Compound

Abstract

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

Description

Technical Field

[0001] This application claims priority to Australian Provisional Application No. 2022901458, filed on May 30, 2022, the entire content of which is incorporated herein by reference.

[0002] The present disclosure generally relates to serotoninergic 5-HT 2A receptor-active compounds useful in the treatment of mental illness or central nervous system disorders. The present disclosure also relates to methods of synthesizing the compounds, compositions containing the compounds, and methods of using them.

Background Art

[0003] Mental illness encompasses many neuropsychiatric disorders that impose a significant burden on the lives of those affected. Diagnoses such as treatment-resistant depression, major depressive disorder, eating disorders, substance use disorders, post-traumatic stress disorder, obsessive-compulsive disorder, attention deficit disorder, schizophrenia, etc. can cause devastating symptoms that can cause many affected individuals to lose the ability to live a normal life.

[0004] A variety of serotoninergic drugs, such as antidepressants, serotonin reuptake inhibitors, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, etc., are commercially available for treating mental illness. Unfortunately, in many indications, these therapeutic agents provide only limited benefit compared to placebo. Additionally, these therapeutic agents can cause a wide range of side effects including loss of libido, insomnia, fatigue, weight gain, etc. Despite their limited effectiveness, these drugs continue to be used to treat neuropsychiatric conditions and a wide range of adjunctive medical indications. Since many of these drugs were launched, progress in new treatment options has been limited, and the pharmaceutical industry is under increasing financial pressure not to fully emphasize neuroscience programs. The unmet need for more effective mental health treatments is increasing, and the global COVID-19 pandemic has the potential to increase the disease burden worldwide.

[0005] From the 1950s to the 1960s, the use of psychedelic drugs for treating various mental illnesses was widely studied, and these substances showed promise as treatments for many diseases of the central nervous system (CNS). After decades of prohibition, scientific research on the application of psychedelics as treatments for mental illness has been on the rise. The serotonin-acting psychedelic 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 many species of mushrooms collectively known as psilocybin mushrooms or "magic mushrooms". Psilocybin is rapidly metabolized into the bioactive compound psilocin, which produces altered states of consciousness including changes in perception, visual hallucinations, and distorted feelings 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 over 50 clinical trials for neuropsychiatric indications, including numerous anxiety disorders, obsessive-compulsive disorder, anorexia nervosa, alcohol dependence, and tobacco dependence. Psilocybin, as well as other psychedelic compounds such as N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), have both immediate and lasting effects on mental state, the latter likely resulting from their ability to induce increased neuroplasticity, promote neurogenesis, and increase the spine density of synaptic neurons in the brain, lasting well beyond the duration of action.

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

[0007] Despite their therapeutic potential, psilocybin and other psychedelics remain scheduled as drugs of abuse in most countries, and commercial routes to market for these drugs as medicines are uncertain. As an adjunct to psychotherapy, the long duration of action of psilocybin and LSD makes treatment sessions costly and not practical for widespread implementation. Despite a long history of safe human use, some adverse events have been reported in clinical trials, which may be due to signal transduction bias at the 5-HT 2A (primary target), or off-target activity at, for example, 5-HT 2B receptors (cardiac liability antitarget) or 5-HT 1A (anxiolytic antitarget) or 5-HT 2C receptors (e.g., obesity and some genetic epilepsy disease-related targets). Naturally occurring psychedelics provide important lead structures for a new generation of neurotherapeutics with novel mechanisms of action and / or greater clinical efficacy than currently available neuropsychiatric drugs.

[0008] In view of the foregoing, there is a continuing need to develop new compounds that may be useful in the treatment of psychiatric or central nervous system disorders.

[0009] Any reference to prior art herein does not admit or suggest that this prior art forms part of the common general knowledge in any jurisdiction, or that this prior art is considered relevant, and / or reasonably foreseeable to be combined with other parts of the prior art, by a person skilled in the art. SUMMARY OF THE INVENTION

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

Chemical formula

[0011] In any aspect or embodiment described herein, the compounds of the invention can be provided in the form of their pharmaceutically acceptable salts, solvates, tautomers, N-oxides, stereoisomers, metabolites, polymorphs, and / or prodrugs.

[0012] In another aspect, the present disclosure provides a pharmaceutical product comprising a compound of formula (I) described in any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, and / or prodrug thereof.

[0013] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) described in 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.

[0014] 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) described in any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, and / or prodrug thereof.

[0015] 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) 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 the treatment of said disease, disorder, or condition.

[0016] In another aspect, the present disclosure provides a method for treating a mental disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, and / or prodrug thereof.

[0017] In some embodiments, the mental disorder is selected from anxiety disorders, depressive disorders, mood disorders, psychotic disorders, impulse control and addiction disorders, substance use disorders, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), stress response syndromes, dissociative disorders, depersonalization disorder, factitious disorder, sexual and gender disorders, somatic symptom disorders, hallucinations, delusions, psychosis, and combinations thereof.

[0018] In another aspect, the present disclosure provides a method for treating a central nervous system (CNS) disorder, disease, or condition, and / or a nervous system disorder, disease, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, and / or prodrug thereof.

[0019] In some embodiments, the CNS disease, disorder, or condition, and / or the nervous system disease, disorder, or condition is a neurodegenerative disease such as a neurodevelopmental disorder and Alzheimer's disease; mild cognitive impairment; senile cognitive impairment; vascular cognitive impairment; Lewy body dementia; cognitive dysfunction, Parkinson's disease, and Parkinson's disease-related diseases such as Parkinson's dementia, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorder; fragile X syndrome; Angelman syndrome; hereditary ataxia; neuro-otological disorders and oculomotor disorders; retinal neurodegenerative diseases, amyotrophic lateral sclerosis; tardive dyskinesia; hyperkinetic disorders; 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; hyperphagic disorders, trichotillomania, skin picking, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology, and combinations thereof, selected from diseases of the nervous system.

[0020] In another aspect, the present disclosure provides a method for increasing neuroplasticity and / or increasing dendritic spine density, the method comprising contacting a nerve cell with a therapeutically effective amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, and / or prodrug thereof, thereby increasing the neuroplasticity and / or increasing the dendritic spine density of the nerve cell.

[0021] In another aspect, the present disclosure provides a method for treating body weight, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention. Treatment of body weight can include weight gain; weight loss; metabolic disorders; weight gain associated with pharmaceutical intervention; weight gain associated with psychiatric disorders (including those described herein); eating disorders such as anorexia, bulimia, cachexia; eating behavior; obesity; diabetes; insulin resistance; prediabetes; glucose intolerance; hyperlipidemia; and treatment of cardiovascular diseases.

[0022] In another aspect, the present disclosure provides a method for activating a serotonin receptor in a biological sample or any cell of a patient, the method comprising administering to the cell a compound of formula (I) described herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, and / or prodrug thereof.

[0023] The present disclosure should not be limited in scope by the specific embodiments described herein which are intended to be illustrative only. Functionally equivalent products, compositions, and methods are clearly within the scope of the present invention as described herein.

Best Mode for Carrying Out the Invention

[0024] The invention disclosed and defined herein is understood to extend to all alternative combinations of two or more of the individual features mentioned or apparent from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

[0025] Definitions For the purposes of interpreting this specification, terms used in the singular include the plural and vice versa.

[0026] As used herein, the term "comprise", and variations such as "comprising", "comprises", and "comprised", are not intended to exclude further additives, components, integers, or steps, unless the context requires otherwise.

[0027] The term "treatment" or "treating" as used herein is intended to include delaying, slowing, stabilizing, curing, healing, reducing, alleviating, modifying, repairing, making less bad, improving, or affecting a disease or condition, a symptom or manifestation of a disease or condition, or a risk (or susceptibility) of a disease or condition. The term "treating" refers to any objective or subjective parameter including, for example, regression; remission; decrease in rate of worsening; decrease in severity of a disease; stabilization; reduction of a symptom or manifestation or making an injury more tolerable to an individual; slowing of a rate of degeneration or decline; making an endpoint of degeneration less debilitating, and the like, and refers to any indication of success in the treatment or improvement of an injury, condition, or disease.

[0028] In particularly preferred embodiments, the methods of the invention can be to prevent or reduce the severity of a symptom or manifestation of a disease or condition described herein, or to inhibit or minimize its progression. Accordingly, the methods of the invention have utility as both a treatment and a prophylaxis.

[0029] As used herein, "preventing" or "prevention" is intended to refer at least to reducing the likelihood (i.e., making it less likely) of acquiring a risk (or susceptibility) of a disease or disorder (i.e., preventing at least one of the clinical symptoms or manifestations of the disease from occurring in an individual who may be at risk of or susceptible to exposure to the disease but who has not yet experienced or exhibited the symptoms or manifestations of the disease). Biological and physiological parameters for identifying such patients are provided herein and are well known to physicians.

[0030] As used herein, the terms "subject" or "patient" can be used interchangeably. The terms "individual" or "patient" each refer to an animal treatable by a compound and / or method, including, but not limited to, for example, dogs, cats, horses, sheep, pigs, cows, etc., as well as humans and non-human primates. Unless otherwise specified, "subject" or "patient" can include both male and female genders. Further, this includes subjects or patients suitable for treatment with the pharmaceutical compositions and / or methods of the present invention, preferably humans.

[0031] The term "selective" means higher activity against a first target (e.g., a first 5-HT receptor subtype) compared to a second target (e.g., a second 5-HT receptor subtype). In some embodiments, the compound has a selectivity ratio that 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 higher against the first target compared to the second target. In some embodiments, the compounds described herein are selective for the 5-HT 2B and / or 5-HT 2C , preferably 5-HT 2B and the like, compared to one or more other 5-HT receptor subtypes. In some embodiments, the compounds described herein are selective for the 5-HT 2A receptor compared to one or more other 5-HT receptor subtypes such as 5-HT 2A and / or 5-HT 2B , preferably 5-HT 2B . In some embodiments, the compounds described herein are selective for the 5-HT 2C receptor compared to one or more other 5-HT receptor subtypes such as 5-HT

[0032] Various features of the present disclosure are described with reference to certain values or ranges of values. These values are intended to relate to the results of various suitable measurement techniques and, accordingly, should be construed as including the error ranges inherent in any particular measurement technique. Some of the values referred to herein are indicated by the term "about" to account for at least part of this variability. The term "about" when used to describe a value can mean an amount within ±10%, ±5%, ±1%, or ±0.1% of that value.

[0033] Ranges: Throughout the present disclosure, various aspects of the invention can be presented in range format. The description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Thus, a range recitation is to be considered as specifically disclosing all the possible subranges and individual numerical values within that range. For example, a range recitation such as 1 - 6 is to be considered as specifically disclosing subranges such as 1 - 3, 1 - 4, 1 - 5, 2 - 4, 2 - 6, 3 - 6, etc., as well as individual numbers within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the width of the range.

[0034] As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon radical having from 1 to 12 carbon atoms, or any range 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 substituents. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, t - butyl, n - pentyl, isopentyl, etc.

[0035] As used herein, the terms "C1-C2 alkyl", "C1-C3 alkyl", and "C1-C6 alkyl" refer to alkyl groups as defined herein, each containing at least 1 and up to 2, 3, or 6, or any range therebetween (e.g., an alkyl group containing 2-5 carbon atoms is also within the C1-C6 range) carbon atoms respectively.

[0036] The term "alkylene" refers to a straight or branched saturated aliphatic radical having the indicated number of carbon atoms and connecting at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties connected to the alkylene may be connected to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene can be a divalent radical of -(CH2) n -, where 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.

[0037] 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 two of its termini. The possible number of carbon atoms in the alkylene group being referred to is indicated by the prefix "C n1~n2 ". For example, the term C 2~6 alkylene means an alkylene group having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups 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.

[0038] As used herein, the term "alkynyl", whether used alone or as part of another group, means a straight-chain or branched-chain unsaturated alkynyl group containing at least one triple bond. The number of carbon atoms possible in the alkynyl group referred to is indicated by the prefix "C n1~n2 ". For example, C 2~6 The term 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, butadynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatriynyl.

[0039] The term "cycloalkyl" is intended to include monocyclic, bicyclic, or tricyclic alkyl groups. The number of carbon atoms possible in the cycloalkyl group referred to is indicated by the prefix "C n1~n2 ". For example, C 3~8The term "cycloalkyl" means a cycloalkyl group having 3, 4, 5, 6, 7, or 8 carbon atoms. In some embodiments, the cycloalkyl group has 3 to 12, 3 to 10, 3 to 8, 3 to 6, or 3 to 5 carbon atoms in the ring. In some embodiments, the cycloalkyl group has 5 or 6 ring carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group 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, spiro, and fused cycloalkyl ring systems. Examples of bicyclic and tricyclic cycloalkyl systems include, but are not limited to, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, adamantyl, and decalinyl.

[0040] The term "alkylenecycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, wherein the alkyl component links the cycloalkyl component at a point of attachment. The alkyl component is as previously defined, except that the alkyl component is at least a divalent alkylene and is linked to the cycloalkyl component and the point of attachment. In some instances, the alkyl component may be absent. The alkyl component may contain any number of carbons, 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 etc. The cycloalkyl component is as defined herein. "C x~y alkylenecycloalkyl 」The numerical range of x to y is related to the total number of alkyl carbons and cycloalkyl ring atoms. Exemplary alkylene cycloalkyl groups include, but are not limited to, methylene cyclopropyl, methylene cyclobutyl, methylene cyclopentyl, and methylene cyclohexyl.

[0041] 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 possible in the aryl groups referred to is indicated by the prefix "C" n1~n2 ". For example, C 6~12 The term aryl means an aryl group having 6, 7, 8, 9, 10, 11, or 12 carbon atoms. An aryl group can contain any suitable number of ring atoms, e.g., 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. An aryl group can be monocyclic, fused to form a bicyclic or tricyclic group, or linked by bonds to form a biaryl group. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl having a methylene linking group. Some aryl groups have 6 to 12 ring members such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members such as phenyl or naphthyl. Some other aryl groups have 6 ring members such as phenyl.

[0042] The term "alkylene aryl" refers to a radical having an alkyl component and an aryl component, wherein the alkyl component links the aryl component at a point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene and links the aryl component and the point of attachment. The alkyl component is C 1~6 , C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 2~3 , C 2~4 , C2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 , and C 5~6 can contain any number of carbons such as C, etc. In some cases, there may be no alkyl component. The aryl component is as defined above. The numerical range of x to y for "C x~y alkylene aryl" is related to the total number of alkyl carbons and aryl ring atoms. Examples of alkylene aryl groups include, but are not limited to, benzyl and ethylene phenyl.

[0043] As used herein, the term "alkoxy" refers to an alkyl group as defined herein that is covalently bonded through an O-linkage. The alkoxy group is optionally substituted with substituents. As used herein, examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and pentoxy.

[0044] As used herein, the terms "C1-C2 alkoxy", "C1-C3 alkoxy", and "C1-C6 alkoxy" refer to alkoxy groups as defined herein that contain at least 1 and at most 2, 3, or 6, or any range in between (e.g., an alkoxy group containing 2-5 carbon atoms is also within the C1-C6 range) carbon atoms, respectively.

[0045] As used herein, the term "alkylamine" refers to an alkyl group as defined herein having one or more amino groups. The amino group can be primary, secondary, or tertiary. The alkylamine can be further substituted with a hydroxy group to form an amino-hydroxy group. Examples of alkylamines include, but are not limited to, ethylamine, propylamine, isopropylamine, ethylenediamine, and ethanolamine. The amino group can be linked to the point of attachment of the alkylamine to the rest of the compound, at the omega position of the alkyl group, or can link together at least two carbon atoms of the alkyl group.

[0046] As used herein, the terms "C1-C2 alkylamine", "C1-C3 alkylamine", and "C1-C6 alkylamine" refer to alkylamine groups as defined herein each containing at least one and up to a maximum of 2, 3, or 6, or any range therebetween (e.g., an alkylamine group containing 2-5 carbon atoms is also within the C1-C6 range) carbon atoms.

