AMINOALKYL SUBSTITUTED ARYL SULFAMIDE DERIVATIVES AND METHODS OF THEIR USE

Info

Publication number: 20080161366
Type: Application
Filed: Dec 12, 2007
Publication Date: Jul 3, 2008
Applicant: Wyeth (Madison, NJ)
Inventors: Casey Cameron McComas (Phoenixville, PA), Stephen Todd Cohn (Spring, TX), Matthew Lantz Crawley (Phoenixville, PA), Andrew Fensome (Wayne, PA), Joel Adam Goldberg (Philadelphia, PA), Douglas John Jenkins (Cincinnati, OH), Callain Younghee Kim (Collegeville, PA), Paige Erin Mahaney (Pottstown, PA), Charles William Mann (Plymouth Meeting, PA), Michael Anthony Marella (Limerick, PA), David John O'Neill (Collegeville, PA), Joseph Peter Sabatucci (Collegeville, PA), Eugene Anthony Terefenko (Center Valley, PA), Eugene John Trybulski (Huntingdon Valley, PA), An Thien Vu (Pottstown, PA), Richard Page Woodworth (North Wales, PA), Puwen Zhang (Audubon, PA)
Application Number: 11/955,195

Abstract

The present invention is directed to aminoalkyl-substituted aryl sulfamide derivatives of formula I: or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, 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, sexual dysfunction, gastrointestinal disorders and genitourinary disorder, depression disorders, endogenous behavioral disorders, cognitive disorders, diabetic neuropathy, pain, and other diseases or disorders.

Description

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) to co-pending U.S. Provisional Application Ser. No. 60/869,644, filed Dec. 12, 2006, which is hereby incorporated by reference in its entirety.

FIELD

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.

BACKGROUND

Vasomotor symptoms (VMS), referred to as hot flushes and night sweats, 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. Psychological and emotional symptoms are also observed, such as nervousness, fatigue, irritability, insomnia, depression, memory loss, headache, anxiety, nervousness or inability to concentrate, and are caused by the sleep deprivation following hot flush and night sweats (Kramer et al., In: Murphy et al., 3^rdInt'l Symposium on Recent Advances in Urological Cancer Diagnosis and Treatment-Proceedings, Paris, France: SCI: 3-7 (1992)).

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 (Loprinzi, et al., Lancet, 2000, 356(9247): 2059-2063).

Men also experience hot flushes following steroid hormone (androgen) withdrawal. This is true in cases of age-associated androgen decline (Katovich, et al., Proceedings of the Society for Experimental Biology & Medicine, 1990, 193(2): 129-35) as well as in extreme cases of hormone deprivation associated with treatments for prostate cancer (Berendsen, et al., European Journal of Pharmacology, 2001, 419(1): 47-54. As many as one-third of these patients will experience persistent and frequent symptoms severe enough to cause significant discomfort and inconvenience.

The precise mechanism of these vasomotor symptoms is unknown but generally is thought to represent disturbances to normal homeostatic mechanisms controlling thermoregulation and vasomotor activity (Kronenberg et al., “Thermoregulatory Physiology of Menopausal Hot Flashes: A Review,” Can. J. Physiol. Pharmacol., 1987, 65:1312-1324).

The fact that estrogen treatment (e.g. estrogen replacement therapy) relieves the symptoms establishes the link between these symptoms and an 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.

It has been suggested that 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). 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. In fact, the physiological aspects and the CNS/PNS involvement in VMS may account for the lower doses proposed to treat VMS (Loprinzi, 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.

Although 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). In addition, 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). Thus, non-hormonal therapies (e.g. fluoxetine, paroxetine [SRIs] and clonidine) are being evaluated clinically. WO9944601 discloses a method for decreasing hot flushes in a human female by administering fluoxetine. Other options have been studied for the treatment of hot flushes, including steroids, alpha-adrenergic agonists, and beta-blockers, with varying degree of success (Waldinger et al., Maturitas, 2000, 36(3): 165-168).

α₂-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_α2receptors, i.e., are α_2A, α_2B, α_2Cand α_2D(Mackinnon et al., TIPS, 1994, 15: 119; French, Pharmacol. Ther., 1995, 68: 175). A non-select α₂-adrenoceptor antagonist, yohimbine, induces a flush and an α₂-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.

Chronic pain comes in many forms, including visceral, inflammatory or neuropathic and crosses all therapeutic areas. It is a debilitating condition that exerts a high social cost in terms of productivity, economic impact and quality of life and current therapies have limited efficacy. Currently, first-line pharmacological treatments for neuropathic pain (i.e., diabetic neuropathy and post-herpetic neuralgia) and 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. 2000, 20(6):449-58; and Marcus Expert Opin Pharmacother. 2003, 4(10): 1687-95). However, these therapies are only effective in 30-50% of patients and produce only a partial reduction in pain (˜50%). In addition, the clinical benefits of these therapies are often outweighed by the side effects, including dry mouth and sedation. Therefore, newer classes of compounds including non-TCA antidepressants are being evaluated preclinically and clinically for chronic pain indications, and recently duloxetine was approved for the treatment of diabetic neuropathy. Although more tolerable than the older tricyclic antidepressants, these newer compounds are not devoid of side effects that include sexual dysfunction, weight gain and nausea.

While the precise pathophysiological mechanisms involved in the development and maintenance of chronic pain states are not fully understood, the pathways involved in pain perception and modulation have been well described and characterized (Gebhart, In: Yaksh T L, editor. Spinal afferent processing, New York: Plenum, 1986. pp 391-416; Fields, et al., Annual Review of Neuroscience 1991, 14: 219-245; Fields, et al. In: Wall P D, Melzack R, editors. Textbook of pain, London: Churchill Livingstone, 1999, pp 309-329; Millan, et al Progress in Neurobiology; 2002, 66:355-474). 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. A meta-analysis of antidepressants and neuropathic pain comparing the efficacy of known NRIs, mixed NRI/SRIs and SRIs determined that compounds with NRI activity were more effective in reducing pain, and that select SRIs did not significantly differ from placebo (Collins et al., J. Pain Symptom Manage. 2000, 20(6): 449-58). This analysis suggests that compounds with greater NRI versus SRI activity will be more effective for the treatment of pain.

Given the complex multifaceted nature of pain and of thermoregulation and the interplay between the CNS and PNS in maintaining thermoregulatory the homeostasis, multiple therapies and approaches can be developed to target the treatment of pain and vasomotor symptoms. The present invention provides novel compounds and compositions containing these compounds directed to these and other important uses.

SUMMARY

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.

One aspect of the invention provides a compound of formula I:

- or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof;
- wherein:
- n is an integer from 0 to 4;
- m is an integer from 0 to 6;
- X is —CH₂—;
- R¹is, independently at each occurrence, H, alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein each aryl or heteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido is independently substituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido groups;
- R²is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;
- R³and R⁴are, independently, H, alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are indepently substituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided that neither R³or R⁴contain an aminoalkyl group;
- and
- wherein 1-3 carbon atoms in ring A may optionally be replaced with N.

Another aspect of the invention provides a composition, comprising:

a. at least one compound of formula I; and

b. at least one pharmaceutically acceptable carrier.

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:

administering to said subject an effective amount of a compound of formula I.

Another aspect of the invention provides a process for the preparation of a compound of formula I, the process comprising:

(d) reacting a compound of formula IA:

with a compound of formula IB:

wherein,

T is an —N(R³)(R⁴) or an activating group;

wherein,

if T is —N(R³)(R⁴), then the compound of formula I is formed; or

if T is an activating group, then a compound of formula IC is formed:

and the process further comprises:

(e) reacting the compound formula IC with —N(R⁴)R^Pto form a compound of formula ID:

wherein,

R^Pis R⁴or a protecting group;

wherein,

if R^Pis R³, the compound of formula I is formed; or

if R^Pis a protecting group, the process further comprises:

(f) deprotecting the compound of formula ID to form a deprotected compound; and

(g) reacting the deprotected compound with an activated-R³group, provided that R³in the activated-R³group is not H;

wherein the compound of formula I is formed.

Another aspect of the invention provides a process for the preparation of a compound of formula I:

- or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof;
- wherein:
- n is an integer from 0 to 4;
- m is an integer from 0 to 6;
- X is —CH₂—;
- R¹is, independently at each occurrence, H, alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein each aryl or heteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido is independently substituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido groups;
- R²is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;
- R³and R⁴are, independently, H, alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are indepently substituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided that neither R³or R⁴contain an aminoalkyl group; and

wherein 1-3 carbon atoms in ring A may optionally be replaced with N;

the process comprising:

(d) reacting R²(BOH)₂and a transitional metal salt with a compound of formula IH:

wherein,

R^Pis R³or a protecting group; and

if R^Pis R³, the compound of formula I is formed; or

if R^Pis a protecting group, the process further comprises:

(e) deprotecting the compound of formula IH to form a deprotected compound; and

(f) reacting the deprotected compound with an activated-R³group, provided that R³group in the activated-R³group is not H;

wherein the compound of formula I is formed.

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.

Another aspect of the invention provides a composition comprising:

- (a) one or more of the compounds of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL or IM; and
- (b) one or more of: a base, an acid, a solvent, a hydrogenating agent, a reducing agent, an oxidizing agent, or a catalyst.

Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION

The following definitions are provided for the full understanding of terms and abbreviations used in this specification.

As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly indicates otherwise. Thus, for example, a reference to “an antagonist” includes a plurality of such antagonists, and a reference to “a compound” is a reference to one or more compounds and equivalents thereof known to those skilled in the art, and so forth.

The abbreviations in the specification correspond to units of measure, techniques, properties, or compounds as follows: “min” means minutes, “h” means hour(s), “μL” means microliter(s), “mL” means milliliter(s), “mM” means millimolar, “M” means molar, “mmole” means millimole(s), “cm” means centimeters, “SEM” means standard error of the mean and “IU” means International Units. “Δ° C.” and Δ “ED₅₀value” means dose which results in 50% alleviation of the observed condition or effect (50% mean maximum endpoint).

“Norepinephrine transporter” is abbreviated NET.

“Human norepinephrine transporter” is abbreviated hNET.

“Serotonin transporter” is abbreviated SERT.

“Human serotonin transporter” is abbreviated hSERT.

“Norepinephrine reuptake inhibitor” is abbreviated NRI.

“Selective norepinephrine reuptake inhibitor” is abbreviated SNRI.

“Serotonin reuptake inhibitor” is abbreviated SRI.

“Selective serotonin reuptake inhibitor” is abbreviated SSRI.

“Norepinephrine” is abbreviated NE.

“Serotonin is abbreviated 5-HT.

“Subcutaneous” is abbreviated sc.

“Intraperitoneal” is abbreviated ip.

“Oral” is abbreviated po.

In the context of this disclosure, a number of terms are utilized. The term “treat,” “treatment” or “treating” as used herein includes preventative (e.g., prophylactic), curative or palliative treatment.

The term “effective amount,” as used herein, 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. In particular, with respect to vasomotor symptoms, “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.

Preferably, 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. With respect to sexual dysfunction, gastrointestinal disorder, genitourinary disorder, chronic fatigue syndrome, fibromyalgia syndrome, depression disorder, diabetic neuropathy, or pain, the compounds of the present invention are administered at a dosage and for a time sufficient to treat the symptom or condition.

For example, for a patient, 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.

The terms “component,” “composition,” “composition of compounds,” “compound,” “drug,” or “pharmacologically active agent” or “active agent” or “medicament” are used interchangeably herein to refer to a compound or compounds or composition of matter which, when administered to a subject (human or animal) induces a desired pharmacological and/or physiologic effect by local and/or systemic action.

The term “modulation” refers to the capacity to either enhance or inhibit a functional property of a biological activity or process; for example, receptor binding or signaling activity. Such enhancement or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway and/or may be manifest only in particular cell types. The modulator is intended to comprise any compound; e.g., antibody, small molecule, peptide, oligopeptide, polypeptide, or protein, and is preferably small molecule, or peptide.

As used herein, the term “inhibitor” refers to any agent that inhibits, suppresses, represses, or decreases a specific activity, such as norepinephrine reuptake activity. The term “inhibitor” is intended to comprise any compound; e.g., antibody, small molecule, peptide, oligopeptide, polypeptide, or protein (preferably small molecule or peptide) that exhibits a partial, complete, competitive and/or inhibitory effect on mammalian (preferably the human) norepinephrine reuptake or both serotonin reuptake and the norepinephrine reuptake, thus diminishing or blocking (preferably diminishing) some or all of the biological effects of endogenous norepinephrine reuptake or of both serotonin reuptake and the norepinephrine reuptake.

Within the present invention, the compounds of formula I, may be prepared in the form of pharmaceutically acceptable salts. As used herein, the term “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,” as used herein, 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.

The term “subject” or “patient” refers to an animal including the human species that is treatable with the compounds, compositions, and/or methods of the present invention. The term “subject” or “subjects” is intended to refer to both the male and female gender unless one gender is specifically indicated. Accordingly, the term “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. Furthermore, the term 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. However, the term “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. In the case, for example, of high doses of NRIs or NRI/SRI compounds alone, 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).

“Vasomotor symptoms,” (also called “vasomotor instability symptoms” and “vasomotor disturbances”) include, but are not limited to, hot flushes (flushes), insomnia, sleep disturbances, mood disorders, irritability, excessive perspiration, night sweats, fatigue, and the like, caused by, inter alia, thermoregulatory dysfunction.

The term “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.

The terms “premature menopause” or “artificial menopause” refer to ovarian failure of unknown cause that may occur before age 40. It may be associated with smoking, living at high altitude, or poor nutritional status. Artificial menopause may result from oophorectomy, chemotherapy, radiation of the pelvis, or any process that impairs ovarian blood supply.

The term “pre-menopausal” means before the menopause, the term “peri-menopausal” means during the menopause and the term “post-menopausal” means after the menopause. “Ovariectomy” means removal of an ovary or ovaries and can be effected according to Merchenthaler et al., Maturitas, 1998, 30(3): 307-316.

The term “sexual dysfunction” includes, but is not limited to, conditions relating to disorders of sexual desire and/or arousal.

As used herein, “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 proctalgia).

As used herein, “chronic fatigue syndrome” (CFS) is a condition characterized by physiological symptoms selected from weakness, muscle aches and pains, excessive sleep, malaise, fever, sore throat, tender lymph nodes, impaired memory and/or mental concentration, insomnia, disordered sleep, localized tenderness, diffuse pain and fatigue, and combinations thereof, whether or not correlated with Epstein-Barr virus infection.

As used herein, “fibromyalgia syndrome” (FMS) includes 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.

As used herein, the term “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.

The compounds of the present invention can also be used to treat a cognitive disorder or an endogenous behavioral disorder. As used herein, 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). 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. As used herein, 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).

As used herein, “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.

As used herein, the term “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.

As used herein, the term “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.

As used herein, the term “neuropathic pain” refers to chronic pain caused by damage to or pathological changes in the peripheral or central nervous systems. Examples of 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. 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. Also included in the definition of neuropathic pain is a condition secondary to metastatic infiltration, adiposis dolorosa, burns, central pain conditions related to thalamic conditions, and combinations thereof.

As used herein, the term “hyperalgesia” refers to pain where there is an increase in sensitivity to a typically noxious stimulus.

As used herein, the term “allodynia” refers to an increase in sensitivity to a typically non-noxious stimulus.

As used herein, 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.

As used herein, the term “female-specific pain” refers to pain that may be acute and/or chronic pain associated with female conditions. Such 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,” as used herein, 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 (C₁-C₆) 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,” as used herein, 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 (C₂-C₆). Alkenyl groups can be optionally substituted.

“Alkynyl,” as used herein, 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 (C₂-C₆). Alkynyl groups can be optionally substituted.

“Alkylenyl”, “alkenylenyl”, “alkynylenyl”, and “arylenyl” refer 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. Examples of C₁-C₆alkylenyl include methylenyl (—CH₂—), ethylenyl (—CH₂CH₂—), propylenyl (—CH₂CH₂CH₂—), and dimethylpropylenyl (—CH₂C(CH₃)₂CH₂—). Likewise, examples of C₂-C₆alkenylenyl include ethenylenyl (—CH═CH— and propenylenyl (—CH═CH—CH₂—). Examples of C₂-C₆alkynylenyl include ethynylenyl (—C≡C—) and propynylenyl (—C═C—CH₂—). Examples of arylenyl groups include phenylenyl;

Preferably, arylenyl groups contain 6 carbon atoms (C₆).

“Halo,” as used herein, refers to chloro, bromo, fluoro, and iodo.

“Aryl” as used herein, 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 (C₆-C₁₀) being preferred. Non-limiting examples include, for example, phenyl, naphthyl, anthracenyl, and phenanthrenyl.

“Heteroaryl,” as used herein, 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. Non-limiting examples of 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,” as used herein, 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. The 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. Examples of 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, α-, β-, or γ-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylpyrimidinyl, phenanthridinyl, phenanthrolinyl, phenoxazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. 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,” as used herein, 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 (C₁-C₆).

“Arylalkyl,” as used herein, 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 (C₇-C₁₆).

“Heteroarylalkyl,” as used herein, 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,” as used herein, refers to the group R″—CH₂— where R″ is a heteroaryl group, as defined herein.

“Alkanoyloxy,” as used herein, refers to the group R—C(═O)—O— where R is an alkyl group, as defined herein, of 1 to 5 carbon atoms (C₁-C₅).

“Alkylsulfoxide,” as used herein, 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 (C₁-C₆).

“Arylsulfoxide,” as used herein, 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 (C₆-C₁₀).

“Alkylsulfone,” as used herein, refers to —S(═O)₂—R, where R is alkyl, as defined herein. Preferred alkylsulfone groups have from 1 to 6 carbon atoms (C₁-C₆).

“Arylsulfone,” as used herein, refers to —S(═O)₂—R′, where R′ is aryl, as defined herein. Preferred arylsulfone groups have from 6 to 10 carbon atoms (C₆-C₁₀).

“Alkylsulfonamide,” as used herein, 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 (C₁-C₆).

“Arylsulfonamide,” as used herein, 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 (C₆-C₁₀).

“Heteroarylsulfonamide,” as used herein, refers to —NR—S(═O)₂—R″, where R is H or alkyl, as defined herein, and R″ is aryl, as defined herein.

“Alkylamido,” as used herein, 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 (C₁-C₆).

“Arylamido,” as used herein, 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 (C₆-C₁₀).

“Phenylamido,” as used herein, refers to —NR—C(═O)-phenyl, where R is H or alkyl, as defined above.

As used herein, the terms “optionally substituted” or “substituted or unsubstituted” are intended to refer to the optional replacement of up to four hydrogen atoms with up to four independently selected substituent groups as defined herein. Unless otherwise specified, suitable 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, heteroaryloxy, heteroarylalkyl, and the like. 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. For example, 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).

Unless indicated otherwise, the nomenclature of 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. For example, the substituent “arylalkoxycabonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.

At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term “C_1-6alkyl” is specifically intended to individually disclose C₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆alkyl. By way of another example, 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.

The term “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. 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.

Reference to “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. Examples of preferred 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.

The term “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:

- or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof;
- wherein:
- n is an integer from 0 to 4;
- m is an integer from 0 to 6;
- X is —CH₂—;
- R¹is, independently at each occurrence, H, alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein each aryl or heteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido is independently substituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido groups;
- R²is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;
- R³and R⁴are, independently, H, alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are indepently substituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided that neither R³or R⁴contain an aminoalkyl group;
- and
- wherein 1-3 carbon atoms in ring A may optionally be replaced with N.

In another embodiment, each R¹is H.

In another embodiment, R²is:

wherein,

each R⁵, R³, R⁷, R⁸and R⁹are independently selected from the group consisting of H, alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl substituted, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, or arylamido.

In another embodiment, R⁷and R⁹are F. In another embodiment, R⁵, R⁶, R⁷and R⁸are H. In another embodiment, R⁹is F. In another embodiment, R⁵, R⁶and R⁸are H. In another embodiment R⁵is H or F, R⁶is H or F, R⁷is H or F, R³is H or F and R⁹is H or F. In another embodiment, R⁵, R⁶, R⁷, R⁸and R⁹are H, halo, alkyl or alkoxy.

In another embodiment, R³is alkyl. More particularly, methyl.

In another embodiment, R⁴is H.

In another embodiment, 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.

In another embodiment, ring A comprises all carbon atoms.

In another embodiment, R²is pyridinyl, methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or quinolinyl.

In another embodiment, R²is 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.

In another embodiment:

each R¹is H;

m is 1;

R³is methyl; and

R⁴is H.

In another embodiment:

each R¹is H;

R⁷and R⁹are F;

R⁵, R⁶and R⁸are H;

R³is methyl;

R⁴is H; and

m is 1.

