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US20080161366A1 - Aminoalkyl substituted aryl sulfamide derivatives and methods of their use - Google Patents

Aminoalkyl substituted aryl sulfamide derivatives and methods of their use Download PDF

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Publication number
US20080161366A1
US20080161366A1 US11/955,195 US95519507A US2008161366A1 US 20080161366 A1 US20080161366 A1 US 20080161366A1 US 95519507 A US95519507 A US 95519507A US 2008161366 A1 US2008161366 A1 US 2008161366A1
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dioxido
benzothiadiazol
amine
methylpropan
compound
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Inventor
Casey Cameron McComas
Stephen Todd Cohn
Matthew Lantz Crawley
Andrew Fensome
Joel Adam Goldberg
Douglas John Jenkins
Callain Younghee Kim
Paige Erin Mahaney
Charles William Mann
Michael Anthony Marella
David John O'Neill
Joseph Peter Sabatucci
Eugene Anthony Terefenko
Eugene John Trybulski
An Thien Vu
Richard Page Woodworth
Puwen Zhang
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Wyeth LLC
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Wyeth LLC
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Priority to US11/955,195 priority Critical patent/US20080161366A1/en
Assigned to WYETH reassignment WYETH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MAHANEY, PAIGE ERIN, SABATUCCI, JOSEPH PETER, TRYBULSKI, EUGENE JOHN, O'NEILL, DAVID JOHN, COHN, STEPHEN TODD, VU, AN THIEN, FENSOME, ANDREW, CRAWLEY, MATTHEW LANTZ, GOLDBERG, JOEL ADAM, JENKINS, DOUGLAS JOHN, KIM, CALLAIN YOUNGHEE, MANN, CHARLES WILLIAM, TEREFENKO, EUGENE ANTHONY, WOODWORTH JR., RICHARD PAGE, MARELLA, MICHAEL ANTHONY, MC COMAS, CASEY CAMERON, ZHANG, PUWEN
Publication of US20080161366A1 publication Critical patent/US20080161366A1/en
Priority to US12/548,844 priority patent/US20100029641A1/en
Assigned to WYETH LLC reassignment WYETH LLC CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: WYETH
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to aminoalkyl-substituted aryl sulfamide derivatives, which are monoamine reuptake inhibitors, compositions containing these derivatives, and methods of their use for the prevention and treatment of diseases or disorders including vasomotor symptoms, depression disorders, endogenous behavioral disorders, cognitive disorders, sexual dysfunction, or pain conditions, in particular vasomotor symptoms.
  • Vasomotor symptoms are the most common symptoms associated with menopause, occurring in 60% to 80% of all women following natural or surgically-induced menopause. VMS are likely an adaptive response of the central nervous system (CNS) to declining sex steroids. To date, the most effective therapies for VMS are hormone-based treatments, including estrogens and/or some progestins. Hormonal treatments are very effective at alleviating VMS, but they are not appropriate for all women.
  • VMS are caused by fluctuations of sex steroid levels and can be disruptive and disabling in both males and females.
  • a hot flush can last up to thirty minutes and vary in their frequency from several times a week to multiple occurrences per day.
  • the patient experiences a hot flush as a sudden feeling of heat that spreads quickly from the face to the chest and back and then over the rest of the body. It is usually accompanied by outbreaks of profuse sweating, and may sometimes occur several times an hour, and it often occurs at night. Hot flushes and outbreaks of sweats occurring during the night can cause sleep deprivation.
  • Hot flushes may be even more severe in women treated for breast cancer for several reasons. Many survivors of breast cancer are given tamoxifen, the most prevalent side effect of which is hot flush, and many women treated for breast cancer undergo premature menopause from chemotherapy Women with a history of breast cancer are also generally been denied estrogen therapy because of concerns about potential recurrence of breast cancer (Loblui, et al., Lancet, 2000, 356(9247): 2059-2063).
  • estrogen treatment e.g. estrogen replacement therapy
  • relieves the symptoms establishes the link between these symptoms and an estrogen deficiency.
  • estrogen deficiency For example, the menopausal stage of life is associated with a wide range of other acute symptoms as described above and these symptoms are generally estrogen responsive.
  • estrogens may stimulate the activity of both the norepinephrine (NE) and/or serotonin (5-HT) systems ( J. Pharmacology & Experimental Therapeutics, 1986, 236(3) 646-652). It is hypothesized that estrogens modulate NE and 5-HT levels providing homeostasis in the thermoregulatory center of the hypothalamus. The descending pathways from the hypothalamus via brainstem/spinal cord and the adrenals to the skin are involved in maintaining normal skin temperature. The action of NE and 5-HT reuptake inhibitors is known to impinge on both the CNS and peripheral nervous system (PNS).
  • PNS peripheral nervous system
  • the pathophysiology of VMS is mediated by both central and peripheral mechanisms and, therefore, the interplay between the CNS and PNS may account for the efficacy of dual acting SRI/NRIs in the treatment of thermoregulatory dysfunction.
  • the physiological aspects and the CNS/PNS involvement in VMS may account for the lower doses proposed to treat VMS (Loblui, et al., Lancet, 2000, 356:2059-2063; Stearns et al., JAMA, 2003, 289:2827-2834) compared to doses used to treat the behavioral aspects of depression.
  • the interplay of the CNS/PNS in the pathophysiology of VMS supports the claims that the norepinephrine system could be targeted to treat VMS.
  • VMS are most commonly treated by hormone therapy, some patients cannot tolerate estrogen treatment (Berendsen, Maturitas, 2000, 36(3): 155-164, Fink et al., Nature, 1996, 383(6598): 306).
  • hormone replacement therapy is usually not recommended for women or men with or at risk for hormonally sensitive cancers (e.g. breast or prostate cancer).
  • non-hormonal therapies e.g. fluoxetine, paroxetine [SRIs] and clonidine
  • WO9944601 discloses a method for decreasing hot flushes in a human female by administering fluoxetine.
  • ⁇ 2 -Adrenergic receptors play a role in thermoregulatory dysfunctions (Freedman et al., Fertility & Sterility, 2000, 74(1): 20-3). These receptors are located both pre- and post-synaptically and mediate an inhibitory role in the central and peripheral nervous system. There are four distinct subtypes of the adrenergic ⁇ 2 receptors, i.e., are ⁇ 2A , ⁇ 2B , ⁇ 2C and ⁇ 2D (Mackinnon et al., TIPS, 1994, 15: 119; French, Pharmacol. Ther., 1995, 68: 175).
  • a non-select ⁇ 2 -adrenoceptor antagonist, yohimbine induces a flush and an ⁇ 2 -adrenergic receptor agonist, clonidine, alleviates the yohimbine effect (Katovich, et al., Proceedings of the Society for Experimental Biology & Medicine, 1990, 193(2): 129-35, Freedman et al., Fertility & Sterility, 2000, 74(1): 20-3).
  • Clonidine has been used to treat hot flush. However, using such treatment is associated with a number of undesired side effects caused by high doses necessary to abate hot flush described herein and known in the related arts.
  • neuropathic pain i.e., diabetic neuropathy and post-herpetic neuralgia
  • fibromyalgia include off-label use of the tricyclic (TCA) antidepressants (e.g., amytriptyline) and anticonvulsants (e.g., gabapentin) (Collins et al., J. Pain Symptom Manage.
  • TCA tricyclic
  • antidepressants e.g., amytriptyline
  • anticonvulsants e.g., gabapentin
  • noradrenergic pathway A major component of this descending pain inhibitory system involves the noradrenergic pathway (Zhuo, et al., Brain Research 1991; 550:35-48; Holden, et al. Neuroscience 1999; 91: 979-990). It is assumed that norepinephrine (NE), and to a lesser extent serotonin (5-HT) reuptake inhibitor NRIs and SRIs, attenuate pain by preventing presynaptic reuptake of NE/5-HT leading to increased postsynaptic NE/5-HT levels and sustained activation of this descending pain inhibitory pathway.
  • NE norepinephrine
  • 5-HT serotonin
  • the present invention provides novel compounds and compositions containing these compounds directed to these and other important uses.
  • the present invention is directed to aryl sulfamide derivatives, which are monoamine reuptake inhibitors, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions, including, inter alia, vasomotor symptoms (such as hot flush), sexual dysfunction (such as desire-related or arousal-related dysfunction), gastrointestinal disorders and genitourinary disorder (such as stress incontinence or urge incontinence), chronic fatigue syndrome, fibromyalgia syndrome, depression disorders (such as major depressive disorder, generalized anxiety disorder, panic disorder, attention deficit disorder with or without hyperactivity, sleep disturbance, and social phobia), diabetic neuropathy, pain, and combinations thereof.
  • vasomotor symptoms such as hot flush
  • sexual dysfunction such as desire-related or arousal-related dysfunction
  • gastrointestinal disorders and genitourinary disorder such as stress incontinence or urge incontinence
  • chronic fatigue syndrome fibromyalgia syndrome
  • depression disorders such as major depressive disorder, generalized anxiety disorder, panic disorder,
  • One aspect of the invention provides a compound of formula I:
  • composition comprising:
  • Another aspect of the invention provides a method for treating or preventing a condition selected from the group consisting of a vasomotor symptom, sexual dysfunction, gastrointestinal disorder, genitourinary disorder, chronic fatigue syndrome, fibromyalgia syndrome, depression disorder, diabetic neuropathy, endogenous behavioral disorder, cognitive disorder, pain, and combinations thereof in a subject in need thereof, comprising the step of:
  • Another aspect of the invention provides a process for the preparation of a compound of formula I, the process comprising:
  • T is an —N(R 3 )(R 4 ) or an activating group
  • R P is R 4 or a protecting group
  • the process further comprises:
  • Another aspect of the invention provides a process for the preparation of a compound of formula I:
  • R P is R 3 or a protecting group
  • the process further comprises:
  • Another aspect of the invention provides a compound comprising a compound of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL or IM.
  • composition comprising:
  • Norepinephrine transporter is abbreviated NET.
  • hNET Human norepinephrine transporter
  • SERT Sterotonin transporter
  • Human serotonin transporter is abbreviated hSERT.
  • NRI Norepinephrine reuptake inhibitor
  • SNRI Selective norepinephrine reuptake inhibitor
  • SSRI Selective serotonin reuptake inhibitor
  • Norepinephrine is abbreviated NE.
  • Subcutaneous is abbreviated sc.
  • treat includes preventative (e.g., prophylactic), curative or palliative treatment.
  • an effective amount refers to an amount effective, at dosages, and for periods of time necessary, to achieve the desired result with respect to treatment of a given disease or disorder.
  • An effective amount is also one in which any toxic or detrimental effects of the components are outweighed by the therapeutically beneficial effects.
  • “effective amount” refers to the amount of compound or composition of compounds that would increase norepinephrine levels to compensate in part or total for the lack of steroid availability in subjects subject afflicted with a vasomotor symptom. Varying hormone levels will influence the amount of compound required in the present invention. For example, the pre-menopausal state may require a lower level of compound due to higher hormone levels than the peri-menopausal state.
  • the effective amount of components of the present invention will vary from patient to patient not only with the particular compound, component or composition selected, the route of administration, and the ability of the components (alone or in combination with one or more additional active agents) to elicit a desired response in the individual, but also with factors such as the disease state or severity of the condition to be alleviated, hormone levels, age, sex, weight of the individual, the state of being of the patient, and the severity of the pathological condition being treated, concurrent medication or special diets then being followed by the particular patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. Dosage regimens may be adjusted to provide the improved therapeutic response.
  • the compounds of the present invention are administered at a dosage and for a time such that the number of hot flushes is reduced as compared to the number of hot flushes prior to the start of treatment.
  • Such treatment can also be beneficial to reduce the overall severity or intensity distribution of any hot flushes still experienced, as compared to the severity of hot flushes prior to the start of the treatment.
  • the compounds of the present invention are administered at a dosage and for a time sufficient to treat the symptom or condition.
  • compounds of formula I, or a pharmaceutically acceptable salt thereof may be administered, preferably, at a dosage of from about 0.1 mg/day to about 1500 mg/day, dosed one or two times daily, more preferably from about 1 mg/day to about 200 mg/day and most preferably from about 1 mg/day to 100 mg/day for a time sufficient to reduce and/or substantially eliminate the number and/or severity of hot flushes or symptom or condition of the sexual dysfunction, gastrointestinal disorder, genitourinary disorder, chronic fatigue syndrome, fibromyalgia syndrome, depression disorder, diabetic neuropathy, or pain.
  • composition component
  • composition of compounds component
  • compound component
  • drug drug
  • pharmacologically active agent active agent or “medicament”
  • the compounds of formula I may be prepared in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic salts and organic salts.
  • Suitable non-organic salts include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, malic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most preferred is the hydrochloride salt.
  • administering means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body.
  • subject refers to an animal including the human species that is treatable with the compounds, compositions, and/or methods of the present invention.
  • subject or “subjects” is intended to refer to both the male and female gender unless one gender is specifically indicated.
  • patient comprises any mammal which may benefit from treatment or prevention of a disease or disorder, such as a human, especially if the mammal is female, either in the pre-menopausal, peri-menopausal, or post-menopausal period.
