Analogs of MDMA for modulating SERT, DAT, and / or NET activity

Abstract

Analogues of 3,4-methylenedioxymethamphetamine (MDMA), processes for their preparation, medicaments and medical methods of treatment that include said MDMA analogues, and medical uses of said MDMA analogues. MDMA analogues can modulate SERT, DAT, and / or NET activity.

Description

[Technical Field]

[0001] Disclosed herein are compounds that are analogs of 3,4-methylenedioxymethamphetamine (MDMA), processes for their preparation, medicaments and medical methods of treatment that include the MDMA analogs, and medical uses of the MDMA analogs. [Background technology]

[0002] The following discussion of the background art is intended only to facilitate an understanding of the present invention and is not an admission or acknowledgement that any of the referenced material is or was part of the common general knowledge as of the priority date of this application.

[0003] 3,4-Methylenedioxymethamphetamine (MDMA), the active ingredient in the illegal drug ecstasy, is a psychotropic substance whose entactogenic effects are primarily mediated by the serotonergic system. In recent years, numerous research studies have shown that MDMA possesses therapeutic potential for a wide range of medical conditions.

[0004] [ka]

[0005] The U.S. Food and Drug Administration (FDA) has approved limited research into MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), and Phase III clinical trials indicate that MDMA has clinical benefits in promoting psychotherapeutic effects for PTSD.

[0006] In humans, MDMA increases the amount of serotonin in the synaptic cleft of serotonergic neurons by inhibiting its uptake into neurons and directly releasing it from the neurons.The released serotonin binds to various serotonin receptors and overactivates them, which is the main mechanism by which MDMA causes intoxication.MDMA also induces significant norepinephrine and dopamine release.

[0007] Extracellular MDMA binds to the presynaptic serotonin reuptake transporter (SERT), norepinephrine reuptake transporter (NET), and dopamine reuptake transporter (DAT) as a reuptake inhibitor, causing these transporters to take up smaller amounts of their corresponding monoamine neurotransmitters, inducing higher concentrations and / or residence times of serotonin, norepinephrine, and dopamine in the synaptic cleft.

[0008] Burkitt lymphoma (BL) is an aggressive lymphoma that attacks B-lymphocytes. B-cell lines have been shown to possess a functional serotonin reuptake transporter (SERT). MDMA binds strongly to SERT, demonstrating its potential as a target for chemotherapy in BL patients, and exhibits antiproliferative and proapoptotic responses in the BL cell line L3055.

[0009] Transport of endogenous serotonin by SERT terminates the action of serotonin and recycles it in a sodium-dependent manner. SERT acts to remove serotonin from the synaptic cleft and return it to the synaptic bouton; that is, it terminates the effect of serotonin while simultaneously allowing its recycling by the presynaptic neuron. SERT is the target of many antidepressants in the selective serotonin reuptake inhibitor (SSRI) and tricyclic antidepressant classes.

[0010] Abnormal serotonin reuptake rates have been implicated in sudden infant death syndrome, aggressive behavior in Alzheimer's disease patients, post-traumatic stress disorder, and depression susceptibility in people who have experienced trauma. Numerous studies have shown that alterations in SERT metabolism appear to be related to many different phenomena, including alcoholism, clinical depression, obsessive-compulsive disorder (OCD), romantic attachment, hypertension, and generalized social phobia. SERT is also present in platelets, and serotonin functions as a vasoconstrictor and a signaling molecule that induces platelet aggregation.

[0011] Compounds such as MDMA analogs that possess the ability to modulate SERT activity therefore represent a great area of ​​potential in the treatment of a vast number of medical conditions, including but not limited to those related to the central nervous system (CNS).

[0012] Parkinson's disease (PD) is a neurodegenerative disorder whose symptoms are commonly treated with levodopa, which, after long-term therapy, leads to adverse side effects, including levodopa-induced dyskinesia (LID), thereby negating the benefits of the therapy. MDMA has been shown to have limited anti-Parkinson's disease and anti-LID activity in primate models and extends the duration of levodopa treatment.

[0013] The dopamine active transporter (DAT) is a transmembrane protein that transports the neurotransmitter dopamine from the synaptic cleft back into the cytosol. Reuptake of dopamine through the DAT provides the primary mechanism by which dopamine is removed from synapses. In addition to MDMA, other amphetamines (including amphetamine itself) bind strongly to the DAT.

[0014] Amphetamine enters the presynaptic neuron either directly across the neuronal membrane or through the DAT, where it competes with dopamine for reuptake. Once inside the presynaptic neuron, amphetamine causes a series of effects, including an increase in the firing rate of the postsynaptic neuron, induces protein kinase signaling, resulting in DAT phosphorylation (causing DAT to reverse and / or withdraw into the presynaptic neuron, completely ceasing transport), and enters synaptic vesicles, inducing the efflux of dopamine into the cytosol. The drug's dopaminergic mechanism is thought to underlie the pleasurable feelings it induces.

[0015] DAT is involved in many dopamine-related disorders, including attention deficit hyperactivity disorder, bipolar disorder, clinical depression, alcoholism, and substance use disorders.Dopamine underlies several aspects of cognition, including reward, and DAT facilitates the regulation of its signaling.The rate at which DAT removes dopamine from synapses can have a significant impact on the amount of dopamine in cells, as evidenced by the severe cognitive deficits, motor abnormalities, and hyperactivity in dopamine transporter-deficient mice, which show striking similarities to the symptoms of ADHD.

[0016] Specific alleles and mutations in the DAT gene are associated with nonsmoking behavior and ease of quitting smoking, a statistically significant affinity for antisocial peers in adolescent males, dopamine transporter deficiency syndrome, and a chromosomal recessive movement disorder characterized by progressively worsening dystonia and parkinsonism. Clinical depression is correlated with increased DAT activity.

[0017] Amphetamine family compounds, such as MDMA and its analogs, which possess the ability to modulate DAT activity, therefore represent a significant area of ​​potential in the treatment of a vast number of medical conditions, including, but not limited to, those related to the central nervous system (CNS).

[0018] The norepinephrine transporter (NET) is a monoamine transporter responsible for the sodium chloride-dependent reuptake of extracellular norepinephrine. NET can also reuptake extracellular dopamine. The reuptake of these two neurotransmitters regulates their concentrations in the synaptic cleft. NET, along with other monoamine transporters (DAT and SERT), is a target of many antidepressants and recreational drugs.

[0019] Overexpression of NETs is associated with individuals diagnosed with ADHD. Mutations in NETs are involved in ADHD, psychiatric disorders, postural tachycardia, orthostatic intolerance, postural orthostatic tachycardia syndrome, and panic disorder. Norepinephrine plays an important role in regulating mood, arousal, memory, learning, and pain perception. Dysregulation of norepinephrine removal by NETs is associated with many neuropsychiatric disorders, including schizophrenia, affective disorders, and autonomic disorders. Furthermore, many antidepressants and recreational drugs compete with norepinephrine for NET binding.

[0020] Inhibition of NETs has potential therapeutic applications in the treatment of a wide range of pathologies, including, but not limited to, attention-deficit hyperactivity disorder (ADHD), substance abuse, neurodegenerative disorders (e.g., Alzheimer's disease (AD) and Parkinson's disease (PD)), and clinical depression. NET inhibitors, such as reboxetine, have been shown to reduce the excitatory effects of MDMA in humans, demonstrating the important role that NETs play in the cardiovascular and stimulant-like effects of MDMA.

[0021] Compounds such as MDMA analogs that possess the ability to modulate NET activity therefore represent a great area of ​​potential in the treatment of a vast number of medical conditions, including but not limited to those related to the central nervous system (CNS).

[0022] Monoamine oxidase (MAO) is a family of enzymes found bound to the outer membrane of mitochondria in most cell types of the body that catalyzes the oxidative deamination of monoamines, using oxygen to remove their amine groups. MAO is important in the breakdown of exogenously ingested monoamines and also serves to inactivate monoamine neurotransmitters (including serotonin, dopamine, and norepinephrine). Due to their actions on monoamine neurotransmitters, MAO is involved in many psychiatric and neurological disorders, some of which can be treated through MAO inhibition. Monoamine oxidase subtype A (MAO-A) is found in neurons and astroglia in the central nervous system (CNS) and outside the CNS in the liver, pulmonary vascular endothelium, gastrointestinal tract, and placenta.

[0023] Mutations in the MAO gene are correlated with Brunner's syndrome, antisocial behavior disorder, adolescent conduct disorder, sympathetic arousal and agitation, and a predisposition to novelty-seeking. Because of the important role MAO plays in the inactivation of neurotransmitters, MAO dysfunction (too much or too little MAO activity) is associated with a wide range of psychiatric and neurological disorders. For example, abnormally high or low levels of MAO in the body are correlated with schizophrenia, depression, attention deficit disorder, substance abuse, migraine, and irregular sexual maturation. Abnormally high levels of catecholamines (including epinephrine, norepinephrine, and dopamine) can lead to hypertensive crisis, and abnormally high levels of serotonin can lead to serotonin syndrome. Meanwhile, inhibition of MAO often provides useful antidepressant and anxiolytic therapeutic effects and can be used in the treatment of a wide range of conditions, including, but not limited to, Alzheimer's disease, Parkinson's disease, psychomotor retardation, weight gain, interpersonal sensitivity, and resistant depression.

[0024] Compounds such as MDMA analogs that possess the ability to modulate MAO activity therefore represent a great area of ​​potential in the treatment of a vast number of medical conditions, including but not limited to those related to the central nervous system (CNS).

[0025] 5-HT receptors, or serotonin receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in both the central and peripheral nervous systems. They mediate excitatory and inhibitory neurotransmission and are activated by their natural endogenous ligand, the neurotransmitter serotonin. 5-HT receptors regulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine, norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others. 5-HT receptors influence many biological and neurological processes, including aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation.

[0026] The 5-HT receptor is the target of a variety of pharmaceutical and recreational drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastrokinetic agents, antimigraine agents, hallucinogens, and entactogens such as MDMA.

[0027] MDMA binds as an agonist to the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C serotonin receptors. Modulation of these receptor subtypes is; 5-HT1A; addiction, aggression, anxiety, appetite, autoreceptor signaling, blood pressure, cardiovascular function, vomiting, heart rate, impulsivity, memory, mood, nausea, nociception, penile erection, pupil dilation, respiration, sexual behavior, sleep, sociability, thermoregulation, and vasoconstriction; 5-HT2A; addiction (potentially modulating), anxiety, appetite, cognition, imagination, learning, memory, mood, perception, sexual behavior, sleep, thermoregulation, and vasoconstriction; 5-HT2B; anxiety, appetite, cardiovascular function, gastrointestinal motility, sleep, and vasoconstriction; 5-HT2C; Addiction (potentially modulating), anxiety, appetite, gastrointestinal motility, heteroreceptor signaling for norepinephrine and dopamine, movement, mood, penile erection, sexual behavior, sleep, thermoregulation, and vasoconstriction are involved in a wide range of functions, behaviors, and their associated pathologies, including

[0028] Activation of the 5-HT2B receptor, in particular, has also been strongly implicated in drug-induced valvular heart disease, and as a result, this receptor subtype is generally considered an anti-target. Similarly, 5-HT2B receptor antagonists, such as aripiprazole and clozapine (among others), have found clinical use in antipsychotic therapy. More recent studies suggest that 5-HT2B antagonists may be useful in the treatment of chronic heart disease, attenuating fibrogenesis, and improving liver function in diseases where fibrosis is pre-established and progressive.

[0029] Compounds such as MDMA analogs that possess the ability to modulate 5-HT receptor activity therefore represent a great area of ​​potential in the treatment of a vast number of medical conditions, including but not limited to those related to the central nervous system (CNS).

[0030] As discussed above, MDMA has shown great potential, and numerous research studies in recent years have found it to possess therapeutic effects for a range of medical conditions, including clinical benefits in PTSD therapy. However, significant problems exist with its implementation as a prescribed treatment. Chief among these issues is its potential for abuse, stemming from the drug's potentially induced extrapyramidal and euphoric effects. Controversially, long-term use of high doses of MDMA has also been associated with neurotoxicity. Long-term use of MDMA can lead to memory impairment, paranoia, and difficulty sleeping. Even short-term use can produce adverse effects, including teeth grinding, blurred vision, sweating, and rapid heartbeat. Furthermore, deaths have been reported due to elevated body temperature, dehydration, and hyponatremia (low blood sodium levels). Following use, subjects often feel depressed and fatigued.

[0031] There is a need to provide alternative compounds that possess similar structural and biological properties to MDMA and avoid one or more of the problems associated with producing extrapyramidal and euphoric effects, leading to abuse or addiction, neurotoxicity, or other adverse effects such as memory loss, paranoia, difficulty sleeping, teeth grinding, blurred vision, sweating, rapid heart rate, depression, fatigue, or death.

[0032] There is a need to provide new compounds that have the ability to modulate the activity of one or more of the SERT, DAT, NET, MAO and / or 5-HT receptors, preferably, but not necessarily (depending on the condition being treated), while avoiding agonist activity at the 5-HT2B receptor.

[0033] It is against this background that the present invention was developed. Summary of the Invention

[0034] The present disclosure provides novel MDMA analog compounds, processes for their synthesis, medicaments containing them, and methods of medical use and medical treatment including their administration to subjects in need thereof.

[0035] In one embodiment, the present disclosure provides compounds of Formula I, including stereoisomers, individual enantiomers, racemates, non-racemic mixtures, isotopically substituted compounds, prodrugs and / or pharmaceutically acceptable salts thereof;

[0036] [ka]

[0037] (In formula; One or more hydrogen atoms in the compounds of formula I may be replaced by fluorine;

[0038] R 1 and R 2 are independently H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12 Bicyclohaloalkyl, -C 6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicyclohaloalkynyl, -C 9-14 Spirocyclohaloalkynyl, -C 3-9 Heterocycloalkyl, -C 6-12 Heterobicycloalkyl, -C 6-12 Heterospirocycloalkyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8 Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C 1-8 Alkyl-CO2R a , -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c, -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8 Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C 2-8 Haloalkynyl-CN, -CH2-OR a , -C 2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-R a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a selected from the group consisting of:

[0039] where R 1 and R 2can together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heterocycloalkenyl ring, or a 6-membered heteroaryl ring, each of which can be unsubstituted or R 4 or R 5 may be substituted by one or more groups selected from

[0040] R 3 is selected from the group consisting of CF3, CN, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, vinyl, allyl, acetylenyl, cyclohexyl, cyclopentenyl, cyclohexenyl, propargyl, cyanomethyl, oxetanyl, thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolyl, oxanyl, dioxolanyl, pyridinyl, naphthyl, and phenyl; each of which can be unsubstituted or R 4 or R 5 or

[0041] R 3 is a 4- to 6-membered fused ring system or a 4- to 6-membered spiro ring system, each of which is a saturated carbocyclic ring system containing 0 heteroatoms or a saturated heterocyclic ring system containing 1 heteroatom selected from O or S, and each of which can be unsubstituted or can be selected from R 4 or R 5 may be substituted by one or more groups selected from

[0042] R 4 and R 5 is independently in each occurrence; halogen, -OR a , -SR a , -NR b R c , methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12 Bicyclohaloalkyl, -C 6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a, -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8 Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C 1-8 Alkyl-CO2R a , -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c, -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8 Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C 2-8 Haloalkynyl-CN, -CH2-OR a , -C 2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a or selected from the group consisting of;

[0043] Or, where R 4 and / or R 5 are bonded to the same carbon atom, and 4 and / or R 5 two of which together can form a carbonyl group; and

[0044] R a , R b and R cis independently in each occurrence: H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl and -C 2-5 haloalkynyl-heteroaryl) wherein the compound of formula I is:

[0045] [ka]

[0046] [ka]

[0047] [ka]

[0048] rather than a compound selected from the group consisting of:

[0049] and wherein the compound of formula I is not a compound published prior to the earliest priority date of the present disclosure, or wherein the compound of formula I is not a compound not previously identified by the inventors as having been published prior to the earliest priority date of the present disclosure.

[0050] In one embodiment, the present disclosure provides compounds of Formula II, including stereoisomers, individual enantiomers, racemates, non-racemic mixtures, isotopically substituted compounds, prodrugs and / or pharmaceutically acceptable salts thereof;

[0051] [ka]

[0052] (In formula; One or more hydrogen atoms in the compound of formula II may be replaced by fluorine;

[0053] R 1 and R 2 are independently H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12 Bicyclohaloalkyl, -C 6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicyclohaloalkynyl, -C 9-14 Spirocyclohaloalkynyl, -C 3-9 Heterocycloalkyl, -C 6-12 Heterobicycloalkyl, -C 6-12 Heterospirocycloalkyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8 Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C 1-8 Alkyl-CO2R a , -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2Ra , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8 Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C 2-8 Haloalkynyl-CN, -CH2-OR a , -C 2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-ORa , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-R a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a selected from the group consisting of:

[0054] where R 1 and R 2 can together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heterocycloalkenyl ring, or a 6-membered heteroaryl ring, each of which can be unsubstituted or R 4 or R 5 may be substituted by one or more groups selected from

[0055] R 3 is selected from the group consisting of CF3, CN, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, vinyl, allyl, acetylenyl, cyclohexyl, cyclopentenyl, cyclohexenyl, propargyl, cyanomethyl, oxetanyl, thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolyl, oxanyl, dioxolanyl, pyridinyl, naphthyl, and phenyl; each of which can be unsubstituted or R 4 or R 5or

[0056] R 3 is a 4- to 6-membered fused ring system or a 4- to 6-membered spiro ring system, each of which is a saturated carbocyclic ring system containing 0 heteroatoms or a saturated heterocyclic ring system containing 1 heteroatom selected from O or S, and each of which can be unsubstituted or can be selected from R 4 or R 5 may be substituted by one or more groups selected from

[0057] R 4 and R 5 is independently in each occurrence; halogen, -OR a , -SR a , -NR b R c , methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12 Bicyclohaloalkyl, -C 6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12Cyclohaloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8 Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C 1-8 Alkyl-CO2R a , -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8 Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C 2-8 Haloalkynyl-CN, -CH2-OR a , -C 2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-SR a, -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a or selected from the group consisting of;

[0058] Or, where R 4 and / or R 5 are bonded to the same carbon atom, and 4 and / or R 5 two of which together can form a carbonyl group; and

[0059] R a , R b and R c is independently in each occurrence: H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl and -C2-5 haloalkynyl-heteroaryl); The present invention provides a use for the manufacture of a medicament for the treatment or prevention of a disease, disorder, injury or trauma.

[0060] In one embodiment, the present disclosure provides a method of treating or preventing a disease, disorder, injury, or trauma comprising administering to a subject in need thereof an effective amount of a compound of Formula II, including stereoisomers, individual enantiomers, racemates, non-racemic mixtures, isotopically substituted variants, prodrugs, and / or pharmaceutically acceptable salts thereof;

[0061] [ka]

[0062] (In formula; One or more hydrogen atoms in the compound of formula II may be replaced by fluorine;

[0063] R 1 and R 2 are independently H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12 Bicyclohaloalkyl, -C 6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicyclohaloalkynyl, -C 9-14 Spirocyclohaloalkynyl, -C 3-9 Heterocycloalkyl, -C 6-12 Heterobicycloalkyl, -C 6-12 Heterospirocycloalkyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8 Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C 1-8 Alkyl-CO2R a , -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2Ra , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8 Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C 2-8 Haloalkynyl-CN, -CH2-OR a , -C 2-9 Alkyl-OR a , -C 2-9Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-R a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a selected from the group consisting of:

[0064] where R 1 and R 2 can together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heterocycloalkenyl ring, or a 6-membered heteroaryl ring, each of which can be unsubstituted or R 4 or R 5 may be substituted by one or more groups selected from

[0065] R 3is selected from the group consisting of CF3, CN, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, vinyl, allyl, acetylenyl, cyclohexyl, cyclopentenyl, cyclohexenyl, propargyl, cyanomethyl, oxetanyl, thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolyl, oxanyl, dioxolanyl, pyridinyl, naphthyl, and phenyl; each of which can be unsubstituted or R 4 or R 5 or

[0066] R 3 is a 4- to 6-membered fused ring system or a 4- to 6-membered spiro ring system, each of which is a saturated carbocyclic ring system containing 0 heteroatoms or a saturated heterocyclic ring system containing 1 heteroatom selected from O or S, and each of which can be unsubstituted or can be selected from R 4 or R 5 may be substituted by one or more groups selected from

[0067] R 4 and R 5 is independently in each occurrence; halogen, -OR a , -SR a , -NR b R c , methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12Bicyclohaloalkyl, -C 6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8 Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C1-8 Alkyl-CO2R a , -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8 Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C2-8 Haloalkynyl-CN, -CH2-OR a , -C 2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a or selected from the group consisting of;

[0068] Or, where R 4 and / or R 5 are bonded to the same carbon atom, and 4 and / or R 5 two of which together can form a carbonyl group; and

[0069] R a , R b and R c is independently in each occurrence: H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, aryl, heteroaryl, -C 1-5Alkyl-aryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl and -C 2-5 haloalkynyl-heteroaryl).

[0070] In one embodiment, the present disclosure provides a compound of Formula II', including stereoisomers, individual enantiomers, racemates, non-racemic mixtures, isotopically substituted compounds, prodrugs and / or pharmaceutically acceptable salts thereof;

[0071] [ka]

[0072] (In formula; One or more hydrogen atoms in the compound of formula II' may be replaced by fluorine;

[0073] R 1 and R 2 are independently H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12 Bicyclohaloalkyl, -C6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicyclohaloalkynyl, -C 9-14 Spirocyclohaloalkynyl, -C 3-9 Heterocycloalkyl, -C 6-12 Heterobicycloalkyl, -C 6-12 Heterospirocycloalkyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8 Haloalkenyl-C(=O)R a, -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C 1-8 Alkyl-CO2R a , -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8 Alkenyl-CN, -C 2-8Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C 2-8 Haloalkynyl-CN, -CH2-OR a , -C 2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-R a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a selected from the group consisting of:

[0074] where R 1 and R 2 can together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heterocycloalkenyl ring, or a 6-membered heteroaryl ring, each of which can be unsubstituted or R 4 or R 5 may be substituted by one or more groups selected from

[0075] R 3is selected from the group consisting of CF3, CN, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, vinyl, allyl, acetylenyl, cyclohexyl, cyclopentenyl, cyclohexenyl, propargyl, cyanomethyl, oxetanyl, thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolyl, oxanyl, dioxolanyl, pyridinyl, naphthyl, and phenyl; each of which can be unsubstituted or R 4 or R 5 or

[0076] R 3 is a 4- to 6-membered fused ring system or a 4- to 6-membered spiro ring system, each of which is a saturated carbocyclic ring system containing 0 heteroatoms or a saturated heterocyclic ring system containing 1 heteroatom selected from O or S, and each of which can be unsubstituted or can be selected from R 4 or R 5 may be substituted by one or more groups selected from

[0077] R 4 and R 5 is independently in each occurrence; halogen, -OR a , -SR a , -NR b R c , methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12Bicyclohaloalkyl, -C 6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8 Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C1-8 Alkyl-CO2R a , -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8 Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C2-8 Haloalkynyl-CN, -CH2-OR a , -C 2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a or selected from the group consisting of;

[0078] Or, where R 4 and / or R 5 are bonded to the same carbon atom, and 4 and / or R 5 two of which together can form a carbonyl group; and

[0079] R a , R b and R c is independently in each occurrence: H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, aryl, heteroaryl, -C 1-5Alkyl-aryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl and -C 2-5 1. A process for the preparation of a compound according to claim 1, wherein the compound is selected from the group consisting of haloalkynyl-heteroaryl;

[0080] wherein the process is represented by formula III;

[0081] [ka]

[0082] (Wherein, R is methyl, ethyl, and —C 3-9 a compound according to the formula (I) selected from the group consisting of alkyl; Formula IVa, or Formula IVb, or Formula IVc;

[0083] [ka]

[0084] (In the formula, R 3 is as defined for the compound of formula II', and wherein for compounds of formula IVb, each R 3 may be the same or different, and wherein R' is; methyl, ethyl, -C 3-9 a compound according to the formula (I) selected from the group consisting of alkyl, aryl, and haloaryl; reacting under a first set of reaction conditions to form a compound of formula V;

[0085] [ka]

[0086] and preparing a compound of formula (I): The compound of formula V is then subjected to a second set of reaction conditions to produce a compound of formula VI;

[0087] [ka]

[0088] producing a ketone intermediate of the formula: and subsequently, the compound of formula VI, formula VII;

[0089] [ka]

[0090] (In the formula, R 1 and R 2 is as defined for said compound of formula II'; and by reductive amination under a third set of reaction conditions to produce said compound of formula II'.

[0091] BRIEF DESCRIPTION OF THE DRAWINGS Further features of the present invention will be more fully described in the following description of some non-limiting embodiments thereof. This description is included for purposes of illustrating the invention only. It should not be understood as a limitation on the broad summary, disclosure, or description of the invention presented above. The description is made with reference to the accompanying drawings:

[0092] definition Throughout this specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0093] As used herein, the term "stereoisomer," and its grammatical variations, such as "stereoisomers," "stereoisomerism," and "stereoisomeric," refer to spatial isomerism in molecular entities to which it is applied in context. More specifically, the term should be understood to include molecules that have the same molecular formula and arrangement of bonded atoms (configuration) but differ in the three-dimensional orientation of their atoms in space. That is, stereoisomers should be understood to include optical isomers or enantiomers, diastereoisomers, cis-trans or EZ isomers, conformers, anomers, atropisomers, configurational isomers, and epimers of the molecular entities to which the term is applied. By definition, molecules that are stereoisomers of each other represent structural isomers and constitutional isomers.

[0094] All chiral, diastereomeric, racemic, non-racemic mixtures, and geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomers of the compounds shown or described are also considered to be part of the present invention.

[0095] As used herein, the term "isotopologue," and grammatical variations thereof, such as "isotopologue," should be understood to mean molecules that differ only in their isotopic composition. That is, the term refers to molecules having the same chemical formula and bonding arrangement of atoms, but at least one atom has a different number of neutrons than the parent.

[0096] As used herein, the term "prodrug" and grammatical variations thereof, such as "prodrugs," should be understood to mean a compound that is hydrolyzed or metabolized in vivo (i.e., converted within the body) into a pharmacologically active drug after administration. That is, a "prodrug" refers to a compound that is metabolized in the host, e.g., hydrolyzed or oxidized, to form a compound of Formula (I) or Formula (II). Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs can include compounds that can be, for example, oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce an active compound. Those skilled in the art will know that compounds containing, for example, hydroxyl, carboxylic acid, or amine substituents can be derivatized as esters or amides, and that such derivatives are susceptible to in vitro hydrolysis and / or metabolism to yield the parent underivatized compound. Such derivatives are to be understood as falling within the scope of the term “prodrugs.” Prodrugs can be readily prepared from compounds of Formula (I) or Formula (II) using methods known in the art.See, for example, Notari, R.E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology, 112:309-323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future, 6(3): 165-182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, NY (1985); Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172-178, 949-982 (1995).

[0097] As used herein, the term "pharmaceutically acceptable" will be understood to mean a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual, together with a compound or composition of this invention, without causing substantial adverse biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The material would, of course, be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.

[0098] The compounds of the present invention can exist in free form or in salt form, for example, as acid addition salts. In this specification, unless otherwise indicated, terms such as "compounds of the present invention" should be understood to include the compounds in any form, for example, in free form or in acid addition salt form, or, if the compound contains an acidic substituent, in base addition salt form. The compounds of the present invention are intended for use as pharmaceuticals or veterinary medicines, and therefore pharmaceutically acceptable salts are preferred. Salts unsuitable for pharmaceutical use may be useful, for example, for the isolation or purification of the free compounds of the present invention or their salts or pharmaceutically acceptable salts, and therefore are also included. "Pharmaceutically acceptable salts" include, without limitation, for example, sodium, magnesium, calcium, lithium, potassium, chloride, bromide, iodide, hydrochloride, hydrobromide, sulfate, acetate, tartrate, malate, mesylate, and tosylate.

[0099] As used herein, the term "alkyl," by itself or as part of another substituent, unless otherwise stated, and where specified, has the number of carbon atoms designated (i.e., "-C 1-10 "Alkyl" will be understood to mean a straight or branched chain hydrocarbon, meaning an alkyl having from 1 to 10 carbon atoms. By way of example, and without limitation, the term "-C 1-8 "Alkyl" refers to a straight or branched chain hydrocarbon moiety having from 1 to 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 "Alkyl" refers to a straight or branched chain hydrocarbon moiety having from 1 to 2, 3, 4, 5, or 6 carbon atoms. 1-4 "Alkyl" refers to a straight or branched chain hydrocarbon moiety having from 1, 2, 3, or 4 carbon atoms, including methyl, ethyl, n-propyl, n-propyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. 1-9 "Haloalkyl" refers to a straight or branched chain hydrocarbon moiety having from 1 to 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, wherein one or more of said carbon atoms is substituted with one or more halogen atoms selected from F, Cl, Br, or I.

[0100] As used herein, the terms "parent molecular structure," "parent molecule," and grammatical variations thereof, when used in the context of defining variable substituents of a Markush formula, will be understood to refer to the core structure or non-variable structure of the Markush formula to which it is applied. For example, Formula I, as defined herein, is the parent molecular structure:

[0101] [ka]

[0102] Variable R bound to 1 , R 2 and R 3 It has.

[0103] As used herein, and unless otherwise stated, the term "alkenyl," used alone or in combination with other terms, refers to a straight or branched chain hydrocarbon group containing at least one double bond and, where specified, having the specified number of carbon atoms, for example, from 2 to 10 carbon atoms (i.e., -C 2-10 alkenyl). Whenever it appears herein, a numerical range such as "2 to 10" or "2-10" refers to each integer in the given range; for example, "2 to 10 carbon atoms" would be -C 2-10 This means that the alkenyl group can consist of 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Alkenyl groups are attached to the parent molecular structure by a single bond, such as ethenyl (i.e., vinyl), propen-1-yl (i.e., allyl), buten-1-yl, penten-1-yl, penta-1,4-dienyl, and the like. The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). -C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), 2-methylprop-2-enyl (C4), butadienyl (C4), and the like.2-6 Examples of alkenyl groups include the aforementioned -C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), 2,3-dimethyl-2-butenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Further examples include vinyl, propenyl (i.e., allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher homologs and isomers. An example of a functional group representing an alkene is -CH2-CH=CH2. The term "-C 2-9 "Haloalkenyl" refers to a straight or branched chain hydrocarbon moiety containing at least one double bond and having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, wherein one or more of said carbon atoms is substituted with one or more halogen atoms selected from F, Cl, Br, or I.

[0104] As used herein, and unless otherwise stated, the term "alkynyl," used alone or in combination with other terms, refers to an alkyl group containing at least one triple bond and having the number of carbon atoms specified (i.e., -C 2-10 alkynyl) straight or branched chain hydrocarbon groups. Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range; for example, "-C 2-10 "Alkynyl" means that the alkynyl group can consist of 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. In certain embodiments, the alkynyl contains 2 to 9 carbon atoms. The alkynyl is attached to the parent molecular structure by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, 3-methyl-4-pentenyl, hexynyl, and the like. Non-limiting examples include ethynyl and propynyl, as well as higher homologs and isomers. Grammatical variations such as the terms "propargylic" and "propargyl" refer to a group exemplified by -CH-C≡CH. The term "-C 2-9"Haloalkynyl" refers to a straight or branched chain hydrocarbon moiety containing at least one triple bond and having from 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, wherein one or more of said carbons are substituted with one or more halogen atoms selected from F, Cl, Br, or I.

[0105] As used herein, the term "halo," used alone or in combination with other terms, unless otherwise stated, will be understood to mean one or more halogen atom substituents independently selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). The term "halo" will be understood to be used interchangeably with the term "halogen."

[0106] As used herein, the term "cyclo", when used in combination with other terms, will be understood to mean a cyclic moiety, unless otherwise stated.

[0107] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic properties, e.g., having (4n+2) delocalized π (pi) electrons under classical circumstances, where n is an integer. Those skilled in the art will know that there are exceptions to the general (4n+2) delocalized π (pi) electron rule that still possess aromatic properties and therefore also fall within the definition of "aromatic."

[0108] As used herein, the term "aryl," used alone or in combination with other terms, unless otherwise stated, means a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), where such rings may be fused, such as naphthalene. In polycyclic groups, only one ring is required to be aromatic, so groups such as indanyl are encompassed by the definition of aryl, provided that the aromatic ring of such groups is directly attached to the parent molecule. The ring or ring system may have from 6 to 14 ring atoms (e.g., C 6-14 Aromatic or C 6-14Whenever it appears herein, a numerical range such as "6 to 14 aryl" refers to each integer in the given range; for example, "C 6-14 "Aryl" means that the aryl group can consist of 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms. Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl, indanyl, and the like.

[0109] As used herein, and in combination with other terms, the term "hetero", unless otherwise stated, will be understood to mean the replacement of one or more carbon atoms in the other term to which it applies with a heteroatom, in each instance independently selected from the group consisting of oxygen (O), nitrogen (N), sulfur (S), selenium (Se), silicon (Si) or phosphorus (P).

[0110] As used herein, the term "heteroaryl" includes 5-, 6-, and 7-membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring systems having ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur. For example, a heteroaryl can have one or two 5-, 6-, or 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S. A heteroaryl bicyclic ring system can contain 1, 2, 3, or 4 heteroatoms in one or both rings. Exemplary heteroaryls include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, oxadiazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, azepine, oxepin, oxazine, triazine, pyrimidine, indole, and benzimidazole. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics."

[0111] As used herein, the term "cycloalkyl," used alone or in combination with other terms, will be understood to mean a cycloalkyl moiety, unless otherwise stated. When a number of carbon atoms is specified, the cycloalkyl moiety will contain the specified number of carbon atoms. When a range in the number of carbon atoms is specified, the cycloalkyl moiety will contain a number of carbon atoms selected from the integers within the specified range. For example, "-C 3-9 "Cycloalkyl" shall be understood to mean a saturated carbocyclic moiety containing 3, 4, 5, 6, 7, 8, or 9 carbon atoms, and shall thus be understood to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl moieties. 6-12 "Bicycloalkyl" will be understood to mean a saturated carbocyclic ring system containing two fused carbocyclic rings and having 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 6-12 "Spirocycloalkyl" will be understood to mean a saturated carbocyclic ring system containing two carbocyclic rings, in which only one carbon atom is common to both rings, and having 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-9 "Cyclohaloalkyl" will be understood to mean a saturated carbocyclic moiety containing 3, 4, 5, 6, 7, 8, or 9 carbon atoms, wherein one or more of the carbon atoms are substituted in each instance with one or more halo groups independently selected from F, Cl, Br, and I. 6-12 "Bicyclohaloalkyl" will be understood to mean a saturated carbocyclic ring system containing two fused carbocyclic rings and having 6, 7, 8, 9, 10, 11 or 12 carbon atoms, wherein one or more of the carbon atoms are substituted in each instance with one or more halo groups independently selected from F, Cl, Br and I. 6-12"Spirocyclohaloalkyl" will be understood to mean a saturated carbocyclic ring system comprising two carbocyclic rings, in which only one carbon atom is common to both rings, and having 6, 7, 8, 9, 10, 11 or 12 carbon atoms, in which one or more of the carbon atoms are substituted in each case with one or more halo groups independently selected from F, Cl, Br and I.

[0112] As used herein, the term "cycloalkenyl," used alone or in combination with other terms, unless otherwise stated, will be understood to mean a cycloalkyl moiety containing one or more double bonds. When a number of carbon atoms is specified, the cycloalkenyl moiety will contain the specified number of carbon atoms. When a range in the number of carbon atoms is specified, the cycloalkenyl moiety will contain a number of carbon atoms selected from the integers within the specified range. For example, "-C 3-9 "Cycloalkenyl" is understood to mean a carbocyclic moiety having at least one double bond and containing 3, 4, 5, 6, 7, 8, or 9 carbon atoms, and thus will be understood to include cyclopropenyl, cyclobutenyl, cyclobutadienyl, cyclopentenyl, cyclopentadienyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclononatrienyl, and cyclononatetraenyl moieties. 6-12 "Bicycloalkenyl" will be understood to mean a carbocyclic ring system having at least one double bond, containing two fused carbocyclic rings and having 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 6-12 "Spirocycloalkenyl" will be understood to mean a carbocyclic ring system containing two carbocyclic rings and at least one double bond, where only one carbon atom is common to both rings, and having 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-9"Cyclohaloalkenyl" will be understood to mean a carbocyclic moiety having at least one double bond and containing 3, 4, 5, 6, 7, 8, or 9 carbon atoms, wherein one or more of the carbon atoms are substituted in each instance with one or more halo groups independently selected from F, Cl, Br, and I. 6-12 "Bicyclohaloalkenyl" will be understood to mean a carbocyclic ring system having at least one double bond, containing two fused carbocyclic rings and having 6, 7, 8, 9, 10, 11 or 12 carbon atoms, wherein one or more of the carbon atoms are substituted in each instance with one or more halo groups independently selected from F, Cl, Br and I. 6-12 "Spirocyclohaloalkenyl" will be understood to mean a carbocyclic ring system having at least one double bond and comprising two carbocyclic rings, wherein only one carbon atom is common to both rings, and having 6, 7, 8, 9, 10, 11 or 12 carbon atoms, wherein one or more of the carbon atoms are substituted in each case with one or more halo groups independently selected from F, Cl, Br and I.

[0113] As used herein, the term "cycloalkynyl," used alone or in combination with other terms, unless otherwise stated, will be understood to mean a cycloalkyl moiety containing one or more triple bonds. When a number of carbon atoms is specified, the cycloalkynyl moiety will contain the specified number of carbon atoms. When a range in the number of carbon atoms is specified, the cycloalkynyl moiety will contain a number of carbon atoms selected from the integers within the specified range. For example, "-C 8-12"Cycloalkynyl" is understood to mean a carbocyclic moiety having at least one triple bond and containing 8, 9, 10, 11, or 12 carbon atoms, and thus will be understood to include the cyclooctynyl, cyclooctadiynyl, cyclononynyl, cyclononadiynyl, cyclononatriynyl, cyclodecynyl, cyclodecadiynyl, cyclodecatriynyl, cycloundecynyl, cycloundecdiynyl, cycloundecatriynyl, cyclododecynyl, cyclododecadiynyl, cyclododecatriynyl, and cyclododecatetranyl moieties. 9-14 "Bicycloalkynyl" will be understood to mean a carbocyclic ring system having at least one triple bond, containing two fused carbocyclic rings and having 9, 10, 11, 12, 13 or 14 carbon atoms. 9-14 "Spirocycloalkynyl" will be understood to mean a carbocyclic ring system containing two carbocyclic rings and at least one triple bond, where only one carbon atom is common to both rings, and having 9, 10, 11, 12, 13 or 14 carbon atoms. 8-12 "Cyclohaloalkenyl" will be understood to mean a carbocyclic moiety having at least one triple bond and containing 8, 9, 10, 11, or 12 carbon atoms, wherein one or more of the carbon atoms are substituted, at each occurrence, with one or more halo groups independently selected from F, Cl, Br, and I. 9-14 "Bicyclohaloalkenyl" will be understood to mean a carbocyclic ring system having at least one triple bond, comprising two fused carbocyclic rings and having 9, 10, 11, 12, 13 or 14 carbon atoms, wherein one or more of the carbon atoms are substituted in each instance with one or more halo groups independently selected from F, Cl, Br and I. 9-14"Spirocyclohaloalkenyl" will be understood to mean a carbocyclic ring system having at least one triple bond and comprising two carbocyclic rings, wherein only one carbon atom is common to both rings, and having 9, 10, 11, 12, 13 or 14 carbon atoms, wherein one or more of the carbon atoms are substituted in each case with one or more halo groups independently selected from F, Cl, Br and I.

[0114] The term “-C 1-5 "Alkyl-aryl" will be understood to mean a substituent that includes an aryl (aromatic) group that is attached to a parent molecule via a branched or straight-chain fully saturated linker, wherein said linker contains 1, 2, 3, 4 or 5 carbon atoms.

[0115] The term “-C 2-5 "Alkenyl-aryl" will be understood to mean a substituent that includes an aryl (aromatic) group that is attached to a parent molecule via a branched or straight-chain linker, wherein said linker has at least one double bond and contains 2, 3, 4 or 5 carbon atoms.

[0116] The term “-C 2-5 "Alkynyl-aryl" will be understood to mean a substituent that includes an aryl (aromatic) group that is attached to a parent molecule via a branched or straight-chain linker, wherein said linker has at least one triple bond and contains 2, 3, 4 or 5 carbon atoms.

[0117] The term “-C 1-5 "Alkyl-heteroaryl" will be understood to mean a substituent that includes a heteroaryl (heteroaromatic) group that is attached to a parent molecule via a branched or straight-chain fully saturated linker, wherein said linker contains 1, 2, 3, 4 or 5 carbon atoms.

[0118] The term “-C 2-5"Alkenyl-heteroaryl" will be understood to mean a substituent that includes a heteroaryl (heteroaromatic) group that is attached to a parent molecule via a branched or straight-chain linker, wherein said linker has at least one double bond and contains 2, 3, 4, or 5 carbon atoms.

[0119] The term “-C 2-5 "Alkynyl-heteroaryl" will be understood to mean a substituent that includes a heteroaryl (heteroaromatic) group that is attached to a parent molecule via a branched or straight-chain linker, wherein said linker has at least one triple bond and contains 2, 3, 4, or 5 carbon atoms.

[0120] The term “-C 1-5 "Haloalkyl-aryl" will be understood to mean a substituent comprising an aryl (aromatic) group attached to a parent molecule via a branched or straight-chain fully saturated linker, wherein said linker comprises 1, 2, 3, 4 or 5 carbon atoms, and wherein one or more of the carbon atoms of the linker are substituted in each instance with one or more halo groups independently selected from F, Cl, Br and I.

[0121] The term “-C 2-5 "Haloalkenyl-aryl" will be understood to mean a substituent comprising an aryl (aromatic) group attached to a parent molecule via a branched or straight-chain linker, wherein said linker has at least one double bond and comprises 2, 3, 4 or 5 carbon atoms, wherein one or more of the carbon atoms of the linker are substituted in each instance with one or more halo groups independently selected from F, Cl, Br and I.

[0122] The term “-C 2-5"Haloalkynyl-aryl" will be understood to mean a substituent comprising an aryl (aromatic) group attached to a parent molecule via a branched or straight-chain linker, wherein said linker has at least one triple bond and comprises 2, 3, 4 or 5 carbon atoms, wherein one or more of the carbon atoms of the linker are substituted in each instance with one or more halo groups independently selected from F, Cl, Br and I.

[0123] The term “-C 1-5 "Haloalkyl-heteroaryl" will be understood to mean a substituent comprising a heteroaryl (heteroaromatic) group attached to a parent molecule via a branched or straight-chain fully saturated linker, wherein said linker contains 1, 2, 3, 4 or 5 carbon atoms, and wherein one or more of the carbon atoms of the linker are substituted in each instance with one or more halo groups independently selected from F, Cl, Br and I.