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:

3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
N-{3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]propyl}cyclopropanamine;
3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine;
3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine;
3-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
N-methyl-3-[3-(4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
3-[3-(2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(3-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
N-methyl-3-[3-(1-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
N-methyl-3-[3-(2-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]propan-1-amine;
N-methyl-3-[3-(3-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
N-methyl-3-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
3-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylbutan-1-amine;
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine;
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N-methylbutan-1-amine;
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine;
n-butyl-4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine;
4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N-ethyl-N-methylbutan-1-amine;
3-(2,2-dioxido-3-phenyl[1,2,5]thiadiazolo[3,4-b]pyridin-1(3H)-yl)-N-methylpropan-1-amine;
3-(2,2-dioxido-1-phenyl[1,2,5]thiadiazolo[3,4-c]pyridin-3(1H)-yl)-N-methylpropan-1-amine;
N-methyl-3-[3-(5-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
N-methyl-3-[3-(3-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
3-[3-(6-methoxypyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(5-ethylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
N-methyl-3-[3-(4-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
3-(2,2-dioxido-3-pyridin-2-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine;
N-methyl-3-[3-(6-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
N-methyl-3-[3-(4-methylpyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
3-(2,2-dioxido-3-pyridin-3-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine;
3-(6-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine;
3-(5-Chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine;
3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine;
N-methyl-3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propan-1-amine;
3-(7-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine;
N-methyl-3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzo-thiadiazol-1(3H)-yl)propan-1-amine;
3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine;
3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(methylamino)propyl]-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole-5-carbonitrile 2,2-dioxide;
3-(5-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine;
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(3,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N-methylpropan-1-amine;
3-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-{2,2-dioxido-3-[3-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)-yl}-N-methylpropan-1-amine;
3-{2,2-dioxido-3-[2-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)-yl}-N-methylpropan-1-amine;
3-{2,2-dioxido-3-[3-(trifluoromethyl)phenyl]-2,1,3-benzothiadiazol-1(3H)-yl}-N-methylpropan-1-amine;
3-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(3-bromophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethanamine;
2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylethanamine;
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
N-ethyl-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine;
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N-methylbutan-1-amine;
3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
3-[3-(4-fluoro-2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pentan-1-amine;
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpentan-1-amine;
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpentan-1-amine;
3-[3-(3-Chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
3-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
3-[3-(2-fluorophenyl)-2,2-dioxido-5-phenyl-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N-methylpropan-1-amine;
3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine;
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[7-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(2,4-Difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(2,4-Difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(2,4-Difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpropan-1-amine;
4-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine;
4-[3-(4-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine;
4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine;
N-{3-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopropanamine;
N-{3-[3-(2,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopropanamine;
N-{4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}cyclopropanamine;
4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine;
4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine;
5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpentan-1-amine;
5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpentan-1-amine;
3-[3-(2-fluoro-4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-fluoro-4-{3-[3-(methylamino)propyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenol;
3-fluoro-4-{3-[4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenol;
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine;
3-[3-(4-chloro-2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]cyclopropanamine;
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopropanamine;
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butyl]cyclopropanamine;
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}cyclopropanamine;
3-[3-(4-chloro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylhexan-1-amine;
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]hexan-1-amine;
6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylhexan-1-amine;
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine;
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]butan-1-amine;
4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine;
N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine;
3-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N-methylpropan-1-amine;
3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N-methylbutan-1-amine;
3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-(2,2,2-trifluoroethyl)propan-1-amine;
3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1 (3H)-yl]-N-ethylpropan-1-amine;
3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine;
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpentan-1-amine;
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pentan-1-amine;
5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpentan-1-amine;
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpropan-1-amine;
3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine;
4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine;
4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylbutan-1-amine;
4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylbutan-1-amine;
4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-isopropylbutan-1-amine;
N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}cyclobutanamine;
N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}cyclohexanamine;
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine;
3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-isopropylpropan-1-amine;
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclobutanamine;
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopentanamine;
N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,13-benzothiadiazol-1(3H)-yl]propyl}cyclohexanamine;
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-amine;
N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidin-4-amine;
N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-4-amine;
N-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]piperidin-4-amine;
2-({3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}amino) ethanol; and

pharmaceutically acceptable salts thereof.

In another embodiment, said pharmaceutically acceptable salt is a hydrochloride or dihydrochloride.

Another aspect of the invention provides a composition, comprising:

a. at least one compound of formula I; and

b. at least one pharmaceutically acceptable carrier.

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:

administering to said subject an effective amount of a compound of formula I.

In certain embodiments, the vasomotor symptom is hot flush.

In certain embodiments, the sexual dysfunction is desire-related or arousal-related.

In certain embodiments, the gastrointestinal disorder or the genitourinary disorder is stress incontinence or urge incontinence.

In certain embodiments, the condition is chronic fatigue syndrome.

In certain embodiments, the condition is fibromyalgia syndrome.

In certain embodiments, 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.

In certain embodiments, the disorder is an endogenous behavioral disorder or a cognitive disorder.

In certain embodiments, the condition is diabetic neuropathy.

In certain embodiments, the condition is pain.

In certain embodiments, the pain is acute centralized pain, acute peripheral pain, or a combination thereof.

In certain embodiments, the pain is chronic centralized pain, chronic peripheral pain, or a combination thereof.

In certain embodiments, the pain is neuropathic pain, visceral pain, musculoskeletal pain, bony pain, cancer pain, inflammatory pain, or a combination thereof.

In certain embodiments, 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.

In certain embodiments, the neuropathic pain is post-herpetic neuralgia.

In certain embodiments, 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.

In certain embodiments, the pain is female-specific pain.

The present invention provides a treatment for vasomotor symptoms by methods of recovering the reduced activity of norepinephrine. Without wishing to be bound by any theory, 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 _α2receptor with an antagonist, or (iii) blocking the activity of 5-HT on NE neurons with a 5-HT_2aantagonist.

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. One skilled in the art will recognize that these pains may overlap one another. For example, a pain caused by inflammation may also be visceral or musculoskeletal in nature.

In a preferred embodiment of the present invention 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.

In a more preferred embodiment, 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.

As mentioned previously, the methods of the present invention may be used to treat pain that is somatic and/or visceral in nature. For example, 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. Examples of 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. One skilled in the art will also recognize that 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. Such 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:

(d) reacting a compound of formula IA:

with a compound of formula IB:

wherein,

T is an —N(R³)(R⁴) or an activating group;

wherein,

if T is —N(R³)(R⁴), then the compound of formula I is formed; or

if T is an activating group, then a compound of formula IC is formed:

and the process further comprises:

(e) reacting the compound formula IC with —N(R⁴)R^Pto form a compound of formula ID:

wherein,

R^Pis R⁴or a protecting group;

wherein,

if R^Pis R³, the compound of formula I is formed; or

if R^Pis a protecting group, the process further comprises:

(f) deprotecting the compound of formula ID to form a deprotected compound; and

(g) reacting the deprotected compound with an activated-R³group, provided that R³in the activated-R³group is not H;

wherein the compound of formula I is formed.

In another embodiment, step (d) further comprises contacting the compound of formula IA and IB with dialkyl azodicarboxylate and triphenylphosphine.

In another embodiment, the dialkyl azodicarboxylate is diisopropyl azodicarboxylate.

In another embodiment, the activating group is selected from the group consisting of halo, tosylate, mesylate, triflate, and oxo.

In another embodiment, the activating group is Br.

In another embodiment, the protecting group is selected from the group consisting of BOC, benzyl, acetyl, PMB, C₁-C₆alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and triphenylmethyl.

In another embodiment, the protecting group is BOC.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, the activated-R³group is halo-R³.

In another embodiment, the compound of formula IA is prepared by:

(a) reacting a compound of formula IE:

wherein R^Bis F or Cl;

with R²—NH₂to form a compound of formula IF:

(b) hydrogenating the compound of formula IF to form a compound of formula IG:

and (c) reacting the compound of formula IG with sulfamide in diglyme to form the compound of formula IA.

In another embodiment, the hydrogenating step is performed in the presence of hydrogen (H₂) and Pd/C.

In another embodiment, any one of steps (a)-(c) is performed at or above 30° C.

In another embodiment, 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:

- or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof;
- wherein:
- n is an integer from 0 to 4;
- m is an integer from 0 to 6;
- X is —CH₂—;
- R¹is, independently at each occurrence, H, alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein each aryl or heteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido is independently substituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido groups;
- R²is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;
- R³and R⁴are, independently, H, alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are indepently substituted with 0-3 alkyl, alkoxy, halo, CF₃, OCF₃, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided that neither R³or R⁴contain an aminoalkyl group; and

wherein 1-3 carbon atoms in ring A may optionally be replaced with N;

the process comprising:

(d) reacting R²(BOH)₂and a transitional metal salt with a compound of formula IH:

wherein,

R^Pis R³or a protecting group; and

if R^Pis R³, the compound of formula I is formed; or

if R^Pis a protecting group, the process further comprises:

(e) deprotecting the compound of formula IH to form a deprotected compound; and

(f) reacting the deprotected compound with an activated-R³group, provided that R³group in the activated-R³group is not H;

wherein the compound of formula I is formed.

In another embodiment, the transitional metal salt is copper(II) acetate.

In another embodiment, the activated-R³group is halo-R³.

In another embodiment, the protecting group is selected from the group consisting of BOC, benzyl, acetyl, PMB, C₁-C₆alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and triphenylmethyl.

In another embodiment, the protecting group is BOC.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, the compound of formula IH is prepared by:

(a) reacting a compound of formula IJ:

wherein R^Bis F or Cl;

with a compound of formula IK:

to form a compound of formula IL:

(b) hydrogenating the compound of formula IL to form a compound of formula IM:

and (c) reacting the compound of formula IM with sulfamide and diglyme to form the compound of formula IH.

In another embodiment, the hydrogenating step is performed in the presence of hydrogen (H₂) and Pd/C.

In another embodiment, any one of steps (a)-(c) is performed at or above 30° C.

In another embodiment, any one of steps (a)-(c) includes a purification step comprising at least one of: filtration, extraction, chromatography, trituration, or recrystallization.

In another embodiment, 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.

Another aspect of the invention provides a composition comprising:

(a) one or more of the compounds of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL or IM; and

(b) 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

Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron, 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds, (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions, p. 268 (E. L. Eliel, Ed., University of Notre Dame Press, Notre Dame, Ind. 1972), the entire disclosures of which are herein incorporated by reference.

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). “Design and Application of Prodrugs,” Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Deliver Reviews, 1992, 8:1-38, Bundgaard, J. of Pharmaceutical Sciences, 1988, 77:285 et seq.; and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), the entire disclosures of which are herein incorporated by reference.

Further, 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. In general, 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.

As will be readily understood, functional groups present 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.

Compounds of the present invention are suitably prepared in accordance with the following general description and specific examples. Variables used are as defined for formula I, unless otherwise noted. The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds of formula I may be produced by the following reaction schemes (Schemes 1-3).

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.

Following Scheme 1, an appropriate fluoronitroarene 1 may be substituted with an aryl amine using a base under standard conditions to provide an aminonitroarene 2. Typically conditions for this reaction 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. In a typical example, 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. In accordance with the embodiment of the invention, 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. Typically 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 additional method for the synthesis of compounds of formula I is described in Scheme 2. An appropriate fluoronitroarene is substituted with an amine bearing the desired side chain to give compounds of structure 7. Reduction of the nitro group under conditions described in Scheme 1 provides 8. Compounds of structure 8 can be converted to arylsulfamide of structure 9 by treatment with a suitable sulfate containing reagent. In a typical example, 8 was heated with sulfamide in diglyme to provide the cyclized product 9. An aryl group may then be attached to the sulfamide 9 using conventional methods for formation of an aryl-nitrogen bond. In a typical example 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. Subsequent deprotection of the protecting group P in 6 affords compounds of formula I. As described in Scheme 1, 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.

In other embodiments, the invention is directed to pharmaceutical compositions, comprising:

a. at least one compound of formula I, or pharmaceutically acceptable salt thereof; and
b. at least one pharmaceutically acceptable carrier.

Generally, 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. Preferably, 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. Even more preferably, 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.

Such 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. In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, 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) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, 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.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, 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.

In another embodiment of the present invention, 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. Examples of such 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.

The term “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. 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. Furthermore, the administration of compound of formula I, or pharmaceutically acceptable salt thereof, with other active ingredients may be separate, consecutive or simultaneous.

The present invention is further defined in the following Examples, in which all parts and percentages are by weight and degrees are Celsius, unless otherwise stated. It should be understood that these examples, while indicating preferred embodiments of the invention, are given by way of illustration only. From the above discussion and these examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

EXAMPLES Example 1 3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

Genera Procedure A for Synthesis of Sulfamides of Structure I;

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. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-50% (ethyl acetate containing 2% formic acid) in hexane) to afford 1-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide 0.66 g (47%).

MS (ESI) m/z 279

HPLC purity 94.7% at 210-370 nm, 9.3 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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. Purification via Isco chromatography (Redisep, silica, gradient 5-50% ethyl acetate in hexane) afforded 0.13 g (32%) 1-(3-bromo-propyl)-3-(4-chlorophenyl)-1,3-dihydro-benzo[1,2,5]thiadiazole 2,2-dioxide which was immediately carried on to the next step.

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. The crude product was purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 70 mg of 3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine. The free base was dissolved in ether (2 mL) and treated with 1N hydrochloric acid in ether (1 equivalent). The white precipitate was collected and dried under vacuum to give 70 mg (71%) of 3-=3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl-N-methylpropan-1-amine hydrochloride. HPLC purity 100% at 210-370 nm, 7.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

HRMS: calculated for C₁₆H₁₈ClN₃O₂S+H⁺, 352.08810; found (ESI, [M+H]⁺), 352.0875

Example 2 3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine

1-(3-Bromo-propyl)-3-(4-chloro-phenyl)-1,3-dihydrobenzo[1,2,5]thia-diazole 2,2-dioxide (0.10 g, 0.25 mmol) was dissolved in 7N ammonia in methanol (20 mL), heated to 60° C. and stirred for 16 hours in a sealed flask. The mixture was cooled and 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 73 mg (87%) of 3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine. The free base was dissolved in ether (2 mL) and treated with 1N hydrochloric acid in ether (1 equivalent). The white precipitate was collected, dissolved in water, and lyophilized to give 56 mg of 3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride.

MS (ES) m/z 337.9;

HPLC purity 100% at 210-370 nm, 7.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 3 N-{3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopropanamine

In an analogous manner to General Procedure A, 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).

MS (ES) m/z 378

HPLC purity 100% at 210-370 nm, 8.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5195 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 4 3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine

In an analogous manner to General Procedure A, 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).

MS (ES) m/z 366.1;

HPLC purity 92.4% at 210-370 nm, 8.0 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 5 3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine

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).

MS (ES) m/z 244.9;

HPLC purity 97.7% at 210-370 nm, 8.5 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 367.0;

HPLC purity 98.5% at 210-370 nm, 10.4 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 318.0;

HPLC purity 99.5% at 210-370 nm, 6.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 6 3-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

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 NH₄Cl and diluted with ethyl acetate and ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-25% ethyl acetate in hexane) to afford 3.2 g of N-(4-fluorophenyl)-N-(2-nitrophenyl)amine that was carried on directly to the next step.

HRMS: calculated for C₁₂H₉FN₂O2+H⁺, 233.07208; found (ESI⁺, [M+H]⁺), 233.07207

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.

MS (ES) m/z 203.1;

HPLC purity 100.0% at 210-370 nm, 8.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 263.0;

HPLC purity 100.0% at 210-370 nm, 8.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 385.3;

HPLC purity 100.0% at 210-370 nm, 10.6 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 335.9;

HPLC purity 100.0% at 210-370 nm, 7.1 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 7 3-[3-(4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

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 NH₄Cl and diluted with ethyl acetate and ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-25% ethyl acetate in hexane) to afford 0.4 g of N-(4-methoxyphenyl)-2-nitroaniline that was carried on directly to the next step.

HRMS: calculated for C₁₃H₁₂N₂O₃+H⁺, 245.09207; found (ESI⁺, [M+H]⁺), 245.09144;

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.

HRMS: calculated for C₁₃H₁₄N₂O+H⁺, 215.11789; found (ESI⁺, [M+H]⁺), 215.11733

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).

MS (ES) m/z 275.0;

HPLC purity 100.0% at 210-370 nm, 8.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 396.8;

HPLC purity 98.1% at 210-370 nm, 10.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 347.9;

HPLC purity 100.0% at 210-370 nm, 7.1 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 8 N-methyl-3-[3-(4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine

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 NH₄Cl and diluted with ethyl acetate and ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.6 g N-(4-methylphenyl)-N-(2-nitrophenyl)amine that was carried on directly to the next step.

HRMS: calculated for C₁₃H₁₂N₂O₂+H⁺, 229.09715; found (ESI⁺, [M+H]⁺), 229.09737

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.

HRMS: calculated for C₁₃H₁₄N₂+H⁺, 199.12297; found (ESI⁺, [M+H]⁺), 199.12318

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).

MS (ES) m/z 259.0;

HPLC purity 95.5% at 210-370 nm, 9.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

HPLC purity 98.4% at 210-370 nm, 10.9 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 331.9;

HPLC purity 100.0% at 210-370 nm, 6.9 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 9 3-[3-(2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

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 NH₄Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.7 g N-(2-methoxyphenyl)-N-(2-nitrophenyl)amine that was carried on directly to the next step.

HRMS: calculated for C₁₃H₁₂N₂O₃+H⁺, 245.09207; found (ESI⁺, [M+H]⁺), 245.09187

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.

HRMS: calculated for C₁₃H₁₄N₂O+H⁺, 215.11789; found (ESI⁺, [M+H]⁺), 215.11761

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).

MS (ES) m/z 275.0;

HPLC purity 100.0% at 210-370 nm, 8.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 397.0;

HPLC purity 100.0% at 210-370 nm, 10.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 347.9;

HPLC purity 100.0% at 210-370 nm, 6.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 10 3-[3-(3-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

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 NH₄Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 1.2 g (3-fluoro-2-methyl-phenyl)-(2-nitro-phenyl)-amine that was carried on directly to the next step.

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).

MS (ES) m/z 277.0;

HPLC purity 98.8% at 210-370 nm, 10.0 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

HPLC purity 100.0% at 210-370 nm, 11.0 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 350.0;

HPLC purity 100.0% at 210-370 nm, 7.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 11 3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

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 NH₄Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 1.4 g 2-fluoro-N-(2-nitrophenyl)aniline that was carried on directly to the next step.

MS (ES) m/z 232.9

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.

MS (ES) m/z 203.0

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).

MS (ES) m/z 263.0;

HPLC purity 100.0% at 210-370 nm, 8.9 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 384.9

HPLC purity 99.4% at 210-370 nm, 10.3 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 335.9;

HPLC purity 99.2% at 210-370 nm, 8.5 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 12 3-[3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

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 NH₄Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.77 g N-(3-fluorophenyl)-N-(2-nitrophenyl)amine that was carried on directly to the next step.

HRMS: calculated for C₁₂H₉FN₂O₂, 232.06481; found (EI, M⁺), 232.06482

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.

HRMS: calculated for C₁₂H₁₁FN₂+H⁺, 203.09790; found (ESI⁺, [M+H]⁺), 203.09795

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).

MS (ES) m/z 263.0;

HPLC purity 97.4% at 210-370 nm, 8.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5195 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 385

HPLC purity 97.9% at 210-370 nm, 10.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 336.0;

HPLC purity 100.0% at 210-370 nm, 7.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 13 N-methyl-3-[3-(1-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine

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 NH₄Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.41 g N-(2-nitrophenyl)naphthalen-1-amine that was carried on directly to the next step.

MS (ES) m/z 265.0;

HPLC purity 100.0% at 210-370 nm, 11.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 295.0

HPLC purity 94.3% at 210-370 nm, 9.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 416.8

HPLC purity 99.4% at 210-370 nm, 11.1 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 367.9;

HPLC purity 99.5% at 210-370 nm, 7.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 14 N-methyl-3-[3-(2-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine

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 NH₄Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.37 g N-(2-nitrophenyl)naphthalen-2-amine that was carried on directly to the next step.

MS (ES) m/z 265.0;

HPLC purity 100.0% at 210-370 nm, 11.4 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 295.0

HPLC purity 99.2% at 210-370 nm, 9.9 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH-3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 415.9

HPLC purity 98.4% at 210-370 nm, 11.4 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 368.0;

HPLC purity 100.0% at 210-370 nm, 8.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 15 N-methyl-3-[3-(3-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine

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 NH₄Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.95 g N-(3-methylphenyl)-2-nitroaniline that was carried on directly to the next step.

HRMS: calculated for C₁₃H₁₂N₂O₂+H⁺, 229.09715; found (ESI⁺, [M+H]⁺), 229.09727

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.

HRMS: calculated for C₁₃H₁₄N₂+H⁺, 199.12297; found (ESI⁺, [M+H]⁺), 199.1232

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).

MS (ES) m/z 259.0

HPLC purity 94.8% at 210-370 nm, 9.3 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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.

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).

MS (ES) m/z 332.0;

HPLC purity 100.0% at 210-370 nm, 7.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85115-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 16 N-methyl-3-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine

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 NH₄Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.75 g (2-Nitro-phenyl)-o-tolyl-amine.

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).

