FRANKOWSKI KEVIN (US)
FERRER MARC (US)
FREE R BENJAMIN (US)
SIBLEY DAVID R (US)
MORITZ AMY E (US)
SOUTHALL NOEL TERRENCE (US)
HU XIN (US)
KELLEY AMBER (US)
UNIV NORTH CAROLINA CHAPEL HILL (US)
WO2016090313A1 | 2016-06-09 | |||
WO2012162249A1 | 2012-11-29 | |||
WO2014144606A2 | 2014-09-18 | |||
WO2017160552A1 | 2017-09-21 |
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CLAIMS What is claimed is: 1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; R is H, methyl, or ethyl; R1 is chosen from hydrogen, methyl, and ethyl, and R2 is chosen from methyl and ethyl; or R1 and R2 are joined to form a heterocycloalkyl ring optionally containing 1 additional heteroatom chosen from N, O, and S, and the heterocycloalkyl ring is unsubstituted or substituted by 1 or more substituents independently chosen from halogen, hydroxyl, amino, C1-C3alklyl, C1-C3alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy; R3 and R4 are independently chosen from hydrogen, methyl, ethyl, and trifluoromethyl R5 is chosen from hydrogen, methyl, and ethyl; and R6, R7, R8, R9, and R10 are independently chosen from hydrogen, halogen, hydroxyl, amino, -SF5, C1-C4alkyl, C1-C4alkoxy, C1-C4alkylester, C3-C6cycloalkyl, C1-C2haloalkyl, and C1-C2haloalkoxy; wherein at least one of R7, R8, and R9 is not hydrogen. 2. The compound or salt of claim 1, wherein R1 and R2 are both methyl, R1 is methyl and R2 is ethyl, or R1 is hydrogen and R2 is ethyl. 3. The compound or salt of claim 1, wherein R1 and R2 are joined to form a heterocycloalkyl ring selected from an azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl ring and the heterocycloalkyl ring is unsubstituted or substituted by 1 or more substituents independently chosen from halogen, hydroxyl, amino, C1-C3alkyl, C1-C3alkoxy, C1- C2haloalkyl, and C1-C2haloalkoxy. 4. The compound or salt of claim 3, wherein the azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl ring is unsubstituted or substituted with one or two halogen or methyl substituents. 5. The compound or salt of any one of claims 1 to 4, wherein R3 and R4 are both methyl. 6. The compound or salt of any one of claims 1 to 5 wherein R is hydrogen. 7. The compound or salt of any one of claims 1 to 6, wherein R5 is hydrogen. 8. The compound or salt of any one of claims 1 to 7, wherein n is 1. 9. The compound or salt of any one of claims 1 to 7, wherein n is 0. 10. The compound or salt of any one of claims 1 to 9, wherein R6, R9, and R10, are all hydrogen. 11. The compound or salt of any one of claims 1 to 10, wherein R7 and R8 are independently chosen from hydrogen, fluoro, chloro, bromo, methyl, ethyl, and trifluoromethyl, where at least one of R7 and R8 is not hydrogen. 12. The compound or salt of claim 1, of Formula I-A (Formula I-A). 13. The compound or salt of claim 12, wherein R1 and R2 are both methyl, or R1 is hydrogen and R2 is ethyl, or R1 is methyl and R2 is ethyl; or R1 and R2 are joined to form a heterocycloalkyl ring selected from an azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl ring, which ring is unsubstituted or substituted with or more methyl or fluoro substituents; and R7 and R8 are chosen from hydrogen, halogen, methyl, ethyl, trifluoromethyl and cyclopropyl, wherein at least one of R7 and R8 is not hydrogen. 14. The compound or salt of claim 1, of Formula I-B R1 is methyl and R2 is ethyl, or R1 is hydrogen and R2 is ethyl, or R1 is methyl and R2 is ethyl; or R1 and R2 are joined to form a heterocycloalkyl ring selected from an azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl ring, which ring is unsubstituted or substituted with or more methyl or fluoro substituents; and R3 and R4 are both methyl, or one of R3 and R4 is hydrogen and the other is trifluoromethyl, or oner of R3 and R4 is methyl and the other is trifluoromethyl; and R6, R7, R8, R9, and R10 are independently chosen from hydrogen, halogen, C1-C2alkyl, C1-C2alkoxy, cyclopropyl, SF5, and CF3, wherein at least one of R6, R7, R8, R9, and R10 is not hydrogen and no more than 4 of R6, R7, R8, R9, and R10 are non-hydrogen. 15. The compound or salt of claim 12, wherein R1 and R2 are both methyl, or R1 and R2 are joined to form a heterocycloalkyl ring selected from an azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl ring and the heterocycloalkyl ring is unsubstituted or substituted by 1 or more substituents independently chosen from halogen, hydroxyl, amino, C1-C3alkyl, C1-C3alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy; and R7 and R8 are independently chosen from hydrogen, fluoro, chloro, bromo, methyl, ethyl, and trifluoromethyl, where at least one of R7 and R8 is not hydrogen. 16. A compound or salt of claim 1, wherein the compound is 17. A compound of Formula II-A or II-B, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C4 alkyl; R2 is 1 or more optional substituents independently chosen from halogen, hydroxyl, amino, cyano, or C1-C6alkyl, in which any one CH2 in the C1-C6alkyl is optionally replaced by NR3, O, S, or SO2 and which C1-C6alkyl is optionally substituted by one or more substituents independently chosen from halogen, hydroxyl, amino, oxo, and cyano; and R3 is hydrogen or C1-C4alkyl. 18. The compound of claim 17, or salt thereof, wherein the compound is: 19. A compound of Formula III, or a pharmaceutically acceptable salt thereof, n is 0, 1, or 2; m is 0, 1, or 2; R1 and R3 are each 1 or more optional substituents independently chosen from halogen, hydroxyl, amino, cyano, or C1-C6alkyl, in which any one CH2 in the C1-C6alkyl is optionally replaced by NR4, O, S, or SO2 and which C1-C6alkyl is optionally substituted by one or more substituents independently chosen from halogen, hydroxyl, amino, oxo, and cyano; and R2 and R4 are each independently hydrogen or C1-C4alkyl. 20. The compound of claim 19, or salt thereof, wherein the compound is: 21. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 20, together with a pharmaceutically acceptable excipient. 22. A method of treating a central nervous system disorders, comprising Parkinson's disease and related syndromes, dyskinesia, neurodegenerative disorders, schizophrenia, cognitive dysfunction, or substance use disorder and/or withdrawal syndrome in a patient, comprising administering a therapeutically effective amount of a compound or salt thereof of any one of Claims 1 to 20 to the patient. 23. The method of claim 22, wherein the disorder is selected from the group comprising of obesity, anxiety, depression (e.g., refractory depression, MDD, or bipolar depression), psychosis (including psychosis associated with dementia such as hallucinations in progressive Parkinson's disease or paranoid ideas), schizophrenia, sleep disorders (in particular sleep disorders associated with schizophrenia and other psychiatric and neurological diseases), sexual disorders, migraines, conditions associated with headaches, social phobias, agitation in dementia (e.g., agitation in Alzheimer's disease), agitation in autism and related autistic disorders, gastrointestinal disorders such as gastrointestinal motility dysfunction, and dementia, such as dementia of Alzheimer's disease or Parkinson's disease; mood disorders; or substance use disorder and/or withdrawal syndrome, for example, opiate dependence and / or alcohol dependence or withdrawal from drug or alcohol dependence (for example, opiate dependence); or compulsive overeating. 24. The method of claim 22, wherein the disorder is the substance use disorder and/or the withdrawal syndrome. 25. The method of claim 24, wherein the substance use disorder is related to substances comprising tobacco, alcohol, caffeine, opioids, cannabis, stimulants, sedatives, inhalants, hypnotics or anxiolytics, or hallucinogen. 26. The method of any one of claims 22 to 25, further comprising administering to the patient in need thereof at least one additional therapeutic agent. |
[0066] The disclosure further includes compounds of Formula II, which comprises Formula II-A and II-B, or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 4 alkyl; R 2 is 1 or more optional substituents independently chosen from halogen, hydroxyl, amino, cyano, or C 1 -C 6 alkyl, in which any one CH 2 in the C 1 -C 6 alkyl is optionally replaced by NR 3 , O, S, or SO 2 and which C 1 -C 6 alkyl is optionally substituted by one or more substituents independently chosen from halogen, hydroxyl, amino, oxo, and cyano; and R 3 is hydrogen or C 1 -C 4 alkyl. [0067] In an embodiment, the compound of Formula II is Compound 25, or a pharmaceutically acceptable salt thereof: [0068] In an embodiment, the compound of Formula II is Compound 44, or a pharmaceutically acceptable salt thereof. [0069] The disclosure further includes compounds of Formula III, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2; m is 0, 1, or 2; R 1 and R 3 are each 1 or more optional substituents independently chosen from halogen, hydroxyl, amino, cyano, or C 1 -C 6 alkyl, in which any one CH 2 in the C 1 -C 6 alkyl is optionally replaced by NR 4 , O, S, or SO 2 and which C 1 -C 6 alkyl is optionally substituted by one or more substituents independently chosen from halogen, hydroxyl, amino, oxo, and cyano; and R 2 and R 4 are each independently hydrogen or C 1 -C 4 alkyl. [0070] In an embodiment, the compound of Formula III is Compound 26: Compound 26, , or a pharmaceutically acceptable salt thereof. [0071] Compounds were identified that showed antagonist activity a high-throughput D3 DAR β-arrestin