Pyridine derivatives for treatment of psychiatric disorders

Abstract

The present disclosure relates to compounds of the formula; or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5 and R6 are as defined herein. It also relates to pharmaceutical compositions comprising the compounds of formula I and to the use of the compounds of formula I in the treatment of psychiatric disorders. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to aminoalkyl-pyridine derivatives for treating different medical conditions treated by activating serotonin receptors, such as mental illness and other disorders and conditions in the field of psychiatry. The present disclosure also relates to various methods for preparing these aminoalkyl-pyridine derivatives and corresponding intermediates and methods of using these aminoalkyl-pyridine derivatives to treat mental disorders. Background Art

[0002] Mental disorder is a psychological disorder that causes abnormal thinking and perception. People suffering from mental illness are out of touch with reality. Mental disorder (psychiatric disorder), also referred to as mental illness and mental disorder (mental disorder), includes a wide range of illnesses, including but not limited to depression, anxiety and panic disorder, schizophrenia, eating disorders, substance use disorders, post-traumatic stress disorder, attention deficit / hyperactivity disorder and obsessive-compulsive disorder. The severity of the symptoms is different, so that some individuals experience debilitating diseases that hinder normal social functions, while other individuals suffer from milder symptoms or follow the intermittent repetitive outbreaks across their life cycle. Although performance and diagnostic criteria are partially different among the mental illness condition, there are common endophenotypes worth noting between the diseases, and comorbidities are usually present. Specifically, there are endophenotypes associated with changes in mood, cognition and behavior. Interestingly, many of these endophenotypes also extend to neurological conditions. For example, attention deficits have been reported in patients with attention deficit disorder, attention deficit hyperactivity disorder, eating disorders, substance use disorders, schizophrenia, depression, obsessive-compulsive disorder, traumatic brain injury, fragile X, Alzheimer's disease, Parkinson's disease, and frontotemporal dementia.

[0003] Depression and anxiety are two of the most common mental disorders worldwide. Depression is a multifaceted condition characterized by the onset of mood disturbances, accompanied by other symptoms such as anhedonia, psychomotor disorders, feelings of guilt, attention deficits and suicidal tendencies, all of which may vary in severity. According to the World Health Organization, the discovery of mainstream antidepressants has revolutionized the management of depression to a large extent, yet up to 60% of patients remain undertreated. This is often due to delayed therapeutic effects of the drugs (usually 6 weeks from the start of treatment), side effects that lead to non-compliance, or inherent non-responsiveness to them. Similarly, anxiety disorders are a collection of etiologically complex conditions characterized by intense psychosocial distress and other symptoms depending on the subtype. Anxiety associated with life-threatening illnesses is the only anxiety subtype that has been studied in terms of psychedelic-assisted therapy. This form of anxiety affects up to 40% of individuals diagnosed with life-threatening diseases such as cancer. It manifests as worries about future danger or misfortune, accompanied by feelings of dysphoria or nervous physical symptoms, and often coexists with depression. It is associated with reduced quality of life, reduced treatment adherence, prolonged hospitalizations, increased morbidity and hopelessness, which overall contribute to reduced survival. Pharmacological and psychosocial interventions are commonly used to manage this type of anxiety, but their efficacy is mixed and limited, such that they often fail to provide satisfactory mood relief.

[0004] The receptor of serotonin (5-hydroxytryptamine, 5-HT) is an important class of G protein coupled receptors. Serotonin is considered to play a role in the process of learning and memory, sleep, temperature regulation, mood, motor activity, pain, sexual behavior and aggressive behavior, appetite, neurodegenerative regulation and biorhythm. Not surprisingly, many mental health disorders and neurological disorders are affected by changes, dysfunctions, degeneration and / or damage of the serotonin signaling system of the brain, which can partially explain the common endophenotypes and comorbidities in neuropsychiatry and neurological diseases. For example, the dysfunction of serotonin signaling is associated with pathophysiological conditions, such as anxiety, depression, obsessive-compulsive disorder, schizophrenia, suicide, autism, migraine, vomiting, alcoholism, neurodegenerative disorders, chronic pain, existential pain, bipolar disorder, obsessive-compulsive disorder and smoking. Many therapeutic agents that modulate serotonergic function are commercially available, including serotonin reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors, and although primarily developed for depression, many of these therapeutic agents are used for a variety of other medical indications, including, but not limited to, depression in Alzheimer's disease and other neurodegenerative diseases, chronic pain, existential pain, bipolar disorder, obsessive-compulsive disorder, anxiety disorders, and smoking cessation. However, in many cases, marketed drugs show limited benefit compared to placebo, may take six weeks or longer to work, and for some patients, are associated with several side effects, including difficulty sleeping, sleepiness, fatigue, weakness, changes in blood pressure, memory problems, digestive problems, weight gain, and sexual problems. Therefore, there is an industry need for more effective drugs for treating these conditions.

[0005] Due to strict legal controls, the field of psychedelic neuroscience has witnessed a recent renaissance after decades of limited research. Psychedelic drugs are one of the oldest classes of psychopharmacological agents known to mankind and cannot be fully understood without reference to various fields of research including anthropology, ethnopharmacology, psychiatry, psychology, sociology and others. Psychedelic drugs (serotonergic hallucinogens), such as lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT) and mescaline, are powerful psychoactive substances that alter sensory perception and mood and affect many cognitive processes. They are able to induce severe distortions in visual and auditory processing along with altered self-perception and self-relationship with the outside world, which are described by many users as mystical experiences. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origins predate written history, and early cultures adopted them in many sociocultural and ritual contexts. After the almost contemporary discovery of LSD and the determination of serotonin in the brain, early research focused on the possibility that LSD and other psychedelic drugs had a serotonergic basis for their effects. The consensus that exists today is that classic psychedelics are agonists or partial agonists at brain 5-hydroxytryptamine (serotonin) 2A (5-HT2A) receptors. Several useful rodent models have been developed over the years to help understand the neurochemical effects of 5-HT2A receptor activation in the brain, and various imaging techniques have been employed to determine the key brain regions that are directly affected by psychedelics.

[0006] Hallucinogens induce both acute effects and long-term persistent effects after their acute effects have subsided, including changes in mood and brain function. Long-term persistent effects may come from their unique receptor affinity, which affects neurotransmission via a neuromodulatory system, which is used to modulate brain activity, i.e., neuroplasticity, and promote cell survival, is neuroprotective, and modulates the brain neuroimmune system. The mechanisms that cause these long-term neuromodulatory changes are still under study, but may include epigenetic modifications, gene expression changes, and modulation of presynaptic and postsynaptic receptor densities. Therefore, previously understudied hallucinogens may potentially provide the next generation of neurotherapeutics, in which treatment-resistant mental and neurological diseases (e.g., depression, post-traumatic stress disorder, dementia, and addiction) may become treatable, with a reduced pharmacological risk profile. Randomized controlled clinical studies have confirmed the antidepressant and other therapeutic effects of classic hallucinogens in humans. Importantly, these therapeutic effects are induced quickly (hours to days) and are often more intense and lasting than the effects of commercially available serotonergic antidepressants (e.g., SSRIs). Based on such studies, it is apparent that agonists of the 5-HT2A receptor may represent a new class of rapidly acting and highly potent antidepressants that will be particularly useful in treating patients who do not respond to conventional management approaches.

[0007] In general, the psychedelic therapy model consists of administering hallucinogenic drugs to induce a mystical experience, the duration of which depends on the hallucinogenic drug, but in the case of psilocybin (the most commonly used agent for this purpose today), often lasts four hours or more. This allows participants to resolve and integrate difficult feelings and situations, causing lasting antidepressant and antianxiety effects. Classical hallucinogens such as psilocybin and LSD are being studied as potential candidates. In a study of classic hallucinogens for the treatment of depression and anxiety associated with life-threatening illnesses, psilocybin was found to produce significant and lasting antidepressant and antianxiety effects in a supportive environment.

[0008] In addition, emerging clinical research and evidence suggest that psychedelic-assisted therapy also shows potential as an alternative treatment for refractory substance use disorders and other mental health conditions. For example, recent studies have shown that psilocybin-assisted therapy can be used to treat alcohol use disorder. Also recently, psilocybin-assisted therapy was found to be potentially useful for treating tobacco use disorder, demonstrating an 80% abstinence rate at 6-month follow-up and a 67% abstinence rate at 12-month follow-up; such rates are considerably higher than any rates documented in the smoking cessation literature. These results are consistent with the rapidly growing evidence from recent clinical trials that provides support for the effectiveness of psilocybin-assisted therapy for the treatment of resistant depression and end-of-life anxiety. Research on the potential benefits of psychedelic-assisted therapy for opioid use disorder (OUD) is beginning to emerge, and accumulating evidence supports the need to advance this line of research. Available evidence from early randomized clinical trials suggests a promising role in treating OUD: in long-term follow-up, higher abstinence rates were observed among participants who received high doses of LSD for heroin addiction compared with controls.

[0009] Psychosis often refers to an abnormal mental state characterized by hallucinatory experiences, delusional thinking and confused ideas. In addition, this state is accompanied by social cognitive impairment, inappropriate emotional expression and bizarre behavior. Most often, psychosis develops as part of a mental disorder, and it represents an integral part of schizophrenia. It corresponds to the most fully developed stage of the disease. The first manifestation of a patient's psychosis is called the first episode of psychosis. It reflects a critical transitional stage toward chronic establishment of the disease, which is presumably mediated by the progressive structural and functional abnormalities observed in diagnosed patients. Anecdotal evidence suggests that regular administration of low, non-hallucinogenic doses (microdosing) of hallucinogens can alleviate the symptoms of schizophrenia and psychosis.

[0010] Despite this great therapeutic promise, existing psychedelic drugs face several challenges both in their pharmacology and delivery that must be addressed to maximize safety and increase adoption in clinical practice. Although psychedelic drugs are generally considered safe from a physiological perspective, some physical side effects have been reported. For example, psilocybin has been reported to frequently cause transient delayed headaches when administered in a controlled setting, with incidence, duration, and severity increasing in a dose-related manner [Johnson et al., Drug Alcohol Depend 2012, 123, 132-140]. Cardiovascular effects, including vasoconstriction and increases in blood pressure and heart rate, have also been reported following administration of classic psychedelic drugs that activate 5-HT2A receptors. Many existing psychedelic drugs are also modulators of other monoamine receptors in addition to 5-HT2A receptors as secondary targets, and in many cases, it remains unclear how those secondary targets contribute to the efficacy and safety of such compounds. For example, many psychedelic drugs are agonists of the 5-HT2B receptor, activation of which has been linked to valvular heart disease. Other psychedelic drugs activate the 5-HT1A receptor, activation of which is also known to cause effects on mood and thus may also contribute to the efficacy of such agents. Thus, there remains a need for new psychedelic drugs that possess primary and secondary pharmacology that are better optimized for the treatment of psychiatric disorders with minimal side effects.

[0011] Furthermore, given the severe hallucinations induced by hallucinogenic drugs, hallucinogenic therapies are most safely delivered in a supervised medical setting. This comes with significant inconvenience and expense for patients and health care providers, especially given the extended duration of effect (4 hours+) of the most commonly used agents (e.g., psilocybin). Thus, there remains a need for new hallucinogenic drugs with shorter durations of action to facilitate more effective supervised therapy, or with sufficiently attenuated hallucinogenic effects that they can be safely used at home away from medical supervision.

[0012] The present disclosure relates to a new class of psychedelic drugs with improved properties. Summary of the invention

[0013] The present disclosure relates to compounds of formula I

[0014]

[0015] or a pharmaceutically acceptable salt thereof,

[0016] in

[0017] R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, 3-membered to 6-membered heterocyclic group, C3-C 10Cycloalkyl C1-C8 alkyl, 3-membered to 6-membered heterocyclyl C1-C8 alkyl, -OR7, -SR7, halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NR8R9, aryl, heteroaryl, aryl C1-C8 alkyl or heteroaryl C1-C8 alkyl;

[0018] R2 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, -OR 10 、-SR 10 , halogenated, -CF3, -SF5, -OCF3, -CN, -NO2 or -NR 11 R 12 ;

[0019] R3 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, -OR 13 、-SR 13 , halogenated, -CF3, -SF5, -OCF3, -CN, -NO2, -NR 14 R 15 、-C(O)R 16 、-C(O)OR 16 、-OC(O)R 16 or -C(O)NR 17 R 18 ;

[0020] R4 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, -OR 19 、-SR 19 , halogenated, -CF3, -SF5, -OCF3, -CN, -NO2, -NR 20 R 21 、-C(O)R 22 、-C(O)OR 22 、-OC(O)R 22 or -C(O)NR 23 R 24 ;

[0021] R5 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, cyclopropyl or cyclopropylmethyl; and

[0022] R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1 to 5 examples of R 6a Replace, and for each occurrence of each R 6a independently selected from hydroxyl, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, halo, -CF3, -SF5, -OCF3, -OR 25 、-SR 25 、-CN、-NO2、-NR 26 R 27 、-C(O)R 28 、-C(O)OR 28 、-OC(O)R 28 and -C(O)NR 29 R 30 , or any two adjacent R 6a Together with the atoms to which they are attached, they form a C4-C6 cycloalkyl or a 4- to 6-membered heterocyclyl;

[0023] in

[0024] R7 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, aryl, heteroaryl, aryl C1-C8 alkyl, heteroaryl C1-C8 alkyl, 3-membered to 6-membered heterocyclyl or 3-membered to 6-membered heterocyclyl C1-C8 alkyl;

[0025] R8 and R9 are independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, aryl, aryl C1-C8 alkyl, heteroaryl, heteroaryl C1-C8 heteroaryl, 3-membered to 6-membered heterocyclyl or 3-membered to 6-membered heterocyclyl C1-C8 alkyl;

[0026] R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R25 , R 26 , R 27 , R 28 , R 29 and R 30 are independently hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C5 alkyl, 3- to 6-membered heterocyclyl, or 3- to 6-membered heterocyclylC1-C5 alkyl;

[0027] Aryl is a monocyclic or bicyclic aromatic ring containing 6 or 10 ring carbon atoms;

[0028] Heteroaryl is a 5- to 10-membered ring that is monocyclic or bicyclic containing 1, 2, 3 or 4 ring heteroatoms and 2 to 9 ring carbon atoms;

[0029] Aryl and heteroaryl groups may be unsubstituted or substituted with one or more substituents independently selected from hydroxy, C1-C5 alkyl, C2-C5 alkenyl, C 2-5 Alkynyl, C3-C6 cycloalkyl, C1-C5 alkoxy, halo, -CF3, -CN, -NO2, -NH2, aryl, heteroaryl, C3-C6 cycloalkyl C1-C3 alkyl, aryl C1-C3 alkyl, heteroaryl C1-C3 alkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered heterocyclyl C1-C3 alkyl;

[0030] Cycloalkyl and heterocyclyl may be unsubstituted or substituted with one or more substituents independently selected from hydroxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C1-C5 alkoxy, halo, -CF3, -CN, -NO2, -NH2, aryl, heteroaryl, C3-C6 cycloalkyl C1-C3 alkyl, aryl C1-C3 alkyl, heteroaryl C1-C3 alkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered heterocyclyl C1-C3 alkyl; and

[0031] Alkyl, alkenyl and alkynyl groups may be unsubstituted or substituted with one or more substituents independently selected from hydroxy, C3-C6 cycloalkyl, C1-C5 alkoxy, halo, -CF3, -CN, -NO2, -NH2, aryl, heteroaryl, C3-C6 cycloalkylC1-C3 alkyl, arylC1-C3 alkyl, heteroarylC1-C3 alkyl, 3- to 6-membered heterocyclyl and 3- to 6-membered heterocyclylC1-C3 alkyl.

[0032] These compounds are useful in the treatment of psychiatric disorders. DETAILED DESCRIPTION

[0033] Unless otherwise indicated, the definitions and embodiments described in this section and other sections are intended to apply to all embodiments and aspects of the disclosure described herein for which they are appropriate, as will be understood by those skilled in the art.

[0034] All features disclosed in this specification (including claims, abstracts and all steps of any disclosed method or process) may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. Unless otherwise expressly stated, each feature disclosed in this specification (including claims and abstracts) may be replaced by an alternative feature serving the same, equivalent or similar purpose.

[0035] As used herein, the term "compound(s) of the disclosure" or "compound(s) of the present disclosure" and the like refers to a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0036] As used herein, the term "composition(s) of the disclosure" or "composition(s) of the present disclosure" and the like refers to a composition, such as a pharmaceutical composition, comprising one or more compounds of the disclosure.

[0037] As used herein, the term "and / or" means that the listed items are present or used individually or in combination. In practice, this term means that "at least one" or "one or more" of the listed items are used or present. With respect to pharmaceutically acceptable salts, the term "and / or" means that the compounds of the present disclosure are present as individual salts and solvates as well as combinations of salts of compounds of the present disclosure, for example.

[0038] As used in this disclosure, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. For example, embodiments including "a compound" should be understood to present certain aspects having one compound or two or more additional compounds.

[0039] As used in the present disclosure and claims, the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "include" and "includ es"), or "containing" (and any form of containing, such as "contain" and "contains") are inclusive or open-ended, and do not exclude additional, unrecited elements or process steps. A subgroup of comprising is "consisting essentially of," which is defined below, and a subgroup of "consisting essentially of is "consisting of," which is defined below. Therefore, it should be understood that whenever the term comprising is used, it can be replaced with "consisting essentially of" or "consisting of," and these embodiments are considered within the present disclosure.

[0040] As used herein, the term "consisting of" and its derivatives are intended to be closed terms that specify the presence of stated features, elements, components, groups, integers and / or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0041] As used herein, the term "consisting essentially of is intended to specify the presence of the described features, elements, components, groups, integers and / or steps, as well as the presence of those that do not materially affect the basic and novel characteristics of these features, elements, components, groups, integers and / or steps. A subset of "consisting essentially of is "consisting of 3- to 6-membered heterocyclyl or 3- to 6-membered heterocyclyl, C1-C8 alkyl", which is defined above. Therefore, it should be understood that whenever the term "consisting essentially of is used, it can be replaced by "consisting of", and these embodiments are considered within the present disclosure.

[0042] The term "suitable" as used herein with respect to synthetic pathways means that the selection of a particular compound or condition will depend on the specific synthetic operation to be performed, the identity of the molecule to be converted, and / or the specific use of the compound, but the selection will be within the skill of those skilled in the art. All process / method steps described herein are carried out under conditions that effectively provide the displayed product. It will be understood by those skilled in the art that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio, and whether the reaction should be carried out under anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product, and it is within their skill to do so.

[0043] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, according to the practice of the art, "about" can mean within 3 or more than 3 standard deviations. Alternatively, "about" can mean a range of up to 20%, a range of up to 10%, a range of up to 5%, and / or a range of up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within the order of magnitude of a value, such as within 10 times, or within 3 times. "About" and "approximately" are synonymous and are used interchangeably herein.

[0044] As used herein, the term "substantially" means a reasonable amount of deviation of the modified term so that the final result will not change significantly. If this deviation does not negate the meaning of the word it modifies, these degree terms should be interpreted as including at least ± 0.5% deviation of the modified term, unless the context otherwise prompts those skilled in the art. As an example, in one embodiment, the term "substantially" means about 95% of a given value. For example, the term "substantially all" means all or at least 95% of all members of a given group.

[0045] This specification refers to several chemical terms and abbreviations used by those skilled in the art. However, definitions of selected terms are provided for clarity and consistency.

[0046] As used herein, the term "alkyl", whether used alone or as part of another group, means a straight or branched chain saturated hydrocarbon group (alkyl). The possible number of carbon atoms in a reference to an alkyl group is indicated by the prefix "C n1-n2 ” or “C n1 -C n2 ” indicates that n1 and n2 are independently integers in the range of 1 to 8, including the end values. Thus, for example, the term “C 1-6 "C1-C6 alkyl" or "C1-C6 alkyl" means an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, and includes, for example, hexylalkyl and pentylalkyl isomers, and any of n-butyl, isobutyl, sec-butyl and tert-butyl, n-propyl and isopropyl, ethyl and methyl. As another example, "C 1-4 "Alkyl" refers to n-butyl, isobutyl, sec-butyl and tert-butyl, n-butyl and isopropyl, ethyl and methyl. Alkyl may be unsubstituted or substituted and the substituents thereon are as described above to the extent that such substitution makes chemical sense.

[0047] As used herein, the term "alkenyl", whether used alone or as part of another group, means a straight or branched chain unsaturated hydrocarbon group containing at least one carbon-carbon double bond and containing up to four carbon-carbon double bonds. The possible number of carbon atoms in the alkenyl group is indicated by the prefix "C n3-n4 ” or “C n3 -C n4 ” indicates that n3 and n4 are independently integers in the range of 2 to 8, including the end values. Thus, for example, the term “C 2-8 "Alkenyl" or "C2-C8 alkenyl" means an alkenyl group containing 2 to 8 carbon atoms. Examples include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, 2,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-pentadienyl, 2,4-pentadienyl, 4-hexadieny, 1,5-hexadienyl, 2-4-hexadieny, 2,5-hexadienyl, 1,3,5-hexatrienyl, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, 4-octene, 1,3,5,7-octatetraene, etc. The alkenyl group may be unsubstituted or substituted, and the substituents thereon are as described above to the extent that such substitutions have chemical significance.

[0048] As used herein, the term "alkynyl", whether used alone or as part of another group, means a straight or branched unsaturated hydrocarbon group containing at least one carbon-carbon triple bond and containing up to four carbon-carbon triple bonds. The possible number of carbon atoms in the alkynyl group is indicated by the prefix "C n5-n6 ” or “C n5 -C n6 ” indicates that n5 and n6 are independently integers in the range of 2 to 8, including the end values. Thus, for example, the term “C 2-8 "Alkynyl" or "C2-C8 alkynyl" means an alkynyl group containing 2 to 8 carbon atoms. Examples include 1-ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 1-hexynyl, 1,5-hexadiynyl, 1-heptynyl, 1-octynyl, 1,3,5-heptatriynyl, and the like. Alkynyl groups may be unsubstituted or substituted, and the substituents thereon are as described above to the extent that such substitutions make chemical sense.

[0049] The terms "cycloalkyl" and "cyclyl" are synonymous and, as used herein, whether used alone or as part of another group, refer to a saturated carbocyclic group containing at least three ring carbon atoms and one or more rings. The number of possible carbon ring atoms in a reference to a cycloalkyl group is indicated by the numerical prefix "C n7-n8"Cycloalkyl" indicates that n7 and n8 are independently integers in the range of 3 to 10, inclusive. For example, the term C 3至10 Cycloalkyl means a cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 ring carbon atoms and one or two condensed rings, and the term C3-C6 cycloalkyl refers to a cycloalkyl having 3, 4, 5 or 6 ring carbon atoms. However, the term includes cycloalkyl substituted with up to 20 carbon atoms, wherein each substituent itself is an alkyl with 1-10 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, 2,3-dimethylcyclohexyl, 2-ethylcyclopentyl, etc. As used herein, the term "cycloalkyl" also includes a bicyclic ring system in which one or two rings are cycloalkyls, such as decalinyl. Cycloalkyl can be unsubstituted or substituted, and the substituents thereon are as described above, to the extent that such substitutions have chemical significance.

[0050] As used herein, the term cycloalkenyl refers to a cyclic unsaturated hydrocarbon, other than an aromatic compound, containing 3 to 10 ring carbon atoms and one or more rings and at least one carbon-carbon double bond. It may contain 1, 2, 3 or 4 carbon-carbon double bonds. The number of possible carbon ring atoms in the cycloalkenyl mentioned is indicated by the numerical prefix "C n9-n10 Cycloalkenyl" indicates that n9 and n 10 are independently integers in the range of 4 to 10, inclusive. Examples include cyclobutene, cyclopentene, cyclohexene, cycloheptene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, and the like. The cycloalkenyl group may be unsubstituted or substituted, and the substituents thereon are as described above to the extent that such substitutions make chemical sense.

[0051] The terms "aryl" and "aromatic" are synonymous, and as used herein, whether used alone or as part of another group, refer to a carbocyclic group containing at least one aromatic ring, 6-20 carbon atoms, and 6, 10, 14, and 18 ring carbon atoms. As used herein, this term excludes heteroaryl. Aryl can be monocyclic, bicyclic, tricyclic, or tetracyclic. Aromatic rings can be substituted by, for example, alkyl groups. Aromatic rings can be fused to cycloalkyl groups, and for the purposes of this disclosure, are considered to be aromatic groups. Examples of aryl include phenyl, α-naphthyl, β-naphthyl, anthracenyl, azulenyl, phenanthrenyl, indanyl, indenyl, tolyl, xylyl, fluorenyl, etc. Aryl can be unsubstituted or substituted, and the substituents thereon are as described above, to the extent that such substitutions have chemical significance.

[0052] The terms "heterocyclyl" or "heterocycle" may be used interchangeably to refer to a non-aromatic, saturated or partially unsaturated ring system containing the specified number of ring atoms including as a ring member at least one ring heteroatom selected from N, O and S, wherein the ring S atoms are optionally substituted with one or two oxo groups (i.e., S(O) X , wherein x is 0, 1 or 2), and wherein the heterocyclic ring is connected to the base molecule via a ring atom, the ring atom can be C or N, and wherein the heterocyclic ring does not contain two connected oxygen atoms. Unless otherwise indicated, the heterocyclic radical contains 3 to 10 ring atoms and 1 to 9 ring carbon atoms. In one embodiment, the heterocyclic radical contains 1 to 4 ring heteroatoms, as defined herein. In one embodiment, the heterocyclic ring contains 5 to 10 ring atoms and 2 to 9 ring carbon atoms. The heterocyclic ring includes a spirocycle, a bridged ring or a ring fused to one or more other heterocycles or carbocyclic rings, wherein such spirocycles, bridged rings or fused rings themselves can be saturated, partially unsaturated or aromatic, to the extent that unsaturation or aromaticity has chemical significance, provided that the point of attachment to the base molecule is an atom of the heterocyclic moiety of the ring system. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and thiomorpholinyl, each of which is optionally substituted as described for the particular substituent to the extent that such substitution makes chemical sense.

[0053] As used herein, the term "3- to 6-membered heterocyclyl" refers to a heterocyclyl containing 3, 4, 5 or 6 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O or S, and contains 1 to 5 carbon atoms, without connected ring oxygen atoms. As used herein, "4- to 6-membered heterocyclyl" refers to a heterocyclyl containing 4, 5 or 6 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O or S, and contains 1 to 5 carbon atoms, without connected ring oxygen atoms. Thus, for example, a 3-membered heterocyclyl contains 1 or 2 ring carbon atoms, a 4-membered heterocyclyl contains 1, 2 or 3 ring carbon atoms, a 5-membered heterocyclyl contains 1, 2, 3 or 4 ring carbon atoms, and a 6-membered heterocyclyl contains 1, 2, 3, 4 or 5 ring carbon atoms. These heterocyclyls may be unsubstituted or substituted. Unless otherwise indicated, substituents are as defined below for heterocyclyl.

[0054] Similarly, "heteroaryl" or "heteroaromatic" refers to a monocyclic or fused bicyclic ring system containing 1, 2, 3 or 4 ring heteroatoms and 2 to 9 ring carbon atoms with well-known aromatic characteristics, which contains the specified number of ring atoms and includes at least one heteroatom selected from N, O and S as a ring member in the aromatic ring. The heteroaryl ring is attached to the base molecule via the ring atoms of the heteroaromatic ring so that aromaticity is maintained. Thus, a 6-membered heteroaryl ring can be attached to the base molecule via a ring C atom, while a 5-membered heteroaryl ring can be attached to the base molecule via a ring C or N atom. The heteroaryl group can also be fused to another aryl or heteroaryl ring or to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided that the point of attachment to the base molecule on such a fused ring system is an atom of the heteroaromatic portion of the ring system. It is understood that no more than two N, O or S atoms are typically linked sequentially, except where an oxo group is attached to N or S to form a nitro or sulfonyl group, or in the case of certain heteroaromatic rings, such as triazine, triazole, tetrazole, oxadiazole, thiadiazole, and the like. Examples of unsubstituted heteroaryl groups often include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, quinoline, isoquinoline, purine, triazine, naphthyridine, carbazole, and the like. Heteroaryl groups may be unsubstituted or substituted, and the substituents thereon are as described above to the extent that such substitutions make chemical sense.

[0055] The term "heterocyclic C n19 -C n20 Alkyl" and "heterocyclic C n19 -C n20 "Alkyl" are used interchangeably and are synonymous and may be used to describe a heterocyclic group as defined herein which is represented by n 19 to n 20 An alkylene linker of a specified length of carbon atoms is attached to the base molecule, where n 19 and n 20 is independently 1, 2, 3, 4, 5, 6, 7 or 8. For example, such groups contain an optionally substituted heterocyclic ring which is n19 -C n20 An alkylene linker is attached to the base molecule, such as a C1-C8, C1-C5, or C1-C3 linker. Where so indicated, such groups are optionally substituted on the alkylene portion with the same groups described herein as applicable to the alkyl group, and on the heterocycle portion with the groups described as applicable to the heterocycle ring.

[0056] The term "heteroaryl C n17 -C n18 Alkyl", which is related to "C n17 -C n18"alkylheteroaryl" and when these terms are used herein, they describe a heteroaryl group as defined herein, which is represented by n 17 to n 18 An alkylene linker of a specified length of carbon atoms is attached to the base molecule, where n 17 and n 18 is independently 1, 2, 3, 4, 5, 6, 7 or 8. For example, such groups contain optionally substituted heteroaryl groups which are substituted by C n17 -C n18 An alkylene linker is attached to the base molecule, such as a C1-C8, C1-C5, or C1-C3 linker. Where so indicated, such groups are optionally substituted on the alkylene portion with the same groups described herein as applicable to the alkyl group, and on the heterocycle portion with the groups described as applicable to the heterocyclic ring.

[0057] The term "cycloalkyl C n15 -C n16 "Alkyl" may be used to describe a cycloalkyl group as defined herein, which is represented by n 15 to n 16 An alkylene linker of a specified length of carbon atoms is attached to the base molecule, where n 15 and n 16 is independently 1, 2, 3, 4, 5, 6, 7 or 8. For example, such groups contain optionally substituted cycloalkyl groups which are substituted by C n15 -C n16 Alkylene linkers are attached to the base molecule, such as C1-C8, C1-C5 or C1-C3 linkers. Where so specified, such groups are optionally substituted in the alkylene moiety with the same groups described herein as being applicable to the alkyl group, and in the cycloalkyl moiety with the groups described as being applicable to the cycloalkyl ring. Examples of such groups include, but are not limited to, cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopentylethyl, cyclohexyl-4-pentyl, etc.

[0058] The term "aryl C n13 -C n14 "Alkyl" can be used to describe 13 or 14 An alkylene linker of a specified length of carbon atoms is attached to an aryl group of a specified size as defined herein to a base molecule, wherein n 13 and n 14 is independently 1, 2, 3, 4, 5, 6, 7 or 8. For example, such groups contain optionally substituted aryl groups which are substituted by C n13 -C n14Alkylene linkers are attached to the base molecule, such as C1-C8, C1-C5 or C1-C3 linkers. Where so indicated, such groups are optionally substituted on the alkylene portion with the same groups described herein as being applicable to the alkyl group, and on the aryl portion with the groups described as being applicable to the aryl ring. Examples include benzyl, phenethyl, phenyl-2-propyl, naphthylmethyl, etc.

[0059] The term "halogen" (or "halo"), whether used alone or as part of another group, refers to a halogen atom and includes fluorine, chlorine, bromine and iodine.

[0060] As used herein, the term "alkoxy", alone or in combination, refers to an alkyl group as defined above, attached to an oxygen linking atom. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, 2-methyl-1-propoxy, and the like.

[0061] As used herein, the term "C n11 -C n12 "Alkylthio" refers to an alkyl group as defined above, wherein n 11 and n 12 is independently 1, 2, 3, 4, 5, 6, 7 or 8, the alkyl group is connected to a sulfur linking atom, which in turn is connected to the base molecule. Examples include, but are not limited to, methylthio, ethylthio, and the like.

[0062] As used herein, the term "hydroxyalkyl", alone or in combination, refers to an alkyl group as defined above, substituted with one or more hydroxy groups. Examples include, but are not limited to, -CH2-OH, -CH2-CH2-OH, -CH2-CH(OH)-CH3, etc.

