Compounds

Abstract

The present disclosure relates generally to compounds of formula (I), methods for their synthesis and their use in the treatment of mental or central nervous system disorders.

Description

[0001] This application claims priority to Australian Provisional Application No. 2022901458 (filed on 30 May 2022), the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present disclosure relates generally to the treatment of serotonergic 5-HT 2A The present invention also relates to a compound active at a receptor, which can be used to treat a psychiatric disorder or a central nervous system disorder. The present invention also relates to a method for synthesizing the compound, a composition comprising the compound, and a method of using the same. Background Art

[0003] Mental illness encompasses many neuropsychiatric conditions that place a huge burden on the lives of their sufferers. Diagnoses such as treatment-resistant depression, major depressive disorder, eating disorders, substance abuse disorders, post-traumatic stress disorder, obsessive-compulsive disorder, attention deficit disorder, schizophrenia, etc. can produce horrific symptoms that render many sufferers incapable of leading a normal life.

[0004] A wide variety of serotonergic drugs, such as antidepressants, serotonin reuptake inhibitors, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors, are commercially available for the treatment of psychiatric disorders. Unfortunately, these therapeutics provide limited benefit compared to placebo in many indications. In addition, these therapeutics may cause a variety of side effects, including loss of libido, insomnia, fatigue, weight gain, etc. Despite their limited efficacy, these drugs continue to be used to treat neuropsychiatric conditions and for a wide range of complementary medicine indications. The progress of new treatment options has been limited by the fact that many of these drugs are on the market, and the pharmaceutical industry has also been under increasing financial pressure to completely ignore neuroscience programs. The need for more effective mental health treatments is increasingly unmet, and the global COVID-19 pandemic is likely to increase the burden of disease around the world.

[0005] In the 1950s and 1960s, the use of psychedelic drugs for the treatment of various psychiatric disorders was extensively explored, and these substances showed promise as treatments for many central nervous system (CNS) disorders. After decades of prohibition, scientific research into the use of psychedelics as treatments for psychiatric disorders is gaining momentum. The serotonergic hallucinogen psilocybin has been designated by the FDA as a breakthrough therapy for the treatment of major depressive disorder (2019) and treatment-resistant depression (2018). Psilocybin is a prodrug compound produced by more than a number of species of mushrooms, which are collectively referred to as psilocybin mushrooms or "magic mushrooms." Psilocybin is rapidly metabolized to the bioactive compound dephosphorylated psilocin, which produces altered states of consciousness that include changes in perception, visual hallucinations, and distortions in the sense of space, time, and self. Many patients report spiritual or "mystical" experiences that have profound and lasting effects on the patient's mood and behavior. Psilocybin has shown promise in more than 50 clinical trials for neuropsychiatric indications, including various anxiety disorders, obsessive-compulsive disorder, anorexia nervosa, alcohol dependence, and tobacco addiction. Psilocybin and other psychedelic compounds such as N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) have both immediate effects on mental states and lasting effects that extend far beyond the duration of action, likely due to their ability to stimulate increased neuroplasticity, promote neurite outgrowth, and increase dendritic spine density of synaptic neurons in the brain.

[0006] To date, psilocybin is still classified as a controlled substance of abuse and / or drug under national drug laws in most countries. However, recently, clinical research has led to a growing awareness of the potential of psychedelic drugs as breakthrough therapies for the treatment of CNS disorders with a large unmet medical need.

[0007] Despite their therapeutic potential, psilocybin and other hallucinogens remain planned drugs of abuse in most countries, and the commercial pathway for these drugs to enter the market as pharmaceuticals is uncertain. As an adjunct to psychotherapy, the long duration of action of psilocybin and LSD makes treatment courses expensive and impractical for widespread implementation. Despite a long history of safe human use, several adverse events have been reported in clinical trials and may be attributed to signaling biases at 5-HT2A (the primary target) or off-target activity at, for example, the 5-HT2B receptor (cardiac burden anti-target) or 5-HT1A (anxiety target) or 5-HT2C receptor (e.g., disease-associated targets for obesity and some genetic epilepsy). Naturally occurring hallucinogens provide important lead structures for a new generation of neurotherapeutics with novel mechanisms of action and / or clinical efficacy superior to currently available neuropsychiatric drugs.

[0008] In view of the foregoing, there is a continuing need to develop new compounds that can be used to treat psychiatric disorders or central nervous system disorders.

[0009] The reference to any prior art in this specification does not constitute an acknowledgement or implication that this prior art forms part of the common general knowledge in any jurisdiction, nor does it constitute an acknowledgement or implication that this prior art can be reasonably understood by a person skilled in the art, regarded as related to and / or combined with other prior art. Summary of the invention

[0010] In one aspect, the present disclosure provides a compound of formula (I):

[0011]

[0012] in

[0013] R 1 and R 2 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-8 Cycloalkyl, C 4-14 Alkylene cycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl and C 6-16 Alkylene heteroaryl,

[0014] The C 1-6 Alkyl, the C1-6 haloalkyl, the C 2-6 Alkenyl, the C 2-6 haloalkenyl, the C 2-6 Alkynyl, the C 2-6 Haloalkynyl, the C 3-8 Cycloalkyl, the C 4-14 Alkylene cycloalkyl, the C3-C8 heterocycloalkyl, the C4-C 14 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 6-16 Each alkylene heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 2. OR 4 、N(R 4 )2, NO2, SR 4 and SO2R 4 ,

[0015] The C 3-8 Cycloalkyl, the C 4-14 Alkylene cycloalkyl, the C3-C8 heterocycloalkyl, the C4-C 14 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 6-16 Each alkylene heteroaryl is further optionally substituted with a substituent independently selected from: (O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 ;

[0016] Alternatively, R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms C 3-8Heterocycloalkyl, the C 3-8 The heterocycloalkyl group includes 1 or 2 additional ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 4 ,

[0017] The C 3-8 The heterocycloalkyl group is further optionally substituted by a substituent selected from the group consisting of halogen, (O), CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 2. OR 4 、N(R 4 )2, NO2, SR 4 、SO2R 4 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 ;

[0018] R 3 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-14 alkylenecycloalkyl;

[0019] Alternatively, R 3 and R 1 and R 2 One of them together with the atom to which it is attached forms C 3-12 Heterocycloalkyl,

[0020] The C 3-12 The heterocycloalkyl group is further optionally substituted by a substituent selected from the group consisting of halogen, (O), CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 2. OR 4 、N(R 4 )2, NO2, SR4 、SO2R 4 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 ;

[0021] Each R 4 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-7 Cycloalkyl and C 3-7 Heterocycloalkyl, the C 3-7 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 5 ,

[0022] The C 1-6 Alkyl, the C 1-6 haloalkyl, the C 2-6 Alkenyl, the C 2-6 haloalkenyl, the C 2-6 Alkynyl, the C 2-6 Haloalkynyl, the C 3-7 Cycloalkyl and the C 3-7 The heterocycloalkyl groups are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 5 、C(O)N(R 5 2. OR 5 、N(R 5 )2, NO2, SR 5 and SO2R 5 ,

[0023] The C3-C7 cycloalkyl group and the C 3-7 Each heterocycloalkyl group is further optionally substituted with a substituent independently selected from: (O), C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 5 ;

[0024] Each R 5 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 5-10 Heterocycloalkyl, C 6-12 Aryl and C 5-10 Heteroaryl,

[0025] The C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 3-8 Cycloalkyl, the C 5-10 Heterocycloalkyl, the C 6-12 The aryl group and the C 5-10 The heteroaryl groups are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N, NH and NCH3;

[0026] L is selected from C 1-4Alkylene, C2-C4 alkenylene and C2-C4 alkynylene;

[0027] Z 1 CR 8 or N;

[0028] Z 4 CR 11 or N;

[0029] R 8 , R 9 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 、N(R 13 2. SR 13 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C2-C6 haloalkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CO2R 13 、C(O)R 13 、C(O)N(R 13 )2、C(O)C(O)N(R 13 )2、OC(O)R 13 、OC(O)OR 13 、OC(O)N(R 13 2. OS(O)R 13 、OS(O)N(R 13 2. OSO2R 13 OP(O)(OR 13 )2.OC 1-6 Alkylene P(O)(OR 13 )2. S(O)R 13 、S(O)N(R 13 2. SO2R 13 、N(R 13 )2、N(R 13 )C(O)R 13 、N(R 13 )C(O)OR 13 、N(R 13 )C(O)N(R 13 )2, NO2, C 3-8 Cycloalkyl, C 3-14 Alkylenecycloalkyl, C 3-10 Heterocycloalkyl, C 4-16 Alkylene heterocycloalkyl, C 6-12Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl, C 4-16 Alkylene heteroaryl,

[0030] The C 1-6 Alkyl, the C 1-6 haloalkyl, the C 2-6 alkenyl, the C2-C6 haloalkenyl, the C 2-6 Alkynyl, the C 2-6 Haloalkynyl, the C 1-6 Alkylamine, the C 1-6 Alkoxy, the C 1-6 Haloalkoxy, the C 3-8 Cycloalkyl, the C 3-14 Alkylene cycloalkyl, the C 3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 4-16 Alkylene heteroaryl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 13 、C(O)N(R 13 2. OR 13 、N(R 13 )2, NO2, SR 13 and SO2R 13 ,

[0031] The C 3-8 Cycloalkyl, the C 3-14 Alkylene cycloalkyl, the C 3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 4-16 Each alkylene heteroaryl group is further optionally substituted with a substituent selected from: (O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 13 ;

[0032] Each R 13 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 4-14 Alkylenecycloalkyl, C 3-10 Heterocycloalkyl, C 4-16 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl and C 6-16 Alkylene heteroaryl,

[0033] The C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 3-8 Cycloalkyl, the C 4-14 Alkylene cycloalkyl, the C 3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 6-16 Each alkylene heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N, NH and NCH3.

[0034] In any aspect or embodiment described herein, the compounds of the invention may be provided in the form of pharmaceutically acceptable salts, solvates, tautomers, N-oxides, stereoisomers, metabolites, polymorphs and / or prodrugs thereof.

[0035] In another aspect, the present disclosure provides a medicament comprising a compound of formula (I) according to any one of the embodiments disclosed herein or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0036] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) according to any one of the embodiments disclosed herein or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof and a pharmaceutically acceptable excipient.

[0037] In another aspect, the present disclosure provides a method for treating a disease, disorder or condition associated with the activity of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) according to any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0038] In another aspect, the present disclosure provides a method of treating a disease, disorder and / or condition associated with the activity of a serotonin receptor, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, in combination with a therapeutically effective amount of another agent useful for treating the disease, disorder or condition.

[0039] In another aspect, the present disclosure provides a method of treating a mental disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0040] In some embodiments, the psychiatric disorder is selected from anxiety disorders; depression; mood disorders; psychotic disorders; impulse control and addiction disorders; drug addiction; obsessive-compulsive disorder (OCD); post-traumatic stress disorder (PTSD); stress response syndrome; dissociative disorders; depersonalization disorder; factitious disorder; sexual and gender disorders; somatic symptom disorder; hallucinations; delusions; psychosis; and combinations thereof.

[0041] In another aspect, the present disclosure provides a method for treating a central nervous system (CNS) disease, disorder or condition and / or a nervous system disease, disorder or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0042] In some embodiments, the CNS disease, disorder or condition and / or the nervous system disease, disorder or condition is selected from a nervous system disease including neurodevelopmental and neurodegenerative diseases, such as Alzheimer's disease; Alzheimer's disease; vascular dementia; Lewy body dementia; 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 disease; fragile X syndrome; Angelman syndrome; syndrome); hereditary ataxias; neurological ear and eye movement disorders; neurodegenerative diseases of the retina amyotrophic lateral sclerosis; tardive dyskinesia; ADHD; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorders; tuberous sclerosis; Rett syndrome; cerebral palsy; reward system disorders, including eating disorders such as anorexia nervosa and bulimia nervosa; binge eating disorder, trichotillomania, scratching disorder, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology; and combinations thereof.

[0043] In another aspect, the present disclosure provides a method for increasing neuronal plasticity and / or increasing dendritic spine density, the method comprising contacting a neuronal cell with an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, thereby increasing the neuronal plasticity of the neuronal cell and / or increasing the dendritic spine density of the neuronal cell.

[0044] In another aspect, the present disclosure provides a method for treating weight, the method comprising administering an effective amount of a compound of the present invention to a subject in need thereof. Treating weight can include treating weight gain; weight loss; metabolic disorders; weight gain associated with drug intervention; weight gain associated with psychiatric disorders (including psychiatric disorders described herein); eating disorders such as anorexia, bulimia, cachexia, etc.; eating behavior; obesity; diabetes; insulin resistance; prediabetes; glucose intolerance; hyperlipidemia; and cardiovascular disease.

[0045] In another aspect, the present disclosure provides a method for activating a serotonin receptor in a cell of a biological sample or a patient, the method comprising administering to the cell a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0046] The scope of the present disclosure is not to be limited by the specific embodiments described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions, and methods, as described herein, are clearly within the scope of the present invention. DETAILED DESCRIPTION

[0047] It should be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the various features mentioned or evident in the text or drawings. All these different combinations constitute various alternative aspects of the invention.

[0048] definition

[0049] For the purpose of interpreting this specification, terms used in the singular form will also include the plural form, and vice versa.

[0050] As used herein, the term "comprise" and variations of the term, such as "comprising," "comprises," and "comprised," are not intended to exclude additional additives, components, integers or steps, unless the context requires otherwise.

[0051] The term "treatment" or "treating" a subject includes delaying, slowing down, stabilizing, curing, healing, alleviating, mitigating, altering, remedying, reducing deterioration, ameliorating, improving or affecting a disease or condition, a sign or symptom of a disease or condition, or the risk (or susceptibility) of a disease or condition. The term "treat" refers to any indicator of successful treatment or improvement of an injury, pathology or condition, including any objective or subjective parameter, such as alleviation; remission; reduction in the rate of deterioration; reduction in the severity of the disease; stabilization, attenuation of signs or symptoms or making an injury, pathology or condition more tolerable to an individual; slowing the rate of degeneration or decline; making the end stage of degeneration less debilitating.

[0052] In particularly preferred embodiments, the methods of the present invention can prevent the signs or symptoms of a disease or condition as described herein, or reduce the severity of the signs or symptoms, or inhibit the progression of the signs or symptoms or minimize the progression. Therefore, the methods of the present invention can be used for treatment and prevention.

[0053] As used herein, "preventing" or "prevention" is intended to refer to at least reducing the likelihood of the risk (or susceptibility) of acquiring a disease or condition (i.e., preventing an individual who may be exposed to a disease or susceptible to a disease but has not yet experienced the disease or does not show signs or symptoms of the disease from developing at least one of the clinical signs or symptoms of the disease). Biological and physiological parameters for identifying such patients are provided herein and are also well known to physicians.

[0054] As used herein, the terms "subject" or "patient" can be used interchangeably. The terms "individual" or "patient" refer to animals and humans, non-human primates that can be treated by compounds and / or methods, respectively, including but not limited to, for example, dogs, cats, horses, sheep, pigs, cattle, etc. Unless otherwise specified, "subject" or "patient" can include both male and female genders. In addition, it also includes subjects or patients, preferably humans, who are suitable for receiving treatment using the pharmaceutical composition and / or method of the present invention.

[0055] The term "selective" means that the activity at a first target (e.g., a first 5-HT receptor subtype) is greater than the activity at a second target (e.g., a second 5-HT receptor subtype). In some embodiments, the selectivity of the compound for the first target is at least 1.25-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 10-fold, or at least 100-fold greater than the selectivity for the second target. In some embodiments, the compound is selective for the first target relative to one or more other 5-HT receptor subtypes (e.g., 5-HT 2B and / or 5-HT 2C , preferably 5-HT 2B), the compounds described herein have an effect on 5-HT 2A The receptors are selective. In some embodiments, the 5-HT receptors are selective for one or more other 5-HT receptor subtypes (e.g., 5-HT 2A and / or 5-HT 2B , preferably 5-HT 2B ), the compounds described herein have an effect on 5-HT 2C Receptors are selective.

[0056] The various features of the present disclosure are described with reference to a certain value or range of values. These values ​​are intended to be related to the results of various appropriate measurement techniques, and should therefore be interpreted as including the error range inherent to any particular measurement technique. Some of the values ​​mentioned herein are represented by the term "about" to at least partially explain this variability. When used to describe a value, the term "about" can mean an amount within ±10%, ±5%, ±1% or ±0.1% of the value.

[0057] Range: Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that description in range format is merely for convenience and brevity, and should not be construed as a rigid limitation on the scope of the invention. Therefore, descriptions of ranges should be considered to have all possible subranges specifically disclosed as well as individual numerical values ​​within the ranges. For example, descriptions of ranges such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within the ranges, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies no matter how broad the range is.

[0058] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon group having from one to twelve carbon atoms or any range of carbon atoms therebetween, i.e., it contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The alkyl group is optionally substituted with a substituent. As used herein, examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, etc.

[0059] As used herein, the terms "C1-C2 alkyl", "C1-C3 alkyl" and "C1-C6 alkyl" refer to alkyl groups as defined herein, respectively containing at least 1 and up to 2, 3 or 6 carbon atoms, or any range of carbon atoms therebetween (e.g., alkyl groups containing 2-5 carbon atoms are also within the range of C1-C6).

[0060] The term "alkylene" refers to a straight or branched chain saturated aliphatic group having the indicated number of carbon atoms and connecting at least two other groups, i.e., divalent hydrocarbon groups. The two moieties connected to the alkylene group can be connected to the same atom or to different atoms of the alkylene group. For example, a straight chain alkylene group can be -(CH2) n - a divalent radical of wherein n is 1, 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.

[0061] The term "alkenyl" whether used alone or as part of another group, means a straight or branched saturated alkylene group, i.e., a saturated carbon chain containing substituents at both ends. The number of carbon atoms that may be present in the cited alkylene group is indicated by the prefix "C n1-n2 " means. For example, the term C 2-6 Alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl include, but are not limited to, vinyl / ethenyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl or 1,3,5-hexatrienyl.

[0062] As used herein, the term "alkynyl," whether used alone or as part of another group, refers to a straight or branched chain unsaturated alkynyl group containing at least one triple bond. The number of carbon atoms that may be present in the cited alkyl group is indicated by the prefix "C n1-n2 " means. For example, the term C 2-6 Alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentenyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl or 1,3,5-hexatriynyl.

[0063] The term "cycloalkyl" is intended to include monocycloalkyl, bicycloalkyl or tricycloalkyl. The number of carbon atoms that may be present in the cited cycloalkyl group is indicated by the prefix "C n1-n2 " means. For example, the term C 3-8Cycloalkyl means a cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms. In certain embodiments, cycloalkyl has 3 to 12, 3 to 10, 3 to 8, 3 to 6 or 3 to 5 carbon atoms in the ring. In certain embodiments, cycloalkyl has 5 or 6 ring carbon atoms. Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In certain embodiments, cycloalkyl has 3 to 8, 3 to 7, 3 to 6, 4 to 6, 3 to 5 or 4 to 5 ring carbon atoms. Bicyclic and tricyclic ring systems include bridged spirocyclic and fused cycloalkyl ring systems. Examples of bicyclic and tricyclic cycloalkyl systems include but are not limited to bicyclic [2.1.1] hexyl, bicyclic [2.2.1] heptyl, adamantyl and decahydronaphthyl.

[0064] The term "alkylenecycloalkyl" refers to a group having an alkyl component and a cycloalkyl component, wherein the alkyl component connects the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene group that is connected to the cycloalkyl component and the point of attachment. In some cases, the alkyl component may not be present. The alkyl component may include any number of carbon atoms, such as C 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 The cycloalkyl component is as defined above. x-y The numerical range of x to y in "alkylenecycloalkyl" refers to the total number of alkyl carbons and cycloalkyl ring atoms. Exemplary alkylenecycloalkyls include, but are not limited to, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, and methylenecyclohexyl.

[0065] The term "aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. The number of carbon atoms that may be present in the cited aryl group is indicated by the prefix "C n1-n2 " means. For example, the term C 6-12Aryl means an aryl having 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Aryl can include any suitable number of ring atoms (such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms) and 6 to 10, 6 to 12 or 6 to 14 ring members. Aryl can be monocyclic, fused to form a dicyclic or tricyclic group, or connected by a bond to form a biaryl. Representative aryl includes phenyl, naphthyl and biphenyl. Other aryl includes benzyl with a methylene linking group. Some aryl has 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl has 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl has 6 ring members, such as phenyl.

[0066] The term "alkylene aryl" refers to a group having an alkyl component and an aryl component, wherein the alkyl component connects the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene group that is connected to the aryl component and the point of attachment. The alkyl component may include any number of carbon atoms, such as C 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 In some cases, the alkyl component may be absent. The aryl component is as defined above. x-y The numerical range of x to y in "alkylene aryl" refers to the total number of alkyl carbon and aryl ring atoms. Examples of alkylene aryl include, but are not limited to, benzyl and ethylene phenyl.

[0067] As used herein, the term "alkoxy" refers to an alkyl group as defined herein covalently bonded via an O bond. Alkoxy groups are optionally substituted with substituents. As used herein, examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, isopropyl, butoxy, isobutoxy, tert-butoxy, and pentoxy.

[0068] As used herein, the terms "C1-C2 alkoxy", "C1-C3 alkoxy" and "C1-C6 alkoxy" refer to alkoxy groups as defined herein, respectively containing at least 1 and up to 2, 3 or 6 carbon atoms, or any range of carbon atoms therebetween (e.g., alkoxy groups containing 2-5 carbon atoms are also within the range of C1-C6).

[0069] As used herein, the term "alkylamine" refers to an alkyl group as defined herein having one or more amino groups. The amino group may be a primary amino group, a secondary amino group, or a tertiary amino group. The alkylamine may be further substituted with a hydroxyl group to form an amino-hydroxyl group. Examples of alkylamines include, but are not limited to, ethylamine, propylamine, isopropylamine, ethylenediamine, and ethanolamine. The amino group may connect the alkylamine to the point of attachment and the rest of the compound, may be located at the ω position of the alkyl group, or may connect at least two carbon atoms of the alkyl group together.

[0070] As used herein, the terms "C1-C2 alkylamine", "C1-C3 alkylamine" and "C1-C6 alkylamine" refer to alkylamines as defined herein, each containing at least 1 and at most 2, 3 or 6 carbon atoms, or any range of carbon atoms therebetween (e.g., alkylamines containing 2-5 carbon atoms are also within the range of C1-C6).

[0071] As used herein, the term "alkylsulfonyl" refers to an alkyl group as defined herein having one or more sulfonyl groups. The sulfonyl group may link the alkylsulfonyl group to the point of attachment and the remainder of the compound, may be located at the ω position of the alkyl group, or may link at least two carbon atoms of the alkyl group together.

[0072] As used herein, the terms "C1-C2 alkylsulfonyl", "C1-C3 alkylsulfonyl" and "C1-C6 alkylsulfonyl" refer to alkylsulfonyl groups as defined herein, respectively containing at least 1 and up to 2, 3 or 6 carbon atoms, or any range of carbon atoms therebetween (e.g., alkylsulfonyl groups containing 2-5 carbon atoms are also within the range of C1-C6).

[0073] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus. Preferred heteroatoms include N, O and / or S, preferably N and O.

[0074] As used herein, the term "hetero moiety" means a chemical group containing a heteroatom. Examples of hetero moieties include O, S, S(O), SO2, N and NH.

[0075] As used herein, a "substituent" refers to a molecular moiety covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" can be a moiety that is a ring member covalently bonded to an atom, preferably a carbon atom or a nitrogen atom, such as a halogen, an alkyl group, or other substituents described herein. As used herein, the term "substituted" means that any one or more hydrogens on the designated atom are replaced with a selection from the indicated substituent, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound, i.e., a compound that can be isolated, characterized, and tested for biological activity.

[0076] As used throughout the specification, the term "optionally substituted" or "may be substituted" and the like means that a group may or may not be further substituted or fused (to form a polycyclic system) with one or more non-hydrogen substituents. Suitable chemically feasible substituents for a particular functional group will be apparent to one skilled in the art.

[0077] Examples of substituents include, but are not limited to, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C3-C7 heterocyclyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, arylsulfonamino, alkylcarboxyl, alkylformamide, oxo, hydroxyl, sulfhydryl, amino, acyl, carboxyl, carbamoyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo, urea, C1-C6 perfluoroalkyl. Preferably, substituents include amino, halo, C1-C6 alkyl, amine, hydroxyl.

[0078] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), and the term "halo" refers to the halogen groups fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I). Preferably, "halo" is fluoro or chloro.

[0079] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein in which one or more (up to all) available hydrogen atoms have been replaced by halogen. In some cases, the term "perfluoro" may be used to define a compound or group in which all hydrogens are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0080] As used herein, the terms "C1-C2 haloalkyl", "C1-C3 haloalkyl" and "C1-C6 haloalkyl" refer to haloalkyl groups as defined herein, respectively containing at least 1 and up to 2, 3 or 6 carbon atoms, or any range of carbon atoms therebetween (e.g., haloalkyl groups containing 2-5 carbon atoms are also within the range of C1-C6).

[0081] For example, the C1 haloalkyl group can be, but is not limited to, fluoromethyl, difluoromethyl or trifluoromethyl.

[0082] As used herein, the term "haloalkenyl" refers to an alkenyl group as defined above in which one or more (up to all) available hydrogen atoms have been replaced by a halogen. Thus, for example, "C 1-6 "Haloalkenyl" (or "C1-C6 haloalkenyl") refers to a C1 to C6 straight or branched chain alkenyl group as defined above having one or more halogen substituents.

[0083] As used herein, the term "haloalkynyl" refers to an alkynyl group as defined above in which one or more (up to all) available hydrogen atoms have been replaced by a halogen. Thus, for example, "C 1-6 "Haloalkynyl" (or "C1-C6 haloalkynyl") refers to a C1 to C6 straight or branched chain alkynyl group as defined above having one or more halogen substituents.

[0084] As used herein, the term haloalkoxy refers to an alkoxy group as defined herein substituted with at least one halogen.

[0085] The term "amino" or "amine" refers to the group -NH2.

[0086] The term "substituted amino" or "secondary amino" refers to an amino group in which hydrogen is replaced by, for example, a C1-C6 alkyl group ("C1-C6 alkylamino"), an aryl group or an aralkyl group ("arylamino", "aralkylamino"), etc. C1-C3 alkylamino groups are preferred, such as methylamino (NHMe), ethylamino (NHEt) and propylamino (NHPr).

[0087] The term "disubstituted amino" or "tertiary amino" refers to an amino group in which hydrogen is replaced by, for example, C1-C6 alkyl (which may be the same or different ("dialkylamino")), aryl and alkyl ("aryl(alkyl)amino"), etc. Di(C1-C3 alkyl)amino is preferred, for example, dimethylamino (NMe2), diethylamino (NEt2), dipropylamino (NPr2) and variants thereof (e.g., N(Me)(Et), etc.).

[0088] The term "nitro" refers to the group -NO2.

[0089] The terms "cyano" and "nitrile" refer to the group -CN.

[0090] The term "amine" or "amide" refers to the group -C(O)NH2.

[0091] The term "substituted amine" or "substituted amide" refers to an amine group in which hydrogen is replaced by, for example, a C1-C6 alkyl group ("C1-C6 alkylamine" or "C1-C6 alkylamide"), an aryl group ("arylamine"), an aralkyl group ("aralkylamine"), or the like. 1- C3 alkylamide groups are preferred, such as methylamide (-C(O)NHMe), ethylamide (-C(O)NHEt), and propylamide (-C(O)NHPr), and include reverse amides thereof (e.g., NHMeC(O)-, -NHEtC(O)-, and -NHPrC(O)-).

[0092] The term "disubstituted amine" or "disubstituted amide" refers to an amine group in which hydrogen is replaced by, for example, C1-C6 alkyl ("di(C1-C6 alkyl)amine" or "di(C1-C6 alkyl)amide"), aralkyl and alkyl ("alkyl(aralkyl)amine"), etc. Di(C1-C3 alkyl)amide groups are preferred, for example, dimethylamide (-C(O)NMe2), diethylamide (-C(O)NEt2) and dipropylamide (-C(O)NPr2) and variants thereof (e.g., C(O)N(Me)Et, etc.), and include reverse amides thereof.

[0093] The term "sulfonyl" refers to the group -SO2H.

[0094] The term "substituted sulfonyl" refers to a sulfonyl group in which the hydrogen is replaced by, for example, a C1-C6 alkyl group ("sulfonyl C1-C6 alkyl"), an aryl group ("arylsulfonyl"), an aralkyl group ("aralkylsulfonyl"), or the like. 1- C3 alkyl groups are preferred, for example, -SO2Me, -SO2Et and -SO2Pr.

[0095] The term "sulfonylamino" or "sulfonamide" refers to the group -SO2NH2.

[0096] The term "substituted sulfonylamino" or "substituted sulfonamide" refers to a sulfonylamino group in which hydrogen is replaced by, for example, a C1-C6 alkyl group ("sulfonylamino C1-C6 alkyl"), an aryl group ("arylsulfonamide"), an aralkyl group ("aralkylsulfonamide"), etc. Sulfonylamino C1-C3 alkyl is preferred, for example, -SO2NHMe, -SO2NHEt and -SO2NHPr, and includes its reverse sulfonamide (for example, -NHSO2Me, -NHSO2Et and -NHSO2Pr).

[0097] The term "disubstituted sulfonamido" or "disubstituted sulfonamide" refers to a sulfonylamino group in which two hydrogens are replaced by, for example, C1-C6 alkyl (which may be the same or different ("sulfonylaminodi(C1-C6)alkyl"), aralkyl, and alkyl ("sulfonylamino(aralkyl)alkyl"), etc. Sulfonylaminodi(C1-C3alkyl) groups are preferred, for example, -SO2NMe2, -SO2NEt2, and -SO2NPr2, and variants thereof (e.g., -SO2N(Me)Et, etc.), and include reverse sulfonamides thereof (e.g., -N(Me)SO2Me, etc.).

[0098] The term "sulfate" refers to the group OS(O)2OH and includes groups in which the hydrogen is replaced by, for example, C1-C6 alkyl ("alkyl sulfate"), aryl ("aryl sulfate"), aralkyl ("aralkyl sulfate"), etc. C1-C3 alkyl sulfates are preferred, for example, OS(O)2OMe, OS(O)2OEt and S(O)2OPr.

[0099] The term "sulfonate" refers to the group SO3H and includes groups in which the hydrogen is replaced by, for example, C1-C6 alkyl ("alkyl sulfonate"), aryl ("aryl sulfonate"), aralkyl ("aralkyl sulfonate"), etc. C1-C3 alkyl sulfonates are preferred, for example, SO3Me, SO3Et and SO3Pr.

[0100] As defined herein, the term "amino acid" refers to a moiety containing an amino group and a carboxyl group connected by at least one carbon. Amino acids may refer to natural or non-natural amino acids, preferably natural amino acids, such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, preferably the amino acid is arginine, lysine or histidine, most preferably lysine.

[0101] The term "carboxylate" or "carboxy" refers to the group -COO- or -COOH.

[0102] The term "carbamate" or "carbamyl" refers to the group -OC(O)NH2. Carbamate may be substituted or disubstituted, for example, by alkyl (such as but not limited to C1-C6 alkyl).

[0103] The term "carbonate" refers to the group -OC(O)O- or -OC(O)OH.

[0104] As defined herein, the term "alkyl carbonate" refers to a ester of carbonic acid ester replaced by hydrogen, such as C 1-Carbonates substituted with C6 alkyl, aryl or aralkyl ("aryl carbonate" or "aralkyl carbonate"). 1- C3 alkyl groups are preferred, for example, methyl carbonate (CO3Me), ethyl carbonate (CO3Et) and propyl carbonate (CO3Pr).

[0105] The term "ester" refers to a hydrogen atom replaced by a C 1- C6 alkyl ("carboxyl C 1- C6 alkyl" or "alkyl ester"), aryl or aralkyl ("aryl ester" or "aralkyl ester"), etc. 1- C3 alkyl groups are preferred, for example, methyl esters (CO2Me), ethyl esters (CO2Et), and propyl esters (CO2Pr), and include reverse esters thereof (eg, -OC(O)Me, -OC(O)Et, and -OC(O)Pr).

[0106] The term "heterocyclyl" refers to a moiety obtained by removing hydrogen atoms from a ring atom of a heterocyclic compound, the moiety having from 3 to 12 ring atoms (unless otherwise specified), of which 1, 2, 3, 4 or more are ring heteroatoms (e.g., ring heteroatoms independently selected from O, S and N) or ring hetero moieties, e.g., ring hetero moieties independently selected from O, S, S(O), SO2, N and NH. When the heterocyclyl contains the prefix C n1-n2 or "n1 to n2", this prefix indicates the number of carbon atoms in the corresponding carbocyclic group in which one or more of the ring atoms (suitably 1, 2, 3, 4 or more reducing atoms) are replaced by heteroatoms or hetero moieties.

[0107] In this case, the prefixes 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, and 10-membered indicate the number of ring atoms or the range of ring atoms, whether carbon atoms or heteroatoms. For example, as used herein, the term "C 3-10 The term "heterocyclyl" or "3-10 membered heterocyclyl" refers to a heterocyclic group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. Examples of heterocyclic groups include 5-6 membered monocyclic heterocyclic groups and 9-10 membered fused bicyclic heterocyclic groups.