recruitment assay. These hit compounds were then triaged by counter screening against the closely related D2 DAR to identify compounds that were active at the D3 DAR but not at the D2 DAR. From the resulting pool of D3 DAR-selective antagonists, putative negative allosteric modulator (NAM) ligands were identified by conducting radioligand competition binding assays with [ 3 H]-methylspiperone, an antagonist compound known to interact with the D3 DAR orthosteric binding pocket. Any compound that did not inhibit the binding of the orthosteric [ 3 H]-methylspiperone ligand was assumed to act by binding to an ectopic allosteric site on the D3 DAR. [0072] Three separate scaffolds are identified, Compound 1 (Cmp.1, a Formula I compound), Compound 25 (Cmp.25, a Formula II compound), and Compound 26 (Cmp.26, a Formula III compound) that exhibited a D3 DAR NAM chemotype. Cmp.1 inhibits dopamine-stimulated β-arrestin recruitment to the D3 DAR with a potency of ~16 µM as assessed using the DiscoverX β-arrestin recruitment assay while displaying no activity at other dopamine receptor subtypes (FIGURE 1). FIG.1A shows that Cmp.1 is fully selective for the D3 DAR vs. other DARs as assessed in the DiscoverX arrestin assay with an IC50 of 16 µM ± 2.5 µM, average curves are shown (mean ± SEM from at least 3 experiments performed in triplicate). FIG.1B shows Cmp.1 lacks ability to inhibit the binding of the orthosteric antagonist [ 3 H]-methylspiperone to the D3R, indicating it does not bind to the orthosteric site where dopamine binds. Homogenates from cells expressing the D3 DAR were incubated with indicated concentrations of Cmp.1 or DMSO vehicle and [ 3 H]- methylspiperone. Non-specific binding was determined in the presence of 4 μM (+)- butaclamol. These results indicate that the Cmp.1 does not bind to the conserved orthosteric binding site on the D3 DAR, supporting an allosteric mechanism of action. Cmp.25 and Cmp.26 were found to inhibit dopamine-stimulated β-arrestin recruitment to the D3 DAR with potencies of ~13 µM and ~30 µM, respectively, while displaying no activity at the D2R (FIGURE 2). Importantly, neither compound exhibited measurable ability to inhibit the binding of the orthosteric antagonist [ 3 H]-methylspiperone to the D3 DAR when using single high 40 µM concentrations of each compound (data not shown), which is consistent with an allosteric mechanism of action. FIG.2A (left) shows that Cmp.25 inhibits the D3 DAR as assessed in the DiscoverX β-arrestin assay with an IC 50 of ~15 µM, FIG.2A (right) shows Cmp.26 inhibits the D3 DAR as assessed in the DiscoverX beta-arrestin assay with an IC50 of ~30 µM. FIG. 2B (left) shows Cmp. 25 lacks ability to antagonize dopamine activation of the D2 DAR as assessed in the DiscoverX β-arrestin assay, and FIG 2B (right) shows Cmp. 26 lacks ability to antagonize dopamine activation of the D2 DAR as assessed in the DiscoverX β-arrestin assay. Average curves from two experiments, each performed in triplicate are shown. [0073] In FIGURE 3, Cmp.1 was further examined for its ability to antagonize various functional pathways of D3 DAR-mediated signaling including dopamine-stimulated β-arrestin recruitment (using a different assay technique than in FIGURE 1), G protein (Go) activation, cAMP inhibition, and pERK stimulation, while failing to block these same signaling pathways mediated by the closely related D2 DAR. FIG. 3A (left) shows Cmp. 1 is a selective D3 DAR antagonist as assessed in a BRET-based β-arrestin assay (IC50 = 13 µM ± 2 µM), FIG.3B (left) shows Cmp.1 is a selective D3 DAR antagonist as assessed in a BRET-based assay of Go activation (IC50 = 16 µM ± 2.5 µM), FIG.3C (left) shows Cmp.1 is a selective D3 DAR antagonist as assessed in a BRET-based CAMYEL cAMP accumulation assay (IC50 = 2.9 µM ± 0.7 µM), and FIG.3D (left) shows Cmp.1 is a selective D3 DAR antagonist as assessed in an antibody capture assay used to assess pERK levels (IC50 = 5.6 µM ± 1.6 µM). Cmp.1 lacked antagonist activity at the D2 DAR in all of these assays (FIGs 3A to 3D right hand panels). Average curves are shown (mean ± SEM from at least 3 experiments each performed in triplicate). These findings indicate that Cmp.1 is a selective antagonist for all D3 DAR-mediated signaling pathways that have been tested to-date. [0074] To further assess the mechanism of action of Cmp.1, curve-shift assays were conducted using the DiscoverX β-arrestin recruitment assay while using the orthosteric competitive antagonist sulpiride as a comparator. FIG.4 shows cells expressing the D3 DAR that were incubated with either dopamine (FIGs.4A and 4B) or the D3 DAR agonist pramipexole (FIGs.4C and 4D) in the presence or absence of increasing concentrations of either the orthosteric competitive antagonist sulpiride (FIGs 4A and 4C) or Cmp.1 (FIGs 4B and 4D). Results and Schild plot analyses (FIGs 4A and C, insets) indicate that sulpiride behaves in a competitive manner with dopamine and pramipexole (increasing concentrations of antagonist produces an apparent decrease in DA potency (increase in EC 50 ) with no effect on efficacy (Emax) while Cmp.1 behaves in a non-competitive manner with both agonists (increasing concentrations of Cmp.1 inhibits DA efficacy (Emax) with no effect on DA potency (EC 50 )). Functional IC 50 s for Cmp.1 for decreasing the Emax of dopamine or pramipexole were 17 µM and 14 µM, respectively (FIGs 4C and D, insets show Emax decrease as a function of compound concentration). Average curves are shown (mean ± SEM from at least 3 experiments each performed in triplicate). Increasing concentrations of sulpiride result in right-ward shifts in the agonist concentration-response curves with no effect on the maximum responses as would be expected for a competitive orthosteric antagonist (FIG.4). In contrast, increasing concentrations of Cmp.1 have no effect on the agonist potencies (EC 50 ) but produce a dose-dependent decrease in the maximum responses (Emax) indicative of noncompetitive antagonism (FIG.4) as would be expected for a negative allosteric modulator. [0075] As there is no evolutionary pressure to conserve an allosteric receptor site, compounds that interact with these sites offer the potential for greater target selectivity than compounds that bind to orthosteric sites, which are evolutionary conserved to optimally interact with endogenous ligands. The target selectivity of Cmp.1 was assessed using both the DiscoverX gpcrMAX SM GPCR functional assay panel of 168 unique GPCRs, and the Psychoactive Drug Screening Program (PDSP) binding affinity panel that contains 45 GPCRs, ion channels, and neurotransmitter transporters (FIGURE 5). [0076] Cmp.1 was tested as both an agonist (FIG.5A) or an antagonist (FIG.5B) at a single high concentration (30 µM) on 168 different GPCRs in the DiscoverX gpcrMAX TM β-arrestin recruitment assay panel (FIGs.5A and 5B). Assay results are presented as the mean percent activation of indicated GPCRs (for n = 2 replicates). For a full description of the DiscoverX gpcrMAX TM -GPCR assay panel and methods (see: http://www.DiscoverX.com). FIG.5C shows that Cmp. 1 (10 µM) also showed limited off- target affinity in a radioligand binding panel. Data represent mean % inhibition (n = 4) for radioligand binding to various receptor subtypes, transporters, and ion channels. Data were provided by the National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (PDSP) (University of North Carolina, Chapel Hill, NC). For experimental details including radioligands used and associated Kd values for each individual target, refer to the PDSP website: http://pdsp.med.unc.edu/. While Cmp.1 displayed affinity for the H1 receptor in the radioligand binding panel, no functional activity was identified in the functional panels. The 5-HT6 receptor was not present in the functional panels, however, subsequent testing found Cmp.1 displays negligible, if any, antagonism of the 5-HT6 receptor (IC 50 > 50 µM) as assessed in a cAMP recruitment assay. [0077] Notably, Cmp.1 lacked agonist activity at all 168 GPCRs in the functional panel (FIG.5A), and the only GPCR that was antagonized was the D3 DAR (FIG.5B), thus describing the most selective D3 DAR antagonist ever identified. In the PDSP binding panel, Cmp.1 exhibited minimal displacement at only the H1 histamine and 5-HT6 serotonin receptors. Notably, no functional activity at the H1 receptor was identified in the gpcrMAX SM panel suggesting that Cmp. 1 may be negatively cooperative with the H1 histamine receptor radioligand used in the PDSP screen, but not with histamine itself. The 5- HT6 receptor was not represented in the gpcrMAX SM panel, but subsequent functional assays indicated negligible, if any (IC 50 >50 µM) antagonism of this receptor. Taken together, these panels highlight the unprecedented selectivity of this compound for antagonizing the D3 DAR. [0078] Analogs of Cmp.1 have been developed that exhibit improved characteristics, primarily through increasing the scaffold’s potency for the D3 DAR. Preliminary data are included in Table 1. [0079] Further testing of a select group of more potent analogs in curve-shift assays show that these analogs also behave in a noncompetitive manner with agonists at the D3 DAR (FIGURE 6) and display up to 10-fold greater potency for antagonizing D3 DAR signaling activity when compared to the parent Cmp.1. FIGURE 6A - C panels show concentration-response curves of dopamine in the absence or presence of