[0063] With respect to R6, the term “where any two adjacent R 6a Together with the atoms to which they are attached, they form a C4-C6 cycloalkyl or a 4- to 6-membered heterocyclyl", indicating that the aryl ring in the benzyl group is fused to a C4-C6 cycloalkyl or a 4- to 6-membered heterocyclyl ring.

[0064] The term "available" as in "available hydrogen atom" or "available atom" refers to an atom known by those skilled in the art to be capable of being substituted with a substituent.

[0065] The term "pharmaceutically acceptable" means compatible with the treatment of the subject.

[0066] The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant or other material with which the active ingredient is mixed to allow for formation of a pharmaceutical composition, ie, a dosage form capable of being administered to a subject.

[0067] The term "pharmaceutically acceptable salt" means an acid addition salt or a base addition salt that is suitable for or compatible with the treatment of a subject.

[0068] The acid addition salt of the compound of formula I is the salt of amine functionality by acid addition. Suitable for the treatment of the subject or the acid addition salt compatible with the treatment of the subject is any nontoxic organic or inorganic acid addition salt of any basic compound. Illustrative inorganic acids forming suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and acidic metal salts, such as disodium hydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids forming suitable salts include monocarboxylic acids, dicarboxylic acids and tricarboxylic acids. Illustrative examples of such organic acids are, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid and other sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts also include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate (methanesulfonate) ("mesylate"), naphthylsulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (toluenesulfonate) (also known as toluenesulfonate (tosylate)) and the like. In some embodiments, monoacid or diacid salts are formed, and such salts exist in hydrated, solvated or substantially anhydrous forms. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally exhibit higher melting points compared to their free alkali forms. The selection criteria for suitable salts are known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as but not limited to picrates, can be used, for example, for the isolation of compounds of the present disclosure for laboratory use, or for subsequent conversion into pharmaceutically acceptable acid addition salts. Methods for preparing such salts are well known to those skilled in the art. For example, the salt can be prepared by adding a free base compound to a solution of the counterion in a solvent. The solvent can be a polar protic solvent, such as 2-propanol or methanol, and can include a polar aprotic co-solvent, such as dichloromethane. The salt can be precipitated or crystallized by adding a counter solvent in which the salt has a low solubility, such as ether or ethyl acetate.

[0069] Basic addition salts suitable for treatment of a subject or compatible with treatment of a subject are any nontoxic organic or inorganic base addition salts of any acidic compound. Acidic compounds forming basic addition salts include, for example, compounds comprising a carboxylic acid group or a phenolic group. The selection criteria for suitable salts are known to those skilled in the art. In some embodiments, exemplary basic salts also include ammonium salts, alkali metal salts such as sodium salts, lithium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts, and illustrative inorganic bases forming suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or barium hydroxide and ammonia. Illustrative organic bases which form suitable salts include aliphatic, cycloaliphatic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picolinamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, cyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.

[0070] Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides (e.g. methyl, ethyl and butyl chlorides, bromides and iodides), di(lower) alkyl sulfates (e.g. dimethyl, diethyl and dibutyl sulfates), such as C 10-20 Long chain halides, hydrocarbon halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aryl alkyl halides (e.g., benzyl and phenethyl bromides), etc., wherein lower alkyl is defined as C1-C6 alkyl. Compounds carrying acidic moieties can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts) and salts formed with suitable organic ligands, such as quaternary ammonium salts. In addition, in the presence of an acid (-COOH) or phenolic group, a pharmaceutically acceptable ester can be used to modify the solubility or hydrolysis characteristics of the compound.

[0071] All such acid salts and basic salts are intended to be pharmaceutically acceptable salts within the scope of the present application, and for the purposes of the present application, all acid salts and basic salts are considered to be equivalent to the free form of the corresponding compound. In addition, when the compounds of the present application contain both a basic portion and an acidic portion, zwitterions ("inner salts") can be formed and are included in the term "salt" as used herein. It should be understood that certain compounds of the present application can exist in the form of zwitterions, having both anionic and cationic centers and a net neutral charge in the same compound. Such zwitterions are included within the scope of the present disclosure.

[0072] As used herein, the term "solvate" means a compound or a salt or prodrug of a compound in which molecules of a suitable solvent are incorporated into the crystal lattice. Suitable solvents are physiologically tolerable at the doses administered.

[0073] As used herein, the term "prodrug" means a compound or salt of a compound that is converted to an active drug after administration.

[0074] As used herein, the term "protecting group" or "PG" etc. refers to the chemical part of protecting or masking the reactive part of a molecule to prevent side reactions in those reactive parts of the molecule, while manipulating or reacting different parts of the molecule. After the operation or reaction is completed, the protecting group is removed under the conditions of the remainder of the molecule that is not degraded or decomposed. The selection of suitable protecting groups can be carried out by those skilled in the art. Many conventional protecting groups are known in the art, such as described in "Protective groups in Organic Chemistry" McOmie, JFW edited, Plenum Press, 1973, Greene, TW and Wuts, PgM, "Protective groups in Organic Synthesis", John Wiley & Sons, 3. Supplement 1st edition, 1999 and Kocienski, P. Protecting groups, 3rd edition, 2003, georg Thieme Verlag (The Americas).

[0075] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and suitably refers to humans. Thus, the methods of the present disclosure are suitable for both human therapy and veterinary applications.

[0076] As used herein and as known in the art, the term "treating" or "treatment" means a method for obtaining a beneficial or desired result, including a clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation or improvement of one or more symptoms or conditions, reduction in the extent of the disease, a stable (i.e., non-deteriorating) disease state, prevention of disease spread, delay or slowing of disease progression, improvement or slowing of disease state, reduction and alleviation of disease relapse (whether partial or total), whether detectable or undetectable. "Treatment" and "treatment" may also mean extending survival compared to the expected survival if not treated. As used herein, "treating" and "treatment" also include preventive treatment to prevent further development of the disease. For example, a subject with early psychosis may be treated to prevent progression, or alternatively a subject in remission may be treated with a compound or composition of the present disclosure to prevent relapse. The method of treatment comprises administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure, and optionally consists of a single administration or iteratively comprises a series of administrations.

[0077] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of one or more compounds of the present disclosure that is effective at dosages and durations necessary to achieve the desired result. For example, in the context of treating a disease, disorder or condition mediated or treated by agonism or activation of serotonin receptors and downstream second messengers, an effective amount is, for example, an amount that increases the activation compared to the activation without administration of the one or more compounds. For example, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound, material, composition, drug or other material effective to achieve a specific pharmacological and / or physiological effect, including but not limited to reducing the frequency or severity of sadness or lethargy, depressed mood, feelings of anxiety or sadness, decreased interest in all or nearly all activities, significantly increased or decreased appetite leading to weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness, feelings of helplessness, inability to concentrate, and recurring thoughts of death or suicide, or providing a desired pharmacological and / or physiological effect, such as alleviating, inhibiting or reversing one or more of the underlying pathophysiological mechanisms of neurological dysfunction, modulating dopamine levels or signaling, modulating serotonin levels or signaling, modulating norepinephrine levels or signaling, modulating glutamate or GABA levels or signaling, modulating synaptic connectivity or neurogenesis in certain brain regions, or a combination thereof.

[0078] The term "therapeutic index" used with reference to any compound and its associated therapeutic effects and side effects refers to the ratio of the dose of the compound required to induce a particular negative side effect to the dose of the compound required to induce the desired therapeutic effect. For example, in some embodiments, the antidepressant therapeutic effect and the hallucinogenic side effect occur at similar doses, and thus, the therapeutic index of this compound in this context is about 1:1. In contrast, the compounds disclosed herein may have an improved therapeutic index, such as 3:1, where a dose 3 times higher than that required for the antidepressant therapeutic effect is required to induce a hallucinogenic side effect.

[0079] By "alleviating" a disease, disorder or condition, it is meant that the extent and / or undesirable clinical manifestations of the disease, disorder or condition are reduced and / or the time course of progression is slowed or prolonged compared to not treating the disorder.

[0080] As used herein, the term "administering" means administering a therapeutically effective amount of one or more compounds or compositions of the present disclosure to a cell, tissue, organ, or subject.

[0081] As used herein, the terms "prevent" or "prevention" or synonyms thereof refer to a reduction in the risk or probability of a patient developing a disease, disorder or condition, or exhibiting symptoms associated with a disease, disorder or condition.

[0082] As used herein, the terms "disease," "disorder," or "condition" refer to a disease, disorder, or condition that is treated or treatable by activating a serotonin receptor, such as the 5-HT2A receptor, and particularly using a serotonin receptor agonist, such as one or more of the compounds described herein.

[0083] As used herein, the term "treating a disease, disorder or condition by activating a serotonin receptor" means that the disease, disorder or condition to be treated is influenced by, modulated by and / or has some biological basis, either directly or indirectly, that includes serotonergic activity. When the serotonergic activity associated with the disease, disorder or condition is agitated by one or more of the compounds or compositions of the present disclosure, the disease responds favorably.

[0084] As used herein, the term "activation" includes agonism, partial agonism, and positive allosteric modulation of serotonin receptors.

[0085] As used herein, the term "5-HT2A" means the 5-HT2A serotonin receptor.

[0086] The present disclosure includes compounds of Formula I or pharmaceutically acceptable salts thereof:

[0087]

[0088] in

[0089] or a pharmaceutically acceptable salt thereof,

[0090] in

[0091] R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, 3-membered to 6-membered heterocyclic group, C3-C 10 Cycloalkyl C1-C8 alkyl, 3-membered to 6-membered heterocyclyl C1-C8 alkyl, -OR7, -SR7, halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NR8R9, aryl, heteroaryl, aryl C1-C8 alkyl or heteroaryl C1-C8 alkyl;

[0092] R2 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, -OR 10 、-SR 10 , halogenated, -CF3, -SF5, -OCF3, -CN, -NO2 or -NR 11 R 12 ;

[0093] R3 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, -OR 13 、-SR 13 , halogenated, -CF3, -SF5, -OCF3, -CN, -NO2, -NR 14 R 15 、-C(O)R 16 、-C(O)OR 16 、-OC(O)R 16 or -C(O)NR 17 R 18 ;

[0094] R4 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, -OR 19 、-SR 19 , halogenated, -CF3, -SF5, -OCF3, -CN, -NO2, -NR 20 R 21 、-C(O)R 22 、-C(O)OR 22、-OC(O)R 22 or -C(O)NR 23 R 24 ;

[0095] R5 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, cyclopropyl or cyclopropylmethyl; and

[0096] R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1 to 5 examples of R 6a Replace, and for each occurrence of each R 6a independently selected from hydroxyl, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, halo, -CF3, -SF5, -OCF3, -OR 25 、-SR 25 、-CN、-NO2、-NR 26 R 27 、-C(O)R 28 、-C(O)OR 28 、-OC(O)R 28 and -C(O)NR 29 R 30 , or any two adjacent R 6a Together with the atoms to which they are attached, they form a C4-C6 cycloalkyl or a 4- to 6-membered heterocyclyl;

[0097] in

[0098] R7 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, aryl, heteroaryl, aryl C1-C8 alkyl, heteroaryl C1-C8 alkyl, 3-membered to 6-membered heterocyclyl or 3-membered to 6-membered heterocyclyl C1-C8 alkyl;

[0099] R8 and R9 are independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, aryl, aryl C1-C8 alkyl, heteroaryl, heteroaryl C1-C8 heteroaryl, 3-membered to 6-membered heterocyclyl or 3-membered to 6-membered heterocyclyl C1-C8 alkyl;

[0100] R 10 , R 11 , R 12 , R 13 , R14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 are independently hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C5 alkyl, 3- to 6-membered heterocyclyl, or 3- to 6-membered heterocyclylC1-C5 alkyl;

[0101] Aryl is a monocyclic or bicyclic aromatic ring containing 6 or 10 ring carbon atoms;

[0102] Heteroaryl is a monocyclic or bicyclic 5- to 10-membered ring containing 1, 2, 3 or 4 ring heteroatoms and 2 to 9 ring carbon atoms;

[0103] Aryl and heteroaryl groups may be unsubstituted or substituted with one or more substituents independently selected from hydroxy, C1-C5 alkyl, C2-C5 alkenyl, C 2-5 Alkynyl, C3-C6 cycloalkyl, C1-C5 alkoxy, halo, -CF3, -CN, -NO2, -NH2, aryl, heteroaryl, C3-C6 cycloalkyl C1-C3 alkyl, aryl C1-C3 alkyl, heteroaryl C1-C3 alkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered heterocyclyl C1-C3 alkyl;

[0104] Cycloalkyl and heterocyclyl may be unsubstituted or substituted with one or more substituents independently selected from hydroxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C1-C5 alkoxy, halo, -CF3, -CN, -NO2, -NH2, aryl, heteroaryl, C3-C6 cycloalkyl C1-C3 alkyl, aryl C1-C3 alkyl, heteroaryl C1-C3 alkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered heterocyclyl C1-C3 alkyl; and

[0105] Alkyl, alkenyl and alkynyl groups may be unsubstituted or substituted with one or more substituents independently selected from hydroxy, C3-C6 cycloalkyl, C1-C5 alkoxy, halo, -CF3, -CN, -NO2, -NH2, aryl, heteroaryl, C3-C6 cycloalkylC1-C3 alkyl, arylC1-C3 alkyl, heteroarylC1-C3 alkyl, 3- to 6-membered heterocyclyl and 3- to 6-membered heterocyclylC1-C3 alkyl.

[0106] In one embodiment, unless indicated to the contrary in the definitions of substituents described above, heteroaryl and aryl are independently unsubstituted or substituted with one or more substituents independently selected from hydroxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C5 cycloalkyl, C1-C5 alkoxy, halo, -CF3, -CN, -NH2 and -NO2.

[0107] In another embodiment, unless indicated to the contrary in a definition, alkyl, alkenyl, and alkynyl are independently unsubstituted or substituted with one or more substituents independently selected from fluoro, C3-C5 cycloalkyl, hydroxy, and C1-C5 alkoxy.

[0108] In another embodiment, unless indicated to the contrary in a definition, cycloalkyl and 3 to 6 membered heterocyclyl are independently unsubstituted or substituted with one or more substituents independently selected from fluoro, C1-C5 alkyl, hydroxy or C1-C5 alkoxy.

[0109] In one embodiment, R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C6 cycloalkylC1-C5 alkyl, -OR7, -SR7, halo, -CF3, -SF5, -OCF3, -CN, -NO2, or -NR8R9. In another embodiment, R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, -OR7, -SR7, halo, -CF3, -OCF3, -CN, -NO2, or -NR8R9. In another embodiment, R1 is C1-C8 alkyl, -S(C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2. In another embodiment, R1 is C1-C8 alkyl, -S(C1-C8 alkyl), halo, -CF3, -OCF3, -CN, -NO2, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2. In another embodiment, R1 is C1-C8 alkyl, -S(C1-C8 alkyl), halo, -CF3 or -SF5. In another embodiment, R1 is C1-C8 alkyl, -S(C1-C8 alkyl), halo or -CF3. In a further embodiment, R1 is C1-C6 alkyl, -S(C1-C6 alkyl), halo or -CF3. In a further embodiment, R1 is C1-C6 alkyl, halo or -CF3. In a further embodiment, R1 is C1-C8 alkyl or halo. In a further embodiment, R1 is C1-C6 alkyl or halo. In further embodiments, R1 is methyl, ethyl, n-propyl, I, Br or Cl. In further embodiments, halo is I, Br or Cl. In one embodiment, halo is Br or Cl, and in further embodiments, halo is Br.

[0110] In one embodiment, R2 is hydrogen, hydroxy, C1-C3 alkyl, halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, C1-C3 alkoxy or -S(C1-C3 alkyl). In another embodiment, R2 is hydrogen, hydroxy, C1-C3 alkyl, halo, -CF3, -OCF3, -CN, -NO2, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, C1-C3 alkoxy or -S(C1-C3 alkyl). In another embodiment, R2 is hydrogen, hydroxy, C1-C3 alkyl, halo, -CF3, -CN, -NO2, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, C1-C3 alkoxy or -S(C1-C3 alkyl). In another embodiment, R2 is hydrogen, hydroxyl, C1-C3 alkyl, halo, -CF3 or -C1-C3 alkoxy. In another embodiment, R2 is hydrogen or -C1-C3 alkoxy. In another embodiment, R2 is hydrogen or methoxy. In another embodiment, R2 is hydrogen.

[0111] In one embodiment, R3 is hydrogen, hydroxy, -OR 13 、-SR 13 、-C(O)NH2 or -OC(O)R 16 In another embodiment, R3 is hydrogen, hydroxy, -OR 13 or -SR 13 In another embodiment, R3 is hydroxy, -OR 13 or -SR 13 In another embodiment, R3 is hydrogen or OR 13 In a further embodiment, R3 is OR 13 In yet further embodiments, R3 is C1-C8 alkoxy or hydrogen, and in another embodiment, R3 is C1-C5 alkoxy or hydrogen. In another embodiment, R3 is C1-C5 alkoxy. In one embodiment, R3 is C1-C3 alkoxy or hydrogen, and in another embodiment, R3 is C1-C3 alkoxy. In a further embodiment, R3 is hydrogen, methoxy or ethoxy, and in another embodiment, R3 is ethoxy or methoxy. In a further embodiment, R3 is hydrogen or methoxy, and in yet further embodiments, R3 is methoxy.

[0112] In one embodiment, R4 is hydroxy, -OR 19 、-SR 19 、-C(O)NH2 or -OC(O)R 22 In another embodiment, R4 is hydroxy, -OR 19 or -SR19 In another embodiment, R4 is hydroxy or -OR 19 In a further embodiment, R4 is -OR 19 In another embodiment, R4 is C1-C8 alkoxy, and in another embodiment, R4 is C1-C5 alkoxy, and in a further embodiment, R4 is C1-C3 alkoxy. In yet further embodiments, R4 is methoxy or ethoxy, and in yet further embodiments, R4 is methoxy.

[0113] In one embodiment, R5 is hydrogen or C1-C3 alkyl. In a further embodiment, R5 is hydrogen or C1-C2 alkyl, and in yet a further embodiment, R5 is hydrogen, methyl or ethyl.

[0114] In one embodiment, R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1 to 5 examples of R 6a Replace, and for each occurrence of each R 6a R is independently selected from hydroxy, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C5 cycloalkyl, halo, -CF3, -SF5, -OCF3, C1-C3 alkoxy, -S(C1-C3 alkyl), -CN, -NO2, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, -C(O)(C1-C3 alkyl), -C(O)O(C1-C3 alkyl), -OC(O)(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl) and -C(O)N(C1-C3 alkyl)2, or any two adjacent R 6a Together with the atoms to which they are attached, they form an optionally substituted 4-6 membered cycloalkyl or 4-6 membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from oxygen, nitrogen and sulfur, and wherein the cycloalkyl and heterocyclyl are as defined above. It is understood by those of ordinary skill in the art that when two adjacent R 6a When the substituents are taken together to form a 4-6 membered cycloalkyl ring, the resulting ring is a cycloalkyl ring but contains a single carbon-carbon double bond between the carbons through which the resulting ring is fused to the benzene ring of the benzyl group. 6a When the substituents are taken together to form a 4-6 membered heterocyclyl ring, the resulting ring is a heterocyclic ring and contains a carbon-carbon double bond between the carbons through which the resulting ring is fused to the benzyl ring. In further embodiments, R6 is hydrogen or benzyl, wherein the benzyl ring is optionally replaced by 1-5 instances of R 6a Replace, and for each occurrence of each R 6a are independently selected from hydroxy, C1-C3 alkyl, halo and C1-C3 alkoxy, or any two adjacent R 6aTogether with the atoms to which they are attached, they form an optionally substituted 4-5 membered cycloalkyl or 4-5 membered heterocyclyl. In even further embodiments, R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally substituted with 1-5 instances of R 6a Replace, and for each occurrence of each R 6a are independently selected from hydroxy, halo, methoxy and ethoxy, or any two adjacent R 6a Together with the atoms to which they are attached, they form an optionally substituted 5-membered cycloalkyl or 5-membered heterocyclyl. In another embodiment, R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally substituted with 1-5 examples of R 6a Replace, and for each occurrence of each R 6a are independently selected from hydroxy, halo and methoxy, or any two adjacent R 6a Together with the atoms to which they are attached, they form an optionally substituted 5-membered cycloalkyl or 5-membered heterocyclyl group fused to a benzene ring. In another embodiment, R6 is hydrogen or benzyl, wherein the benzyl ring is optionally substituted with 1-2 R 6a , and for each occurrence of each R 6a are independently selected from hydroxy, fluoro and methoxy, or any two adjacent R 6a Together with the atoms to which they are attached, they form a methylenedioxy ring. In even further embodiments, R6 is benzyl, wherein the phenyl ring of the benzyl group is optionally substituted with 1-2 R 6a , and for each occurrence of each R 6a are independently selected from hydroxy, fluoro and methoxy, or any two adjacent R 6a Together with the atoms to which they are attached they form a methylenedioxy ring. In a further embodiment, R6 is hydrogen.

[0115] In one embodiment, R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19Can be the same or different. In one embodiment, R3 and R4 are independently C1-C8 alkoxy, and in another embodiment, are independently C1-C5 alkoxy. In one embodiment, R3 and R4 are independently methoxy, ethoxy, n-propoxy or isopropoxy. In a further embodiment, R3 and R4 are independently methoxy or ethoxy. In a further embodiment, R3 and R4 are identical. In one embodiment, both R3 and R4 are C1-C8 alkoxy and are identical, and in another embodiment, both R3 and R4 are C1-C5 alkoxy and are identical. In one embodiment, R3 and R4 are methoxy, ethoxy, n-propoxy or isopropoxy and are identical. In a further embodiment, R3 and R4 are methoxy or ethoxy and are identical. In one embodiment, R3 and R4 are methoxy.

[0116] In one embodiment, R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19 can be the same or different, and R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 CycloalkylC1-C8 alkyl, -OR7, -SR7, halo, -CF3, -SF5, -OCF3, -CN, -NO2, or -NR8R9. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl)2, and R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19 In another embodiment, R1 is C1-C8 alkyl, -S(C1-C8 alkyl), halo, -CF3, -SF5, and R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19In a further embodiment, R1 is C1-C6 alkyl, -S(C1-C6 alkyl), halo or -CF3, and R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19 In yet further embodiments, R1 is C1-C8 alkyl or halo, and R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19 In a further embodiment, R1 is C1-C6 alkyl or halo, and R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19 Can be the same or different. In one embodiment, halo is Br, Cl or I, and in a further embodiment, halo is Br or Cl, and in yet a further embodiment, halo is Br.

[0117] In one embodiment, R3 is C1-C8 alkoxy and R4 is C1-C8 alkoxy, and R3 and R4 can be the same or different, and R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2 or -NR8R9. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl)2, R3 is C1-C8 alkoxy and R4 is C1-C8 alkoxy, and R3 and R4 can be the same or different. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, and R3 is C1-C8 alkoxy and R4 is C1-C8 alkoxy, and R3 and R4 can be the same or different. In a further embodiment, R1 is C1-C6 alkyl, -S(C1-C6 alkyl), halo or -CF3, and R3 is C1-C8 alkoxy and R4 is C1-C8 alkoxy, and R3 and R4 can be the same or different. In a further embodiment, R1 is C1-C8 alkyl or halo, and R3 is C1-C8 alkoxy and R4 is C1-C8 alkoxy, and R3 and R4 can be the same or different. In a further embodiment, R1 is C1-C6 alkyl or halo, and R3 is C1-C8 alkoxy and R4 is C1-C8 alkoxy, and R3 and R4 can be the same or different. In a further embodiment, halo is Br, Cl or I, and in a further embodiment, halo is Br or Cl, and in a further embodiment, halo is Br.

[0118] In one embodiment, R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different, and R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2 or -NR8R9. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl)2, R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, and R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different. In further embodiments, R1 is C1-C6 alkyl, -S (C1-C6 alkyl), halo or -CF3, and R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different. In further embodiments, R1 is C1-C8 alkyl or halo, and R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different. In further embodiments, R1 is C1-C6 alkyl or halo, and R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different. In further embodiments, R1 is C1-C6 alkyl or halo, and R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different. In one embodiment, halo is Br, Cl or I, and in further embodiments, halo is Br or Cl, and in further embodiments, halo is Br.

[0119] In one embodiment, R3 is C1-C3 alkoxy and R4 is C1-C3 alkoxy, and R3 and R4 can be the same or different, and R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2 or -NR8R9. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl)2, R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, and R3 is C1-C3 alkoxy and R4 is C1-C3 alkoxy, and R3 and R4 can be the same or different. In a further embodiment, R1 is C1-C6 alkyl, -S (C1-C6 alkyl), halo or -CF3, and R3 is C1-C3 alkoxy and R4 is C1-C3 alkoxy, and R3 and R4 can be the same or different. In a further embodiment, R1 is C1-C8 alkyl or halo, and R3 is C1-C3 alkoxy and R4 is C1-C3 alkoxy, and R3 and R4 can be the same or different. In a further embodiment, R1 is C1-C6 alkyl or halo, and R3 is C1-C3 alkoxy and R4 is C1-C3 alkoxy, and R3 and R4 can be the same or different. In one embodiment, halo is Br, Cl or I, and in a further embodiment, halo is Br or Cl, and in a further embodiment, halo is Br.

[0120] In one embodiment, R3 is methoxy and R4 is methoxy, and R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10CycloalkylC1-C8 alkyl, -OR7, -SR7, halo, -CF3, -SF5, -OCF3, -CN, -NO2 or -NR8R9. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl)2, R3 is methoxy and R4 is methoxy. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, and R3 is methoxy and R4 is methoxy. In a further embodiment, R1 is C1-C6 alkyl, -S (C1-C6 alkyl), halo or -CF3, and R3 is methoxy and R4 is methoxy. In yet further embodiments, R1 is C1-C8 alkyl or halo, R3 is methoxy and R4 is methoxy. In further embodiments, R1 is C1-C6 alkyl or halo, and R3 is methoxy and R4 is methoxy. In one embodiment, halo is Br, Cl or I, and in further embodiments, halo is Br or Cl, and in yet further embodiments, halo is Br.

[0121] In one embodiment, R3 is OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19Can be identical or different, and R5 is C1-C3 alkyl or hydrogen.In one embodiment, R3 and R4 are independently C1-C8 alkoxy, and R5 is C1-C3 alkyl or hydrogen.In one embodiment, R3 and R4 are independently C1-C5 alkoxy, and R5 is C1-C3 alkyl or hydrogen.In one embodiment, R3 and R4 are independently methoxy, ethoxy, n-propoxy or isopropoxy, and R5 is C1-C3 alkyl or hydrogen.In a further embodiment, R3 and R4 are independently methoxy or ethoxy, and R5 is C1-C3 alkyl or hydrogen.In a further embodiment, R3 and R4 are identical, and R5 is C1-C3 alkyl or hydrogen.In one embodiment, R3 and R4 are both C1-C8 alkoxy and are identical, and R5 is C1-C3 alkyl or hydrogen. In one embodiment, R3 and R4 are both C1-C5 alkoxy and are the same, and R5 is C1-C3 alkyl or hydrogen. In one embodiment, R3 and R4 are methoxy, ethoxy, n-propoxy or isopropoxy and are the same, and R5 is C1-C3 alkyl or hydrogen. In a further embodiment, R3 and R4 are methoxy or ethoxy and are the same, and R5 is C1-C3 alkyl or hydrogen. In one embodiment, R3 and R4 are both methoxy and R5 is C1-C3 alkyl or hydrogen.

[0122] In one embodiment, R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19 can be the same or different, and R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, and R3 is -OR7, -SR7, halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, and R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, and R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In a further embodiment, R1 is C1-C6 alkyl, -S(C1-C6 alkyl), halo or -CF3, and R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In yet further embodiments, R1 is C1-C8 alkyl or halo, and R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In a further embodiment, R1 is C1-C6 alkyl or halo, and R3 is -OR 13 And R4 is -OR 19 , where R 13 and R 19 As defined above, and -OR 13 AND-OR 19 Can be the same or different, and R5 is C1-C3 alkyl or hydrogen.In one embodiment, halo is Br, Cl or I, and in further embodiments, halo is Br or Cl, and in yet further embodiments, halo is Br.

[0123] In one embodiment, R3 is C1-C8 alkoxy and R4 is C1-C8 alkoxy, and R3 and R4 can be the same or different, and R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl)2, R3 is C1-C8 alkoxy and R4 is C1-C8 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, and R3 is C1-C8 alkoxy and R4 is C1-C8 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In a further embodiment, R1 is C1-C6 alkyl, -S (C1-C6 alkyl), halo or -CF3, and R3 is C1-C8 alkoxy and R4 is C1-C8 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In a further embodiment, R1 is C1-C8 alkyl or halo, and R3 is C1-C8 alkoxy and R4 is C1-C8 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In further embodiments, R1 is C1-C6 alkyl or halo, and R3 is C1-C8 alkoxy and R4 is C1-C8 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In one embodiment, halo is Br, Cl or I, and in further embodiments, halo is Br or Cl, and in yet further embodiments, halo is Br.

[0124] In one embodiment, R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different, and R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl)2, R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, and R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In a further embodiment, R1 is C1-C6 alkyl, -S (C1-C6 alkyl), halo or -CF3, and R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In a further embodiment, R1 is C1-C8 alkyl or halo, and R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In further embodiments, R1 is C1-C6 alkyl or halo, and R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In one embodiment, halo is Br, Cl or I, and in further embodiments, halo is Br or Cl, and in yet further embodiments, halo is Br.

[0125] In one embodiment, R3 is C1-C3 alkoxy and R4 is C1-C3 alkoxy, and R3 and R4 can be the same or different, R5 is C1-C3 alkyl or hydrogen, and R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10CycloalkylC1-C8 alkyl, -OR7, -SR7, halo, -CF3, -SF5, -OCF3, -CN, -NO2 or -NR8R9. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, R3 is C1-C5 alkoxy and R4 is C1-C5 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, and R3 is C1-C3 alkoxy and R4 is C1-C3 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In a further embodiment, R1 is C1-C6 alkyl, -S (C1-C6 alkyl), halo or -CF3, and R3 is C1-C3 alkoxy and R4 is C1-C3 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In a further embodiment, R1 is C1-C8 alkyl or halo, and R3 is C1-C3 alkoxy and R4 is C1-C3 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In further embodiments, R1 is C1-C6 alkyl or halo, and R3 is C1-C3 alkoxy and R4 is C1-C3 alkoxy, and R3 and R4 can be the same or different, and R5 is C1-C3 alkyl or hydrogen. In one embodiment, halo is Br, Cl or I, and in further embodiments, halo is Br or Cl, and in yet further embodiments, halo is Br.

[0126] In one embodiment, R3 is methoxy and R4 is methoxy, R5 is C1-C3 alkyl or hydrogen, and R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2 or -NR8R9. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl)2, R3 is methoxy and R4 is methoxy, and R5 is C1-C3 alkyl or hydrogen. In another embodiment, R1 is C1-C8 alkyl, -S (C1-C8 alkyl), halo, -CF3, -SF5, and R3 is methoxy and R4 is methoxy, and R5 is C1-C3 alkyl or hydrogen. In further embodiments, R1 is C1-C6 alkyl, -S(C1-C6 alkyl), halo or -CF3, and R3 is methoxy and R4 is methoxy, and R5 is C1-C3 alkyl or hydrogen. In further embodiments, R1 is C1-C8 alkyl or halo, R3 is methoxy and R4 is methoxy, and R5 is C1-C3 alkyl or hydrogen. In further embodiments, R1 is C1-C6 alkyl or halo, and R3 is methoxy and R4 is methoxy, and R5 is C1-C3 alkyl or hydrogen. In further embodiments, R1 is C1-C6 alkyl or halo, and R3 is methoxy and R4 is methoxy, and R5 is C1-C3 alkyl or hydrogen. In one embodiment, halo is Br, Cl or I, and in further embodiments, halo is Br or Cl, and in further embodiments, halo is Br.