[0108] Examples of monocyclic heterocyclic groups include, but are not limited to, monocyclic heterocyclic groups containing one nitrogen atom, such as aziridine (3-membered ring), azetidine (4-membered ring), pyrrolidine (tetrahydropyrrole), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoxazole) or pyrrolidone (5-membered ring), piperidine, dihydropyridine, tetrahydropyridine (6-membered ring) and azepine (7-membered ring); monocyclic heterocyclic groups containing two nitrogen atoms, such as imidazoline, pyrazolidine ( diazolidine), imidazoline, pyrazoline (dihydropyrazole) (5-membered ring), piperazine (6-membered ring), etc.; monocyclic heterocyclic groups containing one oxygen atom, such as oxirane (3-membered ring), oxetane (4-membered ring), oxolane (tetrahydrofuran), furan (dihydrofuran) (5-membered ring), oxirane (tetrahydropyran), dihydropyran, pyran (6-membered ring), oxepin (7-membered ring); monocyclic heterocyclic groups containing two oxygen atoms, such as dioxolane (5-membered ring), dioxane ( 6-membered ring) and dioxepane (7-membered ring); monocyclic heterocyclic groups containing three oxygen atoms, such as trioxane (6-membered ring); monocyclic heterocyclic groups containing one sulfur atom, such as thioethane (3-membered ring), thiamidine (4-membered ring), thiapentane (tetrahydrothiophene) (5-membered ring), thiamidine (tetrahydrothiopyran) (6-membered ring), thiaheptane (7-membered ring); monocyclic heterocyclic groups containing one nitrogen atom and one oxygen atom, such as tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole (5-membered ring), morpholine, tetrahydrooxazole, The invention also includes the following: monocyclic heterocyclic groups: oxazine, dihydrooxazine, oxazine (6-membered ring); monocyclic heterocyclic groups containing one nitrogen atom and one sulfur atom, such as thiazoline, thiazolidine (5-membered ring), thiomorpholine (6-membered ring); monocyclic heterocyclic groups containing two nitrogen atoms and one oxygen atom, such as oxadiazine (6-membered ring); monocyclic heterocyclic groups containing one oxygen and one sulfur, such as oxathiole (5-membered ring) and thioxane (thioxane) (6-membered ring); and monocyclic heterocyclic groups containing one nitrogen atom, one oxygen atom and one sulfur atom, such as oxathiazine (6-membered ring).

[0109] Heterocyclyl also encompasses heteroaryl (aromatic heterocyclyl) and heterocycloalkyl (non-aromatic heterocyclyl). Such groups may be substituted or unsubstituted.

[0110] The term "aromatic heterocyclic group" can be used interchangeably with the term "heteroaromatic" or the term "heteroaryl" or "heteroaryl". The heteroatoms in the aromatic heterocyclic group can be independently selected from N, S and O. The aromatic heterocyclic group can contain 1, 2, 3, 4 or more ring heteroatoms. When the heteroaryl contains the prefix C n1-n2When the prefix is ​​substituted with "n1 to n2", it indicates the number of carbon atoms in the corresponding aromatic group in which one or more of the ring atoms (suitably 1, 2, 3, 4 or more reducing atoms) are replaced by heteroatoms. In the case of fused aromatic heterocyclic groups, only one of the rings may contain heteroatoms, and not all rings need to be aromatic.

[0111] "Heteroaryl" is used herein to refer to heterocyclic groups with aromatic properties, and encompasses aromatic monocyclic systems and polycyclic (e.g., bicyclic) systems containing one or more aromatic rings. The term aromatic heterocyclic group also encompasses quasi-aromatic heterocyclic groups. The term "quasi-aromatic" refers to a ring system that is not strictly aromatic, but is stabilized by delocalization of electrons and functions in a manner similar to that of an aromatic ring. Thus, the term aromatic heterocyclic group encompasses polycyclic systems in which all fused rings are aromatic, as well as ring systems in which one or more rings are non-aromatic (provided that at least one ring is aromatic). In polycyclic systems containing aromatic and non-aromatic rings fused together, the group can be connected to another part through an aromatic ring or a non-aromatic ring.

[0112] The example of heteroaryl is monocyclic and bicyclic groups containing five to ten ring members.Heteroaryl can be, for example, a five-membered or six-membered monocyclic ring or a bicyclic structure formed by a fused five-membered ring and a six-membered ring or two fused six-membered rings or two fused five-membered rings.Each ring can contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen.The heteroaryl ring will contain up to 4 heteroatoms, more specifically up to 3 heteroatoms, more generally up to 2, such as a single heteroatom.In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom.The nitrogen atom in the heteroaryl ring can be alkaline, such as in the case of imidazoles or pyridine, or substantially non-alkaline, such as in the case of indole or pyrrole nitrogen.Usually, the number of the basic nitrogen atoms (including any amino substituents of the ring) present in the heteroaryl will be less than five.

[0113] The aromatic heterocyclic group may be a 5-membered or 6-membered monocyclic aromatic ring system.

[0114] Examples of 5-membered monocyclic heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4 oxadiazolyl and furanyl, i.e., 1,2,5-oxadiazolyl), thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1,2,3, 1,2,4 and 1,3,4 triazolyl), oxatotriazolyl, tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyl), and the like.

[0115] Examples of 6-membered monocyclic heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl, etc. Examples of 6-membered aromatic heterocyclic groups containing nitrogen include pyridinyl (1 nitrogen), pyrazinyl, pyrimidinyl, and pyridazinyl (2 nitrogens).

[0116] The aromatic heterocyclic group may also be a bicyclic or polycyclic heteroaromatic ring system, such as a fused ring system (including purine, pteridinyl, naphthyridinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furanyl, etc.) or a linked ring system (such as oligothiophene, polypyrrole, etc.). The fused ring system may also include an aromatic 5-membered or 6-membered heterocyclic group fused to a carbocyclic aromatic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, etc., such as a 5-membered aromatic heterocyclic group fused to phenyl containing nitrogen, and a 5-membered aromatic heterocyclic group fused to phenyl containing 1 or 2 nitrogen atoms.

[0117] The bicyclic heteroaryl group can be, for example, a group selected from the following: a) a benzene ring containing 1, 2 or 3 ring heteroatoms fused to a 5-membered or 6-membered ring; b) a pyridine ring containing 1, 2 or 3 ring heteroatoms fused to a 5-membered or 6-membered ring; c) a pyrimidine ring containing 1 or 2 ring heteroatoms fused to a 5-membered or 6-membered ring; d) a pyrrole ring containing 1, 2 or 3 ring heteroatoms fused to a 5-membered or 6-membered ring; e) a pyrazole ring containing 1 or 2 ring heteroatoms fused to a 5-membered or 6-membered ring; f) an imidazole ring containing 1 or 2 ring heteroatoms fused to a 5-membered or 6-membered ring; g) a pyridine ring containing 1 or 2 ring heteroatoms fused to a 5-membered or 6-membered ring; oxazole ring; h) an isoxazole ring containing 1 or 2 ring heteroatoms fused to a 5- or 6-membered ring; i) a thiazole ring containing 1 or 2 ring heteroatoms fused to a 5- or 6-membered ring; j) an isothiazole ring containing 1 or 2 ring heteroatoms fused to a 5- or 6-membered ring; k) a thiophene ring containing 1, 2 or 3 ring heteroatoms fused to a 5- or 6-membered ring; l) a furan ring containing 1, 2 or 3 ring heteroatoms fused to a 5- or 6-membered ring; m) a cyclohexyl ring containing 1, 2 or 3 ring heteroatoms fused to a 5- or 6-membered ring; and n) a cyclopentyl ring containing 1, 2 or 3 ring heteroatoms fused to a 5- or 6-membered ring.

[0118] Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazole (eg, imidazo[2,1-b]thiazole) and imidazoimidazole (eg, imidazo[1,2-a]imidazole).

[0119] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindolin, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine), benzodioxole, and pyrazolopyridine (e.g., pyrazolo[1,5-a]pyridine) groups. Another example of a six-membered ring fused to a five-membered ring is a pyrrolopyridine group, such as a pyrrolo[2,3-b]pyridine group.

[0120] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxane, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, and pteridine groups.

[0121] Examples of heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro-benzo[1,4]dioxin, benzo[1,3]cyclopentadiene, 4,5,6,7-tetrahydrobenzofuran, indoline, isoindoline, and indan groups.

[0122] Thus, examples of aromatic heterocyclic groups fused to a carbocyclic aromatic ring may include, but are not limited to, benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, isobenzoxazolyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnoazinyl, benzotriazinyl, phthalazinyl, carbolinyl, and the like.

[0123] The term "heterocycloalkyl" or "non-aromatic heterocyclyl" encompasses optionally substituted saturated and unsaturated rings containing at least one heteroatom (such as N, S and O) or a hetero moiety, such as O, S, S(O), SO2, N and NH. The ring may contain 1, 2, 3, 4 or more heteroatoms or hetero moieties. When the heterocycloalkyl contains the prefix C n1-n2 or "n1 to n2", this prefix indicates the number of ring atoms, one or more of which (suitably, 1, 2, 3, 4 or more reducing substituents) are replaced by heteroatoms or hetero moieties in the corresponding carbocyclic group. The ring may be part of a monocyclic or polycyclic system. Polycyclic systems include fused rings and spirocyclic rings. Not every ring in a non-aromatic heterocyclic polycyclic system must contain heteroatoms, as long as at least one ring contains one or more heteroatoms.

[0124] The non-aromatic heterocyclic group may be a 3-8 membered monocyclic ring.

[0125] Examples of 5-membered non-aromatic heterocyclyl rings include 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl, 3-dioxolanyl, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl, and the like.

[0126] Examples of the 6-membered non-aromatic heterocyclic group include piperidinyl, piperidonyl, pyranyl, dihydropyranyl, tetrahydropyranyl, 2H pyranyl, 4H pyranyl, thiopyranyl, oxythiopyranyl, dioxythiopyranyl, piperazinyl, dioxanyl, 1,4-dioxinyl, 1,4-dithianyl, 1,3,5-trithianyl, 1,3,5-trithianyl, 1,4-morpholinyl, thiomorpholinyl, 1,4-oxathianyl, triazinyl, 1,4-thiazinyl, and the like.

[0127] Examples of the 7-membered non-aromatic heterocyclic group include azepanyl, oxepinyl, thiolpanyl and the like.

[0128] The non-aromatic heterocyclyl ring can also be a bicyclic heterocyclyl ring, such as a linked ring system (e.g., uridine, etc.) or a fused ring system. A fused ring system includes a non-aromatic 5-, 6-, or 7-membered heterocyclyl fused to a carbocyclic aromatic ring, such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, etc. Examples of non-aromatic 5-, 6-, or 7-membered heterocyclyl fused to a carbocyclic aromatic ring include indolinyl, benzodiazepine, benzazepine, dihydrobenzofuranyl, etc.

[0129] The term "alkylene heteroaryl" refers to a group having an alkyl component and a heteroaryl component, wherein the alkyl component connects the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent (e.g., alkylene) to connect to the heteroaryl component and the point of attachment. In some cases, the alkyl component may be absent. The alkyl component may include any number of carbon atoms, such as C 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 The heteroaryl component is as defined above. x-yThe numerical range of x to y in "alkylenecycloalkyl" refers to the total number of alkyl carbon and heteroaryl ring atoms (carbon and heteroatoms together).

[0130] The term "alkylene heterocycloalkyl" refers to a group having an alkyl component and a heterocycloalkyl component, wherein the alkyl component connects the heterocycloalkyl component to the point of attachment. The heterocycloalkyl component is as defined above except that the alkyl component is at least divalent (e.g., alkylene) to connect to the heteroaryl component and the point of attachment. In some cases, the alkyl component may be absent. The alkyl component may include any number of carbon atoms, such as C 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 The heterocycloalkyl component may be any heterocycloalkyl group as defined herein. x-y The numerical range of x to y in "alkyleneheterocycloalkyl" refers to the total number of alkyl carbons and heterocycloalkyl ring atoms (carbon and heteroatoms together).

[0131] The term "pharmaceutically acceptable" may be used to describe any salt, solvate, tautomer, N-oxide, stereoisomer and / or prodrug thereof, or any other compound that, upon administration to a subject, is capable of providing (directly or indirectly) a compound as described herein, or an active metabolite or residue thereof, and is typically not harmful to the subject.

[0132] As used herein, the term "solvate" refers to a complex of a compound with a stoichiometric or non-stoichiometric amount of a solvent. Solvates are usually formed during the crystallization process using a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.

[0133] As used herein, the term "polymorph" refers to different crystal packing arrangements of a compound of the same elemental composition. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors (such as recrystallization solvent, crystallization rate, and storage temperature) may lead to a single crystal form being dominant.

[0134] As used herein, the term "metabolite" refers to a derivative of a compound formed when the compound is metabolized. The term "active metabolite" refers to a derivative of a compound formed when the compound is metabolized with biological activity. As used herein, the term "metabolized" refers to the sum of processes (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes) by which an organism changes a specific substance. Therefore, an enzyme can produce a specific structural change to a compound. The metabolites of the compounds disclosed herein are optionally identified by administering the compound to a host and analyzing a tissue sample from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound.

[0135] As used herein, "prodrugs" are compounds that may not fully meet the structural requirements of the compounds provided herein, but are modified in vivo to produce compounds of formula (I) provided herein after being administered to a subject or patient. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds in which a hydroxyl, carboxyl, amine group or sulfhydryl group is bonded to any group, and when administered to a mammalian subject, the group is cleaved to form a free hydroxyl, carboxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups in the compounds provided herein. Prodrugs of compounds provided herein can be prepared by modifying the functional groups present in the compound in such a way that the modifier is cleaved in vivo to produce the parent compound.

[0136] Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently linked to the free amino group and amide group of the compound of formula (I). Amino acid residues include 20 naturally occurring amino acids generally represented by three letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds in which carbonates, carbamates, amides and alkyl esters are covalently bonded to the substituents of the above-mentioned formula (I) through the carbonyl carbon prodrug side chain.

[0137] Compounds of formula (I) may exhibit tautomerism. Tautomers are two interchangeable forms of a molecule that usually exist in equilibrium. Any tautomers of compounds of formula (I) are understood to be within the scope of the present invention.

[0138] The stereochemical definitions and conventions used herein generally follow those of S. P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. The term "stereoisomer" refers to compounds having the same chemical composition but different arrangements of atoms or groups in space. As used herein, the term "stereoisomer" includes, but is not limited to, diastereomers, enantiomers and atropisomers and mixtures thereof, such as racemic mixtures. All stereoisomers of compounds of formula (I) are within the scope of the present invention. In some embodiments, the compound is a stereoisomerically enriched form of a compound of formula (I) at any stereocenter. The enrichment of a compound in one stereoisomer may be at least about 60%, 70%, 80%, 90%, 95%, 98% or 99% of the enrichment in another stereoisomer.

[0139] Salts of compounds of formula (I) are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure, for example because these are useful as intermediates in methods for preparing pharmaceutically acceptable salts or which do not require administration to a subject.

[0140] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in the Journal of Pharmaceutical Sciences (J. Pharmaceutical Sciences), 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts with an amino group formed with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods such as ion exchange used in the art. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0141] Further aspects of the invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, which is given by way of example and with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0142] Figure 1 : Plasma concentrations of 1-7 in male C57BL / 6 mice following intraperitoneal (IP) administration at 10 mg / kg, as described in Example 49.

[0143] Figure 2 : Plasma concentrations of 1-15 in male C57BL / 6 mice following IP administration at 10 mg / kg, as described in Example 49.

[0144] Figure 3: Time binned and mean±SD (n=3) head twitch response (HTR) counts of I-7 in C57BL / 6 mice following subcutaneous (SC) administration of several doses, as described in Example 49.

[0145] Figure 4 : Temperature and locomotion results are shown as mean ± standard deviation (SD) (n=3) HTR counts of I-7 in C57BL / 6 mice after SC administration of several doses, as described in Example 49.

[0146] Compound

[0147] The present disclosure relates to compounds of formula (I) which surprisingly exhibit activity at at least one serotonin receptor subtype. Preferred embodiments are 5-HT 2A 5-HT 2C The receptors are selective, usually for 5-HT 2A 5-HT 2C Isotype selectivity exceeds that of 5-HT 2B subtype selectivity and can further be used to determine the 5-HT 2A Selectivity over 5-HT 2C Selectivity for 5-HT 2C Selectivity over 5-HT 2A The activity of 6,6-bicyclic compounds as defined in formula (I) is particularly surprising in view of their unique structure.

[0148] The present disclosure provides compounds of formula (I):

[0149]

[0150] or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof,

[0151] in

[0152] R 1 and R 2 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-8 Cycloalkyl, C 4-14 Alkylene cycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18Alkylene aryl, C 5-10 Heteroaryl and C 6-16 Alkylene heteroaryl,

[0153] The C 1-6 Alkyl, the C 1-6 haloalkyl, the C 2-6 Alkenyl, the C 2-6 haloalkenyl, the C 2-6 Alkynyl, the C 2-6 Haloalkynyl, the C 3-8 Cycloalkyl, the C 4-14 Alkylene cycloalkyl, the C3-C8 heterocycloalkyl, the C 4- C 14 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 6-16 Each alkylene heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 2. OR 4 、N(R 4 )2, NO2, SR 4 and SO2R 4 ,

[0154] The C 3-8 Cycloalkyl, the C 4-14 Alkylene cycloalkyl, the C3-C8 heterocycloalkyl, the C4-C 14 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 6-16 Each alkylene heteroaryl is further optionally substituted with a substituent independently selected from: (O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 ;

[0155] Alternatively, R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms C 3-8 Heterocycloalkyl, the C 3-8 The heterocycloalkyl group includes 1 or 2 additional ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 4 ,

[0156] The C 3-8 The heterocycloalkyl group is further optionally substituted by a substituent selected from the group consisting of halogen, (O), CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 )2.OR 4 、N(R 4 )2, NO2, SR 4 、SO2R 4 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 ;

[0157] R 3 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-14 alkylenecycloalkyl;

[0158] Alternatively, R 3 and R 1 and R 2 One of them together with the atom to which it is attached forms C 3-12 Heterocycloalkyl,

[0159] The C 3-12 The heterocycloalkyl group is further optionally substituted by a substituent selected from the group consisting of halogen, (O), CN, C1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 )2.OR 4 、N(R 4 )2, NO2, SR 4 、SO2R 4 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 ;

[0160] Each R 4 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-7 Cycloalkyl and C 3-7 Heterocycloalkyl, the C 3-7 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 5 ,

[0161] The C 1-6 Alkyl, the C 1-6 haloalkyl, the C 2-6 Alkenyl, the C 2-6 haloalkenyl, the C 2-6 Alkynyl, the C 2-6 Haloalkynyl, the C 3-7 Cycloalkyl and the C 3-7 The heterocycloalkyl groups are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 5 、C(O)N(R 5 )2.OR 5 、N(R 5 )2, NO2, SR5 and SO2R 5 ,

[0162] The C3-C7 cycloalkyl group and the C 3-7 Each heterocycloalkyl group is further optionally substituted with a substituent independently selected from: (O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 5 ;

[0163] Each R 5 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 5-10 Heterocycloalkyl, C 6-12 Aryl and C 5-10 Heteroaryl,

[0164] The C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 3-8 Cycloalkyl, the C 5-10 Heterocycloalkyl, the C 6-12 The aryl group and the C 5-10 The heteroaryl groups are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N, NH and NCH3;

[0165] L is selected from C 1-4 Alkylene, C2-C4 alkenylene and C2-C4 alkynylene;

[0166] Z 1 CR 8 or N;

[0167] Z 4 CR 11 or N;

[0168] R 8 , R 9 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 、N(R 13 2. SR 13 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C2-C6 haloalkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CO2R 13 、C(O)R 13 、C(O)N(R 13 )2、C(O)C(O)N(R 13 )2、OC(O)R 13 、OC(O)OR 13 、OC(O)N(R 13 2. OS(O)R 13 、OS(O)N(R 13 2. OSO2R 13 OP(O)(OR 13 )2.OC 1-6 Alkylene P(O)(OR 13 )2. S(O)R 13 、S(O)N(R 13 2. SO2R 13 、N(R 13 )2、N(R 13 )C(O)R 13 、N(R 13 )C(O)OR 13 、N(R13 )C(O)N(R 13 )2, NO2, C 3-8 Cycloalkyl, C 3-14 Alkylenecycloalkyl, C 3-10 Heterocycloalkyl, C 4-16 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl, C 4-16 Alkylene heteroaryl,

[0169] The C 1-6 Alkyl, the C 1-6 haloalkyl, the C 2-6 alkenyl, the C2-C6 haloalkenyl, the C 2-6 Alkynyl, the C 2-6 Haloalkynyl, the C 1-6 Alkylamine, the C 1-6 Alkoxy, the C 1-6 Haloalkoxy, the C 3-8 Cycloalkyl, the C 3-14 Alkylene cycloalkyl, the C 3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 4-16 Alkylene heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 13 、C(O)N(R 13 )2.OR 13 、N(R 13 )2, NO2, SR 13 and SO2R 13 ,

[0170] The C 3-8 Cycloalkyl, the C 3-14 Alkylene cycloalkyl, the C 3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 4-16 Each alkylene heteroaryl group is further optionally substituted with a substituent selected from: (O), C 1-6Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 13 ;

[0171] Each R 13 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 4-14 Alkylenecycloalkyl, C 3-10 Heterocycloalkyl, C 4-16 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl and C 6-16 Alkylene heteroaryl,

[0172] The C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 3-8 Cycloalkyl, the C 4-14 Alkylene cycloalkyl, the C 3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 6-16 Each alkylene heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N, NH and NCH3.

[0173] R 1 and R 2

[0174] In some embodiments, R 1 and / or R 2 The C 3-8 Cycloalkyl, the C 4-14 Alkylene cycloalkyl, the C3-C8 heterocycloalkyl, the C4-C 14 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 6-16 The alkylene heteroaryl group is further optionally substituted with substituents independently selected from: (O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 .

[0175] In some embodiments, R 1 and R 2 Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-8 Cycloalkyl, C 7-18 Alkylene aryl and C 4-14 Alkylenecycloalkyl.

[0176] In some embodiments, R 1 and R 2 Each independently selected from hydrogen, C 1-6Alkyl, C 3-8 Cycloalkyl and C 7-18 Alkylenyl.

[0177] In some embodiments, R 1 and R 2 are each independently selected from hydrogen, C 1-4 Alkyl, C 3-4 Cycloalkyl and C 7-8 Alkylenyl.

[0178] In some embodiments, R 1 and R 2 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl.

[0179] In some embodiments, R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl.

[0180] In some embodiments, R 1 and R 2 are each independently selected from hydrogen, C 3-8 Cycloalkyl, C 4-14 Alkylene cycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl and C 6-16 Alkylene heteroaryl.

[0181] In some embodiments, R 1 and R 2 Each independently selected from C 3-8 Cycloalkyl, C 4-14 Alkylene cycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl and C 6-16 Alkylene heteroaryl.

[0182] In some embodiments, R 1 and R 2 In some embodiments, both of R 1 and R 2 In some embodiments, R 1 and R 2 Neither is hydrogen.

[0183] In some embodiments, R 1 and / or R 2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 The haloalkynyl group is straight chain. 1 and / or R 2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 A haloalkynyl group is branched.

[0184] In some embodiments, wherein R 1 and R 2 One or both of them are C 1-6 Alkyl, the C 1-6 One or both of the alkyl groups are linear. 1 and R 2 One or both of them are C 1-6 Alkyl, the C 1-6 In some embodiments, one of the alkyl groups is linear. 1 and R 2 One or both of them are C 1-6 Alkyl, the C 1-6 In some embodiments, wherein R 1 and R 2 One or both of them are C 1-6 Alkyl, the C 1-6 In some embodiments, one of the alkyl groups is branched. 1 and R 2 One or both of them are C 1-6 Alkyl, the C 1-6 One or both of the alkyl groups are branched. 1 and R 2 One or both of them are C1-6 Alkyl, the C 1-6 One of the alkyl groups is straight chain and the other C 1-6 The alkyl group is branched.

[0185] In some embodiments, wherein R 1 and R 2 One or both of them are C 1-4 Alkyl (preferably C 1-3 Alkyl), the C 1-4 Alkyl (preferably C 1-3 In some embodiments, one or both of R 1 and R 2 One or both of them are C 1-4 Alkyl (preferably C 1-3 Alkyl), the C 1-4 Alkyl (preferably C 1-3 In some embodiments, one of R 1 and R 2 One or both of them are C 1-4 Alkyl (preferably C 1-3 Alkyl), the C 1-4 Alkyl (preferably C 1-3 In some embodiments, wherein R 1 and R 2 One or both of them are C 1-4 Alkyl (preferably C 1-3 Alkyl), the C 1-4 Alkyl (preferably C 1-3 In some embodiments, one of R 1 and R 2 One or both of them are C 1-4 Alkyl (preferably C 1-3 Alkyl), the C 1-4 Alkyl (preferably C 1-3 In some embodiments, one or both of R 1 and R 2 The two are C 1-4 Alkyl (preferably C 1-3 Alkyl), the C 1-4 Alkyl (preferably C 1-3 alkyl, more preferably methyl) is linear, and the other C 1-4 Alkyl (preferably C 1-3 The alkyl group is branched.

[0186] In some embodiments, R 1 and / or R2 C 3-8 Cycloalkyl, C 4-14 Alkylene cycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl and C 6-16 The alkylene heteroaryl group is unsubstituted. In some embodiments, R 1 and / or R 2 C 3-8 Cycloalkyl, C 4-14 Alkylene cycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl and C 6-16 Alkylene heteroaryl is substituted, preferably relative to alkylene (if the group specifies alkylene) or to R. 1 / R 2 The nitrogen atom of the radical (if the radical does not specify an alkylene group) is meta-substituted.

[0187] In some embodiments, R 1 and R 2 One of them is C 7-18 Alkylene aryl, preferably C 7-8 In some embodiments, R 1 and R 2 One of them is C 7-18 Alkylene aryl, preferably C 7-8 alkylenearyl, more preferably benzyl; and R 1 and R 2 The other is hydrogen.

[0188] In some embodiments, wherein R 1 and R 2 One or both of them are C 7-18 Alkylene aryl, the C 7-18 The alkylene aryl group is unsubstituted. In some embodiments, wherein R 1 and R 2 One or both of them are C 7-18 Alkylene aryl, the C 7-18 Alkylene aryl is substituted with one or more halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 preferably one or more halogen, C 1-6 Alkyl, C1-6 Alkoxy; more preferably substituted with fluorine, methyl or methoxy.

[0189] In some embodiments, R 1 and R 2 One of them is C 3-8 Cycloalkyl, preferably C 3-4 In some embodiments, R 1 and R 2 One of them is C 3-8 Cycloalkyl, preferably C 3-4 Cycloalkyl, more preferably C3 cycloalkyl; and R 1 and the other one in R2 is C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably C1 alkyl.

[0190] In some embodiments, wherein R 1 and R 2 One or both of them are C 3-8 Cycloalkyl or C 4-14 Alkylenecycloalkyl, preferably C 3-8 Cycloalkyl; said C 3-8 Cycloalkyl or C 4-14 Alkylenecycloalkyl, preferably C 3-8 Cycloalkyl groups are unsubstituted.

[0191] In some embodiments, R 1 and / or R 2 is unsubstituted. In some embodiments, R 1 and R 2 is unsubstituted. In some embodiments, R 1 and / or R 2 In some embodiments, R 1 and R 2 It is replaced.

[0192] In some embodiments, R 1 and R 2 In other embodiments, R 1 and R 2 are different, making R 1 and R 2 The attached nitrogen atom is an asymmetric non-cyclic amine.

[0193] In some embodiments, R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms C 3-8 Heterocycloalkyl, the C 3-8The heterocycloalkyl group includes 1 or 2 additional ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 4 ,

[0194] The C 3-8 The heterocycloalkyl group is further optionally substituted by a substituent selected from the group consisting of halogen, (O), CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 )2.OR 4 、N(R 4 )2, NO2, SR 4 、SO2R 4 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 In such embodiments, R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms a cyclic amine.

[0195] In some embodiments, R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-8 Cycloalkyl and C 4-14 Alkylenecycloalkyl.

[0196] In some embodiments, R 1 and R 2 Each independently selected from C 1-4 In some embodiments, R 1 and R 2 Each independently selected from C 1-3 In some embodiments, R 1 and R2 Each independently selected from C 1-2 In some embodiments, R 1 and R 2 Both are methyl groups.

[0197] In some embodiments, R 1 and R 2 Together with the nitrogen to which it is attached, it forms any of the following:

[0198]

[0199] In some embodiments, R 1 and R 2 Together with the nitrogen to which it is attached, it forms any of the following:

[0200]

[0201] In some embodiments, R 1 and R 2 Together with the nitrogen to which it is attached, it forms any of the following:

[0202]

[0203] In some embodiments, R 1 and R 2 Together with the nitrogen to which it is attached, it forms any of the following:

[0204] Preferably

[0205] In some embodiments, R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group is optionally substituted by one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 2. OR 4 、N(R 4 )2, NO2, SR 4 and SO2R 4 、(O)、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 , where R 4 As defined in any of the preceding paragraphs.

[0206] R 3

[0207] In some embodiments, R 3 For hydrogen.

[0208] In some embodiments, R 3 and R 1 and R 2 One of them together with the atom to which it is attached forms C 3-8 Heterocycloalkyl, the C 3-8 The heterocycloalkyl group is further optionally substituted by a substituent selected from the group consisting of halogen, (O), CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 )2.OR 4 、N(R 4 )2, NO2, SR 4 、SO2R 4 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 , where R 4 As defined in any of the preceding paragraphs.

[0209] Z 1 and Z 4

[0210] In some embodiments, Z 1 CR 8 In some embodiments, Z 4 CR 11 In some embodiments, Z 1 CR8 And Z 4 CR 11 .

[0211] In some embodiments, Z 1 CR 8 , Z 4 CR 11 And R 9 is not hydrogen. In some embodiments, Z 1 CR 8 , Z 4 CR 11 And R 9 For hydrogen.

[0212] In some embodiments, Z 1 is N. In some embodiments, Z 4 is N. In some embodiments, Z 1 CR 8 And Z 4 is N. In some embodiments, Z 1 is N and Z 4 CR 11 .

[0213] In some embodiments, Z 1 N and R 9 is not hydrogen. In some embodiments, Z 4 N and R 9 is not hydrogen. In some embodiments, Z 1 CR 8 , Z 4 N and R 9 is not hydrogen. In some embodiments, Z 1 N, Z 4 CR 11 And R 9 Not hydrogen.

[0214] In some embodiments, Z 1 N and R 1 and R 2 Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and C 7-18 In some embodiments, Z 1 CR 8 And R 1 and R 2 Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and C 7-18 In some embodiments, Z4 N and R 1 and R 2 Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and C 7-18 In some embodiments, Z 4 CR 11 And R 1 and R 2 Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and C 7-18 Alkylenyl.

[0215] R 8 , R 9 and R 11

[0216] In some embodiments, R 8 , R 9 and R 11 In some embodiments, R 8 , R 9 and R 11 In some embodiments, both of R 8 , R 9 and R 11 All hydrogen.

[0217] In some embodiments, R 8 , R 9 and R 11 At least one of is halogen, preferably chlorine or fluorine, more preferably fluorine. In some embodiments, R 8 , R 9 and R 11 One of is halogen, preferably chlorine or fluorine, more preferably fluorine. In some embodiments, R 9 is halogen, preferably chlorine or fluorine, more preferably fluorine.

[0218] In some embodiments, R 8 , R 9 and R 11 At least one of them is C 1-6 Alkoxy, preferably C 1-4 In some embodiments, R 8 , R 9 and R 11 One of them is C 1-6 Alkoxy, preferably C 1-4 In some embodiments, R 8 C 1-6Alkoxy, preferably C 1-4 In some embodiments, R 9 C 1-6 Alkoxy, preferably C 1-4 In some embodiments, R 11 C 1-6 Alkoxy, preferably C 1-4 Alkoxy, more preferably methoxy.

[0219] In some embodiments, R 8 , R 9 and R 11 At least one of them is OR 13 , preferably wherein R 13 is hydrogen. In some embodiments, R 8 , R 9 and R 11 One of them is OR 13 , preferably wherein R 13 is hydrogen. In some embodiments, R 8 OR 13 , preferably R 13 is hydrogen. In some embodiments, R 9 OR 13 , preferably R 13 is hydrogen. In some embodiments, R 11 OR 13 , preferably R 13 For hydrogen.

[0220] In some embodiments, R 8 , R 9 and R 11 At least one of is hydrogen, and R 8 , R 9 and R 11 At least one of them is halogen (preferably chlorine or fluorine, more preferably fluorine), C 1-6 Alkoxy (preferably C 1-4 alkoxy, more preferably methoxy) or OR 13 (Preferably wherein R 13 is hydrogen), in some embodiments, R 8 , R 9 and R 11 Two of them are hydrogen, R 8 , R 9 and R 11 The remaining one of them is halogen (preferably chlorine or fluorine, more preferably fluorine), C 1-6 Alkoxy (preferably C 1-4 alkoxy, more preferably methoxy) or OR 13(Preferably wherein R 13 is hydrogen), in some embodiments, R 9 and R 11 is hydrogen, and R 8 is halogen (preferably chlorine or fluorine, more preferably fluorine), C 1-6 Alkoxy (preferably C 1-4 alkoxy, more preferably methoxy) or OR 13 (Preferably wherein R 13 is hydrogen), in some embodiments, R 8 and R 11 is hydrogen, and R 9 is halogen (preferably chlorine or fluorine, more preferably fluorine), C 1-6 Alkoxy (preferably C 1-4 alkoxy, more preferably methoxy) or OR 13 (Preferably wherein R 13 is hydrogen). In some embodiments, R 8 and R 9 is hydrogen, and R 11 is halogen (preferably chlorine or fluorine, more preferably fluorine), C 1-6 Alkoxy (preferably C 1-4 alkoxy, more preferably methoxy) or OR 13 (Preferably wherein R 13 is hydrogen). In some embodiments, R 9 and R 11 is hydrogen, and R 8 OR 13 (Preferably wherein R 13 is hydrogen).