[0124] The term “-C 2-5 "Haloalkenyl-heteroaryl" will be understood to mean a substituent comprising a heteroaryl (heteroaromatic) group attached to a parent molecule via a branched or straight-chain linker, wherein said linker has at least one double bond and comprises 2, 3, 4 or 5 carbon atoms, wherein one or more of the carbon atoms of the linker are substituted in each instance with one or more halo groups independently selected from F, Cl, Br and I.

[0125] The term “-C 2-5 "Haloalkynyl-heteroaryl" will be understood to mean a substituent comprising a heteroaryl (heteroaromatic) group attached to a parent molecule via a branched or straight-chain linker, wherein said linker has at least one triple bond and comprises 2, 3, 4 or 5 carbon atoms, wherein one or more of the carbon atoms of the linker are substituted in each instance with one or more halo groups independently selected from F, Cl, Br and I.

[0126] It will be understood that the description of compounds herein is limited by principles of chemical bonding and valence known to those skilled in the art. Thus, where a group may be substituted with one or more of a number of substituents, such substitutions will be selected to comply with principles of chemical bonding related to valence and to provide compounds that are not inherently unstable.

[0127] The words "treatment" and "treating" should be understood as including prevention and treatment or amelioration of symptoms of a disease, disorder, condition or illness as well as treatment of the cause of the disease, disorder, condition or illness, as appropriate.

[0128] The term "subject" in the context of methods of treatment can include a human subject or a non-human subject.

[0129] As used herein, the term "effective amount" refers to an amount sufficient to produce beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages. Determining the effective amount for a given administration is well within the ordinary skill of the pharmaceutical arts.

[0130] As used herein, the term "diluent" refers to a pharmacologically inactive substance that serves as an excipient in a dosage form but is suitable for human consumption. Diluents serve to dilute the active pharmaceutical ingredient in the dosage form so that tablets of typical size can be prepared incorporating a wide range of actual doses of the active pharmaceutical ingredient. If it is desired to maximize the content of one or both pharmaceutical ingredients per dosage form for a specific dosage unit size, a diluent need not be included. Diluents may include microcrystalline cellulose, such as AVICEL. Lactose and isomalt are other common diluents. AVICEL, a form of microcrystalline cellulose, is a commercially available product made from acid-treated cellulose, a process that tends to dissolve more amorphous regions of the cellulose and leave more crystalline regions of the cellulose. Microcrystalline cellulose may be a diluent in the dosage form of the present invention.

[0131] Other diluents familiar to those skilled in the art include monobasic calcium phosphate, dibasic calcium phosphate, and tribasic calcium phosphate. Almost completely water-insoluble, calcium phosphate is a particularly well-known pharmacologically inert diluent or filler that is compatible with a wide range of active pharmaceutical ingredients. The term "calcium phosphate" as used herein refers to any form of calcium phosphate, including, for example, monobasic calcium phosphate (Ca(H2PO4)2), dibasic calcium phosphate (CaHPO4), and tricalcium phosphate (Ca2(PO4)S), as well as any orthophosphate, pyrophosphate, or superphosphate salt, or other polymeric phosphate salts whose counterion contains calcium.

[0132] As used herein, the term "excipient" refers to an ingredient of a dosage form that is not pharmaceutically active but serves other functions such as diluting the active pharmaceutical ingredient, assisting in the dispersion of the tablet in the patient's stomach, binding the tablet together, and stabilizing the active pharmaceutical ingredient against degradation.

[0133] As used herein, the term "pharmaceutically acceptable carrier," and grammatical variations thereof, refers to adjuvants, binders, and the like known to those skilled in the art that are suitable for administration to an individual (e.g., a mammal or non-mammal). The pharmaceutically acceptable carrier(s) and any additional ingredients described herein should be compatible for use in the intended route of administration (e.g., oral, parenteral) for the particular dosage form. Pharmaceutically acceptable carriers or excipients preferably meet the required specifications for toxicological and manufacturing testing and / or are included on the inactive ingredient guide prepared by the U.S. Food and Drug Administration (FDA).

[0134] Other definitions for selected terms used herein may be found within the detailed description of the invention and are applied throughout. Unless defined otherwise, all other scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. DETAILED DESCRIPTION OF THE INVENTION

[0135] Detailed Description The present invention seeks to address the need to provide alternative analogs of MDMA that possess the same methylenedioxy-phenylethylamine skeleton as MDMA, but vary the substituents on the ethylamine nitrogen and / or at the alpha position, and thereby provide compounds that possess similar structural and biological properties as MDMA and other phenethylamine or tryptamine drugs and neurotransmitter compounds, including their significant therapeutic potential in the treatment of a vast number of medical conditions, while avoiding, circumventing, overcoming or obviating one or more of the problems associated with prescribing MDMA and other phenethylamine or tryptamine-based compounds as therapeutic treatments.

[0136] In a first aspect, the present disclosure provides compounds of Formula I, including stereoisomers, individual enantiomers, racemates, non-racemic mixtures, isotopically substituted compounds, prodrugs and / or pharmaceutically acceptable salts thereof;

[0137] [ka]

[0138] (In formula; One or more hydrogen atoms in the compounds of formula I may be replaced by fluorine;

[0139] R 1 and R 2 are independently H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C6-12 Bicyclohaloalkyl, -C 6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicyclohaloalkynyl, -C 9-14 Spirocyclohaloalkynyl, -C 3-9 Heterocycloalkyl, -C 6-12 Heterobicycloalkyl, -C 6-12 Heterospirocycloalkyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C 1-8 Alkyl-CO2R a , -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C 2-8 Haloalkynyl-CN, -CH2-OR a , -C 2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-R a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a selected from the group consisting of:

[0140] where R 1 and R 2 can together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heterocycloalkenyl ring, or a 6-membered heteroaryl ring, each of which can be unsubstituted or R 4 or R 5 may be substituted by one or more groups selected from

[0141] R 3is selected from the group consisting of CF3, CN, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, vinyl, allyl, acetylenyl, cyclohexyl, cyclopentenyl, cyclohexenyl, propargyl, cyanomethyl, oxetanyl, thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolyl, oxanyl, dioxolanyl, pyridinyl, naphthyl, and phenyl; each of which can be unsubstituted or R 4 or R 5 or

[0142] R 3 is a 4- to 6-membered fused ring system or a 4- to 6-membered spiro ring system, each of which is a saturated carbocyclic ring system containing 0 heteroatoms or a saturated heterocyclic ring system containing 1 heteroatom selected from O or S, and each of which can be unsubstituted or can be selected from R 4 or R 5 may be substituted by one or more groups selected from

[0143] R 4 and R 5 is independently in each occurrence; halogen, -OR a , -SR a , -NR b R c , methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12Bicyclohaloalkyl, -C 6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8 Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C1-8 Alkyl-CO2R a , -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8 Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C2-8 Haloalkynyl-CN, -CH2-OR a , -C 2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a or selected from the group consisting of;

[0144] Or, where R 4 and / or R 5 are bonded to the same carbon atom, and 4 and / or R 5 two of which together can form a carbonyl group; and

[0145] R a , R b and R c is independently in each occurrence: H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, aryl, heteroaryl, -C 1-5Alkyl-aryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl and -C 2-5 haloalkynyl-heteroaryl); wherein the compound of formula I is:

[0146] [ka]

[0147] [ka]

[0148] [ka]

[0149] rather than a compound selected from the group consisting of:

[0150] and wherein the compound of formula I is not a compound published prior to the earliest priority date of the present disclosure, or wherein the compound of formula I is not a compound not previously identified by the inventors as having been published prior to the earliest priority date of the present disclosure.

[0151] In a preferred embodiment, the compound of formula I is R 1 and R 2are independently H, methyl, ethyl, propyl, isopropyl, allyl, cyclopropylmethyl, propargyl, butyl, isobutyl, t-butyl, cyclobutyl, -C 1-9 Haloalkyl, -C 2-9 Alkyl-OR a , -C 3-9 is selected from the group consisting of heterocycloalkyl, cyclopropyl, phenyl, benzyl, and 1-phenylethyl; or R 1 and R 2 together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.

[0152] In a particularly preferred embodiment, the compound of formula I is R 1 is H or methyl and R 2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, allyl, cyclopropylmethyl, propargyl, butyl, isobutyl, t-butyl, -CHCF, -Calkyl-OH, oxanyl, cyclopropyl, cyclobutyl, phenyl, benzyl, and 1-phenylethyl; or R 1 and R 2 together form a pyrrolidinyl ring or a morpholinyl ring.

[0153] In a further particularly preferred embodiment, the compound of formula I is R 3CF3, CN, cyclopropyl, cyclopropylmethyl, fluorocyclopropyl, 1-fluorocyclopropan-1-yl, cyclobutyl, fluorocyclobutyl, difluorocyclobutyl, 3,3-difluorocyclobutan-1-yl, methylcyclobutyl, dimethylcyclobutyl, 3,3-dimethylcyclobutan-1-yl, cyclopentyl, vinyl, allyl, acetylenyl, cyclohexyl, propargyl, cyanomethyl, thiophen-2-yl, thiophen-3-yl, furan-2-yl, furan-3-yl, triazol-1-yl yl, triazol-4-yl, triazol-5-yl, oxan-4-yl, oxan-3-yl, oxan-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, 1,1'-biphenyl, 1,2'-biphenyl, 1,3'-biphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, o-tolyl, m-tolyl, p-tolyl, naphthalen-1-yl, naphthalen-2-yl, cyclopent-1-en-1-yl , cyclopent-1-en-3-yl, cyclopent-1-en-4-yl, cyclopenta-1,3-dien-2-yl, cyclopenta-1,3-dien-1-yl, cyclopenta-1,3-dien-5-yl, cyclohex-1-en-1-yl, cyclohex-1-en-3-yl, cyclohex-1-en-5-yl, cyclohexa-1,3-dien-1-yl, cyclohexa-1,3-dien-2-yl, cyclohexa-1,3-dien-5-yl, cyclohexa-1,4-dien-1-yl, cyclohexa-1,4-dien-3-yl, Tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, oxazolidin-5-yl, oxazolidin-4-yl, oxazolidin-2-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl, bicyclo[1.1.0]butan-1-yl, tricyclo[1.1.0]butan-1-yl 2,4]butan-1-yl, bicyclo[1.1.0]butan-2-yl, spiro[2.2]pentan-1-yl, bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-5-yl, bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, bicyclo[1.1.1]pentan-2-yl, bicyclo[1.1.1]pentan-1-yl, spiro[2.3]hexan-4-yl, spiro[2.3]hexan-5-yl, oxetane- 2-yl, thietan-2-yl, oxetan-3-yl, thietan-3-yl, 2-oxabicyclo[2.1.0]pentan-1-yl, 2-thiabicyclo[2.1.0]pentan-1-yl, 2-oxabicyclo[2.1.0]pentan-5-yl, 2-thiabicyclo[2.1.0]pentan-5-yl, 2-oxabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-4-yl, 2-oxabicyclo[2.1.0]pentan-3-yl, 2- Thiabicyclo[2.1.0]pentan-3-yl, 2-oxabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-4-yl, oxabicyclo[2.1.0]pentan-5-yl, 2-thiabicyclo[2.1.0]pentan-5-yl, 2-oxabicyclo[2.1.0]pentan-1-yl, 2-thiabicyclo[2.1.0]pentan-1-yl, 2-oxabicyclo[1.1.1]pentan-4-yl, 2-oxabicyclo[1.1.1]pentan and -4-thiaspiro[2.3]hexan-6-yl.

[0154] In a further particularly preferred embodiment, the compound of formula I is:

[0155] [ka]

[0156] [ka]

[0157] is a compound selected from the group consisting of:

[0158] In a second aspect, the present disclosure provides a compound according to the first aspect, and / or a composition comprising a compound according to the first aspect and one or more pharmaceutically acceptable carrier(s) and / or diluent(s) and / or excipient(s), for use as a medicament.

[0159] In a third aspect, the present disclosure provides use of a compound of formula II for the manufacture of a medicament for the treatment or prevention of a disease, disorder, injury or trauma; and / or a compound of formula II for use in the treatment or prevention of a disease, disorder, injury or trauma; and / or a method of treating or preventing a disease, disorder, injury or trauma comprising administering to a subject in need thereof an effective amount of a compound of formula II; wherein said compound of formula II includes stereoisomers, individual enantiomers, racemates, non-racemic mixtures, isotopically substituted forms, prodrugs and / or pharmaceutically acceptable salts thereof;

[0160] [ka]

[0161] (In formula; One or more hydrogen atoms in the compound of formula II may be replaced by fluorine;

[0162] R 1 and R 2 are independently H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12 Bicyclohaloalkyl, -C 6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicyclohaloalkynyl, -C 9-14 Spirocyclohaloalkynyl, -C 3-9 Heterocycloalkyl, -C 6-12 Heterobicycloalkyl, -C 6-12 Heterospirocycloalkyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)Ra , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8 Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C 1-8 Alkyl-CO2R a , -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8 Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C 2-8 Haloalkynyl-CN, -CH2-OR a , -C 2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-R a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a selected from the group consisting of:

[0163] where R 1 and R 2 can together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heterocycloalkenyl ring, or a 6-membered heteroaryl ring, each of which can be unsubstituted or R 4 or R5 may be substituted by one or more groups selected from

[0164] R 3 is selected from the group consisting of CF3, CN, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, vinyl, allyl, acetylenyl, cyclohexyl, cyclopentenyl, cyclohexenyl, propargyl, cyanomethyl, oxetanyl, thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolyl, oxanyl, dioxolanyl, pyridinyl, naphthyl, and phenyl; each of which can be unsubstituted or R 4 or R 5 or

[0165] R 3 is a 4- to 6-membered fused ring system or a 4- to 6-membered spiro ring system, each of which is a saturated carbocyclic ring system containing 0 heteroatoms or a saturated heterocyclic ring system containing 1 heteroatom selected from O or S, and each of which can be unsubstituted or can be selected from R 4 or R 5 may be substituted by one or more groups selected from

[0166] R 4 and R 5 is independently in each occurrence; halogen, -OR a , -SR a , -NR b R c , methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12 Bicyclohaloalkyl, -C 6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C 1-8 Alkyl-CO2R a , -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C 2-8 Haloalkynyl-CN, -CH2-OR a , -C 2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a or selected from the group consisting of;

[0167] Or, where R 4 and / or R 5 are bonded to the same carbon atom, and 4 and / or R 5 two of which together can form a carbonyl group; and

[0168] R a , R b and R c is independently in each occurrence: H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl and -C 2-5 haloalkynyl-heteroaryl).

[0169] In some embodiments, the disease, disorder, injury or trauma is: (i) serotonin transporter (SERT) activity; and / or (ii) dopamine transporter (DAT) activity; and / or (iii) norepinephrine transporter (NET) activity; and / or (iv) monoamine oxidase A (MAO-A) activity; and / or (v) Serotonin receptor (5-HT2B) activity These conditions can be treated or prevented through modulation of the

[0170] In some embodiments, the disease, disorder, injury or trauma is a disease, disorder, injury or trauma associated with the central nervous system.

[0171] In some embodiments, the disease, disorder, injury, or trauma associated with the central nervous system is; dementia in Alzheimer's disease (including early-onset, late-onset, atypical, mixed, or unspecified), vascular dementia (including arteriosclerotic, acute-onset, multi-infarct, subcortical, mixed cortical, or unspecified), dementia in Pick's disease, dementia in Creutzfeldt-Jakob disease, dementia in Huntington's disease, dementia in Parkinson's disease, dementia in human immunodeficiency virus [HIV] disease, dementia in cerebral lipidosis, dementia in epilepsy, dementia in hepatolenticular degeneration, dementia in hypercalcemia, dementia in hypothyroidism, dementia in intoxication, dementia in Lewy body disease, dementia in multiple sclerosis, dementia in neurosyphilis, dementia in niacin deficiency, dementia in polyarteritis nodosa, dementia in systemic lupus erythematosus, dementia in trypanosomiasis, dementia due to uremia, dementia in vitamin B 12Dementia in deficiency disorders, unspecified dementia (including dementia not otherwise specified, psychosis not otherwise specified, senile, delirium, depression, paranoia, or acute confusional state), organic amnesic syndrome, Korsakoff's psychosis, Korsakoff's syndrome, delirium, cerebral syndrome, confusional state, infectious psychosis, organic reaction, psychoorganic syndrome, organic hallucinosis, organic catatonic disorder, organic delusional [schizophreniform] disorder, organic mood [affective] disorder, organic anxiety disorder, organic Dissociative disorder, organic affective [apathy] disorder, mild cognitive impairment, epileptic psychosis, brain syndrome not otherwise specified, mental disorder not otherwise specified, organic personality disorder, pseudopsychotic personality disorder, pseudodevelopmental personality disorder, frontal lobe syndrome, limbic epileptic personality syndrome, lobotomy syndrome, post-leukotomy syndrome, post-encephalitis syndrome, post-concussion syndrome, post-contusion syndrome (encephalopathy), post-traumatic brain syndrome, non-psychotic Sexuality, right hemisphere organic affective disorders, organic mental syndromes, mental and behavioral disorders due to alcohol use, mental and behavioral disorders due to opioid use, mental and behavioral disorders due to cannabinoid use, mental and behavioral disorders due to sedative or hypnotic use, mental and behavioral disorders due to cocaine use, mental and behavioral disorders due to caffeine-containing stimulant use, mental and behavioral disorders due to hallucinogen use, mental and behavioral disorders due to tobacco use, mental and behavioral disorders due to volatile solvent use, mental and behavioral disorders due to use of other psychoactive substances (including any combination of psychoactive substances), schizophrenia, paranoid schizophrenia, paranoid schizophrenia, dehydration, dehydration, disorganized schizophrenia, catatonic schizophrenia, catatonic stupor, schizophrenic catalepsy, schizophrenic catatonia, schizophrenic flexibilitascerea), undifferentiated schizophrenia, atypical schizophrenia, post-schizophrenic depression, residual schizophrenia, chronic undifferentiated schizophrenia, schizophrenic restzustand, simple schizophrenia, somatosensory schizophrenia, schizophreniform disorder, schizophreniform psychosis, schizophrenia not otherwise specified, schizotypal disorder, subclinical schizophrenia, borderline schizophrenia, prepsychotic schizophrenia, prodromal schizophrenia, pseudoneurotic schizophrenia, pseudopsychotic schizophrenia, schizophrenic personality disorder, persistent delusional disorder, delusional disorder, paranoia, paranoid psychosis, paranoid state, paraphrenia (late stage), sensitive beziehungswahn, paranoid body dysmorphic disorder, recurrent delusional state, Paranoia querulans, acute and transient psychotic disorder, acute polymorphic psychotic disorder without schizophrenic symptoms, acute polymorphic psychotic disorder with schizophrenic symptoms, buffet delirante, cycloid psychosis, acute schizophreniform psychotic disorder, acute (undifferentiated) schizophrenia, brief schizophreniform disorder, brief schizophreniform psychosis, dreamlike psychosis, schizophrenic reaction, delusional reaction, psychogenic delusional psychosis, acute transient psychotic disorder, induced delusional disorder, folie à deux deux), induced delusional disorder, induced psychotic disorder, schizoaffective disorder (including manic, depressive, mixed and unspecified), non-organic psychotic disorder, chronic hallucinatory psychosis, manic episode disorder, bipolar disorder, single manic episode disorder, hypomania, mania without psychotic symptoms, mania with psychotic symptoms, mania with mood-concordant psychotic symptoms, manic stupor, mania not otherwise specified, bipolar affective disorder, manic depression, manic-depressive illness, manic-depressive psychosis, manic-depressive reaction, bipolar II disorder, Depression, psychogenic depression, reactive depression, mild depression, moderate depression, severe depression, agitated depression, major depression, vital depression, atypical depression, unipolar depression, depressive disorder not otherwise specified, recurrent depressive disorder, seasonal depressive disorder, cyclothymia, affective personality disorder, cyclothymic personality, cyclothymic personality, dysthymia, depressive neurosis, depressive personality disorder, neurotic depression, persistent anxious depression, phobic anxiety disorder, agoraphobia, panic disorder, social phobia, social phobia, social neurosisneurosis, fear of heights, fear of animals, claustrophobia, simple phobia, phobic state not otherwise specified, episodic paroxysmal anxiety, generalized anxiety disorder, anxiety hysteria, anxiety not otherwise specified, obsessive-compulsive disorder, anakastic neurosis, obsessive-compulsive neurosis, predominantly obsessional thoughts or ruminations, predominantly compulsive e) Behavior [compulsive rituals], acute stress reaction, acute crisis reaction, acute reaction to stress, combat fatigue, crisis state, psychiatric shock, post-traumatic stress disorder (PTSD), traumatic neurosis, adjustment disorder, culture shock, grief reaction, pediatric hospitalization, dissociative [conversion] disorder, conversion hysteria, conversion reaction, dissociative amnesia, dissociative fugue, dissociative stupor, trance disorder, possession disorder, dissociative movement disorder, psychogenic aphonia, psychogenic dysphonia, dissociative convulsion, dissociative anesthesia, dissociative Dissociative anesthesia, Gansser syndrome, multiple personality dissociative disorder, psychogenic confusion, psychogenic twilight state, somatoform disorder, somatization disorder, charcoal briquettes disorder, multiple psychosomatic disorders, undifferentiated somatoform disorder, undifferentiated psychosomatic disorder, hypochondriac disorder, body dysmorphic disorder, body dysmorphophobia (non-delusional), hypochondriacal neurosis, hypochondriasis, nosophobia, somatoform autonomic dysfunction, cardiac neurosis, Da Costa syndrome, gastroneurosis, neurocirculatory asthenia, psychogenic aerophagia, psychogenic cough, psychogenic diarrhea, psychogenic dyspepsia, psychogenic dysuria, psychogenic tympanic dyspepsia Intestine, psychogenic hiccups, psychogenic hyperventilation, psychogenic increased frequency of urination, psychogenic irritable bowel syndrome, psychogenic pyloric spasm, persistent somatoform pain disorder, psychiatric pain, psychogenic lower back pain, psychogenic headache, somatoform pain disorder, psychogenic dysmenorrhea, psychogenic dysphagia, globus hystericus, psychogenic pruritus, psychogenic torticollis, psychogenic bruxism, psychosomatic disorder not otherwise specified, neurasthenia, fatigue syndrome, depersonalization-derealization syndrome, Dhat syndrome, occupational neurosis, writer's crampcramp neurosis, psychasthenia, psychasthenic neurosis, psychogenic syncope, neurosis not otherwise specified, eating disorder, anorexia nervosa, atypical anorexia nervosa, bulimia nervosa, bulimia not otherwise specified, bulimia nervosa, atypical bulimia nervosa, binge eating associated with other psychological disturbances, psychogenic binge eating, vomiting associated with other psychological disturbances, psychogenic vomiting, pica, psychogenic anorexia, non-organic sleep disorder, non-organic insomnia, non-organic hypersomnia, non-organic disorders of sleep-wake schedule, psychogenic inversion of circadian rhythm, psychogenic inversion of noctohemeral rhythm, psychogenic inversion of sleep rhythm, sleepwalking, sleep terrors terrors)], nightmares, dream anxiety disorder, emotional sleep disorder not otherwise specified, sexual dysfunction not caused by organic disorder or disease, absence or loss of sexual desire, frigidity, hypoactive sexual desire disorder, sexual aversion, lack of sexual enjoyment, sexual anhedonia, genital response dysfunction, female sexual arousal disorder, male erectile dysfunction, psychogenic impotence, orgasmic dysfunction, orgasmic inhibition, psychogenic abnormal orgasm, premature ejaculation, psychogenic vaginismus, non-organic dyspareunia, psychogenic sexual dyspareunia, nymphomania, satyriasis, sexual dysfunction not otherwise specified, postpartum depression, postpartum depression, postpartum psychosis, postpartum psychosis, psychological and behavioral factors related to physical disability or disease (including but not limited to asthma, dermatitis, gastric ulcer, irritable bowel syndrome, ulcerative colitis, and urticaria), non-addictive substance abuse (including but not limited to antacids, herbal medicines, folk remedies, steroids, hormones, vitamins, and laxatives), Psychogenic physiological dysfunction not otherwise specified, Paranoid personality disorder, Expansive paranoid personality disorder, Fanatic paranoid personality disorder, Petitionistic paranoid personality disorder, Sensitive paranoid personality disorder, Schizoid personality disorder, Antisocial personality disorder, Amoral personality disorder, Antisocial personality disorder, Asocial personality disorder, Psychopathic personality disorder, Sociopathic personality disorder, Emotionally unstable personality disorder personality disorder, aggressive personality disorder, borderline personality disorder, explosive personality disorder, histrionic personality disorder, hysterical personality disorder, psychoinfantile personality disorder, anorexic personality disorder, obsessive-compulsive personality disorder, obsessional personality disorder, obsessive-compulsive personality disorder, anxious [avoidant] personality disorder, dependent personality disorder, helpless personality disorder, inappropriate personality disorder Harm, Passive Personality Disorder, Self-Destructive Personality Disorder, Eccentric Personality Disorder, Halt-Roth Personality Disorder, Immature Personality Disorder, Narcissistic Personality Disorder, Passive-Aggressive Personality Disorder, Psychoneurotic Personality Disorder, Personality Neurosis Not Elsewhere Specified, Pathological Personality Not Elsewhere Specified, Mixed Personality Disorder, Personality and Behavioral Disorders Due to Brain Disease, Personality and Behavioral Disorders Due to Brain Damage, Personality and Behavioral Disorders Due to Brain Dysfunction, Catastrophic Permanent personality changes after experiences (including, but not limited to, concentration camp experiences, disasters, prolonged incarceration with imminent possibility of death, prolonged exposure to life-threatening situations such as being a victim of terrorism, or prolonged torture), permanent personality changes after psychiatric illness, chronic pain personality syndrome, unspecified permanent personality changes, habit disorders, impulse disorders, pathological gambling, compulsive gambling, pathological arson [pyromania], pathological kleptomania [kleptomania], trichotillomania, intermittent explosive disorder, gender identity disorder, transsexualism, gender role transvestism, sex role disorder,Sexual preference disorder, fetishism, fetishistic transvestism, exhibitionism, voyeurism, pedophilia, sadomasochism, touchophilia, necrophilia, sexual deviance not otherwise specified, sexual maturation disorder, ego-dysphoric sexual orientation, sexual relationship disorder, psychosexual development disorder, elaboration of physical symptoms for psychological reasons, reparation neurosis, deliberate creation or pretense of symptoms or disorders, either physical or psychological [factitious disorder], hospital crawling syndrome, Munchausen syndrome, inveterate patient, personality disorder not otherwise specified, interpersonal relationship disorder not otherwise specified, hyperactivity disorder, activity and attention disorder, attention deficit disorder with hyperactivity, attention deficit hyperactivity disorder, attention deficit syndrome with hyperactivity, hyperactivity conduct disorder, hyperactivity syndrome not otherwise specified, conduct disorder, non-socialized conduct disorder, socialized conduct disorder, oppositional defiant disorder, depressive conduct disorder, separation anxiety disorder, Selected from the group consisting of sibling rivalry disorder, hyperanxiety disorder, childhood affective disorder not otherwise specified, selective mutism, selective mutism, reactive attachment disorder, disinhibited attachment disorder, attachmentless psychopathy, institutionalization syndrome, childhood social functioning disorder, tic disorder, transient tic disorder, chronic motor tic disorder, chronic vocal tic disorder, complex vocal and multiple motor tic disorder [de la Tourette], Tourette syndrome, non-organic nocturnal enuresis, functional nocturnal enuresis, psychogenic nocturnal enuresis, urinary incontinence of non-organic causes, non-organic enuresis, functional enuresis, fecal incontinence of non-organic causes, psychogenic enuresis, feeding disorders of infancy and childhood, rumination disorder of infancy, stereotyped movement disorder, stuttering, noise, attention deficit disorder without hyperactivity, excessive masturbation, nail biting, nose picking, thumb sucking, and psychiatric disorders not otherwise specified.

[0172] In a preferred embodiment, the compound of formula II is:

[0173] [ka]

[0174] [ka]

[0175] [ka]

[0176] [ka]

[0177] is selected from the group consisting of:

[0178] In a fourth aspect, the present disclosure provides a compound of Formula II', including stereoisomers, individual enantiomers, racemates, non-racemic mixtures, isotopically substituted compounds, prodrugs and / or pharmaceutically acceptable salts thereof;

[0179] [ka]

[0180] (In formula; One or more hydrogen atoms in the compound of formula II' may be replaced by fluorine;

[0181] R 1 and R 2 are independently H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12 Bicyclohaloalkyl, -C 6-12 Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicyclohaloalkynyl, -C 9-14 Spirocyclohaloalkynyl, -C 3-9 Heterocycloalkyl, -C 6-12 Heterobicycloalkyl, -C 6-12 Heterospirocycloalkyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8 Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C 1-8 Alkyl-CO2R a , -C 2-8Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8 Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C 2-8 Haloalkynyl-CN, -CH2-OR a , -C2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-R a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a selected from the group consisting of:

[0182] where R 1 and R 2 can together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heterocycloalkenyl ring, or a 6-membered heteroaryl ring, each of which can be unsubstituted or R 4 or R 5 may be substituted by one or more groups selected from

[0183] R 3is selected from the group consisting of CF3, CN, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, vinyl, allyl, acetylenyl, cyclohexyl, cyclopentenyl, cyclohexenyl, propargyl, cyanomethyl, oxetanyl, thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolyl, oxanyl, dioxolanyl, pyridinyl, naphthyl, and phenyl; each of which can be unsubstituted or R 4 or R 5 or R 3 is a 4- to 6-membered fused ring system or a 4- to 6-membered spiro ring system, each of which is a saturated carbocyclic ring system containing 0 heteroatoms or a saturated heterocyclic ring system containing 1 heteroatom selected from O or S, and each of which can be unsubstituted or can be selected from R 4 or R 5 may be substituted by one or more groups selected from

[0184] R 4 and R 5 is independently in each occurrence; halogen, -OR a , -SR a , -NR b R c , methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, -C 6-12 Bicycloalkyl, -C 6-12 Spirocycloalkyl, -C 3-9 Cyclohaloalkyl, -C 6-12 Bicyclohaloalkyl, -C 6-12Spirocyclohaloalkyl, -C 3-9 Cycloalkenyl, -C 6-12 Bicycloalkenyl, -C 6-12 Spirocycloalkenyl, -C 3-9 Cyclohaloalkenyl, -C 6-12 Bicyclohaloalkenyl, -C 6-12 Spirocyclohaloalkenyl, -C 8-12 Cycloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, -C 8-12 Cyclohaloalkynyl, -C 9-14 Bicycloalkynyl, -C 9-14 Spirocycloalkynyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl, -C 1-5 Haloalkyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Haloalkynyl-heteroaryl, —C(═O)R a , -C 1-8 Alkyl-C(=O)R a , -C 2-8 Alkenyl-C(=O)R a , -C 2-8 Alkynyl-C(=O)R a , -C 1-8 Haloalkyl-C(=O)R a , -C 2-8 Haloalkenyl-C(=O)R a , -C 2-8 Haloalkynyl-C(=O)R a , -CO2R a , -C 1-8 Alkyl-CO2R a, -C 2-8 Alkenyl-CO2R a , -C 2-8 Alkynyl-CO2R a , -C 1-8 Haloalkyl-CO2R a , -C 2-8 Haloalkenyl-CO2R a , -C 2-8 Haloalkynyl-COR a , -SO2R a , -C 1-8 Alkyl-SO2R a , -C 2-8 Alkenyl-SO2R a , -C 2-8 Alkynyl-SO2R a , -C 1-8 Haloalkyl-SO2R a , -C 2-8 Haloalkenyl-SO2R a , -C 2-8 Haloalkynyl-SO2R a , -C(=O)NR b R c , -C 1-8 Alkyl-C(=O)NR b R c , -C 2-8 Alkynyl-C(=O)NR b R c , -C 2-8 Alkenyl-C(=O)NR b R c , -C 1-8 Haloalkyl-C(=O)NR b R c , -C 2-8 Haloalkynyl-C(=O)NR b R c , -C 2-8 Haloalkenyl-C(=O)NR b R c , -CN, -C 1-8 Alkyl-CN, -C 2-8 Alkenyl-CN, -C 2-8 Alkynyl-CN, -C 1-8 Haloalkyl-CN, -C 2-8 Haloalkenyl-CN, -C 2-8 Haloalkynyl-CN, -CH2-ORa , -C 2-9 Alkyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Alkenyl-OR a , -C 2-9 Haloalkyl-OR a , -C 2-9 Haloalkenyl-OR a , -C 2-9 Haloalkenyl-OR a , -CH2-SR a , -C 2-9 Alkyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Alkenyl-SR a , -C 2-9 Haloalkyl-SR a , -C 2-9 Haloalkenyl-SR a , and -C 2-9 Haloalkenyl-SR a or selected from the group consisting of;

[0185] Or, where R 4 and / or R 5 are bonded to the same carbon atom, and 4 and / or R 5 two of which together can form a carbonyl group; and

[0186] R a , R b and R c is independently in each occurrence: H, methyl, ethyl, -C 3-9 Alkyl, -C 1-9 Haloalkyl, -C 2-9 Alkenyl, -C 2-9 Haloalkenyl, -C 2-9 Alkynyl, -C 2-9 Haloalkynyl, -C 3-9 Cycloalkyl, aryl, heteroaryl, -C 1-5 Alkyl-aryl, -C 1-5Haloalkyl-aryl, -C 2-5 Alkenyl-aryl, -C 2-5 Haloalkenyl-aryl, -C 2-5 Alkynyl-aryl, -C 2-5 Haloalkynyl-aryl, -C 1-5 Alkyl-heteroaryl, -C 1-5 Haloalkyl-heteroaryl, -C 2-5 Alkenyl-heteroaryl, -C 2-5 Haloalkenyl-heteroaryl, -C 2-5 Alkynyl-heteroaryl and -C 2-5 1. A process for the preparation of a compound according to claim 1, wherein the compound is selected from the group consisting of haloalkynyl-heteroaryl;

[0187] wherein the process is represented by formula III;

[0188] [ka]

[0189] (Wherein, R is methyl, ethyl, and —C 3-9 a compound according to the formula (I) selected from the group consisting of alkyl; Formula IVa, or Formula IVb, or Formula IVc;

[0190] [ka]

[0191] (In the formula, R 3 is as defined for the compound of formula II', and wherein for compounds of formula IVb, each R 3 may be the same or different, and wherein R' is; methyl, ethyl, -C 3-9 a compound according to the formula (I) selected from the group consisting of alkyl, aryl, and haloaryl; reacting under a first set of reaction conditions to form a compound of formula V;

[0192] [ka]

[0193] and preparing a compound of formula (I): The compound of formula V is then subjected to a second set of reaction conditions to produce a compound of formula VI;

[0194] [ka]

[0195] producing a ketone intermediate of the formula: and subsequently, the compound of formula VI, formula VII;

[0196] [ka]

[0197] (In the formula, R 1 and R 2 is as defined for said compound of formula II'; and by reductive amination under a third set of reaction conditions to produce said compound of formula II'.

[0198] In some embodiments, the first set of reaction conditions comprises reacting one equivalent of a compound of Formula III with an excess of a compound of Formula IVa or Formula IVb or Formula IVc in an organic solvent in the presence of an excess of base.

[0199] In some embodiments, the organic solvent in the first set of reaction conditions is a polar aprotic solvent, preferably tetrahydrofuran (THF), and the base in the first set of reaction conditions is a strong base, such as sodium hexamethyldisilazide (NaHMDS) or potassium hexamethyldisilazide (KHMDS), most preferably a lithium base, such as lithium hexamethyldisilazide (LiHMDS).

[0200] In some embodiments, the second set of reaction conditions comprises heating a solution of the compound of Formula V in a mixture of DMSO and water in the presence of a chloride ion source, preferably KCl or LiCl or NaCl, most preferably NaCl. Those skilled in the art will know that alternative Krapko decarboxylation conditions to the above preferred conditions would be equally applicable and effective in the second set of reaction conditions.

[0201] In some embodiments, the third set of reaction conditions preferably involves the reductive amination of a compound of Formula VI with a compound of Formula VII in the presence of acetic acid and sodium cyanoborohydride in a mixture of anhydrous THF and anhydrous methanol. One skilled in the art will know that alternative reductive amination conditions to the above preferred conditions will be equally applicable and effective in the third set of reaction conditions. For example, acetic acid and sodium cyanoborohydride in ethanol alone (or ethanol in combination with anhydrous THF) will be equally effective in the third set of reaction conditions.

[0202] In a fifth aspect, the present disclosure provides a compound of formula II', when prepared via the process of the fourth aspect.

[0203] In a sixth aspect, the present disclosure provides a compound of formula VI;

[0204] [ka]

[0205] (In the formula, R 3 is as defined for compounds of formula II' when compounds of formula VI are prepared via the process of the fourth aspect, to provide compounds according to [Example]

[0206] synthesis General Procedure for Obtaining the Hydrochloride Salt of Free Base Compounds of the Invention The free base is dissolved in MeOH (1 mL) and 32% HCl (2 equiv.) is added dropwise. The solution is evaporated to dryness under a stream of N, and the residue is recrystallized using an appropriate solvent (e.g., 2-propanol or 2-propanol / EtO, or toluene, or toluene / cyclohexane) to give the desired hydrochloride salt.

[0207] General Procedure A for Reductive Amination with Methylamine An 8.0 M solution of methylamine in EtOH (10.0 equiv.) and AcOH (10.0 equiv.) are added sequentially to a cold (0 °C) stirred mixture of a specific ketone (1.0 equiv.) and 3A sieves (1 mg / mg ketone) in 2:1 THF / MeOH (6.0 mL / mmol ketone). Sodium cyanoborohydride (1.10 equiv.) is added, and the reaction vessel is flushed with N2, sealed, and stirred at 50 °C until TLC analysis indicates complete consumption of the starting ketone. The reaction mixture is cooled to room temperature, quenched with 1 M HCl (pH approx. 1), vacuum filtered through a pad of Celite, and rinsed with water and MeOH. The filtrate is concentrated under reduced pressure, and the residue is diluted with 0.1 M HCl and washed with Et2O. The aqueous phase is basified with 1 M NaOH (pH approx. 12) and extracted with CHCl2. The extract is washed with brine, dried and evaporated to give the desired free base, which can be purified by chromatographic techniques if necessary.

[0208] Type 1 Compounds Compounds of type 1 can be prepared by following general procedure 1;

[0209] [ka]

[0210] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2is as defined for compounds of formula II'). Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 1 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0211] 2-(1,3-benzodioxol-5-yl)-1-cyclopropylethanone ("ketone K1")

[0212] [ka]

[0213] A solution of 1.0 M LiHMDS in THF (375 mL, 0.38 mol) and cyclopropanecarbonyl chloride (20 mL, 0.22 mol) was added to a solution of methyl homopiperonylate in THF (250 mL). 1 (35 g, 0.18 mol) at −78° C. The solution was allowed to warm to room temperature for 30 min. The reaction mixture was then cooled to 0° C. and quenched with 1 M HCl (400 mL), then diluted with water (600 mL) and extracted with EtO (3 × 300 mL). The extracts were washed with water (2 × 300 mL) and brine (300 mL), dried, and evaporated to give a brown oil, which was partially purified by rapid silica filtration (1:4, EtOAc / hexanes). The resulting yellow oil was immediately dissolved in 2:1 DMSO / H2O (300 mL) and treated with NaCl (40 g, 0.69 mol), and the mixture was stirred at 140° C. for 24 h. The reaction mixture was diluted with water (1 L) and extracted with EtO (3 × 300 mL). The extract was washed with water (2 × 300 mL) and brine (300 mL), dried, and evaporated. The residual oil was subjected to flash chromatography. Elution with 1:20 EtOAc / hexanes gave ketone K1 as a colorless oil (30 g, 82%). Characterization data were in good agreement with the previously published synthesis of ketone K1. 4

[0214] 2-(1,3-benzodioxol-5-yl)-1-cyclopropylethanamine (UWA-033, MNG6012, "Compound 1A")

[0215] [ka]

[0216] Following adapted literature procedures, 3 To freshly activated 3 Å sieves (approximately 300 mg) was added a solution of ketone K1 (1.03 g, 5.05 mmol) in anhydrous MeOH (20 mL), ammonium acetate (2.75 g, 35.7 mmol), and sodium cyanoborohydride (438 mg, 6.97 mmol). The mixture was stirred at room temperature under N for 3 days. The reaction was quenched, and the product was extracted and chromatographed eluting with 2:3 EtOAc / hexane followed by 1:20:79 NEt / MeOH / EtOAc to give the desired product as a yellow oil (700 mg, 68%). 1 H NMR(500MHz,CDCl3):δ6.69(d,J=8.0Hz,1H,H7'),6.64(d,J=2.0Hz,1H,H4'),6.60(dd,J=8.0,2.0Hz,1H,H6'),5.85(s,2H, H2'),2.79(dd,J=13.5,4.5Hz,1H,H2a),2.50(dd,J=13.5,8.5Hz,1H,H2b),2.50(dd,J=13.5,8.5Hz,1H,H2b),2.11(ddd[app dt],J=8.5,8.5,4.5,1H,H1),1.59(br s,NH2+H2O),0.76-0.68(m,1H),0.46-0.38(m,2H),0.17-0.04(m,2H). 13C NMR (125 MHz, CDCl3): δ 147.3 and 145.7 (C3a' and C7a'), 133.0 (C5'), 122.0 (C6'), 109.4 and 107.9 (C4' and C7'), 100.6 (C2'), 58.2 (C1), 43.5 (C2), 18.0 (C1''), 2.92 and 2.89 (C2'' and C3''). HRMS-EI (m / z): M + C 12 H 15 Calculated value for NO2: 205.1103; measured value: 205.1111.

[0217] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol as a colorless amorphous powder (mp 138-141°C). 1 H NMR(500MHz,CDCl3):δ6.79(s,1H),6.73(s,2H),5.93-5.91(m[app AB system],2H,H2''),3.21(dd,J=14.0,5.5Hz,1H,H2a),3.04(dd,J=14.0,8.0Hz,1H ,H2b),2.68-2.58(m,1H),1.13-1.03(m,1H),0.68-0.51(m,3H),0.10-0.02(m,1H). Analysis C 12 H 16 Calculated for ClNO2: C, 59.63; H, 6.67; N, 5.79. Found: C, 59.33; H, 6.78; N, 5.67.