[0127] In one embodiment, R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, -OR7, -SR7, halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NR8R9, aryl, heteroaryl, arylC1-C8alkyl or heteroarylC1-C8alkyl;

[0128] R2 is hydrogen, hydroxy, C1-C8 alkyl, halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH(C1-C8 alkyl), -N(C1-C8 alkyl)2, C1-C8 alkoxy or -S(C1-C8 alkyl);

[0129] R3 is hydrogen, hydroxyl, -OR 13 、-SR 13 、-C(O)NH2、-OC(O)R 16 ;

[0130] R4 is hydroxyl, OR 19 、-SR 19 、-C(O)NH2、-OC(O)R 22 ;

[0131] R5 is hydrogen or C1-C2 alkyl; and

[0132] R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1 to 5 examples of R 6a Replace, and for each occurrence of each R 6a Independently selected from hydroxyl, C 1-8 Alkyl, halo, -CF3, -SF5, -OCF3, C1-C8 alkoxy, -S(C1-C8 alkyl), -CN, -NO2, -NH2, -NH(C1-C8 alkyl), -N(C1-C8 alkyl)2, -C(O)(C1-C8 alkyl), -C(O)O(C1-C8 alkyl), -OC(O)(C1-C8 alkyl), -C(O)NH2, -C(O)NH(C1-C8 alkyl) and -C(O)N(C1-C8 alkyl)2, or any two adjacent R 6a Together with the atoms to which they are attached they form an optionally substituted 4-6 membered cyclyl or 4-6 membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from oxygen, nitrogen and sulfur.

[0133] In one embodiment, R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, 3-membered to 6-membered heterocyclic group, C3-C 10 Cycloalkyl C1-C8 alkyl, 3-membered to 6-membered heterocyclyl C1-C8 alkyl, -OR7, -SR7, halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NR8R9, aryl, heteroaryl, aryl C1-C8 alkyl or heteroaryl C1-C8 alkyl;

[0134] R2 is hydrogen, hydroxy, C1-C3 alkyl, halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, C1-C3 alkoxy or -S(C1-C3 alkyl);

[0135] R3 is hydrogen, hydroxyl, -OR 13 、-SR 13 、-C(O)NH2、-OC(O)R 16 ;

[0136] R4 is hydroxyl, OR 19 、-SR 19 、-C(O)NH2、-OC(O)R 22 ;

[0137] R5 is hydrogen or C1-C2 alkyl; and

[0138] R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1 to 5 examples of R 6a Replace, and for each occurrence of each R 6a Independently selected from hydroxyl, C 1-3 Alkyl, halo, -CF3, -SF5, -OCF3, C1-C8 alkoxy, -S(C1-C3 alkyl), -CN, -NO2, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, -C(O)(C1-C3 alkyl), -C(O)O(C1-C8 alkyl), -OC(O)(C1-C8 alkyl), -C(O)NH2, -C(O)NH(C1-C8 alkyl) and -C(O)N(C1-C3 alkyl)2, or any two adjacent R 6a Together with the atoms to which they are attached they form an optionally substituted 4-6 membered cyclyl or 4-6 membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from oxygen, nitrogen and sulfur.

[0139] In a further embodiment, R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C6 cycloalkylC1-C5 alkyl, -OR7, -SR7, halo, -CF3, -SF5, -OCF3, -CN, -NO2 or -NR8R9;

[0140] R2 is hydrogen or C1-C3 alkoxy;

[0141] R3 is hydrogen or C1-C3 alkoxy;

[0142] R4 is C1-C3 alkoxy;

[0143] R5 is hydrogen or C1-C2 alkyl;

[0144] R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1 to 5 examples of R 6a Replace, and for each occurrence of each R 6a are independently selected from hydroxy, C1-C3 alkyl, halo and C1-C3 alkoxy, or any two adjacent R 6a Together with the atoms to which they are attached, they form an optionally substituted 4-5 membered cyclyl or 4-5 membered heterocyclyl; and

[0145] R7, R8 and R9 are independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl and C3-C6 cycloalkylC1-C5 alkyl.

[0146] In yet further embodiments, R1 is C1-C8 alkyl, -S(C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2;

[0147] R2 is hydrogen or methoxy;

[0148] R3 is hydrogen or methoxy;

[0149] R4 is a methoxy group;

[0150] R5 is hydrogen or C1-C2 alkyl; and

[0151] R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1 to 5 examples of R 6a Replace, and for each occurrence of each R 6a are independently selected from hydroxy, halo and methoxy, or any two adjacent R 6a Together with the atoms to which they are attached, they form an optionally substituted 5-membered cyclyl or 5-membered heterocyclyl.

[0152] In another embodiment, R1 is C1-C8 alkyl, -S(C1-C8 alkyl), halo, -CF3, -SF5.

[0153] R2 is hydrogen or methoxy;

[0154] R3 is hydrogen or methoxy;

[0155] R4 is a methoxy group;

[0156] R5 is hydrogen or C1-C2 alkyl; and

[0157] R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1-2 examples of R 6a Replace, and for each occurrence of each R 6a are independently selected from hydroxy, fluoro and methoxy, or any two adjacent R 6a Together with the atoms to which they are attached they form a methylenedioxy ring.

[0158] In further embodiments, R1 is C1-C8 alkyl, -S(C1-C8 alkyl), halo or -CF3, and R2, R3, R4, R5 and R6 are as defined herein. In further embodiments, R1 is C1-C6 alkyl, -S(C1-C6 alkyl), halo or -CF3, and R2, R3, R4, R5 and R6 are as defined herein. In further embodiments, R2 is hydrogen, and R1, R3, R4, R5 and R6 are as defined herein. In yet another embodiment, R3 and R4 are methoxy, and R1, R2, R5 and R6 are as defined herein. In even further embodiments, R5 is hydrogen, methyl or ethyl, and R1, R2, R3, R4 and R6 are as defined herein. In yet further embodiments, R6 is hydrogen, and R1, R2, R3, R4 and R5 are as defined herein. In another embodiment, R6 is benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1-2 instances of R 6a Replace, and for each occurrence of each R 6a are independently selected from hydroxy, fluoro and methoxy, or any two adjacent R 6a Together with the atoms to which they are attached, they form a methylenedioxy ring, and R1, R2, R3, R4 and R5 are as defined herein.

[0159] In one embodiment, R3 is -OR 13 , where R 13 is C1-C5 alkyl, such as C1-C5 alkoxy, such as methoxy; R4 is -OR 19 , where R 19 is C1-C5 alkyl, such as C1-C5 alkoxy, such as methoxy, R2 is hydrogen, R1 is C1-C8 alkyl, halo (such as chlorine or bromine), -CF3, -SR7, wherein R7 is C1-C8 alkyl, i.e. C1-C5 alkylthio; R5 is hydrogen or C1-C3 alkyl, and R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1-2 examples of R 6a Replace, and for each occurrence of each R 6a Independently selected from hydroxy, halo (eg fluoro) and C1-C5 alkoxy (eg methoxy).

[0160] In a further embodiment, the compound of Formula I has the following structure:

[0161]

[0162]

[0163]

[0164] It is to be understood that all combinations and permutations of R1, R2, R3, R4, R5 and R6 are contemplated within the compounds of the present disclosure.

[0165] The present disclosure includes isotopes of atoms occurring on the compounds of Formula I and the various embodiments described herein. As defined herein, isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include protium, deuterium, and tritium, and isotopes of carbon include carbon-12, carbon-13, and carbon-14.

[0166] It should be understood that any carbon symbol in structures throughout this disclosure, when used without additional symbols, is intended to represent all isotopes of carbon, e.g. 12 C. 13 C or 14 C. In addition, it contains 13 C or 14 The compound of C may specifically have the structure of any compound disclosed herein.

[0167] It is also to be understood that any hydrogen symbol in the structures of the present disclosure, when used without additional symbols, is intended to represent all isotopes of hydrogen, e.g. 1 H. 2 H or 3 H. In addition, 2 H or 3 Any compound of H may specifically have the structure of any compound disclosed herein.

[0168] Isotopically labeled compounds can generally be prepared by conventional techniques known to the skilled artisan using an appropriate isotopically labeled reagent in place of the non-labeled reagent employed.

[0169] It should be further understood and appreciated that, in some embodiments, the compounds of the present disclosure may have at least one chiral center, and therefore may exist as enantiomers and / or diastereomers. It should be understood that all such isomers and mixtures of any ratio thereof are encompassed within the scope of the present disclosure. It should be further understood that, although the stereochemistry of the compound may be shown in any given compound listed herein, such compounds may also contain a certain amount (e.g., less than 20%, suitably less than 10%, more suitably less than 5%) of the compounds of the present disclosure with alternative stereochemistry. It is contemplated that any optical isomers such as separated, pure or partially purified optical isomers or their racemic or scalemic mixtures are included within the scope of the present disclosure.

[0170] The compounds of the present disclosure are suitably formulated into compositions using one or more carriers in a conventional manner. Therefore, the present disclosure also includes compositions comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier. The compounds of the present disclosure are suitable for being formulated into pharmaceutical compositions for administration to a subject in a biocompatible form suitable for in vivo administration. Therefore, the present disclosure further includes pharmaceutical compositions comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier. In an embodiment of the present disclosure, the pharmaceutical composition is used to treat any disease, disorder or condition described herein.

[0171] The compound of the present disclosure is applied to the subject in various forms, and the form depends on the route of administration selected, as will be understood by those skilled in the art. For example, the compound of the present disclosure is applied by oral, inhalation, intravenous, vaporization, parenteral, buccal, sublingual, insufflation, epidural, nasal, rectal, vaginal, patch, pump, mini pump, topical or transdermal administration, and the pharmaceutical composition is formulated accordingly. In some embodiments, it is applied by a pump for periodic or continuous delivery. Conventional procedures and ingredients for selecting and preparing suitable compositions are described in, for example, Remington's Pharmaceutical Sciences (2000-20th edition) and the U.S. Pharmacopeia published in 1999: National Formulary (USP24NF19).

[0172] Parenteral administration includes systemic routes of delivery other than the gastrointestinal (GI) tract, and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (e.g., by use of an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0173] In some embodiments, the compounds of the present disclosure are administered orally, for example, with an inert diluent or with an assimilable edible carrier, or enclosed in a hard or soft shell gelatin capsule, or compressed into tablets, or mixed directly with the food of the diet. In some embodiments, the compounds are mixed with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gums, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, etc. In the case of tablets, carriers used include lactose, corn starch, sodium citrate and phosphates. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silicon dioxide); disintegrants (e.g., potato starch or sodium hydroxymethyl starch); wetting agents (e.g., sodium lauryl sulfate); or solvents (e.g., medium chain triglycerides, ethanol, water). In an embodiment, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets, or granules for oral administration, a pH-sensitive enteric coating, such as one designed to control the release of the active ingredient, is optionally used. Oral dosage forms also include modified release formulations, such as immediate release and timed release formulations. Examples of modified release formulations include, for example, sustained release (SR), extended release (ER, XR or XL), timed release (time-release) or timed release (timed-release), controlled release (CR) or sustained release (CR or Contin), which are, for example, in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, aggregated particles (e.g., molecular sieve-type particles), or fine hollow permeable fiber bundles, or short cut hollow permeable fibers aggregated or retained in fiber capsules. Timed release compositions are formulated, for example, as liposomes or those in which the active compound is protected with different degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. In some embodiments, liposomes are formed by various phospholipids such as cholesterol, stearylamine or phosphatidylcholine. For oral administration in capsule form, useful carriers, solvents or diluents include lactose, medium chain triglycerides, ethanol and dried corn starch.

[0174] In some embodiments, the liquid preparation for oral administration takes the form of, for example, solution, syrup or suspension, or they are suitable for presentation as a dry product for redissolving with water or other suitable vehicles before use. When aqueous suspensions and / or emulsions are administered orally, the compound of the present disclosure is appropriately suspended or dissolved in an oil phase combined with an emulsifier and / or suspending agent. If desired, some sweeteners and / or flavoring agents and / or coloring agents are added. Such liquid preparations for oral administration are prepared by conventional means with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., medium chain triglycerides, almond oil, oily esters or ethanol); and preservatives (e.g., methylparaben or propylparaben or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0175] It is also possible to freeze-dry the compounds of the disclosure and to use the lyophilisates obtained, for example, for the preparation of products for injection.

[0176] In some embodiments, the compound of the present disclosure is administered parenterally. For example, a solution of the compound of the present disclosure is prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycol, DMSO and mixtures thereof with or without alcohol, and in oil. Under common storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms. Those skilled in the art will know how to prepare suitable preparations. For parenteral administration, a sterile solution of the compound of the present disclosure is usually prepared, and the pH of the solution is suitably adjusted and buffered. For intravenous use, the total concentration of the solute should be controlled to make the preparation isotonic. For ocular administration, ointments or drop-in liquids are delivered, for example, by an ocular delivery system known in the art such as an applicator or an eye dropper. In some embodiments, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and a diluent or carrier in a common amount. For pulmonary administration, a diluent or carrier is selected that is suitable to allow formation of an aerosol.

[0177] In some embodiments, the compound of the present disclosure is formulated for parenteral administration by injection including the use of conventional catheter insertion techniques or infusions. Injectable preparations are presented, for example, in unit dosage forms, such as in ampoules or in multiple dose containers, with preservatives added. In some embodiments, the composition takes the form of a sterile suspension, solution or emulsion, for example, in an oily or aqueous vehicle, and contains a preparatant, such as a suspending agent, a stabilizer and / or a dispersant. In all cases, the form must be sterile and must be fluid, to the extent that easy injectability exists. Alternatively, the compound of the present disclosure is suitably in the form of a sterile powder for reconstitution with a suitable vehicle before use, such as sterile pyrogen-free water.

[0178] In some embodiments, the composition for nasal administration is conveniently formulated as aerosol, drops, gel and powder. For intranasal administration or administration by inhalation, the compound of the present disclosure is conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container squeezed or pumped by the patient, or delivered as an aerosol spray presentation form from a pressurized container or atomizer. Aerosol formulations typically include a solution or fine suspension of active substances in a physiologically acceptable aqueous or non-aqueous solvent, and are usually present in a sealed container in a sterile form with a single or multiple dose amount, the container for example taking the form of a cartridge or a refill used with an atomizing device. Alternatively, the sealed container is a unit dispensing device, such as a single dose nasal inhaler or an aerosol dispenser equipped with a metering valve, which is intended to be discarded after use. In the case where the dosage form includes an aerosol dispenser, it will contain a propellant, which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorocarbons. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, sevoflurane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, a pressurized container or spray contains a solution or suspension of the active compound. Capsules and cartridges (e.g., made of gelatin) for use in inhalers or insufflators are, for example, formulated as a powder mixture containing a compound of the present disclosure and a suitable powder base (e.g., lactose or starch). Aerosol dosage forms can also take the form of a pump-atomizer.

[0179] Compositions suitable for buccal or sublingual administration include tablets, lozenges, films and pastilles in which a compound of the disclosure is formulated with a carrier such as sugar, acacia, tragacanth or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing conventional suppository bases such as cocoa butter.

[0180] The suppository form of the compound of the present disclosure can be used for vaginal, urethral and rectal administration. Such suppositories are usually constructed by a mixture of substances that are solid at room temperature but melt at body temperature. The materials commonly used to create such vehicles include, but are not limited to, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th edition, Mack Publishing, Easton, Pa., 1980, pp. 1530-1533 for further discussion of suppository dosage forms.

[0181] In some embodiments, the compounds of the present disclosure are coupled with soluble polymers as target drug carriers. Such polymers include, for example, polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxy-ethyl asparagine-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues, etc. In addition, in some embodiments, the compounds of the present disclosure are coupled with a class of biodegradable polymers that can be used to achieve controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, crosslinked or amphiphilic block copolymers of polycyanoacrylates and hydrogels, etc.

[0182] The compounds of the present disclosure, including their pharmaceutically acceptable salts, solvates and / or prodrugs, are suitably used alone, but will generally be administered in the form of a pharmaceutical composition in which one or more compounds of the present disclosure (active ingredients) are combined with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will contain from about 0.05% to about 99% by weight or from about 0.10% to about 70% by weight of the active ingredient and from about 1% to about 99.95% by weight or from about 30% to about 99.90% by weight of a pharmaceutically acceptable carrier, all percentages by weight based on the total composition.

[0183] In the above, the term "compound" also includes embodiments wherein one or more compounds are mentioned.

[0184] The compounds of formula I and pharmaceutically acceptable salts thereof are serotonin receptor binding agents that act as agonists or partial agonists of serotonin receptors.

[0185] Thus, the present disclosure includes methods for activating serotonin receptors in cells in a biological sample or in a subject comprising administering to the cells an effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt thereof.

[0186] Since the compounds of Formula I or their pharmaceutically acceptable salts are able to activate serotonin receptors, they can also be used to treat diseases, disorders or conditions by activating serotonin receptors. Therefore, the compounds of Formula I can be used as medicaments.

[0187] The present disclosure also includes methods for treating diseases, disorders or conditions by activating serotonin receptors, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the serotonin receptor is a 5-HT2A receptor. Thus, the present disclosure includes methods for activating 5-HT2A receptors in cells in a biological sample or in a patient, comprising administering to the cells an effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt thereof.

[0188] The present disclosure also includes methods of treating a disease, disorder or condition by activating the 5-HT2A receptor, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt thereof.

[0189] In one embodiment, the disclosure relates to a method for treating a psychiatric disorder in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Mental disorders under consideration include depression, such as major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, disruptive mood disorders, substance / drug-induced depression, and depression attributed to another medical condition. In addition, in another embodiment, the disclosure relates to a method for treating refractory depression in a subject, such as a patient with depression, who has not and / or has not responded to a sufficient course of treatment of at least one or at least two other antidepressant compounds or therapeutic agents, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. As used herein, "depression" encompasses refractory depression.

[0190] In another embodiment, the psychiatric disorder in a subject for which the compounds of Formula I, or pharmaceutically acceptable salts thereof, can be used to treat is bipolar and related disorders, such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar and related disorders, and bipolar and related disorders due to another medical condition.

[0191] In another embodiment, by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt to a subject in need, a compound of formula I or a pharmaceutically acceptable salt thereof is used to treat a mental disorder, including a substance abuse-related disorder, such as preventing substance abuse craving, reducing substance abuse craving and / or promoting substance abuse withdrawal or de-addiction. Substance abuse disorders are related to the abuse of psychoactive compounds such as alcohol, caffeine, marijuana, inhalants, opioids, sedatives, hypnotics, antianxiety drugs, stimulants, nicotine and tobacco. As used herein, the term "substance abuse" or "substance abuse" or "substances" for substance abuse disorders is a psychoactive compound that can be addictive, such as alcohol, caffeine, marijuana, hallucinogens, inhalants, opioids, sedatives, hypnotics, antianxiety drugs, stimulants, nicotine and tobacco. For example, in one embodiment, methods and compositions of the present disclosure can be used to promote cessation of smoking or cessation of opioid use.

[0192] In some embodiments, the psychiatric disorders that the compound of Formula I or its pharmaceutically acceptable salt can be used to treat include anxiety disorders, such as separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, and anxiety disorder due to another medical condition, by administering a therapeutically effective amount of the compound of Formula I or its pharmaceutically acceptable salt to a subject in need thereof.

[0193] In some embodiments, the psychiatric disorders that the compounds of Formula I or their pharmaceutically acceptable salts can be used to treat include obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), excoriation (skin picking) disorder, substance / drug-induced obsessive-compulsive disorder and related disorders, and obsessive-compulsive disorder and related disorders due to another medical condition, by administering a therapeutically effective amount of the compound of Formula I or its pharmaceutically acceptable salt to a subject in need thereof.

[0194] In some embodiments, the psychiatric disorders that can be treated by the compound of Formula I or its pharmaceutically acceptable salt include trauma and stress-related disorders, such as reactive attachment disorder, disinhibited social engagement disorder, post-traumatic stress disorder, acute stress disorder and adjustment disorder, by administering a therapeutically effective amount of the compound of Formula I or its pharmaceutically acceptable salt to a subject in need thereof.

[0195] In some embodiments, the psychiatric disorders that the compound of Formula I or its pharmaceutically acceptable salt can be used to treat include food intake and eating disorders, such as anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder and avoidant / restrictive food intake disorder, by administering a therapeutically effective amount of the compound of Formula I or its pharmaceutically acceptable salt to a subject in need thereof.

[0196] In some embodiments, the psychiatric disorders that the compounds of Formula I or their pharmaceutically acceptable salts can be used to treat include neurocognitive disorders, such as delirium, severe neurocognitive disorder, mild neurocognitive disorder, severe or mild neurocognitive disorder due to Alzheimer's disease, severe or mild frontotemporal neurocognitive disorder, severe or mild neurocognitive disorder with Lewy bodies, severe or mild vascular neurocognitive disorder, severe or mild neurocognitive disorder due to traumatic brain injury, substance / drug-induced severe or mild neurocognitive disorder, severe or mild neurocognitive disorder due to HIV infection, severe or mild neurocognitive disorder due to prion disease, severe or mild neurocognitive disorder due to Parkinson's disease, severe or mild neurocognitive disorder due to Huntington's disease, severe or mild neurocognitive disorder due to another medical condition, and severe or mild neurocognitive disorder due to multiple etiologies, by administering a therapeutically effective amount of the compound of Formula I or its pharmaceutically acceptable salt to a subject in need thereof.

[0197] In some embodiments, by administering a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof, the psychiatric disorders that the compound of Formula I or a pharmaceutically acceptable salt thereof can be used to treat include neurodevelopmental disorders, such as autism spectrum disorders, attention-deficit / hyperactivity disorder, stereotypic movement disorder, tic disorder, Tourette's disorder, persistent (chronic) motor or vocal tic disorder, and transient tic disorder.

[0198] In some embodiments, the psychiatric disorders that the compounds of Formula I or their pharmaceutically acceptable salts can be used to treat include personality disorders, such as borderline personality disorder, by administering a therapeutically effective amount of the compounds of Formula I or their pharmaceutically acceptable salts to a subject in need thereof.

[0199] In some embodiments, by administering a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof, the psychiatric disorders that the compound of Formula I or a pharmaceutically acceptable salt thereof can be used to treat include sexual dysfunction, such as delayed ejaculation, erectile dysfunction, female orgasm disorder, female sexual interest / arousal disorder, genital-pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation (premature ejaculation), and substance / drug-induced sexual dysfunction.

[0200] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof can be used to treat psychiatric disorders including gender dysphoria, such as gender dysphoria, by administering a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0201] In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be used to treat depression, mood disorders, anxiety disorders, or substance use disorders, and any symptoms associated therewith, in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula I.

[0202] In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to prevent, treat and / or reduce the severity of a subject's mental illness, disorder and / or condition. Therefore, in some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a mental illness. Therefore, the present disclosure also includes a method for treating a mental illness, which includes administering a therapeutically effective amount of one or more compounds of the present disclosure to a subject in need. The present disclosure also includes the use of one or more compounds of the present disclosure or their pharmaceutically acceptable salts for the treatment of mental illness, and the use of one or more compounds of the present disclosure for the preparation of a medicament for the treatment of mental illness. The present disclosure further includes one or more compounds of the present disclosure for the treatment of mental illness.

[0203] In some embodiments, the psychiatric disorder is selected from anxiety disorders, such as generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia; depression, such as hopelessness, loss of pleasure, fatigue, and suicidal thoughts; mood disorders, such as major depressive disorder, bipolar disorder, cancer-related depression, anxiety disorders, and cyclothymic disorder; psychotic disorders, such as hallucinations, delusions, schizophrenia; impulse control and addiction disorders, such as pyromania (setting fires), kleptomania (theft), and compulsive gambling; alcohol addiction; drug addiction, such as opioid addiction; personality disorders, such as Antisocial personality disorder, obsessive-compulsive personality disorder, and paranoid personality disorder; obsessive-compulsive disorder (OCD), such as thoughts or fears that cause the subject to perform certain rituals or routines; post-traumatic stress disorder (PTSD); stress response syndrome (formerly known as adjustment disorder); dissociative disorders, formerly known as multiple personality disorder, or "split personality" and depersonalization disorder; factitious disorder; sexual and gender disorders, such as sexual dysfunction, gender identity disorder, and paraphilic disorder; somatic symptom disorder, formerly known as psychosomatic disorder or somatoform disorder; and combinations thereof.

[0204] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is neurodegeneration. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is reduced brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR) activation and / or inflammation.

[0205] In some embodiments, the diseases, disorders or conditions treated by activating serotonin receptors include cognitive impairment; ischemia including stroke; neurodegeneration; refractory substance abuse disorders; sleep disorders; pain, such as social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, neuralgia, referred pain, phantom pain, neuropathic pain, cluster headaches and migraines; obesity and eating disorders; epilepsy and seizures; neuronal cell death; excitotoxic cell death; or a combination thereof. In some embodiments, the psychiatric disorder is selected from hallucinations, delusions, and combinations thereof.

[0206] In some embodiments, the hallucination is selected from the group consisting of visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, balance hallucinations, nociceptive hallucinations, thermal hallucinations, and temporal hallucinations, and combinations thereof.

[0207] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a psychotic disorder or a symptom of a psychotic disorder. Thus, the present disclosure also includes a method of treating a psychotic disorder or a symptom of a psychotic disorder comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof.

[0208] The present disclosure also includes the use of one or more compounds of the present disclosure or their pharmaceutically acceptable salts for treating psychosis or psychotic symptoms, and the use of one or more compounds of the present disclosure for preparing a medicament for treating psychosis or psychotic symptoms. The present disclosure further includes one or more compounds of the present disclosure or their pharmaceutically acceptable salts for treating psychosis or psychotic symptoms.

[0209] In some embodiments, administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need thereof does not cause a worsening of psychosis or psychotic symptoms, such as, but not limited to, hallucinations and delusions. In some embodiments, administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need thereof causes an improvement in psychosis or psychotic symptoms, such as, but not limited to, hallucinations and delusions. In some embodiments, administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof causes an improvement in psychosis or psychotic symptoms.

[0210] In some embodiments, the compounds of the present disclosure and pharmaceutically acceptable salts thereof are useful for treating central nervous system (CNS) diseases, disorders or conditions and / or neurological diseases, disorders or conditions in a subject in need of therapy, wherein the treatment comprises administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0211] Therefore, in some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition. Therefore, the present disclosure also includes a method for treating a CNS disease, disorder or condition and / or a neurological disease, disorder or condition, which includes administering a therapeutically effective amount of one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need. The present disclosure also includes the use of one or more compounds of Formula I or a pharmaceutically acceptable salt thereof for treating CNS diseases, disorders or conditions and / or neurological diseases, disorders or conditions, and the use of one or more compounds of the present disclosure for preparing a drug for treating CNS diseases, disorders or conditions and / or neurological diseases, disorders or conditions. The present disclosure further includes one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof for treating CNS diseases, disorders or conditions and / or neurological diseases, disorders or conditions.

[0212] In some embodiments, the CNS disease, disorder or condition and / or neurological disease, disorder or condition is selected from a neurological disease, which includes neurodevelopmental diseases and neurodegenerative diseases, such as Alzheimer's disease; pre-senile dementia; Alzheimer's disease; vascular dementia; dementia with Lewy bodies; cognitive impairment, Parkinson's disease and Parkinson's related disorders, such as Parkinson's dementia, corticobasal degeneration and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; fragile X syndrome; Angelman syndrome; hereditary ataxias; neurological and ocular motility disorders; retinal Neurodegenerative diseases of the membrane amyotrophic lateral sclerosis; tardive dyskinesia; hyperkinetic disorder; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis; Rett syndrome; cerebral palsy; disorders of the reward system, including eating disorders, such as anorexia nervosa ("AN") and bulimia nervosa ("BN"); and binge eating disorder ("BED"), trichotillomania, dermotillomania, onychophagia; migraine; fibromyalgia; and peripheral neuropathy of any etiology, and combinations thereof.

[0213] In some embodiments, the subject is a mammal. In another embodiment, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a canine. In some embodiments, the subject is a feline. Thus, the compounds, methods, and uses of the present disclosure relate to human and veterinary diseases, disorders, and conditions.

[0214] In some embodiments, the Compounds of the Disclosure are useful for treating behavioral problems in a subject that is a feline or a canine.

[0215] The present disclosure also includes the use of one or more compounds of the present disclosure for treating behavioral problems in non-human subjects, and the use of one or more compounds of the present disclosure for preparing a medicament for treating behavioral problems in non-human subjects. The present disclosure further includes one or more compounds of the present disclosure for treating behavioral problems in non-human subjects.

[0216] In some embodiments, the behavioral problem in the non-human subject is selected from, but not limited to, anxiety, fear, stress, sleep disturbance, cognitive dysfunction, aggressive behavior, excessive noise production, scratching, biting, and combinations thereof.

[0217] In some embodiments, the non-human subject is a canine. In some embodiments, the non-human subject is a feline.

[0218] In some embodiments, the method comprises treating a psychiatric disorder by administering to a subject in need thereof a pharmaceutical composition comprising from about 0.01 mg to about 400 mg of a compound disclosed herein. In some embodiments, the dosage can be, for example, in the range of from about 0.01 to about 300 mg, or from about 0.01 to about 250 mg, or from about 0.01 to about 200 mg, or from about 0.01 to 150 mg, or from about 0.01 to about 100 mg, or from about 0.01 to about 75 mg, or from about 0.01 to about 50 mg, or from about 0.01 to about 25 mg, or from about 0.01 to about 20 mg, or from about 0.01 to about 5 mg, or from about 0. 0.1 to about 10 mg, or about 0.01 to about 5 mg, or about 0.01 to about 1 mg, or about 0.01 to about 0.1 mg, or about 0.1 to about 300 mg, or about 0.1 to about 250 mg, or about 0.1 to about 200 mg, or about 0.1 to 150 mg, or about 0.1 to about 100 mg, or about 0.1 to about 75 mg, or about 0.1 to about 50 mg, or about 0.1 to about 25 mg, or about 0.1 to about 20 mg g, or about 0.1 to about 5 mg, or about 0.1 to about 10 mg, or about 0.1 to about 5 mg, or about 0.1 to about 1 mg, or about 10 to about 300 mg, or about 10 to about 250 mg, or about 10 to about 200 mg, or about 10 to about 150 mg, or about 10 to about 100 mg, or about 10 to about 50 mg, or about 10 to about 25 mg, or about 10 to about 15 mg, or about 20 to about 300 mg, or about 2 0 to about 250 mg, or about 20 to about 200 mg, or about 20 to about 150 mg, or about 20 to about 100 mg, or about 20 to about 50 mg, or about 50 to about 300 mg, or about 50 to about 250 mg, or about 50 to about 200 mg, or about 50 to about 150 mg, or about 50 to about 100 mg, or about 100 mg to about 300 mg, or about 100 to about 250 mg, or about 100 to about 200 mg.Specific examples of dosages include about 0.01 mg, 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.25 mg, about 0.5 mg, about 075 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, and about 400 mg.

[0219] In some embodiments, the dosage may include an amount of a compound of Formula I or a pharmaceutically acceptable salt thereof in the range of, for example, about 1 mg to about 200 mg, or about 1 mg to about 100 mg, or about 1 mg to about 50 mg, or about 1 mg to about 40 mg, or about 1 mg to about 30 mg, or about 1 mg to about 20 mg, or about 1 mg to about 15 mg, or about 0.1 mg to about 10 mg, or about 0.1 mg to about 15 mg, or about 1.5 mg to about 12.5 mg, or about 2 mg to about 10 mg, or about 0.01 mg to about 1 mg, or about 0.01 mg to about 0.1 mg. Specific examples include the following dosages: about 0.01 mg, about 0.025 mg, about 0.05 mg, about 0.075 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.25 mg, about 1.50 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4. about 25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg and about 200 mg.

[0220] Typically, a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof at the following dosing intervals: once a day, twice a day, three times a day, or four times a day, or every other day, or every three days, or once a week, or once a month, or every other month, or every three months, or every six months, or once a year. In some embodiments, the dosage is, for example, about 0.01 to about 400 mg / dosing interval, or about 0.01 to about 300 mg / dosing interval, or about 0.01 to about 250 mg / dosing interval, or about 0.01 to about 200 mg / dosing interval, for example, about 300 mg / dosing interval, or about 250 mg / dosing interval, or 200 mg / dosing interval, or about 150 mg / dosing interval, or about 100 mg / dosing interval, or about 75 mg / dosing interval, or about 50 mg / dosing interval, or about 25 mg / dosing interval, or about 20 mg / dosing interval, or about 10 mg / dosing interval, or about 5 mg / dosing interval, or about 1 mg / dosing interval, or about 0.5 mg / dosing interval, or about 0.1 mg / dosing interval, or about 0.05 mg / dosing interval, or about 0.01 mg / dosing interval.

