardiotonic agent is digoxin.
139. The method of Claim 117, wherein the corticosteroid is selected from the group consisting of hydrocortisone and prednisone.
140. The method of Claim 117, wherein the H2 receptor antagonist is selected from the group consisting of cimetidine and ranitidine.
141. The method of Claim 1 17, wherein the immunosuppressive agent is selected from the group consisting of cyclosporine and interferon.
142. The method of Claim 117, wherein the narcotic analgesic is selected from the group consisting of codeine, hydrocodone oxycodone, meperidine, and propoxyphene.
143. The method of Claim 117, wherein the muscle relaxant is selected from the group consisting of baclofen, cyclobenzaprine, and methocarbimol.
144. The method of Claim 1 17, wherein the non-steroids anti-inflammatory agent is selected from the group consisting of aspirin, ibuprofen, indomethacin, naproxen, and sulindac.
145. The method of Claim 1 17, radiocontrast agent is selected from the group consisting of metrizamide, iothalamate and iohexol.
146. The method of Claim 117, wherein the sedative is selected from the group consisting of benzodiazepine, alprazolam, diazepam, lorazepam, phenobarbital, butabarbital, and chloral hydrate.
147. The method of Claim 1 17, wherein informing the subject comprises providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the therapeutic compound ameliorates or inhibits a loss of cognition or improves cognition.
148. A method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a propensity for gambling in a subject taking a compound used to treat Parkinson's disease comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or the propensity for gambling, wherein the cannabinoid antagonist or inverse agonist is a compound selected from the group consisting of a compound of Formula (I) and a compound of Formula (II).
149. The method of Claim 148, wherein informing the subject comprises providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits the propensity for gambling.
150. A method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit dyskinesia associated with a compound used to treat Parkinson's disease in a subject comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits dyskinesia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from the group consisting of a compound of Formula (I) and a compound of Formula (II).
151. The method of Claim 150, wherein informing the subject comprises providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits dyskinesia associated with a compound used to treat Parkinson's disease.
152. A method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit psychosis associated with a compound used to treat Parkinson's disease in a subject comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits psychosis, wherein the cannabinoid antagonist or inverse agonist is a compound selected from the group consisting of a compound of Formula (I) and a compound of Formula (II).
153. The method of Claim 152, wherein informing the subject comprises providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits psychosis associated with a compound used to treat Parkinson's disease.
154. A method of using a cannabinoid antagonist or inverse agonist to shorten or prevent the need for a drug holiday in a subject comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease shortens or prevents the need for a drug holiday, wherein the cannabinoid antagonist or inverse agonist is a compound selected from the group consisting of a compound of Formula (I) and a compound of Formula (II).
155. The method of Claim 154, wherein informing the subject comprises providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease shortens or prevents the need for a drug holiday.
156. A method of using a cannabinoid antagonist or inverse agonist to inhibit or prevent weight gain in a subject comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with an antipsychotic or a compound used to treat Parkinson's disease inhibits or prevents weight gain, wherein the cannabinoid antagonist or inverse agonist is a compound selected from the group consisting of a compound of Formula (I) and a compound of Formula (II).
157. The method of Claim 156, wherein the antidepressant is selected from the group consisting of Buproprion HCL (Wellbutrin®), Mitrazapine (Remeron®), Nefazadone (Serzone®), Trazadone (Desyrel®), and Venlafaxine (Effexor®).
158. The method of Claim 156, wherein the antidepressant is selected form the group consisting of a selective serotonin reuptake inhibitor (SSRI), a tricyclic antidepressant and a monoamine oxidase inhibitor,
159. The method of Claim 156, wherein informing the subject comprises providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease inhibits or prevents weight gain.
160. The method of any one of Claims 95 to 159, wherein the printed matter is a label.
161. A method for lowering the amount of an antipsychotic needed to elicit the same therapeutic effect compared to when the first compound is administered alone comprising a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from the group consisisting of a compound of Formula (I) and a compound of Formula (II).