[0218] 2-(1,3-benzodioxol-5-yl)-1-cyclopropyl-N-methylethanamine (UWA-101, "Compound 1B")

[0219] [ka]

[0220] Compound 1B is a known compound that has been previously synthesized. 4Following general procedure 1, reaction of ketone K1 (378 mg, 1.85 mmol) with 8.03 M methylamine in MeOH (2.28 mL, 18.3 mmol) and elution with EtOAc gave the product as a pale yellow oil (331 mg, 82%). 1 H NMR and 13 The C NMR spectrum was identical to that reported. 4 The free base was dissolved in methanolic hydrogen chloride and evaporated to dryness under a stream of N. The crude hydrochloride salt was recrystallized from 2-propanol to a colorless amorphous powder: mp 157-159 °C (lit. mp 156-158 °C). 1 The 1 H NMR spectrum was identical to that reported. 4

[0221] (S)-2-(1,3-benzodioxol-5-yl)-1-cyclopropyl-N-methylethanamine ("Compound 1BS")

[0222] [ka]

[0223] Compound 1BS is a known compound that has been previously synthesized and was obtained according to literature procedures. 2-119ページ

[0224] (R)-2-(1,3-benzodioxol-5-yl)-1-cyclopropyl-N-methylethanamine ("Compound 1BR")

[0225] [ka]

[0226] Compound 1BR is a known compound that has been previously synthesized and was obtained according to literature procedures. 2-118ページ

[0227] 2-(1,3-benzodioxol-5-yl)-1-cyclopropyl-N-ethylethanamine (MNG5164, "Compound 1C")

[0228] [ka]

[0229] Compound 1C is a known compound that has been previously synthesized. 2-88ページ Following general procedure 1, reaction of ketone K1 (208 mg, 1.02 mmol) with 2.0 M ethylamine in MeOH (5.00 mL, 10.0 mmol) and elution with EtOAc afforded the product as a pale yellow oil (101 mg, 43%). 1 H NMR (500MHz, CDCl3): δ6.72(d,J=8.0Hz,1H,H7'),6.69(d,J=1.5Hz,1H,H4'),6.65(dd,J=8.0,1.5Hz,1H,H6'),5.94-5.91(m,2H,H2'),2.87-2. 79(m,2H,H2a+H1a'''),2.68(dd,J=14.0,7.5Hz,1H,H2b),2.56(dq,J=11.5,7.0Hz,1H,H1b'''),1.89(ddd,J=9.0,8.0,5.0Hz,1H,H1),1.46(br s,1H,NH+H2O),1.05(t,J=7.0Hz,3H,H2'''),0.73-0.64(m,1H),0.58-0.51(m,1H),0.45-0.38(m,1H),0.25-0.19(m[app sextet],1H),0.02-0.05(m[app sextet],1H). 13 C NMR (125 MHz, CDCl3): δ 147.5 and 145.8 (C3a' and C7a'), 133.2 (C5'), 122.2 (C6'), 109.6 and 108.0 (C4' and C7'), 100.7 (C2'), 65.0 (C1), 42.1 and 41.7 (C2 and C1''), 16.0 and 15.5 (C1'' and C2''), 4.9 and 2.0 (C2'' and C3''). HRMS-ESI (m / z): [M+H] + C 14 H 19Calculated value for NO2: 234.1494; measured value: 234.1486.

[0230] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol / Et2O as colorless rods (mp 154-156°C). 1 H NMR (500MHz, CDCl3): δ9.8-9.5(2×br s,2H,NH2),6.78-6.72(m,3H,H4',H6',H7'),5.98-5.93(m[app d],2H,H2'),3.53(dd,J=13.5,4.0Hz,1H,H1a),3.36-3.25(m,1H,H1a''),3.18-3.07(m,2H,H1b+H1b''),2.54-2.45( m,1H,H2),1.54(t,J=7.5Hz,3H,H2''),1.17-1.07(m,1H),0.72-0.64(m,1H),0.53-0.45(m,2H),-0.15--0.23(m,1H). Analysis C 14 H 20 Calculated for ClNO2: C, 62.33; H, 7.47; N, 5.19. Found: C, 62.54; H, 7.87; N, 5.17.

[0231] N-[2-(1,3-benzodioxol-5-yl)-1-cyclopropylethyl]propan-2-amine (UWA-004, KDL03-158, "Compound 1D")

[0232] [ka]

[0233] Compound 1D is a known compound that has been previously synthesized. 2-87ページAccording to general procedure 1, ketone K1 (204 mg, 1.00 mmol) was reacted with isopropylamine (852 μL, 9.92 mmol). After 24 h, TLC analysis indicated some starting material remained, and the reaction was supplemented with additional sodium cyanoborohydride (63 mg, 1.00 mmol) to completely consume the starting material. The reaction was quenched, and the product was extracted and chromatographed eluting with EtOAc to give the product as a yellow oil (113 mg, 46%). 1 H NMR (500MHz, CDCl3): δ6.72(d,J=8.0Hz,1H,H7''),6.69(d,J=1.5Hz,1H,H4''),6.64(dd,J=8.0,1.5Hz,1H,H6''),5.93-5.91(m[AB system],2H,H2''),2.99(septet,J=6.0Hz,1H,H2),2.77(dd,J=13.5,5.5Hz,1H,H2a'),2.67(dd,J=13.5,6.5Hz,1H,H2b'),2.02(ddd,J=8.5,6.5 ,5.5Hz,1H,H1'),1.02(d,J=6.0Hz,3H,H1),0.94(d,J=6.0Hz,3H,H3),0. 69-0.61(m,1H),0.54-0.47(m,1H),0.44-0.37(m,1H),0.22-0.15(m[app sextet],1H),0.02--0.04(m[app sextet],1H). 13 C NMR (125 MHz, CDCl3): δ 147.4 and 145.8 (C3a'' and C7a''), 133.2 (C5'', 122.3 (C6'', 109.7 and 108.0 (C4'' and C7'', 100.7 (C2'', 61.4 (C1'), 45.4 (C2), 41.7 (C2'), 23.6 and 23.1 (C1 and C3), 16.5 (C1''', 4.5 and 2.5 (C2''' and C3'''). HRMS-EI (m / z): M + C 15 H 21 Calculated value for NO2: 247.1572; measured value: 247.1579.

[0234] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol as colorless rods (mp 156-159°C). 1 H NMR(500MHz,CDCl3):δ9.55-9.32(m[app br d],2H,NH2),6.77-6.70(m,3H,H4''+H6''+H7''),5.95-5.91(m[AB system],2H,H2''),3.70-3.60(m[app septet],1H,H2),3.56(dd,J=13.5,4.5Hz,1H,H2a'),3.20(dd,J=13.5,9.5Hz,1H,H2b'),2.56-2.46(m,1H,H1'),1.56(d ,J=6.5Hz,3H,H1),1.46(d,J=6.5Hz,3H,H3),1.27-1.18(m,1H),0.71-0.63(m,1H),0.49-0.41(m,1H),0.38-0.31(m[app sextet],1H),-0.20--0.27(m[app sextet],1H). Analysis C 15 H 22 Calculated for ClNO2: C, 63.48; H, 7.81; N, 4.94. Found: C, 63.56; H, 8.05; N, 4.85.

[0235] N-[2-(1,3-benzodioxol-5-yl)-1-cyclopropylethyl]cyclopropanamine (UWA-037, MNG6028, GAP-068, “Compound 1E”)

[0236] [ka]

[0237] According to adapted literature methods, 5To a suspension of freshly activated sieves (approximately 100 mg) in anhydrous MeOH (2 mL) was added compound 1A (202 mg, 0.984 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (200 μL, 0.995 mmol). The mixture was stirred under N for 1 h, then sodium cyanoborohydride (94 mg, 1.50 mmol) was added, and the mixture was heated at 50° C. for 20 h. The reaction was quenched, extracted, and the product was then eluted with 4:1 EtOAc / hexane followed by EtOAc to give the desired product as a colorless oil (56 mg, 23%). 1 H NMR (500MHz, CDCl3): δ6.73(d,J=8.0Hz,1H,H7''),6.70(d,J=1.5Hz,1H,H4''),6.65(dd,J=8.0,1.5Hz,1H,H6''),5.93(s,2H,H2''),2.8 1(dd,J=13.5,5.0Hz,1H,H2a'),2.74(dd,J=13.5,7.5Hz,1H,H2b'),2.12-2.07(m,1H,H1),1.99(ddd,J=9.0,7.5,5.5Hz,1H,H1'),1.70(br s,1H,NH+H2O),0.73-0.64(m,1H),0.59-0.52(m,1H),0.52-0.24(m,6H),0.02--0.04(m,1H). 13 C NMR (125 MHz, CDCl3): δ 147.5 and 145.8 (C3a'' and C7a''), 133.3 (C5'', 122.2 (C6'', 109.6 and 108.0 (C4'' and C7'', 100.8 (C2'', 65.6 (C1'), 41.7 (C2'), 29.3 and 16.1 (C1 and C1'''), 7.5, 6.4, 5.0, 2.6 (C2, C3, C2''', C3'''). HRMS-EI (m / z): M + C 15 H 19 Calculated value for NO2: 245.1416; measured value: 245.1414.

[0238] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol / Et2O as a colorless amorphous powder (mp 128-131 °C). 1H NMR(500MHz.CDCl3):δ9.84(br s,1H,NHa),9.62(br s,1H,NHb),6.75(dd,J=7.5,1.5Hz,1H,H6''),6.73(d,J=1.5Hz,1H,H4''),6.71(d,J=7.5Hz,1H,H7''),5.94-5.91(m[AB system],2H,H2''),3.55(dd,J=13.5,3.5Hz,1H,H2a'),3.09(dd,J=13.5,9.5Hz,1H,H2b'),2.67-2.67(m,1H),2.58-2.50(m,1H),1.48-1.41( m,1H),1.34-1.26(m,1H),1.18-1.09(m,1H),0.93-0.78(m,2H),0.69-0 .61(m,1H),0.57-0.49(m,1H),0.49-0.42(m,1H),-0.21--0.29(m,1H). Analysis C 15 H 20 Calculated for ClNO2: C, 63.94; H, 7.15; N, 4.97. Found: C, 64.05; H, 7.43; N, 4.89.

[0239] Alternatively, following general procedure 1, cyclopropylamine (2.10 mL, 30.3 mmol) and AcOH (1.90 mL, 33.2 mmol) were added sequentially to a cold (0 °C) stirred mixture of ketone K1 (623 mg, 3.05 mmol) and 3 Å sieves (652 mg) in 1:1 THF / MeOH (18 mL). Sodium cyanoborohydride (216 mg, 3.44 mmol) was added, and the reaction vessel was flushed with N, sealed, and stirred at 50 °C for 96 h before being cooled to room temperature and quenched with 4 M HCl (15 mL). The resulting mixture was vacuum filtered through a pad of Celite and rinsed with water (50 mL) and MeOH (3 × 50 mL). The filtrate was concentrated under reduced pressure, and the residue was basified with 4 M NaOH (30 mL) and extracted with CHCl (3 × 75 mL). The extract was washed with brine (60 mL), dried, evaporated, and the residue subjected to flash chromatography. Gradient elution with 1:3 EtOAc / hexane → 1:1 EtOAc / hexane → 1:49:50 NEt3 / EtOAc / hexane gave the secondary amine 1E as a colorless oil (635 mg, 85%). Spectroscopic data for 1E synthesized via this method are consistent with those obtained previously.

[0240] N-[2-(1,3-benzodioxol-5-yl)-1-cyclopropylethyl]propan-1-amine (UWA-031, MNG5166, "Compound 1F")

[0241] [ka]

[0242] Following general procedure 1, reaction of ketone K1 (204 mg, 1.00 mmol) with n-propylamine (822 μL, 10.0 mmol) and elution with 2:3 EtOAc / hexane followed by EtOAc afforded the product as a pale yellow oil (105 mg, 42%). 1H NMR (500MHz, CDCl3): δ6.72(d,J=7.5Hz,1H,H7''),6.69(d,J=1.5Hz,1H,H4''),6.65(dd,J=8.0,1.5Hz,1H,H6'') ,5.92(s,2H,H2''),2.81(dd,J=8.5,5.0Hz,1H,H2a'),2.74(ddd,J=11.0,8.5,6.0Hz,1H,H1a),2.67(dd,J=13.5,8 .0Hz,1H,H2b'),2.49(ddd,J=11.5,8.5,6.0Hz,1H,H1b),1.87(ddd,J=9.0,8.0,5.0Hz,1H,H1'),1.80-1.20(m,3H, H2+NH+H2O),0.85(t,J=7.5Hz,3H,H3),0.73-0.64(m,1H),0.58-0.51(m,1H),0.44-0.37(m,1H),0.25-0.18(m[app sextet],1H),0.02--0.05(m[app sextet],1H). 13 C NMR (125 MHz, CDCl3): δ 147.5 and 145.8 (C3a'' and C7a''), 133.3 (C5'', 122.2 (C6'', 109.6 and 108.0 (C4'' and C7'', 100.7 (C2'', 64.9 (C1'), 49.8 and 41.7 (C1 and C2'), 23.3 (C2), 16.0 and 11.7 (C3 and C1''', 4.8 and 2.0 (C2''' and C3'''). HRMS-EI (m / z): M + C 15 H 21 Calculated value for NO2: 247.1572; measured value: 247.1525.

[0243] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol / Et2O as colorless rods (mp 157-158°C). 1H NMR (500MHz, CDCl3): δ9.66(br s,1H,NHa),9.38(br s,1H,NHb),6.77-6.70(m,3H,H4''+H6''+H7''),5.95-5.92(m[AB [app sextet],2H,H2),1.14-1.05(m,1H),0.99(t,J=7.0Hz,3H,H3),0.70-0.62(m,1H),0.55-0.45(m,2H),-0.14--0.22(m,1H). Analysis C 15 H 22 Calculated for ClNO2: C, 63.48; H, 7.81; N, 4.94. Found: C, 63.59; H, 8.02; N, 4.88.

[0244] N-[2-(1,3-benzodioxol-5-yl)-1-cyclopropylethyl]prop-2-en-1-amine (UWA-032, MNG6006, "Compound 1G")

[0245] [ka]

[0246] Following general procedure 1, reaction of ketone K1 (204 mg, 1.00 mmol) with allylamine (750 μL, 10.0 mmol) and elution with EtOAc afforded the product as a pale yellow oil (172 mg, 70%). 1H NMR(500MHz,CDCl3):δ6.73(d,J=7.5Hz,1H,H7''),6.69(d,J=1.5Hz,1H,H4''),6.65( dd,J=8.0,1.5Hz,1H,H6''),5.93(s,2H,H2''),5.88-5.78(m,1H,H2),5.09(dddd[app dq],J=17.0,1.5,1.5,1.5Hz,1H,H3a),5.06-5.02(m[app dq],1H,H3b),3.43(dddd,J=14.0,6.0,1.5,1.5Hz,1H,H1a),3.23(dddd,J=14.5,6.5,1.5,1.5Hz,1H,H1b),2.83( dd,J=14.0,5.0Hz,1H,H2a'),2.70(dd,J=14.0,8.0Hz,1H,H2b'),1.94(ddd,J=8.5,8.0,5.0Hz,1H,H1'),1.59(br s,1H,NH+H2O),0.73-0.64(m,1H),0.60-0.53(m,1H),0.46-0.39(m,1H),0.27-0.20(m[app sextet],1H),0.03--0.04(m[app sextet],1H). 13 C NMR (125 MHz, CDCl): δ 147.5 and 145.9 (C3a'' and C7a''), 137.2 (C2), 133.1 (C5'', 122.3 (C6'', 115.5 (C3), 109.6 and 108.1 (C4'' and C7'', 100.8 (C2'', 63.9 (C1'), 50.1 and 41.8 (C1 and C2'), 15.9 (C1''', 5.0 and 2.0 (C2''' and C3'''). HRMS-ESI (m / z): [M+H] + C 15 H 19 Calculated value for NO2: 246.1494; measured value: 246.1496.

[0247] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol / Et2O as a colorless amorphous powder (mp 148-150°C). 1H NMR (500MHz, CDCl3): δ9.90-9.68(m[app br d],2H,NH2),6.76-6.71(m,3H,H4''+H6''+H7''),6.20-6.11(m,1H,H2),5.95-5.92(m[AB system],2H,H2''),5.47-5.40(m,2H,H3a+H3b),3.80-3.68(m,2H,H1),3.44(dd ,J=13.5,4.5Hz,1H,H2a'),3.09(dd,J=13.5,9.0Hz,1H,H2b'),2.55-2.45(m[app octet],1H,H1'),1.19-1.10(m,1H),0.73-0.65(m,1H),0.54-0.41(m,2H),-0.13--0.20(m,1H). Analysis C15H 20 Calculated for ClNO2: C, 63.94; H, 7.15; N, 4.97. Found: C, 63.88; H, 7.16; N, 4.94.

[0248] N-[2-(1,3-benzodioxol-5-yl)-1-cyclopropylethyl]-2-methylpropan-1-amine (UWA-035, MNG6018, "Compound 1H")

[0249] [ka]

[0250] Following general procedure 1, reaction of ketone K1 (203 mg, 0.994 mmol) with isobutylamine (993 μL, 9.99 mmol) and elution with 2:3 EtOAc / hexane followed by EtOAc afforded the product as a colorless oil (93 mg, 36%). 1H NMR (500MHz, CDCl3): δ6.73(d,J=8.0Hz,1H,H7''),6.70(d,J=1.5Hz,1H,H4''),6. 65(dd,J=8.0,1.5Hz,1H,H6''),5.92(s,1H,H2''),2.80(dd,J=13.5,5.0Hz,1H,H2a '),2.67(dd,J=13.5,7.5Hz,1H,H2b'),2.57(dd,J=11.5,7.0Hz,1H,H1a),2.34(dd ,J=11.5,6.5Hz,1H,H1b),1.85(ddd,J=9.0,7.5,5.0Hz,1H,H1'),1.72-1.60(m[app nonet],1H,H2),1.49(br s,1H,NH+H2O),0.85-0.80(m[app dd],6H,2×CH3)0.72-0.64(m,1H),0.57-0.50(m,1H),0.44-0.37(m,1H),0.24-0.17(m[app sextet],1H),0.02--0.05(m[app sextet],1H). 13 C NMR (125 MHz, CDCl): δ 147.5 and 145.8 (C3a'' and C7a''), 133.4 (C5'', 122.2 (C6'', 109.7 and 108.0 (C4'' and C7'', 100.7 (C2'', 64.9 (C1'), 55.9 and 41.6 (C1 and C2'), 28.2, 20.7, 20.6, 16.1 (C2, 2 × CH3, C1'''), 4.7 and 2.1 (C2''' and C3'''). HRMS-ESI (m / z): [M+H] + C 16 H 23 Calculated value for NO2: 262.1807; measured value: 262.1803.

[0251] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol as a colorless amorphous powder (mp 185-187°C). 1H NMR (500MHz, CDCl3): δ9.64(br s,1H,NHa),8.97(br s,1H,NHb),6.79-6.75(m,2H,H4''+H6''),6.71(d,J=8.0Hz,1H,H7''),5.95-5.92(m[AB system],2H,H2''),3.57(dd,J=13.5,4.5Hz,1H,H2a'),3.07(dd,J=13.5,9.5Hz,1H,H2b') ,3.00-2.91(m,1H,H1a),2.88-2.79(m,1H,H1b),2.64-2.56(m,1H,H1'),2.37-2.25(m[app nonet], 1H, H2), 1.15-1.06 (m, 7H, 2 × CH3 + cyclopropyl), 0.68-0.61 (m, 2H), 0.56-0.48 (m, 1H), -0.09--0.16 (m, 1H). Analytical C 16 H 24 Calculated for ClNO2: C, 64.53; H, 8.12; N, 4.70. Found: C, 64.60; H, 8.36; N, 4.62.

[0252] N-[2-(1,3-benzodioxol-5-yl)-1-cyclopropylethyl]butan-1-amine (UWA-036, MNG6026, "Compound 1I")

[0253] [ka]

[0254] Following general procedure 1, reaction of ketone K1 (203 mg, 0.994 mmol) with n-butylamine (852 μL, 8.62 mmol) and elution with 3:7 EtOAc / hexane followed by EtOAc afforded the product as a colorless oil (223 mg, 86%). 1H NMR(500MHz,CDCl3):δ6.70(d,J=8.0Hz,1H,H7''),6.67(d,J=1.5Hz,1H,H4''),6.63(dd,J=8.0,1.5Hz,1H,H6''),5.90(s,2H,H2''),2.82-2.72(m[app dd+ddd],2H,H1a+H2a'),2.66(dd,J=13.5,7.5Hz,1H,H2b'),2.50(ddd,J=11.5,8.5,6.5Hz,1H,H1b),1.85(ddd,J=9.0,7.5,5.0Hz,1H,H1'),1.53(br s,NH+H2O),1.45-1.31(m,2H,H2),1.30-1.21(m,2H,H3),0.85(t,J=7.0Hz,3H,H4),0.71- 0.63(m,1H),0.55-0.49(m,1H),0.42-0.36(m,1H),0.23-0.17(m,1H),0.00--0.06(m,1H). 13 C NMR (125 MHz, CDCl): δ 147.4 and 145.8 (C3a'' and C7a''), 133.2 (C5'', 122.2 (C6'', 109.6 and 108.0 (C4'' and C7'', 100.7 (C2'', 65.0 (C1'), 47.6, 41.6, 32.3, 20.4 (C1, C2, C3, C2'), 16.0 and 13.9 (C4 and C1''', 4.7 and 2.0 (C2''' and C3'''). HRMS-ESI (m / z): [M+H] + C 16 H 23 Calculated value for NO2: 262.1807; measured value: 262.1800.

[0255] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol / Et2O as a colorless amorphous powder (mp 163-165°C). 1H NMR (500MHz, CDCl3): δ9.65(br s,1H,NHa),6.50(br s,1H,NHb),6.77-6.73(m,2H,H4''+H6''),6.71(d,J=8.0Hz,1H,H7''),5.94-5.91(m[AB system],2H,H2''),3.54(dd,J=13.5,3.5Hz,1H,H2a'),3.20-3.10(m,1H,H1a),3.07(dd,J=13.5,10.5 Hz,1H,H2b'),3.02-2.92(m,1H,H1b),2.54-2.46(m,1H,H1'),1.99-1.89(m,2H,H2),1.44-1.35(m[app sextet],2H,H3),1.13-1.04(m,1H),0.91(t,J=7.0Hz,3H,H4),0.68-0.61(m,1H),0.53-0.42(m,2H),-0.18--0.26(m,1H). Analysis C 16 H 24 Calculated for ClNO2: C, 64.53; H, 8.12; N, 4.70. Found: C, 64.52; H, 8.22; N, 4.64.

[0256] 2-(1,3-benzodioxol-5-yl)-N-benzyl-1-cyclopropylethanamine (UWA-034, MNG6016, "Compound 1J")

[0257] [ka]

[0258] Following general procedure 1, reaction of ketone K1 (209 mg, 1.02 mmol) with benzylamine (1.09 mL, 9.98 mmol) and elution with 2:3 EtOAc / hexanes afforded the product as a pale yellow oil (261 mg, 86%). 1H-NMR (500MHz, CDCl3): δ7.31-7.17(m,5H,H2'',H3'',H4'',H5'' and H6''),6.73(d,J=8.0Hz ,1H,H7'),6.68(d,J=1.5Hz,1H,H4'),6.65(dd,J=8.0,1.5Hz,1H,H6'),5.94-5.92(m[AB system],2H,H2'),3.93(d,J=13.5Hz,1H,NCHaH),3.80(d,J=13.5Hz,1H,NCHHb),2.85(dd,J=13.5 ,5.0Hz,1H,H2a),2.73(dd,J=13.5,7.5Hz,1H,H2b),1.95(ddd,J=9.0,8.0,5.0Hz,1H,H1),1.71(br s,NH+H2O),0.79-0.70(m,1H),0.56(dddd,J=9.0,8.0,5.5,4.5Hz,1H),0.42(dddd,J=9.0,8.0,5.5,4.5Hz,1H),0.23-0.16(m[app sextet],1H),0.01--0.06(m,1H). 13 C NMR (125 MHz, CDCl3): δ 147.5 and 145.9 (C3a' and C7a'), 140.5 (C1'), 133.1 (C5'), 128.3, 127.9, 126.8 (C2', C3', C4', C5', C6'), 122.3 (C6'), 109.7 and 108.1 (C4' and C7'), 100.8 (C2'), 63.7 (C1), 51.6 and 41.6 (C2 and NCH2), 15.9 (C1''), 4.8 and 2.0 (C2''' and C3'''). HRMS-EI (m / z): [M+H] + C 19 H 21 Calculated value for NO2: 296.1645; measured value: 296.1648.

[0259] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol / Et2O as a colorless amorphous powder (mp 144-146 °C). 1H NMR (500MHz, CDCl3): δ9.95(br s,2H,NH2),7.63-7.59(m[app d],2H,H2'' and H6''),7.38-7.33(m[app t],2H,H3'' and H5''),7.31-7.27(m,1H,H4''),6.70(d,J=8.0Hz,1H,H7'),6 .63(dd,J=8.0,1.5Hz,2H,H6'),6.61(d,J=1.5Hz,1H,H4'),5.95-5.92(m[AB system],2H,H2''),4.16-4.03(m,2H,NCH2),3.38(dd,J=13.5,4.0Hz,1H,H2a),3.00(dd,J=13.5,9.5Hz,1 H,H2b),2.26-2.18(m,1H,H1),1.15-1.06(m,1H),0.63-0.60(m,1H),0.44-0.36(m,1H),0.29-0.22(m[app sextet],1H),-0.33--0.39(m,1H). Analysis C 19 H 22 Calculated for ClNO2: C, 68.77; H, 6.68; N, 4.22. Found: C, 68.78; H, 6.70; N, 4.19.

[0260] N-[2-(1,3-benzodioxol-5-yl)-1-cyclopropylethyl]cyclopropanecarboxamide (MNG6022, "Compound 1K")

[0261] [ka]

[0262] Following adapted literature procedures, 6To a stirred solution of compound 1A (310 mg, 1.51 mmol) and NEt (210 μL, 1.51 mmol) in anhydrous CHCl (2.5 mL) at 0 °C under N was slowly added a solution of cyclopropanecarbonyl chloride (53, 172 mg, 1.65 mmol) in CHCl (2.5 mL). The solution was then allowed to warm to room temperature. After 2 h, the mixture was diluted with CHCl (20 mL) and then washed with water (20 mL), 1 M HCl (20 mL), saturated NaHCO solution (20 mL), water (20 mL), brine (20 mL), dried, and evaporated to give a white solid. This material was recrystallized from EtOAc / hexane as colorless rods (244 mg, 59%): mp 128-129 °C. IR (dry film) ν - max(cm -1 ):3302(m,NH),1632(s,CO). 1 H NMR (500MHz, CDCl3): δ6.74(d,J=8.0Hz,1H,H7''),6.72(d,J=1.5Hz,1H,H4''),6.66(dd,J=8.0,1.5Hz,1H,H6''),5.95-5.92(m[AB system],2H,H2''),5.52(br d,J=7.5Hz,1H,NH),3.44-3.36(m,1H,H1'),2.85(d,J=6.0Hz,2H,H2'),1.32-1.25(m,1H),0 .99-0.90(m,2H),0.81-0.68(m,3H),0.54-0.47(m,1H),0.46-0.39(m,1H),0.36-0.28(m[app sextet],1H),0.19-0.12(m[app sextet],1H). 13 C NMR (125 MHz, CDCl): δ 172.7 (C=O), 147.4 and 146.0 (C3a'' and C7a''), 131.7 (C5'', 122.7 (C6'', 110.2 and 108.0 (C4'' and C7'', 100.8 (C2'', 55.0 (C1'), 40.5 (C2'), 15.0 and 14.9 (C1 and C1''',), 7.0, 6.9, 4.0, 3.2 (C2, C3, C2''', C3'''). HRMS-ESI (m / z): [M+H] + C 16 H19 Calculated value for NO3: 274.1443; Measured value: 274.1438. Analysis C 16 H 19 Calculated values ​​for NO3: C, 70.31; H, 7.01; N, 5.12. Found values: C, 70.17; H, 7.18; N, 5.06.

[0263] N-(2-(benzo[d][1,3]dioxol-5-yl)-1-cyclopropylethyl)prop-2-yn-1-amine (UWA-005, "Compound 1L")

[0264] [ka]

[0265] Compound 1L is a known compound obtained by a previously reported procedure. 2-86ページ

[0266] 2-(benzo[d][1,3]dioxol-5-yl)-1-cyclopropyl-N-((R)-1-phenylethyl)ethan-1-amine ("Compound 1M")

[0267] [ka]

[0268] Compound 1M is a known compound obtained by previously reported procedures. 2-115ページ

[0269] (R)-2-(benzo[d][1,3]dioxol-5-yl)-1-cyclopropyl-N-((R)-1-phenylethyl)ethan-1-amine ("Compound 1MR")

[0270] [ka]

[0271] Compound 1MR is a known compound obtained by a previously reported procedure. 2-115ページ

[0272] (S)-2-(benzo[d][1,3]dioxol-5-yl)-1-cyclopropyl-N-((R)-1-phenylethyl)ethan-1-amine ("Compound 1MS")

[0273] [ka]

[0274] Compound 1MS is a known compound obtained by previously reported procedures. 2-115ページ

[0275] 2-(benzo[d][1,3]dioxol-5-yl)-1-cyclopropyl-N-methyl-N-((R)-1-phenylethyl)ethan-1-amine ("Compound 1N")

[0276] [ka]

[0277] Compound 1N is a known compound obtained by previously reported procedures. 2-116ページ

[0278] (R)-2-(benzo[d][1,3]dioxol-5-yl)-1-cyclopropyl-N-methyl-N-((R)-1-phenylethyl)ethan-1-amine ("Compound 1NR")

[0279] [ka]

[0280] Compound 1NR is a known compound obtained by a previously reported procedure. 2-116ページ

[0281] (S)-2-(benzo[d][1,3]dioxol-5-yl)-1-cyclopropyl-N-methyl-N-((R)-1-phenylethyl)ethan-1-amine ("Compound 1NS")

[0282] [ka]

[0283] Compound 1NS is a known compound obtained by a previously reported procedure. 2-116ページ

[0284] 2-(1,3-benzodioxol-5-yl)-1-cyclopropyl-N-(2,2,2-trifluoroethyl)ethan-1-amine (UWA-044, JLK2098, "Compound 1O")

[0285] [ka]

[0286] A sealed mixture of freshly activated 3 Å sieves (approximately 300 mg), ketone K1 (205 mg, 1.00 mmol), 2,2,2-trifluoroethylamine hydrochloride (1.36 g, 10.0 mmol), sodium acetate (820 mg, 10.0 mmol), and sodium cyanoborohydride (63 mg, 1.0 mmol) in anhydrous THF (2 mL) was stirred at 50 °C for 3 days. The reaction was quenched with concentrated HCl, filtered through a pad of Celite with HO, basified, and extracted with DCM (3 × 50 mL). The extracts were washed with HO (2 × 50 mL) and brine (50 mL), dried, evaporated, and the residue subjected to flash chromatography. Elution with 1:9 EtOAc / Hex followed by 3:7 EtOAc / Hex gave the secondary amine 10 as a colorless oil (48 mg, 17%). 1H NMR (400MHz, CDCl3): δ6.74(d,J=7.9Hz,1H,H7'),6.69(d,J=1.5Hz,1H,H4'),6.65 (dd,J=7.9,1.6Hz,1H,H6'),5.93(s,2H,H2'),3.37-3.26(m,1H,H1''a),3.26-3.1 5(m,1H,H1''b),2.83(dd,J=13.8,4.9Hz,1H,H2a),2.66(dd,J=13.8,7.7Hz,1H,H2 b),2.10-2.02(m,1H,H1),0.73-0.55(m,2H),0.50-0.41(m,1H),0.29-0.20(m[app. sextet],1H),0.08 to -0.02(m,1H). 13 C NMR (100 MHz, CDCl3): δ 147.8 and 146.2 (C3a' and C7a'), 132.4 (C5'), 125.7 (q, J = 279.4 Hz, C2''), 122.4 (C6'), 109.7 (C4'), 108.3 (C7'), 101.0 (C2'), 63.5 (C1), 48.1 (q, J = 30.9 Hz, C1''), 41.9 (C2), 15.7 (C1'''), 4.9 and 1.9 (C2''' and C3'''). HRMS (ESI+) m / z [M+H] + C 14 H 17 F3NO2 + Calculated value: 288.1206; measured value: 288.1205.

[0287] The free base was converted to the hydrochloride salt, which crystallized as off-white diamonds from DCM / hexanes. 1 H NMR(400MHz,CDCl3):δ10.39(br. s,2H,NH2),6.80-6.71(m,3H,H4' / 6' / 7'),5.94(m[AB],2H,H2'),3.89-3.67(m,2H,H1''),3.50(dd,J=13.4,3.7Hz,1H,H2a),3.13( dd,J=13.4,9.2Hz,1H,H2b),2.81-2.69(m,1H,H1),1.18-1.06(m,1H),0.77-0.66(m,1H),0.61-0.51(m,2H),-0.02 to -0.13(m,1H).

[0288] 2-(1,3-benzodioxol-5-yl)-1-cyclopropyl-N-(3-hydroxypropyl)ethan-1-amine (UWA-047, JLK2100, "Compound 1P")

[0289] [ka]

[0290] According to general procedure 1, ketone K1 (204 mg, 1.00 mmol) was reacted with propanolamine (765 μL, 10.0 mmol) and the crude product was subjected to flash chromatography. Elution with 35:65:1 EtOAc / Hex / NEt3 gave the secondary amine 1P as a pale yellow oil (233 mg, 88%). 1 H NMR(400MHz,CDCl3):δ6.72(d,J=7.9Hz,1H,H7'),6.66(d,J=1.6Hz,1H,H4'),6.62(dd,J=7.8,1.6Hz,1 H,H6'),5.91(s,2H,H2'),3.80-3.70(m,2H,H3''),3.03(ddd,J=11.7,6.9,5.0Hz,1H,H1''a),3.00(br. s,2H,OH+NH),2.85-2.73(m,2H,H1''b / 2a),2.65(dd,J=13.7,7.7Hz,1H,H2b),1.87(ddd,J=8.6,7.8,5.0Hz,1H, H1),1.71-1.57(m,2H,H2''),0.72-0.61(m,1H,H1'''),0.61-0.53(m,1H),0.49-0.40(m,1H),0.29-0.21(m[app. sextet],1H),0.05 to -0.03(m[app. sextet],1H). 13C NMR (100 MHz, CDCl3): δ 147.7 and 146.1 (C3a' and C7a'), 132.7 (C5'), 122.4 (C6'), 109.7 (C4'), 108.3 (C7'), 100.9 (C2'), 65.1 (C1), 64.4 (C3'', 47.8 (C1'', 41.7 (C2), 31.5 (C2'', 15.9 (C1'''), 5.3 and 2.3 (C2''' and C3'''). HRMS (ESI+) m / z [M+H] + C 15 H 22 No. 3 + Calculated value: 264.1594; measured value: 264.1593.

[0291] The free base was converted to the hydrochloride salt, which was crystallized as white plates from i-PrOH / Et2O. 1 H NMR(400MHz,CDCl3):δ9.41(br. s,1H,NH),9.04(br. s,1H,NH),6.79-6.72(m,3H,H4' / 6' / 7'),5.94(s,2H,H2'),3.91-3.79(m, 2H,H3''),3.54-3.42(m,1H,H1''a),3.34(dd,J=13.8,6.0Hz,1H,H2a),3.2 2-3.07(m,2H,H1''b / 2b),2.54-2.43(m,1H,H1),2.15-1.99(m,2H,H2''),1 .24-1.13(m,1H),0.78-0.68(m,1H),0.63-0.53(m,1H),0.50-0.41(m[app. sextet],1H), 0.01 to -0.08(m[app. sextet],1H).

[0292] 2-(1,3-benzodioxol-5-yl)-1-cyclopropylethyl-N-cyclobutanamine; N-(2-(benzo[d][1,3]dioxol-5-yl)-1-cyclopropylethyl)cyclobutanamine; (UWA-055, JLK2043, "Compound 1Q")

[0293] [ka]

[0294] Following General Procedure 1, but using half the amine in excess, ketone K1 (102 mg, 0.500 mmol) was reacted with cyclobutylamine (0.21 mL, 2.5 mmol). The reaction was quenched with concentrated HCl and filtered through a pad of Celite with HO. The solution was washed with DCM (3 × 50 mL), then basified and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with HO (2 × 20 mL) and brine (20 mL), then dried and evaporated to give secondary amine 1Q as a light brown oil (111 mg, 86%). 1 H NMR (400MHz, CDCl3): δ6.73(d,J=7.8Hz,1H,H7'),6.67(d,J=1.5Hz,1H,H4'),6.64(dd,J=7.9,1. 6Hz,1H,H6'),5.93(s,2H,H2'),3.54-3.44(m,1H,H1''),2.79(dd,J=13.6,5.1Hz,1H,H2a),2.62 (dd, J = 13.6, 8.0 Hz, 1H, H2b), 2.26-2.09 (m, 2H), 1.88-1.81 (m, 1H, H1), 1.63-1.51 (m, 3H), 1.45-1.34 (m, 1H), 0.71-0.60 (m, 1H, H1''), 0.58-0.49 (m, 1H), 0.45-0.36 (m, 1H), 0.23-0.14 (m[app. sextet], 1H), 0.01 to -0.07 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 147.7 and 146.0 (C3a' and C7a'), 133.4 (C5'), 122.4 (C6'), 109.7 (C4'), 108.2 (C7'), 100.9 (C2'), 62.3 (C1), 51.8 (C1'', 42.1 (C2), 32.0 and 31.8 (C2'' and C4'', 16.3 (C1''', 14.6 (C3'', 5.0 and 2.3 (C2''' and C3'''). HRMS (ESI+) m / z [M+H] + C 16 H 22 NO2 + Calculated value: 260.1645; measured value: 260.1643.

[0295] The free base was converted to the hydrochloride salt, which was crystallized from PhMe (toluene) as white granules. 1 H NMR (400MHz, CDCl3): δ9.78(br. s,2H,NH2),6.76-6.68(m,3H,H4' / 6' / 7'),5.93(m[AB],2H,H2'),3.96(dddd[app. pentet],J1=J2=J3=J4=8.2Hz,1H,H1''),3.52(dd,J=13.4,3.8Hz,1H,H2a),3.05(dd,J=13.4,10.3Hz,1H,H2b),2.43-2.19( m,3H),2.05-1.93(m,1H),1.88-1.72(m,1H),1.11-0.99(m,1H),0.68-0.58(m,1H),0.49-0.35(m,2H),-0.23 to -0.34(m,1H).

[0296] 1-[2-(1,3-benzodioxol-5-yl)-1-cyclopropylethyl]pyrrolidine (UWA-048, JLK2101, "Compound 1R")

[0297] [ka]

[0298] According to general procedure 1, ketone K1 (205 mg, 1.00 mmol) was reacted with pyrrolidine (727 μL, 10.0 mmol) and the crude product was subjected to flash chromatography. Elution with 1:4 EtOAc / Hex followed by 20:80:1 EtOAc / Hex / NEt3 afforded tertiary amine 1R as a pale yellow oil (230 mg, 89%). 1H NMR (400MHz, CDCl3): δ6.70(d,J=1.2Hz,1H,H4'),6.65(dd,J=7.8,0.3Hz,1H,H7'),6.63(dd,J=7. 9,1.4Hz,1H,H6'),5.85(m[AB],2H,H2'),2.91(dd,J=13.7,4.5Hz,1H,H2a),2.74(dd,J=13.7,7.0 Hz,1H,H2b),2.71-2.60(m,4H,H2'' / 5''),1.78-1.67(m,4H,H3'' / 4''),1.51(ddd,J=11.6,7.0,4 .5Hz,1H,H1),0.73-0.61(m,1H,H1'''),0.51-0.41(m,1H),0.31-0.22(m,1H),0.20-0.10(m[app. sextet],1H), -0.25 to -0.35(m,1H). 13 C NMR (100 MHz, CDCl3): δ 147.1 and 145.5 (C3a' and C7a'), 134.2 (C5'), 122.5 (C6'), 110.1 (C4'), 107.7 (C7'), 100.6 (C2'), 70.9 (C1), 52.2 (C2'' / 5''), 40.9 (C2), 23.3 (C3'' / 4''), 14.6 (C1'''), 6.1 and 3.0 (C2''' and C3'''). HRMS (ESI+) m / z [M+H] + C 16 H 22 NO2 + Calculated value: 260.1645; measured value: 260.1643.

[0299] The free base was converted to the hydrochloride salt, which was crystallized as colorless plates from i-PrOH / Et2O. 1H NMR (400MHz, CDCl3): δ6.75-6.72(m,3H,H4' / 6' / 7'),5.95(m[AB],2H,H2'),3.94-3.84(m,1H),3 .78-3.68(m,1H),3.44(dd,J=14.0,4.6Hz,1H,H2a),3.15(dd,J=14.0,8.8Hz,1H,H2b),3.01-2.85 (m,2H),2.51-2.42(m,1H,H1),2.34-2.19(m,2H,H3''a / 4''a),2.08-1.93(m,2H,H3''b / 4''b),1 .29-1.18(m,1H), 0.80-0.72(m,1H), 0.60-0.51(m,1H), 0.44-0.35(m,1H), -0.12 to -0.21(m,1H).

[0300] 4-[2-(1,3-benzodioxol-5-yl)-1-cyclopropylethyl]morpholine (UWA-049, JLK2102, "Compound 1S")

[0301] [ka]

[0302] According to general procedure 1, ketone K1 (205 mg, 1.00 mmol) was reacted with morpholine (872 μL, 10.0 mmol) and the crude product was subjected to flash chromatography. Elution with 5:95:1 EtOAc / Hex / NEt3 gave the tertiary amine 1S as a colorless oil (206 mg, 75%). 1H NMR (400MHz, CDCl3): δ6.73(d,J=1.6Hz,1H,H4'),6.70(d,J=7.9Hz,1H,H7'), 6.65(dd,J=7.9,1.6Hz,1H,H6'),5.91(m[AB],2H,H2'),3.74-3.64(m,4H,H2'' / 6''),2.83(dd,J=13.1,6.9Hz,1H,H2a),2.82-2.74(m,2H,H3''a / 5''a),2.7 0(dd,J=13.9,6.5Hz,1H,H2b),2.65-2.58(m,2H,H3''b / 5''b),1.75(ddd[app. dt], J = 9.5, 6.3, 6.3 Hz, 1H, H1), 0.77-0.66 (m, 1H, H1'''), 0.58-0.49 (m, 1H), 0.39-0.30 (m, 1H), 0.28-0.19 (m[app. sextet], 1H), -0.17 to -0.26 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 147.3 and 145.6 (C3a' and C7a'), 134.6 (C5'), 122.4 (C6'), 110.0 (C4'), 107.9 (C7'), 100.8 (C2'), 71.8 (C1), 67.7 (C2'' / 6''), 50.6 (3'' / 5''), 38.4 (C2), 11.7 (C1'''), 5.5 and 2.7 (C2''' and C3'''). HRMS (ESI+) m / z [M+H] + C 16 H 22 No. 3 + Calculated value: 276.1594; measured value: 276.1592.

[0303] The free base was converted to the crude hydrochloride salt, which was precipitated as white diamonds from i-PrOH / Et2O. 1H NMR (400MHz, CDCl3): δ6.82(d,J=1.6Hz,1H,H4'),6.78(dd,J=7.9,1.6Hz,1H,H 6'),6.72(d,J=7.9Hz,1H,H7'),5.94(m[AB],2H,H2'),4.49-4.35(m,2H),4.06 -3.92(m,2H),3.68(dd,J=13.3,3.3Hz,1H,H2a),3.58-3.50(m,1H),3.37-3.24 (m,2H),3.17-3.05(m,1H),2.97(dd,J=13.3,9.6Hz,1H,H2b),2.58(dddd[app. tt], J1 = J2 = 10.2 Hz, J3 = J4 = 3.4 Hz, 1H, H1), 1.05-0.94 (m, 1H), 0.82-0.72 (m, 1H), 0.62-0.52 (m, 1H), 0.48-0.39 (m, 1H), -0.14 to -0.23 (m, 1H).