[0221] In some embodiments, pharmaceutical compositions for parenteral or inhalation, such as sprays or mists of a compound of Formula I or a pharmaceutically acceptable salt thereof, comprise a concentration of about 0.001 mg / mL to about 500 mg / mL. In some embodiments, the composition includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, at a concentration of, for example, about 0.05 mg / mL to about 50 mg / mL, about 0.05 mg / mL to about 100 mg / mL, about 0.005 mg / mL to about 500 mg / mL, about 0.1 mg / mL to about 50 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 25 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, about 0.05 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 0.1 mg / mL, about 0.001 mg / mL to about 0.01 mg / mL.

[0222] In some embodiments, the composition includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, at a concentration of, for example, about 0.001 mg / mL to about 0.01 mg / mL, about 0.01 mg / mL to about 0.1 mg / mL, about 0.1 mg / mL to about 1 mg / mL, about 0.05 mg / mL to about 15 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.25 mg / mL to about 5 mg / mL, about 0.5 mg / mL to about 7 mg / mL, about 1 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 5 mg / mL to about 15 mg / mL, about 5 mg / mL to about 25 mg / mL, about 5 mg / mL to about 50 mg / mL, or about 10 mg / mL to about 100 mg / mL. In some embodiments, the pharmaceutical composition is formulated to have a total volume of about 0.1 mL, 0.2 mL, 0.5 mL, 1 mL, 2 mL, 5 mL, 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL, for example.

[0223] Typically, the dosage can be administered to the subject once a day, twice a day, three times a day, or four times a day, every other day, every three days, twice a week, once a week, twice a month, once a month, every other month, every 3 months, twice a year, or once a year. In some embodiments, the compounds disclosed herein are administered to the subject once in the morning or once in the evening. In some embodiments, the compounds disclosed herein are administered to the subject once in the morning and once in the evening. In some embodiments, disclosed herein is administered to the subject three times a day (e.g., at breakfast, lunch, and dinner) at a dosage of, for example, 50 mg / administration (e.g., 150 mg / day).

[0224] In some embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.01 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.1 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to the subject at a dose of 0.5 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to the subject at a dose of 1 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to the subject at a dose of 2.5 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to the subject at a dose of 5 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to the subject at a dose of 10 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to the subject at a dose of 15 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to the subject at a dose of 25 mg / day in one or more doses. In some embodiments, the compounds disclosed herein are administered to the subject in one or more doses at a dosage of 50mg / day. In some embodiments, the compounds disclosed herein are administered to the subject in one or more doses at a dosage of 75mg / day. In some embodiments, the compounds disclosed herein are administered to the subject in one or more doses at a dosage of 100mg / day. In some embodiments, the compounds disclosed herein are administered to the subject in one or more doses at a dosage of 150mg / day. In some embodiments, the compounds disclosed herein are administered to the subject in one or more doses at a dosage of 200mg / day. In some embodiments, the compounds disclosed herein are administered to the subject in one or more doses at a dosage of 250mg / day.

[0225] In some embodiments, the dosage of the compound disclosed herein is 0.0001-10 mg / kg, 0.0001-0.01 mg / kg, 0.001-1 mg / kg, 0.01-1 mg / kg, 0.5-5 mg / kg or 0.5-10 mg / kg, once a day, twice a day, three times a day or four times a day. For example, in some embodiments, the dosage is 0.0001 mg / kg, 0.001 mg / kg, 0.01 mg / kg, 0.025 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 1 mg / kg, 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg or 10 mg / kg, once a day, twice a day, three times a day or four times a day. In some embodiments, a total daily dose of 0.01 mg to 500 mg of a compound disclosed herein is administered to a subject once daily, twice daily, three times daily, or four times daily. In some embodiments, the total amount administered to a subject in a 24 hour period is, for example, 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg. In some embodiments, a subject can start with a low dose and the dose is increased. In some embodiments, a subject can start with a high dose and the dose is reduced.

[0226] In some embodiments, compounds disclosed herein or compositions can be administered at specified intervals. For example, during treatment, compounds or compositions can be administered to patients at the following intervals, such as every 1 year, 6 months, 120 days, 90 days, 60 days, 30 days, 14 days, 7 days, 3 days, 24 hours, 12 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours or 0.25 hours.

[0227] In some embodiments, the compound is administered under the supervision of a health care provider.

[0228] In some embodiments, the compound is administered in a clinic that specializes in the administration of hallucinogenic drugs.

[0229] In some embodiments, the compound is administered at home or otherwise away from the supervision of a health care provider.

[0230] In some embodiments, the compounds disclosed herein are in the form of pharmaceutically acceptable salts thereof.

[0231] In some embodiments, pharmaceutical compositions comprise one or more compounds disclosed herein.

[0232] In some embodiments, salts of the compounds disclosed herein are used in any method, use, or composition.

[0233] In some embodiments, pharmaceutically acceptable salts of the compounds disclosed herein are used in any method, use, or composition.

[0234] The compound of formula I is prepared by procedures recognized in the art. The synthesis of the compound of formula I is illustrated by the following examples. The synthesis utilizes organic reaction types, some of which are described in standard organic chemistry textbooks, including "Advanced Organic Chemistry", the 5th edition, Michael Smith and Jerry March, John Wiley & Sons, company, New York (2001). It is obvious to those skilled in the art that the synthesis schemes in the examples presented below can be modified to provide other related compounds. The following non-limiting examples further illustrate the subject matter of the present disclosure.

[0235] The following schemes illustrate exemplary procedures for preparing compounds of Formula I.

[0236]

[0237] As shown in the scheme above, in the reaction shown, a pyridine-3-ol compound (Compound Z) is halogenated, for example, brominated with a halogenating agent such as N-bromosuccinimide (NBS), bromine, 1,3-dibromo-5,5-dimethylhydantoin, tetrabutylammonium tribromide, N-bromobenzoylpyridinium tribromide or benzyltrimethylammonium tribromide, etc., in a solvent such as acetonitrile, acetonitrile-water, dioxane or dioxane-water at a temperature in the range of about 25° C. to about 100° C., optimally at the reflux temperature of the selected solvent, to form a halogenated derivative (Compound A), wherein X is a halogen, for example, Br. The 2-halogeno-3-hydroxypyridine is treated with a base such as sodium carbonate or potassium carbonate, sodium bicarbonate or potassium bicarbonate, sodium hydroxide or potassium hydroxide, or a sodium alkoxide (e.g., sodium methoxide) in a neutral solvent such as DMF, DMA, THF, or dimethylacetamide and reacted with a halide R such as iodomethane in a solvent at a temperature ranging from about 25° C. to about 100° C., optimally about 60° C., under standard ether-forming conditions. 13 X1 is reacted to produce compound B. Compound B is then formylated under conditions known in the art. For example, in a solvent such as THF, ether or similar solvent, at a temperature ranging from about -78°C to about 0°C, under bovor aldehyde synthesis conditions, the halide (compound B) is reacted with an organolithium reagent such as n-butyl or sec-butyl lithium, with an N,N-disubstituted formamide such as dimethylformamide to form an aldehyde (compound C). Aldehyde compound C can also be prepared by a three-step sequence, the three-step sequence comprising a palladium-catalyzed coupling of a vinyl borate ester in a suitable solvent such as THF or dioxane with a suitable base such as an alkali metal carbonate or bicarbonate at about room temperature to about the reflux temperature of the solvent to provide an olefin, which can then be hydroxylated by the action of catalytic osmium tetroxide with a catalyst such as periodate in a solvent such as THF-water or acetone-water at room temperature to provide a diol, which is then cleaved by the action of periodate to provide the aldehyde compound C. In one case, compound C is halogenated, for example, brominated with a halogenating agent such as N-bromosuccinimide (NBS), bromine, 1,3-dibromo-5,5-dimethylhydantoin, tetrabutylammonium tribromide, N-bromobenzoylbenzyltribromide pyridinium tribromide or benzyltrimethylammonium tribromide, in a solvent such as acetonitrile, acetonitrile-water, dioxane or dioxane-water at a temperature in the range of about 25°C to about 100°C, most preferably at the reflux temperature of the selected solvent, to form a halogenated derivative (compound D). Compound D is reacted with a sodium or potassium alkoxide such as R7O in a suitable solvent such as DMF, THF, DMSO or DMA at a temperature of about 75°C to about 150°C under palladium or copper catalysis to form an ether (compound E). -Salt, wherein R7 is as defined herein. Compound E is reacted with an organic nitro compound such as R5CH2NO2, wherein R5 is as defined herein, in the presence of a base such as an alkali metal hydroxide, carbonate, bicarbonate or alkoxide, an alkaline earth metal hydroxide, aluminum ethoxide, an organic base such as a primary, secondary and tertiary amine, or ammonium acetate or other salts, under Henry reaction conditions, using a nitroalkane as a solvent or by using a solvent such as THF, ether, acetonitrile or dichloromethane, at a temperature ranging from about room temperature to about the reflux point of the solvent to form Compound F. The carbon-carbon double bond in Compound F is reduced with a reducing agent such as sodium borohydride, lithium aluminum hydride, hydrogen and nickel, hydrogen, etc., in a solvent such as methanol, ethanol, ethyl acetate, THF or a similar solvent, at room temperature to the reflux point of the solvent in the presence of palladium or platinum catalyst or other reducing agents known in the art to produce Compound J. If the nitro group of compound J is not reduced in the previous step, the nitro group of compound J is reduced with a reducing agent such as Fe, Zn or Sn in the presence of an acid or Raney Nickel and hydrogen in a suitable solvent such as water, methanol or ethanol to form the corresponding primary amine of compound K.

[0238] Compound C formed above is an intermediate in other reactions. For example, in the presence of a base such as an alkali metal hydroxide, carbonate, bicarbonate or alkoxide, an alkaline earth metal hydroxide, aluminum ethoxide, an organic base such as a primary, secondary and tertiary amine, or ammonium acetate or other salts, under Henry reaction conditions, using a nitroalkane as a solvent or by using a solvent such as THF, ether, acetonitrile or dichloromethane, at a temperature ranging from about room temperature to about the reflux point of the solvent, Compound C is reacted with an organic nitro compound such as R5CH2NO2, wherein R5 is as defined herein. The carbon-carbon double bond in Compound G is reduced with a carbon-carbon double bond reducing agent such as sodium borohydride, lithium aluminum hydride, hydrogen with nickel, hydrogen with palladium or platinum catalysis in a solvent such as methanol, ethanol, ethyl acetate, THF or a similar solvent at room temperature to the reflux point of the solvent to produce Compound H. If the nitro group is not reduced in the previous step, the nitro group is reduced to the corresponding primary amine to form the corresponding amine compound I with a nitro reducing agent such as Fe, Zn or Sn in the presence of acid or Raney nickel and hydrogen in a suitable solvent such as water, methanol or ethanol. The amine is protected with an amine protecting group known in the art, for example, the amine is converted into a carbamate, for example, the amine is converted into tert-butyl carbamate (Boc group) with Boc anhydride or Boc-ON, or the amine is converted into benzyl carbamate (Cbz) with Cbz-Cl, and solvents such as THF, dioxane or acetonitrile are used alone or in combination with water as a co-solvent. Alternatively, dichloromethane, toluene or other solvents can be used with or without water and with or without a base, such as aqueous sodium bicarbonate or sodium carbonate, triethylamine, DMAP or Hunig's base. The reaction is conveniently run at room temperature to the reflux point of the solvent to provide compound L. Compound L is converted to compound O, wherein the R1 group as defined herein is bonded to the pyridine ring. This can be achieved by reacting compound L with a halogenating agent such as NBS, bromine, 1,3-dibromo-5,5-dimethylhydantoin, tetrabutylammonium tribromide, N-bromo-o-sulfonylbenzamide, pyridinium tribromide or benzyltrimethylammonium tribromide, etc., in a solvent such as acetonitrile, acetonitrile-water, dioxane or dioxane-water, at a temperature in the range of about 25°C to about 100°C, most preferably at the reflux temperature of the selected solvent, to form compound M.Compound M is subjected to an oxidative carbon-carbon coupling by reactions known in the art, for example, by reacting Compound M with an organometallic reagent, such as a copper lithium complex, e.g., (R1)2CuLi, wherein R1 is as defined herein, in a solvent such as THF or ether at a temperature ranging from about room temperature to about -78°C, or by using a variation of the Suzuki coupling reaction by reacting Compound M with a boronic acid R1B(OH)2 in the presence of a palladium catalyst such as Pd(dppf)Cl2, tetrakis(triphenylphosphine)Pd, or a similar coordinated palladium(0) or palladium(II) complex in the presence of a base such as cesium carbonate, sodium carbonate, or potassium carbonate, or sodium or potassium bicarbonate, in a solvent such as toluene-water, THF-water, or dioxane-water at a temperature from about room temperature to about the reflux point of the solvent to produce Compound N. The protecting group t-Boc is removed by reactions known in the art, such as by treatment under acidic conditions with TFA, HCl or HBr, etc., in solvents such as dichloromethane, acetonitrile, toluene or ethyl acetate, at room temperature or below room temperature, with or without triethylsilane or anisole. If the Cbz group is used, deprotection is carried out in ethyl acetate using palladium on carbon or palladium hydroxide catalyst under a hydrogen atmosphere. Alternatively, a solution of HBr in acetic acid can be used to remove the Cbz group. Protecting group removal causes compound O to form in both cases. Alternatively, compound M can be directly deprotected to provide a halogenated derivative (e.g. bromide) of an amine.

[0239] Compound Q is formed from compound N. The amine protecting group is removed by reactions described above and known in the art. In this case, since the amine protecting group is Boc, the amine protecting group is removed with acid, or if the amine protecting group is Cbz, the amine protecting group is removed by palladium catalyzed hydrogenation, and then the resulting primary amine is reacted with R under reductive amination conditions with or without the removal of water. 6a The substituted benzaldehyde is reacted to form an imine, the C=N bond of which is reduced by a reducing agent known in the art, for example by hydrogenation, or by using zinc and HCl or sodium cyanoborohydride, sodium triacetoxyborohydride or sodium borohydride in a solvent such as dichloromethane, acetonitrile, 1,2-dichloroethane or a similar inert solvent at room temperature to give compound Q.

[0240] Compound P is formed from compound M. In the presence of a base such as a hydroxide base and a transition metal such as palladium, R7SH (wherein R7 is as defined herein) forms a thiolate nucleophile that reacts with compound M to form an amine protected thioether. The amine protecting group is then removed by techniques known in the art and as described above. (Boc is removed by reacting the resulting product with an acid to form compound P). Halogenation of compound L, for example with N-iodosuccinimide (NIS) under halogenating conditions in a solvent such as acetonitrile, acetonitrile-water, dioxane or dioxane-water at a temperature of about 25°C to about 100°C, optimally at the reflux temperature of the selected solvent, forms the iodinated product compound R. Compound R is reacted with a trifluoromethylating agent, such as a chlorodifluoroacetic acid copper (I) complex formed by the reaction of CuI with ClCF2COOCH3 and KF to form compound S. Removal of the amine protecting group by techniques known in the art and as described above provides the amine product T.

[0241] Those of ordinary skill in the art can use known techniques combined with the teachings herein to prepare compounds of formula I. Once the functional group is placed in a certain position, those of ordinary skill in the art can prepare compounds in which R1, R2, R3, R4, R5 and R6 are as defined herein. For example, with respect to the definition of R1 at the 5-position of a pyridine derivative, compounds in which R1 is hydrogen can be prepared by the deprotection of compound L. Alternatively, they can be prepared by converting the OR7 group, for example, on compound J, into a mesylate or triflate, and then reacting the resulting product with a nickel catalyst and hydrogen in DMF, and then removing the amine protecting group. Alternatively, a 5-halo substituent is dehalogenated by hydrogenation in the presence of a transition metal catalyst such as palladium or nickel, such as a substituent prepared in compound M. Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclic or heterocycloalkyl substituents can be prepared by carbon-carbon coupling reactions known in the art, such as those shown in Examples 1, 2, 4, 5, 7 and 8 below. Compounds wherein R1 is CN can be prepared by techniques known in the art, such as by treating a 5-OR7 substituted pyridine, wherein R7 is H, with a cyanogen halide in the presence of a base, or by reacting a halogenated pyridine, such as compound M, with anhydrous CuCN under Rosenmund-von Braun reaction conditions. Reduction of the cyano group with a reducing agent known in the art such as LiAlH4, BH3-Me2S or NaB H4 in an alcohol solvent and CoCl2 produces a primary amine. Secondary and tertiary amines can be prepared by reacting the primary amine thus formed with R8X2 to form a secondary amine, wherein X2 is a halide, and reacting the secondary amine with R9X2 to form a tertiary amine, wherein R8 and R9 are as defined herein. Alternatively, the primary amine can be reacted with an aldehyde under reductive amination conditions to provide a secondary or tertiary amine. Nitration of the pyridine compound is carried out by techniques known in the art, for example, by reacting a 5-bromopyridine derivative such as compound M with Nitrite or Sodium Nitrite Reaction under Zincke nitration conditions in acetic acid. Alternatively, compound L can be directly nitrated, for example with HNO3, in various acids such as acetic acid, sulfuric acid or trifluoromethanesulfonic acid to provide 5-nitropyridine derivatives. These can be reduced with Fe, Zn or Sn under conditions known in the art to provide 5-aminopyridine derivatives, which in turn can be substituted with alkyl groups via alkylation or reductive amination, as described above.

[0242] Using the techniques described herein, the 3-substituent, i.e., R3, can be prepared as described herein. As shown in the schemes above and the examples below, the 3-substituent, i.e., R3, can be prepared as described herein. 13 of pyridine derivatives.

[0243] 3-Hydroxypyridine derivatives, such as compound M, wherein R 13 is H, can be converted to the corresponding bromide via a boronate intermediate by reacting a 2-hydroxypyridine derivative with Tf2O in pyridine and reacting the product with bis(pinacolato)diboron in PdCl2(dppf) in NE t3 and reacting the resulting product with cuprous bromide in a 1:1 mixture of H2O / MeOH under reflux. For example, with respect to the definition of R3 at the 3-position of pyridine, by, for example, placing -OR on compound N 13 The group is converted into mesylate or triflate, and then products therefrom is reacted in DMF with hydrogen and nickel catalyst, and then the amine protecting group is removed, and R3 can be prepared as a compound of hydrogen. Alternatively, 3-halo-substituted derivatives are dehalogenated by hydrogenation with transition metal catalysts such as palladium or nickel. The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, cycloalkylalkyl, heterocycle or heterocycloalkyl substituents at this position are prepared by carbon-carbon coupling reaction known in the art, such as shown in Examples 1, 2, 4, 5, 7 and 8 below. Wherein R3 is a compound of CN that can be prepared by technology known in the art, such as by treating 3-OH with cyanogen halides in the presence of a base to replace pyridine, wherein R3 is OH, or by reacting pyridine halides with anhydrous CuCN under Rosenmund-von Braun reaction conditions, wherein R3 is a halide such as I or Br. Reduction of the cyano group in an alcohol solvent and CoCl2 using a reducing agent known in the art, such as LiAlH4, BH3-Me2S or NaBH4, etc., produces a primary amine. Secondary and tertiary amines can be prepared by reacting the primary amine thus formed with R 14 X2 is reacted to form a secondary amine, wherein X2 is a halide, and the secondary amine is reacted with R 15 X2 reacts to form a tertiary amine, where R 14 and R 15 As defined herein. Alternatively, primary amines can react with aldehydes under reductive amination conditions to provide secondary or tertiary amines. Esterification of 3-hydroxypyridine derivatives with acyl chlorides under esterification conditions provides esters. In order to form 3-carboxypyridine derivatives, the starting material is 3-carboxy-6-hydroxypyridine, and the carboxyl group is then protected with a carboxyl protecting group known in the art, and then the reaction in the scheme above is followed. However, before the nitro group is converted into an amine or the amine protecting group is removed, the carboxyl protecting group is removed. The carboxylic acid thus formed reacts with an alcohol or amine under esterification or amide formation conditions to form an ester or amide, respectively.

[0244] Similarly, a 6-hydroxypyridine derivative, such as compound M, wherein R 19 It's H.

[0245] The following schemes illustrate additional exemplary procedures for the preparation of compounds of Formula I.

[0246]

[0247] As shown in the scheme above, 4-substituted pyridines and the resulting compounds of the invention wherein R2 is not H can be prepared from common intermediates such as compound Z using methods well known in the literature after the addition of anion directing substituents such as methoxymethyl or tetrahydropyran. The formation of the anion is accomplished with a strong base such as lithium diisopropylamide, lithium hexamethyldisilazane, lithium tetramethylpiperidinium or butyllithium or methyllithium with TMEDA in a suitable solvent such as THF or other aprotic ethers at a temperature of -78°C to 0°C. The anion can be reacted with a halogenating agent such as bromine or NBS and NCS, N-iodosuccinimide or a fluorinating agent. The anion can also be reacted with DMF to form an aldehyde. For example, the resulting bromide can be refined to introduce alkyl or aryl substituents using palladium, nickel or copper catalysis under Suzuki conditions with boron reagents and related Kumada, Molander or Weix coupling schemes and other well-known coupling forms involving metal insertion and reductive elimination. Bromide can also be subjected to many other forms of refining by known methods well known in the art. Anion-directed substituents can be easily removed by hydrolysis, and the resulting phenol can be alkylated as described above. Further refining of other compounds of the present disclosure is completed as described above to provide the desired pyridylalkylamine of formula I.

[0248] The R5 substituent is attached to the organic moiety linked to the backbone by carbon-carbon coupling reactions known in the art. Some are illustrated in the Schemes and in the Examples.

[0249] The R6 substituent is added to the chain by reaction with a free amino group via alkylation or reductive amination, as described above.

[0250] In all of these reactions, if necessary, if a moiety reactive under the necessary reaction conditions is present on the compound, such group is protected with a protecting group which is stable under the conditions to be employed.

[0251] Example 1: Preparation of 1-(3,6-dimethoxy-5-pentylpyridin-2-yl)butan-2-amine (1)

[0252]

[0253] Step 1: Preparation of 2-bromo-6-methoxypyridin-3-ol

[0254] NBS (35.56 g, 199.80 mmol, 1 equivalent) was added to a solution of 6-methoxypyridine-3-ol (25 g, 199.80 mmol, 1 equivalent) in acetonitrile (250 mL) and water (25 mL). The mixture was stirred at 60 ° C for 12 hours, then diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 50: 1 to 3: 1). Compound 2-bromo-6-methoxypyridine-3-ol (33 g, 161.75 mmol, 80.95% yield) was obtained as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.89 (s, 3H), 5.04 (br s, 1H), 6.66 (d, J=8.66 Hz, 1H), 7.27 (d, J=8.66 Hz, 1H).

[0255] Step 2: Preparation of 2-bromo-3,6-dimethoxypyridine

[0256] To a solution of 2-bromo-6-methoxypyridin-3-ol (33 g, 161.75 mmol, 1 eq.) in DMF (150 mL) was added K2CO3 (67.06 g, 485.24 mmol, 3 eq.) and CH3I (57.40 g, 404.37 mmol, 25.17 mL, 2.5 eq.). The mixture was stirred at 50 ° C for 0.5 hours, then diluted with 100 mL of water and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. Compound 2-bromo-3,6-dimethoxypyridine (35 g, 160.52 mmol, 99.24% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 3.87 (d, J = 15.88 Hz, 6H), 6.67 (d, J = 8.63 Hz, 1H), 7.20 (d, J = 8.76 Hz, 1H).

[0257] Step 3: Preparation of 3,6-dimethoxy-2-vinylpyridine

[0258] A mixture of 2-bromo-3,6-dimethoxypyridine (30 g, 137.58 mmol, 1 eq.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (31.78 g, 206.38 mmol, 35.01 mL, 1.5 eq.) and K2CO3 (57.05 g, 412.75 mmol, 3 eq.) in water (10 mL) and dioxane (100 mL) was degassed and purged with N2 (3x), then the mixture was stirred at 0°C for 10 min, then Pd(dppf)Cl2 (10.07 g, 13.76 mmol, 0.1 eq.) was added at 90°C and stirred under N2 atmosphere for 6 h. After completion, the residue was diluted with 80 mL of water and extracted with ethyl acetate (80 mL×3). The combined organic layers were washed with 80 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 50:1 to 10:1). Compound 3,6-dimethoxy-2-vinylpyridine (12.5 g, 75.67 mmol, 55.00% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.81 (s, 3H), 3.94 (s, 3H), 5.43 (dd, J = 10.67, 2.38 Hz, 1H), 6.38 (dd, J = 17.25, 2.45 Hz, 1H), 6.63 (d, J = 8.78 Hz, 1H), 7.13 (dd, J = 17.25, 10.73 Hz, 1H), 7.21 (d, J = 8.91 Hz, 1H).

[0259] Step 4: Preparation of 3,6-dimethoxypyridinecarboxaldehyde

[0260] At 0°C, to a solution of 3,6-dimethoxy-2-vinylpyridine (11.5 g, 69.62 mmol, 1 eq.) in THF (200 mL) and water (50 mL) was added OsO4 (884.94 mg, 3.48 mmol, 180.60 μL, 0.05 eq.), NaIO4 (37.23 g, 174.04 mmol, 9.64 mL, 2.5 eq.) and water (100 mL). The mixture was stirred at 25°C for 4 hours. The mixture was then extracted with ethyl acetate (80 mL×3). The combined organic layers were washed with 80 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 50:1 to 3:1). Compound 3,6-dimethoxypicolinaldehyde (6 g, 35.89 mmol, 51.56% yield) was obtained as a pink solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.94 (d, J = 1.10 Hz, 3H), 3.98 (d, J = 1.34 Hz, 3H), 6.99 (dd, J = 9.11, 1.16 Hz, 1H), 7.44 (d, J = 9.05 Hz, 1H), 10.26 (s, 1H).

[0261] Step 5: Preparation of (E)-3,6-dimethoxy-2-(2-nitrobut-1-en-1-yl)pyridine

[0262] To a solution of 3,6-dimethoxypyridinecarboxaldehyde (1 g, 5.98 mmol, 1 eq.) in 1-nitropropane (3 mL) was added ammonium acetate (461.13 mg, 5.98 mmol, 1 eq.). The mixture was stirred at 90 ° C for 3 hours. After completion, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 mL×3). The combined organic layer was washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 50: 1 to 3: 1). Compound (E)-3,6-dimethoxy-2-(2-nitrobut-1-ene-1-yl)pyridine (540 mg, 2.27 mmol, 37.89% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.28 Hz, 3H), 3.38 (q, J = 7.36 Hz, 2H), 3.88 (s, 3H), 3.92 (s, 3H), 6.82 (d, J = 9.03 Hz, 1H), 7.30 (d, J = 9.03 Hz, 1H), 8.30 (s, 1H).

[0263] Step 6: Preparation of 3,6-dimethoxy-2-(2-nitrobutyl)pyridine

[0264] At 0°C, NaBH4 (952.80 mg, 25.18 mmol, 6 eq.) was added to a solution of (E)-3,6-dimethoxy-2-(2-nitrobut-1-en-1-yl)pyridine (1 g, 4.20 mmol, 1 eq.) in THF (10 mL) and MeOH (20 mL), and the mixture was warmed to 20°C. After 5 hours, the mixture was diluted with NH4Cl (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with 15 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. Compound 3,6-dimethoxy-2-(2-nitrobutyl)pyridine (1 g, 4.16 mmol, 99.16% yield) was obtained as a white solid.

[0265] Step 7: Preparation of 1-(3,6-dimethoxypyridin-2-yl)butan-2-amine

[0266] To a solution of 3,6-dimethoxy-2-(2-nitrobutyl)pyridine (1 g, 4.16 mmol, 1 equiv) in ethanol (9 mL) and water (3 mL) was added iron powder (2.79 g, 49.95 mmol, 12 equiv) and NH4Cl (1.78 g, 33.30 mmol, 8 equiv). The mixture was stirred at 80 ° C for 5 hours. After completion, the mixture was filtered and concentrated under reduced pressure to obtain an aqueous solution. The pH was adjusted to 9 by saturated sodium bicarbonate, and the suspension was filtered to obtain a white solid. Compound 1-(3,6-dimethoxypyridin-2-yl)butyl-2-amine (0.8 g, 3.80 mmol, 91.41% yield) was obtained as a white solid.

[0267] Step 8: Preparation of tert-butyl (1-(3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate

[0268] To a solution of 1-(3,6-dimethoxypyridin-2-yl)butyl-2-amine (0.8 g, 3.80 mmol, 1 eq.) in THF (10 mL), Boc2O (1.66 g, 7.61 mmol, 1.75 mL, 2 eq.) was added. The mixture was stirred at 20 ° C for 0.5 hours. After completion, the mixture was filtered and concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 100: 1 to 3: 1) to provide tert-butyl (1-(3,6-dimethoxypyridin-2-yl)butyl-2-yl)carbamate (880 mg, 2.84 mmol, 74.52% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95 (t, J = 7.47 Hz, 3H), 1.39 (s, 9H), 1.45-1.53 ​​(m, 2H), 2.81-2.98 (m, 2H), 3.77-3.80 (m, 3H), 3.82-3.87 (m, 1H), 3.89 (s, 3H), 5.58 (br d, J = 5.02 Hz, 1H), 6.57 (d, J = 8.78 Hz, 1H), 7.17 (d, J = 8.78 Hz, 1H).

[0269] Step 9: Preparation of tert-butyl (1-(5-bromo-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate

[0270] To a solution of tert-butyl (1-(3,6-dimethoxypyridin-2-yl)butyl-2-yl)carbamate (880 mg, 2.84 mmol, 1 equiv) in acetonitrile (10 mL) was added NBS (756.92 mg, 4.25 mmol, 1.5 equiv). The mixture was stirred at 20 ° C for 12 hours. After completion, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 100: 1 to 20: 1) to provide tert-butyl (1-(5-bromo-3,6-dimethoxypyridin-2-yl)butyl-2-yl)carbamate (780 mg, 2.00 mmol, 70.67% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95 (t, J = 7.45 Hz, 3H), 1.38 (s, 9H), 1.45-1.53 ​​(m, 2H), 2.85 (d, J = 6.36 Hz, 2H), 3.79 (s, 3H), 3.83-3.93 (m, 1H), 3.97 (s, 3H), 5.15-5.25 (m, 1H), 7.38 (s, 1H).

[0271] Step 10: Preparation of tert-butyl (1-(3,6-dimethoxy-5-pentylpyridin-2-yl)butan-2-yl)carbamate

[0272] A mixture of tert-butyl N-[1-[(5-bromo-3,6-dimethoxy-2-pyridyl)methyl]propyl]carbamate (780 mg, 2.00 mmol, 1 eq), amylboronic acid (348.54 mg, 3.01 mmol, 1.5 eq), cesium carbonate (1.96 g, 6.01 mmol, 3 eq) in toluene (10 mL) and water (1 mL) was degassed and purged with N2 for 3 times at 20°C for 10 minutes, and then Pd(dppf)Cl2.CH2Cl2 (163.63 mg, 200.37 μmol, 0.1 eq) was added to the mixture and stirred at 90°C for 13 hours under N2 atmosphere. After completion, the residue was diluted with water (2 mL) and extracted with ethyl acetate (3 mL×3). The combined organic layers were washed with brine (1 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 100:1 to 30:1) to provide tert-butyl (1-(3,6-dimethoxy-5-pentylpyridin-2-yl)butan-2-yl)carbamate (400 mg, 1.05 mmol, 52.46% yield) as a white solid. 1H NMR (400MHz, chloroform-d) δppm 0.88-0.98(m, 6H), 1.29-1.38(m, 4H), 1.40(s, 9H), 1.43-1.52(m, 2H), 1.53-1.61(m, 2H), 2.46-2.58(m, 2H), 2.76-2 .86 (m, 1H), 2.87-2.96 (m, 1H), 3.77 (s, 3H), 3.81-3.88 (m, 1H), 3.90 (s, 3H), 5.84 (brd, J=6.58Hz, 1H), 6.99 (s, 1H).