MS (ES) m/z 261.0;

HPLC purity 92.8% at 210-370 nm, 9.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

HPLC purity 95.3% at 210-370 nm, 10.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 331.9;

HPLC purity 100.0% at 210-370 nm, 7.4 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 17 3-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

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 NH₄Cl and diluted with ether. The mixture was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 1.3 g N-(3-methoxyphenyl)-N-(2-nitrophenyl)amine.

HRMS: calculated for C₁₃H₁₂N₂O₃+H⁺, 245.09207; found (ESI⁺, [M+H]⁺), 245.0919

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.

HRMS: calculated for C₁₃H₁₄N₂O+H⁺, 215.11789; found (ESI⁺, [M+H]⁺), 215.11774

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).

MS (ES) m/z 276.9;

HPLC purity 99.4% at 210-370 nm, 8.9 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85115-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 396.9;

HPLC purity 100.0% at 210-370 nm, 10.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85115-5195 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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).

MS (ES) m/z 347.9;

HPLC purity 100.0% at 210-370 nm, 7.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5195 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 18 4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylbutan-1-amine

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. The crude product was purified via Isco chromatography (Redisep, silica, gradient 2-30% ethyl acetate in hexane) to afford 0.155 g of 1-(4-bromobutyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.

HPLC purity 100.0% at 210-370 nm, 10.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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. The free base was dissolved in ether (2 mL) and treated with 1N hydrochloric acid in ether (1 equivalent). The white precipitate was collected and dried under vacuum to give 120 mg of 4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylbutan-1-amine hydrochloride.

HPLC purity 100.0% at 210-370 nm, 7.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 19 4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-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. The crude product was pre-adsorbed onto Celite and purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.22 g (59%) of 1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.

mp 65-68° C.

HPLC purity 100.0% at 210-370 nm, 11.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH-3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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. Further purification by reverse phase HPLC(X-terra MS C₁₈19×150 mm, using a gradient of 10-100% water-acetonitrile with 0.1% TFA at a rate of 20 mL/minute at 254 nm) gave 11 mg (20%) of 4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine as the TFA salt.

MS (ESI) m/z 352.0844

HPLC purity 97.0% at 210-370 nm, 9.3 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium Bicarbonate Buffer pH=9.5/ACN+MeOH) for 10 minutes, hold 4 minutes

Example 20 4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine

10 mL of Methylamine (ca. 8M in ethanol) was added to a round bottom flask containing (50 mg, 0.12 mmol) of 1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. The reaction flask was covered with a septum and stirred overnight at room temperature. The reaction solution was concentrated in vacuo and the crude product was pre-adsorbed onto Celite and purified via Isco chromatography (Redisep, silica, gradient 1-8% methanol in dichloromethane with ammonia) to afford 33 mg (78%) of product. Further purification by reverse phase HPLC(X-terra MS C₁₈19×150 mm, using a gradient of 10-100% water-acetonitrile with 0.1% TFA at a rate of 20 mL/minute at 254 nm) gave 24 mg (41%) of 4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine as the TFA salt.

HPLC purity 100.0% at 210-370 nm, 8.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

HRMS: calculated for C₁₇H₂₀ClN₃O₂S+H⁺, 366.10375; found (ESI, [M+H]⁺), 366.1019

Example 21 4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine

In an analogous manner to Example 2, dimethylamine (10 mL, [˜5.6 M]) and 1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (50 mg, 0.12 mmol) were stirred overnight to prepare 9 mg (16%) of 4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine as the TFA salt. HPLC purity 100.0% at 210-370 nm, 8.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

HRMS: calculated for C₁₈H₂₂ClN₃O₂S+H⁺, 380.11940; found (ESI, [M+H]⁺), 380.1177

Example 22 n-butyl-4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine

In an analogous manner to Example 2, butylamine (2.0 mL, 20.2 mmol) and 1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (50 mg, 0.12 mmol) was stirred overnight to prepare 13 mg (21%) of n-butyl-4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine as the TFA salt.

HPLC purity 100.0% at 210-370 nm, 9.0 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

HRMS: calculated for C₂₀H₂₆ClN₃O₂S+H⁺, 408.15070; found (ESI, [M+H]⁺), 408.1506

Example 23 4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-ethyl-N-methylbutan-1-amine

In an analogous manner to Example 2, 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.

MS (ESI) m/z 394.132;

HPLC purity 100.0% at 210-370 nm, 8.4 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 24 3-(2,2-dioxido-3-phenyl[1,2,5]thiadiazolo[3,4-b]pyridin-1(3H)-yl)-N-methylpropan-1-amine

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.

HRMS: calculated for C₁₁H₉N₃O₂+H⁺, 216.07675; found (ESI, [M+H]⁺), 216.0787 HPLC purity 100.0% at 210-370 nm, 9.5 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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. The combined organic portions were washed once with water and once with brine (100 mL each), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-100% ethyl acetate in hexane) to afford 2.6 g of N²-phenylpyridine-2,3-diamine.

HPLC purity 99.4% at 210-370 nm, 6.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium Bicarbonate Buffer pH=9.5/ACN+MeOH) for 10 minutes, hold 4 minutes.

Step 3: A mixture of N²-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). The material obtained was re-chromatographed via Isco chromatography (Redisep, silica, isocratic 25% ethyl acetate in hexane for 15 minutes, then gradient 15-100% ethyl acetate in hexane to afford 0.19 g of 1-phenyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide.

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.

SFC Instrument: Berger MuitiGram Prep SFC (Berger Instruments, Inc. Newark, DE) Column: Kromasil DIOL; 5 μm; 250 mm L × 21 mm ID (EKA Chemicals, Dobbs Ferry, NY) Column temperature: 35° C. SFC Modifier: 15% MeOH/85% CO2 Flow rate: 50 mL/min Detector: UV at 220 nm

The residue obtained was taken up in 4M HCl/dioxane (5 mL) and stirred at ambient temperature for 2 hours. The mixture was diluted with water (15 mL) and lyophilized. The resulting oil was triturated with diethyl ether until solids formed. The off-white solids were collected and dried under vacuum to give 96 mg of 3-(2,2-dioxido-3-phenyl[1,2,5]thiadiazolo[3,4-b]pyridin-1(3H)-yl)-N-methylpropan-1-amine dihydrochloride.

HRMS: calculated for C₁₅H₁₈N₄O₂S+H⁺, 319.12232; found (ESI, [M+H]⁺), 319.1227

HPLC purity 100.0% at 210-370 nm, 5.4 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5195 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 25 3-(2,2-dioxido-1-phenyl[1,2,5]thiadiazolo[3,4-c]pyridin-3(1H)-yl)-N-methylpropan-1-amine

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). The combined organic portions were washed once with water and once with brine (100 mL each), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-100% ethyl acetate in hexane) to afford 2.2 g of N⁴-phenylpyridine-3,4-diamine.

HRMS: calculated for C₁₁H₁₁N₃+H⁺, 186.10257; found (ESI, [M+H]⁺), 186.1036

HPLC purity 98.6% at 210-370 nm, 4.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Step 3: A mixture of N⁴-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.

HPLC purity 98.4% at 210-370 nm, 4.5 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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 μm; 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

The residue obtained was taken up in 4M HCl/dioxane (5 mL) and stirred at ambient temperature for 2 hours. The mixture was diluted with water (15 mL) and lyophilized. The resulting oil was triturated with diethyl ether until solids formed. The beige solids were collected and dried under vacuum to give 127 mg of 3-(2,2-dioxido-3-phenyl[1,2,5]thiadiazolo[3,4-c]pyridin-1(3H)-yl)-N-methylpropan-1-amine dihydrochloride.

HRMS: calculated for C₁₅H₁₈N₄O₂S+H⁺, 319.12232; found (ESI, [M+H]⁺), 319.1197 HPLC purity 98.6% at 210-370 nm, 4.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 26 N-methyl-3-[3-(5-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride

General Procedure B for Synthesis of Sulfamides of Structure I:

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.

MS (ES) m/z 230.0 ([M+H]⁺).

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.

MS (ES) m/z 200.0 ([M+H]⁺); HRMS: calculated for C₁₂H₁₃N₃+H⁺, 200.11822; found (ESI, [M+H]⁺), 200.125.

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.

MS (ES) m/z 261.8 ([M+H]⁺); HRMS: calculated for C₁₂H₁₁N₃O₂S+H⁺, 262.06447; found (ESI, [M+H]⁺), 262.0642.

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.

MS (ES) m/z 337.7 ([M+H]⁺); HRMS: calculated for C₁₅H₁₆ClN₃O₂S+H⁺, 338.07245; found (ESI, [M+H]⁺), 338.0724.

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. The crude product was crystallized from dichloromethane by adding minutesimum amount of ethyl acetate and diethyl ether to afford the title compound, N-methyl-3-[3-(5-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride as a light tan solid.

MS (ES) m/z 333.0 ([M+H]⁺); HRMS: calculated for C₁₆H₂₀N₄O₂S+H⁺, 333.13797; found (ESI, [M+H]⁺), 333.1383; HPLC purity 100% at 210-370 nm, 6.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 ml/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 27 N-methyl-3-[3-(3-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride

In an analogous manner to General Procedure B. Step 1, 3-methyl-N-(2-nitrophenyl)pyridin-2-amine was prepared from 2-amino-3-picoline as an orange solid.

MS (ES) m/z 230.0 ([M+H]⁺); HRMS: calculated for C₁₂H₁N₃O₂+H⁺, 230.09240; found (ESI, [M+H]⁺), 230.0923.

In an analogous manner to General Procedure B, Step 2, N-(3-methylpyridin-2-yl)benzene-1,2-diamine was prepared from 3-methyl-N-(2-nitrophenyl)pyridin-2-amine as a white solid. MS (ES) m/z 200 ([M+H]⁺); HRMS: calculated for C₁₂H₁₃N₃+H⁺, 200.11822; found (ESI, [M+H]⁺), 200.

In an analogous manner to General Procedure B, Step 3, 1-(3-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from N-(3-methylpyridin-2-yl)benzene-1,2-diamine as a white solid. MS (ES) m/z 261.8; HRMS: calculated for C₁₂H₁₁N₃O₂S+H⁺, 262.06447; found (ESI, [M+H]⁺), 262.0644.

In an analogous manner to General Procedure B, 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]⁺).

In an analogous manner to General Procedure B, Step 5, 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. MS (ES) m/z 332.9; HPLC purity 100% at 210-370 nm, 5.3 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 ml/min, 85/15-5195 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 28 3-[3-(6-methoxypyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure B, Step 1, 6-methoxy-N-(2-nitrophenyl)pyridin-3-amine was prepared from 5-amino-2-methoxypyridine as an orange oil. MS (ES) m/z 245.9 ([M+H]⁺).

In an analogous manner to General Procedure B, Step 2, 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. MS (ES) m/z 216.0 ([M+H]⁺);

HRMS: calculated for C₁₂H₁₃N₃O+H⁺, 216.11314; found (ESI, [M+H]⁺), 216.1128.

In an analogous manner to General Procedure B, Step 3, 1-(6-methoxypyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from N-(6-methoxylpyridin-3-yl)benzene-1,2-diamine without further purification. MS (ES) m/z 278 ([M+H]⁺).

In an analogous manner to General Procedure B, Step 4, 1-(3-chloropropyl)-3-(6-methoxypyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from 1-(6-methoxypyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as an oil. MS (ES) m/z 353.7.

In an analogous manner to General Procedure B, Step 5, 3-[3-(6-methoxypyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-chloropropyl)-3-(6-methoxylpyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as a white solid. MS (ES) m/z 348.9 ([M+H]⁺); HRMS: calculated for C₁₆H₂₀N₄O₃S+H⁺, 349.13289; found (ESI, [M+H]⁺), 349.1385; HPLC purity 100% at 210-370 nm, 6.6 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 ml/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 29 3-[3-(5-ethylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure B, Step 1, 5-ethyl-N-(2-nitrophenyl)pyridin-2-amine was prepared from 6-amino-3-ethylpyridine as an oil. MS (ES) m/z 243.5 ([M+H]⁺); HRMS: calculated for C₁₃H₁₃N₃O₂+H⁺, 244.10805; found (ESI, [M+H]⁺), 244.1068.

In an analogous manner to General Procedure B, Step 2, N-(5-ethylpyridin-2-yl)benzene-1,2-diamine was prepared from 5-ethyl-N-(2-nitrophenyl)pyridin-2-amine as an oily solid. MS (ES) m/z 214.0 ([M+H]⁺).

In an analogous manner to General Procedure B, Step 3, 1-(5-ethylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from N-(5-ethylpyridin-2-yl)benzene-1,2-diamine without further purification. MS (ES) m/z 276 ([M+H]⁺).

In an analogous manner to General Procedure B, Step 4, 1-(3-chloropropyl)-3-(5-ethylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from 1-(5-ethylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as an oil. MS (ES) m/z 351.7 ([M+H]⁺).

In an analogous manner to General Procedure B, Step 5, 3-[3-(5-ethylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-chloropropyl)-3-(5-ethylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as a white solid. MS (ES) m/z 346.9 ([M+H]⁺); HRMS: calculated for C₁₇H₂₂N₄O₂S+H⁺, 347.15362; found (ESI, [M+H]⁺), 347.1536; HPLC purity 94.9% at 210-370 nm, 8.3 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 ml/min, 85/15-5195 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 30 N-methyl-3-[3-(4-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride

In an analogous manner to General Procedure B, Step 1, 4-methyl-N-(2-nitrophenyl)pyridin-2-amine was prepared from 2-amino-4-picoline as an orange solid. MS (ES) m/z 230.0 ([M+H]⁺); HRMS: calculated for C₁₂H₁₁N₃O₂+H⁺, 230.09240; found (ESI, [M+H]⁺), 230.0923.

In an analogous manner to General Procedure B, Step 2, N-(4-methylpyridin-2-yl)benzene-1,2-diamine was prepared from 4-methyl-N-(2-nitrophenyl)pyridin-2-amine as a white solid. MS (ES) m/z 200 ([M+H]⁺); HRMS: calculated for C₁₂H₁₃N₃+H⁺, 200.11822; found (ESI, [M+H]⁺), 200.1217.

In an analogous manner to General Procedure B, Step 3, 1-(4-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from N-(4-methylpyridin-2-yl)benzene-1,2-diamine without further purification. MS (ES) m/z 262 ([M+H]⁺).

In an analogous manner to General Procedure B, 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]⁺).

In an analogous manner to General Procedure B, Step 5, 3-[3-(4-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-chloropropyl)-3-(4-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as a white solid. MS (ES) m/z 333.0 ([M+H]⁺); HRMS: calculated for CO₆H₂₀N₄O₂S+H⁺, 333.13797; found (ESI, [M+H]⁺), 333.1366; HPLC purity 100% at 210-370 nm, 5.3 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 ml/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 31 3-(2,2-dioxido-3-pyridin-2-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure B, Step 1, N-(2-nitrophenyl)pyridin-2-amine was prepared from 2-aminopyridine as an orange solid. MS (ES) m/z 216.1 ([M+H]⁺).

In an analogous manner to General Procedure B, Step 2, N-pyridin-2-ylbenzene-1,2-diamine was prepared from N-(2-nitrophenyl)pyridin-2-amine as a white solid.

MS (ESI) m/z 186 ([M+H]⁺).

In an analogous manner to General Procedure B, Step 3, 1-(N-pyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from N-pyridin-2-ylbenzene-1,2-diamine without further purification. MS (ES) m/z 248 ([M+H]⁺).

In an analogous manner to General Procedure B, Step 4, 1-(3-chloropropyl)-3-pyridin-2-yl-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from 1-(N-pyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as an oil. MS (ES) m/z 323.7 ([M+H]⁺); HRMS: calculated for C₁₄H₄ClN₃O₂S+H⁺, 324.05680; found (ESI, [M+H]⁺), 324.0574.

In an analogous manner to General Procedure B, Step 5, 3-(2,2-dioxido-3-pyridin-2-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-chloropropyl)-3-pyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as a white solid. MS (ES) m/z 318.9 ([M+H]⁺); HRMS: calculated for C₁₅H₁₈N₄O₂S+H⁺, 319.12232; found (ESI, [M+H]⁺), 319.122; HPLC purity 98.7% at 210-370 nm, 5.5 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 ml/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 32 N-methyl-3-[3-(6-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride

In an analogous manner to General Procedure B, Step 1, 6-methyl-N-(2-nitrophenyl)pyridin-2-amine was prepared from 2-amino-6-picoline as an orange solid. MS (ES) m/z 230.0 ([M+H]⁺).

In an analogous manner to General Procedure B, Step 2, N-(6-methylpyridin-2-ylbenzene-1,2-diamine was prepared from 6-methyl-N-(2-nitrophenyl)pyridin-2-amine as a white solid. MS (ES) m/z 200 ([M+H]⁺); HRMS: calculated for C₁₂H₁₃N₃+H⁺, 200.11822; found (ESI, [M+H]⁺), 200.1248.

In an analogous manner to General Procedure B, Step 3, 1-(6-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from N-(6-methyl)pyridin-2-ylbenzene-1,2-diamine without further purification. MS (ES) m/z 262 ([M+H]⁺).

In an analogous manner to General Procedure B, 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]⁺).

In an analogous manner to General Procedure B, Step 5, 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. MS (ES) m/z 332.9 ([M+H]⁺); HPLC purity 100% at 210-370 nm, 6.9 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 ml/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 33 N-methyl-3-[3-(4-methylpyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride

In an analogous manner to General Procedure B, Step 1, 4-methyl-N-(2-nitrophenyl)pyridin-3-amine was prepared from 3-amino-4-methylpyridine as an orange solid. MS (ES) m/z 229.9 ([M+H]⁺); HRMS: calculated for C₁₂H₁₁N₃O₂+H⁺, 230.09240; found (ESI, [M+H]⁺), 230.09.

In an analogous manner to General Procedure B, Step 2, 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]⁺).

In an analogous manner to General Procedure B, Step 3, 1-(4-methylpyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from N-(4-methylpyridin-3-yl)benzene-1,2-diamine without further purification. MS (ES) m/z 262 ([M+H]⁺).

In an analogous manner to General Procedure B, Step 4, 1-(3-chloropropyl)-3-(4-methylpyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from 1-(4-methylpyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as an oil. MS (ES) m/z 337.7 ([M+H]⁺).

In an analogous manner to General Procedure B, Step 5, 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. MS (ES) m/z 332.9 ([M+H]⁺); HPLC purity 100% at 210-370 nm, 5.3 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 ml/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 34 3-(2,2-dioxido-3-pyridin-3-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure B, Step 1, N-(2-nitrophenyl)pyridin-3-amine was prepared from 3-aminopyridine as an orange solid. MS (ES) m/z 216.1 ([M+H]⁺). HRMS: calculated for C₁₁H₉N₃O₂+H⁺, 216.07675; found (ESI, [M+H]⁺), 216.0783.

In an analogous manner to General Procedure B, Step 2, N-pyridin-3-ylbenzene-1,2-diamine was prepared from N-(2-nitrophenyl)pyridin-3-amine as a white solid.

MS (ESI) m/z 186 ([M+H]⁺). HRMS: calculated for C₁₁H₁₁N₃+H⁺, 186.10257; found (ESI, [M+H]⁺), 186.1083.

In an analogous manner to General Procedure B, Step 3, 1-(N-pyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide was prepared from N-pyridin-3-ylbenzene-1,2-diamine without further purification. MS (ES) m/z 248 ([M+H]⁺).

In an analogous manner to General Procedure B, 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]⁺).

In an analogous manner to General Procedure B, Step 5, 3-(2,2-dioxido-3-pyridin-3-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-chloropropyl)-3-pyridin-3-yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide as a white solid. MS (ES) m/z 318.9 ([M+H]⁺); HPLC purity 100% at 210-370 nm, 5.6 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 ml/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

Example 35 3-(6-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine

General Procedure C for Synthesis of Sulfamides of Formula I:

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%).

HPLC purity 94.8% at 210-370 nm, 10.5 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. MS (ES) [M+H]⁺ m/z 233.1.

Step 2: 4-fluoro-N¹-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). The organic layer was separated and washed with water (100 mL), brine (100 mL), and dried over sodium sulfate. After concentration in vacuo silica gel chromatography (10-30% ethyl acetate in hexanes) afforded a slightly red powder (0.90 g, 99%).

HPLC purity 97.3% at 210-370 nm, 9.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₂H₁₁FN₂+H⁺, 203.09790; found (ESI, [M+H]⁺), 203.0975.

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-N¹-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%).

MS (ES) [M+H]⁺ m/z 264.3;

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). After stirring for 1 hour at room temperature, the solution was diluted with ethyl acetate (50 mL) and washed with water (100 mL). The organic layer was dried over sodium sulfate and the concentrated in vacuo. Silica gel chromatography (0-10% ethyl acetate in hexanes) afforded product as a slightly yellow oil (162 mg, 73%).

HPLC purity 100.0% at 210-370 nm, 10.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₂₁H₂₆FN₃O₄S+H⁺, 436.17008; found (ESI, [M+H]⁺), 436.1688.

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%).

