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WO2015066344A1 - Agonistes du récepteur 5-ht2c et compositions et procédés d'utilisation - Google Patents

Agonistes du récepteur 5-ht2c et compositions et procédés d'utilisation Download PDF

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Publication number
WO2015066344A1
WO2015066344A1 PCT/US2014/063191 US2014063191W WO2015066344A1 WO 2015066344 A1 WO2015066344 A1 WO 2015066344A1 US 2014063191 W US2014063191 W US 2014063191W WO 2015066344 A1 WO2015066344 A1 WO 2015066344A1
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WIPO (PCT)
Prior art keywords
diazepino
hexahydro
indole
individual
selective
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2014/063191
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English (en)
Inventor
Graeme Semple
Dominic P. Behan
Konrad Feichtinger
Alan GLICKLICH
Andrew J. Grottick
Maria Matilde Sanchez KAM
Michelle Kasem
Juerg Lehmann
Albert S. Ren
Thomas O. Schrader
William R. Shanahan
Amy Siu-Ting Wong
Xiuwen Zhu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Arena Pharmaceuticals Inc
Original Assignee
Arena Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Arena Pharmaceuticals Inc filed Critical Arena Pharmaceuticals Inc
Publication of WO2015066344A1 publication Critical patent/WO2015066344A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems

Definitions

  • Obesity is a life-threatening disorder in which there is an increased risk of morbidity and mortality arising from concomitant diseases such as type II diabetes, hypertension, stroke, cancer, and gallbladder disease.
  • Obesity is now a major healthcare issue in the Western World and increasingly in some third world countries.
  • the increase in numbers of obese people is due largely to the increasing preference for high fat content foods but also the decrease in activity in most people' s lives.
  • Currently about 30% of the population of the USA is now considered obese.
  • BMI body mass index
  • BMI body mass that is muscle in relation to fat (adipose tissue).
  • obesity can also be defined on the basis of body fat content: greater than 25% in males and greater than 30% in females.
  • Kidney disease also called nephropathy
  • Diabetes occurs when the kidney' s "filter mechanism” is damaged and protein leaks into urine in excessive amounts and eventually the kidney fails. Diabetes is also a leading cause of damage to the retina at the back of the eye and increases risk of cataracts and glaucoma.
  • diabetes is associated with nerve damage, especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes complications are one of the nation' s leading causes of death.
  • the first line of treatment is to offer diet and life style advice to patients such as reducing the fat content of their diet and increasing their physical activity.
  • patients find this difficult and need additional help from drug therapy to maintain results from these efforts.
  • orlistat a drug that prevents absorption of fat by the inhibition of pancreatic lipase
  • sibutramine ReductilTM
  • side effects associated with these products may limit their long-term utility.
  • Treatment with Xenical is reported to induce gastrointestinal distress in some patients, while sibutramine has been associated with raised blood pressure in some patients.
  • Serotonin (5-HT) neurotransmission plays an important role in numerous physiological processes both in physical and in psychiatric disorders.
  • 5-HT has been implicated in the regulation of feeding behavior. 5-HT is believed to work by inducing a feeling of satiety, such that a subject with enhanced 5-HT stops eating earlier and fewer calories are consumed. It has been shown that a stimulatory action of 5-HT on the 5-HT 2 c receptor plays an important role in the control of eating and in the anti-obesity effect of d-fenfluramine. As the 5-HT 2C receptor is expressed in high density in the brain (notably in the limbic structures, extrapyramidal pathways, thalamus and hypothalamus i.e.
  • a selective 5-HT 2 c receptor agonist can be a more effective and safe anti-obesity agent.
  • 5-HT 2C knockout mice are overweight with cognitive impairment and susceptibility to seizure. It is believed that the 5-HT 2 c receptor may play a role in obsessive compulsive disorder, some forms of depression, and epilepsy. Accordingly, agonists can have anti-panic properties, and properties useful for the treatment of sexual dysfunction.
  • the 5-HT 2C receptor is a receptor target for the treatment of obesity and psychiatric disorders, and it can be seen that there is a need for selective 5-HT 2 c agonists which safely decrease food intake and body weight.
  • the 5-HT 2 c receptor is one of 14 distinct serotonin receptor subtypes.
  • Two receptors that are closely related to the 5-HT 2C receptor are the 5-HT 2A and 5-HT 2B receptors, which share considerable sequence homology. It is believed that activation of central 5-HT 2A receptors is a cause for a number of adverse central nervous system effects of nonselective serotonergic drugs including changes in perception and hallucination.
  • Activation of 5-HT 2B receptors located in the cardiovascular system is hypothesized to result in the heart valve disease and pulmonary hypertension associated with the use of fenfluramine and a number of other drugs that act via serotonergic mechanisms.
  • Lorcaserin (disclosed in PCT patent publication WO2003/086303) is an agonist of the 5-HT 2C receptor and shows effectiveness at reducing obesity in animal models and humans.
  • Arena Pharmaceuticals submitted a New Drug Application, or NDA, for lorcaserin to the US Food and Drug Administration (FDA).
  • the NDA submission is based on an extensive data package from lorcaserin' s clinical development program that includes 18 clinical trials totaling 8,576 patients.
  • the pivotal phase 3 clinical trial program evaluated nearly 7,200 patients treated for up to two years, and showed that lorcaserin consistently produced significant weight loss with excellent tolerability. About two-thirds of patients achieved at least 5% weight loss and over one-third achieved at least 10% weight loss.
  • lorcaserin was evaluated in a randomized, placebo-controlled, multi-site, double-blind trial of 604 adults with poorly controlled type 2 diabetes mellitus treated with oral hyperglycemic agents ("BLOOM-DM"). Analysis of the overall study results showed significant weight loss with lorcaserin, measured as proportion of patients achieving > 5% or > 10% weight loss at 1 year, or as mean weight change (Diabetes 60, Suppl 1, 2011). Lorcaserin significantly improved glycemic control in the overall patient population. Accordingly, in addition to being useful for weight management, lorcaserin is also useful for the treatment of type 2 diabetes.
  • Tobacco Fact Sheet No 339 Tobacco, www.who.int/mediacentre/factsheets/fs339/en/index.html. Updated July 2013. Accessed September 10, 2013). Tobacco use is directly related to cardiovascular disease, lung and other cancers, and chronic lower respiratory diseases (chronic bronchitis, emphysema, asthma, and other chronic lower respiratory diseases) (Health Effects of Cigarette Smoking. Centers for Disease Prevention website.
  • the prescribing information for both CHANTIX and ZYBAN include black box warnings.
  • the CHANTIX prescribing information carries a warning for serious neuropsychiatric events, to include symptoms of agitation, hostility, depressed mood changes, behavior or thinking that are not typical for the patient, and suicidal ideation or suicidal behavior (CHANTIX (varenicline) (package insert), New York, NY: Pfizer Labs, Division of Pfizer, Inc.; 2012).
  • the warning notes that a meta-analysis found cardiovascular events were infrequent, but some were reported more frequently in individuals treated with CHANTIX; the difference was not statistically significant
  • the ZYBAN prescribing information includes a similar black box warning for serious neuropsychiatric events during treatment as well as after discontinuation of treatment (ZYBAN (bupropion
  • weight gain is a well-recognized side effect of quitting smoking.
  • Smoking cessation leads to weight gain in about 80% of smokers.
  • the average weight gain in the first year after quitting is 4-5 kg, most of which is gained during the first 3 months. This amount of weight is typically viewed as a modest inconvenience compared with the health benefits of smoking cessation, but 10-20% of quitters gain more than 10 kg.
  • PCWG post-cessation weight gain
  • X is selected from O and S;
  • R 1 is selected from: C 1 -C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-Ci-C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: Ci-C 6 alkoxy, Ci-C 6 alkoxycarbonyl, Ci-C 6 alkylthio, Ci-C 6 alkylsulfonyl, aryloxy, halogen, and Ci-C 6 haloalkyl.
  • X 1 is selected from O and S;
  • R 11 is selected from: C 1 -C6 alkyl, optionally substituted with one or more substituents independently selected from: C 1 -C6 alkoxy, C 1 -C6 alkoxycarbonyl, and halogen;
  • R 12 and R 12b are each independently H, C3-C7 cycloalkyl or C 1 -C6 alkyl, wherein the C3-C7 cycloalkyl and C 1 -C6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, C 1 -C6 alkyl and C 1 -C6 alkoxy;
  • R 13 and R 13b are each independently H, C3-C7 cycloalkyl or C 1 -C6 alkyl, wherein the C3-C7 cycloalkyl and C 1 -C6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, C 1 -C6 alkyl and C 1 -C6 alkoxy;
  • n 0, 1, or 2;
  • R 14 is Ci-Ce alkyl
  • each R 14 is C 1 -C6 alkyl bonded to the same carbon, or two R 14 taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring; provided that if R 12a , R 12b , R 13a and R 13b are each H then n is 1 or 2.
  • each of R 25 and R 26 is independently hydrogen or Ci-C6 alkyl
  • R 27 is hydrogen, Ci-C6 alkyl or C 3 -C 7 cycloalkyl
  • R 28 is hydrogen or Ci-C6 alkyl
  • each of R 22 and R 23 is independently hydrogen or Ci-C6 alkyl optionally substituted with one or more halogens;
  • R 22 and R 23 taken together with the carbon they are bonded to form a three-, four-, five-, six- or seven-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy;
  • R 24 is hydrogen, halogen, hydroxy, C 3 -C 7 cycloalkyl, Ci-C6 alkoxy or Ci-C6 alkyl optionally substituted with Ci-C6 alkoxy;
  • R 21 is selected from the group consisting of:
  • C 1 -C6 alkyl optionally substituted with one or more substituents each of which is independently halogen, hydroxy, Ci-C6 alkoxy, amino, heteroarylamino, arylamino, C 1 -C6 dialkylamino, aryl, Ci-C6 alkoxycarbonyl, Ci-C6 alkylamino optionally substituted with Ci-C6 alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with Ci-C6 alkoxy, or C 3 -C 7 cycloalkyl optionally substituted with Ci-C6 alkoxy;
  • C 1 -C6 alkylamino optionally substituted with C 1 -C6 alkoxy or with hydroxy
  • C 1 -C6 dialkylamino optionally substituted with C 1 -C6 alkoxy or with hydroxy
  • arylamino
  • R 24 is hydrogen or halogen, at least one of R 21 , R 22 , R 23 , R 25 , R 26 R 27 and R 28 is other than hydrogen.
  • compositions comprising a compound provided herein and a
  • compositions comprising admixing a compound provided herein and a pharmaceutically acceptable carrier.
  • compositions comprising a compound provided herein and a pharmaceutically acceptable carrier.
  • compositions comprising admixing a compound provided herein a pharmaceutically acceptable carrier.
  • a method for reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT 2C receptor agonist.
  • Also provided is a method for aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT 2 c receptor agonist.
  • Also provided is a method for aiding in smoking cessation and preventing associated weight gain in an individual attempting to cease smoking and prevent weight gain comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT 2 c receptor agonist.
  • Also provided is a method for controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT 2 c receptor agonist.
  • Also provided is a method of treatment for nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT 2C receptor agonist.
  • Also provided is a method of reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT 2C receptor agonist.
  • Also provided is a method for reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT 2C receptor agonist.
  • composition comprising a selective 5-HT 2 c receptor agonist and at least one supplemental agent.
  • a selective 5-HT 2 c receptor agonist for use in combination with a supplemental agent.
  • a supplemental agent chosen from nicotine replacement therapies, for use in combination with a selective 5-HT 2 c receptor agonist.
  • Figure 1 shows a schematic of the study design used in the Phase 2 clinical trial described in Example 4.
  • Figures 2 and 3 show the baseline characteristics of subjects in the Phase 2 clinical trial.
  • Figure 4 shows the disposition of subjects from the Phase 2 clinical trial.
  • Figure 5 shows CO-confirmed 4-week CARs for Weeks 9 to 12 in the MITT population from the Phase 2 clinical trial
  • "n" in Figures 5-8 is the number of subjects that reported not smoking (not even a puff or other nicotine use) and exhibited an end-expiratory CO level of ⁇ 10 ppm.
  • Figure 6 shows CO-confirmed 4-week CARs for Weeks 5 to 8 in the MITT population.