increasing concentrations of compound. Cmp.1 analogs behave in a non-competitive manner as would be expected for a negative allosteric modulator (inset shows Emax decrease as a function of compound concentration). Functional IC50s were calculated from concentration-response curves (insets) and found to be 3.6 µM, 2.3 µM, and 1.7 µM for Cmp.18 (FIG.6A), Cmp.5 (FIG.6B), and Cmp.17 (FIG.6C), respectively. Average curves are shown (mean ± SEM from at least 3 experiments, each performed in triplicate). [0080] FIGURE 7A shows that cmp 17 is brain penetrant in a pharmacokinetic study conducted in male CD1 mice using a single 40 mg/kg i.p. injection. FIGURE 7B displays the calculated pharmacokinetic parameters for cmp 17, indicating that it achieves a sufficient concentration in the brain to antagonize the D3 DAR in vivo and has a half-life of approximately 4 hours. PHARMACEUTICAL PREPARATIONS [0081] Compounds disclosed herein can be administered as the neat chemical, but are preferably administered as a pharmaceutical composition. Accordingly, the disclosure provides pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of Formulae I, II, or III, together with at least one pharmaceutically acceptable carrier. The pharmaceutical composition/ combination may contain a compound or salt of Formulae I, II, or III as the only active agent or may be combined with one or more additional active agents. In certain embodiments the pharmaceutical composition is in a dosage form that contains from about 0.1 milligrams (mg) to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of a compound of Formulae I, II, or III. [0082] Compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, or by other means routine in the art for administering pharmaceutical compositions. The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. [0083] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. [0084] Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention. [0085] The pharmaceutical compositions/combinations can be formulated for oral administration. These compositions contain between 0.1 and 99 weight % (wt.%) of a compound of Formulae I, II, or III and usually at least about 5 wt.% of a compound of Formulae I, II, or III. Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the compound of Formulae I, II, or III. METHODS OF TREATMENT [0086] The disclosure provides methods of treating central nervous system disorders, including Parkinson's disease and related syndromes, dyskinesia, especially dyskinesias secondary to treating Parkinson's disease with L-DOPA, neurodegenerative disorders such as Alzheimer’s disease and dementia, Huntington’s disease, restless legs syndrome, bipolar disorder, psychosis, and depression, schizophrenia, cognitive dysfunction, and substance use disorder (SUD) and/or withdrawal syndrome. In particular, the disclosure describes methods of treating depressive disorder, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, substance use disorders and/or withdrawal syndrome, trauma- and stressor- related disorder, and disruptive, impulsive-control, and conduct disorder comprising administering an effective amount of a compound of Formulae I, II, or III to a patient having one of these disorders. [0087] A compound of Formulae I, II, or III may be the only active agent administered (monotherapy) or may be combined with one or more other active agents (combination, adjunct, or augmentation therapy). [0088] In another embodiment the invention provides a method of treating substance use disorder comprising (i) diagnosing a patient as having any substance use disorder and (ii) providing an effective amount of compound of Formulae I, II, or III to the patient, wherein the compound of Formulae I, II, or III is provided as the only active agent or is provided together with one or more additional active agents. [0089] Psychosocial intervention may play an important role in treatment of any central nervous system disorder. Psychosocial intervention includes cognitive-behavior therapy, dialectical-behavior therapy, interpersonal therapy, psychodynamic therapy, and group therapy. In another embodiment, the disclosure provides a method of treating a central nervous system disorder in a patient including administration of an effective amount of a compound of Formulae I, II, or III to the patient, the method further including providing psychosocial intervention to the patient. [0090] In another embodiment the disclosure provides a method for lessening the symptoms of depressive disorders, bipolar disorders, psychosis, anxiety disorders, obsessive- compulsive disorders, substance use disorders (SUDs) and/or withdrawal syndrome, trauma- and stressor-related disorders, and disruptive, impulsive-control, and conduct disorders comprising providing an effective amount of compound of Formulae I, II, or III to the patient. In another embodiment the disclosure provides a method for lessening the symptoms of depressive disorders, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, substance use disorders and/or withdrawal syndrome, trauma- and stressor-related disorders, and disruptive, impulsive control, and conduct disorders comprising providing an effective amount of compound of Formulae I, II, or III to the patient and a therapeutically effective quantity of one or more additional active agents to lessen the symptoms of depressive disorders, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, substance use disorders and/or withdrawal syndrome, trauma- and stressor-related disorders, and disruptive, impulsive-control, and conduct disorders. [0091] Further included are methods of treating the SUDs by providing a compound of Formula I, Formula II, or Formula III to a patient wherein the SUD is abuse and dependence, as they relate to substances such as tobacco (nicotine), alcohol, caffeine, opioids, cannabis, stimulants (including amphetamine-type substances, cocaine, and other stimulants), sedatives, inhalants, hypnotics or anxiolytics, and hallucinogen (phencyclidine or similarly acting arylcyclohexylamines, and other hallucinogens, such as LSD). [0092] Methods of treatment include providing certain dosage amounts of a compound of Formula I, Formula II, or Formula III to a patient. Dosage levels of each compound of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of compound that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of each active compound. In certain embodiments 25 mg to 500 mg, or 25 mg to 200 mg of a compound of Formula I, Formula II, or Formula III are provided daily to a patient. Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most diseases and disorders, a dosage regimen of 4 times daily or less can be used and in certain embodiments a dosage regimen of 1 or 2 times daily is used. [0093] In an embodiment, a method of treating central nervous system disorders, comprises Parkinson's disease and related syndromes, dyskinesia, neurodegenerative disorders, schizophrenia, psychosis, cognitive dysfunction, or substance use disorder and/or withdrawal syndrome in a patient, comprising a step of providing to a patient in need thereof a therapeutic agent, wherein the therapeutic agent is a compound or salt thereof of any one of compound of Formula I, Formula II, or Formula III. [0094] The method of treating a central nervous system disorders, wherein the disorder is selected from the group comprising of obesity, anxiety, depression (e.g., refractory depression, MDD, or bipolar depression), psychosis (including psychosis associated with dementia such as hallucinations in progressive Parkinson's disease or paranoid ideas), schizophrenia, sleep disorders (in particular sleep disorders associated with schizophrenia and other psychiatric and neurological diseases), sexual disorders, migraines, conditions associated with headaches, social phobias, agitation in dementia (e.g., agitation in Alzheimer's disease), agitation in autism and related autistic disorders, gastrointestinal disorders such as gastrointestinal motility dysfunction, and dementia, such as dementia of Alzheimer's disease or Parkinson's disease; mood disorders; or substance use disorder and/or withdrawal syndrome, for example, opiate dependence and / or alcohol dependence or withdrawal from drug or alcohol dependence (for example, opiate dependence); or compulsive overeating. [0095] In an embodiment, the disorder is the substance use disorder and/or the withdrawal syndrome. [0096] In an embodiment, the substance use disorder is related to substances comprising tobacco, alcohol, caffeine, opioids, cannabis, stimulants, sedatives, inhalants, hypnotics or anxiolytics, or hallucinogen. [0097] In an embodiment, the method further comprises administering to the patient in need thereof at least one additional therapeutic agent. [0098] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. [0099] Methods of treatment provided herein are also useful for treatment of mammals other than humans, including for veterinary applications such as to treat horses and livestock e.g. cattle, sheep, cows, goats, swine and the like, and pets (companion animals) such as dogs and cats. [0100] The term "room temperature" (rt or RT) used herein refers to a temperature of about 25 °C. EXAMPLES ABBREVIATIONS BOC or Boc tert-butoxycarbonyl Dec Decomposition DIPEA Diisopropylethylamine DCE Dichloroethane DCM Dichloromethane DMAP 4-(N,N-dimethylamino)pyridine DMF Dimethylformamide DMSO Dimethyl Sulfoxide