  • patient includes female animals including humans and, among humans, not only women of advanced age who have passed through menopause but also women who have undergone hysterectomy or for some other reason have suppressed estrogen production, such as those who have undergone long-term administration of corticosteroids, suffer from Cushing's syndrome or have gonadal dysgenesis.
  • patient is not intended to be limited to a woman.
  • “Side effect” refers to a consequence other than the one(s) for which an agent or measure is used, as one or more adverse effects produced by a drug, especially on a tissue or organ system other then the one sought to be benefited by its administration.
  • the term “side effect” may refer to such conditions as, for example, vomiting, nausea, sweating, and hot flushes (Janowsky, et al., Journal of Clinical Psychiatry, 1984, 45(10 Pt 2): 3-9).
  • hot flush (sometimes called “hot flash”) is an art-recognized term that refers to an episodic disturbance in body temperature typically consisting of a sudden skin flushing, usually accompanied by perspiration in a subject.
  • pre-menopausal means before the menopause
  • peri-menopausal means during the menopause
  • post-menopausal means after the menopause.
  • Oxidectomy means removal of an ovary or ovaries and can be effected according to Merchenthaler et al., Maturitas, 1998, 30(3): 307-316.
  • sexual dysfunction includes, but is not limited to, conditions relating to disorders of sexual desire and/or arousal.
  • gastrointestinal and genitourinary disorders includes irritable bowel syndrome, symptomatic GERD, hypersensitive esophagus, nonulcer dyspepsia, noncardiac chest pain, biliary dyskinesia, sphincter of Oddi dysfunction, incontinence (i.e., urge incontinence, stress incontinence, genuine stress incontinence, and mixed incontinence, including the involuntary voiding of feces or urine, and dribbling or leakage or feces or urine which may be due to one or more causes including but not limited to pathology altering sphincter control, loss of cognitive function, overdistention of the bladder, hyperreflexia and/or involuntary urethral relaxation, weakness of the muscles associated with the bladder or neurologic abnormalities), interstitial cystitis (irritable bladder), and chronic pelvic pain (including, but not limited to vulvodynia, prostatodynia, and
  • CFS chronic fatigue syndrome
  • FMS fibromyalgia syndrome
  • FMS and other somatoform disorders include FMS and other somatoform disorders, including FMS associated with depression, somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated somatoform disorder, and somatoform NOS.
  • FMS and other somatoform disorders are accompanied by physiological symptoms selected from a generalized heightened perception of sensory stimuli, abnormalities in pain perception in the form of allodynia (pain with innocuous stimulation), abnormalities in pain perception in the form of hyperalgesia (increased sensitivity to painful stimuli), and combinations thereof.
  • depression disorder includes major depressive disorder, generalized anxiety disorder, panic disorder, attention deficit disorder with or without hyperactivity, sleep disturbance, social phobia, and combinations thereof.
  • a cognitive disorder includes changes or defects in alertness; mild cognitive impairment (MCI), characterized by problems with memory, language, or other mental functions which is severe enough to be noticeable or be detected by tests, but not serious enough to significantly interfere with daily life; cognitive disorder NOS (not otherwise specified), characterized by a syndrome of cognitive impairment that does not meet the criteria for delirium, dementia or amnesic disorders; age-related cognitive decline (ARCD); and cognitive arousal (such as increased arousal states).
  • MCI mild cognitive impairment
  • NOS not otherwise specified
  • a cognition disorder can be idiopathic, or can be caused by a variety of other factors such as a congenital defect, alcohol or drug addiction, transient or permanent pharmacologic effects of drugs, organic or infectious disease (e.g., Alzheimer's disease, Parkinson's disease, AIDS), trauma (e.g., brain injury, stroke) or advanced age.
  • a congenital defect e.g., alcohol or drug addiction
  • transient or permanent pharmacologic effects of drugs e.g., organic or infectious disease (e.g., Alzheimer's disease, Parkinson's disease, AIDS), trauma (e.g., brain injury, stroke) or advanced age.
  • an “endogenous behavioral disorder” includes attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD, including adult and pediatric forms of predominantly inattentive, predominantly hyperactive, or combined types), obsessive-compulsive disorder (OCD), oppositional or oppositional explosive defiant disorder (ODD/OEDD), anxiety and panic disorders (APD) and temper, rage and outburst behavior disorder (TROBD).
  • ADD/ADHD attention deficit disorder/attention deficit hyperactivity disorder
  • OCD obsessive-compulsive disorder
  • ODD/OEDD oppositional or oppositional explosive defiant disorder
  • APD anxiety and panic disorders
  • temper rage and outburst behavior disorder
  • pain includes both acute and chronic nociceptic or neuropathic pain, which includes centralized pain, peripheral pain, or combination thereof.
  • the term includes many different types of pain, including, but not limited to, visceral pain, musculoskeletal pain, bony pain, cancer pain, inflammatory pain, and combinations thereof, such as lower back pain, atypical chest pain, headache such as cluster headache, migraine, herpes neuralgia, phantom limb pain, pelvic pain, myofascial face pain, abdominal pain, neck pain, central pain, dental pain, opioid resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, post partum pain, angina pain, peripheral neuropathy and diabetic neuropathy, post-operative pain, and pain which is co-morbid with nervous system disorders described herein.
  • acute pain refers to centralized or peripheral pain that is intense, localized, sharp, or stinging, and/or dull, aching, diffuse, or burning in nature and that occurs for short periods of time.
  • chronic pain refers to centralized or peripheral pain that is intense, localized, sharp, or stinging, and/or dull, aching, diffuse, or burning in nature and that occurs for extended periods of time (i.e., persistent and/or regularly reoccurring), including, for the purposes of the present invention, neuropathic pain and cancer pain.
  • Chronic pain includes neuropathic pain, hyperalgesia, and/or allodynia.
  • neuropathic pain refers to chronic pain caused by damage to or pathological changes in the peripheral or central nervous systems.
  • pathological changes related to neuropathic pain include prolonged peripheral or central neuronal sensitization, central sensitization related damage to nervous system inhibitory and/or exhibitory functions and abnormal interactions between the parasympathetic and sympathetic nervous systems.
  • neuropathic pain A wide range of clinical conditions may be associated with or form the basis for neuropathic pain including, for example, diabetes, post traumatic pain of amputation (nerve damage cause by injury resulting in peripheral and/or central sensitization such as phantom limb pain), lower back pain, cancer, chemical injury, toxins, other major surgeries, peripheral nerve damage due to traumatic injury compression, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, reflex sympathetic dystrophy or post thoracotomy pain, nutritional deficiencies, or viral or bacterial infections such as shingles or human immunodeficiency virus (HIV), and combinations thereof.
  • neuropathic pain is a condition secondary to metastatic infiltration, adiposis dolorosa, burns, central pain conditions related to thalamic conditions
  • hypoalgesia refers to pain where there is an increase in sensitivity to a typically noxious stimulus.
  • allodynia refers to an increase in sensitivity to a typically non-noxious stimulus.
  • the term “visceral pain” refers to pain associated with or resulting from maladies of the internal organs, such as, for example, ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, biliary tract disorders, and combinations thereof.
  • maladies of the internal organs such as, for example, ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, biliary tract disorders, and combinations thereof.
  • female-specific pain refers to pain that may be acute and/or chronic pain associated with female conditions.
  • groups of pain include those that are encountered solely or predominately by females, including pain associated with menstruation, ovulation, pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, rupture of a follicular or corpus luteum cyst, irritation of the pelvic viscera, uterine fibroids, adenomyosis, endometriosis, infection and inflammation, pelvic organ ischemia, obstruction, intra-abdominal adhesions, anatomic distortion of the pelvic viscera, ovarian abscess, loss of pelvic support, tumors, pelvic congestion or referred pain from non-gynecological causes, and combinations thereof.
  • Alkyl refers to an optionally substituted, saturated straight, branched, or cyclic hydrocarbon having from about 1 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 1 to about 8 carbon atoms or 1 to 6 carbon atoms (C 1 -C 6 ) being preferred, and with from about 1 to about 4 carbon atoms, herein referred to as “lower alkyl”, being more preferred.
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclopentyl, cyclopropyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclohexyl, cyclooctyl, adamantyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • a branched alkyl group has at least 3 carbon atoms (e.g., an isopropyl group), and in various embodiments, has up to 6 carbon atoms, i.e., a branched lower alkyl group.
  • a branched alkyl group has at least 3 carbon atoms (e.g., an isopropyl group), and in various embodiments, has up to 6 carbon atoms, i.e., a branched lower alkyl group.
  • Examples of branched lower alkyl groups include, but are not limited to:
  • Alkenyl refers to an alkyl group of at least two carbon atoms having one or more double bonds, wherein alkyl is as defined herein. Preferred alkenyl groups have from 2 to 6 carbon atoms (C 2 -C 6 ). Alkenyl groups can be optionally substituted.
  • Alkynyl refers to an alkyl group of at least two carbon atoms having one or more triple bonds, wherein alkyl is as defined herein. Preferred alkynyl groups have from 2 to 6 carbon atoms (C 2 -C 6 ). Alkynyl groups can be optionally substituted.
  • Alkylenyl refers to the subsets of alkyl, alkenyl, alkynyl and aryl groups, respectively, as defined herein, including the same residues as alkyl, alkenyl, alkynyl, and aryl but having two points of attachment within a chemical structure.
  • C 1 -C 6 alkylenyl examples include methylenyl (—CH 2 —), ethylenyl (—CH 2 CH 2 —), propylenyl (—CH 2 CH 2 CH 2 —), and dimethylpropylenyl (—CH 2 C(CH 3 ) 2 CH 2 —).
  • examples of C 2 -C 6 alkenylenyl include ethenylenyl (—CH ⁇ CH— and propenylenyl (—CH ⁇ CH—CH 2 —).
  • C 2 -C 6 alkynylenyl examples include ethynylenyl (—C ⁇ C—) and propynylenyl (—C ⁇ C—CH 2 —).
  • arylenyl groups include phenylenyl;
  • arylenyl groups contain 6 carbon atoms (C 6 ).
  • Halo refers to chloro, bromo, fluoro, and iodo.
  • Aryl refers to an optionally substituted, mono-, di-, tri-, or other multicyclic aromatic ring system having from about 5 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 6 to about 10 carbons (C 6 -C 10 ) being preferred.
  • Non-limiting examples include, for example, phenyl, naphthyl, anthracenyl, and phenanthrenyl.
  • Heteroaryl refers to an optionally substituted, mono-, di-, tri-, or other multicyclic aromatic ring system that includes at least one, and preferably from 1 to about 4 heteroatom ring members selected from sulfur, oxygen and nitrogen. Heteroaryl groups can have, for example, from about 3 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 4 to about 10 carbons being preferred.
  • heteroaryl groups include, for example, pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.
  • Heterocyclic ring refers to a stable 4- to 12-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring that is saturated, partially unsaturated or unsaturated (aromatic), and which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above defined heterocyclic rings is fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen atom in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds one, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than two.
  • heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4H-carbazolyl, ⁇ -, ⁇ -, or ⁇ -carbolinyl, chromanyl, chromenyl, cinnolinyl, de
  • Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
  • Alkoxy refers to the group R—O— where R is an alkyl group, as defined herein. Preferred alkoxy groups have from 1 to 6 carbon atoms (C 1 -C 6 ).
  • Arylalkyl refers to the group R′—R— where R′ is an aryl group, as defined herein, and R is an alkyl group, as defined herein. Preferred arylalkyl groups have from 7 to 16 carbon atoms (C 7 -C 16 ).
  • Heteroarylalkyl refers to the group R′′—R— where R′′ is a heteroaryl group, as defined herein, and R is an alkyl group, as defined herein.
  • Heteroarylmethyl refers to the group R′′—CH 2 — where R′′ is a heteroaryl group, as defined herein.
  • Alkanoyloxy refers to the group R—C( ⁇ O)—O— where R is an alkyl group, as defined herein, of 1 to 5 carbon atoms (C 1 -C 5 ).
  • Alkylsulfoxide refers to as used herein, refers to —S( ⁇ O)—R, where R is alkyl, as defined herein.
  • Preferred alkysulfoxide groups have from 1 to 6 carbon atoms (C 1 -C 6 ).
  • Arylsulfoxide refers to as used herein, refers to —S( ⁇ O)—R′, where R′ is aryl, as defined herein.
  • Preferred arylsulfoxide groups have from 6 to 10 carbon atoms (C 6 -C 10 ).
  • Alkylsulfone refers to —S( ⁇ O) 2 —R, where R is alkyl, as defined herein.
  • Preferred alkylsulfone groups have from 1 to 6 carbon atoms (C 1 -C 6 ).
  • Arylsulfone refers to —S( ⁇ O) 2 —R′, where R′ is aryl, as defined herein. Preferred arylsulfone groups have from 6 to 10 carbon atoms (C 6 -C 10 ).
  • Alkylsulfonamide refers to —NR—S( ⁇ O) 2 —R, where each R is independently, alkyl, as defined above, or the NR part may also be NH.
  • Preferred alkylsulfonamide groups have from 1 to 6 carbon atoms (C 1 -C 6 ).
  • Arylsulfonamide refers to —NR—S( ⁇ O) 2 —R′, where R is H or alkyl, as defined herein, and R′ is aryl, as defined herein. Preferred arylsulfonamide groups have from 6 to 10 carbon atoms (C 6 -C 10 ).