  • Figure 7 shows CO-confirmed 4-week CARs for Weeks 5 to 12 in the MITT population.
  • Figure 8 shows CO-confirmed 4-week CARs for Weeks 3 to 12 in the MITT population.
  • Figure 9 shows the 7-day point prevalence smoking abstinence at Week 12 in the MITT population
  • "n" in Figure 9 is the number of subjects who were continuously abstinent for the 7-day period preceding a clinical visit and exhibited an end-expiratory CO level of ⁇ 10 ppm.
  • Figure 10 shows the change from baseline in number of cigarettes smoked at Week 12 in the MITT population.
  • Figure 11 shows the change from baseline in body weight (in kg) at Week 12 in the MITT population.
  • Figure 12 shows the change from baseline in body weight (in kg) at Week 12 for responders in the MITT population.
  • "Responders” in Figure 12 are subjects who had 4 weeks of continuous abstinence from Week 9 to Week 12 and exhibited an end-expiratory CO level of ⁇ 10 ppm.
  • Figure 13 shows the change from baseline in body weight (in kg) at Week 12 by responder status in the MITT population.
  • "Responders” in Figure 13 are subjects who had 4 weeks of continuous abstinence from Week 9 to Week 12 and exhibited an end-expiratory CO level of ⁇ 10 ppm.
  • Figure 14 shows the change from baseline in body weight (in kg) at Week 12 by baseline BMI in the MITT population.
  • Figure 15 shows the change from baseline in body weight (in kg) at Week 12 by baseline BMI in the MITT population.
  • Figure 16 shows the change from baseline in body weight (in kg) at Week 12 by baseline BMI and responder status in the MITT population.
  • "Responders" in Figure 16 are subjects who had 4 weeks of continuous abstinence from Week 9 to Week 12 and exhibited an end-expiratory CO level of ⁇ 10 ppm.
  • Figure 17 shows a summary of treatment-emergent adverse events in the Phase 2 clinical trial.
  • Figure 18 shows potency and efficacy of lorcaserin in human, rat, and monkey 5-HT 2A , 5-HT 2B , and 5- HT 2 c receptors.
  • Figure 19 shows differences in exposure and 5-HT 2 receptor selectivity in humans and rats.
  • Figure 20 shows a general synthetic scheme for preparing compounds provided herein.
  • Figure 21a shows an exemplary synthetic scheme for preparing intermediates useful for preparing compounds provided herein.
  • Figure 21b shows an exemplary synthetic scheme for preparing compounds provided herein.
  • Figure 21c shows another exemplary synthetic scheme for preparing compounds provided herein.
  • Figure 21d shows another exemplary synthetic scheme for preparing compounds provided herein.
  • Figure 22 shows another exemplary synthetic scheme for preparing compounds provided herein.
  • Figure 23 shows another exemplary synthetic scheme for preparing compounds provided herein.
  • Figure 24 shows an example of food intake 1 hour after dosing the 2 nd eluting enantiomer in example
  • Figure 25 shows an example of food intake 1 hour after dosing the 2 nd eluting enantiomer in example
  • Figure 26 shows an example of a synthetic scheme for preparing compounds provided herein.
  • Figure 27 shows plots of (a) food intake vs. dose, and (b) % inhibition of food intake vs. dose, in rats for compound 215.
  • Figure 28 shows plots of (a) food intake vs. dose, and (b) % inhibition of food intake vs. dose, in rats for compound 250.
  • agonist refers to a moiety that interacts with and activates a receptor, such as the 5-HT 2 c serotonin receptor, and initiates a physiological or pharmacological response characteristic of that receptor.
  • composition refers to a compound, including but not limited to, salts, hydrates, and solvates of a compound provided herein, in combination with at least one additional component.
  • composition refers to a composition comprising at least one active ingredient, such as a compound as described herein; including but not limited to, salts, hydrates, and solvates of compounds provided herein, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • active ingredient such as a compound as described herein
  • solvates of compounds provided herein whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • the term "individual” refers to a human.
  • An individual can be an adult or prepubertal (a child) and can be of any gender.
  • the individual can be a patient or other individual seeking treatment.
  • the methods disclosed herein can also apply to non-human mammals such as livestock or pets.
  • a "plurality of individuals” means more than one individual.
  • administering means to provide a compound or other therapy, remedy or treatment.
  • a health care practitioner can directly provide a compound to an individual in the form of a sample, or can indirectly provide a compound to an individual by providing an oral or written prescription for the compound.
  • an individual can obtain a compound by themselves without the involvement of a health care practitioner.
  • Administration of the compound may or may not involve the individual actually internalizing the compound. In the case where an individual internalizes the compound, the body is transformed by the compound in some way.
  • precribing means to order, authorize or recommend the use of a drug or other therapy, remedy or treatment.
  • a health care practitioner can orally advise, recommend or authorize the use of a compound, dosage regimen or other treatment to an individual.
  • the health care practitioner may or may not provide a prescription for the compound, dosage regimen or treatment.
  • the health care practitioner may or may not provide the recommended compound or treatment.
  • the health care practitioner can advise the individual where to obtain the compound without providing the compound.
  • a health care practitioner can provide a prescription for the compound, dosage regimen or treatment to the individual.
  • a health care practitioner can give a written or oral prescription to an individual.
  • a prescription can be written on paper or on electronic media such as a computer file, for example, on a hand-held computer device.
  • a health care practitioner can transform a piece of paper or electronic media with a prescription for a compound, dosage regimen or treatment.
  • a prescription can be called in (oral) or faxed in (written) to a pharmacy or a dispensary.
  • a sample of the compound or treatment can be given to the individual.
  • giving a sample of a compound constitutes an implicit prescription for the compound.
  • Different health care systems around the world use different methods for prescribing and administering compounds or treatments and these methods are encompassed by the disclosure.
  • a prescription can include, for example, an individual's name and/or identifying information such as date of birth.
  • a prescription can include, the medication name, medication strength, dose, frequency of administration, route of administration, number or amount to be dispensed, number of refills, physician name, and/or physician signature.
  • a prescription can include a DEA number or state number.
  • a healthcare practitioner can include, for example, a physician, nurse, nurse practitioner, physician assistant, clinician, or other related healthcare professional who can prescribe or administer compounds (drugs) for weight management, decreasing food intake, inducing satiety, and treating or preventing obesity.
  • a healthcare practitioner can include anyone who can recommend, prescribe, administer or prevent an individual from receiving a compound or drug including, for example, an insurance provider.
  • prevent refers to the prevention of the occurrence or onset of one or more symptoms associated with a particular disorder and does not necessarily mean the complete prevention of a disorder. For example, weight gain may be prevented even if the individual gains some amount of weight.
  • the terms “prevent,” “preventing,” and “prevention” refer to the administration of therapy on a prophylactic or preventative basis to an individual who may ultimately manifest at least one symptom of a disease or condition but who has not yet done so. Such individuals can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease. Alternatively, prevention therapy can be administered without prior identification of a risk factor, as a prophylactic measure. Delaying the onset of the at least one symptom can also be considered prevention or prophylaxis.
  • prevention may refer to prevention of weight gain associated with smoking cessation.
  • the salts, hydrates, and solvates described herein are pharmaceutically acceptable salts, hydrates, and solvates. It is understood that when the phrase “pharmaceutically acceptable salts, hydrates, and solvates” or the phrase “pharmaceutically acceptable salt, hydrate, or solvate” is used when referring to compounds described herein, it embraces pharmaceutically acceptable hydrates and/or solvates of the compounds, pharmaceutically acceptable salts of the compounds, as well as pharmaceutically acceptable hydrates and/or solvates of pharmaceutically acceptable salts of the compounds.
  • treat includes the administration of therapy to an individual who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition.
  • “treating” can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • treating a disorder does not necessarily mean a reduction in severity of one or more symptoms associated with a particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.
  • a method for treatment of obesity can result in weight loss; however, the weight loss does not need to be enough such that the individual is no longer obese. It has been shown that even modest decreases in weight or related parameters such as BMI, waist circumference and percent body fat, can result in improvement of health, for example, lower blood pressure, improved blood lipid profiles, or a reduction in sleep apnea.
  • a method for treatment of an addiction can result in a reduction in the number, frequency, or severity of cravings, seeking behaviors, or relapses, or it can result in abstention.
  • treat refers to the administration of therapy to an individual who already manifests, or who has previously manifested, at least one symptom of a disease, disorder, condition, dependence, or behavior, such as at least one symptom of a disease or condition.
  • “treating” can include any of the following with respect to a disease, disorder, condition, dependence, or behavior: alleviating, abating, ameliorating inhibiting (e.g., arresting the development), relieving, or causing regression.
  • Treating can also include treating the symptoms, preventing additional symptoms, preventing the underlying physiological causes of the symptoms, or stopping the symptoms (either prophylactically and/or therapeutically) of a disease, disorder, condition, dependence, or behavior, such as the symptoms of a disease or condition.
  • weight management refers to controlling body weight and in the context of the present disclosure is directed toward weight loss and the maintenance of weight loss (also called weight maintenance herein).
  • weight management includes controlling parameters related to body weight, for example, BMI, percent body fat and waist circumference.
  • BMI body weight
  • weight management for an individual who is overweight or obese can mean losing weight with the goal of keeping weight in a healthier range.
  • weight management for an individual who is overweight or obese can include losing body fat or circumference around the waist with or without the loss of body weight.
  • Maintenance of weight loss includes preventing, reducing or controlling weight gain after weight loss. It is well known that weight gain often occurs after weight loss.
  • Weight loss can occur, for example, from dieting, exercising, illness, drug treatment, surgery or any combination of these methods, but often an individual that has lost weight will regain some or all of the lost weight. Therefore, weight maintenance in an individual who has lost weight can include preventing weight gain after weight loss, reducing the amount of weight gained after weight loss, controlling weight gain after weight loss or slowing the rate of weight gain after weight loss.
  • weight management in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from weight management treatment. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner's expertise, but that includes the knowledge that the individual has a condition that is treatable by the methods disclosed herein.
  • Weight management also includes preventing weight gain, controlling weight gain, reducing weight gain, maintaining weight, or inducing weight loss. Weight management also refers to controlling weight (also called weight control) and/or controlling parameters related to weight, for example, BMI, percent body fat and/or waist circumference. In addition, weight management also includes preventing an increase in BMI, reducing an increase in BMI, maintaining BMI, or reducing BMI; preventing an increase in percent body fat, reducing an increase in percent body fat, maintaining percent body fat, or reducing percent body fat; and preventing an increase in waist circumference, reducing an increase in waist circumference, maintaining waist circumference, or reducing waist circumference
  • decreasing food intake in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from decreasing food intake. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner' s expertise, but that includes the knowledge that the individual has a condition, for example, obesity, that is treatable by the methods disclosed herein.
  • an individual in need of decreasing food intake is an individual who is overweight.
  • an individual in need of decreasing food intake is an individual who is obese.
  • satiety refers to the quality or state of being fed or gratified to or beyond capacity. Satiety is a feeling that an individual has and so it is often determined by asking the individual, orally or in writing, if they feel full, sated, or satisfied at timed intervals during a meal. For example, an individual who feels sated may report feeling full, feeling a decreased or absent hunger, feeling a decreased or absent desire to eat, or feeling a lack of drive to eat. While fullness is a physical sensation, satiety is a mental feeling. An individual who feels full, sated or satisfied is more likely to stop eating and therefore inducing satiety can result in a decrease in food intake in an individual.
  • inducing satiety in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from inducing satiety. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner's expertise, but that includes the knowledge that the individual has a condition, for example, obesity, that is treatable by the methods of the disclosure.
  • treatment of obesity in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from treatment of obesity. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner' s expertise, but that includes the knowledge that the individual has a condition that is treatable by the methods of the disclosure.
  • a body weight a body mass index (BMI)
  • BMI body mass index
  • waist circumference or a body fat percentage of the individual determine if the individual meets a body weight threshold, a BMI threshold, a waist circumference threshold or a body fat percentage threshold.
  • prevention of obesity in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from prevention of obesity. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner' s expertise, but that includes the knowledge that the individual has a condition that is treatable by the methods disclosed herein.
  • an individual in need of prevention of obesity is an individual who is overweight (also called pre-obese).