162. A method for lowering the amount of a compound used to treat Parkinson's disease needed to elicit the same therapeutic effect compared to when the first compound is administered alone comprising a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from the group consisisting of a compound of Formula (I) and a compound of Formula (II).
163. The method of any of Claim 1 to 162, wherein the cannabinoid antagonist or inverse agonist is selected from the group consisting of:
Figure imgf000494_0001
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106
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546
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Figure imgf000566_0001
Figure imgf000567_0001
Figure imgf000568_0001

Figure imgf000569_0001
Figure imgf000570_0001

Figure imgf000571_0001
Figure imgf000571_0003
Figure imgf000571_0002
570
Figure imgf000572_0001
Figure imgf000573_0001
572
Figure imgf000574_0001
Figure imgf000574_0002
Figure imgf000574_0003
Figure imgf000575_0001
Figure imgf000576_0001
575
Figure imgf000577_0001
The compound of Claim 1, wherein the compound is selected from the group consisting of:
Figure imgf000577_0002
Figure imgf000578_0001
Figure imgf000579_0001
The compound of Claim 1, wherein the compound is selected from the group consisting of:
Figure imgf000579_0002
Figure imgf000580_0001
Figure imgf000580_0002
Figure imgf000580_0004
Figure imgf000580_0003
Figure imgf000580_0005
Figure imgf000581_0001
The compound of Claim 1, wherein the compound is selected from the group consisting of:
Figure imgf000581_0002
Figure imgf000582_0001
Figure imgf000582_0002
Figure imgf000582_0004
Figure imgf000582_0003
581
Figure imgf000583_0001
582
Figure imgf000584_0001
Figure imgf000585_0001
584
Figure imgf000586_0001
Figure imgf000587_0001
Figure imgf000588_0001
Figure imgf000589_0001
a
Figure imgf000590_0001
Figure imgf000591_0001
Figure imgf000592_0001
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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7960376B2 (en) 2007-09-14 2011-06-14 Cara Therapeutics, Inc. Benzo-fused heterocycles
JP2011162472A (en) * 2010-02-09 2011-08-25 Nippon Soda Co Ltd Nitrogen-containing heterocyclic compound or salt thereof, and germicide for agriculture and horticulture
CN102807574A (en) * 2011-05-30 2012-12-05 长春吉大天元化学技术股份有限公司 Novel pyrido sulfur nitrogen 7-membered ring derivatives adopted as anti-tumor drugs, preparation method and applications thereof
US20130337052A1 (en) * 2012-06-19 2013-12-19 Patricia Linert System and Method of Reducing Impairment of Alertness, Concentration, Motivation, and Creativity Caused by Medication
US8952034B2 (en) 2009-07-27 2015-02-10 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8962610B2 (en) 2011-07-01 2015-02-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9079901B2 (en) 2010-07-02 2015-07-14 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9598435B2 (en) 2011-07-01 2017-03-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9682998B2 (en) 2011-05-10 2017-06-20 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
WO2018102296A1 (en) * 2016-11-29 2018-06-07 Axim Biotechnologies, Inc. Chewing gum composition comprising cannabinoids and gabapentin
US10183936B2 (en) 2014-03-13 2019-01-22 Indiana University Research And Technology Corporation Hepatitis B core protein allosteric modulators
US10377748B2 (en) 2015-09-15 2019-08-13 Assembly Biosciences, Inc. Hepatitis B core protein modulators
US10835501B2 (en) 2016-10-01 2020-11-17 Indication Bioscience Llc Pharmaceutical compositions comprising a statin and a cannabinoid and uses thereof
US10987360B2 (en) 2016-09-15 2021-04-27 Assembly Biosciences, Inc. Hepatitis B core protein modulators