  • Heteroarylsulfonamide refers to —NR—S( ⁇ O) 2 —R′′, where R is H or alkyl, as defined herein, and R′′ is aryl, as defined herein.
  • Alkylamido refers to —NR—C( ⁇ O)—R, where each R is independently, alkyl, as defined above, or the NR part may also be NH.
  • Preferred alkylamido groups have from 1 to 6 carbon atoms (C 1 -C 6 ).
  • Arylamido refers to —NR—C( ⁇ O)—R′′, where R is H or alkyl, as defined herein, and R′′ is aryl, as defined herein. Preferred arylamido groups have from 6 to 10 carbon atoms (C 6 -C 10 ).
  • Phenylamido refers to —NR—C( ⁇ O)-phenyl, where R is H or alkyl, as defined above.
  • substituent groups independently include hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, aminocarbonyl, carbonylamino, carbonyl, oxo, guanidine, carboxyl, formyl, alkyl, perfluoroalkyl, alkyamino, dialkylamino, alkoxy, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, alkylthio, aryl, heteroaryl, a heterocyclic ring, cycloalkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, alkenyl, alkynyl, arylalkyl, aryloxy,
  • Substituent groups that have one or more available hydrogen atoms can in turn optionally bear further independently selected substituents, to a maximum of three levels of substitutions.
  • the term “optionally substituted alkyl” is intended to mean an alkyl group that can optionally have up to four of its hydrogen atoms replaced with substituent groups as defined above (i.e., a first level of substitution), wherein each of the substituent groups attached to the alkyl group can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a second level of substitution), and each of the substituent groups of the second level of substitution can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a third level of substitution).
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent “arylalkoxycabonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups.
  • impermissible substitution patterns are well known to the skilled artisan.
  • C 1-6 alkyl is specifically intended to individually disclose C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 alkyl.
  • the term “5-9 membered heteroaryl group” is specifically intended to individually disclose a heteroaryl group having 5, 6, 7, 8, 9, 5-9, 5-8, 5-7, 5-6, 6-9, 6-8, 6-7, 7-9, 7-8, and 8-9 ring atoms.
  • protecting group or “G p ” with respect to amine groups, hydroxyl groups and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art, such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999) which can be added or removed using the procedures set forth therein.
  • Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
  • a reagent such as, but not limited to
  • Examples of protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; carbamates; e.g. BOC; imides, such as phthalimide, Fmoc, Cbz, PMB, benzyl, and dithiosuccinimide; and others.
  • Examples of protected or capped sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • activated or “an activating group” or “G a ” as used herein indicates having an electrophilic moiety bound to a substituent, capable of being displaced by a nucleophile.
  • activating groups are halogens, such as Cl, Br or I, and F; triflate; mesylate, or tosylate; esters; aldehydes; ketones; epoxides; and the like.
  • An example of an activated group is acetylchloride, which is readily attacked by a nucleophile, such as piperidine group to form a N-acetylpiperidine functionality.
  • deprotecting refers to removal of a protecting group, such as removal of a benzyl or BOC group bound to an amine. Deprotecting may be preformed by heating and/or addition of reagents capable of removing protecting groups. In preferred embodiments, the deprotecting step involves addition of an acid, base, reducing agent, oxidizing agent, heat, or any combination thereof.
  • One preferred method of removing BOC groups from amino groups is to add HCl in ethyl acetate.
  • Many deprotecting reactions are well known in the art and are described in Protective Groups in Organic Synthesis, Greene, T. W., John Wiley & Sons, New York, N.Y., (1st Edition, 1981), the entire disclosure of which is herein incorporated by reference.
  • One aspect of the invention provides a compound of formula I:
  • each R 1 is H.
  • R 2 is:
  • each R 5 , R 3 , R 7 , R 8 and R 9 are independently selected from the group consisting of H, alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl substituted, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, or arylamido.
  • R 7 and R 9 are F.
  • R 5 , R 6 , R 7 and R 8 are H.
  • R 9 is F.
  • R 5 , R 6 and R 8 are H.
  • R 5 is H or F
  • R 6 is H or F
  • R 7 is H or F
  • R 3 is H or F
  • R 9 is H or F.
  • R 5 , R 6 , R 7 , R 8 and R 9 are H, halo, alkyl or alkoxy.
  • R 3 is alkyl. More particularly, methyl.
  • R 4 is H.
  • m is an integer from 2 to 6. More particularly, m is 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, or 4 to 5. In another embodiment, m is 1, m is 2, m is 3, m is 4, m is 5 or m is 6.
  • ring A comprises all carbon atoms.
  • R 2 is pyridinyl, methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or quinolinyl.
  • R 2 is phenyl, fluoro-phenyl, difluoro-phenyl, trifluorophenyl, chloro-phenyl, fluoro-chloro-phenyl, bromo-phenyl, trifluoromethyl-phenyl trifluoromethoxy-phenyl, methyl-fluoro-phenyl, methoxy-fluoro-phenyl, or naphthyl.
  • each R 1 is H
  • n 1;
  • R 3 is methyl
  • R 4 is H.
  • each R 1 is H
  • R 7 and R 9 are F
  • R 5 , R 6 and R 8 are H
  • R 3 is methyl
  • R 4 is H
  • Another aspect of the invention provides a compound is selected from the group consisting of:
  • Another aspect of the invention provides a compound selected from the group consisting of:
  • said pharmaceutically acceptable salt is a hydrochloride or dihydrochloride.
  • composition comprising:
  • Another aspect of the invention provides a method for treating or preventing a condition selected from the group consisting of a vasomotor symptom, sexual dysfunction, gastrointestinal disorder, genitourinary disorder, chronic fatigue syndrome, fibromyalgia syndrome, depression disorder, diabetic neuropathy, endogenous behavioral disorder, cognitive disorder, pain, and combinations thereof in a subject in need thereof, comprising the step of:
  • the vasomotor symptom is hot flush.
  • the sexual dysfunction is desire-related or arousal-related.
  • the gastrointestinal disorder or the genitourinary disorder is stress incontinence or urge incontinence.
  • the condition is chronic fatigue syndrome.
  • the condition is fibromyalgia syndrome.
  • the condition is a depression disorder selected from the group consisting of major depressive disorder, generalized anxiety disorder, panic disorder, attention deficit disorder with or without hyperactivity, sleep disturbance, social phobia, and combinations thereof.
  • the disorder is an endogenous behavioral disorder or a cognitive disorder.
  • the condition is diabetic neuropathy.
  • the condition is pain.
  • the pain is acute centralized pain, acute peripheral pain, or a combination thereof.
  • the pain is chronic centralized pain, chronic peripheral pain, or a combination thereof.
  • the pain is neuropathic pain, visceral pain, musculoskeletal pain, bony pain, cancer pain, inflammatory pain, or a combination thereof.
  • the neuropathic pain is associated with diabetes, post traumatic pain of amputation, lower back pain, cancer, chemical injury, toxins, major surgery, peripheral nerve damage due to traumatic injury compression, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, reflex sympathetic dystrophy or post thoracotomy pain, nutritional deficiencies, viral infection, bacterial infection, metastatic infiltration, adiposis dolorosa, burns, central pain conditions related to thalamic conditions, or a combination thereof.
  • the neuropathic pain is post-herpetic neuralgia.
  • the visceral pain is associated with ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, biliary tract disorders, or a combination thereof.
  • the pain is female-specific pain.
  • norepinephrine activity in the hypothalamus or in the brainstem can be elevated by (i) blocking the activity of the NE transporter, (ii) blocking the activity of the presynaptic adrenergic ⁇ 2 receptor with an antagonist, or (iii) blocking the activity of 5-HT on NE neurons with a 5-HT 2a antagonist.
  • the compounds of the invention are also useful to prevent and treat pain.
  • the pain may be, for example, acute pain or chronic pain.
  • the pain may also be centralized or peripheral.
  • Examples of pain that can be acute or chronic and that can be treated in accordance with the methods of the present invention include inflammatory pain, musculoskeletal pain, bony pain, lumbosacral pain, neck or upper back pain, visceral pain, somatic pain, neuropathic pain, cancer pain, pain caused by injury or surgery such as burn pain or dental pain, or headaches such as migraines or tension headaches, or combinations of these pains.
  • a pain caused by inflammation may also be visceral or musculoskeletal in nature.
  • the compounds useful in the present invention are administered in mammals to treat chronic pain such as neuropathic pain associated for example with damage to or pathological changes in the peripheral or central nervous systems; cancer pain; visceral pain associated with for example the abdominal, pelvic, and/or perineal regions or pancreatitis; musculoskeletal pain associated with for example the lower or upper back, spine, fibromyalgia, temporomandibular joint, or myofascial pain syndrome; bony pain associated with for example bone or joint degenerating disorders such as osteoarthritis, rheumatoid arthritis, or spinal stenosis; headaches such migraine or tension headaches; or pain associated with infections such as HIV, sickle cell anemia, autoimmune disorders, multiple sclerosis, or inflammation such as osteoarthritis or rheumatoid arthritis.
  • chronic pain such as neuropathic pain associated for example with damage to or pathological changes in the peripheral or central nervous systems; cancer pain; visceral pain associated with for example the abdominal, pelvic, and/or
  • the compounds useful in this invention are used to treat chronic pain that is neuropathic pain, visceral pain, musculoskeletal pain, bony pain, cancer pain or inflammatory pain or combinations thereof, in accordance with the methods described herein.
  • Inflammatory pain can be associated with a variety of medical conditions such as osteoarthritis, rheumatoid arthritis, surgery, or injury.
  • Neuropathic pain may be associated with for example diabetic neuropathy, peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, or nerve damage cause by injury resulting in peripheral and/or central sensitization such as phantom limb pain, reflex sympathetic dystrophy or postthoracotomy pain, cancer, chemical injury, toxins, nutritional deficiencies, or viral or bacterial infections such as shingles or HIV, or combinations thereof.
  • the methods of use for compounds of this invention further include treatments in which the neuropathic pain is a condition secondary to metastatic infiltration, adiposis dolorosa, burns, or central pain conditions related to thalamic conditions.
  • somatic pain that can be treated in accordance with the methods of the present invention include pains associated with structural or soft tissue injury experienced during surgery, dental procedures, burns, or traumatic body injuries.
  • visceral pain that can be treated in accordance with the methods of the present invention include those types of pain associated with or resulting from maladies of the internal organs such as ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, or biliary tract disorders, or combinations thereof.
  • the pain treated according to the methods of the present invention may also be related to conditions of hyperalgesia, allodynia, or both. Additionally, the chronic pain may be with or without peripheral or central sensitization.
  • the compounds useful in this invention may also be used to treat acute and/or chronic pain associated with female conditions, which may also be referred to as female-specific pain.
  • groups of pain include those that are encountered solely or predominately by females, including pain associated with menstruation, ovulation, pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, rupture of a follicular or corpus luteum cyst, irritation of the pelvic viscera, uterine fibroids, adenomyosis, endometriosis, infection and inflammation, pelvic organ ischemia, obstruction, intra-abdominal adhesions, anatomic distortion of the pelvic viscera, ovarian abscess, loss of pelvic support, tumors, pelvic congestion or referred pain from non-gynecological causes.
  • Another aspect of the invention provides a process for the preparation of a compound of formula I, the process comprising:
  • T is an —N(R 3 )(R 4 ) or an activating group
  • R P is R 4 or a protecting group
  • the process further comprises:
  • step (d) further comprises contacting the compound of formula IA and IB with dialkyl azodicarboxylate and triphenylphosphine.
  • dialkyl azodicarboxylate is diisopropyl azodicarboxylate.
  • the activating group is selected from the group consisting of halo, tosylate, mesylate, triflate, and oxo.
  • the activating group is Br.
  • the protecting group is selected from the group consisting of BOC, benzyl, acetyl, PMB, C 1 -C 6 alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and triphenylmethyl.
  • the protecting group is BOC.
  • the deprotecting step is performed in the presence of at least one agent selected from hydrochloric acid (HCl), tin(II) chloride, ammonium chloride, zinc, trifluoroacetic acid (TFA), tosic acid, a halotrimethylsilane, or aluminum chloride.
  • at least one agent selected from hydrochloric acid (HCl), tin(II) chloride, ammonium chloride, zinc, trifluoroacetic acid (TFA), tosic acid, a halotrimethylsilane, or aluminum chloride.
  • any one of steps (d)-(g) is performed at or above 30° C. or any one of steps (d)-(g) includes a purification step comprising at least one of: filtration, extraction, chromatography, trituration, or recrystallization.
  • the activated-R 3 group is halo-R 3 .
  • the compound of formula IA is prepared by:
  • R B is F or Cl
  • the hydrogenating step is performed in the presence of hydrogen (H 2 ) and Pd/C.
  • any one of steps (a)-(c) is performed at or above 30° C.
  • any one of steps (a)-(c) includes a purification step comprising at least one of: filtration, extraction, chromatography, trituration, or recrystallization.
  • Another aspect of the invention provides a process for the preparation of a compound of formula I:
  • R P is R 3 or a protecting group
  • the process further comprises:
  • the transitional metal salt is copper(II) acetate.