[0221] In some embodiments, R 8 , R 9 and R 11 One of them is hydrogen, and R 1 and R 2 Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and C 7-18 In some embodiments, R 8 , R 9 and R 11 Both of them are hydrogen, and R 1 and R 2 Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and C 7-18 In some embodiments, R 8 , R 9 and R 11 All hydrogen, and R1 and R 2 Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and C 7-18 Alkylenyl.

[0222] In some embodiments, R 8 , R 9 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 、N(R 13 2. SR 13 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C2-C6 haloalkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CO2R 13 、C(O)N(R 13 )2、OC(O)R 13 、OSO2R 13 OP(O)(OR 13 )2.OC 1-6 Alkylene P(O)(OR 13 )2. S(O)R 13 、SO2R 13 、N(R 13 )2, NO2, C 3-8 Cycloalkyl, C 3-14 Alkylenecycloalkyl, C 3-10 Heterocycloalkyl, C 4-16 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl, C 4-16 Alkylene heteroaryl,

[0223] The C 1-6 Alkyl, the C 1-6 haloalkyl, the C 2-6 alkenyl, the C2-C6 haloalkenyl, the C 2-6 Alkynyl, the C 2-6 Haloalkynyl, the C 1-6 Alkylamine, the C 1-6 Alkoxy, the C 1-6 Haloalkoxy, the C 3-8 Cycloalkyl, the C 3-14 Alkylene cycloalkyl, the C3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 4-16 Alkylene heteroaryl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NO2, NHCH3, SH, SCH3, SO2CH3 and SOCH3,

[0224] The C 3-8 Cycloalkyl, the C 3-14 Alkylene cycloalkyl, the C 3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 4-16 Each alkylene heteroaryl group is further optionally substituted with a substituent selected from: (O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N, NH and NCH3;

[0225] Where R 13 As defined in any of the preceding paragraphs.

[0226] In some embodiments, R 8 , R 9 and R 11 One of the two, when present, is independently selected from halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and OR 13 , where R 13 Selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl, and R8 , R 9 and R 11 The others in are each hydrogen.

[0227] In some embodiments, R 8 , R 9 and R 11 One of them, when present, is independently selected from halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and OR 13 , where R 13 Selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl, and R 8 , R 9 and R 11 The others in are each hydrogen.

[0228] In some embodiments, R 8 , R 9 and R 11 One of them, when present, is independently selected from halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl and OR 13 , where R 13 Selected from hydrogen, C 1-4 Alkyl and C 1-4 haloalkyl, and R 8 , R 9 and R 11 The others in are each hydrogen.

[0229] In some embodiments, R 8 , R 9 and R 11 One of is fluorine, chlorine, hydroxyl or OCH3 when present, and R 8 , R 9 and R 11 The others in are each hydrogen.

[0230] In some embodiments, R 8 , R 9 and R 11 One of the two, when present, is OCH3, and R 8 , R 9 and R 11 In some embodiments, R 8 , R 9 and R 11 One of is hydroxyl when present, and R 8 , R 9 and R 11In some embodiments, R 8 , R 9 and R 11 One of is fluorine when present, and R 8 , R 9 and R 11 In some embodiments, R 8 , R 9 and R 11 One of is chlorine when present, and R 8 , R 9 and R 11 The others of are each hydrogen.

[0231] In some embodiments, R 8 is OCH3, and R 9 and R 11 (if present) are each hydrogen. In some embodiments, R 8 is a hydroxyl group, and R 9 and R 11 (if present) are each hydrogen.

[0232] In some embodiments, R 9 is OCH3, and R 8 and R 11 (if present) are each hydrogen. In some embodiments, R 9 is a hydroxyl group, and R 8 and R 11 (if present) are each hydrogen. In some embodiments, R 9 is fluorine, and R 8 and R 11 (if present) are each hydrogen. In some embodiments, R 9 is chlorine, and R 8 and R 11 (if present) are each hydrogen.

[0233] In some embodiments, R 11 is OCH3, and R 8 and R 9 (if present) are each hydrogen. In some embodiments, R 11 is a hydroxyl group, and R 8 and R 9 (if present) are each hydrogen.

[0234] L

[0235] In some embodiments, L is C 1-4 Alkylene.

[0236] In some embodiments, L is methylene.

[0237] Other formula

[0238] In some embodiments, the compound of formula (I) has formula (Ia):

[0239]

[0240] or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof,

[0241] Where R 1 , R 2 , R 3 , R 8 , R 9 and R 11 As defined herein.

[0242] In some embodiments, the compound of formula (I) has formula (Ib):

[0243]

[0244] or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof,

[0245] Where R 1 , R 2 , R 3 , R 9 and R 11 As defined herein.

[0246] In some embodiments, the compound of formula (I) has formula (Ic):

[0247]

[0248] or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof,

[0249] Where R 1 , R 2 , R 3 , R 8 and R 9 As defined herein.

[0250] In some embodiments, the compound of formula (I) is selected from any one of the following:

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257] or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0258] In some embodiments, the compound of formula (I) is selected from any one of the following: I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-13, I-8 and I-9 or pharmaceutically acceptable salts, solvates, tautomers, N-oxides, stereoisomers, metabolites, polymorphs and / or prodrugs thereof.

[0259] In some embodiments, the compound of formula (I) is selected from any one of the following: I-1, I-5, I-7, I-13, I-8 and I-9 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0260] In some embodiments, the compound of formula (I) is selected from any one of the following: I-1, I-5, I-7, I-13 and I-8 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0261] In some embodiments, the compound of formula (I) is selected from any one of the following: I-1, I-5, I-7 and I-13 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0262] In some embodiments, the compound of formula (I) is: I-8 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0263] In some embodiments, the compound of formula (I) is: I-9 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0264] In some embodiments, the compound of formula (I) is selected from any one of the following: I-1, I-2, I-3, I-4, I-5, I-6, 1-7, I-14, I-15, I-16, I-17, I-20, I-13, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-37, I-52, I-38, I-39, I-40, I-41, I-42, I-50, I-52 and I-53 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0265] In some embodiments, the compound of formula (I) is selected from any one of the following: 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 1-24, 1-25, 1-26, 1-27, 1-28, 1-29, 1-30, 1-31, 1-32, 1-33, 1-34, 1-35, 1-37, 1-52, 1-38, 1-39, 1-40, 1-41, 1-42, 1-50, 1-52 and 1-53 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0266] The form of the compound

[0267] In the case of solid compounds, those skilled in the art will appreciate that the compounds, agents and salts of the invention may exist in different crystalline or polymorphic forms, all of which are intended to fall within the scope and specific formula of the invention.

[0268] The present invention includes all crystalline forms of compounds of formula (I), including anhydrous crystalline forms, hydrates, solvates and mixed solvates. If any of these crystalline forms exhibit polymorphism, all polymorphs are within the scope of the present invention.

[0269] Formula (I) is intended to encompass, where applicable, solvated as well as unsolvated forms of the compounds. Thus, Formula (I) includes compounds having the indicated structures in both hydrated or solvated forms, as well as unhydrated and unsolvated forms.

[0270] The compound of formula (I) or its salt, tautomer, N-oxide, polymorph or prodrug may be provided in the form of a solvate. Solvates of the compounds of the invention may be conveniently prepared or formed during the process described herein. Generally, for the purposes of the present invention, solvated forms are considered to be equivalent to non-solvated forms.

[0271] Basic nitrogen groups can be quaternized with the following agents: C 1-6 Alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl sulfate and diethyl sulfate; etc.

[0272] Nitrogen-containing groups can also be oxidized to form N-oxides.

[0273] Compounds of formula (I) or their salts, tautomers, N-oxides, solvates and / or prodrugs that form crystalline solids may exhibit polymorphism. All polymorphic forms of compounds, salts, tautomers, N-oxides, solvates and / or prodrugs are within the scope of the present invention.

[0274] Compounds of formula (I) may exhibit tautomerism. Tautomers are two interchangeable forms of a molecule that usually exist in equilibrium. Any tautomers of compounds of formula (I) are understood to be within the scope of the present invention.

[0275] The compound of formula (I) may contain one or more stereocenters. All stereoisomers of the compound of formula (I) are within the scope of the present invention. Stereoisomers include enantiomers, diastereomers, geometric isomers (E-type and Z-type ene forms and cis- and trans-substitution patterns) and atropisomers. In some embodiments, the compound is a stereoisomerically enriched form of the compound of formula (I) at any stereocenter. The enrichment of the compound in one stereoisomer can be at least about 60%, 70%, 80%, 90%, 95%, 98% or 99% of the enrichment in another stereoisomer.

[0276] The compound of formula (I) or its salt, tautomer, solvate, N-oxide and / or stereoisomer can be isotopically enriched with one or more isotopes of the isotopes of the atoms present in the compound. For example, the compound can be enriched with one or more of the following minor isotopes: 2 H. 3 H. 13 C. 14 C. 15 N and / or 17 O, preferably 2 H. An isotope is considered enriched when its abundance is greater than its natural abundance.

[0277] "Prodrugs" are compounds that may not fully meet the structural requirements of the compounds provided herein, but are modified in vivo to produce compounds of formula (I) provided herein after being administered to a subject or patient. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds in which a hydroxyl, carboxyl, amine group or sulfhydryl group is bonded to any group, and when administered to a mammalian subject, the group is cleaved to form a free hydroxyl, carboxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups in the compounds provided herein. Prodrugs of compounds provided herein can be prepared by modifying the functional groups present in the compound in such a way that the modifier is cleaved in vivo to produce the parent compound.

[0278] Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently linked to the free amino group and amide group of the compound of formula (I). Amino acid residues include 20 naturally occurring amino acids generally represented by three letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds in which carbonates, carbamates, amides and alkyl esters are covalently bonded to the substituents of the above formula (I) via a carbonyl carbon prodrug side chain.

[0279] Compositions, formulations and modes of administration

[0280] The compound of formula (I) can be administered alone or in the form of a pharmaceutical composition. In practice, the compound of formula (I) is usually administered in the form of a pharmaceutical composition, i.e., in the form of a mixture with at least one pharmaceutically acceptable excipient. The proportion and properties of any pharmaceutically acceptable excipient are determined by the characteristics of the selected compound of the present invention, the selected route of administration, and standard pharmaceutical practice.

[0281] In another embodiment, a pharmaceutical composition is provided, comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite and / or polymorph thereof and at least one pharmaceutically acceptable excipient.

[0282] The pharmaceutical composition of the present disclosure generally comprises a mixture of one or more active ingredients of a therapeutically effective amount and one or more pharmaceutically and physiologically acceptable formulation materials. Suitable formulation materials include, but are not limited to, antioxidants, preservatives, colorants, flavoring agents and diluents, emulsifiers, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, diluents, excipients and / or pharmaceutical adjuvants. For example, a suitable vehicle can be water for injection, physiological saline solution or artificial perilymph, possibly supplemented with other materials common in the composition for parenteral administration. Neutral buffered saline or saline mixed with serum albumin is another exemplary vehicle.

[0283] The pharmaceutical compositions of the present disclosure further include a pharmaceutically acceptable carrier, as used herein, comprising any and all solvents, diluents or other liquid vehicles, dispersing aids or suspending aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. suitable for the desired specific dosage form. Remington's Pharmaceutical Sciences, 16th Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with the compounds of the present invention, such as by producing any undesirable biological effects or otherwise interacting with any other components of the pharmaceutical composition in a harmful manner, it is contemplated that its use will be within the scope of the present disclosure. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions and other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, depending on the judgment of the formulator.

[0284] The various dosage units are each preferably provided in the form of discrete doses of tablets, capsules, lozenges, dragees, gels or other types of solid formulations. Capsules can encapsulate powders, liquids or gels. Solid formulations can be swallowed, or can be of the type that can be sucked or chewed (fragile or oral jelly). The present invention contemplates dosage unit holding devices other than blister packs; for example, packaging such as bottles, tubes, cans, bags, etc. The dosage unit may further include conventional excipients well known in the practice of pharmaceutical formulations, such as binders, gelling agents, fillers, tableting lubricants, disintegrants, surfactants and colorants; and conventional excipients for suckable or chewable formulations.

[0285] The compounds of formula (I) may be administered in any form and by any route which makes the compound bioavailable.

[0286] The compositions described herein can be administered systemically or topically.

[0287] The compositions described herein can be formulated for any suitable route of administration from a compound according to formula (I), including, for example, oral, rectal, nasal, vaginal, topical (including transdermal, buccal, ocular and sublingual), parenteral (including subcutaneous, intraperitoneal, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, intracisternal injection and any other similar injection or infusion technique), inhalation, insufflation, infusion or implantation techniques (e.g., sterile injectable aqueous or non-aqueous solutions or suspensions). In some embodiments, the compositions described herein can be administered orally, nasally, intravenously, intramuscularly, topically, subcutaneously, rectally, vaginally or by urethral administration.

[0288] Compositions intended for oral use may further include one or more components, such as sweeteners, flavoring agents, coloring agents and / or preservatives, to provide attractive and palatable preparations. Tablets contain a mixture of active ingredients and physiologically acceptable excipients, and the physiologically acceptable excipients are suitable for preparing tablets. Such excipients include, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating agents and disintegrants (such as corn starch or alginic acid), adhesives (such as starch, gelatin or gum arabic) and lubricants, such as magnesium stearate, stearic acid or talcum. Tablets can be uncoated, or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, and thus provide a lasting effect over a long period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used.

[0289] Formulations for oral use can also be presented in the form of hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules, in which the active ingredient is mixed with water or an oil medium (for example, peanut oil, liquid paraffin or olive oil).

[0290] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil (such as liquid paraffin). Oily suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweeteners such as the sweeteners described above and / or flavorings can be added to provide a palatable oral preparation. Such suspensions can be preserved by adding antioxidants such as ascorbic acid.

[0291] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide a mixture of the active ingredient with a dispersant or wetting agent, a suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweeteners, flavoring agents and coloring agents may also be present.

[0292] Pharmaceutical composition can also be in the form of water-in-oil emulsion.Oil phase can be vegetable oil (such as olive oil or peanut oil), mineral oil (such as liquid paraffin) or its mixture.Suitable emulsifier includes naturally occurring gum (such as gum arabic and tragacanth), naturally occurring phospholipid (such as soybean lecithin) and ester or partial ester derived from fatty acid and hexitol, anhydride (such as sorbitan monooleate) and condensation product of partial ester and ethylene oxide (such as polyoxyethylene sorbitan monooleate) derived from fatty acid and hexitol.Emulsion can also include one or more sweeteners and / or flavorings.

[0293] Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain one or more demulcents, preservatives, flavorings and / or coloring agents.

[0294] The composition may further include one or more components suitable for improving the stability or effectiveness of the applied formulation, such as stabilizers, suspending agents, emulsifiers, viscosity modifiers, gelling agents, preservatives, antioxidants, skin penetration enhancers, humectants and sustained release materials. Examples of such components are described in Martin (ed.), Remington's Pharmaceutical Sciences. The formulation may include microcapsules, such as hydroxymethylcellulose or gelatin microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.

[0295] Preservatives include, but are not limited to, antimicrobial agents such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate / ascorbic acid, and propyl gallate. Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerol, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate, and mineral oil. Suitable flavors and pigments include, but are not limited to, FD&C Red 40 and FD&C Yellow 5. Other suitable additional ingredients that may be included in topical formulations include, but are not limited to, abrasives, absorbents, anti-caking agents, anti-foaming agents, antistatic agents, astringents (such as witch hazel), alcohols and herbal extracts (such as chamomile extracts), binders / excipients, buffers, chelating agents, film formers, conditioners, propellants, opacifiers, pH adjusters, and protective agents.

[0296] Liquid dosage forms for oral administration include but are not limited to pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oil (specifically, cottonseed oil, peanut, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition to the inert diluent, oral compositions can also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and aromatics.

[0297] Injectable preparations (e.g., sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in the form of nontoxic parenteral acceptable diluents or solvents, such as solutions in the form of 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are routinely used as solvents or suspension media. For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injectables.

[0298] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

[0299] The pharmaceutical composition can be formulated as an inhalation formulation, which comprises sprays, mists or aerosols. For inhalation formulations, the compositions or combinations provided herein can be delivered by any inhalation method known to those skilled in the art. Such inhalation methods and devices include but are not limited to metered-dose inhalers with propellants such as CFC or HFA or physiologically and environmentally acceptable propellants. Other suitable devices are inhalers operated by breathing, multi-dose dry powder inhalers and aerosol nebulizers. Aerosol formulations used for the inventive method typically comprise propellants, surfactants and cosolvents, and can be filled into conventional aerosol containers closed by suitable metering valves.

[0300] Inhalant compositions can comprise liquid or powdered compositions containing active ingredients suitable for atomization and intrabronchial use, or aerosol compositions applied by an aerosol unit distributing a metered dose. Suitable liquid compositions are contained in active ingredients in aqueous pharmaceutically acceptable inhalant solvents (such as isotonic saline or antibacterial water). The solution is applied by any other conventional means by a pump or an extrusion-braked atomizing spray dispenser or for making or enabling the liquid composition of the necessary dosage to be sucked into the patient's lungs. Suitable formulations (such as nasal sprays or nasal drops) for application, wherein the carrier is a liquid, include aqueous or oily solutions of active ingredients.

[0301] Compositions suitable for rectal administration are preferably presented in the form of unit dose suppositories. These unit dose suppositories can be prepared by dispersing the active ingredient at least partially in one or more lipophilic bases and then shaping the mixture.

[0302] Pharmaceutical composition can be formulated as sustained release formulation, such as capsules that produce the slow release of active substance after administration. Such formulations can be prepared using well-known technology usually, and can be used by, for example, oral, rectal or subcutaneous implantation or by implantation at the desired target site. The carrier used in such formulations is biocompatible, and can also be biodegradable. Preferably, formulation provides a relatively constant level of active substance release. The amount of the activating agent contained in the sustained release formulation depends on, for example, the nature of the implantation site, release rate and expected duration and the disease to be treated.

[0303] One skilled in the art can readily select the appropriate administration form and route according to the specific characteristics of the compound chosen, the disease or condition to be treated, the stage of the disease or condition, and other relevant circumstances.

[0304] In some embodiments, the pharmaceutical composition comprises a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, an additional therapeutic agent, and a pharmaceutically acceptable excipient.

[0305] The additional agent may be any suitable agent described herein. In some embodiments, the additional agent is a psychoactive drug, including the psychoactive drugs described herein. In some embodiments, the additional agent may be used to treat a disease, disorder, or condition that is improved by activating a serotonin receptor, including a serotonin receptor described herein. In some embodiments, the additional agent is selected from any of the following, including the agents described herein: agents for mental illness and / or neuropsychiatric conditions; agents for psychosis and / or psychotic symptoms; agents for attention deficit hyperactivity disorder and / or attention deficit disorder; agents for dementia and / or Alzheimer's disease; and agents for addiction disorders.

[0306] Methods and uses

[0307] The present disclosure provides methods of using the compounds and compositions of formula (I) described in any of the preceding paragraphs. The present disclosure also provides methods of delivering a compound or composition of formula (I) of the present disclosure (eg, an effective amount of a compound or composition) to a subject in need thereof.

[0308] In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount (eg, a therapeutically effective amount) of a compound or composition (eg, a pharmaceutical composition) of the present disclosure.

[0309] In another aspect, the present disclosure provides a method for preventing a disease in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount (e.g., a therapeutically effective amount) of a compound of formula (I) or a composition (e.g., a pharmaceutical composition) of the present disclosure.

[0310] In another aspect, provided herein is the use of a compound of formula (I) or a composition of the present disclosure for the preparation of a medicament for use in any of the methods of the present disclosure (e.g., a method of delivering an active agent to a subject in need thereof, a method of treating a disease in a subject in need thereof, a method of preventing a disease in a subject in need thereof).

[0311] In another aspect, provided herein is the use of a compound of formula (I) or a composition of the present disclosure for use in any of the methods of the present disclosure (e.g., a method of delivering an active agent to a subject in need thereof, a method of treating a disease in a subject in need thereof, a method of preventing a disease in a subject in need thereof).

[0312] In certain embodiments, an effective amount is effective to treat a disease. In certain embodiments, an effective amount is effective to prevent a disease.

[0313] In another aspect, the present disclosure provides a method of treating a disease, disorder or condition associated with the activity of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.

[0314] In another aspect, the disclosure provides the use of a compound of formula (I) as described herein in the preparation of a medicament for treating a disease, disorder or condition associated with the activity of a serotonin receptor.

[0315] In another aspect, the present disclosure provides the use of a compound of formula (I) or a pharmaceutical composition as described herein for treating a disease, disorder or condition associated with the activity of a serotonin receptor.

[0316] In another aspect, the disclosure provides a compound of formula (I) or a pharmaceutical composition as described herein for use in treating a disease, disorder or condition associated with serotonin receptor activity.

[0317] In another aspect, the present disclosure provides a method of preventing a disease, disorder or condition associated with the activity of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.

[0318] In another aspect, the disclosure provides the use of a compound of formula (I) as described herein in the preparation of a medicament for preventing a disease, disorder or condition associated with the activity of a serotonin receptor.

[0319] In another aspect, the present disclosure provides the use of a compound of formula (I) or a pharmaceutical composition as described herein for preventing a disease, disorder or condition associated with the activity of a serotonin receptor.

[0320] In another aspect, the disclosure provides a compound of formula (I) or a pharmaceutical composition as described herein for use in preventing a disease, disorder or condition associated with serotonin receptor activity.

[0321] In another aspect, the present disclosure provides a method for treating a disease, disorder or condition associated with the activity of a serotonin receptor, the method comprising administering to a subject in need thereof a combination of a compound of formula (I) or a pharmaceutical composition as described herein and another agent useful for treating the disease, disorder or condition. The other agent may be any agent useful for treating and / or preventing the disease, disorder or condition, including agents known in the art and described herein. The other agent may be a serotonin receptor agonist. The other agent may be another compound of formula (I). The other agent may be a compound other than a compound of formula (I), including those known in the art and described herein.

[0322] In another aspect, the disclosure provides the use of a compound of formula (I) as described herein in the preparation of a medicament for treating a disease, disorder or condition associated with the activity of a serotonin receptor, wherein the medicament is formulated for administration with another agent useful for treating the disease, disorder or condition as described herein.

[0323] In another aspect, the present disclosure provides the use of a compound of formula (I) or a pharmaceutical composition as described herein for treating a disease, disorder or condition associated with the activity of a serotonin receptor, wherein the compound of formula (I) or the pharmaceutical composition is formulated for administration with another agent useful for treating the disease, disorder or condition as described herein.

[0324] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutical composition as described herein for use in treating a disease, disorder or condition associated with the activity of a serotonin receptor, wherein the compound of formula (I) or the pharmaceutical composition is formulated for administration with another agent useful for treating the disease, disorder or condition as described herein.

[0325] In another aspect, the present disclosure provides a method for preventing a disease, disorder or condition associated with the activity of a serotonin receptor, the method comprising administering to a subject in need thereof a combination of a compound of formula (I) or a pharmaceutical composition as described herein and another agent that can be used to prevent the disease, disorder or condition. The other agent can be any agent that can be used to treat and / or prevent the disease, disorder or condition, including agents known in the art and described herein. The other agent can be a serotonin receptor agonist. The other agent can be another compound of formula (I). The other agent can be a compound other than a compound of formula (I), including those compounds known in the art and described herein.

[0326] In another aspect, the disclosure provides the use of a compound of formula (I) as described herein in the preparation of a medicament for preventing a disease, disorder or condition associated with the activity of a serotonin receptor, wherein the medicament is formulated for administration with another agent useful for treating the disease, disorder or condition as described herein.

[0327] In another aspect, the present disclosure provides the use of a compound of formula (I) or a pharmaceutical composition as described herein for preventing a disease, disorder or condition associated with the activity of a serotonin receptor, wherein the compound of formula (I) or the pharmaceutical composition is formulated for administration with another agent useful for treating the disease, disorder or condition as described herein.

[0328] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutical composition as described herein for use in preventing a disease, disorder or condition associated with the activity of a serotonin receptor, wherein the compound of formula (I) or the pharmaceutical composition is formulated for administration with another agent useful for treating the disease, disorder or condition as described herein.

[0329] In certain embodiments, the serotonin receptor is 5-HT 2A In certain embodiments, the serotonin receptor is 5-HT 2C .

[0330] In certain embodiments, the serotonin receptor is 5-HT 2A and 5-HT 2C Additionally or alternatively, in some embodiments, the serotonin receptor is not 5-HT 2B .

[0331] In some embodiments, the compounds of formula (I) disclosed herein have an effect on 5-HT 2A The receptor selectivity is better than that of 5-HT 2C Receptors and 5-HT 2B The selectivity for one or both of the receptors is preferably superior to that for 5-HT 2B In some embodiments, the compounds of formula (I) have selectivity for 5-HT 2C The receptor selectivity is better than that of 5-HT 2A Receptors and 5-HT 2B The selectivity of the two receptors is preferably better than that of the 5-HT 2B In some embodiments, the compounds of formula (I) have selectivity for 5-HT 2A Receptors and 5-HT 2C The receptor selectivity is better than that of 5-HT 2B Receptor selectivity.

[0332] In some embodiments, the compounds of formula (I) disclosed herein exhibit an activity against 5-HT as determined by an assay described herein (e.g., a calcium flux activity assay, such as measuring changes in intracellular calcium). 2A EC of receptor 50 The value is less than about 1 mM, less than about 100 μM, less than about 10 μM, less than about 1 μM, or less than about 100 nM or less than about 10 nM. In some embodiments, the compound of formula (I) exhibits an inhibitory effect on 5-HT as determined by a calcium flux activity assay. 2A EC of receptor 50The value is less than about 1 mM, less than about 900 μM, less than about 800 μM, less than about 700 μM, less than about 600 μM, less than about 500 μM, less than about 400 μM, less than about 300 μM, less than about 200 μM, less than about 100 μM, less than about 90 μM, less than about 80 μM, less than about 70 μM, less than about 60 μM, less than about 50 μM, less than about 40 μM, less than about 30 μM, less than about 20 μM, less than about 1 ... About 9 μM, less than about 8 μM, less than about 7 μM, less than about 6 μM, less than about 5 μM, less than about 4 μM, less than about 3 μM, less than about 2 μM, less than about 1 μM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 600 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM or less than about 100 nM, or any equivalent unit of measurement (e.g., mol / L).

[0333] In some embodiments, the compounds of formula (I) disclosed herein exhibit an activity against 5-HT as determined by an assay described herein (e.g., a calcium flux activity assay, such as measuring changes in intracellular calcium). 2C EC of receptor 50 The value is less than about 1 mM, less than about 100 μM, less than about 10 μM, less than about 1 μM, or less than about 100 nM or less than about 10 nM. In some embodiments, the compound of formula (I) exhibits an inhibitory effect on 5-HT as determined by a calcium flux activity assay. 2C EC of receptor 50 The value is less than about 1 mM, less than about 900 μM, less than about 800 μM, less than about 700 μM, less than about 600 μM, less than about 500 μM, less than about 400 μM, less than about 300 μM, less than about 200 μM, less than about 100 μM, less than about 90 μM, less than about 80 μM, less than about 70 μM, less than about 60 μM, less than about 50 μM, less than about 40 μM, less than about 30 μM, less than about 20 μM, less than about 1 ... About 9 μM, less than about 8 μM, less than about 7 μM, less than about 6 μM, less than about 5 μM, less than about 4 μM, less than about 3 μM, less than about 2 μM, less than about 1 μM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 600 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM or less than about 100 nM, or any equivalent unit of measurement (e.g., mol / L).

[0334] In some embodiments, the compounds of formula (I) disclosed herein exhibit an activity against 5-HT as determined by an assay described herein (e.g., a calcium flux activity assay, such as measuring changes in intracellular calcium). 2B EC of receptor50 The value is greater than about 1 μM, greater than about 10 μM, or greater than about 100 μM.

[0335] In some embodiments, the present disclosure also includes a method for treating a mental illness or a neuropsychiatric condition, the method comprising administering a compound of formula (I) or a composition as described herein to a subject in need thereof. The present disclosure also includes a use of a compound of formula (I) of the present disclosure for treating a mental illness or a neuropsychiatric condition and a use of a compound of formula (I) of the present disclosure for preparing a drug for treating a mental illness or a neuropsychiatric condition. The application further includes a compound of formula (I) of the present disclosure for treating a mental illness or a neuropsychiatric condition.

[0336] In some embodiments, the compounds of formula (I) of the present disclosure are administered in combination with one or more additional agents for mental illness or neuropsychiatric conditions. The one or more additional agents for mental illness or neuropsychiatric conditions may be any suitable agent known in the art, including the agents described herein. In some embodiments, the additional agents for mental illness or neuropsychiatric conditions are selected from antipsychotics, including typical antipsychotics and atypical antipsychotics; antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and monoamine oxidase inhibitors (MAOIs) (e.g., bupropion); antianxiety drugs, including benzodiazepines, such as alprazolam; agents for addiction disorders, such as agents for alcohol addiction (e.g., disulfiram); These include anticonvulsants, such as carbamazepine, divalproex, lamotrigine, gabapentin, and topiramate.

[0337] In some embodiments, the present disclosure also includes a method for treating neurodegeneration, the method comprising administering a compound of formula (I) or composition as described herein to a subject in need. Also provided is a use of a compound of formula (I) of the present disclosure for treating neurodegeneration and a compound of formula (I) of the present disclosure for preparing a medicament for treating neurodegeneration. The application further includes a compound of formula (I) of the present disclosure for treating neurodegeneration. In some embodiments, the disease, disorder or condition is a reduction in brain-derived neurotrophic factor (BDNF), activation of mammalian target of rapamycin (mTOR) and / or inflammation.

[0338] In some embodiments, the diseases, disorders, or conditions to be treated by the methods described herein comprise cognitive impairment; ischemia, including stroke; neurodegeneration; refractory substance use disorder; sleep disorders; pain, such as social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, neuralgia, referred pain, phantom limb pain, neuropathic pain, cluster headache, and migraine; obesity and eating disorders; epilepsy and seizure disorders; neuronal cell death; excitotoxic cell death; or a combination thereof.

[0339] In some embodiments, the present disclosure also includes a method for treating psychosis or psychotic symptoms, the method comprising administering a compound of formula (I) or composition as described herein to a subject in need. The present disclosure also includes a use of a compound of formula (I) of the present disclosure for treating psychosis or psychotic symptoms and a use of a compound of formula (I) of the present disclosure for preparing a drug for treating psychosis or psychotic symptoms. The application further includes a compound of formula (I) of the present disclosure for treating psychosis or psychotic symptoms.

[0340] In some embodiments, the disease, disorder or condition to be treated by the methods of the present disclosure is a psychotic disorder or a psychotic symptom, and the compounds of formula (I) of the present disclosure are administered in combination with one or more additional agents for psychotic disorders or psychotic symptoms. The one or more additional agents for psychotic disorders or psychotic symptoms may be any suitable agent known in the art, including agents described herein. In some embodiments, the additional agent for psychotic disorders or psychotic symptoms is a selected typical antipsychotic and atypical antipsychotic.Typical antipsychotics may be selected from the group consisting of promazine, acetophenazine, benperidol, bromperidol, butaperazine, carfenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, dixylazine, xyrazine, droperidol, fluanisone, flupentixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, metitepine, molindone, moperone, one), oxypertine, oxyprotepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, piperacetazine, pipotiazine, prochlorperazine, promazine, prothiopentide, pendyl, spiperone, sulforidazine, thiopropazate, thioproperazine, thioridazine, thiothixene, timiperone, trifluoperazine, trifluperidol, triflupromazine, and zuclopenthixol, and combinations thereof.The atypical antipsychotic may be selected from amoxapine, amisulpride, aripiprazole, asenapine, blondanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, clorotepine, clotiapine, clozapine, iloperidone, levosulpiride, lurasidone, melperone,

[0013] The invention relates to sedapride, melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone and zotepine, and combinations thereof.

[0341] In some embodiments, administering a therapeutically effective amount of a compound of formula (I) of the present disclosure to a subject in need thereof does not worsen 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 formula (I) to a subject in need thereof improves 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 formula (I) to a subject in need thereof improves psychosis or psychotic symptoms.

[0342] In some embodiments, the disease, illness or condition to be treated by the method of the present disclosure is a central nervous system (CNS) disease, illness or condition and / or a nervous system disease, illness or condition. Therefore, the present disclosure also includes a method for treating a CNS disease, illness or condition and / or a nervous system disease, illness or condition, the method comprising administering a therapeutically effective amount of a compound of formula (I) or composition of the present disclosure to a subject in need. The present disclosure also includes a compound of formula (I) of the present disclosure for treating a CNS disease, illness or condition and / or a nervous system disease, illness or condition and a compound of formula (I) of the present disclosure for preparing a drug for treating a CNS disease, illness or condition and / or a nervous system disease, illness or condition. The application further includes a compound of formula (I) of the present disclosure of the present application, which is used to treat a CNS disease, illness or condition and / or a nervous system disease, illness or condition.