EtOAc Ethyl Acetate HATU 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethy lisouronium hexafluorophosphate (V) Mp Melting point NMR Nuclear Magnetic Resonance PyBOP Bzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate rt or RT Room temperature THF Tetrahydrofuran TLC Thin layer chromatography GENERAL METHODS [0101] All air- or moisture-sensitive reactions were performed under positive pressure of argon with oven-dried glassware. All reagents were used as received from the following suppliers: Alfa Aesar, Ark Pharm, Aldrich, and Fisher Scientific. The 1 H and 13 C NMR spectra were recorded on either a Bruker Avance 400 MHz or 500 MHz spectrometer or Varian MR 400 Megahertz (MHz) spectrometer. Chemical shifts are reported in parts per million and were referenced to residual proton solvent signals. When indicated, 13 C multiplicities were determined with the aid of an APT (Attached Proton Test) pulse sequence, differentiating the signals for methyl and methane carbons as “d” from methylene and quaternary carbons as “u”. [0102] The infrared (IR) spectra were acquired as thin on a PerkinElmer Spectrum One FT-IR spectrometer equipped with a universal Attenuated total reflection (ATR) sampling accessory and the absorption frequencies are reported in cm -1 . Flash column chromatography separations were performed using the Teledyne Isco CombiFlash R F using RediSep R F silica gel columns. TLC was performed on Analtech UNIPLATE silica gel GHLF plates (gypsum inorganic hard layer with fluorescence). TLC plates were visualized under a long wave/short wave ultraviolet (UV) lamp. [0103] Compound purity was measured on the basis of peak integration (area under the curve) from UV/Vis absorbance (at 214 nm), and compound identity was determined on the basis of mass analysis. All compounds used for biological studies have purity >90%. SYNTHESIS OF SELECTED COMPOUNDS [0104] General Synthetic Scheme for the synthesis of pyrrole D3 NAM Analogues [0105] Synthetic Routes for the Synthesis of Compounds 22, 21, 5, 17, 30, 19, 20, 28, 31, 33, 34, 35, 36, 39, 40, 41, 42 and 43 EXAMPLE 1. SYNTHESIS OF METHYL 4-(N-(3-CHLORO-4- (TRIFLUOROMETHYL)PHENYL)SULFAMOYL)-2,5-DIMETHYL-1H-PYRROLE-3 -CARBOXYLATE [0106] Chlorosulfonic acid (4.090 grams (g), 2.333 milliliters (ml), 35.10 millimoles (mmol), 10 equivalents (equiv.)) was added in small portions to methyl 2,5-dimethyl-1H- pyrrole-3-carboxylate (537.7 milligrams (mg), 3.510 mmol, 1 equiv.) at 0 ºC under vigorous stirring. After 2.5 hours (h), the reaction was warmed to rt over 15 mins then heated at 60 °C for 14 h. After cooling again to 0 °C, the reaction was quenched by pouring into ice. The solid was filtered and washed with water to afford the crude product as a purple-brown solid, which was dried via toluene azeotrope (four times) and used without further purification (crude yield = 282.8 mg). The above sulfonyl chloride was added to a solution of 4-chloro-3- (trifluoromethyl)aniline (343.2 mg, 1.755 mmol, 0.5 equiv.) in pyridine (6 ml) and stirred at rt overnight. The solvent removed and the residue purified by flash chromatography (hexanes/EtOAc, 0 to 100%) to afford the sulfonamide product as an off-white solid (350.6 mg, 3.510 mmol, 24% yield over two steps). Rf = 0.48 (50% EtOAc/hexanes); mp = 187–198 °C. [0107] 1 H NMR (400 MHz, acetone-d6) δ 2.34 (s, 3H), 2.37 (s, 3H), 3.84 (s, 3H), 7.42 (dd, J = 2.7, 8.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 2.6 Hz, 1H), 8.86 (br s, 1H), 10.74 (br s, 1H); 13 C NMR (101 MHz, acetone-d6, APT pulse sequence) δ d (CH, CH3) 11.7, 12.6, 51.0, 118.7 (q, J = 5.7 Hz), 124.8, 132.3; u (C, CH 2 ) 109.1, 116.0, 122.8 (q, J = 273.9 Hz), 125.9 (q, J = 1.9 Hz), 127.9 (q, J = 60.0 Hz), 134.9, 136.0, 138.5, 164.8. EXAMPLE 2. SYNTHESIS OF 4-(N-(3-CHLORO-4-(TRIFLUOROMETHYL)PHENYL)SULFAMOYL)- 2,5-DIMETHYL-1H-PYRROLE-3-CARBOXYLIC ACID (COMPOUND 22) [0108] Methyl 4-(N-(3-chloro-4-(trifluoromethyl)phenyl)sulfamoyl)-2,5-dime thyl- 1H-pyrrole-3-carboxylate (400 mg, 0.974 mmol) was dissolved in MeOH (1.5 ml) and THF (4.5 ml). A solution of LiOH (233 mg, 9.74 mmol) in water (1.5 ml) was added and the reaction was heated at 55 °C for 5 h. After cooling to rt, the reaction was acidified with 1 normal (N) aqueous HCl, precipitating the carboxylic acid product. The crude product was collected by filtration, washed with water, dried under vacuum and purified by C-18 flash chromatography to afford Compound 22 as an off-white solid (420 mg, 1.06 mmol, 68% yield). [0109] 1 H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.36 (s, 3H), 6.95–7.16 (m, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 11.52 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 12.8, 13.5, 110.9, 117.1, 117.2, 118.8 (q, J = 31.2 Hz), 120.5, 123.7 (q, J = 272.8 Hz), 129.0 (q, J = 5.3 Hz), 131.4 (q, J = 1.9 Hz), 132.7, 135.3, 147.3 (q, J = 3.5 Hz), 165.6; 19 F NMR (376 MHz, DMSO-d6) δ -59.77. E XAMPLE 3. S YNTHESIS OF 4-(N-(3- CHLORO -4-( TRIFLUOROMETHYL ) PHENYL ) SULFAMOYL )- N,N,2,5-TETRAMETHYL-1H-PYRROLE-3-CARBOXAMIDE (COMPOUND 21) [0110] To a solution of 4-(N-(3-chloro-4-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (50 mg, 0.13 mmol) in DMF (2 mL) was added HATU (58 mg, 0.15 mmol, 1.2 equiv.). After 10 mins, a solution of dimethylamine (40 wt % in THF, 17 mg, 0.15 mmol, 1.2 equiv.) was added followed by DIEA (20 mg, 0.15 mmol, 1.2 equiv). The reaction was stirred at rt for 26 h, the solvent removed and the residue purified by flash chromatography (CH 2 Cl 2 /MeOH) to afford the amide product as a tan solid (13 mg, 0.031 mmol, 24% yield). [0111] 1 H NMR (400 MHz, Methanol-d 4 ) δ 2.05 (s, 3H), 2.32 (s, 3H), 2.91 (s, 3H), 3.08 (s, 3H), 7.19 (dd, J = 1.4, 8.7 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H); 13 C NMR (100 MHz, methanol-d 4 ) δ 9.6, 10.5, 33.8, 37.8, 113.7, 114.7, 116.6, 120.7, 122.5 (q, J = 31.8 Hz), 123.1 (q, J = 272.6 Hz), 128.0 (q, J = 5.4 Hz), 125.1, 132.1 (q, J =1.9 Hz), 132.9, 143.2, 168.0. EXAMPLE 4. SYNTHESIS OF N-(3-CHLORO-4-(TRIFLUOROMETHYL)PHENYL)-2,5-DIMETHYL-4- (PYRROLIDINE-1-CARBONYL)-4,5-DIHYDRO-1H-PYRROLE-3-SULFONAMID E (Compound 5) [0112] To a solution of 4-(N-(3-chloro-4-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (60.8 mg, 0.153 mmol) in DMF (2 mL) was added HATU (87.4 mg, 1.5 equiv, 230 micromole (µmol)) and the reaction stirred for 10 min at rt. Pyrrolidine (21.8 mg, 0.306 mmol, 2.0 equiv) was added followed by DIEA (80.1 microliters (µL), 0.460 mmol, 3.0 equiv) and the reaction stirred at rt for 29 h. The solvent was removed and the residue purified by silica then C-18 flash chromatography (EtOAc/hexanes then water/MeOH, respectively) to afford the amide product as a white solid (28.5 mg, 0.634 mmol, 41 % yield). R f = 0.09 (50% EtOAc/hexanes); mp = 126–141 °C. [0113] 1 H NMR (400 MHz, chloroform-d) δ 1.66 (m, 2 H), 1.74 (m, 2H), 1.90 (s, 3H), 2.03 (s, 3H), 3.13 (m, 2H), 3.39 (m, 2H), 7.03 (m, 1H), 7.27 (m, 2H), 8.07 (bs, 1H), 8.15 (bs, 1H); 13 C NMR (101 MHz, chloroform-d) δ 11.9, 24.5, 25.7, 45.9, 48.7, 50.7, 114.6, 115.9, 118.8, 122.9 (q, J = 273.7 Hz), 123.1, 124.9 (q, J = 31.9 Hz), 125.5, 128.0 (q, J = 5.4 Hz), 132.7, 132.9, 142.7, 166.3; 19 F NMR (376 MHz, chloroform-d) δ -61.9; IR (neat): 1606, 1576, 1454 cm -1 . EXAMPLE 5. SYNTHESIS OF N-(3-CHLORO-4-(TRIFLUOROMETHYL)PHENYL)-4-(3,3- DIFLUOROPYRROLIDINE-1-CARBONYL)-2,5-DIMETHYL-1H-PYRROLE-3-SU LFONAMIDE (Compound 17) [0114] To a solution of 4-(N-(3-chloro-4-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (47.1 mg, 0.119 mmol) in DMF (2 mL) was added HATU (67.7 mg, 0.178 mmol, 1.5 equiv.). After 10 min 3,3-difluoropyrrolidin-1-ium chloride (34.1 mg, 0.237 mmol, 2.0 equiv.) was added followed by DIEA (76 µL, 0.43 mmol, 3.7 equiv.). The reaction was stirred at rt for 28 h, the solvent evaporated and the residue purified by flash chromatography to afford the amide product as a white solid (21.3 mg, 0.0438 mmol, 37 % yield). Rf = 0.22 (50% EtOAc/hexanes). [0115] 1 H NMR (400 MHz, Methanol-d4) δ 2.08 (s, 3H), 2.32 (s, 3H), 2.44 (s, 2H), 3.37 (t, J = 7.2 Hz, 2H), 3.49 (t, J = 12.9 Hz, 2H), 7.14 – 7.20 (m, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H); 19 F NMR (376 MHz, methanol-d4) δ -63.13. EXAMPLE 6. SYNTHESIS OF N-(3-CHLORO-4-(TRIFLUOROMETHYL)PHENYL)-2,5-DIMETHYL-4- (MORPHOLINE-4-CARBONYL)-1H-PYRROLE-3-SULFONAMIDE (Compound 30) [0116] To a solution of 4-(N-(3-chloro-4-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (50 mg, 0.13 mmol) in DMF (2 mL) was added HATU (58 mg, 0.15 mmol, 1.2 equiv.). After 10 mins, a solution of morpholine (13 mg, 0.15 mmol, 1.2 equiv.) in DMF (0.5 mL) was added followed by DIEA (26 μL, 0.15 mmol, 1.2 equiv.). The reaction was stirred at rt for 27 h, the solvent removed and the residue purified by C-18 flash chromatography (water/MeOH) to afford the amide product as an off-white solid (25 mg, 0.054 mmol, 42% yield). [0117] 1 H NMR (400 MHz, Chloroform-d) δ 2.50 (d, J = 4.0 Hz, 6H), 2.81 – 3.09 (m, 4H), 3.46 – 3.73 (m, 4H), 7.52 – 7.57 (m, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.94 – 8.13 (m, 1H), 8.69 (s, 1H), 9.88 (s, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 13.3, 13.6, 45.1, 65.9, 110.2, 114.1, 116.6, 121.3, 123.2 (q, J = 31.8 Hz), 124.3, 128.2 (q, J = 5.3 Hz), 133.2 (q, J = 1.9 Hz), 134.9, 135.6, 142.4, 162.3. EXAMPLE 7. SYNTHESIS OF TERT-BUTYL 4-(4-(N-(3-CHLORO-4- (TRIFLUOROMETHYL)PHENYL)SULFAMOYL)-2,5-DIMETHYL-1H-PYRROLE-3 - CARBONYL)PIPERAZINE-1-CARBOXYLATE (Compound 19)