[0304] 2-(1,3-benzodioxol-5-yl)-1-cyclopropyl-N-(oxan-4-yl)ethan-1-amine (UWA-046, JLK2103, "Compound 1T")

[0305] [ka]

[0306] According to general procedure 1, ketone K1 (204 mg, 1.00 mmol) was reacted with 4-aminotetrahydropyran (570 μL, 10.0 mmol), and the crude product was subjected to flash chromatography. Elution with 3:7 EtOAc / Hex followed by 30:70:1 EtOAc / Hex / NEt3 afforded the secondary amine 1T as a pale yellow oil (240 mg, 83%). 1H NMR (400MHz, CDCl3): δ6.66(d,J=7.9Hz,1H,H7'),6.63(d,J=1.6Hz,1H,H4'),6.58(dd,J=7. 9,1.6Hz,1H,H6'),5.85(s,2H,H2'),3.90-3.77(m,2H,H2''a / 6''a),3.36-3.21(dddd[app. tdd], J=15.5, 11.5, 11.5, 2.3Hz, 2H, H2''b / 6''b), 2.82-2.69(m, 2H, H2a / 4''), 2.63-2.53(dd, J=13.6, 7.4Hz, 1H, H2b), 2.05(ddd, J=8.67.4, 5.2Hz, 1H, H1), 1.81-1.73(m, 1H, H3''a or H5''a) , 1.72-1.64(m,1H,H3''a or H5''a), 1.28-1.15(m,1H,H3''b or H5''b), 1.13-1.00(m,1H,H3''b or H5''b), 0.69-0.57(m,1H,H1'''), 0.52-0.42(m,1H), 0.42-0.32(m,1H), 0.16-0.07(m[app. sextet],1H), 0.01 to -0.08(m[app. sextet],1H). 13 C NMR (100 MHz, CDCl3): δ 147.5 and 145.8 (C3a' and C7a'), 132.9 (C5'), 122.2 (C6'), 109.3 (C4'), 108.0 (C7'), 100.7 (C2'), 67.0 and 66.9 (C2'' and C6''), 60.3 (C1), 50.6 (C4'', 41.9 (C2), 34.7 and 33.9 (C3'' and C5'', 16.5 (C1'''), 4.5 and 2.4 (C2'''' and C3''''). HRMS (ESI+) m / z [M+H] + C 17 H 24 No. 3 + Calculated value: 290.1751; measured value: 290.1749.

[0307] The free base was converted to the hydrochloride salt, which was precipitated as white granules from i-PrOH / Et2O. 1H NMR(400MHz,CDCl3):δ9.76(br. s,1H,NH),9.65(br. s,1H,NH),6.76-6.69(m,3H,H4' / 6' / 7'),5.93(m[AB],2H,H2'),4.08-3.96(m,2H, H2''a / 6''a),3.64-3.45(m,2H,H2a / 4''),3.38-3.24(m,2H,H2''b / 6''b),3.16(d d, J = 13.4, 9.8 Hz, 1H, H2b), 2.65-2.53 (m, 1H, H1), 2.26-2.10 (m, 3H), 2.03-1.94 (m, 1H), 1.28-1.16 (m, 1H), 0.75-0.64 (m, 1H), 0.53-0.42 (m, 1H), 0.38-0.29 (m[app. sextet], 1H), -0.18 to -0.27 (m[app. sextet], 1H).

[0308] 2-(benzo[d][1,3]dioxol-5-yl)-1-cyclopropyl-N-(cyclopropylmethyl)ethanamine (UWA-050, GAP-045, "Compound 1U")

[0309] [ka]

[0310] According to general procedure 1, a sealed mixture of freshly activated 3A sieves (144 mg), ketone K1 (103 mg, 0.504 mmol), cyclopropylmethanamine hydrochloride (570 mg, 5.30 mmol), sodium acetate (433 mg, 5.28 mmol), and sodium cyanoborohydride (33 mg, 0.53 mmol) in anhydrous THF (2.5 mL) was stirred at 50 °C for 3 days. The reaction mixture was cooled to room temperature, quenched with 1 M HCl (10 mL), vacuum filtered through a pad of Celite, and rinsed with MeOH (3 × 25 mL). The filtrate was concentrated under reduced pressure, and the residue was basified with 1 M NaOH (30 mL) and extracted with CHCl (3 × 30 mL). The extract was washed with brine (30 mL), dried, and evaporated, and the residue was subjected to flash chromatography. Elution with 1:1 EtOAc / hexanes followed by 1:49:50 NEt3 / EtOAc / hexanes gave amine 1U as a colorless oil (89 mg, 68%). 1 H NMR (400MHz, CDCl3): δ6.73(d,J=7.8Hz,1H),6.70(d,J=1.5Hz,1H),6.66(dd, J=7.8,1.6Hz,1H),5.93(s,2H),2.81(dd,J=13.6,5.3Hz,1H),2.73-2.63(m,2H ),2.35(dd,J=11.8,7.0Hz,1H),1.89(ddd,J=9.0,7.6,5.3Hz,1H),0.95-0.84 (m,1H),0.75-0.66(m,1H),0.57-0.50(m,1H),0.46-0.37(m,3H),0.20(m[app. sextet],J=5.0Hz,1H),0.09-0.04(m,1H),0.02-(-0.06)(m,2H)ppm. 13 C NMR (100MHz, CDCl3) δ147.6,146.0,133.3,122.4,109.8,108.2,100.9,65.1,53.2,41.7,16.2,11.5,4.8,3.6,3.4,2.4ppm. HRMS(ESI+)m / z[M+H] + C 16 H 22 NO2 + Calculated value: 260.1645; measured value: 260.1642.

[0311] The free base was converted to the crude hydrochloride salt and recrystallized as colorless rosettes from PhMe. 1 H NMR(400MHz,CDCl3)δ9.70(br s,1H),9.57(br s,1H),6.77-6.73(m,2H),6.71(d,J=8.0Hz,1H),5.93(d[AB],J=1.4Hz,1H),5.92(d[A B],J=1.4Hz,1H),3.55(dd,J=13.4,4.1Hz,1H),3.11(dd,J=13.4,9.9Hz,1H),2.99(br d,J=6.8Hz,2H),2.64-2.55(m,1H),1.38-1.28(m,1H),1.17-1.06(m,1H),0.69-0.61(m,3H),0.54-0.42(m,4H),(-0.15)-(-0.23)(m,1H)ppm.

[0312] Type 2 Compounds Compounds of type 2 can be prepared following general procedure 2;

[0313] [ka]

[0314] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 2 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0315] 2-(1,3-benzodioxol-5-yl)-1-cyclobutylethanone ("Ketone K2")

[0316] [ka]

[0317] Modified literature procedure 7 According to the method described above, to a solution of freshly prepared piperonylcuprate (150 mM, 180 nL) in THF at −70° C., a solution of cyclobutanecarbonyl chloride (3.07 g, 25.9 mmol) in THF (5 mL) was slowly added. The reaction mixture was allowed to warm to room temperature over 2.5 h and then quenched by the addition of 1 M HCl (40 mL). The mixture was diluted with EtO (100 mL) and water (200 mL) and then filtered through a Celite pad. The aqueous layer was separated, shaken with additional EtO (100 mL), and both phases were passed through a Celite pad to remove the precipitate that had formed. This process was repeated one more time. The combined organic extracts were washed with water until no more precipitate formed, then with saturated NaHCO solution (50 mL), brine (50 mL), dried, and evaporated to give a pale yellow oil. The crude material was purified using flash chromatography (1:10 EtO / hexanes) to give the product as a pale yellow oil (2.79 g, 48%). IR (thin film) v - max(cm -1 ):1709(s,CO). 1 H NMR (500MHz, CDCl3): δ6.74(d,J=8.0Hz,1H,H7'),6.67(d,J=1.5Hz,1H,H4'),6.62 (dd,J=8.0,1.5Hz,1H,H6'),5.93(s,2H,H2'),3.55-3.53(m,2H,H2),3.33(dtt[app quintet doublet], J=8.5,8.5,1.0Hz,1H,H1''),2.27-2.17(m,2H),2.11-2.02(m,2H),1.98-1.87(m,1H),1.84-1.75(m,1H). 13C NMR (125 MHz, CDCl3): δ 209.2 (C1), 147.8 and 146.5 (C3a' and C7a'), 127.9 (C5'), 122.5 (C6'), 109.8 and 108.3 (C4' and C7'), 101.0 (C2'), 47.1 (C1), 44.6 (C1'', 24.5 (C2'' and C4'', 17.6 (C3''). HRMS-EI (m / z): M + C 13 H 14 Calculated value for O3: 218.0943; measured value: 218.0948.

[0318] 2-(benzo[d][1,3]dioxol-5-yl)-1-cyclobutylethan-1-amine (UWA-045, JLK2097, "Compound 2A")

[0319] [ka]

[0320] Compound 2A can be obtained via the following adaptation of the procedure for the preparation of compound 1A, using ketone K2 instead of ketone K1.

[0321] To freshly activated 3 Å sieves (approximately 150 mg) was added a solution of ketone K2 (218 mg, 1.00 mmol), ammonium acetate (771 mg, 10.0 mmol), and sodium cyanoborohydride (63 mg, 1.00 mmol) in anhydrous THF (2 mL). The mixture was stirred at 50 °C for 16 h and then capped. The reaction was quenched with concentrated HCl, filtered through a pad of Celite with HO, basified, and extracted with DCM (3 × 50 mL). The extracts were washed with HO (2 × 50 mL) and brine (50 mL), dried, evaporated, and the residue subjected to flash chromatography. Elution with 40:60:1 EtOAc / Hex / AcOH followed by 60:40:1 EtOAc / Hex / NEt3 gave primary amine 2A as a pale yellow oil (87 mg, 40%). 1H NMR(400MHz,CDCl3):δ6.74(d,J=7.9Hz,1H,H7'),6.68(d,J=1.6Hz,1H,H4'),6.63(dd,J=7.9,1.6Hz,1H,H6'),5.92(s,2H,H2'),2.82(ddd[app. td],J1=J2=8.8,J3=3.9Hz,1H,H1),2.68(dd,J=13.5,3.9Hz,1H,H2a),2.25-2.17(m,2H),2.10-1.68(m,6H),0.97(br. s,2H,NH2). 13 C NMR (100 MHz, CDCl3): δ 147.7 and 146.0 (C3a' and C7a'), 133.5 (C5'), 122.3 (C6'), 109.7 (C4'), 108.3 (C7'), 100.9 (C2'), 58.6 (C1), 42.1 (C1'', 41.1 (C2), 25.7, 25.6, 17.8 (C2'', C3'' and C4''). HRMS (ESI+) m / z [M+H] + C 13 H 18 NO2 + Calculated value: 220.1332; measured value: 220.1330.

[0322] The free base was converted to the crude hydrochloride salt, which crystallized as colorless diamonds from DCM / Hex. 1 H NMR(400MHz,CDCl3):δ8.37(br. s,3H,NH3),6.76(d,J=1.3Hz,1H,H7'),6.73(d,J=7.9Hz,1H,H4'),6.69(dd,J=7.9,1.3Hz,1H,H6'),5.91(s,2H,H2'),3.42-3.26(m,1 H,H1),3.05(dd,J=14.0,5.7Hz,1H,H2a),2.79(dd,J=14.0,7.9Hz,1H,H2b),2.66-2.52(m,1H),2.22-2.02(m,2H),1.93-1.71(m,4H).

[0323] 2-(1,3-benzodioxol-5-yl)-1-cyclobutyl-N-methylethanamine (UWA-038, MNG6050, "Compound 2B")

[0324] [ka]

[0325] Following general procedure 2, reaction of ketone K2 (221 mg, 1.02 mmol) with 8.03 M methylamine in EtOH (1.25 ml, 10.0 mmol) and elution with 2:3 EtOAc / hexane followed by 1:9 MeOH / EtOAc gave the product as a pale yellow oil (159 mg, 67%). 1 H NMR (500MHz, CDCl3): δ6.72(d,J=8.0Hz,1H,H7'),6.67(d,J=1.5Hz,1H,H4'),6.61(dd,J=8.0,1.5Hz,1H,H6'),5.93-5.91(m,2H,H2'),2.62(dd,J=13 .5,4.5Hz,1H,H2a),2.54(ddd,J=9.0,7.5,4.5Hz,1H,H1),2.41(dd,J=14.0 ,7.5Hz,1H,H2b),2.36(s,3H,NCH3),2.34-2.22(m,1H),2.10-1.68(m,6H). 13 C NMR (125 MHz, CDCl3): δ 147.5 and 145.8 (C3a' and C7a'), 133.2 (C5'), 122.2 (C6'), 109.6 and 108.1 (C4' and C7'), 100.7 (C2'), 66.4 (C1), 40.2 and 34.5 (NCH3 and C1''), 36.9 (C2), 27.2, 26.3, 18.2 (C2'', C3'', C4''). HRMS-ESI (m / z): [M+H] + C 14 H 19 Calculated value for NO2: 234.1494; measured value: 234.1486.

[0326] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol as a colorless amorphous powder (mp 165-166°C). 1H NMR (500MHz, CDCl3): δ9.5-9.1(2×br s,2H,NH2),6.78-6.73(m,3H,H4'+H6'+H7'),5.94-5.93(m[AB system],2H,H2'),3.23-3.15(br m,1H),3.12(dd,J=14.0,6.5Hz,1H,H2a),2.83(dd,J=14.0,7.0Hz,1H,H2b),2.78-2.68(m,1H),2.59-2.54(m[app br t],3H,NCH3),2.29-2.21(m,1H),2.14-2.04(m,1H),1.93-1.82(m,2H),1.81-1.66(m,2H). Analysis C 14 H 20 Calculated for ClNO2: C, 62.33; H, 7.47; N, 5.19. Found: C, 62.35; H, 7.59; N, 5.15.

[0327] 2-(1,3-benzodioxol-5-yl)-1-cyclobutyl-N,N-dimethylethan-1-amine (UWA-016, JLK2094, GAP-070, "Compound 2C")

[0328] [ka]

[0329] To freshly activated 3 Å sieves (approximately 150 mg) was added a solution of ketone K2 (109 mg, 0.50 mmol) in anhydrous THF (2 mL), dimethylamine hydrochloride (408 mg, 5.00 mmol), sodium acetate (411 mg, 5.01 mmol), and sodium cyanoborohydride (32 mg, 0.51 mmol). The mixture was stirred at 50 °C for 16 h and then capped. The reaction was quenched with concentrated HCl, filtered through a pad of Celite with HO, basified, and extracted with DCM (3 × 50 mL). The extracts were washed with HO (2 × 50 mL) and brine (50 mL), dried, evaporated, and the residue subjected to flash chromatography. Elution with 40:60:1 EtOAc / Hex / AcOH followed by 40:60:1 EtOAc / Hex / Net3 gave the tertiary amine 2C as a yellow oil (87 mg, 71%). 1 H NMR (400MHz, CDCl3): δ6.71-6.66(m,2H,H4' / 7'),6.62(dd,J=7.9,1.3Hz,H6'),5.90(s,2H,H2'),2.69-2.60(m,2H,H1 / 2a),2 .52-2.40(m,1H,H1''),2.37-2.30(m,1H,H2b),2.27(s,6H,2×CH3),2.05-1.94(m,1H),1.89-1.60(m,4H),1.55-1.43(m,1H). 13 C NMR (100 MHz, CDCl3): δ 147.4 and 145.5 (C3a' and C7a'), 135.4 (C5'), 122.0 (C6'), 109.6 (C4'), 108.0 (C7'), 100.8 (C2'), 71.7 (C1), 41.2 (CH3), 39.1 (C1''), 33.3 (C2), 28.6 and 28.4 (C2'' and C4''), 18.8 (C3''). HRMS (ESI+) m / z [M+H] + C 15 H 22 NO2 + Calculated value: 248.1645; measured value: 248.1643.

[0330] The free base was converted to the hydrochloride salt and evaporated to leave a light brown gum. 1H NMR(400MHz,CDCl3):δ11.85(br. S,1H,NH),6.78-6.71(m,3H,H4' / 6' / 7'),5.94(s,2H,H2'),3.47-3.36(m,1H,H1),3.15(dd,J=14.6,4.8Hz,1H,H2a),2.78(dd,J=14 .6,7.1Hz,1H,H2b),2.72(d,J=4.4Hz,3H,CH3),2.68(d,J=4.4Hz,3H,CH3),2.23-2.07(m,2H),1.98-1.79(m,3H),1.78-1.61(m,2H).

[0331] 2-(1,3-benzodioxol-5-yl)-1-cyclobutylethyl-N-cyclopropanamine; N-(2-(benzo[d][1,3]dioxol-5-yl)-1-cyclobutylethyl)cyclopropanamine; (UWA-054, JLK2045, "Compound 2D")

[0332] [ka]

[0333] According to general procedure 2, ketone K2 (220 mg, 1.01 mmol) was reacted with cyclopropylamine (572 mL, 10.0 mmol). The reaction was quenched with concentrated HCl and filtered through a pad of Celite with HO. The solution was washed with DCM (3 × 50 mL), then basified and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with HO (2 × 30 mL) and brine (30 mL), then dried and evaporated to give the secondary amine 2D as a light brown oil (233 mg, 90%). 1H NMR (400MHz, CDCl3): δ6.73(d,J=8.0Hz,1H,H7'),6.69(d,J=1.4Hz,1H,H4'),6.62(dd,J=7.9,1. 5Hz,1H,H6'),5.93(s,2H,H2'),2.77-2.71(m,1H,H1),2.64(dd,J=13.7,4.7Hz,1H,H2a),2.48(dd ,J=13.7,7.6Hz,1H,H2b), 2.34-2.24(m,1H,H1''), 2.08-1.99(m,2H), 1.94-1.86(m,1H), 1.86-1.78(m,2H), 1.76-1.66(m,2H), 0.42-0.38(m,2H,H2'' or H3''), 0.25-0.21(m,2H,H2'' or H3''). 13 C NMR (100 MHz, CDCl3): δ 147.6 and 145.9 (C3a'' and C7a''), 133.6 (C5'), 122.4 (C6'), 109.8 (C4'), 108.2 (C7'), 100.9 (C2'), 65.4 (C1), 40.6 (C1'', 38.1 (C2), 29.3 (C1'''), 27.3 and 26.3 (C2''' and C4'''), 18.2 (C3'''), 7.4 and 7.1 (C2'' and C3''). HRMS (ESI+) m / z [M+H] + C 16 H 22 NO2 + Calculated value: 260.1645; measured value: 260.1643.

[0334] The free base was converted to the hydrochloride salt, which was crystallized as white rosettes from i-PrOH / Et2O. 1 H NMR (400MHz, CDCl3): δ6.81-6.75(m,2H,H4' / H6'),6.75-6.70(m,1H,H7'),5.93(s,2H,H2'),3.38-3.25(m,2H,H1 / 2a),2.92-2.75( m,2H,1'' / H2b),2.37-2.22(m,2H),2.13-2.01(m,1H),1.92-1.79(m,2H),1.77-1.58(m,2H),1.36-1.17(m,2H),0.80-0.70(m,2H).

[0335] 2-(1,3-benzodioxol-5-yl)-1-cyclobutylethyl-N-cyclobutanamine; N-(2-(benzo[d][1,3]dioxol-5-yl)-1-cyclobutylethyl)cyclobutanamine; (UWA-056, JLK2044, "Compound 2E")

[0336] [ka]

[0337] Following General Procedure 2, but using half the excess amine, ketone K2 (111 mg, 0.51 mmol) was reacted with cyclobutylamine (213 mL, 2.50 mmol). The reaction was quenched with concentrated HCl and filtered through a pad of Celite with HO. The solution was washed with DCM (3 × 50 mL), then basified and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with HO (2 × 20 mL) and brine (20 mL), then dried and evaporated to give the secondary amine 2E as a light brown oil (109 mg, 80%). 1 H NMR (400MHz, CDCl3): δ6.72(d,J=7.9Hz,1H,H7'),6.67(d,J=1.1Hz,1H,H4'),6. 61(dd,J=7.9,1.1Hz,1H,H6'),5.93(s,2H,H2'),3.30-3.20(m,1H,H1''),2.64-2 .54(m,2H,H1 / H2a),2.39-2.30(m,1H,H2b),2.29-2.20(m,1H,H1'''),2.20-2.1 0(m,2H,H2'' or H4''), 2.09-1.98(m,1H), 1.93-1.64(m,5H), 1.61-1.34(m,4H). 13C NMR (100 MHz, CDCl3): δ 147.6 and 145.9 (C3a' and C7a'), 133.6 (C5'), 122.3 (C6'), 109.7 (C4'), 108.2 (C7'), 100.9 (C2'), 62.0 (C1), 52.1 (C1'', 40.9 (C1''', 38.4 (C2), 32.03 and 31.95 (C2'' and C4'', 27.2 and 26.3 (C2''' and C4''', 18.2 (C3''',), 14.6 (C3''). HRMS (ESI+) m / z [M+H] + C 17 H 24 NO2 + Calculated value: 274.1802; measured value: 274.1799.

[0338] The product was converted to the hydrochloride salt, which was precipitated as white granules from i-PrOH / Et2O. 1 H NMR(400MHz,CDCl3):δ9.40(br. S,1H,NH),9.35(br. S,1H,NH),6.79(dd,J=7.9,1.5Hz,1H,H6'),6.77(d,J=1.4Hz,1H,H4'),6.74(d,J=7.9H z,1H,H7'),5.95(m[AB],2H,H2'),3.61-3.48(m,1H,H1''),3.25(dd,J=14.5,6.2Hz,1H ,H2a),3.16-3.05(m,1H,H1),2.87-2.71(m,2H,H1''' / 2b),2.70-2.57(m,1H),2.56-2. 43(m,1H),2.41-2.30(m,1H),2.27-2.16(m,2H),2.07-1.79(m,4H),1.79-1.56(m,3H).

[0339] Type 3 Compounds Compounds of type 3 can be prepared following general procedure 3;

[0340] [ka]

[0341] (In the formula, R 1 and R2 is as defined for compounds of formula II').

[0342] 1-(1,3-benzodioxol-5-yl)but-3-yn-2-ol ("propargyl alcohol P1")

[0343] [ka]

[0344] Propargylic alcohol P1 is a known compound that has been previously synthesized by other methods. 8 Adapted literature procedures 7 To a stirred solution of 0.5 M ethynylmagnesium chloride in THF (41 mL, 20 mmol) at 0° C. was added freshly prepared homopiperonal in THF (100 mL). 9 A solution of (57, 3.34 g, 20.3 mmol) was added dropwise over 45 min. The resulting solution was stirred at 0 °C for 0.5 h and then allowed to warm to room temperature. The mixture was quenched with saturated NH4Cl solution (50 mL) and stirred for an additional 5 min. The aqueous layer was separated and extracted with additional Et2O (3 x 50 mL). The combined organic extracts were washed with water (2 x 100 mL), brine (50 mL), dried, and evaporated to give a crude orange oil. This material was adsorbed onto silica gel and purified by flash chromatography (1:9 EtOAc / hexane followed by 1:4 EtOAc / hexane) to give a yellow oil (2.96 g, 76%). Characterization data were consistent with those found in the literature. 8

[0345] 1-(1,3-Benzodioxol-5-yl)but-3-yn-2-yl 4-methylbenzenesulfonate ("Propargyl Tosylate P2")

[0346] [ka]

[0347] Adapted literature procedures 10 According to the method described above, to a stirred solution of propargyl alcohol P1 (2.96 g, 15.6 mmol), Net3 (4.35 mL, 31.2 mmol), and 4-(dimethylamino)pyridine (95 mg, 0.78 mmol) in anhydrous CHCl (50 mL) at 0 °C, tosyl chloride (3.06 g, 16.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 h under a CaCl guard tube. The reaction mixture was washed with 1 M HCl (2 × 20 mL), saturated NaHCO solution (10 mL), water (10 mL), and brine (10 mL), dried, and evaporated to give a white solid that turned pink on standing overnight. The crude material was triturated with hexane. The liquid was separated and allowed to cool to give the desired product as white crystals (4.07 g, 76%). The sample was recrystallized from CH2Cl2 / hexane as a white amorphous solid: mp 71-72 °C. IR (dry film) ν - max(cm -1 ):3290(s,C≡CH),2125(w,C≡CH),1363(vs,SO2),1176(vs,SO2). 1 H NMR (400MHz, CDCl3): δ7.71-7.66(m,2H,H2'' and H6''), 7.28-7.23(m,2H,H3'' and H5''), 6.69-6.66(m,1H), 6.63-6.59(m,2H), 5.93-5.91(m[AB system],2H,H2'),5.10(ddd[app dt],J=6.8,6.8,2.2Hz,1H,H2),3.03(dd,J=14.0,7.0Hz,1H,H1a),2.99(dd,J=14.0,6.6Hz,1H,H1b),2.47(d,J=2.2Hz,1H,H4),2.42(s,3H,ArCH3). 13C NMR (100MHz, CDCl3): δ147.5,146.8,144.8(C3a',C7a',C1''),133.5(C5'),129.6(C3''+C5''),128.1(C4''),128.0(C2 ''+C6''), 123.0 (C6'), 110.0 and 108.2 (C4' and C7'), 101.0 (C2'), 78.7 (C3), 76.9 (C4), 71.4 (C2), 41.7 (C1), 21.6 (CH3). HRMS-EI(m / z):M + C 18 H 16 Calculated value for O5S: 344.0718; Measured value: 344.0720. Analysis C 18 H 16 Calculated values ​​for O5S: C, 62.78; H, 4.68; N, 0.00. Found values: C, 62.67; H, 4.60; N, 0.02.

[0348] General method for the final step of General Procedure 3

[0349] [ka]

[0350] Propargyl tosylate P2 (0.90-1.00 mmol) is dissolved in the appropriate amine (3-20 equiv.) and stirred overnight at room temperature under N2. The reaction is poured onto 1 M NaOH (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts are dried, evaporated, and purified by RSF chromatography to give the desired product.

[0351] 1-(1,3-benzodioxol-5-yl)-N-methylbut-3-yn-2-amine (UWA-017, MNG016, "Compound 3A")

[0352] [ka]

[0353] To a solution of propargyl tosylate P2 (517 mg, 1.50 mmol) in dry THF (10 mL) was added an 8.03 M solution of methylamine in EtOH (3.74 mL, 30.0 mmol), and the solution was stirred overnight at room temperature under N2. TLC analysis the next day revealed that only partial conversion had been achieved, so the reaction was heated to reflux for 3 h. The reaction was worked up and purified according to General Procedure 3. Elution with 2:3 EtOAc / hexane followed by EtOAc afforded the desired amine as a yellow oil (213 mg, 70%). IR (thin film) ν - max(cm -1 ):3289(s,C≡CH). 1 H NMR(500MHz,CDCl3):δ6.79(d,J=1.5Hz,1H,H4'),6.74(d,J=8.0Hz,1H,H7'),6.72(dd,J=8.0,1.5Hz,1H,H6'),5.93(s,2H,H2'),3.50(ddd[app dt],J=6.5,6.5,2.0Hz,1H,H2),2.91-2.82(m[AB part of ABX system],2H,H1a+H1b),2.48(s,3H,NCH3),2.31(d,J=2.5Hz,2H,H4). 13 C NMR (125 MHz, CDCl3): δ 147.4 and 146.3 (C3a' and C7a'), 131.1 (C5'), 122.6 (C6'), 109.9 and 108.1 (C4' and C7'), 100.8 (C2'), 84.4 (C3), 72.5 (C4), 53.0 (C2), 41.4 (C1), 33.9 (NCH3). HRMS-ESI (m / z): [M+H] + C 12 H 12 Calculated value for NO2: 204.1025; measured value: 204.1021.

[0354] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol as a colorless amorphous powder (mp 184-189°C). 1H NMR(500MHz,D2O):δ6.93(d,J=1.5Hz,1H,H4'),6.90(d,J=7.5Hz,1H,H7'),6.87(dd,J=8.0,1.5Hz,1H,H6'), 5.98(s,2H,H2'),4.33(ddd,J=8.5,6.0,2.0Hz,1H,H2),3.17(dd,J=14.0,6.0Hz,1H,H1a),3.15-3.08(m[app dd+d],2H,H1b+H4),2.83(s,3H,NCH3). Analysis C 12 H 14 Calculated for ClNO2: C, 60.13; H, 5.89; N, 5.84. Found: C, 60.01; H, 5.75; N, 5.69.

[0355] 1-(1,3-benzodioxol-5-yl)-N-ethylbut-3-yn-2-amine (UWA-024, MNG5130, "Compound 3B")

[0356] [ka]

[0357] Propargyl tosylate P2 (344 mg, 1.00 mmol) was dissolved in a 2.0 M solution of ethylamine in MeOH (10.0 mL, 20.0 mmol), and the solution was stirred at room temperature under N for 7 days. The reaction was worked up according to General Procedure 3 using 2:3 EtOAc / hexane followed by EtOAc for chromatography to give the desired amine as a yellow oil (174 mg, 80%). IR (thin film) v - max(cm -1 ):3290(s,C≡CH). 1H NMR (500MHz, CDCl3): δ6.80(d,J=2.0Hz,1H,H4'),6.75(d,J=8.0Hz,1H,H7'),6.73 (dd,J=8.0,2.0Hz,1H,H6'),5.95-5.93(m,2H,H2'),2.39(ddd,J=7.0,6.0,2.0Hz, 1H,H2),2.95-2.88(m,2H,H1a+H1a''),2.84(dd,J=13.5,7.0Hz,1H,H1b),2.62(dq ,J=11.5,7.0Hz,1H,H1b''),2.29(d,J=2.5Hz,1H,H4),1.10(t,J=7.5Hz,3H,H2''). 13 C NMR (125 MHz, CDCl3): δ 147.5 and 146.3 (C3a' and C7a'), 131.2 (C5'), 122.6 (C6'), 109.9 and 108.1 (C4' and C7'), 100.9 (C2'), 84.8 (C3), 72.3 (C4), 51.2 (C2), 41.63 and 41.60 (C1 and C1''), 15.0 (C2''). HRMS-EI (m / z): M + The calculated value for C 13 H 15 NO2, 217.1103; Actual value, 217.1098.

[0358] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol as a colorless amorphous powder (mp 203-206°C). 1 H NMR (500MHz, CDCl3): δ10.1(br s,2H,NH2),6.83(d,J=1.5Hz,1H,H4'),6.80(dd,J=8.0,1.5Hz,1H,H6'),6.73(d,J=8.0Hz,1H,H7'),5.94-5.92(m[AB system],2H,H2'),4.02-3.97(m[app dq],1H,H2),3.59(dd,J=8.0,3.5Hz,1H,H1a),3.38(dq,J=12.5,7.0Hz,1H,H1a''), 3.23-3.0(m,2H,H1b+H1b''),2.59(d,J=1.5Hz,1H,H4),1.52(t,J=7.0Hz,3H,H2''). Analysis C 13 H 16Calculated for ClNO2: C, 61.54; H, 6.36; N, 5.52. Found: C, 61.40; H, 6.61; N, 5.44.

[0359] 1-(1,3-benzodioxol-5-yl)-N-(propan-2-yl)but-3-yn-2-amine (UWA-026, MNG5136, "Compound 3C")

[0360] [ka]

[0361] Following general procedure 3, reaction of propargyl tosylate P2 (343 mg, 1.00 mmol) with isopropylamine (1.64 mL, 19.3 mmol) and elution with 1:19 EtOAc / hexanes followed by 1:5 EtOAc / hexanes gave the product as a dark tan oil (197 mg, 86%). IR (thin film) v - max(cm -1 ):3290(s,C≡CH). 1 H NMR (500MHz, CDCl3): δ6.83-6.81(m,1H),6.77-6.72(m,2H),5.95-5.92(m,2H,H2'),3.67(ddd,J=8.0,5.5,2.0Hz,1H,H2),3.16(s eptet,J=6.0Hz,1H,H2''),2.93(dd,J=13.5,5.5Hz,1H,H1a),2.81(dd,J=13.5,8.0Hz,1H,H1b),2.29(d,J=2.0Hz,1H,H4),1.97(br s,NH+H2O),1.10(d,J=6.5Hz,3H,H1''),1.01(d,J=6.0Hz,3H,H3''). 13C NMR (125 MHz, CDCl3): δ 147.4 and 146.4 (C3a' and C7a'), 130.9 (C5'), 122.7 (C6'), 110.0 and 108.1 (C4' and C7'), 100.9 (C2'), 84.2 (C3), 72.8 (C4), 48.7 and 46.2 (C2 and C2''), 41.6 (C1), 23.7 and 21.2 (C1'' and C3''). HRMS-EI (m / z): M + C 14 H 17 Calculated value for NO2: 231.1259; measured value: 231.1264.

[0362] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol as a colorless amorphous powder (mp 197-199°C). 1 H NMR(500MHz,CDCl3):δ10.22(br s,1H,NHa),9.81(br s,1H,NHb),6.84(d,J=1.5Hz,1H,H4'),6.80(dd,J=8.0,2.0Hz,1H,H6'),6.73(d,J=7.5Hz,1H,H7'),5.94-5.92(m[AB system],2H,C2'),4.05-3.98(m,1H,H2),3.81-3.71(m,1H,H2''),3.66(dd,J=12.5,3.5Hz,1H,H1a),3.33(dd[app t],J=12.0,12.0Hz,1H,H1b),2.57(d,J=2.0Hz,1H,H4),1.64(d,J=6.5Hz,3H,H1''),1.43(d,J=6.5Hz,3H,H3''). Analysis C 14 H 18 Calculated for ClNO2: C, 62.80; H, 6.78; N, 5.23. Found: C, 62.62; H, 7.00; N, 5.17.

[0363] 1-(1,3-benzodioxol-5-yl)-N-propylbut-3-yn-2-amine (UWA-025, MNG5134, "Compound 3D")

[0364] [ka]

[0365] Following general procedure 3, reaction of propargyl tosylate P2 (344 mg, 1.00 mmol) with n-propylamine (1.64 mL, 19.9 mmol) and elution with 2:3 EtOAc / hexanes afforded the product as a dark tan oil (181 mg, 85%). IR (thin film) v - max(cm -1 ):3292(s,C≡CH). 1 H NMR(600MHz,CDCl3):δ6.79(d,J=1.8Hz,1H,H4'),6.74(d,J=7.8Hz,1H,H7'),6.71(dd,J=7.8,1.8Hz, 1H,H6'),5.92(s,2H,H2'),3.58-3.54(m,1H,H2),2.81(dd,J=13.2,6.0Hz,1H,H1a),2.85-2.77(m[app dd+ddd],2H,H1b and H1a''),2.55(ddd,J=10.8,8.4,6.0Hz,1H,H1b''),2.29(d, J=2.4Hz,1H,H4),1.55-1.35(m,3H,H2''+NH+H2O),0.89(t,J=7.2Hz,3H,H3''). 13 C NMR (150 MHz, CDCl3): δ 147.4 and 146.3 (C3a' and C7a'), 131.2 (C5'), 122.6 (C6'), 109.9 and 108.0 (C4' and C7'), 100.8 (C2'), 84.2 (C3), 72.2 (C4), 51.3 (C2), 49.2 and 41.5 (C1 and C1''), 23.0 (C2''), 11.7 (C3''). HRMS-ESI (m / z): [M+H] + C 14 H 17 Calculated value for NO2: 232.1338; measured value: 232.1334.

[0366] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol / Et2O as a colorless amorphous powder (mp 171-173 °C). 1H NMR (500MHz, CDCl3): δ10.05(br s,2H,NH2),6.83(d,J=1.5Hz,1H,H4'),6.80(dd,J=8.0,2.0Hz,1H,H6'),6.73(d,J=8.0Hz,1H,H7'),5.94-5.92(m[AB system],2H,H2'),4.02(ddd,J=11.0,3.5,2.0Hz,1H,H2),3.61(dd,J=13.0,3.5Hz,1H,H1a),3.24-3.14(m[app ddd+dd],2H,H1b+H1a''),3.03(ddd,J=12.0,9.0,7.0Hz,1H,H1b''),2.59(d,J=2.5Hz,1H,H4),2.04-1.93(m,2H,H2''),1.03(t,J=7.5Hz,1H,H3''). Analysis C 14 H 18 Calculated for ClNO2: C, 62.80; H, 6.78; N, 5.23. Found: C, 62.83; H, 6.95; N, 5.15.

[0367] 1-(1,3-benzodioxol-5-yl)-N-(prop-2-en-1-yl)but-3-yn-2-amine (UWA-028, "Compound 3E")

[0368] [ka]

[0369] Following general procedure 3, reaction of propargyl tosylate P2 (310 mg, 0.90 mmol) with allylamine (675 μL, 9.00 mmol) and elution with 1:5 EtOAc / hexane followed by 2:3 EtOAc / hexane afforded the product as a pale yellow oil (174 mg, 84%). IR (thin film) ν - max(cm -1 ):3292(s,C≡CH)1643(w,HC-CH2). 1H NMR (500MHz, CDCl3): δ6.80(d,J=1.5Hz,1H,H4'),6.75(d,J=8.0Hz,1H,H7'),6.73(dd,J=8.0,1.5Hz,1H,H6'),5.94-5.92(m,2H,H 2'),5.87(dddd,J=17.0,10.5,6.5,5.5Hz,1H,H2''),5.18(dddd,J=17.0,1.5,1.5,1.5Hz,1H,H3a''),5.08(dddd,J=10.5,1.5,1. 5,1.5Hz,1H,H3b''),3.60(ddd,J=7.0,6.0,2.0Hz,1H,H2),3.47(dddd,J=14.0,5.5,1.5,1.5Hz,1H,H1a''),3.26(dddd,J=14.0,6 .5,1.5,1.5Hz,1H,H1b''),2.90(dd,J=13.5,6.0Hz,1H,H1a),2.85(dd,J=13.5,7.0Hz,1H,H1b),2.31(d,J=2.5Hz,1H,H4),1.6(br s,NH+H2O). 13 C NMR (125 MHz, CDCl3): δ 147.5 and 146.3 (C3a' and C7a'), 136.1 (C2'', 131.0 (C5'), 122.6 (C6'), 116.4 (C3'', 109.9 and 108.1 (C4' and C7'), 100.8 (C2'), 84.5 (C3), 72.6 (C4), 50.5 (C2), 49.8 and 41.6 (C1 and C1''). HRMS-EI (m / z): M + C 14 H 15 Calculated value for NO2: 229.1103; measured value: 229.1104.

[0370] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol as colorless rods (mp 183-185°C). 1H NMR(500MHz,CDCl3):δ10.3(br s,2H,NH2),6.83(d,J=2.0Hz,1H,H4'),6.79(dd,J=8.0,2.0Hz,1H,H6'),6.74(d,J =8.0Hz,1H,H7'),6.14(dddd,J=17.0,10.0,8.5,6.0Hz,1H,H2''),5.94-5.92(m[AB system],2H,H2'),5.59-5.54(m,1H,H3a''),5.49-5.45(m,1H,H3b''),3.99(ddd,J=11.0,4.0,2.0Hz,1H,H2),3.95-3.89(m[app dd],1H,H1a''),3.72(dd,J=13.5,8.5Hz,1H,H1b''),3.56(dd,J=13.0,4.0Hz,1H,H1a),3.21(dd,J=13.0,11.0Hz,1H,H1b),2.62(d,J=2.0Hz,1H,H4). Analysis C 14 H 16 Calculated for ClNO2: C, 63.28; H, 6.07; N, 5.27. Found: C, 63.21; H, 6.30; N, 5.23.

[0371] 1-(1,3-benzodioxol-5-yl)-N-(prop-2-yn-1-yl)but-3-yn-2-amine (UWA-029, MNG5152, "Compound 3F")

[0372] [ka]

[0373] Following general procedure 3, reaction of propargyl tosylate P2 (220 mg, 0.658 mmol) with propargylamine (421 μL, 0.657 mmol) and elution with 1:5 EtOAc / hexanes afforded the product as a pale yellow oil (118 mg, 79%). IR (thin film) ν - max(cm -1 ):3288(s,C≡CH). 1H NMR(500MHz,CDCl3):δ6.80(d,J=1.5Hz,1H,H4'),6.75(d,J=8.0Hz,1H,H7'),6.73(dd,J=8.0,1.5Hz,1H,H6'),5.94(s,2H,H2'),3.81(ddd[app dt],J=7.0,7.0,2.0Hz,1H,H2),3.60(dd,J=17.0,2.5Hz,1H,H1a''),3.53(dd,J=16.5,2.0Hz,1H,H1b''),2.94-2.86(m[ABX AB part of system],2H,H1a+H1b),2.32(d,J=2.0Hz,1H,H4),2.21(dd[app t],J=2.5,2.5Hz,1H,H3''). 13 C NMR (125 MHz, CDCl3): δ 147.6 and 146.5 (C3a' and C7a'), 130.6 (C5'), 122.6 (C6'), 109.8 and 108.2 (C4' and C7'), 100.9 (C2'), 83.5 and 81.3 (C3 and C2'', 73.0 and 71.7 (C4 and C3'', 49.8 (C2), 41.3 and 36.0 (C1 and C1''). HRMS-ESI (m / z): [M+H] + C 14 H 13 Calculated value for NO2: 228.1025; measured value: 228.1029.

[0374] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol as colorless needles (mp 190-191° C.). 1 H NMR(500MHz,D2O):δ6.95(d,J=1.0Hz,1H,H4'),6.92(d,J=7.5Hz,1H,H7'),6.88(dd,J=8.0,1.5Hz,1H,H6'),6.00(s,2H,H2'),4.53(ddd,J=8.0,6 .0,2.5Hz,1H,H2),4.15(dd,J=16.5,2.5Hz,1H,H1a''),4.08(dd,J=16.5,2.5Hz,1H,H1b''),3.22(dd,J=14.0,6.0Hz,1H,H1a),3.18-3.11(m[app d+dd],2H,H4+H1b''),3.03(t,J=2.5Hz,1H,H3''). Analysis C14 H 14 Calculated for ClNO2: C, 63.76; H, 5.35; N, 5.31. Found: C, 63.83; H, 5.56; N, 5.22.

[0375] 1-(1,3-benzodioxol-5-yl)-N-butylbut-3-yn-2-amine (UWA-027, MNG5146, "Compound 3G")

[0376] [ka]

[0377] Following general procedure 3, reaction of propargyl tosylate P2 (310 mg, 0.900 mmol) with n-butylamine (889 μL, 9.00 mmol) and elution with 1:5 EtOAc / hexane followed by 2:3 EtOAc / hexane gave the product as a light brown oil (183 mg, 84%). IR (thin film) ν - max(cm -1 ):3292(s,C≡CH). 1 H NMR (500MHz, CDCl3): δ6.78(d,J=1.5Hz,1H,H4'),6.73(d,J=8.0Hz,1H,H7'),6.70(dd, J=8.0,1.5Hz,1H,H6''),5.91(s,2H,H2'),3.56-3.52(m,1H,H2),2.88(dd,J=13.5,6.0 Hz,1H,H1a),2.85-2.78(m,2H,H1b+H1a''),2.53(ddd,J=11.0,9.0,5.5Hz,1H,H1b''), 2.29(d,J=2.0Hz,1H,H4),1.6-1.0(m,5H,NH+H2''+H3''),0.87(t,J=7.5Hz,3H,H4''). 13C NMR (125 MHz, CDCl3): δ 147.2 and 16.1 (C3a' and C7a'), 130.8 (C5'), 122.5 (C6'), 109.8 and 108.0 (C4' and C7'), 100.7 (C2'), 84.5 (C3), 72.4 (C4), 51.2 (C2), 47.0, 41.3, 31.8, 20.3 (C1, C1'', C2'', C3'', 13.9 (C4''). HRMS-EI (m / z): M + C 15 H 19 Calculated value for NO2: 245.1416; measured value: 245.1427.