[0343] In some embodiments, the disease, disorder or condition to be treated by the methods of the present disclosure is a central nervous system (CNS) disease, disorder or condition and / or a nervous system disease, disorder or condition, and the compounds of formula (I) of the present disclosure are administered in combination with one or more additional agents for central nervous system (CNS) diseases, disorders or conditions and / or nervous system diseases, disorders or conditions. The one or more additional agents for central nervous system (CNS) diseases, disorders or conditions and / or nervous system diseases, disorders or conditions may be any suitable agent known in the art, including agents described herein. In some embodiments, the additional agent for a central nervous system (CNS) disease, disorder or condition and / or a nervous system disease, disorder or condition is selected from lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, The present invention relates to a method for treating depression. The present invention relates to a method for treating depression. The present invention relates to a method for treating depression. The present invention relates to a method for treating depression. The present invention relates to a method for treating depression. The present invention relates to a method for treating depression. The present invention relates to a method for treating depression. The present invention relates to a method for treating depression.

[0344] In some embodiments, the present disclosure also includes a method for treating attention deficit hyperactivity disorder and / or attention deficit disorder, the method comprising administering a compound of formula (I) or a composition as described herein to a subject in need. The present disclosure also includes a use of a compound of formula (I) of the present disclosure for treating attention deficit hyperactivity disorder and / or attention deficit disorder and a use of a compound of formula (I) of the present disclosure for preparing a medicament for treating attention deficit hyperactivity disorder and / or attention deficit disorder. The application further includes a compound of formula (I) of the present disclosure for treating attention deficit hyperactivity disorder and / or attention deficit disorder.

[0345] In some embodiments, the disease, illness or condition to be treated by the method of the present disclosure is attention deficit hyperactivity disorder and / or attention deficit disorder and combinations thereof, and the compound of formula (I) of the present disclosure is administered in combination with one or more other medicaments for attention deficit hyperactivity disorder and / or attention deficit disorder and combinations thereof. The one or more other medicaments for attention deficit hyperactivity disorder and / or attention deficit disorder can be any suitable medicament known in the art, including medicaments described herein. In some embodiments, the other medicaments for attention deficit hyperactivity disorder and / or attention deficit disorder and combinations thereof are selected from methylphenidate (methylphenidate), dexamphetamine (dexamphetamine), lisdexamfetine (lisdexamfetine), atomoxetine (atomoxetine) and amphetamine and combinations thereof.

[0346] In some embodiments, the disease, disorder or condition to be treated by the method of the present disclosure is selected from dementia and Alzheimer's disease and combinations thereof. Therefore, the present disclosure also includes a method for treating dementia and / or Alzheimer's disease, the method comprising administering a compound of formula (I) or composition as described herein to a subject in need thereof. The present disclosure also includes a compound of formula (I) of the present disclosure for use in treating dementia and / or Alzheimer's disease and a compound of formula (I) of the present disclosure for use in preparing a drug for treating dementia and / or Alzheimer's disease. The application further includes a compound of formula (I) of the present disclosure for use in treating dementia and / or Alzheimer's disease.

[0347] In some embodiments, the disease, illness or condition to be treated by the method of the present disclosure is dementia or Alzheimer's disease, and the compound of formula (I) of the present disclosure is administered in combination with one or more other agents for dementia or Alzheimer's disease. The one or more other agents for dementia or Alzheimer's disease can be any suitable agent known in the art, including agents described herein. In some embodiments, the other agents for dementia and Alzheimer's disease are selected from acetylcholinesterase inhibitors, NMDA antagonists and nicotine agonists. The acetylcholinesterase inhibitor can be selected from donepezil, galantamine, rivastigmine and phenserine and combinations thereof. NMDA antagonists can be selected from MK-801, ketamine, phencyclidine and memantine and combinations thereof. The nicotine agonist may be selected from nicotine, nicotinic acid, a nicotine α7 agonist or an α2β4 agonist or a combination thereof.

[0348] In another aspect, the present disclosure provides a method for treating a mental illness, the method comprising administering a compound of formula (I) or a pharmaceutical composition as described herein to a subject in need thereof. In another aspect, the present disclosure provides a method for preventing a mental illness, the method comprising administering a compound of formula (I) or a pharmaceutical composition as described herein to a subject in need thereof. The mental illness may be a neuropsychiatric condition.

[0349] In certain embodiments, the psychiatric disorder is selected from anxiety disorders, such as generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobias; depression, such as feelings of hopelessness, loss of interest, fatigue, and suicidal thoughts; mood disorders, such as major depressive disorder, bipolar disorder, cancer-related depression, anxiety, and cyclothymia; psychotic disorders, such as hallucinations, delusions, mania, schizophrenia, schizoaffective disorder, schizophreniform disorder; impulse control and addiction disorders, such as pyromania (setting fires), kleptomania (stealing), and compulsive gambling; alcohol addiction; drug addiction, such as opioid addiction / dependence, nicotine dependence, Caine dependence, marijuana abuse, etc.; personality disorders, such as antisocial personality disorder, aggression, 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 disorder, previously 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 paraphilia; somatic symptom disorder, previously known as psychosomatic disorder or somatic symptom disorder.

[0350] In certain embodiments, the mental illness is selected from hallucinations and delusions and combinations thereof. In these embodiments, the hallucinations can be selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, balance-feeling hallucinations, nociceptive hallucinations, thermal-feeling hallucinations, and time-feeling hallucinations and combinations thereof.

[0351] In another aspect, the disclosure provides a method for treating a central nervous system (CNS) disease, disorder or condition and / or a nervous system disease, disorder or condition, comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.

[0352] In another aspect, the present disclosure provides a method for preventing a central nervous system (CNS) disease, disorder or condition and / or a nervous system disease, disorder or condition, comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.

[0353] In some embodiments, the CNS disease, disorder or condition and / or the nervous system disease, disorder or condition is selected from a nervous system disease including neurodevelopmental diseases and neurodegenerative diseases, such as Alzheimer's disease; Alzheimer's disease; vascular dementia; Lewy body dementia; 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 disease; fragile X syndrome; Angelman's disease; syndrome; hereditary ataxias; neurological ear and eye movement disorders; neurodegenerative diseases of the retina amyotrophic lateral sclerosis; tardive dyskinesia; ADHD; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis; Rett syndrome; cerebral palsy; reward system disorders, including eating disorders such as anorexia nervosa and bulimia nervosa; binge eating disorder, trichotillomania, scratching disorder, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology; and combinations thereof.

[0354] In another aspect, the present disclosure provides a method for increasing neuronal plasticity, the method comprising contacting a neuronal cell with a compound of formula (I) or a pharmaceutical composition as described herein, which is sufficient to increase the neuronal plasticity of the neuronal cell. "Neuronal plasticity" refers to the ability of the brain to continuously change its structure and / or function throughout the life of a subject. Examples of brain changes include, but are not limited to, the ability to adapt to or respond to internal and / or external stimuli (such as stimuli caused by damage), and the ability to produce new neurites, dendritic spines and synapses. Increasing neuronal plasticity includes, but is not limited to, promoting neuronal growth, promoting neurite generation, promoting synaptogenesis, promoting dendrite generation, increasing dendritic branch complexity, increasing dendritic spine density, and increasing excitatory synapses in the brain. In certain embodiments, increasing neuronal plasticity comprises promoting neuronal growth, promoting neurite generation, promoting synaptogenesis, promoting dendrite generation, increasing dendritic branch complexity, and increasing dendritic spine density.

[0355] In some embodiments, increasing neuronal plasticity can treat a neurodegenerative disease, Alzheimer's disease, Parkinson's disease, a psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or a substance use disorder.

[0356] In another aspect, the present disclosure provides a method for treating weight, the method comprising administering an effective amount of a compound of the present invention to a subject in need thereof. Treating weight can include treating weight gain; weight loss; metabolic disorders; weight gain associated with drug intervention; weight gain associated with psychiatric disorders (including psychiatric disorders described herein); eating disorders such as anorexia, bulimia, cachexia, etc.; eating behavior; obesity; diabetes; insulin resistance; prediabetes; glucose intolerance; hyperlipidemia; and cardiovascular disease.

[0357] In another aspect, the disclosure provides a method for increasing dendritic spine density, the method comprising contacting a neuronal cell with an amount of a compound of formula (I) or a pharmaceutical composition as described herein sufficient to increase the density of dendritic spines of the neuronal cell.

[0358] In certain embodiments, compounds of Formula (I) produce a greater than 1.0-fold increase in the maximum number of dendritic intersections as measured by Sholl analysis.

[0359] In another aspect, the present disclosure provides a method for activating a serotonin receptor in a cell of a biological sample or a patient, the method comprising administering to the cell a compound of formula (I) as defined herein. The serotonin receptor may be a 5-HT receptor subtype, preferably 5-HT 2A and 5-HT 2CIn some embodiments, the compound of formula (I) has an effect on 5-HT 2A and 5-HT 2C One or both of them are optional.

[0360] It should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, weight, health status, sex, diet, time of administration, route of administration, number of doses and rate of excretion, drug combination (i.e., other drugs used to treat the patient) and the severity of the specific condition being treated.

[0361] In some embodiments, the effective amount varies depending on factors such as the disease state, age, sex, and / or weight of the subject or species. In some embodiments, the amount of a given compound or compounds that would correspond to an effective amount would vary depending on factors such as the given drug or compound, the drug formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, but can be routinely determined by one skilled in the art.

[0362] As used herein, the term "effective amount" means the amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human being that is being sought, for example, by a researcher or clinician. In addition, the phrase "therapeutically effective amount" generally refers to an amount of one or more active ingredients of the invention that (i) treats a specific disease, condition or disorder, (ii) alleviates, ameliorates or eliminates one or more signs or symptoms of a specific disease, condition or disorder, or (iii) delays the onset of one or more signs or symptoms of a specific disease, condition or disorder described herein.

[0363] Typically, a therapeutically effective dose is formulated to contain a concentration (by weight) of at least about 0.1% to about 50% or greater and all combinations and subcombinations of ranges therein. The composition can be formulated to contain one or more actives described herein at a concentration of about 0.1% to less than about 50%, for example, about 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41% or 40%, wherein the concentration is greater than about 0.1% (e.g., about 0.2%, 0.3%, 0.4% or 0.5%) to less than about 40% (e.g., about 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31% or 30%). Exemplary compositions can contain about 0.5% to less than about 30%, for example about 29%, 28%, 27%, 26%, 25%, 25%, 24%, 23%, 22%, 21% or 20%, wherein the concentration is greater than about 0.5% (for example about 0.6%, 0.7%, 0.8%, 0.9% or 1%) to less than about 20% (for example about 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11% or 10%). Compositions can contain greater than about 1% (for example, about 2%) to less than about 10% (for example, about 9% or 8%), including greater than about 2% (for example, about 3% or 4%) to less than about 8% (for example, about 7% or 6%) concentration. Active agent can be present, for example, at a concentration of about 5%. In all cases, the amount may be adjusted to compensate for differences in the amount of active ingredient actually delivered to the treated cells or tissues.

[0364] In some embodiments, the compounds of formula (I) of the present disclosure are applied once, twice, three times or four times per year. In some embodiments, the compounds of the present disclosure are applied at least once per week. However, in another embodiment, the compound is applied to the subject every two weeks, every three weeks or about once a month. In another embodiment, the compound is applied about once a week to about once a day. In another embodiment, the compound is applied 1 time, 2 times, 3 times, 4 times, 5 times or 6 times a day. The length of the treatment period depends on various factors, such as the severity of the disease, illness or condition, the age of the subject, the concentration and / or activity of the compound of this application and / or its combination. The treatment period can be the duration of a detectable disease. It should also be understood that the effective dose of the compound for treatment can be increased or decreased within the course of a specific treatment regimen. By standard diagnostic assays known in the art, changes in dosage can be produced and become apparent. In some cases, chronic administration is required. For example, the compound is applied to the subject in an amount and duration sufficient to treat the subject.

[0365] In some embodiments, the compound of the present application is administered at a dose of a hallucinogen or psychotomimetic, and is combined with psychotherapy or therapy, and may occur once, twice, three times, or four times per year. However, in some embodiments, the compound is administered at a dose that is not a hallucinogen or psychotomimetic. In some preferred embodiments, the therapeutically effective amount of the compound of formula (I) described herein is not a hallucinogen or psychotomimetic. Sub-hallucinogen or psychotomimetic doses may be administered to a subject once a day, once every two days, once every 3 days, once a week, once every two weeks, once a month, once every two months, or once every three months.

[0366] The compounds of formula (I) disclosed herein can be used alone or in combination with other agents that can be used to treat diseases, disorders or conditions to be treated by the methods of the present disclosure (including diseases, disorders or conditions improved by activating serotonin receptors (such as compounds of the present disclosure). The other agent can be any agent that can be used to treat the disease, disorder or condition, including agents known in the art and described herein. The other agent can be a serotonin receptor agonist. In some embodiments, the other agent is another compound of formula (I). In some embodiments, the other agent is a compound other than the compound of formula (I), including those compounds known in the art and described herein. When used in combination with other agents, one embodiment is that the compound of formula (I) is administered simultaneously with these agents. As used herein, "simultaneous administration" of two substances to a subject means providing each of the two substances so that they are active in the individual at the same time. The exact details of administration will depend on the pharmacokinetics of the two substances when they are present in each other, and may include administering the two substances within a few hours of each other, or even administering the other substance within 24 hours of administering one substance (if the pharmacokinetics are suitable). The design of a suitable dosage regimen is conventional for those skilled in the art. In a particular embodiment, the two substances will be administered substantially simultaneously, i.e., within a few minutes of each other, or in the form of a single composition containing the two substances. Another embodiment of the present disclosure is that the combination of medicaments is administered to the subject in a non-simultaneous manner. In some embodiments, the compound of formula (I) of the present disclosure is administered simultaneously or sequentially with another therapeutic agent in a single unit dosage form, or is administered together in a single unit dosage form. Therefore, the present disclosure provides a single unit dosage form, which comprises one or more compounds of formula (I) as described herein, another therapeutic agent, and a pharmaceutically acceptable carrier. However, it should be understood that when administered in a separate dosage form, the route of administration may be the same or different.

[0367] In some embodiments, the compounds of formula (I) as described herein are used or administered in an effective amount, which comprises administering a dose or dosage regimen that does not have a clinically significant hallucinogenic / psychotomimetic effect. In some embodiments, the compounds of the present application are used or administered in an effective amount, which comprises administering a dose or dosage regimen that provides a Cmax of 4 ng / mL or less in human plasma dephosphorylated psilocybin and / or human 5-HT 2A A dose or dose regimen that produces 40% or less human CNS receptor occupancy or that demonstrates a human plasma dephosphorylated psilocybin Cmax of 1 ng / mL or less and / or human 5-HT 2A A dose or dosage regimen that provides a clinical effect similar to that of a dose or dosage regimen that provides a human CNS receptor occupancy of 30% or less. In some embodiments, the compounds of the present application are used or administered in an effective amount, which comprises administering a dose or dosage regimen that provides a clinical effect similar to that of a dose or dosage regimen that provides a human plasma dephosphorylated psilocybin Tmax of more than 60 minutes, more than 120 minutes, or more than 180 minutes.

[0368] Reagent test kit

[0369] In another embodiment, a kit or article of manufacture is provided, comprising one or more compounds, pharmaceutically acceptable salts, stereoisomers, solvates, metabolites or polymorphs and / or pharmaceutical compositions as described above.

[0370] In other embodiments, a kit for the above-mentioned therapeutic application is provided, the kit comprising:

[0371] a container holding one or more compounds, pharmaceutically acceptable salts, stereoisomers, solvates, metabolites and / or polymorphs and / or pharmaceutical compositions as described herein;

[0372] A label or package insert having instructions for use. The instructions may be according to any of the methods or uses described herein.

[0373] It should be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the various features mentioned or evident in the text or drawings. All these different combinations constitute various alternative aspects of the invention.

[0374] Examples

[0375] Reference will now be made to specific embodiments of the present invention. Although the synthetic schemes outlined below will describe specific embodiments of the present invention, it should be appreciated that its purpose is not to limit the present invention to these embodiments. On the contrary, the present invention is intended to encompass all alternatives, modifications and equivalents, which may be included within the scope of the present invention and defined by the claims.

[0376] Those skilled in the art will recognize many methods and materials similar or equivalent to the methods and materials described herein. The present invention is by no means limited to the described materials and methods. It should be understood that the selection of the structural features or alternative modes around the core support outlined above will affect the selection of a process rather than another process. Starting material can be obtained from commercial sources, or can be easily prepared by available precursors after direct conversion known to those skilled in the art.

[0377] General

[0378] In the following examples, unless otherwise indicated, temperatures are given in degrees Celsius (°C); operations are carried out at room or ambient temperature, "rt" or "RT" (usually in the range of about 18-25°C); evaporation of solvents is carried out under reduced pressure (usually 4.5-30 mmHg) using a rotary evaporator with a bath temperature of up to 60°C; the progress of the reaction is usually followed by thin layer chromatography (TLC); melting points are uncorrected; the products exhibit satisfactory 1 H NMR and / or microanalytical data; and the following conventional abbreviations are used: L (liter), mL (milliliter), mmol (millimole), g (gram), mg (milligram), min (minute), and h (hour).

[0379] Unless otherwise specified, all solvents and reagents were purchased from suppliers and used without further purification. Unless otherwise stated, reactions were performed under a nitrogen blanket. Compounds were visualized under a UV lamp (254 nm). Recorded on a 300 MHz or 400 MHz NMR instrument as indicated 1 H NMR spectroscopy. Column and flash chromatography were performed using SiO2 as the stationary phase, and "MeOH / NH3" refers to a 9:1 solution of methanol and 15 M aqueous ammonia.

[0380] Synthesis of compounds

[0381] General Procedures

[0382] General Procedure A: Preparation of hydrochloride salts from amines

[0383] The starting free base amine was dissolved in a minimal amount of solvent (MeOH, iPrOH or a mixture thereof) and acidified by the addition of concentrated HCl (32-37%) to pH 1. Precipitation was initiated by the addition of Et2O and the mixture was allowed to stand at 0° C. The product was collected by vacuum filtration and washed with Et2O.

[0384] General Procedure B: Formulation of Fumarates from Amines

[0385] A solution of the free base amine in a minimal amount of solvent (acetone or iPrOH) is added to a hot solution of fumaric acid in acetone or iPrOH (1-3 eq, 0.02-0.2 M), and the mixture is heated to 40-60° C. The mixture is cooled and precipitation is initiated by adding Et2O or hexanes, and then allowed to stand at 0° C. The product is collected by vacuum filtration and washed with Et2O.

[0386] The compound of formula (I) can be synthesized by appropriately substituted 6,6-aromatic systems according to the steps outlined in the following schemes 1-9 or similar steps that may be considered by those skilled in the art. Various substituted 6,6-aromatic systems are commercially available or can be prepared by techniques known in the art, for example, as described in WO2015 / 158313 and Landagaray E et al. (European Journal of Medicinal Chemistry, Vol. 127, February 15, 2017, pp. 621-631).

[0387] Scheme 1: Compounds of general formula (I) can be synthesized from appropriately substituted 6,6-aromatic systems following the sequence of steps outlined in Scheme 1 or similar to the sequence of steps that one skilled in the art may utilize. Appropriately substituted 6,6-aromatic systems can undergo sequential one-pot reductive alkylation to obtain compounds of general formula (I) (illustrated by Examples I-1 and I-18).

[0388]

[0389] Example 1: Synthesis of 2-(7-methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-1)

[0390]

[0391] Step 1: 2-(7-methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-1)

[0392] At 0 ℃, 2-(7-methoxynaphthalene-1-yl) second-1-amine hydrochloride (0.3g, 1.26mmol) is in MeOH (6mL) solution AcOH (303mg, 5.05mmol), NaBHCN (159mg, 2.52mmol) and 37% (w / w) formaldehyde aqueous solution (102mg, 1.26mmol) are processed.Then the reaction solution is stirred at RT for 24 hours.After completion, pH is adjusted to 8 with saturated NaCOaqueous solution, and then extracted with CHCl (8mL×3).The combined organic layer is washed with brine (5mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex C18 80*40mm*3μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 10%-40%, 8 minutes) to give 2-(7-methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-1, 52 mg, 18%) in the form of an off-white solid. HPLC purity: 98.4% (220nm); LCMS (ESI+) m / z 230.1 [M+H] + ; 1 H NMR (400MHz, MeOD-d4) δ7.76 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.32-7.35 (m, 2H), 7.24-7. 26(m,1H),7.14(d,J=2.4Hz,1H),3.95(s,3H),3.21-3.25(m,2H),2.65-2.69(m,2H),2.41(s,6H).

[0393] Scheme 2: Compounds of general formula (I) can be synthesized from appropriately substituted 6,6-aromatic systems following the sequence of steps outlined in Scheme 2 or similar to the sequence of steps that one skilled in the art may utilize. 6,6-aromatic systems with suitable nitrile substituents can be selectively reduced to aldehyde intermediates, which can then undergo reductive alkylation with appropriately substituted amines to produce compounds of general formula (I) (exemplified by Examples I-2, I-3, I-4, I-5, I-6, and I-7).

[0394]

[0395] Example 2: Synthesis of N,N-diethyl-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-2):

[0396]

[0397] Step 1: 2-(7-methoxynaphthalen-1-yl)acetaldehyde (3)

[0398] A solution of 2-(7-methoxynaphthalene-1-yl)acetonitrile (0.3 g, 1.52 mmol) in CH2Cl2 (10 mL) was treated dropwise with 1M DiBAL-H in toluene (2.28 mL, 2.28 mmol) at 0 ° C, and the resulting mixture was stirred at 0 ° C for 3 hours. After completion, the reaction solution was quenched with 3M HCl aqueous solution (30 mL) and extracted with CH2Cl2 (15 mL × 3). The combined organic layer was washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (petroleum ether containing 10% EtOAc) to produce 2-(7-methoxynaphthalene-1-yl)acetaldehyde (164 mg, 54%) in the form of a yellow oil. 1 H NMR (300MHz, CDCl3) δ9.74 (t, J = 2.1Hz, 1H), 7.78 (m, 2H), 7.31-7.42 (m, 2H), 7.18(dd,J=9.0,2.1Hz,1H),7.11(s,1H),4.05(d,J=2.1Hz,2H),3.92(s,3H).

[0399] Step 2: N,N-diethyl-2-(7-methoxynaphthalen-1-yl)ethan-1-amine hydrochloride (I-2·HCl)

[0400] At RT, a solution of 2-(7-methoxynaphthalene-1-yl)acetaldehyde (80 mg, 0.4 mmol), iPr2NEt (78 mg, 0.6 mmol) and N,N-diethylamine (44 mg, 0.6 mmol) in CH2Cl2 (3 mL) was treated with NaBH(OAc)3 (212 mg, 1.0 mmol) in batches, and the resulting mixture was stirred at RT for 16 hours. After completion, the reaction solution was quenched with H2O (20 mL) and extracted with CH2Cl2 (15 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by preparative TLC to produce N,N-diethyl-2-(7-methoxynaphthalene-1-yl)ethyl-1-amine (40 mg) in the form of free base (I-2). The free base was dissolved in MeOH (0.5 mL) and treated with HCl / Et2O at RT and stirred at RT for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was triturated with Et2O. The solid was collected to give the hydrochloride salt (I-2·HCl, 20 mg, 17%). HPLC purity: 98.9% (254 nm); LCMS (ESI+) m / z 258.4 [M+H] + ; 1HNMR(300MHz,CD3OD-d4)δ7.82(d,J=8.1Hz,1H),7.75(d,J=8.1Hz,1H),7.40(d,J=6.9Hz,1H),7 .35-7.25(m,2H),7.19(d,J=9.0Hz,1H),3.98(s,3H),3.56-3.35(m,8H),1.39(t,J=6.6Hz,6H).

[0401] Example 3: Synthesis of N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-propylpropan-1-amine (I-3):

[0402]

[0403] Step 1: N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-propylpropan-1-amine (II-3)

[0404] A solution of 2-(7-methoxynaphthalen-1-yl)acetaldehyde (0.1 g, 0.50 mmol), iPr2NEt (97 mg, 0.75 mmol) and N,N-dipropylamine (76 mg, 0.75 mmol) in CH2Cl2 (5 mL) was treated with NaBH(OAc)3 (265 mg, 1.25 mmol) in batches at RT, and the resulting mixture was stirred at RT for 16 hours. After completion, the reaction solution was quenched with H2O (10 mL) and extracted with CH2Cl2 (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC to yield the title compound (I-3, 20 mg, 14%) as a white solid. HPLC purity: 99.9% (254 nm); LCMS (ESI+) m / z 286.4 [M+H] + ; 1 H NMR (300MHz, CD3OD-d4) δ7.81(d,J=8.1Hz,1H),7.74(d,J=8.1Hz,1H),7.44(d,J=6.9Hz,1H),7.38-7.25(m,2H),7 .19(d,J=6.9Hz,1H),3.98(s,3H),3.58-3.42(m,4H),3.30-3.18(m,4H),1.91-1.73(m,4H),1.04(t,J=7.2Hz,6H).

[0405] Example 4: Synthesis of N-isopropyl-N-(2-(7-methoxynaphthalen-1-yl)ethyl)propan-2-amine (I-4):

[0406]

[0407] Step 1: N-isopropyl-N-(2-(7-methoxynaphthalen-1-yl)ethyl)propan-2-amine (I-4)

[0408] A solution of 2-(7-methoxynaphthalen-1-yl)acetaldehyde (0.1 g, 0.50 mmol), iPr2NEt (97 mg, 0.75 mmol) and N,N-diisopropylamine (76 mg, 0.75 mmol) in CH2Cl2 (5 mL) was treated with NaBH(OAc)3 (265 mg, 1.25 mmol) in batches at RT, and the resulting mixture was stirred at RT for 16 hours. After completion, the reaction solution was quenched with H2O (20 mL) and extracted with CH2Cl2 (15 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC to produce the title compound (I-4, 20 mg, 14%) in the form of a white solid. HPLC purity: 99.8% (254 nm); LCMS (ESI+): m / z 286.3 [M+H] + ; 1 H NMR (300MHz, CD3OD-d4) δ7.82(d,J=8.1Hz,1H),7.75(d,J=8.1Hz,1H),7.45(d,J=6.9Hz,1H),7.38-7.28(m,2H),7.2 0(dd,J=6.9,2.1Hz,1H),3.97(s,3H),3.92-3.82(m,2H),3.60-3.50(m,2H),3.50-3.35(m,2H),1.60-1.40(m,12H).

[0409] Example 5: Synthesis of N-ethyl-2-(7-methoxynaphthalen-1-yl)-N-methylethan-1-amine (I-5):

[0410]

[0411] Step 1: N-ethyl 2-(7-methoxynaphthalen-1-yl)-N-methylethan-1-amine (I-5·HCl)

[0412] A solution of 2-(7-methoxynaphthalene-1-yl)acetaldehyde (0.1 g, 0.5 mmol), iPrNEt (97 mg, 0.75 mmol) and N-ethyl-N-methylamine (44 mg, 0.75 mmol) in CHCl (5 mL) was treated with NaBH (OAc) (265 mg, 1.25 mmol) in batches at RT, and the resulting mixture was stirred at RT for 16 hours. After completion, the reaction solution was quenched with HO (20 mL) and extracted with CHCl (15 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous NaSO, filtered and concentrated in vacuo. The residue was purified by preparative TLC to produce the title compound (I-5, 60 mg) in the form of a free base as a colorless oil. The free base was dissolved in MeOH (0.5 mL) and treated with HCl / EtO at RT, and stirred for 30 minutes at RT. The reaction mixture was concentrated in vacuo and the residue was triturated with Et2O. The solid was collected to yield N-ethyl-2-(7-methoxynaphthalen-1-yl)-N-methylethan-1-amine hydrochloride (I-5·HCl, 20 mg, 14%). HPLC purity: 98.0% (254 nm); LCMS (ESI+): m / z 244.3 [M+H] + ; 1 H NMR (300MHz, CD3OD-d4) δ7.78(d,J=7.5Hz,1H),7.71(d,J=7.2Hz,1H),7.48-7.32(m,2H),7.31-7.2 2(m,1H),7.15(d,J=8.7Hz,1H),3.98(s,3H),3.65-3.32(m,6H),2.98(s,3H),1.38(t,J=6.0Hz,3H).

[0413] Example 6: Synthesis of N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-1-amine (I-6):

[0414]

[0415] Step 1: N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-1-amine (I-6·HCl)

[0416] A solution of 2-(7-methoxynaphthalen-1-yl)acetaldehyde (70 mg, 0.35 mmol), iPrNEt (68 mg, 1.5 eq., 0.52 mmol) and N-methyl-N-propylamine (39 mg, 0.52 mmol) in CHCl (5 mL) was treated with NaBH(OAc) (185 mg, 0.87 mmol) in batches at RT, and the resulting mixture was stirred at RT for 16 hours. After completion, the reaction solution was quenched with HO (30 mL) and extracted with CHCl (10 mL×3). The combined organic layers were washed with brine (15 mL×2), dried over anhydrous NaSO, filtered and concentrated in vacuo. The residue was purified by preparative TLC to produce the title compound (I-6, 85 mg) in free base form as a colorless oil. The free base was dissolved in MeOH (0.5 mL) and treated with HCl / Et2O and stirred at RT for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was triturated with Et2O. The solid was collected to produce N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-1-amine hydrochloride (I-6·HCl, 20 mg, 19%). HPLC purity: 99.6% (254 nm); LCMS (ESI+): m / z 258.4 [M+H] + ; 1 H NMR (300MHz, CD3OD-d4) δ7.81(d,J=8.1Hz,1H),7.75(d,J=8.1Hz,1H),7.43(d,J=6.9Hz,1H),7.38-7.28(m,2H),7.19(d, J=6.6Hz,1H),3.99(s,3H),3.60-3.40(m,4H),3.29-3.11(m,2H),3.02(s,3H),1.95-1.68(m,2H),1.04(t,J=7.2Hz,3H).

[0417] Example 7: Synthesis of N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (I-7):

[0418]

[0419] Step 1: N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (I-7)

[0420] At RT, 2-(7-methoxynaphthalene-1-yl)acetaldehyde (0.1g, 0.5mmol), iPrNEt (97mg, 0.75mmol) and N-isopropyl-N-methylamine (55mg, 0.75mmol) in CHCl (5mL) were treated with NaBH (OAc) (265mg, 1.25mmol) in batches, and the resulting mixture was stirred at RT for 16 hours. After completion, the reaction solution was quenched with HO (10mL) and extracted with CHCl (10mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC to produce the title compound (I-7, 50mg) in the form of free alkali as a colorless oil. The free alkali was dissolved in MeOH (0.5mL) and treated with HCl / EtO, and the resulting suspension was stirred at RT for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was triturated with Et2O. The solid was collected to yield N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-2-amine hydrochloride (I-7·HCl, 20 mg, 16%). HPLC purity: 99.7% (254 nm); LCMS (ESI+): m / z 258.3 [M+H] + ; 1 H NMR (300MHz, CD3OD-d4) δ7.82(d,J=8.1Hz,1H),7.75(d,J=8.1Hz,1H),7.44(d,J=6.3Hz,1H),7.40-7.28(m,2H),7.20(d,J =9.0Hz,1H),3.98(s,3H),3.88-3.72(m,1H),3.60-3.40(m,4H),2.95(s,3H),1.40(d,J=6.6Hz,3H),1.34(d,J=6.3Hz,3H).

[0421] Example 14: Synthesis of 8-(2-(isopropyl(methyl)amino)ethyl)naphthalen-2-ol (I-14):

[0422]

[0423] Step 1: 8-(2-(Isopropyl(methyl)amino)ethyl)naphthalen-2-ol (I-14)

[0424] To an ice-cold solution of N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (620 mg, 2.41 mmol) in anhydrous CH2Cl2 (30 mL) was added BBr3 (0.57 mL, 2.5 eq., 6.02 mmol), and the mixture was stirred at 0°C for 1.5 hours. The reaction was quenched by dropwise addition of 6M HCl aqueous solution until effervescence ceased after the addition. Another 1 mL of 6M HCl aqueous solution was added, followed by 5 mL of MeOH, and the resulting solution was refluxed for 1 hour. The solvent was then removed under a stream of N2, and the aqueous residue was neutralized with saturated Na2CO3 aqueous solution. The suspension was made alkaline with 15% NaOH aqueous solution (1 mL), and then extracted with CH2Cl2 (50 mL×3). The combined organic layers were washed with saturated aqueous NaCO (50 mL x 2), then with brine (50 mL), and then dried over anhydrous NaSO, filtered, and the filtrate was concentrated under a stream of N. The residue was purified by flash chromatography (CHCl containing 0.1% to 5% MeOH / NH) to produce the title compound (480 mg, 82%) in the form of a light brown oil. 1 H NMR (400MHz, CDCl3) δ7.72(d,J=8.8Hz,1H),7.62(d,J=7.9Hz,1H),7.52(d,J=2.1Hz,1H),7.25–7.12(m,3H),6.6 4(br.s,1H),3.38–3.24(m,2H),3.19(sept,J=6.6Hz,1H),3.00–2.85(m,2H),2.50(s,3H),1.15(d,J=6.6Hz,6H). 13 C NMR (101MHz, CDCl3) δ155.77,133.43,133.40,130.71,128.91,127.20,126.99,122.66,118.97,105.97,54.45,54.40,36.15,30.82,17.52.