[0273] Step 11: Preparation of 1-(3,6-dimethoxy-5-pentylpyridin-2-yl)butan-2-amine (1)

[0274] To a solution of tert-butyl (1-(3,6-dimethoxy-5-pentylpyridin-2-yl)butan-2-yl)carbamate (400 mg, 1.05 mmol, 1 eq.) in TFA (1 mL) and DCM (4 mL) was added triethylsilane (366.69 mg, 3.15 mmol, 503.69 μL, 3 eq.). The mixture was stirred at 20 °C for 1 hour. After completion, the residue was purified by preparative HPLC (column: Phenomenex Luna C18 80x40 mm×3 μm; mobile phase: [water (0.1% HCl)-ACN]; B%: 5%-40%, 7 minutes). Compound 1 (100 mg, 356.63 μmol, 33.93% yield) was obtained as a white solid. 1 H NMR (400MHz, methanol-d4) δppm 0.91 (t, J=6.97Hz, 3H), 1.07 (t, J=7.52Hz, 3H), 1.27-1.41 (m, 4H), 1.59 (dt, J=14.92, 7.46Hz, 2H), 1.72 (quin, J=7.31Hz, 2H), 2.52- 2.61 (m, 2H), 2.92 (dd, J=15.71, 8.13Hz, 1H), 3.11 (dd, J=15.65, 4.65Hz, 1H), 3.55-3.67 (m, 1H) 3.83 (s, 3H) 3.90 (s, 3H) 7.27 (s, 1H); 13 C NMR (101 MHz, methanol-d4) δ ppm 155.50, 148.80, 138.07, 124.30, 123.07, 55.54, 52.47, 52.33, 31.69, 31.36, 29.38, 28.78, 25.44, 22.13, 12.94, 8.66.

[0275] Example 2: Preparation of 1-(3,6-dimethoxy-5-methylpyridin-2-yl)butan-2-amine (2) hydrochloride

[0276]

[0277] Step 1: Preparation of tert-butyl (1-(3,6-dimethoxy-5-methylpyridin-2-yl)butan-2-yl)carbamate

[0278] To a stirred solution of (1-(5-bromo-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamic acid tert-butyl ester (0.100 g, 1 eq., 0.257 mmol) in toluene (4 mL) and water (1 mL) was added trimethyl-1,3,5,2,4,6-trioxatricyclohexaborane (80.6 mg, 1.2 eq., 0.321 mmol) and potassium carbonate (107 mg, 3 eq., 0.771 mmol). The reaction mixture was degassed with argon for 5 minutes, then PdCl2(dppf)·DCM (21 mg, 0.1 eq., 0.0257 mmol) was added, and the reaction mixture was heated at 100 ° C for 12 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and the solvent evaporated under reduced pressure to give a crude material which was purified by column chromatography (SiO2, 10% ethyl acetate / heptane). The desired fractions were concentrated under reduced pressure to provide tert-butyl (1-(3,6-dimethoxy-5-methylpyridin-2-yl)butan-2-yl)carbamate (65 mg, 78% yield) as a colorless liquid. LC-MS m / z 325.10 [M+1] + ; 1 HNMR (400MHz, DMSO-d6) δ = 7.26 (s, 1H), 6.53 (d, J = 8.8Hz, 1H), 3.80 (s, 3H), 3.72 ( s, 3H), 2.76-2.63 (m, 2H), 2.10 (s, 3H), 1.39-1.23 (m, 11H), 0.80 (t, J=7.6Hz, 3H).

[0279] Step 2: Preparation of 1-(3,6-dimethoxy-5-methylpyridin-2-yl)butan-2-amine (2) hydrochloride

[0280] To a stirred solution of tert-butyl (1-(3,6-dimethoxy-5-methylpyridin-2-yl)butan-2-yl)carbamate (60 mg, 0.185 μmol) in 1,4-dioxane (3 mL, 35.2 mmol) cooled to 0 ° C was added 4N HCl in 1,4-dioxane (2 mL). The reaction progress was monitored by TLC and LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure to provide a crude material, which was ground with DCM (0.2 mL) and ether (2.0 mL) followed by n-pentane (5 mL). The resulting compound was dried under reduced pressure to provide compound 2HCl (yield: 23 mg, 55.44%) as a semisolid. LC-MS m / z 225.30 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.82 (br s, 3H), 7.38 (s, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.53-3.52 (m, 1H), 2.96-2.83 (m, 2H), 2.14 (s, 3H), 1.58-1.54 (m, 2H), 0.93 (t, J=7.6Hz, 3H).

[0281] Example 3: Preparation of 1-(5-bromo-3,6-dimethoxypyridin-2-yl)butan-2-amine (3) hydrochloride

[0282]

[0283] Step 1: Preparation of (E)-3,6-dimethoxy-2-(2-nitrobut-1-en-1-yl)pyridine

[0284] To a stirred solution of 3,6-dimethoxypyridinecarboxaldehyde (1 g, 1 equivalent, 6.05 mmol) in 1-nitropropane (40 mL) was added ammonium acetate (0.7 g, 1.5 equivalents, 9.08 mmol) in batches. After addition, the reaction mixture was allowed to stir at 90 ° C for 3 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was diluted with water and extracted with ethyl acetate. The crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / heptane). The desired fraction was concentrated under reduced pressure to obtain (E)-3,6-dimethoxy-2-(2-nitrobut-1-ene-1-yl)pyridine (790 mg, 54.78% yield) as a yellow solid. LC-MS m / z 239.10[M+1] + ; 1 H NMR (400MHz, CD CL3) δ=8.294 (s, 1H), 7.29-7.26 (m, 1H), 6.80 (d, J=9.2Hz, 1H), 3.90-3.77 (m, 6H), 3.39-3.34 (m, 2H), 1.28-1.23 (m, 3H).

[0285] Step 2: Preparation of 3,6-dimethoxy-2-(2-nitrobutyl)pyridine

[0286] To a stirred solution of (E)-3,6-dimethoxy-2-(2-nitrobut-1-en-1-yl)pyridine (0.790 g, 1 eq., 3.32 mmol) in methanol (10 mL) and THF (5 mL) cooled to 0 ° C. was added NaBH4 (752 mg, 8 eq., 19.90 mmol) in portions over 15 minutes. After addition, the reaction mixture was stirred at room temperature for 5 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with NH4Cl solution (20 ml) and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 3,6-dimethoxy-2-(2-nitrobutyl)pyridine (crude compound), which was used directly in the next step without further purification. LC-MS m / z 241.20 [M+1] + .

[0287] Step 3: Preparation of 1-(3,6-dimethoxypyridin-2-yl)butan-2-amine

[0288] To a stirred solution of 3,6-dimethoxy-2-(2-nitrobutyl)pyridine (640 mg, 2.66 mmol, 1 eq.) in ethanol (7 mL) and H2O (3 mL) was added iron powder (1.79 g, 31.97 mmol, 12 eq.) and NH4Cl (854 mg, 15.98 mmol, 10 eq.). The mixture was stirred at 90 ° C for 5 hours. After completion, the mixture was filtered and concentrated under reduced pressure to obtain an aqueous solution. The pH was adjusted to 9 with saturated sodium bicarbonate and the suspension was filtered and dried to obtain 1-(3,6-dimethoxypyridin-2-yl)butan-2-amine (yield: 550 mg, 97.21%) as a brown solid (crude). The crude compound was used directly in the next step without further purification. LC-MS m / z 211.20 [M+1] + .

[0289] Step 4: Preparation of tert-butyl (1-(3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate

[0290] Under an inert atmosphere, trimethylamine (1.1 mL, 3 equivalents, 7.85 mmol) and di-tert-butyl dicarbonate (0.9 mL, 1.5 equivalents, 3.92 mmol) were added to a solution of 1-(3,6-dimethoxypyridin-2-yl)butyl-2-amine (550 mg, 2.62 mmol) in tetrahydrofuran (5 mL) cooled to 0 ° C. The mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure to provide a crude compound. The crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / heptane). The desired fraction was concentrated under reduced pressure to provide tert-butyl (1-(3,6-dimethoxypyridin-2-yl)butyl-2-yl)carbamate (yield: 510 mg, 56%) as a light yellow solid. LC-MS m / z 311.10[M+1] + .

[0291] Step 5: Synthesis of tert-butyl (1-(5-bromo-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate

[0292] NBS (439 mg, 2.46 mmol, 1.5 eq.) was added to a stirred solution of tert-butyl (1-(3,6-dimethoxypyridin-2-yl)butyl-2-yl)carbamate (510 mg, 1.64 mmol, 1 eq.) in acetonitrile (10 mL) cooled to 0 ° C. The reaction mixture was allowed to stir at room temperature for 2.5 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure to provide a crude compound. The crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / heptane). The desired fraction was concentrated under reduced pressure to provide tert-butyl (1-(5-bromo-3,6-dimethoxypyridin-2-yl)butyl-2-yl)carbamate (yield: 460 mg, 72%) as an off-white solid. LC-MS m / z 390.90[M+1] + ; 1 H NMR(400MH z, DMSO-d6) δ = 7.69 (s, 1H), 6.54 (d, J = 9.2Hz, 1H), 3.85 (s, 3H), 3.77 (s, 3H) , 2.79-2.61 (m, 2H), 1.44-1.36 (m, 2H), 1.34 (s, 9H), 0.82 (t, J=7.2Hz, 3H).

[0293] Step 6: Preparation of 1-(5-bromo-3,6-dimethoxypyridin-2-yl)butan-2-amine (3) hydrochloride

[0294] To a stirred solution of tert-butyl (1-(5-bromo-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate (80 mg, 206 μmol) in 1,4-dioxane (3 mL) cooled to 0 ° C was added 4N HCl (3 mL) in 1,4-dioxane. The reaction mixture was then allowed to stir at room temperature for 3 hours. The reaction progress was monitored by TLC and LC-MS. After the reaction was complete, the mixture was concentrated under reduced pressure to give a crude material, which was ground with DCM (0.2 mL) and ether (2 mL) followed by n-pentane (5 mL). The resulting compound was dried under reduced pressure to provide compound 3HCl (yield: 48 mg, 71.7%) as a semisolid. LC-MS m / z 289.05 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ = 7.82 (s, 1H), 7.73 (br s, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 3.56-3.53 (m, 1H), 2.94 (d, J=6&15.6Hz, 1H), 2.84 (d, J=7.2&15.2Hz, 1H), 1.61-1.54 (m, 2H), 0.94 (t, J=7.6Hz, 3H).

[0295] Example 4: Preparation of 1-(3,6-dimethoxy-5-pentylpyridin-2-yl)propan-2-amine (4) formate

[0296]

[0297] Step 1: Preparation of tert-butyl (1-(3,6-dimethoxy-5-pentylpyridin-2-yl)propan-2-yl)carbamate

[0298] Under an inert atmosphere, PdCl2(dppf)·DCM (64.8 mg, 0.1 eq., 79.9 μmol) was added to a mixture of tert-butyl N-[1-(5-bromo-3,6-dimethoxypyridin-2-yl)propan-2-yl]carbamate (0.3 g, 799 μmol), amylboronic acid (232 mg, 2.5 eq., 2 mmol), potassium carbonate (110 mg, 3 eq., 799 μmol) in 1,4-dioxane (15 mL, 176 mmol) and water (3 mL, 167 mmol) and stirred at 100 ° C for 12 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and the organic layer was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography using ethyl acetate and hexane as eluents. The desired fractions were concentrated under reduced pressure to provide tert-butyl N-[1-(3,6-dimethoxy-5-pentylpyridin-2-yl)propan-2-yl]carbamate (44 mg, 191 μmol) as an off-white solid. LC-MS m / z 367 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.23 (s, 1H), 6.64 (d, J = 8Hz, 1H), 3.96-3.93 (m, 1H), 3.80 (s, 3H) 3.74 (s, 3H), 2.70-2.66 (m, 3H), 1.55-1.47 (m, 2H), 1.31 (m 12H), 1.29-1.28 (m, 2H), 0.98 (d, J=6.4Hz, 3H)), 0.82 (d, J=11.6Hz, 3H).

[0299] Step 2: Preparation of 1-(3,6-dimethoxy-5-pentylpyridin-2-yl)propan-2-amine (4) formate

[0300] At 0 ° C under an inert atmosphere, to a stirred solution of tert-butyl N-[1-(3,6-dimethoxy-5-pentylpyridin-2-yl)propan-2-yl]carbamate (44 mg, 1 eq.) in 1,4-dioxane (3 mL, 35.2 mmol) was added 4N HCl (43.8 mg, 5 eq.) in 1,4-dioxane. The reaction mixture was then allowed to stir at room temperature for 3 hours. The reaction progress was monitored by TLC and LC-MS. After the reaction was complete, the mixture was concentrated under reduced pressure to provide a crude material, which was ground with DCM and ether followed by n-pentane. This material was dried under reduced pressure to provide a crude compound 4HCl as a brown sticky solid. This was further purified by preparative HPLC with formic acid to provide compound 4 formate (yield: 17 mg, 46.76%). LC-MS m / z 367[M+1] + ;1 H NMR (400MHz, DMSO-d6) δ8.40 (br s, 1H), 7.29 (s, 1H), 3.81 (s, 3H), 3.75 (s, 3H) 3.74 (s, 3H), 3.54-3.52 (m, 1H), 2.50-2.47 (m, 2H), 1.56-1.53 ​​(m 2H), 1.33-1.23 (m, 4H), 1.11 (d, J=6.4Hz, 3H)), 0.86 (t, J=13.6Hz, 3H).

[0301] Example 5: Preparation of 1-(3,6-dimethoxy-5-methylpyridin-2-yl)propan-2-amine (5) hydrochloride

[0302]

[0303] Step 1: Preparation of tert-butyl (1-(3,6-dimethoxy-5-methylpyridin-2-yl)propan-2-yl)carbamate

[0304] To a stirred solution of (1-(5-bromo-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamic acid tert-butyl ester (0.050 g, 0.133 mmol, 1 eq) in 1,4-dioxane (2 mL) and water (1 mL) was added trimethyl-1,3,5,2,4,6-trioxatricyclohexaborane (46.6 μL, 1.5 eq, 0.167 mmol) and potassium carbonate (55.2 mg, 3 eq, 0.4 mmol). The reaction mixture was degassed with argon for 5 minutes, then PdCl2(dppf)·DCM (10.9 mg, 0.1 eq, 0.0133 mmol) was added, and the mixture was heated at 100 ° C for 12 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with aqueous solution and dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure to give a crude compound, which was purified by column chromatography (SiO2, 10% ethyl acetate / heptane). The desired fractions were concentrated under reduced pressure to provide tert-butyl (1-(3,6-dimethoxy-5-methylpyridin-2-yl)propan-2-yl)carbamate as a colorless liquid (yield: 30 mg, 72.54% yield). LC-MS m / z 311.10 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.28 (s, 1H), 6.65 (d, J = 8Hz, 1H), 3.95-3.90 (m, 1H), 3.80 (s, 3H), 3.72 (s, 3H).

[0305] Step 2: Preparation of 1-(3,6-dimethoxy-5-methylpyridin-2-yl)propan-2-amine (5) hydrochloride

[0306] To a stirred solution of tert-butyl (1-(3,6-dimethoxy-5-methylpyridin-2-yl)propan-2-yl)carbamate (60 mg, 193 mmol) in 1,4-dioxane (3 mL, 35.2 mmol) was added 4N HCl (3 mL) in 1,4-dioxane at 0 ° C. The reaction mixture was then allowed to stir at room temperature for 3 hours. The reaction progress was monitored by TLC and LC-MS. After the reaction was complete, the mixture was concentrated under reduced pressure to give a crude material, which was ground with DCM (0.2 mL) and ether (2.0 mL) followed by n-pentane (5 mL). The resulting compound was dried under reduced pressure to provide compound 5HCl (yield: 45 mg, 94%) as an off-white solid. LC-MS m / z 211.20 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.82 (s, 3H), 7.38 (s, 1H), 3.80 (s, 3H), 3.75 (s, 3H) ), 3.63-3.57 (m, 1H), 2.93-2.82 (m, 2H), 2.14 (s, 3H), 1.18 (d, J=6.4Hz, 3H).

[0307] Example 6: Preparation of 1-(5-bromo-3,6-dimethoxypyridin-2-yl)propan-2-amine (6) hydrochloride

[0308]

[0309] Step 1: Preparation of (E)-3,6-dimethoxy-2-(2-nitroprop-1-en-1-yl)pyridine

[0310] To a stirred solution of 3,6-dimethoxypyridinecarboxaldehyde (4g, 23.9mmol) in nitroethane (40mL) was added ammonium acetate (2.77g, 1.5 equivalents, 35.9mmol) in batches. After addition, the reaction mixture was allowed to stir at 90°C for 3 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure to obtain a crude compound. The crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / heptane). The desired fraction was concentrated under reduced pressure to provide (E)-3,6-dimethoxy-2-(2-nitroprop-1-ene-1-yl)pyridine (yield: 2.2g, 41.01%) as a yellow solid. LC-MS m / z225.20[M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.19 (s, 1H), 7.67 (d, J = 9.2Hz, 1H), 6.98 (d, J = 8.8Hz, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 2.75 (s, 3H).

[0311] Step 2: Preparation of 3,6-dimethoxy-2-(2-nitropropyl)pyridine

[0312] To a stirred solution of (E)-3,6-dimethoxy-2-(2-nitroprop-1-en-1-yl)pyridine (1.0 g, 1 eq., 4.46 mmol) in THF (15 mL, 184 mmol) and MeOH (30 mL, 494 mmol) was added NaBH4 (1.34 g, 8 eq., 35.68 mmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 5 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with NH4Cl solution (20 ml) and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 3,6-dimethoxy-2-(2-nitropropyl)pyridine. The crude compound was used directly in the next step for further purification (yield: 980 mg, 97%). LC-MS m / z227.10[M+1] + .

[0313] Step 3: Preparation of 1-(3,6-dimethoxypyridin-2-yl)propan-2-amine

[0314] To a stirred solution of 3,6-dimethoxy-2-(2-nitropropyl)pyridine (980 mg, 4.33 mmol, 1 eq.) in ethanol (15 mL) and H2O (5 mL) was added iron powder (2.9 g, 52 mmol, 12 eq.) and NH4Cl (2.32 g, 43.3 mmol, 10 eq.). The mixture was stirred at 90 °C for 5 hours. Upon completion, the mixture was filtered and concentrated under reduced pressure to give an aqueous solution. The pH was adjusted to 9 with saturated sodium bicarbonate, and the suspension was filtered and dried under reduced pressure to provide 1-(3,6-dimethoxypyridin-2-yl)propan-2-amine (yield: 800 mg, 94.1%) as a brown solid (crude), which was used directly in the next step without further purification. LC-MS m / z 197.20 [M+1] + .

[0315] Step 4: Preparation of tert-butyl (1-(3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate

[0316] At 0 ℃ under inert atmosphere, triethylamine (3.02mL, 5 equivalents, 21.7mmol) and di-tert-butyl dicarbonate (1.99mL, 2 equivalents, 8.66mmol) were added to a stirred solution of 1-(3,6-dimethoxypyridin-2-yl)propan-2-amine (850mg, 1 equivalent, 4.33mmol) in cooling THF (10mL). The reaction mixture was then allowed to stir at room temperature for 3 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure to provide a crude compound. The crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / heptane). The desired fractions were concentrated under reduced pressure to provide tert-butyl (1-(3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate as a pale yellow solid (yield: 0.790 g, 61.54%). LC-MS m / z 269.10 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ=7.39 (d, J=8Hz, 1H), 6.67 (d, J=8Hz, 1H), 6.61 (d, J=8Hz, 1H), 3.99- 3.95 (m, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 2.73 (d, J=8Hz, 2H), 1.32 (s, 9H), 0.98 (d, J=8Hz, 3H).

[0317] Step 5: Preparation of tert-butyl (1-(5-bromo-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate

[0318] At 0 ° C, NBS (541 mg, 1.5 equivalents, 3.04 mmol) was added to a stirred solution of (1- (3,6-dimethoxypyridin-2-yl) propan-2-yl) tert-butyl carbamate (0.6 g, 2.02 mmol, 1 equivalent) in acetonitrile (20 mL, 383 mmol). The reaction mixture was allowed to stir at room temperature for 2.5 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure to provide a crude compound. The crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / heptane). The desired fraction was concentrated under reduced pressure to provide (1- (5-bromo-3,6-dimethoxypyridin-2-yl) propan-2-yl) tert-butyl carbamate (yield: 610 mg, 80.29%). LC-MS m / z 376.85[M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 7.70 (s, 1H), 6.66 (d, J = 8Hz, 1H), 3.98 (br s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 2.72-2.66 (m, 2H), 1.30 (s, 9H), 1.00 (d, J=6.4Hz, 3H).

[0319] Step 6: Preparation of 1-(5-bromo-3,6-dimethoxypyridin-2-yl)propan-2-amine (6) hydrochloride

[0320] To a stirred solution of (1-(5-bromo-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamic acid tert-butyl ester (120 mg, 0.320 mmol, 1 eq.) in 1,4-dioxane (2 mL) cooled to 0 ° C was added 4N HCl (3 mL) in 1,4-dioxane. The reaction mixture was then allowed to stir at room temperature for 3 hours. The reaction progress was monitored by TLC and LC-MS. After the reaction was complete, the mixture was concentrated under reduced pressure to provide a crude product, which was ground with DCM (0.2 mL) and ether (2.0 mL) followed by n-pentane (5.0 mL). The resulting compound was dried under reduced pressure to provide compound 6HCl (70 mg, 79.56% yield) as an off-white solid. LC-MS m / z 275.15[M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 6.89 (s, 1H), 3.13 (s, 3H), 3.05 (s, 3H) 3.03-2.99 (m, 1H), 2.20-2.14 (m, 2H), 0.53 (d, J = 8Hz, 3H).

[0321] Example 7: Preparation of 2-(3,6-dimethoxy-5-pentylpyridin-2-yl)ethan-1-amine (7) hydrochloride

[0322]

[0323] Step 1: Preparation of tert-butyl (2-(3,6-dimethoxy-5-pentylpyridin-2-yl)ethyl)carbamate

[0324] To a stirred solution of tert-butyl (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (1.1 g, 1 eq., 3.05 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added amylboronic acid (0.706 g, 2 eq., 6.09 mmol) and potassium carbonate (1.26 g, 3 eq., 9.14 mmol). The reaction mixture was degassed with argon for 5 minutes, then PdCl2(dppf)·DCM (247 mg, 0.1 eq., 0.305 mmol) was added, and the resulting reaction mixture was heated at 100 ° C for 12 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine solution and dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure (residue pressure). This crude material was purified by column chromatography (SiO2, 10% ethyl acetate / heptane), and the desired fractions were concentrated under reduced pressure to afford tert-butyl (2-(3,6-dimethoxy-5-pentylpyridin-2-yl)ethyl)carbamate as a colorless liquid (yield: 0.3 g, 27.95%). LC-MS m / z 353.25 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.23 (s, 1H), 6.79 (brs, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.23-3.20 (m, 2H ), 2.72 (t, J=7.6Hz, 2H), 1.53-1.51 (m, 2H), 1.35 (s, 9H), 1.19-1.15 (m, 6H), 0.86 (t, J=8Hz, 3H).

[0325] Step 2: Preparation of 2-(3,6-dimethoxy-5-pentylpyridin-2-yl)ethan-1-amine (7) hydrochloride

[0326] To a stirred solution of tert-butyl (2-(3,6-dimethoxy-5-pentylpyridin-2-yl)ethyl)carbamate (35 mg, 1 eq., 0.0993 mmol) in 1,4-dioxane (3 mL) was added 4N HCl (1 mL) in 1,4-dioxane at 0 °C. The reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure to provide a crude product, which was triturated with DCM (0.2 mL) and ether (2.0 mL) followed by n-pentane (5 mL). The resulting compound was dried under reduced pressure to provide compound 7HCl (yield: 23 mg, 91.78%) as an off-white solid. LC-MS

[0327] m / z 253.30[M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 7.94 (bs, 3H),

[0328] 7.31 (s, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.18-3.13 (m, 2H), 2.93 (t, J=7.6Hz, 2H) , 2.50-2.46 (m, 2H), 1.54-1.50 (m, 2H), 1.31-1.25 (m, 4H), 0.86 (t, J=6.8Hz, 3H).

[0329] Example 8: Preparation of 2-(3,6-dimethoxy-5-methylpyridin-2-yl)ethan-1-amine (8) hydrochloride

[0330]

[0331] Step 1: Preparation of tert-butyl (2-(3,6-dimethoxy-5-methylpyridin-2-yl)ethyl)carbamate

[0332] 2,4,6-trimethyl-1,3,5,2,4,6-trioxatricyclohexaborane (41.70 mg, 1.2 equivalents, 0.332 mmol) and potassium carbonate (115 mg, 3 equivalents, 0.830 mmol) were added to a stirred solution of tert-butyl (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.100 g, 1 equivalent, 0.277 mmol) in toluene (4 mL) and water (1 mL). The reaction mixture was degassed with argon for 5 minutes, PdCl2(dppf)·DCM (22 mg, 0.1 equivalents, 0.027 mmol) was added, and the resulting mixture was heated at 100 ° C for 12 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure to give a crude material, which was purified by column chromatography (SiO2, 10% ethyl acetate / heptane). The desired fractions were concentrated under reduced pressure to provide tert-butyl (2-(3,6-dimethoxy-5-methylpyridin-2-yl)ethyl)carbamate as a colorless liquid (yield: 60 mg, 73%). LC-MS m / z 297.05 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ = 7.28 (s, 1H), 6.79 (s, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.24-3.19 (m, 2H), 2.75 (m, 2H), 2.11 (s, 3H), 1.35 (s, 9H)ppm

[0333] Step 2: Preparation of 2-(3,6-dimethoxy-5-methylpyridin-2-yl)ethan-1-amine (8) hydrochloride

[0334] To a stirred solution of tert-butyl (2-(3,6-dimethoxy-5-methylpyridin-2-yl)ethyl)carbamate (68 mg, 1 eq., 0.229 mmol) in 1,4-dioxane (3 mL) cooled to 0 ° C was added 4N HCl (1 mL) in 1,4-dioxane. The reaction was allowed to stir at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LC-MS. After the reaction was complete, the mixture was concentrated under reduced pressure to provide a crude material, which was triturated with DCM (0.2 mL) and ether (2 mL) followed by n-pentane (5 mL). The resulting compound was dried under reduced pressure to provide compound 8HCl (yield: 42 mg, 93.27%) as an off-white solid. LC-MS m / z 197.20 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ=7.86 (bs, 3H), 7.36 (s, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.18-3.13 (m, 2H), 2.93 (t, J=7.6, 2H), 2.13 (s, 3H).

[0335] Example 9: Preparation of 2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethan-1-amine (9) hydrochloride

[0336]

[0337] Step 1: Preparation of tert-butyl (2-(3,6-dimethoxypyridin-2-yl)ethyl)carbamate

[0338] To a stirred solution of 2-bromo-3,6-dimethoxypyridine (5 g, 1 eq., 22.9 mmol) in 1,4-dioxane (100 mL) and water (30 mL) was added (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (10.4 g, 1.8 eq., 41.3 mmol) and potassium carbonate (9.51 g, 3 eq., 68.8 mmol). The reaction mixture was degassed with argon for 15 min, then Pd(dppf)Cl2.DCM (1.87 g, 0.1 eq., 2.29 mmol) was added and the resulting mixture was heated at 100 °C for 12 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and the solvent evaporated under reduced pressure to provide a crude material, which was purified by column chromatography (SiO2, 10% ethyl acetate / heptane). The desired fractions were concentrated under reduced pressure to provide tert-butyl (2-(3,6-dimethoxypyridin-2-yl)ethyl)carbamate as a pale yellow oil (yield: 1.60 g, 24.71%). LC-MS m / z 283.15 [M+1] + ; 1H NMR (400MHz, DMSO-d6): δ=7.40 (d, J=8.8Hz, 1H), 6.77 (bs, 1H), 6.62 (d, J=8.8Hz , 1H), 3.79-3.75(m, 6H), 3.30-3.25(m, 2H), 2.78(t, J=7.6Hz, 2H), 1.36(s, 9H).

[0339] Step 2: Preparation of tert-butyl (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamate

[0340] At 0 ° C, NBS (0.946 g, 1.5 equivalents, 5.31 mmol) was added to a stirred solution of (2-(3,6-dimethoxypyridin-2-yl)ethyl)carbamic acid tert-butyl ester (1.0 g, 3.54 mmol, 1 equivalent) in acetonitrile (20 mL). The reaction mixture was allowed to stir at room temperature for 3 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure to provide a crude material, which was purified by column chromatography (SiO2, 10% ethyl acetate / heptane). The desired fraction was concentrated under reduced pressure to provide (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamic acid tert-butyl ester (yield: 1.1 g, 85.98%). LC-MS m / z 362.95[M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.71 (s, 1H), 6.87 (s, 1H), 4.03 (s, 3H), 3.77 (s, 1H), 3.27-3.22 (m, 2H), 2.74 (t, J = 7.2Hz, 2H), 1.34 (s, 9H).

[0341] Step 3: Preparation of 2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethan-1-amine (9) hydrochloride

[0342] At 0°C, to a stirred solution of tert-butyl (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (60 mg, 1 eq.) in 1,4-dioxane (2 mL) cooled to 0°C was added 4N HCl (5 eq.) in 1,4-dioxane. The reaction mixture was then allowed to stir at room temperature for 3 hours. The reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure to provide a crude material, which was ground with DCM (0.2 mL) and ether (2.0 mL) followed by n-pentane (5.0 mL). The resulting compound was dried under reduced pressure to provide compound 9HCl (yield: 38 mg, 87%) as an off-white solid. LC-MS m / z 263.0[M+1] + ; 1H

[0343] NMR (400MHz, DMSO-d6) δ = 7.71 (s, 1H), 3.84 (s, 3H), 3.75 (s,

[0344] 3H), 3.19 (t, J=7.2Hz, 2H), 2.91 (t, J=6.8Hz, 2H).

[0345] Example 10: Preparation of 1-(2,5-dimethoxy-4-pentylphenyl)butan-2-amine (10) hydrochloride

[0346]

[0347] Step 1: Preparation of 2,5-dimethoxy-4-pentylbenzaldehyde

[0348] A mixture solution of 4-bromo-2,5-dimethoxybenzaldehyde (6 g, 24.48 mmol, 1 eq.), pentylboronic acid (4.26 g, 36.72 mmol, 1.5 eq.), Pd(dppf)Cl2 (895.71 mg, 1.22 mmol, 0.05 eq.) and K3PO4 (15.59 g, 73.45 mmol, 3 eq.) in toluene (100 mL) was stirred at 110 °C for 12 hours. After completion, the mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 100: 1 to 50: 1) to give 2,5-dimethoxy-4-pentylbenzaldehyde (5.1 g, 21.58 mmol, 88.15% yield) as a yellow oil.

[0349] Step 2: Preparation of (E)-1,4-dimethoxy-2-(2-nitrobut-1-en-1-yl)-5-pentylbenzene

[0350] A mixture of 2,5-dimethoxy-4-pentylbenzaldehyde (1 g, 4.23 mmol, 1 eq) and NH4OAc (652.37 mg, 8.46 mmol, 2 eq) in 1-nitropropane (6.79 g, 76.17 mmol, 6.80 mL, 18 eq) was stirred and warmed to 115 ° C for 5 hours. After completion, the solvent was removed. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 80: 1 to 60: 1) to provide (E)-1,4-dimethoxy-2-(2-nitrobut-1-ene-1-yl)-5-pentylbenzene (830 mg, 2.70 mmol, 64% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.26 (s, 1H), 6.79 (s, 1H), 6.757 (s, 1H), 3.83-3.85 (m, 3H), 3.79-3.81 (m, 3H), 2.869 (d, J = 7.2 Hz, 2H), 2.60

[0351] -2.66 (m, 2H), 1.58-1.62 (m, 2H), 1.34-1.38 (m, 4H), 1.30 (t, J=7.2Hz, 3H), 0.92 (t, J=6.8Hz, 4H).