[0378] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol as colorless rods (mp 166-168°C). 1 H NMR (500MHz, CDCl3): δ10.6-9.5(2×br s,2H,NH2),6.83(d,J=1.5Hz,1H,H4'),6.80(dd,J=8.0,1.5Hz,1H,H6'),6.73(d,J=8.0Hz,1H,H7'),5.95-5.92(m[AB system],2H,H2'),4.04-3.95(m[app dt],1H,H2),3.63(dd,J=13.0,3.5Hz,1H,H1a),3.28-3.15(m[app m+dd],2H,H1b+H1a''),3.09-3.01(m,1H,H1b''),2.59(d,J=2.5Hz,1H,H4),2 .00-1.87(m,2H,H2''),1.50-1.36(m,2H,H3''),0.92(t,J=7.5Hz,3H,H4''). Analysis C 15 H 20 Calculated for ClNO2: C, 63.94; H, 7.15; N, 4.97. Found: C, 63.75; H, 7.34; N, 4.86.

[0379] 1-(1,3-benzodioxol-5-yl)-N-benzylbut-3-yn-2-amine (UWA-087, "Compound 3H")

[0380] [ka]

[0381] Following general procedure 3, reaction of propargyl tosylate P2 (310 mg, 0.900 mmol) with benzylamine (2.56 mL, 2.44 mmol) and elution with 1:5 EtOAc / hexane followed by 2:3 EtOAc / hexane gave the product as a pale yellow oil that solidified on standing (202 mg, 80%). IR (thin film) ν - max(cm -1 ):3288(s,C≡CH). 1 H NMR (500MHz, CDCl3): δ7.36-7.23(m,5H,H2'',H3'',H4'',H5'',H6''),6.80(d,J=1.5Hz,1H,H4' ),6.76(d,J=8.0Hz,1H,H7'),6.73(dd,J=8.0,1.5Hz,1H,H6'),5.94-5.93(m,2H,H2'),4.04(d,J =13.0Hz,1H,NCHaH),3.83(d,J=13.0Hz,1H,NCHHb),3.59(ddd,J=7.0,6.5,2.0Hz,1H,H2),2.92( dd,J=13.5,6.5Hz,1H,H1a),2.89(dd,J=13.5,7.0Hz,1H,H1b),2.38(d,J=2.5Hz,1H,H4),1.48(br s,NH+H2O). 13 C NMR (125 MHz, CDCl3): δ 147.4 and 146.3 (C3a' and C7a'), 139.7 (C1'), 131.1 (C5'), 128.3 and 128.2 (C2'+C6' and C3'+C5'), 127.0 (C4'), 122.6 (C6'), 109.9 and 108.0 (C4' and C7'), 100.8 (C2'), 84.6 (C3), 72.6 (C4), 51.1 (NCH2), 50.4 (C2), 41.5 (C1). HRMS-EI (m / z): M + C 18 H 17 Calculated value for NO2: 279.1259; measured value: 279.1273.

[0382] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol as a colorless amorphous powder (mp 196-199°C). 1 H NMR(500MHz,CDCl3):δ10.5(br s,2H,NH2),7.67-7.62(m[app d],2H,H2''+H6''),7.38-7.32(m[app t],2H,H3''+H5''),7.28-7.23(m,1H,H4''),6.76-6.69(m,3H,H4',H6',H7'),5.93-5.91(m[AB system],2H,H2'),4.26(d,J=13.0Hz,1H,NCHaH),4.13(d,J=13.0Hz,1H,NCHHb),3.73(ddd,J=11.5,4.0,2.0 Hz,1H,H2),3.39(dd,J=13.0,4.0Hz,1H,H1a),3.08(dd,J=13.0,11.0Hz,1H,H1b),2.68(d,J=2.5Hz,1H,H4). Analysis C 18 H 17 Calculated values ​​for NO2: C, 68.46; H, 5.75; N, 4.44. Found values: C, 68.12; H, 5.58; N, 4.30.

[0383] Type 4 Compounds Compounds of type 4 can be prepared following general procedure 4;

[0384] [ka]

[0385] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'). Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 4 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0386] 2-(benzo[d][1,3]dioxol-5-yl)-1-phenylethan-1-one ("ketone K4")

[0387] [ka]

[0388] Ketone K4 is a known compound that can also be obtained by previously reported methods. 4

[0389] 2-(benzo[d][1,3]dioxol-5-yl)-1-phenylethan-1-amine (UWA-074, "Compound 4A")

[0390] [ka]

[0391] Ketone K4A is a known compound that can also be obtained by previously published methods. 2-78ヘ゜ーシ゛

[0392] (R)-2-(benzo[d][1,3]dioxol-5-yl)-1-phenylethan-1-amine ("Compound 4AR") and (S)-2-(benzo[d][1,3]dioxol-5-yl)-1-phenylethan-1-amine ("Compound 4AS")

[0393] [ka]

[0394] Compounds 4AR and 4AS can be obtained via crystallization of the diastereomeric tartrate salts of compound 4A or via chiral column chromatography.

[0395] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-phenylethan-1-amine (UWA-001, "Compound 4B")

[0396] [ka]

[0397] Compound 4B is a known compound that can also be obtained by previously published methods. 4

[0398] 2-(benzo[d][1,3]dioxol-5-yl)-N-ethyl-1-phenylethan-1-amine (UWA-066, "Compound 4C")

[0399] [ka]

[0400] Compound 4C is a known compound that can also be obtained by previously published methods. 2-78ヘ゜ーシ゛

[0401] N-(2-(3a,4-dihydrobenzo[d][1,3]dioxol-5-yl)-1-phenylethyl)propan-1-amine (UWA-068, "Compound 4D")

[0402] [ka]

[0403] Compound 4D is a known compound that can also be obtained by previously published methods. 2-79ヘ゜ーシ゛

[0404] N-(2-(benzo[d][1,3]dioxol-5-yl)-1-phenylethyl)propan-2-amine (UWA-065, "Compound 4E")

[0405] [ka]

[0406] Compound 4E is a known compound that can also be obtained by previously published methods. 2-81ヘ゜ーシ゛

[0407] N-(2-(benzo[d][1,3]dioxol-5-yl)-1-phenylethyl)butan-1-amine (UWA-064, "Compound 4F")

[0408] [ka]

[0409] Compound 4F is a known compound that can also be obtained by previously published methods. 2-80ヘ゜ーシ゛

[0410] N-(2-(benzo[d][1,3]dioxol-5-yl)-1-phenylethyl)-2-methylpropan-2-amine ("Compound 4G")

[0411] [ka]

[0412] Compound 4G is a known compound that can also be obtained by previously published methods. 2

[0413] N-(2-(benzo[d][1,3]dioxol-5-yl)-1-phenylethyl)prop-2-en-1-amine (UWA-069, "Compound 4H")

[0414] [ka]

[0415] Compound 4H is a known compound that can also be obtained by previously published methods. 2-82ヘ゜ーシ゛

[0416] N-(2-(benzo[d][1,3]dioxol-5-yl)-1-phenylethyl)prop-2-yn-1-amine (UWA-070, "Compound 4I")

[0417] [ka]

[0418] Following general procedure 4, reaction of ketone K4 (144 mg, 0.60 mmol) with propargylamine (384 μL, 6.00 mmol) and elution with 20:80:1 EtOAc / Hex / NEt3 gave secondary amine 4I as a colorless gum (138 mg, 82%). 1 H NMR (400MHz, CDCl3): δ7.37-7.23(m,5H,Ph),6.71(d,J=7.8Hz,1H,H7'),6.68(d,J=1.6H z,1H,H4'),6.61(dd,J=7.9,1.6Hz,1H,H6'),5.92(s,2H,H2'),4.06(dd,J=8.7,5.5Hz,1H ,H1),3.31(dd,J=17.2,2.5Hz,1H,H1''a),3.05(dd,J=17.2,2.4Hz,1H,H1''b),2.90(dd ,J=13.7,5.4Hz,1H,H2a),2.79(dd,J=13.7,8.7Hz,1H,H2b),2.17(t,J=2.4Hz,1H,H3''). 13 C NMR (100 MHz, CDCl3): δ 147.8 and 146.3 (C3a' and C7a'), 142.5 (C1''', 132.2 (C5'), 128.6 (C3''' / 5''', 127.6 (C2''' / 6''', 127.5 (C4''', 122.4 (C6'), 109.5 (C4'), 108.3 (C7'), 101.0 (C2'), 82.1 (C2'', 71.5 (C3'', 62.6 (C1), 44.7 (C2), 35.9 (C1''). HRMS (ESI+) m / z [M+H] + C18 H 18 NO2 + Calculated value: 280.1332; measured value: 280.1331.

[0419] The free base was converted to the crude hydrochloride salt and recrystallized from 2-propanol / Et2O as colorless diamonds. 1 H NMR(400MHz,d6-DMSO):δ9.99(br. s,2H,NH2),7.46-7.34(m,5H,Ph),6.73(d,J=7.9Hz,1H,H7'),6.60(d,J=1.6Hz,1H,H4'),6.47(dd,J=7.9,1.6Hz,1H,H6' ),5.93(s,2H,H2'),4.51-4.37(m,1H,H1),3.76-3.61(m,2H,H1''),3.46-3.36(m,2H,H2),3.06(t,J=11.8Hz,1H,H3'').

[0420] Compound 4I is a known compound that can also be obtained by previously published methods. 2-83ヘ゜ーシ゛

[0421] N-(2-(benzo[d][1,3]dioxol-5-yl)-1-phenylethyl)aniline (UWA-067, "Compound 4J")

[0422] [ka]

[0423] Compound 4J is a known compound that can also be obtained by previously published methods. 2-85ヘ゜ーシ゛

[0424] 2-(benzo[d][1,3]dioxol-5-yl)-N-benzyl-1-phenylethan-1-amine (UWA-063, "Compound 4K")

[0425] [ka]

[0426] Compound 4K is a known compound that can also be obtained by previously published methods. 2-84ヘ゜ーシ゛

[0427] Type 5 Compounds Compounds of type 5 can be prepared following general procedure 5;

[0428] [ka]

[0429] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 5 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0430] 2-(benzo[d][1,3]dioxol-5-yl)-1-cyclohexylethan-1-one ("Ketone K5")

[0431] [ka]

[0432] Ketone K5 is a known compound that can also be obtained by previously published methods. 4

[0433] 2-(benzo[d][1,3]dioxol-5-yl)-1-cyclohexyl-N-methylethan-1-amine (UWA-079, "Compound 5A")

[0434] [ka]

[0435] Compound 5A is a known compound that can also be obtained by previously published methods. 4

[0436] Type 6 Compounds Compounds of type 6 can be prepared following general procedure 6;

[0437] [ka]

[0438] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 6 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0439] 2-(benzo[d][1,3]dioxol-5-yl)-1-(thiophen-2-yl)ethan-1-one ("ketone K6")

[0440] [ka]

[0441] Ketone K6 is a known compound that can also be obtained by previously published methods. 2-44ヘ゜ーシ゛

[0442] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(thiophen-2-yl)ethan-1-amine (UWA-059, "Compound 6A")

[0443] [ka]

[0444] Compound 6A is a known compound that can also be obtained by previously published methods. 2-49ヘ゜ーシ゛

[0445] Type 7 Compounds Compounds of type 7 can be prepared following general procedure 7;

[0446] [ka]

[0447] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 7 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0448] 2-(benzo[d][1,3]dioxol-5-yl)-1-(thiophen-3-yl)ethan-1-one ("Ketone K7")

[0449] [ka]

[0450] Ketone K7 is a known compound that can also be obtained by previously published methods. 2-44および45ヘ゜ーシ゛

[0451] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(thiophen-3-yl)ethan-1-amine ("Compound 7A")

[0452] [ka]

[0453] Compound 7A is a known compound that can also be obtained by previously published methods. 2-49および50ヘ゜ーシ゛

[0454] Type 8 Compound Compounds of type 8 can be prepared following general procedure 8;

[0455] [ka]

[0456] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 8 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0457] 2-(benzo[d][1,3]dioxol-5-yl)-1-(furan-3-yl)ethan-1-one ("Ketone K8")

[0458] [ka]

[0459] Ketone K8 is a known compound that can also be obtained by previously published methods. 2-44ヘ゜ーシ゛

[0460] 2-(benzo[d][1,3]dioxol-5-yl)-1-(furan-3-yl)-N-methylethan-1-amine (UWA-071, "Compound 8A")

[0461] [ka]

[0462] Compound 8A is a known compound that can also be obtained by previously published methods. 2-50ヘ゜ーシ゛

[0463] 2-(benzo[d][1,3]dioxol-5-yl)-1-(tetrahydrofuran-2-yl)ethanone ("ketone K8TH")

[0464] [ka]

[0465] A solution of 1.0 M LiHMDS in THF (12.4 mL, 12.4 mmol) was added to a stirred solution of methyl homopiperonylate (2.32 g, 12.0 mmol) in anhydrous THF (15 mL) at −78 °C under N. The reaction solution was stirred at −78 °C for 1.5 h and then treated dropwise with methyl tetrahydrofuran-2-carboxylate (1.04 g, 8.01 mmol). The resulting solution was allowed to warm gradually to room temperature overnight, quenched with half-saturated NH.sub.4Cl (60 mL), and extracted with CHCl.sub.2 (3.times.60 mL). The extracts were washed with brine (30 mL), dried, evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:19 EtOAc / hexanes → 1:4 EtOAc / hexanes gave the partially purified β-ketoester as a yellow oil (1.45 g), which was dissolved in 8:8:1 water / AcOH / H2SO4 (17 mL). The resulting solution was stirred under reflux for 1.5 h, cooled to room temperature, diluted with water (50 mL), and extracted with C2Cl2 (3 × 50 mL). The extract was washed with brine (50 mL), dried, evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:19 EtOAc / hexanes → 3:17 EtOAc / hexanes gave the ketone K8TH as a pale yellow oil (436 mg, 23%). 1 H NMR (400MHz, CDCl3): δ6.75(d,J=7.9Hz,1H,H7′),6.71(d,J=1.5Hz,1H,H4′), 6.65(dd,J=7.9,1.6Hz,1H,H6′),5.94(s,2H,H2′),4.39(dd,J=8.0,5.9Hz,1H, H2′′),3.97-3.87(m,2H,H5′′),3.80(d[AB],J=15.8Hz,1H,H2),3.74(d[AB], J=15.8Hz,1H,H2),2.20-2.10(m,1H,H3′′),1.97-1.78(m,3H,H3′′&H4′′)ppm. 13 C NMR (100MHz, CDCl3) δ209.9,147.9,146.7,127.4,122.9,110.2,108.5,101.1,83.1,69.5,45.1,29.3,25.8ppm.

[0466] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(tetrahydrofuran-2-yl)ethanamine (UWA-106, GAP-058, "Compound 8ATH")

[0467] [ka]

[0468] An 8.03 M solution of methylamine in EtOH (0.71 mL, 5.7 mmol) and AcOH (0.36 mL, 6.3 mmol) were added sequentially to a cold (0 °C) stirred mixture of the ketone K8TH (124 mg, 0.529 mmol) and 3A sieves (156 mg) in 2:1 THF / MeOH (3.0 mL). Sodium cyanoborohydride (41 mg, 0.65 mmol) was added, and the reaction vessel was flushed with N2, sealed, and stirred at 50 °C for 48 h before being cooled to room temperature and quenched with 1 M HCl (15 mL). The resulting mixture was vacuum filtered through a pad of Celite and rinsed with MeOH (3 × 25 mL). The filtrate was concentrated under reduced pressure, and the residue was basified with 1 M NaOH (30 mL) and extracted with CHCl (3 × 30 mL). The extract was washed with brine (30 mL), dried, evaporated, and the residue was subjected to flash chromatography. Gradient elution with 1:1 EtOAc / hexane to 1:24:25 NEt3 / EtOAc / hexane afforded the amine 8ATH as a 1:1 mixture of diastereomers as a colorless oil (110 mg, 83%). 1 H NMR (400 MHz, CDCl3): δ 6.75-6.71 (m, 2H), 6.68-6.63 (m, 1H), 5.93 (s, 2H), 3.91-3.80 (m, 1H), 3.79-3.66 (m, 2H), 2.83-2.71 (m, 1H), 2.69-2.57 (m, 2H), 2.42 and 2.41 (s, 3H, NCH3), 1.92-1.78 (m, 3H), 1.90-1.85 and 1.66-1.58 (m, 1H) ppm. 13C NMR(100MHz,CDCl3)δ147.8,147.7,146.04,146.00,133.4,132.9,122.34,122.29,109.8,109.7,108.31 ,108.27,101.0,80.7,80.5,68.3,68.165.1,64.0,36.63,36.57,35.1,34.6,28.5,26.7,26.3,26.2ppm. HRMS(ESI+)m / z[M+H] + C 14 H 20 No. 3 + Calculated value: 250.1438; measured value: 250.1434.

[0469] The free base was converted to the crude hydrochloride salt to give the diastereomeric 5 * :4 # The mixture recrystallized as colorless granules. 1 H NMR(400MHz,CDCl3)δ10.11(br s,1H) * ,9.48(br s,1H) # ,9.19(br s,1H) # ,8.52(br s,1H) * ,6.80-6.69(m,3H),5.95(s,2H) * ,5.94(s,2H) # ,4.16-4.05(m,1H),4.02-3.92(m,1H),3.79-3.70(m,1H),3.51-3.43(m,1H) * ,3.35-3.27(m,1H),3.20(br m,1H) # ,2.95-2.89(m,1H),2.72(br s,3H),2.13-2.05(m,1H),2.05-2.00(m,1H) * ,1.96-1.86(m,2H),1.60-1.49(m,1H) # ppm.

[0470] Type 9 Compounds Compounds of type 9 can be prepared following general procedure 9;

[0471] [ka]

[0472] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 9 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0473] 2-(benzo[d][1,3]dioxol-5-yl)-1-(furan-2-yl)ethan-1-one ("Ketone K9")

[0474] [ka]

[0475] Ketone K9 is a known compound that can also be obtained by previously published methods. 2-43ヘ゜ーシ゛

[0476] 2-(benzo[d][1,3]dioxol-5-yl)-1-(furan-2-yl)-N-methylethan-1-amine ("Compound 9A")

[0477] [ka]

[0478] Compound 9A is a known compound that can also be obtained by previously published methods. 2-51ヘ゜ーシ゛

[0479] Type 10 Compound Compounds of type 10 can be prepared following general procedure 10;

[0480] [ka]

[0481] (In the formula, R 1 and R 2 is as defined for compounds of formula II').

[0482] 2-(benzo[d][1,3]dioxol-5-yl)-1-(pyridin-2-yl)ethan-1-one ("Ketone K10")

[0483] [ka]

[0484] Ketone K10 is a known compound that can be obtained by previously published methods following general procedure 10. 17-49ヘ゜ーシ゛

[0485] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(pyridin-2-yl)ethan-1-amine ("Compound 10A")

[0486] [ka]

[0487] Compound 10A is a known compound that can be obtained by previously published methods following general procedure 10. 17-59ヘ゜ーシ゛

[0488] Type 11 Compound Compounds of type 11 can be prepared following general procedure 11;

[0489] [ka]

[0490] (In the formula, R 1 and R 2 is as defined for compounds of formula II').

[0491] 2-(benzo[d][1,3]dioxol-5-yl)-1-(pyridin-3-yl)ethan-1-one ("ketone K11")

[0492] [ka]

[0493] Ketone K11 is a known compound that can be obtained by previously published methods following general procedure 11. 17-49ヘ゜ーシ゛

[0494] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(pyridin-3-yl)ethan-1-amine ("Compound 11A")

[0495] [ka]

[0496] Compound 11A is a known compound that can be obtained by previously published methods following general procedure 11. 17-60ヘ゜ーシ゛

[0497] Type 12 Compound Compounds of type 12 can be prepared following general procedure 12;

[0498] [ka]

[0499] (In the formula, R 1 and R 2 is as defined for compounds of formula II').

[0500] 2-(benzo[d][1,3]dioxol-5-yl)-1-(pyridin-4-yl)ethan-1-one ("ketone K12")

[0501] [ka]

[0502] Ketone K12 is a known compound that can be obtained by previously published methods following general procedure 12. 17-50ヘ゜ーシ゛

[0503] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(pyridin-4-yl)ethan-1-amine ("Compound 12A")

[0504] [ka]

[0505] Compound 12A is a known compound that can be obtained by previously published methods following general procedure 12. 17-61ヘ゜ーシ゛

[0506] Type 13 Compound Compounds of type 13 can be prepared following general procedure 13;

[0507] [ka]

[0508] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 13 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0509] 1-([1,1'-biphenyl]-4-yl)-2-(benzo[d][1,3]dioxol-5-yl)ethan-1-one ("Ketone K13")

[0510] [ka]

[0511] Ketone K13 is a known compound that can also be obtained by previously published methods. 4

[0512] 1-([1,1'-biphenyl]-4-yl)-2-(benzo[d][1,3]dioxol-5-yl)-N-methylethan-1-amine ("Compound 13A")

[0513] [ka]

[0514] Compound 13A is a known compound that can also be obtained by previously published methods. 4

[0515] Type 14 Compound Compounds of type 14 can be prepared following general procedure 14;

[0516] [ka]

[0517] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 14 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0518] 2-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxyphenyl)ethan-1-one ("ketone K14")

[0519] [ka]

[0520] Ketone K14 is a known compound that can also be obtained by previously published methods. 4

[0521] 2-(benzo[d][1,3]dioxol-5-yl)-1-(2-methoxyphenyl)-N-methylethan-1-amine ("Compound 14A")

[0522] [ka]

[0523] Compound 14A is a known compound that can also be obtained by previously published methods. 4

[0524] Type 15 Compounds Compounds of type 15 can be prepared following general procedure 15;

[0525] [ka]

[0526] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 15 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0527] 2-(benzo[d][1,3]dioxol-5-yl)-1-(3-methoxyphenyl)ethan-1-one ("Ketone K15")

[0528] [ka]

[0529] Ketone K15 is a known compound that can also be obtained by previously published methods. 4

[0530] 2-(benzo[d][1,3]dioxol-5-yl)-1-(3-methoxyphenyl)-N-methylethan-1-amine ("Compound 15A")

[0531] [ka]

[0532] Compound 15A is a known compound that can also be obtained by previously published methods. 4

[0533] Type 16 Compound Compounds of type 16 can be prepared following general procedure 16;

[0534] [ka]

[0535] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 16 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0536] 2-(benzo[d][1,3]dioxol-5-yl)-1-(4-methoxyphenyl)ethan-1-one ("Ketone K16")

[0537] [ka]

[0538] Ketone K16 is a known compound that can also be obtained by previously published methods. 4

[0539] 2-(benzo[d][1,3]dioxol-5-yl)-1-(4-methoxyphenyl)-N-methylethan-1-amine ("Compound 16A")

[0540] [ka]

[0541] Compound 16A is a known compound that can also be obtained by previously published methods. 4

[0542] Type 17 Compound Compounds of type 17 can be prepared following general procedure 17;

[0543] [ka]

[0544] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 17 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0545] 2-(benzo[d][1,3]dioxol-5-yl)-1-(4-fluorophenyl)ethan-1-one ("Ketone K17")

[0546] [ka]

[0547] Ketone K17 is a known compound that can also be obtained by previously published methods. 4

[0548] 2-(benzo[d][1,3]dioxol-5-yl)-1-(4-fluorophenyl)-N-methylethan-1-amine (UWA-076, "Compound 17A")

[0549] [ka]

[0550] Compound 17A is a known compound that can also be obtained by previously published methods. 4

[0551] Type 18 Compound Compounds of type 18 can be prepared following the general procedure 18;

[0552] [ka]

[0553] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 18 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0554] 2-(benzo[d][1,3]dioxol-5-yl)-1-(o-tolyl)ethan-1-one ("ketone K18")

[0555] [ka]

[0556] Ketone K18 is a known compound that can also be obtained by previously published methods. 4

[0557] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(o-tolyl)ethan-1-amine ("Compound 18A")

[0558] [ka]

[0559] Compound 18A is a known compound that can also be obtained by previously published methods. 4

[0560] Type 19 Compound Compounds of type 19 can be prepared following the general procedure 19;

[0561] [ka]

[0562] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 19 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0563] 2-(benzo[d][1,3]dioxol-5-yl)-1-(m-tolyl)ethan-1-one ("Ketone K19")

[0564] [ka]

[0565] Ketone K19 is a known compound that can also be obtained by previously published methods. 4

[0566] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(m-tolyl)ethan-1-amine ("Compound 19A")

[0567] [ka]

[0568] Compound 19A is a known compound that can also be obtained by previously published methods. 4

[0569] Type 20 Compound Compounds of type 20 can be prepared following the general procedure 20;

[0570] [ka]

[0571] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 20 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0572] 2-(benzo[d][1,3]dioxol-5-yl)-1-(p-tolyl)ethan-1-one ("Ketone K20")

[0573] [ka]

[0574] Ketone K20 is a known compound that can also be obtained by previously published methods. 4

[0575] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(p-tolyl)ethan-1-amine ("Compound 20A")

[0576] [ka]

[0577] Compound 20A is a known compound that can also be obtained by previously published methods. 4

[0578] Type 21 Compound Compounds of type 21 can be prepared following the general procedure 21;

[0579] [ka]

[0580] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 21 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0581] 2-(benzo[d][1,3]dioxol-5-yl)-1-(naphthalen-2-yl)ethan-1-one ("ketone K21")

[0582] [ka]

[0583] Ketone K21 is a known compound that can also be obtained by previously published methods. 4

[0584] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(naphthalen-2-yl)ethan-1-amine ("Compound 21A")

[0585] [ka]

[0586] Compound 21A is a known compound that can also be obtained by previously published methods. 4

[0587] Type 22 Compound Compounds of type 22 can be prepared following general procedure 22;

[0588] [ka]

[0589] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'. Those skilled in the art will understand that the acid chloride precursor utilized in general procedure 22 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride, or potassium chloride.

[0590] 2-(benzo[d][1,3]dioxol-5-yl)-1-(naphthalen-1-yl)ethan-1-one ("ketone K22")

[0591] [ka]

[0592] Ketone K22 is a known compound that can also be obtained by previously published methods. 4

[0593] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(naphthalen-1-yl)ethan-1-amine ("Compound 22A")

[0594] [ka]

[0595] Compound 22A is a known compound that can also be obtained by previously published methods. 4

[0596] Type 23 Compound Compounds of type 23 can be prepared following general procedure 23;

[0597] [ka]

[0598] (In the formula, R 1 and R 2 is as defined for the compound of formula II') from homopiperonal via the previously reported partial Strecker synthesis. 18

[0599] 3-(benzo[d][1,3]dioxol-5-yl)-2-(piperidin-1-yl)propanenitrile ("Compound 23A")

[0600] [ka]

[0601] Compound 23A may be obtained via adaptation of a previously published method, following general procedure 23 and using homopiperonal as the starting material instead of 2-phenylacetaldehyde. 18

[0602] Compounds of types 24 to 87 Compounds of type 24-87 can be prepared by following general procedures 24-87;

[0603] [ka]

[0604] (Wherein, R is methyl, ethyl, and —C 3-9 alkyl, and R 1 and R 2 is as defined for compounds of formula II'). Those skilled in the art will understand that the acid chloride precursor utilized in general procedures 24 to 87 can be replaced with the corresponding acid anhydride precursor or mixed acid anhydride precursor. Those skilled in the art will also understand that the sodium chloride utilized in the Krapko decarboxylation step can be replaced with an alternative chloride ion source, such as lithium chloride or potassium chloride. The substituent "Cy" in general procedures 24 to 87 can be selected from the group consisting of Cy24 to Cy87, thereby producing ketones K24 to K87 and corresponding compounds of type 24 to 87, examples of which are compounds 24A to 87A produced by reductive amination of ketones K24 to K87 with methylamine, as summarized in the table below;

[0605] [Table 1-1]

[0606] [Table 1-2]

[0607] [Table 1-3]

[0608] [Table 1-4]

[0609] [Table 1-5]

[0610] [Table 1-6]

[0611] [Table 1-7]

[0612] [Table 1-8]

[0613] [Table 1-9]

[0614] [Table 1-10]

[0615] [Table 1-11]

[0616] 2-(benzo[d][1,3]dioxol-5-yl)-1-(spiro[2.2]pentan-1-yl)ethanone ("Ketone K27")

[0617] [ka]

[0618] A stirred solution of spiro[2.2]pentane-1-carboxylic acid (12 mg, 0.11 mmol) in PhMe (0.2 mL) was treated with oxalyl chloride (10 μL, 0.12 mmol) followed by 1 drop of DMF. The resulting solution was stirred at room temperature under N for 2.5 h. Simultaneously, and in a separate flask, a 1.0 M solution of LiHMDS in THF (0.22 mL, 0.22 mmol) was added to a stirred solution of methyl homopiperonylate (19 mg, 0.10 mmol) in anhydrous THF (0.4 mL) at −78 °C under N. This solution was stirred at −78 °C for 1.5 h and then treated dropwise via syringe with a solution of the in situ generated acid chloride in PhMe. The reaction mixture was gradually warmed to room temperature over 2 h, quenched with half-saturated NH4Cl (15 mL), and extracted with CHCl (3 × 15 mL). The extract was washed with brine (20 mL), dried, and evaporated to give a light brown oil (34 mg), which was dissolved in 9:1 DMSO / water (0.60 mL). The resulting solution was degassed and stirred under N at 120 °C for 64 h. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with CHCl (3 × 15 mL). The extract was washed with brine (15 mL), dried, and evaporated, and the crude residue was subjected to preparative thin-layer chromatography. Development with 3:17 EtOAc / hexanes gave ketone K27 as a colorless oil (17 mg, 75%). 1 H NMR (500MHz, CDCl3): δ6.76(d,J=7.9Hz,1H),6.67(d,J=1.5Hz,1H),6.62(dd,J=7.9,1.5Hz,1H),5.94(s, 2H),3.63(d[AB],J=15.1Hz,1H),3.59(d[AB],J=15.1Hz,1H),2.29(dd,J=7.3,4.4Hz,1H),1.61(dd[app. t],J=4.0Hz,1H),1.38(dd,J=7.3,3.6Hz,1H),0.95-0.90(m,1H),0.86-0.75(m,2H),0.66-0.61(m,1H)ppm. 13C NMR (125MHz, CDCl3) δ207.5,147.9,146.6,128.0,122.6,109.9,108.5,101.1,49.7,28.2,22.0,16.9,6.9,5.4ppm.

[0619] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(spiro[2.2]pentan-1-yl)ethanamine (UWA-115, GAP-146, "Compound 27A")

[0620] [ka]

[0621] Following general procedure A, ketone K27 (15 mg, 65 μmol) was reacted for 20 h to give amine 27A as the diastereomeric 11 * :9 # The mixture was obtained as a pale yellow oil (13 mg, 81%). 1 H NMR(600MHz, CDCl3)δ6.73(d,J=7.8Hz,1H) # ,6.72(d,J=1.6Hz,1H) # ,6.71(d,J=7.8Hz,1H) * ,6.67(dd,J=7.8,1.6Hz,1H) # ,6.62(d,J=1.6Hz,1H) * ,6.58(dd,J=7.8,1.6Hz,1H) * ,5.921(s,2H) # ,5.918(s,2H) * ,2.87(dd,J=13.7,4.5Hz,1H) # ,2.67(dd,J=13.7,8.0Hz,1H) # ,2.64(dd,J=13.5,7.0Hz,1H) * ,2.55(dd,J=13.5,5.9Hz,1H) * ,2.48(s,3H) * ,2.26(s,3H) # ,2.21(ddd,J=8.5,8.5,4.5Hz,1H) #,2.14(ddd,J=9.1,7.0,6.1Hz,1H) * ,1.12-1.03(m,1H) #,* ,0.99(dd,J=7.7,4.0Hz,1H) * ,0.93(dd,J=8.2,4.2Hz,1H) # ,0.81-0.71(m,4H) 3×#,* ,0.69-0.66(m,1H) * ,0.63-0.58(m,1H) #,* ,0.57-0.54(m,1H) * ,0.47(dd[app. t],J=4.5Hz,1H) # ,0.31-0.27(m,1H)*ppm. 13 C NMR(150MHz, CDCl3)δ147.7,147.6,146.03,146.00,133.3,133.2,122.43,122.38,109.9,109.8,108. 2,100.9,65.7,64.4,41.4,41.1,34.8,34.4,22.9,22.4,15.0,12.9,12.1,10.2,6.1,5.6,5.1,3.7ppm. HRMS(ESI+)m / z[M+H] + C 15 H 20 NO2 + Calculated value: 246.1489; measured value: 246.1487.

[0622] The free base was converted to the crude hydrochloride salt and the diastereomeric 3 * :2 # The mixture crystallized as colorless granules. 1 H NMR(500MHz,CDCl3)δ9.61(br s,1H) * ,9.57(br s,1H) * ,9.40(br s,2H) # ,6.83-6.80(m,2H) # ,6.76(d,J=8.4Hz,1H) # ,6.73(d,J=7.8Hz,1H) * ,6.66(d,J=1.0Hz,1H) * ,6.64(dd,J=7.9,1.0Hz,1H)* ,5.94(s,2H) #,* ,3.37(dd,J=13.9,6.1Hz,1H) # ,3.32(br d,J=10Hz,1H) * ,3.16(dd,J=14.0,7.8Hz,1H) # ,2.89-2.81(m,2H) * ,2.78(br s,3H) * ,2.78-2.70(m,1H) # ,2.53(br s,3H) # ,1.58-1.54(m,1H) # ,1.48-1.43(m,1H) * ,1.19-1.15(m,1H) * ,1,14-1.08(m,1H) #,* ,1.03-0.98(m,2H) # ,0.84-0.79(m,1H) # ,0.77-0.72(m,1H) # ,0.65-0.59(m,1H) * ,0.46-0.38(m,2H) * ,0.33(dd[app. t],J=4.6Hz,1H) # ,(-0.46)-(-0.51)(m,1H) * ppm.

[0623] 3-(benzo[d][1,3]dioxol-5-yl)-1,1,1-trifluoropropan-2-one ("Ketone K88")

[0624] [ka]

[0625] A solution of 1.0 M LiHMDS in THF (8.1 mL, 8.1 mmol) was added to a stirred solution of methyl homopiperonylate (750 mg, 3.86 mmol) in anhydrous THF (8 mL) at −78 °C under N. The reaction solution was stirred at −78 °C for 1.5 h and then treated dropwise with trifluoroacetic anhydride (0.64 mL, 4.6 mmol). The resulting solution was allowed to warm gradually to room temperature overnight, quenched with 0.5 M HCl (80 mL), and extracted with CHCl (3 × 40 mL). The extracts were washed with brine (40 mL), dried, and evaporated to give a yellow oil (1039 mg), which was dissolved in 9:1 DMSO / water (15 mL). The resulting solution was degassed and stirred at 130 °C under N for 18 h. The reaction solution was cooled to room temperature, diluted with water (120 mL), and extracted with CHCl (3 × 50 mL). The extracts were washed with brine (2 × 50 mL), dried, evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:19 EtOAc / hexanes to 3:17 EtOAc / hexanes afforded a 7:3 mixture of ketone K88 and its hydrate as a pale yellow oil (296 mg). This oil was dissolved in anhydrous CHCl and treated with anhydrous MgSO (502 mg). The resulting mixture was stirred under reflux under N for 4 h, then filtered and evaporated to afford ketone K88 as a pale yellow oil (281 mg, 31%). 1 H NMR (400MHz, CDCl3): δ6.79(d,J=7.9Hz,1H),6.69(d,J=1.5Hz,1H),6.66(dd,J=7.9,1.8Hz,1H),5.97(s,2H),3.92(s,2H)ppm. 19 F NMR(376MHz, CDCl3)δ-78.2(s,3F)ppm. 13 C NMR (100MHz, CDCl3) δ189.1(q,J=34.8Hz),148.3,147.6,123.8,123.1,115.9(q,J=291Hz),110.0,108.8,101.4,42.8ppm.

[0626] 3-(benzo[d][1,3]dioxol-5-yl)-1,1,1-trifluoro-N-methylpropan-2-amine (UWA-132, GAP-145, "Compound 88A")

[0627] [ka]

[0628] Following general procedure A; ketone K88 (114 mg, 0.492 mmol) was reacted for 72 h to give amine 88A as a colorless oil (17 mg, 14%). 1 H NMR(400MHz,CDCl3)δ6.77(d,J=7.9Hz,1H),6.72(d,J=1.6Hz,1H),6.67(dd,J=7.9,1.6Hz,1H),5.95(s,2H),3.10(d dq,J=10.2,3.6,7.1Hz,1H),3.00(dd,J=14.3,3.6Hz,1H),2.58(dd,J=14.3,10.2Hz,1H),2.42(q,J=1.0Hz,3H)ppm. 19 F NMR(376MHz, CDCl3)δ-74.6(s,3F)ppm. 13 C NMR(100MHz,CDCl3)δ148.1,146.8,130.3,126.9(q,J=282Hz),122.4,109.3 ,108.6,101.2,62.8(q,J=26.8Hz),35.7(q,J=1.1Hz),34.5(q,J=2.4Hz)ppm. HRMS(ESI+)m / z[M+H] + C 11 H 13 F3NO2 + Calculated value: 248.0893; measured value: 248.0890.

[0629] The free base was converted to the crude hydrochloride salt and recrystallized from iPrOH / PhMe as colorless granules. 1H NMR(400MHz,CDCl3)δ10.57(br s,2H),6.86-6.82(m,2H),6.78(dd,J=7.1,1.4Hz,1H),5.96(s,2H),3.86(m[app. sextet]=7.0Hz,1H),3.46(dd,J=14.8,5.9Hz,1H),3.19(dd,J=14.7,7.7Hz,1H),2.76(s,3H)ppm.

[0630] 2-(benzo[d][1,3]dioxol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)ethanone ("Ketone K89")

[0631] [ka]

[0632] A solution of 1.0 M LiHMDS in THF (8.4 mL, 8.4 mmol) was added to a stirred solution of methyl homopiperonylate (767 mg, 3.95 mmol) in anhydrous THF (8 mL) at −78 °C under N. The reaction solution was stirred at −78 °C for 1.5 h and then treated dropwise with oxane-4-carbonyl chloride (645 mg, 4.34 mmol). The resulting solution was allowed to warm gradually to room temperature overnight, quenched with saturated NH.sub.4Cl (60 mL), and extracted with CHCl.sub.2 (3.times.40 mL). The extracts were washed with brine (40 mL), dried, and evaporated to give a light brown oil (1.37 g), which was dissolved in 9:1 DMSO / water (14 mL) and treated with NaCl (941 mg, 16.1 mmol). The resulting mixture was degassed and stirred under N at 140° C. for 20 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with CHCl (3×50 mL). The extracts were washed with brine (2×50 mL), dried, evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:9 EtOAc / hexanes to 1:3 EtOAc / hexanes afforded ketone K89 as a pale yellow solid (871 mg, 89%). 1H NMR(400MHz,CDCl3)δ6.76(d,J=7.9Hz,1H),6.67(d,J=1.7Hz,1H),6.62(dd,J=7.9,1.7Hz,1H),5.95(s,2H),3.98(ddd[app. dt],J=11.4,3.4Hz,2H),3.65(s,2H),3.45-3.34(m,2H),2.72-2.60(m,1H),1.77-1.67(m,4H)ppm. 13 C NMR (100MHz, CDCl3) δ209.4,148.1,146.8,127.6,122.6,109.9,108.6,101.2,67.3,47.3,46.8,28.4ppm.

[0633] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)ethanamine (UWA-141, GAP-114, "Compound 89A")

[0634] [ka]

[0635] Following general procedure A; ketone K89 (125 mg, 0.503 mmol) was reacted for 40 h to give amine 89A as a colorless oil (116 mg, 88%). 1 H NMR(400MHz,CDCl3)δ6.74(d,J=7.9Hz,1H),6.68(d,J=1.6Hz,1H),6.63(dd,J=7.9,1.6Hz,1H),5.94(s,2H),4.06-3.98(m,2H),3 .41-3.32(m,2H),2.75-2.67(m,1H),2.50-2.42(m,2H),2.33(s,3H),1.77-1.68(m,1H),1.62-1.56(m,2H),1.55-1.43(m,2H)ppm. 13 C NMR (100MHz, CDCl3) δ147.9,146.1,133.6,122.2,109.4,108.4,101.0,68.52,68.49,65.6,37.5,36.5,34.7,29.5,29.0ppm. HRMS(ESI+)m / z[M+H]+ C 15 H 22 No. 3 + Calculated value: 264.1594; measured value: 264.1591.

[0636] The free base was converted to the crude hydrochloride salt and recrystallized as colorless fine needles from PhMe. 1 H NMR(400MHz,CDCl3)δ9.46(br s,2H),6.81(dd,J=8.0,1.6Hz,1H),6.79-6.75(m,2H),5.96(s,2H),4.05-3.99(m,2H),3.43-3.35(m,2H),3.10(dd,J=13.1, 6.7Hz,1H),3.06-2.94(m,2H),2.53(s,3H),2.26-2.15(m,1H),1.83-1.75(m,2H),1.74-1.67(m,1H),1.66-1.55(m,1H)ppm.

[0637] Perfluorophenyl oxetane-3-carboxylate (ester E90)

[0638] [ka]

[0639] A solution of N,N'-dicyclohexylcarbodiimide (1.08 g, 5.23 mmol) and DMAP (53 mg, 0.43 mmol) in CHCl (5 mL) was added to a cold (0 °C) stirred mixture of oxetane-3-carboxylic acid (403 mg, 3.95 mmol) and pentafluorophenol (910 mg, 4.94 mmol) in CHCl (10 mL). The resulting mixture was stirred at room temperature for 24 h and vacuum filtered through a pad of Celite, rinsing with CHCl (3 × 30 mL). The filtrate was concentrated, and the crude residue was subjected to flash chromatography. Repeated gradient elution with 1:49 EtOAc / hexanes → 1:9 EtOAc / hexanes afforded a 17:3 mixture of ester E90 and pentafluorophenol as a pale yellow oil (339 mg, 29% by qNMR). 1H NMR (400MHz, CDCl3) δ4.98(d,J=7.6Hz,4H),4.21(quintet,J=7.6Hz,1H)ppm. 19 F NMR(376MHz, CDCl3)δ(-152.8)-(-153.0)(m,2F),-157.1(t,J=21.7Hz,1F),(-161.7)-(-161.9)(m,2F)ppm.