[0425] Step 2: 8-(2-(Isopropyl(methyl)amino)ethyl)naphthalen-2-ol hydrochloride (I-14·HCl)

[0426] 8-(2-(Isopropyl(methyl)amino)ethyl)naphthalen-2-ol (380 mg, 1.56 mmol) was formulated as the hydrochloride salt according to general procedure A which was isolated as pink crystals (116 mg, 31%). 1H NMR (400MHz, DMSO-d6): δ10.49(br s,1H),9.90(s,1H),7.79(d,J=8.8Hz,1H),7.73–7.68(m,1H),7.40–7.33(m,2H),7.22(dd,J=8.2,7.0Hz,1H),7.14(d d,J=8.8,2.3Hz,1H),3.66(sept,J=6.6Hz,1H),3.46–3.36(m,2H),3.28–3.11(m,2H),2.79(s,3H),1.34–1.20(m,6H); 13 C NMR (101MHz, DMSO-d6): δ155.9,132.9,131.1,130.3,128.0,127.2,126.9,122.2,118.4,105.0,56.1,52.3,34.5,27.2,16.9,15.2.

[0427] Scheme 3: Compounds of formula (I) can be synthesized from appropriately substituted 6,6-aromatic systems following the sequence of steps outlined in Scheme 3 or similar to the sequence of steps that one skilled in the art may utilize. 6,6-aromatic systems with suitable carboxylic acid substituents can be activated in a variety of ways, including but not limited to conversion to acid chlorides, mixed anhydrides, activated esters requiring the use of peptide coupling reagents, activated ureas requiring the use of imide coupling reagents, followed by amidation with appropriately substituted amines. The resulting amides can undergo reduction with a variety of reducing agents, which one skilled in the art may consider to result in the formation of compounds of formula (I) (illustrated by Examples 1-15, 1-17, 1-19, and 1-20).

[0428]

[0429] Example 15: Synthesis of N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylcyclopropylamine (I-15):

[0430]

[0431] Step 1: N-cyclopropyl-2-(7-methoxynaphthalen-1-yl)-N-methylacetamide (71)

[0432] Thionyl chloride (0.34mL, 4.62mmol) is added to an ice-cold solution of (7-methoxy-1-naphthyl)acetic acid (500mg, 2.31mmol) in toluene (10mL), and stirred for 1 hour at 60°C. The reaction mixture is then concentrated overnight under N2 gas flow to produce a solid. The solid is suspended in CH2Cl2 (10mL) and treated with N-methyl (cyclopropyl) amine hydrochloride (373mg, 3.47mmol), and then treated with iPr2NEt (2.0mL, 5 equivalents, 11.6mmol) and stirred at RT for 30 minutes. The reaction solution is then diluted with 20mL of CH2Cl2 and a 0.1M HCl aqueous solution is added until the water layer is acidic. The layers are separated, and the organic layer is washed with saturated NaHCO3 aqueous solution (20mL) and brine (50mL). The organic layer is dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated in a vacuum. The residue was purified by flash chromatography (0.1% to 3% MeOH / NH 3 in CH 2 Cl 2 ) to give the title compound (571 mg, 92%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ7.84(d,J=9.4Hz,1H),7.77–7.68(m,1H),7.34–7.23(m,2H) ,7.22–7.14(m,2H),4.24(s,2H),3.86(s,3H),2.95–2.76(m,4H),0.97–0.79(m,4H). 13 C NMR (101MHz, DMSO-d6) δ172.7,157.2,133.3,131.8,130.0,128.7,128.0,126.7,123.0,117.6,103.2,55.1,38.3,33.6,31.3,8.8.

[0433] Step 2: N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylcyclopropylamine (I-15)

[0434] LiAlH4(590mg, 15.4mmol) was added in batches to ice-cold anhydrous THF (50mL), followed by a solution of N-cyclopropyl-N-methyl (7-methoxy-1-naphthyl) acetamide (520mg, 1.93mmol) in anhydrous THF (5mL). The reaction solution was then stirred for 16 hours under N2 atmosphere at reflux. The reaction solution was then cooled to 0°C, and quenched by sequentially adding H2O(0.6mL), NaOH (0.6mL, 15%, w / v aqueous solution), H2O(1.8mL), then dried (Na2SO4) and filtered through a diatomaceous earth plug. The residue was washed with hot THF (50mL×2). The combined filtrate was concentrated, and the residue was purified by flash chromatography (CH2Cl2 containing 0.1% to 2% MeOH / NH3) to produce the title compound (400mg, 81%) in the form of a clear oil. 1 H NMR(400MHz, CDCl3) δ7.75(d,J=8.9Hz,1H),7.65(d,J=8.0Hz,1H),7.40–7.22(m,3H),7.15(dd,J=8.9,2.5Hz, 1H),3.94(s,3H),3.35–3.20(m,2H),3.01–2.81(m,2H),2.53(s,3H),1.86–1.75(m,1H),0.54(d,J=6.5Hz,4H). 13 C NMR (101MHz, CDCl3) δ157.9,135.3,133.2,130.4,129.4,127.0,126.7,123.4,118.2,102.4,58.9,55.4,42.9,38.6,31.1,6.9.

[0435] Step 3: N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylcyclopropylamine fumarate (I-15·fum)

[0436] A solution of N-cyclopropyl-N-methyl[2-(7-methoxy-1-naphthyl)ethyl]amine (365 mg, 1.43 mmol) dissolved in minimal anhydrous Et2O was added to a solution of fumaric acid (166 mg, 1.43 mmol) dissolved in minimal refluxing acetone. The resulting solution was cooled to 4°C and maintained at this temperature for 72 hours to produce a white crystalline solid identified as the fumarate salt of the title compound. (149 mg, 28%). 1H NMR (400MHz, DMSO-d6) δ7.83(d,J=9.0Hz,1H),7.70(d,J=8.1Hz,1H),7.37–7.30(m,2H),7.26(dd,J=8.0,7.0Hz,1H),7.17(dd,J=8.9,2.5Hz ,1H),6.61(s,2H),3.90(s,3H),3.29–3.11(m,2H),2.93–2.78(m,2H), 2.48(s,3H),1.98–1.85(m,1H),0.56–0.46(m,2H),0.43–0.33(m,2H). 13 C NMR (101MHz, DMSO-d6) δ166.2,157.3,134.9,134.1,132.6,130.2,128.8,126.9,126.3,123.2,117.9,102.2,57.8,55.0,41.9,37.9,29.8,6.3; 1 H qNMR purity: 97.2% (ERETIC); LCMS (ESI+) m / z 256.1 ([M+H] + ).

[0437] Example 16: Synthesis of 8-(2-(cyclopropyl(methyl)amino)ethyl)naphthalen-2-ol (I-16):

[0438]

[0439] Step 1: 8-(2-(Cyclopropyl(methyl)amino)ethyl)naphthalen-2-ol (I-16·fum)

[0440] To an ice-cold solution of N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylcyclopropylamine (250 mg, 0.98 mmol) in anhydrous CH2Cl2 (15 mL) was added BBr3 (0.19 mL, 1.96 mmol), and the mixture was stirred at 0°C for 1.5 hours. The reaction solution was diluted with CH2Cl2 (20 mL) and washed with saturated Na2CO3 aqueous solution (10 mL×2), and then washed with brine (10 mL). The organics were evaporated under a stream of N2 and the residue was purified by column chromatography (CH2Cl2 containing 0.1% to 2% MeOH / NH3) to produce the product in the form of a borane complex. This complex was dissolved in 5 mL of MeOH and 1 mL of 6M HCl aqueous solution and heated to reflux for 1 hour. The solvent was removed under a stream of N2 to give the title compound as a yellow oil, which was used directly for fumarate formation using General Procedure B to give the title compound as an off-white solid in the form of a fumarate salt (90 mg, 26%). HPLC purity: 99.8% (220 nm); 1 H NMR (400MHz, DMSO-d6): δ7.75(d,J=8.8Hz,1H),7.63(d,J=8.0Hz,1H),7.27(dd,J=7.1,1.6Hz,2H),7.17(dd,J=8.1,6.9Hz,1H),7 .07(dd,J=8.8,2.3Hz,1H),6.62(s,4H),3.18–3.07(m,2H),2.90–2.80(m,2H),2.49(s,3H),1.99–1.91(m,1H),0.59–0.39(m,4H). 13 C NMR (101MHz, DMSO-d6): δ166.2,155.5,134.1,133.9,133.0,130.2,128.0,126.6,126.4,122.3,118.1,105.0,57.9,42.1,38.0,29.8,6.2.

[0441] Example 17: Synthesis of N-(3-methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-17):

[0442]

[0443] Step 1: N-(3-methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)acetamide (72)

[0444] To a solution of 2-(7-methoxynaphthalen-1-yl)acetic acid (0.30 g, 1.39 mmol) in DMF (2.0 mL) at 0°C was added a solution of 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea hexafluorophosphate (1.06 g, 2.77 mmol), i Pr2NEt (0.72g, 5.55mmol), and then add (3-methoxyphenyl) methylamine (190mg, 1.39mmol), and then stir the mixture at RT for 3 hours. The reaction solution is diluted with H2O (30mL), and then extracted with EtOAc (3×20mL). The combined organic matter is washed with brine (20mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material is purified by flash chromatography (0-40% EtOAc / hexane) to produce N-(3-methoxybenzyl)-2-(7-methoxynaphthalene-1-yl) acetamide (403mg, 87%) in the form of white crystals. 1 H NMR (400MHz, CDCl3) δ7.77(d,J=8.9Hz,1H),7.75(d,J=7.8Hz,1H),7.38(dd,J=7. 0,1.3Hz,1H),7.30(dd,J=8.2,7.0Hz,1H),7.22–7.16(m,2H),7.10(t,J=7.9Hz,1H ),6.74–6.68(m,1H),6.59(ddd,J=7.6,1.7,0.9Hz,1H),6.51(t,J=2.1Hz,1H),5. 65(t,J=5.9Hz,1H),4.33(d,J=6.0Hz,2H),4.05(s,2H),3.86(s,3H),3.63(s,3H).

[0445] Step 2: N-(3-methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-17)

[0446] To a stirred solution of N-(3-methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)acetamide (379 mg, 1.13 mmol) in anhydrous THF (10 mL) was added dropwise 2M borane-dimethyl sulfide complex in THF (2.3 mL, 4.52 mmol), and the mixture was stirred at 60° C. for 1 hour. After cooling, the mixture was carefully treated with 6M aqueous HCl (2.0 mL), followed by MeOH (4.0 mL), and then stirred at reflux for 1 hour. After cooling, the volatiles were removed under a stream of N2, and the remaining aqueous phase was extracted with Et2O (2×10 mL), which was then discarded. The pH of the aqueous layer was adjusted to 14 with NaOH (1M aqueous solution), and then extracted with Et2O (3×10 mL). The combined organics were washed with brine (15 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude material was purified by flash chromatography (2% to 10% MeOH / NH3 in CH2Cl2) to yield N-(3-methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (274 mg, 74%) as a clear oil. 1 H NMR (400MHz, CDCl3) δ7.75(d,J=8.9Hz,1H),7.66(d,J=8.0Hz,1H),7.36–7.11(m,5H),6.91–6.84(m,2H),6. 82–6.73(m,1H),3.90(s,3H),3.83(s,2H),3.77(s,3H),3.27(t,J=7.3Hz,2H),3.02-3.10(t,J=7.3Hz,2H).

[0447] Step 3: N-(3-methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine fumarate (I-17·Fum)

[0448] N-(3-methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (274 mg, 0.85 mmol) was formulated as a fumarate salt which was isolated as white crystals (296 mg, 79%) according to general procedure B. HPLC purity: 95.4% (254 nm). 1H NMR(400MHz, DMSO-d6)δ7.84(d,J=9.0Hz,1H),7.77–7.69(m,1H),7.36(d,J=2.6Hz, 1H),7.35–7.32(m,1H),7.27(dd,J=8.1,7.2Hz,2H),7.18(dd,J=8.9,2.5Hz,1H),7.0 7(dd,J=2.6,1.5Hz,1H),7.04–6.97(m,1H),6.88(ddd,J=8.3,2.6,1.0Hz,1H),6.55( s,2H),4.01(s,2H),3.88(s,3H),3.74(s,3H),3.36–3.29(m,2H),3.07–2.98(m,2H). 13 C NMR(101MHz,DMSO-d6)δ167.3,159.3,157.6,137.3,134.8,133.4,132.6,130.2,129.5,12 8.8,127.2,126.8,123.2,121.2,117.9,114.4,113.4,102.4,55.3,55.0,50.8,47.6,30.7.

[0449] Example 18: Synthesis of N-(3-fluorobenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-18):

[0450]

[0451] Step 1: 2-(7-methoxynaphthalen-1-yl)ethan-1-amine (1)

[0452] To a solution of 2-(7-methoxynaphthalen-1-yl)acetonitrile (1.09 g, 5.07 mmol) in anhydrous THF (10 mL) was added 2M borane-dimethyl sulfide complex in THF (10.1 mL, 20.3 mmol), and the mixture was stirred at 80° C. for 4 hours. After cooling, the mixture was carefully treated with 6M aqueous HCl (4.0 mL), followed by MeOH (8.0 mL), and then stirred at reflux for 1 hour. After cooling, the volatiles were removed under a stream of nitrogen, and the remaining aqueous phase was extracted with Et2O (2×10 mL), which was then discarded. The pH was adjusted to 14 with 5M aqueous NaOH, and then extracted with Et2O (3×10 mL). The combined organics were washed with brine (15 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 2-10% MeOH / NH3 in CH2Cl2) to yield 2-(7-methoxynaphthalen-1-yl)ethan-1-amine (877 mg, 86%) as a clear oil. 1 H NMR(400MHz, CDCl3)δ7.76(d,J=8.9Hz,1H),7.67(dt,J=8.0,1.1Hz,1H),7.34–7.25(m ,3H),7.16(dd,J=8.9,2.5Hz,1H),3.94(s,3H),3.23–3.17(m,2H),3.16–3.09(m,2H).

[0453] Step 1: N-(3-fluorobenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-18)

[0454] 3-Fluorobenzaldehyde (57 mg, 0.46 mmol) and NaBH(OAc) (116 mg, 0.55 mmol) were added to a stirred solution of 2-(7-methoxynaphthalene-1-yl)ethyl-1-amine (92 mg, 0.46 mmol) in CH2Cl2 (5.0 mL), and the reaction solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under a stream of nitrogen and then treated with 1M NaOH aqueous solution (3.0 mL) and extracted with EtOAc (3 × 5.0 mL). The combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, CH2Cl2 containing 1% MeOH / NH3) to provide N-(3-fluorobenzyl)-2-(7-methoxynaphthalene-1-yl)ethyl-1-amine (86 mg, 61%) in the form of a clear oil. 1H NMR (400MHz, DMSO-d6) δ7.76(d,J=8.9Hz,1H),7.69–7.65(m,1H),7.33(dd,J=7.0,1.4Hz,1H),7.30(d,J=2.5Hz,1H),7.29–7.22(m,2H ),7.16(dd,J=8.9,2.5Hz,1H),7.07–7.01(m,2H),6.96–6.89(m,1H),3.91(s,3H),3.83(s,2H),3.31–3.22(m,2H),3.09–3.01(m,2H).

[0455] Example 19: Synthesis of N-(3-methylbenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-19):

[0456]

[0457] Step 1: N-(3-methylbenzyl)-2-(7-methoxynaphthalen-1-yl)acetamide (74)

[0458] To a solution of 2-(7-methoxynaphthalene-1-yl)acetic acid (0.30 g, 1.39 mmol) in DMF (2.0 mL) at 0 ° C., a solution of 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea hexafluorophosphate (1.06 g, 2.77 mmol), iPr2NEt (0.72 g, 5.55 mmol), and then m-tolylmethylamine (168 mg, 1.39 mmol) was added, and then the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with H2O (30 mL), and then extracted with EtOAc (3×20 mL). The combined organics were washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 0-40% EtOAc / hexanes) to give 2-(7-methoxynaphthalen-1-yl)-N-(3-methylbenzyl)acetamide (348 mg, 79%) as white crystals. 1H NMR (400MHz, CDCl3) δ7.78(d,J=8.7Hz,1H),7.75(d,J=8.3Hz,1H),7.38(dd,J= 7.3,1.1Hz,1H),7.30(dd,J=8.1,7.0Hz,1H),7.22–7.16(m,2H),7.07(t,J=7.5 Hz,1H),6.97(d,J=7.6Hz,1H),6.80(d,J=7.4Hz,1H),6.74–6.71(m,1H),5.62( t,J=6.1Hz,1H),4.32(d,J=6.0Hz,2H),4.05(s,2H),3.85(s,3H),2.18(s,3H).

[0459] Step 2: N-(3-methylbenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-19)

[0460] To a solution of 2-(7-methoxynaphthalen-1-yl)-N-(3-methylbenzyl)acetamide (320 mg, 1.00 mmol) in anhydrous THF (10 mL) was added dropwise 2M borane-dimethyl sulfide complex in THF (2.0 mL, 4.01 mmol), and the mixture was stirred at 60° C. for 1 hour. After cooling, the mixture was carefully treated with 6M aqueous HCl (2.0 mL), followed by MeOH (4.0 mL), and then stirred at reflux for 1 hour. After cooling, the volatiles were removed under a stream of nitrogen, and the remaining aqueous phase was extracted with Et2O (2×10 mL), which was then discarded. The pH was adjusted to 14 with 5M aqueous NaOH, and then extracted with Et2O (3×10 mL). The combined organics were washed with brine (15 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 2-10% MeOH / NH3 in CH2Cl2) to yield 2-(7-methoxynaphthalen-1-yl)-N-(3-methylbenzyl)ethan-1-amine (242 mg, 79%) as a clear oil. 1 H NMR (400MHz, CDCl3) δ7.76(d,J=8.9Hz,1H),7.66(d,J=8.0Hz,1H),7.34–7.31(m,1H),7.31(d,J=2.5Hz ,1H),7.29–7.02(m,6H),3.90(s,3H),3.82(s,2H),3.31–3.23(m,2H),3.09–3.04(m,2H),2.31(s,3H).

[0461] Step 3: N-(3-methylbenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine fumarate (I-19·Fum)

[0462] Following general procedure B, N-(3-methylbenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (237 mg, 0.78 mmol) was formulated as the fumarate salt which afforded white crystals (266 mg, 81%). 1 H NMR (400MHz, DMSO-d6) δ7.84(d,J=9.0Hz,1H),7.76–7.70(m,1H),7.37(d,J=2.5Hz,1H),7.34(dd,J=7.1,1.4Hz,1H),7.30–7.23(m,4H),7 .18(dd,J=8.9,2.4Hz,1H),7.16–7.11(m,1H),6.54(s,2H),4.02(s,2H),3.88(s,3H),3.39–3.31(m,2H),3.09–3.00(m,2H),2.29(s,3H). 13 CNMR(101MHz,DMSO-d6)δ167.7,157.6,137.6,135.0,133.2,132.6,130.3,129.9,128.9 ,128.7,128.4,127.3,126.9,126.3,123.2,118.0,102.4,55.3,50.6,47.4,30.4,20.9.

[0463] Example 20: Synthesis of N-benzyl-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-20):

[0464]

[0465] Step 1: N-Benzyl-2-(7-methoxynaphthalen-1-yl)acetamide (75)

[0466] To a solution of (7-methoxy-1-naphthyl)acetic acid (1.0 g, 4.62 mmol) in DMF (5 mL), 2-(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl)-1,1,3,3-tetramethylisourea hexafluorophosphate (3.5 g, 9.25 mmol) in DMF (10 mL) was added, followed by iPrNEt (3.2 mL, 18.5 mmol), and then benzylamine (0.6 mL, 5.55 mmol) was added. The resulting reaction solution was stirred at room temperature for 1 hour, and then diluted with H2O (100 mL). The precipitate was collected by vacuum filtration and washed with H2O to produce the title compound (1.4 g, quantitative) in the form of an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ8.66(t,J=5.7Hz,1H),7.84(d,J=8.9Hz,1H),7.74(d,J=8.1Hz,1H ),7.45–7.36(m,2H),7.32–7.11(m,7H),4.30(d,J=5.9Hz,2H),3.93(s,2H),3.79(s,3H). 13 CNMR(101MHz,DMSO-d6)δ170.1,157.31,139.5,133.2,131.5,123.0,128.7 ,128.5,128.2,127.3,126.8,126.8,123.1,117.8,103.2,55.1,42.3,40.3.

[0467] Step 2: N-Benzyl-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-20)

[0468] To a solution of N-benzyl(7-methoxy-1-naphthyl)acetamide (1.4 g, 4.58 mmol) in anhydrous THF (30 mL) was added THF (9.0 mL, 18.3 mmol) containing 2 M borane dimethyl sulfide under an inert atmosphere, and the reaction solution was stirred at reflux for 1 hour. After completion, the hot solution was quenched dropwise with a 6 M aqueous HCl solution until effervescence ceased, then MeOH (5 mL) was added, followed by an additional portion of HCl (1 mL, 6 M aqueous solution). The solution was stirred at reflux for 1 hour, and then concentrated under a stream of N2. The aqueous residue was neutralized with a saturated Na2CO3 aqueous solution, and then made alkaline with NaOH (1 mL, 15% aqueous solution). The suspension was extracted with CH2Cl2 (50 mL×3), and the combined organic layers were washed with saturated Na2CO3 aqueous solution (20 mL×3), brine (50 mL), and then dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2 containing 0.1% to 2% MeOH / NH3) to produce the title compound (1.23 g, 92%) in the form of a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.76(d,J=8.9Hz,1H),7.66(d,J=8.0Hz,1H),7.37–7.20(m,8H),7.15(d d,J=8.9,2.5Hz,1H),3.90(s,3H),3.85(s,2H),3.27(t,J=7.3Hz,2H),3.07(t,J=7.3Hz,2H). 13 C NMR (101MHz, CDCl3) δ157.82,140.31,134.78,133.22,130.42,129.47,128.54,128 .21,127.12,127.09,126.82,123.37,118.12,102.60,55.48,54.03,49.51,33.86.

[0469] Step 3: N-Benzyl-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-20·fum)

[0470] N-Benzyl-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (200 mg, 0.69 mmol) was formulated as a fumarate salt which afforded the product as white crystals (215 mg, 82%) according to General Procedure B. HPLC purity: 99.9% (254 nm); 1H NMR (400MHz, DMSO-d6) δ7.83(d,J=9.0Hz,1H),7.72(d,J=7.9Hz,1H),7.45(dd,J=8.1,1.3Hz,2H),7.42–7.23(m, 6H),7.17(dd,J=8.9,2.5Hz,1H),6.53(s,1.6H),4.01(s,2H),3.87(s,3H),3.39–3.26(m,2H),3.09–2.91(m,2H). 13 C NMR(101MHz,DMSO-d6)δ167.9,157.5,136.2,135.1,133.6,132.6,130.2,129.0, 128.8,128.4,127.7,127.1,126.7,123.2,118.0,102.4,55.3,51.0,47.7,30.9.

[0471] Scheme 4: Compounds of general formula (I) can be synthesized from appropriately substituted acenaphthene-1-ones following the sequence of steps outlined in Scheme 4 or similar to the sequence of steps that one skilled in the art may utilize. Baeyer-Villiger oxidation forms a chromanone intermediate which, upon reduction, provides the appropriately substituted naphthalene. Chemoselective phenol methylation with methyl iodide followed by partial oxidation of the terminal alcohol with Dess-Martin periodinane produces the desired aldehyde intermediate which can then undergo reductive amination to produce compounds of general formula (I) (exemplified by Examples 1-13, 1-22, 1-23, 1-24, 1-25, 1-27, 1-28, and 1-30). Subsequent demethylation of the methyl ether allows access to phenols of general formula (I) (exemplified by Examples 1-21, 1-26, 1-29, and 1-31).

[0472]

[0473] Example 13: Synthesis of 2-(8-methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-13)

[0474]

[0475] Step 1: Benzo[de]chromen-2(3H)-one (15)

[0476] Acenaphthylene-1 (2H) -one (3.5g, 20.8mmol) in CHCl (105mL) solution NaHCO (8.74g, 104mmol) and 3-chloroperbenzoic acid (80% purity) (8.98g, 41.6mmol) are treated, and the mixture is refluxed for 18 hours. The reaction mixture is diluted with CHCl (50mL), and washed with HO (150mL), saturated NaSO aqueous solution (130mL), NaHCO aqueous solution (130mL) and brine (100mL) successively. The organic layer is then dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO, petroleum ether containing 1% to 2% EtOAc) to produce the title compound (2.0g, 52%) in the form of off-white solid. 1 H NMR (400MHz, CDCl3): δ7.78 (d, J = 8.4Hz, 1H), 7.62 (d, J = 8.0Hz, 1H), 7.45-7.53 (m, 2H), 7.27 (m, 1H), 7.14 (d, J = 7.6Hz, 1H), 4.31 (s, 2H).

[0477] Step 2: 8-(2-Hydroxyethyl)naphthalen-1-ol (16)

[0478] Solution of benzo [de] chromene -2 (3H) -one (1.4g, 7.6mmol) in THF (28mL) is cooled to 0 ℃, and treated with LiAlH (288mg, 7.6mmol) under N. The reaction mixture is stirred at RT for 15 minutes. After completion, Na is added by 10H2O (1.40g) and the reaction solution is quenched, and the precipitate is removed by filtration and the filter cake is washed with THF (50mL). The filtrate combined is concentrated to produce the crude title compound (1.4g) in the form of brown solid, which is used for the next step without further purification.

[0479] Step 3: 2-(8-Methoxynaphthalen-1-yl)ethan-1-ol (17)

[0480] At RT, a solution of crude 8-(2-hydroxyethyl)naphthalene-1-ol (1.4 g, 7.44 mmol) in DMF (14 mL) was treated with KCO (3.08 g, 22.3 mmol) and MeI (2.11 g, 14.9 mmol) and stirred for 12 hours. After completion, the reaction solution was quenched by adding HO (50 mL) and extracted with EtOAc (20 mL × 2). The combined organic layer was washed with brine (15 mL), dried over anhydrous NaSO, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether containing 3% to 8% EtOAc) to produce the title compound (0.7 g, 46% over 2 steps) in the form of an off-white solid. 1 H NMR (400MHz, CDCl3): δ7.70(d,J=8.4Hz,1H),7.45(d,J=8.0Hz,1H),7.36-7.40(m, 2H), 7.27 (m, 1H), 6.87 (d, J = 7.2Hz, 1H), 3.95-3.99 (m, 5H), 3.59 (t, J = 6.4Hz, 2H).

[0481] Step 4: 2-(8-Methoxynaphthalen-1-yl)acetaldehyde (18)

[0482] A solution of 2-(8-methoxynaphthalene-1-yl)ethan-1-ol (250 mg, 1.24 mmol) in DMF (5 mL) was cooled to 0 ° C, treated with Dess-Martin periodinane (629 mg, 1.48 mmol) under N2, and then stirred at RT for 1 hour. After completion, the reaction solution was quenched with saturated NaHCO3 aqueous solution (10 mL) and extracted with CH2Cl2 (5 mL×3). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (1: 1, petroleum ether: EtOAc) to produce the title compound (240 mg, 97%) in the form of a colorless oil. 1 H NMR (400MHz, CDCl3): δ9.82 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.40-7.47 (m, 3H), 7.24 (d, J = 6.8 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 4.20 (s, 2H), 3.88 (s, 3H).

[0483] Step 5: 2-(8-methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-13)

[0484] 2-(8-methoxynaphthalene-1-yl)acetaldehyde (240mg, 1.2mmol) is cooled to 0 ℃ in CH2Cl2 (7mL) solution, and is treated and stirred for 15 minutes with THF (0.90mL, 1.8mmol) containing 2M Me2NH under N2.Then at 0 ℃ under N2, NaBH (OAc) 3 (508mg, 2.4mmol) is added to the reaction mixture, and the reaction solution is stirred for another 12 hours at RT.After completion, the reaction solution is quenched with MeOH (10mL) and concentrated in vacuo.The residue is diluted with CH2Cl2 (10mL) and washed with H2O (4mL).The organic layer is dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex C18, 80*40mm*3μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 10%-40%, 8 minutes) to give the title compound (I-13, 59 mg, 21%) as a colorless oil. HPLC purity: 96.6% (220nm); 1 H NMR(400MHz,MeOD-d4)δ7.66(d,J=8.0Hz,1H),7.41(d,J=8.0Hz,1H),7.32-7.37(m,2H),7.25(d,J=7.2Hz,1 H), 6.94 (d, J = 7.6Hz, 1H), 3.99 (s, 3H), 3.44-3.49 (m, 2H), 2.59-2.63 (m, 2H), 2.38 (s, 6H); LCMS (ESI+): m / z 230.1[M+H] + .

[0485] Example 21: Synthesis of 8-(2-(dimethylamino)ethyl)naphthalen-1-ol (I-21)

[0486]

[0487] Step 1: 8-(2-(Dimethylamino)ethyl)naphthalen-1-ol (I-21)

[0488] A suspension of 2-(8-methoxynaphthalen-1-yl)-N,N-dimethylethane-1-amine (0.4 g, 1.74 mmol) and TBAB (56 mg, 0.17 mmol) in HBr (4 mL) was degassed and purged with N2 gas, then heated at 100°C for 2 hours. The reaction solution was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18, 100*30mm*10μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 10–50%, over 8 minutes) to give the title compound (I-21, 20 mg, 7%) in the form of a brown solid. HPLC purity: 98.0% (220nm); 1 H NMRδ (400MHz, MeOD-d4) 7.61 (d, J = 8.2 Hz, 1H), 7.17-7.32 (m, 4H), 6.78-6.84 (m, 1H), 3.50-3.56 (m, 2H), 2.71-2.79 (m, 2H), 2.38 (s, 6H). LCMS(ESI+):m / z 216.1[M+H] + (1.83 minutes).

[0489] Example 22: Synthesis of N,N-diethyl-2-(8-methoxynaphthalen-1-yl)ethan-1-amine (I-22)

[0490]

[0491] Step 1: N,N-diethyl-2-(8-methoxynaphthalen-1-yl)ethan-1-amine (I-22)

[0492] At 0 ° C under N2, 2- (8- methoxynaphthalene -1- bases) acetaldehyde (0.30g, 1.50mmol) in CH2Cl2 (9.0mL) solution was added Et2NH (165mg, 2.26mmol). The reaction mixture was stirred at RT for 15 minutes. Then, at 0 ° C under N2, NaBH (OAc) 3 (636mg, 3.0mmol) was added, and the reaction mixture was stirred at RT for 12 hours. The reaction mixture was quenched with MeOH (20mL) and volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (30mL), washed with H2O (10mL), then dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge OBD C18, 150*40mm*10μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 25-55%, 8 minutes) to obtain the title compound (I-22, 222 mg, 58%) in the form of a brown oil. HPLC purity: 98.6% (220nm); 1 H NMR (400MHz, MeOD-d4) δ7.66(d,J=8.0Hz,1H),7.41(d,J=8.0Hz,1H),7.37–7.32(m,2H),7.25(d,J=7.2H z,1H),6.94(d,J=7.6Hz,1H),3.98(s,3H),3.47–3.43(m,2H),2.77–2.68(m,6H),1.14(t,J=7.2Hz,6H). LCMS(ESI+):m / z 258.0[M+H] + .

[0493] Example 23: Synthesis of N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-propylpropan-1-amine (I-23)

[0494]

[0495] Step 1: N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-propylpropan-1-amine (I-23)

[0496] At 0 ° C under N2, to a solution of 2- (8- methoxynaphthalene -1- bases) acetaldehyde (0.30g, 1.50mmol) in CH2Cl2 (9.0mL) was added Pr2NH (228mg, 2.25mmol). The reaction mixture was stirred at RT for 15 minutes, and then cooled to 0 ° C. Then NaBH (OAc) 3 (636mg, 3.0mmol) was added, and the resulting suspension was stirred at RT for 12 hours. The reaction mixture was then quenched with MeOH (20mL) and volatiles were removed in vacuo. The residue was dissolved in CH2Cl2 (20mL), washed with H2O (5mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge OBD C18, 150 mm*40 mm*10 μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 40-70%, over 8 minutes) to obtain the title compound (I-23, 190 mg, 44%) as a brown oil. HPLC purity: 98.5% (220 nm); 1 H NMR (400MHz, MeOD-d4) δ7.65(d,J=8.4Hz,1H),7.41(d,J=8.0Hz,1H),7.37–7.32(m,2H),7.24(d,J=7.2Hz,1H),6.94(d,J=7 .6Hz,1H),3.98(s,3H),3.47–3.43(m,2H),2.78–2.74(m,2H),2.59–2.55(m,4H),1.60–1.54(m,4H),0.95(t,J=7.4Hz,6H). LCMS(ESI+):m / z 286.1[M+H] + .

[0497] Example 24: Synthesis of N-isopropyl-N-(2-(8-methoxynaphthalen-1-yl)ethyl)propan-2-amine (I-24)

[0498]

[0499] Step 1: N-isopropyl-N-(2-(8-methoxynaphthalen-1-yl)ethyl)propan-2-amine (I-24)

[0500] At 0 ° C under N2, 2- (8- methoxynaphthalene -1- bases) acetaldehyde (0.30g, 1.50mmol) in CH2Cl2 (9.0mL) solution was added iPr2NH (228mg, 2.25mmol). The reaction mixture was stirred at RT for 15 minutes, and then cooled to 0 ° C. Then NaBH (OAc) 3 (636mg, 3.0mmol) was added, and the resulting suspension was stirred at RT for 12 hours. Then the reaction mixture was quenched with MeOH (20mL) and volatiles were removed in vacuo. The residue was dissolved in CH2Cl2 (30mL), washed with H2O (10mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge OBD C18, 150 mm*40 mm*10 μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 30-60%, over 8 minutes) to obtain the title compound (I-24, 182 mg, 42%) as a brown oil. HPLC purity: 97.8% (220 nm); 1 H NMR(400MHz,MeOD-d4)δ7.66(d,J=8.4Hz,1H),7.41(d,J=8.0Hz,1H),7.37–7.32(m,2H),7.24(d,J=7.2Hz,1H),6. 94(d,J=7.6Hz,1H),3.98(s,3H),3.45–3.41(m,2H),3.21–3.15(m,2H),2.75–2.71(m,2H),1.11(d,J=6.8Hz,12H). LCMS(ESI+):m / z 286.1[M+H] + ,2.18 minutes.