  • an individual in need of prevention of obesity is an individual who has a family history of obesity.
  • a body weight a body mass index (BMI)
  • BMI body mass index
  • waist circumference a body fat percentage of the individual to determine if the individual meets a body weight threshold
  • BMI threshold a waist circumference threshold or a body fat percentage threshold.
  • an "adverse event” or “toxic event” is any untoward medical occurrence that may present itself during treatment.
  • Adverse events associated with treatment may include, for example, headache, nausea, blurred vision, paresthesias, constipation, fatigue, dry mouth, dizziness, abnormal dreams, insomnia, nasopharyngitis, toothache, sinusitis, back pain, somnolence, viral gastroenteritis, seasonal allergy, or pain in an extremity.
  • Additional possible adverse effects include, for example, gastrointestinal disorders (such as constipation, abdominal distension, and diarrhea), asthenia, chest pain, fatigue, drug hypersensitivity, fibromyalgia, temporomandibular joint syndrome, headache, dizziness, migraine, anxiety, depressed mood, irritability, suicidal ideation, bipolar disorder, depression, drug abuse, and dyspnea.
  • gastrointestinal disorders such as constipation, abdominal distension, and diarrhea
  • asthenia chest pain, fatigue, drug hypersensitivity, fibromyalgia, temporomandibular joint syndrome, headache, dizziness, migraine, anxiety, depressed mood, irritability, suicidal ideation, bipolar disorder, depression, drug abuse, and dyspnea.
  • gastrointestinal disorders such as constipation, abdominal distension, and diarrhea
  • asthenia chest pain, fatigue, drug hypersensitivity, fibromyalgia, temporomandibular joint syndrome, headache, dizziness, migraine, anxiety, depressed mood,
  • agonist refers to a moiety that interacts with and activates a receptor, such as the 5-HT 2 c serotonin receptor, and initiates a physiological or pharmacological response characteristic of that receptor.
  • immediate-release dosage form refers to a formulation which rapidly disintegrates upon oral administration to a human or other animal releasing an active pharmaceutical ingredient (API) from the formulation.
  • API active pharmaceutical ingredient
  • the T80 of the immediate-release dosage form is less than 3 hours. In some embodiments, the T80 of the immediate-release dosage form is less than 1 hour. In some embodiments, the T80 of the immediate-release dosage form is less than 30 minutes. In some embodiments, the T80 of the immediate-release dosage form is less than 10 minutes.
  • T80 refers to the time needed to achieve 80% cumulative release of an API from a particular formulation comprising the API.
  • modified-release dosage form refers to any formulation that, upon oral administration to a human or other animal, releases an API after a given time (i.e., delayed release) or for a prolonged period of time (extended release), e.g., at a slower rate over an extended period of time when compared to an immediate-release dosage-form of the API (e.g., sustained release).
  • nicotine replacement therapy refers to the remedial administration of nicotine to the body by means other than a tobacco product.
  • nicotine replacement therapy may include transdermal nicotine delivery systems, including patches and other systems that are described in the art, for example, in U.S. Pat. Nos. 4,597,961, 5,004,610, 4,946,853, and 4,920,989.
  • Inhaled nicotine e.g., delivery of the nicotine through pulmonary routes
  • Transmucosal administration e.g., delivery of nicotine to the systemic circulation through oral drug dosage forms
  • Oral drug dosage forms e.g., lozenge, capsule, gum, tablet, suppository, ointment, gel, pessary, membrane, and powder
  • Oral drug dosage forms are typically held in contact with the mucosal membrane and disintegrate and/or dissolve rapidly to allow immediate systemic absorption.
  • a plurality of different treatments and means of administration can be used to treat a single individual.
  • an individual can be simultaneously treated with nicotine by transdermal administration and nicotine which is administered to the mucosa.
  • the nicotine replacement therapy is chosen from nicotine gum (e.g., NICORETTE), nicotine transdermal systems such as nicotine patches (e.g., HABITROL and NICODERM), nicotine lozenges (e.g., COMMIT), nicotine microtabs (e.g., NICORETTE Microtabs), nicotine sprays or inhalers (e.g., NICOTROL), and other nicotine replacement therapies known in the art.
  • nicotine replacement therapy includes electronic cigarettes, personal vaporizers, and electronic nicotine delivery systems.
  • “combination” as used in reference to drug combinations and/or combinations of a selective 5-HT 2 c agonist with at least one supplemental agent refers to (1) a product comprised of two or more components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; (2) two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products; (3) a drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or (4) any investigational drug,
  • Combinations include without limitation a fixed-dose combination product (FDC) in which two or more separate drug components are combined in a single dosage form; a co-packaged product comprising two or more separate drug products in their final dosage forms, packaged together with appropriate labeling to support the combination use; and an adjunctive therapy in which a patient is maintained on a second drug product that is used together with (i.e., in adjunct to) the primary treatment, although the relative doses are not fixed, and the drugs or biologies are not necessarily given at the same time.
  • Adjunctive therapy products may be co-packaged, and may or may not be labeled for concomitant use.
  • responder refers to an individual who experiences continuous abstinence from tobacco use during a specified period of administration of a selective 5-HT 2 c receptor agonist. In some embodiments, “responder” refers to an individual who reports no smoking or other nicotine use from Week 9 to Week 12 of administration of a selective 5-HT 2 c receptor agonist and exhibits an end- expiratory exhaled carbon monoxide-confirmed measurement of ⁇ 10 ppm.
  • tobacco product refers to a product that incorporates tobacco, i.e., the agricultural product of the leaves of plants in the genus Nicotiana.
  • tobacco products can generally be divided into two types: smoked tobacco including without limitation pipe tobacco, cigarettes (including electronic cigarettes) and cigars, as well as Mu'assel, Dokha, shisha tobacco, hookah tobacco, or simply shisha; and smokeless tobacco including without limitation chewing tobacco, dipping tobacco, also known as dip, moist snuff (or snuff), American moist snuff, snus, Iqmik, Naswar, Gutka,
  • Toombak Toombak, shammah, tobacco water, spit tobacco, creamy snuff or tobacco paste, dissolvable tobacco, and tobacco gum.
  • Fagerstrom test refers to a standard test for nicotine dependence which is a test for assessing the intensity of nicotine addiction. See Heatherton, T. F., Kozlowski, L. T., Frecker, R. C, Fagerstrom, K. O. The Fagerstrom test for Nicotine Dependence: A revision of the Fagerstrom Tolerance Questionnaire. Br J Addict 1991 ; 86: 1119-27.
  • the test consists of a brief, self-report survey that measures nicotine dependence on a scale of 0-10, with 10 being the highest level of dependence. A score of 0-2 corresponds to very low dependence. A score of 3-4 corresponds to low dependence. A score of 5 corresponds to moderate dependence. A score of 6-7 corresponds to high dependence. A score of 8-10 corresponds to very high dependence.
  • DSM-III-R Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition
  • MPSS Mood and Physical Symptoms Scale
  • the core elements of MPSS involve a 5-point rating of depressed mood, irritability, restlessness, difficulty concentrating and hunger and a 6-point rating of strength of urges to smoke and time spent with these urges.
  • lorcaserin refers to (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l/f-3- benzazepine.
  • lorcaserin hydrochloride refers to the hydrochloric acid salt of (R)-8-chloro-l - methyl-2,3,4,5-tetrahydro-l/f-3-benzazepine (see Statement on Nonproprietary Name Adopted by the USAN Council for Lorcaserin Hydrochloride).
  • phentermine refers to l, l-dimethyl-2-phenyl-ethylamine, including phentermine derivatives and pharmaceutically acceptable salts thereof, such as, but not limited to, chlorphentermine (2-(4-chloro-phenyl)-l,l-dimethyl-ethylamine) and the like.
  • phentermine is in the HC1 salt form of 1 , 1 -dimethyl-2-phenyl-ethylamine.
  • amhetamine refers to l-phenylpropan-2-amine and salts, hydrates, and solvates thereof.
  • a substituted amphetamine refers to a class of chemicals based on amphetamine with additional substitutions.
  • substituted amphetamines include, but are not limited to: methamphetamine (iV-methyl-l -phenylpropan-2-amine); ephedrine (2-(methylamino)-l -phenylpropan- l-ol); cathinone (2 - amino -1-pheny 1- 1 -prop anone); MDMA (3,4-methylenedioxy-iV- methylamphetamine); and DOM (2,5-Dimethoxy-4-methylamphetamine); and salts, hydrates, and solvates thereof.
  • methamphetamine iV-methyl-l -phenylpropan-2-amine
  • ephedrine (2-(methylamino)-l -phenylpropan- l-ol
  • cathinone (2 - amino -1-pheny 1- 1 -prop anone
  • MDMA
  • a benzodiazepine includes, but is not limited to alprazolam, bretazenil, bromazepam, brotizolam, chlordiazepoxide, cinolazepam, clonazepam, clorazepate, clotiazepam, cloxazolam, cyclobenzaprine, delorazepam, diazepam, estazolam, etizolam, ethyl, loflazepate, flunitrazepam, 5-(2-bromophenyl)-7-fluoro-l/f-benzo[e] [l,4]diazepin-2(3//)-one, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam,
  • an atypical benzodiazepine receptor ligand includes, but is not limited to clobazam, DMCM, flumazenil, eszopiclone, zaleplon, Zolpidem, and zopiclone and salts, hydrates, and solvates thereof.
  • marijuana refers to a composition comprising one or more compound selected from tetrahydrocannabinol, cannabidiol, cannabinol, and tetrahydrocannabivarin and salts, hydrates, and solvates thereof.
  • cocaine refers to benzoylmethylecgonine and salts, hydrates, and solvates thereof.
  • eszopiclone refers to (3 ⁇ 4-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5/f- pyrrolo[3,4-3 ⁇ 4]pyrazin-5-yl 4-methylpiperazine-l-carboxylate and salts, hydrates, and solvates thereof.
  • GHB refers to 4-hydroxybutanoic acid and salts, hydrates, and solvates thereof.
  • LSD refers to lysergic acid diethylamide and salts, hydrates, and solvates thereof.
  • ketamine refers to 2-(2-chlorophenyl)-2-(methylamino)cyclohexanone and salts, hydrates, and solvates thereof.
  • a monoamine reuptake inhibitor refers to a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters.
  • Examples of monoamine reuptake inhibitors include alaproclate, citalopram, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, omiloxetine, panuramine, paroxetine, pirandamine, RTI- 353, sertraline, zimelidine, desmethylcitalopram, desmethylsertraline, didesmethylcitalopram, seproxetine, cianopramine, litoxetine, lubazodone, SB-649,915, trazodone, vilazodone, vortioxetine, dextromethorphan, dimenhydrinate, diphenhydramine, mepyramine, pyrilamine, methadone, propoxyphene, mesembrine, roxindole, amedalin, tomoxetine, CP-39,332, daledalin, edivoxetine
  • nicotine refers to 3-(l-methylpyrrolidin-2-yl)pyridine.
  • an opiate includes, but is not limited to the following compounds and salts, hydrates, and solvates thereof: alfentanil, alphaprodine, anileridine, bezitramide, buprenorphine, butorphanol, dextropropoxyphene, carfentanil, codeine, diamorphine, dextromoramide, dezocine, poppy straw, dihydrocodeine, dihydroetorphine, diphenoxylate, ethylmorphine, etorphine, hydrochloride, fentanyl, hydrocodone, hydromorphone, isomethadone, levo-alphacetylmethadol, levomethorphan, levorphanol, meptazinol, metazocine, methadone, metopon, morphine, nalbuphine, opium, oripavine, oxycodone, oxymorphone, pentazocine, pethidine, phenazo
  • the term includes the following compounds and salts, hydrates, and solvates thereof: alfentanil, alphaprodine, anileridine, bezitramide, dextropropoxyphene, carfentanil, codeine, poppy straw, dihydrocodeine, dihydroetorphine, diphenoxylate, ethylmorphine, etorphine, hydrochloride, fentanyl, hydrocodone, hydromorphone, isomethadone, levo-alphacetylmethadol, levomethorphan, levorphanol, metazocine, methadone, metopon, morphine, opium, oripavine, oxycodone, oxymorphone, pethidine, phenazocine, piminodine, racemethorphan, racemorphan, remifentanil, sufentanil, tapentadol, and thebaine.