[0118] To a solution of 4-(N-(3-chloro-4-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (60 mg, 0.15 mmol) in DMF (2 mL) was added HATU (69 mg, 0.18 mmol, 1.2 equiv.). After 10 mins, tert-butyl piperazine-1-carboxylate (34 mg, 0.18 mmol, 1.2 equiv.) was added followed by DIEA (40 μL, 0.18 mmol, 1.2 equiv.). The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by C-18 flash chromatography (water/MeOH) to afford the amide product as a tan solid (44.1 mg, 0.078 mmol, 52% yield). [0119] 1 H NMR (400 MHz, Chloroform-d) δ 1.41 (s, 9H), 2.50 (s, 3H), 2.51 (s, 3H), 2.94 (t, J = 5.1 Hz, 4H), 3.35–3.43 (m, 4H), 7.58 (d, J = 1.9 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 8.03 (s, 1H), 8.84 (br s, 1H), 9.89 (br s, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 13.3, 13.6, 28.3, 45.0, 80.6, 110.4, 114.0, 116.6, 121.3, 122.9 (q, J = 273.4 Hz), 123.5 (q, J = 31.9 Hz), 128.2 (q, J = 5.3 Hz), 133.1, 134.8, 135.7, 142.5, 154.1, 162.2; 19 F NMR (376 MHz, chloroform-d) δ -61.73. EXAMPLE 8. SYNTHESIS OF N-(3-CHLORO-4-(TRIFLUOROMETHYL)PHENYL)-2,5-DIMETHYL-4- (PIPERAZINE-1-CARBONYL)-1H-PYRROLE-3-SULFONAMIDE (Compound 20) [0120] To a solution of tert-Butyl 4-(4-(N-(3-chloro-4- (trifluoromethyl)phenyl)sulfamoyl)-2,5-dimethyl-1H-pyrrole-3 -carbonyl)piperazine-1- carboxylate (20 mg, 0.035 mmol) in CH 2 Cl 2 (2 mL) was added concentrated hydrochloric acid (1 mL). The deprotection was stirred at rt for 3 h and neutralized with 1 N sodium hydroxide and extracted with CH 2 Cl 2 (3 × 3 mL). The combined organic layers were evaporated and purified by C-18 flash chromatography (water/MeOH) to afford the amide product as an off-white solid (25 mg, 0.054 mmol, 42% yield). [0121] 1 H NMR (400 MHz, Methanol-d 4 ) δ 2.37 (s, 3H), 2.44 (s, 3H), 2.73 (t, J = 5.0 Hz, 4H), 2.95 (t, J = 5.0 Hz, 4H), 7.60 (ddd, J = 0.9, 2.0, 8.6 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H); 13 C NMR (100 MHz, Methanol-d 4 ) δ δ 11.0, 11.5, 44.3, 45.4, 110.0, 114.2, 116.8, 121.0, 122.3 (q, J = 31.9 Hz), 123.0 (q, J = 272.7 Hz), 127.9 (q, J = 5.4 Hz), 132.3 (q, J = 1.8 Hz), 133.4, 134.9, 143.1, 164.0. EXAMPLE 9. SYNTHESIS OF N-(3-CHLORO-4-(TRIFLUOROMETHYL)PHENYL)-2,5- DIMETHYL-4-(3,3,4,4-TETRAFLUOROPYRROLIDINE-1-CARBONYL)-1H-PY RROLE- 3-SUFLONAMIDE (Compound 27) [0122] To a solution of 4-(N-(3-chloro-4-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.25 mmol) in DMF (2 mL) was added PyBOP (195 mg, 0.38 mmol, 1.5 equiv.). After 10 mins, 2,2,3,3-tetrafluoropyrrolidine (72 mg, 0.50 mmol, 2.0 equiv.) was added. The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by flash chromatography (EtOAc/hexanes) to afford amide as white solid (21 mg, 0.25 mmol, 16% yield). [0123] 1 H NMR (400 MHz, CDCl 3 ) δ 2.21 (s, 3H), 2.30 (s, 3H), 3.78-4.29 (m, 4H), 7.22 (d, J = 8.5 Hz, 1H) 7.43 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.63 (s, 1H), 8.02, (s, 1H); HPLC purity = 98%. EXAMPLE 10. SYNTHESIS OF 4-(N-(3-CHLORO-4- (TRIFLUOROMETHYL)PHENYL)SULFAMOYL)-N-ETHYL-2,5-DIMETHYL-1H- PYRROLE-3-CARBOXAMIDE (Compound 33). [0124] To a solution of 4-(N-(3-chloro-4-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (60 mg, 0.15 mmol) in DMF (2 mL) was added PyBOP (117 mg, 0.23 mmol, 1.5 equiv.). After 10 mins, ethylamine solution (1 M in THF, 0.3 mL, 0.30 mmol, 2.0 equiv.) was added. The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by flash chromatography (EtOAc/hexanes) to afford amide as white solid (54 mg, 0.13 mmol, 84% yield). [0125] NMR (400 MHz, Acetone-D 6 ) δ 1.21 (t, J= 7.2 Hz, 3H), 2.30 (s, 3H), 2.33 (s, 3H), 3.42 (m, 2H), 7.35 (d, J = 8.6 Hz, 1H), 7.51 (d, J= 1.8 Hz, 1H), 7.71 (d, J= 8.6 Hz, 1H), 9.73 (s, 1H), 10.44 (s, 1H); 19 F NMR (376 MHz) δ -62.2; HPLC purity = 99 %. EXAMPLE 11. SYNTHESIS OF 4-(3,3-DIFLUOROPYRROLIDINE-1-CARBONYL)-2,5- DIMETHYL-N-)4-(PENTAFLUORO-I6-SULFANEYL)PHENYL)1H-PYRROLE-3- SULFONAMIDE (Compound 28) [0126] To a solution of methyl-4-(chlorosulfonyl)-2,5-dimethyl-1H-pyrrole-3- carboxylate (231 mg, 0.91 mmol) in DCE cooled in an ice bath was added 4- (sulfurpentafluoro)aniline (311 mg, 1.59 mmol, 1 equiv.) and the reaction was stirred for 18 h, slowly warming to rt. The solvents were removed in vacuo and the residue purified by flash chromatography (EtOAc/hexanes) to afford the sulfonamide product as a pink solid (101 mg, 0.92 mmol, 25% yield). [0127] 1 H NMR (400 MHz, CDCl 3 ) δ 2.39 (s, 3H), 2.40 (s, 3H), 3.89 (s, 3H), 7.23 (d, J= 8.5 Hz, 2H), 7.60 (d, J= 9.0 Hz, 2H), 8.19 (s, 1H), 8.76 (s, 1H). [0128] Methyl 2,5-dimethyl-4-(sulfurpentafluoro)phenyl)sulfamoyl)-1H-pyrro le-3- carboxylate (450 mg, 1.05 mmol) was dissolved in THF:MeOH (10 mL, 2:1) and lithium hydroxide (50.4 mg, 2.10 mmol, 2.0 equiv.) added and the reaction stirred at 60 °C for 72 h then cooled to rt. The reaction was acidified with 1 M aqueous HCl and the mixture extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography (MeOH/DCM) to afford the carboxylic acid product as a white solid (127 mg, 0.3 mmol, 29% yield). [0129] 1 H NMR (400 MHz, MeO-D 4 ) δ 2.34 (s, 6H), 7.25 (d, J=8.0 Hz, 2H), 7.57 (d, J=9 Hz, 2H). [0130] To a solution of 2,5-dimethyl-4-(N-(4-(sulfurpentafluoro)phenyl)sulfamoyl)- 1H-pyrrole-3-carboxylic acid (76 mg, 0.18 mmol) in DMF (2 mL) was added PyBOP (141 mg, 0.27 mmol, 1.5 equiv.). After 10 mins, 3,3-difluoropyrrolidine (39 mg, 0.36 mmol, 2.0 equiv.) was added. The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by flash chromatography (EtOAc/hexanes) to afford the amide product as a white solid (20 mg, 0.04 mmol, 20% yield). [0131] 1 H NMR (400 MHz, CDCl 3 ) δ 2.15 (s, 3H), 2.21 (s, 3H), 2.31-2.51 (bm, 2H), 3.65 (bm, 2H), 3.91 (bs, 2H), 7.32 (d, J =8.9 Hz, 2H), 7.60 (d, J =9.0 Hz, 2 H), 7.97 (bs, 1H), 8.31 (bs, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 11.9, 12.0, 34.3, 43.4, 46.2, 52.7, 55.2, 115.2, 127.0, 127.5, 128.4, 130.2, 133.5, 141.1, 150.1, 167.0; HPLC purity = 99%. EXAMPLE 12. SYNTHESIS OF N-(3-CHORO-4-METHYLPHENYL)-2,5-DIMETHYL-4- (PYRROLIDNE-1-CARBONYL)-1H-PYRROLE-3-SULFONAMIDE (Compound 31) [0132] To a solution of Methyl 4-(chlorosulfonyl)-2,5-dimethyl-1H-pyrrole-3- carboxylate (356 mg, 1.4 mmol) in DCE (14 mL) cooled in an ice bath was added 3-chloro-4- methylaniline (198 mg, 1.4 mmol, 1 equiv.) and the reaction was stirred for 18 h, slowly warming to rt. The solvents were removed in vacuo and the residue purified by flash chromatography (EtOAc/hexanes) to afford product as a white solid (465 mg, 1.3 mmol, 92% yield). [0133] 1 H NMR (400 MHz, CDCl 3 ) δ 2.27 (s, 3H), 2.34 (s, 3H), 2.39 (s, 3H), 3.90 (s, 3H), 6.98 (dd, J =8.1, 2.1 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.18 (d, J =2.5 Hz, 1H), 8.07 (bs, 1H), 8.36 (s, 1H). [0134] Methyl 4-(N-(3-chloro-4-methylphenyl)sulfamoyl)-2,5-dimethyl-1H-pyr role- 3-carboxylate (450 mg, 1.3 mmol) was dissolved in THF:MeOH (14 mL, 2:1) and lithium hydroxide (67.2 mg, 2.80 mmol, 2.0 equiv.) added and the reaction stirred at 60 °C for 72 h then cooled to rt. The reaction was acidified with 1 M aqueous HCl and the mixture extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography (MeOH/DCM) to afford the acid product as a white solid (285 mg, 0.83 mmol, 66% yield). [0135] 1 H NMR (400 MHz, MeO-D 4 ) δ 2.24 (s, 3H), 2.26 (s, 3H), 2.37 (s, 3H), 6.91 (d, J= 8.2 Hz, 1H), 7.10 (d, J= 8 Hz, 1H), 7.16 (s, 1H). [0136] To a solution of 4-(N-(3-chloro-4-methylphenyl)sulfamoyl)-2,5-dimethyl-1H- pyrrole-3-carboxylic acid (285 mg, 0.83 mmol) in DMF (2 mL) was added PyBOP (648 mg, 1.25 mmol, 1.5 equiv.). After 10 mins, pyrrolidine (117 mg, 1.64 mmol, 2.0 equiv.) was added. The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by flash chromatography (EtOAc/hexanes) to afford the amide product as a white solid (158 mg, 0.39 mmol, 48% yield). [0137] 1 H NMR (400 MHz, CDCl 3 ) 1.86 (bm, 2H), 1.94 (m, 2H), 2.13 (s, 3H), 2.16 (s, 3H), 2.25 (s, 3H), 3.36 (t, J= 6.6 Hz, 2H), 3.55 (bm.2H). EXAMPLE 13. SYNTHESIS OF N-(3-CHLORO-4-(TRIFLUOROMETHYL)PHENYL)- 2,5-DIETHYL-4-(PYRROLIDINE-1-CARBONYL)-1H-PYRROLE-3-SULFONAM IDE (Compound 34) [0138] Methyl 4-(N-(4-chloro-3-(trifluoromethyl)phenyl)sulfamoyl)-2,5-dime thyl- 1H-pyrrole-3-carboxylate (93 mg, 0.23 mmol) was dissolved in THF:MeOH (3 mL, 2:1) and lithium hydroxide (11 mg, 0.46 mmol, 2.0 equiv.) added and the reaction stirred at 60 °C for 72 h then cooled to rt. The reaction was acidified with 1 M aqueous HCl and the mixture extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography (MeOH/DCM) to afford product as a white solid (58 mg, 0.15 mmol, 65% yield). [0139] To a solution of 4-(N-(4-chloro-3-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (50 mg, 0.13 mmol) in DMF (2 mL) was added PyBOP (104 mg, 0.20 mmol, 1.5 equiv.). After 10 mins, 3,3-difluoropyrrolidine (28 mg, 0.26 mmol, 2.0 equiv.) was added. The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by flash chromatography (EtOAc/hexanes) to afford the amide product as a white solid (23 mg, 0.047 mmol, 38% yield). [0140] MP = 92-106 ºC; 1 H NMR (500 MHz, Acetone-D 6 ) δ 2.17 (s, 3H), 2.22 (s, 3H), 2.47 (bm, 2H), 3.66 (bm, 2H), 3.73-4.13 (bm, 2H), 7.49 (dd, J =, 1H), 7.55 (d, J = , 1H), 7.70 (d, J =, 1H), 8.52 (s, 1H), 10.50 (s, 1H); 19 F NMR (376 MHz) δ -63.2; HPLC purity = 99%. EXAMPLE 14. SYNTHESIS OF N-(3,5-DICHLORO-4- (TRIFLUOROMETHYL)PHENYL)-4-(3,3-DIFLUOROPYRROLIDINE-1-CARBON YL)- 2,5-DIMETHYL-1H-PYRROLE-3-SULFONAMIDE (Compound 35) [0141] To a solution of methyl 4-(chlorosulfonyl)-2,5-dimethyl-1H-pyrrole-3- carboxylate (250 mg, 0.993 mmol) in DCE (12 mL) cooled in an ice bath was added 3,5- dichloro-4-(trifluoromethyl)aniline (228 mg, 0.993 mmol, 1 equiv.) and the reaction was stirred for 18 h, slowly warming to rt. The solvents were removed in vacuo and the residue purified by flash chromatography (EtOAc/hexanes) to afford the sulfonamide product as a white solid (413 mg, 0.928 mmol, 93% yield). [0142] Mp = 202-228 ºC; 1 H NMR (500 MHz, Acetone-D 6 ) δ 2.37 (s, 3H), 2.52 (s, 3H), 3.85 (s, 3H), 7.44 (s, 2H), 9.15 (s, 1H), 10.88 (bs, 1H); 13 C NMR (101 MHz, Acetone- D 6 ) δ 12.9, 13.5, 51.9, 110.2, 116.5, 120.6, 122.4, 125.1, 135.3, 136.4, 137.2, 144.1, 165.3; 19 F NMR (376 MHz) δ -55.1 [0143] Methyl 4-(N-(3,5-dichloro-4-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylate (262 mg, 0.6 mmol) was dissolved in THF:MeOH (9 mL, 2:1) and lithium hydroxide (28.8 mg, 1.20 mmol, 2.0 equiv.) added and the reaction stirred at 60 °C for 72 h then cooled to rt. The reaction was acidified with 1 M aqueous HCl and the mixture extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography (MeOH/DCM) to afford the carboxylic acid product as a white solid (113 mg, 0.26 mmol, 44% yield). [0144] Mp = 214–218 ºC; 1 H NMR (400 MHz, MeO-D 4 ) δ 2.37 (s, 3H), 2.45 (s, 3H), 7.28 (s, 2H); 13 C NMR (101 MHz, MeO-D 6 ) δ 12.8, 13.4, 111.1, 116.2, 120.9 (q, ), 121.3, 123.0, 125.2, 127.4, 135.8, 136.8, 138.0, 144.3, 167.8; 19 F NMR (376 MHz) δ -56.3; FTIR (neat): 3307, 2916, 2848, 1639, 1291, 1117. [0145] To a solution of 4-(N-(3,5-dichloro-4-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (56 mg, 0.13 mmol) in DMF (2 mL) was added PyBOP (104 mg, 0.20 mmol, 1.5 equiv.). After 10 mins, 3,3-difluoropyrrolidine (28 mg, 0.26 mmol, 2.0 equiv.) was added. The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by flash chromatography (EtOAc/hexanes) to afford the amide product as a white solid (16 mg, 0.031 mmol, 24% yield). [0146] Mp = 119–128 ºC; 1 H NMR (500 MHz, Acetone-D 6 ) δ 2.16 (s, 3H), 2.43 (s, 3H), 3.62 (bm, 2H), 3.69-4.09 (bm, 4H), 7.46 (s, 2H), 10.62 (bs, 1H). EXAMPLE 15. SYNTHESIS OF N-(3-CCHLORO-4-CYCLOPROPYLPHENYL)-4-(3,3- DIFLUOROPYRROLIDINE-1-CARBONYL)-2,5-DIMETHYL-1H-PYRROLE-3- SULFONAMIDE (Compound 36) [0147] To a solution of methyl 4-(chlorosulfonyl)-2,5-dimethyl-1H-pyrrole-3- carboxylate (98 mg, 0.39 mmol) in DCE (8 mL) cooled in an ice bath was added 3-chloro-4- cyclopropylaniline (65 mg, 0.39 mmol, 1 equiv.) and the reaction was stirred for 18 h, slowly warming to rt. The solvents were removed in vacuo and the residue purified by flash chromatography (EtOAc/hexanes) to afford the sulfonamide product as a white solid (120 mg, 0.31 mmol, 80% yield. [0148] Mp =119–135 ºC; 1 H NMR (400 MHz, CDCl 3 ) δ 0.60 (m, 2H), 0.95 (m, 2H), 2.07 (m, 1H), 2.32 (s, 3H), 2.38 (s, 3H), 3.88 (s, 3H), 6.55 (d, J= , 1H), 6.97 (dd, J=, 1H), 7.17 (d, J=, 1H), 8.28 (s, 1H), 8.38 (s, 1H); 3 C NMR (101 MHz) δ 8.0, 12.9, 14.2, 51.9, 109.7, 117.1, 120.2, 122.0, 126.6, 134.4, 135.4, 136.6, 137.4, 165.3; FTIR (neat): 3275 ,3160, 2950, 1683, 1448, 1230, 1190 cm -1 . [0149] Methyl 4-(N-(3-chloro-4-cyclopropylphenyl)sulfamoyl)-2,5-dimethyl-1 H- pyrrole-3-carboxylate (65 mg, 0.17 mmol) was dissolved in THF:MeOH (3 mL, 2:1) and lithium hydroxide (8.2 mg, 0.34 mmol, 2.0 equiv.) added and the reaction stirred at 60 °C for 72 h then cooled to rt. The reaction was acidified with 1 M aqueous HCl and the mixture extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography (MeOH/DCM) to afford the carboxylic acid product as a white solid (34 mg, 0.092 mmol, 54% yield). [0150] Mp = 178–190 ºC (Dec); 1 H NMR (400 MHz, MeO-D 4 ) δ 0.57 (m, 2H), 0.92 (m, 2H), 2.04 (m, 1H), 2.27 (s, 3H), 2.36 (s, 3H), 6.75 (d, J= , 1H), 6.90 (dd, J= , 1H), 7.18 (d, J-, 1H). [0151] To a solution of 4-(N-(3-Chloro-4-cyclopropylphenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (17 mg, 0.05 mmol) in DMF (2 mL) was added PyBOP (39 mg, 0.075 mmol, 1.5 equiv.). After 10 mins, 3,3-difluoropyrrolidine (11 mg, 0.10 mmol, 2.0 equiv.) in THF (0.5 mL) was added. The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by flash chromatography (EtOAc/hexanes) to afford the amide product as a white solid (13 mg, 0.028 mmol, 62% yield). [0152] Mp = 90–107 ºC 1 H NMR (500 MHz, Acetone-D 6 ) ; 13 C NMR (101 MHz, CDCl 3 ) δ 19 F NMR (376 MHz) δ FTIR (neat): HRMS (m/z): calcd; (98% purity). EXAMPLE 16. SYNTHESIS OF N-(3-CHLORO-4-(TRIFLUOROMETHYL)PHENYL)- 2,5-DIETHYL-4-(PYRROLIDINE-1-CARBONYL)-1H-PYRROLE-3-SULFONAM IDE (Compound 39) [0153] To a solution of 4-(N-(3-chloro-4-(trifluoromethyl)phenyl)sulfamoyl)-2,5- diethyl-1H-pyrrole-3-carboxylic acid (27 mg, 0.064 mmol) in DMF (2 mL) was added PyBOP (50 mg, 0.096 mmol, 1.5 equiv.). After 10 mins, pyrrolidine (9.1 mg, 0.128 mmol, 2.0 equiv.) in THF (0.5 mL) was added. The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by flash chromatography (EtOAc/hexanes) to afford the amide product as a white solid (14 mg, 0.029 mmol, 46% yield). EXAMPLES 17. SYNTHESIS OF N-(3-CHLORO-5-(TRIFLUOROMETHYL)PHENYL)-4- (3,3-DIFLUOROPYRROLIDINE-1-CARBONYL)-2,5-DIMETHYL-1H-PYRROLE -3- SULFONAMIDE (Compound 40) [0154] To a solution of Methyl 4-(chlorosulfonyl)-2,5-dimethyl-1H-pyrrole-3- carboxylate (90 mg, 0.36 mmol, 1 equiv.) in DCE (4 mL) cooled in an ice bath was added 3- chloro-4-cyclopropylaniline (65 mg, 0.36 mmol, 1 equiv.) and the reaction was stirred for 18 h, slowly warming to rt. The solvents were removed in vacuo and the residue purified by flash chromatography (EtOAc/hexanes) to afford the sulfonamide product as a white solid (132 mg, 0.321 mmol, 90% yield). [0155] Mp = 226–235 ºC; 1 H NMR (400 MHz, Acetone-D 6 ) δ 2.36 (s, 3H), 2.43 (s, 3H), 3.86 (s, 3H), 7.39 (s, 1H), 7.49 (s, 1H), 7.54 (s, 1H) 8.94 (s, 1H), 10.79 bs, 1H); 13 C NMR (101 MHz) δ 12.7, 13.5, 51.9, 110.2, 115.3, 116.8, 122.9, 123.6, 125.6, 132.9, 133.3, 135.9, 142.4, 165.6; 19 F NMR (376 MHz) -63.6; FTIR (neat): 3266, 2922, 1672, 1448, 1319 cm -1 . [0156] Methyl 4-(N-(3-chloro-5-(trifluoromethyl)phenyl)sulfamoyl)-2,5-dime thyl- 1H-pyrrole-3-carboxylate (92 mg, 0.22 mmol, 1 equiv.) was dissolved in THF:MeOH (3 mL, 2:1) and lithium hydroxide (10.6 mg, 0.44 mmol, 2.0 equiv.) added and the reaction stirred at 60 °C for 72 h then cooled to rt. The reaction was acidified with 1 M aqueous HCl and the mixture extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography (MeOH/DCM) to afford the carboxylic acid product as a white solid (40 mg, 0.22 mmol, quantitative yield). [0157] Mp = 194–206 ºC (Dec); 1 H NMR (400 MHz, MeO-D 4 ) δ 2.34 (s, 3H), 7.33 (s, 1H), 7.36 (t, J= , 1H), 7.40 (s, 1H) 13 C NMR (101 MHz, MeO-D 4 ) δ; 19 F NMR (376 MHz) δ -64.6; FTIR (neat): 3303, 2917, 2848, 1451, 1321, 1126 cm -1 ; HRMS (ESI) m/z calcd for C 14 H 11 N 2 O 4 SF 3 Cl [M-H]- 395.01584; found 395.00848. [0158] To a solution of 4-(N-(3-chloro-5-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (25 mg, 0.063 mg, 1 equiv.) in DMF (2 mL) was added PyBOP (50 mg, 0.094 mmol, 1.5 equiv.). After 10 mins, 3,3-difluoropyrrolidine (13.5 mg, 0.126 mmol, 2.0 equiv.) in THF (0.5 mL) was added. The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by flash chromatography (EtOAc/hexanes) to afford the amide product as a white solid (14 mg, 0.029 mmol, 48% yield). [0159] Mp = 182–185ºC (Dec); 1 H NMR (500 MHz, Acetone-D 6 ) δ 2.17 (s, 3H), 2.28 (s, 3H), 2.48 (bm, 2H), 3.54 (bm, 1H), 7.43 (s, 1H), 7.54 (s, 1H), 7.56 (s, 1H); 13 C NMR (126 MHz, Acetone-D 6 ) δ 11.6, 11.7, 33.5, 35.1, 43.9, 46.7, 53.1, 55.1, 115.0, 116.4, 121.2, 123.1, 124.7, 125.3, 132.7, 134.3, 135.7, 142.4, 167.0; 19 F NMR (376 MHz) δ -63.6; FTIR (neat): 3386, 3162, 2916, 2848, 1602, 1576, 1319, 1124; HRMS (ESI) m/z calcd for C 18 H 16 N 3 O 3 SF 5 Cl [M-H]- 484.05993; found 484.05272. EXAMPLE 18. SYNTHESIS OF N-(2-BROMO-5-CHLORO-4- (TRIFLUOROMETHYL)PHENYL)-4-(3,3-DIFLUOROPYRROLIDINE-1-CARBON YL)- 2,5-DIMETHYL-1H-PYRROLE-3-SULFONAMIDE (Compound 41) [0160] Methyl 4-(chlorosulfonyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (90 mg, 0.36 mmol) in DCE (4 mL) cooled in an ice bath was added 2-bromo-5-chloro-4- (trifluoromethyl)aniline (99 mg, 0.36 mmol, 1 equiv.) and the reaction was stirred for 18 h, slowly warming to rt. The solvents were removed in vacuo and the residue purified by flash chromatography (EtOAc/hexanes) to afford the sulfonamide product as a white solid (129 mg, 0.263 mmol, 74% yield). [0161] Mp = 168 –204 ºC (Dec); 1 H NMR (400 MHz, CDCl 3 ) δ 2.41 (s, 3H), 2.56 (s, 3H), 3.87 (s, 3H), 7.76 (s, 1H), 7.80 (s, 1H), 8.46 (s, 1H), 8.76 (s, 1H); 13 C NMR (101 MHz) δ 13.2, 14.1, 51.9, 110.1, 116.6, 120.3, 120.8, 123.5, 123.9, 131.8, 132.3, 135.2, 136.2, 140.6, 164.1; 19 F NMR (376 MHz) δ -62.2; FTIR (neat): 3199, 2117, 2923, 2852, 1690, 1577, 1306, 1107 cm -1 ; HRMS (ESI) m/z calcd for C 15 H 12 N 2 O 4 SF 3 ClBr [M-H]- 486.94200; found 486.93491. [0162] Methyl 4-(N-(2-bromo-5-chloro-4-(trifluoromethyl)phenyl)sulfamoyl)- 2,5- dimethyl-1H-pyrrole-3-carboxylate (96 mg, 0.20 mmol, 1 equiv.) was dissolved in THF:MeOH (3 mL, 2:1) and lithium hydroxide (9.6 mg, 0.40 mmol, 2.0 equiv.) added and the reaction stirred at 60 °C for 72 h then cooled to rt. The reaction was acidified with 1 M aqueous HCl and the mixture extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography (MeOH/DCM) to afford the carboxylic acid product as a white solid (35 mg, 0.074 mmol, 38% yield). [0163] 1 H NMR (400 MHz, MeO-D 4 ) δ 2.39 (s, 3H), 2.50 (s, 3H), 7.80 (s, 1H), 7.88 (s, 1H); 19 F NMR (376 MHz) δ -63.5; HRMS (ESI) m/z calcd for C 14 H 12 N 2 O 4 SF 3 ClBr [M+H]+ 473.92635; found 474.93413. [0164] To a solution of 4-(N-(2-bromo-5-chloro-4 (trifluoromethyl)phenyl)sulfamoyl)-2,5-dimethyl-1H-pyrrole-3 -carboxylic acid (18 mg, 0.038 mmol, 1 equiv.) in DMF (2 mL) was added PyBOP (30 mg, 0.057 mmol, 1.5 equiv.). After 10 mins, difluoropyrrolidine (8.1 mg, 0.076 mmol, 2.0 equiv.) in THF (0.5 mL) was added. The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by flash chromatography (EtOAc/hexanes) to afford the amide product as a white solid (8 mg, 0.01 mmol, 40% yield). EXAMPLE 19. SYNTHESIS OF N-(4-CHLORO-2-(TRIFLUOROMETHYL)PHENYL)-4- (2,2-DIFLUOROPYRROLIDINE-1-CARBONYL)-2,5-DIMETHYL-1H-PYRROLE -3- SULFONAMIDE (Compound 42) [0165] To a solution of methyl 4-(chlorosulfonyl)-2,5-dimethyl-1H-pyrrole-3- carboxylate (93 mg, 0.37 mmol, 1 equiv.) in DCE (4 mL) cooled in an ice bath was added 4- chloro-2-(trifluoromethyl)aniline (72.3 mg, 0.37 mmol, 1 equiv.) and the reaction was stirred for 18 h, slowly warming to rt. The solvents were removed in vacuo and the residue purified by flash chromatography (EtOAc/hexanes) to afford the sulfonamide product as a white solid (65 mg, 0.16 mmol, 43% yield). [0166] Mp= 159–173 (Dec); 1 H NMR (400 MHz, Acetone-D 4 ) δ 2.41 (s, 3H), 2.47 (s, 3H), 3.83 (s, 3H), 7.63 (m, 3H), 8.73 (s, 1H), 10.97 (s, 1H); 13 C NMR (101 MHz, Acetone-D 6 ) δ; 12.6, 13.6, 51.8, 110.1, 118.4, 122.7, 124.2, 125.4, 127.4, 129.6, 134.0, 134.8, 136.4, 137.2, 165.5; 19 F NMR (376 MHz) δ -61.2; FTIR (neat): 3247, 2954, 2922, 2851, 1681, 1311, 1116 cm -1 ; HRMS (ESI) m/z calcd for C 15 H 13 N 2 O 4 SF 3 Cl [M-H]- 409.03149; found 409.02426. [0167] Methyl 4-(N-(4-chloro-2-(trifluoromethyl)phenyl)sulfamoyl)-2,5-dime thyl- 1H-pyrrole-3-carboxylate (42 mg, 0.10 mmol, 1 equiv.) was dissolved in THF:MeOH (3 mL, 2:1) and lithium hydroxide (4.8 mg, 0.20 mmol, 2.0 equiv.) added and the reaction stirred at 60 °C for 72 h then cooled to rt. The reaction was acidified with 1 M aqueous HCl and the mixture extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography (MeOH/DCM) to afford the carboxylic acid product as a white solid (28 mg, 0.071 mmol, 69% yield). [0168] Mp = 188–204 (Dec); 1 H NMR (400 MHz, Acetone-D 6 ) δ 2.45 (s, 3H), 2.47 (s, 3H), 7.57-7.67 (m, 3H), 10.86 (s, 1H); 13 C NMR (101 MHz, Acetone-D 6 ) δ 12.6, 13.6, 118.7, 122.6, 124.3, 125.4, 127.4, 129.5, 133.9, 134.6, 136.7, 137.4, 166.3; 19 F NMR (376 MHz) δ -61.2; FTIR (neat): 3300, 2918, 2849, 1641, 1314, 1120 cm -1 . [0169] To a solution of 4-(N-(4-Chloro-2-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (21 mg, 0.053 mmol, 1 equiv.) in DMF (1 mL) was added PyBOP (41 mg, 0.079 mmol, 1.5 equiv.). After 10 mins, difluoropyrrolidine (11.4 mg, 0.106 mmol, 2.0 equiv.) in THF (0.5 mL) was added. The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by flash chromatography (EtOAc/hexanes) to afford the amide product as a white solid (15 mg, 0.031 mmol, 58% yield) . [0170] NMR (400 MHz, Acetone-D 6 ) δ 2.24 (s, 3H), 2.32 (s, 3H), 2.45 (m, 2H), 3.60-4.00 (m, 4H), 7.47 (d, J =8.99 Hz, 1H), 7.60 (dd, J = 8.88 Hz, 2.49 Hz, 1H), 7.67 (d, J= 2.56 Hz, 1H), 8.31 (s, 1H), 10.59 (s, 1H); 19 F NMR (376 MHz, Acetone-D 6 ) δ -71.8, -71.9, - 60.5; HPLC purity = 99 %. EXAMPLE 20. SYNTHESIS OF N-(2-CHLORO-6-(TRIFLUOROMETHYL)PHENYL)-4- (2,2-DIFLUOROPYRROLIDINE-1-CARBONYL)-2,5-DIMETHYL-1H-PYRROLE -3- SULFONAMIDE (Compound 43) [0171] To a solution of methyl 4-(chlorosulfonyl)-2,5-dimethyl-1H-pyrrole-3- carboxylate (93 mg, 0.37 mmol, 1 equiv.) in DCE (2 mL) cooled in an ice bath was added 3- chloro-2-(trifluoromethyl)aniline (72.3 mg, 0.37 mmol, 1 equiv.) and the reaction was stirred for 18 h, slowly warming to rt. The solvents were removed in vacuo and the residue purified by flash chromatography (EtOAc/hexanes) to afford the sulfonamide product as a white solid (135 mg, 0.32 mmol, 89% yield). [0172] Mp = 181–211 ºC (Dec); 1 H NMR (400 MHz, Acetone-D 6 ) δ 2.38 (s, 3H), 2.40 (s, 3H) 3.83 (s, 3H) 7.36 (d, J = 7.9 Hz, 1H), 7.48 (m, 2H), 8.86 (s, 1H), 10.84 (bs, 1H); 13 C NMR (101 MHz, Acetone-D 6 ) δ; 12.6, 13.6, 51.8, 110.1, 117.7, 119.9, 120.2, 122.1, 122.3, 123.1, 125.9, 128.5, 134.0, 135.4, 137.1, 139.6, 165.6; 19 F NMR (376 MHz) δ -54.6; FTIR (neat): 3281, 1679, 1450, 1285, 1157,1111 cm -1 ; HRMS (ESI) m/z calcd for C15H13N2O4SF3Cl [M-H]- 409.03149; found 409.02430. [0173] Methyl 4-(N-(2-chloro-6-(trifluoromethyl)phenyl)sulfamoyl)-2,5-dime thyl- 1H-pyrrole-3-carboxylate (83 mg, 0.2 mmol, 1 equiv.) was dissolved in THF:MeOH (3 mL, 2:1) and lithium hydroxide (9.6 mg, 0.40 mmol, 2.0 equiv.) added and the reaction stirred at 60 °C for 72 h then cooled to rt. The reaction was acidified with 1 M aqueous HCl and the mixture extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography (MeOH/DCM) to afford the carboxylic acid product as a white solid (27 mg, 0.068 mmol, 34% yield). Mp = 197–198 ºC (Dec); 1 H NMR (400 MHz, Acetone-D 6 ) δ 2.40 (s, 3H), 2.45 (s, 3H), 7.35 (d, J= 7.6 Hz, 1H), 7.44-7.52 (m, 2H), 10.84 (s, 1H); 13 C NMR (101 MHz, Acetone-D 6 ) δ 12.6, 13.6, 110.3, 117.9, 122.1, 123.1, 125.8, 128.4, 133.9, 134.3, 135.2, 137.4, 139.8, 166.3; 19 F NMR (376 MHz) δ -54.6; FTIR (neat): 3287, 2916, 2848, 1643, 1456, 1201 cm -1 . [0174] To a solution of 4-(N-(2-chloro-6-(trifluoromethyl)phenyl)sulfamoyl)-2,5- dimethyl-1H-pyrrole-3-carboxylic acid (24 mg, 0.060 mmol, 1 equiv.) in DMF (1 mL) was added PyBOP (47 mg, 0.09 mmol, 1.5 equiv.). After 10 mins, difluoropyrrolidine (12.9 mg, 0.12 mmol, 2.0 equiv.) in THF (0.5 mL) was added. The reaction was stirred at rt for 30 h, the solvent removed and the residue purified by flash chromatography (EtOAc/hexanes) to afford the amide product as a white solid (25 mg, 0.051 mmol, 85% yield). Mp = 167–174 ºC (Dec); 1 H NMR (400 MHz, (CD 3 ) 2 CO) δ 2.12 (s, 3H), 2.24 (s, 3H), 2.47 (m, 2H), 3.62-4.02 (m, 4H), 7.21 (m, 1H), 7.47 (m, 2H), 8.40 (m, 1H), 10.53 (m, 1H); 19 F NMR (376 MHz, (CD 3 ) 2 CO) δ -73.7, -71.9, -54.9; FTIR (neat): 3264, 2919, 2849, 1615, 1447, 1286 cm -1 ; HPLC purity = 99%. EXAMPLE 21. SYNTHESIS OF ETHYL 2-OXO-5-(TRIFLUOROMETHOXY)-4'H-SPIRO[INDOLINE- 3,5'-ISOXAZOLE]-3'-CARBOXYLATE (Compound 25) Step I: Synthesis of 3-Hydroxy-5-(trifluoromethoxy)-3-((trimethylsilyl)methyl)ind olin-2-one [0175] A solution of (trimethylsilyl)methyl)magnesium chloride (1 molar (M) in THF, 2.60 mL, 2.60 mmol, 2.0 equiv.) was added to a cold (-78 °C) suspension of 5- (trifluoromethoxy)indoline-2,3-dione (300.0 mg, 1.30 mmol) in diethyl ether (15 mL). The reaction was stirred at -78 °C then allowed to warm to rt. Once warmed to rt, the reaction was quenched with methanol and the reaction adsorbed onto Celite and purified by flash chromatography to afford the product as an off-white solid (237 mg, 0.742 mmol, 42% yield). R f = 0.4 (50% EtOAc in hexanes). [0176] 1 H NMR (400 MHz, chloroform-d) δ 1.73 (s, 2H), 7.10 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H); Step II: Synthesis of 3-Methylene-5-(trifluoromethoxy)indolin-2-one [0177] To a cold (-78 °C) solution of 3-hydroxy-5-(trifluoromethoxy)-3- ((trimethylsilyl)methyl)indolin-2-one (225 mg, 0.705 mmol) in CH 2 Cl 2 (15 mL) was added boron trifluoride diethyl etherate (0.45 mL, 3.52 mmol, 5.0 equiv.). The reaction was stirred at -78 °C for 2 h then warmed to 0 °C for 1 h, poured into saturated, aqueous NaHCO3 (25 mL) and extracted with diethyl ether (3 × 20 mL). The combined organic layers were dried with anhydrous MgSO4, evaporated and used without further purification (160 mg, 0.698 mmol, 99% yield). [0178] 1 H NMR (400 MHz, Chloroform-d) δ 6.12 (d, J = 0.9 Hz, 1H), 6.41 (s, 1H), 6.77 (d, J = 8.5 Hz, 1H), 7.06 (s, 1H), 7.27 (s, 1H). Step III: Synthesis of Ethyl 2-oxo-5-(trifluoromethoxy)-4'H-spiro[indoline-3,5'-isoxazole ]-3'- carboxylate (Compound 25) [0179] A solution of 3-methylene-5-(trifluoromethoxy)indolin-2-one (150 mg, 0.655 mmol) in CH 2 Cl 2 (1.5 mL) was added to flamed-dried and cooled (rt) molecular sieves (230 mg). A solution of (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (298 mg, 1.96 mmol, 3.0 equiv.) in CH 2 Cl 2 (15 mL) was added to the reaction through a tube containing Aberlyst A21 resin (2.4 g) at a rate of 0.16 mL/min. After complete addition, the reaction was stirred at rt for 15 h, adsorbed onto Celite and purified by flash chromatography to afford the spirocyclic product as a yellow oil (100 mg, 0.290 mmol, 44% yield). Compound 25 is obtained as a 1:1 racemic mixture. [0180] 1 H NMR (400 MHz, chloroform-d) δ 1.62 (t, J = 7.1 Hz, 3H), 3.75 (d, J = 18.3 Hz, 1H), 4.02 (d, J = 18.3 Hz, 1H), 4.62 (q, J = 7.1 Hz, 2H), 7.13 (d, J = 9.1 Hz, 1H), 7.38– 7.46 (m, 2H), 8.07 (br s, 1H). EXAMPLE 22. D3 DAR β-ARRESTIN RECRUITMENT ASSAY [0181] A D3 DAR β-arrestin cell line from DiscoverX (Fremont, CA) was used as described in the protocol below (Table 2). A CHO cell line engineered to overexpress the D3 DAR fused with a small 42-amino acid fragment of β-galactosidase called ProLink™ and a fusion protein consisting of β-arrestin and a larger N-terminal deletion mutant of β- galactosidase was used (DiscoverX catalogue number 93-0579C2). When the D3 DAR is activated by dopamine, it stimulates binding of β-arrestin to ProLink-tagged D 3 DARs, and the two complementary parts of β-galactosidase form a functional enzyme. When substrate (PathHunter® Detection reagent, DiscoverX 93-0001) is added, β-galactosidase hydrolyzes it and generates a chemiluminescent signal.