HPLC purity 100.0% at 210-370 nm, 7.3 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₆H₁₈FN₃O₂S+H⁺, 336.11765; found (ESI, [M+H]⁺), 336.1169.

Example 36 3-(5-Chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine

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-N²-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%).

HPLC purity 95.7% at 210-370 nm, 9.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium Bicarbonate Buffer pH=9.5/ACN+MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₂H₁₁ClN₂+H+, 219.06835; found (ESI, [M+H]⁺), 219.0671.

Step 3: 6-chloro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. Following the General Procedure C, Step 3, 4-chloro-N²-phenylbenzene-1,2-diamine (437 mg, 2.00 mmol) afforded product as a slightly red solid (417 mg, 74%).

HPLC purity 98.6% at 210-370 nm, 9.3 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. MS (ES) [M+H]⁺ m/z 278.9.

Step 4: tert-butyl[3-(5-chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate. Following the General Procedure C, 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%).

HPLC purity 98.9% at 210-370 nm, 11.3 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₂₁H₂₆ClN₃O₄S+H+, 452.14053; found (ESI, [M+H]⁺), 452.1465.

Step 5: 3-(5-chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine. Following the General Procedure C, 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%).

HPLC purity 99.0% at 210-370 nm, 8.1 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

HRMS: calculated for C₁₆H₁₈ClN₃O₂S+H+, 352.08810; found (ESI, [M+H]⁺), 352.0861.

Example 37 3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine

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%).

MS (ES) [M+H]⁺ m/z 293.0.

Step 2: 4-bromo-N¹-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%).

HPLC purity 98.2% at 210-370 nm, 10.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₂H₁BrN₂+H+, 263.01783; found (ESI, [M+H]⁺), 263.0178.

Step 3: 5-bromo-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. Following the General Procedure C, Step 3, starting with 4-bromo-N¹-phenylbenzene-1,2-diamine (1.05 g, 4.00 mmol) afforded product as a purple solid (664 mg, 51%).

HPLC purity 100.0% at 210-370 nm, 9.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. MS (ES) [M−H]⁺ m/z 322.8.

Step 4: tert-butyl[3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate. Following the General Procedure C, 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%).

HPLC purity 100.0% at 210-370 nm, 11.3 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. MS (ES) [M+hours-Boc]⁺ m/z 395.8.

Step 5: 3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine. Following the General Procedure C, 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%).

HPLC purity 100.0% at 210-370 nm, 8.1 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₆H₁₈BrN₃O₂S+H+, 396.03758; found (ESI, [M+H]⁺), 396.0371.

Example 38 N-methyl-3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propan-1-amine

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%).

MS (ES) [M+H]⁺ m/z 229.1.

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%).

MS (ES) [M+H]⁺ m/z 199.1.

Step 3: 5-methyl-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. Following the General Procedure C, Step 3, 4-methyl-N¹-phenylbenzene-1,2-diamine (397 mg, 2.00 mmol) afforded product as a tan solid (422 mg, 81%).

MS (ES) [M−H]⁺ m/z 259.2.

Step 4: tert-butyl methyl[3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]carbamate. Following the General Procedure C, 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%).

HPLC purity 100.0% at 210-370 nm, 11.0 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₂₂H₂₉N₃O₄S+H+, 432.19515; found (ESI, [M+H]⁺), 432.1967.

Step 5: N-methyl-3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propan-1-amine. Following the General Procedure C, 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%).

HPLC purity 100.0% at 210-370 nm, 7.5 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₇H₂₁N₃O₂S+H+, 332.14272; found (ESI, [M+H]⁺), 332.1422.

Example 39 3-(7-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine

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%).

MS (ES) [M+H]⁺ m/z 233.2.

Step 2: 3-fluoro-N¹-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%).

HPLC purity 100.0% at 210-370 nm, 9.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₂H₁₁FN₂+H+, 203.09790; found (ESI, [M+H]⁺), 203.0907.

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-N¹-phenylbenzene-1,2-diamine (606 mg, 3.00 mmol) afforded product as a rose colored solid (294 mg, 37%).

HPLC purity 100.0% at 210-370 nm, 8.1 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. MS (ES) [M−H]⁺ m/z 263.0.

Step 4: tert-butyl[3-(7-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate. Following the General Procedure C, 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%).

HPLC purity 100.0% at 210-370 nm, 10.9 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5195 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₂₁H₂₆FN₃O₄S+H+, 436.17008; found (ESI, [M+H]⁺), 436.1713.

Step 5: 3-(7-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine. Following the General Procedure C, 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%).

HPLC purity 100.0% at 210-370 nm, 7.0 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C, H₁₈FN₃O₂S+H+, 336.11765; found (ESI, [M+H]⁺), 336.1154.

Example 40 N-methyl-3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propan-1-amine

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%).

MS (ES) [M+H]⁺ m/z 229.2.

Step 2: 4-methyl-N¹-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%).

MS (ES) [M+H]⁺ m/z 199.1.

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-N¹-phenylbenzene-1,2-diamine (397 mg, 2.00 mmol) afforded product as a colorless oil (107 mg, 21%).

HPLC purity 96.8% at 210-370 nm, 9.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₃H₁₄N₂+H+, 199.12297; found (ESI, [M+H]⁺), 199.1209;

Step 4: tert-butyl methyl[3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]carbamate. Following the General Procedure C, 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%).

HPLC purity 100.0% at 210-370 nm, 11.0 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₂₂H N₃O₄S+H+, 432.19515; found (ESI, [M+H]⁺), 432.1977.

Step 5: N-methyl-3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propan-1-amine. Following the General Procedure C, 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%).

HPLC purity 100.0% at 210-370 nm, 7.6 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₇H₂₁N₃O₂S+H+, 332.14272; found (ESI, [M+H]⁺), 332.1478.

Example 41 3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine

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%).

HPLC purity 97.5% at 210-370 nm, 9.9 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. MS (ES) [M+H]⁺ m/z 233.0.

Step 2: 3-fluoro-N²-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%).

HPLC purity 98.3% at 210-370 nm, 8.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₂H₁₁FN₂+H+, 203.09790; found (ESI, [M+H]⁺), 203.0973.

Step 3: 7-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. Following the General Procedure C, 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%).

HPLC purity 94.3% at 210-370 nm, 8.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₂H FN₂O₂S+H++Na+, 288.03337; found (ESI, [M+H+Na]⁺), 297.0687.

Step 4: tert-butyl[3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate. Following the General Procedure C, 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%).

HPLC purity 96.4% at 210-370 nm, 10.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₂₁H₂₆FN₃O₄S+H+, 436.17008; found (ESI, [M+H]⁺), 436.17102.

Step 5; 3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine. Following the General Procedure C, 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%).

HPLC purity 98.1% at 210-370 nm, 7.1 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₆H₁₈FN₃O₂S+H+, 336.11765; found (ESI, [M+H]⁺), 336.1186.

Example 42 3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

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%).

MS (ES) [M+H]⁺ m/z 251.2.

Step 2: 3-fluoro-N¹-(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%).

HPLC purity 99.3% at 210-370 nm, 9.6 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. MS (ES) [M+H]⁺ m/z 221.

Step 3: 5-methyl-1-(3-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. Following the General Procedure C, Step 3, starting with 3-fluoro-N¹-(3-fluorophenyl)benzene-1,2-diamine (881 mg, 4.00 mmol) afforded product as a red oil (418 mg, 37%).

MS (ES) [M+H]⁺ m/z 283.1.

Step 4: tert-butyl {3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}methylcarbamate. Following the General Procedure C, 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%).

HPLC purity 98.4% at 210-370 nm, 11.1 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. MS (ES) [M+H]⁺ m/z 353.8.

Step 5: 3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine. Following the General Procedure C, 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%).

HPLC purity 100.0% at 210-370 nm, 8.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes; MS (ES) [M+H]⁺ m/z 353.8.

Example 43 3-[3-(methylamino)propyl]-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole-5-carbonitrile 2,2-dioxide

Step 1: tert-butyl[3-(6-cyano-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate. A solution of tert-butyl[3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]methylcarbamate (118 mg, 0.24 mmol), zinc(II) cyanide (56 mg, 0.48 mmol), and palladium tetrakis-triphenylphosphine (58 mg, 0.050 mmol) in DMF (2 mL) was heated in the microwave at 150° C. for 0.25 hours. The solution was diluted with ethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography (5-30% ethyl acetate in hexanes) afforded product as a white foam (105 mg, 99%).

HPLC purity 100.0% at 210-370 nm, 10.5 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₂₂H₂₆N₄O₄S+H+, 443.17475; found (ESI, [M+H]⁺), 443.1788.

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%).

HPLC purity 100.0% at 210-370 nm, 6.9 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS; calculated for C₁₇H₁₈N₄O₂S+H+, 343.12232; found (ESI, [M+H]⁺), 343.1236.

Example 44 3-(5-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine

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, 93%).

MS (ES) [M+H]⁺ m/z 233.2.

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. The solution was diluted with ethyl acetate (200 mL) and filtered through Celite with ethyl acetate washing (2×200 mL). The organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography (5-30% ethyl acetate in hexanes) afforded product as a white solid (4.03 g, 78%).

HPLC purity 100.0% at 210-370 nm, 9.0 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. MS (ES) [M+H]⁺ m/z 198.

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%).

HPLC purity 100.0% at 210-370 nm, 9.1 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5195 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₁₅H₂₂FN₃O₄S+H+, 360.13878; found (ESI, [M+H-tBoc]⁺), 260.0627.

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. The solution was filtered through Celite with methylene chloride washing (3×50 mL) and then concentrated in vacuo. Silica gel chromatography (0-25% ethyl acetate in hexanes) afforded product as a colorless oil (374 mg, 43%).

HPLC purity 100.0% at 210-370 nm, 10.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. HRMS: calculated for C₂₁H₂₆FN₃O₄S+H+, 436.17008; found (ESI, [M+H-tBoc]⁺), 336.1128.

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%).

HPLC purity 100.0% at 210-370 nm, 8.0 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes. MS (ES) [M+H]⁺ m/z 335.9.

Example 45 3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

General Procedure D for Synthesis of Sulfamides of Structure I:

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. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (40 mL), then and water (150 mL), and extracted with diethyl ether (3×150 mL). The combined organic extracts were washed with water, brine, dried (anhydrous sodium sulfate) and concentrated. The crude product was recrystallized from hot hexane, cooled to −30° C. to give 6.05 g (68%) of pure 2,6-difluoro-N-(2-nitrophenyl)aniline as orange crystals. MS (EI) m/z 250 (M^+□).

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 C₁₂H₁₀F₂N₂+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. The residue was purified by Isco flash column chromatography (silica gel, 10-35% ethyl acetate/hexane) to give 1.00 g (31%) of 1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 280.9 ([M−H]⁻).

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. The residue was and purified by Isco flash column chromatography (silica gel, 0-25% ethyl acetate/hexane) to give 362 mg (90%) of 1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a viscous, colorless liquid. MS (ESI) m/z 338.9 ([M+H−SO₂]⁺).

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. The residue was purified by Isco flash column chromatography (silica gel, 0-20% methanol/dichloromethane/with 1% triethylamine) to give 238 mg (85%) of 3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine. This free base was dissolved in a minimum amount of dichloromethane (2 mL), and treated with an ethereal hydrochloric acid solution (1.0 in diethyl ether, 2 mL). To the mixture was added diethyl ether until it became cloudy. The mixture was stored at −30° C. for 12 hours. The white crystals formed were collected by decantation and dried in vacuo to yield 95 mg (31%) 3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride. MS (ESI) m/z 354.0 ([M+H]⁺).

Example 46 3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure D, 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]⁺).

In an analogous manner to General Procedure D, Step 2, 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 C₁₂H₁₀F₂N₂+H⁺, 221.0885; found (ESI, [M+H]+), 221.0895.

In an analogous manner to General Procedure D, Step 3, 1-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from N-(2,3-difluorophenyl)benzene-1,2-diamine as white crystals. MS (ESI) m/z 280.9 ([M−H]⁻).

In an analogous manner to General Procedure D, 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−SO₂]⁺).

In an analogous manner to General procedure D, Step 5, 3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 354.0 ([M+H]⁺).

Example 47 3-[3-(3,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure D, Step 1, 3,5-difluoro-N-(2-nitrophenyl)aniline was prepared from 3,5-difluoroaniline and 1-fluoro-2-nitrobenzene as orange crystals. MS (ESI) m/z 248.9 ([M−H]⁻).

In an analogous manner to General Procedure D, Step 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 C₁₂H₁₀F₂N₂+H⁺, 221.0885; found (ESI, [M+H]⁺), 221.0874.

In an analogous manner to General Procedure D, Step 3, 1-(3,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from N-(3,5-difluorophenyl)benzene-1,2-diamine as white crystals. MS (ESI) m/z 280.9 ([M−H]⁻).

In an analogous manner to General Procedure D, 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.

In an analogous manner to General Procedure D, Step 5, 3-[3-(3,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-(3,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 354.1 ([M+H]⁺).

Example 48 3-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure D, 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]⁺).

In an analogous manner to General Procedure D, Step 2, 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 C₁₂H₁₀F₂N₂+H⁺, 221.0885; found (ESI, [M+H]⁺), 221.0898.

In an analogous manner to General Procedure D, Step 3, 1-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from N-(2,5-difluorophenyl)benzene-1,2-diamine as white crystals. MS (ESI) m/z 280.9 ([M−H]⁻).

In an analogous manner to General Procedure D, 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−SO₂]⁺).

In an analogous manner to General Procedure D, Step 5, 3-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 354.1 ([M+H]⁺).

Example 49 3-{2,2-dioxido-3-[3-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)-yl}-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure D, Step 1, 2-nitro-N-[3-(trifluoromethoxy)phenyl]aniline was prepared from 3-(trifluoromethoxy)aniline and 1-fluoro-2-nitrobenzene as an orange oil. MS (ESI) m/z 298.7 ([M+H]⁺).

In an analogous manner to General Procedure D, Step 2, N-[3-(trifluoromethoxy)phenyl]benzene-1,2-diamine was prepared from 2-nitro-N-[3-(trifluoromethoxy)phenyl]aniline as an off-white solid. MS (ESI) m/z 269.0 ([M+H]⁺). HRMS: calculated for C₁₃H₁₁F₃N₂O+H⁺, 269.0896; found (ESI, [M+H]⁺), 269.0908.

In an analogous manner to General Procedure D, Step 3, 1-[3-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from N-[3-(trifluoromethoxy)phenyl]benzene-1,2-diamine as white crystals. MS (ESI) m/z 328.8 ([M−H]⁻).

In an analogous manner to General Procedure D, 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−SO₂]⁺).

In an analogous manner to General Procedure D, Step 5, 3-{2,2-dioxido-3-[3-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)-yl}-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-[3-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 402.1 ([M+H]⁺).

Example 50 3-{2,2-dioxido-3-[2-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)-yl}-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure D, Step 1, 2-nitro-N-[2-(trifluoromethoxy)phenyl]aniline was prepared from 2-(trifluoromethoxy)aniline and 1-fluoro-2-nitrobenzene as an orange oil. MS (ESI) m/z 298.7 ([M+H]⁺). HRMS: calculated for C₁₃H₉F₃N₂O₃+H⁺, 299.0638; found (ESI, [M+H]⁺), 299.0648.

In an analogous manner to General Procedure D, Step 2, N-[2-(trifluoromethoxy)phenyl]benzene-1,2-diamine was prepared from 2-nitro-N-[2-(trifluoromethoxy)phenyl]aniline as an off-white solid. MS (ESI) m/z 269.0 ([M+H]⁺). HRMS: calculated for C₁₃H₁₁F₃N₂O+H⁺, 269.0896; found (ESI, [M+H]⁺), 269.0882.

In an analogous manner to General Procedure D, Step 3, 1-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from N-[2-(trifluoromethoxy)phenyl]benzene-1,2-diamine as white crystals. MS (ESI) m/z 328.8 ([M−H]⁻).

In an analogous manner to General Procedure D, 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−SO₂]⁺).

In an analogous manner to General Procedure D, Step 5, 3-{2,2-dioxido-3-[2-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1 (3H)-yl}-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 402.1 ([M+H]⁺).

Example 51 3-{2,2-dioxido-3-[3-(trifluoromethyl)phenyl]-2,1,3-benzothiadiazol-1(3H)-yl}-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure D, 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]⁺).

In an analogous manner to General Procedure D, Step 2, N-[3-(trifluoromethyl)phenyl]benzene-1,2-diamine was prepared from (2-nitrophenyl)[3-(trifluoromethyl)phenyl]amine as an off-white solid. MS (ESI) m/z 252.9 ([M+H]⁺). HRMS: calculated for C₁₃H₁₁F₃N₂+H⁺, 253.0947; found (ESI, [M+H]⁺), 253.0963.

In an analogous manner to General Procedure D, Step 3, 1-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from N-[3-(trifluoromethyl)phenyl]benzene-1,2-diamine as white crystals. MS (ESI) m/z 312.8 ([M−H]⁻).

In an analogous manner to General Procedure D, 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.

In an analogous manner to General Procedure D, Step 5, 3-{2,2-dioxido-3-[3-(trifluoromethyl)phenyl]-2,1,3-benzothiadiazol-1 (3H)-yl}-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 386.1 ([M+H]⁺).

Example 52 3-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure D, Step 1, 2-chloro-N-(2-nitrophenyl)aniline was prepared from 2-chloroaniline and 1-fluoro-2-nitrobenzene as orange crystals. MS (ESI) m/z 248.8 ([M+H]⁺).

In an analogous manner to General Procedure D, Step 2, 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 C₁₂H₁₁ClN₂+H⁺, 219.0684; found (ESI, [M+H]⁺), 219.0693.

In an analogous manner to General Procedure D, Step 3, 1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from N-(2-chlorophenyl)benzene-1,2-diamine as white crystals. MS (ESI) m/z 278.8 ([M−H]⁻).

In an analogous manner to General Procedure D, 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—SO₂]⁺).

In an analogous manner to General Procedure D, Step 5, 3-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-[2-chlorophenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 351.9 ([M+H]⁺).

Example 53 3-[3-(3-bromophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure D, Step 1, N-(3-bromophenyl)-2-nitroaniline was prepared from 3-bromoaniline and 1-fluoro-2-nitrobenzene as orange crystals. MS (EI) m/z 291.9 (M^+•). HRMS: calculated for C₁₂H₉BrN₂O₂, 291.9847; found (EI, M⁺), 291.9841.

In an analogous manner to General Procedure D, Step 2, N-(3-bromophenyl)benzene-1,2-diamine was prepared from N-(3-bromophenyl)-2-nitroaniline as an off-white solid. MS (ESI) m/z 262.8 ([M+H]⁺). HRMS: calculated for C₁₂H₁₁BrN₂+H⁺, 263.0178; found (ESI, [M+H]⁺), 263.0185.

In an analogous manner to General Procedure D, Step 3, 1-(3-bromophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from N-(3-bromophenyl)benzene-1,2-diamine as white crystals.

MS (ESI) m/z 322.8 ([M−H]⁻).

In an analogous manner to General Procedure D, 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−SO₂]⁺).

In an analogous manner to General Procedure D, Step 5, 3-[3-(3-bromophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-[3-bromophenyl]-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 396.0 ([M+H]⁺).

Example 54 2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethanamine

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. The crude product was pre-adsorbed onto Celite and purified via Isco chromatography (redisep, silica gradient 5-50% ethyl acetate in hexane) to afford 0.70 g (84%) of 1-(2-bromoethyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. mp 86-89° C. HPLC purity 100% at 210-370 nm, 10.6 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5 acetonitrile/MeOH) for 10 minutes, hold 4 minutes.

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. HRMS: calcd for C₁₄H₁₄ClN₃O₂S+H+, 324.05680; found (ESI, [M+H]+), 324.0566. HPLC purity 91.9% at 210-370 nm, 7.4 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 minutes, hold 4 minutes.

Example 55 2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylethanamine

In an analogous manner to Example 20, 1-(2-bromoethyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (68 mg, 0.17 mmol) and methylamine (15 mL, 8M in ethanol) were stirred for 16 hours. 31 mg (53%) of 2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylethanamine was provided after purification. Treatment with 1.0 M HCl in diethyl ether afforded 3 mg of the salt. HRMS: calcd for C₁₅H₁₆ClN₃O₂S+H+, 338.07245; found (ESI, [M+H]+), 338.0727. HPLC purity 100% at 210-370 nm, 7.4 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 minutes, hold 4 minutes.

Example 56 3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine

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.

MS (ESI) m/z 322.1026

HPLC purity 98.7% at 210-370 nm, 6.6 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes hold 4 minutes

Example 57 N-ethyl-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine

This compound was prepared according to the General Procedure A.

MS (ESI) m/z 350.135

HPLC purity 100% at 210-370 nm, 7.0 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes hold 4 minutes

Example 58 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine

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. The reaction was transferred to a separatory funnel with ethyl acetate and washed with a saturated solution of ammonium chloride, water, brine and dried (MgSO₄), 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.