  • PCP refers to l-(l-phenylcyclohexyl)piperidine and salts, hydrates, and solvates thereof.
  • a substituted phenethylamine includes, but is not limited to, the following compounds and salts, hydrates, and solvates thereof: 2-(4-bromo-2,5-dimethoxyphenyl)-iV-[(2- methoxyphenyl)methyl]ethanamine, 2-(4-chloro-2,5-dimethoxyphenyl)-iV-[(2- methoxyphenyl)methyl]ethanamine, 2-(4-iodo-2,5-dimethoxyphenyl)-iV-[(2- methoxyphenyl)methyl]ethanamine, 4-bromo-2,5-dimethoxyphenethylamine, 1 -(4-chloro-2,5- dimethoxyphenyl)-2-aminoethane, 1 -(2,5-dimethoxy-4-methylphenyl)-2-aminoethane, 1 -(2,5- dimethoxy-4-ethylphenyl)-2
  • locybin refers to [3-(2-dimethylaminoethyl)-l/f-indol-4-yl] dihydrogen phosphate, and salts, hydrates, and solvates thereof.
  • an anabolic steroid includes, but is not limited to, the following compounds and salts, hydrates, and solvates thereof: 1 -androstenediol, androstenediol, 1-androstenedione,
  • composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.
  • a method that recites prescribing or administering a compound provided herein can be separated into two methods; one reciting prescribing a compound provided herein and the other reciting administering a compound provided herein.
  • a method that recites prescribing a compound provided herein and a separate method reciting administering a compound provided herein can be combined into a single method reciting prescribing and/or administering a compound provided herein.
  • a method that recites prescribing or administering a selective 5-HT 2 c receptor agonist can be separated into two methods— one reciting prescribing a selective 5-HT 2 c receptor agonist and the other reciting administering a selective 5-HT 2 c receptor agonist.
  • a method that recites prescribing a selective 5-HT 2C receptor agonist and a separate method of the invention reciting administering a selective 5-HT 2C receptor agonist can be combined into a single method reciting prescribing and/or administering a selective 5-HT 2C receptor agonist.
  • C 1 -C6 alkoxy refers to a radical comprising a C 1 -C6 alkyl group attached to an oxygen atom, wherein Ci-C6 alkyl has the same definition as found herein. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 to 2 carbons. Examples include, but are not limited to methoxy, ethoxy, M-propoxy, isopropoxy, w-butoxy, ieri-butoxy, isobutoxy, and sec-butoxy.
  • aryl refers to an aromatic ring radical containing 6 to 10 ring carbons. Examples include, but are not limited to, phenyl and naphthyl.
  • Ci-C6 alkoxycarbonyl refers to a radical comprising a Ci-C6 alkoxy group attached to a carbonyl, wherein Ci-C 6 alkoxy has the same definition as found herein. Examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
  • Ci-C6 alkyl refers to a straight or branched carbon radical containing 1 to 6 carbons.
  • Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 to 2 carbons.
  • Examples of an alkyl group include, but are not limited to, methyl, ethyl, n -propyl, isopropyl, n -butyl, sec-butyl, isobutyl, feri-butyl, pentyl, isopentyl, i-pentyl, neopentyl, 1-methylbutyl [i.e., -CH(CH 3 )CH 2 CH 2 CH 3 ], 2- methylbutyl [i.e., -CH 2 CH(CH 3 )CH 2 CH 3 ], and n-hexyl.
  • Ci-C 6 alkylsulfonyl refers to a radical comprising a Ci-C 6 alkyl group attached to the sulfur of a sulfonyl group, wherein Ci-C 6 alkyl has the same definition as described herein.
  • Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, w-propylsulfonyl,
  • Ci-C6 alkylthio refers to a radical comprising a Ci-C6 alkyl group attached to a sulfur atom, wherein Ci-C 6 alkyl has the same definition as described herein. Examples include, but are not limited to, methylthio, ethylthio, w-propylthio, isopropylthio, w-butylthio, sec-butylthio, isobutylthio, and ieri-butylthio.
  • Carbocyclic ring refers to a saturated ring containing 3 to 7 carbons. Some embodiments contain 3 to 4 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 4 to 6 carbons. Some embodiments contain 5 to 6 carbons.
  • C 3 -C 7 cycloalkyl refers to a saturated ring radical containing 3 to 7 carbons. Some embodiments contain 3 to 4 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 4 to 6 carbons. Some embodiments contain 5 to 6 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 3 -C 7 cycloalkyl-Ci-C6 alkylene refers to a radical comprising a C 3 -C 7 cycloalkyl group attached to a Ci-C 6 alkyl group, wherein the C 3 -C 7 cycloalkyl and Ci-C 6 alkyl groups have the same definitions as described herein. Examples include, but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cyclopropylethyl.
  • Ci-C6 haloalkyl refers to a radical comprising a Ci-C6 alkyl group substituted with one or more halogens, wherein Ci-C 6 alkyl has the same definition as found herein.
  • the Ci-C 6 haloalkyl may be fully substituted in which case it can be represented by the formula C q L 2q+ i, wherein L is a halogen and "q" is 1, 2, 3, 4, 5 or 6. When more than one halogen is present then they may be the same or different and selected from: fluorine, chlorine, bromine, and iodine.
  • haloalkyl contains 1 to 5 carbons.
  • haloalkyl contains 1 to 4 carbons.
  • haloalkyl contains 1 to 3 carbons. In some embodiments, haloalkyl contains 1 to 4 carbons.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoropropan-2-yl, 1, 1-difluoropropyl, 1,3- difluoropropan-2-yl, (SJ-l-fluoropropan-2-yl, fRJ-l-fluoropropan-2-yl, l,l ,l-trifluoropropan-2-yl, and
  • heterocyclic ring refers to a saturated ring containing 3 to 7 atoms, one or more of which are heteroatoms. In some embodiments one, two or three of the ring atoms are heteroatoms. In some embodiments, one, two or three of the ring atoms are heteroatoms each of which is independently
  • 3- to 7-membered heterocycloalkyl refers to a saturated ring radical containing 3 to 7 atoms, one or more of which are heteroatoms. In some embodiments one, two or three of the ring atoms are heteroatoms. In some embodiments, one, two or three of the ring atoms are heteroatoms each of which is independently O, N or S. Examples include aziridinyl, azetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and morpholinyl.
  • halogen refers to a fluoro, chloro, bromo or iodo group.
  • heteroaryl refers to a ring system containing 5 to 10 ring atoms, that may contain a single ring or two fused rings, and wherein at least one ring is aromatic and at least one ring atom of the aromatic ring is a heteroatom selected from, for example: O, S and N, wherein N is optionally substituted with H, Ci-C 4 acyl, Ci-C 4 alkyl, or O (i.e., forming an iV-oxide) and S is optionally substituted with one or two oxygens.
  • the aromatic ring contains one heteroatom.
  • the aromatic ring contains two heteroatoms.
  • the aromatic ring contains three heteroatoms.
  • 5-membered heteroaryl rings examples include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, and thiadiazolyl.
  • 6-membered heteroaryl rings examples of a 6- membered heteroaryl ring include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
  • heteroaryl-Ci-C6 alkylene refers to a radical comprising a heteroaryl group attached to a Ci-C 6 alkyl group, wherein the C 3 -C 7 cycloalkyl and Ci-C 6 alkyl groups have the same definitions as described herein. Examples include, but are not limited to pyridinylmethyl, pyridinylethyl, pyridinylpropyl, pyridinylbutyl, pyridinylpentyl, pyridinylhexyl, and pyrazinylmethyl.
  • phenyl refers to the group -CeH 5 .
  • aryloxy refers to a radical comprising an aryl group, attached to an oxygen, wherein aryl has the same definition as found herein. Examples include, but are not limited to, phenoxy and naphthyloxy.
  • the number of occurrences of a given substituent in a compound may be specified by a subscript (such as "n" and the like).
  • the subscript may be a positive integer or it may be 0.
  • a value of 0 for the subscript is intended to indicate that the substituent is absent.
  • X is selected from O and S;
  • R 1 is selected from: Ci-C6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-Ci-C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy, Ci-C6 alkoxycarbonyl, Ci-C6 alkylthio, Ci-C6 alkylsulfonyl, aryloxy, halogen, and Ci-C6 haloalkyl.
  • X 1 is selected from O and S;
  • R 11 is selected from: C 1 -C6 alkyl, optionally substituted with one or more substituents independently selected from: C 1 -C6 alkoxy, C 1 -C6 alkoxycarbonyl, and halogen;
  • R 12 and R 12b are each independently H, C 3 -C 7 cycloalkyl or C 1 -C6 alkyl, wherein the C 3 -C 7 cycloalkyl and C 1 -C6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, Ci-C6 alkyl and Ci-C6 alkoxy;
  • R 13 and R 13b are each independently H, C 3 -C 7 cycloalkyl or Ci-C6 alkyl, wherein the C 3 -C 7 cycloalkyl and Ci-C6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, Ci-C6 alkyl and Ci-C6 alkoxy;
  • n 0, 1, or 2;
  • R 14 is Ci-Ce alkyl
  • each R 14 is Ci-C6 alkyl bonded to the same carbon, or two R 14 taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring;
  • n 1 or 2.
  • each of R and R is independently hydrogen or Ci-C6 alkyl
  • R 27 is hydrogen, Ci-C6 alkyl or C 3 -C 7 cycloalkyl
  • R 28 is hydrogen or C 1 -C6 alkyl
  • each of R 22 and R 23 is independently hydrogen or C 1 -C6 alkyl optionally substituted with one or more halogens;
  • R 22 and R 23 taken together with the carbon they are bonded to form a three-, four-, five-, six- or seven-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1 -C6 alkyl, and C 1 -C6 alkoxy;
  • R 24 is hydrogen, halogen, hydroxy, C 3 -C 7 cycloalkyl, Ci-C 6 alkoxy or Ci-C 6 alkyl optionally substituted with C 1 -C6 alkoxy;
  • R 21 is selected from the group consisting of:
  • Ci-C 6 alkyl optionally substituted with one or more substituents each of which is independently halogen, hydroxy, Ci-C6 alkoxy, amino, heteroarylamino, arylamino, C 1 -C6 dialkylamino, aryl, Ci-C6 alkoxycarbonyl, Ci-C6 alkylamino optionally substituted with Ci-C6 alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with Ci-C 6 alkoxy, or C 3 -C 7 cycloalkyl optionally substituted with Ci-C 6 alkoxy;
  • C 1 -C6 alkylamino optionally substituted with C 1 -C6 alkoxy or with hydroxy
  • C 1 -C6 dialkylamino optionally substituted with C 1 -C6 alkoxy or with hydroxy
  • arylamino
  • Ci-C 6 alkoxy optionally substituted with one or more halogens
  • R 24 is hydrogen or halogen, at least one of R 21 , R 22 , R 23 , R 25 , R 26 R 27 and R 28 is other than hydrogen.
  • some embodiments include every combination of one or more embodiments pertaining to the chemical groups represented by the variables and generic chemical formulae as described herein or every combination of one or more compounds disclosed herein together/in combination with every combination of one or more weight loss drug chosen from sodium/glucose cotransporter-2 (SGLT2) inhibitors, lipase inhibitors, monoamine reuptake inhibitors, anticonvulsants, glucose sensitizers, incretin mimetics, amylin analogs, GLP-1 analogs, Y receptor peptides, 5-HT 2 c receptor agonists, opioid receptor antagonists, appetite suppressants, anorectics, and hormones and the like, either specifically disclosed herein or specifically disclosed in any reference recited herein just as if each and every combination was individually and explicitly recited.