[0352] Step 3: Preparation of 1-(2,5-dimethoxy-4-pentylphenyl)butan-2-amine (10) hydrochloride

[0353] A solution of (E)-1,4-dimethoxy-2-(2-nitrobut-1-en-1-yl)-5-pentylbenzene (830 mg, 2.70 mmol, 1 eq.) in THF (20 mL) was cooled to 0 ° C. LiAlH4 (409.89 mg, 10.80 mmol, 4 eq.) was then added. The mixture was stirred at 60 ° C for 5 hours. After completion, the mixture was cooled to 0 ° C. Water (0.6 mL) was then added. 30% aqueous NaOH (0.6 mL) was then added. The mixture was stirred into a smooth dispersion, then filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 80x40mm×3μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 22%-50%, 7 minutes) to provide compound 10HCl (350 mg, 1.07 mmol, 40% yield, 96.8% purity, HCl) as a white solid. LC-MS (R T = 2.320 min, MS calculated value: 279.42, [M+H] + Measured value = 280.2); 1 H NMR (400MHz, DMSO-d6) δppm 8.06-7.90 (m, 3H), 6.82 (s, 1H), 6.78 (s, 1H), 3.77-3.69 (m, 6H), 3.28-3.20 (m, 1H), 2.80 (d, J=6. 4Hz, 2H), 2.54-2.51 (m, 2H), 1.55-1.46 (m, 4H), 1.35-1.25 (m, 4H), 0.89 (td, J=7.2, 18.4Hz, 6H); 13 C NMR (101MHz, DMSO-d6) δppm 151.00, 150.71, 129.77, 122.17, 114.06, 112.99, 55.84, 55.81, 52.19, 32.58, 31.16, 29.57, 29.22, 24.73, 21.91, 13.87, 9.40.

[0354] Example 11: Preparation of 1-(2,5-dimethoxy-6-pentylpyridin-3-yl)butan-2-amine (11) hydrochloride

[0355]

[0356] Step 1: Preparation of 2-bromo-6-methoxypyridin-3-ol

[0357] NBS (15.02 g, 84.40 mmol, 1.1 eq.) was added to a solution of 6-methoxypyridine-3-ol (9.6 g, 76.72 mmol, 1 eq.) in acetonitrile (50 mL) and water (7 mL). The mixture was stirred at 60 ° C for 5 hours. After completion, the residue was diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 50: 1 to 30: 1). 2-Bromo-6-methoxypyridine-3-ol (7 g, 34.31 mmol, 44.72% yield) was obtained as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.89 (s, 3H), 5.04 (br s, 1H), 6.66 (d, J=8.66 Hz, 1H), 7.26 (s, 1H), 7.28 (s, 1H).

[0358] Step 2: Preparation of 2-bromo-3,6-dimethoxypyridine

[0359] To a solution of 2-bromo-6-methoxypyridin-3-ol (7 g, 34.31 mmol, 1 eq.) in DMF (70 mL) was added K2CO3 (14.23 g, 102.93 mmol, 3 eq.) and CH3I (12.17 g, 85.78 mmol, 5.34 mL, 2.5 eq.). The mixture was stirred at 50 °C for 0.5 h. Upon completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-bromo-3,6-dimethoxypyridine (6.7 g, 30.73 mmol, 89.56% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 3.87 (d, J = 15.88 Hz, 6H), 6.67 (d, J = 8.63 Hz, 1H), 7.20 (d, J = 8.76 Hz, 1H).

[0360] Step 3: Preparation of 3,6-dimethoxy-2-pentylpyridine

[0361] To a solution of 2-bromo-3,6-dimethoxypyridine (6.7 g, 30.73 mmol, 1 eq.) in toluene (100 mL) and water (10 mL) was added amylboronic acid (5.35 g, 46.09 mmol, 1.5 eq.), Pd(dppf)Cl2.CH2Cl2 (2.51 g, 3.07 mmol, 0.1 eq.) and cesium carbonate (30.03 g, 92.18 mmol, 3 eq.) under N2 atmosphere. The mixture was stirred at 90°C for 2 hours. After completion, the mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate gradient, 50:1 to 3:1) to afford 3,6-dimethoxy-2-pentylpyridine (4.2 g, 20.07 mmol, 65.31% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.86-0.95 (m, 3H), 1.30-1.42 (m, 4H), 1.65-1.77 (m, 2H), 2.64-2.77 (m, 2H), 3.78 (s, 3H), 3.89 (s, 3H), 6.52 (d, J=8.75 Hz, 1H), 7.14 (d, J=8.75 Hz, 1H).

[0362] Step 4: Preparation of 3-bromo-2,5-dimethoxy-6-pentylpyridine

[0363] To a solution of 3,6-dimethoxy-2-pentylpyridine (3.8 g, 18.16 mmol, 1 eq.) in DMF (30 mL) was added NBS (4.85 g, 27.24 mmol, 1.5 eq.). The mixture was stirred at 70 ° C for 12 hours. After completion, the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 1:0 to 30:1) to provide 3-bromo-2,5-dimethoxy-6-pentylpyridine (3 g, 10.41 mmol, 57.33% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 0.90 (t, J=6.94 Hz, 3H), 1.28-1.43 (m, 4H), 1.68 (quin, J=7.41 Hz, 2H), 2.63-2.71 (m, 2H), 3.78 (s, 3H), 3.96 (s, 3H), 7.34 (s, 1H).

[0364] Step 5: Preparation of 2,5-dimethoxy-6-pentyl-3-vinylpyridine

[0365] To a solution of 3-bromo-2,5-dimethoxy-6-pentylpyridine (1 g, 3.47 mmol, 1 eq) in water (1 mL) and dioxane (10 mL) was added vinylboronic acid pinacol ester (1.60 g, 10.41 mmol, 1.77 mL, 3 eq) and K2CO3 (1.44 g, 10.41 mmol, 3 eq) at 20°C. Pd(dppf)Cl2 (253.91 mg, 347.01 μmol, 0.1 eq) was then added under N2 atmosphere, and the mixture was stirred at 85°C for 12 hours. After completion, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (8 mL×3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 1:0 to 50:1) to provide 2,5-dimethoxy-6-pentyl-3-vinylpyridine (0.2 g, 849.90 μmol, 24.49% yield) as a yellow oil.

[0366] Step 6: Preparation of 2,5-dimethoxy-6-pentylnicotinaldehyde

[0367] To a solution of 2,5-dimethoxy-6-pentyl-3-vinylpyridine (0.3 g, 1.27 mmol, 1 eq) in THF (10 mL) and water (2.5 mL) was added OsO4 (16.21 mg, 63.74 μmol, 3.31 μL, 0.05 eq) at 0°C, and the mixture was stirred for 10 minutes. Then NaIO4 (681.70 mg, 3.19 mmol, 176.61 μL, 2.5 eq) and water (5 mL) were added, and the mixture was stirred at 25°C for 4 hours. After completion, water (10 mL) was added and the mixture was extracted with ethyl acetate (8 mL×3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 10:1) to provide 2,5-dimethoxy-6-pentylnicotinaldehyde (0.3 g, 1.26 mmol, 99.17% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.89-0.94 (m, 3H), 1.33-1.40 (m, 4H), 1.68-1.76 (m, 2H), 2.74-2.83 (m, 2H), 3.81-3.86 (m, 3H), 3.95-4.05 (m, 3H), 7.55 (s, 1H), 10.32 (s, 1H).

[0368] Step 7: Preparation of (E)-2,5-dimethoxy-3-(2-nitrobut-1-en-1-yl)-6-pentylpyridine

[0369] To a solution of 2,5-dimethoxy-6-pentylnicotinaldehyde (0.25 g, 1.05 mmol, 1 eq.) in 1-nitropropane (3 mL) was added ammonium acetate (81.21 mg, 1.05 mmol, 1 eq.). The mixture was stirred at 90 ° C for 4 hours. After completion, the mixture was extracted with ethyl acetate (3 mL×3). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate=10:1) to provide (E)-2,5-dimethoxy-3-(2-nitrobut-1-ene-1-yl)-6-pentylpyridine (0.12 g, 389.14 μmol, 36.94% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.89-0.96 (m, 3H), 1.29 (t, J=7.40 Hz, 2H), 1.33-1.43 (m, 4H), 1.66-1.78 (m, 2H), 2.70-2.87 (m, 3H), 3.81 (s, 3H), 3.91-4.03 (m, 3H), 7.12 (s, 1H), 8.13 (s, 1H).

[0370] Step 8: Preparation of 1-(2,5-dimethoxy-6-pentylpyridin-3-yl)butan-2-amine (11) hydrochloride

[0371] At 0 ° C, to a solution of (E)-2,5-dimethoxy-3-(2-nitrobut-1-ene-1-yl)-6-pentylpyridine (0.1 g, 324.28 μmol, 1 eq) in THF (10 mL), LiAlH4 (49.23 mg, 1.30 mmol, 4 eq) was added, and the mixture was stirred at 60 ° C for 3 hours. After completion, the reaction mixture was quenched by adding water (5 mL) and 30% aqueous NaOH (5 mL) at 0 ° C. The obtained suspension was filtered and the filter cake was washed with THF (20 mL × 3). The filtrate was concentrated to give a residue, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100x30mmx10μm; mobile phase: [water(HCl)-ACN]; B%: 1%-25%, 8 minutes) to provide compound 11HCl (0.032 g, 114.14 μmol, 35.2% yield, HCl) as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 0.88-0.94 (m, 3H), 1.06 (t, J=7.50 Hz, 3H), 1.28-1.42 (m, 5H), 1.68 (m, 5H), 2.68-2.77 (m, 2H), 2.82-2.91 (m, 1H), 2.94-3.02 (m, 1H), 3.39-3.50 (m, 1H), 3.84 (s, 3H), 3.96 (s, 3H), 7.39 (s, 1H); 13 C NMR (101 MHz, methanol-d4) δ ppm 154.97, 148.72, 146.64, 125.03, 116.02, 55.84, 52.88, 48.29, 47.86, 47.65, 47.43, 47.22, 47.01, 31.45, 30.47, 27.65, 25.35, 22.22, 13.04, 8.60.

[0372] Example 12: Preparation of 1-(3,6-dimethoxy-5-pentylpyrazin-2-yl)butan-2-amine (12) hydrochloride

[0373]

[0374] Step 1: Preparation of (Z)-1-acetyl-6-pentylidenepiperazine-2,5-dione

[0375] Under N2 atmosphere, t-BuOK (1M in THF, 75.69 mL, 1 eq.) and valeraldehyde (13.04 g, 151.38 mmol, 16.10 mL, 2 eq.) were added to a solution of 1,4-diacetylpiperazine-2,5-dione (15 g, 75.69 mmol, 1 eq.) in DCM (90 mL). Under N2 atmosphere, the mixture was stirred at 20 °C for 0.5 hours. After completion, the reaction mixture was filtered. The filtrate was poured into saturated aqueous NH4Cl (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was then concentrated. The crude product was purified by recrystallization from petroleum ether (100 mL) to afford (Z)-1-acetyl-6-pentylidenepiperazine-2,5-dione (13 g, 48.82 mmol, 64.50% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.93 (br s, 1H), 6.34 (t, J = 7.9 Hz, 1H), 4.42 (s, 2H), 2.61 (s, 3H), 2.23 (q, J = 7.6 Hz, 2H), 1.52-1.40 (m, 4H), 0.96-0.93 (m, 3H).

[0376] Step 2: Preparation of (Z)-3-pentylenepiperazine-2,5-dione

[0377] To a solution of (Z)-1-acetyl-6-pentylidenepiperazine-2,5-dione (14.6 g, 54.83 mmol, 1 eq.) in DMF (150 mL) was added hydrazine hydrate (5.54 g, 109.65 mmol, 5.38 mL, 99% purity, 2 eq.). The mixture was stirred at 20 ° C for 1 hour. After completion, the reaction mixture was quenched by adding water (100 mL) and extracted with DCM (100 mL×3). The combined organic layers were washed with brine (100 mL) and dried over Na2SO4. The mixture was filtered and concentrated in vacuo to provide (Z)-3-pentylidenepiperazine-2,5-dione (8 g, 43.90 mmol, 80.08% yield) as a white solid. 1 H NMR (400MHz, chloroform-d) δppm 9.92 (br s, 1H), 8.05 (br s, 1H), 5.72 (t, J=7.9Hz, 1H), 3.91 (d, J=2.0Hz, 2H), 2.16 (q, J=7.4Hz, 2H), 1.38-1.25 (m, 4H), 0.90-0.84 (m, 3H).

[0378] Step 3: Preparation of (Z)-5-methoxy-6-pentylidene-3,6-dihydropyrazin-2(1H)-one

[0379] To a solution of (Z)-3-pentylidenepiperazine-2,5-dione (8.5 g, 46.65 mmol, 1 eq.) in DCM (240 mL) and CH3NO2 (64 mL) was added Me3OBF4 (6.90 g, 46.65 mmol, 1 eq.). The mixture was stirred at 20 ° C for 50 hours. After completion, the reaction mixture was quenched by adding water (500 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. The mixture was filtered and concentrated in vacuo to provide (Z)-5-methoxy-6-pentylidene-3,6-dihydropyrazine-2(1H)-one (5 g, 25.48 mmol, 54.62% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.83 (br s, 1H), 5.59 (t, J=7.7 Hz, 1H), 4.33 (s, 2H), 3.76 (s, 3H), 2.08 (q, J=7.4 Hz, 2H), 1.49-1.32 (m, 4H), 0.95-0.90 (m, 3H).

[0380] Step 4: Preparation of 5-methoxy-6-pentylpyrazin-2-ol

[0381] A solution of (Z)-5-methoxy-6-pentylidene-3,6-dihydropyrazine-2(1H)-one (5 g, 25.48 mmol, 1 eq) in aqueous NaOH (1 M, 25.48 mL, 1 eq) was stirred at 20 °C for 0.5 h. After completion, the mixture was quenched with 1 M aqueous HCl (30 mL). The mixture was filtered and concentrated in vacuo to provide 5-methoxy-6-pentylpyrazine-2-ol (3.2 g, 16.31 mmol, 64.00% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.66 (s, 1H), 3.92 (s, 3H), 2.75-2.65 (m, 2H), 1.70-1.58 (m, 2H), 1.41-1.28 (m, 5H), 0.95-0.88 (m, 3H).

[0382] Step 5: Preparation of 2,5-dimethoxy-3-pentylpyrazine

[0383] To a solution of 5-methoxy-6-pentylpyrazine-2-ol (3.2 g, 16.31 mmol, 1 eq.) in DCM (100 mL) was added Ag2O (7.56 g, 32.61 mmol, 2 eq.) and CH3I (4.63 g, 32.61 mmol, 2.03 mL, 2 eq.). The mixture was stirred at 20 °C for 12 hours. After completion, the mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate gradient, 50: 1 to 1: 1) to obtain 2,5-dimethoxy-3-pentylpyrazine (3.2 g, 15.22 mmol, 93.33% yield) as a yellow oil.

[0384] Step 6: Preparation of 2-bromo-3,6-dimethoxy-5-pentylpyrazine

[0385] To a solution of 2,5-dimethoxy-3-pentylpyrazine (3.2 g, 15.22 mmol, 1 eq.) in DMF (32 mL) was added NBS (4.06 g, 22.83 mmol, 1.5 eq.). The mixture was stirred at 70 ° C for 5 hours. After completion, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate, 50:1 to 1:1) to obtain 2-bromo-3,6-dimethoxy-5-(2-bromo-3,6-dimethoxy-3-pentylpyrazine) as a yellow oil.

[0386] -pentylpyrazine (2.5 g, 8.65 mmol, 56.81% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.98 (s, 3H), 3.93 (s, 3H), 2.71-2.66 (m, 2H), 1.69 (m, 2H), 1.42-1.30 (m, 4H), 0.96-0.86 (m, 3H).

[0387] Step 7: Preparation of 2,5-dimethoxy-3-pentyl-6-vinylpyrazine

[0388] To a solution of 2-bromo-3,6-dimethoxy-5-pentylpyrazine (1 g, 3.46 mmol, 1 eq.) in dioxane (10 mL) and water (1 mL) was added vinylboronic acid pinacol ester (1.60 g, 10.37 mmol, 1.76 mL, 3 eq.) and K2CO3 (1.43 g, 10.37 mmol, 3 eq.) under N2 atmosphere. The mixture was stirred at 20°C for 10 minutes. Pd(dppf)Cl2 (253.04 mg, 345.82 μmol, 0.1 eq.) was then added, and the mixture was stirred at 90°C for 12 hours. Upon completion, the aqueous phase was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate gradient, 100:1 to 50:1) to afford 2,5-dimethoxy-3-pentyl-6-vinylpyrazine (400 mg, 1.69 mmol, 48.95% yield, 100% purity) as a colorless oil. 1 H NMR (400MHz, chloroform-d) δppm 6.98 (dd, J=10.9, 17.4Hz, 1H), 6.32 (dd, J=2.1, 17.3Hz, 1H), 5.44 (dd, J=2.1, 10.9Hz, 1H), 3. 95 (s, 6H), 2.72 (t, J=7.6Hz, 2H), 1.75-1.64 (m, 2H), 1.40-1.33 (m, 4H), 0.91 (t, J=6.8Hz, 3H).

[0389] Step 8: Preparation of 3,6-dimethoxy-5-pentylpyrazine-2-carbaldehyde

[0390] At 0 ° C, to a solution of 2,5-dimethoxy-3-pentyl-6-vinylpyrazine (400 mg, 1.69 mmol, 1 eq.) in water (2.5 mL) and THF (10 mL), OsO4 (21.52 mg, 84.63 μmol, 4.39 μL, 0.05 eq.) was added. Then NaIO4 (905.13 mg, 4.23 mmol, 234.49 μL, 2.5 eq.) in water (5 mL) was added dropwise. The mixture was stirred at 20 ° C for 4 hours. After completion, water (10 mL) was added and the mixture was extracted with ethyl acetate (5 mL×3). The combined organic layer was washed with water and dried over Na2SO4. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate gradient, 100:1 to 50:1) to afford 3,6-dimethoxy-5-pentylpyrazine-2-carbaldehyde (350 mg, 1.40 mmol, 82.44% yield, 95% purity) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 10.20 (s, 1H), 4.07 (s, 3H), 4.01 (s, 3H), 2.86-2.77 (m, 2H), 1.76 (quin, J=7.4 Hz, 2H), 1.42-1.35 (m, 4H), 0.97-0.89 (m, 3H).

[0391] Step 9: Preparation of (E)-2,5-dimethoxy-3-(2-nitrobut-1-en-1-yl)-6-pentylpyrazine

[0392] Under N2 atmosphere, ammonium acetate (32.35 mg, 419.67 μmol, 1 equivalent) was added to a solution of 3,6-dimethoxy-5-pentylpyrazine-2-carboxaldehyde (100 mg, 419.67 μmol, 1 equivalent) in nitropropane (3 mL). The mixture was stirred at 90 ° C for 12 hours. After completion, the mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate gradient = 10: 1) to obtain (E)-2,5-dimethoxy-3-(2-nitrobut-1-ene-1-yl)-6-pentylpyrazine (85 mg, 274.76 μmol, 65.47% yield, 100% purity) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.20 (s, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.33 (q, J = 7.3 Hz, 2H), 2.77 (t, J = 7.6 Hz, 2H), 1.74 (quin, J = 7.2 Hz, 2H), 1.43-1.34 (m, 4H), 1.26 (t, J = 7.3 Hz, 3H), 0.92 (t, J = 6.8 Hz, 3H).

[0393] Step 10: Preparation of 2,5-dimethoxy-3-(2-nitrobutyl)-6-pentylpyrazine

[0394] To a solution of (E)-2,5-dimethoxy-3-(2-nitrobut-1-en-1-yl)-6-pentylpyrazine (50 mg, 161.62 μmol, 1 eq.) in THF (1 mL) and MeOH (2 mL) was added NaBH4 (18.34 mg, 484.87 μmol, 3 eq.) at 0°C. The mixture was stirred at 20°C for 5 hours. Upon completion, the reaction mixture was cooled to 0°C. Aqueous NH4Cl (5 mL) was slowly added to the mixture, and the mixture was extracted with ethyl acetate (20 mL). The extract was washed with water (20 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide 2,5-dimethoxy-3-(2-nitrobutyl)-6-pentylpyrazine (50 mg, crude) as a colorless oil.

[0395] Step 11: Preparation of 1-(3,6-dimethoxy-5-pentylpyrazin-2-yl)butan-2-amine (12) hydrochloride

[0396] To a solution of 2,5-dimethoxy-3-(2-nitrobutyl)-6-pentylpyrazine (50 mg, 160.58 μmol, 1 eq) in EtOH (2 mL) and water (0.5 mL) was added aqueous HCl (12 M, 40.14 μL, 3 eq), and the mixture was stirred for 10 min at 20° C. Iron powder (~200 mesh, 44.84 mg, 802.89 μmol, 5 eq) was then added, and the mixture was stirred at 20° C. for 8 h. After completion, the mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna 80x30mm×3μm; mobile phase: [water(HCl)-ACN]; B%: 15%-45%, 8 minutes) to give Compound 12HCl (2.56 mg, 9.10μmol, 5.67% yield, 100% purity) as a white solid. LC-MS (R T = 2.382 min, MS calculated value: 281.39, [M+H] + Measured value = 282.1); 1 H NMR (400MHz, CD3OD) δ = 3.94 (s, 3H), 3.93 (s, 3H), 3.70-3.61 (m, 1H), 3.14-3.06 (m, 1H), 3.00-2.91 (m, 1H) ), 2.72 (t, J=7.6Hz, 2H), 1.78-1.66 (m, 4H), 1.41-1.32 (m, 4H), 1.08 (t, J=7.5Hz, 3H), 0.95-0.89 (m, 3H).

[0397] Examples 13-15

[0398] Compounds 13-15 were prepared using the teachings herein, methods analogous to the procedures described herein, and the knowledge of one of ordinary skill in the art.

[0399] Example 16: Preparation of 2-(5-chloro-3,6-dimethoxypyridin-2-yl)ethan-1-amine (16) hydrochloride

[0400]

[0401] Step 1: Preparation of tert-butyl (2-(5-chloro-3,6-dimethoxypyridin-2-yl)ethyl)carbamate

[0402] To a stirred solution of tert-butyl (2-(3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.100 g, 0.354 mmol) in dry acetonitrile (5 mL) was added N-chlorosuccinimide (0.071 g, 0.531 mmol) in small portions at 0 ° C over 3 minutes. After the addition was complete, the reaction mixture was heated at 50 ° C for 9 hours. The reaction progress was monitored by LC-MS. Once completed, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water (10 mL) and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. This crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / hexanes) and the desired fractions were concentrated under reduced pressure to provide tert-butyl (2-(5-chloro-3,6-dimethoxypyridin-2-yl)ethyl)carbamate as a light brown sticky solid (yield: 0.055 g, 49.02%). HRMS m / z 317.10 [M+1] + .

[0403] Step 2: Preparation of 2-(5-chloro-3,6-dimethoxypyridin-2-yl)ethan-1-amine (16) hydrochloride

[0404] To a stirred solution of tert-butyl (2-(5-chloro-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.055 g, 0.174 mmol) in dichloromethane (2 mL) was added 4N hydrochloric acid in 1,4-dioxane (2 mL) at 0 °C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure. This crude material was triturated using n-pentane (3 mL) and diethyl ether (1 mL) to provide compound 16HCl (yield: 0.041 g, 93%) as an off-white solid. HRMS m / z 217.15 [M+1] + ; 1H NMR (400MHz, DM SO-d6) δ = 7.74 (br s, 3H), 7.71 (s, 1H), 3.92 (s, 3H), 3.77 (s, 3H), 3.19-3.18 (m, 2H), 2.95 (t, J = 7.2Hz, 2H).

[0405] Example 17: Preparation of 1-(5-chloro-3,6-dimethoxypyridin-2-yl)propan-2-amine (17) hydrochloride

[0406]

[0407] Step 1: Preparation of tert-butyl (1-(5-chloro-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate

[0408] A stirred solution of tert-butyl (1-(3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate (150 mg, 0.506 mmol, 1.0 equiv) in dry acetonitrile (5 mL) was treated with N-chlorosuccinimide (101 mg, 1.5 equiv, 0.759 mmol) in batches over 3 minutes at 0 °C. After completion, the reaction mixture was heated at 50 °C for 9 hours. The reaction progress was monitored by LC-MS. Once completed, the reaction mixture was cooled to room temperature. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue. This crude material was purified by column chromatography (SiO2, 10% ethyl acetate / hexanes) and the desired fractions were concentrated under reduced pressure to provide tert-butyl (1-(5-chloro-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate as a light brown viscous compound (yield: 0.080 g, 47.78%). HRMS m / z 331.15 [M+1] + .

[0409] Step 2: Preparation of 1-(5-chloro-3,6-dimethoxypyridin-2-yl)propan-2-amine (17) hydrochloride

[0410] To a stirred solution of tert-butyl (1-(5-chloro-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate (0.055 g, 0.166 mmol) in dichloromethane (2 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0 °C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. Once completed, the reaction mixture was concentrated under reduced pressure. This crude material was triturated using n-pentane (2 mL) and diethyl ether (1 mL) to provide compound 17HCl (yield: 0.038 g, 85%) as an off-white solid. HRMS m / z 231.10 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 9.68 (br s, 1H), 7.76 (3H), 7.72 (s, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 3.74-3.62 (m, 1H), 2.90-2.85 (m, 2H), 1.19 (d, J = 4Hz, 3H).

[0411] Example 18: Preparation of 1-(5-chloro-3,6-dimethoxypyridin-2-yl)butan-2-amine (18) hydrochloride

[0412]

[0413] Step 1: Preparation of tert-butyl (1-(5-chloro-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate

[0414] A stirred solution of tert-butyl (1-(3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate (0.150 g, 0.483 mmol) in dry acetonitrile (5 mL) was treated with N-chlorosuccinimide (96.8 mg, 0.725 mmol) in portions at 0 °C over 3 minutes. After the addition was complete, the reaction mixture was heated at 50 °C for 9 hours. The reaction progress was monitored by LC-MS. Once complete, the reaction mixture was cooled to room temperature. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 10% ethyl acetate / hexanes) and the desired fractions were concentrated under reduced pressure to give tert-butyl (1-(5-chloro-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate as a white solid (yield: 0.078 g, 48.01%). HRMS m / z 345.20 [M+1] + .

[0415] Step 2: Preparation of 1-(5-chloro-3,6-dimethoxypyridin-2-yl)butan-2-amine (18) hydrochloride

[0416] To a stirred solution of tert-butyl (1-(5-chloro-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate (0.074 g, 0.215 mmol) in dichloromethane (3 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure to obtain a crude residue. The crude material was ground using n-pentane (2 mL) and diethyl ether (1 mL) to obtain compound 18HCl (yield: 0.052 g, 86.18%) as a colorless sticky solid. HRMS m / z 245.06 [M+1] + ; 1HNMR (400MHz, DMSO-d6): δ=7.72 (s, 3H), 3.90 (s, 3H), 3.80 (s, 3H), 3.58-3.53 (m, 1H), 2.99-2.84 (m, 2H), 1.61-1.54 (m, 2H), 0.94 (t, J=7.4Hz, 3H).

[0417] Example 19: Preparation of 2-(5-ethyl-3,6-dimethoxypyridin-2-yl)ethan-1-amine (19) hydrochloride

[0418]

[0419] Step 1: Preparation of tert-butyl (2-(5-ethyl-3,6-dimethoxypyridin-2-yl)ethyl)carbamate

[0420] A stirred solution of (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamic acid tert-butyl ester (0.150g, 0.415mmol) in 1,4-dioxane / water (5.0mL of 7:3v / v mixture) was treated with ethyl boronic acid (0.061g, 0.831mmol) and potassium carbonate (0.172g, 1.25mmol). The mixture was purged with nitrogen for 10 minutes, and then PdCl2(dppf)·DCM (0.034g 0.041mmol) was added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was then heated to 100°C for 12h and monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (10mL), passed through a diatomaceous earth pad to remove the catalyst and washed with ethyl acetate (2×10mL). The combined organic layer was diluted with water (10mL), and the aqueous layer was extracted with ethyl acetate (2×25mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / hexane) and the desired fractions were concentrated under reduced pressure to give tert-butyl (2-(5-ethyl-3,6-dimethoxypyridin-2-yl)ethyl)carbamate as a white solid (yield: 0.050 g, 39%). HRMS m / z 311.05 [M+1] + .

[0421] Step 2: Preparation of 2-(5-ethyl-3,6-dimethoxypyridin-2-yl)ethan-1-amine (19) hydrochloride

[0422] To a stirred solution of tert-butyl (2-(5-ethyl-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.050 g, 0.161 mmol) in dichloromethane (2 mL) was added 4N hydrochloric acid in 1,4-dioxane (2 mL) at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the mixture was concentrated under reduced pressure to provide a crude residue. The product was isolated after trituration with n-pentane (2 mL) and diethyl ether (1 mL) to provide compound 19HCl (yield: 0.030 g, 75%) as an off-white solid. HRMS m / z 211.15 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm=7.89 (br s, 3H), 7.33 (s, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.19-3.14 (m, 2H), 2.93 (t, J=7.6Hz, 2H), 2.55 (m, 2H), 1.13 (t, J=7.6Hz, 3H).

[0423] Example 20: Preparation of 1-(5-ethyl-3,6-dimethoxypyridin-2-yl)propan-2-amine (20) hydrochloride

[0424]

[0425] Step 1: Preparation of tert-butyl (1-(5-ethyl-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate

[0426] To a stirred solution of (1-(5-bromo-3,6-dimethoxypyridin-2-yl)propan-2-yl)t-butyl carbamate (0.150 g, 0.4 mmol) in 1,4-dioxane / water (5.0 mL of a 7:3 v / v mixture), ethylboric acid (0.074 g, 0.999 mmol) and potassium carbonate (0.166 g, 1.2 mmol) were added. The mixture was purged with nitrogen for 10 minutes, and then treated with PdCl2(dppf)·DCM (0.033 g, 0.044 mmol) under a nitrogen atmosphere, and then heated to 100 ° C for 12 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to room temperature, and then diluted with ethyl acetate (10 mL). The mixture was passed through a diatomaceous earth pad to remove the catalyst, and diatomaceous earth was washed with ethyl acetate (2 × 10 mL). The combined organic layers were diluted with water (10 mL) and the aqueous phase was extracted with ethyl acetate (2×25 mL). The organic extract was washed with brine (20 mL), then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 10% ethyl acetate / hexane), and the desired fractions were concentrated under reduced pressure to give tert-butyl (1-(5-ethyl-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate as an off-white solid (yield: 0.055 g, 42%). HRMS m / z 325.30[M+1] + .

[0427] Step 2: Preparation of 1-(5-ethyl-3,6-dimethoxypyridin-2-yl)propan-2-amine (20) hydrochloride

[0428] To a stirred solution of tert-butyl (1-(5-ethyl-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate (0.055 g, 0.169 mmol) in dichloromethane (2 mL) was added 4N hydrochloric acid in 1,4-dioxane (2 mL) at 0°C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure. This crude material was triturated using n-pentane (2 mL) and diethyl ether (1 mL) to provide Compound 20HCl (yield: 0.042 g, 95%) as a colorless, sticky solid. HRMS m / z 225.20 [M+1] + ; 1 H NMR (400MH z, DMSO-d6) δ = 7.87 (br s, 3H), 7.35 (s, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.70-3.64 (m, 1H), 2.94- 2.83 (m, 2H), .2.56-2.52 (m, 2H), 1.29-1.22 (m, 3H), 1.18-1.12 (M, 3H).

[0429] Example 21: Preparation of 1-(5-ethyl-3,6-dimethoxypyridin-2-yl)butan-2-amine (21) hydrochloride

[0430]

[0431] Step 1: Preparation of tert-butyl (1-(5-ethyl-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate

[0432] To a stirred solution of (1-(5-bromo-3,6-dimethoxypyridin-2-yl)butan-2-yl)t-butylcarbamate (0.130 g, 0.334 mmol) in 1,4-dioxane / water (5.0 mL of a 7:3 v / v mixture), ethylboric acid (60.95 mg, 2.0 equivalents, 0.664 mmol) and potassium carbonate (0.138 g, 1.002 mmol) were added. The mixture was purged with nitrogen for 10 minutes, and then PdCl2(dppf)·DCM (27.25 mg, 0.0334 mmol) was added to the reaction mixture under a nitrogen atmosphere, and then heated to 100 ° C for 12 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (10 mL), diatomaceous earth pad was passed to remove the catalyst and diatomaceous earth was washed with ethyl acetate (2 × 10 mL). The combined organic fractions were diluted with water (10 mL), and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / hexane), and the desired fractions were concentrated under reduced pressure to provide tert-butyl (1-(5-ethyl-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate as an off-white solid (yield: 0.060 g, 46%). HRMS m / z 339.15[M+1] + .