MS (ESI) m/z 335.0552

HPLC purity 100% at 210-370 nm, 10.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (ammonium bicarbonate buffer pH=9.5, acetonitrile/MeOH) for 10 minutes hold 4 minutes

Example 59 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine

4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine was prepared using 1-(4-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide according to the General Procedure A.

MS (ESI) m/z 350.13331

HPLC purity 100% at 210-370 nm, 7.1 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes hold 4 minutes

Example 60 3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

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 C₁₆H₁₇ClFN₃O₂S+H+, 370.07868; found (ESI, [M+H]⁺), 370.0788

HPLC purity 96.7% at 210-370 nm, 7.4 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes

Example 61 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 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. HRMS: calculated for C₁₅H₁₅ClFN₃O₂S+H⁺, 356.06303; found (ESI, [M+H]⁺), 356.0631, HPLC purity 99.3% at 210-370 nm, 7.4 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes

Example 62 3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

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). HPLC purity 96.3% at 210-370 nm, 7.6 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes HRMS: calculated for C₁₇H₂₀FN₃O₂S+H+, 350.13330; found (ESI, [M+H]⁺), 350.1336.

Example 63 3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine

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.

HPLC purity 89.8% at 210-370 nm, 7.5 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes

HRMS: calculated for C₁₆H₁₈FN₃O₂S+H+, 336.11765; found (ESI, [M+H]⁺), 336.118.

Example 64 3-[3-(4-fluoro-2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

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).

MS (ES) m/z 294.8;

HRMS: calculated for C₁₃H₁₁FN₂O₃S−H+, 293.04017; found (ESI, [M−H]−), 293.0392

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).

HPLC purity 96.8% at 210-370 nm, 7.0 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes HRMS: calculated for C₁₇H₂₀FN₃O₃S+H+, 366.12822; found (ESI, [M+H]⁺), 366.1283.

Example 65 Preparation of 5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pentan-1-amine

Step 1: In an analogous manner to general procedure A, step 1, N-(2-fluorophenyl)benzene-1,2-diamine (1.0 g, 5.0 mmol) was treated with sulfamide (0.58 g, 6.0 mmol) to provide 0.52 g (40%) of 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. HRMS: calculated for C₂H₉FN₂O₂S+Na⁺, 287.02609; found (ESI, [M+Na]⁺), 287.0263; HPLC purity 100.0% at 210-370 nm, 8.4 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes

Step 2: In an analogous manner to Example 18, step 1,1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.30 g, 1.1 mmol) was treated with cesium carbonate (0.37 g, 1.1 mmol) and 1,5-dibromopentane (0.62 mL, 4.5 mmol) to prepare 0.32 g (69%) of 1-(5-bromopentyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. HRMS: calculated for C₁₇H₈BrFN₂O₂S+H⁺, 413.03291; found (ESI, [M+H]⁺), 413.0: HPLC purity 100.0% at 210-370 nm, 10.9 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes

Step 3: In an analogous manner to Example 2,1-(5-bromopentyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.08 g, 0.19 mmol) was treated with ammonia (10 mL) to provide 0.06 g (98%) of 5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pentan-1-amine. MS (ES) m/z 350.0; HRMS: calculated for C₁₇H₂₀FN₃O₂S+H⁺, 350.13330; found (ESI, [M+H]⁺), 350.1338; HPLC purity 96.3% at 210-370 nm, 8.6 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes hold 4 minutes

Example 66 Preparation of 5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpentan-1-amine

In an analogous manner to general procedure A, step 3, 1-(5-bromopentyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.08 g, 0.19 mmol) was treated with methylamine (10 mL) to provide 0.06 g (94%) of 5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpentan-1-amine. MS (ES) m/z 364.0; HRMS: calculated for C₈H₂₂FN₃O₂S+H⁺, 364.14895; found (ESI, [M+H]⁺), 364.1494; HPLC purity 100.0% at 210-370 nm, 8.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85115-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes hold 4 minutes

Example 67 Preparation of 5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpentan-1-amine

In an analogous manner to general procedure A, step 3, 1-(5-bromopentyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.08 g, 0.19 mmol) was treated with dimethylamine (10 mL) to provide 0.06 g (94%) of 5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpentan-1-amine. MS (ES) m/z 377.5; HRMS: calculated for C₁₉H₂₄FN₃O₂S+H⁺, 378.16460; found (ESI, [M+H]⁺), 378.1649; HPLC purity 96.8% at 210-370 nm, 9.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85115-5195 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes hold 4 minutes

Example 68 3-[3-(3-Chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

In an analogous manner to General procedure D, step 1, N-(3-chlorophenyl)-2-nitroaniline was prepared from 3-chloroaniline and 1-fluoro-2-nitrobenzene as orange solid. MS (ESI) m/z 248.8 ([M+H]⁺).

In an analogous manner to General procedure D, step 2, N-(3-chlorophenyl)benzene-1,2-diamine was prepared from N-(3-chlorophenyl)-2-nitroaniline as an off-white solid. HRMS: calculated for C₁₂H₁₁ClN₂+H⁺, 219.0684; found (ESI, [M+H]⁺), 219.0662.

In an analogous manner to General procedure D, step 3, 1-(3-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from N-(3-chlorophenyl)benzene-1,2-diamine as white crystals. MS (ESI) m/z 278.8 ([M−H]⁻).

In an analogous manner to General procedure D, step 4,1-(3-bromopropyl)-3-(3-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(3-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 337.0 ([M+H−SO₂]⁺).

In an analogous manner to General procedure D, step 5,3-[3-(3-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-(3-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as white crystals. MS (ESI) m/z 352.1 ([M+H]⁺). HRMS: calculated for C₁₆H₁₈ClN₃O₂S+H+, 352.0881; found (ESI, [M+H]⁺), 352.0877.

Example 69 3-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride

In an analogous manner to General Procedure C, step 4, tert-butyl {3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}carbamate was prepared from 1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Example 45, step 3) and tert-butyl N-(3-hydroxypropyl)carbamate as a viscous, colorless liquid.

In an analogous manner to General Procedure C, step 5, 3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride was prepared from tert-butyl {3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}carbamate as a white solid. MS (ESI) m/z 340.2 ([M+H]⁺). HRMS: calculated for C₁₅H₁₅F₂N₃O₂S+H⁺, 340.0926; found (ESI, [M+H]⁺), 340.0927.

Example 70 3-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride

In an analogous manner to General Procedure C, step 4, tert-butyl {3-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]propyl}carbamate was prepared from 1-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and tert-butyl N-(3-hydroxypropyl)carbamate as a viscous, colorless liquid. MS (ESI) m/z 357.8 ([M+H-Boc]⁺).

In an analogous manner to General Procedure C, step 5, 3-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride was prepared from tert-butyl {3-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]propyl}carbamate as a white solid. MS (ES I) m/z 358.3 ([M+H]⁺).

Example 71 3-[3-(2-fluorophenyl)-2,2-dioxido-5-phenyl-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

In an analogous manner to General procedure D, step 4,1-(3-bromopropyl)-3-(2-fluorophenyl)-5-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 3-(2-fluorophenyl)-5-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromo-1-propanol as a white solid. MS (ES) m/z 461.3.

In an analogous manner to General procedure D, step 5, 3-[3-(2-fluorophenyl)-2,2-dioxido-5-phenyl-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-(2-fluorophenyl)-5-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and methyl amine as an off-white solid. MS (ES) m/z 412.2.

Example 72 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride

In an analogous manner to General procedure D, step 4,1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 11-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromo-1-propanol as a brown oil. MS (ES) m/z [M+H−SO₂]⁺338.7.

In an analogous manner to General procedure D, step 5,3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1′-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and ammonia in methanol as an off-white solid. MS (ES) m/z 340.1; HRMS: calculated for C₁₅H₁₅F₂N₃O₂S+H+, 340.09258; found (ESI, [M+H]⁺), 340.0941.

Example 73 3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

In an analogous manner to General procedure D, step 1, 2-fluoro-N-(2-fluorophenyl)-6-nitroaniline was prepared from 2,3-difluoronitroaniline and 2-fluoroaniline as a yellow solid. MS (ES) m/z 250.9

In an analogous manner to General procedure D, steps 2-4, 1-(3-bromopropyl)-4-fluoro-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 2-fluoro-N-(2-fluorophenyl)-6-nitroaniline as a white solid. MS (ES) m/z 400.9

In an analogous manner to General procedure D, step 5, 3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-4-fluoro-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 33% methanolic methylamine as a light pink solid. MS (ES) m/z 354.1; HRMS: calculated for C₁₆H₁₇F₂N₃O₂S+H+, 354.10823; found (ESI, [M+H]+), 354.1085.

Example 74 3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride

In an analogous manner to General procedure D, step 5, 3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-4-fluoro-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 7 N methanolic ammonia as a white amorphous solid. HRMS: calculated for C₁₅H₁₅F₂N₃O₂S+H+, 340.09258; found (ESI, [M+H]+), 340.0931

Example 75 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

In an analogous manner to General procedure D, step 5, 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 33% methanolic methyl amine as a light blue solid. MS (ES) m/z 354.3; HRMS: calculated for C₁₆H₁₇F₂N₃O₂S+H+, 354.10823; found (ESI, [M+H]+), 354.1073.

Example 76 3-[7-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

Step 1: In an analogous manner to General Procedure D, Step 1, 2-fluoroaniline (4.8 mL, 50 mmol) was treated with n-butyllithium (2.5 M in hexane, 20 mL, 50 mmol) followed by 2,6-difluoronitrobenzene (7.8 g, 49 mmol) to give 3-fluoro-N-(2-fluorophenyl)-2-nitroaniline (11.1 g).

HPLC purity 100.0% at 210-370 nm, 10.2 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes

HRMS: calculated for C₁₂H₈F₂N₂O₂+H⁺, 251.06266; found (ESI, [M+H]⁺), 251.0629;

Step 2: In an analogous manner to Example 11, Step 2, 3-fluoro-N-(2-fluorophenyl)-2-nitroaniline (8.0 g, 32 mmol) was dissolved in ethyl acetate (30 mL), treated with 10% palladium on carbon (250 mg), and shaken under hydrogen to give 3-fluoro-N-1-(2-fluorophenyl)benzene-1,2-diamine (3.4 g).

HPLC purity 100.0% at 210-370 nm, 9.4 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes

HRMS: calculated for C₁₂H₁₀F₂N₂+H⁺, 221.08848; found (ESI, [M+H]⁺), 221.0888

Step 3: In an analogous manner to General Procedure A, Step 1, 3-fluoro-N1-(2-fluorophenyl)benzene-1,2-diamine (0.55 g, 2.5 mmol) was treated with sulfamide (0.31 g, 3.25 mmol) and sulfonyl diimidazole (48 mg, 0.25 mmol) to give 4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.36 g).

HPLC purity 99.0% at 210-370 nm, 7.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes

HRMS: calculated for C₁₂H₈F₂N₂O₂S−H⁺, 281.02018; found (ESI, [M−H]⁻), 281.0202;

Step 4: In an analogous manner to General Procedure A, Step 2, 4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.4 g, 1.42 mmol), was treated with triphenylphosphine (0.44 g, 1.7 mmol), 3-bromopropanol (0.12 mL, 1.42 mmol), and diisopropylazodicarboxylate (0.33 mL, 1.7 mmol) to provide 0.54 g 3-(3-bromopropyl)-4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.

HPLC purity 92.1% at 210-370 nm, 10.7 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85115-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes

Step 5: In an analogous manner to General Procedure A, Step 3, 3-(3-bromopropyl)-4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.54 g, 1.34 mmol) was treated with methylamine to provide 3-[7-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride (0.36 g) after treatment with HCl.

HPLC purity 99.5% at 210-370 nm, 6.8 minutes; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes

HRMS: calculated for C₁₆H₁₇F₂N₃O₂S+H⁺, 354.10823; found (ESI, [M+H]⁺), 354.1086;

Example 77 3-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

Step 1: To a solution of 3-(methylamino)-1-propanol (8.91 g, 100 mmol) in ethyl acetate (50 mL) at 0° C. was added dropwise a solution of di-tert-butyl dicarbonate (21.83 g, 100 mmol, 1 equiv.) in ethyl acetate (20 mL) via an addition funnel. The resulting solution was stirred for 2 h while warming to room temperature. More ethyl acetate (80 mL) was added and the mixture was washed with water, brine, dried (anhydrous sodium sulfate), filtered, and concentrated. The crude liquid was purified by Isco CombiFlash Companion column chromatography to give pure tert-butyl (3-hydroxypropyl)methylcarbamate as a colorless liquid. Yield: 17.80 g (94%). MS (ESI) m/z 190.2 ([M+H]⁺). HRMS: calcd for C₉H₁₉NO₃+H⁺, 190.1438; found (ESI, [M+H]⁺), 190.1437.

Step 2: In an analogous manner to General Procedure C, step 4, tert-butyl {3-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]propyl}methylcarbamate was prepared from 1-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and tert-butyl (3-hydroxypropyl)methylcarbamate as a viscous, colorless liquid. MS (ESI) m/z 471.7 ([M+H]⁺). HRMS: calcd for C₂₁H₂₄F₃N₃O₄S+H⁺, 472.1512; found (ESI, [M+H]⁺), 472.1515. HPLC purity 99.3% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.

Step 3: In an analogous manner to General Procedure C, step 5, 3-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from tert-butyl {3-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]propyl}methylcarbamate as a white powder. MS (ESI) m/z 371.8 ([M+H]⁺). HRMS: calcd for C₁₆H₁₆F₃N₃O₂S+H⁺, 372.0988; found (ESI, [M+H]⁺), 372.0990. HPLC purity 99.2% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 78 3-[3-(2,4-Difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

Step 1: In an analogous manner to General procedure D (Example 45), step 4, 3-(3-bromopropyl)-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromo-1-propanol as a viscous, colorless liquid. HRMS: calcd for C₁₅H₁₂BrF₃N₂O₂S⁺, 419.9755; found (EI, M⁺), 419.9757.

Step 2: In an analogous manner to General procedure D (Example 45), step 5, 3-[3-(2,4-difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 3-(3-bromopropyl)-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a white powder. MS (ESI) m/z 371.8 ([M+H]⁺). HRMS: calcd for C₁₆H₁₆F₃N₃O₂S+H⁺, 372.0988; found (ESI, [M+H]⁺), 372.0990.

Example 79 3-[3-(2,4-Difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

In an analogous manner to General Procedure C, step 4, tert-butyl {3-[3-(2,4-difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]propyl}methylcarbamate was prepared from 1-(2,4-difluorophenyl)-7-fluoro-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and tert-butyl (3-hydroxypropyl)methylcarbamate as a viscous, colorless liquid, MS (ESI) m/z 371.7 ([M+H−Boc]⁺). HPLC purity 100.0% at 210-370 nm, 10.8 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.

In an analogous manner to General Procedure C, step 5,3-[3-(2,4-difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from tert-butyl {3-[3-(2,4-difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}methylcarbamate as white crystals. MS (ESI) m/z 371.8 ([M+H]⁺). HRMS: calcd for C₁₆H₁₆F₃N₃O₂S+H⁺, 372.0988; found (ESI, [M+H]⁺), 372.0989. HPLC purity 99.2% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 80 3-[3-(2,4-Difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpropan-1-amine hydrochloride

In an analogous manner to General procedure D (Example 45), step 5, 3-[3-(2,4-difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpropan-1-amine hydrochloride was prepared from 3-(3-bromopropyl)-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Example 78, Step 1) using excess dimethylamine as a white powder. MS (ESI) m/z 386.1 ([M+H]⁺). HRMS: calcd for C₁₇H₁₈F₃N₃O₂S+H⁺, 386.1145; found (ESI, [M+H]⁺), 386.1148.

Example 81 4-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine hydrochloride

Step 1: Ethanolic methylamine (33% in ethanol, 80 mL) was added to a solution of 4-bromo-1-butanol (80% in tetrahydrofuran, 7.00 g, 36.6 mmol). The reaction mixture was sealed tightly and stirred for 12 h, then concentrated. The residue was dissolved in dichloromethane (80 mL), triethylamine (16 mL, 115 mmol, 3 equiv.) was added. To this solution was added dropwise a solution of di-tert-butyl dicarbonate (10.0 g, 45.8 mmol, 1.25 equiv.) in dichloromethane (25 mL) via an addition funnel. The reaction mixture was stirred at room temperature for 5 h, then pour into a mixture of dichloromethane (200 mL) and water (200 mL). The organic layer was washed with water, dried (anhydrous sodium sulfate), filtered, and concentrated. The crude liquid was pre-adsorbed onto Florisil and purified via Isco flash column chromatography (330-g redisep silica gel column, 0-65% ethyl acetate/hexane) to give pure tert-butyl (4-hydroxybutyl)methylcarbamate as a colorless liquid. Yield: 4.15 g (56%).

Step 2: In an analogous manner to General Procedure C, step 4, tert-butyl {4-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]butyl}methylcarbamate was prepared from 1-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and tert-butyl (4-hydroxybutyl)methylcarbamate as a viscous, colorless liquid. MS (ESI) m/z 486.1 ([M+H]⁺). HRMS: calcd for C₂₂H₂₆F₃N₃O₄S+H⁺, 486.1669; found (ESI, [M+H]⁺), 486.1680. HPLC purity 100.0% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.

Step 3: In an analogous manner to General Procedure C, step 5, 4-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1 (3H)-yl]-N-methylbutan-1-amine hydrochloride was prepared from tert-butyl {4-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]butyl}methylcarbamate as a white powder. MS (ESI) m/z 386.2 ([M+H]⁺). HRMS: calcd for C₁₇H₁₈F₃N₃O₂S+H⁺, 386.1145; found (ESI, [M+H]⁺), 386.1153. HPLC purity 99.4% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85115-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 82 4-[3-(4-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine hydrochloride

In an analogous manner to General Procedure C, step 4, tert-butyl {4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}methylcarbamate was prepared from 1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Example 6, step 3) and tert-butyl (4-hydroxybutyl)methylcarbamate as a viscous, colorless liquid. MS (ESI) m/z 450.1 ([M+H]⁺). HRMS: calcd for C₂₂H₂₈FN₃O₄S+H⁺, 450.1857; found (ESI, [M+H]⁺), 450.1865. HPLC purity 100.0% at 210-370 nm, 10.9 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.

In an analogous manner to General Procedure C, step 5, 4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine hydrochloride was prepared from tert-butyl {4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}methylcarbamate as a white powder. MS (ESI) m/z 350.2 ([M+H]⁺). HRMS: calcd for C₁₇H₂₀FN₃O₂S+H⁺, 350.1333; found (ESI, [M+H]⁺), 350.1344. HPLC purity 99.7% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 83 4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine hydrochloride

In an analogous manner to General Procedure C, step 4, tert-butyl {4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}methylcarbamate was prepared from 1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Example 45, step 3) and tert-butyl (4-hydroxybutyl)methylcarbamate as a viscous, colorless liquid. MS (ESI) m/z 468.1 ([M+H]⁺). HRMS: calcd for C₂₂H₂₇F₂N₃O₄S+H⁺, 468.1763; found (ESI, [M+H]⁺), 468.1763. HPLC purity 99.5% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.

In an analogous manner to General Procedure C, step 5, 4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine hydrochloride was prepared from tert-butyl {4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}methylcarbamate as a white powder. MS (ESI) m/z 368.1 ([M+H]⁺). HRMS: calcd for C₁₇H₁₉F₂N₃O₂S+H⁺, 368.1239; found (ESI, [M+H]⁺), 368.1246. HPLC purity 99.5% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 84 N-{3-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopropanamine hydrochloride

In an analogous manner to General procedure D (Example 45), step 5, N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopropanamine hydrochloride was prepared as a white powder from 1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Example 45, step 4) using excess cyclopropylamine at 60° C. for 6 h. HRMS: calcd for C₁₈H₁₉F₂N₃O₂S+H⁺, 380.1239; found (ESI, [M+H]⁺), 380.1246. HPLC purity 99.7% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 min, hold 4 min.

Example 85 N-{3-[3-(2,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopropanamine hydrochloride

In an analogous manner to General procedure D (Example 45), step 5, N-{3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopropanamine hydrochloride was prepared as a white powder from 1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide using excess cyclopropylamine at 60° C. for 6 h. HRMS: calcd for C₁₈H₁₉F₂N₃O₂S+H⁺, 380.1239; found (ESI, [M+H]⁺), 380.1245. HPLC purity 99.5% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 min, hold 4 min.

Example 86 N-{4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}cyclopropanamine hydrochloride

In an analogous manner to General procedure D (Example 45), step 4, 1-(4-bromobutyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Example 45, step 3) and 4-bromo-1-butanol as a viscous, colorless liquid. MS (EI) m/z 416 [M+•]. HPLC purity 95.2% at 210-370 nm, 10.3 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.

In an analogous manner to General procedure D (Example 45), step 5, N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}cyclopropanamine hydrochloride was prepared as a white powder from 1-(4-bromobutyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide using excess cyclopropylamine at 60° C. for 6 h. MS (ESI) m/z 393.9 ([M+H]⁺). HRMS: calcd for C₁₉H₂₁F₂N₃O₂S+H⁺, 394.1395; found (ESI, [M+H]⁺), 394.1403. HPLC purity 99.7% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 min, hold 4 min.