  • SGLT2 sodium/glucose cotransporter-2
  • the weight loss drug is chosen from dapagliflozin, canagliflozin, ipragliflozin, tofogliflozin, empagliflozin, remogliflozin etabonate, orlistat, cetilistat, alaproclate, citalopram, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, omiloxetine, panuramine, paroxetine, pirandamine, sertraline, zimelidine, desmethylcitalopram, desmethylsertraline, didesmethylcitalopram, seproxetine, cianopramine, litoxetine, lubazodone, trazodone, vilazodone, vortioxetine,
  • dextromethorphan dimenhydrinate, diphenhydramine, mepyramine, pyrilamine, methadone, propoxyphene, mesembrine, roxindole, amedalin, tomoxetine, daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, reboxetine, talopram, talsupram, tandamine, viloxazine, maprotiline, bupropion, ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, ginkgo biloba, altropane, difluoropine, iometopane, vanoxerine, medifoxamine, Chaenomeles speciosa, hyperforin, adhyperforin, bupropion, pramipexole, cabergoline, venlafaxine, desvenlafaxine
  • methylenedioxypyrovalerone methylphenidate, nomifensine, oxolinic acid, pipradrol, prolintane, pyrovalerone, tametraline, nefopam, amitifadine, tesofensine, tedatioxetine, bicifadine, brasofensine, diclofensine, taxil, naphyrone, hyperforin, topiramate, zonisamide, metformin, acarbose, rosiglitazone, pioglitazone, troglitazone, exenatide, liraglutide, taspoglutide, obinepitide, pramlintide, peptide YY, vabicaserin, naltrexone, naloxone, phentermine, diethylpropion, oxymetazoline, benfluorex, butenolide cathine,
  • substituted indicates that at least one hydrogen atom of the chemical group is replaced by a non-hydrogen substituent or group, the non-hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group.
  • a chemical group herein when a chemical group herein is "substituted" it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1 , 2, or 3 substituents, a methylene group can be substituted by 1 to 4 substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents, and the like.
  • substituted with one or more substituents refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group. Further, when a group is substituted with more than one group they can be identical or they can be different.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is understood that the various tautomeric forms are within the scope of the compounds provided herein.
  • X is selected from O and S;
  • R 1 is selected from: Ci-C6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-Ci-C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy, Ci-C6 alkoxycarbonyl, Ci-C6 alkylthio, Ci-C6 alkylsulfonyl, aryloxy, halogen, and Ci-C6 haloalkyl.
  • R 1 is selected from: C 1 -C6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy, C 1 -C6 alkoxycarbonyl, C 1 -C6 alkylthio, C 1 -C6 alkylsulfonyl, aryloxy, halogen, and Ci-C 6 haloalkyl.
  • R 1 is selected from: C 1 -C6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: chloro, ethoxy, ethylthio, fluoro, isopropoxy, methoxy, methoxycarbonyl, methylthio, methylsulfonyl, propoxy, phenoxy, and trifluoromethyl.
  • R 1 is selected from: butyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, n-propyl, pyridinyl, and pyridinylmethyl; each optionally substituted with one or more substituents selected from: chloro, ethoxy, ethylthio, fluoro, isopropoxy, methoxy, methoxycarbonyl, methylthio, methylsulfonyl, propoxy, phenoxy, and trifluoromethyl.
  • R 1 is selected from: (6-(trifluoromethyl)pyridin-3-yl)methyl, 1- ethoxypropan-2yl, 1 -methoxypropan-2-yl, 2-(ethylthio)ethyl, 2-(methylsulfonyl)ethyl, 2- (methylthio)ethyl, 2-chloroethyl, 2-ethoxyethyl, 2-ethoxypropyl, 2-fluoroethyl, 3-fluoropropyl, 2- isopropoxyethyl, 2-methoxy-2-oxoethyl, 2-methoxyethyl, 2-methoxypropyl, 2-phenoxyethyl, 2- propoxyethyl, 3-methoxypropyl, butyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, propyl, pyridin-2-ylmethyl, and pyridin
  • R 1 is (6-(trifluoromethyl)pyridin-3-yl)methyl.
  • R 1 is l-ethoxypropan-2yl.
  • R 1 is l-methoxypropan-2-yl.
  • R 1 is 2-(ethylthio)ethyl.
  • R 1 is 2-(methylsulfonyl)ethyl.
  • R 1 is 2-(methylthio)ethyl.
  • R 1 is 2-chloroethyl.
  • R 1 is 2-ethoxyethyl.
  • R 1 is 2-ethoxypropyl.
  • R 1 is 2-fluoroethyl.
  • R 1 is 3-fluoropropyl.
  • R 1 is 2-isopropoxyethyl.
  • R 1 is 2-methoxy-2-oxoethyl.
  • R 1 is 2-methoxyethyl.
  • R 1 is 2-methoxypropyl.
  • R 1 is 2-phenoxyethyl.
  • R 1 is 2-propoxyethyl.
  • R 1 is 3-methoxypropyl.
  • R 1 is butyl
  • R 1 is cyclopropyl. In some embodiments, R 1 is cyclopropylmethyl.
  • R 1 is ethyl
  • R 1 is isopropyl
  • R 1 is methyl
  • R 1 is propyl
  • R 1 is pyridin-2-ylmethyl.
  • R 1 is pyridin-3-yl.
  • X is selected from
  • X is O.
  • X is S.
  • R 1 is selected from: C 1 -C6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-Ci-C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy, C 1 -C6 alkoxycarbonyl, C 1 -C6 alkylthio, C 1 -C6 alkylsulfonyl, aryloxy, halogen, and C 1 -C6 haloalkyl.
  • R 1 is selected from: C 1 -C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-Ci-C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: chloro, ethoxy, ethylthio, fluoro, isopropoxy, methoxy, methoxycarbonyl, methylthio, methylsulfonyl, propoxy, phenoxy, and trifluoromethyl.
  • R 1 is selected from: butyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, w-propyl, pyridinyl, and pyridinylmethyl; each optionally substituted with one or more substituents selected from: chloro, ethoxy, ethylthio, fluoro, isopropoxy, methoxy, methoxycarbonyl, methylthio, methylsulfonyl, propoxy, phenoxy, and trifluoromethyl.
  • R 1 is selected from: (6-(trifluoromethyl)pyridin-3-yl)methyl, l-ethoxypropan-2yl, 1- methoxypropan-2-yl, 2-(ethylthio)ethyl, 2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2-chloroethyl, 2- ethoxyethyl, 2-ethoxypropyl, 2-fluoroethyl, 2-fluoropropyl, 2-isopropoxyethyl, 2-methoxy-2-oxoethyl, 2-methoxyethyl, 2-methoxypropyl, 2-phenoxyethyl, 2-propoxyethyl, 3-methoxypropyl, butyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, propyl, pyridin-2-ylmethyl, and pyridin-3-yl
  • R 1 is selected from: Ci-C 6 alkyl optionally substituted with one or more substituents selected from: Ci-C6 alkoxy.
  • R 1 is selected from: Ci-C6 alkyl optionally substituted with one or more substituents selected from: methoxy.
  • R 1 is selected from: ethyl and methyl; each optionally substituted with one or more substituents selected from: methoxy.
  • R 1 is selected from: 2-methoxyethyl and methyl.
  • the salts, hydrates, and solvates of the compounds of Formula II or of Formula III are pharmaceutically acceptable salts, hydrates, and solvates.
  • Some embodiments of the compounds of Formula I include every combination of one or more compounds and pharmaceutically acceptable salts, hydrates, and solvates thereof selected from the following group shown in Table A.
  • X 1 is selected from O and S;
  • R 11 is selected from: Ci-C6 alkyl, optionally substituted with one or more substituents independently selected from: Ci-C6 alkoxy, Ci-C6 alkoxycarbonyl, and halogen;
  • R 12 and R 12b are each independently H, C 3 -C 7 cycloalkyl or Ci-C6 alkyl, wherein the C 3 -C 7 cycloalkyl and Ci-C 6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, Ci-C6 alkyl and Ci-C6 alkoxy;
  • R 13 and R 13b are each independently H, C 3 -C 7 cycloalkyl or Ci-C6 alkyl, wherein the C 3 -C 7 cycloalkyl and Ci-C6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, Ci-C6 alkyl and Ci-C6 alkoxy;
  • n 0, 1 , or 2;
  • R 14 is Ci-Ce alkyl, and wherein if n is 2, each R is C 1 -C6 alkyl bonded to the same carbon, or two R taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring;
  • n 1 or 2.
  • R 11 is Ci-C6 alkyl, optionally substituted with one or more substituents independently selected from: Ci-C6 alkoxy, Ci-C6 alkoxycarbonyl, and halogen.
  • R 11 is Ci-C 6 alkyl optionally substituted with one or more substituents independently selected from: chloro, ethoxy, fluoro, isopropoxy, methoxy, methoxycarbonyl, and propoxy.
  • R 11 is selected from: butyl, ethyl, isopropyl, methyl, and w-propyl; each optionally substituted with one or more substituents independently selected from: chloro, ethoxy, fluoro, isopropoxy, methoxy, methoxycarbonyl, and propoxy.
  • R 11 is selected from: l-ethoxypropan-2yl, l-methoxypropan-2-yl, 2- chloroethyl, 2-ethoxyethyl, 2-ethoxypropyl, 2-fluoroethyl, 3-fluoropropyl, 2-isopropoxyethyl, 2- methoxy-2-oxoethyl, 2-methoxyethyl, 2-methoxypropyl, 2-propoxyethyl, 3-methoxypropyl, butyl, ethyl, isopropyl, methyl, and propyl.
  • R 11 is selected from: ethyl and methyl each optionally substituted with more substituents independently selected from ethoxy and methoxy.
  • R 11 is selected from methyl, ethoxyethyl and methoxyethyl
  • R 11 is 1 -ethoxypropan-2yl.
  • R 11 is 1 -methoxypropan-2-yl.
  • R 11 is 2-chloroethyl.
  • R 11 is 2-ethoxyethyl.
  • R 11 is 2-ethoxypropyl.
  • R 11 is 2-fluoroethyl.
  • R 11 is 3-fluoropropyl.
  • R 11 is 2-isopropoxyethyl.
  • R 11 is 2-methoxy-2-oxoethyl.
  • R 11 is 2-methoxyethyl.
  • R 11 is 2-methoxypropyl.
  • R 11 is 2-phenoxyethyl.
  • R 11 is 2-propoxyethyl.
  • R 11 is 3-methoxypropyl.
  • R 11 is butyl
  • R 11 is ethyl
  • R 11 is isopropyl.
  • R 11 is methyl. In some embodiments, R 11 is propyl.
  • R 11 is C 1 -C6 alkyl substituted with one or more substituents independently selected from halogen.
  • R 11 is Ci-C 6 alkyl substituted with one or more fluorine.
  • R 11 is 2,2-difluoroethyl.
  • R 11 is 2,2,2-trifluoroethyl.
  • R 11 is 3,3,3-trifluoropropyl.
  • R 11 is 2,2,3,3,3-pentafluoropropyl.
  • X 1 is selected from O and S.
  • X 1 is O.
  • X 1 is S.
  • R 12 and R 12b are each independently H, C 3 -C 7 cycloalkyl or C 1 -C6 alkyl, wherein the C 3 -C 7 cycloalkyl and Ci-C 6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, C 1 -C6 alkyl and C 1 -C6 alkoxy.
  • R 12 and R 12b are each independently selected from: H, methyl, ethyl and propyl, wherein methyl, ethyl and propyl are each optionally substituted with one or more substituents independently selected from methoxy and fluorine.
  • R 12 and R 12b are each independently selected from: H, methyl, ethyl, propyl, methoxymethyl, CF 3 and 2,2,2-trifluoroethyl.
  • each of R 12 and R 12b is H.
  • each of R 12 and R 12b is C 1 -C6 alkyl.
  • each of R 12 and R 12b is Ci-C 6 alkyl and is the same.
  • each of R 12 and R 12b is methyl.
  • each of R 12 and R 12b is ethyl.
  • each of R 12 and R 12b is propyl.
  • each of R 12 and R 12b is C 1 -C6 alkyl substituted with one or more substituents independently selected from halogen and Ci-C 6 alkoxy.
  • each of R 12 and R 12b is C 1 -C6 alkyl substituted with one or more halogen
  • each of R 12 and R 12b is CF 3 .
  • each of R 12 and R 12b is 2,2,2-trifluoroethyl.
  • IInn ssoommee eemmbbooddiimmeennttss,, eeaacchh ooff 1 R and R is C 1 -C6 alkyl substituted with one or more substituents selected from C 1 -C6 alkoxy
  • each of R and R is methoxymethyl. In some embodiments, each of R and R is 2-methoxyethyl.
  • each of R 12 and R 12b is 2-ethoxyethyl.
  • each of R 12 and R 12b is C 3 -C 7 cycloalkyl.