[0047] As used herein, the term "alkylsulfonyl" refers to an alkyl group as defined herein having one or more sulfonyl groups. The sulfonyl group can be linked to the point of attachment of the alkylsulfonyl to the rest of the compound, at the omega position of the alkyl group, or can link together at least two carbon atoms of the alkyl group.

[0048] As used herein, the terms "C1-C2 alkylsulfonyl", "C1-C3 alkylsulfonyl", and "C1-C6 alkylsulfonyl" refer to alkylsulfonyl groups as defined herein each containing at least one and up to a maximum of 2, 3, or 6, or any range therebetween (e.g., an alkylsulfonyl group containing 2-5 carbon atoms is also within the C1-C6 range) carbon atoms.

[0049] As used herein, the term "heteroatom" means 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 S, preferably N and O.

[0050] 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.

[0051] As used herein, "substituent" refers to a molecular moiety that is covalently bonded to an atom within the molecule of interest. For example, a "ring substituent" can be a moiety such as a halogen, an alkyl group, or another substituent described herein that is covalently bonded to an atom that is a ring member, preferably a carbon atom or a nitrogen atom. As used herein, the term "substituted" means that any one or more hydrogens on the designated atom are replaced with a selection from the designated substituents, 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.

[0052] Terms such as "optionally substituted" or "substitutable" are used throughout this specification to indicate that a group may or may not be further substituted or condensed with one or more non-hydrogen substituents (such as to form a polycyclic system). Suitable chemically practicable substituents for a particular functional group will be apparent to those skilled in the art.

[0053] 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 alkylsulfenyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, arylsulfonoamino, alkylcarboxy, alkylcarboxamide, oxo, hydroxy, mercapto, amino, acyl, carboxy, carbamoyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo, ureido, C1-C6 perfluoroalkyl. Preferably, the substituents include amino, halo, C1-C6 alkyl, amide, and hydroxyl.

[0054] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), and the term "halo" refers to the fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I) halogen radicals. Preferably, "halo" is fluoro or chloro.

[0055] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein in which one or more (up to all) of the available hydrogen atoms are replaced by halogen. In some instances, the term "perfluoro" can be used to define a compound or radical in which all hydrogens are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0056] As used herein, the terms "C1-C2 haloalkyl", "C1-C3 haloalkyl", and "C1-C6 haloalkyl" refer to haloalkyl groups as defined herein that each contain at least 1 and up to 2, 3, or 6, or any range in between (e.g., a haloalkyl group containing 2-5 carbon atoms is also within the C1-C6 range) carbon atoms respectively.

[0057] For example, a C1 haloalkyl group can be, but is not limited to, fluoromethyl, or difluoromethyl, or trifluoromethyl.

[0058] As used herein, the term "haloalkenyl" refers to an alkenyl group as previously defined in which one or more of the available hydrogen atoms are replaced by halogen. Thus, for example, "C 1~6 haloalkenyl" (or "C1-C6 haloalkenyl") refers to a C1-C6 straight-chain or branched alkenyl group as previously defined having one or more halogen substituents.

[0059] As used herein, the term "haloalkynyl" refers to an alkynyl group as previously defined in which one or more of the available hydrogen atoms are replaced by halogen. Thus, for example, "C 1~6 haloalkynyl" (or "C1-C6 haloalkynyl") refers to a C1-C6 straight-chain or branched alkynyl group as previously defined having one or more halogen substituents.

[0060] As used herein, the term haloalkoxy refers to an alkoxy group as defined herein that is substituted with at least one halogen.

[0061] The term "amino" or "amine" refers to the group -NH2.

[0062] The term "substituted amino" or "secondary amino" refers to an amino group in which hydrogen is substituted with, for example, a C1-C6 alkyl group ("C1-C6 alkylamino"), an aryl or aralkyl group ("arylamino", "aralkylamino"), etc. For example, C1-C3 alkylamino groups such as methylamino (NHMe), ethylamino (NHEt), and propylamino (NHPr) are preferred.

[0063] The term "disubstituted amino" or "tertiary amino" refers to an amino group in which two hydrogens are substituted with, for example, C1-C6 alkyl groups (which may be the same or different) ("dialkylamino"), aryl and alkyl groups ("aryl(alkyl)amino"), etc. For example, di(C1-C3 alkyl)amino groups such as dimethylamino (NMe2), diethylamino (NEt2), dipropylamino (NPr2), and their modified forms (e.g., N(Me)(Et), etc.) are preferred.

[0064] The term "nitro" refers to the group -NO2.

[0065] The terms "cyano" and "nitrile" refer to the group -CN.

[0066] The term "amido" or "amide" refers to the group -C(O)NH2.

[0067] The term "substituted amido" or "substituted amide" refers to an amide group in which hydrogen is substituted with, for example, a C1-C6 alkyl group ("C1-C6 alkylamide" or "C1-C6 alkylamide"), an aryl ("arylamide"), an aralkyl group ("aralkylamide"), etc. For example, C1-C3 alkylamide groups such as methylamide (-C(O)NHMe), ethylamide (-C(O)NHEt), and propylamide (-C(O)NHPr) are preferred, including their reverse amides (e.g., NHMeC(O)-, -NHEtC(O)-, and -NHPrC(O)-).

[0068] The term "disubstituted amido" or "disubstituted amide" refers to an amide group in which two hydrogens are replaced, for example, by C1-C6 alkyl groups ("di(C1-C6 alkyl)amide" or "di(C1-C6 alkyl)amide"), aralkyl and alkyl groups ("alkyl(aralkyl)amide"), etc. For example, di(C1-C3 alkyl)amide groups such as dimethylamide (-C(O)NMe2), diethylamide (-C(O)NEt2) and dipropylamide ((-C(O)NPr2), and their variants (e.g., C(O)N(Me)Et, etc.) are preferred, including their reverse amides.

[0069] The term "sulfonyl" refers to the group -SO2H.

[0070] The term "substituted sulfonyl" refers to a sulfonyl group in which hydrogen is replaced, for example, by C1-C6 alkyl groups ("sulfonyl C1-C6 alkyl"), aryl ("arylsulfonyl"), aralkyl ("aralkylsulfonyl"), etc. For example, sulfonyl C1-C3 alkyl groups such as -SO2Me, -SO2Et, and -SO2Pr are preferred.

[0071] The term "sulfonylamido" or "sulfonamide" refers to the group -SO2NH2.

[0072] The term "substituted sulfonamido" or "substituted sulphonamide" refers to a sulfonylamide group in which hydrogen is substituted by, for example, a C1-C6 alkyl group ("sulfonylamide C1-C6 alkyl"), aryl ("arylsulfonamide"), aralkyl ("aralkylsulfonamide"), etc. For example, sulfonylamide C1-C3 alkyl groups such as SO2NHMe, SO2NHEt, and SO2NHPr are preferred, and include their reverse sulfonamides (for example, -NHSO2Me, NHSO2Et, and -NHSO2Pr).

[0073] The term "disubstituted sufonamido" or "disubstituted sulphonamide" refers to a sulfonylamide group in which two hydrogens are substituted by, for example, C1-C6 alkyl groups (which may be the same or different) ("sulfonylamide di(C1-C6 alkyl)"), aralkyl, and alkyl groups ("sulfonamide(aralkyl)alkyl"), etc. For example, sulfonylamide di(C1-C3 alkyl) groups such as -SO2NMe2, -SO2NEt2, and -SO2NPr2, and their modified forms (for example, SO2N(Me)Et, etc.) are preferred, and include their reverse sulfonamides (for example, -N(Me)SO2Me, etc.).

[0074] The term "sulfate" refers to the group OS(O)2OH and includes groups in which hydrogen is replaced by, for example, a C1-C6 alkyl group ("alkyl sulfate"), aryl ("aryl sulfate"), aralkyl ("aralkyl sulfate"), etc. For example, C1-C3 alkyl sulfates such as OS(O)2OMe, OS(O)2OEt, and OS(O)2OPr are preferred.

[0075] The term "sulfonate" refers to the group SO3H, where the hydrogen is replaced by, for example, a C1-C6 alkyl group ("alkyl sulfonate"), aryl ("aryl sulfonate"), aralkyl ("aralkyl sulfonate"), etc. For example, C 1~ C3 alkyl sulfonate is preferred.

[0076] The term "amino acid" as defined herein refers to a moiety containing an amino group and a carboxyl group linked by at least one carbon. Amino acids can refer to natural or unnatural 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, and valine, and preferably the amino acid is arginine, lysine, or histidine, most preferably lysine.

[0077] The term "carboxylate" or "carboxyl" refers to the group -COO- or -COOH.

[0078] The term "carbamate" or "carbamoyl" refers to the group -OC(O)NH2. Carbamate can be substituted or disubstituted with, for example, an alkyl group such as a C1-C6 alkyl, but is not limited thereto.

[0079] The term "carbonate" refers to the group -OC(O)O- or -OC(O)OH.

[0080] As used herein, the term "alkyl carbonate" refers to a carbonate group in which hydrogen is replaced by, for example, a C1-C6 alkyl group, an aryl or an aralkyl group ("aryl carbonate" or "aralkyl carbonate"). For example, CO3C1-C3 alkyl groups such as methyl carbonate (CO3Me), ethyl carbonate (CO3Et), and propyl carbonate (CO3Pr) are preferred.

[0081] The term "ester" refers to a carboxyl group in which hydrogen is replaced by, for example, a C 1~ C6 alkyl group ("C1-C6 alkyl carboxylate" or "alkyl ester"), an aryl or an aralkyl group ("aryl ester" or "aralkyl ester"). For example, CO2C1-C3 alkyl groups such as methyl ester (CO2Me), ethyl ester (CO2Et), and propyl ester (CO2Pr) are preferred, and their reverse esters (e.g., -OC(O)Me, -OC(O)Et, and -OC(O)Pr) are included.

[0082] The term "heterocyclyl" (unless otherwise specified) refers to a moiety obtained by removing a hydrogen atom from the ring atoms of a heterocyclic compound having 3 to 12 ring atoms (one or more, two or more, three or more, four or more of which are ring heteroatoms independently selected from, for example, O, S, and N, or ring heteroatoms selected from ring hetero moieties independently selected from, for example, O, S, S(O), SO2, N, and NH). When the heterocyclyl group contains the prefix C n1~n2 or "n1-n2", this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, and one or more, preferably one, two, three, four or more of the ring atoms are replaced by heteroatoms or hetero moieties.

[0083] In this context, the prefixes 3-, 4-, 5-, 6-, 7-, 8-, 9-, and 10-membered indicate the number of ring atoms, or the range of ring atoms, regardless of whether they are carbon atoms or heteroatoms. For example, as used herein, "C 3~10The term "heterocyclyl" or "3- to 10-membered heterocyclyl" relates to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms. Examples of heterocyclyl groups include 5- to 6-membered monocyclic heterocyclyls and 9- to 10-membered fused bicyclic heterocyclyls.

[0084] Examples of monocyclic heterocyclyl groups include those 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, isazole) or pyrrolidinone (5-membered ring), piperidine, dihydropyridine, tetrahydropyridine (6-membered ring), and azepine (7-membered ring); those containing two nitrogen atoms such as imidazoline, pyrazolidine (diazolidine), imidazoline, pyrazoline (dihydropyrazole) (5-membered ring), piperazine (6-membered ring); those containing one oxygen atom such as oxirane (3-membered ring), oxetane (4-membered ring), oxolane (tetrahydrofuran), oxole (dihydrofuran) (5-membered ring), oxane (tetrahydropyran), dihydropyran, pyran (6-membered ring), oxepine (7-membered ring); those containing two oxygen atoms such as dioxolane (5-membered ring), dioxane (6-membered ring), and dioxepane (7-membered ring); those containing three oxygen atoms such as trioxane (6-membered ring); those containing one sulfur such as thiirane (3-membered ring), thietane (4-membered ring), thiolane (tetrahydrothiophene) (5-membered ring), thiane (tetrahydrothiopyran) (6-membered ring), thiepine (7-membered ring); those containing one nitrogen and one oxygen atom such as tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole (5-membered ring), morpholine, tetrahydrooxazine, dihydrooxazine, oxazine (6-membered ring); those containing one nitrogen and one sulfur atom such as thiazoline, thiazolidine (5-membered ring), thiomorpholine (6-membered ring); those containing two nitrogen and one oxygen atom such as oxadiazine (6-membered ring); those containing one oxygen and one sulfur such as oxathiol (5-membered ring) and oxathiane (thioxane) (6-membered ring); and those containing one nitrogen, one oxygen and one sulfur atom such as oxathiazine (6-membered ring), but are not limited thereto.

[0085] Heterocyclyl includes heteroaryl (aromatic heterocyclyl) and heterocycloalkyl (non-aromatic heterocyclyl). Such groups may or may not be substituted.

[0086] The term "aromatic heterocyclyl" can be used interchangeably with the term "heteroaromatic", or the terms "heteroaryl" or "hetaryl". The heteroatoms in an aromatic heterocyclyl group can be independently selected from N, S, and O. An aromatic heterocyclyl group can contain 1, 2, 3, 4 or more ring heteroatoms. When a heteroaryl group contains a prefix C n1~n2 or "n1-n2", this prefix indicates the number of carbon atoms in the corresponding aryl group, and one or more, preferably 1, 2, 3, 4 or more of the ring atoms are replaced by heteroatoms. In the case of a fused aromatic heterocyclyl group, only one of the rings may contain heteroatoms, and not all of the rings need to be aromatic.

[0087] As used herein, "heteroaryl" is used to denote a heterocyclic ring having aromatic character and includes aromatic monocyclic ring systems and polycyclic (e.g., bicyclic) ring systems containing one or more aromatic rings. The term aromatic heterocyclyl also includes pseudoaromatic heterocyclyl. The term "pseudoaromatic" refers to a ring system that is not strictly aromatic but is stabilized by electron delocalization and acts in a similar manner to an aromatic ring. Thus, the term aromatic heterocyclyl includes polycyclic ring systems in which all of the fused rings are aromatic, provided that at least one ring is aromatic, as well as ring systems in which one or more rings are non-aromatic. In a polycyclic system containing both fused aromatic and non-aromatic rings, the group may be attached to another moiety by an aromatic ring or by a non-aromatic ring.

[0088] Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 10 ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring, or a bicyclic structure formed from fused 5- and 6-membered rings, or 2 fused 6-membered rings, or 2 fused 5-membered rings. Each ring can typically contain up to about 4 heteroatoms selected from nitrogen, sulfur, and oxygen. The heteroaryl ring contains up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2 heteroatoms, for example, a single heteroatom. In one embodiment, the heteroaryl ring contains at least 1 ring nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or can be essentially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents on the ring, is less than 5.

[0089] The aromatic heterocyclyl group can be a 5- or 6-membered monocyclic aromatic ring system.

[0090] 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 furazanyl, i.e., 1,2,5-oxadiazolyl), thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1,2,3, 1,2,4, and 1,3,4 triazolyl), oxatriazolyl, tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyl), and the like.

[0091] 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 heterocyclyls containing nitrogen include pyridyl (one nitrogen), pyrazinyl, pyrimidinyl, and pyridazinyl (two nitrogens).

[0092] The aromatic heterocyclyl group can also be a bicyclic or polycyclic heteroaromatic ring system, for example, a fused ring system (including purine, pteridinyl, naphthyridinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, etc.) or a linked ring system (oligothiophene, polypyrrole, etc.). The fused ring system can also include a 5-membered or 6-membered heterocyclyl fused to a carbocyclic aromatic ring such as phenyl, naphthyl, indenyl, azulene, fluorenyl, anthracenyl, etc., for example, a 5-membered aromatic heterocyclyl containing nitrogen fused to a phenyl ring, or a 5-membered aromatic heterocyclyl containing one or two nitrogens fused to a phenyl ring.