US11040965B2 (en) 2017-03-13 2021-06-22 Assembly Biosciences, Inc. Process for making Hepatitis B core protein modulators
US11046651B2 (en) 2019-10-21 2021-06-29 Alairion, Inc. Piperazine substituted azapine derivatives and uses thereof
US11078170B2 (en) 2017-03-02 2021-08-03 Assembly Biosciences, Inc. Cyclic sulfamide compounds and methods of using same
WO2024104815A1 (en) 2022-11-16 2024-05-23 Basf Se Substituted benzodiazepines as fungicides
WO2024104822A1 (en) 2022-11-16 2024-05-23 Basf Se Substituted tetrahydrobenzodiazepine as fungicides
WO2024104818A1 (en) 2022-11-16 2024-05-23 Basf Se Substituted benzodiazepines as fungicides

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002049652A1 (en) * 2000-12-20 2002-06-27 Astrazeneca Ab Method of treatment
WO2004073639A2 (en) * 2003-02-19 2004-09-02 Merck & Co. Inc. Treatment of psychosis with a muscarinic m1 receptor ectopic activator
WO2005000809A1 (en) * 2003-06-11 2005-01-06 Merck & Co., Inc. Substituted 3-alkyl and 3-alkenyl azetidine derivatives
WO2005002586A1 (en) * 2003-07-02 2005-01-13 Astrazeneca Ab Metabolite of quetiapine
WO2005023243A1 (en) * 2003-09-04 2005-03-17 H. Lundbeck A/S The combination of a serotonin reuptake inhibitor and loxapine
US20050096311A1 (en) * 2003-10-30 2005-05-05 Cns Response Compositions and methods for treatment of nervous system disorders
WO2005063254A2 (en) * 2003-12-22 2005-07-14 Acadia Pharmaceuticals Inc. Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
WO2005070461A2 (en) * 2004-01-13 2005-08-04 Duke University Compositions of an anticonvulsant and an antipsychotic drug for affecting weight loss
WO2005115977A1 (en) * 2004-05-28 2005-12-08 Tanabe Seiyaku Co., Ltd. Pyrrolidine derivatives as cb1-receptor antagonists
WO2006107948A2 (en) * 2005-04-04 2006-10-12 Acadia Pharmaceuticals Inc. Use of n-desmethylclozapine and related compounds as dopamine stabilizing agents
WO2007018460A1 (en) * 2005-08-08 2007-02-15 Astrazeneca Ab Therapeutic agents
WO2007047737A1 (en) * 2005-10-17 2007-04-26 Acadia Pharmaceuticals Inc. Cb-1 modulating compounds and their use

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002049652A1 (en) * 2000-12-20 2002-06-27 Astrazeneca Ab Method of treatment
WO2004073639A2 (en) * 2003-02-19 2004-09-02 Merck & Co. Inc. Treatment of psychosis with a muscarinic m1 receptor ectopic activator
WO2005000809A1 (en) * 2003-06-11 2005-01-06 Merck & Co., Inc. Substituted 3-alkyl and 3-alkenyl azetidine derivatives
WO2005002586A1 (en) * 2003-07-02 2005-01-13 Astrazeneca Ab Metabolite of quetiapine
WO2005023243A1 (en) * 2003-09-04 2005-03-17 H. Lundbeck A/S The combination of a serotonin reuptake inhibitor and loxapine
US20050096311A1 (en) * 2003-10-30 2005-05-05 Cns Response Compositions and methods for treatment of nervous system disorders
WO2005063254A2 (en) * 2003-12-22 2005-07-14 Acadia Pharmaceuticals Inc. Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
WO2005070461A2 (en) * 2004-01-13 2005-08-04 Duke University Compositions of an anticonvulsant and an antipsychotic drug for affecting weight loss
WO2005115977A1 (en) * 2004-05-28 2005-12-08 Tanabe Seiyaku Co., Ltd. Pyrrolidine derivatives as cb1-receptor antagonists
WO2006107948A2 (en) * 2005-04-04 2006-10-12 Acadia Pharmaceuticals Inc. Use of n-desmethylclozapine and related compounds as dopamine stabilizing agents
WO2007018460A1 (en) * 2005-08-08 2007-02-15 Astrazeneca Ab Therapeutic agents
WO2007047737A1 (en) * 2005-10-17 2007-04-26 Acadia Pharmaceuticals Inc. Cb-1 modulating compounds and their use

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ANDERSON JEFFREY J ET AL: "Effects of cannabinoid receptor stimulation and blockade on catalepsy produced by dopamine receptor antagonists" EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 295, no. 2-3, 1996, pages 163-168, XP002495957 ISSN: 0014-2999 *