  • each of R 12 and R 12b is C 3 -C 7 cycloalkyl and is the same.
  • one of R 12a and R 12b is H and the other is Ci-C 6 alkyl.
  • one of R 12 and R 12b is H and the other is methyl.
  • one of R 12a and R 12b is H and the other is ethyl.
  • one of R 12 and R 12b is H and the other is propyl.
  • one of R 12 and R 12b is H and the other is C 1 -C6 alkyl substituted with one or more substituents independently selected from halogen and Ci-C6 alkoxy.
  • one of R 12 and R 12b is H and the other is Ci-C6 alkyl substituted with one or more halogen.
  • one of R 12a and R 12b is H and the other is CR.
  • one of R 12 and R 12b is H and the other is 2,2,2-trifluoroethyl.
  • one of R 12 and R 12b is H and the other is Ci-C6 alkyl substituted with one or more substituents selected from Ci-C6 alkoxy.
  • one of R 12a and R 12b is H and the other is methoxymethyl.
  • one of R 12a and R 12b is H and the other is 2-methoxyethyl.
  • one of R 12a and R 12b is H and the other is 2-ethoxyethyl.
  • one of R 12a and R 12b is H and the other is C3-C7 cycloalkyl.
  • one of R 12a and R 12b is H and the other is cyclopropyl.
  • one of R 12a and R 12b is H and the other is cyclobutyl.
  • one of R 12a and R 12b is H and the other is cyclopentyl.
  • one of R 12a and R 12b is H and the other is cyclohexyl.
  • one of R 12a and R 12b is H and the other is cycloheptyl.
  • the carbon bearing R and R has (R) stereochemistry.
  • the carbon bearing R 12 and R 12b has (S) stereochemistry.
  • R 13 and R 13b are each independently H, C3-C7 cycloalkyl or C 1 -C6 alkyl, wherein the C 3 -C 7 cycloalkyl and Ci-C 6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, C 1 -C6 alkyl and C 1 -C6 alkoxy;
  • R 13 and R 13b taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring.
  • R 13 and R 13b are each independently selected from: H, methyl, and ethyl.
  • each of R 13 and R 13b is H.
  • each of R 13 and R 13b is C 1 -C6 alkyl. In some embodiments, each of R and R is Ci-C 6 alkyl and is the same.
  • each of R 13 and R 13b is methyl.
  • each of R 13 and R 13b is ethyl.
  • each of R 13 and R 13b is propyl.
  • each of R 13 and R 13b is Ci-C 6 alkyl substituted with
  • each of R and R is C C 6 alkyl substituted with one or more halogen
  • each of R and R is CF 3 .
  • each of R 13 and R 13b is 2,2,2-trifluoroethyl.
  • each of R 13 and R 13b is Ci-C 6 alkyl substituted with one or more substituents selected from Ci-C6 alkoxy.
  • each of R 13 and R 13b is methoxymethyl.
  • each of R 13 and R 13b is 2-methoxyethyl.
  • each of R 13 and R 13b is 2-ethoxyethyl.
  • each of R lja and R 13b is C 3 -C 7 cycloalkyl.
  • each of R 13 and R 13b is C 3 -C 7 cycloalkyl and is the same.
  • R 13a and R 13b taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring.
  • R 13 and R 13b taken together with the carbon they are bonded to form a
  • R lja and R 13b taken together with the carbon they are bonded to form a
  • R lja and R ljb taken together with the carbon they are bonded to form a
  • one of R 13a and R 13b is H and the other is C C 6 alkyl.
  • one of R 13 and R 13b is H and the other is methyl.
  • one of R 13a and R 13b is H and the other is ethyl.
  • one of R 13 and R 13b is H and the other is propyl.
  • one of R 13 and R 13b is H and the other is Ci-C 6 alkyl substituted with one or more substituents independently selected from halogen and C C 6 alkoxy.
  • one of R lja and R 13b is H and the other is C C 6 alkyl substituted with one or more halogen.
  • one of R 13a and R 13b is H and the other is CF 3 .
  • one of R 13a and R 13b is H and the other is 2,2,2-trifluoroethyl.
  • one of R 13 and R 13b is H and the other is Ci-C 6 alkyl substituted with one or more substituents selected from Ci-C6 alkoxy.
  • one of R 13 and R 13b is H and the other is methoxymethyl. In some embodiments, 13a and R 13b is
  • 13a and R 13b is
  • 13a and R 13b is
  • 13a renewingJ D 13b ⁇
  • n 0, 1, or 2.
  • n 0.
  • n 1
  • n is 2.
  • R 14 is Ci-C6 alkyl.
  • R 14 is methyl
  • R 14 is ethyl
  • R 14 is propyl
  • the carbon bearing R 14 has (R) stereochemistry.
  • the carbon bearing R 14 has (S) stereochemistry.
  • two R 14 groups are each Ci-C6 alkyl bonded to the same carbon. In some embodiments, two R 14 groups are each Ci-C6 alkyl bonded to the same carbon and are the same.
  • two R 14 groups are each methyl bonded to the same carbon.
  • two R 14 groups are each ethyl bonded to the same carbon.
  • two R 14 groups are each propyl bonded to the same carbon.
  • two R 14 taken together with the carbon they are bonded to form a
  • two R 14 taken together with the carbon they are bonded to form a
  • 4- membered spirocyclic ring In some embodiments, two R taken together with the carbon they are bonded to form a 5-membered spirocyclic ring.
  • n 0 and the compound of formula XI is selected from compounds of Formula Xlla-i, and salts, hydrates, and solvates thereof:
  • R 11 is C 1 -C6 alkyl optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy;
  • R 12 and R 12b is H and the other is C 1 -C6 alkyl optionally substituted with one or more substituents independently selected from halogen and C 1 -C6 alkoxy.
  • X 1 is O.
  • R 11 is selected from methyl, ethoxy ethyl and methoxyethyl.
  • R 11 is methyl
  • R 11 is ethoxyethyl.
  • R 11 is methoxyethyl.
  • one of R 12 and R 12b is H and the other is selected from: methyl, ethyl, propyl, methoxymethyl, CF 3 and 2,2,2-trifluoroethyl.
  • one of R 12 and R 12b is H and the other is methyl. In some embodiments of formula Xlla-i, one of R 12a and R 12b is H and the other is ethyl. In some embodiments of formula Xlla-i, one of R 12 and R 12b is H and the other is propyl. In some embodiments of formula Xlla-i, one of R 12a and R 12b is H and the other is CF 3 . In some embodiments of formula Xlla-i, one of R 12 and R 12b is H and the other is 2,2,2- trifluoroethyl.
  • one of R 12a and R 12b is H and the other is CH 2 OMe.
  • the carbon bearing R 12 and R 12b has (R) stereochemistry.
  • the carbon bearing R 12 and R 12b has (S) stereochemistry.
  • n is 0 and the compound of formula XI is selected from compounds of Formula Xlla-i, and salts, hydrates, and solvates thereof:
  • R 11 is C 1 -C6 alkyl optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy;
  • R 12 and R 12b are each Ci-C 6 alkyl optionally independently substituted with one or more substituents independently selected from halogen and C 1 -C6 alkoxy.
  • X 1 is O.
  • R 11 is selected from methyl, ethoxy ethyl, and methoxyethyl.
  • R 11 is methyl
  • R 11 is ethoxyethyl.
  • R 11 is methoxyethyl.
  • R 12 and R 12b are each selected from: methyl, ethyl, propyl, methoxymethyl, CF 3 and 2,2,2-trifluoroethyl.
  • R 12 and R 12b are each methyl.
  • R 12 and R 12b are each ethyl.
  • R 12 and R 12b are each propyl.
  • n is 0 and the compound of formula XI is selected from compounds of
  • R 11 is C 1 -C6 alkyl optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy;
  • R 13 and R 13b is H and the other is C 1 -C6 alkyl optionally substituted with one or more substituents independently selected from halogen and C 1 -C6 alkoxy.
  • X 1 is O.
  • R 11 is selected from methyl, ethoxyethyl and methoxyethyl.
  • R 11 is methyl
  • R 11 is ethoxyethyl.
  • R 11 is methoxyethyl.
  • one of R 13 and R 13b is H and the other is selected from methyl and ethyl.
  • one of R 13 and R 13b is H and the other is methyl. In some embodiments of formula XIIb-i, one of R 13a and R 13b is H and the other is ethyl. In some embodiments of formula XIIb-i, the carbon bearing R 13 and R 13b has (R) stereochemistry.
  • the carbon bearing R 13 and R 13b has (S) stereochemistry.
  • n is 0 and the compound of formula XI is selected from compounds of Formula XIIb-i, and salts, hydrates, and solvates thereof:
  • R 11 is Ci-C 6 alkyl optionally substituted with one or more substituents selected from: Ci-C 6 alkoxy; and
  • R 13 and R 13b are each C 1 -C6 alkyl optionally independently substituted with one or more substituents independently selected from halogen and C 1 -C6 alkoxy.
  • X 1 is O.
  • R 11 is selected from methyl, ethoxyethyl and methoxyethyl. In some embodiments of formula Xllb-i, R 11 is methyl.
  • R 11 is ethoxyethyl.
  • R 11 is methoxyethyl.
  • R 13 and R 13b are each selected from methyl and ethyl. In some embodiments of formula Xllb-i, R 13 and R 13b are each methyl.
  • R 13 and R 13b are each ethyl.
  • n 1 and the compound of formula XI is selected from compounds of Formula XIIc, and salts, hydrates, and solvates thereof:
  • R 11 is C 1 -C6 alkyl optionally substituted with one or more substituents selected from: Ci-C6 alkoxy; and
  • each of R 12a and R 12b is H; or one of R 12a and R 12b is H and the other is Ci-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen and Ci-C6 alkoxy.
  • X 1 is O.
  • R 11 is selected from methyl, ethoxyethyl and methoxyethyl.
  • R 11 is methyl
  • R 11 is ethoxyethyl.
  • R 11 is methoxyethyl.
  • R 14 is methyl
  • the carbon bearing R 14 has (R) stereochemistry.
  • the carbon bearing R 14 has (S) stereochemistry.
  • each of R 12 and R 12b is H.
  • one of R 12a and R 12b is H and the other is Ci-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen and Ci-C6 alkoxy.
  • one of R 12 and R 12b is H and the other is selected from:
  • one of R 12 and R 12b is H and the other is methyl. In some embodiments of formula XIIc, one of R 12a and R 12b is H and the other is ethyl. In some embodiments of formula XIIc, one of R and R is H and the other is propyl,
  • one of R 12a and R 12b is H and the other is CF 3 .
  • one of R 12a and R 12b is H and the other is 2,2,2- trifluoroethyl.
  • one of R 12a and R 12b is H and the other is CH 2 OMe.
  • the carbon bearing R 12 and R 12b has (R)
  • the carbon bearing R 12 and R 12b has (S)
  • n 1 and the compound of formula XI is selected from compounds of Formula Xlld, and salts, hydrates, and solvates thereof:
  • R 11 is C 1 -C6 alkyl optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy;
  • each of R 12a and R 12b is H; or one of R 12a and R 12b is H and the other is Ci-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen and C 1 -C6 alkoxy.
  • X 1 is O.
  • R 11 is selected from methyl, ethoxyethyl and methoxyethyl.
  • R 11 is methyl
  • R 11 is ethoxyethyl.
  • R 11 is methoxyethyl.
  • R 14 is methyl
  • the carbon bearing R 14 has (R) stereochemistry. In some embodiments, the carbon bearing R 14 has (S) stereochemistry.
  • each of R 12 and R 12b is H.
  • one of R 12a and R 12b is H and the other is Ci-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen and C 1 -C6 alkoxy.
  • one of R and R is H and the other is selected from: H, methyl, ethyl, propyl, methoxymethyl, CF 3 and 2,2,2-trifluoroethyl.
  • one of R 12a and R 12b is H and the other is CH 2 OMe.
  • the carbon bearing R 12 and R 12b has (R)
  • n 1 and the compound of formula XI is selected from compounds of Formula Xlle, and salts, hydrates, and solvates thereof:
  • R 11 is C 1 -C6 alkyl optionally substituted with one or more substituents selected from: Ci-C6 alkoxy; and
  • each of R 12a and R 12b is H; or one of R 12a and R 12b is H and the other is Ci-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen and Ci-C6 alkoxy.