[0433] Step 2: Preparation of 1-(5-ethyl-3,6-dimethoxypyridin-2-yl)butan-2-amine (21) hydrochloride

[0434] To a stirred solution of tert-butyl (1-(5-ethyl-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate (0.060 g, 0.177 mmol) in dichloromethane (2 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure. This crude material was triturated using n-pentane (2 mL) and diethyl ether (1 mL) to provide Compound 21HCl (yield: 0.043 g, 88.08%) as an off-white solid. HRMS m / z 239.20 [M+1] + ; 1H NMR (400MH z, DMSO-d6): δ = 7.73 (br s, 3H), 7.35 (s1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.54-3.53 (m, 1H), 2.96-2.91 (m, 1H), 2.86- 2.80 (m, 1H), 2.54 (m, 2H), 1.60-1.53 ​​(m, 2H), 1.46 (t, J=7.6Hz, 3H), 0.95 (t, J=7.6Hz, 3H).

[0435] Example 22: Preparation of 2-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)ethan-1-amine (22) hydrochloride

[0436]

[0437] Step 1: Preparation of tert-butyl (2-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)ethyl)carbamate

[0438] To a stirred solution of tert-butyl (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.200 g, 0.554 mmol) in toluene (3 mL) was added sodium ethanethiolate (0.045 g, 0.720 mmol) and DIPEA (0.29 mL, 1.66 mmol). The reaction mixture was purged with nitrogen for 10 minutes, and then DPPF (0.030 g, 0.055 mmol) and Pd2(dba)3 (0.050 g, 0.055 mmol) were added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was heated to 110 ° C for 4 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (10 mL). The mixture was passed through a diatomaceous earth pad to remove the catalyst, and the diatomaceous earth was washed with ethyl acetate (2×10 mL). Water (10 mL) was added to the organic layer, and the aqueous phase was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL) and then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 10% ethyl acetate / hexanes), and the desired fractions were concentrated under reduced pressure to provide tert-butyl (2-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)ethyl)carbamate as a yellow solid (yield: 0.120 g, 63.29%). HRMS m / z 343.15 [M+1] + .

[0439] Step 2: Preparation of 2-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)ethan-1-amine (22) hydrochloride

[0440] To a stirred solution of tert-butyl (2-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.100 g, 0.292 mmol) in dichloromethane (3 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0°C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure. This crude material was triturated using n-pentane (3 mL) and diethyl ether (1.5 mL) to provide compound 22HCl (yield: 70 mg, 86% yield) as an off-white solid. HRMS m / z 243.15 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.86 (br s, 3H), 7.31 (s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.19-3.17 (m, 2H), 3.01-2.92 (m, 4H), 1.23 (t, J = 7.6Hz, 3H).

[0441] Example 23: 1-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)propan-2-amine (23) hydrochloride (23) preparation

[0442]

[0443] Step 1: Preparation of tert-butyl (1-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate Preparation

[0444] To a stirred solution of (1-(5-bromo-3,6-dimethoxypyridin-2-yl)propan-2-yl)t-butyl carbamate (0.1g, 0.266mmol) and sodium ethanethiolate (0.021g, 0.346mmol) in toluene (3mL) was added DIPEA (0.15mL, 0.799mmol). The reaction mixture was purged with nitrogen for 10 minutes. Under a nitrogen atmosphere, DPPF (0.015mg, .026mmol) and Pd2(dba)3 (0.024g, 0.027mmol) were added to the reaction mixture, and the reaction mixture was then heated to 110°C for 4 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (10mL). The mixture was passed through a diatomaceous earth pad to remove the catalyst and the pad was washed with ethyl acetate (2×10mL). The combined organic layer was diluted with water (10 mL), and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL) and then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / hexane), and the desired fractions were concentrated under reduced pressure to provide tert-butyl (1-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate (yield: 0.070 g, 73.69%) as a yellow solid. HRMS m / z 357.10[M+1] + .

[0445] Step 2: Preparation of 1-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)propan-2-amine (23) hydrochloride

[0446] To a stirred solution of tert-butyl (1-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate (0.070 g, 0.196 mmol) in dichloromethane (3 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure. This crude compound was ground by using n-pentane (3 mL) and diethyl ether (1.5 mL) to provide compound 23HCl (yield: 0.050 g, 87% yield) as an off-white sticky solid. HRMS m / z 257.20 [M+1] + ; 1 H

[0447] NMR (400MHz, DMSO-d6) δ = 7.84 (br s, 3H), 7.32 (s, 1H), 3.85 (s,

[0448] 3H), 3.81 (s, 3H), 3.69-3.62 (m, 1H), 3.09-2.96 (m, 2H), 2.90-2.82 (m, 2H), 1.24 (t, J=7.6Hz, 3H), 1.20-1.18 (d, J=6.8Hz, 3H).

[0449] Example 24: Preparation of 1-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)butan-2-amine (24) hydrochloride

[0450]

[0451] Step 1: Preparation of tert-butyl (1-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate Preparation

[0452] To a stirred solution of (1-(5-bromo-3,6-dimethoxypyridin-2-yl)butan-2-yl)t-butylcarbamate (0.100 g, 0.257 mmol) and sodium ethanethiolate (0.021 g, 0.334 mmol) in toluene (3 mL) was added DIPEA (99.6 mg, 0.771 mmol). The reaction mixture was purged with nitrogen for 10 minutes, and then DPPF (0.014 g, 0.0257 mmol) and Pd2(db a)3 (0.023 g, 0.0257 mmol) were added under a nitrogen atmosphere. The reaction mixture was heated to 110 ° C for 4 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to room temperature and then diluted with ethyl acetate (10 mL) and passed through a diatomaceous earth pad to remove the catalyst. The diatomaceous earth pad was washed with ethyl acetate (2 × 10 mL). Water (10 mL) was added to the combined organic layers, and the water was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 10% ethyl acetate / hexane), and the desired fractions were concentrated under reduced pressure to provide tert-butyl (1-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)butyl-2-yl)carbamate (yield: 0.060 g, 63.04%) as a yellow solid. HRMS m / z371.00[M+1] + .

[0453] Step 2: Preparation of 1-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)butan-2-amine (24) hydrochloride

[0454] To a stirred solution of tert-butyl (1-(5-(ethylthio)-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate (60 mg, 0.161 mmol, 1) in dichloromethane (3 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure to provide a crude residue. The crude material was ground using n-pentane (2 mL) and ether (1 mL) to provide compound 24HCl (yield: 0.042 g, 84.52% yield) as an off-white solid. HRMS m / z 271.20 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.81 (br s, 3H), 7.31 (s, 1H), 3.88-3.85 (s, 3H), 3.81-377 (s, 3H), 3.52-3.50 (m, 1H), 3.03-2.96 (m , 2H), 2.92-2.83 (m, 2H), 1.59-1.55 (m, 2H), 1.24 (t, J=7.6Hz, 3H), 0.93 (t, J=7.6Hz, 3H).

[0455] Example 25: 2-(5-bromo-3,6-dimethoxypyridin-2-yl)-N-(2-methoxybenzyl)ethan-1-amine (25) preparation

[0456]

[0457] Step 1: Preparation of 2-(5-bromo-3,6-dimethoxypyridin-2-yl)-N-(2-methoxybenzyl)ethan-1-amine (25) Preparation

[0458] To a stirred solution of 2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl-1-amine (0.12 g, 0.459 mmol) and 2-methoxybenzaldehyde (0.075 g, 0.551 mmol) in toluene (5.0 mL) was added a catalytic amount of acetic acid (approximately 75 μl). Under a nitrogen atmosphere, the reaction mixture was heated to 70 ° C for 12 hours. The reaction progress was monitored by LC-MS. After completion, the reaction mixture was concentrated under reduced pressure to provide a crude intermediate of an imine. Sodium borohydride (0.035 g, 0.919 mmol) was added to a stirred solution of the crude imine intermediate in methanol at 0 ° C, and the mixture was stirred for 5 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 80% ethyl acetate / hexanes), and the desired fractions were concentrated under reduced pressure to provide compound 25 as a white solid (yield: 0.46 g, 26%). HRMS m / z 381.15 [M+1] + ; 1 HNMR (400MHz, DMSO-d6) δ = 7.70 (s, 1H), 7.25-7.16 (m, 2H), 6.92 (d, J = 8.0Hz, 1H ), 6.88-6.85(m, 1H), 3.80(s, 3H), 3.76(s, 3H), 3.67(s, 1H), 2.86-2.78(m, 2H).

[0459] Example 26: Preparation of 2-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)ethan-1-amine (26) hydrochloride

[0460]

[0461] Step 1: Preparation of tert-butyl (2-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)ethyl)carbamate

[0462] The stirred solution of (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.200g, 0.554mmol), cyclopropylboronic acid (0.095g, 1.10mmol) and potassium carbonate (0.230g, 1.66mmol) in 1,4-dioxane / water (5.0mL of 7:3v / v mixture) was purged with nitrogen for 10 minutes. This mixture was treated with PdCl2(dppf)·DCM (0.045g, 0.055mmol) under a nitrogen atmosphere, and then heated to 100°C for 12 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to room temperature and then diluted with ethyl acetate (10mL), passed through a diatomaceous earth pad to remove the catalyst, and washed with diatomaceous earth with ethyl acetate (2×10mL). The combined organic layer was diluted with water (10mL) and the aqueous phase was re-extracted with ethyl acetate (2×25mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 10% ethyl acetate / hexanes) and the desired fractions were concentrated under reduced pressure to provide tert-butyl (2-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)ethyl)carbamate as an off-white solid (yield: 0.150 g, 84%). HRMS m / z 323.20 [M+1] + .

[0463] Step 2: Preparation of 2-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)ethan-1-amine (26) hydrochloride

[0464] To a stirred solution of tert-butyl (2-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.150 g, 0.465 mmol) in dichloromethane (2 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0 °C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure. This crude material was triturated using n-pentane (4 mL) and diethyl ether (2 mL) to provide compound 26HCl (yield: 0.115 g, 91%) as an off-white solid. HRMS m / z 223.20 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.86 (br s, 3H), 6.95 (s, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.18-3.13 (m, 2H), 2.91 (t , J=7.2Hz, 2H), 2.02-1.95 (m, 1H), 0.92-0.89 (m, 2H), 0.78-0.73 (m, 2H).

[0465] Example 27: Preparation of 1-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)propan-2-amine (27) formate

[0466]

[0467] Step 1: Preparation of tert-butyl (1-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate

[0468] By (1-(5-bromo-3,6-dimethoxypyridin-2-yl)propan-2-yl) tert-butyl carbamate (0.200g, 0.533mmol), cyclopropylboronic acid (0.092g, 1.07mmol) and potassium carbonate (0.221g, 1.6mmol) in 1,4-dioxane / water (5.0mL of 7:3v / v mixture) stirring solution purged with nitrogen for 10 minutes. The solution is treated with PdCl under a nitrogen atmosphere (dppf) DCM (0.043g, 0.053mmol) and then heated to 100 DEG C for 12 hours. The reaction progress is monitored by TLC and LC-MS. Once completed, the reaction mixture is cooled to room temperature, and then diluted with ethyl acetate (10mL). The mixture is passed through a diatomaceous earth pad to remove the catalyst, and diatomaceous earth is washed with ethyl acetate (2×10mL). The combined organic layers were diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / hexane), and the desired fractions were concentrated under reduced pressure to provide tert-butyl (1-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate as a white solid (yield: 0.100 g, 56%). HRMS m / z 337.25[M+1] + .

[0469] Step 2: Preparation of 1-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)propan-2-amine (27) formate

[0470] To a stirred solution of tert-butyl (1-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate (0.100 g, 0.297 mmol) in dichloromethane (3 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0°C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by preparative HPLC using 0.1% formic acid buffer in water, and the desired fractions were lyophilized to provide compound 27 formate (yield: 0.030 g, 43%) as an off-white, sticky solid. HRMS m / z 237.10 [M+1] + ; 1HNMR (400MHz, DMSO-d6) δ = 8.40 (s, 1H), 6.93 (s, 1H), 3.83 (s, 3H), 3.73 (s, 3H), 3.55-3.46 (m, 2H), 2.8 1-2.75 (m, 2H), 2.01-1.94 (m, 1H), 1.11-1.09 (d, J=6.4Hz, 3H), 0.92-0.87 (m, 2H), 0.74-0.70 (m, 2H).

[0471] Example 28: Preparation of 1-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)butan-2-amine (28) hydrochloride

[0472]

[0473] Step 1: Preparation of tert-butyl (1-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate

[0474] By (1-(5-bromo-3,6-dimethoxypyridin-2-yl) butan-2-yl) tert-butyl carbamate (0.150g, 0.385mmol), cyclopropylboronic acid (0.066g, 0.771mmol) and potassium carbonate (0.160g, 1.16mmol) in 1,4-dioxane / water (5.0mL of 7:3v / v mixture) stirring solution purged with nitrogen for 10 minutes. In nitrogen atmosphere, add PdCl to this solution (dppf) DCM (0.031g, 0.0385mmol), then heat to 100 DEG C for 12 hours. Monitor reaction progress by TLC and LC-MS. Once completed, the reaction mixture is cooled to room temperature and then diluted with ethyl acetate (10mL). The mixture is passed through a diatomaceous earth pad to remove the catalyst, and diatomaceous earth is washed with ethyl acetate (2×10mL). The combined organic layers were diluted with water (10 mL), and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / hexane), and the desired fractions were concentrated under reduced pressure to provide tert-butyl (1-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate as a white solid (yield: 0.100 g, 74%). HRMS m / z 351.20[M+1] + .

[0475] Step 2: Preparation of 1-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)butan-2-amine (28) hydrochloride

[0476] To a stirred solution of tert-butyl (1-(5-cyclopropyl-3,6-dimethoxypyridin-2-yl)butan-2-yl)carbamate (0.100 g, 0.285 mmol) in dichloromethane (3 mL) was added 4N HCl (3 mL) in 1,4-dioxane at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure to provide a crude residue, which was triturated using n-pentane (3 mL) and diethyl ether (1.5 mL) to provide Compound 28HCl (yield: 0.056 g, 78%) as an off-white solid. HRMS m / z 251.15 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 77.85 (br s, 3H), 6.96 (s, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.55-3.50 (m, 1H), 2.95-2.81 (m, 2H), 2.01-1.96(m, 1H), 1.60-1.53(m, 2H), 0.94-0.88(m, 5H), 0.75-0.71(m, 2H).

[0477] Example 29: Preparation of 2-(5-hexyl-3,6-dimethoxypyridin-2-yl)ethan-1-amine (29) formate

[0478]

[0479] Step 1: Preparation of tert-butyl (2-(5-hexyl-3,6-dimethoxypyridin-2-yl)ethyl)carbamate

[0480] The stirred solution of (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.100g, 0.277mmol), n-hexylboronic acid (0.072g, 0.554mmol) and potassium carbonate (0.115g, 830mmol) in 1,4-dioxane / water (5.0mL of 7:3v / v mixture) was purged with nitrogen for 10 minutes. The solution was treated with PdCl2(dppf)·DCM (0.022g, 0.027mmol) under a nitrogen atmosphere and then heated to 100°C for 12 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (10mL), passed through a diatomaceous earth pad to remove the catalyst, and the diatomaceous earth pad was washed with ethyl acetate (2×10mL). The combined organic layer was diluted with water (10mL) and the aqueous phase was extracted with ethyl acetate (2×25mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 10% ethyl acetate / hexane) and the desired fractions were concentrated under reduced pressure to give tert-butyl (2-(5-hexyl-3,6-dimethoxypyridin-2-yl)ethyl)carbamate as a white solid (yield: 0.080 g, 79%). HRMS m / z 367.20 [M+1] + .

[0481] Step 2: Preparation of 2-(5-hexyl-3,6-dimethoxypyridin-2-yl)ethan-1-amine (29) formate

[0482] To a stirred solution of tert-butyl (2-(5-hexyl-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.080 g, 0.591 mmol) in dichloromethane (2 mL) was added 4N HCl in 1,4-dioxane (3 mL) at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure to provide a crude residue. The crude compound was purified by preparative HPLC using 0.1% formic acid buffer in water. The desired fractions were lyophilized to provide compound 29 formate (yield: 0.044 g, 64%) as an off-white solid. HRMS m / z 267.3[M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.41 (s, 1H), 7.28 (s, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.05 (t, J = 7.2Hz, 2 H), 2.85 (t, J=7.2Hz, 2H), 2.47 (m, 2H), 1.55-1.48 (m, 2H), 1.28-1.27 (s, 6H), 0.87-0.84 (m, 3H).

[0483] Example 30: 2-(3,6-dimethoxy-5-(6,6,6-trifluorohexyl)pyridin-2-yl)ethan-1-amine (30) hydrochloric acid Salt preparation

[0484]

[0485] Step 1a: Preparation of 4,4,5,5-tetramethyl-2-(6,6,6-trifluorohexyl)-1,3,2-dioxaborolane

[0486] Triphenylphosphine (0.467g, 1.78mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (5.2g, 20.5mmol) and lithium methylate (1.04g, 27.4mmol) were added to a stirred solution of anhydrous copper iodide (I) (0.261g, 1.37mmol) in anhydrous DMF (30mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 5 minutes, and then the 6-bromo-1,1,1-trifluorohexane (3.0g, 13.7mmol) in anhydrous DMF (5mL) was added dropwise under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was quenched with water (30mL) and diluted with ethyl acetate (50mL). The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude residue, which was purified by column chromatography (SiO2, 5% ethyl acetate / hexane). The desired fractions were concentrated under reduced pressure to provide 4,4,5,5-tetramethyl-2-(6,6,6-trifluorohexyl)-1,3,2-dioxaborolane as a colorless liquid (yield: 2.5 g, 68.5%). 1 H NMR (400MHz, CDCl3) δ = 2.11-1.99 (m, 2H), 1.60-1.54 (m, 2H), 1.46-1.36 (m, 4H), 1.24 (s, 12H), 0.80 (t, J = 6.0Hz, 2H).

[0487] Step 1: tert-Butyl (2-(3,6-dimethoxy-5-(6,6,6-trifluorohexyl)pyridin-2-yl)ethyl)carbamate Preparation of esters

[0488] By (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamic acid tert-butyl ester (0.650g, 1.8mmol), 4,4,5,5-tetramethyl-2-(6,6,6-trifluorohexyl)-1,3,2-dioxaborolane (1.42g, 5.4mmol) and potassium carbonate (0.746g, 5.40mmol) in 1,4-dioxane / water (5.0mL 7:3v / v mixture) stirring solution purged with nitrogen for 10 minutes. In nitrogen atmosphere, PdCl is added to this solution (dppf) DCM (0.073g, 0.090mmol), then heated to 100 DEG C for 12 hours. Reaction progress is monitored by TLC and LC-MS. Once completed, the reaction mixture is cooled to room temperature and then diluted with ethyl acetate (30mL). The mixture was passed through a diatomaceous earth pad to remove the catalyst, and the diatomaceous earth was washed with ethyl acetate (2×20 mL). The combined organic layer was diluted with water (25 mL), and the aqueous phase was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude residue. The crude compound was purified by column chromatography (SiO2, 10% ethyl acetate / hexane), and the desired fractions were concentrated under reduced pressure to provide tert-butyl (2-(3,6-dimethoxy-5-(6,6,6-trifluorohexyl)pyridin-2-yl)ethyl)carbamate (yield: 0.250 g, 33%) as a white solid. HRMS m / z 421.35[M+1] + ; 1 H NMR (400MHz, CDCl3) δ = 8.41 (s, 1H), 7.33 (s, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.06 (t, J= 7.2Hz, 2H), 2.86 (t, J=7.6Hz, 2H), 2.60 (m, 2H), 2.32-2.20 (m, 2H), 1.79-1.71 (m, 2H).

[0489] Step 2: Preparation of 2-(3,6-dimethoxy-5-(6,6,6-trifluorohexyl)pyridin-2-yl)ethan-1-amine (30) hydrochloride preparation

[0490] To a stirred solution of tert-butyl (2-(3,6-dimethoxy-5-(6,6,6-trifluorohexyl)pyridin-2-yl)ethyl)carbamate (0.250 g, 0.594 mmol) in dichloromethane (4 mL) was added 4N hydrochloric acid in 1,4-dioxane (4 mL) at 0 °C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to provide a crude residue, which was triturated with n-pentane (4 mL) and diethyl ether (2 mL) to provide compound 30HCl (yield: 0.140 g, 66%) as an off-white solid. HRMS m / z 321.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.88 (brs, 3H), 7.33 (s, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.17-3.14 (t, J = 7.2Hz, 2H), 2.93-2.91(t, J=7.2Hz, 2H), 2.46(m, 2H), 2.32-2.11(m, 2H), 1.55-1.43(m, 4H), 1.34-1.32(m, 2H).

[0491] Example 31: Preparation of 2-(5-butyl-3,6-dimethoxypyridin-2-yl)ethan-1-amine (31) hydrochloride

[0492]

[0493] Step 1: Preparation of tert-butyl (2-(5-butyl-3,6-dimethoxypyridin-2-yl)ethyl)carbamate

[0494] By (2- (5- bromo -3,6- dimethoxypyridin-2-yl) ethyl) carbamic acid tert-butyl ester (0.200g, 0.554mmol), 2- butyl -4,4,5,5- tetramethyl -1,3,2- dioxaborolane (0.204g, 1.11mmol) and potassium carbonate (0.230g, 1.66mmol) in 1,4- dioxane / water (5.0mL of 7: 3v / v mixture) stirred solution was purged with nitrogen for 10 minutes. Under nitrogen atmosphere, PdCl (dpp f) DCM (0.045g, 0.055mmol) was used to treat the solution and then the reaction mixture was heated to 100 ° C for 12 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (10mL). The mixture was passed through a diatomaceous earth pad to remove the catalyst, and diatomaceous earth was washed with ethyl acetate (2 × 10mL). The combined organic layers were diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude residue, which was purified by column chromatography (SiO2, 10% ethyl acetate / hexane). The desired fractions were concentrated under reduced pressure to provide tert-butyl (2-(5-butyl-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (yield: 0.056 g, 30%) as a white solid. HRM S m / z 339.15 [M+1] + .

[0495] Step 2: Preparation of 2-(5-butyl-3,6-dimethoxypyridin-2-yl)ethan-1-amine (31) hydrochloride

[0496] To a stirred solution of tert-butyl (2-(5-butyl-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.056 g, 0.165 mmol) in dichloromethane (2 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0 °C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure. This crude compound was triturated by using n-pentane (2 mL) and diethyl ether (1 mL) to provide compound 31HCl (yield: 0.045 g, 99%) as an off-white solid. HRMS m / z 239.30 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 7.90 (br s, 3H), 7.31 (s, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.19-3.14 (m, 2H), 2.93 (t, J=7.2H z, 2H), 2.52 (m, 2H), 1.54-1.46 (m, 2H), 1.35-1.26 (m, 2H), 0.89 (t, J=7.6Hz, 3H).

[0497] Example 32: Preparation of 2-(5-(4-fluorobutyl)-3,6-dimethoxypyridin-2-yl)ethan-1-amine (32) hydrochloride Preparation

[0498]

[0499] Step 1: Preparation of tert-butyl (2-(5-(4-fluorobutyl)-3,6-dimethoxypyridin-2-yl)ethyl)carbamate Preparation

[0500] By (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamic acid tert-butyl ester (0.300g, 0.830mmol), 2-(4-fluorobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.335g, 1.66mmol) and potassium carbonate (0.344g, 2.49mmol) in 1,4-dioxane / water (5.0mL 7:3v / v mixture) stirring solution purged with nitrogen for 10 minutes. In nitrogen atmosphere, PdCl is added to this solution (dppf) DCM (0.068g, 0.083mmol), and the reaction mixture is heated to 100 DEG C for 12 hours. The reaction progress is monitored by TLC and LC-MS. Once completed, the reaction mixture is cooled to room temperature, and then diluted with ethyl acetate (10mL). The mixture was passed through a diatomaceous earth pad to remove the catalyst, and the diatomaceous earth was washed with ethyl acetate (2×10 mL). The combined organic layer was diluted with water (15 mL), and the aqueous phase was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude residue, which was purified by column chromatography (SiO2, 10% ethyl acetate / hexane). The desired fractions were concentrated under reduced pressure to provide tert-butyl (2-(5-(4-fluorobutyl)-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (yield: 0.180 g, 60%) as a white solid. HRMS m / z 357.10[M+1] + .

[0501] Step 2: Preparation of 2-(5-(4-fluorobutyl)-3,6-dimethoxypyridin-2-yl)ethan-1-amine (32) hydrochloride

[0502] To a stirred solution of tert-butyl (2-(5-(4-fluorobutyl)-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.180 g, 0.510 mmol) in dichloromethane (3 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure. The crude material was ground by using n-pentane (2 mL) and diethyl ether (1 mL) to provide compound 32 HCl (yield: 0.060 g, 40%) as an off-white solid. HRMS m / z 257.3 [M+1] + ; 1 H NMR (400MH z, DMSO-d6) δ = 7.85 (br s, 3H), 7.34 (s, 1H), 4.51 (t, J=6Hz, 1H), 4.41-4.38 (m, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.17 (t, J=7.2Hz, 2H), 2.92 (t, J=7.2Hz, 2H), 2.55 (m, 2H), 1.69-1.59 (m, 4H).

[0503] Example 33: 2-(3,6-dimethoxy-5-(4,4,4-trifluorobutyl)pyridin-2-yl)ethan-1-amine (33) carboxylic acid Salt preparation

[0504]

[0505] Step 1a: Preparation of 4,4,5,5-tetramethyl-2-(4,4,4-trifluorobutyl)-1,3,2-dioxaborolane

[0506] Under nitrogen atmosphere at room temperature, triphenylphosphine (0.179g, 0.681mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (1.9g, 7.85mmol) and lithium methoxide (0.398g, 10.5mmol) were added to a stirred solution of anhydrous copper iodide (I) (0.100g, 0.524mmol) in anhydrous DMF (10mL) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes, and then 4-bromo-1,1,1-trifluorobutane (1.0g, 5.24mmol) in anhydrous DMF (3mL) was added dropwise under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was quenched with water (30mL) and extracted with ethyl acetate (2×50mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude residue, which was purified by column chromatography (SiO2, 5% ethyl acetate / hexane). The desired fractions were concentrated under reduced pressure to provide 4,4,5,5-tetramethyl-2-(4,4,4-trifluorobutyl)-1,3,2-dioxaborolane as a colorless liquid (yield: 0.600 g, 48%). 1 HNMR (400MHz, CDCl3) δ=2.27-2.06 (m, 2H), 1.81-1.65 (m, 2H), 1.22 (s, 12H), 0.84 (t, J=8Hz, 2H).

[0507] Step 1: tert-Butyl (2-(3,6-dimethoxy-5-(4,4,4-trifluorobutyl)pyridin-2-yl)ethyl)carbamate Preparation of esters

[0508] Under nitrogen atmosphere, a stirred solution of (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamic acid tert-butyl ester (0.200g, 0.554mmol), 4,4,5,5-tetramethyl-2-(4,4,4-trifluorobutyl)-1,3,2-dioxaborolane (0.395g, 1.66mmol) and potassium carbonate (0.230g, 1.66mmol) in 1,4-dioxane / water (5.0mL of 7:3v / v mixture) was heated to 100°C for 12 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to room temperature and then diluted with ethyl acetate (10mL). The mixture was passed through a diatomaceous earth pad to remove the catalyst, and diatomaceous earth was washed with ethyl acetate (2×10mL). The combined organic layer was diluted with water (10mL) and the aqueous layer was extracted with ethyl acetate (2×25mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude residue, which was purified by column chromatography (SiO2, 10% ethyl acetate / hexanes), and the desired fractions were concentrated under reduced pressure to provide tert-butyl (2-(3,6-dimethoxy-5-(4,4,4-trifluorobutyl)pyridin-2-yl)ethyl)carbamate as a white solid (yield: 0.120 g, 55%). HRMS m / z 393.3 [M+1] + .

[0509] Step 2: Preparation of 2-(3,6-dimethoxy-5-(4,4,4-trifluorobutyl)pyridin-2-yl)ethan-1-amine (33) formate preparation

[0510] A stirred solution of tert-butyl (2-(3,6-dimethoxy-5-(4,4,4-trifluorobutyl)pyridin-2-yl)ethyl)carbamate (0.120 g, 0.306 mmol) in dichloromethane (3 mL) was treated with 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure to provide a crude residue. The crude compound was purified by preparative HPLC using 0.1% formic acid buffer in water and the desired fractions were lyophilized to provide compound 33 formate (yield: 0.020 g, 19.89%) as an off-white solid. HRMS m / z 293.25 [M+1] + ; 1H NMR (400MHz, DM SO-d6)δ=8.41(s, 1H), 7.33(s, 1H), 3.82(s, 3H), 3.76(s, 3H), 3.06(t, J=7.2Hz , 2H), 2.86 (t, J=7.6Hz, 2H), 2.60 (m, 2H), 2.32-2.20 (m, 2H), 1.79-1.71 (m, 2H).

[0511] Example 34: 2-(5-(5-fluoropentyl)-3,6-dimethoxypyridin-2-yl)ethan-1-amine (34) trifluoroacetate Preparation

[0512]

[0513] Step 1a: Preparation of 2-(5-fluoropentyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0514] Under nitrogen atmosphere, anhydrous copper iodide (I) (56.3mg, 0.296mmol), triphenylphosphine (0.101g, 0.385mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (1.13g, 4.44mmol) and lithium methoxide (0.224g, 5.92mmol) were stirred at room temperature for 5 minutes. 1-Bromo-5-fluoropentane (0.5g, 2.96mmol) in anhydrous DMF (2mL) was added dropwise to the solution under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was quenched with water (30mL) and diluted with ethyl acetate (50mL). The aqueous phase was extracted with ethyl acetate (2×50mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude residue, which was purified by column chromatography (SiO2, 5% ethyl acetate / hexane). The desired fractions were concentrated under reduced pressure to provide 2-(5-fluoropentyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.3 g, 47% yield) as a colorless liquid. 1 HNMR (400MHz, CDCl3) δ = 4.48 (t, J = 6.4Hz, 1H), 4.36 (t, J = 6.0Hz, 1H), 1.77-1.62 (m, 2H), 1.51-1.34 (m, 4H), 1.28-1.21 (m, 12H), 0.79 (t, J = 8Hz, 2H); 19 F NMR (400MHz, CDC l3): δ-217.91.

[0515] Step 1: Preparation of tert-butyl (2-(5-(5-fluoropentyl)-3,6-dimethoxypyridin-2-yl)ethyl)carbamate Preparation

[0516] To (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamic acid tert-butyl ester (0.350g, 0.969mmol), 2-(5-fluoropentyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.628g, 2.91mmol) and potassium carbonate (0.402g, 2.91mmol) in 1,4-dioxane / water (5.0mL of 7:3v / v mixture) in a stirred solution was purged with nitrogen for 10 minutes. The solution was treated with PdCl2(dppf)·DCM (0.079g, 0.096mmol) under a nitrogen atmosphere and then heated to 100°C for 12 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (20 mL), passed through a diatomaceous earth pad to remove the catalyst, and the diatomaceous earth was washed with ethyl acetate (2 × 20 mL). The combined organic layer was diluted with water (20 mL) and the aqueous phase was extracted with ethyl acetate (2 × 25 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude residue, which was purified by column chromatography (SiO2, 10% ethyl acetate / hexane). The desired fraction was concentrated under reduced pressure to provide tert-butyl (2-(5-(5-fluoropentyl)-3,6-dimethoxypyridin-2-yl)ethyl)carbamate as a white solid. (yield: 0.100 g, 28%). HRM S m / z 371.10[M+1] + .