  • the activated-R 3 group is halo-R 3 .
  • the protecting group is selected from the group consisting of BOC, benzyl, acetyl, PMB, C 1 -C 6 alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and triphenylmethyl.
  • the protecting group is BOC.
  • the deprotecting step is performed in the presence of at least one agent selected from hydrochloric acid (HCl), tin(II) chloride, ammonium chloride, zinc, trifluoroacetic acid (TFA), tosic acid, a halotrimethylsilane, or aluminum chloride.
  • at least one agent selected from hydrochloric acid (HCl), tin(II) chloride, ammonium chloride, zinc, trifluoroacetic acid (TFA), tosic acid, a halotrimethylsilane, or aluminum chloride.
  • any one of steps (d)-(f) is performed at or above 30° C. or any one of steps (d)-(f) includes a purification step comprising at least one of: filtration, extraction, chromatography, trituration, or recrystallization.
  • the compound of formula IH is prepared by:
  • R B is F or Cl
  • the hydrogenating step is performed in the presence of hydrogen (H 2 ) and Pd/C.
  • any one of steps (a)-(c) is performed at or above 30° C.
  • any one of steps (a)-(c) includes a purification step comprising at least one of: filtration, extraction, chromatography, trituration, or recrystallization.
  • any one of the steps is performed in: a protic solvent, an aprotic solvent, a polar solvent, a nonpolar solvent, a protic polar solvent, an aprotic nonpolar solvent, or an aprotic polar solvent.
  • any one of the steps is performed in: a protic solvent, an aprotic solvent, a polar solvent, a nonpolar solvent, a protic polar solvent, an aprotic nonpolar solvent, or an aprotic polar solvent.
  • Another aspect of the invention provides a compound comprising a compound of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL or IM.
  • composition comprising:
  • a base one or more of: a base, an acid, a solvent, a hydrogenating agent, a reducing agent, an oxidizing agent, or a catalyst.
  • Some of the compounds of the present invention may contain chiral centers and such compounds may exist in the form of stereoisomers (i.e. enantiomers or diastereomers).
  • the present invention includes all such stereoisomers and any mixtures thereof including racemic mixtures. Racemic mixtures of the stereoisomers as well as the substantially pure stereoisomers are within the scope of the invention.
  • the term “substantially pure,” as used herein, refers to at least about 90 mole %, more preferably at least about 95 mole %, and most preferably at least about 98 mole % of the desired stereoisomer is present relative to other possible stereoisomers.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by methods described herein. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley
  • the present invention includes prodrugs of the compounds of formula I.
  • “Prodrug,” as used herein, means a compound which is convertible in vivo by chemical or metabolic means (e.g. by hydrolysis) to a compound of formula I.
  • Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs , Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology , vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed).
  • the compounds of formula I may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purpose of the present invention.
  • the compounds of the present invention may be prepared in a number of ways well known to those skilled in the art.
  • the compounds can be synthesized, for example, by the methods described below, or variations thereon as appreciated by the skilled artisan. All processes disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale.
  • protecting groups may contain protecting groups during the course of synthesis.
  • Protecting groups are known per se as chemical functional groups that can be selectively appended to and removed from functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention.
  • Protecting groups that may be employed in accordance with the present invention may be described in Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons, 1991, the entire disclosure of which is herein incorporated by reference.
  • the compounds of this invention contain chiral centers, providing for various stereoisomeric forms such as diastereomeric mixtures, enantiomeric mixtures as well as optical isomers.
  • the individual optical isomers can be prepared directly through asymmetric and/or stereospecific synthesis or by conventional chiral separation of optical isomers from the enantiomeric mixture.
  • an appropriate fluoronitroarene 1 may be substituted with an aryl amine using a base under standard conditions to provide an aminonitroarene 2.
  • a base such as sodium hydride in DMF or an organometallic base such as butyllithium in THF.
  • Reduction of the nitro group in structure 2 is accomplished under standard conditions using hydrogen and a suitable catalyst such as palladium or Raney nickel to provide a dianiline 3.
  • Nitro reduction is a common transformation and one could employ a number of alternative procedures including reduction conditions using metal salts such as aqueous HCl with tin(II) chloride or aqueous ammonium chloride with zinc metal.
  • the dianiline 3 is then treated a suitable sulfate containing reagent to form arylsulfamide of structure 4.
  • 3 was heated with sulfamide in diglyme to provide the cyclized product 4.
  • the acidic nitrogen is then combined with a suitably substituted side chain providing products 5 or 6 defending on the structure of the desired side chain.
  • An effective method for attaching the side chain to sulfamide 4 is the Mitsunobu reaction in which an alcohol is activated and displaced by treating with a phosphine and an activating reagent.
  • typical conditions for effecting the attachment of the sulfamide to the alcohol containing side chain were treatment with diisopropyl azodicarboxylate and triphenylphosphine in THF.
  • Another suitable method for accomplishing side chain attachment is direct nucleophilic substitution of a leaving group containing side chain with the sulfamide and can be facilitated by addition of a base in a suitable solvent.
  • compounds of structure 5 with a bromine containing side chain were treated with an excess of the desired amine to provide the desired compounds of formula I.
  • An alternative method for the synthesis of compounds of formula I is possible from 6 where the side chain is attached with the amine present in protected form (the protecting group is represented by the letter P). Any suitable amine protecting group, t-butoxycarbonyl in a typical example, may be used. The protecting group is then removed, in the case of t-butoxycarbonyl using an acid such as hydrochloric acid, to give compounds of formula I.
  • an aryl boronic acid forms an aryl-nitrogen bond in the presence of a transition metal salt such as copper(II) acetate to provide 6.
  • a transition metal salt such as copper(II) acetate
  • Subsequent deprotection of the protecting group P in 6 affords compounds of formula I.
  • the protecting group t-butoxycarbonyl was useful for this purpose and is readily removed using an acid such as hydrochloric acid to give compounds of formula I.
  • compositions comprising:
  • the compound of formula I, or a pharmaceutically acceptable salt thereof will be present at a level of from about 0.1%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition, based on the total weight of the pharmaceutical composition.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof will be present at a level of at least about 1%, by weight, based on the total weight of the pharmaceutical composition. More preferably, the compound of formula I, or a pharmaceutically acceptable salt thereof, will be present at a level of at least about 5%, by weight, based on the total weight of the pharmaceutical composition.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof will be present at a level of at least about 10%, by weight, based on the total weight of the pharmaceutical composition. Yet even more preferably, the compound of formula I, or a pharmaceutically acceptable salt thereof, will be present at a level of at least about 25%, by weight, based on the total weight of the pharmaceutical composition.
  • compositions are prepared in accordance with acceptable pharmaceutical procedures, such as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is herein incorporated by reference.
  • Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.
  • the compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances that may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
  • the carrier is a finely divided solid that is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to about 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups, and elixirs.
  • the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols
  • oils e.g. fractionated coconut oil and arachis oil
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • Liquid pharmaceutical compositions for parenteral administration which are sterile solutions or suspensions, can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the compounds useful in the present invention may be administered to a mammal with one or more other pharmaceutical active agents such as those agents being used to treat any other medical condition present in the mammal.
  • pharmaceutical active agents include pain relieving agents, anti-angiogenic agents, anti-neoplastic agents, anti-diabetic agents, anti-infective agents, or gastrointestinal agents, or combinations thereof.
  • the one or more other pharmaceutical active agents may be administered in a therapeutically effective amount simultaneously (such as individually at the same time, or together in a pharmaceutical composition), and/or successively with one or more compounds of the present invention.
  • combination therapy refers to the administration of two or more therapeutic agents or compounds to treat a therapeutic condition or disorder described in the present disclosure, for example hot flush, sweating, thermoregulatory-related condition or disorder, or other condition or disorder.
  • a therapeutic condition or disorder described in the present disclosure for example hot flush, sweating, thermoregulatory-related condition or disorder, or other condition or disorder.
  • Such administration includes use of each type of therapeutic agent in a concurrent manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • the route of administration may be any enteral or parenteral route which effectively transports the active compound of formula I, or a pharmaceutically acceptable salt thereof, to the appropriate or desired site of action; such as oral, nasal, pulmonary, transdermal, such as passive or iontophoretic delivery, or parenteral, e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intrathecal, intra-articular, intranasal, ophthalmic solution or an ointment.
  • the administration of compound of formula I, or pharmaceutically acceptable salt thereof, with other active ingredients may be separate, consecutive or simultaneous.
  • Step 1 Dry diglyme (10 mL) was added to a flask equipped with a dropping funnel under a nitrogen atmosphere and brought to a vigorous reflux. N-(4-chlorophenyl)-benzene-1,2-diamine (1.09 g, 5.0 mmol) and sulfamide (0.58 g, 6.0 mmol) were dissolved in 5 mL of diglyme and placed in the dropping funnel. The mixture was added dropwise to the flask over 15 minutes and then refluxing was continued for an additional 15 minutes. The mixture was cooled to ambient temperature and diluted with ether, washed with water, 2N HCl, water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 1-(4-Chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.28 g, 1.0 mmol) was dissolved in THF (10 mL). Triphenylphosphine (314 mg, 1.2 mmol) and 3-bromopropanol (0.089 mL, 1.0 mmol) were added followed by diisopropylazodicarboxylate (0.23 mL, 1.2 mmol). The mixture was stirred for 16 hours and then concentrated.
  • Step 3 1-(3-Bromo-propyl)-3-(4-chloro-phenyl)-1,3-dihydro benzo[1,2,5]thia-diazole 2,2-dioxide (0.12 g, 0.29 mmol) was dissolved in 8N methylamine in methanol (20 mL) and stirred for 16 hours in a sealed flask. The mixture was concentrated in vacuo to give the crude product.
  • Step 3 1-(3-bromo-propyl)-3-(4-chloro-phenyl)-1,3-dihydrobenzo[1,2,5]thiadiazole 2,2-dioxide (0.10 g, 0.25 mmol) was treated with cyclopropyl amine to provide N- ⁇ 3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl ⁇ cyclopropanamine (87 mg).
  • Step 3 1-(3-bromo-propyl)-3-(4-chloro-phenyl)-1,3-dihydrobenzo[1,2,5]thiadiazole 2,2-dioxide (0.06 g, 0.15 mmol) was treated with ethyl amine to provide 3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine (42 mg).
  • Step 1 In an analogous manner to General Procedure A, Step 1, N-phenyl-o-phenylenediamine (0.10 g, 5.4 mmol) was treated with sulfamide (0.63 g, 6.5 mmol) to provide 1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.90 g).
  • Step 2 In an analogous manner to General Procedure A, Step 2, 1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (246 mg, 1.0 mmol) was treated with triphenylphosphine (0.31 g, 1.2 mmol), 3-bromopropanol (0.087 mL, 1 mmol), and diisopropylazodicarboxylate (0.23 mL, 1.2 mmol) to provide 1-(3-bromopropyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.19 g).
  • Step 3 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.17 g, 0.46 mmol) was treated with methylamine to provide 3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine (120 mg).
  • Step 1 4-Fluoroaniline (5.5 g, 50 mmol) was dissolved in DMF (100 mL) and sodium hydride (1.9 g, 50 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (4.4 mL, 42 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH 4 Cl and diluted with ethyl acetate and ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 N-(4-fluorophenyl)-N-(2-nitrophenyl)amine (3.0 g, 12.9 mmol) was dissolved in ethyl acetate (30 mL) and 10% palladium on activated carbon (250 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 1 hour. The mixture was filtered through a pad of Celite and concentrated to give N-(4-fluorophenyl)benzene-1,2-diamine (2.6 g) that was carried on directly to the next step.
  • Step 3 in an analogous manner to General Procedure A, Step 1, N-(4-fluorophenyl)benzene-1,2-diamine (2.4 g, 11.9 mmol) was treated with sulfamide (1.36 g, 14.3 mmol) to provide 1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (2.2 g).
  • Step 4 In an analogous manner to General Procedure A, Step 2, 1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (2.2 g, 8.3 mmol) was treated with triphenylphosphine (2.62 g, 10 mmol), 3-bromopropanol (0.72 mL, 8.3 mmol), and diisopropylazodicarboxylate (1.94 mL, 10 mmol) to provide 1-(3-bromopropyl)-3-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (2.3 g).
  • Step 5 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (2.3 g, 6 mmol) was treated with methylamine to provide 3-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine (1.65 g).
  • Step 1 p-Anisidine (1.0 g, 8.1 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.31 g, 8.1 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (0.86 mL, 8.1 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH 4 Cl and diluted with ethyl acetate and ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 N-(4-methoxyphenyl)-2-nitroaniline (0.4 g, 1.6 mmol) was dissolved in ethyl acetate (15 mL) and 10% palladium on activated carbon (100 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 2 hours. The mixture was filtered through a pad of Celite and concentrated to give N-(4-methoxyphenyl)benzene-1,2-diamine (0.34 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to General Procedure A, Step 1, N-(4-methoxyphenyl)benzene-1,2-diamine (0.34 g, 1.6 mmol) was treated with sulfamide (0.18 g, 1.9 mmol) to provide 1-(4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.17 g).