[0093] The bicyclic heteroaryl group can be, for example, a) a benzene ring condensed to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, b) a pyridine ring condensed to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, c) a pyrimidine ring condensed to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, d) a pyrrole ring condensed to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, e) a pyrazole ring condensed to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, f) an imidazole ring condensed to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, g) an oxazole ring condensed to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, h) an isoxazole ring condensed to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, i) a thiazole ring condensed to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, j) an isothiazole ring condensed to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, k) a thiophene ring condensed to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, I) a furan ring condensed to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, m) a cyclohexyl ring condensed to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, and n) a cyclopentyl ring condensed to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms.

[0094] Specific examples of bicyclic heteroaryl groups containing a 5-membered ring condensed to another 5-membered ring include, but are not limited to, imidazothiazole (e.g., imidazo[2,1-b]thiazole) and imidazoimidazole (e.g., imidazo[1,2-a]imidazole).

[0095] 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, benzoisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, 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. Further examples of six-membered rings fused to a five-membered ring are pyrrolopyridine groups such as the pyrrolo[2,3-b]pyridine group.

[0096] 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.

[0097] 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]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoiine, isoindoline, and indane groups.

[0098] Accordingly, examples of aromatic heterocycles fused to a carbocyclic aromatic ring include, but are not limited to, benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, isobenzoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl, etc.

[0099] 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 hetero moieties 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 a heterocycloalkyl group contains the prefix C n1~n2 or "n1~n2", this prefix indicates the number of ring atoms, and one or more of the ring atoms, preferably 1, 2, 3, 4 or more, are replaced by heteroatoms or hetero moieties. The ring can be a monocyclic ring or part of a polycyclic ring system. The polycyclic ring system includes fused rings and spiro rings. Not all rings in a non-aromatic heterocyclic polycyclic system have to contain heteroatoms, provided that at least one ring contains one or more heteroatoms.

[0100] Non-aromatic heterocyclyl can be a 3- to 8-membered monocyclic ring.

[0101] 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-dioxalanyl, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl, etc.

[0102] Examples of 6-membered non-aromatic heterocyclyls include piperidinyl, piperidinonyl, pyranyl, dihydropyranyl, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, thianyl, thianyl oxide, thianyl dioxide, piperazinyl, dioxanyl, 1,4-dioxinyl, 1,4-dithianyl, 1,3,5-trioxalanyl, 1,3,5-trithianyl, 1,4-morpholinyl, thiomorpholinyl, 1,4-oxathianyl, triazinyl, 1,4-thiazinyl, and the like.

[0103] Examples of 7-membered non-aromatic heterocyclyls include azepanyl, oxepanyl, thiepanyl, and the like.

[0104] The non-aromatic heterocyclyl ring can also be a bicyclic heterocyclyl ring such as a linked ring system (e.g., uridinyl, etc.) or a fused ring system. Examples of the fused ring system include non-aromatic 5-membered, 6-membered, or 7-membered heterocyclyls fused to a carbocyclic aromatic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, and the like. Examples of non-aromatic 5-membered, 6-membered, or 7-membered heterocyclyls fused to a carbocyclic aromatic ring include indolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl, and the like.

[0105] The term "alkylene heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, and the alkyl component links 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) and links to the heteroaryl component and the point of attachment. In some cases, the alkyl component may be absent. The alkyl component is 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 C3~6 , C 4~5 , C 4~6 , and C 5~6 may contain any number of carbons such as. The heteroaryl component is as defined herein. "C x~y alkylene cycloalkyl 」 The numerical range of x to y of "" is related to the total number of alkyl carbons and heteroaryl ring atoms (carbons and heteroatoms combined).

[0106] The term "alkylene heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, and the alkyl component connects the heterocycloalkyl component at the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene and is connected to the heterocycloalkyl component and the point of attachment. In some cases, the alkyl component may be absent. The alkyl component is 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 may contain any number of carbons such as. The heterocycloalkyl component can be any heterocycloalkyl as defined herein. "C x~y The numerical range of x to y of "" alkylene heterocycloalkyl is related to the total number of alkyl carbons and heterocycloalkyl ring atoms (carbons and heteroatoms combined).

[0107] The term "pharmaceutically acceptable" is used to describe any salt, solvate, tautomer, N-oxide, stereoisomer, and / or prodrug of a compound, or any other compound, which when administered to a subject is capable of providing (directly or indirectly) the compound described herein or an active metabolite or residue thereof, and which is typically not harmful to the subject.

[0108] As used herein, the term "solvate" refers to a complex of a compound with a solvent, in either a stoichiometric or non-stoichiometric amount. Solvates are often 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.

[0109] As used herein, the term "polymorph" refers to different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Depending on various factors such as the recrystallization solvent, the rate of crystallization, and the storage temperature, a single crystal form can become dominant.

[0110] 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 biologically active derivative of a compound formed when the compound is metabolized. As used herein, the term "is metabolized" refers to the sum of processes by which a particular substance is changed by an organism (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes). Thus, enzymes can bring about specific structural changes to a compound. Metabolites of the compounds disclosed herein are optionally identified by either administration of the compound to a host and analysis of tissue samples from the host, or incubation of the compound with hepatocytes in vitro and analysis of the resulting compounds.

[0111] A "prodrug" is a compound that may not fully meet the structural requirements of the compounds provided herein, but is modified in vivo after administration to a subject or patient to produce a compound of formula (I) provided herein. For example, a prodrug can be an acylated derivative of a compound provided herein. A prodrug includes a compound in which a hydroxy, carboxy, amine, or sulfhydryl group is attached to any group that cleaves upon administration to a mammalian subject to form a free hydroxy, carboxy, 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 within the compounds provided herein. The prodrugs of the compounds provided herein can be prepared by modifying the functional groups present in the compounds in such a way that the modification is cleaved in vivo to produce the parent compound.

[0112] A prodrug includes a compound 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 bonded to a free amino and an amide group of a compound of formula (I). Amino acid residues include the 20 naturally occurring amino acids commonly designated by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. A prodrug also includes a compound in which a carbonate, carbamate, amide, and alkyl ester are covalently bonded to a previous substituent of formula (I) via a carbonyl carbon prodrug side chain.

[0113] The compounds of formula (I) can exhibit tautomerism. Tautomers are typically two exchangeable forms of a molecule that exist in equilibrium. Any tautomer of a compound of formula (I) should be understood to be within the scope of the present invention.

[0114] The definitions and conventions of stereochemistry used herein generally follow 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. Compounds of the present invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. The term “stereoisomer” refers to compounds having the same chemical composition but differing in the arrangement 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 the compounds of formula (I) are within the scope of the present invention. In some embodiments, the compounds are in a stereoisomerically enriched form of the compounds of formula (I) at any stereocenter. The compound may be enriched in one stereoisomer by at least about 60, 70, 80, 90, 95, 98, or 99% compared to another stereoisomer.

[0115] Salts of the compounds of formula (I) are preferably pharmaceutically acceptable, but non-pharmaceutically acceptable salts may also be useful as intermediates, for example, in the preparation of pharmaceutically acceptable salts or in methods that do not require administration to a subject, and are understood to be within the scope of the present disclosure.

[0116] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or using organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange. 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, laurylsulfate, maleate, 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 salts, and the like.

[0117] Further aspects of the present invention and further embodiments of the aspects described in the previous paragraphs will become apparent from the following description and are given by way of example and with reference to the accompanying drawings.

Brief Description of the Drawings

[0118]

Figure 1

Figure 2

Figure 3

Figure 4

[0119] Compound The present disclosure relates to compounds of formula (I) that are surprisingly active at at least one serotonin receptor subtype. Preferred embodiments are 5-HT 2A receptor or 5-HT 2C receptor, typically being selective for either 5-HT 2B subtype over 5-HT 2A or 5-HT 2C and more selective for 5-HT 2C over 5-HT 2A or more selective for 5-HT 2A over 5-HT 2C and can be even more selective for 5-HT

[0120] The present disclosure relates to formula (I): [Chemistry] a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, and / or prodrug thereof, wherein: In the formula: 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 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl, C 3~8 cycloalkyl, C 4~14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 alkylenheterocycloalkyl, C 6~12 aryl, C 7~18 alkylenearyl, C 5~10 heteroaryl, and C 6~16 alkylenheteroaryl; wherein said C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl, C 3~8 cycloalkyl, C 4~14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 alkylenheterocycloalkyl, C 6~12 aryl, C 7~18 alkylenearyl, C 5~10 heteroaryl, and C 6~16 alkylenheteroaryl are optionally substituted with 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(R4 ) 2, NO2, SR 4 and SO2R 4 each optionally substituted with one or more substituents independently selected from the C 3~8 cycloalkyl, C 4~14 alkylenecycloalkyl, C3 - C8 heterocycloalkyl, C4 - C 14 alkylenheterocycloalkyl, C 6~12 aryl, C 7~18 alkylenearyl, C 5~10 heteroaryl, and C 6~16 alkylenheteroaryl, (O), C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl, C 3~6 cycloalkyl, and C with one or two ring hetero moieties selected from O, S, N, S(O), SO2, and NR 4 each further optionally substituted with substituents independently selected from heterocycloalkyl 3~6 or alternatively, R and R 1 together with the nitrogen atom to which they are attached form a C 2 heterocycloalkyl containing one or two additional ring hetero moieties selected from O, S, S(O), SO2, N, and NR 4 wherein the C 3~8 heterocycloalkyl is halogen, (O), CN, C the C 3~8 heterocycloalkyl is 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, C1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~8 Alkylamino, C 1~8 Alkylsulfonyl, C 3~6 Cycloalkyl, and C containing one or two ring hetero moieties selected from O, S, N, S(O), SO2, and NR 4 Optionally further substituted with a substituent selected from heterocycloalkyl, 3~6 wherein R is hydrogen, C 3 alkyl, C 1~6 cycloalkyl, or C 3~8 alkylenecycloalkyl, 4~14 selected from, alternatively, R 3 and one of R 1 and R 2 together with the atom to which they are attached form a C 3~12 heterocycloalkyl, wherein said C 3~12 heterocycloalkyl is 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 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl, C 3~6 cycloalkyl, and C containing one or two ring hetero moieties selected from O, S, N, S(O), SO2, and NR 4 Optionally further substituted with a substituent selected from heterocycloalkyl, 3~6 wherein each R 4 is independently selected from hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl, C 3~7 cycloalkyl, and C containing one or two ring hetero moieties selected from O, S, S(O), SO2, N, and NR 5 heterocycloalkyl, and is optionally substituted with one or more substituents independently selected from 3~7 halogen, CN, C said C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl, C 3~7 cycloalkyl, and C 3~7 heterocycloalkyl is optionally substituted with one or more substituents independently selected from 1~8 halogen, CN, C 1~8 alkoxy, C 1~8 alkylamino, C 5 alkylsulfonyl, CO2R 5 , C(O)N(R 5 )2, OR 5 , N(R 5 )2, NO2, SR 5 , and SO2R said C3-C7 cycloalkyl and C 3~7 heterocycloalkyl is (O), C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl, C 3~6 cycloalkyl, and C containing one or two ring hetero moieties selected from O, S, S(O), SO2, N, and NR 5 heterocycloalkyl 3~6Each is further optionally substituted with a substituent independently selected from heterocycloalkyl, each R 5 is 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, and said 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 is optionally substituted with one or more substituents independently selected from 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 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl, C 3~6 cycloalkyl, and C 3~6 heterocycloalkyl optionally substituted with one or more substituents independently selected from 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 is CR 8 or N, Z4 is CR 11 or N, R 8 , R 9 , and R 11 are 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 alkyleneP(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 alkylenheterocycloalkyl, C 6~12 aryl, C 7~18 alkylenearyl, C 5~10 heteroaryl, C 4~16Independently selected from alkylene heteroaryl, said 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, C 3~8 cycloalkyl, C 3~14 alkylenecycloalkyl, C 3~10 heterocycloalkyl, C 4~16 alkylenheterocycloalkyl, C 6~12 aryl, C 7~18 alkylenearyl, C 5~10 heteroaryl, and C 4~16 alkylene heteroaryl is optionally substituted with one or more substituents independently selected from 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 and is optionally substituted with one or more substituents independently selected from said C 3~8 cycloalkyl, C 3~14 alkylenecycloalkyl, C 3~10 heterocycloalkyl, C 4~16 alkylenheterocycloalkyl, C 6~12 aryl, C 7~18 alkylenearyl, C 5~10 heteroaryl, and C 4~16 alkylene heteroaryl is (O), C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl, C 3~6Cycloalkyl, and one or two ring hetero moieties selected from O, S, S(O), SO2, N, and NR 13 optionally further substituted, each with a substituent selected from C 3~6 heterocycloalkyl, each R 13 being 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 alkylenheterocycloalkyl, C 6~12 aryl, C 7~18 alkylenearyl, C 5~10 heteroaryl, and C 6~16 alkylenheteroaryl, wherein said 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 alkylenheterocycloalkyl, C 6~12 aryl, C 7~18 alkylenearyl, C 5~10 heteroaryl, and C 6~16 alkylenheteroaryl is optionally further substituted with 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 haloalkenyl, C 2~6 alkynyl, C2~6 Haloalkynyl, C 3~6 Cycloalkyl, and C containing one or two ring hetero moieties selected from O, S, S(O), SO2, N, NH, and NCH3 3~6 A compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, and / or prodrug thereof, each optionally substituted with one or more substituents independently selected from

[0121] R 1 and R 2 In some embodiments, R 1 and / or R 2 The C in 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 (O), C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, and C containing one or two ring hetero moieties selected from O, S, N, S(O), SO2, and NR 4 Heterocycloalkyl and is further optionally substituted with substituents independently selected from 3~6

[0122] In some embodiments, R 1 and R 2 are hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 Cycloalkyl, C 7~18 Alkylene aryl, and C 4~14 Alkylene cycloalkyl are each independently selected.

[0123] In some embodiments, R 1 and R 2 are hydrogen, C 1~6 alkyl, C 3~8 cycloalkyl, and C 7~18 alkylene aryl are each independently selected.

[0124] In some embodiments, R 1 and R 2 are C 1~4 alkyl, C 3~4 cycloalkyl, and C 7~8 alkylene aryl are each independently selected.

[0125] In some embodiments, R 1 and R 2 are hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl are each independently selected.

[0126] In some embodiments, R 1 and R 2 are C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl are each independently selected.

[0127] In some embodiments, R 1 and R 2 are hydrogen, C 3~8Cycloalkyl, 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 are each independently selected from.

[0128] In some embodiments, R 1 And R 2 Are, 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 are each independently selected from.

[0129] In some embodiments, R 1 And R 2 Both are hydrogen. In some embodiments, R 1 And R 2 One of them is hydrogen. In some embodiments, R 1 And R 2 Neither is hydrogen.

[0130] In some embodiments, R 1 And / or R 2 In C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl is linear. In some embodiments, R 1 And / or R 2 In C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 The haloalkynyl is branched.

[0131] R 1 and R 2 One or both of the following are C 1~6 In some embodiments where the alkyl group is C 1~6 One or both of the alkyls are linear. 1 and R 2 One or both of the following are C 1~6 In some embodiments where the alkyl group is C 1~6 One of the alkyl groups is linear. 1 and R 2 One or both of the following are C 1~6 In some embodiments where the alkyl group is C 1~6 Both alkyl groups are linear. 1 and R 2 One or both of the following are C 1~6 In some embodiments where the alkyl group is C 1~6 One of the alkyl groups is branched. 1 and R 2 One or both of the following are C 1~6 In some embodiments where the alkyl group is C 1~6 One or both of the alkyls are branched. 1 and R 2 Both are C 1~6 In some embodiments where the alkyl group is C 1~6 One of the alkyls is linear and the other C 1~6 The alkyl is branched.