  • X 1 is O.
  • R 11 is selected from methyl, ethoxyethyl and methoxyethyl.
  • R 11 is methyl
  • R 11 is ethoxyethyl.
  • R 11 is methoxyethyl.
  • R 14 is methyl
  • the carbon bearing R 14 has (R) stereochemistry.
  • the carbon bearing R 14 has (S) stereochemistry. In some embodiments of formula Xlle, each of R and R is H.
  • one of R 12a and R 12b is H and the other is Ci-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen and C 1 -C6 alkoxy.
  • one of R 12 and R 12b is H and the other is selected from:
  • one of R 12 and R 12b is H and the other is methyl. In some embodiments of formula Xlle, one of R 12a and R 12b is H and the other is ethyl.
  • one of R 12 and R 12b is H and the other is propyl.
  • one of R 12a and R 12b is H and the other is CF 3 .
  • one of R 12 and R 12b is H and the other is 2,2,2- trifluoroethyl.
  • one of R 12a and R 12b is H and the other is CH 2 OMe.
  • the carbon bearing R 12 and R 12b has (R)
  • the carbon bearing R 12 and R 12b has (S)
  • n 1 and the compound of formula XI is selected from compounds of Formula Xllf, and salts, hydrates, and solvates thereof:
  • R 11 is C 1 -C6 alkyl optionally substituted with one or more substituents selected from: Ci-C6 alkoxy; and
  • R 13 and R 13b is H and the other is Ci-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen and Ci-C6 alkoxy.
  • X 1 is O.
  • R 11 is selected from methyl, ethoxyethyl and methoxyethyl.
  • R 11 is methyl
  • R 11 is ethoxyethyl. In some embodiments of formula Xllf, R 11 is methoxyethyl.
  • R 14 is methyl
  • the carbon bearing R 14 has (R) stereochemistry.
  • the carbon bearing R 14 has (S) stereochemistry.
  • one of R 13a and R 13b is H and the other is Ci-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen and C 1 -C6 alkoxy.
  • one of R 13 and R 13b is H and the other is selected from methyl and ethyl.
  • one of R 13 and R 13b is H and the other is methyl. In some embodiments of formula Xllf, one of R 13a and R 13b is H and the other is ethyl.
  • the carbon bearing R 13 and R 13b has (R) stereochemistry.
  • the carbon bearing R 13 and R 13b has (S) stereochemistry.
  • n 1 and the compound of formula XI is selected from compounds of Formula Xllg, and salts, hydrates, and solvates thereof:
  • R 11 is C 1 -C6 alkyl optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy;
  • R 13 and R 13b is H and the other is C 1 -C6 alkyl optionally substituted with one or more substituents independently selected from halogen and C 1 -C6 alkoxy.
  • X 1 is O.
  • R 11 is selected from methyl, ethoxyethyl and methoxyethyl.
  • R 11 is methyl
  • R 11 is ethoxyethyl.
  • R 11 is methoxyethyl.
  • R 14 is methyl. In some embodiments of formula Xllg, the carbon bearing R has (R) stereochemistry. In some embodiments of formula Xllg, the carbon bearing R 14 has (S) stereochemistry. In some embodiments of formula Xllg, one of R 13a and R 13b is H and the other is Ci-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen and Ci-C 6 alkoxy.
  • one of R 13 and R 13b is H and the other is selected from methyl and ethyl.
  • one of R 13 and R 13b is H and the other is methyl. In some embodiments of formula Xllg, one of R 13a and R 13b is H and the other is ethyl. In some embodiments of formula Xllg, the carbon bearing R 13 and R 13b has (R) stereochemistry.
  • the carbon bearing R 13 and R 13b has (S)
  • n 1 and the compound of formula XI is selected from compounds of Formula XlJh, and salts, hydrates, and solvates thereof:
  • R 11 is C 1 -C6 alkyl optionally substituted with one or more substituents selected from: Ci-C6 alkoxy; and
  • R 13 and R 13b is H and the other is Ci-C6 alkyl optionally substituted with one or more substituents independently selected from halogen and Ci-C6 alkoxy.
  • X 1 is O.
  • R 11 is selected from methyl, ethoxyethyl and methoxyethyl.
  • R 11 is methyl
  • R 11 is ethoxyethyl.
  • R 11 is methoxyethyl.
  • R 14 is methyl
  • the carbon bearing R 14 has (R) stereochemistry. In some embodiments of formula XlJh, the carbon bearing R 14 has (S) stereochemistry. In some embodiments of formula XlJh, one of R and R is H and the other is C 1 -C6 alkyl optionally substituted with one or more substituents independently selected from halogen and C 1 -C6 alkoxy.
  • one of R 13 and R 13b is H and the other is selected from methyl and ethyl.
  • one of R 13 and R 13b is H and the other is methyl.
  • one of R 13a and R 13b is H and the other is ethyl.
  • the carbon bearing R 13 and R 13b has (R)
  • the carbon bearing R 13 and R 13b has (S)
  • n 2 and the compound of Formula XI is selected from compounds of Formula XIIi, and salts, hydrates, and solvates thereof:
  • R 11 is C 1 -C6 alkyl optionally substituted with one or more substituents selected from: C 1 -C6 alkoxy.
  • each R 14 is the same.
  • each R 14 is methyl.
  • each R 14 is ethyl.
  • each R 14 is propyl.
  • X 1 is O.
  • R 11 is selected from methyl, ethoxyethyl and methoxyethyl.
  • R 11 is methyl
  • R 11 is ethoxyethyl.
  • R 11 is methoxyethyl.
  • the salts, hydrates, and solvates of the compounds of Formula XII including Formulae Xlla-i, Xllb-i, and XIIc, Xlld, ⁇ , Xllf, Xllg, Xllh and Xlli, are
  • Some embodiments of Formula XI include every combination of one or more compounds and pharmaceutically acceptable salts, hydrates, and solvates thereof selected from the following group shown in Table AA.
  • Some embodiments of Formula XI include every combination of one or more compounds and pharmaceutically acceptable salts, hydrates, and solvates thereof selected from the following group:
  • each of R 25 and R 26 is independently hydrogen or C 1 -C6 alkyl
  • R 27 is hydrogen, Ci-C 6 alkyl or C 3 -C 7 cycloalkyl
  • R 28 is hydrogen or C 1 -C6 alkyl
  • each of R 22 and R 23 is independently hydrogen or C 1 -C6 alkyl optionally substituted with one or more halogens;
  • R 22 and R 23 taken together with the carbon they are bonded to form a three-, four-, five-, six- or seven-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy;
  • R 24 is hydrogen, halogen, hydroxy, C 3 -C 7 cycloalkyl, Ci-C6 alkoxy or Ci-C6 alkyl optionally substituted with Ci-C 6 alkoxy;
  • R 21 is selected from the group consisting of:
  • Ci-C 6 alkyl optionally substituted with one or more substituents each of which is independently halogen, hydroxy, Ci-C6 alkoxy, amino, heteroarylamino, arylamino, C 1 -C6 dialkylamino, aryl, Ci-C6 alkoxycarbonyl, Ci-C6 alkylamino optionally substituted with Ci-C6 alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with Ci-C6 alkoxy, or C 3 -C 7 cycloalkyl optionally substituted with Ci-C6 alkoxy;
  • R 24 is hydrogen or halogen, at least one of R 21 , R 22 , R 23 , R 25 , R 26 R 27 and R 28 is other than hydrogen.
  • R 21 is selected from the group consisting of:
  • C 1 -C6 alkyl optionally substituted with one or more substituents each of which is independently halogen, hydroxy, Ci-C 6 alkoxy, amino, heteroarylamino, arylamino, C C6 dialkylamino, aryl, Ci-C6 alkoxycarbonyl, Ci-C6 alkylamino optionally substituted with C 1 -C6 alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with Ci-
  • Ci-C 6 dialkylamino optionally substituted with Ci-C 6 alkoxy or with hydroxy
  • R 21 is selected from the group consisting of:
  • C 1 -C6 alkyl optionally substituted with one or more substituents each of which is independently halogen or C 3 -C 7 cycloalkyl optionally substituted with Ci-C 6 alkoxy;
  • R 21 is hydrogen. In some embodiments, R is halogen. In some embodiments, R is chlorine. In some embodiments, R 21 is bromine. In some embodiments, R 21 is fluorine. In some embodiments, R 21 is iodine.
  • R 21 is Ci-C 6 alkyl optionally substituted with one or more substituents each of which is independently halogen, hydroxy, C 1 -C6 alkoxy, amino, heteroarylamino, arylamino, C 1 -C6 dialkylamino, aryl, C 1 -C6 alkoxycarbonyl, C 1 -C6 alkylamino optionally substituted with alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with C 1 -C6 alkoxy, or C3-C7 cycloalkyl optionally substituted with Ci-C 6 alkoxy.
  • R 21 is C 1 -C6 alkyl.
  • R 21 is C 1 -C6 alkyl optionally substituted with one or more substituents each of which is independently halogen or C3-C7 cycloalkyl optionally substituted with C 1 -C6 alkoxy.
  • R 21 is C 1 -C6 alkyl optionally substituted with one or more substituents each of which is halogen. In some embodiments, R 21 is Ci-C 6 alkyl optionally substituted with one or more substituents each of which is fluorine. In some embodiments, R 21 is 3,3,3-trifluoropropyl.
  • R 21 is C 1 -C6 alkyl optionally substituted with one or more substituents each of which is C3-C7 cycloalkyl optionally substituted with C 1 -C6 alkoxy.
  • R 21 is methyl. In some embodiments, R 21 is ethyl. In some embodiments, R 21 is propyl. In some embodiments, R 21 is isobutyl.
  • R 21 is aryl
  • R 21 is heteroaryl
  • R 21 is heteroaryl, wherein the heteroaryl is triazolyl.
  • the triazolyl is 1,2,4-triazol-l-yl.
  • R 21 is heteroaryl, wherein the heteroaryl is pyrazolyl.
  • the pyrazol is pyrazol-l-yl.
  • R 21 is heteroaryl, wherein the heteroaryl is pyrazolyl.
  • the pyrazol is pyrazol-3-yl.
  • R 21 is heteroaryl, wherein the heteroaryl is pyrazolyl.
  • the pyrazol is pyrazol-4-yl.
  • R 21 is heteroaryl, wherein the heteroaryl is pyrazolyl.
  • the pyrazol is pyrazol-5-yl.
  • R 21 is heteroaryl, wherein the heteroaryl is imidazolyl.
  • the imidazol is imidazol-l-yl.
  • R 21 is heteroaryl, wherein the heteroaryl is pyrrolyl.
  • the pyrrolyl is pyrrol-2-yl.
  • R 21 is heteroaryl, wherein the heteroaryl is thiophenyl. In some embodiments, the thiophenyl is thiophen-3-yl.
  • R 21 is heteroaryl, wherein the heteroaryl is furanyl.
  • the furanyl is furan-2-yl.
  • R is C 1 -C6 alkyl substituted with C 1 -C6 alkoxy.
  • R 21 is methoxymethyl. In some embodiments, R 21 is isopropoxymethyl.
  • R is C3-C7 cycloalkyl optionally substituted with C 1 -C6 alkoxy.
  • R 21 is amino
  • R 21 is C 1 -C6 alkylamino optionally substituted with C 1 -C6 alkoxy or with hydroxy.
  • R 21 is C 1 -C6 dialkylamino optionally substituted with C 1 -C6 alkoxy or with hydroxy.
  • R 21 is arylamino
  • R 21 is C 1 -C6 alkoxy optionally substituted with one or more halogens.
  • R 21 is hydroxyl
  • R 21 is -NHCO-Ci-Ce alkyl.
  • R 21 is -NHCO(0)C C 6 alkyl.
  • R 21 is -OCO(NH)Ci-C 6 alkyl.
  • R 21 is CN
  • each of R 22 and R 23 is independently hydrogen or C 1 -C6 alkyl optionally substituted with one or more halogens.
  • R 22 is hydrogen
  • R 23 is hydrogen
  • each of R 22 and R 23 is hydrogen.
  • R 22 is Ci-C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines.
  • R 23 is Ci-C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines.
  • each of R 22 and R 23 is Ci-C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines.
  • each of R 22 and R 23 is methyl.