  • Step 4 In an analogous manner to General Procedure A, Step 2, 1-(4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.13 g, 0.47 mmol) was treated with triphenylphosphine (146 mg, 0.56 mmol), 3-bromopropanol (0.041 mL, 0.47 mmol), and diisopropylazodicarboxylate (0.11 mL, 0.56 mmol) to provide 1-(3-bromopropyl)-3-(4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.12 g).
  • Step 5 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-(4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (100 mg, 0.25 mmol) was treated with methylamine to provide 3-[3-(4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine (70 mg).
  • Step 1 p-Toluidine (1.4 g, 13 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL, 10 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH 4 Cl and diluted with ethyl acetate and ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 N-(4-methylphenyl)-N-(2-nitrophenyl)amine (0.59 g, 2.6 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium on activated carbon (50 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered through a pad of Celite and concentrated to give N-(4-methylphenyl)benzene-1,2-diamine (0.5 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to General Procedure A, Step 1, N-(4-methylphenyl)benzene-1,2-diamine (0.5 g, 2.5 mmol) was treated with sulfamide (0.29 g, 3.0 mmol) to provide 1-(4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.31 g).
  • Step 4 In an analogous manner to General Procedure A, Step 2, 1-(4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.24 g, 0.92 mmol) was treated with triphenylphosphine (0.288 g, 1.1 mmol), 3-bromopropanol (0.081 mL, 0.92 mmol), and diisopropylazodicarboxylate (0.21 mL, 1.1 mmol) to provide 1-(3-bromopropyl)-3-(4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.26 g).
  • Step 5 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-(4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (240 mg, 0.63 mmol) was treated with methylamine to provide N-methyl-3-[3-(4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine (190 mg).
  • Step 1 o-Anisidine (1.7 mL, 15 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL, 10 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH 4 Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 N-(2-methoxyphenyl)-N-(2-nitrophenyl)amine (0.66 g, 2.7 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium on activated carbon (50 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered through a pad of Celite and concentrated to give N-(2-methoxyphenyl)benzene-1,2-diamine (0.56 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to General Procedure A, Step 1, N-(2-methoxyphenyl)benzene-1,2-diamine (0.56 g, 2.6 mmol) was treated with sulfamide (0.30 g, 3.1 mmol) to provide 1-(2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.41 g).
  • Step 4 In an analogous manner to General Procedure A, Step 2, 1-(2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.35 g, 1.27 mmol) was treated with triphenylphosphine (400 mg, 1.5 mmol), 3-bromopropanol (0.11 mL, 1.27 mmol), and diisopropylazodicarboxylate (0.29 mL, 1.5 mmol) to provide 1-(3-bromopropyl)-3-(2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.44 g).
  • Step 5 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-(2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (410 mg, 1.0 mmol) was treated with methylamine to provide 3-[3-(2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine (330 mg).
  • Step 1 3-Fluoro-2-methylaniline (1.7 mL, 15 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL, 10 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH 4 Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 (3-Fluoro-2-methyl-phenyl)-(2-nitro-phenyl)-amine (1.1 g, 4.5 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium on activated carbon (100 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered through a pad of Celite and concentrated to give N-(3-Fluoro-2-methyl-phenyl)-benzene-1,2-diamine (0.86 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to General Procedure A, Step 1, N-(3-Fluoro-2-methyl-phenyl)-benzene-1,2-diamine (0.86 g, 4.0 mmol) was treated with sulfamide (0.46 g, 4.8 mmol) to provide 1-(3-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.48 g).
  • Step 4 In an analogous manner to General Procedure A, Step 2, 1-(3-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.43 g, 1.55 mmol) was treated with triphenylphosphine (470 mg, 1.8 mmol), 3-bromopropanol (0.134 mL, 1.55 mmol), and diisopropylazodicarboxylate (0.34 mL, 1.8 mmol) to provide 1-(3-bromopropyl)-3-(3-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.43 g).
  • Step 5 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-(3-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (420 mg, 1.0 mmol) was treated with methylamine to provide 3-[3-(3-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine (350 mg).
  • Step 1 2-Fluoroaniline (1.45 mL, 15 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL, 10 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH 4 Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 2-fluoro-N-(2-nitrophenyl)aniline (1.4 g, 6.0 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium on activated carbon (150 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 2 hours. The mixture was filtered through a pad of Celite and concentrated to give N-(2-fluorophenyl)benzene-1,2-diamine (1.2 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to General Procedure A, Step 1, N-(2-fluorophenyl)benzene-1,2-diamine (1.2 g, 6.0 mmol) was treated with sulfamide (0.69 g, 7.2 mmol) to provide 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.37 g).
  • Step 4 In an analogous manner to General Procedure A, Step 2, 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.37 g, 1.4 mmol) was treated with triphenylphosphine (440 mg, 1.68 mmol), 3-bromopropanol (0.12 mL, 1.4 mmol), and diisopropylazodicarboxylate (0.33 mL, 1.68 mmol) to provide 1-(3-bromopropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.41 g).
  • triphenylphosphine 440 mg, 1.68 mmol
  • 3-bromopropanol (0.12 mL, 1.4 mmol
  • diisopropylazodicarboxylate 0.33 mL, 1.68 mmol
  • Step 5 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.4 g, 1.04 mmol) was treated with methylamine to provide 3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine (350 mg).
  • Step 1 3-Fluoroaniline (1.43 mL, 15 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL, 10 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH 4 Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 N-(3-fluorophenyl)-N-(2-nitrophenyl)amine (0.77 g, 3.3 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium on activated carbon (50 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered through a pad of Celite and concentrated to give N-(3-fluorophenyl)benzene-1,2-diamine (0.64 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to General Procedure A, Step 1, N-(3-fluorophenyl)benzene-1,2-diamine (0.64 g, 3.2 mmol) was treated with sulfamide (0.36 g, 3.8 mmol) to provide 1-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.17 g).
  • Step 4 In an analogous manner to General Procedure A, Step 2, 1-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.16 g, 0.61 mmol) was treated with triphenylphosphine (190 mg, 0.73 mmol), 3-bromopropanol (0.053 mL, 0.61 mmol), and diisopropylazodicarboxylate (0.14 mL, 0.73 mmol) to provide 1-(3-bromopropyl)-3-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.15 g).
  • Step 5 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.14 g, 0.36 mmol) was treated with methylamine to provide 3-[3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine (120 mg).
  • Step 1 1-naphthylamine (2.14 g, 15 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL, 10 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH 4 Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 N-(2-nitrophenyl)naphthalen-1-amine (0.41 g, 1.55 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium on activated carbon (50 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered through a pad of Celite and concentrated to give N-Naphthalen-1-yl-benzene-1,2-diamine (0.36 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to General Procedure A, Step 1, N-Naphthalen-1-yl-benzene-1,2-diamine (0.36 g, 1.55 mmol) was treated with sulfamide (0.18 g, 1.86 mmol) to provide 1-(1-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.28 g).
  • Step 4 In an analogous manner to General Procedure A, Step 2, 1-(1-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.25 g, 0.84 mmol) was treated with triphenylphosphine (262 mg, 1.0 mmol), 3-bromopropanol (0.074 mL, 0.84 mmol), and diisopropylazodicarboxylate (0.19 mL, 1.0 mmol) to provide 1-(3-bromopropyl)-3-(1-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.12 g).
  • Step 5 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-(1-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.12 g, 0.28 mmol) was treated with methylamine to provide N-methyl-3-[3-(1-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine (110 mg).
  • Step 1 2-naphthylamine (1.0 g, 7 mmol) was dissolved in DMF (5 mL) and sodium hydride (0.27 g, 7 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (0.61 mL, 5.8 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH 4 Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 N-(2-nitrophenyl)naphthalen-2-amine (0.36 g, 1.4 mmol) was dissolved in ethyl acetate (10 mL) and 10% palladium on activated carbon (50 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered through a pad of Celite and concentrated to give N-Naphthalen-2-yl-benzene-1,2-diamine (0.32 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to General Procedure A, Step 1, N-Naphthalen-2-yl-benzene-1,2-diamine (0.32 g, 1.36 mmol) was treated with sulfamide (0.16 g, 1.63 mmol) to provide 1-(2-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.29 g).
  • Step 4 In an analogous manner to General Procedure A, Step 2, 1-(2-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.25 g, 0.84 mmol) was treated with triphenylphosphine (262 mg, 1.0 mmol), 3-bromopropanol (0.074 mL, 0.84 mmol), and diisopropylazodicarboxylate (0.19 mL, 1.0 mmol) to provide 1-(3-bromopropyl)-3-(2-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.14 g).
  • Step 5 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-(2-naphthyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.12 g, 0.28 mmol) was treated with methylamine to provide N-methyl-3-[3-(2-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine (100 mg).
  • Step 1 m-Toluidine (1.6 mL, 15 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL, 10 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH 4 Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 N-(3-methylphenyl)-2-nitroaniline (0.93 g, 4.1 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium on activated carbon (50 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered through a pad of Celite and concentrated to give N-(3-methylphenyl)benzene-1,2-diamine (0.81 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to General Procedure A, Step 1, N-(3-methylphenyl)benzene-1,2-diamine (0.81 g, 4.1 mmol) was treated with sulfamide (0.47 g, 4.9 mmol) to provide 1-(3-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.035 g).
  • Step 4 In an analogous manner to General Procedure A, Step 2, 1-(3-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.03 g, 0.12 mmol) was treated with triphenylphosphine (37 mg, 0.14 mmol), 3-bromopropanol (0.001 mL, 0.12 mmol), and diisopropylazodicarboxylate (0.027 mL, 0.14 mmol) to provide 1-(3-bromopropyl)-3-(3-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (14 mg) that was carried on to the next step.
  • triphenylphosphine 37 mg, 0.14 mmol
  • 3-bromopropanol 0.001 mL, 0.12 mmol
  • diisopropylazodicarboxylate 0.027 mL, 0.14 m
  • Step 5 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-(3-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (14 mg, 0.04 mmol) was treated with methylamine to provide N-methyl-3-[3-(3-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine (9 mg).
  • Step 1 o-Toluidine (1.6 mL, 15 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL, 10 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH 4 Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 (2-Nitro-phenyl)-o-tolyl-amine (0.75 g, 3.3 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium on activated carbon (50 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered through a pad of Celite and concentrated to give N-o-tolyl-benzene-1,2-diamine (0.65 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to General Procedure A, Step 1, N-o-Tolyl-benzene-1,2-diamine (0.65 g, 3.3 mmol) was treated with sulfamide (0.38 g, 4.0 mmol) to provide 1-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.24 g).
  • Step 4 In an analogous manner to General Procedure A, Step 2, 1-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.22 g, 0.84 mmol) was treated with triphenylphosphine (262 mg, 1.0 mmol), 3-bromopropanol (0.074 mL, 0.84 mmol), and diisopropylazodicarboxylate (0.19 mL, 1.0 mmol) to provide 1-(3-bromopropyl)-3-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.29 g).
  • Step 5 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.27 g, 0.7 mmol) was treated with methylamine to N-methyl-3-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine (220 mg).
  • Step 1 m-Anisidine (1.7 mL, 15 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL, 10 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated NH 4 Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 N-(3-methoxyphenyl)-N-(2-nitrophenyl)amine (1.27 g, 5.2 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium on activated carbon (50 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 2 hour. The mixture was filtered through a pad of Celite and concentrated to give N-(3-methoxyphenyl)benzene-1,2-diamine (1.11 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to General Procedure A, Step 1, N-(3-methoxyphenyl)benzene-1,2-diamine (1.1 g, 5.1 mmol) was treated with sulfamide (0.59 g, 6.2 mmol) to provide 1-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.3 g).
  • Step 4 In an analogous manner to General Procedure A, Step 2, 1-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.3 g, 1.09 mmol) was treated with triphenylphosphine (340 mg, 1.3 mmol), 3-bromopropanol (0.095 mL, 1.09 mmol), and diisopropylazodicarboxylate (0.25 mL, 1.3 mmol) to provide 1-(3-bromopropyl)-3-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.22 g).
  • triphenylphosphine 340 mg, 1.3 mmol
  • 3-bromopropanol 0.095 mL, 1.09 mmol
  • diisopropylazodicarboxylate 0.25 mL, 1.3 mmol
  • Step 5 In an analogous manner to General Procedure A, Step 3, 1-(3-bromopropyl)-3-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.21 g, 0.5 mmol) was treated with methylamine to give 3-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine (170 mg).
  • Step 1 1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (110 mg, 0.45 mmol) was dissolved in DMF (2 mL) and 1,4-dibromobutane (0.27 mL, 2.25 mmol) was added followed by cesium carbonate (0.22 g, 0.68 mmol). The mixture was stirred for 16 hours then diluted with ether and washed with 1N HCl, water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
  • Step 2 1-(4-bromobutyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.14 g, 0.37 mmol) was dissolved in 8N methylamine in methanol (20 mL) and stirred for 16 hours in a sealed flask. The mixture was concentrated in vacuo to give the crude product. The crude product was purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 110 mg of 4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylbutan-1-amine.
  • Step 1 Cesium carbonate (0.29 g, 0.9 mmol) was added to a solution of 1-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.25 g, 0.9 mmol), and 1,4-dibromobutane (0.42 mL, 3.6 mmol) in dry DMF (5.0 mL) under nitrogen. After 3 h, the reaction mixture was diluted with diethyl ether and washed with water and brine. The ether layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.41 g of crude product.
  • Step 2 10 mL of ammonia (ca. 7N in methanol) was added to a pressure tube containing 1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (50 mg, 0.12 mmol). The vessel was sealed and the mixture was stirred at 60° C. overnight then concentrated to give the crude product. The crude product was pre-adsorbed onto Celite and purified via Isco chromatography (Redisep, silica, gradient 1-8% methanol in dichloromethane) to afford 33 mg (78%) of product.
  • Isco chromatography Redisep, silica, gradient 1-8% methanol in dichloromethane
  • N-ethylmethylamine (3 mL, 35 mmol) and 1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide 35 mg, 0.08 mmol were stirred overnight to prepare 4 mg (10%) of 4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethyl-N-methyl butan-1-amine as the TFA salt.
  • Step 1 A mixture of 2-chloro-3-nitropyridine (5.0 g, 31.5 mmol) and aniline (5.8 mL, 63.1 mmol) was heated to 140° C. for 90 minutes. After cooling to ambient temperature, the mixture was diluted with water (200 mL) and extracted with three portions (50 mL each) of dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude solids were recrystallized from isopropyl alcohol to afford 3.50 g of 3-nitro-N-phenylpyridin-2-amine.
  • Step 2 A mixture of 3-nitro-N-phenylpyridin-2-amine (3.50 g, 16.3 mmol), zinc powder (16.0 g, 244 mmol) and ammonium chloride (4.35 g, 81.3 mmol) in 60% aqueous ethanol (250 mL) was heated to 50° C. for 1 hour. The mixture was cooled to ambient temperature, filtered through a plug of Celite and the plug was rinsed with ethyl acetate (100 mL). The filtrate was partitioned against ethyl acetate (75 mL) and the layers separated. The aqueous layer was further extracted with ethyl acetate.
  • Step 3 A mixture of N 2 -phenylpyridine-2,3-diamine (1.0 g, 5.4 mmol) and sulfamide (0.78 g, 8.1 mmol) in diglyme (15 mL) was heated to 160° C. for 90 minutes. The mixture was cooled to ambient temperature, loaded directly onto silica gel and immediately purified via Isco chromatography (Redisep, silica, gradient 0-100% ethyl acetate in hexane).
  • Step 4 To a solution of 1-phenyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (190 g, 0.76 mmol), tert-butyl 3-hydroxypropyl(methyl)carbamate (198 mg, 1.0 mmol) and triphenylphosphine (262 mg, 1.0 mmol) in tetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (0.19 mL, 1.0 mmol). The mixture was stirred at ambient temperature for 30 minutes and then concentrated in vacuo. The residue was filtered through a plug of silica and rinsed through with 50% ethyl acetate in hexane. The filtrate was concentrated and the residue purified via Supercritical Fluid Chromatography using the conditions described below.
  • Step 1 A mixture of 4-chloro-3-nitropyridine (5.0 g, 31.5 mmol) and aniline (5.8 mL, 63.1 mmol) was stirred at ambient temperature. Within a few minutes, a strong exotherm was observed. At ten minutes, the mixture had become solid. The solids were dissolved in dichloromethane (50 mL) and partitioned against water (200 mL). The layers were separated and the aqueous layer was extracted with two additional portions (50 mL each) of dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 5.7 g of 3-nitro-N-phenylpyridin-4-amine, which was used without further purification.
  • Step 2 A mixture of 3-nitro-N-phenylpyridin-4-amine (5.70 g, 26.5 mmol), zinc powder (26.0 g, 397 mmol) and ammonium chloride (7.10 g, 132 mmol) in 60% aqueous ethanol (250 mL) was heated to 50° C. for 1 hour. The mixture was cooled to ambient temperature, filtered through a plug of Celite and the plug was rinsed with ethyl acetate (100 mL). The filtrate was partitioned against ethyl acetate (75 mL) and the layers separated. The aqueous layer was extracted with one additional portion of ethyl acetate (75 mL).
  • Step 3 A mixture of N 4 -phenylpyridine-3,4-diamine (1.18 g, 6.37 mmol) and sulfamide (0.918 g, 9.55 mmol) in diglyme (15 mL) was heated to 160° C. for 90 minutes. The mixture was cooled to ambient temperature, loaded directly onto silica gel and immediately purified via Isco chromatography (Redisep, silica, gradient 0-100% ethyl acetate in hexane) to afford 0.35 g of 1-phenyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-c]pyridine 2,2-dioxide.
  • Step 4 To a solution of 1-phenyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-c]pyridine 2,2-dioxide (300 g, 1.21 mmol), tert-butyl 3-hydroxypropyl(methyl)carbamate (300 mg, 1.58 mmol) and triphenylphosphine (414 mg, 1.58 mmol) in tetrahydrofuran (15 mL) was added diisopropyl azodicarboxylate (0.31 mL, 1.58 mmol). The mixture was stirred at ambient temperature for 45 minutes and then concentrated in vacuo. The residue was filtered through a plug of silica and rinsed through with 50% ethyl acetate in hexane. The filtrate was concentrated and the residue purified via Supercritical Fluid Chromatography using the conditions described below.
  • SFC Instrument Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE) Column: Kromasil DIOL; 5 ⁇ m; 250 mm L ⁇ 21 mm ID (EKA Chemicals, Dobbs Ferry, NY) Column temperature: 35° C.
  • SFC Modifier 10% MeOH/90% CO2 Flow rate: 50 mL/min Detector: UV at 220 nm
  • Step 1 In an analogous manner to Example 6, Step 1, 5-methyl-N-(2-nitrophenyl)pyridin-2-amine was prepared from 2-amino-5-picoline as an orange solid.
  • Step 2 5-methyl-N-(2-nitrophenyl)pyridin-2-amine (0.74 g, 3.2 mmol) was dissolved in ethanol (50 ml) and treated with 10% palladium on carbon. The reaction mixture was placed under 50 psi of hydrogen on a Parr shaker for 3 hours. The reaction mixture was then filtered through a Celite pad and the filtrate was concentrated in vacuo. The crude product was crystallized from ethyl acetate by adding a minutesimum amount of diethyl ether to yield (5-methylpyridin-2-yl)benzene-1,2-diamine (0.66 g, 98%) as a white solid.
  • Step 3 (5-methylpyridin-2-yl)benzene-1,2-diamine (0.66 g, 3.3 mmol) was dissolved in diglyme (5 ml) and stirred at reflux for 5 minutes. To this was added sulfamide (0.32 g, 3.3 mmol) in diglyme (5 ml) dropwise through a dropping funnel in a period of 5 minutes. Additional sulfamide (0.32 g, 3.3 mmol) in diglyme (5 ml) was added in a same manner and the mixture was further stirred at reflux for 5 minutes. The reaction mixture was then placed in an ice-water bath and partitioned between water and a solution of dichloromethane/isopropanol (3/1).
  • the separated organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • the crude product was purified via Biotage Horizon (Flash 40 M, silica, gradient from 0% to 60% of 10% methanol-dichloromethane in dichloromethane) to yield 1-(5-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide (0.71 g, 83%) as a white solid.
  • Step 4 A heterogeneous mixture of 1-(5-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide (0.71 g, 2.7 mmol), potassium carbonate (0.33 g, 5.4 mmol) and cesium carbonate (0.88 g, 2.7 mmol) in anhydrous acetonitile (30 ml) was stirred at room temperature under nitrogen. To this was added excess of 1-bromo-3-chloropropane (2.7 ml, 27 mmol) and the reaction mixture was heated at 70° C. for 3 hours. The resulted mixture was then partitioned between water and ethyl acetate.
  • the separated organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • the crude product was purified via Biotage Horizon (Flash 40 M, silica, gradient from 0% to 60% of ethyl acetate in hexane) to yield 1-(3-chloropropyl)-3-(5-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide (0.55 g, 74%) as an oil.
  • Step 5 1-(3-chloropropyl)-3-(5-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide (0.55 g, 1.6 mmol) was treated with a solution of methylamine in ethanol (2.0 M, 8 ml, 16 mmol) and the solution was heated at 50° C. in a sealed vessel for 15 hours. After dilution with a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with a solution of dichloromethane/isopropanol (3/1). The extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • N-(3-methylpyridin-2-yl)benzene-1,2-diamine was prepared from 3-methyl-N-(2-nitrophenyl)pyridin-2-amine as a white solid.
  • Step 4 1-(3-chloropropyl)-3-(3-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from 1-(3-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as an oil. MS (ES) m/z 337.7 ([M+H] + ).
  • N-methyl-3-[3-(3-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride was prepared from 1-(3-chloropropyl)-3-(3-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as light tan solid.
  • N-(6-methoxypyridin-3-yl)benzene-1,2-diamine was prepared from 6-methoxy-N-(2-nitrophenyl)pyridin-3-amine as an off white solid.
  • N-(5-ethylpyridin-2-yl)benzene-1,2-diamine was prepared from 5-ethyl-N-(2-nitrophenyl)pyridin-2-amine as an oily solid.
  • N-(4-methylpyridin-2-yl)benzene-1,2-diamine was prepared from 4-methyl-N-(2-nitrophenyl)pyridin-2-amine as a white solid.
  • Step 4 1-(3-chloropropyl)-3-(4-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from 1-(4-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as an oil. MS (ES) m/z 338 ([M+H] + ).
  • N-pyridin-2-ylbenzene-1,2-diamine was prepared from N-(2-nitrophenyl)pyridin-2-amine as a white solid.
  • N-(6-methylpyridin-2-ylbenzene-1,2-diamine was prepared from 6-methyl-N-(2-nitrophenyl)pyridin-2-amine as a white solid.
  • Step 4 1-(3-chloropropyl)-3-(6-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from 1-(6-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as an oil. MS (ES) m/z 337.7 ([M+H] + ).
  • N-methyl-3-[3-(6-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride was prepared from 1-(3-chloropropyl)-(6-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as a white solid.
  • N-(4-methylpyridin-3-ylbenzene-1,2-diamine was prepared from 4-methyl-N-(2-nitrophenyl)pyridin-3-amine as a white solid.
  • MS (ES) m/z 200 ([M+H] + ).
  • N-methyl-3-[3-(4-methylpyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride was prepared from 1-(3-chloropropyl)-(4-methylpyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as a light tan solid.
  • N-pyridin-3-ylbenzene-1,2-diamine was prepared from N-(2-nitrophenyl)pyridin-3-amine as a white solid.
  • Step 4 1-(3-chloropropyl)-3-pyridin-3-yl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(N-pyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as an oil. MS (ES) m/z 323.7 ([M+H] + ).
  • Step 1 4-fluoro-2-nitro-N-phenylaniline: A solution of 2,5-difluoronitrobenzene (1.59 g, 10.0 mmol), aniline (0.96 mL, 10.5 mmol), and triethylamine (2.78 mL, 20.0 mmol) in DMF (5.0 mL) were heated in a sealed tube in the microwave at 200° C. for 1 hour. The solution was allowed to cool to room temperature and was diluted with ethyl acetate (75 mL). The organic layer was washed with water (75 mL), brine (75 mL), and dried over sodium sulfate. After concentration in vacuo silica gel chromatography (5-15% ethyl acetate in hexanes) afforded product as an orange oil (2.21 g, 95%).
  • Step 2 4-fluoro-N 1 -phenylbenzene-1,2-diamine: A solution of 4-fluoro-2-nitro-N-phenylaniline (1.04 g, 4.48 mmol) in ethanol (100 mL) was added to a solution of ammonium chloride (1.20 g, 22.4 mmol) in water (50 mL). The solution was heated to 60° C. and zinc powder (4.39 g, 67.2 mmol) was added. The suspension was stirred for 2 hours at 60° C. The suspension was allowed to cool to room temperature and was filtered through a pad of Celite using ethyl acetate washing (3 ⁇ 100 mL).
  • Step 3 5-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide: Sulfamide (961 mg, 10.0 mmol) was added to a solution of 4-fluoro-N 1 -phenylbenzene-1,2-diamine (404 mg, 2.00 mmol) in diglyme (10 mL). The solution was heated open to the air at 160° C. for 3 hours. The reaction was allowed to cool to room temperature, was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL). After the organic layer was dried over sodium sulfate, the solution was concentrated in vacuo. Silica gel chromatography (5-25% ethyl acetate in hexanes) afforded product as an orange solid (418 mg, 79%).
  • Step 4 tert-butyl[3-(6-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate: A solution of 5-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (135 mg, 0.510 mmol), 3-(N-tert-butoxycarbonyl-N-methylamino)propanol (189 mg, 1.00 mmol), and triphenylphosphine (262 mg, 1.00 mmol) in THF was treated with diisobutylazodicarboxylate (202 mg, 1.00 mmol).
  • Step 5 3-(6-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine: tert-Butyl[3-(6-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate (91 mg, 0.207 mmol) was treated with 4N HCl in dioxane (5 mL) and stirred at room temperature for 1 hour. The solution was concentrated to 1 mL in vacuo, diluted with water (9 mL), frozen, and placed under vacuum to afford the HCl salt of product as a white powder (74 mg, 96%).