[0132] R 1 and R 2 One or both of the following are C 1~4 Alkyl (preferably C 1~3 In some embodiments, C 1~4 Alkyl (preferably C 1~3 One or both of R is linear. 1 and R2 One or both of them are C 1~4 alkyl (preferably C 1~3 alkyl). In some embodiments, C 1~4 alkyl (preferably C 1~3 alkyl), one of them is linear. R 1 and R 2 One or both of them are C 1~4 alkyl (preferably C 1~3 alkyl). In some embodiments, both C 1~4 alkyl (preferably C 1~3 alkyl) are linear. R 1 and R 2 One or both of them are C 1~4 alkyl (preferably C 1~3 alkyl). In some embodiments, one of C 1~4 alkyl (preferably C 1~3 alkyl) is branched. R 1 and R 2 One or both of them are C 1~4 alkyl (preferably C 1~3 alkyl). In some embodiments, one or both of C 1~4 alkyl (preferably C 1~3 alkyl) are branched. R 1 and R 2 Both are C 1~4 alkyl (preferably C 1~3 alkyl). In some embodiments, one of 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 alkyl) is branched.

[0133] In some embodiments, R 1 and / or R 2 The C 3~8 cycloalkyl, C 4~14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C 14Alkylene heterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 Alkylene heteroaryl is unsubstituted. In some embodiments, R 1 and / or R 2 In the 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 with respect to an alkylene group (when the group specifies an alkylene group) or a nitrogen atom bonded to R 1 / R 2 (when the group does not specify an alkylene group), preferably meta-substituted.

[0134] In some embodiments, one of R 1 and R 2 is C 7~18 Alkylene aryl, preferably C 7~8 Alkylene aryl, more preferably benzyl. In some embodiments, one of R 1 and R 2 is C 7~18 Alkylene aryl, preferably C 7~8 Alkylene aryl, more preferably benzyl, and the other of R 1 and R 2 is hydrogen.

[0135] R 1 and R 2 In some embodiments where one or both of them are C 7~18 Alkylene aryl, C 7~18 Alkylene aryl is unsubstituted. One or both of R 1 and R 2 are C 7~18In some embodiments where it is alkylene aryl, C 7~18 The alkylene aryl is substituted with one or more halogens, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, preferably substituted with one or more halogens, C 1~6 alkyl, C 1~6 alkoxy, more preferably fluoro, methyl, methoxy.

[0136] 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. 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 the other of R 1 and R 2 is C 1~6 alkyl, preferably C 1~3 alkyl, more preferably C1 alkyl.

[0137] 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. In some embodiments, C 3~8 cycloalkyl or C 4~14 alkylenecycloalkyl, preferably C 3~8 cycloalkyl is unsubstituted.

[0138] In some embodiments, R 1 and / or R 2 is unsubstituted. In some embodiments, R 1 and R 2 are unsubstituted. In some embodiments, R 1and / or R 2 is substituted. In some embodiments, R 1 and R 2 is substituted.

[0139] In some embodiments, R 1 and R 2 are the same. In other embodiments, R 1 and R 2 are different, such that the nitrogen atom to which R 1 and R 2 are attached forms an asymmetric acyclic amine.

[0140] In some embodiments, R 1 and R 2 together with the nitrogen atom to which they are attached, form a C 4 heterocycloalkyl containing one or two additional ring hetero moieties selected from O, S, S(O), SO2, N, and NR 3~8 such that the C heterocycloalkyl is halogen, (O), CN, C 3~8 alkoxy, C 1~8 alkylamino, C 1~8 alkylsulfonyl, CO2R 1~8 4 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 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl, C 1~8 alkylamino, C 1~8 alkylsulfonyl, C 3~6 cycloalkyl, and one or two ring hetero moieties selected from O, S, N, S(O), SO2, and NR 4 such that the C 3~6Optionally further substituted with a substituent selected from heterocycloalkyl. In such embodiments, R 1 and R 2 together with the nitrogen atom to which they are attached form a cyclic amine.

[0141] In some embodiments, R 1 and R 2 are each independently selected from C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl, C 3~8 cycloalkyl, and C 4~14 alkylenecycloalkyl.

[0142] In some embodiments, R 1 and R 2 are each independently selected from C 1~4 alkyl. In some embodiments, R 1 and R 2 are each independently selected from C 1~3 alkyl. In some embodiments, R 1 and R 2 are each independently selected from C 1~2 alkyl. In some embodiments, both R 1 and R 2 are methyl.

[0143] In some embodiments, R 1 and R 2 together with the nitrogen to which they are attached form one of the following:

Chemical formula

[0144] In some embodiments, R 1 and R 2 together with the nitrogen to which they are attached form one of the following: [Chemistry] Form any one of the following.

[0145] In some embodiments, R 1 and R 2 together with the nitrogen to which they are attached, are as follows: [Chemistry] Form any one of the following.

[0146] In some embodiments, R 1 and R 2 together with the nitrogen to which they are attached, are as follows: [Chemistry] Any one of the following, preferably [Chemistry] Form.

[0147] In some embodiments, R 1 and R 2 together with the nitrogen atom to which they are attached, form a C 3~6 heterocycloalkyl, and the C 3~6 heterocycloalkyl is 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 haloalkenyl, C 2~6 alkynyl, C2~6 Haloalkynyl, C 3~6 Cycloalkyl, and one or two ring hetero moieties selected from O, S, N, S(O), SO2, and NR 4 Optionally substituted with one or more substituents independently selected from C 3~6 Heterocycloalkyl, wherein R 4 is as defined in any one of the preceding paragraphs.

[0148] R 3 In some embodiments, R 3 is hydrogen.

[0149] In some embodiments, R 3 and one of R 1 and R 2 together with the atom to which they are attached form a C 3~8 heterocycloalkyl, and the C 3~8 heterocycloalkyl is 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 haloalkenyl, C 2~6 alkynyl, C 2~6 haloalkynyl, C 3~6 cycloalkyl, and one or two ring hetero moieties selected from O, S, N, S(O), SO2, and NR 4 Optionally further substituted with a substituent selected from C 3~6 heterocycloalkyl, wherein R 4 is as defined in any one of the preceding paragraphs.

[0150] Z 1 and Z 4 In some embodiments, Z 1 is CR 8 In some embodiments, Z 4 is CR 11 In some embodiments, Z 1 is CR 8 and Z 4 is CR 11 In some embodiments, Z

[0151] In some embodiments, Z 1 is CR 8 and Z 4 is CR 11 and R 9 is not hydrogen. In some embodiments, Z 1 is CR 8 and Z 4 is CR 11 and R 9 is hydrogen.

[0152] In some embodiments, Z 1 is N. In some embodiments, Z 4 is N. In some embodiments, Z 1 is CR 8 and Z 4 is N. In some embodiments, Z 1 is N and Z 4 is CR 11 In some embodiments, Z

[0153] is N and R 1 is not hydrogen. In some embodiments, Z 9 is N and R 4 is not hydrogen. In some embodiments, Z 9 is N and R 1 is CR 8 and Z 4 is N and R 9 is not hydrogen. In some embodiments, Z 1 is N and Z 4is CR 11 and R 9 is not hydrogen.

[0154] In some embodiments, Z 1 is N, and R 1 and R 2 are each independently selected from hydrogen, C 1~6 alkyl, C 3~8 cycloalkyl, and C 7~18 alkylene aryl. In some embodiments, Z 1 is CR 8 and R 1 and R 2 are each independently selected from hydrogen, C 1~6 alkyl, C 3~8 cycloalkyl, and C 7~18 alkylene aryl. In some embodiments, Z 4 is N, and R 1 and R 2 are each independently selected from hydrogen, C 1~6 alkyl, C 3~8 cycloalkyl, and C 7~18 alkylene aryl. In some embodiments, Z 4 is CR 11 and R 1 and R 2 are each independently selected from hydrogen, C 1~6 alkyl, C 3~8 cycloalkyl, and C 7~18 alkylene aryl.

[0155] R 8 , R 9 and R 11 In some embodiments, one of R 8 , R 9 , and R 11 is hydrogen. In some embodiments, two of R 8 , R 9 , and R 11 are hydrogen. In some embodiments, R 8 , R 9 , and R 11All are hydrogen.

[0156] In some embodiments, R 8 , R 9 , and R 11 At least one of is halogen, preferably chloro or fluoro, more preferably fluoro. In some embodiments, R 8 , R 9 , and R 11 One of is halogen, preferably chloro or fluoro, more preferably fluoro. In some embodiments, R 9 is halogen, preferably chloro or fluoro, more preferably fluoro.

[0157] In some embodiments, R 8 , R 9 , and R 11 At least one of is C 1~6 alkoxy, preferably C 1~4 alkoxy, more preferably methoxy. In some embodiments, R 8 , R 9 , and R 11 One of is C 1~6 alkoxy, preferably C 1~4 alkoxy, more preferably methoxy. In some embodiments, R 8 is C 1~6 alkoxy, preferably C 1~4 alkoxy, more preferably methoxy. In some embodiments, R 9 is C 1~6 alkoxy, preferably C 1~4 alkoxy, more preferably methoxy. In some embodiments, R 11 is C 1~6 alkoxy, preferably C 1~4 alkoxy, more preferably methoxy.

[0158] In some embodiments, R 8 , R 9 , and R 11 At least one of is OR 13and preferably, in the formula, R 13 is hydrogen. In some embodiments, R 8 , R 9 , and R 11 one of which is OR 13 and preferably, in the formula, R 13 is hydrogen. In some embodiments, R 8 is OR 13 and preferably, in the formula, R 13 is hydrogen. In some embodiments, R 9 is OR 13 and preferably, in the formula, R 13 is hydrogen. In some embodiments, R 11 is OR 13 and preferably, in the formula, R 13 is hydrogen.

[0159] In some embodiments, at least one of R 8 , R 9 , and R 11 is hydrogen, and at least one of R 8 , R 9 , and R 11 is halogen (preferably chloro or fluoro, more preferably fluoro), C 1~6 alkoxy (preferably C 1~4 alkoxy, more preferably methoxy), or OR 13 (preferably, in the formula, R 13 is hydrogen), and in some embodiments, two of R 8 , R 9 , and R 11 are hydrogen, and the remaining one of R 8 , R 9 , and R 11 is halogen (preferably chloro or fluoro, more preferably fluoro), C 1~6 alkoxy (preferably C 1~4 alkoxy, more preferably methoxy), or OR 13 (preferably, in the formula, R 13 is hydrogen), and in some embodiments, R 9 and R11 is hydrogen, and R 8 is halogen (preferably chloro or fluoro, more preferably fluoro), C 1~6 alkoxy (preferably C 1~4 alkoxy, more preferably methoxy), or OR 13 (preferably, in the formula, R 13 is hydrogen), and in some embodiments, R 8 and R 11 are hydrogen, and R 9 is halogen (preferably chloro or fluoro, more preferably fluoro), C 1~6 alkoxy (preferably C 1~4 alkoxy, more preferably methoxy), or OR 13 (preferably, in the formula, R 13 is hydrogen). In some embodiments, R 8 and R 9 are hydrogen, and R 11 is halogen (preferably chloro or fluoro, more preferably fluoro), C 1~6 alkoxy (preferably C 1~4 alkoxy, more preferably methoxy), or OR 13 (preferably, in the formula, R 13 is hydrogen). In some embodiments, R 9 and R 11 are hydrogen, and R 8 is OR 13 (preferably, in the formula, R 13 is hydrogen).

[0160] In some embodiments, one of R 8 , R 9 , and R 11 is hydrogen, and R 1 and R 2 are each independently selected from hydrogen, C 1~6 alkyl, C 3~8 cycloalkyl, and C 7~18 alkylene aryl. In some embodiments, R 8 , R 9 , and R 11Two of which are hydrogen, R 1 and R 2 are each independently selected from hydrogen, C 1~6 alkyl, C 3~8 cycloalkyl, and C 7~18 alkylene aryl. In some embodiments, R 8 , R 9 , and R 11 are all hydrogen, and R 1 and R 2 are each independently selected from hydrogen, C 1~6 alkyl, C 3~8 cycloalkyl, and C 7~18 alkylene aryl.

[0161] In some embodiments, R 8 , R 9 , and R 11 are 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 alkylene cycloalkyl, C 3~10 heterocycloalkyl, C 4~16 alkylene heterocycloalkyl, C 6~12 aryl, C 7~18Alkylene aryl, C 5~10 Heteroaryl, C 4~16 Alkylene heteroaryl, each independently selected from Said 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, C 3~8 Cycloalkyl, C 3~14 Alkylene cycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkylene heterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 Alkylene heteroaryl is optionally substituted with one or more substituents independently selected from 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 Said C 3~8 Cycloalkyl, C 3~14 Alkylene cycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkylene heterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 Alkylene heteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6Haloalkynyl, C 3~6 Cycloalkyl, and C containing one or two ring hetero moieties selected from O, S, S(O), SO2, N, NH, and NCH3 3~6 Each further optionally substituted with a substituent selected from heterocycloalkyl, wherein R 13 is as defined in any one of the preceding paragraphs.

[0162] In some embodiments, one or two of R 8 , R 9 , and R 11 , if present, are each independently selected from halogen, CN, C 1~6 alkyl, C 1~6 haloalkyl, and OR 13 , wherein R 13 is selected from hydrogen, C 1~6 alkyl, and C 1~6 haloalkyl, and the others of R 8 , R 9 , and R 11 are each hydrogen.

[0163] In some embodiments, one of R 8 , R 9 , and R 11 , if present, is each independently selected from halogen, CN, C 1~6 alkyl, C 1~6 haloalkyl, and OR 13 , wherein R 13 is selected from hydrogen, C 1~6 alkyl, and C 1~6 haloalkyl, and the others of R 8 , R 9 , and R 11 are each hydrogen.

[0164] In some embodiments, one of R 8 , R 9 , and R 11 , if present, is each independently selected from halogen, CN, C 1~4 alkyl, C 1~4Haloalkyl, and OR 13 Each independently selected from, wherein R 13 is hydrogen, C 1~4 alkyl, and C 1~4 haloalkyl, and the others of R 8 , R 9 , and R 11 are each hydrogen.

[0165] In some embodiments, one of R 8 , R 9 , and R 11 , if present, is fluoro, chloro, hydroxyl, or OCH3, and the others of R 8 , R 9 , and R 11 are each hydrogen.

[0166] In some embodiments, one of R 8 , R 9 , and R 11 , if present, is OCH3, and the others of R 8 , R 9 , and R 11 are each hydrogen. In some embodiments, one of R 8 , R 9 , and R 11 , if present, is hydroxy, and the others of R 8 , R 9 , and R 11 are each hydrogen. In some embodiments, one of R 8 , R 9 , and R 11 , if present, is fluoro, and the others of R 8 , R 9 , and R 11 are each hydrogen. In some embodiments, one of R 8 , R 9 , and R 11 , if present, is chloro, and the others of R 8 , R 9 , and R 11 are each hydrogen.

[0167] In some embodiments, R 8 is OCH3, and R 9 and R 11 (when present) are each hydrogen. In some embodiments, R 8 is hydroxy, and R 9 and R 11 (when present) are each hydrogen.

[0168] In some embodiments, R 9 is OCH3, and R 8 and R 11 (when present) are each hydrogen. In some embodiments, R 9 is hydroxy, and R 8 and R 11 (when present) are each hydrogen. In some embodiments, R 9 is fluoro, and R 8 and R 11 (when present) are each hydrogen. In some embodiments, R 9 is chloro, and R 8 and R 11 (when present) are each hydrogen.

[0169] In some embodiments, R 11 is OCH3, and R 8 and R 9 (when present) are each hydrogen. In some embodiments, R 11 is hydroxy, and R 8 and R 9 (when present) are each hydrogen.

[0170] L In some embodiments, L is C 1~4 alkylene.

[0171] In some embodiments, L is methylene.

[0172] Further formula In some embodiments, the compound of formula (I) is of formula (Ia):

Chemical formula

[0173] In some embodiments, the compound of formula (I) is of formula (Ib):

Chemical formula

[0174] In some embodiments, the compound of formula (I) is of formula (Ic):

Chemical formula

[0175] In some embodiments, the compound of formula (I) is as follows:

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

[0176] 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 a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, and / or prodrug thereof.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] In some embodiments, the compound of formula (I) is selected from any one of the following: I-14, I-15, I-16, I-17, I-18, I-19, I-20, 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.