Example 87 4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine hydrochloride

Step 1: In an analogous manner to Example 6, step 1, N-(2-chloro, 4-fluorophenyl)-N-(2-nitrophenyl)amine was prepared from 2-chloro, 4-fluoroaniline and 2-fluoronitrobenzene.

Step 2: N-(2-chloro,4-fluorophenyl)-N-(2-nitrophenyl)amine (6 g, 22.5 mmol) was dissolved in ethanol (30 mL) and 10% palladium on activated carbon (500 mg) was added. The mixture was shaken under a hydrogen atmosphere (50 psi) until hydrogen absorption was complete. The mixture was filtered through a pad of silica and concentrated to give N-(2-chloro-4-fluorophenyl)benzene-1,2-diamine (4.8 g) that was carried on directly to the next step.

Step 3: In an analogous manner to general procedure A, step 1, 2.1 g of 1-(2-chloro, 4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 4.1 g of N-(2-choro, 4-fluorophenyl)benzene-1,2-diamine and 2.5 g of sulfamide.

MS (ES) m/z 296.8.

Step 4: In an analogous manner to Example 18, step 1 1-(4-bromobutyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2-chloro, 4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 1,4-dibromobutane. MS (ES) m/z 368.6; HPLC purity 94.9% at 210-370 nm, 10.9 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Step 5: In an analogous manner to general procedure A, step 3, 4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine hydrochloride was prepared from 1-(4-bromobutyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and methylamine (33% in ethanol). MS (ES) m/z 383.8; HPLC purity 99.0% at 210-370 nm, 8.8 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Bicarb Buff. Ph=9.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C17H19ClFN3O2S+H+, 384.09433; found (ESI, [M+H]+ Obs'd), 384.0943.

Example 88 4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine hydrochloride

In an analogous manner to Example 214-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine hydrochloride was prepared from 1-(4-bromobutyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole and dimethyl amine (˜5.6 M in ethanol). MS (ES) m/z 397.7; HPLC purity 96.3% at 210-370 nm, 8.3 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C18H21ClFN3O2S+H+, 398.10998; found (ESI, [M+H]+ Obs'd), 398.1101.

Example 89 5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpentan-1-amine hydrochloride

Step 1: In an analogous manner to Example 18, step 1, 1-(5-bromopentyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2-chloro, 4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 1,5-dibromopentane. MS (ES) m/z 382.7.

Step 2: In an analogous manner to general procedure A, step 3, 5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpentan-1-amine hydrochloride was prepared from 1-(5-bromopentyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and methylamine (33% in ethanol). MS (ES) m/z 397.8; HRMS: calcd for C18H21ClFN3O2S+H+, 398.10998; found (ESI, [M+H]+Obs'd), 398.1103.

Example 90 5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpentan-1-amine hydrochloride

In an analogous manner to Example 21, 5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpentan-1-amine hydrochloride was prepared from 1-(5-bromopentyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole and dimethyl amine (˜5.6 M in ethanol). MS (ES) m/z 411.8; HRMS: calcd for C19H23ClFN3O2S+H+, 412.12563; found (ESI, [M+H]+ Obs'd), 412.1257.

Example 91 3-[3-(2-fluoro-4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

Step 1: In an analogous manner to Example 6 step 1, N-(2-fluoro, 4-methoxyphenyl)-N-(2-nitrophenyl)amine was prepared from 2-fluoro, 4-methoxy aniline and 2-fluoronitrobenzene.

Step 2: In an analogous manner to Example 87 step 2, N-(2-fluoro-4-methoxyphenyl)benzene-1,2-diamine was prepared from N-(2-fluoro, 4-methoxyphenyl)-N-(2-nitrophenyl)amine and was carried on directly to the next step.

Step 3: In an analogous manner to general procedure A, step 1, 2.1 g of 1-(2-fluoro, 4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from N-(2-fluoro, 4-methoxyphenyl)benzene-1,2-diamine and sulfamide.

Step 4: In an analogous manner general procedure A, step 2, 1-(3-bromopropyl)-3-(2-fluoro-4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2-fluoro-4-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromopropanol.

Step 5: In an analogous manner to general procedure A, step 3, 3-[3-(2-fluoro-4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride was prepared from 1-(3-bromopropyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and methylamine (33% in ethanol). MS (ES) m/z 365.6; HPLC purity 100.0% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C17H20FN3O3S+H+, 366.12822; found (ESI, [M+H]+ Obs'd), 366.1283.

Example 92 3-fluoro-4-{3-[3-(methylamino)propyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenol hydrochloride

Step 1: A solution of 3-fluoro, 4-nitro phenol (5.6 g, 36.6 mmol) in 15 mL of DMF was added dropwise to a suspension of sodium hydride (1.6 g, 41 mmol) in 10 mL of DMF at 0° C. After 15 minutes added trimethylsilyl ethoxy methyl chloride (7.5 mL, 41 mmol) via syringe. At stirred for 1 hr. The solution was poured into water and extracted three times with hexane. Drying (MgSO₄) and concentrating afforded 10.4 g of an orange oil. This oil was dissolved in ethanol, placed in a Parr bottle and ˜1.0 g of 10% Pd/C added. The solution was hydrogenated at 50 psi until absorption of hydrogen ceased. The catalyst was removed by filtration through silica gel and the filtrate concentrated to afford 9.1 g of 2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy) aniline used in the next step without further purification.

Step 2: 6.2 g (24 mmol) of 2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy) aniline was dissolved in 50 mL of THF and cooled to −78° C. A solution of n-butyllithium (16.5 mL, 26 mmol) was diluted with 20 mL of THF and added dropwise. After 0.5 hr added a solution of 2-fluoronitrobenzene (3.4 g, 24.1 mmol) in 15 mL of THF. The cooling was removed after 1.5 hr. After stirring an additional 16 h the reaction was quenched with saturated ammonium chloride and extracted twice with ethyl acetate. The solution was dried and concentrated and the residue purified by column chromatography (Biotage 10-30% ethyl acetate:hexane). The orange oil was hydrogenated as in step 1 to yield 3.1 g (33% overall) of N-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)benzene-1,2-diamine.

Step 3: In an analogous manner to general procedure A, step 1, 2.1 g of 1-(2-fluoro, 4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from N-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)benzene-1,2-diamine and sulfamide.

Step 4: In an analogous manner to General Procedure C, Step 4, tert-butyl 3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide propyl carbamate was prepared from 1-(2-fluoro, 4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and tert-butyl 3-hydroxypropylcarbamate.

Step 5: tert-Butyl-3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide propyl(methyl)-carbamate was prepared from tert-butyl 3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide propyl carbamate by treatment with methyl iodide and sodium hydride in DMF.

Step 6: The product from Step 5 was dissolved in 9:1 ether:methanol and 2N HCl in ether added. After allowing to stand overnight a solid formed which was removed by filtration to afford 3-fluoro-4-{3-[3-(methylamino)propyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenol hydrochloride. MS (ES) m/z 352.0; HPLC purity 94.6% at 210-370 nm, 6.5 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C16H18FN3O3S+H+, 352.11257; found (ESI, [M+H]+ Obs'd), 352.1133.

Example 93 3-fluoro-4-{3-[4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenol hydrochloride

Step 1: In an analogous manner to Example 18, step 1, 1-(4-bromobutyl)-3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2-fluoro, 4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 1,4-dibromobutane.

Step 2: In an analogous manner to general procedure A, step 3, 4-[3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine was prepared from 1-(4-bromobutyl)-3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and methyl amine (33% in ethanol).

Step 3: In an analogous manner to Example 92, step 6, 3-fluoro-4-{3-[4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenol hydrochloride was prepared from 4-[3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine. HPLC purity 99.1% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C17H20FN3O3S+H+, 366.12822; found (ESI, [M+H]+ Obs'd), 366.1287.

Example 94 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine

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 hr. The reaction was transferred to a separatory funnel with ethyl acetate and washed with a saturated solution of ammonium chloride, water, brine and dried (MgSO₄), filtered, the solvent removed and the material adsorbed onto silica and purified using column chromatography (Isco: 0-20% ethyl acetate in hexane) to afford the product as a clear oil (960 mg, 83% Yield).

HRMS: calcd for C16H16BrFN2O2S+H+, 398.01. found (EI M+) 398.0104 HPLC purity 99.0% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Step 2: 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine (275 mg, 0.714 mmol) was stirred in methylamine solution (33% in absolute ethanol) in a capped vial at room temperature for 18 hr. The reaction mixture was concentrated then loaded directly onto silica gel and purified via Isco chromatography (Redisep, silica, gradient 0-10% NH₃-MeOH in dichloromethane to afford 0.250 g of 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine as a white solid. This material was dissolved in diethyl ether and methanol and 4N HCl in dioxane was added a precipitate formed. The mixture was filtered to afford 0.197 g of (2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2-methoxy-N-methylbutan-1-amine as a white solid.

HRMS: calcd for C17H20FN3O2S+H+, 350.13331; found (ESI, [M+H]1+, 350.13365 HPLC purity 100% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85115-5195 (ammonium formate buffer pH-3.5, acetonitrile/MeOH) for 10 min, hold 4 min.

Example 95 3-[3-(4-chloro-2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

Example 95 was prepared using 1-(3-bromopropyl)-3-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide analogous to the conditions used in step 2 of example 94.

HRMS: calcd for HPLC purity 95.0% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 96 N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]cyclopropanamine

Example 96 was prepared using 1-(3-bromopropyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the conditions used in step 2 of example 94.

HRMS: calcd for C18H21N3O2S+H+, 344.1427; found (ESI, [M+Na]+, 344.1432

HPLC purity 92.5% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 97 N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopropanamine

Example 97 was prepared using 1-(3-bromopropyl)-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the conditions used in step 2 of example 94.

HRMS: calcd for C18H20FN3O2S+H+, 362.1333; found (ESI, [M+Na]+, 362.1333 HPLC purity 98.1% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 98 N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butyl]cyclopropanamine

Example 98 was prepared using 1-(3-bromobutyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the conditions used in step 2 of example 94.

HRMS: calcd for C19H23N3O2S+H+, 358.1584; found (ESI, [M+Na]+, 358.1588 HPLC purity 99.3% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85115-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 99 N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}cyclopropanamine

99 was prepared using 1-(4-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the conditions used in step 2 of example 94.

HRMS: calcd for C19H22FN3O2S+H+, 376.1490; found (ESI, [M+Na]+, 376.1494 HPLC purity 98.7% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 100 3-[3-(4-chloro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

Example 100 was prepared using 1-(3-bromopropyl)-3-(4-chloro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide analogous to the conditions used in step 2 of example 94.

HRMS: calcd for C17H20ClN3O2S+H+, 366.1037; found (ESI, [M+H]+, 366.1038 HPLC purity 97.8% at 210-370 nm, 8.4 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85115-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 101 6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylhexan-1-amine

Step 1: In an analogous manner to example 18, step 1,1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.40 g, 1.51 mmol) was treated with cesium carbonate (0.50 g, 1.51 mmol) and 1, 6 dibromohexane (0.93 mL, 6.04 mmol) to prepare 0.49 g (76%) of 1-(6-bromohexyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. HRMS: calcd for C₁₈H₂₀BrFN₂O₂S+H+, 427.04856; found (ESI, [M+H]+), 427.0488; HPLC purity 100.0% at 210-370 nm, 11.1 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Step 2: In an analogous manner to general procedure A, step 3, 1-(6-bromohexyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.08 g, 0.18 mmol) was treated with methylamine (10 mL) to provide 0.03 g (46%) of 6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylhexan-1-amine. MS (ES) m/z 378;

HPLC purity 99.1% at 210-370 nm, 7.8 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 102 6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]hexan-1-amine

In an analogous manner to Example 2,1-(6-bromohexyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.08 g, 0.18 mmol) was treated with ammonia (10 mL) to prepare 0.04 g (68%) of 6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]hexan-1-amine. MS (ES) m/z 364; HPLC purity 98.9% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 103 6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylhexan-1-amine

In an analogous manner to general procedure A, step 3, 1-(6-bromohexyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.08 g, 0.18 mmol) was treated with dimethylamine (10 mL) to provide 0.03 g (49%) of 6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylhexan-1-amine. MS (ES) m/z 327.9; HPLC purity 99.5% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Example 104 4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine

A solution of (2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbut-2-en-1-amine hydrochloride (0.1 g) in methanol (3 mL) was hydrogenated using a Thales Nanotechnology H-cube apparatus (palladium-charcoal, 0 bar, 1 mL/minute flow rate) to provide 4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine hydrochloride (80 mg) as a white solid:

HPLC purity 95.1% at 210-370 nm, 7.8 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

HRMS: calcd for C18H22FN3O2S+H+, 364.14895; found (ESI, [M+H]+ Obs'd), 364.1493.

Example 105 4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine

In an analogous manner to example 104 1 (2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-2-en-1-amine hydrochloride was hydrogenated to provide 4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine hydrochloride: HPLC purity 87.5% at 210-370 nm, 8.5 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

HRMS: calcd for C17H20FN3O2S+H+, 350.13330; found (ESI, [M+H]+ Obs'd), 350.1336.

Example 106 4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine

In an analogous manner to example 104, (2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbut-2-en-1-amine hydrochloride was hydrogenated to provide 4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine hydrochloride:

HPLC purity 97.4% at 210-370 nm, 7.8 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

HRMS: calcd for C19H24FN3O2S+H+, 378.16460; found (ESI, [M+H]+ Obs'd), 378.1651.

Example 107 N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine

In an analogous manner to example 104, (2Z)-N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-2-en-1-amine hydrochloride was hydrogenated to provide N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amineydrochloride:

HPLC purity 94.6% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

HRMS: calcd for C19H24FN3O2S+H+, 378.16460; found (ESI, [M+H]+ Obs'd), 378.1651.

Example 108 3-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

Step 1: A solution of 1-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.56 g, 2 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. and treated with triphenylphosphine (0.78 g, 3 mmol), 3-bromopropanol (0.28 mL, 4 mmol), and diisopropyl azodicarboxylate (0.6 mL, 3 mmol), warmed to 22° C. and stirred for 2 h. The reaction mixture was concentrated and the residue purified by flash chromatography (5-50% ethyl acetate/hexanes) provided 1-(3-bromopropyl)-3-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.55 g) as a tan powder:

HPLC purity 100.0% at 210-370 nm, 10.8 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

HRMS: calcd for C16H16BrFN2O2S+Na+, 420.99920; found (ESI, [M+Na]+), 420.9995.

Step 2: A solution of 1-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.15 g) in an 8 M methylamine-ethanol solution was heated to 70° C. for 16 h. The reaction mixture was concentrated, and flash chromatography (0-10% 8 M NH-methanol/dichloromethane) provided the free purified free base, which was dissolved in methanol (10 mL) and treated with 2 M HCl-ether and concentrated to provide 3-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine (0.16 g) as a white solid: HPLC purity 97.5% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85115-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

HRMS: calcd for C17H20FN3O2S+H+, 350.13330; found (ESI, [M+H]+ Obs'd), 350.1341

Example 109 3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

Step 1: In an analogous manner to General Procedure A, step 2, a solution of 1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.65 g, 2.2 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C., treated with triphenylphosphine (0.87 g, 3.3 mmol), 3-bromo-1-propanol (0.39 mL, 4.5 mmol) were added followed by diisopropylazodicarboxylate (0.65 mL, 3.3 mmol) to provide 1-(3-bromopropyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.82 g, 92%) as a brown oil:

HPLC purity 98.2% at 210-370 nm, 10.8 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

HRMS: calcd for C15H13BrF2N2O2S, 401.98491; found (EI, M+), 401.9842;

Step 2: 1-(3-bromopropyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.2, 0.5 mmol) was dissolved in an 8 M solution of methylamine in ethanol (8 mL, 64 mmol) and was stirred in a capped vial at room temperature for 2 h. The reaction mixture was evaporated and the residue purified by flash chromatography (SiO₂, 0-5% 7 M NH₃-methanol/dichloromethane). The purified free-base was dissolved in dichloromethane (3 mL) and treated with hydrogen chloride (1.0 mL of a 2 M solution in ethyl ether), resulting in a white precipitate that was evaporated and dried under vacuum to provide 3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine (0.177 g, 78%) as a white solid:

HPLC purity 98.6% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

HRMS: calcd for C16H17F2N3O2S+H+, 354.10823; found (ESI, [M+H]+ Obs'd), 354.1086;

HRMS: calcd for C16H17F2N3O2S+H+, 354.10823; found (ESI, [M+H]+ Calc'd), 354.1082;

Example 110 4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine

Step 1: A solution of 1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.45 g, 1.6 mmol) in dimethylformamide (10 mL) was treated with 1,4-dibromobutane (1 mL, 8.4 mmol) and cesium carbonate (0.52 g, 1.6 mmol). The reaction mixture stirred at ambient for 72 h. The reaction mixture was diluted with ethyl ether (50 mL) and washed with H₂O (2×20 mL), the organic layer was isolated, dried with MgSO₄and evaporated. The crude reaction product was purified by flash chromatography (SiO₂, 3-50% ethyl acetate/hexane) to provided 1-(4-bromobutyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.64 g, 95%) as a brown oil:

HPLC purity 87.0% at 210-370 nm, 10.9 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Step 2: In an analogous manner as Example 109, step 2, 1-(4-bromobutyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.21 g, 0.5 mmol) was dissolved in an 8 M solution of methylamine in ethanol (5 mL, 40 mmol) to provide 4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine (0.16 g, 83%) as a white solid:

HPLC purity 93.5% at 210-370 nm, 7.8 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

HRMS: calcd for C17H19F2N3O2S+H+, 368.12388; found (ESI, [M+H]+ Obs'd), 368.1239;

Example 111 3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-(2,2,2-trifluoroethyl)propan-1-amine

A solution of 1-(3-bromopropyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.12 g, 0.3 mmol) in 2,2,2-trifluoroethylamine (0.5 mL, 6.4 mmol) was heated to 130° C. for 2 h. in a microwave. The crude reaction product was purified by flash chromatography (SiO₂, 370% ethyl acetate/hexane) to provide the intended free-base that was taken up in dichloromethane (5 mL) was treated with hydrogen chloride (1.0 mL of a 2 M solution in ethyl ether), resulting in a white precipitate that was evaporated and dried under vacuum to provided 3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-(2,2,2-trifluoroethyl)propan-1-amine (0.11 g, 85%) as a white solid:

HPLC purity 96.7% at 210-370 nm, 10.2 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

HRMS: calcd for C17H16F5N3O2S+H+, 422.09561; found (ESI, [M+H]+ Obs'd), 422.0959;

Example 112 3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine

Step 1: In an analogous manner to General Procedure A, step 2, a solution of 1-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.74 g, 2.5 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C., treated with triphenylphosphine (0.97 g, 3.7 mmol), 3-bromo-1-propanol (0.42 mL, 4.9 mmol) were added followed by diisopropylazodicarboxylate (0.72 mL, 3.7 mmol) to provide 1-(3-bromopropyl)-3-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.71 g, 69%) as a brown oil:

HPLC purity 100.0% at 210-370 nm, 10.8 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

Step 2: In an analogous manner as Example 109, step 2, 1-(3-bromopropyl)-3-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.2 g, 0.48 mmol) was dissolved in an 2 M solution of ethylamine in methanol (10 mL, 20 mmol) to provide 3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine (0.13 g 73%) as a white solid:

HPLC purity 88.2% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

HRMS: calcd for C17H18F3N3O2S+H+, 386.11446; found (ESI, [M+H]+ Obs'd), 386.1153;

Example 113 3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine

In an analogous manner as Example 109, step 2, 1-(3-bromopropyl)-3-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.2 g, 0.48 mmol) was dissolved in an 8 M solution of methylamine in ethanol (5 mL, 40 mmol) to provide 3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine (0.13 g, 88%) as a white solid:

HPLC purity 97.5% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

HRMS: calcd for C16H16F3N3O2S+H+, 372.09881; found (ESI, [M+H]+ Obs'd), 372.0991;

Example 114 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride

Step 1: A.) 2,4-Difluoroaniline (72 mL, 710 mmol) was dissolved in tetrahydrofuran (500 mL), cooled to −78° C., and 2.5 M n-butyl lithium in hexanes (185 mL, 462 mmol) was added. The mixture was warmed to −20° C. and stirred for 30 minutes. The mixture was cooled down to −78° C. and 2-fluoronitrobenzene (37.4 mL, 355 mmol) in tetrahydrofuran (50 mL) was added dropwise. After stored in a freezer for 16 hours, the mixture was quenched with saturated ammonium chloride (100 mL) and diluted with ethyl acetate (100 mL). 1N hydrochloric acid (100 mL) was added to break up the emulsion. The organic layer was separated, washed with sodium bicarbonate (100 mL), dried over anhydrous magnesium sulfate, and concentrated to give 2,4-difluoro-N-(2-nitrophenyl)aniline (52.5 g, 59%) as an orange solid. 2,4-Difluoro-N-(2-nitrophenyl)aniline (10 g, 40 mmol) in methanol (130 mL) was subjected to hydrogenation (30 psi) in the presence of 5% Pd/C (200 mg) to give N-(2,4-difluorophenyl)benzene-1,2-diamine (8.15 g, 93%) as a brown oil.