  • Step 1 4-chloro-2-nitro-N-phenylaniline.
  • 4-chloro-2-nitro-N-phenylaniline was obtained commercially from the Sigma-Aldrich company.
  • Step 2 4-chloro-N 2 -phenylbenzene-1,2-diamine. Following the General Procedure C, Step 2, starting with 4-chloro-2-nitro-N-phenylaniline (2.49 g, 10.0 mmol) afforded product as a brown solid (2.17 g, 99%).
  • Step 3 6-chloro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
  • Step 3 4-chloro-N 2 -phenylbenzene-1,2-diamine (437 mg, 2.00 mmol) afforded product as a slightly red solid (417 mg, 74%).
  • Step 4 tert-butyl[3-(5-chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate.
  • Step 4 starting with 6-chloro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (417, 1.49 mmol) afforded product as a yellow oil (604 mg, 89%).
  • Step 5 3-(5-chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine.
  • Step 5 starting with tert-butyl[3-(5-chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]-methylcarbamate (226 mg, 0.500 mmol) afforded product HCl salt as a off-white powder (193 mg, 99%).
  • Step 1 4-bromo-2-nitro-N-phenylaniline. Following the General Procedure C, Step 1, starting with 4-bromo-1-fluoro-2-nitrobenzene (2.20 g, 10.0 mmol) afforded product as an orange solid (2.90 g, 99%).
  • Step 2 4-bromo-N 1 -phenylbenzene-1,2-diamine. Following the General Procedure C, Step 2, starting with 4-bromo-2-nitro-N-phenylaniline (2.90 g, 9.90 mmol) afforded product as an off-white solid (2.10 g, 80%).
  • Step 3 5-bromo-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
  • Step 3 starting with 4-bromo-N 1 -phenylbenzene-1,2-diamine (1.05 g, 4.00 mmol) afforded product as a purple solid (664 mg, 51%).
  • Step 4 tert-butyl[3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate.
  • Step 4 starting with 5-bromo-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (423 mg, 1.30 mmol) afforded product as a colorless oil (522 mg, 81%).
  • Step 5 3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine.
  • Step 5 starting with tert-butyl[3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]-methylcarbamate (100 mg, 0.201 mmol) afforded the HCl salt of product as a white powder (87 mg, 99%).
  • Step 1 4-methyl-2-nitro-N-phenylaniline. Following the General Procedure C, Step 1, starting with 3-fluoro-4-nitrotoluene (2.33 g, 15.0 mmol) afforded product as an orange solid (3.09 g, 90%).
  • Step 2 4-methyl-N′-phenylbenzene-1,2-diamine. Following the General Procedure C, Step 2, 4-methyl-2-nitro-N-phenylaniline (1.18 g, 5.17 mmol) afforded product as a brown solid (1.02 g, 99%).
  • Step 3 5-methyl-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
  • Step 3 4-methyl-N 1 -phenylbenzene-1,2-diamine (397 mg, 2.00 mmol) afforded product as a tan solid (422 mg, 81%).
  • Step 4 tert-butyl methyl[3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]carbamate.
  • Step 4 starting with 5-methyl-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (381 mg, 1.46 mmol) afforded product as a colorless gel (592 mg, 94%).
  • Step 5 N-methyl-3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propan-1-amine.
  • Step 5 starting with tert-butyl methyl[3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]carbamate (432 mg, 1.00 mmol) afforded the HCl salt of product as a tan powder (367 mg, 100%).
  • Step 1 3-fluoro-2-nitro-N-phenylaniline. Following a modification of the General Procedure C, Step 1, 2,6-difluoronitrobenzene (1.59 g, 10.0 mmol), at a changed microwave temperature of 150° C., afforded product as an orange solid (1.86 g, 80%).
  • Step 2 3-fluoro-N 1 -phenylbenzene-1,2-diamine. Following the General Procedure C, Step 2, starting with 3-fluoro-2-nitro-N-phenylaniline (1.80 g, 7.74 mmol) afforded product as a red solid (1.12 g, 65%).
  • Step 3 4-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. Following the General Procedure C, Step 3, starting with 3-fluoro-N 1 -phenylbenzene-1,2-diamine (606 mg, 3.00 mmol) afforded product as a rose colored solid (294 mg, 37%).
  • Step 4 tert-butyl[3-(7-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate.
  • Step 4 starting with 4-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (201 mg, 0.760 mmol) afforded product as a tan oil (281 mg, 85%).
  • Step 5 3-(7-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine.
  • Step 5 starting with tertbutyl-[3-(7-fluoro-2,2-dioxido-3-phenyl-2,3-benzothiadiazol-1(3H)-yl)propyl]-methyl carbamate (248 mg, 0.570 mmol) afforded product as a white powder (212 mg, 100%).
  • Step 1 4-methyl-2-nitro-N-phenylaniline. Following the General Procedure C, Step 1, starting with 4-fluoro-3-nitrotoluene (2.32 g, 15.0 mmol) afforded product as an orange oil (2.38 g, 67%).
  • Step 2 4-methyl-N 1 -phenylbenzene-1,2-diamine. Following the General Procedure C, Step 2, starting with 4-methyl-2-nitro-N-phenylaniline (2.28 g, 10.0 mmol) afforded product as a white solid (1.32 g, 67%).
  • Step 3 5-methyl-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. Following the General Procedure C, Step 3, starting with 4-methyl-N 1 -phenylbenzene-1,2-diamine (397 mg, 2.00 mmol) afforded product as a colorless oil (107 mg, 21%).
  • Step 4 tert-butyl methyl[3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]carbamate.
  • Step 4 starting with 5-methyl-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (78 mg, 0.300 mmol) afforded product as a colorless oil (93 mg, 72%).
  • Step 5 N-methyl-3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propan-1-amine.
  • Step 5 starting with tert-butyl methyl[3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]-carbamate (61 mg, 0.140 mmol) afforded product as a white powder (51 mg, 99%).
  • Step 1 2-fluoro-6-nitro-N-phenylaniline. Following the General Procedure C, Step 1, starting with 2,3-difluoronitrobenzene (2.80 g, 17.6 mmol) afforded product as an orange oil (3.21 g, 79%).
  • Step 2 3-fluoro-N 2 -phenylbenzene-1,2-diamine. Following the General Procedure C, Step 2, starting with 2-fluoro-6-nitro-N-phenylaniline (3.00 g, 12.9 mmol) afforded product as an off-white solid (2.14 g, 82%).
  • Step 3 7-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
  • Step 3 starting with 3-fluoro-1-phenylbenzene-1,2-diamine (607 mg, 3.00 mmol) afforded product as a red oil (318 mg, 40%).
  • Step 4 tert-butyl[3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate.
  • Step 4 starting with 7-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (200 mg, 0.757 mmol) afforded product as a tan oil (228 mg, 69%).
  • Step 5 3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine.
  • Step 4 starting with tert-butyl[3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]-methylcarbamate (161 mg, 0.370 mmol) afforded product as a white solid (136 mg, 99%).
  • Step 1 3-fluoro-2-nitro-N-(3-fluorophenyl)aniline. Following a modified General Procedure C, Step 1, starting with 2,6-difluoronitrobenzene (2.39 g, 15.0 mmol) and replacing aniline with 3-fluoroaniline (1.67 g, 15.0 mmol) afforded product as an orange oil (2.43 g, 90% pure, 72%).
  • Step 2 3-fluoro-N 1 -(3-fluorophenyl)benzene-1,2-diamine. Following the General Procedure C, Step 2, starting with 3-fluoro-2-nitro-N-(3-fluorophenyl)aniline (2.20 g, 8.00 mmol) afforded product as a yellow oil (1.32 g, 75%).
  • Step 3 5-methyl-1-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
  • Step 3 starting with 3-fluoro-N 1 -(3-fluorophenyl)benzene-1,2-diamine (881 mg, 4.00 mmol) afforded product as a red oil (418 mg, 37%).
  • Step 4 tert-butyl ⁇ 3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl ⁇ methylcarbamate.
  • Step 4 starting with 5-methyl-1-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (186 mg, 0.660 mmol) afforded product as a white solid (162 mg, 54%).
  • Step 5 3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine.
  • Step 5 starting with tert-butyl ⁇ 3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl ⁇ methylcarbamate (89 mg, 0.200 mmol) afforded the HCl salt of product as a white solid (76 mg, 97%).
  • Step 1 tert-butyl[3-(6-cyano-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate.
  • Step 2 3-[3-(methylamino)propyl]-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole-5-carbonitrile 2,2-dioxide.
  • tert-Butyl[3-(6-cyano-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate (81 mg, 0.183 mmol) was treated with a solution of 3N hydrochloric acid in dioxane (5 mL) and stirred 3 hours at room temperature. The solution was concentrated to 1 mL, diluted with water (9 mL), frozen, and placed under vacuum to afford the HCl salt of product as a white powder (66 mg, 96%).
  • Step 1 tert-Butyl ⁇ 3-[(2-nitro-4-fluorophenyl)amino]propyl ⁇ methylcarbamate.
  • a solution of 2,5-difluoronitrobenzene (3.18 g, 20.0 mmol), 3-(N-tert-butoxycarbonyl-N-methylamino)propylamine (4.14 g, 22.0 mmol), and diisopropylethylamine (5.23 mL, 30.0 mmol) in DMF (50 mL) was stirred at 50° C. for 2 hours.
  • the solution was diluted with ethyl acetate (200 mL) and washed with water (200 mL) and brine (200 mL).
  • the organic layer was dried over sodium sulfate and concentrated in vacuo.
  • Silica gel chromatography (10-50% ethyl acetate in hexanes) afforded product as an orange oil (6.08 g,
  • Step 2 tert-Butyl ⁇ 3-[(2-amino-4-fluorophenyl)amino]propyl ⁇ methylcarbamate.
  • a solution of tert-butyl ⁇ 3-[(2-nitro-4-fluorophenyl)amino]propyl ⁇ methylcarbamate (5.70 g, 17.4 mmol) in ethanol (150 mL) was added to a solution of ammonium chloride (4.65 g, 87.0 mmol) in water (100 mL).
  • the suspension was heated to 50° C. and zinc powder (17.1 g, 261 mmol) was added in portions over 15 minutes. The solution was allowed to stir at 50° C. for 1 hour.
  • Step 3 tert-butyl[3-(5-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate.
  • a solution of tert-Butyl ⁇ 3-[(2-amino-4-fluorophenyl)amino]propyl ⁇ methylcarbamate (892 mg, 3.00 mmol) in diglyme (10 mL) was treated with sulfamide (432 mg, 4.50 mmol) and heated to 160° C. with stirring for 1 hour. The solution was allowed to cool to room temperature and was diluted with diethyl ether (100 mL). The diethyl ether solution was directly concentrated onto silica gel and dried under vacuum. Silica gel chromatography (15-40% ethyl acetate in hexanes) afforded product as a colorless oil (905 mg, 84%).
  • Step 4 tert-butyl[3-(5-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-1-yl)propyl]methylcarbamate.
  • a suspension of tert-butyl[3-(5-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate (719 mg, 2.00 mmol), phenyl boronic acid (732 mg, 6.00 mmol), copper(II) acetate (545 mg, 3.00 mmol), and 4
  • a molecular sieves in methylene chloride (20 mL) was treated with pyridine (316 mg, 4.00 mmol) and allowed to stir under an atmosphere of air for 8 hours.
  • Step 5 3-(5-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine.
  • tert-Butyl[3-(5-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate (184 mg, 0.422 mmol) was treated with a solution of 4N hydrochloric acid in dioxane (5 mL) and allowed to stir at room temperature for 1 hour. The solution was concentrated to 1 mL volume and then diluted with 9 mL of water. The solution was frozen and placed under vacuum to afford product as a white powder (155 mg, 99%).
  • Step 1 To a mixture of 2,6-difluoroaniline (6.90 g, 35.4 mmol) in tetrahydrofuran (75 mL) at ⁇ 78° C. was added a solution of tert-butyllithium (1.7 M in pentane, 30 mL, 51.4 mmol) dropwise via a syringe and the reaction mixture was stirred for 10 minutes at ⁇ 78° C. After warming to 0° C., 1-fluoro-2-nitrobenzene (5.00 g, 35.4 mmol) was added dropwise via a syringe. The reaction mixture immediately turned deep purple. It was stirred for an additional 30 minutes while warming to room temperature.
  • Step 2 To a solution of 2,6-difluoro-N-(2-nitrophenyl)aniline (5.80 g, 23.2 mmol) in ethanol (200 mL) was added Raney Nickel (0.60 g). The mixture was shaken on a Parr apparatus for 1 hour under hydrogen pressure (40 psi). Reaction color turned from orange to colorless indicated complete consumption of starting material. The reaction mixture was filtered through Celite and concentrated to dryness to give 5.02 g (98%) of pure N-(2,6-difluorophenyl)benzene-1,2-diamine as an off-white solid. MS (ESI) m/z 221.0 ([M+H] + ); HRMS: calculated for C 12 H 10 F 2 N 2 +H + , 221.0885; found (ESI, [M+H] + ), 221.0888.