[0640] 2-(benzo[d][1,3]dioxol-5-yl)-1-(oxetan-3-yl)ethanone ("Ketone K90")

[0641] [ka]

[0642] A solution of 1.0 M LiHMDS in THF (1.28 mL, 1.28 mmol) was added to a stirred solution of methyl homopiperonylate (236 mg, 1.22 mmol) in anhydrous THF (2.5 mL) at −78 °C under N. The reaction solution was stirred at −78 °C for 1.5 h and then treated dropwise with a solution of the ester E90 and pentafluorophenol (17:3 mixture, 151 mg; containing 0.50 mmol of E90 by qNMR) in THF (2.0 mL). The resulting solution was allowed to warm gradually to room temperature overnight, quenched with half-saturated NH4Cl (30 mL), and extracted with CHCl (3 × 30 mL). The extract was washed with brine (30 mL), dried, evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:9 EtOAc / hexanes → 1:4 EtOAc / hexanes afforded the partially purified β-ketoester as a pale yellow oil (139 mg), which was dissolved in 9:1 DMSO / water (5 mL). The resulting solution was degassed and stirred under N at 110 °C for 14 h. The reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with CHCl (3 × 20 mL). The extracts were washed with brine (20 mL), dried, evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:9 EtOAc / hexanes → 1:3 EtOAc / hexanes afforded ketone K90 as a colorless solid (54 mg, 48%). 1 H NMR (600MHz, CDCl3): δ6.77(d,J=7.9Hz,1H),6.65(d,J=1.6Hz,1H),6.61(dd,J=7.9,1.6Hz,1H),5.96 (s,2H),4.75(dd,J=6.7,6.2Hz,2H),4.66(dd,J=8.8,6.2Hz,2H),4.05-3.99(m,1H),3.60(s,2H)ppm. 13 C NMR (600MHz, CDCl3) δ205.5,148.2,147.1,126.7,122.7,109.8,108.8,101.3,72.5,48.4,44.6ppm.

[0643] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(oxetan-3-yl)ethanamine (UWA-142 GAP-167, "Compound 90A")

[0644] [ka]

[0645] An 8.03 M solution of methylamine in EtOH (0.26 mL, 2.1 mmol) and AcOH (0.13 mL, 2.3 mmol) were added sequentially to a cold (0 °C) stirred mixture of ketone K90 (47 mg, 0.21 mmol) and 3A sieves (54 mg) in 2:1 THF / MeOH (1.5 mL). Sodium cyanoborohydride (16 mg, 0.25 mmol) was added, and the reaction vessel was flushed with N, sealed, and stirred at 50 °C for 14 h. After that, it was cooled to room temperature, quenched with 1 M NaOH (15 mL), and extracted with CHCl (3 × 20 mL). The extract was vacuum filtered through a pad of Celite, rinsing with CHCl (3 × 15 mL). The filtrate was dried and evaporated to give secondary amine 90A as a colorless oil (47 mg, 94%). 1 H NMR (600MHz, CDCl3): δ6.73(d,J=7.9Hz,1H),6.62(d,J=1.6Hz,1H),6.56(dd,J=7.9,1 .6Hz,1H),5.93(s,2H),4.73(dd,J=7.6,6.1Hz,1H),4.63-4.58(m,2H),4.39(dd[app. t],J=6.3Hz,1H),3.03-2.95(m,2H),2.57(dd,J=13.8,4.7Hz,1H),2.53(dd,J=13.8,6.5Hz,1H),2.37(s,3H)ppm. 13 C NMR (150MHz, CDCl3) δ147.9,146.3,131.9,122.3,109.6,108.4,101.1,76.1,75.0,63.6,39.8,37.3,34.3ppm. HRMS(ESI+)m / z[M+H] + C 13 H 18 No. 3 +Calculated value: 236.1281; measured value: 236.1279.

[0646] 2-(benzo[d][1,3]dioxol-5-yl)-1-(oxazol-5-yl)ethanone ("Ketone K91")

[0647] [ka]

[0648] A stirred solution of oxazole-5-carboxylic acid (154 mg, 1.36 mmol) in PhMe (2.5 mL) was treated with oxalyl chloride (0.12 mL, 1.40 mmol) followed by two drops of DMF. The resulting solution was stirred at room temperature under N for 5 h. Simultaneously, and in a separate flask, a 1.0 M solution of LiHMDS in THF (2.9 mL, 2.9 mmol) was added to a stirred solution of methyl homopiperonylate (253 mg, 1.30 mmol) in anhydrous THF (4 mL) at −78 °C under N. This solution was stirred at −78 °C for 1.5 h and then treated dropwise via syringe with the in situ generated solution of the acid chloride in PhMe. The reaction mixture was allowed to warm gradually to room temperature overnight, quenched with half-saturated NH4Cl (70 mL), and extracted with CHCl (3 × 40 mL). The extract was washed with brine (40 mL), dried, and evaporated to give an orange residue (356 mg), which was dissolved in 4:1 trifluoroacetic acid / water (15 mL). The resulting solution was degassed and stirred under N at 80 °C for 24 h. The reaction solution was cooled to room temperature, diluted with water (50 mL), basified with saturated NaHCO (180 mL), and extracted with EtOAc (3 × 50 mL). The extract was washed with brine (50 mL), dried, evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:9 EtOAc / hexane to 3:7 EtOAc / hexane gave ketone K91 as a beige solid (60 mg, 20%). 1H NMR (400MHz, CDCl3): δ8.01(s,1H),7.77(s,1H),6.79-6.76(m,2H),6.73(dd,J=8.0,1.6Hz,1H),5.95(s,2H),4.02(s,2H)ppm. 13 C NMR (100MHz, CDCl3) δ186.0,153.4,148.2,147.2,133.5,126.4,122.9,110.0,108.7,101.3,46.1ppm.

[0649] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(oxazolidin-5-yl)ethanamine (UWA-143, GAP-156, "Compound 91A")

[0650] [ka]

[0651] An 8.03 M solution of methylamine in EtOH (0.13 mL, 1.0 mmol) and AcOH (60 μL, 1.0 mmol) were added sequentially to a cold (0 °C) stirred mixture of ketone K91 (24 mg, 0.10 mmol) and 3A sieves (34 mg) in 2:1 THF / MeOH (1.5 mL). Sodium cyanoborohydride (9.0 mg, 0.14 mmol) was added, and the reaction vessel was flushed with N, sealed, and stirred at 50 °C for 18 h. After that, it was cooled to room temperature, quenched with 1 M NaOH (15 mL), and extracted with CHCl (3 × 20 mL). The extract was vacuum filtered through a pad of Celite, rinsing with CHCl (3 × 15 mL). The filtrate was dried and evaporated to give a brown oil (23 mg), which was dissolved in dry MeOH (1.5 mL) and treated with NaBH (27 mg, 0.71 mmol). The resulting mixture was stirred under N at room temperature for 96 h, then quenched with brine (15 mL) and extracted with CHCl (3 × 20 mL). The extracts were dried and evaporated, and the crude yellow residue was subjected to preparative thin-layer chromatography. Development with 3:3:94 NEt / MeOH / CHCl gave amine 91A as a pale yellow solid (10 mg, 39%).1 H NMR (500MHz, CDCl3): δ6.75-6.72(m,2H),6.70(dd,J=7.9,1.3Hz,1H),5.92(s,2H),3.77(d,J=11.3Hz,1H),3.22(d,J=1. 4Hz,1H),3.10(d,J=11.3Hz,1H),3.00-2.93(m,2H),2.66(dd,J=13.0,10.8Hz,1H),2.63(dd,J=14.0,1.5Hz,1H),2.48(br s,2H),2.28(s,3H),2.28-2.23(m,1H)ppm. 13 C NMR (125MHz, CDCl3) δ147.8,146.2,131.5,122.7,110.1,108.4,101.0,72.0,68.7,63.1,51.7,38.9,35.2ppm. HRMS(ESI+)m / z[M+H] + C 13 H 19 N2O3 + Calculated value: 251.1390; measured value: 251.1386.

[0652] 2-(benzo[d][1,3]dioxol-5-yl)-1-(1-fluorocyclopropyl)ethanone ("ketone K92")

[0653] [ka]

[0654] A stirred solution of 1-fluorocyclopropanecarboxylic acid (454 mg, 4.36 mmol) in PhMe (4.4 mL) was treated with oxalyl chloride (0.38 mL, 4.40 mmol) followed by two drops of DMF. The resulting solution was stirred at room temperature under N for 2 h. Simultaneously, and in a separate flask, a 1.0 M solution of LiHMDS in THF (8.7 mL, 8.7 mmol) was added to a stirred solution of methyl homopiperonylate (774 mg, 3.98 mmol) in anhydrous THF (12 mL) at −78 °C under N. This solution was stirred at −78 °C for 1.5 h and then treated dropwise via syringe with the in situ generated PhMe solution of the acid chloride. The reaction mixture was allowed to warm gradually to room temperature overnight, quenched with 0.5 M HCl (80 mL), and extracted with CHCl (3 × 40 mL). The extract was washed with brine (40 mL), dried, and evaporated to give a dark yellow oil (1.13 g), which was dissolved in 9:1 DMSO / water (16 mL) and treated with NaCl (1.05 g, 18.0 mmol). The resulting mixture was degassed and stirred under N at 140 °C for 40 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with CHCl (3 × 50 mL). The extract was washed with brine (2 × 50 mL), dried, and evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:49 EtOAc / hexanes to 1:19 EtOAc / hexanes afforded ketone K92 as a colorless oil (375 mg, 42%). 1 H NMR(400MHz,CDCl3)δ6.77(d,J=7.9Hz,1H),6.73(d,J=1.6Hz,1H),6.68(dd,J=7.9,1 .6Hz,1H),5.95(s,2H),4.00(d,J=3.4Hz,2H),1.41-1.38(m,2H),1.37-1.34(m,2H). 19 F NMR (376MHz, CDCl3)δ-196.9ppm. 13 C NMR (100MHz, CDCl3) δ206.4(d,J=24.9Hz),147.9,146.8,126.8,123.0,110.3,108.5,101.2,82.8(d,J=230Hz),45.4,17.3(d,J=10.2Hz)ppm.

[0655] 2-(benzo[d][1,3]dioxol-5-yl)-1-(1-fluorocyclopropyl)-N-methylethanamine (UWA-144, GAP-128, "Compound 92A")

[0656] [ka]

[0657] Following general procedure A; ketone K92 (112 mg, 0.504 mmol) was reacted for 24 h to give amine 92A as a colorless oil (94 mg, 79%). 1 H NMR(400MHz,CDCl3)δ6.74(d,J=7.9Hz,1H),6.72(d,J=1.6Hz,1H),6.68(dd,J=7.8,1.7Hz,1H),5.93(s,2H),2.95(dd,J=13.8,6.1Hz,1H),2.81(dd, J=13.8,8.1Hz,1H),2.49(s,3H),2.34(ddd,J=24.7,8.1,6.1Hz,1H),1.16 -1.03(m,1H),0.95-0.82(m,1H),0.71-0.60(m,1H),0.35-0.24(m,1H)ppm. 19 F NMR (376MHz, CDCl3)δ-196.5ppm. 13 C NMR(100MHz,CDCl3)δ147.8,146.2,132.9,122.4,109.7,108.3,101.0,78.7(d,J=219Hz) ,65.3(d,J=19.8Hz),38.3(d,J=1.6Hz),35.0,10.6(d,J=12.3Hz),8.3(d,J=11.5Hz)ppm. HRMS(ESI+)m / z[M+H] + C 13 H 17 FNO2 + Calculated value: 238.1238; measured value: 238.1235.

[0658] The free base was converted to the crude hydrochloride salt and recrystallized from iPrOH / PhMe as colorless granules. 1H NMR(400MHz,CDCl3)δ9.99(br s,1H),9.92(br s,1H),6.81(d,J=1.5Hz,1H),6.79(dd,J=7.9,1.5Hz,1H),6.74(d,J=7.9Hz, 1H),5.95(d[AB],J=1.4Hz,1H),5,94(d[AB],J=1.4Hz,1H),3.38(dd,J=13.2 ,4.4Hz,1H),3.28(dd,J=13.2,11.0Hz,1H),3.14-3.00(m,1H),2.86(dd,J=5 .6,4.8Hz,3H),1.28-1.06(m,2H),1.01-0.87(m,1H),0.29-0.18(m,1H)ppm.

[0659] 1-(benzo[d][1,3]dioxol-5-yl)-3-cyclopropylpropan-2-one ("ketone K93")

[0660] [ka]

[0661] A stirred solution of cyclopropylacetic acid (445 mg, 4.44 mmol) in PhMe (4.4 mL) was treated with oxalyl chloride (0.39 mL, 4.5 mmol) followed by 1 drop of DMF. The resulting solution was stirred at room temperature under N for 2.5 h. Simultaneously, in a separate flask, a 1.0 M solution of LiHMDS in THF (8.7 mL, 8.7 mmol) was added to a stirred solution of methyl homopiperonylate (770 mg, 3.96 mmol) in anhydrous THF (12 mL) at −78 °C under N. This solution was stirred at −78 °C for 1.5 h and then treated dropwise via syringe with the in situ generated PhMe solution of the acid chloride. The reaction mixture was allowed to warm gradually to room temperature overnight, quenched with 0.5 M HCl (80 mL), and extracted with CHCl (3 × 40 mL). The extract was washed with brine (40 mL), dried, and evaporated to give a yellow oil (1.24 g), which was dissolved in 9:1 DMSO / water (16 mL) and treated with NaCl (1.21 g, 20.7 mmol). The resulting mixture was degassed and stirred under N at 140 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with CHCl (3 × 50 mL). The extract was washed with brine (2 × 50 mL), dried, and evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:49 EtOAc / hexanes → 1:19 EtOAc / hexanes gave ketone K93 as a colorless oil (674 mg, 78%). 1 H NMR(400MHz,CDCl3)δ6.76(d,J=7.9Hz,1H),6.68(d,J=1.4Hz,1H),6.63(dd,J=7.9,1.7Hz,1H),5.94(s ,2H),3.64(s,2H),2.32(d,J=7.0Hz,1H),1.04-0.92(m,1H),0.60-0.50(m,2H),0.11-0.02(m,2H)ppm. 13 C NMR (100MHz, CDCl3) δ208.5,148.0,146.8,128.0,122.7,110.0,108.6,101.2,49.4,47.2,6.4,4.7ppm.

[0662] 1-(benzo[d][1,3]dioxol-5-yl)-3-cyclopropyl-N-methylpropan-2-amine (UWA-145, GAP-125, "Compound 93A")

[0663] [ka]

[0664] Following general procedure A; ketone K93 (112 mg, 0.513 mmol) was reacted for 24 h to give amine 93A as a colorless oil (112 mg, 93%). 1 H NMR(400MHz,CDCl3)δ6.74(d,J=7.8Hz,1H),6.70(d,J=1.6Hz,1H),6.64(dd,J=7.8,1.6Hz,1H),5.93(s,2H),2.76-2.66 (m,2H),2.65-2.58(m,1H),2.39(s,3H),1.38-1.25(m,2H),0.76-0.66(m,1H),0.51-0.42(m,2H),0.10-0.00(m,2H)ppm. 13 C NMR (100MHz, CDCl3) δ147.8,146.0,133.6,122.3,109.6,108.3,100.9,62.0,40.4,38.5,34.1,7.9,4.9,4.6ppm. HRMS(ESI+)m / z[M+H] + C 14 H 20 NO2 + Calculated value: 234.1489; measured value: 234.1485.

[0665] The free base was converted to the crude hydrochloride salt and recrystallized from PhMe as colorless granules. 1H NMR(400MHz,CDCl3)δ9.56(br s,1H),9.50(br s,1H),6.76(d,J=7.8Hz,1H),6.74-6.70(m,2H),5.95(s,2H),3.33-3.24(m,2H),2.94(dd,J=15.2,10.3Hz,1H),2.68(dd[app. t],J=5.6Hz,3H),1.79(ddd[app. dt].

[0666] 2-(benzo[d][1,3]dioxol-5-yl)-1-cyclopentylethanone ("ketone K94")

[0667] [ka]

[0668] A solution of 1.0 M LiHMDS in THF (9.4 mL, 9.4 mmol) was added to a stirred solution of methyl homopiperonylate (869 mg, 4.47 mmol) in anhydrous THF (9 mL) at −78 °C under N. The reaction solution was stirred at −78 °C for 1.5 h and then treated dropwise with cyclopentanecarbonyl chloride (661 mg, 4.99 mmol). The resulting solution was allowed to warm gradually to room temperature overnight, quenched with 0.5 M HCl (80 mL), and extracted with CHCl (3 × 40 mL). The extracts were washed with brine (40 mL), dried, and evaporated to give a yellow oil (1.67 g), which was dissolved in 9:1 DMSO / water (15 mL) and treated with NaCl (1.07 g, 18.4 mmol). The resulting mixture was degassed and stirred under N at 140° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with CHCl (3×50 mL). The extracts were washed with water (50 mL) and brine (2×50 mL), dried, evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:49 EtOAc / hexane to 1:19 EtOAc / hexane afforded ketone K94 as a colorless oil (952 mg, 92%). 1 H NMR(400MHz,CDCl3)δ6.76(d,J=7.9Hz,1H),6.69(d,J=1.6Hz,1H),6.64(dd,J=7.9,1.7 Hz, 1H), 5.94 (s, 2H), 3.64 (s, 2H), 2.96 (quintet, J=8.0Hz, 1H), 1.82-1.49 (m, 8H) ppm. 13 C NMR (100MHz, CDCl3) δ210.9,147.9,146.7,128.3,122.7,110.0,108.5,101.1,50.6,48.9,29.3,26.2ppm.

[0669] 2-(benzo[d][1,3]dioxol-5-yl)-1-cyclopentyl-N-methylethanamine (UWA-146, GAP-116, "Compound 94A")

[0670] [ka]

[0671] Following general procedure A; ketone K94 (119 mg, 0.512 mmol) was reacted for 60 h to give amine 94A as a colorless oil (109 mg, 86%). 1 H NMR(400MHz,CDCl3)δ6.73(d,J=7.9Hz,1H),6.71(d,J=1.6Hz,1H),6.64(dd,J=7.8,1.7Hz,1H),5.92(s,2H),2.70(dd,J=13.6,4.6Hz,1H),2 .56(dd,J=13.6,7.6Hz,1H),2.52-2.48(m,1H),2.36(s,3H),1.98-1.87(m,1H),1.82-1.69(m,2H),1.66-1.47(m,4H),1.35-1.24(m,2H)ppm. 13 C NMR (100MHz, CDCl3) δ147.7,145.9,133.9,122.2,109.7,108.2,100.9,65.5,43.2,38.0,34.1,29.7,29.4,25.8,25.7ppm. HRMS(ESI+)m / z[M+H] + C 15 H 22 NO2 + Calculated value: 248.1645; measured value: 248.1642.

[0672] The free base was converted to the crude hydrochloride salt and recrystallized from iPrOH / PhMe as colorless granules. 1 H NMR(400MHz,CDCl3)δ9.54(br s,1H),8.99(br s,1H),6.82(dd,J=7.9,1.6Hz,1H),6.78(d,J=1.5Hz,1H),6.76(d,J=7.9Hz,1H),5.95(s,2H),3.21-3.12(m,2H),2.96(ddd[app. q],J=8.5Hz,1H),2.55(dd[app.

[0673] 2-(benzo[d][1,3]dioxol-5-yl)-1-(3,3-difluorocyclobutyl)ethanone ("Ketone K95")

[0674] [ka]

[0675] A stirred solution of 3,3-difluorocyclobutanecarboxylic acid (607 mg, 4.46 mmol) in PhMe (4.4 mL) was treated with oxalyl chloride (0.38 mL, 4.4 mmol) followed by two drops of DMF. The resulting solution was stirred at room temperature under N for 2 h. Simultaneously, in a separate flask, a 1.0 M solution of LiHMDS in THF (8.8 mL, 8.8 mmol) was added to a stirred solution of methyl homopiperonylate (779 mg, 4.01 mmol) in anhydrous THF (12 mL) at −78 °C under N. This solution was stirred at −78 °C for 1.5 h and then treated dropwise via syringe with the in situ generated PhMe solution of the acid chloride. The reaction mixture was allowed to warm gradually to room temperature overnight, quenched with 0.5 M HCl (80 mL), and extracted with CHCl (3 × 40 mL). The extract was washed with brine (40 mL), dried, and evaporated to give a yellow oil (1.59 g), which was dissolved in 9:1 DMSO / water (14 mL) and treated with NaCl (1.01 g, 17.3 mmol). The resulting mixture was degassed and stirred under N at 140 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with CHCl (3 × 50 mL). The extract was washed with brine (2 × 50 mL), dried, and evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:19 EtO / hexane to 3:17 EtO / hexane gave ketone K95 as a colorless oil (628 mg, 62%). 1H NMR(400MHz,CDCl3)δ6.77(d,J=7.8Hz,1H),6.66(d,J=1.5Hz,1H),6.63(dd,J=7.9,1.7Hz,1H),5.96(s, 2H),3.63(s,2H),3.13(doublet quintet,J=8.7,2.6Hz,1H),2.81-2.66(m,2H),2.65-2.52(m,2H)ppm. 19 F NMR(376MHz, CDCl3) δ-82.4(d,J=192Hz,1F),-97.5(d,J=192Hz,1F)ppm. 13 C NMR(100MHz,CDCl3)δ206.5(dd[app. t],J=1.8Hz),148.2,147.1,126.9,122.7,118.5(dd,J=284,268Hz),109.8,108.8,101.3,48.4(d,J=1.1Hz),38.0(dd[app. t],J=24.2Hz),32.2(dd,J=13.5,4.5Hz)ppm.

[0676] 2-(benzo[d][1,3]dioxol-5-yl)-1-(3,3-difluorocyclobutyl)-N-methylethanamine (UWA-147, GAP-119, "Compound 95A")

[0677] [ka]

[0678] Following general procedure A; ketone K95 (128 mg, 0.503 mmol) was reacted for 40 h to give amine 95A as a colorless oil (121 mg, 89%). 1 H NMR(400MHz,CDCl3)δ6.74(d,J=7.8Hz,1H),6.64(d,J=1.6Hz,1H),6.59(dd,J=7.8,1.7Hz,1H),5.94 (s,2H),2.68-2.47(m,5H),2.43-2.31(m,1H),2.39(s,3H),2.30-2.17(m,1H),2.13-2.00(m,1H)ppm. 19F NMR(376MHz, CDCl3) δ-81.5(d,J=192Hz,1F),-98.3(d,J=192Hz,1F)ppm. 13 C NMR(100MHz,CDCl3)δ147.9,146.3,132.1,122.3,119.9(dd,J=284,269Hz),109.6,108.5,101.1,65.1(dd,J= ppm. HRMS(ESI+)m / z[M+H] + C 14 H 18 F2NO2 + Calculated value: 270.1300; measured value: 270.1297.

[0679] The free base was converted to the crude hydrochloride salt and recrystallized from PhMe as colorless granules. 1 H NMR(400MHz,CDCl3)δ9.72(br s,1H),9.58(br s,1H),6.79-6.72(m,3H),5.97(s,2H),3.34-3.21(m,2H),2.95-2.72(m,3H),2.60(dd[app. t],J=5.6Hz,3H),2.59-2.42(m,2H),2.26-2.12(m,1H)ppm.

[0680] 2-(benzo[d][1,3]dioxol-5-yl)-1-(3,3-dimethylcyclobutyl)ethanone ("Ketone K96")

[0681] [ka]

[0682] A stirred solution of 3,3-dimethylcyclobutanecarboxylic acid (448 mg, 3.49 mmol) in PhMe (3.5 mL) was treated with oxalyl chloride (0.31 mL, 3.6 mmol) followed by two drops of DMF. The resulting solution was stirred at room temperature under N for 2 h. Simultaneously, in a separate flask, a 1.0 M solution of LiHMDS in THF (7.0 mL, 7.0 mmol) was added to a stirred solution of methyl homopiperonylate (615 mg, 3.17 mmol) in anhydrous THF (9.5 mL) at −78 °C under N. This solution was stirred at −78 °C for 1.5 h and then treated dropwise via syringe with the in situ generated PhMe solution of the acid chloride. The reaction mixture was allowed to warm gradually to room temperature overnight, quenched with 0.5 M HCl (80 mL), and extracted with CHCl (3 × 40 mL). The extract was washed with brine (40 mL), dried, and evaporated to give a yellow oil (1.11 g), which was dissolved in 9:1 DMSO / water (12 mL) and treated with NaCl (838 mg, 14.3 mmol). The resulting mixture was degassed and stirred under N at 140 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with CHCl (3 × 50 mL). The extract was washed with brine (2 × 50 mL), dried, and evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:49 EtOAc / hexanes → 1:19 EtOAc / hexanes gave ketone K96 as a colorless oil (629 mg, 81%). 1 H NMR(400MHz,CDCl3)δ6.75(d,J=7.9Hz,1H),6.67(d,J=1.5Hz,1H),6.62(dd,J=7.9,1.7Hz,1H),5.94(s,2H),3 .54(s,2H),3.23(quintet,J=8.9Hz,1H),2.03-1.96(m,2H),1.87-1.80(m,2H),1.14(s,3H),1.03(s,3H)ppm. 13 C NMR (100MHz, CDCl3) δ209.9,147.9,146.7,128.2,122.7,110.0,108.5,101.1,47.5,38.2,37.1,31.5,30.1,28.8ppm.

[0683] 2-(benzo[d][1,3]dioxol-5-yl)-1-(3,3-dimethylcyclobutyl)-N-methylethanamine (UWA-148, GAP-133, "Compound 96A")

[0684] [ka]

[0685] Following general procedure A; ketone K96 (124 mg, 0.503 mmol) was reacted for 24 h to give amine 96A as a colorless oil (90 mg, 69%). 1 H NMR(400MHz,CDCl3)δ6.73(d,J=7.8Hz,1H),6.67(d,J=1.6Hz,1H),6.61(dd,J=7.8,1.6Hz,1H),5.93(s,2H),2.62(dd,J=13.5,4.3Hz,1H),2.51 (ddd,J=9.0,7.5,4.3Hz,1H),2.39(dd,J=13.5,7.5Hz,1H),2.35(s,3H),2.22-2.10(m,1H),1.90-1.83(m,1H),1.80-1.72(m,1H),1.58(dd[app. t],J=9.9Hz,1H),1.48(dd[app. t],J=10.0Hz,1H),1.13(s,3H),1.03(s,3H)ppm. 13 C NMR (100MHz, CDCl3) δ147.7,145.9,133.4,122.3,109.7,108.2,100.9,67.3,40.1,39.1,37.4,34.8,33.2,31.6,31.2,28.5ppm. HRMS(ESI+)m / z[M+H] + C 16 H 24 NO2 + Calculated value: 262.1802; measured value: 262.1799.

[0686] The free base was converted to the crude hydrochloride salt and recrystallized as colorless fine needles from PhMe. 1H NMR(400MHz,CDCl3)δ9.34(br s,1H),9.20(br s,1H),6.80-6.73(m,3H),5.95(s,2H),3.20-3.08(m,2H),2.88-2.80(m,1H),2.71-2.58(m,1H),2.54(dd[app. t],J=5.6Hz,3H),2.16-2.07(m,1H),1.83(dd,J=11.1,9.6Hz,1H),1.76-1.69(m,1H),1.41(dd,J=11.0,9.5Hz,1H),1.13(s,3H),1.04(s,3H)ppm.

[0687] tert-Butyl (1-(benzo[d][1,3]dioxol-5-yl)but-3-yn-2-yl)(methyl)carbamate ("Carbamate CX97")

[0688] [ka]

[0689] A stirred solution of UWA-017·HCl (“Compound 3A·HCl”; 50 mg, 0.21 mmol) in water (1.6 mL) was treated with Na2CO3 (80 mg, 0.75 mmol) followed by di-tert-butyl dicarbonate (164 mg, 0.751 mmol). The resulting mixture was stirred at room temperature for 48 h, diluted with water (15 mL), and extracted with CHCl2 (3 × 15 mL). The extract was washed with brine (15 mL), dried, evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with hexane → 1:9 EtOAc / hexane afforded carbamate CX97 as a colorless oil (61 mg, 96%). 1 H NMR (400 MHz, CDCl3; mixture of rotamers) δ 6.73 (d, J = 7.8 Hz, 1H), 6.72–6.60 (br m, 2H), 5.92 (q[AB], J = 1.3 Hz, 2H), 5.19 and 5.00 (2 × br s, 1H, rotamers), 2.91–2.79 (br m, 5H), 2.36 and 2.32 (2 × br s, 1H, rotamers), 1.40 and 1.34 (2 × br s, 9H, rotamers) ppm.13 C NMR (100 MHz, CDCl3; mixture of rotamers) δ 154.6 (br), 147.6, 146.6, 130.8, 122.5, 109.9, 108.3, 101.0, 81.6 (br), 80.2, 73.4, 50.1, and 49.2 (2 × br, rotamers), 40.1 and 39.7 (2 × br, rotamers), 29.9 and 29.2 (2 × br, rotamers), 28.4 ppm.

[0690] tert-Butyl (2-(benzo[d][1,3]dioxol-5-yl)-1-(1H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate ("Carbamate CY97")

[0691] [ka]

[0692] CuI (4.0 mg, 0.021 mmol, 12 mol%), iPrNEt (50 μL, 0.29 mmol), and TMSN (45 μL, 0.34 mmol) were added to a stirred solution of carbamate CX97 (55 mg, 0.18 mmol) in 9:1 DMF / MeOH (2.0 mL). The reaction vessel was flushed with argon, sealed, and the reaction mixture was stirred at 80 °C for 20 h. The resulting mixture was cooled to room temperature, diluted with water (20 mL), and extracted with CHCl (3 × 20 mL). The extracts were washed with saturated NH Cl (2 × 20 mL), dried, evaporated, and the crude residue was subjected to flash chromatography. Gradient elution with 1:4 EtOAc / hexanes to 1:39:60 NEt / EtOAc / hexanes afforded carbamate CY97 as a pale yellow oil (49 mg, 77%). 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.63 and 7.60 (2 × br s, 1H, rotamers), 6.74–6.63 (br m, 3H), 5.90 (s, 2H), 5.66 and 5.55 (2 × br s, 1H, rotamers), 3.37–3.25 (br m, 1H), 3.24–3.05 (br m, 1H), 2.69 (s, 3H), 1.39 and 1.35 (2 × br s, 9H, rotamers) ppm. 13 C NMR (100 MHz, CDCl3) δ 156.2 and 155.6 (2 × br, rotamers), 147.7, 146.3, 131.6 (br), 131.3, 122.2, 109.6, 108.4, 101.0, 80.4, 53.8 and 52.4 (2 × br, rotamers), 36.9, 30.4 and 29.3 (2 × br, rotamers), 28.4 ppm. Note: For C4'' 13 The C signal was not observed due to rotamer and tautomer broadening.

[0693] 2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-(1H-1,2,3-triazol-4-yl)ethanamine (UWA-149, GAP-168, "Compound 97A")

[0694] [ka]

[0695] A solution of carbamate CY97 (14 mg, 41 μmol) in MeOH (0.6 mL) was treated with 4.0 M HCl in dioxane (0.15 mL, 0.60 mmol) and stirred at 40 °C for 3 h. The resulting solution was cooled to room temperature and evaporated, and the residue was triturated with EtO to give the dihydrochloride salt 97A·2HCl as a beige solid (12 mg, 93%). 1H NMR(600MHz,CD3OD)δ7.75(s,1H),6.70(d,J=7.9Hz,1H),6.64(d,J=1.7Hz,1H),6.58(dd,J=7.9,1.7Hz,1H),5.90(q[AB] ,J=1.3Hz,2H),4.67(dd,J=9.6,5.6Hz,1H),3.34(dd,J=13.4,5.6Hz,1H),3.22(dd,J=13.4,9.8Hz,1H),2.60(s,3H)ppm.

[0696] A sample of the dihydrochloride salt 97A·2HCl was dissolved in saturated NaHCO3 and extracted with EtOAc. The extracts were dried and evaporated to give the amine 97A as a colorless solid. 1 H NMR(600MHz,CD3OD)δ7.58(br s,1H),6.65(d,J=7.9Hz,1H),6.57(d,J=1.3Hz,1H),6.53(dd,J=7.9,1.2Hz,1H),5.86(q [AB],J=1.4Hz,2H),4.03(dd,J=8.1,6.6Hz,1H),3.05(dd,J=13.3,6.4Hz,1H),2.96(br dd,J=13.0,8.0Hz,1H),2.25(s,3H)ppm. 13 C NMR (150MHz, CD3OD) δ149.0,147.6,146.9(br),132.7,129.3(br),123.4,110.4,109.0,102.1,59.1,42.5,33.9ppm. HRMS(ESI+)m / z[M+H] + C 12 H 15 N4O2 + Calculated value: 247.1190; measured value: 247.1188.

[0697] Bioactivity Screening Test Particularly preferred compounds of the present invention were subjected to the following biological screening tests to determine their activity profile.

[0698] Serotonin transporter (SERT) activity Representing the gene superfamily, Na + / Cl -Neurotransmitters are essential for controlling neurotransmitter function. The function of serotonin is partially mediated by the plasma membrane norepinephrine transporter (SERT), which transports serotonin into presynaptic serotonergic neurons. Psychostimulants and antidepressants have high affinity for monoamine transporters such as SERT. These drugs increase extracellular neurotransmitter concentrations in both the central and peripheral nervous systems by inhibiting transporters, thereby preventing neuronal uptake, which contributes to their behavioral and autonomic effects.

[0699] The screening procedure followed that reported in the literature. 11(a)、(b) Using modified Tris-HCl buffer at pH 7.4, human recombinant serotonin transporter expressed in human HEK-293 cells was added to a 9 μg aliquot at 0.4 nM [ 3 The transporters are then incubated with [H]paroxetine in the presence of 10 μM imipramine (as an exemplary compound) to estimate nonspecific binding. The transporters are filtered and washed, and the filters are counted to determine the specifically bound [H]paroxetine. 3 The IC2000 standard reference agent used for this screening study was paroxetine. 50 (nM)=8.6, Ki(nM)=1.4, and nH=0.9.

[0700] Dopamine transporter (DAT) activity Representing the gene superfamily, Na + / Cl -Dependent neurotransmitters are essential for controlling neurotransmitter function. The function of dopamine is partially mediated by the plasma membrane norepinephrine transporter (DAT), which transports dopamine into presynaptic dopaminergic neurons. Psychostimulants and antidepressants have high affinity for monoamine transporters such as DAT. These drugs increase the concentration of extracellular neurotransmitters in both the central and peripheral nervous systems by inhibiting the transporters, thereby preventing their uptake into neurons, which contributes to their behavioral and autonomic effects.

[0701] The screening procedure followed that reported in the literature. 12(a)、(b) Human recombinant dopamine transporter expressed in CHO-S cells is used in modified Tris-HCl buffer at pH 7.4. 0.4 μg aliquots are diluted to 0.15 nM [ 125 The transporters are then filtered and washed, and the filters are then counted to determine the specific bound [I]RTI-55. 125 I]RTI-55 is determined. Compounds are screened at 10 μM. The standard reference agent used for this screening test is the IC 50 The compound is GBR-12909 (1-[2[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride), with (nM)=1.7, Ki(nM)=1.3, and nH=0.9.

[0702] Norepinephrine transporter (NET) activity Representing the gene superfamily, Na + / Cl -Dependent neurotransmitters are essential for regulating neurotransmitter function. The function of norepinephrine is partially mediated by the plasma membrane norepinephrine transporter (NET), which transports norepinephrine into presynaptic noradrenergic neurons. Psychostimulants and antidepressants have high affinity for monoamine transporters such as NET. These drugs increase extracellular neurotransmitter concentrations in both the central and peripheral nervous systems by inhibiting transporters, thereby preventing neuronal uptake, which contributes to their behavioral and autonomic effects.

[0703] The screening procedure followed that reported in the literature. 13 Human recombinant norepinephrine transporter expressed in canine kidney MDCK cells is used in modified Tris-HCl buffer at pH 7.4. 40 μg aliquots are diluted to 0.2 nM [ 125 The transporters are filtered and washed, and the filters are then counted to determine the specific bound [I]RTI-55. 125 I]RTI-55 is determined. Compounds are screened at 10 μM. The standard reference agent used for this screening test is the IC 50 and desipramine with (nM)=0.93, Ki(nM)=0.92, and nH=0.6.

[0704] Monoamine oxidase A (MAO-A) activity Monoamine oxidases (MAOs, EC 1.4.3.4) catalyze the removal of amine groups via oxidative deamination from a variety of substrates, including endogenous substances and neurotransmitters (norepinephrine, epinephrine, dopamine, tyramine, serotonin) and many amine drugs. MAOs provide an important protective mechanism against exogenous, biologically active amines. There are at least two types of MAOs that exhibit varying substrate preferences and differing sensitivities to selective inhibitors. Relatively selective MAO-A inhibitors (e.g., clorgyline) are correlated with efficacy in the treatment of major depression, and relatively selective MAO-B inhibitors are correlated with beneficial effects on Parkinson's disease and dyskinesia.

[0705] The screening procedure followed that reported in the literature. 14(a)、(b) This uses human recombinant MAO-A expressed in insect cells. Test compounds and / or vehicle are pre-incubated with 4.2 μg / ml of enzyme in pH 7.4 phosphate buffer at 37°C for 15 minutes. The reaction is initiated by the addition of 50 μM kynuramine (as substrate) for an additional 60-minute incubation period and terminated by the addition of 1.2 N NaOH. The amount of 4-hydroxyquinoline formed is determined spectrofluorometrically at 325 nm / 465 nm. Compounds are screened at 10 μM. The standard reference agent used for this screening test is IC 50 (μM)=0.0022, clorgyline.

[0706] Serotonin receptor (5-HT2B) activity The agonist and antagonist activity of compounds at human 5-HT2B receptors expressed in transfected CHO cells is determined by measuring their effect on IP1 production using homogeneous time-resolved fluorescence (HTRF) detection.

[0707] The screening procedure followed that reported in the literature. 15Thereby, CHO cells were suspended in a buffer containing 10 mM Hepes / NaOH (pH 7.4), 4.2 mM KCl, 146 mM NaCl, 1 mM CaCl, 0.5 mM MgCl, 5.5 mM glucose and 50 mM LiCl, and then plated in a microplate at approximately 2.10 4 Cells are distributed at a density of 100 cells / well and incubated for 30 minutes at 37° C. in the presence of buffer (basal control), test compound, reference agonist or reference antagonist.

[0708] For stimulated control measurements, separate assay wells contain 1 μM 5-HT. For basal control measurements, separate assay wells contain no 5-HT.

[0709] Following incubation, cells are lysed and a fluorescent acceptor (D2-labeled IP1) and a fluorescent donor (anti-IP1 antibody labeled with europium cryptate) are added. After 60 minutes at room temperature, the fluorescence transfer is measured at λex = 337 nm and λem = 620 and 665 nm using a microplate reader (Envision, Perkin Elmer). The IP1 concentration is determined by dividing the signal measured at 665 nm by the signal measured at 620 nm (ratio).

[0710] Agonist results are expressed as percent of the control response to 1 μM 5-HT. Antagonist results are expressed as percent inhibition of the control response to 30 nM 5-HT.

[0711] A standard reference agonist is tested at several concentrations in each experiment, from which its EC 50 Generate a concentration-response curve to calculate the values ​​of 5-HT (serotonin).

[0712] A standard reference antagonist is tested at several concentrations in each experiment, from which its IC 50Generate a concentration-response curve to calculate the values, SB206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole).

[0713] Human potassium channel (HERG) activity HERG potassium channels mediate the delayed rectifier current (I) that underlies cardiac repolarization. Kr ) mediates the activation of HERG. Decreased HERG activity, either due to genetic defects in its pore-forming subunit or adverse drug effects, can prolong the QT interval and lead to the potentially fatal ventricular arrhythmia torsade de pointes. (I) Kr ) has stimulated intensive research interest in its structure-function relationships, the association between LQT-associated mutations and alterations in channel function, and mechanisms of drug action.

[0714] The screening procedure for HERG binding followed that reported in the literature: 16(a)、(b) Thereby, human recombinant potassium channel HERG expressed in human HEK-293 cells is used in modified Tris-HCl buffer at pH 7.4. A 7.5 μg aliquot is diluted to 3 nM [ 3 The channels are incubated with [H]dofetilide for 60 minutes at 25°C. Nonspecific binding is estimated in the presence of 10 µM dofetilide. The channel proteins are filtered and washed, and the filters are then counted to determine the specific bound [ 3 The IC50 of [H] dofetilide is determined. Compounds are screened at 10 μM. The standard reference agent used in this screen is IC50. 50 (nM)=2.5, Ki(nM)=1.7 and nH=1.0.

[0715] DAT / NET / SERT inhibition results The results of the screening tests for DAT, NET, and SERT are presented in the following table as a measure of the compound's affinity for the transporter (shading) and the % inhibition (value) as a percentage displacement of the radioligand by MDMA analog compounds at (10 μM) concentrations at the three monoamine transporters. In addition to the compounds of the present invention, the following known compounds were screened for comparison: MDA = 3,4-methylenedioxyamphetamine; MDDM = 3,4-methylenedioxy-N,N-dimethylamphetamine; MDMA = racemic 3,4-methylenedioxy-N-methylamphetamine; R-MDMA = enantiomerically pure 3,4-methylenedioxy-N-methylamphetamine of absolute configuration Rectus; S-MDMA = enantiomerically pure 3,4-methylenedioxy-N-methylamphetamine of absolute configuration Sinister.

[0716] JPEG2024544586000189.jpg194111 JPEG2024544586000190.jpg28126

[0717] Dose response data for selected compounds of embodiments of the present invention compared to known compounds (MDA = 3,4-methylenedioxyamphetamine; MDDM = 3,4-methylenedioxy-N,N-dimethylamphetamine; MDMA = racemic 3,4-methylenedioxy-N-methylamphetamine; R-MDMA = enantiomerically pure 3,4-methylenedioxy-N-methylamphetamine of absolute configuration Rectus; S-MDMA = enantiomerically pure 3,4-methylenedioxy-N-methylamphetamine of absolute configuration Sinister) are provided in the following table:

[0718] JPEG2024544586000191.jpg167158

[0719] general Each document, reference, patent application, or patent cited in this text is expressly incorporated herein by reference in its entirety, meaning that it should be read and considered by the reader as part of this text. It is for reasons of brevity only that documents, references, patent applications, or patents cited in this text are not repeated in this text.

[0720] It should be recognized that throughout this specification, any reference to any prior publication, including prior patent publications and prior non-patent publications, is not an admission or acknowledgement that any of the material contained in the referenced prior publication was part of the common general knowledge as of the priority date of this application.

[0721] Any manufacturer's instructions, descriptions, product specifications, and product sheets for any product mentioned herein or in any document incorporated by reference herein are incorporated by reference herein and may be used in the practice of this invention.

[0722] The inventions described herein may include one or more ranges of values ​​(e.g., size, displacement, field strength, etc.) A range of values ​​will be understood to include all values ​​within the range, including the values ​​defining the range and values ​​immediately adjacent to the range that achieve the same or substantially the same result as the values ​​defining the boundaries to the range.

[0723] The present invention is not to be limited in scope by any of the specific embodiments described herein. These embodiments are intended for the purpose of illustration only. Functionally equivalent products, formulations, and methods are clearly within the scope of the invention described herein.