B.) A mixture of N-(2,4-difluorophenyl)benzene-1,2-diamine (8.15 g, 37 mmol) and sulfamide (4.3 g, 44.4 mmol) in diglyme (20 mL) was added to a solution of sulfamic acid (0.9 g, 9.3 mmol) in diglyme (20 mL) that had been heated to 190° C. After 20 minutes, the mixture was cooled to room temperature, diluted with ethyl ether (100 mL) and washed with 2N hydrochloric acid (100 mL). The organic layer was extracted with 2N sodium hydroxide (100 mL). The aqueous layer was then washed with ethyl ether (2×100 mL), acidified with 6N hydrochloric acid, and extracted with ethyl ether (2×100 mL). The combined ethereal extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-100% ethyl acetate/hexane) to afford 1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a white solid (4.6 g, 41%). MS (ES) m/z 280.8

Step 2: In an analogous manner to general procedure A of Example 1, step 2, 1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.34 g, 1.2 mmol) was treated with triphenylphosphine (0.37 g, 1.4 mmol), 3-bromopropanol (0.12 mL, 1.4 mmol), and diisopropylazodicarboxylate (0.27 mL, 1.4 mmol) to provide 1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.2 g, 41%) as a brown oil. MS (ES) m/z 338.7.

Step 3: In an analogous manner to general procedure A of Example 1, step 3, 1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.2 g, 0.5 mmol) was treated with 8N methylamine in methanol to give 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine. The free base was converted to the title compounds as hydrochloride salt as a light blue solid (0.087 g, 46%). MS (ES) m/z 354.3 ([M+H]⁺). HRMS: calcd for C₁₆H₁₇F₂N₃O₂S+H⁺, 354.10823; found (ESI, [M+H]⁺), 354.1073. HPLC retention time: 6.9 min.

Example 115 5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpentan-1-amine hydrochloride

Step 1: In an analogous manner to example 18, step 1, 1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1.3 g, 4.6 mmol) was treated with 1,5-dibromopentane (2.2 mL, 16.1 mmol) and cesium carbonate (1.5 g, 4.6 mmol) to give 1-(5-bromopentyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1.2 g, 60%) as a white amorphous solid. MS (ES) m/z 366.7 [M+H−SO₂]⁺.

Step 2: In an analogous manner to example 18, step 2, 1-(5-bromopentyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.5 g, 1.2 mmol) was treated with 8N methylamine in methanol to give 5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpentan-1-amine which was treated with 1N hydrochloric acid in ether to afford its hydrochloride salt as a white solid (0.31 g, 64%). MS (ES) m/z 382.4 ([M+H]⁺). HRMS: calcd for C₁₈H₂₁F₂N₃O₂S+H⁺, 382.13953; found (ESI, [M+H]⁺), 382.1412. HPLC retention time: 7.5 min.

Example 116 5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pentan-1-amine hydrochloride

Step 1: In an analogous manner to example 18, step 2, 1-(5-bromopentyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.29 g, 0.67 mmol) was treated with 7N ammonium in methanol to give 5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pentan-1-amine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.06 g, 20%). MS (ES) m/z 367.9 ([M+H]⁺). HPLC retention time: 7.6 min.

Example 117 5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpentan-1-amine hydrochloride

Step 1: In an analogous manner to example 18, step 2, 1-(5-bromopentyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.29 g, 0.67 mmol) was treated with 33% dimethylamine in ethanol to give 5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpentan-1-amine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.09 g, 31%). MS (ES) m/z 395.9 ([M+H]⁺). HPLC retention time: 7.6 min.

Example 118 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpropan-1-amine hydrochloride

Step 1: In an analogous manner to general procedure A, step 3, 1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.45 g, 1.1 mmol) was treated with 33% dimethylamine in ethanol to give 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpropan-1-amine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.309 g, 69%). MS (ES) m/z 367.8 ([M+H]⁺). HPLC retention time: 7.0 min.

Example 119 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine hydrochloride

Step 1: In an analogous manner to general procedure A, step 3, 1-(3-bromopropyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.45 g, 1.1 mmol) was treated with 2M ethylamine in ethanol to give 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.332 g, 81%). MS (ES) m/z 367.9;

HPLC retention time: 7.2 min.

Example 120 4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine hydrochloride

In an analogous manner to Example 45, step 5, the title compound was prepared from 1-(4-bromobutyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (example NNN) and dimethyl amine and was converted to its HCl salt as a white solid. MS (ES) m/z 382.3; HRMS: calcd for C₁₈H₂₁F₂N₃O₂S+H+, 382.13953; found (ESI, [M+H]+ Obs'd), 382.1395. HPLC retention time: 7.2 min.

Example 121 4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylbutan-1-amine hydrochloride

In an analogous manner to Example 45, step 5, the title compound was prepared from 1-(4-bromobutyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (example NNN) and ethyl amine and was converted to its HCl salt as a white solid. MS (ES) m/z 381.8; HRMS: calcd for C₁₈H₂₁F₂N₃O₂S+H+, 382.13953; found (ESI, [M+H]+ Obs'd), 382.1402. HPLC retention time: 7.5 min.

Example 122 4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylbutan-1-amine hydrochloride

In an analogous manner to Example 45, step 5, the title compound was prepared from 1-(4-bromobutyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and ethyl amine and was converted to its HCl salt as a white solid. MS (ES) m/z 381.9; HPLC retention time: 7.1 min.

Example 123 4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-isopropylbutan-1-amine hydrochloride

In an analogous manner to Example 45, step 5, the title compound was prepared from 1-(4-bromobutyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and isopropyl amine and was converted to its HCl salt as a white solid. MS (ES) m/z 395.9. HPLC retention time: 7.4 min.

Example 124 N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}cyclobutanamine hydrochloride

In an analogous manner to Example 45, step 5, the title compound was prepared from 1-(4-bromobutyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclobutyl amine and was converted its HCl salt as a white solid. MS (ES) m/z 407.9. HPLC retention time: 7.6 min.

Example 125 N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-yl]butyl}cyclohexanamine hydrochloride

In an analogous manner to Example 45, step 5, the title compound was prepared from 1-(4-bromobutyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and cyclohexanyl amine and was converted to its HCl salt as a white solid. MS (ES) m/z 436.0. HPLC retention time: 8.3 min.

Example 126 3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine hydrochloride

In an analogous manner to Example 45, Step 5, the title compound was prepared from 1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Example 45, step 4) and ethyl amine and converted to its HCl salt as a white solid. MS (ES) m/z 367.9. HPLC retention time: 6.8 min.

Example 127 3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-isopropylpropan-1-amine hydrochloride

In an analogous manner to Example 45, Step 5, the title compound was prepared from 1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Example 45, step 4) and isopropyl amine and converted to its HCl salt as a white solid. (ES) m/z 382.1. HPLC retention time: 7.1 min.

Example 128 N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclobutanamine hydrochloride

In an analogous manner to Example 45, Step 5, the title compound was prepared from 1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Example 45, step 4) and cyclobutyl amine and converted to its HCl salt as a white solid. (ES) m/z 394.1. HPLC retention time: 7.3 min.

Example 129 N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopentanamine hydrochloride

In an analogous manner to Example 45, Step 5, the title compound was prepared from 1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Example 45, step 4) and cyclopentyl amine and converted to its HCl salt as a white solid. (ES) m/z 408.2. HPLC retention time: 7.6 min.

Example 130 N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclohexanamine hydrochloride

In an analogous manner to Example 45, Step 5, the title compound was prepared from 1-(3-bromopropyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Example 45, step 4) and cyclohexanyl amine and converted to its HCl salt as a white solid. (ES) m/z 422.2. HPLC retention time: 8.1 min.

Example 131 N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-amine dihydrochloride

Step 1: 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 (0.61 g, 1.56 mmol) was treated with 430 mg (3.1 mmol) of potassium carbonate and 0.32 g (1.56 mol) tert-butyl 4-aminopiperidine-1-carboxylate to provide tert butyl N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-amine carbonate (0.16 g).

Step 2: In an analogous manner to General Procedure C, step 5, N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-amine dihydrochloride was prepared from tert butyl N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-amine carbonate (0.12 g). HPLC purity 97.4% at 210-370 nm, 5.5 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C₂₀H₂₅FN₄O₂S+H+, 405.17550; found (ESI, [M+H]+ Obs'd), 405.1768.

Example 132 N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidin-4-amine dihydrochloride

Step 1: 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 (0.34 g, 0.92 mmol) was treated with 255 mg (1.85 mmol) of potassium carbonate and 0.32 g (1.56 mol) of tert-butyl 4-aminopiperidine-1-carboxylate to afford tert-butyl (1-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-amine)carbamate (0.18 g).

Step 2: In an analogous manner to General Procedure C, step 5, N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidin-4-amine dihydrochloride was prepared from tert-butyl (1-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-amine)carbamate (0.12 g). MS (ES) m/z 386.8; HPLC purity 100.0% at 210-370 nm, 5.7 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C20H26N4O2S+H+, 387.18492; found (ESI, [M+H]+ Obs'd), 387.1849.

Example 133 N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-4-amine dihydrochloride

Step 1: In an analogous manner to General Procedure A, step 3, tert butyl N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-4-amine carbonate was prepared from 1-(3-bromoethyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and tert-butyl 4-aminopiperidine-1-carboxylate.

Step 2: In an analogous manner to General Procedure C, step 5, N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-4-amine dihydrochloride was prepared from tert butyl N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-4-amine carbonate. MS (ES) m/z 390.8; HPLC purity 64.0% at 210-370 nm, 5.3 min., Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C19H23FN4O2S+H+, 391.15985; found (ESI, [M+H]+ Obs'd), 391.1598.

Example 134 N-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]piperidin-4-amine dihydrochloride

Step 1: In an analogous manner to General Procedure A, step 3, tert butyl N-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-4-amine carbonate was prepared from 1-(3-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and tert-butyl 4-aminopiperidine-1-carboxylate.

Step 2: In an analogous manner to General Procedure C, step 5, N-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]piperidin-4-amine dihydrochloride was prepared from tert butyl N-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-4-amine carbonate. MS (ES) m/z 372.8; HPLC purity 93.4% at 210-370 nm, 5.3 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C19H24N4O2S+H+, 373.16927; found (ESI, [M+H]+ Obs'd), 373.1696.

Example 135 2-({3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}amino)ethanol

1-(3-bromopropyl)-3-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (100 mg, 0.260 mmol) was stirred in neat ethanolamine (25 mL) at room temperature in a sealed vial for 18 hr. The reaction was transferred to a separatory funnel with diethyl ether and washed with water, brine, dried (MgSO₄), filtered, and the solvent removed in vacuo. The material was purified by Gilson RP-HPLC (YMC CombiPrep ProC18 50×20 mm I.D. column, S-5 μm, 12 nm. Flow rate 20 mL/min. Gradient: 10/90 Acetonitrile/Water to 100% acetonitrile over 10 minutes then hold for three minutes at 100% acetonitrile and ramp back to 10/90 acetonitrile/water over two minutes). This material was dissolved in diethyl ether and methanol and 4N HCl in dioxane was added to give a red solid (12 mg, 12% Yield) as the mono-HCl salt.

HRMS: calcd for

HPLC purity 100% at 210-370 nm, 6.6 min.; Xterra RP18, 3.5u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.

hNET Assay Procedure Protocol A: Inhibition of [³H] NE Uptake into Cloned Human NE Transporters (MDCK Cells) (“hNET uptake”)

The hNET uptake assay procedure was used to screen for compounds that inhibit the reuptake of norepinephrine and to determine IC₅₀values for compounds identified as hNET reuptake inhibitors.

Materials and Methods: Cell Line and Culture Reagents:

[³H] NE uptake studies were performed using MDCK cells stably expressing human norepinephrine transporter (hNET) (See Pacholczyk T, Blakely R D and Amara S G (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature. 350:350-354) cultured in growth medium containing high glucose DMEM (Gibco, Cat. No. 11995), 10% FBS (dialyzed, heat-inactivated, US Bio-Technologies, Lot FBD1129HI) and 500 μg/ml G418 (Gibco, Cat. No. 10131). Cells were seeded at 300,000/T75 flask, and split twice weekly.

Norepinephrine Uptake Assays:

All uptake experiments were performed in 96-well plates (Falcon Optilux, cat #353947) in a total volume of 250 μl/well. MDCK cells were plated at 50,000 cells/well. At the time of the assay, the media was removed, and 200 μl assay buffer (25 mM Hepes, 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl₂, 1.2 mM MgSO₄.7H₂O, 2 mg/ml glucose, 0.2 mg/ml ascorbic acid, 1 μM pargyline, pH 7.4) was added to each well. 25 μl of each test compound was subsequently added to plates in triplicate and incubated at 37° C. for 5 minutes. All test compounds were dissolved in 100% DMSO and diluted in 4% DMSO/H₂O, and assayed using a 7-point dose response curve (1 nM-10 μM). Next, 25 μl of [³H] NE (74.9 Ci/mmol, Perkin Elmer, Boston, Mass.) was added to all wells and incubated at 37° C. for an additional 5 minutes. Non-specific uptake was defined by 20 μM desipramine. The final concentrations of [³H] NE was 16 nM, respectively. The reaction was terminated by aspiration and washed with ice cold 50 mM Tris (pH 7.4). The plates were left to air dry for roughly 30 min, and MDCK cells were lysed by the addition of 25 μl of 0.25 M NaOH. 100 μl of Microscint-20 were added to each well (Packard, Perkin Elmer, Boston, Mass.), and the plates were counted using a TopCount (Perkin Elmer, Downer's Grove, Ill.) liquid scintillation counter.

Analysis of Results:

% Inhibition of uptake=((mean cpm control wells−each cpm drug well)/(mean cpm control wells−non-specific wells)×100.

IC₅₀values were calculated using a Prism® nonlinear regression program where % inhibition is plotted versus concentration of inhibitor.

See: Pacholczyk T, Blakely R D and Amara S G (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature. 350:350-354.

See also: Ramamoorthy J D, Ramamoorthy S, Papapetropoulos A, Catravas J D, Leibach F H and Ganaphthy V (1995) Cyclic AMP-independent up-regulation of the human serotonin transporter by staurosporine in choriocarcinoma cells. Journal of Biological Chemistry. 270:17189-17195, the contents of which is hereby incorporated by reference.

hNET Assay Procedure Protocol B: Cell Based Norepinephrine (NE) Reuptake Assay Using the Recombinant Human Norepinephrine Transporter (hNET) (“hNET Uptake”)

The hNET uptake assay procedure was used to screen for compounds that inhibit the reuptake of norepinephrine and to determine IC₅₀values for compounds identified as hNET reuptake inhibitors.

Materials and Methods: Compounds:

For screening, hydrochloride salts of compounds were dissolved in solution and 25 μl aliquots of compound solution at a 1 μM or 10 μM final concentration delivered directly to cells. For IC₅₀determinations, stock compounds were prepared at 10 mM from powder. The stock solution was diluted according to compound testing range. Typically, the compound testing range was from 6 nM to 6 μM by half log dilutions. On the day of assay, 25 μl of compound solution at the specified concentrations was added to the plates containing cells. A DMSO stock of desipramine was prepared at 10 mM in DMSO and diluted for a final concentration of 20 μM to determine the non-specific reuptake. The radioligand in this assay is ³H-norepinephrine (NE) (PerkinElmer; NET678; 40-80 Ci/mmol) was delivered at approximately 16 nM final concentration for both single point testing and compound IC₅₀determinations.

Tissue Culture Conditions:

MDCK-Net6 cells, stably transfected with human hNET (See Pacholczyk T, Blakely R D and Amara S G (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature. 350:350-354) was maintained in growth media [high glucose DMEM (Gibco Cat. 11995), 10% FBS (dialyzed, heat-inactivated, Sigma, dialysed, heat inactivated, Lot# K0922 or equivalent) 1× Pen/Strep, and 500 μg/ml G418 (Gibco Cat. 10131)]. Cells were plated at 300,000/T75 flask and cells were split twice weekly.

Functional Reuptake Assay:

Cells were plated at 3,000 cells/well on day 1 in BD Falcon Microtest 96-well sterile cell culture plates, Optilux White/Clear Bottom TC plate (VWR; # 62406-466 or equivalent) in growth media and maintained in a cell incubator (37° C., 5% CO₂). On Day 2, cells were removed from the cell incubator and the growth media is replaced by 200 μl of assay buffer (25 mm HEPES 120 mM NaCL; 5 mM KCl; 2.5 mM CaCl₂; 1.2 mM MgSO₄; 2 mg/ml glucose (pH 7.4, 37° C.)) containing 0.2 mg/ml ascorbic acid and 1 μM parglyine. For screening, 25 μl of compound in 4% DMSO is added directly to each well and the plate is incubated for 5 min (37° C.). To initiate the norepinephrine reuptake, 16 nM (final concentration) of ³H norepinephrine (specific activity; 40-80 Ci/mmol) in assay buffer was delivered in 25 μl aliquots to each well, and the plates were incubated for 5 min at 37° C. The reaction was aspirated from the plate and the cells washed with 250 μl of 50 mM Tris Buffer (4° C.). The plates were left to dry for 1 hour. The cells were lysed using 0.25 M NaOH solution then placed on a shake table and vigorously shaken for 10 min. After cell lysis, 100 μl of Microscint 20 (PerkinElmer; #87-051101) was added to the plates and the plates were sealed with film tape and replaced on the shake table for a minimum of 10 min. The plates were counted in a TopCount counter (PerkinElmer).

Analysis of Results:

For screening single point determinations, each compound plate contained at least 3 control wells (maximum NE reuptake determinant) and 3 non-specific wells determined by adding 20 μM of desipramine (minimum NE reuptake determinant). Determination of active compounds were calculated using a Microsoft Excel spread sheet applying the following formula:

$% inhibition = \frac{\begin{matrix} [1 - ((mean cpm test compound wells - \\ mean cpm non - specific wells) \end{matrix}}{\begin{matrix} (mean cpm control wells - \\ mean cpm non - specific wells))] \end{matrix}} \times 100$

For IC₅₀determination, raw cpm values were generated in a data file from the TopCount counter. The data was organized Microsoft Excel and transferred into PRIZM graphing and statistical program, which calculated the estimated IC₅₀value. Calculation of IC₅₀values was made using non-linear regression analysis with a sigmoidal dose response with variable slope. The statistical program used wells containing ³H norepinephrine only as the maximal NE reuptake determinant and wells containing ³H norepinephrine plus 20 μM desipramine as the minimal NE reuptake determinant (non-specific determinant). Estimation of the IC₅₀value is completed on a log scale and the line is fit between the maximal and minimal NE reuptake values. In the event that the highest test concentration does not exceed 50% reuptake inhibition, data will be reported as percent maximal NE reuptake at the highest concentration tested.

See: Pacholczyk, T., Blakely, R. D., and Amara, S. G. (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature, 350, 350-354, the contents of which is hereby incorporated by reference.

Results are shown in the following table:

NE uptake (Protocol A) NE uptake (Protocol B) Example IC₅₀(nM) IC₅₀(nM) 1 20.5 2 2529 3 4217 4 37% inh. @ 2 uM 5 2.63 6 6.87 7 1775 8 35.7 9 12.6 10 40.2 11 1.3 12 12.2 13 534 14 2620 15 96.2 16 7.06 17 10.8 18 0.3 19 1130 20 478 21 5889 22 27% inh. @ 2 uM 23 28% inh. @ 2 uM 24 60.9 25 146 26 57.1 27 11.7 28 1899 29 434 30 15.3 31 23.6 32 192 33 282 34 85 35 20.6 36 11.3 37 2364 38 13.9 39 29.3 40 252 41 2.41 42 86.3 43 1320 44 4.26 45 0.116 46 4.84 47 2.73 48 2.78 49 147 50 190 51 3174 52 2.74 53 24.5 54 3% inh. @ 2 uM 55 15% inh. @ 2 uM 56 13.1 57 2.56 58 3273 59 0.4 60 40.2 61 113 62 50.9 63 324 64 295 65 14.1 66 14.2 67 298 68 84.1 69 10.4 70 277 71 206 72 259 73 2.81 74 2.7 75 4.17 76 5.24 77 15 78 45 79 9 80 448 81 19 82 46 83 2 84 21 85 203 86 21 87 82 88 57% inhibition @ 6 uM 89 2109 90 49% inhibition @ 6 uM 91 325 92 3 93 3 94 4 95 30 96 113 97 21 98 36 99 22 100 370 101 1158 102 26 103 1202 104 26 105 125 106 591 107 582 108 4 109 20 110 39 111 0% @ 6 uM 112 2770 113 109 114 11 115 61 116 binding IC50 679.1 nM* 117 7195 118 153 119 77 120 411 121 1503 122 48 123 1173 124 132 125 440 126 15 127 148 128 222 129 195 130 224 131 365 132 267 133 45 134 67 135 43 *For hNET binding performed according to: P. E. Mahaney et al. Bioorg. Med. Chem. 14 (2006) 8455-8466, the contents of which is hereby incorporated by reference in its entirety.