EXAMPLE 23. D2 DAR β-ARRESTIN RECRUITMENT ASSAY [0182] For a secondary-screen and selectivity assays, DAR PathHunter® β-arrestin GPCR cell lines from DiscoverX (Fremont, CA) were used. In the D2 DAR PathHunter® β- arrestin GPCR cell line, the D2 DAR is overexpressed and fused with a small 42-amino acid fragment of β-galactosidase called ProLink™ on a CHO cellular background expressing a fusion protein of β-arrestin and a larger N-terminal deletion mutant of β -galactosidase (“enzyme acceptor”). When the D2 DAR is activated by dopamine, it stimulates binding of β-arrestin to the ProLink-tagged DAR and the two complementary parts of β-galactosidase form a functional enzyme. When substrate (PathHunter TM Detection reagent) is added, β- galactosidase hydrolyzes it and generates a chemiluminescent signal. Table 3 summarizes the protocol for the D2 DAR β-arrestin recruitment assay. EXAMPLE 24. ADDITIONAL COMPOUNDS [0183] Table 4 shows compounds of Examples 1-21 with pharmacological data derived from the DiscoverX β-arrestin recruitment functional assay in Examples 22 and 23, and shows additional compounds prepared by the methods shown in Example 1. Table 4 shows further additional compounds which were prepared by the methods shown in Examples 1-21. Routine changes in starting materials and reaction conditions, readily apparent to those of one skilled in the art, were used to make the particular compounds disclosed in Table 4. A “*” is used to denote compounds with an IC 50 greater than 100 micromolar, a “**” indicates compound with an IC50 between 50 micromolar and 100 micromolar, a “***” denotes compounds with an IC 50 between 10 micromolar and 50 micromolar, a “****” denotes compounds with an IC50 less than 10 micromolar. A “+” is used to denote compounds with D3 DAR Imax (Imax = maximum inhibition) between 80% to 100%, “NA” indicates not active.
EXAMPLE 25. D3RADIOLIGAND BINDING ASSAY [0184] Compounds were tested for their ability to compete with the orthosteric radioligand [ 3 H]-methylspiperone for binding to the D3 DAR using HEK cells transiently transfected with the D3 DAR as described in the detailed protocol below presented in Table 5. Cells were cultured in Dulbecco’s modified Eagle’s Medium (Corning, catalogue no.10- 013) containing 10% FBS, 1,000 units/mL Penicillin, 1,000 mg/mL Streptomycin, 100 mM sodium pyruvate, 1 μg/mL Gentamicin, and 250 mg/mL G418. All cells were maintained at 37 °C in 5% CO 2 and 90% humidity. For radioligand binding assays cells were removed mechanically using calcium-free Earle’s balanced salt solution (EBSS). Intact cells were collected by centrifugation and then lysed with 5 mM Tris-HCl and 5 mM MgCl 2 at pH 7.4. Homogenates were centrifuged at 30,000 x g for 30 minutes. The membranes were re- suspended in EBSS (US Biological, catalogue no. E0249-05) pH 7.4 to a concentration of 16 µg/mL. For competition binding studies, membrane preparations were incubated for 90 minutes at room temperature with various concentrations of compound and a single concentration of [ 3 H]-methylspiperone (Perkin Elmer, NET856) in a reaction volume of 250 µL. Non-specific binding was determined in the presence of 4 μM (+)-butaclamol (Sigma- Aldrich, catalogue no. D033). Bound ligand was separated from unbound by filtration through GF/C filters using a PerkinElmer cell harvester and quantified on a Top-count (PerkinElmer). Ki values were determined using Cheng-Prusoff equation from observed IC 50 values and ligand Kd values from separate saturation experiments. EXAMPLE 26. ORTHOGONAL SCREENING ASSAYS [0185] BRET β-arrestin recruitment assay: As an orthogonal test using an unrelated assay of D2- or D3 DAR-mediated β-arrestin recruitment, an arrestin BRET assay was conducted. HEK293T cells transiently expressing D2-Rluc8, Arrestin3-mvenus and GRK2, or D3-Rluc8, Arrestin3-mvenus, and GRK3 were harvested with EBSS, plated in 96- well plates in Dulbecco's phosphate-buffered saline (DPBS) and incubated at rt for 45 min. Cells were incubated with 5 µM coelenterazine H (the substrate of Rluc8, Nanolight Technology, Pinetop AZ) for 5 min, then stimulated with the indicated concentrations of either sulpiride or a test compound of Formulae I, II or III in the presence of an EC80 concentration of DA (1 µM for D2 DAR and 30 nM for D3 DAR) for 5 min. BRET signal was determined by quantifying and calculating the ratio of the light emitted by mVenus (525 nm) over that emitted by RLuc8 (485 nm) using a PHERAstar FSX Microplate Reader (BMG Labtech). [0186] Go BRET activation assay: To determine if a test compound of Formulae I, II, or III displays functional selectivity (the ability to selectively activate one signaling pathway versus another), a G o BRET activation assay was utilized as described in the protocol below (Table 6). Briefly, HEK293T cells transiently expressing either the D2 DAR or D3 DAR and Gα oA -Rluc8, untagged-β 1 , and mVenus-γ 2 were harvested with EBSS-, plated in 96-well white plates at 20,000 cells/well in DPBS and incubated at RT for 45 min. Cells were incubated with 5 µM coelenterazine h (Nanolight Technology, Pinetop, AZ) for 5 min, then stimulated with the indicated concentrations of either sulpiride or a test compound of Formulae I, II, or III in the presence of an EC80 concentration of DA (1 µM for D2 DAR and 30 nM for D3 DAR) for 5 min. BRET signal was determined by quantifying and calculating the ratio of the light emitted by mVenus (525 nm) over that emitted by RLuc8 (485 nm) using a PHERAstar FSX Microplate Reader (BMG Labtech). Certain compounds have been tested in the D3 Go BRET activation assay and their activity is present in Table 7. A “*” is used to denote compounds with an IC 50 greater than 50 micromolar, a “**” denotes compounds with an IC50 between 10 micromolar and 50 micromolar, a “***” denotes compounds with an IC 50 between 1 micromolar and 10 micromolar, and “****” indicates and IC50 of less than 1 micromolar. A “+” indicates a detectable Imax of between 80% and 100%, a “++” indicates a detectable Imax of more than 100%, indicative of possible inverse agonist activity. NA means not active.
[0187] cAMP CAMYEL biosensor assay: HEK293 cells transiently expressing the D2 DAR or D3 DAR and the CAMYEL cAMP biosensor (yellow fluorescence protein-Epac- Rluc) were harvested with EBSS-, plated in 96-well white plates at 20,000 cells/well in DPBS and incubated at room temperature for 45 min. Cells were pretreated for 5 min with 10 μM forskolin and 10 μM propranolol (to block endogenous β-adrenergic receptors), then incubated with 5 µM coelenterazine h (Nanolight Technology, Pinetop, AZ) for 5 min, then stimulated with the indicated concentrations of either sulpiride or a test compound of Formulae I, II or III in the presence of an EC 80 concentration of DA (1 µM for D2 DAR and 30 nM for D3 DAR) for 5 min. BRET signal was determined by quantifying and calculating the ratio of the light emitted by mVenus (525 nm) over that emitted by RLuc8 (485 nm) using a PHERAstar FSX Microplate Reader (BMG Labtech). [0188] ERK1/2 Phosphorylation assay: ERK1/2 phosphorylation was measured using the Alphascreen SureFire Ultra ERK kit (PerkinElmer, Waltham, USA). CHO-K1 cells stably expressing either the D2 DAR or D3 DAR were seeded into 384-well small volume white plates at a density of 40,000 cells/well in serum-free Ham’s F12 media overnight. Cells were stimulated with the indicated concentrations of either sulpiride or a test compound of Formulae I, II or III in the presence of an EC 80 concentration of DA (1 µM for D2 DAR and 30 nM for D3 DAR) for 15 min, followed by cell lysis as specified by manufacture’s protocol. The plate was shaken for 10 min at RT, followed by the addition of Surefire activation buffer, Surefire reaction buffer, Alphascreen acceptor beads, and Alphascreen donor beads in ratios specified by the manufacturer. The plate was incubated in the dark for 2 h, then read using a PHERAstar FSX Microplate Reader (BMG Labtech). [0189] Mouse Plasma and Brain Tissue Sampling: The pharmacokinetic study was conducted by CRO Pharmaron (Beijing, China). The levels of cmp 17 in mouse plasma and brain tissue samples were assessed as follows. A single IP dose (40 mg/kg) of cmp 17 was administered to male CD1 mice. The formulation consisted of NMP/Solutol/PEG-400/normal saline (v/v/v/v, 10:5:30:55). Plasma and brain samples were collected 0.5 h, 1 h, 2 h, 4 h and 8 h post dose. Brain samples were homogenized at a ratio of 1:3 with PBS (W/V, 1:3). The desired serial concentrations of working solutions were achieved by diluting stock solution of analyte with 50% acetonitrile in water solution.10 µL of working solutions (0.5, 1, 2, 5, 10, 50, 100, 500, 1000, 10000 ng/mL) were added to 10 μL of the blank CD1 mouse plasma/brain homogenate to achieve calibration standards of 0.5~10000 ng/mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000, 10000 ng/mL) in a total volume of 20μL. Five quality control samples at 1 ng/mL, 2 ng/mL, 5 ng/mL, 100 ng/mL and 8000 ng/mL for plasma/brain homogenate were prepared independently of those used for the calibration curves.20μL standards, 20 μL QC samples and 20 μL unknown samples (10 µL plasma/brain homogenate with 10 µL blank solution) were added to 200 μL of acetonitrile containing IS mixture for precipitating protein respectively. Then the samples were vortexed for 30 s. After centrifugation at 4 °C, 4700 rpm for 15 min, the supernatant was diluted at a ratio of 1:2 with water, and 10 µL of diluted supernatant was injected into the LC/MS/MS system (SCIEX AB API 4000) for quantitative analysis. Three mice were used for each time point collected, and the data represent means ± SD.
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