[0184] Form of the compound In the case of a compound that is a solid, it will be understood by those skilled in the art that the compounds, agents, and salts of the present invention can exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specified formula.

[0185] The present invention includes all crystalline forms of the compound 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 this invention.

[0186] Formula (I) is intended to encompass the solvated and non-solvated forms of the compound where applicable. Thus, formula (I) includes compounds having the indicated structure, including hydrated or solvated forms, as well as non-hydrated and non-solvated forms.

[0187] The compound of formula (I), or a salt, tautomer, N-oxide, polymorph, or prodrug thereof, may be provided in the form of a solvate. Solvates of the compounds of the present invention can be conveniently prepared or formed during the processes described herein. Generally, the solvated form is considered equivalent to the non-solvated form for the purposes of the present invention.

[0188] Basic nitrogen-containing groups are C such as chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl 1~6Alkyl halides; can be quaternized with agents such as dialkyl sulfates such as dimethyl and diethyl sulfate.

[0189] The nitrogen-containing group can also be oxidized to form an N-oxide.

[0190] The compound of formula (I) forming a crystalline solid, or a salt, tautomer, N-oxide, solvate, and / or prodrug thereof, may exhibit polymorphism. All polymorphic forms of the compound, salt, tautomer, N-oxide, solvate, and / or prodrug are within the scope of the present invention.

[0191] The compound of formula (I) may exhibit tautomerism. Tautomers are typically two interchangeable forms of a molecule existing in equilibrium. Any tautomer of the compound of formula (I) should be understood to be within the scope of the present invention.

[0192] 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 and Z olefin forms, and cis and trans substitution patterns), and atropisomers. In some embodiments, the compound is in a stereoisomerically enriched form of the compound of formula (I) at any stereocenter. The compound may be enriched in one stereoisomer by at least about 60, 70, 80, 90, 95, 98, or 99% compared to another stereoisomer.

[0193] The compound of formula (I), or a salt, tautomer, solvate, N-oxide, and / or stereoisomer thereof, may be isotopically enriched with one or more of the isotopes of the atoms present in the compound. For example, the compound may 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 2H. An isotope can be considered enriched if its abundance is greater than its natural abundance.

[0194] A "prodrug" is a compound that may not fully meet the structural requirements of the compounds provided herein, but is modified in vivo after administration to a subject or patient to produce a compound of formula (I) provided herein. For example, a prodrug can be an acylated derivative of a compound provided herein. A prodrug includes a compound in which a hydroxy, carboxy, amine, or sulfhydryl group is bonded to any group that cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively, when administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate, and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein can be prepared by modifying the functional groups present in the compounds in such a way that the modification is cleaved in vivo to produce the parent compound.

[0195] A prodrug includes a compound 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 bonded to a free amino and an amide group of a compound of formula (I). Amino acid residues include the 20 naturally occurring amino acids generally designated by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. A prodrug also includes a compound in which a carbonate, carbamate, amide, and alkyl ester are covalently bonded to a previous substituent of formula (I) via a carbonyl carbon prodrug side chain.

[0196] Compositions, Formulations, and Modes of Administration The compounds of formula (I) can be administered alone or in the form of a pharmaceutical composition. In practice, the compounds of formula (I) are usually administered in the form of a pharmaceutical composition, i.e., in admixture with at least one pharmaceutically acceptable excipient. The proportion and nature of any pharmaceutically acceptable excipient are determined by the properties of the selected compound of the invention, the selected route of administration, and standard pharmaceutical practice.

[0197] In another embodiment, there is provided a pharmaceutical composition 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.

[0198] The pharmaceutical compositions of the present disclosure typically comprise a therapeutically effective amount of one or more active ingredients admixed with one or more pharmaceutical and physiologically acceptable formulation materials. Suitable formulation materials include, but are not limited to, antioxidants, preservatives, coloring agents, flavoring agents and diluents, emulsifying agents, suspending agents, solvents, fillers, extenders, buffers, delivery vehicles, diluents, excipients, and / or pharmaceutical adjuvants. For example, suitable vehicles can be water for injection, physiological saline aqueous solution, or artificial perilymph, optionally supplemented with other materials common to compositions for parenteral administration. Neutral buffered saline, or saline mixed with serum albumin, are further exemplary vehicles.

[0199] The pharmaceutical compositions of the present disclosure further comprise a pharmaceutically acceptable carrier comprising any solvent, diluent, or other liquid vehicle, dispersion or suspension aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc. suitable for the desired particular dosage form, as used herein. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. The use of any conventional carrier medium is contemplated within the scope of the present disclosure, except when it is incompatible with the compounds of the present invention, such as by producing any undesired biological effects or otherwise interacting in a detrimental manner with other components of the pharmaceutical composition. Some examples of materials that can function as pharmaceutically acceptable carriers include sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, 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; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, and coloring agents, release agents, coating agents, sweetening agents, flavoring agents, and fragrances, although not limited thereto, and preservatives and antioxidants may also be present in the composition, at the discretion of the formulator.

[0200] The various dosage units are preferably each provided as separate dosage tablets, capsules, lozenges, dragees, gums, or other types of solid formulations. Capsules can encapsulate powders, liquids, or gels. The solid formulations can be swallowable or of the type that can be aspirated or chewed (either brittle or gum-like). The present invention contemplates dosage unit holding devices other than blister packs, such as packages like bottles, tubes, canisters, packets, etc. The dosage units can further include conventional excipients well-known in the practice of pharmaceutical formulations, such as binders, gelling agents, fillers, tableting lubricants, disintegrants, surfactants, and coloring agents, as well as formulations that can be aspirated or chewed.

[0201] The compounds of formula (I) can be administered in any form and via any route that makes the compound bioavailable.

[0202] The compositions disclosed herein can be administered systemically or locally.

[0203] The compositions described herein can be formulated from the compounds of formula (I) for any suitable route of administration, including, for example, oral, rectal, nasal, vaginal, local (including transdermal, buccal, ophthalmic, and sublingual), parenteral (subcutaneous, intraperitoneal, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial, and intraperitoneal injection, intracisternal injection, and other similar injections, or infusion techniques), inhalation, insufflation, instillation, or implantation techniques (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension). In some embodiments, the compositions described herein can be administered by oral, nasal, intravenous, intramuscular, local, subcutaneous, rectal, vaginal, or urethral application.

[0204] Compositions intended for oral use may further contain one or more ingredients such as sweeteners, flavoring agents, coloring agents, and / or preservatives in order to provide an attractive and palatable preparation. Tablets contain the active ingredient in admixture with physiologically acceptable excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may or may not be coated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used.

[0205] Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

[0206] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents and / or flavoring agents such as those described previously may be added to provide a palatable oral preparation. Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0207] Dispersible powders and granules suitable for preparing aqueous suspensions by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening agents, flavoring agents, and coloring agents may also be present.

[0208] The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents include naturally occurring gums such as acacia gum or tragacanth gum, naturally occurring phosphatides such as soy lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides such as sorbitan monooleate, and condensation products of partial esters derived from fatty acids and hexitols with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain one or more sweetening agents and / or flavoring agents.

[0209] Syrups and elixirs may be formulated with a sweetening agent such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain one or more analgesics, preservatives, flavoring agents, and / or coloring agents.

[0210] The composition may further contain one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizers, suspending agents, emulsifying agents, 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 contain microcapsules such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microparticles, microemulsions, nanoparticles, or nanocapsules.

[0211] Examples of preservatives include antibacterial 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, but are not limited thereto. Examples of suitable humectants include lactic acid and other hydroxy acids, and their salts, glycerin, propylene glycol, and butylene glycol, but are not limited thereto. Examples of suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate, and mineral oil. Examples of suitable fragrances and colors include FD&C Red No.40 and FD&C Yellow No.5, but are not limited thereto. Other suitable additional components that may be included in topical formulations include abrasives, absorbents, anticoagulants, antifoaming agents, antistatic agents, astringents (such as witch hazel), alcohol and herb extracts, for example, chamomile extract, binders / excipients, buffers, chelating agents, film formers, conditioning agents, propellants, opacifying agents, pH adjusters, and protective agents, but are not limited thereto.

[0212] 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 forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (specifically, cottonseed oil, peanut oil, 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, the oral compositions may also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0213] Injectable preparations, such as sterile injectable aqueous or oily suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension, or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil containing synthetic mono- or diglycerides may be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0214] Injectable formulations may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a bactericide in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0215] The pharmaceutical composition can be formulated as an inhalation preparation including a spray, mist, or aerosol. In the case of an inhalation preparation, the composition or combination provided herein can be delivered via any inhalation method known to those skilled in the art. Such inhalation methods and devices include, but are not limited to, metered-dose inhalers having a propellant such as CFC or HFA or a physiologically and environmentally acceptable propellant. Other suitable devices are breath-actuated inhalers, multi-dose dry powder inhalers, and aerosol nebulizers. An aerosol formulation for use in the subject method typically includes a propellant, a surfactant, and a co-solvent and can be filled into a conventional aerosol container closed by a suitable metering valve.

[0216] The inhalant composition can include a liquid or powder composition containing an active ingredient suitable for spraying and intratracheal use, or an aerosol composition administered via an aerosol unit that dispenses a metered dose. Suitable liquid compositions include the active ingredient in an aqueous pharmaceutically acceptable inhalant solvent such as isotonic saline or bacteriostatic water. The solution is administered by a pump or a push-actuated spray dispenser or by other conventional means that result in or enable the required dosage of the liquid composition to be inhaled into the patient's lungs. For example, suitable formulations where the carrier is liquid for administration as a nasal spray or nasal drops include aqueous or oily solutions of the active ingredient.

[0217] Compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by at least partially dispersing the active agent in one or more lipophilic bases and then forming a mixture.

[0218] The pharmaceutical composition can be formulated as a sustained-release preparation, such as a capsule, which creates a sustained release of the active substance after administration. Such preparations can generally be prepared using well-known techniques and can be administered, for example, orally, rectally, or by subcutaneous implantation, or by implantation at the desired target site. The carrier for use in such preparations can be biocompatible and can also be biodegradable. Preferably, the preparation provides a relatively constant level of active substance release. The amount of the active substance contained in the sustained-release preparation depends, for example, on the implantation site, the rate and expected duration of release, and the nature of the condition to be treated.

[0219] One skilled in the art can readily select the appropriate dosage form and route of administration according to the specific characteristics of the selected compound, the disease or condition to be treated, the stage of the disease or condition, and other relevant circumstances.

[0220] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) 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.

[0221] The additional agent can be any suitable agent described herein. In some embodiments, the additional agent is a psychotropic drug, including those described herein. In some embodiments, the additional agent is useful for the treatment of a disease, disorder, or condition that is improved by activation of a serotonin receptor, including those described herein. In some embodiments, the additional agent is selected from any one of the following, including those described herein: an agent for psychosis and / or neuropsychiatric disorders; an agent for mental abnormalities and / or psychotic symptoms; an agent for attention deficit hyperactivity disorder and / or attention deficit disorder; an agent for dementia and / or Alzheimer's disease; and an agent for addiction disorders.

[0222] Methods and Uses The present disclosure provides methods of using the compounds and compositions of formula (I) described in any one of the preceding paragraphs. The present disclosure also provides methods of delivering a compound or composition of formula (I) of the present disclosure (e.g., an effective amount of the compound or composition) to a subject in need thereof.

[0223] 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 (e.g., a therapeutically effective amount) of a compound or composition (e.g., a pharmaceutical composition) of the present disclosure.

[0224] In another aspect, the present disclosure provides a method of 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 or composition of formula (I) of the present disclosure (e.g., a pharmaceutical composition).

[0225] In another aspect, the use of a compound or composition of formula (I) of the present disclosure in the manufacture 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) is provided herein.

[0226] In another aspect, the use of a compound or composition of formula (I) of the present disclosure 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) is provided herein.

[0227] In certain embodiments, the effective amount is effective in the treatment of a disease. In certain embodiments, the effective amount is effective in the prevention of a disease.

[0228] 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 or pharmaceutical composition of formula (I) described herein.

[0229] In another aspect, the present disclosure provides the use of a compound of formula (I) described herein in the manufacture of a medicament for treating a disease, disorder, or condition associated with the activity of a serotonin receptor.

[0230] In another aspect, the present disclosure provides the use of a compound or pharmaceutical composition of formula (I) described herein for treating a disease, disorder, or condition associated with the activity of a serotonin receptor.

[0231] In another aspect, the present disclosure provides a compound or pharmaceutical composition of formula (I) described herein for use in the treatment of a disease, disorder, or condition associated with the activity of a serotonin receptor.

[0232] 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 or pharmaceutical composition of formula (I) described herein.

[0233] In another aspect, the present disclosure provides the use of a compound of formula (I) described herein in the manufacture of a medicament for preventing a disease, disorder, or condition associated with the activity of a serotonin receptor.

[0234] In another aspect, the present disclosure provides the use of a compound or pharmaceutical composition of formula (I) described herein for preventing a disease, disorder, or condition associated with the activity of a serotonin receptor.

[0235] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutical composition described herein for use in the prevention of a disease, disorder, or condition associated with the activity of a serotonin receptor.

[0236] 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 described herein in combination with another agent useful in the treatment of the disease, disorder, or condition. The other agent can be any agent useful in the treatment and / or prevention of the disease, disorder, or condition, including those known in the art and described herein. The other agent can be a serotonin receptor agonist. The other agent can be a compound of another formula (I). The other agent can be a compound other than a compound of formula (I), including those known in the art and described herein.

[0237] In another aspect, the present disclosure provides the use of a compound of formula (I) described herein in the manufacture 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 in the treatment of the disease, disorder, or condition described herein.

[0238] In another aspect, the present disclosure provides the use of a compound of formula (I) or a pharmaceutical composition 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 in the treatment of the disease, disorder, or condition described herein.

[0239] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutical composition described herein for use in the treatment of a disease, disorder, or condition associated with the activity of a serotonin receptor, wherein, in use, the compound of formula (I) or the pharmaceutical composition is formulated for administration in combination with another agent useful for the treatment of the disease, disorder, or condition described herein.

[0240] 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 described herein in combination with another agent useful for the prevention of the disease, disorder, or condition. The other agent can be any agent known in the art and described herein that is useful for the treatment and / or prevention of the disease, disorder, or condition. The other agent can be a serotonin receptor agonist. The other agent can be a compound of another formula (I). The other agent can be a compound other than a compound of formula (I) that is known in the art and described herein.

[0241] In another aspect, the present disclosure provides the use of a compound of formula (I) described herein in the manufacture 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 in combination with another agent useful for the prevention of the disease, disorder, or condition described herein.

[0242] In another aspect, the present disclosure provides the use of a compound of formula (I) or a pharmaceutical composition 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 in combination with another agent useful for the treatment of the disease, disorder, or condition described herein.

[0243] In another aspect, the present disclosure provides a compound or pharmaceutical composition of formula (I) described herein for use in the prevention of a disease, disorder, or condition associated with the activity of a serotonin receptor, wherein, in use, the compound or pharmaceutical composition of formula (I) is formulated for administration with another agent useful for the treatment of the disease, disorder, or condition described herein.

[0244] In certain embodiments, the serotonin receptor is 5-HT 2A . In certain embodiments, the serotonin receptor is 5-HT 2C .

[0245] In certain embodiments, the serotonin receptor is 5-HT 2A and 5-HT 2C or both. Additionally, or alternatively, in some embodiments, the serotonin receptor is not 5-HT 2B .

[0246] In some embodiments, the compound of formula (I) of the present disclosure is more selective for the 5-HT 2C receptor and / or the 5-HT 2B receptor, preferably more selective for the 5-HT 2B receptor than for the 5-HT 2A receptor. In some embodiments, the compound of formula (I) is more selective for the 5-HT 2A receptor and / or the 5-HT 2B receptor, preferably more selective for the 5-HT 2B receptor than for the 5-HT 2C receptor. In some embodiments, the compound of formula (I) is more selective for the 5-HT 2B receptor than for the 5-HT 2A receptor and / or the 5-HT 2C receptor.