[0517] Step 2: Preparation of 2-(5-(5-fluoropentyl)-3,6-dimethoxypyridin-2-yl)ethan-1-amine (34) trifluoroacetate Preparation

[0518] To a stirred solution of tert-butyl (2-(5-(5-fluoropentyl)-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.100 g, 0.270 mmol) in dichloromethane (3 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure to provide a crude residue, which was purified by preparative HPLC using 0.1% TFA buffer in water. The desired fractions were lyophilized to provide compound 34 trifluoroacetate (yield: 0.082 g, 83%) as an off-white solid. HRMS m / z 271.25 [M+1] + ; 1H NMR (400MH z, DMSO-d6) δ = 7.73 (br s, 3H), 7.34 (s, 1H), 4.49 (t, J=6Hz, 1H), 4.37 (t, J=6.4Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.1 7 (t, J=7.6Hz, 2H), 2.92 (t, J=7.2Hz, 2H), 2.51 (m, 2H), 1.73-1.52 (m, 4H), 1.40-1.32 (m, 2H).

[0519] Example 35: 2-(3,6-dimethoxy-5-(4,4,4-trifluorobutyl)pyridin-2-yl)ethan-1-amine (35) hydrochloric acid Salt preparation

[0520]

[0521] Step 1a: Preparation of 4,4,5,5-tetramethyl-2-(5,5,5-trifluoropentyl)-1,3,2-dioxaborolane

[0522] To a stirred solution of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (1.86 g, 1.5 equivalents, 7.32 mmol) in dimethylformamide (20 mL, 258 mmol), LiOMe (370 mg, 2 equivalents, 9.76 mmol) was added. The reaction was then purged with argon for 10 minutes, followed by the addition of 5-bromo-1,1,1-trifluoropentane (1 g, 4.88 mmol) and CuI (92.9 mg, 0.1 equivalents, 0.488 mmol), triphenylphosphine (166 mg, 0.13 equivalents, 0.634 mmol). The reaction mixture was stirred at room temperature for 12 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was quenched by NH4Cl and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide a crude material which was purified by flash silica gel chromatography. The desired product was eluted in 10% ethyl acetate in hexane to provide 4,4,5,5-tetramethyl-2-(5,5,5-trifluoropentyl)-1,3,2-dioxaborolane (0.7 g, 57% yield) as a colorless liquid. 1 H NMR (400MHz, CDC 13): δ=2.11-1.99 (m, 2H), 1.59-1.44 (m, 3H), 1.24 (s, 12H), 0.80 (t, J=7.6Hz, 3H).

[0523] Step 1: tert-Butyl (2-(3,6-dimethoxy-5-(5,5,5-trifluoropentyl)pyridin-2-yl)ethyl)carbamate Synthesis of esters

[0524] 4,4,5,5-tetramethyl-2-(5,5,5-trifluoropentyl)-1,3,2-dioxaborolane (698 mg, 2 eq., 2.77 mmol) and potassium carbonate (0.574 g, 3 eq., 4.15 mmol) were added to a stirred solution of tert-butyl (2-(5-bromo-3,6-dimethoxypyridin-2-yl)ethyl)carbamate (0.5 g, 1 eq., 1.38 mmol) in toluene (7 mL) and water (3 mL). The reaction mixture was degassed with argon for 5 minutes, then PdCl2(dppf)·DCM (56.5 mg, 0.05 eq., 0.069 mmol) was added, and the resulting reaction mixture was heated at 100 ° C for 12 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure to give a crude compound, which was purified by preparative HPLC to provide tert-butyl (2-(3,6-dimethoxy-5-(5,5,5-trifluoropentyl)pyridin-2-yl)ethyl)carbamate as a colorless liquid (yield: 90 mg, 16%). LC-MS m / z 407.20 [M+1] + .

[0525] Step 2: Preparation of 2-(3,6-dimethoxy-5-(5,5,5-trifluoropentyl)pyridin-2-yl)ethan-1-amine (35) hydrochloride preparation

[0526] To a stirred solution of tert-butyl N-{2-[3,6-dimethoxy-5-(5,5,5-trifluoropentyl)pyridin-2-yl]ethyl}carbamate (90 mg, 123 μmol) in dichloromethane (3 mL) was added 4N HCl in 1,4-dioxane (1 mL) at 0 ° C. The reaction was stirred at room temperature for 3 hours. The reaction progress was monitored by LC-MS. After completion, the reaction was concentrated under reduced pressure to provide a crude material, which was ground with DCM (0.2 mL) and ether (2.0 mL) followed by n-pentane (5 mL), and the resulting compound was dried under reduced pressure to provide a compound 35 HCl (yield: 49 mg, 73%) as an off-white solid. LC-MS m / z 307.2[M+1] + ; 1 H NMR (400MH z, DMSO-d6) δ = 7.90 (br s, 2H), 7.35 (s, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.19-3.14 (m, 2H), 2.93 (t, J=7.2Hz , 2H), 2.56-2.49(m, 2H), 2.32-2.13(m, 2H), 1.64-1.59(m, 2H), 1.57-1.52(m, 2H).

[0527] Example 36: Preparation of 2-(3,6-dimethoxy-5-propylpyridin-2-yl)ethan-1-amine (36) hydrochloride

[0528]

[0529] Step 1: Preparation of tert-butyl (2-(3,6-dimethoxy-5-propylpyridin-2-yl)ethyl)carbamate

[0530] By (2- (5- bromo -3,6- dimethoxypyridin-2-yl) ethyl) carbamic acid tert-butyl ester (0.350g, 0.969mmol), 4,4,5,5- tetramethyl -2- propyl -1,3,2- dioxaborolane (0.330g, 1.94mmol) and potassium carbonate (0.402g, 2.91mmol) in 1,4- dioxane / water (5.0mL of 7: 3v / v mixture) stirred solution was purged with nitrogen for 10 minutes. PdCl was added to this mixture under a nitrogen atmosphere (dppf) DCM (0.079g, 0.097mmol), and then the mixture was heated to 100 ° C for 12 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was allowed to cool to room temperature. The reaction was diluted with ethyl acetate (10mL), passed through a diatomaceous earth pad to remove the catalyst, and then washed with ethyl acetate (2 × 10mL). The combined organic layers were diluted with water (10 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL), then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude residue, which was purified by column chromatography (SiO2, 10% ethyl acetate / hexane), and the desired fractions were concentrated under reduced pressure to provide tert-butyl (2-(3,6-dimethoxy-5-propylpyridin-2-yl)ethyl)carbamate as a white solid (yield: 0.070 g, 22%). HRMS m / z 325.10 [M+1] + .

[0531] Step 2: Preparation of 2-(3,6-dimethoxy-5-propylpyridin-2-yl)ethan-1-amine (36) hydrochloride

[0532] To a stirred solution of tert-butyl (2-(3,6-dimethoxy-5-propylpyridin-2-yl)ethyl)carbamate (0.070 mg, 0.216 mmol) in dichloromethane (2 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure to provide a crude residue, which was triturated by using n-pentane (2 mL) and diethyl ether (1 mL) to provide compound 36HCl (yield: 0.050 g, 89%) as an off-white solid. HRMS m / z 225.20 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 7.83 (br s, 3H), 7.32 (s, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.17-3.08 (m, 2H), 2.92 ( t, J=7.2Hz, 2H), 2.46 (m, 2H), 1.59-1.50 (m, 2H), 0.89 (t, J=7.2Hz, 3H).

[0533] Example 37: Preparation of 1-(3,6-dimethoxy-5-propylpyridin-2-yl)butan-2-amine (37) formate

[0534]

[0535] Step 1: Preparation of tert-butyl (1-(3,6-dimethoxy-5-propylpyridin-2-yl)butan-2-yl)carbamate

[0536] By (1-(5-bromo-3,6-dimethoxypyridin-2-yl) butan-2-yl) tert-butyl carbamate (0.26g, 0.668mmol), 4,4,5,5-tetramethyl-2-propyl-1,3,2-dioxaborolane (0.227g, 1.34mmol) and potassium carbonate (0.277g, 2.0mmol) in 1,4-dioxane / water (5.0mL of 7:3v / v mixture) stirring solution purged with nitrogen for 10 minutes. The solution is treated with PdCl under a nitrogen atmosphere (dppf) DCM (0.027g, 0.066mmol) and then heated to 100 DEG C for 12 hours. The reaction progress is monitored by TLC and LC-MS. Once completed, the reaction mixture is cooled to room temperature and then diluted with ethyl acetate (10mL). The mixture is passed through a diatomaceous earth pad to remove the catalyst, and the aqueous phase is washed with ethyl acetate (2×10mL). The combined organic layers were diluted with water (15 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude residue, which was purified by column chromatography (SiO2, 10% ethyl acetate / hexane), and the desired fractions were concentrated under reduced pressure to provide tert-butyl (1-(3,6-dimethoxy-5-propylpyridin-2-yl)butan-2-yl)carbamate as a white solid (yield: 0.090 g, 38%). HRMS m / z 353.30 [M+1] + .

[0537] Step 2: Preparation of 1-(3,6-dimethoxy-5-propylpyridin-2-yl)butan-2-amine (37) formate

[0538] To a stirred solution of tert-butyl (1-(3,6-dimethoxy-5-propylpyridin-2-yl)butan-2-yl)carbamate (0.090 g, 0.255 mmol) in dichloromethane (2 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL) at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure to provide a crude residue, which was purified by preparative HPLC using 0.1% formic acid buffer in water, and the desired fractions were lyophilized to provide compound 37 formate (yield: 0.031 g, 48%) as an off-white solid. HRMS m / z 253.25 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.39 (s, 1H), 7.29 (s, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.51-3.25 (m, 1H), 2.86-2. 81 (m, 1H), 2.76-2.72 (m, 1H), 2.45 (m, 2H), 1.59-1.49 (m, 2H), 1.48-1.41 (m, 2H), 0.899 (t, J=7.2Hz, 6H).

[0539] Example 38: Preparation of 1-(5-hexyl-3,6-dimethoxypyridin-2-yl)propan-2-amine (38) hydrochloride

[0540]

[0541] Step 1: Preparation of tert-butyl (1-(5-hexyl-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate

[0542] The stirred solution of (1-(5-bromo-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamic acid tert-butyl ester (0.2g, 0.533mmol), n-hexylboronic acid (0.138g, 1.06mmol) and potassium carbonate (0.221g, 1.60mmol) in 1,4-dioxane / water (5.0mL of 7:3v / v mixture) was purged with nitrogen for 10 minutes. PdCl2(dppf)·DCM (0.043g, 0.053mmol) was added to this solution under a nitrogen atmosphere, and the mixture was heated to 100°C for 12 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to room temperature and then diluted with ethyl acetate (10mL). The mixture was passed through a diatomaceous earth pad to remove the catalyst, and the diatomaceous earth was washed with ethyl acetate (2×10mL). The combined organic layer was diluted with water (10mL) and extracted with ethyl acetate (2×25mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude residue, which was purified by column chromatography (SiO2, 10% ethyl acetate / hexanes). The desired fractions were concentrated under reduced pressure to provide tert-butyl (1-(5-hexyl-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate as a white solid (yield: 0.051 g, 25%). HRMS m / z 381.20 [M+1] + .

[0543] Step 2: Preparation of 1-(5-hexyl-3,6-dimethoxypyridin-2-yl)propan-2-amine (38) hydrochloride

[0544] To a stirred solution of tert-butyl (1-(5-hexyl-3,6-dimethoxypyridin-2-yl)propan-2-yl)carbamate (0.051 mg, 1 eq, 0.134 mmol) in dichloromethane (2 mL) was added 4N HCl (2 mL) in 1,4-dioxane at 0 ° C over a period of 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure to provide a crude residue, which was triturated with n-pentane (2 mL) and ether (1 mL) to provide compound 38HCl (yield: 0.035 g, 88%) as an off-white solid. HRMS m / z 281.35 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.88 (br s, 3H), 7.33 (s, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 2.92 (m, 2H), 2.51-2.49 (m, 2H) , 1.54 (m, 2H), 1.30-1.25 (m, 6H), 1.19 (d, J=6.4Hz, 3H), 0.83 (t, J=6.4Hz, 3H).

[0545] Example 39: Preparation of Phenyl Comparative Compounds

[0546] The phenyl comparison compounds shown below were prepared according to previously described procedures (WO2022192781A1):

[0547]

[0548]

[0549] Example 40: 5-HT2A receptor binding

[0550] The binding affinity of the disclosed compounds at the ketanserin binding site of the 5-HT2A receptor was determined in a radioligand binding assay, the results of which are summarized in Table 1. The disclosed compounds exhibit substantial binding affinity for the 5-HT2A receptor. The affinity of compound 1 is much higher than that of the other pyridine isomer compound 11 and the pyrazine compound 12, indicating a preferred positioning of the pyridine nitrogen in the compounds of the present invention. In general, compounds with ethyl substituents at the alpha position of the basic amine are less potent than compounds with hydrogen or methyl substituents at this position. Longer alkyl or fluoroalkyl substituents at the 5 position of the pyridine also tend to increase potency compared to smaller substituents at this position.

[0551] Table 1. 5-HT2A receptor binding affinities of disclosed compounds.

[0552]

[0553]

[0554] method:

[0555] 5-HT2A receptor radioligand binding. DOI, 25D-NBOMe, 2C-TFM, mescaline, 2C-B and 2C-E were commercially available. Other compounds were prepared as described above. The 5-HT2A receptor radioligand binding was obtained from WuXi AppT ec (Hong Kong) Limited using a method adapted from the literature and under the conditions described in Table 2. 3 The affinity of the test compounds for the 5-HT2A receptor was determined in a radioligand binding assay.

[0556] Table 2. Assay conditions for radioligand binding to the 5-HT2A receptor.

[0557]

[0558]

[0559] Example 41: Functional activity at 5-HT2A, 5-HT2B, 5-HT2C and 5-HT1A receptors

[0560] In Ca 2+ The functional activity of the disclosed compounds at several 5-HT receptor subtypes (5-HT2A, 5-HT2B, 5-HT2C and 5-HT1A) was determined in a flow assay, with the results summarized in Table 3. The reference phenylalkylamine compounds tested exhibited high potency agonist activity at the 5-HT2A receptor. The novel pyridine compound 1 showed only 25% activation at the maximum dose, which is a much lower potency compared to the 72% activation exhibited by its phenyl counterpart compound 10. This trend of lower maximum potency at the 5-HT2A receptor was also observed for other disclosed pyridine compounds, including compounds 2, 37, 29, 32 and 35, compared to their phenyl counterparts compounds 39, 40, 44, 45 and 46, respectively. Therefore, these pyridine compounds represent low potency partial agonists that may exhibit reduced hallucinogenic effects compared to more potent 5-HT2A agonists. In contrast, the other pyridine isomer, compound 11, is less potent and exhibits greater potency compared to compound 1. Furthermore, the pyrazine analog, compound 12, possesses very low potency and efficacy. These observations support the preferred positioning of the pyridine nitrogen in the compounds of the present invention. At the 5-HT2B receptor, many of the disclosed pyridine compounds, including compounds 4, 38, 7, 9, 19, 29, 32, and 3

[0561] 5, respectively, showed lower maximum efficacy than their phenyl counterparts compounds 41, 42, 43, 2C-B, 2C-E, 44, 45 and 46, suggesting that they may have improved cardiovascular safety. The disclosed pyridine compounds also consistently showed slight agonist activity at the 5-HT1A receptor (EC 50 Greater than 10 μM), demonstrating the high selectivity of these compounds for agonism of 5-HT2A receptors relative to 5-HT1A receptors.

[0562] Table 3. Functional activity of disclosed compounds at 5-HT receptor subtypes.

[0563]

[0564]

[0565]

[0566] NT = Not tested; NC = Not calculated due to very low efficacy

[0567] method:

[0568] Functional assays at 5-HT2A, 5-HT2B, and 5-HT1A receptors. DOI, 25D-NBOMe, 2C-TFM, mescaline, 2C-B, and 2C-E were commercially available. Other compounds were prepared as described above. The FLIPR Ca 2+ Flow assays were performed according to their standard protocol to determine agonist activity at 5-HT2A, 5-HT2B, and 5-HT1A receptors. Briefly, cells expressing stable transfections of the receptors of interest (HEK293 for 5-HT2A and 5-HT2B; CHO cells for 5-HT1A) were grown and plated in 384-well plates and incubated overnight at 37°C and 5% CO2. A fresh solution of 250 mM probenecid in 1 mL FLIPR assay buffer was prepared. This was combined with a fluorescent dye (Fluo-4 DirectTM) to make the final assay concentration 2.5 mM. Compound 1:3.16 was diluted 10 points, and 750 nL was added to a 384-well compound plate together with 30 μL assay buffer using ECHO. The fluorescent dye was then added to the assay plate together with assay buffer to a final volume of 40 μL. The cell plate was incubated at 37°C and 5% CO2 for 50 minutes and placed in the FLIPR Tetra along with the compound plate. 10 μL of reference and compound were then transferred from the compound plate to the cell plate and the fluorescence signal was read.

[0569] Functional assay at the 5-HT2C receptor. The FLIPRCa was used at Eurofins DiscoverX (Fremont, CA). 2+ Flow assay measures the agonist activity at 5-HT2C receptors according to their standard protocols. In brief, cells expressing stable transfection of human 5-HT2C receptors are grown and plated in 384-well plates, and incubated overnight at 37°C and 5% CO2. Measured in 1x dye loading buffer consisting of 1x dye, 1x additive A and 2.5mM probenecid in HBSS / 20mM Hepes. Prepare fresh probenecid. Before testing, cells are loaded with dye and incubated at 37°C for 30-60 minutes. After dye loading, cells are taken out from the incubator and 10 μL HBSS / 20mM Hepes are added. 3x vehicles are included in the assay buffer. Cells are incubated at room temperature in the dark for 30 minutes to balance the plate temperature. The intermediate dilution of the sample stock solution is carried out to generate the 4x sample in the assay buffer. Compound agonist activity is measured on FLIPR Tetra (MDS). Calcium mobilization was monitored for 2 minutes and 10 μL of 4X sample in HBSS / 20 mM Hepes was added to the cells 5 seconds into the assay.

[0570] Example 42: Effects on Head Twitch Response (HTR) in Mice

[0571] Compounds were tested for their ability to induce a head twitch response (HTR) in mice, with the results summarized in Table 4. Agonists of the 5-HT2A receptor are known to induce this effect in rodents, and the potency of this HTR correlates with hallucinogenic potency in humans. The control 5-HT2A receptor agonist DOI exhibited a high E in this assay. max , which is consistent with the strong hallucinogenic effects of this compound reported in humans. In contrast, compound 1 showed a reduced E in HTR max , which indicates a reduced hallucinogenic effect and is consistent with the compound's partial agonist activity in vitro .

[0572] Table 4. Activity of disclosed compounds in a manual HTR assay in mice.

[0573] Compound <![CDATA[ED 50 (mg / kg)]]> <![CDATA[E max (HTR counts / 20 minutes)]]> DOI 0.428 35.7 1 0.897 18.78

[0574] method:

[0575] Animals. Adult male C57BL / 6 mice aged 8-10 weeks (weight 20-25 g) were used in these experiments. The animals were caged under controlled temperature and 12-hour light / dark cycle (lighting between 07:00-19:00 h) with free access to food and water. The protocol was approved by the Institutional Animal Care and Use Committee at the research site. This study was conducted in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Every effort was made to minimize suffering.

[0576] Drugs and drug administration. DOI was commercially available. All other compounds were synthesized as described above. All drugs were dissolved in saline vehicle (or saline acidified with 1-2 molar equivalents of HCl to form salts of free base compounds in situ) and administered subcutaneously (SC) in a volume of 10 mL / kg. Drugs were administered at 4 or 5 doses / compound, using n=6 animals / group. Doses were calculated based on the free base form, except for DOI which was calculated based on the HCl salt.

[0577] Procedure. Mice were administered one dose of drug (or vehicle) SC and immediately placed in a small open field for behavioral observation. Animals were observed continuously for 20 minutes and the number of head twitches (HT) was counted by an observer blinded to treatment conditions.

[0578] Statistical analysis. Analyses were performed using GraphPad Prism 9. Dose-response curves were fitted via nonlinear regression using the Gaussian 2020 function in Prism to determine the ED for each compound. 50 and E max .

[0579] Example 43: Effects on the Head Twitch Response (HTR) in Mice Using an Automated Procedure

[0580] The disclosed compounds were tested for their ability to induce a head twitch response (HTR) in mice using an automated video tracking program, with the results summarized in Table 5. The disclosed pyridine compounds generally induced reduced maximum HTRs compared to the control 5-HT2A agonist DOI, suggesting that the disclosed compounds may exhibit reduced hallucinogenic effects. Compounds with longer alkyl or fluoroalkyl substituents at the 5-position of the pyridine typically exhibited smaller maximum HTRs than compounds with shorter chain or otherwise smaller substituents at this position. Phenyl compound 44 was substantially more potent in inducing HTRs than its pyridine counterpart, compound 29, which is consistent with the generally lower maximum potency of the disclosed pyridine compounds in signaling through the 5-HT2A receptor.

[0581] Table 5. Activity of disclosed compounds in the automated HTR assay in mice.

[0582]

[0583] NC = Not calculated due to poor curve fit

[0584] method:

[0585] Animals. Adult male C57BL / 6 mice aged 8-10 weeks (weight 20-25 g) were used in these experiments. The animals were caged under controlled temperature and 12-hour light / dark cycle (lights on between 07:00-19:00 h) with free access to food and water. The protocol was approved by the Laboratory Animal Care and Use Committee of the research site. This study was conducted in strict accordance with the recommendations of the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Every effort was made to minimize suffering.

[0586] Drugs and Drug Administration. DOI was obtained commercially. Disclosed compounds were synthesized as described above. They were dissolved in saline (or saline acidified with 1-2 molar equivalents of HCl to form the salt of the free base compound in situ) and administered subcutaneously (SC) in a volume of 10 mL / kg. Five doses were tested with N=5-8 animals / group. Doses were calculated based on the free base, except for DOI which was calculated based on the HCl salt.

[0587] Procedure. Mice were administered a single dose of drug and immediately placed in a small open field of view for behavioral observation. High-speed video of the animals' behavior was continuously captured for 20 minutes. The video recordings were input into image processing software, which detected multiple points of interest on the body of each animal, including the left and right ears. HTR events were defined as periodic deviations of the ear position from the time-averaged ear position. Predetermined thresholds for the amplitude and frequency of position deviations were used to filter out HTR events from random head movements. The method was validated by comparing the detected events with manual (human) observations and was found to have an accuracy of >95%. The total number of HTR events counted during the 20-minute recording period was determined for each animal at each dose.

[0588] Statistical analysis. Analyses were performed using GraphPad Prism 9. Dose-response curves were fitted via nonlinear regression using the Gaussian 2020 function in Prism to determine the ED for each compound. 50 and E max .

[0589] The described embodiments of the present invention are intended to be illustrative rather than restrictive, and are not intended to represent every embodiment of the present invention. Various modifications and variations may be made without departing from the spirit or scope of the present invention as shown in the literal meaning of the appended claims and in equivalents recognized in law.

Claims

1. A compound of the following structure: or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, 3-membered to 6-membered heterocyclic group, C3-C 10 Cycloalkyl C1-C8 alkyl, 3-membered to 6-membered heterocyclyl C1-C8 alkyl, -OR7, -SR7, halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NR8R9, aryl, heteroaryl, aryl C1-C8 alkyl or heteroaryl C1-C8 alkyl; R2 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C3 alkyl, -OR 10 、-SR 10 , halogenated, -CF3, -SF5, -OCF3, -CN, -NO2 or -NR 11 R 12 ; R3 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, -OR 13 、-SR 13 , halogenated, -CF3, -SF5, -OCF3, -CN, -NO2, -NR 14 R 15 、-C(O)R 16 、-C(O)OR 16 、-OC(O)R 16 or -C(O)NR 17 R 18 ; R4 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, -OR 19 、-SR 19 , halogenated, -CF3, -SF5, -OCF3, -CN, -NO2, -NR 20 R 21 、-C(O)R 22 、-C(O)OR 22 、-OC(O)R 22 or -C(O)NR 23 R 24 ; R5 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, cyclopropyl or cyclopropylmethyl; and R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1 to 5 examples of R 6a Replace, and for each occurrence of each R 6a independently selected from hydroxyl, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl C1-C8 alkyl, halo, -CF3, -SF5, -OCF3, -OR 25 、-SR 25 、-CN、-NO2、-NR 26 R 27 、-C(O)R 28 、-C(O)OR 28 、-OC(O)R 28 and -C(O)NR 29 R 30 , or any two adjacent R 6a Together with the atoms to which they are attached, they form a C4-C6 cycloalkyl or a 4- to 6-membered heterocyclyl; wherein R7 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, 3-membered to 6-membered heterocyclic group, C3-C 10 Cycloalkyl C1-C8 alkyl, 3-membered to 6-membered heterocyclyl C1-C8 alkyl, aryl, heteroaryl, aryl C1-C8 alkyl or heteroaryl C1-C8 alkyl; R8 and R9 are independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, 3-membered to 6-membered heterocyclic group, C3-C 10 Cycloalkyl C1-C8 alkyl, 3-membered to 6-membered heterocyclyl C1-C8 alkyl, aryl, heteroaryl, aryl C1-C8 alkyl or heteroaryl C1-C8 alkyl; R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 are independently hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkylC1-C5 alkyl, or 3- to 6-membered heterocyclylC1-C5 alkyl; Aryl is a monocyclic or bicyclic aromatic ring containing 6 or 10 ring carbon atoms; Heteroaryl is a monocyclic or bicyclic 5- to 10-membered ring containing 1, 2, 3 or 4 ring heteroatoms and 2 to 9 ring carbon atoms; Aryl and heteroaryl may be unsubstituted or substituted with one or more substituents independently selected from hydroxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C1-C5 alkoxy, halo, -CF3, -CN, -NO2, -NH2, aryl, 3- to 6-membered heterocyclyl, heteroaryl, C3-C6 cycloalkylC1-C3 alkyl, arylC1-C3 alkyl, 3- to 6-membered heterocyclylC1-C3 alkyl and heteroarylC1-C3 alkyl; Cycloalkyl and heterocyclyl may be unsubstituted or substituted with one or more substituents independently selected from hydroxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C1-C5 alkoxy, halo, -CF3, -CN, -NO2, -NH2, aryl, 3- to 6-membered heterocyclyl, heteroaryl, C3-C6 cycloalkyl C1-C3 alkyl, aryl C1-C3 alkyl, 3- to 6-membered heterocyclyl C1-C3 alkyl, and heteroaryl C1-C3 alkyl; and Alkyl, alkenyl and alkynyl may be unsubstituted or substituted with one or more substituents independently selected from hydroxy, C3-C6 cycloalkyl, C1-C5 alkoxy, halo, -CF3, -CN, -NO2, -NH2, aryl, 3- to 6-membered heterocyclyl, heteroaryl, C3-C6 cycloalkylC1-C3 alkyl, arylC1-C3 alkyl, 3- to 6-membered heterocyclylC1-C3 alkyl and heteroarylC1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the heteroaryl and aryl groups may be unsubstituted or substituted with one or more substituents independently selected from hydroxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C5 cycloalkyl, C1-C5 alkoxy, halo, -CF3, -CN, -NH2 and -NO2; Alkyl, alkenyl and alkynyl groups may be unsubstituted or substituted with one or more substituents independently selected from fluoro, C3-C5 cycloalkyl, hydroxy and C1-C5 alkoxy; and The cycloalkyl and 3-6 membered heterocyclyl groups may be unsubstituted or substituted with one or more substituents independently selected from fluoro, C1-C5 alkyl, hydroxy and C1-C5 alkoxy.

3. The compound according to claim 1 or 2, wherein R2 is hydrogen, hydroxy, C1-C3 alkyl, halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, C1-C3 alkoxy or -S(C1-C3 alkyl); R3 is hydrogen, hydroxyl, -OR 13 、-SR 13 、-C(O)NH2 or -OC(O)R 16 ; R4 is hydroxyl, -OR 19 、-SR 19 、-C(O)NH2 or -OC(O)R 22 ; R5 is hydrogen or C1-C2 alkyl; and R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1 to 5 examples of R 6a Replace, and for each occurrence of each R 6a R is independently selected from hydroxy, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C5 cycloalkyl, halo, -CF3, -SF5, -OCF3, C1-C3 alkoxy, -S(C1-C3 alkyl), -CN, -NO2, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, -C(O)(C1-C3 alkyl), -C(O)O(C1-C3 alkyl), -OC(O)(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl) and -C(O)N(C1-C3 alkyl)2, or any two adjacent R 6a Together with the atoms to which they are attached they form an optionally substituted 4-6 membered cycloalkyl or 4-6 membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 ring heteroatoms selected from oxygen, nitrogen and sulfur.

4. A compound according to any one of claims 1 to 3, wherein R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C6 cycloalkylC1-C5 alkyl, -OR7, -SR7, halo, -CF3, -SF5, -OCF3, -CN, -NO2 or -NR8R9; R2 is hydrogen or C1-C3 alkoxy; R3 is hydrogen or C1-C3 alkoxy; R4 is a C1-C3 alkoxy group; R5 is hydrogen or C1-C2 alkyl; R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1 to 5 examples of R 6a Replace, and for each occurrence of each R 6a are independently selected from hydroxy, C1-C3 alkyl, halo and C1-C3 alkoxy, or any two adjacent R 6a Together with the atoms to which they are attached, they form an optionally substituted 4-5 membered cycloalkyl or 4-5 membered heterocyclyl; and R7, R8 and R9 are independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl and C3-C6 cycloalkylC1-C5 alkyl.

5. A compound according to any one of claims 1 to 4, wherein R1 is C1-C8 alkyl, -S(C1-C8 alkyl), halo, -CF3, -SF5, -OCF3, -CN, -NO2, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2; R2 is hydrogen or methoxy; R3 is hydrogen or methoxy; R4 is a methoxy group; R5 is hydrogen or C1-C2 alkyl; and R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1 to 5 examples of R 6a Replace, and for each occurrence of each R 6a are independently selected from hydroxy, halo and methoxy, or any two adjacent R 6a Together with the atoms to which they are attached they form an optionally substituted 5-membered cycloalkyl or 5-membered heterocyclyl.

6. The compound according to any one of claims 1-5, wherein R1 is C1-C8 alkyl, -S(C1-C8 alkyl), halo or -CF3.

7. A compound according to any one of claims 1 to 6, wherein R1 is C1-C8 alkyl, -S(C1-C8 alkyl), halo, -CF3 or -SF5; R2 is hydrogen or methoxy; R3 is hydrogen or methoxy; R4 is a methoxy group; R5 is hydrogen or C1-C2 alkyl; and R6 is hydrogen or benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1-2 examples of R 6a Replace, and for each occurrence of each R 6a are independently selected from hydroxy, fluoro and methoxy, or any two adjacent R 6a Together with the atoms to which they are attached they form a methylenedioxy ring.

8. A compound according to any one of claims 1 to 7, wherein R1 is C1-C6 alkyl, -S(C1-C6 alkyl), halo or -CF3.

9. A compound according to any one of claims 1 to 8, wherein R2 is hydrogen.

10. The compound according to any one of claims 1 to 9, wherein R3 and R4 are methoxy.

11. A compound according to any one of claims 1 to 10, wherein R5 is hydrogen, methyl or ethyl.

12. A compound according to any one of claims 1 to 11, wherein R6 is hydrogen.

13. A compound according to any one of claims 1 to 11, wherein R6 is benzyl, wherein the phenyl ring of the benzyl group is optionally replaced by 1 to 2 examples of R 6a Replace, and for each occurrence of each R 6a are independently selected from hydroxy, fluoro and methoxy, or any two adjacent R 6a Together with the atoms to which they are attached they form a methylenedioxy ring.

14. A compound according to any one of claims 1 to 13, wherein all heteroaryl, aryl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups are unsubstituted.

15. The compound according to claim 1, wherein the compound has the following structure: or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier thereof.

17. A method of treating a psychotic disorder in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-15.

18. The method of claim 17, wherein the psychiatric disorder is depression, anxiety, or substance use disorder and any symptoms or conditions associated therewith.

19. A method of activating a 5-HT2A receptor of a cell, the method comprising effecting administration to the cell of an effective amount of a compound according to any one of claims 1 to 15.

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