[0501] Example 25: Synthesis of N-ethyl-2-(8-methoxynaphthalen-1-yl)-N-methylethan-1-amine (I-25)

[0502]

[0503] Step 1: N-ethyl-2-(8-methoxynaphthalen-1-yl)-N-methylethan-1-amine (I-25)

[0504] At 0 ° C under N2, 2- (8- methoxynaphthalene -1- bases) acetaldehyde (0.30g, 1.50mmol) in CH2Cl2 (9mL) solution was added EtNHMe (133mg, 2.25mmol). The reaction mixture was stirred at RT for 15 minutes, and then cooled to 0 ° C. Then NaBH (OAc) 3 (636mg, 3mmol) was added, and the resulting suspension was allowed to stir at RT for 12 hours. The reaction mixture was then quenched with MeOH (20mL) and volatiles were removed in vacuo. The residue was dissolved in CH2Cl2 (30 mL), washed with H2O (10 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product, which was purified by preparative HPLC (column: Waters Xbridge OBD C18, 150 mm*40 mm*10 μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 25-55%, over 8 minutes) to obtain the title compound (I-25, 124 mg, 33%) in the form of a brown oil. HPLC purity: 96.7% (220 nm); 1 H NMR(400MHz,MeOD-d4)δ7.66(d,J=8.4Hz,1H),7.41(d,J=8.0Hz,1H),7.37–7.32(m,2H),7.24(d,J=7.2Hz,1H),6.94(d, J=7.6Hz,1H),3.99(s,3H),3.49–3.45(m,2H),2.70–2.65(m,2H),2.60–2.56(m,2H),2.41(s,3H),1.14(t,J=7.2Hz,3H). LCMS(ESI+):m / z 244.2[M+H] + ,1.42 minutes.

[0505] Example 26: Synthesis of 8-(2-(methyl(ethyl)amino)ethyl)naphthalen-1-ol (I-26)

[0506]

[0507] Step 1: 8-(2-(Methyl(ethyl)amino)ethyl)naphthalen-1-ol (I-26)

[0508] A suspension of N-ethyl-2-(8-methoxynaphthalen-1-yl)-N-methylethyl-1-amine (0.4 g, 1.64 mmol) and TBAB (52 mg, 0.16 mmol) in HBr (4 mL) was degassed and purged with N2 gas, then heated at 100 ° C for 2 hours. The reaction solution was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18, 250*50mm*10 μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 25–55%, over 10 minutes) to produce the title compound (I-26, 20 mg, 5%) in the form of a brown solid. HPLC purity: 98.0% (220 nm); 1 H NMR (400MHz, MeOD-d4) δ7.62 (d, J = 8.2Hz, 1H), 7.27-7.32 (m, 2H), 7.17-7.25 (m, 2H), 6.79-6.83 (m, 1H), 3. 49-3.56(m,2H),2.80-2.87(m,2H),2.57-2.63(m,2H),2.39(s,3H),1.11(t,J=7.2Hz,3H); LCMS(ESI+):m / z 230.1[M+H] + ,1.87 minutes.

[0509] Example 27: Synthesis of N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-1-amine (I-27)

[0510]

[0511] Step 1: N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-1-amine (I-27)

[0512] At 0 ° C under N2, to a solution of 2- (8- methoxynaphthalene -1- bases) acetaldehyde (0.30 g, 1.50 mmol) in CH2Cl2 (9.0 mL) was added N- methylpropan-1-amine (165 mg, 2.26 mmol). The reaction mixture was then stirred at RT for 15 minutes and then cooled to 0 ° C. NaBH (OAc) 3 (636 mg, 3.0 mmol) was then added, and the resulting suspension was stirred at RT for 12 hours. The reaction mixture was then quenched with MeOH (20 mL) and volatiles were removed in vacuo. The residue was dissolved in CH2Cl2 (20 mL), washed with H2O (5 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product, which was purified by preparative HPLC (column: Waters Xbridge OBD C18, 100 mm*30 mm*10 μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 30-70%, over 8 minutes) to obtain the title compound (I-27, 149 mg, 37%) in the form of a brown oil. HPLC purity: 96.6% (220 nm); 1 H NMR (400MHz, MeOD-d4) δ7.68(d,J=8.4Hz,1H),7.42(d,J=8.0Hz,1H),7.39–7.34(m,2H),7.28(d,J=7.2Hz,1H),6.97(d,J=7.6Hz, 1H),4.01(s,3H),3.51–3.47(m,2H),2.73–2.68(m,2H),2.52–2.48(m,2H),2.44(s,3H),1.65–1.58(m,2H),0.97(t,J=7.4Hz,3H). LCMS(ESI+):m / z 258.0[M+H] + ,1.6 minutes.

[0513] Example 28: Synthesis of N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (I-28)

[0514]

[0515] Step 1: N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (I-28)

[0516] To a solution of 2-(8-methoxynaphthalen-1-yl)acetaldehyde (0.30 g, 1.50 mmol) in CH2Cl2 (9.0 mL) was added iPrNHMe (165 mg, 2.26 mmol) and the reaction mixture was stirred at RT for 15 minutes before being cooled to 0 ° C. NaBH(OAc)3 (636 mg, 3.0 mmol) was then added and the resulting suspension was stirred at RT for 12 hours. The reaction mixture was then quenched with MeOH (20 mL) and volatiles were removed in vacuo. The residue was dissolved in CH2Cl2 (30 mL), washed with H2O (10 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product, which was purified by preparative HPLC (column: Waters Xbridge OBD C18, 150 mm*40 mm*10 μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 25-55%, over 8 minutes) to obtain the title compound (I-28, 216 mg, 56%) in the form of a brown oil. HPLC purity: 100% (220 nm); 1 H NMR(400MHz,MeOD-d4)δ7.66(d,J=8.4Hz,1H),7.38(d,J=8.0Hz,1H),7.35–7.32(m,2H),7.24(d,J=7.2Hz,1H),6.94(d, J=7.6Hz,1H),3.98(s,3H),3.47–3.43(m,2H),2.95–2.92(m,1H),2.69–2.65(m,2H),2.40(s,3H),1.08(t,J=6.4Hz,6H). LCMS(ESI+):m / z:258.1[M+H] + ,1.4 minutes.

[0517] Example 29: Synthesis of 8-(2-(methyl(isopropyl)amino)ethyl)naphthalen-1-ol (I-29)

[0518]

[0519] Step 1: 8-(2-(Methyl(isopropyl)amino)ethyl)naphthalen-1-ol (I-29·HCl)

[0520] A suspension of N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (0.4 g, 1.55 mmol) and TBAB (50 mg, 0.16 mmol) in HBr (4 mL) was degassed and purged with N gas, then heated at 100 ° C for 2 hours. The reaction solution was then concentrated under reduced pressure, and the main impurities were first removed from the obtained residue by preparative HPLC (column: Waters Xbridge BEH C18, 100*30mm*10μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 10–40%, over 8 minutes). The obtained crude product was further purified by preparative HPLC (column: Waters Xbridge BEH C18, 100*30mm*10μm; mobile phase: [H2O(HCl)-ACN]; B%: 10-40%, over 8 minutes) to give the title compound (I-29, 20 mg, 5%) as an off-white solid in the form of a hydrochloride salt. HPLC purity: 100% (220nm); 1 H NMR(400MHz,MeOD-d4)δ7.72(d,J=8.2Hz,1H),7.26-7.38(m,4H),6.90(d,J=7.4Hz,1H),3.65-3.80 (m,3H),3.52-3.60(m,1H),3.23-3.29(m,1H),2.91(s,3H),1.37(t,J=6.4Hz,6H); LCMS(ESI+):m / z 244.2[M+H] + ,1.94 minutes.

[0521] Example 30: Synthesis of N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylcyclopropylamine (I-30)

[0522]

[0523] Step 1: N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylcyclopropylamine (I-30)

[0524] A mixture of 2-(8-methoxynaphthalen-1-yl)acetaldehyde (0.30 g, 1.50 mmol), NaBH(OAc) (0.63 g, 3.00 mmol) and N-methylcyclopropylamine (159 mg, 2.25 mmol) in CHCl (9 mL) was degassed and stirred at 25° C. under N atmosphere for 12 hours. The mixture was diluted with HO (50 mL) and extracted with petroleum ether (30 mL×3). The combined organic extracts were washed with H2O (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18, 150*40 mm*10 μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 40–70%, over 8.0 min) to provide N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylcyclopropylamine (0.30 g, 80% yield) in the form of a brown oil. HPLC purity: 97.8% (220 nm); 1 H NMR(400MHz,MeOD-d4)δ7.66(d,J=8.2Hz,1H),7.40-7.44(m,1H),7.31-7.38(m,2H),7.24(d,J=7.0Hz,1H),6.95(d, J=7.4Hz,1H),3.99(s,3H),3.49-3.54(m,2H),2.79-2.85(m,2H),2.51(s,3H),1.81-1.88(m,1H),0.49-0.60(m,4H). LCMS(ESI+):m / z 256.2[M+H] + .

[0525] Example 31: Synthesis of 8-(2-(cyclopropyl(methyl)amino)ethyl)naphthalen-1-ol (I-31)

[0526]

[0527] Step 1: 8-(2-(Cyclopropyl(methyl)amino)ethyl)naphthalen-1-ol (I-31)

[0528] A mixture of N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylcyclopropylamine (0.30 g, 1.17 mmol) and TBAB (0.04 mg, 0.12 μmol) in HBr (3.0 mL) was degassed and purged with N2, followed by stirring at 100 ° C. under a N2 atmosphere for 2 hours. The reaction solution was then concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18, 100*30mm*10 μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 25–55%, over 8.0 minutes) to provide 8-(2-(cyclopropyl(methyl)amino)ethyl)naphthalen-1-ol (0.02 g, 7%) in the form of a brown solid. HPLC purity: 95.8% (220 nm); 1 H NMR (400MHz, MeOD-d4) δ7.61 (d, J = 8.2 Hz, 1H), 7.27-7.32 (m, 2H), 7.16-7.24 (m, 2H), 6.81 (d, J = 7. 4Hz,1H),3.52-3.57(m,2H),2.90-2.96(m,2H),2.48(s,3H),1.83-1.91(m,1H),0.46-0.56(m,4H). LCMS(ESI+):m / z 242.1[M+H] + .

[0529] Option 5: Where Z 1 or Z 4 Compounds of general formula (I) where R is N can be synthesized from appropriately substituted quinolines following the general sequence of steps shown in Scheme 5 or similar to those available to one skilled in the art. 9 Variability in position can be achieved by commercially available raw materials or by nucleophilic aromatic substitution conditions, as described in the specific examples summarized below. Similarly, obtaining aryl bromide can be achieved in various ways known to those skilled in the art, and specific examples are summarized below. Alternatively, aryl bromide can be commercially available. The aryl bromide intermediate is subjected to Heck coupling conditions, followed by olefin reduction to provide a phthalimide protected intermediate, which can obtain an amine analog that can be alkylated in several ways after removal. One such example includes a reductive alkylation reaction with formaldehyde to produce a compound of formula (I) (illustrated by Example 1-8). These steps can also be applied to other appropriately substituted 6,6-aromatic systems.

[0530]

[0531] Example 8: Synthesis of 2-(2-methoxyquinolin-8-yl)-N,N-dimethylethan-1-amine (I-8)

[0532]

[0533] Step 1: 8-Bromo-2-methoxyquinoline (5)

[0534] A solution of 8-bromo-2-chloroquinoline (5.0 g, 20.6 mmol) in methanol (40 mL) was treated with NaOMe (6.68 g, 124 mmol) and stirred at 65 ° C for 12 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc (50 mL) and H2O (50 mL). The layers were separated and the organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to produce 8-bromo-2-methoxyquinoline (4.6 g, 94%) in the form of a white solid. 1 HNMR (400MHz, CDCl3) δ7.93-8.00(m,2H),7.66-7.72(m,1H),7.24(t,J=8.0Hz,1H),6.96(d,J=8.8Hz,1H),4.16(s,3H).

[0535] Step 2: (E)-2-(2-(2-methoxyquinolin-8-yl)vinyl)isoindoline-1,3-dione (6)

[0536] By 8-bromo-2-methoxyquinoline (2.0g, 8.4mmol), N-vinylphthalimide (2.18g, 12.6mmol), Et3N (3.4g, 33.6mmol), tri-o-tolylphosphine (256mg, 0.84mmol) and Pd (OAc)2 (189mg, 0.84mmol) in DMF (15mL) mixture degassed and purged with N2, then stirred at 110 ℃ for 14 hours.After completion, the reaction mixture was diluted with ACN (50mL), and insoluble materials were collected by filtration and the filtrate was discarded. The collected solid was wet-ground with THF (20mL), and the remaining insoluble materials were removed by filtration. The filtrate was concentrated in vacuo and the residue was triturated with CH 2 Cl 2 (5 mL) to give (E)-2-(2-(2-methoxyquinolin-8-yl)vinyl)isoindoline-1,3-dione (960 mg, 35%) as a yellow solid. 1H NMR (400MHz, CDCl3) δ8.50(d,J=15.2Hz,1H),8.27(d,J=15.2Hz,1H),8.01(d,J=8.8Hz,1H),7.93(dd,J=5.6,3.2Hz,2H),7.8 2(d,J=7.2Hz,1H),7.78(dd,J=5.6,3.2Hz,2H),7.65(d,J=7.6Hz,1H),7.36-7.42(m,1H),6.97(d,J=8.8Hz,1H),4.23(s,3H).

[0537] Step 3: 2-(2-(2-methoxyquinolin-8-yl)ethyl)isoindoline-1,3-dione (7)

[0538] 10% Pd / C (0.2 g, 0.18 mmol) was added to a solution of (E)-2-(2-(2-methoxyquinolin-8-yl)vinyl)isoindoline-1,3-dione (960 mg, 2.91 mmol) in THF (20 mL) under an Ar atmosphere. The suspension was degassed and purged with H2 three times, and then stirred under H2 (25 psi) at RT for 12 hours. Upon completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to yield 2-(2-(2-methoxyquinolin-8-yl)ethyl)isoindoline-1,3-dione (0.9 g) as a pale yellow solid and used in the next step without further purification.

[0539] Step 4: 2-(2-Methoxyquinolin-8-yl)ethan-1-amine (8)

[0540] A solution of 2-(2-(2-methoxyquinoline-8-yl)ethyl)isoindoline-1,3-dione (0.8 g) in EtOH (8.0 mL) was treated with hydrazine hydrate (1.51 g, 80% purity, 24.1 mmol) at RT. The reaction mixture was then stirred at 80 ° C for 12 hours. After completion, the reaction solution was filtered and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc (5 mL) and washed with H2O (5 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to produce 2-(2-methoxyquinoline-8-yl)ethyl-1-amine (0.4 g, 68% over 2 steps) in the form of a light yellow oil. 1H NMR(400MHz, CDCl3) δ7.98(d,J=8.8Hz,1H),7.61(dd,J=8.0,1.2Hz,1H),7.50(d,J=7.2Hz,1H) ,7.29-7.35(m,1H),6.91(d,J=8.8Hz,1H),4.07(s,3H),3.30-3.35(m,2H),3.25–3.20(m,2H).

[0541] Step 5: 2-(2-Methoxyquinolin-8-yl)-N,N-dimethylethan-1-amine (I-8)

[0542] A solution of 2-(2-methoxyquinolin-8-yl)ethan-1-amine (0.3 g, 1.48 mmol) in CH2Cl2 (5 mL) was treated with AcOH (178 mg, 2.97 mmol), NaBH(OAc)3 (629 mg, 2.97 mmol) and aqueous formaldehyde (37% w / w, 301 mg, 3.71 mmol) at 0°C and then stirred at RT for 2 hours, at which time the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (column: Phenomenex Luna C18, 75*30 mm*3 μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 10%-45%, 8 minutes) to give 2-(2-methoxyquinolin-8-yl)-N,N-dimethylethan-1-amine (I-8, 52 mg, 15%) as a yellow oil. HPLC purity: 99.5% (220nm); LCMS (ESI+): m / z 231.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.97 (d, J = 8.8 Hz, 1H), 7.59 (dd, J = 8.0, 1.2 Hz, 1H), 7.52 (dd, J = 7.2, 1.2 Hz, 1H), 7.31 (m, 1H), 6.90 (d, J = 8.8 Hz, 1H). 4.08(s,3H),3.33-3.43(m,2H),2.69-2.78(m,2H),2.40(s,6H).

[0543] Option 6: Where Z 4Compounds of formula (I) where N is N can be synthesized from appropriately substituted quinolines in the order of steps outlined in Scheme 6 or in a similar order to that which one skilled in the art may utilize. Bromination of the quinoline derivative followed by Heck coupling produces an intermediate olefin compound which produces a phthalimide-protected amine under reducing conditions. Removal of the phthalimide under standard conditions provides an amine derivative which can be alkylated in several ways. One such example includes a reductive alkylation reaction with formaldehyde to produce compounds of formula (I) (illustrated by Examples 1-9). These steps can also be applied to other appropriately substituted 6,6-aromatic systems.

[0544]

[0545] Example 9: Synthesis of 2-(3-methoxyquinolin-5-yl)-N,N-dimethylethan-1-amine (I-9)

[0546]

[0547] Step 1: 5-Bromo-3-methoxyquinoline (10)

[0548] A solution of 3-methoxyquinoline (3.0 g, 18.8 mmol) in concentrated H2SO4 (12 mL) was treated with NBS (3.35 g, 18.8 mmol) at 0 ° C, and then stirred for 4 hours at RT. After completion, the reaction mixture was cooled to 0 ° C and the pH was adjusted to 7 with a 3M NaOH aqueous solution. The aqueous mixture was then extracted with EtOAc (150 mL × 2) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to produce the title compound (2.8 g, 62%) in the form of a white solid. 1 H NMR (400MHz, CDCl3) δ 8.68 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.42 (m, 1H), 4.01 (s, 3H).

[0549] Step 2: (E)-2-(2-(3-methoxyquinolin-5-yl)vinyl)isoindoline-1,3-dione (11)

[0550] By 5-bromo-3-methoxyquinoline (1.0g, 4.2mmol), N-vinylphthalimide (1.09g, 6.3mmol), Et3N (1.7g, 16.8mmol), tri-o-tolylphosphine (128mg, 0.42mmol), Pd (OAc)2 (94mg, 0.42mmol) in DMF (7mL) mixture degassed and purged three times with N2, and then stirred for 16 hours at 115 ° C under N2. After completion, the reaction mixture was diluted with ACN (50mL), and insoluble materials were collected by filtration and the filtrate was discarded. The collected solid was washed with THF (20mL), and the remaining insoluble materials were removed by filtration. The filtrate was concentrated in a vacuum and the residue was wet-ground with CH2Cl2 (3.0mL) to produce the title compound (400mg) in the form of a yellow solid, which was used for the next step without further purification.

[0551] Step 3: 2-(2-(3-methoxyquinolin-5-yl)ethyl)isoindoline-1,3-dione (12)

[0552] 10% Pd / C (0.1 g, 0.09 mmol) was added to a solution of (E)-2-(2-(3-methoxyquinolin-5-yl)vinyl)isoindoline-1,3-dione (0.5 g, 1.51 mmol) in THF (10 mL) under Ar. The suspension was degassed and purged with H2 three times, and then stirred at RT under H2 (25 psi) for 12 h. Upon completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (360 mg) as a pale yellow solid and used in the next step without further purification.

[0553] Step 4: 2-(3-Methoxyquinolin-5-yl)ethan-1-amine (13)

[0554] A solution of 2-(2-(3-methoxyquinolin-5-yl)ethyl)isoindoline-1,3-dione (260 mg, 0.78 mmol) in EtOH (5.0 mL) was treated with hydrazine hydrate (490 mg, 7.82 mmol) at RT. The reaction mixture was then stirred at 80 ° C for 12 hours. After completion, the reaction solution was filtered and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc (5.0 mL) and washed with H2O (5.0 mL×2), then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (110 mg, 13% over 3 steps) in the form of a light yellow oil. 1H NMR (400MHz, CDCl3) δ8.70(d,J=2.8Hz,1H),7.96(d,J=8.4Hz,1H),7.58(d,J =2.8Hz,1H),7.47-7.53(m,1H),7.37-7.42(m,1H),3.98(s,3H),3.19(m,4H).

[0555] Step 5: 2-(3-methoxyquinolin-5-yl)-N,N-dimethylethan-1-amine (I-9)

[0556] A solution of 2-(3-methoxyquinolin-5-yl)ethyl-1-amine (110 mg, 0.54 mmol) in CH2Cl2 (3.0 mL) was treated with acetic acid (65 mg, 1.09 mmol), NaBH(OAc)3 (231 mg, 1.09 mmol) and aqueous formaldehyde (37% w / w, 110 mg, 1.36 mmol) at 0°C and then stirred for 2 hours at RT. After completion, the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (column: Phenomenex Luna C18, 75*30 mm*3 μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 10%-40%, 8 minutes) to give the title compound (I-9, 26 mg, 21%) in the form of a yellow oil. HPLC purity: 96.0% (220nm); LCMS (ESI+): m / z 231.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.69(d,J=2.8Hz,1H),7.94(d,J=8.4Hz,1H),7.59(d,J=2.4Hz,1H),7.48 (m,1H),7.39(d,J=7.2Hz,1H),3.98(s,3H),3.18-3.26(m,2H),2.62-2.69(m,2H),2.39(s,6H).

[0557] Scheme 7: Compounds of formula (I) can be synthesized from appropriately substituted cyclic ketones following the sequence of steps outlined in Scheme 7 or similar to the sequence of steps that one skilled in the art may utilize. 3,4-Dihydronaphthalen-1(2H)-ones having an appropriate aromatic substitution pattern can be reacted with a phosphonate carbanion of triethylphosphonate generated in situ with a strong base, which yields the corresponding substituted cyclohexene after elimination. The substituted cyclohexene can be oxidized with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) to the corresponding 6,6-aromatic system, which can undergo hydrolysis to yield the carboxylic acid. The carboxylic acid can then be reduced to an alcohol, which can then be converted to an alkyl bromide for alkylation with an appropriately substituted amine to yield compounds of formula (I) (illustrated by Example 1-32). Alternatively, the carboxylic acid can be activated and reacted directly with an appropriately substituted amine to produce an amide which can be reduced to the desired tertiary amine, which is a compound of formula (I) (exemplified by Examples 1-33, 1-34, 1-35, 1-37 and 1-39).

[0558]

[0559] Example 32: Synthesis of 2-(7-chloronaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-32)

[0560]

[0561] Step 1: Ethyl 2-(7-chloro-3,4-dihydronaphthalen-1-yl)acetate (20)

[0562] An ice-cold solution of 7-chloro-1,2,3,4-tetrahydro-1-naphthalenone (3.60 g, 19.9 mmol) and NaOEt (1.49 g, 21.9 mmol) in dry EtOH (25 mL) was treated dropwise with a solution of (diethoxyphosphoryl)ethyl acetate (4.91 g, 21.9 mmol) in dry EtOH (10 mL) over 10 minutes. The reaction mass was warmed to RT and continued to stir for 4 hours, at which point the reaction solution was quenched by adding H2O (10 mL) and concentrated under reduced pressure. The resulting oil was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (50 mL), then dried (MgSO4) and concentrated under reduced pressure. The crude oil was purified by column chromatography (SiO2, 10-40% EtOAc / hexanes (v / v)) to give the title compound (4.1 g, 82%) as a colorless oil. 1H NMR (400MHz, CDCl3) δ7.18(d,J=2.1Hz,1H),7.13(dd,J=8.0,2.1Hz,1H),7.07(d,J=8.0Hz,1H),6.07(tt,J=4.6,1.2H z,1H),4.19(q,J=7.1Hz,2H),3.42(q,J=1.2Hz,2H),2.77(t,J=8.1Hz,2H),2.36–2.31(m,2H),1.28(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ171.5,135.9,134.6,132.1,130.5,129.5,128.7,126.7,122.9,60.9,39.0,27.3,23.1,14.2.

[0563] Step 2: Ethyl 2-(7-chloronaphthalen-1-yl)acetate (21)

[0564] DDQ (3.59 g, 15.8 mmol) was added in portions to a stirred solution of (7-chloro-3,4-dihydro-1-naphthyl)ethyl acetate (3.3 g, 13.2 mmol) in CH2Cl2 (50 mL). Stirring was continued for 4 hours, at which time the reaction mass was filtered and the residue was washed with Et2O (3×20 mL). The combined filtrate was concentrated under reduced pressure, and the resulting crude material was purified by column chromatography to yield (7-chloro-1-naphthyl)ethyl acetate (3.0 g, 92%) in the form of a colorless oil. 1 H NMR (400MHz, CDCl3) δ8.02(d,J=2.0Hz,1H),7.90–7.76(m,2H),7.48–7.43(m,3H),4.20(q,J=7.1Hz,2H),4.04(s,2H),1.28(t,J=7.1Hz,3H).

[0565] Step 3: 2-(7-Chloronaphthalen-1-yl)acetic acid (22)

[0566] A solution of LiOH (867 mg, 36.2 mmol) in H2O (10 mL) was added to a suspension of (7-chloro-1-naphthyl) ethyl acetate (3.0 g, 12.1 mmol) and TBAB (0.12 mmol) in THF (10 mL). Stirring was continued for 12 hours at RT, at which time the solution was concentrated under reduced pressure and washed with Et2O (2 × 25 mL). The aqueous layer was made acidic by adding concentrated HCl (32% aqueous solution), and the resulting suspension was extracted with CH2Cl2 (3 × 25 mL). The combined organic extracts were washed with H2O (50 mL), followed by brine (50 mL), then dried (MgSO4), filtered and concentrated under reduced pressure to produce the title compound (2 g, 96%) in the form of a white crystalline solid. 1 H NMR (400MHz, CDCl3) δ7.97 (d, J = 2.0Hz, 1H), 7.86–7.76 (m, 2H), 7.50–7.41 (m, 3H), 4.07 (s, 2H).

[0567] Step 4: 2-(7-Chloronaphthalen-1-yl)ethan-1-ol (23)

[0568] At 0 ℃, the stirred solution of (7-chloro-1-naphthyl)acetic acid (2.22g, 10.1mmol) in THF (20mL) is used LiAlH (1.53g, 40mmol) and is allowed to warm to RT.Stirring is continued for 6 hours at this temperature, and now the reaction mass is cooled to 0 ℃ and successively uses H o (1.5mL), NaOH (15% aqueous solution, 1.5mL) and H o (4.5mL) is processed, and then filtered through diatomaceous earth pad.Residue is washed with THF (3 × 50mL), and the filtrate combined is concentrated under reduced pressure.The crude oil thus obtained is purified by column chromatography (SiO , 10-40% EtOAc / hexane (v / v)) to produce the desired compound (1.7g, 82%) in the form of colorless oil. 1 H NMR (400MHz, CDCl3) δ8.02 (d, J = 2.0Hz, 1H), 7.79 (d, J = 8.7Hz, 1H), 7.75–7.70 (m, 1H), 7.51–7.34 (m, 3H), 3.98 (t, J = 6.7Hz, 3H), 3.30 (t, J = 6.7Hz, 2H).

[0569] Step 5: 1-(2-Bromoethyl)-7-chloronaphthalene (24)

[0570] Under N2 atmosphere, 2-(7-chloro-1-naphthyl) eth-1-ol (2.08g, 10.1mmol) and CBr (2.12g, 6.39mmol) are added to the flask containing triphenylphosphine (3.95g, 15.1mmol) in dry CH2Cl2 (17.4mL) solution. The mixture obtained is stirred at 40 ℃ for 18 hours. Et2O (29mL) is added and the resulting suspension is stirred at room temperature for 30 minutes. The brown precipitate formed is filtered and washed with Et2O. The filtrate is concentrated under reduced pressure, and the crude product is purified by flash chromatography (SiO2, 0-5% EtOAc / hexane (v / v)) to produce 1-(2-bromoethyl)-7-chloronaphthalene (2.21g, 82%) in the form of colorless oil. 1 H NMR (400MHz, CDCl3) δ7.98(d,J=2.0Hz,1H),7.84(d,J=8.7Hz,1H),7.78(dd,J=7.6,2.0Hz,1 H), 7.50–7.39 (m, 3H), 3.70 (ddd, J=7.9, 6.9, 1.4Hz, 2H), 3.61 (ddd, J=8.8, 6.9, 1.3Hz, 2H). 13 C NMR (101MHz, CDCl3) δ134.2,132.4,132.3,132.2,130.6,128.0,127.6,126.7,125.8,122.3,36.4,31.7.

[0571] Step 6: 2-(7-Chloronaphth-1-yl)-N,N-dimethylethan-1-amine (I-32·HCl)

[0572] At RT, a suspension of 1-(2-bromoethyl)-7-chloronaphthalene (150 mg, 0.56 mmol) and KCO (154 mg, 1.11 mmol) was treated with a solution of 2M MeNH in THF (620 μL, 1.23 mmol). The reaction mass was then heated to 70 ° C for 8 hours, then diluted with H2O (15 mL) and extracted with EtOAc (3 × 25 mL). The combined organic extracts were then washed with H2O (3 × 25 mL), brine (50 mL), then dried (MgSO4), filtered and concentrated under reduced pressure. The resulting oil was purified by column chromatography (SiO2, CH2Cl2 containing 1-10% MeOH / NH3) to produce the title compound (85 mg) in the form of a colorless oil. This oil was converted to the HCl salt following General Procedure A, which produced crystalline needles that were collected by filtration, air dried, and identified as the hydrochloride salt of the title compound (I-32·HCl, 0.1 g, 67%). HPLC purity: 99.4% (254 nm);1 H NMR (400MHz, DMSO-d6) δ10.88–10.83(m,1H),8.29(d,J=1.9Hz,1H),8.02(d,J=8.8Hz,1H),7.95–7.86(m,1H) ,7.57(dd,J=8.7,2.0Hz,1H),7.54–7.51(m,2H),3.54–3.41(m,2H),3.36–3.27(m,2H),2.88(d,J=4.9Hz,6H). 13 C NMR (101MHz, DMSO-d6) δ132.7,132.1,131.9,131.5,130.9,128.0,127.5,126.6,126.2,122.6,56.4,42.0,26.9.

[0573] Example 33: Synthesis of N-ethyl-N-methyl-2-(naphthalen-1-yl)ethan-1-amine (I-33)

[0574]

[0575] Step 1: N-ethyl-N-methyl-2-(naphthalen-1-yl)ethan-1-amine (I-33·Fum)

[0576] A stirred solution of (7-chloro-1-naphthyl)acetic acid (0.5 g, 2.27 mmol) in CH2Cl2 (10 mL) was treated with oxalyl chloride (0.23 mL) followed by a drop of DMF. Stirring was continued for 1 hour, at which point the reaction was concentrated under a stream of N2. The resulting yellow oil was then redissolved in CH2Cl2 (10 mL) and cooled to 0°C, then treated with N-methylethylamine (201 mg, 3.4 mmol), followed by the dropwise addition of triethylamine (0.79 mL, 5.66 mmol) and continued stirring for 3 hours. The reaction was then diluted with H2O (25 mL) and the phases separated. The organic phase was washed with NaHCO3 (saturated aqueous solution, 25 mL), followed by brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The obtained residue is wet-ground with EtO (10mL) and filtered to produce a white powder, which is dissolved in anhydrous THF (25mL), cooled to 0°C, and then treated with LiAlH (166mg, 4.38mmol) in batches, and then the obtained suspension is heated under reflux for 4 hours. The reaction solution is then cooled to 0°C and H is added dropwise successivelyO (0.15mL), NaOH (0.15mL, 15% aqueous solution) and HO (1mL), followed by MgSO (1g) quenching. The suspension is then filtered through a diatomaceous earth pad and the residue is washed with THF (2 × 25mL). The combined filtrate is concentrated under reduced pressure and the crude oil is purified by flash column chromatography (SiO, 0-5%, CH containing MeOH / NHCl (v / v)) to produce the title compound (85mg) in the form of a colorless oil. This free base was converted to the fumarate salt according to General Procedure B to yield a white crystalline product identified as the title compound (I-33·Fum, 0.1 g, 80%). HPLC purity: 96.0% (254 nm); 1 H NMR(400MHz, DMSO-d6)δ8.13(ddd,J=7.9,1.7,0.7Hz,1H),7.99–7.90(m,1H),7.90–7.77(m,1H),7.62–7.49(m,2H),7.49– 7.40(m,2H),6.57(s,2H),3.40–3.31(m,2H),3.03–2.92(m,2H),2.87(q,J=7.2Hz,2H),2.59(s,3H),1.14(t,J=7.2Hz,3H). 13C NMR (101MHz, DMSO-d6) δ167.9,135.4,135.2,133.9,131.8,129.1,127.5,127.3,126.7,126.2,126.1,124.0,56.5,50.5,39.9,28.7,10.8.