[0247] In some embodiments, the compounds of formula (I) of the present disclosure are determined by the assays described herein, such as assays of calcium flux activity, such as measuring changes in intracellular calcium, to have an EC for 5-HT of 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 2A value for the receptor. In some embodiments, the compounds of formula (I) have an EC for 5-HT of 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 10 μM, less than 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), as determined by an assay of calcium flux activity 50 value for the receptor. In some embodiments, the compounds of formula (I) have an EC for 5-HT of 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 10 μM, less than 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), as determined by an assay of calcium flux activity 2A value for the receptor. In some embodiments, the compounds of formula (I) have an EC for 5-HT of 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 10 μM, less than 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), as determined by an assay of calcium flux activity 50 value for the receptor. In some embodiments, the compounds of formula (I) have an EC for 5-HT of 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 10 μM, less than 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), as determined by an assay of calcium flux activity

[0248] In some embodiments, the compounds of formula (I) of the present disclosure are determined by the assays described herein, such as assays of calcium flux activity, such as measuring changes in intracellular calcium, to have an EC for 5-HT of 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 2C value for the receptor. In some embodiments, the compounds of formula (I) have an EC for 5-HT of 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 10 μM, less than 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), as determined by an assay of calcium flux activity 50exhibit. In some embodiments, the compounds of formula (I) exhibit an EC for the 5-HT receptor of 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 10 μM, less than 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 measure (e.g., mol / L). 2C for the EC of the 50 receptor is exhibited.

[0249] In some embodiments, the compounds of formula (I) of the present disclosure exhibit an EC for the 5-HT receptor of greater than about 1 μM, greater than about 10 μM, or greater than about 100 μM, as determined by an assay described herein, for example, an assay of calcium flux activity such as measuring changes in intracellular calcium. 2B for the EC of the 50 receptor is exhibited.

[0250] In some embodiments, the present disclosure also includes a method of treating a psychosis or neuropsychopathy, the method comprising administering to a subject in need thereof a compound or composition of formula (I) described herein. The present disclosure also includes the use of a compound of formula (I) of the present disclosure for treating a psychosis or neuropsychopathy, and the use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treating a psychosis or neuropsychopathy. The present application further includes a compound of formula (I) of the present disclosure for use in the treatment of a psychosis or neuropsychopathy.

[0251] In some embodiments, the compounds of formula (I) of the present disclosure are administered in combination with one or more additional agents for psychosis or neuropsychiatric conditions. The one or more additional agents for psychosis or neuropsychiatric conditions can be any suitable agent known in the art, including those described herein. In some embodiments, the additional agent for psychosis or neuropsychiatric conditions is an antipsychotic agent, including typical and atypical antipsychotics; an antidepressant agent, including selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants, and monoamine oxidase inhibitors (MAOI) (e.g., bupropion); an anxiolytic agent, including benzodiazepines such as alprazolam; an agent for addiction disorders, including alcohol dependence (e.g., disulfiram), nicotine dependence (e.g., varenicline), and opioid use disorder (e.g., methadone, buprenorphine, buprenorphine-naloxone, and buprenorphine extended-release injection); a mood stabilizer, such as lithium, and an anticonvulsant, such as carbamazepine, divalproex (valproic acid), lamotrigine, gabapentin, and topiramate, among others, selected from.

[0252] In some embodiments, the present disclosure also includes a method of treating neurodegeneration, the method comprising administering to a subject in need thereof a compound or composition of formula (I) described herein. The use of the compounds of formula (I) of the present disclosure for treating neurodegeneration and the use of the compounds of formula (I) of the present disclosure for the preparation of a medicament for treating neurodegeneration are also provided. The present application further includes a compound of formula (I) of the present disclosure for use in the treatment of neurodegeneration. In some embodiments, the disease, disorder, or condition is reduction of brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR) activation, and / or inflammation.

[0253] In some embodiments, the disease, disorder, or condition to be treated by the methods described herein includes cognitive dysfunction; ischemia including stroke; neurodegeneration; treatment-resistant substance use disorder; sleep disorder; pain, such as social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, neuralgia, related pain, phantom pain, neuropathic pain, cluster headache, and migraine; obesity and eating disorders; epilepsy and seizure disorders, neuronal cell death; excitotoxic cell death; or combinations thereof.

[0254] In some embodiments, the disclosure also includes a method of treating a mental disorder or psychotic symptom, the method comprising administering to a subject in need thereof a compound or composition of formula (I) described herein. The disclosure also includes the use of a compound of formula (I) of the disclosure for treating a mental disorder or psychotic symptom and the use of a compound of formula (I) of the disclosure for the preparation of a medicament for treating a mental disorder or psychotic symptom. The present application further includes a compound of formula (I) of the disclosure for use in the treatment of a mental disorder or psychotic symptom.

[0255] In some embodiments, the disease, disorder, or condition to be treated by the methods of the present disclosure is a mental disorder or psychotic symptom, and the compound of formula (I) of the present disclosure is administered in combination with one or more additional agents for mental disorders or psychotic symptoms. The one or more additional agents for mental disorders or psychotic symptoms can be any suitable agent known in the art, including those described herein. In some embodiments, the additional agent for mental disorders or psychotic symptoms is selected from typical antipsychotics and atypical antipsychotics. Typical antipsychotics can be selected from acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carfenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, ciamemazine, dixyrazine, droperidol, fluanison, flupenthixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, metitepine, molindone, mopidone, oxyphenperidine, oxyprothepin, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, piperacetazine, pipothiazine, prochlorperazine, promazine, prothipendyl, spiperone, sulforidazine, thiopropazate, thioproperazine, thioridazine, thiotixene, timiperone, trifluoperazine, triflupridol, triflupromazine, and zuclopenthixol, and combinations thereof. Atypical antipsychotics can be selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, chlorotepine, clotiapine, clozapine, iloperidone, levosulpride, lurasidone, melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpride, sultopride, tiapride, veralipride, diprasidone, and zotepine, and combinations thereof.

[0256] 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 result in exacerbation of psychiatric disorders 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 results in improvement of psychiatric disorders 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 results in improvement of psychiatric disorders or psychotic symptoms.

[0257] In some embodiments, the disease, disorder, or condition to be treated by the methods of the present disclosure is a disease, disorder, or condition of the central nervous system (CNS) and / or a disease, disorder, or condition of the nervous system. Accordingly, the present disclosure also includes a method of treating a disease, disorder, or condition of the CNS and / or a disease, disorder, or condition of the nervous system, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of formula (I) of the present disclosure. The present disclosure also includes the use of a compound of formula (I) of the present disclosure for the treatment of a disease, disorder, or condition of the CNS and / or a disease, disorder, or condition of the nervous system, and the use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treating a disease, disorder, or condition of the CNS and / or a disease, disorder, or condition of the nervous system. The present application further includes a compound of formula (I) of the present disclosure for use in the treatment of a disease, disorder, or condition of the CNS and / or a disease, disorder, or condition of the nervous system.

[0258] In some embodiments, the disease, disorder, or condition to be treated by the methods of the present disclosure is a disease, disorder, or condition of the central nervous system (CNS) and / or a disease, disorder, or condition of the nervous system, and the compounds of formula (I) of the present disclosure are administered in combination with one or more additional agents for a disease, disorder, or condition of the central nervous system (CNS) and / or a disease, disorder, or condition of the nervous system. The one or more additional agents for a disease, disorder, or condition of the central nervous system (CNS) and / or a disease, disorder, or condition of the nervous system can be any suitable agent known in the art, including those described herein. In some embodiments, the additional agent for a disease, disorder, or condition of the central nervous system (CNS) and / or a disease, disorder, or condition of the nervous system is selected from lithium, olanzapine, quetiapine, risperidone, aripiprazole, diprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof. Non-limiting examples of standard care therapies for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole. Non-limiting examples of standard care therapies for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline.

[0259] In some embodiments, the disclosure also includes a method of treating attention deficit hyperactivity disorder and / or attention deficit disorder, the method comprising administering to a subject in need thereof a compound or composition of formula (I) described herein. The disclosure also includes the use of a compound of formula (I) of the disclosure for treating attention deficit hyperactivity disorder and / or attention deficit disorder, and the use of a compound of formula (I) of the disclosure for the preparation of a medicament for treating attention deficit hyperactivity disorder and / or attention deficit disorder. The present application further includes a compound of formula (I) of the disclosure for use in the treatment of attention deficit hyperactivity disorder and / or attention deficit disorder.

[0260] In some embodiments, the disease, disorder, or condition to be treated by the methods of the disclosure is attention deficit hyperactivity disorder and / or attention deficit disorder, and combinations thereof, and the compounds of formula (I) of the disclosure are administered in combination with one or more additional agents for attention deficit hyperactivity disorder and / or attention deficit disorder, and combinations thereof. The one or more additional agents for attention deficit hyperactivity disorder and / or attention deficit disorder can be any suitable agent known in the art, including those described herein. In some embodiments, the additional agents for attention deficit hyperactivity disorder and / or attention deficit disorder, and combinations thereof, are selected from methylphenidate, dextroamphetamine, lisdexamfetamine, atomoxetine, and amphetamine, and combinations thereof.

[0261] In some embodiments, the disease, disorder, or condition to be treated by the methods of the present disclosure is selected from dementia and Alzheimer's disease, and combinations thereof. Accordingly, the present disclosure also includes a method of treating dementia and / or Alzheimer's disease, the method comprising administering to a subject in need thereof a compound or composition of formula (I) described herein. The present disclosure also includes the use of a compound of formula (I) of the present disclosure for treating dementia and / or Alzheimer's disease, and the use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treating dementia and / or Alzheimer's disease. The present application further includes a compound of formula (I) of the present disclosure for use in the treatment of dementia and / or Alzheimer's disease.

[0262] In some embodiments, the disease, disorder, or condition to be treated by the methods 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 additional agents for dementia or Alzheimer's disease. The one or more additional agents for dementia or Alzheimer's disease can be any suitable agent known in the art, including those described herein. In some embodiments, the additional agents for dementia and Alzheimer's disease are selected from acetylcholinesterase inhibitors, NMDA antagonists, and nicotinic agonists. The acetylcholinesterase inhibitors can be selected from donepezil, galantamine, rivastigmine, and physostigmine, and combinations thereof. The NMDA antagonists can be selected from MK-801, ketamine, fencyclidine, and memantine, and combinations thereof. The nicotinic agonists can be selected from nicotine, niacin, nicotinic alpha7 agonists, or alpha2beta4 agonists, or combinations thereof.

[0263] In another aspect, the present disclosure provides a method for treating a mental disorder, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition described herein. In another aspect, the present disclosure provides a method for preventing a mental disorder, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition described herein. The mental disorder can be a neuropsychiatric disorder.

[0264] In certain embodiments, the mental disorder is selected from anxiety disorders such as generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia; depression such as despair, loss of pleasure, fatigue, and suicidal thoughts; mood disorders such as depression, bipolar disorder, cancer-related depression, anxiety, and cyclothymic disorder; psychotic disorders such as hallucinations, delusions, mania, schizophrenia, schizoaffective disorder, and schizotypal disorder; impulse control and addiction disorders such as pyromania (fire-setting addiction), kleptomania (theft addiction) and compulsive gambling; alcohol dependence; drug dependence such as opioid dependence / addiction, nicotine dependence, cocaine dependence, marijuana abuse, etc.; smoking cessation; personality disorders such as antisocial personality disorder, aggression, obsessive-compulsive personality disorder, and delusional personality disorder; obsessive-compulsive disorder (OCD) such as thoughts or fears that cause the subject to perform specific habitual behaviors or routines; post-traumatic stress disorder (PTSD); stress response syndrome (formerly called adjustment disorder); dissociative disorders such as formerly multiple personality disorder, or "dissociative personality", and depersonalization disorder; factitious disorder; sexual and gender disorders such as sexual dysfunction, gender identity disorder, and paraphilia; somatic symptom disorder formerly known as psychosomatic disorder or somatoform disorder.

[0265] In certain embodiments, the psychosis 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, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, and timeceptive hallucinations, and combinations thereof.

[0266] In another aspect, the present disclosure provides a method for treating a central nervous system (CNS) disorder, disease, or condition, and / or a nervous system disorder, disease, or condition, the method comprising administering to a subject in need thereof a compound or pharmaceutical composition of formula (I) described herein.

[0267] In another aspect, the present disclosure provides a method for preventing a central nervous system (CNS) disorder, disease, or condition, and / or a nervous system disorder, disease, or condition, the method comprising administering to a subject in need thereof a compound or pharmaceutical composition of formula (I) described herein.

[0268] In some embodiments, the CNS disease, disorder, or condition, and / or the nervous system disease, disorder, or condition is selected from neurodegenerative diseases such as neurodevelopmental diseases and Alzheimer's disease; mild cognitive impairment; senile cognitive impairment; vascular cognitive impairment; Lewy body dementia; cognitive dysfunction, Parkinson's disease, and Parkinson's disease-related diseases such as Parkinson's dementia, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; fragile X syndrome; Angelman syndrome; hereditary ataxia; neuro-otological disorders and eye movement disorders; retinal neurodegenerative diseases, amyotrophic lateral sclerosis; tardive dyskinesia; hyperkinetic disorders; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette syndrome; tic disorders; 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, skin picking, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology, and combinations thereof, including nervous system diseases.

[0269] In another aspect, the present disclosure provides a method for increasing neuroplasticity, the method comprising contacting a nerve cell with a compound or pharmaceutical composition of formula (I) described herein in an amount sufficient to increase the neuroplasticity of the nerve cell. "Neuroplasticity" refers to the brain's ability to continuously change its structure and / or function throughout the life of a subject. Examples of changes to the brain include, but are not limited to, the ability to adapt or respond to internal and / or external stimuli such as injury, and the ability to produce new neurites, dendritic spines, and synapses. Increases in neuroplasticity include, but are not limited to, promotion of nerve growth, promotion of neurite formation, promotion of synapse formation, promotion of dendritic formation, increase in dendritic arbor complexity, increase in dendritic spine density, and increase in excitatory synapses in the brain. In some embodiments, the increase in neuroplasticity includes promotion of nerve growth, promotion of neurite formation, promotion of synapse formation, promotion of dendritic formation, increase in dendritic arbor complexity, and increase in dendritic spine density.

[0270] In some embodiments, by increasing neuroplasticity, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, mental disorders, depression, addiction, anxiety, post-traumatic stress disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorders can be treated.

[0271] In another aspect, the present disclosure provides a method for treating body weight, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention. Treatment of body weight can include weight gain; weight loss; metabolic disorders; weight gain associated with pharmaceutical intervention; weight gain associated with mental illness (including those described herein); eating disorders such as anorexia nervosa, bulimia nervosa, cachexia; eating behavior; obesity; diabetes; insulin resistance; prediabetes; glucose intolerance; hyperlipidemia; and treatment of cardiovascular disease.

[0272] In another aspect, the present disclosure provides a method for increasing dendritic spine density, the method comprising contacting a nerve cell with a compound of formula (I) or a pharmaceutical composition described herein in an amount sufficient to increase the dendritic spine density of the nerve cell.

[0273] In certain embodiments, the compound of formula (I) produces a maximum number of dendritic intersections with an increase of more than 1.0-fold as determined by Shohl analysis.

[0274] In another aspect, the present disclosure provides a method for activating a serotonin receptor in a biological sample or any cell of 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 one or both of 5-HT 2A and 5-HT 2C One or both of. In some embodiments, the compound of formula (I) is selective for one or both of 5-HT 2A and 5-HT 2C It is selective for one or both of.

[0275] It will 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 used, age, weight, general health, sex, diet, time of administration, route of administration, frequency of dosage, and rate of excretion, drug combinations (i.e., other drugs used to treat the patient), as well as the severity of the particular disorder being treated.