  • each of R 22 and R 23 is ethyl.
  • each of R 22 and R 23 is propyl.
  • each of R 22 and R 23 is isobutyl.
  • each of R 22 and R 23 is 2,2,2-trifluoroethyl.
  • one of R 22 and R 23 is hydrogen and the other is Ci-C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines. In some embodiments, one of
  • R 22 and R 23 is hydrogen and the other is methyl.
  • one of R 2 ⁇ 2 and R 2 ⁇ 3 is hydro gen and the other is ethyl.
  • one of R 22 and R 23 is hydrogen and the other is propyl.
  • one of R 22 and R 23 is hydrogen and the other is isobutyl.
  • one of R 22 and R 23 is hydrogen and the other is 2,2,2-trifluoroethyl.
  • one of R and R is hydrogen, the other is C 1 -C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines, and the carbon attached to R 22 and R 23 has (R) stereochemistry.
  • one of R 22 and R 23 is hydrogen, the other is methyl, and the carbon attached to R 22 and R 23 has (R) stereochemistry.
  • one of R 22 and R 23 is hydrogen, the other is Ci-C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines, and the carbon attached to R 22 and R 23 has (S) stereochemistry.
  • one of R 22 and R 23 is hydrogen, the other is methyl, and the carbon attached to R 22 and R 23 has (S) stereochemistry.
  • R 22 and R 23 taken together with the carbon they are bonded to form a three-, four-, five-, six- or seven-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy.
  • R 22 and R 23 taken together with the carbon they are bonded to form a three-membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy.
  • R 22 and R 23 taken together with the carbon they are bonded to form a four-membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy.
  • R 22 and R 23 taken together with the carbon they are bonded to form a five-membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy.
  • R 22 and R 23 taken together with the carbon they are bonded to form a six-membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy.
  • R 22 and R 23 taken together with the carbon they are bonded to form a seven-membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy.
  • R 22 and R 23 taken together with the carbon they are bonded to form a three-membered heterocyclic ring containing one heteroatom which is O, N or S.
  • R 22 and R 23 taken together with the carbon they are bonded to form a four-membered heterocyclic ring containing one heteroatom which is O, N or S.
  • R 22 and R 23 taken together with the carbon they are bonded to form a five-membered heterocyclic ring containing one or two heteroatoms each of which is independently O, N or S.
  • the five-membered heterocyclic ring contains one heteroatom which is O.
  • the five-membered heterocyclic ring contains one heteroatom which is N.
  • R 22 and R 23 taken together with the carbon they are bonded to form a six-membered heterocyclic ring containing one or two heteroatoms each of which is independently O, N or S.
  • the six-membered heterocyclic ring contains one heteroatom which is O.
  • the six-membered heterocyclic ring contains one heteroatom which is N.
  • the six-membered heterocyclic ring contains one heteroatom which is N and one heteroatom which is O.
  • the six-membered heterocyclic ring contains two heteroatoms each of which is N.
  • R 22 and R 23 taken together with the carbon they are bonded to form a seven-membered heterocyclic ring containing one or two heteroatoms each of which is independently O, N or S.
  • the seven-membered heterocyclic ring contains one heteroatom which is N.
  • the seven-membered heterocyclic ring contains two heteroatoms each of which is N.
  • each of R 25 and R 26 is independently hydrogen or Ci-C6 alkyl.
  • R 25 is hydrogen
  • R 26 is hydrogen
  • each of R 25 and R 26 is hydrogen.
  • R 25 is Ci-C6 alkyl.
  • R 26 is Ci-C 6 alkyl.
  • each of R 25 and R 26 is Ci-C6 alkyl. In some embodiments, each of R 25 and R 26 is methyl.
  • one of R 25 and R 26 s hydrogen and the other is Ci-C6 alkyl. In some embodiments, one of R 25 and R 26 is hydrogen and the other is methyl.
  • one of R 25 and R 26 is hydrogen, the other is Ci-C 6 alkyl, and the carbon attached to R 25 and R 26 has (R) stereochemistry.
  • one of R 25 and R 26 is hydro gen, the other is methyl, and the carbon attached to R 25 and R 26 has (R) stereochemistry.
  • one of R 25 and R 26 is hydrogen, the other is Ci-C6 alkyl, and the carbon attached to R 25 and R 26 has (S) stereochemistry.
  • one of R 25 and R 26 is hydro gen, the other is methyl, and the carbon attached to R 25 and R 26 has (S) stereochemistry.
  • R 24 is hydrogen, halogen, hydroxy, C 3 -C 7 cycloalkyl, Ci-C6 alkoxy or
  • Ci-C 6 alkyl optionally substituted with Ci-C 6 alkoxy.
  • R 24 is hydrogen
  • R 24 is halogen. In some embodiments, R 24 is bromine. In some embodiments, R 24 is chlorine. In some embodiments, R 24 is fluorine.
  • R 24 is hydroxy
  • R 24 is C 3 -C 7 cycloalkyl
  • R 24 is cyclopropyl
  • R 24 is Ci-C6 alkoxy. In some embodiments, R is methoxy.
  • R 24 is C 1 -C6 alkyl optionally substituted with Ci-Ce alkoxy.
  • R 24 is methyl
  • R 24 is 2-ethoxyethyl.
  • R 27 is hydrogen, C 3 -C 7 cycloalkyl or Ci-C6 alkyl.
  • R 27 is hydrogen
  • R 27 is C 3 -C 7 cycloalkyl.
  • R 27 is cyclopropyl
  • R 27 is Ci-C 6 alkyl.
  • R 27 is methyl
  • R 27 is Ci-C 6 alkyl, and the carbon attached to R 27 has (R) stereochemistry.
  • R z/ is methyl, and the carbon attached to R z/ has (R) stereochemistry.
  • R 27 is Ci-C6 alkyl, and the carbon attached to R 27 has (S) stereochemistry. In some embodiments, R 27 is methyl, and the carbon attached to R 27 has (S) stereochemistry.
  • R 28 is hydrogen or Ci-C6 alkyl.
  • R 28 is hydrogen
  • R 28 is Ci-C 6 alkyl.
  • R 28 is methyl
  • R 28 is Ci-C6 alkyl, and the carbon attached to R 28 has (R) stereochemistry. In some embodiments, R 28 is methyl, and the carbon attached to R 28 has (R) stereochemistry.
  • R 28 is Ci-C6 alkyl, and the carbon attached to R 28 has (S) stereochemistry. In some embodiments, R 28 is methyl, and the carbon attached to R 28 has (S) stereochemistry. In some embodiments the compounds of Formula XXI are selected from compounds of
  • R is selected from the group consisting of
  • Ci-C 6 alkyl optionally substituted with one or more substituents each of which is independently halogen or C 3 -C 7 cycloalkyl;
  • R 22 is hydrogen or Ci-C 6 alkyl optionally substituted with halogen
  • R 23 is hydrogen or C 1 -C6 alkyl optionally substituted with halogen
  • R and R 23 are the same;
  • R 22 and R 23 taken together with the carbon they are bonded to form a three-membered carbocyclic ring, a four-membered carbocyclic ring, a five-membered carbocyclic ring or a six- membered carbocyclic ring;
  • R 24 is hydrogen, bromine or chlorine
  • R is hydrogen, at least one of R , R , and R is other than hydrogen;
  • R 24 is bromine or chlorine, R 21 is other than hydrogen.
  • the compounds of Formula XXI are selected from compounds of Formula XXII, and salts, hydrates, and solvates thereof:
  • R 21 is selected from the group consisting of
  • C 1 -C6 alkyl optionally substituted with one or more substituents each of which is independently halogen or C3-C7 cycloalkyl;
  • R 22 is hydrogen or C 1 -C6 alkyl optionally substituted with halogen
  • R 23 is hydrogen or C 1 -C6 alkyl optionally substituted with halogen
  • R and R 23 wherein if each of R and R is C 1 -C6 alkyl optionally substituted with halogen, then R and R 23 are the same; or R and R taken together with the carbon they are bonded to form a three-membered carbocyclic ring, a four-membered carbocyclic ring, a five-membered carbocyclic ring or a six- membered carbocyclic ring;
  • R 2 is hydrogen
  • R , R , and R is other than hydrogen.
  • the compounds of Formula XXI are selected from compounds of Formula XXII, and salts, hydrates, and solvates thereof:
  • R 21 is selected from the group consisting of
  • Ci-Ce alkyl optionally substituted with one or more substituents each of which is independently halogen , or C 3 -C 7 cycloalkyl;
  • R 22 is hydrogen or C 1 -C6 alkyl optionally substituted with halogen
  • R 23 is hydrogen or C 1 -C6 alkyl optionally substituted with halogen
  • R and R 23 are the same;
  • R 22 and R 23 taken together with the carbon they are bonded to form a three-membered carbocyclic ring, a four-membered carbocyclic ring, a five-membered carbocyclic ring or a six- membered carbocyclic ring;
  • R 24 is bromine or chlorine.
  • the compounds of Formula XXII are selected from compounds of Formula XXIIa, and salts, hydrates, and solvates thereof:
  • R is selected from the group consisting of
  • Ci-C 6 alkyl optionally substituted with one or more substituents each of which is independently halogen or C 3 -C 7 cycloalkyl;
  • R 22 is hydrogen or Ci-C 6 alkyl optionally substituted with halogen
  • R 21 and R 22 are provided that at least one of R 21 and R 22 is other than hydrogen.
  • the compounds of Formula XXII are selected from compounds of Formula XXIIa, and salts, hydrates, and solvates thereof:
  • R 21 is selected from the group consisting of
  • C 1 -C6 alkyl optionally substituted with one or more substituents each of which is independently halogen or C3-C7 cycloalkyl;
  • R 22 is hydrogen or C 1 -C6 alkyl optionally substituted with halogen
  • R 24 is bromine or chlorine.
  • the compounds of Formula XXIIa are selected from compounds of Formula XXIIa-i, and salts, hydrates, and solvates thereof:

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Abstract

La présente invention concerne des agonistes du récepteur 5-HT2C. L'invention porte en outre sur des procédés de gestion du poids, induisant la satiété, et la diminution d'absorption de nourriture, et de prévention et de traitement de l'obésité, de la prise de poids induite par des neuroleptiques, le diabète de type 2, le syndrome de Prader-Willi, la dépendance au tabac et à la nicotine, drug addiction, la pharmacodépendance, l'alcoolisme, le jeu pathologique, le syndrome de déficit en récompense, et la sexomanie, le spectre des troubles obsessionnels compulsifs et les troubles du contrôle des impulsions (notamment l'onychophagie), les troubles du sommeil (notamment l'insomnie, l'architecture de sommeil fragmenté, et les troubles du sommeil lent profond), l'incontinence urinaire, les troubles psychiatriques (notamment la schizophrénie, l'anorexie mentale et la boulimie mentale), la maladie d'Alzheimer, les dysfonctionnements sexuels, la dysérection, l'épilepsie, les mouvements involontaires (incluant le syndrome parkinsonien et les mouvements involontaires induits par les neuroleptiques), l'hypertension, la dyslipidémie, la stéatose hépatique non-alcoolique, les maladies rénales liées à l'obésité, et l'apnée du sommeil. L'invention porte en outre sur des compositions comprenant un agoniste du récepteur 5-HT2C sélectif, éventuellement en association avec un agent supplémentaire, et des procédés destinés à: réduire la fréquence de la prise de cigarette chez un individu essayant de diminuer sa consommation de tabac ; aider à cesser ou réduire la consommation d'un produit du tabac chez un individu essayant de cesser ou de diminuer sa consommation d'un produit du tabac ; aider au renoncement au tabac et prévenir la prise de poids associé ; contrôler le prise de poids associée au renoncement au tabac par un individu essayant de renoncer au tabac ; réduire la prise de poids associée au renoncement au tabac par un individu essayant de renoncer au tabac ; traiter la dépendance à la nicotine et/ou le sevrage chez un individu tenter de traiter la dépendance à la nicotine, l'addiction et/ou le sevrage ; ou réduire le risque d'une rechute d'utilisation de nicotine par un individu essayer de renoncer à l'utilisation de nicotine, comprenant l'administration d'un agoniste du récepteur 5-HT2C sélectif, éventuellement en association avec un agent supplémentaire.
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