[0577] Example 34: Synthesis of N-methyl-N-(2-(naphthalen-1-yl)ethyl)propan-2-amine (I-34)

[0578]

[0579] Step 1: N-methyl-N-(2-(naphthalen-1-yl)ethyl)propan-2-amine hydrochloride (I-34.HCl)

[0580] A stirred solution of (7-chloro-1-naphthyl)acetic acid (0.5 g, 2.27 mmol) in CH2Cl2 (10 mL) was treated with oxalyl chloride (0.23 mL) followed by a drop of DMF. Stirring was continued for 1 hour, at which point the reaction was concentrated under a stream of N2. The resulting yellow oil was then redissolved in CH2Cl2 (10 mL) and cooled to 0°C, then treated with N-methylisopropylamine (199 mg, 2.72 mmol), followed by the dropwise addition of triethylamine (0.79 mL, 5.66 mmol) and continued stirring for 3 hours. The reaction was then diluted with H2O (25 mL) and the phases separated. The organic phase was washed with NaHCO3 (saturated aqueous solution, 25 mL), followed by brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The obtained residue is wet-ground with EtO (10mL) and filtered to produce a white powder, which is dissolved in anhydrous THF (25mL), cooled to 0°C, and then treated with LiAlH (166mg, 4.38mmol) in batches, and then the obtained suspension is heated under reflux for 4 hours. The reaction solution is then cooled to 0°C and H is added dropwise successivelyO (0.15mL), NaOH (0.15mL, 15% aqueous solution) and HO (1mL), followed by MgSO (1g) quenching. The suspension is then filtered through a diatomaceous earth pad and the residue is washed with THF (2 × 25mL). The combined filtrate is concentrated under reduced pressure and the crude oil is purified by flash column chromatography (SiO, 0-5%, CH containing MeOH / NHCl (v / v)) to produce the title compound in colorless form. This oil was converted to the HCl salt following General Procedure A, and the resulting crystals were collected, washed with cold acetone (3 mL), then with Et2O (5 mL) and air dried to give the title compound as an HCl salt (172 mg, 25%). HPLC purity: 93% (254 nm);1 H NMR (400MHz, DMSO-d6): δ10.93(s,1H),8.29(d,J=8.3Hz,1H),8.03–7.92(m,1H),7.85(dd,J=6.9,2.5Hz,1H),7.67–7.52(m,2H),7.52–7.43(m ,2H),3.78–3.58(m,2H),3.52(td,J=12.5,5.8Hz,1H),3.31–3.13(m,2H),2.77(d,J=5.1Hz,3H),1.32(d,J=6.6Hz,3H),1.23(d,J=6.6Hz,3H). ; 13 C NMR (101MHz, DMSO-d6) δ134.0,133.9,131.8,129.2,128.0,127.5,127.0,126.4,126.1,124.2,56.3,53.0,34.4,27.6,17.4,15.3.

[0581] Example 35: Synthesis of N-(2-(7-chloronaphthalen-1-yl)ethyl)-N-methylcyclopropylamine (I-35)

[0582]

[0583] Step 1: 2-(7-Chloronaphthalen-1-yl)-N-cyclopropyl-N-methylacetamide (25)

[0584] A stirred solution of (7-chloro-1-naphthyl)acetic acid (0.5 g, 2.27 mmol) in CH2Cl2 (10 mL) was treated with oxalyl chloride (0.23 mL) followed by a drop of DMF. Stirring was continued for 1 hour, at which point the reaction was concentrated under a stream of N2. The resulting yellow oil was then redissolved in CH2Cl2 (10 mL) and cooled to 0°C before being treated with N-methylcyclopropylamine hydrochloride (293 mg, 2.72 mmol) followed by the dropwise addition of triethylamine (0.79 mL, 5.66 mmol) and continued stirring for 3 hours. The reaction was then diluted with H2O (25 mL) and the phases separated. The organic phase was washed with NaHCO3 (saturated aqueous solution, 25 mL) followed by brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography (SiO2, 0-50% EtOAc / Hex (v / v)) to give the title compound (275 mg, 44%) as a white solid. 1HNMR(400MHz, CDCl3) δ7.93(d,J=2.0Hz,1H),7.81(d,J=8.7Hz,1H),7.76(d,J=8.0Hz,1 H),7.57–7.37(m,3H),4.29(s,2H),3.02(s,3H),2.81–7.30(m,1H),0.97–0.86(m,4H).

[0585] Step 2: N-(2-(7-chloronaphthalen-1-yl)ethyl)-N-methylcyclopropylamine (I-35·mal)

[0586] At 0 ℃ under inert atmosphere, the stirred solution of 2- (7- chloronaphthalene -1- base) -N- cyclopropyl -N- methylacetamide (0.3g, 1.10mmol) in THF (10mL) is treated with LiAlH4 (166mg, 4.38mmol) in batches, and then the resulting suspension is heated under reflux for 4 hours. Then the reaction solution is cooled to 0 ℃ and H2O (0.15mL), NaOH (0.15mL, 15% aqueous solution) and H2O (1mL) are added dropwise successively, followed by MgSO4 (1g) quenching. The suspension is then filtered through a diatomaceous earth pad and the residue is washed with THF (2 × 25mL). The combined filtrate is concentrated under reduced pressure and the crude oil is purified by flash column chromatography (SiO2, 0-5%, CH2Cl2 (v / v) containing MeOH / NH3) to produce the title compound (174mg) in the form of a colorless oil. The resulting oil was taken up in warm acetone (1 mL) and added to a boiling solution of maleic acid (134 mg, 1.15 mmol) in acetone (15 mL) and allowed to cool to 0°C overnight. The white crystalline precipitate was collected by suction filtration, and the residue was washed with cold Et2O (2×10 mL) and air-dried to give the title compound (I-35.mal, 112 mg, 27%) as a maleate salt. HPLC purity: 95% (280 nm); 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=2.1Hz,1H),8.04(d,J=8.8Hz,1H),7.92(dq,J=8.1,4.0Hz,1H),7.5 9(dd,J=8.8,2.1Hz,1H),7.56–7.51(m,2H),6.10(s,2H),3.47(s,4H),2.99(s,4H),1.23–0.66(m,4H). 13C NMR (101MHz, DMSO-d6) δ167.6,135.1,133.2,132.4,132.4,131.9,131.5,128.6,128.0,127.0,126.7,122.8,57.0,41.7,39.0,27.5,5.0.

[0587] Example 37: Synthesis of N-benzyl-2-(naphthalen-1-yl)ethan-1-amine (I-37)

[0588]

[0589] Step 1: N-Benzyl-2-(7-chloronaphthalen-1-yl)acetamide (26)

[0590] A stirred solution of (7-chloro-1-naphthyl)acetic acid (0.5 g, 2.27 mmol) in CH2Cl2 (10 mL) was treated with oxalyl chloride (0.23 mL) followed by a drop of DMF. Stirring was continued for 1 hour, at which point the reaction was concentrated under a stream of N2. The resulting yellow oil was then redissolved in CH2Cl2 (10 mL) and cooled to 0°C, followed by treatment with benzylamine (364 mg, 3.40 mmol) followed by dropwise addition of triethylamine (0.79 mL, 5.66 mmol) and continued stirring for 3 hours. The reaction was then diluted with H2O (25 mL) and the phases separated. The organic phase was washed with NaHCO3 (saturated aqueous solution, 25 mL) followed by brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography (SiO2, 0-50% EtOAc / hexanes (v / v)) to give the title compound (410 mg, 57%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.73(t,J=6.0Hz,1H),8.20(d,J=2.1Hz,1H),7.99(d,J=8.7Hz,1H),7.88 (dd,J=7.3,2.1Hz,1H),7.58–7.46(m,3H),7.35–7.19(m,5H),4.30(d,J=5.9Hz,2H),3.98(s,2H).

[0591] Step 2: N-Benzyl-2-(naphthalen-1-yl)ethan-1-amine (I-37·HCl)

[0592] At 0 ° C under an inert atmosphere, the stirred solution of N-benzyl-2-(7-chloronaphthalene-1-yl)acetamide (0.35g, 1.13mmol) in THF (10mL) was treated with LiAlH4(172mg, 4.52mmol) in batches, and then the resulting suspension was heated at reflux for 4 hours. The reaction solution was then cooled to 0 ° C and H2O(0.15mL), NaOH(0.15mL, 15% aqueous solution) and H2O(1mL) were added dropwise, followed by MgSO4(1g) quenching. The suspension was then filtered through a diatomaceous earth pad and the residue was washed with THF(2×25mL). The combined filtrate was concentrated under reduced pressure and the crude oil was purified by flash column chromatography (SiO2, 0-5%, CH2Cl2(v / v) containing MeOH / NH3) to produce the title compound (114mg) in the form of a colorless oil. The resulting oil was converted into HCl salt according to General Procedure A. The white crystalline precipitate was collected by suction filtration, and the residue was washed with cold Et2O (2×10 mL) and air-dried to give the title compound (I-37.HCl, 60 mg, 16%) as an HCl salt. HPLC purity: 92% (280 nm); 1 H NMR (400MHz, DMSO-d6) δ9.73–9.61(br.s,2H),8.24–8.18(m,1H),8.01–7.93(m,1H),7.86(dd,J=8.1,1.3Hz,1H),7. 67–7.52(m,4H),7.56–7.44(m,2H),7.49–7.38(m,4H),4.22(t,J=5.9Hz,2H),3.57–3.48(m,2H),3.25–3.15(m,2H). 13 C NMR (101MHz, DMSO-d6) δ134.0,133.8,132.6,131.7,130.5,129.4,129.2,129.1,128.0,127.4,126.9,126.4,126.2,124.0,50.3,47.6,29.3.

[0593] Scheme 8: Compounds of formula (I) can be synthesized from appropriately substituted cyclic ketones following the sequence of steps outlined in Scheme 8 or similar to the sequence of steps that one skilled in the art may utilize. Alternatively, as depicted in Scheme 8, 3,4-dihydronaphthalen-1(2H)-ones having an appropriate aromatic substitution pattern can be reacted with cyanoacetic acid, which after elimination produces the corresponding substituted cyclohexene. The substituted cyclohexene can be oxidized to the corresponding 6,6-aromatic system with various oxidants (e.g., 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)). The nitrile can be reduced to produce a primary amine, which can then undergo reductive N-alkylation with an appropriate aldehyde to produce compounds of formula (I) (exemplified by Examples 1-38, 1-42, 1-50, 1-52, and 1-53).

[0594]

[0595] Example 53: Synthesis of 2-(7-fluoronaphthalen-1-yl)ethan-1-amine (I-53)

[0596]

[0597] Step 1: 2-(7-Fluoro-3,4-dihydronaphthalen-1-yl)acetonitrile (31)

[0598] To a solution of 7-fluoro-3,4-dihydronaphthalene-1(2H)-one (5.0 g, 30.5 mmol) in toluene (50 mL) was added cyanoacetic acid (3.89 g, 45.7 mmol), heptanoic acid (1.08 mL, 7.61 mmol) and benzylamine (0.83 mL, 7.61 mmol). The reaction was then attached to a Dean-Stark apparatus at 135 °C for 16 hours and then cooled to RT after completion. The reaction was diluted with EtOAc (100 mL), washed with 0.5 M NaOH aqueous solution (50 mL), then with saturated NaHCO3 aqueous solution (100 mL), 1 M HCl aqueous solution (100 mL), and subsequently washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The solid residue was recrystallized from isopropanol with a few drops of H2O and allowed to stand in a refrigerator for 16 h to give the title compound (4.6 g, 81%) as off-white crystals. 1H NMR (400MHz, DMSO-d6) δ7.23 (dd, J=8.2, 6.1Hz, 1H), 7.11 (dd, J=10.5, 2.6Hz, 1H), 7.03 (td, J=8. 6,2.6Hz,1H),6.26(t,J=4.4Hz,1H),3.94–3.72(m,2H),2.70(t,J=8.1Hz,2H),2.36–2.17(m,2H). 13 C NMR(101MHz,DMSO-d6)δ161.2(d,J=240.4Hz),134.3(d,J=7.8Hz),131.8(d,J=3.0Hz),129.7,129.1( d, J=8.1Hz), 126.5 (d, J=2.3Hz), 118.7, 113.7 (d, J=20.9Hz), 109.8 (d, J=23.0Hz), 26.2, 22.6, 20.5.

[0599] Step 2: 2-(7-Fluoronaphthalen-1-yl)acetonitrile (32)

[0600] A sealed pressure tube containing (7-fluoro-3,4-dihydro-1-naphthyl)acetonitrile (1.0 g, 5.34 mmol) and DDQ (98% purity, 1.24 g, 5.34 mmol) in CH2Cl2 (26 mL) was heated to 60 ° C for 2 hours. The cooled reaction mixture was filtered through a plug of silica gel and eluted with CH2Cl2. The combined filtrate was concentrated under a stream of N2 and the residue was purified by flash chromatography (0% to 40% CH2Cl2 in hexane) to produce the title compound (570 mg, 58%) in the form of orange crystals. 1 H NMR (400MHz, DMSO-d6) δ8.10 (dd, J=9.0, 6.1Hz, 1H), 7.98 (d, J=8.3Hz, 1H), 7.82 (dd,J=11.3,2.5Hz,1H),7.65(d,J=7.1Hz,1H),7.56–7.43(m,2H),4.47(s,2H). 13 C NMR(101MHz,DMSO-d6)δ160.5(d,J=244.6Hz),131.7(d,J=9.3Hz),131.5(d,J=9.1Hz),130.5,128.5,1 27.4, 127.1 (d, J = 5.6Hz), 125.1 (d, J = 2.5Hz), 118.9, 116.4 (d, J = 25.2Hz), 107.3 (d, J = 21.8Hz), 20.6.

[0601] Step 3: 2-(7-Fluoronaphthalen-1-yl)ethan-1-amine hydrochloride (I-53·HCl)

[0602] The ice-cold solution of (7-fluoro-1-naphthyl)acetonitrile (500mg, 2.70mmol) in anhydrous THF (20mL) is treated with LiAlH4(205mg, 5.40mmol) in batches and the resulting suspension is stirred at reflux for 16 hours.Then the reaction solution is cooled in an ice bath and treated with other LiAlH4(300mg, 8.10mmol) and refluxed for another 8 hours.Then the reaction solution is cooled in an ice bath and quenched with H2O(0.8mL), 15%NaOH aqueous solution (0.8mL) and H2O(2.4mL).Then the suspension is stirred with anhydrous Na2SO4 for 30 minutes, then filtered through a diatomite plug and the filter cake is washed with several portions of hot THF.The combined filtrate is concentrated in a vacuum, and the residue is purified by flash chromatography (CH2Cl2 containing 0.1% to 5%MeOH / NH3) to produce the title compound in the form of a yellow oil. A solution of this oil in CHCl3 (50 mL) and iPrOH (1 mL) was made acidic by addition of HCl (35% in water) and Et2O was added until turbidity persisted, forming the title compound as a hydrochloride salt as white crystals after cooling at 0°C for 18 h (250 mg, 41%). 1 H qNMR purity: 98.4% (ERETIC); 1 H NMR (400MHz, DMSO-d6) δ8.23(br.s,3H),8.05(dd,J=9.0,6.1Hz,1H),7.96(dd,J=11.6,2. 5Hz, 1H), 7.89 (d, J = 7.7Hz, 1H), 7.56–7.36 (m, 3H), 3.41–3.29 (m, 2H), 3.14–2.99 (m, 2H). 13 CNMR (101MHz, DMSO-d6) δ160.5 (d, J = 243.6Hz), 133.2 (d, J = 5.7Hz), 132.3 (d, J = 8.8Hz), 131.7 (d, J = 9. 3Hz), 130.7, 128.1, 127.4, 125.1 (d, J = 2.2Hz), 116.0 (d, J = 25.3Hz), 107.3 (d, J = 21.3Hz), 39.4, 30.2.

[0603] Example 38: Synthesis of 2-(7-fluoronaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-38)

[0604]

[0605] Step 1: 2-(7-Fluoronaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-38)

[0606] A solution of 2-(7-fluoro-1-naphthyl)ethylamine hydrochloride (140 mg, 0.62 mmol) and aqueous formaldehyde solution (37% w / w, 0.23 mL, 3.10 mmol) in 1,2-dichloroethane (5 mL) was treated with NaBH(OAc)3(197 mg, 0.93 mmol) at RT. The reaction solution was stirred for 1 hour at RT, and another portion of NaBH(OAc)3(197 mg, 0.93 mmol) was added and continued to stir for 1 hour. The reaction solution was diluted with CH2Cl2(20 mL), and then quenched with 1 M NaOH aqueous solution (10 mL). The mixture was then extracted with CH2Cl2(20 mL×3) and the combined organic layer was washed with brine (50 mL), and then concentrated under reduced pressure. The residue was purified by flash chromatography (0.1% to 6% MeOH / NH 3 in CH 2 Cl 2 ) to give the title compound (90 mg, 67%) as a yellow oil. 1 HNMR (400MHz, DMSO-d6) δ8.05 (dd, J = 9.0, 6.1Hz, 1H), 7.99–7.86 (m, 2H), 7.55–7.40 (m, 3H), 3.51–3.14 (m, 4H), 2.80 (s, 6H). 13 C NMR (101MHz, DMSO-d6) δ160.5(d,J=243.7Hz), 133.1(d,J=5.8Hz), 132.2(d,J=8.8Hz), 131.7(d,J=9.4Hz ), 130.7, 127.9, 127.4, 125.1 (d, J = 2.2Hz), 116.0 (d, J = 25.2Hz), 107.4 (d, J = 21.3Hz), 56.8, 42.4, 27.6.

[0607] Step 2: 2-(7-Fluoronaphthalen-1-yl)-N,N-dimethylethan-1-amine fumarate (I-38·Fum)

[0608] According to general procedure B, 2-(7-fluoronaphthalen-1-yl)-N,N-dimethylethan-1-amine (135 mg, 0.62 mmol) was formulated as the fumarate salt which afforded the title compound as off-white crystals (65 mg, 31%). 1HNMR(400MHz,DMSO-d6)δ8.03(dd,J=9.0,6.1Hz,1H),7.89–7.80(m,2H),7.49 –7.39(m,3H),6.57(s,2H),3.34–3.23(m,2H),2.96–2.86(m,2H),2.54(s,6H). 13 C NMR (101MHz, DMSO-d6) δ167.2, 160.3 (d, J = 243.4Hz), 134.7, 134.7, 132.3 (d, J = 8.7Hz), 131.6 (d, J = 9.3H z), 130.6, 127.7, 127.0, 125.0 (d, J = 2.3Hz), 115.8 (d, J = 25.4Hz), 107.3 (d, J = 21.2Hz), 58.1, 43.4, 28.7.

[0609] Scheme 9: Compounds of formula (I) can be synthesized from appropriately substituted cyclic ketones following the sequence of steps outlined in Scheme 8 or similar to the sequence of steps that one skilled in the art might utilize. Alternatively, as depicted in Scheme 9, 3,4-dihydronaphthalen-1(2H)-ones having an appropriate aromatic substitution pattern can be subjected to a Horner-Wadsworth-Emmons reaction to produce a cyclohexene analog that, upon oxidation, produces a naphthyl acetate intermediate. Ester hydrolysis produces a naphthyl acetate derivative that can be subjected to an amidation reaction as described above (Scheme 2). The resulting amide can be reduced using a variety of methods as one skilled in the art might employ, including but not limited to borane-dimethyl sulfide complexes or lithium aluminum hydride. This allows access to appropriate amine compounds of formula (I) (illustrated by Examples 1-39, 1-40, and 1-41).

[0610]

[0611] Example 39: Synthesis of N-ethyl-2-(7-fluoronaphthalen-1-yl)-N-methylethan-1-amine (I-39)

[0612]

[0613] Step 1: Ethyl 2-(7-fluoro-3,4-dihydronaphthalen-1-yl)acetate (34)

[0614] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (5.47mL, 27.6mmol) in anhydrous EtOH (30mL) was added sodium ethoxide (3.13g, 45.9mmol) and the mixture was stirred at room temperature for 10 minutes. A solution of 7-fluoro-3,4-dihydronaphthalene-1(2H)-one (3.77g, 23mmol) in anhydrous EtOH (40mL) was added and the reaction solution was stirred under reflux under an inert atmosphere. At 4 hours, another pre-stirred mixture of ethyl 2-(diethoxyphosphoryl)acetate (2.27mL) and sodium ethoxide (1.57g) was added, and the reaction solution was stirred under reflux for another 3 hours. The reaction solution was then cooled and concentrated under a stream of N2. The obtained residue was then treated with H2O (40mL) and subsequently extracted with EtOAc (3×50mL). The combined organics were washed with brine (30mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-5% EtOAc / hexanes) to give the title compound (4.10 g, 76%) as a yellow oil. 1 H NMR(400MHz, CDCl3) δ7.07(ddt,J=8.0,5.9,1.0Hz,1H),6.90(dd,J=10.3,2.6Hz,1H),6.82(td,J=8.4,2.6Hz,1H),6.08 –6.03(m,1H),4.16(q,J=7.1Hz,2H),3.39(q,J=1.2Hz,2H),2.79–2.70(m,2H),2.36–2.26(m,2H),1.24(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ171.7,161.9(d,J=242.3Hz), 136.2(d,J=7.4Hz), 131.8(d,J=3.0Hz), 130.6,129.8( d, J=2.4Hz), 128.7 (d, J=8.0Hz), 113.3 (d, J=21.1Hz), 110.1 (d, J=22.9Hz), 61.0, 39.2, 27.3, 23.5, 14.3.

[0615] Step 2: Ethyl 2-(7-fluoronaphthalen-1-yl)acetate (35)

[0616] A mixture of ethyl 2-(7-fluoro-3,4-dihydronaphthalene-1-yl)acetate (4.10 g, 17.5 mmol), 10% palladium / carbon (3.73 g, 3.5 mmol) and d-limonene (57 mL) was stirred at 180 ° C for 2 hours, when vigorous gas evolution was observed. After cooling, the mixture was diluted with EtOAc (100 mL) and filtered through a celite pad. The filtrate was concentrated under reduced pressure and then purified by flash chromatography (SiO2, 0-5% EtOAc / hexane) to produce the title compound (1.6 g, 39%) in the form of a yellow oil. 1 H NMR (400MHz, CDCl3): δ7.85(dd,J=9.0,5.9Hz,1H),7.80–7.75(m,1H),7.62(dd,J=11.2,2.4Hz,1H),7.46– 7.36(m,2H),7.27(ddd,J=9.0,8.2,2.5Hz,1H),4.17(q,J=7.1Hz,2H),4.00(s,2H),1.24(t,J=7.1Hz,3H).

[0617] Step 4: 2-(7-Fluoronaphthalen-1-yl)acetic acid (36)

[0618] A solution of ethyl 2-(7-fluoronaphthalene-1-yl)acetate (1.6 g, 6.88 mmol) in THF (15 mL) was treated with aqueous NaOH (10.3 mmol, 15 mL), and the mixture was stirred at 45 ° C for 7 hours. The mixture was concentrated under a stream of nitrogen and the remaining aqueous mixture was adjusted to pH 2, and then extracted with EtOAc (3×15 mL). The combined organics were washed with brine (15 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to produce the title compound (1.21 g, 86%) in the form of a yellow oil. 1 H NMR (400MHz, CDCl3): δ7.86 (dd, J=9.0, 5.9Hz, 1H), 7.80 (dt, J=8.0, 1.2Hz, 1H), 7.58 (dd, J=11.0, 2.5Hz, 1H), 7.46–7.43 (m, 1H), 7.42–7.36 (m, 1H), 7.28 (ddd, J = 9.0, 8.2, 2.4Hz, 1H), 4.03 (s, 2H).

[0619] Step 4: N-ethyl-2-(7-fluoronaphthalen-1-yl)-N-methylacetamide (37)

[0620] To a solution of 2-(7-fluoronaphthalene-1-yl)acetic acid (420 mg, 2.06 mmol) in DMF (2.0 mL) was added a solution of 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea hexafluorophosphate (1.56 g, 4.11 mmol) in DMF (4.0 mL) at 0 ° C, iPr2NEt (1.06 g, 8.23 ​​mmol), and then MeNHEt (146 mg, 2.47 mmol) was added, and the mixture was stirred at RT for 3 hours. The reaction solution was then diluted with H2O (30 mL), and then extracted with EtOAc (3×20 mL). The combined organics were washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 0-40% EtOAc / hexanes) to give the title compound (368 mg, 73%) as a yellow oil. 1 H NMR (400MHz, CDCl3): δ7.85(dd,J=9.0,5.9Hz,1H),7.80–7.71(m,1H),7.56(dd,J=11.7,2.5Hz,1H),7.42–7.33 (m,2H),7.27(ddd,J=8.8,8.1,2.5Hz,1H),4.06(s,2H),3.35–3.55(m,2H),3.01(s,3H),1.16(t,J=7.1Hz,3H).

[0621] Step 5: N-ethyl-2-(7-fluoronaphthalen-1-yl)-N-methylethan-1-amine (I-39)

[0622] To a stirred solution of N-ethyl-2-(7-fluoronaphthalen-1-yl)-N-methylacetamide (368 mg, 1.5 mmol) in anhydrous THF (10 mL) was added 2M borane-dimethyl sulfide complex in THF (3.0 mL, 6.0 mmol) in a dropwise manner and the mixture was stirred at 60° C. for 1 hour. After cooling, the mixture was carefully treated with 6M aqueous HCl (2.0 mL) followed by MeOH (4.0 mL) and then stirred at reflux for 1 hour. After cooling, the volatiles were removed under a stream of N2 and the remaining aqueous phase was extracted with Et2O (2×10 mL) and then discarded. The pH was adjusted to 14 with NaOH (15% aqueous solution) and then extracted with Et2O (3×10 mL). The combined organics were washed with brine (15 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 2-10% MeOH / NH3 in CH2Cl2) to give the title compound (219 mg, 63%) as a clear oil. 1 H NMR (400MHz, CDCl3): δ7.84(dd,J=9.0,5.9Hz,1H),7.71(dd,J=7.1,2.4Hz,1H),7.66(dd,J=11.3,2.5Hz,1H),7.42–7.32( m,2H),7.30–7.21(m,1H),3.25–3.16(m,2H),2.77–2.68(m,2H),2.57(q,J=7.2Hz,2H),2.41(s,3H),1.13(t,J=7.2Hz,3H).

[0623] Step 6: N-ethyl-2-(7-fluoronaphthalen-1-yl)-N-methylethan-1-amine fumarate (I-39·Fum)

[0624] N-ethyl-2-(7-fluoronaphthalen-1-yl)-N-methylethan-1-amine (219 mg, 0.95 mmol) was formulated as a fumarate salt according to general procedure B, which afforded the title compound (117 mg, 36%) as white crystals. HPLC purity: 99.8% (254 nm); 1 H NMR (400MHz, DMSO-d6): δ8.03(dd,J=9.0,6.1Hz,1H),7.89–7.81(m,2H),7.51–7.39(m,3H),6.56(s, 2H), 3.32–3.24 (m, 2H), 2.98–2.90 (m, 2H), 2.83 (q, J = 7.2Hz, 2H), 2.56 (s, 3H), 1.12 (t, J = 7.2Hz, 3H).13 C NMR (101MHz, DMSO-d6): δ167.1, 160.3 (d, J = 243.5Hz), 134.8 (d, J = 5.9Hz), 134.6, 132.3 (d, J = 8.8Hz), 131.6 (d, J = 9.4 Hz), 130.6, 127.7, 126.9, 125.0 (d, J = 2.8Hz), 115.8 (d, J = 25.2Hz), 107.3 (d, J = 21.3Hz), 55.9, 50.1, 39.6, 28.4, 10.5.

[0625] Example 40: Synthesis of N-(2-(7-fluoronaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (I-40)

[0626]

[0627] Step 1: 2-(7-Fluoronaphthalen-1-yl)-N-isopropyl-N-methylacetamide (38)

[0628] To a solution of 2-(7-fluoronaphthalene-1-yl)acetic acid (420 mg, 2.06 mmol) in DMF (2.0 mL) was added hexafluorophosphate 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea (1.56 g, 4.11 mmol) in DMF (4.0 mL) at 0 ° C, iPr2NEt (1.06 g, 8.23 ​​mmol), and then N-methyl(isopropyl)amine (181 mg, 2.47 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with H2O (30 mL), and then extracted with EtOAc (3×20 mL). The combined organics were washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 0-40% EtOAc / hexanes) to give the title compound (466 mg, 87%) as a yellow oil. 1 H NMR (400MHz, CDCl3): δ7.85 (dd, J=9.0, 5.9Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 7.54 (m, 1H), 7.37 ( m,2H),7.32–7.22(m,1H),5.02–4.92(m,1H),4.08(m,2H),2.85(s,3H),1.13(d,J=6.7Hz,6H).

[0629] Step 2: N-(2-(7-Fluoronaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (I-40)

[0630] To a stirred solution of 2-(7-fluoronaphthalen-1-yl)-N-isopropyl-N-methylacetamide (466 mg, 1.8 mmol) in anhydrous THF (10 mL) was added 2M borane-dimethyl sulfide complex in THF (3.6 mL, 7.18 mmol) in a dropwise manner and the mixture was stirred at 60° C. for 1 hour. After cooling, the mixture was carefully treated with 6M aqueous HCl (2.0 mL) followed by MeOH (4.0 mL) and then stirred at reflux for 1 hour. After cooling, the volatiles were removed under a stream of N2 and the remaining aqueous phase was extracted with Et2O (2×10 mL) and then discarded. The pH was adjusted to 14 with NaOH (1M aqueous solution) and then extracted with Et2O (3×10 mL). The combined organics were washed with brine (15 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 2-10% MeOH / NH3 in CH2Cl2) to give the title compound (208 mg, 47%) as a clear oil. 1 H NMR (400MHz, CDCl3): δ7.84(dd,J=9.0,5.9Hz,1H),7.72(dd,J=7.8,1.4Hz,1H),7.67(dd,J=11.3,2.5Hz,1H),7.43–7.32 (m,2H),7.31–7.21(m,1H),3.29–3.20(m,2H),3.10–2.96(m,1H),2.82–2.73(m,2H),2.44(s,3H),1.09(d,J=6.6Hz,6H).

[0631] Step 3: N-(2-(7-fluoronaphthalen-1-yl)ethyl)-N-methylpropan-2-amine fumarate (I-40·Fum)

[0632] N-(2-(7-Fluoronaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (208 mg, 0.85 mmol) was formulated as a fumarate salt which afforded the title compound (118 mg, 39%) as white crystals according to General Procedure B. HPLC purity: 99.2% (254 nm); 1 H NMR (400MHz, DMSO-d6): δ8.03(dd,J=9.0,6.1Hz,1H),7.92–7.83(m,2H),7.53–7.40(m,3H) ),6.57(s,3H),3.43–3.26(m,3H),3.02-2.96(m,2H),2.57(s,3H),1.11(d,J=6.6Hz,6H); 13C NMR (101MHz, DMSO-d6): δ166.9, 160.4 (d, J = 243.5Hz), 134.5, 132.3 (d, J = 8.8Hz), 131.6 (d, J = 9.2Hz), 130.6, 127.9, 12 7.0, 125.0 (d, J = 2.1Hz), 115.8 (d, J = 25.2Hz), 115.8 (d, J = 25.2Hz), 107.3 (d, J = 21.3Hz), 54.4, 53.0, 34.9, 28.8, 16.6.

[0633] Example 41: Synthesis of N-(2-(7-fluoronaphthalen-1-yl)ethyl)-N-methylcyclopropylamine (I-41)

[0634]

[0635] Step 1: N-cyclopropyl-2-(7-fluoronaphthalen-1-yl)-N-methylacetamide (39)

[0636] To a solution of 2-(7-fluoronaphthalene-1-yl)acetic acid (420 mg, 2.06 mmol) in DMF (2.0 mL) was added a solution of 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea hexafluorophosphate (1.56 g, 4.11 mmol) in DMF (4.0 mL) and iPrNEt (1.06 g, 8.23 ​​mmol) at 0 ° C., followed by a mixture of MeNHcPr hydrochloride (181 mg, 2.47 mmol) and iPrNet (398 mg, 3.08 mmol) in DMF (2.0 mL). The reaction mass was then stirred at RT for 3 hours before being diluted with H2O (30 mL) and extracted with EtOAc (3×20 mL). The combined organics were washed with brine (20 mL), dried over anhydrous MgSO 4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO 2 , 0-40% EtOAc / hexanes) to give the title compound (371 mg, 70%) as a yellow oil. 1 HNMR (400MHz, CDCl3): δ7.85 (dd, J=9.0, 5.9Hz, 1H), 7.76 (m, 1H), 7.55 (dd, J=11.2, 2.5Hz, 1H), 7.43–7. 34(m,2H),7.31–7.21(m,1H),4.25(s,2H),3.00(s,3H),2.75(tt,J=6.8,4.1Hz,1H),0.97–0.80(m,4H).

[0637] Step 2: N-(2-(7-Fluoronaphthalen-1-yl)ethyl)-N-methylcyclopropylamine (I-41)

[0638] To a stirred solution of N-cyclopropyl-2-(7-fluoronaphthalen-1-yl)-N-methylacetamide (371 mg, 1.44 mmol) in anhydrous THF (10 mL) was added 2M borane-dimethyl sulfide complex in THF (2.9 mL, 5.77 mmol) in a dropwise manner and the mixture was stirred at 60° C. for 1 hour. After cooling, the mixture was carefully treated with 6M aqueous HCl (2.0 mL) followed by MeOH (4.0 mL) and then stirred at reflux for 1 hour. After cooling, the volatiles were removed under a stream of N2 and the remaining aqueous phase was extracted with Et2O (2×10 mL) and then discarded. The pH was adjusted to 14 with NaOH (1M aqueous solution) and then extracted with Et2O (3×10 mL). The combined organics were washed with brine (15 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 2-10% MeOH / NH3 in CH2Cl2) to give the title compound (326 mg, 93%) as a clear oil. 1 H NMR(400MHz, CDCl3) δ7.84(dd,J=9.0,5.9Hz,1H),7.71(dd,J=7.4,2.1Hz,1H),7.67(dd,J=11.4,2.5Hz,1H),7.42–7.32 (m,2H),7.30–7.21(m,1H),3.32–3.23(m,2H),2.97–2.88(m,2H),2.54(s,3H),1.87–1.78(m,1H),0.58(d,J=6.3Hz,4H).