[0276] 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 one or more given compounds corresponding to the effective amount varies depending on factors such as the given drug or compound, pharmaceutical formulation, route of administration, condition, type of disease or disorder, identity of the subject being treated, etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0277] As used herein, the term "effective amount" means, for example, the amount of a drug or pharmaceutical that elicits a biological or medical response in a tissue, system, animal, or human as desired by a researcher or clinician. Further, the phrase "therapeutically effective amount" generally refers to (i) treating a particular disease, condition, or disorder, (ii) attenuating, ameliorating, or eliminating one or more symptoms or manifestations of a particular disease, condition, or disorder, or (iii) delaying the onset of one or more symptoms or manifestations of a particular disease, condition, or disorder described herein, the amount of one or more active ingredients of the present invention.

[0278] Typically, therapeutically effective dosages are formulated to include at least about 0.1% to up to about 50% or more by concentration (weight), as well as all combinations and subcombinations within that range. The composition can be formulated to contain one or more actives described herein at a concentration of from about 0.1% to less than about 50%, for example, about 49, 48, 47, 46, 45, 44, 43, 42, 41, or 40%, and the concentration can be greater than about 0.1%, for example, about 0.2, 0.3, 0.4, or 0.5% to less than about 40%, for example, about 39, 38, 37, 36, 35, 34, 33, 32, 31, or 30%. Exemplary compositions can include from about 0.5% to less than about 30%, for example, about 29, 28, 27, 26, 25, 25, 24, 23, 22, 21, or 20%, and the concentration can be 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%. The composition can include greater than about 1%, for example, about 2% to less than about 10%, for example, about 9 or 8%, which includes a concentration of greater than about 2%, for example, about 3 or 4% to less than about 8%, for example, about 7 or 6%. The active agent can be present, for example, at a concentration of about 5%. In all cases, the amount can be adjusted to compensate for differences in the amount of active ingredient actually delivered to the cell or tissue being treated.

[0279] In some embodiments, the compounds of formula (I) of the present disclosure are administered once, twice, three times, or four times a year. In some embodiments, the compounds of the present disclosure are administered at least once a week. However, in another embodiment, the compound is administered to the subject approximately once every two weeks, three weeks, or one month. In another embodiment, the compound is administered from approximately once a week to once a day. In another embodiment, the compound is administered one, two, three, four, five, or six times a day. The length of the treatment period depends on various factors such as the severity of the disease, disorder, or condition, the age of the subject, the concentration, and / or the activity of the compounds of the present application, and / or combinations thereof. The treatment period can be during the duration of the detectable disease. It will also be understood that the effective dosage of the compound used in the treatment can increase or decrease over the course of a particular treatment regimen. Changes in dosage can occur and become apparent by standard diagnostic assays known in the art. In some cases, chronic administration is required. For example, the compound is administered to the subject in an amount and for a duration sufficient to treat the subject.

[0280] In some embodiments, the compounds of the present application are administered at a dosage that causes hallucinations or mental abnormalities and are used in combination with psychotherapy or treatment, and can occur once, twice, three times, or four times a year. However, in some embodiments, the compound is administered at a dosage that does not cause hallucinations or mental abnormalities. In some preferred embodiments, a therapeutically effective amount of the compound of formula (I) described herein does not cause hallucinations or mental abnormalities. A dosage that does not cause hallucinations or mental abnormalities can be administered to the subject once a day, once every two days, once every three days, once a week, once every two weeks, once a month, once every two months, or once every three months.

[0281] The compounds of formula (I) of the present disclosure can be used either alone or in combination with other agents useful for treating a disease, disorder, or condition to be treated by the methods of the present disclosure, including diseases, disorders, and conditions improved by activation of serotonin receptors such as the compounds of the present disclosure. The other agents can be any agent known in the art and described herein that is useful for treating the disease, disorder, or condition. 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 a compound of formula (I) including those known in the art and described herein. When used in combination with the other agent, this is an embodiment where the compound of formula (I) is administered simultaneously with those agents. As used herein, "co-administration" of two substances to a subject means providing each of them such that both substances are simultaneously active in the individual. The exact details of administration can depend on the pharmacokinetics of the two substances in the presence of each other and, where the pharmacokinetics are favorable, can include administering the two substances within a few hours of each other or even administering one substance within 24 hours of the other's administration. Design of a suitable dosing regimen is routine for those skilled in the art. In certain embodiments, the two substances are administered substantially simultaneously, i.e., within a few minutes of each other or in a single composition containing both substances. A further embodiment of the present disclosure is that the combination of agents is administered to the subject non-simultaneously. In some embodiments, the compounds of formula (I) of the present disclosure are administered together with another therapeutic agent, either simultaneously or sequentially, in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising one or more compounds of formula (I) described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier. However, it will be understood that when administered in separate dosage forms, the route of administration can be the same or different.

[0282] In some embodiments, the compounds of formula (I) described herein are used or administered in an effective amount that includes administration at a dose or dosing regimen that does not produce a clinically significant psychedelic / psychotic effect. In some embodiments, the compounds of the present application have a human plasma creatinine Cmax of 4 ng / mL or less and / or a human 5-HT 2A presented by human CNS receptor occupancy of 40% or less, or a human plasma creatinine Cmax of 1 ng / mL or less and / or a human 5-HT 2A presented by human CNS receptor occupancy of 30% or less and are used or administered in an effective amount that includes administration at a dose or dosing regimen that produces a clinical effect similar to that presented by. In some embodiments, the compounds of the present application are used or administered in an effective amount that includes administration at a dose or dosing regimen that provides a clinical effect similar to that presented by human plasma creatinine Tmax, 60 minutes in excess, 120 minutes in excess, or 180 minutes in excess.

[0283] Kit In another embodiment, there is provided a kit or article of manufacture comprising one or more of the compounds, pharmaceutically acceptable salts, stereoisomers, solvates, metabolites, or polymorphs as described above, and / or a pharmaceutical composition.

[0284] In other embodiments, there is provided a kit for use in the above-described therapeutic uses, the kit comprising a container holding one or more of the compounds, pharmaceutically acceptable salts, stereoisomers, solvates, metabolites, and / or polymorphs described herein, and / or a pharmaceutical composition, a label or package insert with instructions for use. The instructions for use may follow any of the methods or uses described herein.

[0285] The invention disclosed and defined herein is understood to extend to all alternative combinations of two or more of the individual features mentioned or apparent from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

Examples

[0286] Reference is now made to specific embodiments of the present invention. It is understood that the synthetic protocols outlined below illustrate specific embodiments of the present invention but are not intended to limit the present invention to those embodiments. Rather, the present invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the present invention and defined by the claims.

[0287] Those skilled in the art will recognize numerous methods and materials similar or equivalent to those described herein. The present invention is in no way limited to the materials and methods described. It will be understood that the selection of structural features or substitution patterns surrounding the core skeletons outlined above will affect the selection of one process over another. Starting materials are available from commercial sources or can be readily prepared from precursors available after simple transformations well known to those skilled in the art.

[0288] Overview In the following examples, unless otherwise indicated, temperatures are given in degrees Celsius (°C), operations are carried out at room temperature or ambient temperature, "room temperature (rt)" or "room temperature (RT)" (typically in the range of about 18 - 25 °C), evaporation of solvents is carried out using a rotary evaporator under reduced pressure (typically 4.5 - 30 mmHg) at a bath temperature of up to 60 °C, thin layer chromatography (TLC) typically follows after the course of the reaction, melting points are not corrected, and products are satisfactory 1 and show 1H NMR and / or microanalysis data, and the following conventional abbreviations: L (liter), mL (milliliter), mmol (millimole), g (gram), mg (milligram), min (minute), and h (hour) are also used.

[0289] Unless otherwise specified, all solvents and reagents were purchased from suppliers and used without further purification. Unless otherwise described, reactions were carried out under a nitrogen blanket. Compounds were visualized under a UV lamp (254 nm). 11H NMR spectra were recorded on a 300 MHz or 400 MHz NMR instrument as indicated. Column and flash chromatography were performed using SiO2 as the stationary phase, and “MeOH / NH3” refers to a 9:1 methanol / 15 M aqueous ammonia solution.

[0290] Synthesis of Compounds General Procedure General Procedure A: Formulation of hydrochloride salts from amines Dissolve the starting free base amine in the minimum amount of solvent (MeOH, iPrOH, or a mixture thereof), add concentrated HCl (32 - 37%) to acidify to pH 1. Add Et2O to initiate precipitation and allow the mixture to stand at 0 °C. Collect the product by vacuum filtration and wash with Et2O.

[0291] General Procedure B: Formulation of fumarate salts from amines Add a solution of the free base amine in the minimum amount of solvent (acetone or iPrOH) to a hot solution (1 - 3 equivalents, 0.02 - 0.2 M) of fumaric acid in either acetone or iPrOH, and heat the mixture to 40 - 60 °C. Cool the mixture, add Et2O or hexane to initiate precipitation, and then allow it to stand at 0 °C. Collect the product by vacuum filtration and wash with Et2O.

[0292] Compounds of general formula (I) can be synthesized from appropriately substituted 6,6 - aromatic systems according to the steps outlined in Schemes 1 - 9 below or steps similar to those that can be contemplated 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, Volume 127, 15 February 2017, Pages 621 - 631).

[0293] Scheme 1: Compounds of general formula (I) can be synthesized from a suitably substituted 6,6 - aromatic system according to the step procedures outlined in Scheme 1 or step procedures similar to those available to a person skilled in the art. The suitably substituted 6,6 - aromatic system can undergo consecutive one - pot reductive alkylation to obtain compounds of general formula (I) (exemplified by Examples I - 1 and I - 18).

Chemical formula

[0294] Example 1: Synthesis of 2-(7 - methoxynaphthalen - 1 - yl)-N,N - dimethylethan - 1 - amine (I - 1)

Chemical formula

[0295] Scheme 2: Compounds of general formula (I) can be synthesized from appropriately substituted 6,6 - aromatic systems according to the step procedures outlined in Scheme 2 or step procedures similar to those available to those skilled in the art. A 6,6 - aromatic system with a suitable nitrile substituent is selectively reduced to obtain an aldehyde intermediate, which is then subjected to reductive alkylation with an appropriately substituted amine to produce the compounds of general formula (I) (exemplified by Examples I - 2, I - 3, I - 4, I - 5, I - 6, and I - 7). [Chemical Structure]

[0296] Example 2: Synthesis of N,N - diethyl - 2 - (7 - methoxynaphthalen - 1 - yl)ethan - 1 - amine (I - 2): [Chemical Structure] Step 1: 2 - (7 - methoxynaphthalen - 1 - yl)acetaldehyde (3) A solution of 2-(7-methoxynaphthalen-1-yl)acetonitrile (0.3 g, 1.52 mmol) in CH2Cl2 (10 mL) was added dropwise with a 1 M DiBAL-H / toluene solution (2.28 mL, 2.28 mmol) at 0 °C, and the resulting mixture was stirred at 0 °C for 3 h. After completion, the reaction was quenched with 3 M aqueous HCl (30 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 resulting residue was purified by flash chromatography (10% EtOAc in petroleum ether) to give 2-(7-methoxynaphthalen-1-yl)acetaldehyde (164 mg, 54%) as a yellow oil. 1 H NMR (300 MHz, CDCl3) δ 9.74 (t, J = 2.1 Hz, 1H), 7.78 (m, 2H), 7.31 - 7.42 (m, 2H), 7.18 (dd, J = 9.0, 2.1 Hz, 1H), 7.11 (s, 1H), 4.05 (d, J = 2.1 Hz, 2H), 3.92 (s, 3H)

[0297] Step 2: N,N-Diethyl-2-(7-methoxynaphthalen-1-yl)ethan-1-amine hydrochloride (I-2·HCl) A solution of 2-(7-methoxynaphthalen-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 portionwise with NaBH(OAc)3 (212 mg, 1.0 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 16 h. After completion, the reaction 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 give N,N-diethyl-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (40 mg) as the free base (I-2). The free base was dissolved in MeOH (0.5 mL), treated with HCl / Et2O at room temperature, and stirred at room temperature for 30 min. 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] + ; 1 1H NMR (300 MHz, CD3OD-d4) δ 7.82 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 6.9 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.19 (d, J = 9.0 Hz, 1H), 3.98 (s, 3H), 3.56 - 3.35 (m, 8H), 1.39 (t, J = 6.6 Hz, 6H).

[0298] Example 3: Synthesis of N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-propylpropan-1-amine (I-3):

Chemical formula

[0299] Example 4: Synthesis of N-isopropyl-N-(2-(7-methoxynaphthalen-1-yl)ethyl)propan-2-amine (I-4):

Chem.

[0300] Example 5: Synthesis of N-ethyl-2-(7-methoxynaphthalen-1-yl)-N-methylethan-1-amine (I-5):

Chem.

[0301] Example 6: Synthesis of N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-1-amine (I-6):

Chemical formula

[0302] Example 7: Synthesis of N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (I-7):

Chemical Structure

[0303] Example 14: Synthesis of 8-(2-(isopropyl(methyl)amino)ethyl)naphthalen-2-ol (I-14): [Chem.] Step 1: 8-(2-(Isopropyl(methyl)amino)ethyl)naphthalen-2-ol (I-14) To a cooled solution of N-(2-(7-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (620 mg, 2.41 mmol) in anhydrous CH2Cl2 (30 mL) at 0 °C was added BBr3 (0.57 mL, 2.5 eq, 6.02 mmol), and the mixture was stirred at 0 °C for 1.5 h. The reaction was quenched by dropwise addition of aqueous 6 M HCl until the foaming stopped during the addition. An additional 1 mL of aqueous 6 M HCl was added, followed by 5 mL of MeOH, and the resulting solution was refluxed for 1 h. The solvent was then removed under a stream of N2 gas, and the aqueous residue was neutralized with saturated aqueous Na2CO3. The suspension was made basic with 15% aqueous NaOH (1 mL), and then extracted with CH2Cl2 (50 mL × 3). The combined organic layers were washed with saturated aqueous Na2CO3 (50 mL × 2), then brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under a stream of N2 gas. The residue was purified by flash chromatography (0.1% - 5% MeOH / NH3 in CH2Cl2) to give the title compound (480 mg, 82%) as a pale brown oil. 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.25 - 7.12 (m, 3H), 6.64 (br. s, 1H), 3.38 - 3.24 (m, 2H), 3.19 (sept, J = 6.6 Hz, 1H), 3.00 - 2.85 (m, 2H), 2.50 (s, 3H), 1.15 (d, J = 6.6 Hz, 6H). 1313C NMR (101 MHz, CDCl3) δ 155.77, 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。

[0304] Step 2: 8-(2-(Isopropyl(methyl)amino)ethyl)naphthalen-2-ol hydrochloride (I-14·HCl) 8-(2-(Isopropyl(methyl)amino)ethyl)naphthalen-2-ol (380 mg, 1.56 mmol) was formulated as the hydrochloride according to the general procedure A and isolated as pink crystals (116 mg, 31%). 1 1H NMR (400 MHz, DMSO-d6): δ 10.49 (br s, 1H), 9.90 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.73 - 7.68 (m, 1H), 7.40 - 7.33 (m, 2H), 7.22 (dd, J = 8.2, 7.0 Hz, 1H), 7.14 (dd, J = 8.8, 2.3 Hz, 1H), 3.66 (sept, J = 6.6 Hz, 1H), 3.46 - 3.36 (m, 2H), 3.28 - 3.11 (m, 2H), 2.79 (s, 3H), 1.34 - 1.20 (m, 6H); 13 13C NMR (101 MHz, DMSO-d6): δ 155.9, 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。

[0305] Scheme 3: Compounds of general formula (I) can be synthesized from appropriately substituted 6,6 - aromatic systems according to the step procedures outlined in Scheme 3 or step procedures similar to those that can be utilized by those skilled in the art. 6,6 - aromatic systems having suitable carboxylic acid substituents can be activated in a number of ways including, but not limited to, conversion to acid chlorides, mixed anhydrides, activated esters that require the use of peptide coupling reagents, and activated ureas that require the use of imide coupling reagents, and subsequently amidated using appropriately substituted amines. The resulting amides can be reduced using various reducing agents that can be contemplated by those skilled in the art to form the compounds of general formula (I) (exemplified by Examples I - 15, I - 17, I - 19, and I - 20).