[0724] Those skilled in the art will recognize that the invention described herein is susceptible to variations and modifications other than those specifically described. The present invention includes all such variations and modifications. The present invention also includes all of the steps, features, combinations and compounds referred to or shown in the specification, individually or collectively, as well as any and all combinations of said steps or features or any two or more thereof.

[0725] References 1. Zhang Y. et al, Organic & Biomolecular Chemistry, 2021, 19, 5772-5776. 2. Lewis K. A medicinal chemistry investigation of 3,4-Methylenedioxymethamphetamine (MDMA). Doctoral Thesis, University of Western Australia, 2011. 3. Cloonan, SM; Keating, JJ; Butler, SG; Knox, AJS; Jorgensen, AM; Peters, GH; Rai, D.; Corrigan, D.; Lloyd, DG; Williams, DC; Meegan, MJ, Synthesis and serotonin transporter activity of sulphur-substituted α-alkyl phenethylamines as a new class of anticancer agents. Eur. J. Med. Chem. 2009, 44 (12), 4862-4888. 4. Gandy, M. N.; McIldowie, M.; Lewis, K.; Wasik, A. M.; Salomonczyk, D.; Wagg, K.; Millar, Z. A.; Tindiglia, D.; Huot, P.; Johnston, T.; Thiele, S.; Nguyen, B.; Barnes, N. M.; Brotchie, J. M.; Martin-Iverson, M. T.; Nash, J.; Gordon, J.; Piggott, M. J., Redesigning the designer drug ecstasy: non-psychoactive MDMA analogues exhibiting Burkitt's lymphoma cytotoxicity. MedChemComm 2010, 1 (4), 287-293. 5. Gillaspy, M.; Lefker, B. A.; Hada, W. A.; Hoover, D. J., A simple method for the formation of cyclopropylamines: the first synthesis of tricyclopropylamine. Tetrahedron Lett. 1995, 36 (41), 7399-402.

[0726] 6. Li, G.; Zhou, H.; Jiang, Y.; Keim, H.; Topiol, S. W.; Poda, S. B.; Ren, Y.; Chandrasena, G.; Doller, D., Design and synthesis of 4-arylpiperidinyl amide and N-arylpiperidin-3-yl-cyclopropanecarboxamide derivatives as novel melatonin receptor ligands. Bioorg. Med. Chem. Lett. 2011, 21 (4), 1236-1242. 7. Burger, A.; Zimmerman, S. E.; Ariens, E. J., 1-Ethynylphenethylamine. J. Med. Chem. 1966, 9 (4), 469-70. 8. Palmer, M. J.; Kenny, J. A.; Walsgrove, T.; Kawamoto, A. M.; Wills, M., Asymmetric transfer hydrogenation of ketones using amino alcohol and monotosylated diamine derivatives of indane. J. Chem. Soc., Perkin Trans. 1 2002, (3), 416-427. 9. Li, S. W.; Spaziano, V. T.; Burke, W. J., Synthesis of a biochemically important aldehyde, 3,4-dihydroxyphenylacetaldehyde. Bioorg. Chem. 1998, 26 (1), 45-50. 10. Palmer, M. J.; Kenny, J. A.; Walsgrove, T.; Kawamoto, A. M.; Wills, M., Asymmetric transfer hydrogenation of ketones using amino alcohol and monotosylated diamine derivatives of indane. J. Chem. Soc., Perkin Trans. 1 2002, (3), 416-427.

[0727] 11. (a) Shearman, L. P., McReynolds, A. M., Zhou, F. C. and Meyer, J. S. Relationship between [125I]RTI-55-labeled cocaine binding sites and the serotonin transporter in rat placenta. Am. J. Physiol. 275(6 Pt 1): C1621-1629, 1998. (b) Wolf, W. A. and Kuhn, D. M. Role of essential sulfhydryl groups in drug interactions at the neuronal 5-HT transporter. Differences between amphetamines and 5-HT uptake inhibitors. J. Biol. Chem. 267(29): 20820-20825, 1992. 12. (a) Giros, B. and Caron, M. G. Molecular characterization of the dopamine transporter. Trends. Pharmacol. Sci. 14(2): 43-49, 1993. (b) Gu, H., Wal, S. C. and Rudnick, G. Stable expression of biogenic amine transporters reveals differences in inhibitor sensitivity, kinetics and ion dependence. J. Biol. Chem.269(10): 7124-7130, 1994. 13. Galli, A., DeFelice, L. J., Duke, B.-J., Moore, K. R. and Blakely, R. D. Sodium-dependent norepinephrine-induced currents in norepinephrine-transporter-transfected HEK-293 cells blocked by cocaine and antidepressants. J. Exp. Biol. 198(Pt 10): 2197-2212, 1995. 14. (a) Urban P, Andersen JK, Hsu HP and Pompon D. Comparative membrane locations and activities of human monoamine oxidases expressed in yeast. FEBS Lett. 286(1-2): 142-146, 1991. (b) Youdim MB and Finberg JP. New directions in monoamine oxidase A and B selective inhibitors and substrates. Biochem Pharmacol. 41(2): 155-162, 1991. 15. Porter, R.H.P., Benwell, K.R., Lamb, H., Malcolm, C.S., Allen, N.F., Revell, D.F., Adams, D.R. and Sheardown, M.J., Functional characterization of agonists at recombinant human 5-HT2a, 5HT2b and 5-HT2c receptors in CHO-K1 cells, Brit. J. Pharmacol., 128: 13, 1999.

[0728] 16. (a) Huang XP, Mangano T, Hufeisen S, Setola V and Roth BL. Identification of human Ether-a-go-go related gene modulators by three screening platforms in an academic drug-discovery setting. Assay Drug Dev Technol 8(6): 727-742, 2010. (b) Finlayson K, Turnbull L, January CT, Sharkey J, Kelly JS. [ 3 H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen. European Journal of Pharmacology. 430(1): 147-148, 2001. 17. Russell S. J. MDMA Analogues as Lead Compounds for Burkitt’s Lymphoma Drug Discovery. Doctoral Thesis (Part I), University of Western Australia, 2016. 18. Beaufort-Droal, V, et al., Preparation of non-racemic single-stereocentre α-aminonitriles and a study of their fate in Bruylants reactions. Tetrahedron. 62. 11948-11954, 2006.

Claims

1. Formula I, including stereoisomers, individual enantiomers, racemates, non-racemic mixtures, isotopically substituted forms, prodrugs and / or pharmaceutically acceptable salts thereof; 【Chemistry 1】 (In the formula; One or more hydrogen atoms in the compounds of formula I may be replaced by fluorine; R １ is methyl, ethyl, -C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, —C ６－１２ Bicycloalkyl, -C ６－１２ Spirocycloalkyl, -C ３－９ cyclohaloalkyl, —C ６－１２ Bicyclohaloalkyl, —C ６－１２ Spirocyclohaloalkyl, —C ３－９ cycloalkenyl, -C ６－１２ bicycloalkenyl, -C ６－１２ spirocycloalkenyl, -C ３－９ cyclohaloalkenyl, —C ６－１２ bicyclohaloalkenyl, —C ６－１２ spirocyclohaloalkenyl, —C ８－１２ Cycloalkynyl, -C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, -C ８－１２ cyclohaloalkynyl, —C ９－１４ Bicyclohaloalkynyl, —C ９－１４ spirocyclohaloalkynyl, -C ３－９ heterocycloalkyl, —C ６－１２ Heterobicycloalkyl, —C ６－１２ Heterospirocycloalkyl, aryl, heteroaryl, -C １－５ Alkyl-aryl, -C ２－５ alkenyl-aryl, -C ２－５ Alkynyl-aryl, -C １－５ Alkyl-heteroaryl, -C ２－５ alkenyl-heteroaryl, -C ２－５ alkynyl-heteroaryl, —C １－５ haloalkyl-aryl, —C ２－５ haloalkenyl-aryl, —C ２－５ haloalkynyl-aryl, —C １－５ haloalkyl-heteroaryl, —C ２－５ haloalkenyl-heteroaryl, —C ２－５ haloalkynyl-heteroaryl, —C １－８ Alkyl-C(=O)R ａ , -C ２－８ Alkenyl-C(=O)R ａ , -C ２－８ Alkynyl-C(=O)R ａ , -C １－８ Haloalkyl-C(=O)R ａ , -C ２－８ Haloalkenyl-C(=O)R ａ , -C ２－８ Haloalkynyl-C(=O)R ａ , -C １－８ Alkyl-CO ２ R ａ , -C ２－８ Alkenyl-CO ２ R ａ , -C ２－８ Alkynyl-CO ２ R ａ , -C １－８ Haloalkyl-CO ２ R ａ , -C ２－８ Haloalkenyl-CO ２ R ａ , -C ２－８ Haloalkynyl-CO ２ R ａ , -SO ２ R ａ , -C １－８ Alkyl-SO ２ R ａ , -C ２－８ Alkenyl-SO ２ R ａ , -C ２－８ Alkynyl-SO ２ R ａ , -C １－８ Haloalkyl-SO ２ R ａ , -C ２－８ Haloalkenyl-SO ２ R ａ , -C ２－８ Haloalkynyl-SO ２ R ａ , —C(═O)NR ｂ R ｃ , -C １－８ Alkyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkenyl-C(=O)NR ｂ R ｃ , -C １－８ Haloalkyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkenyl-C(=O)NR ｂ R ｃ , -CN, -C １－８ Alkyl-CN, -C ２－８ Alkenyl-CN, -C ２－８ Alkynyl-CN, -C １－８ Haloalkyl-CN, -C ２－８ Haloalkenyl-CN, -C ２－８ Haloalkynyl-CN, -CH ２ -O-R ａ , -C ２－９ Alkyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Haloalkyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -CH ２ -R ａ , -CH ２ -S-R ａ , -C ２－９ Alkyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Haloalkyl-S-R ａ , -C ２－９ Haloalkenyl-S-R ａ , and -C ２－９ Haloalkenyl-S-R ａ selected from the group consisting of: R ２ is H, methyl, ethyl, -C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, —C ６－１２ Bicycloalkyl, -C ６－１２ Spirocycloalkyl, -C ３－９ cyclohaloalkyl, —C ６－１２ Bicyclohaloalkyl, —C ６－１２ Spirocyclohaloalkyl, —C ３－９ cycloalkenyl, -C ６－１２ bicycloalkenyl, -C ６－１２ spirocycloalkenyl, -C ３－９ cyclohaloalkenyl, —C ６－１２ bicyclohaloalkenyl, —C ６－１２ spirocyclohaloalkenyl, —C ８－１２ Cycloalkynyl, -C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, -C ８－１２ cyclohaloalkynyl, —C ９－１４ Bicyclohaloalkynyl, —C ９－１４ spirocyclohaloalkynyl, -C ３－９ heterocycloalkyl, —C ６－１２ Heterobicycloalkyl, —C ６－１２ Heterospirocycloalkyl, aryl, heteroaryl, -C １－５ Alkyl-aryl, -C ２－５ alkenyl-aryl, -C ２－５ Alkynyl-aryl, -C １－５ Alkyl-heteroaryl, -C ２－５ alkenyl-heteroaryl, -C ２－５ alkynyl-heteroaryl, —C １－５ haloalkyl-aryl, —C ２－５ haloalkenyl-aryl, —C ２－５ haloalkynyl-aryl, —C １－５ haloalkyl-heteroaryl, —C ２－５ haloalkenyl-heteroaryl, —C ２－５ haloalkynyl-heteroaryl, —C(═O)R ａ , -C １－８ Alkyl-C(=O)R ａ , -C ２－８ Alkenyl-C(=O)R ａ , -C ２－８ Alkynyl-C(=O)R ａ , -C １－８ Haloalkyl-C(=O)R ａ , -C ２－８ Haloalkenyl-C(=O)R ａ , -C ２－８ Haloalkynyl-C(=O)R ａ , -CO ２ R ａ , -C １－８ Alkyl-CO ２ R ａ , -C ２－８ Alkenyl-CO ２ R ａ , -C ２－８ Alkynyl-CO ２ R ａ , -C １－８ Haloalkyl-CO ２ R ａ , -C ２－８ Haloalkenyl-CO ２ R ａ , -C ２－８ Haloalkynyl-CO ２ R ａ , -SO ２ R ａ , -C １－８ Alkyl-SO ２ R ａ , -C ２－８ Alkenyl-SO ２ R ａ , -C ２－８ Alkynyl-SO ２ R ａ , -C １－８ Haloalkyl-SO ２ R ａ , -C ２－８ Haloalkenyl-SO ２ R ａ , -C ２－８ Haloalkynyl-SO ２ R ａ , —C(═O)NR ｂ R ｃ , -C １－８ Alkyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkenyl-C(=O)NR ｂ R ｃ , -C １－８ Haloalkyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkenyl-C(=O)NR ｂ R ｃ , -CN, -C １－８ Alkyl-CN, -C ２－８ Alkenyl-CN, -C ２－８ Alkynyl-CN, -C １－８ Haloalkyl-CN, -C ２－８ Haloalkenyl-CN, -C ２－８ Haloalkynyl-CN, -CH ２ -O-R ａ , -C ２－９ Alkyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Haloalkyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -CH ２ -R ａ , -CH ２ -S-R ａ , -C ２－９ Alkyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Haloalkyl-S-R ａ , -C ２－９ Haloalkenyl-S-R ａ , and -C ２－９ Haloalkenyl-S-R ａ or selected from the group consisting of: Or, R １ and R ２ together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heterocycloalkenyl ring, or a 6-membered heteroaryl ring, each of which is unsubstituted or ４ Or R ５ may be substituted by one or more groups selected from R ３ CF ３ , cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, vinyl, acetylenyl, cyclohexyl, cyclopentenyl, cyclohexenyl, propargyl, oxetanyl, thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolyl, oxanyl, dioxolanyl, pyridinyl, naphthyl, and phenyl; each of which is unsubstituted or selected from the group consisting of R ４ Or R ５ or R ３ is a 4- to 6-membered fused ring system or a 4- to 6-membered spiro ring system, each of which is a saturated carbocyclic ring system containing zero heteroatoms or a saturated heterocyclic ring system containing one heteroatom selected from O or S, and each of which is unsubstituted or is selected from R ４ Or R ５ may be substituted by one or more groups selected from R ４ and R ５ is independently, at each occurrence, a halogen, —OR ａ , -SR ａ , -NR ｂ R ｃ , methyl, ethyl, -C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, —C ６－１２ Bicycloalkyl, -C ６－１２ Spirocycloalkyl, -C ３－９ cyclohaloalkyl, —C ６－１２ Bicyclohaloalkyl, —C ６－１２ Spirocyclohaloalkyl, —C ３－９ cycloalkenyl, -C ６－１２ bicycloalkenyl, -C ６－１２ spirocycloalkenyl, -C ３－９ cyclohaloalkenyl, —C ６－１２ bicyclohaloalkenyl, —C ６－１２ spirocyclohaloalkenyl, —C ８－１２ Cycloalkynyl, -C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, -C ８－１２ cyclohaloalkynyl, —C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, aryl, heteroaryl, -C １－５ Alkyl-aryl, -C ２－５ alkenyl-aryl, -C ２－５ Alkynyl-aryl, -C １－５ Alkyl-heteroaryl, -C ２－５ alkenyl-heteroaryl, -C ２－５ alkynyl-heteroaryl, —C １－５ haloalkyl-aryl, —C ２－５ haloalkenyl-aryl, —C ２－５ haloalkynyl-aryl, —C １－５ haloalkyl-heteroaryl, —C ２－５ haloalkenyl-heteroaryl, —C ２－５ haloalkynyl-heteroaryl, —C(═O)R ａ , -C １－８ Alkyl-C(=O)R ａ , -C ２－８ Alkenyl-C(=O)R ａ , -C ２－８ Alkynyl-C(=O)R ａ , -C １－８ Haloalkyl-C(=O)R ａ , -C ２－８ Haloalkenyl-C(=O)R ａ , -C ２－８ Haloalkynyl-C(=O)R ａ , -CO ２ R ａ , -C １－８ Alkyl-CO ２ R ａ , -C ２－８ Alkenyl-CO ２ R ａ , -C ２－８ Alkynyl-CO ２ R ａ , -C １－８ Haloalkyl-CO ２ R ａ , -C ２－８ Haloalkenyl-CO ２ R ａ , -C ２－８ Haloalkynyl-CO ２ R ａ , -SO ２ R ａ , -C １－８ Alkyl-SO ２ R ａ , -C ２－８ Alkenyl-SO ２ R ａ , -C ２－８ Alkynyl-SO ２ R ａ , -C １－８ Haloalkyl-SO ２ R ａ , -C ２－８ Haloalkenyl-SO ２ R ａ , -C ２－８ Haloalkynyl-SO ２ R ａ , —C(═O)NR ｂ R ｃ , -C １－８ Alkyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkenyl-C(=O)NR ｂ R ｃ , -C １－８ Haloalkyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkenyl-C(=O)NR ｂ R ｃ , -CN, -C １－８ Alkyl-CN, -C ２－８ Alkenyl-CN, -C ２－８ Alkynyl-CN, -C １－８ Haloalkyl-CN, -C ２－８ Haloalkenyl-CN, -C ２－８ Haloalkynyl-CN, -CH ２ -O-R ａ , -C ２－９ Alkyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Haloalkyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -CH ２ -S-R ａ , -C ２－９ Alkyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Haloalkyl-S-R ａ , -C ２－９ Haloalkenyl-S-R ａ , and -C ２－９ Haloalkenyl-S-R ａ or selected from the group consisting of: Or, where R ４ and / or R ５ are bonded to the same carbon atom, and ４ and / or R ５ two of which together can form a carbonyl group; and R ａ , R ｂ and R ｃ is independently, at each occurrence: H, methyl, ethyl, —C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, aryl, heteroaryl, -C １－５ haloalkyl-aryl, —C ２－５ alkenyl-aryl, -C ２－５ haloalkenyl-aryl, —C ２－５ Alkynyl-aryl, -C ２－５ haloalkynyl-aryl, —C １－５ Alkyl-heteroaryl, -C １－５ haloalkyl-heteroaryl, —C ２－５ alkenyl-heteroaryl, -C ２－５ haloalkenyl-heteroaryl, —C ２－５ Alkynyl-heteroaryl and -C ２－５ haloalkynyl-heteroaryl), wherein the compound of formula I is selected from the group consisting of: 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 (not a compound selected from the group consisting of:

2. R ２ H, methyl, ethyl, propyl, isopropyl, allyl, cyclopropylmethyl, propargyl, butyl, isobutyl, t-butyl, cyclobutyl, -C １－９ Haloalkyl, —C ２－９ Alkyl-O-R ａ , -C ３－９ selected from the group consisting of heterocycloalkyl, cyclopropyl, phenyl, benzyl, and 1-phenylethyl; or R １ and R ２ The compound of claim 1 , wherein together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.

3. R ２ is H or methyl, and R １ Methyl, ethyl, propyl, isopropyl, allyl, cyclopropylmethyl, propargyl, butyl, isobutyl, t-butyl, -CH ２ CF ３ , -C ３ selected from the group consisting of alkyl-OH, oxanyl, cyclopropyl, cyclobutyl, phenyl, benzyl, and 1-phenylethyl; or R １ and R ２ The compound of claim 1 , wherein together form a pyrrolidinyl ring or a morpholinyl ring.

4. R ３ But;CF ３ , cyclopropyl, cyclopropylmethyl, fluorocyclopropyl, 1-fluorocyclopropan-1-yl, cyclobutyl, fluorocyclobutyl, difluorocyclobutyl, 3,3-difluorocyclobutan-1-yl, methylcyclobutyl, dimethylcyclobutyl, 3,3-dimethylcyclobutan-1-yl, cyclopentyl, vinyl, acetylenyl, cyclohexyl, propargyl, thiophen-2-yl, thiophen-3-yl, furan-2-yl, furan-3-yl, triazol-1-yl, triazol-4-yl, thiazol-1-yl, thiazol-2-yl, thiazol-3-yl, thiazol-4-yl, thiazol-1-yl, thiazol-4-yl, thiazol-2-yl, thiazol-3-yl, thiazol-4 ... riazol-5-yl, oxan-4-yl, oxan-3-yl, oxan-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, 1,1'-biphenyl, 1,2'-biphenyl, 1,3'-biphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, o-tolyl, m-tolyl, p-tolyl, naphthalen-1-yl, naphthalen-2-yl, cyclopent-1-en-1-yl, cyclopent-1-en-1-yl cyclopent-1-en-3-yl, cyclopent-1-en-4-yl, cyclopent-1,3-dien-2-yl, cyclopenta-1,3-dien-1-yl, cyclopenta-1,3-dien-5-yl, cyclohex-1-en-1-yl, cyclohex-1-en-3-yl, cyclohex-1-en-5-yl, cyclohexa-1,3-dien-1-yl, cyclohexa-1,3-dien-2-yl, cyclohexa-1,3-dien-5-yl, cyclohexa-1,4-dien-1-yl, cyclohexa-1,4-dien-3-yl, tetrahydro 2-furanyl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, oxazolidin-5-yl, oxazolidin-4-yl, oxazolidin-2-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl, bicyclo[1.1.0]butan-1-yl, tricyclo[1.1.0.0]butan-1-yl, ... ２，４ ]butan-1-yl, bicyclo[1.1.0]butan-2-yl, spiro[2.2]pentan-1-yl, bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-5-yl, bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, bicyclo[1.1.1]pentan-2-yl, bicyclo[1.1.1]pentan-1-yl, spiro[2.3]hexan-4-yl, spiro[2.3]hexan-5-yl, oxetan-2-yl thietan-2-yl, oxetan-3-yl, thietan-3-yl, 2-oxabicyclo[2.1.0]pentan-1-yl, 2-thiabicyclo[2.1.0]pentan-1-yl, 2-oxabicyclo[2.1.0]pentan-5-yl, 2-thiabicyclo[2.1.0]pentan-5-yl, 2-oxabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-4-yl, 2-oxabicyclo[2.1.0]pentan-3-yl, 2-thiabicyclo[2.1.0]pentan-3-yl, 2-thiabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-3-yl, 2-thiabicyclo[2.1.0]pentan-5-yl, 2-oxabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-3 ... Chloro[2.1.0]pentan-3-yl, 2-oxabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-4-yl, oxabicyclo[2.1.0]pentan-5-yl, 2-thiabicyclo[2.1.0]pentan-5-yl, 2-oxabicyclo[2.1.0]pentan-1-yl, 2-thiabicyclo[2.1.0]pentan-1-yl, 2-oxabicyclo[1.1.1]pentan-4-yl, 2-oxabicyclo[1.1.1]pentane- 10. The compound of claim 1, wherein the compound is selected from the group consisting of 2-thiaspiro[2.3]hexan-4-yl, 4-thiaspiro[2.3]hexan-5-yl, 2-thiabicyclo[1.1.1]pentan-4-yl, 2-thiabicyclo[1.1.1]pentan-1-yl, 5-thiaspiro[2.3]hexan-4-yl, 4-thiaspiro[2.3]hexan-5-yl, 4-oxaspiro[2.3]hexan-6-yl, and -4-thiaspiro[2.3]hexan-6-yl.

5. R 3 is CF 3 , cyclopropyl, cyclopropylmethyl, fluorocyclopropyl, 1-fluorocyclopropan-1-yl, cyclobutyl, fluorocyclobutyl, difluorocyclobutyl, 3,3-difluorocyclobutan-1-yl, methylcyclobutyl, dimethylcyclobutyl, 3,3-dimethylcyclobutan-1-yl, cyclopentyl, vinyl, acetylenyl, cyclohexyl, propargyl, thiophen-2-yl, thiophen-3-yl, furan-2-yl, furan-3-yl, triazol-1-yl, triazol-4-yl, thiazol-1-yl, thiazol-2-yl, thiazol-3-yl, thiazol-4-yl, thiazol-1 ... riazol-5-yl, oxan-4-yl, oxan-3-yl, oxan-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, 1,1'-biphenyl, 1,2'-biphenyl, 1,3'-biphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, o-tolyl, m-tolyl, p-tolyl, naphthalen-1-yl, naphthalen-2-yl, cyclopent-1-en-1-yl, cyclopent-1-en-1-yl cyclopent-1-en-3-yl, cyclopent-1-en-4-yl, cyclopent-1,3-dien-2-yl, cyclopenta-1,3-dien-1-yl, cyclopenta-1,3-dien-5-yl, cyclohex-1-en-1-yl, cyclohex-1-en-3-yl, cyclohex-1-en-5-yl, cyclohexa-1,3-dien-1-yl, cyclohexa-1,3-dien-2-yl, cyclohexa-1,3-dien-5-yl, cyclohexa-1,4-dien-1-yl, cyclohexa-1,4-dien-3-yl, tetrahydro 2-furanyl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, oxazolidin-5-yl, oxazolidin-4-yl, oxazolidin-2-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl, bicyclo[1.1.0]butan-1-yl, tricyclo[1.1.0.0 2,4 ]butan-1-yl, bicyclo[1.1.0]butan-2-yl, spiro[2.2]pentan-1-yl, bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-5-yl, bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, bicyclo[1.1.1]pentan-2-yl, bicyclo[1.1.1]pentan-1-yl, spiro[2.3]hexan-4-yl, spiro[2.3]hexan-5-yl, oxetan-2-yl thietan-2-yl, oxetan-3-yl, thietan-3-yl, 2-oxabicyclo[2.1.0]pentan-1-yl, 2-thiabicyclo[2.1.0]pentan-1-yl, 2-oxabicyclo[2.1.0]pentan-5-yl, 2-thiabicyclo[2.1.0]pentan-5-yl, 2-oxabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-4-yl, 2-oxabicyclo[2.1.0]pentan-3-yl, 2-thiabicyclo[2.1.0]pentan-3-yl, 2-thiabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-3-yl, 2-thiabicyclo[2.1.0]pentan-5-yl, 2-oxabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-3 ... Chloro[2.1.0]pentan-3-yl, 2-oxabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-4-yl, oxabicyclo[2.1.0]pentan-5-yl, 2-thiabicyclo[2.1.0]pentan-5-yl, 2-oxabicyclo[2.1.0]pentan-1-yl, 2-thiabicyclo[2.1.0]pentan-1-yl, 2-oxabicyclo[1.1.1]pentan-4-yl, 2-oxabicyclo[1.1.1]pentane- The compound of claim 2, wherein the compound is selected from the group consisting of 2-thiaspiro[2.3]hexan-4-yl, 4-thiaspiro[2.3]hexan-5-yl, 2-thiabicyclo[1.1.1]pentan-4-yl, 2-thiabicyclo[1.1.1]pentan-1-yl, 5-thiaspiro[2.3]hexan-4-yl, 4-thiaspiro[2.3]hexan-5-yl, 4-oxaspiro[2.3]hexan-6-yl, and 4-thiaspiro[2.3]hexan-6-yl.

6. R 3 is CF 3 , cyclopropyl, cyclopropylmethyl, fluorocyclopropyl, 1-fluorocyclopropan-1-yl, cyclobutyl, fluorocyclobutyl, difluorocyclobutyl, 3,3-difluorocyclobutan-1-yl, methylcyclobutyl, dimethylcyclobutyl, 3,3-dimethylcyclobutan-1-yl, cyclopentyl, vinyl, acetylenyl, cyclohexyl, propargyl, thiophen-2-yl, thiophen-3-yl, furan-2-yl, furan-3-yl, triazol-1-yl, triazol-4-yl, thiazol-1-yl, thiazol-2-yl, thiazol-3-yl, thiazol-4-yl, thiazol-1 ... riazol-5-yl, oxan-4-yl, oxan-3-yl, oxan-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, 1,1'-biphenyl, 1,2'-biphenyl, 1,3'-biphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, o-tolyl, m-tolyl, p-tolyl, naphthalen-1-yl, naphthalen-2-yl, cyclopent-1-en-1-yl, cyclopent-1-en-1-yl cyclopent-1-en-3-yl, cyclopent-1-en-4-yl, cyclopent-1,3-dien-2-yl, cyclopenta-1,3-dien-1-yl, cyclopenta-1,3-dien-5-yl, cyclohex-1-en-1-yl, cyclohex-1-en-3-yl, cyclohex-1-en-5-yl, cyclohexa-1,3-dien-1-yl, cyclohexa-1,3-dien-2-yl, cyclohexa-1,3-dien-5-yl, cyclohexa-1,4-dien-1-yl, cyclohexa-1,4-dien-3-yl, tetrahydro 2-furanyl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, oxazolidin-5-yl, oxazolidin-4-yl, oxazolidin-2-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl, bicyclo[1.1.0]butan-1-yl, tricyclo[1.1.0.0 2,4 ]butan-1-yl, bicyclo[1.1.0]butan-2-yl, spiro[2.2]pentan-1-yl, bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-5-yl, bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, bicyclo[1.1.1]pentan-2-yl, bicyclo[1.1.1]pentan-1-yl, spiro[2.3]hexan-4-yl, spiro[2.3]hexan-5-yl, oxetan-2-yl thietan-2-yl, oxetan-3-yl, thietan-3-yl, 2-oxabicyclo[2.1.0]pentan-1-yl, 2-thiabicyclo[2.1.0]pentan-1-yl, 2-oxabicyclo[2.1.0]pentan-5-yl, 2-thiabicyclo[2.1.0]pentan-5-yl, 2-oxabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-4-yl, 2-oxabicyclo[2.1.0]pentan-3-yl, 2-thiabicyclo[2.1.0]pentan-3-yl, 2-thiabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-3-yl, 2-thiabicyclo[2.1.0]pentan-5-yl, 2-oxabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-3 ... Chloro[2.1.0]pentan-3-yl, 2-oxabicyclo[2.1.0]pentan-4-yl, 2-thiabicyclo[2.1.0]pentan-4-yl, oxabicyclo[2.1.0]pentan-5-yl, 2-thiabicyclo[2.1.0]pentan-5-yl, 2-oxabicyclo[2.1.0]pentan-1-yl, 2-thiabicyclo[2.1.0]pentan-1-yl, 2-oxabicyclo[1.1.1]pentan-4-yl, 2-oxabicyclo[1.1.1]pentane- The compound of claim 3, wherein the compound is selected from the group consisting of 2-thiaspiro[2.3]hexan-4-yl, 4-thiaspiro[2.3]hexan-5-yl, 2-thiabicyclo[1.1.1]pentan-4-yl, 2-thiabicyclo[1.1.1]pentan-1-yl, 5-thiaspiro[2.3]hexan-4-yl, 4-thiaspiro[2.3]hexan-5-yl, 4-oxaspiro[2.3]hexan-6-yl, and 4-thiaspiro[2.3]hexan-6-yl. 【Request Item 7】 【Chemistry 5】 【Transformation 6】 A compound selected from the group consisting of:

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7.

9. 8. A composition comprising a compound according to any one of claims 1 to 7 and one or more pharmaceutically acceptable carrier(s) and / or diluent(s) and / or excipient(s).

10. Formula II, including stereoisomers, individual enantiomers, racemates, non-racemic mixtures, isotopically substituted forms, prodrugs and / or pharmaceutically acceptable salts thereof; 【Transformation 7】 (In the formula; One or more hydrogen atoms in the compound of formula II may be replaced by fluorine; R １ and R ２ are independently H, methyl, ethyl, —C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, —C ６－１２ Bicycloalkyl, -C ６－１２ Spirocycloalkyl, -C ３－９ cyclohaloalkyl, —C ６－１２ Bicyclohaloalkyl, —C ６－１２ Spirocyclohaloalkyl, —C ３－９ cycloalkenyl, -C ６－１２ bicycloalkenyl, -C ６－１２ spirocycloalkenyl, -C ３－９ cyclohaloalkenyl, —C ６－１２ bicyclohaloalkenyl, —C ６－１２ spirocyclohaloalkenyl, —C ８－１２ Cycloalkynyl, -C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, -C ８－１２ cyclohaloalkynyl, —C ９－１４ Bicyclohaloalkynyl, —C ９－１４ spirocyclohaloalkynyl, -C ３－９ heterocycloalkyl, —C ６－１２ Heterobicycloalkyl, —C ６－１２ Heterospirocycloalkyl, aryl, heteroaryl, -C １－５ Alkyl-aryl, -C ２－５ alkenyl-aryl, -C ２－５ Alkynyl-aryl, -C １－５ Alkyl-heteroaryl, -C ２－５ alkenyl-heteroaryl, -C ２－５ alkynyl-heteroaryl, —C １－５ haloalkyl-aryl, —C ２－５ haloalkenyl-aryl, —C ２－５ haloalkynyl-aryl, —C １－５ haloalkyl-heteroaryl, —C ２－５ haloalkenyl-heteroaryl, —C ２－５ haloalkynyl-heteroaryl, —C(═O)R ａ , -C １－８ Alkyl-C(=O)R ａ , -C ２－８ Alkenyl-C(=O)R ａ , -C ２－８ Alkynyl-C(=O)R ａ , -C １－８ Haloalkyl-C(=O)R ａ , -C ２－８ Haloalkenyl-C(=O)R ａ , -C ２－８ Haloalkynyl-C(=O)R ａ , -CO ２ R ａ , -C １－８ Alkyl-CO ２ R ａ , -C ２－８ Alkenyl-CO ２ R ａ , -C ２－８ Alkynyl-CO ２ R ａ , -C １－８ Haloalkyl-CO ２ R ａ , -C ２－８ Haloalkenyl-CO ２ R ａ , -C ２－８ Haloalkynyl-CO ２ R ａ , -SO ２ R ａ , -C １－８ Alkyl-SO ２ R ａ , -C ２－８ Alkenyl-SO ２ R ａ , -C ２－８ Alkynyl-SO ２ R ａ , -C １－８ Haloalkyl-SO ２ R ａ , -C ２－８ Haloalkenyl-SO ２ R ａ , -C ２－８ Haloalkynyl-SO ２ R ａ , —C(═O)NR ｂ R ｃ , -C １－８ Alkyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkenyl-C(=O)NR ｂ R ｃ , -C １－８ Haloalkyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkenyl-C(=O)NR ｂ R ｃ , -CN, -C １－８ Alkyl-CN, -C ２－８ Alkenyl-CN, -C ２－８ Alkynyl-CN, -C １－８ Haloalkyl-CN, -C ２－８ Haloalkenyl-CN, -C ２－８ Haloalkynyl-CN, -CH ２ -O-R ａ , -C ２－９ Alkyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Haloalkyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -CH ２ -R ａ , -CH ２ -S-R ａ , -C ２－９ Alkyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Haloalkyl-S-R ａ , -C ２－９ Haloalkenyl-S-R ａ , and -C ２－９ Haloalkenyl-S-R ａ selected from the group consisting of: Here, R １ and R ２ may together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heterocycloalkenyl ring, or a 6-membered heteroaryl ring, each of which is unsubstituted or ４ Or R ５ may be substituted by one or more groups selected from R ３ CF ３ , CN, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, vinyl, allyl, acetylenyl, cyclohexyl, cyclopentenyl, cyclohexenyl, propargyl, cyanomethyl, oxetanyl, thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolyl, oxanyl, dioxolanyl, pyridinyl, naphthyl, and phenyl; each of which is unsubstituted or selected from the group consisting of R ４ Or R ５ or R ３ is a 4- to 6-membered fused ring system or a 4- to 6-membered spiro ring system, each of which is a saturated carbocyclic ring system containing zero heteroatoms or a saturated heterocyclic ring system containing one heteroatom selected from O or S, and each of which is unsubstituted or is selected from R ４ Or R ５ may be substituted by one or more groups selected from R ４ and R ５ is independently, at each occurrence, a halogen, —OR ａ , -SR ａ , -NR ｂ R ｃ , methyl, ethyl, -C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, —C ６－１２ Bicycloalkyl, -C ６－１２ Spirocycloalkyl, -C ３－９ cyclohaloalkyl, —C ６－１２ Bicyclohaloalkyl, —C ６－１２ Spirocyclohaloalkyl, —C ３－９ cycloalkenyl, -C ６－１２ bicycloalkenyl, -C ６－１２ spirocycloalkenyl, -C ３－９ cyclohaloalkenyl, —C ６－１２ bicyclohaloalkenyl, —C ６－１２ spirocyclohaloalkenyl, —C ８－１２ Cycloalkynyl, -C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, -C ８－１２ cyclohaloalkynyl, —C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, aryl, heteroaryl, -C １－５ Alkyl-aryl, -C ２－５ alkenyl-aryl, -C ２－５ Alkynyl-aryl, -C １－５ Alkyl-heteroaryl, -C ２－５ alkenyl-heteroaryl, -C ２－５ alkynyl-heteroaryl, —C １－５ haloalkyl-aryl, —C ２－５ haloalkenyl-aryl, —C ２－５ haloalkynyl-aryl, —C １－５ haloalkyl-heteroaryl, —C ２－５ haloalkenyl-heteroaryl, —C ２－５ haloalkynyl-heteroaryl, —C(═O)R ａ , -C １－８ Alkyl-C(=O)R ａ , -C ２－８ Alkenyl-C(=O)R ａ , -C ２－８ Alkynyl-C(=O)R ａ , -C １－８ Haloalkyl-C(=O)R ａ , -C ２－８ Haloalkenyl-C(=O)R ａ , -C ２－８ Haloalkynyl-C(=O)R ａ , -CO ２ R ａ , -C １－８ Alkyl-CO ２ R ａ , -C ２－８ Alkenyl-CO ２ R ａ , -C ２－８ Alkynyl-CO ２ R ａ , -C １－８ Haloalkyl-CO ２ R ａ , -C ２－８ Haloalkenyl-CO ２ R ａ , -C ２－８ Haloalkynyl-CO ２ R ａ , -SO ２ R ａ , -C １－８ Alkyl-SO ２ R ａ , -C ２－８ Alkenyl-SO ２ R ａ , -C ２－８ Alkynyl-SO ２ R ａ , -C １－８ Haloalkyl-SO ２ R ａ , -C ２－８ Haloalkenyl-SO ２ R ａ , -C ２－８ Haloalkynyl-SO ２ R ａ , —C(═O)NR ｂ R ｃ , -C １－８ Alkyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkenyl-C(=O)NR ｂ R ｃ , -C １－８ Haloalkyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkenyl-C(=O)NR ｂ R ｃ , -CN, -C １－８ Alkyl-CN, -C ２－８ Alkenyl-CN, -C ２－８ Alkynyl-CN, -C １－８ Haloalkyl-CN, -C ２－８ Haloalkenyl-CN, -C ２－８ Haloalkynyl-CN, -CH ２ -O-R ａ , -C ２－９ Alkyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Haloalkyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -CH ２ -S-R ａ , -C ２－９ Alkyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Haloalkyl-S-R ａ , -C ２－９ Haloalkenyl-S-R ａ , and -C ２－９ Haloalkenyl-S-R ａ or selected from the group consisting of: Or, where R ４ and / or R ５ are bonded to the same carbon atom, and ４ and / or R ５ two of which together can form a carbonyl group; and R ａ , R ｂ and R ｃ is independently, at each occurrence: H, methyl, ethyl, —C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, aryl, heteroaryl, -C １－５ Alkyl-aryl, -C １－５ haloalkyl-aryl, —C ２－５ alkenyl-aryl, -C ２－５ haloalkenyl-aryl, —C ２－５ Alkynyl-aryl, -C ２－５ haloalkynyl-aryl, —C １－５ Alkyl-heteroaryl, -C １－５ haloalkyl-heteroaryl, —C ２－５ alkenyl-heteroaryl, -C ２－５ haloalkenyl-heteroaryl, —C ２－５ Alkynyl-heteroaryl and -C ２－５ haloalkynyl-heteroaryl) compounds, wherein The compound of formula II is 【Transformation 8】 (which is not a compound selected from the group consisting of: Use for the manufacture of a medicament for the treatment or prevention of a disease, disorder, injury or trauma; wherein the disease, disorder, injury or trauma is: (i) serotonin transporter (SERT) activity; and / or (ii) dopamine transporter (DAT) activity; and / or (iii) norepinephrine transporter (NET) activity; and / or (iv) serotonin receptor (5-HT2B) activity in response to regulation of; Preferably, wherein the disease, disorder, injury or trauma is a disease, disorder, injury or trauma associated with the central nervous system; Most preferably herein, the disease, disorder, injury or trauma associated with the central nervous system is; dementia in Alzheimer's disease (including early-onset, late-onset, atypical, mixed, or unspecified), vascular dementia (including arteriosclerotic, acute-onset, multi-infarct, subcortical, mixed cortical, or unspecified), dementia in Pick's disease, dementia in Creutzfeldt-Jakob disease, dementia in Huntington's disease, dementia in Parkinson's disease, dementia in human immunodeficiency virus [HIV] disease, dementia in cerebral lipidosis, dementia in epilepsy, dementia in hepatolenticular degeneration, dementia in hypercalcemia, dementia in hypothyroidism, dementia in intoxication, dementia in Lewy body disease, dementia in multiple sclerosis, dementia in neurosyphilis, dementia in niacin deficiency, dementia in polyarteritis nodosa, dementia in systemic lupus erythematosus, dementia in trypanosomiasis, dementia due to uremia, dementia in vitamin B １２ Dementia in deficiency disorders, unspecified dementia (including dementia not otherwise specified, psychosis not otherwise specified, geriatric, delirium, depression, paranoia, or acute confusional state), organic amnesic syndrome, Korsakoff psychosis, Korsakoff syndrome, delirium, cerebral syndrome, confusional state, infectious psychosis, organic reaction, psychoorganic syndrome, organic hallucinosis, organic catatonic disorder, organic delusional [schizophreniform] disorder, organic mood [affective] disorder, organic anxiety disorder, organic confusional state Dissociative disorder, organic affective [apathetic] disorder, mild cognitive impairment, epileptic psychosis, brain syndrome not otherwise specified, mental disorder not otherwise specified, organic personality disorder, pseudopsychotic personality disorder, pseudodevelopmental personality disorder, frontal lobe syndrome, limbic epileptic personality syndrome, lobotomy syndrome, post-leukotomy syndrome, post-encephalitic syndrome, post-concussion syndrome, post-contusion syndrome (encephalopathy), post-traumatic brain syndrome, non-psychotic , right hemisphere organic affective disorders, organic mental syndromes, mental and behavioral disorders due to alcohol use, mental and behavioral disorders due to opioid use, mental and behavioral disorders due to cannabinoid use, mental and behavioral disorders due to sedative or hypnotic use, mental and behavioral disorders due to cocaine use, mental and behavioral disorders due to caffeine-containing stimulant use, mental and behavioral disorders due to hallucinogen use, mental and behavioral disorders due to tobacco use, mental and behavioral disorders due to volatile solvent use, mental and behavioral disorders due to use of other psychoactive substances (including any combination of psychoactive substances), schizophrenia, paranoid schizophrenia, paranoid schizophrenia, deuteranopia, deuteranopia, disorganized schizophrenia, catatonic schizophrenia, catatonic stupor, schizophrenic catalepsy, schizophrenic catatonia, schizophrenic flexibilitas cerea cerea), undifferentiated schizophrenia, atypical schizophrenia, post-schizophrenic depression, residual schizophrenia, chronic undifferentiated schizophrenia, schizophrenic restzustand, simple schizophrenia, somatosensory schizophrenia, schizophreniform disorder, schizophreniform psychosis, schizophrenia not otherwise specified, schizophrenic disorder, subclinical schizophrenia reaction, borderline schizophrenia, subclinical schizophrenia, prepsychotic schizophrenia, prodromal schizophrenia, pseudoneurotic schizophrenia,Pseudopsychotic schizophrenia, Schizophreniform personality disorder, Persistent delusional disorder, Delusional disorder, Paranoia, Paranoid psychosis, Paranoid state, Paraphrenia (late stage), Sensitive Beziehungswahn, Paranoid body dysmorphic disorder, Recurrent delusional state, Paranoia querulans, Acute and transient psychotic disorder, Acute polymorphic psychotic disorder without schizophrenic symptoms, Acute polymorphic psychotic disorder with schizophrenic symptoms, Buffet d'Elirante delirante), cycloid psychosis, acute schizophreniform psychotic disorder, acute (undifferentiated) schizophrenia, brief schizophreniform disorder, brief schizophreniform psychosis, dreamlike psychosis, schizophrenic reaction, delusional reaction, psychogenic delusional psychosis, acute transient psychotic disorder, induced delusional disorder, folie à deux deux), induced delusional disorder, induced psychotic disorder, schizoaffective disorder (including manic, depressive, mixed and unspecified), non-organic psychotic disorder, chronic hallucinatory psychosis, manic episode disorder, bipolar disorder, single manic episode disorder, hypomania, mania without psychotic symptoms, mania with psychotic symptoms, mania with mood-concordant psychotic symptoms, manic stupor, mania not otherwise specified, bipolar affective disorder, manic depression, manic-depressive illness, manic-depressive psychosis, manic-depressive reaction, bipolar II disorder, depression, psychogenic depression, reactive depression, mild depression, moderate depression, severe depression, agitated depression, major depression, vital depression, atypical depression, unipolar depression, depressive disorder not otherwise specified, recurrent depressive disorder, seasonal depressive disorder, cyclothymia, affective personality disorder, cycloid personality, cyclothymic personality, dysthymia, depressive neurosis, depressive personality disorder, neurotic depression, persistent anxiety depression, phobic anxiety disorder, agoraphobia, panic disorder, social phobia, social phobia, social neurosis, fear of heights, phobia of animals, claustrophobia, simple phobia, phobic state not otherwise specified, episodic paroxysmal anxiety, generalized anxiety disorder, anxiety hysteria, anxiety not otherwise specified, obsessive-compulsive disorder,Anankastic neurosis, obsessive-compulsive neurosis, primarily obsessive thinking or rumination, primarily compulsive behavior [compulsive rituals], acute stress reaction, acute crisis reaction, acute reaction to stress, combat fatigue, crisis state, mental shock, post-traumatic stress disorder (PTSD), traumatic neurosis, adjustment disorder Harm, culture shock, grief reaction, pediatric hospitalization, dissociative conversion disorder, conversion hysteria, conversion reaction, dissociative amnesia, dissociative fugue, dissociative stupor, trance disorder, possession disorder, dissociative movement disorder, psychogenic aphonia, psychogenic dysphonia, dissociative convulsions, dissociative anesthesia, dissociative sensory loss, Gansser syndrome, multiple personality dissociative disorder, psychogenic confusion, psychogenic twilight state, somatoform disorder, somatization disorder, charcoal briquet disorder, multiple Psychosomatic disorder, undifferentiated somatoform disorder, undifferentiated psychosomatic disorder, hypochondriacal disorder, body dysmorphic disorder, dysmorphophobia (non-delusional), hypochondriacal neurosis, hypochondriasis, illness phobia, somatoform autonomic nervous disorder, cardiac neurosis, dako Sta syndrome, gastric neuropathy, neurocirculatory asthenia, psychogenic aspiration, psychogenic cough, psychogenic diarrhea, psychogenic dyspepsia, psychogenic urinary disorder, psychogenic flatulence, psychogenic hiccups, psychogenic hyperventilation, psychogenic increased urinary frequency, psychogenic hyperventilation Irritable bowel syndrome, psychogenic pyloric spasm, persistent somatoform pain disorder, psychiatric pain, psychogenic low back pain, psychogenic headache, somatoform pain disorder, psychogenic dysmenorrhea, psychogenic dysphagia, globus hysterica, psychogenic pruritus, psychogenic torticollis, psychogenic bruxism, psychosomatic disorder not otherwise specified, neurasthenia, fatigue syndrome, depersonalization-derealization syndrome, Dhat syndrome, occupational neurosis, writer's cramp cramp neurosis, psychasthenia, psychasthenic neurosis, psychogenic syncope, neurosis not otherwise specified, eating disorders, anorexia nervosa, atypical anorexia nervosa, bulimia nervosa, bulimia not otherwise specified, bulimia nervosa, atypical bulimia nervosa, binge eating associated with other psychological disturbances, psychogenic binge eating, vomiting associated with other psychological disturbances, psychogenic vomiting, pica, psychogenic anorexia, non-organic sleep disorders, non-organic insomnia, non-organic hypersomnia, non-organic disorders of sleep-wake schedules, psychogenic inversion of circadian rhythm, psychogenic inversion of noctohemeral rhythm, psychogenic inversion of sleep rhythm, sleepwalkingNight terrors, nightmares, dream anxiety disorder, emotional sleep disorder not otherwise specified, sexual dysfunction not caused by organic disorder or disease, absence or loss of sexual desire, frigidity, hypoactive sexual desire disorder, sexual aversion, lack of sexual enjoyment, sexual anhedonia, genital response dysfunction, female sexual arousal disorder, male erectile dysfunction, psychogenic impotence, orgasmic dysfunction, orgasmic inhibition, psychogenic abnormal orgasm, premature ejaculation, psychogenic vaginismus, non-organic dyspareunia, psychogenic dyspareunia, nymphomania, satyriasis, sexual dysfunction not otherwise specified, childbirth postpartum depression, postpartum depression, postpartum psychosis, postpartum psychosis, psychological and behavioral factors related to physical disability or illness (including but not limited to asthma, dermatitis, gastric ulcer, irritable bowel syndrome, ulcerative colitis, and urticaria), non-addictive substance abuse (including but not limited to antacids, herbal medicines, folk remedies, steroids, hormones, vitamins, and laxatives), psychogenic physiological dysfunction not otherwise specified, paranoid personality disorder, expansive paranoid personality disorder, fanatic paranoid personality disorder, litigious paranoid personality disorder, sensitive Paranoid personality disorder, schizoid personality disorder, antisocial personality disorder, amoral personality disorder, antisocial personality disorder, asocial personality disorder, psychotic personality disorder, sociopathic personality disorder, emotionally unstable personality disorder, aggressive personality disorder, borderline personality disorder, explosive personality disorder, histrionic personality disorder, hysterical personality disorder , psychoinfantile personality disorder, ananarchic personality disorder, obsessive-compulsive personality disorder, obsessive-compulsive personality disorder, anxious [avoidant] personality disorder, dependent personality disorder, helpless personality disorder, inappropriate personality disorder, passivity personality disorder, self-destructive personality disorder, eccentric personality disorder, Hart-Trouss personality disorder,Immature personality disorder, narcissistic personality disorder, passive-aggressive personality disorder, psychoneurotic personality disorder, personality neurosis not otherwise specified, pathological personality not otherwise specified, mixed personality disorder, personality and behavioral disorders due to brain disease, personality and behavioral disorders due to brain injury, personality and behavioral disorders due to brain dysfunction, permanent personality changes after catastrophic experiences (including, but not limited to, experiences in a concentration camp, disaster, prolonged incarceration with imminent risk of death, prolonged exposure to life-threatening situations such as being a victim of terrorism, or prolonged torture), mental Permanent personality change after illness, Chronic pain personality syndrome, Unspecified permanent personality change, Addiction disorders, Impulse disorders, Pathological gambling, Compulsive gambling, Pathological arson [pyromania], Pathological kleptomania [kleptomania], Trichotillomania, Intermittent explosive disorder, Gender identity disorder, Transsexualism, Androgyne transvestism, Gender role disorder, Sexual preference disorder, Fetishism, Fetishistic transvestism, Exhibitionism, Voyeurism, Pedophilia, Sadomasochism, Touchophilia, Necrophilia, Sexual deviance not otherwise specified, Sexual maturation disorder, Ego heterosexual orientation, Sexual relationship disorder, Psychosexual development disorder, Elaboration of physical symptoms for psychological reasons, Compensatory neurosis, Intentional production or fetishization of symptoms or disorders, whether physical or psychological Factitious Disorder, Hospital Hopping Syndrome, Munchausen Syndrome, Inveterate Patient, Personality Disorder Not Otherwise Specified, Interpersonal Disorder Not Otherwise Specified, Hyperactivity Disorder, Activity and Attention Disorder, Attention Deficit Disorder with Hyperactivity, Attention Deficit Hyperactivity Disorder, Attention Deficit Syndrome with Hyperactivity, Hyperactivity Conduct Disorder, Hyperactivity Syndrome Not Otherwise Specified, Conduct Disorder, Desocialized Conduct Disorder, Socialized Conduct Disorder, Oppositional Defiant Disorder, Depressive Conduct Disorder, Separation Anxiety Disorder, Sibling Rivalry Disorder, Hyperanxiety Disorder, Childhood Affective Disorder Not Otherwise Specified, Selective Mutism, Selective Mutism, Reactive Attachment Disorder, Disinhibited Attachment Disorder, Attachment psychiatric disorders without hyperactivity, institutionalization syndrome, impairment of childhood social functioning, tic disorder, transient tic disorder, chronic motor tic disorder, chronic vocal tic disorder, complex vocal and multiple motor tic disorder [de la Tourette], Tourette's syndrome, non-organic nocturnal enuresis, functional nocturnal enuresis, psychogenic nocturnal enuresis, urinary incontinence of non-organic causes, non-organic enuresis, functional enuresis, fecal incontinence of non-organic causes, psychogenic enuresis, feeding disorders of infancy and childhood, rumination disorder of infancy, stereotypic movement disorder, stuttering, noise, attention deficit disorder without hyperactivity, excessive masturbation, nail biting, nose picking, thumb sucking, and psychiatric disorders not otherwise specified.