[0639] Step 3: N-(2-(7-fluoronaphthalen-1-yl)ethyl)-N-methylcyclopropylamine fumarate (I-41·fum)

[0640] N-(2-(7-Fluoronaphthalen-1-yl)ethyl)-N-methylcyclopropylamine (154 mg, 0.63 mmol) was formulated as a fumarate salt which afforded the title compound (90 mg, 34%) as white crystals according to General Procedure B. HPLC purity: 99.9% (254 nm); 1H NMR (400MHz, DMSO-d6): δ7.84(dd,J=9.0,5.9Hz,1H),7.71(dd,J=7.4,2.1Hz,1H),7.67(dd,J=11.4,2.5Hz,1H),7.42–7.3 2(m,2H),7.30–7.21(m,2H),3.32–3.23(m,2H),2.97–2.88(m,2H),2.54(s,3H),1.87–1.78(m,1H),0.58(d,J=6.3Hz,4H); 13 CNMR (101MHz, DMSO-d6): δ166.1, 160.2 (d, J = 243.3Hz), 136.1 (d, J = 5.7Hz), 134.1, 132.3 (d, J = 8.4Hz), 131.6 (d, J = 9. 2Hz), 130.6, 127.4, 126.5, 125.0 (d, J = 2.8Hz), 115.7 (d, J = 25.1Hz), 107.1 (d, J = 21.2Hz), 58.0, 42.0, 37.9, 29.6, 6.4.

[0641] Example 42: Synthesis of N-benzyl-2-(7-fluoronaphthalen-1-yl)ethan-1-amine (I-42)

[0642]

[0643] Step 1: N-Benzyl-2-(7-fluoronaphthalen-1-yl)ethan-1-amine (I-42)

[0644] To a stirred solution of 2-(7-fluoronaphthalen-1-yl)ethan-1-amine (75 mg, 0.40 mmol) in CH2Cl2 (3.0 mL) was added a solution of benzaldehyde (42.2 μL, 0.40 mmol) in CH2Cl2 (2.0 mL), followed by the addition of NaBH(OAc)3 (101 mg, 0.48 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under a stream of N2 and the residue was treated with 1M NaOH (3.0 mL) aqueous solution, which was extracted with Et2O (3×5.0 mL). The combined organics were washed with brine (4.0 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, CH2Cl2 containing 2-10% MeOH / NH3) to provide the title compound (56 mg, 50%) as a clear oil. 1H NMR (400MHz, CDCl3): δ7.84 (dd, J=9.0, 5.9Hz, 1H), 7.72 (dd, J=7.4, 1.8Hz, 1H), 7.65 (dd, J=1 1.3, 2.5Hz, 1H), 7.39-7.21 (m, 8H), 3.86 (s, 2H), 3.26 (t, J = 7.4Hz, 2H), 3.03 (t, J = 7.4Hz, 2H).

[0645] Step 2: N-Benzyl-2-(7-fluoronaphthalen-1-yl)ethan-1-amine fumarate (I-42·Fum)

[0646] N-Benzyl-2-(7-fluoronaphthalen-1-yl)ethan-1-amine (56 mg, 0.20 mmol) was formulated as a fumarate salt which afforded the title compound (51 mg, 65%) as white crystals according to General Procedure B. HPLC purity: 99.8% (254 nm); 1 H NMR (400MHz, DMSO-d6): δ8.02 (dd, J=9.0, 6.1Hz, 1H), 7.89–7.81 (m, 2H), 7.48 –7.26(m,8H),6.55(s,2H),3.99(s,2H),3.33–3.25(m,2H),3.03–2.95(m,2H); 13 C NMR (101MHz, DMSO-d6): δ167.3, 160.4 (d, J = 243.2Hz), 134.8, 134.7, 132.3 (d, J = 9.0Hz), 136.5, 132.4, 131.6 (d, J = 9.2Hz), 13 0.6, 128.9, 128.4, 127.7 (d, J = 4.4Hz), 127.0, 125.0 (d, J = 2.2Hz), 115.8 (d, J = 25.3Hz), 107.3 (d, J = 21.2Hz), 51.2, 48.1, 30.9.

[0647] Example 52: Synthesis of 2-(5-methoxynaphthalen-1-yl)ethan-1-amine (I-52)

[0648]

[0649] Step 1: 2-(5-methoxy-3,4-dihydronaphthalen-1-yl)acetonitrile (59)

[0650] To a solution of 5-methoxy-3,4-dihydronaphthalene-1(2H)-one (8.0 g, 45.4 mmol) in toluene (60 mL) was added cyanoacetic acid (4.49 mL, 68.1 mmol), heptanoic acid (1.61 mL, 11.3 mmol) and benzylamine (1.24 mL, 11.3 mmol), and the resulting mixture was stirred at 135 ° C for 72 hours. After cooling to RT, the reaction solution was diluted with EtOAc (120 mL), and then washed with 0.5 M NaOH aqueous solution (80 mL), followed by saturated NaHCO3 aqueous solution (80 mL) and brine (80 mL). The organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, CH2Cl2) to provide 2-(5-methoxy-3,4-dihydronaphthalene-1-yl)acetonitrile (3.75 g, 41%) in the form of a light yellow crystalline solid. 1 HNMR (400MHz, CDCl3): δ7.20(ddt,J=8.5,7.8,0.7Hz,1H),6.85(dd,J=8.3,1.0Hz,1H),6.76(d,J=7.8Hz,1H),6.27( tt,J=4.6,1.6Hz,1H),3.84(s,3H),3.47(q,J=1.8Hz,2H),2.80(t,J=8.3Hz,2H),2.32(tdt,J=8.2,4.6,1.9Hz,2H).

[0651] Step 2: 2-(5-Methoxynaphthalen-1-yl)acetonitrile (60)

[0652] DDQ (3.04 g, 13.4 mmol) was added to a solution of 2-(5-methoxy-3,4-dihydronaphthalene-1-yl)acetonitrile (2.05 g, 10.3 mmol) in DCE (60 mL), and the mixture was stirred at 100 ° C under N2 gas for 14 hours. The reaction solution was then diluted with EtOAc (120 mL) and filtered through a celite pad, and the residue was washed with EtOAc (2×25 mL). The combined filtrate was then washed with saturated Na2CO3 aqueous solution (2×100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The dark brown residue was purified by flash chromatography (SiO2, hexane containing 0-20% EtOAc) and the separated material (1.30 g) was recrystallized from EtOAc / hexane to provide 2-(5-methoxynaphthalene-1-yl)acetonitrile (895 mg, 44%) in the form of white fine needles. 1H NMR (400MHz, CDCl3): δ8.36–8.28(m,1H),7.61(dq,J=7.1,1.0Hz,1H),7.56–7.38(m,3H),6.90(dd,J=7.6,0.9Hz,1H),4.12(br s,2H),4.02(s,3H); 13 C NMR (400MHz, CDCl3): δ156.3,132.0,127.4,127.1,126.1,125.5,124.9,123.2,117.9,114.7,104.6,55.8,22.2.

[0653] Step 3: 2-(5-methoxynaphthalen-1-yl)ethan-1-amine (I-52)

[0654] Under N2 atmosphere, LiAlH4(861mg, 22.7mmol) was added in batches to anhydrous THF (30mL) at 0°C. 0°C was maintained, a solution of 2-(5-methoxynaphthalene-1-yl)acetonitrile (895mg, 4.54mmol) in anhydrous THF (10mL) was added dropwise, and the mixture was stirred overnight at room temperature under N2 atmosphere. The reaction mixture was then cooled in an ice / water bath, and cold H2O(1mL) was slowly added, followed by quenching with 15% NaOH aqueous solution (1mL) and H2O(3mL). The mixture was filtered through a diatomaceous earth pad, and the mixture was subsequently washed by THF. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO2, CH2Cl2 containing 2-10% MeOH / NH3) to provide 2-(5-methoxynaphthalene-1-yl)ethanol-1-amine (153mg, 17%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ8.04(ddd,J=7.9,1.9,0.8Hz,1H),7.66(dt,J=8.6,0.9Hz,1H),7.45(dd,J=8.6,7.6Hz,1H ),7.42–7.35(m,2H),6.97(d,J=7.9Hz,1H),3.96(s,3H),3.10(dd,J=8.5,6.4Hz,2H),2.85(dd,J=8.3,6.6Hz,2H).

[0655] Step 4: 2-(5-methoxynaphthalen-1-yl)ethan-1-amine hydrochloride (I-52·HCl)

[0656] 2-(5-Methoxynaphthalen-1-yl)ethan-1-amine (59 mg, 0.29 mmol) was formulated as the hydrochloride salt according to general procedure A which was isolated as white crystals (43 mg, 62%). 1 H qNMR purity: 96.0% (ERETIC). 1 H NMR (400MHz, DMSO-d6): δ8.23(s,3H),8.14–8.08(m,1H),7.72(dt,J=8.6,0.9Hz,1H),7.50(dd,J=8.6,7.7 Hz,1H),7.47–7.40(m,2H),7.01(dd,J=7.8,0.8Hz,1H),3.97(s,3H),3.41–3.32(m,2H),3.11–3.02(m,2H). 13 C NMR (101MHz, DMSO-d6): δ155.4,133.2,132.3,127.4,126.6,125.3,124.9,120.8,115.6,104.4,55.7,30.5.

[0657] Example 50: 2-(5-methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-50)

[0658]

[0659] Step 1: 2-(5-methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-50)

[0660] 40% w / w aqueous formaldehyde solution (106 μL, 1.41mmol) and NaCNBH3 (88mg, 1.41mmol) were added to a solution of 2-(5-methoxynaphthalene-1-yl) ethyl-1-amine (94mg, 0.47mmol) at 0°C, and the mixture was stirred at RT for 3 hours. The reaction solution was quenched by adding 1M NaOH aqueous solution (2.0mL), and then volatiles were removed under N2 gas flow. The aqueous phase was extracted with Et2O (3×10mL), and the combined organic matter was washed with brine (15mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material (92mg) was purified by flash chromatography (SiO2, CH2Cl2 containing 2-10% MeOH / NH3) to produce 2-(5-methoxynaphthalene-1-yl)-N,N-dimethylethyl-1-amine (37mg, 35%) in the form of a yellow oil.

[0661] Step 2: 2-(5-methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine fumarate (I-50·Fum)

[0662] Following general procedure B, 2-(5-methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine (53 mg, 0.45 mmol) was formulated as the fumarate salt which was isolated as white crystals (36 mg, 69%). 1 H qNMR purity: 98.6% (ERETIC); 1 H NMR (400MHz, DMSO-d6): δ8.12–8.03(m,1H),7.66(dt,J=8.6,0.8Hz,1H),7.47(dd,J=8.6,7.7Hz,1H),7.45–7.38( m,2H),6.99(dd,J=7.8,0.8Hz,1H),6.57(s,2H),3.96(s,3H),3.33–3.24(m,2H),2.93–2.85(m,2H),2.53(s,6H); 13 C NMR (101MHz, DMSO-d6): δ167.2,155.3,134.7,134.7,132.4,127.2,126.4,125.2,124.9,120.4,115.7,104.2,58.4,55.6,43.4,29.1.

[0663] Example 51: 5-HT 2A , 5-HT 2B and 5-HT 2C Functional assay of receptors

[0664] Activity at 5-HT2A, 5-HT2B and 5-HT2C receptors was determined at WuXi AppTec Co. Ltd. (Hong Kong China) R&D Biology using the FLIPR Ca2+ flux assay according to their standard protocol. Briefly, stably transfected cells expressing the receptor of interest (HEK293 for 5-HT2A and 5-HT2C; CHO-K1 for 5-HT2B) were grown and plated in 384-well plates and incubated overnight at 37° C. and 5% CO2. A 250 mM stock solution of probenecid was freshly prepared in FLIPR calcium assay buffer (10 mL) and combined with a fluorescent dye (Fluo-4 Direct) to produce a final assay concentration of 2.5 mM. For 10 points, Agilent Bravo was used in 100% DMSO, the reference compound was serially diluted 4 times and the screening compound was serially diluted 3 times, and 750nL was added to the 384-well compound plate using Echo together with 30 μL of assay buffer. Then the fluorescent dye was added to the assay plate together with the 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 with the compound plate. Then 10 μL of reference and compound were transferred from the compound plate to the cell plate, and the fluorescent signal was read. The results are provided in Table 1 below.

[0665] Table 1: Ca 2+ The compounds exemplified have agonist activity at selected serotonin (5-HT) receptors in a flux functional assay.

[0666]

[0667]

[0668] Example 49: In vivo pharmacokinetic experiments

[0669] This study was performed in accordance with established procedures of the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes, and the study protocol was reviewed and approved by the Monash Institute of Pharmaceutical Sciences Animal Ethics Committee.

[0670] Systemic exposure of selected examples was studied in non-fasted male C57BL / 6 mice weighing between 22.3-26.2 g. Mice had free access to food and water throughout the pre-dose and post-dose sampling periods.

[0671] On the day of dosing, formulations of each compound were prepared by dissolving the solid compound in phosphate buffered saline (50 mM) using vortexing to produce a colorless solution of each compound (pH 6.1-6.3).

[0672] Compounds were administered to mice by IP injection (10 mL / kg dose volume, through a 27G needle; n=9 mice per compound), and blood samples were collected at 5 and 30 minutes after administration; 1 hour, 2 hours, and 4 hours (n=3 mice / time point per compound). Up to three blood samples were obtained from each mouse, with plasma samples collected by submandibular bleeding (approximately 120 μL). After collection, blood samples were immediately centrifuged, supernatant plasma removed, and stored at -80°C until analysis by LCMS. In addition, whole brains were quickly removed from animal carcasses soon after blood collection at 5 minutes, 30 minutes, and 4 hours post-dose time points. The whole brain was wiped dry to remove excess blood, placed in a pre-weighed polypropylene vial, and weighed. The brain was quickly frozen in dry ice and then stored frozen (-80°C) until analysis.

[0673] Summary of Bioanalytical Methods:

[0674] The concentrations of the test compounds in plasma and tissue samples were determined using an LCMS / MS method that was validated for linearity, accuracy, precision, matrix factor, and recovery (Table 2).

[0675] Test compound standard solutions were diluted from concentrated stock solutions (1 mg / mL in DMSO) using 50% acetonitrile in water (v / v) and calibration curves were prepared in a matrix matched to the test samples.

[0676] Plasma: A plasma calibration curve was prepared by spiking aliquots of blank mouse plasma (25 μL) with test compound standard solution (5 μL) and internal standard solution (5 μL of diazepam, 5 μg / mL 50% acetonitrile in water). Test plasma samples (25 μL) were thawed, mixed, and then spiked with internal standard solution (5 μL). Plasma protein precipitation was performed by adding acetonitrile (3 times volume ratio) and vortexing thoroughly. The samples were centrifuged (RCF=9391 x g) for 3 minutes, and the supernatant (90 μL) was collected for analysis.

[0677] Tissue: Pre-weighed tissue samples (brain) were homogenized using a glass rod in a buffer containing EDTA / potassium fluoride solution (0.1 M / 4 mg / mL) as a stabilizing mixture (3 mL mixture / g tissue) to minimize the possibility of in vitro degradation. The tissue homogenate was briefly centrifuged (RCF=79 x g) for 10 seconds to separate the foam layer, after which an aliquot (200 μL) of the tissue homogenate was transferred to a fresh Eppendorf tube for sample extraction. Calibration standards were prepared by spiking blank brain homogenate (200 μL) with solution standards (10 μL) and internal standards (10 μL). Study samples were prepared similarly, except that acetonitrile (10 μL) was added instead of solution standards to maintain the same volume. Protein precipitation was performed by adding 3 volumes of acetonitrile, followed by vortex mixing and centrifugation (RCF=9391 x g) for 3 minutes to recover the supernatant for analysis.

[0678] Replicate analysis: Triplicate analytical replicate (AR) samples were similarly prepared at three concentrations (50 ng / mL, 500 ng / mL, and 2,000 ng / mL) of standards for each sample type, and repeated injections of these ARs were included throughout the analytical run to evaluate assay performance. Extraction of test compounds from standards and ARs was performed as described above.

[0679] All test samples quantified within the calibration range of the assay and the assay performance for AR was considered acceptable.The stability of each test compound in the homogenate during the sample processing time period (15 minutes) was confirmed.

[0680] Table 2: Overview of bioanalytical methods for I-7 and I-15

[0681]

[0682] The product ions with the highest abundance and the least interference with the matrix were selected for quantification. MassLynx software (V4.2) was used for data acquisition.

[0683] IS: Internal Standard | * Retention time | # Collision-induced dissociation

[0684] The maximum plasma concentrations of I-7 following IP administration at 10 mg / kg are shown in Table 3. Comprehensive pharmacokinetic data including brain penetration information are presented in Figure 1 and / or Table 4.

[0685] Table 3: Exposure parameters of 1-7 and 1-15 following IP administration at 10 mg / kg in male C57BL / 6 mice.

[0686] parameter I-7 I-15 Apparent t1 / 2 (hours) 0.77 <![CDATA[1.2 c ]]> <![CDATA[Plasma C max (μM)]]> 1.18 1.72 <![CDATA[T max ]]> 0.50 hours 5 minutes Plasma AUC0-4 hours (hours*micromoles) 1.82 1.71 <![CDATA[Plasma AUC 0-inf (hour*micromole)]]> 1.89 <![CDATA[1.90 c ]]> Brain AUC0-4 hours (hours*micromoles) 32.3 13.8 <![CDATA[(Total) Time-Averaged B:P a > 18 8.1 <![CDATA[(Unbound) Time-Averaged B:P b > 3.2 2.0

[0687] a Calculated as AUC brain, 0-4 hours / AUC plasma, 0-4 hours

[0688] b Calculated as (fu, brain * AUC brain, 0-4 hours) / (fu, plasma * AUC plasma, 0-4 hours)

[0689] c The terminal elimination phase of the curve is estimated based on the last two time points, so the values ​​based on extrapolation to infinity are only approximate.

[0690] Table 4: Individual and mean ± SD (n=3) plasma and brain concentrations and brain-to-plasma (B:P) ratios of I-7 and I-15 following IP administration at 10 mg / kg in male C57BL / 6 mice.

[0691]

[0692] Example 54: Biotelemetry and Head Twitch Response (HTR) Experiment

[0693] Mice (C57BL / 6J male) were purchased from Jackson Laboratory (Bar Harbor, ME, USA) at 5-6 weeks of age and given at least 1-2 weeks to adapt to the NIDA Intramural Research Program (IRP), an animal research facility located in Baltimore, Maryland, USA. The animal facility was fully certified by the Association for the Assessment and Accreditation of Laboratory Animal Care, and all procedures were approved by the NIDA IRP Animal Care and Use Committee. During the adaptation period, mice were initially housed in groups of 3-5 / cage, and throughout the study, housed in a 12-hour light-dark cycle, with lights on at 0700 hours. Food and water were provided ad libitum except during the test period. Each test drug used a group consisting of 20-24 mice. Mice were subjected to experimental testing every 1-2 weeks for 2-3 months to complete the dose-effect curve and antagonist experiments. At least 7 days interval was used between treatments to avoid any tolerance to the effects of repeated drug administration. All drug doses represent the weight of salt dissolved in a 0.9% saline vehicle. Mice were first tested in a dose-response study to assess the effect of each compound at a dose of 0.03 mg / kg to 30 mg / kg subcutaneously, and subsequently tested in an antagonist reversal study using pretreatment with M100907 and WAY100635. Since rodents are sensitive to other tryptamine hallucinogens in a diurnal rhythm, all experiments were performed from 0900 local time to 1700 local time during the light phase, with the maximum HTR observed in the middle of the light phase. The experiment was run during the light phase, which also avoided any potential effects of melatonin receptor activity on HTR, because melatonin and related agonists are known to reduce the HTR induced by DOI in rats. For each experiment, mice were acclimated to the testing room in their home cages for at least 1 h prior to the experimental session.Behavioral testing sessions were conducted in a Tru Scan mouse locomotion arena equipped with a beam array (Coulbourn Instruments, Holliston, MA, USA) modified with a cylindrical insert and a transparent bottom plate for detecting mouse HTR.

[0694] Subcutaneous temperature transponder implant. At least 1 week before the start of the experiment, mice were subcutaneously implanted with a temperature transponder (14×2 mm, model IPTT-300, Bio Medic Data Systems, Inc., Seaford, DE, USA) under brief isoflurane anesthesia. After implantation, mice were housed individually for the remainder of the study to protect the transponder from being taken away by cage mates. Temperature was determined non-invasively using a handheld receiver sensitive to the signal emitted from the implanted transponder.

[0695] Before each experiment, mouse weight and body temperature were recorded. The mice were then placed in a test room to adapt. In a dose-response study, after a brief 5-minute adaptation, the mouse body temperature was recorded for baseline measurements, the mice received a subcutaneous injection of the test substance or vehicle, and the animals were returned to the test venue for 30 minutes. During the period, motor activity was monitored by beam tracking on a horizontal plane to obtain the distance in centimeters traveled. HTR was monitored by analyzing GoPro Hero Black 7 video recordings (120 frames per second, and 960p resolution) using a commercially available software package from Clever Sys Inc., Reston, VA, USA. 82 The post-treatment body temperature value was also recorded, and the temperature data was expressed as a change relative to the baseline before treatment.

[0696] In the antagonist reversal experiment, mice received a subcutaneous injection of a receptor antagonist or vehicle and returned to the test room for 30 minutes. During this period, motor activity was monitored to examine the potential effects of antagonist treatment on general behavior or movement. After 30 minutes of antagonist administration, mice were given the test drug or vehicle and returned to the room for another 30 minutes of video recording, which was used for analysis.

[0697] All statistical analyses were performed using GraphPad Prism 9 (La Jolla, CA, USA). Dose-response data from mouse experiments were analyzed using nonlinear regression, and potency values ​​were determined based on the rising phase of the curve for HTR measurement. For mouse studies, one-way ANOVA with Dunnett's post hoc test was used to compare all conditions to vehicle control (0 or 0,0) in dose-response and antagonist experiments. The time course drug effects of all parameters in mouse experiments are shown for reference. Statistical comparisons were made using the average HTR counts, distance traveled, and temperature changes for each condition. For all analyses, the alpha value was set to 0.05.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, in R 1 and R 2 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-8 Cycloalkyl, C 4-14 Alkylene cycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl and C 6-16 Alkylene heteroaryl, The C 1-6 Alkyl, the C 1-6 haloalkyl, the C 2-6 Alkenyl, the C 2-6 haloalkenyl, the C 2-6 Alkynyl, the C 2-6 Haloalkynyl, the C 3-8 Cycloalkyl, the C 4-14 Alkylene cycloalkyl, the C3-C8 heterocycloalkyl, the C 4- C 14 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 6-16 Each alkylene heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 )2.OR 4 、N(R 4 )2, NO2, SR 4 and SO2R 4 , The C 3-8 Cycloalkyl, the C 4-14 Alkylene cycloalkyl, the C3-C8 heterocycloalkyl, the C4-C 14 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 6-16 Each alkylene heteroaryl is further optionally substituted with a substituent independently selected from: (O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 ; Alternatively, R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms C 3-8 Heterocycloalkyl, the C 3-8 The heterocycloalkyl group includes 1 or 2 additional ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 4 , The C 3-8 The heterocycloalkyl group is further optionally substituted by a substituent selected from the group consisting of halogen, (O), CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 )2.OR 4 、N(R 4 )2, NO2, SR 4 、SO2R 4 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 ; R 3 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-14 alkylenecycloalkyl; Alternatively, R 3 and R 1 and R 2 One of them together with the atom to which it is attached forms C 3-12 Heterocycloalkyl, The C 3-12 The heterocycloalkyl group is further optionally substituted by a substituent selected from the group consisting of halogen, (O), CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 )2.OR 4 、N(R 4 )2, NO2, SR 4 、SO2R 4 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 ; Each R 4 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-7 Cycloalkyl and C 3-7 Heterocycloalkyl, the C 3-7 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 5 , The C 1-6 Alkyl, the C 1-6 haloalkyl, the C 2-6 Alkenyl, the C 2-6 haloalkenyl, the C 2-6 Alkynyl, the C 2-6 Haloalkynyl, the C 3-7 Cycloalkyl and the C 3-7 The heterocycloalkyl groups are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 5 、C(O)N(R 5 )2.OR 5 、N(R 5 )2, NO2, SR 5 and SO2R 5 , The C3-C7 cycloalkyl group and the C 3-7 Each heterocycloalkyl group is further optionally substituted with a substituent independently selected from: (O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 5 ; Each R 5 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 5-10 Heterocycloalkyl, C 6-12 Aryl and C 5-10 Heteroaryl, The C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 3-8 Cycloalkyl, the C 5-10 Heterocycloalkyl, the C 6-12 The aryl group and the C 5-10 The heteroaryl groups are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N, NH and NCH3; L is selected from C 1-4 Alkylene, C2-C4 alkenylene and C2-C4 alkynylene; Z 1 CR 8 or N; Z 4 CR 11 or N; R 8 , R 9 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 、N(R 13 2. SR 13 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C2-C6 haloalkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CO2R 13 、C(O)R 13 、C(O)N(R 13 )2、C(O)C(O)N(R 13 )2、OC(O)R 13 、OC(O)OR 13 、OC(O)N(R 13 2. OS(O)R 13 、OS(O)N(R 13 2. OSO2R 13 OP(O)(OR 13 )2.OC 1-6 Alkylene P(O)(OR 13 )2. S(O)R 13 、S(O)N(R 13 2. SO2R 13 、N(R 13 )2、N(R 13 )C(O)R 13 、N(R 13 )C(O)OR 13 、N(R 13 )C(O)N(R 13 )2, NO2, C 3-8 Cycloalkyl, C 3-14 Alkylenecycloalkyl, C 3-10 Heterocycloalkyl, C 4-16 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl, C 4-16 Alkylene heteroaryl, The C 1-6 Alkyl, the C 1-6 haloalkyl, the C 2-6 alkenyl, the C2-C6 haloalkenyl, the C 2-6 Alkynyl, the C 2-6 Haloalkynyl, the C 1-6 Alkylamine, the C 1-6 Alkoxy, the C 1-6 Haloalkoxy, the C 3-8 Cycloalkyl, the C 3-14 Alkylene cycloalkyl, the C 3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 4-16 Alkylene heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 13 、C(O)N(R 13 )2.OR 13 、N(R 13 )2, NO2, SR 13 and SO2R 13 , The C 3-8 Cycloalkyl, the C 3-14 Alkylene cycloalkyl, the C 3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 4-16 Each alkylene heteroaryl group is further optionally substituted with a substituent selected from: (O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N and NR 13 ; Each R 13 are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 4-14 Alkylenecycloalkyl, C 3-10 Heterocycloalkyl, C 4-16 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl and C 6-16 Alkylene heteroaryl, The C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 3-8 Cycloalkyl, the C 4-14 Alkylene cycloalkyl, the C 3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 6-16 Each alkylene heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N, NH and NCH3.

2. The compound according to claim 1, wherein R 1 and R 2 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-8 Cycloalkyl, C 7-18 Alkylene aryl and C 4-14 Alkylenecycloalkyl.

3. The compound according to claim 2, wherein R 1 and R 2 are each independently selected from hydrogen, C 1-4 Alkyl, C 3-4 Cycloalkyl and C 7-8 Alkylenyl.

4. The compound according to claim 3, wherein R 1 and R 2 Together with the nitrogen to which it is attached, it forms any of the following:

5. The compound according to claim 1, wherein R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group is optionally substituted by one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 )2.OR 4 、N(R 4 )2, NO2, SR 4 and SO2R 4 、(O)、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 , where R 4 As defined in claim 1.

6. A compound according to any one of claims 1 to 5, wherein R 3 For hydrogen.

7. The compound according to claim 1, wherein R 3 and R 1 and R 2 One of them together with the atom to which it is attached forms C 3-8 Heterocycloalkyl, the C 3-8 The heterocycloalkyl group is further optionally substituted by a substituent selected from the group consisting of halogen, (O), CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2R 4 、C(O)N(R 4 )2.OR 4 、N(R 4 )2, NO2, SR 4 、SO2R 4 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 The heterocycloalkyl group includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, N, S(O), SO2 and NR 4 , where R 4 As defined in claim 1.

8. A compound according to any one of claims 1 to 7, wherein R 8 , R 9 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 、N(R 13 2. SR 13 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C2-C6 haloalkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CO2R 13 、C(O)N(R 13 )2、OC(O)R 13 、OSO2R 13 OP(O)(OR 13 )2.OC 1-6 Alkylene P(O)(OR 13 )2. S(O)R 13 、SO2R 13 、N(R 13 )2, NO2, C 3-8 Cycloalkyl, C 3-14 Alkylenecycloalkyl, C 3-10 Heterocycloalkyl, C 4-16 Alkylene heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkylene aryl, C 5-10 Heteroaryl, C 4-16 Alkylene heteroaryl, The C 1-6 Alkyl, the C 1-6 haloalkyl, the C 2-6 alkenyl, the C2-C6 haloalkenyl, the C 2-6 Alkynyl, the C 2-6 Haloalkynyl, the C 1-6 Alkylamine, the C 1-6 Alkoxy, the C 1-6 Haloalkoxy, the C 3-8 Cycloalkyl, the C 3-14 Alkylene cycloalkyl, the C 3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 4-16 Alkylene heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1-8 Alkoxy, C 1-8 Alkylamino, C 1-8 Alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NO2, NHCH3, SH, SCH3, SO2CH3 and SOCH3, The C 3-8 Cycloalkyl, the C 3-14 Alkylene cycloalkyl, the C 3-10 Heterocycloalkyl, the C 4-16 Alkylene heterocycloalkyl, the C 6-12 Aryl, the C 7-18 Alkylene aryl, the C 5-10 The heteroaryl group and the C 4-16 Each alkylene heteroaryl group is further optionally substituted with a substituent selected from: (O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl, the C 3-6 Heterocycloalkyl includes 1 or 2 ring hetero moieties selected from the group consisting of O, S, S(O), SO2, N, NH and NCH3; Where R 13 As defined in claim 1.

9. The compound according to claim 8, wherein R 8 , R 9 and R 11 One of them, when present, is independently selected from halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and OR 13 , where R 13 Selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl, and R 8 , R 9 and R 11 The others of are each hydrogen.

10. The compound according to claim 9, wherein R 8 , R 9 and R 11 One of is fluorine, chlorine, hydroxyl or OCH3 when present, and R 8 , R 9 and R 11 The others of are each hydrogen.

11. The compound according to any one of claims 1 to 10, wherein L is C 1-4 Alkylene. The compound according to claim 11 , wherein L is methylene.

13. A compound according to any one of claims 1 to 12, having formula (Ia): Where R 1 , R 2 , R 3 , R 8 , R 9 and R 11 As defined in any one of claims 1 to 10.

14. A compound according to any one of claims 1 to 12, wherein Z 1 is N.

15. The compound according to claim 14, which has formula (Ib): Where R 1 , R 2 , R 3 , R 9 and R 11 As defined in any one of claims 1 to 10.

16. A compound according to any one of claims 1 to 12, wherein Z 4 is N.

17. The compound according to claim 16, which has formula (Ic): Where R 1 , R 2 , R 3 , R 8 and R 9 As defined in any one of claims 1 to 10.

18. The compound according to claim 1, selected from any one of the following: or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

19. A medicament comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof and a pharmaceutically acceptable excipient.

21. A method of treating a disease, disorder or condition associated with the activity of a serotonin receptor, the method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

22. A method of treating a disease, disorder or condition associated with the activity of a serotonin receptor, the method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, in combination with another agent that can be used to treat the disease, disorder or condition.

23. A method for treating a mental illness, the method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

24. The method of claim 23, wherein the psychiatric disorder is selected from anxiety disorders; depression; mood disorders; psychotic disorders; impulse control and addiction disorders; drug addiction; obsessive compulsive disorder (OCD); post-traumatic stress disorder (PTSD); stress response syndrome; dissociative disorders; depersonalization disorder; factitious disorder; sexual and gender disorders; somatic symptom disorder; hallucinations; delusions; psychosis; and combinations thereof.

25. A method for treating a central nervous system (CNS) disease, disorder or condition and / or a nervous system disease, disorder or condition, the method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

26. The method of claim 25, wherein the CNS disease, disorder or condition and / or the nervous system disease, disorder or condition is selected from a nervous system disease including neurodevelopmental and neurodegenerative diseases such as Alzheimer's disease; Alzheimer's disease; vascular dementia; Lewy body dementia; 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 disease; fragile X syndrome; Angelman syndrome syndrome); hereditary ataxias; neurological ear and eye movement disorders; neurodegenerative diseases of the retina amyotrophic lateral sclerosis; tardive dyskinesia; ADHD; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorders; tuberous sclerosis; Rett syndrome; cerebral palsy; reward system disorders, including eating disorders such as anorexia nervosa and bulimia nervosa; binge eating disorder, trichotillomania, scratching disorder, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology; and combinations thereof.

27. A method for increasing neuronal plasticity and / or increasing dendritic spine density, the method comprising contacting a neuronal cell with a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof in an amount sufficient to increase the neuronal plasticity of the neuronal cell and / or increase the dendritic spine density of the neuronal cell.

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