MUCCIOLI G G ET AL: "Current knowledge on the antagonists and inverse agonists of cannabinoid receptors" CURRENT MEDICINAL CHEMISTRY, BENTHAM SCIENCE PUBLISHERS BV, BE, vol. 12, no. 12, 1 January 2005 (2005-01-01), pages 1361-1394, XP008082642 ISSN: 0929-8673 *
ROGERS-EVANS M ET AL: "Identification of novel cannabinoid receptor ligands via evolutionary de novo design and rapid parallel synthesis" QSAR AND COMBINATORIAL SCIENCE 200407 DE, vol. 23, no. 6, July 2004 (2004-07), pages 426-430, XP002495955 ISSN: 1611-020X *
SEGOVIA GREGORIO ET AL: "Effects of CB1 cannabinoid receptor modulating compounds on the hyperkinesia induced by high-dose levodopa in the reserpine-treated rat model of Parkinson's disease." MOVEMENT DISORDERS : OFFICIAL JOURNAL OF THE MOVEMENT DISORDER SOCIETY FEB 2003, vol. 18, no. 2, February 2003 (2003-02), pages 138-149, XP002495956 ISSN: 0885-3185 *
SUNDRAM S ET AL: "Clozapine decreases [3H] CP 55940 binding to the cannabinoid1 receptor in the rat accumbens" NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, SPRINGER, BERLIN, DE, vol. 371, 2 July 2005 (2005-07-02), pages 428-433, XP002420595 ISSN: 0028-1298 *

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Publication number Priority date Publication date Assignee Title
US7960376B2 (en) 2007-09-14 2011-06-14 Cara Therapeutics, Inc. Benzo-fused heterocycles
US8952034B2 (en) 2009-07-27 2015-02-10 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
JP2011162472A (en) * 2010-02-09 2011-08-25 Nippon Soda Co Ltd Nitrogen-containing heterocyclic compound or salt thereof, and germicide for agriculture and horticulture
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WO2012163236A1 (en) * 2011-05-30 2012-12-06 长春吉大天元化学技术股份有限公司 Pyridothiazepine derivative, preparation method and uses therefor
US8962610B2 (en) 2011-07-01 2015-02-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9598435B2 (en) 2011-07-01 2017-03-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9676760B2 (en) 2011-07-01 2017-06-13 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9695192B2 (en) 2011-07-01 2017-07-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US20130337052A1 (en) * 2012-06-19 2013-12-19 Patricia Linert System and Method of Reducing Impairment of Alertness, Concentration, Motivation, and Creativity Caused by Medication
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US10183936B2 (en) 2014-03-13 2019-01-22 Indiana University Research And Technology Corporation Hepatitis B core protein allosteric modulators
US10377748B2 (en) 2015-09-15 2019-08-13 Assembly Biosciences, Inc. Hepatitis B core protein modulators
US11814376B2 (en) 2015-09-15 2023-11-14 Assembly Biosciences, Inc. Hepatitis b core protein modulators
US10766890B2 (en) 2015-09-15 2020-09-08 Assembly Biosciences, Inc. Hepatitis B core protein modulators
US10392379B2 (en) 2015-09-15 2019-08-27 Assembly Biosciences, Inc. Hepatitis B core protein modulators
US10968211B2 (en) 2015-09-15 2021-04-06 Assembly Biosciences, Inc. Hepatitis B core protein modulators
US10987360B2 (en) 2016-09-15 2021-04-27 Assembly Biosciences, Inc. Hepatitis B core protein modulators
US10835501B2 (en) 2016-10-01 2020-11-17 Indication Bioscience Llc Pharmaceutical compositions comprising a statin and a cannabinoid and uses thereof
WO2018102296A1 (en) * 2016-11-29 2018-06-07 Axim Biotechnologies, Inc. Chewing gum composition comprising cannabinoids and gabapentin
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US11040965B2 (en) 2017-03-13 2021-06-22 Assembly Biosciences, Inc. Process for making Hepatitis B core protein modulators
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