  • Step 3 A mixture of sulfamide (1.31 g, 13.6 mmol) and N-(2,6-difluorophenyl)benzene-1,2-diamine (2.50 g, 11.4 mmol) in diethylene glycol dimethyl ether (15 mL) was added dropwise over 15 minutes to refluxing diethylene glycol dimethyl ether (13 mL) in a reaction flask. The reaction mixture was stirred at reflux for an additional 15 minutes, cooled to room temperature, diluted with ether (30 mL), then washed with 1N HCl (30 mL) and brine. The organic layer was dried (anhydrous sodium sulfate) and concentrated.
  • Step 4 To a solution of 1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (282 mg, 1.00 mmol), triphenylphosphine (315 mg, 1.20 mmol), and 3-bromo-1-propanol (153 mg, 1.10 mmol) in tetrahydrofuran (4 mL) at 0° C. was added diisopropyl azodicarboxylate (0.23 mL, 1.20 mmol) dropwise. The reaction mixture was warmed to ambient temperature, stirred for 12 h, and concentrated.
  • Step 5 Ethanolic methylamine (33% in ethanol, 20 mL) was added to 1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (320 mg, 0.790 mmol). The reaction mixture was sealed tightly and stirred for 12 h, then concentrated. The residue was dissolved in dichloromethane (50 mL), washed with aqueous potassium carbonate, water, brine, dried (anhydrous sodium sulfate), and concentrated.
  • Step 1 2,3-difluoro-N-(2-nitrophenyl)aniline was prepared from 2,3-difluoroaniline and 1-fluoro-2-nitrobenzene as orange crystals. MS (ESI) m/z 250.9 ([M+H] + ).
  • N-(2,3-difluorophenyl)benzene-1,2-diamine was prepared from 2,3-difluoro-N-(2-nitrophenyl)aniline as an off-white solid.
  • MS (ESI) m/z 221.0 ([M+H] + ).
  • HRMS calculated for C 12 H 10 F 2 N 2 +H + , 221.0885; found (ESI, [M+H]+), 221.0895.
  • Step 4 1-(3-bromopropyl)-3-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
  • MS (ESI) m/z 338.9 ([M+H ⁇ SO 2 ] + ).
  • N-(3,5-difluorophenyl)benzene-1,2-diamine was prepared from 3,5-difluoro-N-(2-nitrophenyl)aniline as an off-white solid.
  • MS (ESI) m/z 221.0 ([M+H] + ).
  • HRMS calculated for C 12 H 10 F 2 N 2 +H + , 221.0885; found (ESI, [M+H] + ), 221.0874.
  • Step 4 1-(3-bromopropyl)-3-(3,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(3,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
  • Step 1 2,5-difluoro-N-(2-nitrophenyl)aniline was prepared from 2,5-difluoroaniline and 1-fluoro-2-nitrobenzene as orange crystals. MS (ESI) m/z 250.9 ([M+H] + ).
  • N-(2,5-difluorophenyl)benzene-1,2-diamine was prepared from 2,5-difluoro-N-(2-nitrophenyl)aniline as an off-white solid.
  • MS (ESI) m/z 221.0 ([M+H] + ).
  • HRMS calculated for C 12 H 10 F 2 N 2 +H + , 221.0885; found (ESI, [M+H] + ), 221.0898.
  • Step 4 1-(3-bromopropyl)-3-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
  • MS (ESI) m/z 338.9 ([M+H ⁇ SO 2 ] + ).
  • Step 4 1-(3-bromopropyl)-3-[3-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-[3-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
  • MS (ESI) m/z 387.0 ([M+H ⁇ SO 2 ] + ).
  • Step 4 1-(3-bromopropyl)-3-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
  • MS (ESI) m/z 387.0 ([M+H ⁇ SO 2 ] + ).
  • Step 1 (2-nitrophenyl)[3-(trifluoromethyl)phenyl]amine was prepared from 3-(trifluoromethyl)aniline and 1-fluoro-2-nitrobenzene as orange crystals. MS (ESI) m/z 282.8 ([M+H] + ).
  • Step 4 1-(3-bromopropyl)-3-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
  • N-(2-chlorophenyl)benzene-1,2-diamine was prepared from 2-chloro-N-(2-nitrophenyl)aniline as an off-white solid.
  • MS (ESI) m/z 219.0 ([M+H] + ).
  • HRMS calculated for C 12 H 11 ClN 2 +H + , 219.0684; found (ESI, [M+H] + ), 219.0693.
  • Step 4 1-(3-bromopropyl)-3-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
  • MS (ESI) m/z 336.9 ([M+H—SO 2 ] + ).
  • N-(3-bromophenyl)benzene-1,2-diamine was prepared from N-(3-bromophenyl)-2-nitroaniline as an off-white solid.
  • Step 4 1-(3-bromopropyl)-3-(3-bromophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(3-bromophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid.
  • MS (ES I) m/z 380.9 ([M+H ⁇ SO 2 ] + ).
  • Step 1 Diisopropyl azodicarboxylate (0.50 mL, 2.57 mmol) was added to a solution of 1-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.60 g, 2.14 mmol), 2-bromo-ethanol (0.15 mL, 2.14 mmol), triphenylphosphine (0.67 g, 2.57 mmol) in dry THF (21 mL) under nitrogen. The solution was stirred overnight at room temperature. The reaction was concentrated in vacuo to provide the crude product.
  • Step 2 In an analogous manner to Example 19, Step 2, 1-(2-bromoethyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (68 mg, 0.17 mmol) and ammonia (10 mL, ca. 7N in methanol) were stirred overnight at 60° C. 14 mg (25%) of 2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethanamine was provided after purification. Treatment of the free base with 1.0 M HCl in diethyl ether afforded 6 mg of the HCl salt.
  • This compound was prepared using 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and (3-hydroxy-propyl)-carbamic acid tert-butyl ester according to General Procedure C.
  • Step 1 To a stirring solution of 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (770 mg, 2.91 mmol) and cesium carbonate (1.42 g, 4.37 mmol) in anhydrous dimethylformamide was added 1,4-dibromobutane (1.72 mL, 14.6 mmol) and the solution was stirred, under nitrogen, at room temperature for 18 hours.
  • reaction was transferred to a separatory funnel with ethyl acetate and washed with a saturated solution of ammonium chloride, water, brine and dried (MgSO 4 ), filtered, the solvent removed and the material adsorbed onto silica and purified using column chromatography (Isco: 0-20% ethyl acetate in hexane) to afford 1-(4-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a clear oil (960 mg, 83% Yield).
  • Step 2 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine was prepared from 1-(4-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide according to the General Procedure A.
  • Step 1 In an analogous manner to Example 6, step 1, 5.2 g of N-(2-Chloro-4-fluorophenyl)-N-(2-nitrophenyl)amine was prepared from 2-chloro-4-fluoro aniline (5.0 g, 34.5 mmol) and 2-Fluoronitrobenzene (4.9 g, 34.5 mmol). MS (ES) m/z 266.8
  • Step 2 N-(2-chloro-4-fluorophenyl)-N-(2-nitrophenyl)amine (4.0 g, 15.0 mmol) was dissolved in ethanol (50 mL) and 10% palladium on activated carbon (250 mg) was added. The mixture was shaken under a hydrogen atmosphere (50 psi) for 2 hour. The mixture was filtered through a pad of celite and concentrated to give N-(2-chloro-4-fluorophenyl)benzene-1,2-diamine (3.3 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to general procedure A, step 1, N-(2-chloro-4-fluorophenyl)benzene-1,2-diamine (4.1 g, 17.3 mmol) was treated with sulfamide (2.5 g, 26.0 mmol) to provide 1-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (2.1 g). MS (ESI) m/z 296.8 (M ⁇ H) ⁇ .
  • Step 4 In an analogous manner to general procedure A, step 2, 1-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.25 g, 0.85 mmol) was treated with triphenylphosphine (0.36 g, 1.4 mmol), 3-bromopropanol (0.18 g, 1.4 mmol), and diisopropylazodicarboxylate (0.28 g, 1.4 mmol) to provide 1-(3-bromopropyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.22 g).
  • Step 5 In an analogous manner to general procedure A, step 3, 1-(3-bromopropyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.20 g, 0.46 mmol) was treated with methylamine to provide 3-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride (0.18 g).
  • HRMS calculated for C 16 H 17 ClFN 3 O 2 S+H+, 370.07868; found (ESI, [M+H] + ), 370.0788
  • Step 1 In an analogous manner to general procedure A, step 2, 1-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.25 g, 0.85 mmol) (See Example 60, step 3) was treated with triphenylphosphine (0.36 g, 1.4 mmol), 3-BOC amino propanol (0.25 g, 1.4 mmol), and diisopropylazodicarboxylate (0.28 g, 1.4 mmol) to provide 0.19 g of product used as is in the next step.
  • Step 2 The residue isolated from Step 1 was dissolved in ether:methanol (10:1) and 2 mL of 2N HCl in ether added. The solution was allowed to stand for 16 hours whereupon the solid was collected by filtration to provide 0.16 g of 3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride.
  • Step 1 In an analogous manner to Example 6, step 1, 4.6 g of N-(4-fluoro-2-methylphenyl)-N-(2-nitrophenyl)amine was prepared from 4-fluoro-2-methyl aniline (4.8 g, 30.9 mmol) and 2-Fluoronitrobenzene (4.3 g, 30.9 mmol). MS (ES) m/z 266.8
  • Step 2 In an analogous manner to Example 60, step 2, N-(4-fluoro-2-methylphenyl)-N-(2-nitrophenyl)amine (4.6 g, 18.7 mmol) was subjected to hydrogenation to give N-(4-fluoro-2-methylphenyl)benzene-1,2-diamine (4.1 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to general procedure A, step 1, N-(4-fluoro-2-methylphenyl)benzene-1,2-diamine (3.5 g, 15.1 mmol) was treated with sulfamide (1.9 g, 19.6 mmol) to provide 1-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1.5 g).
  • Step 4 In an analogous manner to general procedure A, step 2, 1-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.31 g, 1.1 mmol) was treated with triphenylphosphine (0.46 g, 1.7 mmol), 3-bromopropanol (0.24 g, 1.7 mmol), and diisopropylazodicarboxylate (0.35 g, 1.4 mmol) to provide 1-(3-bromopropyl)-3-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.25 g).
  • Step 5 In an analogous manner to general procedure A, step 3, 1-(3-bromopropyl)-3-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.20 g, 0.46 mmol) was treated with methylamine to provide 3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine (0.15 g).
  • Step 1 In an analogous manner to general procedure A, step 2, 1-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.25 g, 0.90 mmol) was treated with triphenylphosphine (0.36 g, 1.4 mmol), 3-boc amino propanol (0.25 g, 1.4 mmol), and diisopropylazodicarboxylate (0.28 g, 1.4 mmol) to provide 0.23 g of product used as is in the next step.
  • Step 2 The residue isolated from Step 1 was dissolved in ether:methanol (10:1) and 2 mL of 2N HCl in ether added. The solution was allowed to stand for 16 hours whereupon the solid was collected by filtration to provide 0.16 g of 3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride.
  • Step 1 In an analogous manner to Example 6, step 1, 4.1 g of N-(4-fluoro-2-methoxyphenyl)-N-(2-nitrophenyl)amine was prepared from 4-fluoro-2-methoxy aniline (4.3 g, 30.9 mmol) and 2-Fluoronitrobenzene (4.3 g, 30.9 mmol).
  • Step 2 In an analogous manner to Example 60, step 2, N-(4-fluoro-2-methoxyphenyl)-N-(2-nitrophenyl)amine (4.2 g, 18.7 mmol) was subjected to hydrogenation to give N-(4-fluoro-2-methoxyphenyl)benzene-1,2-diamine (3.5 g) that was carried on directly to the next step.
  • Step 3 In an analogous manner to general procedure A, step 1, N-(4-fluoro-2-methylphenyl)benzene-1,2-diamine (3.2 g, 10.8 mmol) was treated with sulfamide (1.5 g, 16.3 mmol) to provide 1-(4-fluoro-2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1.3 g).
  • Step 4 In an analogous manner to general procedure A, step 2, 1-(4-fluoro-2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.41 g, 1.4 mmol) was treated with triphenylphosphine (0.46 g, 1.7 mmol), 3-bromopropanol (0.24 g, 1.7 mmol), and diisopropylazodicarboxylate (0.35 g, 1.4 mmol) to provide 1-(3-bromopropyl)-3-(4-fluoro-2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.35 g).
  • Step 5 In an analogous manner to general procedure A, step 3, 1-(3-bromopropyl)-3-(4-fluoro-2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.20 g, 0.48 mmol) was treated with methylamine to provide 3-[3-(4-fluoro-2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N-methylpropan-1-amine hydrochloride (0.15 g).

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CN107445845A (zh) * 2017-08-24 2017-12-08 重庆沃肯精细化工有限公司 一种合成氯法齐明关键中间体n‑(4‑氯苯基)‑1，2‑苯二胺的方法
JP2023509452A (ja) 2020-01-03 2023-03-08 バーグ エルエルシー がんを処置するためのｕｂｅ２ｋモジュレータとしての多環式アミド

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CN112351969A (zh) * 2018-06-21 2021-02-09 塞莱斯蒂亚生物技术股份公司 用于制备氨基二芳基醚和氨基二芳基醚盐酸盐的方法
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