Rat Liver Microsomal Stability Assay:

DMSO stock solutions of test compounds were prepared at 0.5 mM concentration. Diluted solutions of test compounds were prepared by adding 50 uL of each DMSO stock solution to 200 uL of acetonitrile to make 0.1 mM solutions in 20% DMSO/80% acetonitrile. Rat liver microsomal solution was prepared by adding 1.582 mL of concentrated rat liver microsomes (20 mg/mL protein concentration) to 48.291 mL of pre-warmed (to 37° C.) 0.1M potassium phosphate buffer (pH 7.4) containing 127 uL of 0.5 M EDTA to make a 0.6329 mg/mL (protein) microsomal solution. 11.2 uL of each test compound diluted solution was each added directly to 885 uL of rat liver microsomal solution (allowing direct binding of drugs to microsomal proteins and lipids to minimize precipitation and non-specific binding to the plasticware). This solution was mixed and 180 uL was transferred to “Time 0” and “Time 15 min” plates (each in duplicate wells). For the Time 15 min plate, NADPH regenerating agent (45 uL) was added to each well to initiate the reaction, the plate was incubated at 37° C. for 15 min, followed by quenching of the reaction by adding 450 uL of cold acetonitrile to each well. For the Time 0 plate, 450 uL of cold acetonitrile was added to each well, followed by addition of NADPH regenerating agent (45 uL) and no incubation. All of the plates were centrifuged at 3000 rpm for 15 min and the supernatants were transferred to other well plates for analysis by LC-MS.

Dopamine Transporter (hDAT) Membrane Binding Assay

The method for this radioligand binding assay was modified from the methods supplied with hDAT membranes (catalog number RBHDATM; Perkin Elmer Life Analytical Sciences), and those modifications are listed within this method section. Frozen membrane samples from a cell line that expresses hDAT were diluted to 7.5 ml in binding buffer (50 mM Tris-HCl; pH 7.4, 100 mM NaCl), homogenized with a tissue-tearer (Polytron PT 120° C., Kinematica AG) and delivered at a volume of 75 μl to each well of a polypropylene 96-well plate. The binding reaction was run in polypropylene 96-well plates (Costar General Assay Plate, Cat. No. 3359; Lid, Cat. No. 3930). A stock solution of mazindol was prepared in DMSO (10 mM) and delivered to triplicate wells containing membrane for a final test concentration of 10 uM. Mazindol is a DA transporter inhibitor with a 50% inhibitory concentration (IC₅₀) value of 18.0±6.0 nM in the present assays. Data from wells containing mazindol (10 uM) were used to define non-specific (NSB) hDAT binding (minimum hDAT binding). Total binding is defined by addition of 5 μl of binding buffer alone in the presence of [³H] WIN-35,428. Stock solutions of compounds to be tested were prepared in DMSO at concentrations of 10 mM to 10 uM. On the day of assay, test compounds were diluted in assay buffer according to test range (100,000 to 10 nM) ensuring a maximal DMSO concentration of less than 0.5% in the assay reaction wells. Homogenized membranes were pre-incubated with test compounds for 20 min at 4° C. before the initiation of the binding reaction. The binding reaction is initiated by addition of 25 μl of ³-[H]-WIN 35,428 diluted in binding buffer. The final concentration of ³-[H]-WIN 35,428 delivered was 10 nM. The K_Dvalue estimated for ³-[H]-WIN-35,428 in hDAT membranes (Lot#296-083-A) was 6.9 nM. The radioligand concentration, [L], used in the competition binding assays is a factor difference of 1.4 compared to the K_Dvalue and was used to calculate the K_ivalue. The plate containing the radioligand binding reactions were incubated for 2 h at 4° C. on a shaking table (Bellco, Vineland, N.J.) at 3 revolutions per minute. The MultiScreen-FB opaque 96-well filtration plates contained Millipore glass fiber filters (Millipore glass fiber B, Cat. No. MAFBN0B) were used to terminate the binding reactions and to separate bound from free radioligand. The plates were presoaked with 0.5% polyethylenimine (PEI; Sigma Cat. No. P-3143) in water for a minimum of two hours at room temperature to reduce nonspecific binding of ³-[H]-WIN 35,428 during the harvest procedure. Before harvesting the reaction plates, the PEI solution is aspirated from the filter plates using a vacuum manifold. Aliquots of each reaction (90 μl of each 100 μl reaction well) were transferred from the reaction plates to the filter plates using a Zymark Rapid Plate-96 automated pipette station. The binding reaction is terminated by vacuum filtration through the glass fiber filters. The filter plates were aspirated at 5-10 inches of Hg, and the wells are washed 9 times with 200 μl wash buffer (50 mM Tris-HCl, 0.9% NaCl, pH 7.4; 4° C.) using a 12 channel aspiration/wash system. Plastic bottom supports are removed from the filter plates and the plates are placed in plastic liners. A 100 μl aliquot of scintillation fluid was added to each well and the top of each plate is sealed with adhesive film. The plates are vigorously shaken at 5 rpm for 10-15 minutes to ensure adequate equilibration of aqueous to solvent partitioning. The collection of raw counts per minute (cpm) data was done using a Wallac Microbeta counter (Perkin Elmer).

Evaluation of Results

For each experiment, a data stream of cpm values collected from the Wallac Microbeta counter was downloaded to a Microsoft Excel statistical application program. Calculations of IC₅₀values were made using the transformed-both-sides logistic dose response program that uses mean cpm values from wells representing maximum binding (total)(assay buffer) and mean cpm values from wells representing minimum binding (NSB, 10 μM mazindol). Estimation of the IC₅₀values was completed on a log scale and the line was fit between the maximum and minimum binding values. The K_ivalue is a function of the concentration of the compound required to inhibit 50% of the radioligand (IC₅₀value) divided by the free radioligand concentration [L] divided by the K_Dvalue plus one (K_i=IC₅₀/(1+[L]/K_D)). The K_ivalue for these studies was determined by dividing the IC₅₀value by a factor of 2.4 to account for the concentration of ³-[H]-WIN 35,428 used in the assay.

Results are shown in the following table:

hNET hDAT RLM Function Binding stability Structure IC50 IC50 t1/2 CHEMISTRY (nM) (nM) (min) 2.6 598.0 2.0 0.3 211.0 2.0 3.6 686.0 3.0 0.7 512.4 1.0 9.0 5260.1 2.0 2.3 9333 1 19.8 121.7 18.0 2.7 479.0 2.0 11.3 365.6 10.0 8.4 449.0 11.0 46.1 52.8 19 7.06 276.4 <1 10.8 178 2 2.56 665 1

When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges specific embodiments therein are intended to be included.

The disclosures of each patent, patent application and publication cited or described in this document are hereby incorporated herein by reference, in its entirety.

Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof;

wherein:

n is an integer from 0 to 4;

m is an integer from 0 to 6;

X is —CH2—;

R1 is, independently at each occurrence, H, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein each aryl or heteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido is independently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido groups;

R2 is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;

R3 and R4 are, independently, H, alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are indepently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided that neither R3 or R4 contain an aminoalkyl group;

and

wherein 1-3 carbon atoms in ring A may optionally be replaced with N.

2. The compound of claim 1, wherein each R1 is H.

3. The compound of claim 1, wherein R2 is:

wherein,

each R5, R6, R7, R8 and R9 are independently selected from the group consisting of H, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl substituted, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, or arylamido.

4. The compound of claim 3, wherein R7 and R9 are F.

5. The compound of claim 4, wherein R5R6 and R8 are H.

6. The compound of claim 3, wherein R5, R6, R7, R8 and R9 are independently H, halo, alkyl or alkoxy.

7. The compound of claim 1, wherein R3 is methyl.

8. The compound of claim 7, wherein R4 is H.

9. The compound of claim 1, wherein m is 1-2.

10. The compound of claim 1, wherein m is 1.

11. The compound of claim 3, wherein:

R7 and R9 are F; and

R5, R6 and R8 are H.

12. The compound of claim 1, wherein ring A comprises all carbon atoms.

13. The compound of claim 1, wherein R2 is pyridinyl, methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or quinolinyl.

14. The compound of claim 1, wherein R2 is phenyl, fluoro-phenyl, difluoro-phenyl, trifluoro-phenyl, chloro-phenyl, fluoro-chloro-phenyl, bromo-phenyl, trifluoromethyl-phenyl trifluoromethoxy-phenyl, methyl-fluoro-phenyl, methoxy-fluoro-phenyl, or naphthyl.

15. The compound of claim 1, wherein:

each R1 is H;

m is 1;

R3 is methyl; and

R4 is H.

16. The compound of claim 3, wherein:

each R1 is H;

R7 and R9 are F;

R5, R6 and R8 are H;

R3 is methyl;

R4 is H; and

m is 1.

17. The compound of claim 1, selected from the group consisting of:

18. The compound of claim 1, selected from the group consisting of: 3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; N-{3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopropanamine; 3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine; 3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine; 3-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; N-methyl-3-[3-(4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; 3-[3-(2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(3-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; N-methyl-3-[3-(1-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; N-methyl-3-[3-(2-naphthyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; N-methyl-3-[3-(3-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; N-methyl-3-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; 3-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylbutan-1-amine; 4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine; 4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine; 4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine; 4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethyl-N-methylbutan-1-amine; 3-(2,2-dioxido-3-phenyl[1,2,5]thiadiazolo[3,4-b]pyridin-1(3H)-yl)-N-methylpropan-1-amine; 3-(2,2-dioxido-1-phenyl[1,2,5]thiadiazolo[3,4-c]pyridin-3(1H)-yl)-N-methylpropan-1-amine; N-methyl-3-[3-(5-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; N-methyl-3-[3-(3-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; 3-[3-(6-methoxypyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(5-ethylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; N-methyl-3-[3-(4-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; 3-(2,2-dioxido-3-pyridin-2-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine; N-methyl-3-[3-(6-methylpyridin-2-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; N-methyl-3-[3-(4-methylpyridin-3-yl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; 3-(2,2-dioxido-3-pyridin-3-yl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine; 3-(6-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine; 3-(5-Chloro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine; 3-(6-bromo-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine; N-methyl-3-(5-methyl-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propan-1-amine; 3-(7-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine; N-methyl-3-(6-methyl-2,2-dioxido-3-phenyl-2,1,3-benzo-thiadiazol-1(3H)-yl)propan-1-amine; 3-(4-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine; 3-[7-fluoro-3-(3-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(methylamino)propyl]-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole-5-carbonitrile 2,2-dioxide; 3-(5-fluoro-2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine; 3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N-methylpropan-1-amine; 3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(3,5-difluorophenyl)-2,2-dioxido-2,13-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-{2,2-dioxido-3-[3-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)-yl}-N-methylpropan-1-amine; 3-{2,2-dioxido-3-[2-(trifluoromethoxy)phenyl]-2,1,3-benzothiadiazol-1(3H)-yl}-N-methylpropan-1-amine; 3-{2,2-dioxido-3-[3-(trifluoromethyl)phenyl]-2,1,3-benzothiadiazol-1(3H)-yl}-N-methylpropan-1-amine; 3-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(3-bromophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethanamine; 2-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylethanamine; 3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; N-ethyl-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine; 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine; 3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(2-Chloro-4-fluorophenyl)-2,2-dioxido-2,13-benzothiadiazol-1(3H)-yl]propan-1-amine; 3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(4-fluoro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; 3-[3-(4-fluoro-2-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pentan-1-amine; 5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpentan-1-amine; 5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpentan-1-amine; 3-[3-(3-Chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; 3-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; 3-[3-(2-fluorophenyl)-2,2-dioxido-5-phenyl-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; 3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[4-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propan-1-amine; 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[7-fluoro-3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N-methylpropan-1-amine; 3-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(2,4-Difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(2,4-Difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(2,4-Difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpropan-1-amine; 4-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine; 4-[3-(4-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine; 4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine; N-{3-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopropanamine; N-{3-[3-(2,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]propyl}cyclopropanamine; N-{4-[3-(2,6-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}cyclopropanamine; 4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine; 4-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N,N-dimethylbutan-1-amine; 5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpentan-1-amine; 5-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpentan-1-amine; 3-[3-(2-fluoro-4-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-fluoro-4-{3-[3-(methylamino)propyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenol; 3-fluoro-4-{3-[4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenol; 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine; 3-[3-(4-chloro-2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]cyclopropanamine; N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopropanamine; N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butyl]cyclopropanamine; N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}cyclopropanamine; 3-[3-(4-chloro-2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylhexan-1-amine; 6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]hexan-1-amine; 6-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylhexan-1-amine; 4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine; 4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine; 4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]-N,N-dimethylbutan-1-amine; N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-amine; 3-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine; 3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-(2,2,2-trifluoroethyl)propan-1-amine; 3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,13-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine; 3-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine; 5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpentan-1-amine; 5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]pentan-1-amine; 5-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpentan-1-amine; 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylpropan-1-amine; 3-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine; 4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbutan-1-amine; 4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylbutan-1-amine; 4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylbutan-1-amine; 4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-isopropylbutan-1-amine; N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}cyclobutanamine; N-{4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butyl}cyclohexanamine; 3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-ethylpropan-1-amine; 3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-isopropylpropan-1-amine; N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclobutanamine; N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclopentanamine; N-{3-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}cyclohexanamine; N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-amine; N-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidin-4-amine; N-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-4-amine; N-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]piperidin-4-amine; 2-({3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}amino) ethanol; and

n-butyl-4-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1 (3H)-yl]butan-1-amine;

pharmaceutically acceptable salts thereof.

19. The compound of claim 1,

wherein said pharmaceutically acceptable salt is a hydrochloride or dihydrochloride.

20. A composition, comprising:

a. at least one compound of formula I:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof; wherein: n is an integer from 0 to 4; m is an integer from 0 to 6; X is —CH2—; R1 is, independently at each occurrence, H, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein each aryl or heteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido is independently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido groups; R2 is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl; R3 and R4 are, independently, H, alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are indepently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided that neither R3 or R4 contain an aminoalkyl group; and wherein 1-3 carbon atoms in ring A may optionally be replaced with N; and

b. at least one pharmaceutically acceptable carrier.

21. 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:

administering to said subject an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof;

wherein:

n is an integer from 0 to 4;

m is an integer from 0 to 6;

X is —CH2—;

R1 is, independently at each occurrence, H, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein each aryl or heteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido is independently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido groups;

R2 is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;

R3 and R4 are, independently, H, alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are indepently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided that neither R3 or R4 contain an aminoalkyl group; and

wherein 1-3 carbon atoms in ring A may optionally be replaced with N.

22. The method of claim 21,

wherein said vasomotor symptom is hot flush.

23. The method of claim 21,

wherein said sexual dysfunction is desire-related or arousal-related.

24. The method of claim 21,

wherein said gastrointestinal disorder or said genitourinary disorder is stress incontinence or urge incontinence.

25. The method of claim 21,

wherein said condition is chronic fatigue syndrome or fibromyalgia syndrome.

26. The method of claim 21,

wherein said 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.

27. The method of claim 21,

wherein said condition is diabetic neuropathy.

28. The method of claim 21,

wherein said condition is pain.

29. The method of claim 28,

wherein said pain is acute centralized pain, acute peripheral pain, or a combination thereof.

30. The method of claim 28,

wherein said pain is chronic centralized pain, chronic peripheral pain, or a combination thereof.

31. The method of claim 28,

wherein said pain is neuropathic pain, visceral pain, musculoskeletal pain, bony pain, cancer pain, inflammatory pain, or a combination thereof.

32. The method of claim 31,

wherein said 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.

33. The method of claim 32,

wherein said neuropathic pain is post-herpetic neuralgia.

34. The method of claim 31,

wherein said 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.

35. The method of claim 28,

wherein said subject is female; and

the pain is female-specific pain.

36. A process for the preparation of a compound of formula I:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof;

wherein:

n is an integer from 0 to 4;

m is an integer from 0 to 6;

X is —CH2—;

R1 is, independently at each occurrence, H, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein each aryl or heteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido is independently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido groups;

R2 is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;

R3 and R4 are, independently, H, alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are indepently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided that neither R3 or R4 contain an aminoalkyl group; and

wherein 1-3 carbon atoms in ring A may optionally be replaced with N;

the process comprising:

(d) reacting a compound of formula IA:

with a compound of formula IB:

wherein,

T is an —N(R3)(R4) or an activating group;

wherein,

if T is —N(R3)(R4), then the compound of formula I is formed; or

if T is an activating group, then a compound of formula IC is formed:

and the process further comprises:

(e) reacting the compound formula IC with —N(R4)RP to form a compound of formula ID:

wherein,

RP is R4 or a protecting group;

wherein,

if RP is R3, the compound of formula I is formed; or

if RP is a protecting group, the process further comprises:

(f) deprotecting the compound of formula ID to form a deprotected compound; and

(g) reacting the deprotected compound with an activated-R3 group, provided that R3 in the activated-R3 group is not H;

wherein the compound of formula I is formed.

37. The process of claim 36, wherein step (d) further comprises contacting the compound of formula IA and IB with dialkyl azodicarboxylate and triphenylphosphine.

38. The process of claim 37, wherein the dialkyl azodicarboxylate is diisopropyl azodicarboxylate.

39. The process of claim 36, wherein the activating group is selected from the group consisting of halo, tosylate, mesylate, triflate, and oxo.

40. The process of claim 39, wherein the activating group is Br.

41. The process of claim 36, wherein the protecting group is selected from the group consisting of BOC, benzyl, acetyl, PMB, C1-C6 alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and triphenylmethyl.

42. The process of claim 41, wherein the protecting group is BOC.

43. The process of claim 36, wherein 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.

44. The process of claim 36, wherein 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.

45. The process of any one of claims 36, wherein the activated-R3 group is halo-R3.

46. The process of claim 36, wherein the compound of formula IA is prepared by:

(a) reacting a compound of formula IE:

wherein RB is F or Cl;

with R2—NH2 to form a compound of formula IF:

(b) hydrogenating the compound of formula IF to form a compound of formula IG:

and (c) reacting the compound of formula IG with sulfamide in diglyme to form the compound of formula IA.

47. The process of claim 46, wherein the hydrogenating step is performed in the presence of hydrogen (H2) and Pd/C.

48. The process of claim 46, wherein any one of steps (a)-(c) is performed at or above 30° C.

49. The process of claim 46, wherein any one of steps (a)-(c) includes a purification step comprising at least one of: filtration, extraction, chromatography, trituration, or recrystallization.

50. A process for the preparation of a compound of formula I:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof;

wherein:

n is an integer from 0 to 4;

m is an integer from 0 to 6;

X is —CH2—;

R1 is, independently at each occurrence, H, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein each aryl or heteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido is independently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido groups;

R2 is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;

R3 and R4 are, independently, H, alkyl, a heterocyclic ring, arylalkyl or heteroarylmethyl, wherein each of alkyl, heterocyclic ring, arylalkyl or heteroarylmethyl, are indepently substituted with 0-3 alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided that neither R3 or R4 contain an aminoalkyl group; and

wherein 1-3 carbon atoms in ring A may optionally be replaced with N;

the process comprising:

(d) reacting R2(BOH)2 and a transitional metal salt with a compound of formula IH:

wherein,

RP is R3 or a protecting group; and

if RP is R3, the compound of formula I is formed; or

if RP is a protecting group, the process further comprises:

(e) deprotecting the compound of formula IH to form a deprotected compound; and

(f) reacting the deprotected compound with an activated-R3 group, provided that R3 group in the activated-R3 group is not H;

wherein the compound of formula I is formed.

51. The process of claim 50, wherein the transitional metal salt is copper(II) acetate.

52. The process of claim 50, wherein the activated-R3 group is halo-R3.

53. The process of claim 50, wherein the protecting group is selected from the group consisting of BOC, benzyl, acetyl, PMB, C1-C6 alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and triphenylmethyl.

54. The process of claim 53, wherein the protecting group is BOC.

55. The process of claim 50, wherein 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.

56. The process of claim 50, wherein 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.

57. The process of claim 50, wherein the compound of formula IH is prepared by:

(a) reacting a compound of formula IJ:

wherein RB is F or Cl;

with a compound of formula IK:

to form a compound of formula IL:

(b) hydrogenating the compound of formula IL to form a compound of formula IM:

and (c) reacting the compound of formula IM with sulfamide and diglyme to form the compound of formula IH.

58. The process of claim 57, wherein the hydrogenating step is performed in the presence of hydrogen (H2) and Pd/C.

59. The process of claim 57, wherein any one of steps (a)-(c) is performed at or above 30° C.

60. The process of claim 57, wherein any one of steps (a)-(c) includes a purification step comprising at least one of: filtration, extraction, chromatography, trituration, or recrystallization.

61. The process of claim 36, wherein 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.

62. The process of claim 50, wherein 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.