11. The compound is: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 The use of claim 10, selected from the group consisting of:

12. A pharmaceutical composition for treating or preventing a disease, disorder, injury, or trauma comprising a compound of Formula II, including stereoisomers, individual enantiomers, racemates, non-racemic mixtures, isotopically substituted forms, prodrugs, and / or pharmaceutically acceptable salts thereof: 【Chemistry 13】 (In the formula; One or more hydrogen atoms in the compound of formula II may be replaced by fluorine; R １ and R ２ are independently H, methyl, ethyl, —C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, —C ６－１２ Bicycloalkyl, -C ６－１２ Spirocycloalkyl, -C ３－９ cyclohaloalkyl, —C ６－１２ Bicyclohaloalkyl, —C ６－１２ Spirocyclohaloalkyl, —C ３－９ cycloalkenyl, -C ６－１２ bicycloalkenyl, -C ６－１２ spirocycloalkenyl, -C ３－９ cyclohaloalkenyl, —C ６－１２ bicyclohaloalkenyl, —C ６－１２ spirocyclohaloalkenyl, —C ８－１２ Cycloalkynyl, -C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, -C ８－１２ cyclohaloalkynyl, —C ９－１４ Bicyclohaloalkynyl, —C ９－１４ spirocyclohaloalkynyl, -C ３－９ heterocycloalkyl, —C ６－１２ Heterobicycloalkyl, —C ６－１２ Heterospirocycloalkyl, aryl, heteroaryl, -C １－５ Alkyl-aryl, -C ２－５ alkenyl-aryl, -C ２－５ Alkynyl-aryl, -C １－５ Alkyl-heteroaryl, -C ２－５ alkenyl-heteroaryl, -C ２－５ alkynyl-heteroaryl, —C １－５ haloalkyl-aryl, —C ２－５ haloalkenyl-aryl, —C ２－５ haloalkynyl-aryl, —C １－５ haloalkyl-heteroaryl, —C ２－５ haloalkenyl-heteroaryl, —C ２－５ haloalkynyl-heteroaryl, —C(═O)R ａ , -C １－８ Alkyl-C(=O)R ａ , -C ２－８ Alkenyl-C(=O)R ａ , -C ２－８ Alkynyl-C(=O)R ａ , -C １－８ Haloalkyl-C(=O)R ａ , -C ２－８ Haloalkenyl-C(=O)R ａ , -C ２－８ Haloalkynyl-C(=O)R ａ , -CO ２ R ａ , -C １－８ Alkyl-CO ２ R ａ , -C ２－８ Alkenyl-CO ２ R ａ , -C ２－８ Alkynyl-CO ２ R ａ , -C １－８ Haloalkyl-CO ２ R ａ , -C ２－８ Haloalkenyl-CO ２ R ａ , -C ２－８ Haloalkynyl-CO ２ R ａ , -SO ２ R ａ , -C １－８ Alkyl-SO ２ R ａ , -C ２－８ Alkenyl-SO ２ R ａ , -C ２－８ Alkynyl-SO ２ R ａ , -C １－８ Haloalkyl-SO ２ R ａ , -C ２－８ Haloalkenyl-SO ２ R ａ , -C ２－８ Haloalkynyl-SO ２ R ａ , —C(═O)NR ｂ R ｃ , -C １－８ Alkyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkenyl-C(=O)NR ｂ R ｃ , -C １－８ Haloalkyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkenyl-C(=O)NR ｂ R ｃ , -CN, -C １－８ Alkyl-CN, -C ２－８ Alkenyl-CN, -C ２－８ Alkynyl-CN, -C １－８ Haloalkyl-CN, -C ２－８ Haloalkenyl-CN, -C ２－８ Haloalkynyl-CN, -CH ２ -O-R ａ , -C ２－９ Alkyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Haloalkyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -CH ２ -R ａ , -CH ２ -S-R ａ , -C ２－９ Alkyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Haloalkyl-S-R ａ , -C ２－９ Haloalkenyl-S-R ａ , and -C ２－９ Haloalkenyl-S-R ａ selected from the group consisting of: Here, R １ and R ２ may together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heterocycloalkenyl ring, or a 6-membered heteroaryl ring, each of which is unsubstituted or ４ Or R ５ may be substituted by one or more groups selected from R ３ CF ３ , CN, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, vinyl, allyl, acetylenyl, cyclohexyl, cyclopentenyl, cyclohexenyl, propargyl, cyanomethyl, oxetanyl, thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolyl, oxanyl, dioxolanyl, pyridinyl, naphthyl, and phenyl; each of which is unsubstituted or selected from the group consisting of R ４ Or R ５ or R ３ is a 4- to 6-membered fused ring system or a 4- to 6-membered spiro ring system, each of which is a saturated carbocyclic ring system containing zero heteroatoms or a saturated heterocyclic ring system containing one heteroatom selected from O or S, and each of which is unsubstituted or is selected from R ４ Or R ５ may be substituted by one or more groups selected from R ４ and R ５ is independently, at each occurrence, a halogen, —OR ａ , -SR ａ , -NR ｂ R ｃ , methyl, ethyl, -C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, —C ６－１２ Bicycloalkyl, -C ６－１２ Spirocycloalkyl, -C ３－９ cyclohaloalkyl, —C ６－１２ Bicyclohaloalkyl, —C ６－１２ Spirocyclohaloalkyl, —C ３－９ cycloalkenyl, -C ６－１２ bicycloalkenyl, -C ６－１２ spirocycloalkenyl, -C ３－９ cyclohaloalkenyl, —C ６－１２ bicyclohaloalkenyl, —C ６－１２ spirocyclohaloalkenyl, —C ８－１２ Cycloalkynyl, -C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, -C ８－１２ cyclohaloalkynyl, —C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, aryl, heteroaryl, -C １－５ Alkyl-aryl, -C ２－５ alkenyl-aryl, -C ２－５ Alkynyl-aryl, -C １－５ Alkyl-heteroaryl, -C ２－５ alkenyl-heteroaryl, -C ２－５ alkynyl-heteroaryl, —C １－５ haloalkyl-aryl, —C ２－５ haloalkenyl-aryl, —C ２－５ haloalkynyl-aryl, —C １－５ haloalkyl-heteroaryl, —C ２－５ haloalkenyl-heteroaryl, —C ２－５ haloalkynyl-heteroaryl, —C(═O)R ａ , -C １－８ Alkyl-C(=O)R ａ , -C ２－８ Alkenyl-C(=O)R ａ , -C ２－８ Alkynyl-C(=O)R ａ , -C １－８ Haloalkyl-C(=O)R ａ , -C ２－８ Haloalkenyl-C(=O)R ａ , -C ２－８ Haloalkynyl-C(=O)R ａ , -CO ２ R ａ , -C １－８ Alkyl-CO ２ R ａ , -C ２－８ Alkenyl-CO ２ R ａ , -C ２－８ Alkynyl-CO ２ R ａ , -C １－８ Haloalkyl-CO ２ R ａ , -C ２－８ Haloalkenyl-CO ２ R ａ , -C ２－８ Haloalkynyl-CO ２ R ａ , -SO ２ R ａ , -C １－８ Alkyl-SO ２ R ａ , -C ２－８ Alkenyl-SO ２ R ａ , -C ２－８ Alkynyl-SO ２ R ａ , -C １－８ Haloalkyl-SO ２ R ａ , -C ２－８ Haloalkenyl-SO ２ R ａ , -C ２－８ Haloalkynyl-SO ２ R ａ , —C(═O)NR ｂ R ｃ , -C １－８ Alkyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkenyl-C(=O)NR ｂ R ｃ , -C １－８ Haloalkyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkenyl-C(=O)NR ｂ R ｃ , -CN, -C １－８ Alkyl-CN, -C ２－８ Alkenyl-CN, -C ２－８ Alkynyl-CN, -C １－８ Haloalkyl-CN, -C ２－８ Haloalkenyl-CN, -C ２－８ Haloalkynyl-CN, -CH ２ -O-R ａ , -C ２－９ Alkyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Haloalkyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -CH ２ -S-R ａ , -C ２－９ Alkyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Haloalkyl-S-R ａ , -C ２－９ Haloalkenyl-S-R ａ , and -C ２－９ Haloalkenyl-S-R ａ or selected from the group consisting of: Or, where R ４ and / or R ５ are bonded to the same carbon atom, and ４ and / or R ５ two of which together can form a carbonyl group; and R ａ , R ｂ and R ｃ is independently, at each occurrence: H, methyl, ethyl, —C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, aryl, heteroaryl, -C １－５ Alkyl-aryl, -C １－５ haloalkyl-aryl, —C ２－５ alkenyl-aryl, -C ２－５ haloalkenyl-aryl, —C ２－５ Alkynyl-aryl, -C ２－５ haloalkynyl-aryl, —C １－５ Alkyl-heteroaryl, -C １－５ haloalkyl-heteroaryl, —C ２－５ alkenyl-heteroaryl, -C ２－５ haloalkenyl-heteroaryl, —C ２－５ Alkynyl-heteroaryl and -C ２－５ haloalkynyl-heteroaryl; wherein the compound of formula II is: 【Chemistry 14】 (not a compound selected from the group consisting of: wherein the disease, disorder, injury or trauma is: (a) serotonin transporter (SERT) activity; and / or (b) dopamine transporter (DAT) activity; and / or (c) norepinephrine transporter (NET) activity; and / or (d) Serotonin receptor (5-HT2B) activity in response to regulation of; Preferably, wherein the disease, disorder, injury or trauma is a disease, disorder, injury or trauma associated with the central nervous system; Most preferably herein, the disease, disorder, injury or trauma associated with the central nervous system is; dementia in Alzheimer's disease (including early-onset, late-onset, atypical, mixed, or unspecified), vascular dementia (including arteriosclerotic, acute-onset, multi-infarct, subcortical, mixed cortical, or unspecified), dementia in Pick's disease, dementia in Creutzfeldt-Jakob disease, dementia in Huntington's disease, dementia in Parkinson's disease, dementia in human immunodeficiency virus [HIV] disease, dementia in cerebral lipidosis, dementia in epilepsy, dementia in hepatolenticular degeneration, dementia in hypercalcemia, dementia in hypothyroidism, dementia in intoxication, dementia in Lewy body disease, dementia in multiple sclerosis, dementia in neurosyphilis, dementia in niacin deficiency, dementia in polyarteritis nodosa, dementia in systemic lupus erythematosus, dementia in trypanosomiasis, dementia due to uremia, dementia in vitamin B １２ Dementia in deficiency disorders, unspecified dementia (including dementia not otherwise specified, psychosis not otherwise specified, geriatric, delirium, depression, paranoia, or acute confusional state), organic amnesic syndrome, Korsakoff psychosis, Korsakoff syndrome, delirium, cerebral syndrome, confusional state, infectious psychosis, organic reaction, psychoorganic syndrome, organic hallucinosis, organic catatonic disorder, organic delusional [schizophreniform] disorder, organic mood [affective] disorder, organic anxiety disorder, organic confusional state Dissociative disorder, organic affective [apathetic] disorder, mild cognitive impairment, epileptic psychosis, brain syndrome not otherwise specified, mental disorder not otherwise specified, organic personality disorder, pseudopsychotic personality disorder, pseudodevelopmental personality disorder, frontal lobe syndrome, limbic epileptic personality syndrome, lobotomy syndrome, post-leukotomy syndrome, post-encephalitic syndrome, post-concussion syndrome, post-contusion syndrome (encephalopathy), post-traumatic brain syndrome, non-psychotic , right hemisphere organic affective disorders, organic mental syndromes, mental and behavioral disorders due to alcohol use, mental and behavioral disorders due to opioid use, mental and behavioral disorders due to cannabinoid use, mental and behavioral disorders due to sedative or hypnotic use, mental and behavioral disorders due to cocaine use, mental and behavioral disorders due to caffeine-containing stimulant use, mental and behavioral disorders due to hallucinogen use, mental and behavioral disorders due to tobacco use, mental and behavioral disorders due to volatile solvent use, mental and behavioral disorders due to use of other psychoactive substances (including any combination of psychoactive substances), schizophrenia, paranoid schizophrenia, paranoid schizophrenia, deuteranopia, deuteranopia, disorganized schizophrenia, catatonic schizophrenia, catatonic stupor, schizophrenic catalepsy, schizophrenic catatonia, schizophrenic flexibilitas cerea cerea), undifferentiated schizophrenia, atypical schizophrenia, post-schizophrenic depression, residual schizophrenia, chronic undifferentiated schizophrenia, schizophrenic restzustand, simple schizophrenia, somatosensory schizophrenia, schizophreniform disorder, schizophreniform psychosis, schizophrenia not otherwise specified, schizophrenic disorder, subclinical schizophrenia reaction, borderline schizophrenia, subclinical schizophrenia, prepsychotic schizophrenia, prodromal schizophrenia, pseudoneurotic schizophrenia,Pseudopsychotic schizophrenia, Schizophreniform personality disorder, Persistent delusional disorder, Delusional disorder, Paranoia, Paranoid psychosis, Paranoid state, Paraphrenia (late stage), Sensitive Beziehungswahn, Paranoid body dysmorphic disorder, Recurrent delusional state, Paranoia querulans, Acute and transient psychotic disorder, Acute polymorphic psychotic disorder without schizophrenic symptoms, Acute polymorphic psychotic disorder with schizophrenic symptoms, Buffet d'Elirante delirante), cycloid psychosis, acute schizophreniform psychotic disorder, acute (undifferentiated) schizophrenia, brief schizophreniform disorder, brief schizophreniform psychosis, dreamlike psychosis, schizophrenic reaction, delusional reaction, psychogenic delusional psychosis, acute transient psychotic disorder, induced delusional disorder, folie à deux deux), induced delusional disorder, induced psychotic disorder, schizoaffective disorder (including manic, depressive, mixed and unspecified), non-organic psychotic disorder, chronic hallucinatory psychosis, manic episode disorder, bipolar disorder, single manic episode disorder, hypomania, mania without psychotic symptoms, mania with psychotic symptoms, mania with mood-concordant psychotic symptoms, manic stupor, mania not otherwise specified, bipolar affective disorder, manic depression, manic-depressive illness, manic-depressive psychosis, manic-depressive reaction, bipolar II disorder, depression, psychogenic depression, reactive depression, mild depression, moderate depression, severe depression, agitated depression, major depression, vital depression, atypical depression, unipolar depression, depressive disorder not otherwise specified, recurrent depressive disorder, seasonal depressive disorder, cyclothymia, affective personality disorder, cycloid personality, cyclothymic personality, dysthymia, depressive neurosis, depressive personality disorder, neurotic depression, persistent anxiety depression, phobic anxiety disorder, agoraphobia, panic disorder, social phobia, social phobia, social neurosis, fear of heights, phobia of animals, claustrophobia, simple phobia, phobic state not otherwise specified, episodic paroxysmal anxiety, generalized anxiety disorder, anxiety hysteria, anxiety not otherwise specified, obsessive-compulsive disorder,Anankastic neurosis, obsessive-compulsive neurosis, primarily obsessive thinking or rumination, primarily compulsive behavior [compulsive rituals], acute stress reaction, acute crisis reaction, acute reaction to stress, combat fatigue, crisis state, mental shock, post-traumatic stress disorder (PTSD), traumatic neurosis, adjustment disorder Harm, culture shock, grief reaction, pediatric hospitalization, dissociative conversion disorder, conversion hysteria, conversion reaction, dissociative amnesia, dissociative fugue, dissociative stupor, trance disorder, possession disorder, dissociative movement disorder, psychogenic aphonia, psychogenic dysphonia, dissociative convulsions, dissociative anesthesia, dissociative sensory loss, Gansser syndrome, multiple personality dissociative disorder, psychogenic confusion, psychogenic twilight state, somatoform disorder, somatization disorder, charcoal briquet disorder, multiple Psychosomatic disorder, undifferentiated somatoform disorder, undifferentiated psychosomatic disorder, hypochondriacal disorder, body dysmorphic disorder, dysmorphophobia (non-delusional), hypochondriacal neurosis, hypochondriasis, illness phobia, somatoform autonomic nervous disorder, cardiac neurosis, dako Sta syndrome, gastric neuropathy, neurocirculatory asthenia, psychogenic aspiration, psychogenic cough, psychogenic diarrhea, psychogenic dyspepsia, psychogenic urinary disorder, psychogenic flatulence, psychogenic hiccups, psychogenic hyperventilation, psychogenic increased urinary frequency, psychogenic hyperventilation Irritable bowel syndrome, psychogenic pyloric spasm, persistent somatoform pain disorder, psychiatric pain, psychogenic low back pain, psychogenic headache, somatoform pain disorder, psychogenic dysmenorrhea, psychogenic dysphagia, globus hysterica, psychogenic pruritus, psychogenic torticollis, psychogenic bruxism, psychosomatic disorder not otherwise specified, neurasthenia, fatigue syndrome, depersonalization-derealization syndrome, Dhat syndrome, occupational neurosis, writer's cramp cramp neurosis, psychasthenia, psychasthenic neurosis, psychogenic syncope, neurosis not otherwise specified, eating disorders, anorexia nervosa, atypical anorexia nervosa, bulimia nervosa, bulimia not otherwise specified, bulimia nervosa, atypical bulimia nervosa, binge eating associated with other psychological disturbances, psychogenic binge eating, vomiting associated with other psychological disturbances, psychogenic vomiting, pica, psychogenic anorexia, non-organic sleep disorders, non-organic insomnia, non-organic hypersomnia, non-organic disorders of sleep-wake schedules, psychogenic inversion of circadian rhythm, psychogenic inversion of noctohemeral rhythm, psychogenic inversion of sleep rhythm, sleepwalkingNight terrors, nightmares, dream anxiety disorder, emotional sleep disorder not otherwise specified, sexual dysfunction not caused by organic disorder or disease, absence or loss of sexual desire, frigidity, hypoactive sexual desire disorder, sexual aversion, lack of sexual enjoyment, sexual anhedonia, genital response dysfunction, female sexual arousal disorder, male erectile dysfunction, psychogenic impotence, orgasmic dysfunction, orgasmic inhibition, psychogenic abnormal orgasm, premature ejaculation, psychogenic vaginismus, non-organic dyspareunia, psychogenic dyspareunia, nymphomania, satyriasis, sexual dysfunction not otherwise specified, childbirth postpartum depression, postpartum depression, postpartum psychosis, postpartum psychosis, psychological and behavioral factors related to physical disability or illness (including but not limited to asthma, dermatitis, gastric ulcer, irritable bowel syndrome, ulcerative colitis, and urticaria), non-addictive substance abuse (including but not limited to antacids, herbal medicines, folk remedies, steroids, hormones, vitamins, and laxatives), psychogenic physiological dysfunction not otherwise specified, paranoid personality disorder, expansive paranoid personality disorder, fanatic paranoid personality disorder, litigious paranoid personality disorder, sensitive Paranoid personality disorder, schizoid personality disorder, antisocial personality disorder, amoral personality disorder, antisocial personality disorder, asocial personality disorder, psychotic personality disorder, sociopathic personality disorder, emotionally unstable personality disorder, aggressive personality disorder, borderline personality disorder, explosive personality disorder, histrionic personality disorder, hysterical personality disorder , psychoinfantile personality disorder, ananarchic personality disorder, obsessive-compulsive personality disorder, obsessive-compulsive personality disorder, anxious [avoidant] personality disorder, dependent personality disorder, helpless personality disorder, inappropriate personality disorder, passivity personality disorder, self-destructive personality disorder, eccentric personality disorder, Hart-Trouss personality disorder,Immature personality disorder, narcissistic personality disorder, passive-aggressive personality disorder, psychoneurotic personality disorder, personality neurosis not otherwise specified, pathological personality not otherwise specified, mixed personality disorder, personality and behavioral disorders due to brain disease, personality and behavioral disorders due to brain injury, personality and behavioral disorders due to brain dysfunction, permanent personality changes after catastrophic experiences (including, but not limited to, experiences in a concentration camp, disaster, prolonged incarceration with imminent risk of death, prolonged exposure to life-threatening situations such as being a victim of terrorism, or prolonged torture), mental Permanent personality change after illness, Chronic pain personality syndrome, Unspecified permanent personality change, Addiction disorders, Impulse disorders, Pathological gambling, Compulsive gambling, Pathological arson [pyromania], Pathological kleptomania [kleptomania], Trichotillomania, Intermittent explosive disorder, Gender identity disorder, Transsexualism, Androgyne transvestism, Gender role disorder, Sexual preference disorder, Fetishism, Fetishistic transvestism, Exhibitionism, Voyeurism, Pedophilia, Sadomasochism, Touchophilia, Necrophilia, Sexual deviance not otherwise specified, Sexual maturation disorder, Ego heterosexual orientation, Sexual relationship disorder, Psychosexual development disorder, Elaboration of physical symptoms for psychological reasons, Compensatory neurosis, Intentional production or fetishization of symptoms or disorders, whether physical or psychological Factitious Disorder, Hospital Hopping Syndrome, Munchausen Syndrome, Inveterate Patient, Personality Disorder Not Otherwise Specified, Relationship Disorder Not Otherwise Specified, Hyperactivity Disorder, Activity and Attention Disorder, Attention Deficit Disorder with Hyperactivity, Attention Deficit Hyperactivity Disorder, Attention Deficit Syndrome with Hyperactivity, Hyperactivity Conduct Disorder, Hyperactivity Syndrome Not Otherwise Specified, Conduct Disorder, Desocialized Conduct Disorder, Socialized Conduct Disorder, Oppositional Defiant Disorder, Depressive Conduct Disorder, Separation Anxiety Disorder, Sibling Rivalry Disorder, Hyperanxiety Disorder, Childhood Affective Disorder Not Otherwise Specified, Selective Mutism, Selective Mutism, Reactive Attachment Disorder, Disinhibited Attachment Disorder, Affectionate psychiatric disorders, institutionalization syndrome, impairment of social functioning of childhood, tic disorder, transient tic disorder, chronic motor tic disorder, chronic vocal tic disorder, complex vocal and multiple motor tic disorder [de la Tourette], Tourette's syndrome, non-organic nocturnal enuresis, functional nocturnal enuresis, psychogenic nocturnal enuresis, urinary incontinence of non-organic causes, non-organic enuresis, functional enuresis, fecal incontinence of non-organic causes, psychogenic enuresis, feeding disorders of infancy and childhood, rumination disorder of infancy, stereotypic movement disorder, stuttering, noise, attention deficit disorder without hyperactivity, excessive masturbation, nail biting, nose picking, thumb sucking, and psychiatric disorders not otherwise specified.

13. The compound is: 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 13. The pharmaceutical composition of claim 12, selected from the group consisting of:

14. Formula II', including stereoisomers, individual enantiomers, racemates, non-racemic mixtures, isotopically substituted forms, prodrugs and / or pharmaceutically acceptable salts thereof; 【Chemistry 19】 (In the formula; One or more hydrogen atoms in the compound of formula II' may be replaced by fluorine; R １ and R ２ are independently H, methyl, ethyl, —C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, —C ６－１２ Bicycloalkyl, -C ６－１２ Spirocycloalkyl, -C ３－９ cyclohaloalkyl, —C ６－１２ Bicyclohaloalkyl, —C ６－１２ Spirocyclohaloalkyl, —C ３－９ cycloalkenyl, -C ６－１２ bicycloalkenyl, -C ６－１２ spirocycloalkenyl, -C ３－９ cyclohaloalkenyl, —C ６－１２ bicyclohaloalkenyl, —C ６－１２ spirocyclohaloalkenyl, —C ８－１２ Cycloalkynyl, -C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, -C ８－１２ cyclohaloalkynyl, —C ９－１４ Bicyclohaloalkynyl, —C ９－１４ spirocyclohaloalkynyl, -C ３－９ heterocycloalkyl, —C ６－１２ Heterobicycloalkyl, —C ６－１２ Heterospirocycloalkyl, aryl, heteroaryl, -C １－５ Alkyl-aryl, -C ２－５ alkenyl-aryl, -C ２－５ Alkynyl-aryl, -C １－５ Alkyl-heteroaryl, -C ２－５ alkenyl-heteroaryl, -C ２－５ alkynyl-heteroaryl, —C １－５ haloalkyl-aryl, —C ２－５ haloalkenyl-aryl, —C ２－５ haloalkynyl-aryl, —C １－５ haloalkyl-heteroaryl, —C ２－５ haloalkenyl-heteroaryl, —C ２－５ haloalkynyl-heteroaryl, —C(═O)R ａ , -C １－８ Alkyl-C(=O)R ａ , -C ２－８ Alkenyl-C(=O)R ａ , -C ２－８ Alkynyl-C(=O)R ａ , -C １－８ Haloalkyl-C(=O)R ａ , -C ２－８ Haloalkenyl-C(=O)R ａ , -C ２－８ Haloalkynyl-C(=O)R ａ , -CO ２ R ａ , -C １－８ Alkyl-CO ２ R ａ , -C ２－８ Alkenyl-CO ２ R ａ , -C ２－８ Alkynyl-CO ２ R ａ , -C １－８ Haloalkyl-CO ２ R ａ , -C ２－８ Haloalkenyl-CO ２ R ａ , -C ２－８ Haloalkynyl-CO ２ R ａ , -SO ２ R ａ , -C １－８ Alkyl-SO ２ R ａ , -C ２－８ Alkenyl-SO ２ R ａ , -C ２－８ Alkynyl-SO ２ R ａ , -C １－８ Haloalkyl-SO ２ R ａ , -C ２－８ Haloalkenyl-SO ２ R ａ , -C ２－８ Haloalkynyl-SO ２ R ａ , —C(═O)NR ｂ R ｃ , -C １－８ Alkyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkenyl-C(=O)NR ｂ R ｃ , -C １－８ Haloalkyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkenyl-C(=O)NR ｂ R ｃ , -CN, -C １－８ Alkyl-CN, -C ２－８ Alkenyl-CN, -C ２－８ Alkynyl-CN, -C １－８ Haloalkyl-CN, -C ２－８ Haloalkenyl-CN, -C ２－８ Haloalkynyl-CN, -CH ２ -O-R ａ , -C ２－９ Alkyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Haloalkyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -CH ２ -R ａ , -CH ２ -S-R ａ , -C ２－９ Alkyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Haloalkyl-S-R ａ , -C ２－９ Haloalkenyl-S-R ａ , and -C ２－９ Haloalkenyl-S-R ａ selected from the group consisting of: Here, R １ and R ２ may together form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heterocycloalkenyl ring, or a 6-membered heteroaryl ring, each of which is unsubstituted or ４ Or R ５ may be substituted by one or more groups selected from R ３ CF ３ , CN, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, vinyl, allyl, acetylenyl, cyclohexyl, cyclopentenyl, cyclohexenyl, propargyl, cyanomethyl, oxetanyl, thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolyl, oxanyl, dioxolanyl, pyridinyl, naphthyl, and phenyl; each of which is unsubstituted or selected from the group consisting of R ４ Or R ５ or R ３ is a 4- to 6-membered fused ring system or a 4- to 6-membered spiro ring system, each of which is a saturated carbocyclic ring system containing zero heteroatoms or a saturated heterocyclic ring system containing one heteroatom selected from O or S, and each of which is unsubstituted or is selected from R ４ Or R ５ may be substituted by one or more groups selected from R ４ and R ５ is independently, at each occurrence, a halogen, —OR ａ , -SR ａ , -NR ｂ R ｃ , methyl, ethyl, -C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, —C ６－１２ Bicycloalkyl, -C ６－１２ Spirocycloalkyl, -C ３－９ cyclohaloalkyl, —C ６－１２ Bicyclohaloalkyl, —C ６－１２ Spirocyclohaloalkyl, —C ３－９ cycloalkenyl, -C ６－１２ bicycloalkenyl, -C ６－１２ spirocycloalkenyl, -C ３－９ cyclohaloalkenyl, —C ６－１２ bicyclohaloalkenyl, —C ６－１２ spirocyclohaloalkenyl, —C ８－１２ Cycloalkynyl, -C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, -C ８－１２ cyclohaloalkynyl, —C ９－１４ Bicycloalkynyl, -C ９－１４ spirocycloalkynyl, aryl, heteroaryl, -C １－５ Alkyl-aryl, -C ２－５ alkenyl-aryl, -C ２－５ Alkynyl-aryl, -C １－５ Alkyl-heteroaryl, -C ２－５ alkenyl-heteroaryl, -C ２－５ alkynyl-heteroaryl, —C １－５ haloalkyl-aryl, —C ２－５ haloalkenyl-aryl, —C ２－５ haloalkynyl-aryl, —C １－５ haloalkyl-heteroaryl, —C ２－５ haloalkenyl-heteroaryl, —C ２－５ haloalkynyl-heteroaryl, —C(═O)R ａ , -C １－８ Alkyl-C(=O)R ａ , -C ２－８ Alkenyl-C(=O)R ａ , -C ２－８ Alkynyl-C(=O)R ａ , -C １－８ Haloalkyl-C(=O)R ａ , -C ２－８ Haloalkenyl-C(=O)R ａ , -C ２－８ Haloalkynyl-C(=O)R ａ , -CO ２ R ａ , -C １－８ Alkyl-CO ２ R ａ , -C ２－８ Alkenyl-CO ２ R ａ , -C ２－８ Alkynyl-CO ２ R ａ , -C １－８ Haloalkyl-CO ２ R ａ , -C ２－８ Haloalkenyl-CO ２ R ａ , -C ２－８ Haloalkynyl-CO ２ R ａ , -SO ２ R ａ , -C １－８ Alkyl-SO ２ R ａ , -C ２－８ Alkenyl-SO ２ R ａ , -C ２－８ Alkynyl-SO ２ R ａ , -C １－８ Haloalkyl-SO ２ R ａ , -C ２－８ Haloalkenyl-SO ２ R ａ , -C ２－８ Haloalkynyl-SO ２ R ａ , —C(═O)NR ｂ R ｃ , -C １－８ Alkyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Alkenyl-C(=O)NR ｂ R ｃ , -C １－８ Haloalkyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkynyl-C(=O)NR ｂ R ｃ , -C ２－８ Haloalkenyl-C(=O)NR ｂ R ｃ , -CN, -C １－８ Alkyl-CN, -C ２－８ Alkenyl-CN, -C ２－８ Alkynyl-CN, -C １－８ Haloalkyl-CN, -C ２－８ Haloalkenyl-CN, -C ２－８ Haloalkynyl-CN, -CH ２ -O-R ａ , -C ２－９ Alkyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Alkenyl-O-R ａ , -C ２－９ Haloalkyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -C ２－９ Haloalkenyl-O-R ａ , -CH ２ -S-R ａ , -C ２－９ Alkyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Alkenyl-S-R ａ , -C ２－９ Haloalkyl-S-R ａ , -C ２－９ Haloalkenyl-S-R ａ , and -C ２－９ Haloalkenyl-S-R ａ or selected from the group consisting of: Or, where R ４ and / or R ５ are bonded to the same carbon atom, and ４ and / or R ５ two of which together can form a carbonyl group; and R ａ , R ｂ and R ｃ is independently, at each occurrence: H, methyl, ethyl, —C ３－９ Alkyl, -C １－９ Haloalkyl, —C ２－９ Alkenyl, -C ２－９ haloalkenyl, —C ２－９ Alkynyl, —C ２－９ haloalkynyl, —C ３－９ Cycloalkyl, aryl, heteroaryl, -C １－５ Alkyl-aryl, -C １－５ haloalkyl-aryl, —C ２－５ alkenyl-aryl, -C ２－５ haloalkenyl-aryl, —C ２－５ Alkynyl-aryl, -C ２－５ haloalkynyl-aryl, —C １－５ Alkyl-heteroaryl, -C １－５ haloalkyl-heteroaryl, —C ２－５ alkenyl-heteroaryl, -C ２－５ haloalkenyl-heteroaryl, —C ２－５ Alkynyl-heteroaryl and -C ２－５ 1. A process for the preparation of a compound according to claim 1, wherein the compound is selected from the group consisting of haloalkynyl-heteroaryl; wherein the process is represented by Formula III; 【Chemistry 20】 (Wherein, R is methyl, ethyl, and —C ３－９ a compound according to the formula (I) selected from the group consisting of alkyl; Formula IVa, or Formula IVb, or Formula IVc; 【Chemistry 21】 (In the formula, R ３ is as defined for compounds of formula II', and wherein for compounds of formula IVb, each R ３ may be the same or different, and wherein R′ is; methyl, ethyl, —C ３－９ a compound according to the formula (I) selected from the group consisting of alkyl, aryl, and haloaryl; reacting under a first set of reaction conditions to form a compound of formula V; 【Chemistry 22】 and preparing a compound of formula (I): The compound of formula V is then subjected to a second set of reaction conditions to produce a compound of formula VI; 【Chemistry 23】 producing a ketone intermediate of the formula: and subsequently, the compound of formula VI to the compound of formula VII; 【Chemistry 24】 (In the formula, R １ and R ２ is as defined for said compound of formula II') under a third set of reaction conditions to prepare said compound of formula II'.

15. a first set of reaction conditions comprising reacting one equivalent of a compound of Formula III with an excess of a compound of Formula IVa or Formula IVb or Formula IVc in an organic solvent in the presence of an excess of base; Preferably, wherein the organic solvent is a polar aprotic solvent and the base is a lithium base; 15. The process of claim 14, wherein most preferably the organic solvent is THF and the base is LiHMDS.

16. a second set of reaction conditions comprising heating a solution of a compound of formula V in a mixture of DMSO and water in the presence of NaCl; and / or 16. The process of claim 14 or claim 15, wherein the third set of reaction conditions comprises reductive amination of a compound of formula VI with a compound of formula VII, preferably in the presence of acetic acid and sodium cyanoborohydride in a mixture of anhydrous THF and anhydrous methanol.

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