Chemical formula

[0306] Example 15: Synthesis of N-(2-(7 - methoxynaphthalen - 1 - yl)ethyl)-N - methylcyclopropanamine (I - 15):

Chemical formula

[0307] Step 2: N-(2-(7-Methoxynaphthalen-1-yl)ethyl)-N-methylcyclopropanamine (I-15) To ice-cooled anhydrous THF (50 mL), LiAlH4 (590 mg, 15.4 mmol) was added portionwise, and then a solution of N-cyclopropyl-N-methyl(7-methoxy-1-naphthyl)acetamide (520 mg, 1.93 mmol) in anhydrous THF (5 mL) was added. Subsequently, the reaction mixture was refluxed with stirring under a N2 atmosphere for 16 h. Then, the reaction mixture was cooled to 0 °C and quenched by sequentially adding H2O (0.6 mL), NaOH (0.6 mL, 15 w / v% aqueous solution), and H2O (1.8 mL), dried (Na2SO4), filtered through a plug of Celite. The residue was washed with hot THF (50 mL×2). The combined filtrates were concentrated, and the residue was purified by flash chromatography (0.1%-2% MeOH / NH3 in CH2Cl2) to give the title compound (400 mg, 81%) as a clear oil. 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.40 - 7.22 (m, 3H), 7.15 (dd, J = 8.9, 2.5 Hz, 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 = 6.5 Hz, 4H). 13 C NMR (101 MHz, CDCl3) δ 157.9, 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.

[0308] Step 3: N-(2-(7-Methoxynaphthalen-1-yl)ethyl)-N-methylcyclopropanamine fumarate (I-15·fum) A solution of N-cyclopropyl-N-methyl[2-(7-methoxy-1-naphthyl)ethyl]amine (365 mg, 1.43 mmol) dissolved in the minimum amount of anhydrous Et2O was added to a solution of fumaric acid (166 mg, 1.43 mmol) dissolved in the minimum amount of refluxing acetone. The resulting solution was cooled to 4 °C and maintained at this temperature for 72 h to give a white crystalline solid, which was identified as the fumarate salt of the title compound. (149 mg, 28%). 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.26 (dd, J = 8.0, 7.0 Hz, 1H), 7.17 (dd, J = 8.9, 2.5 Hz, 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 (101 MHz, DMSO-d6) δ 166.2, 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] + )

[0309] Example 16: Synthesis of 8-(2-(cyclopropyl(methyl)amino)ethyl)naphthalen-2-ol (I-16):

Chemical formula

[0310] Example 17: Synthesis of N-(3-methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-17): [Chemical] Step 1: N-(3-Methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)acetamide (72) To a solution of 2-(7-methoxynaphthalen-1-yl)acetic acid (0.30 g, 1.39 mmol) in DMF (2.0 mL), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (1.06 g, 2.77 mmol), i Pr2NEt (0.72 g, 5.55 mmol), and then a solution of (3-methoxyphenyl)methanamine (190 mg, 1.39 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction 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 (0 - 40% EtOAc / hexane) to give N-(3-methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)acetamide (403 mg, 87%) as white crystals. 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.38 (dd, J = 7.0, 1.3 Hz, 1H), 7.30 (dd, J = 8.2, 7.0 Hz, 1H), 7.22 - 7.16 (m, 2H), 7.10 (t, J = 7.9 Hz, 1H), 6.74 - 6.68 (m, 1H), 6.59 (ddd, J = 7.6, 1.7, 0.9 Hz, 1H), 6.51 (t, J = 2.1 Hz, 1H), 5.65 (t, J = 5.9 Hz, 1H), 4.33 (d, J = 6.0 Hz, 2H), 4.05 (s, 2H), 3.86 (s, 3H), 3.63 (s, 3H).

[0311] Step 2: N-(3-Methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-17) 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 / THF solution (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 HCl aqueous solution (2.0 mL), followed by MeOH (4.0 mL), and then stirred under reflux for 1 hour. After cooling, the volatiles were removed under a stream of N2 gas, 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%-10% MeOH / NH3 in CH2Cl2) to give N-(3-methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (274 mg, 74%) as a clear oil. 1 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 8.0 Hz, 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 = 7.3 Hz, 2H), 3.02 - 3.10 (t, J = 7.3 Hz, 2H).

[0312] Step 3: N-(3-Methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine fumarate (I-17·Fum) N-(3-Methoxybenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (274 mg, 0.85 mmol) was formulated as the fumarate salt according to the general procedure B and isolated as white crystals (296 mg, 79%). HPLC purity: 95.4% (254 nm). 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 9.0 Hz, 1H), 7.77 - 7.69 (m, 1H), 7.36 (d, J = 2.6 Hz, 1H), 7.35 - 7.32 (m, 1H), 7.27 (dd, J = 8.1, 7.2 Hz, 2H), 7.18 (dd, J = 8.9, 2.5 Hz, 1H), 7.07 (dd, J = 2.6, 1.5 Hz, 1H), 7.04 - 6.97 (m, 1H), 6.88 (ddd, J = 8.3, 2.6, 1.0 Hz, 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 (101 MHz, DMSO-d6) δ 167.3, 159.3, 157.6, 137.3, 134.8, 133.4, 132.6, 130.2, 129.5, 128.8, 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.

[0313] Example 18: Synthesis of N-(3-fluorobenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-18):

Chemical Structure

[0314] Step 1: N-(3-Fluorobenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-18) To a stirred solution of 2-(7-methoxynaphthalen-1-yl)ethan-1-amine (92 mg, 0.46 mmol) in CH2Cl2 (5.0 mL) were added 3-fluorobenzaldehyde (57 mg, 0.46 mmol) and NaBH(OAc)3 (116 mg, 0.55 mmol), and the reaction was stirred at room temperature for 3 h. The reaction mixture was concentrated under a stream of nitrogen gas, then treated with 1 M aqueous NaOH (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, 1% MeOH / NH3 in CH2Cl2) to give N-(3-fluorobenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (86 mg, 61%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 8.9 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.33 (dd, J = 7.0, 1.4 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 7.29 - 7.22 (m, 2H), 7.16 (dd, J = 8.9, 2.5 Hz, 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).

[0315] Example 19: Synthesis of N-(3-methylbenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-19):

Chemical formula

[0316] Step 2: N-(3-Methylbenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-19) 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 a 2 M borane-dimethyl sulfide complex / THF solution (2.0 mL, 4.01 mmol), and the mixture was stirred at 60 °C for 1 h. After cooling, the mixture was carefully treated with 6 M aqueous HCl (2.0 mL), followed by MeOH (4.0 mL), and then stirred under reflux for 1 h. 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 5 M 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 give 2-(7-methoxynaphthalen-1-yl)-N-(3-methylbenzyl)ethan-1-amine (242 mg, 79%) as a clear oil. 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.34 - 7.31 (m, 1H), 7.31 (d, J = 2.5 Hz, 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).

[0317] Step 3: N-(3-Methylbenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine fumarate (I-19·Fum) N-(3-Methylbenzyl)-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (237 mg, 0.78 mmol) was formulated as the fumarate salt according to the general procedure B to give white crystals (266 mg, 81%). 11H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 9.0 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 7.1, 1.4 Hz, 1H), 7.30 - 7.23 (m, 4H), 7.18 (dd, J = 8.9, 2.4 Hz, 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 13C NMR (101 MHz, DMSO-d6) δ 167.7, 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.

[0318] Example 20: Synthesis of N-benzyl-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-20): [Chemical formula] Step 1: N-benzyl-2-(7-methoxynaphthalen-1-yl)acetamide (75) To a solution of (7-methoxy-1-naphthyl)acetic acid (1.0 g, 4.62 mmol) in DMF (5 mL) was added a solution of 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisuronium hexafluorophosphate (3.5 g, 9.25 mmol) in DMF (10 mL), followed by iPr2NEt (3.2 mL, 18.5 mmol), and then benzylamine (0.6 mL, 5.55 mmol). The resulting reaction mixture was stirred at room temperature for 1 h and then diluted with H2O (100 mL). The precipitate was collected by vacuum filtration, washed with H2O, and the title compound (1.4 g, quantitative) was obtained as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 5.7 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.45 - 7.36 (m, 2H), 7.32 - 7.11 (m, 7H), 4.30 (d, J = 5.9 Hz, 2H), 3.93 (s, 2H), 3.79 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 170.1, 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.

[0319] Step 2: N-Benzyl-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-20) A solution of N-benzyl(7-methoxy-1-naphthyl)acetamide (1.4 g, 4.58 mmol) in anhydrous THF (30 mL) was added with a 2 M borane dimethyl sulfide / THF solution (9.0 mL, 18.3 mmol) under an inert atmosphere, and the reaction mixture was refluxed and stirred for 1 h. After completion, 6 M aqueous HCl was added dropwise until the foaming stopped to quench the hot solution, and then MeOH (5 mL) and subsequently an additional portion of HCl (1 mL, 6 M aqueous solution) were added. The solution was refluxed and stirred for 1 h and then concentrated under a stream of N2 gas. The aqueous residue was neutralized with saturated aqueous Na2CO3 and then made basic with NaOH (1 mL, 15% aqueous solution). The suspension was extracted with CH2Cl2 (50 mL × 3), and then the combined organic layers were washed with saturated aqueous Na2CO3 (20 mL × 3) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (0.1%-2% MeOH / NH3 in CH2Cl2) to give the title compound (1.23 g, 92%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.37 - 7.20 (m, 8H), 7.15 (dd, J = 8.9, 2.5 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 2H), 3.27 (t, J = 7.3 Hz, 2H), 3.07 (t, J = 7.3 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 157.82, 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.

[0320] Step 3: N-benzyl-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (I-20·fum) N-Benzyl-2-(7-methoxynaphthalen-1-yl)ethan-1-amine (200 mg, 0.69 mmol) was formulated as the fumarate salt according to General Procedure B to give the product (215 mg, 82%) as white crystals. HPLC purity: 99.9% (254 nm); 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 8.1, 1.3 Hz, 2H), 7.42 - 7.23 (m, 6H), 7.17 (dd, J = 8.9, 2.5 Hz, 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 (101 MHz, DMSO-d6) δ 167.9, 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.

[0321] Scheme 4: The compounds of general formula (I) can be synthesized from appropriately substituted acenaphthylen-1-one according to the step procedures outlined in Scheme 4 or step procedures similar thereto that can be utilized by those skilled in the art. The chromenone intermediate is generated by Baeyer-Villiger oxidation and reduced to give the appropriately substituted naphthalene. The necessary aldehyde intermediate is generated by chemoselective phenolic methylation with methyl iodide followed by partial oxidation of the terminal alcohol with Dess-Martin periodinane, which is then subjected to reductive amination to give the compounds of general formula (I) (exemplified by Examples I-13, I-22, I-23, I-24, I-25, I-27, I-28, and I-30). Subsequent demethylation of the methyl ether allows for the obtaining of the phenols of general formula (I) (exemplified by Examples I-21, I-26, I-29, and I-31).

Chem.

[0322] Example 13: Synthesis of 2-(8-methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-13)

Chem.

[0323] Step 2: 8-(2-Hydroxyethyl)naphthalen-1-ol (16) A solution of benzo[de]chromen-2(3H)-one (1.4 g, 7.6 mmol) in THF (28 mL) was cooled to 0 °C and treated with LiAlH4 (288 mg, 7.6 mmol) under N2. The reaction mixture was stirred at room temperature for 15 min. After completion, Na2SO4·10H2O (1.40 g) was added to quench the reaction, the precipitate was removed by filtration, and the filter cake was washed with THF (50 mL). The combined filtrates were concentrated to afford the crude title compound (1.4 g) as a brown solid, which was used in the next step without further purification.

[0324] Step 3: 2-(8-Methoxynaphthalen-1-yl)ethan-1-ol (17) A solution of crude 8-(2-hydroxyethyl)naphthalen-1-ol (1.4 g, 7.44 mmol) in DMF (14 mL) was treated with K2CO3 (3.08 g, 22.3 mmol) and MeI (2.11 g, 14.9 mmol) at room temperature and stirred for 12 h. After completion, H2O (50 mL) was added to quench the reaction mixture, and the mixture was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 3%-8% EtOAc in petroleum ether) to afford the title compound as an off-white solid (0.7 g, 46% over 2 steps). 1 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.36 - 7.40 (m, 2H), 7.27 (m, 1H), 6.87 (d, J = 7.2 Hz, 1H), 3.95 - 3.99 (m, 5H), 3.59 (t, J = 6.4 Hz, 2H).

[0325] Step 4: 2-(8-Methoxynaphthalen-1-yl)acetaldehyde (18) A solution of 2-(8-methoxynaphthalen-1-yl)ethan-1-ol (250 mg, 1.24 mmol) in DMF (5 mL) was cooled to 0 °C and treated with Dess-Martin periodinane (629 mg, 1.48 mmol) under N2, and then stirred at room temperature for 1 h. After completion, the reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (5 mL×3). The combined organic layers were 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 afford the title compound as a colorless oil (240 mg, 97%). 11H NMR (400 MHz, CDCl3): δ 9.82 (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).

[0326] Step 5: 2-(8-Methoxynaphthalen-1-yl)-N,N-dimethylethane-1-amine (I-13) A solution of 2-(8-methoxynaphthalen-1-yl)acetaldehyde (240 mg, 1.2 mmol) in CH2Cl2 (7 mL) was cooled to 0 °C and treated with 2 M Me2NH / THF solution (0.90 mL, 1.8 mmol) under N2 and stirred for 15 minutes. Then, NaBH(OAc)3 (508 mg, 2.4 mmol) was added to the reaction mixture at 0 °C under N2 and the reaction was stirred at room temperature for a further 12 hours. After completion, the reaction was quenched with MeOH (10 mL) and concentrated in vacuo. The residue was diluted with CH2Cl2 (10 mL) and washed with H2O (4 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex C18, 80×40 mm×3 μm; 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% (220 nm); 1 1H NMR (400 MHz, MeOD-d4) δ 7.66 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.32 - 7.37 (m, 2H), 7.25 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 7.6 Hz, 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] + .

[0327] Example 21: Synthesis of 8-(2-(dimethylamino)ethyl)naphthalen-1-ol (I-21) [Chemical formula] Step 1: 8-(2-(dimethylamino)ethyl)naphthalen-1-ol (I-21) 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, and then heated at 100 °C for 2 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18, 100×30 mm×10 μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: from 10 to 50% over 8 minutes) to obtain the title compound (I-21, 20 mg, 7%) as a brown solid. HPLC purity: 98.0% (220 nm); 1 H NMR δ (400 MHz, 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).

[0328] Example 22: Synthesis of N,N-diethyl-2-(8-methoxynaphthalen-1-yl)ethane-1-amine (I-22) [Chemical formula] Step 1: N,N-diethyl-2-(8-methoxynaphthalen-1-yl)ethane-1-amine (I-22) A solution of 2-(8-methoxynaphthalen-1-yl)acetaldehyde (0.30 g, 1.50 mmol) in CH2Cl2 (9.0 mL) was added with Et2NH (165 mg, 2.26 mmol) at 0 °C under N2. The reaction mixture was stirred at room temperature for 15 minutes. Then, NaBH(OAc)3 (636 mg, 3.0 mmol) was added at 0 °C under N2, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with MeOH (20 mL), and the volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (30 mL), washed with H2O (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge OBD C18, 150×40 mm×10 μm; mobile phase: [H2O(NH4HCO3)-ACN]; B%: 25-55%, 8 minutes) to obtain the title compound (I-22, 222 mg, 58%) as a brown oil. HPLC purity: 98.6% (220 nm); 1 H NMR (400 MHz, MeOD-d4) δ 7.66 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.25 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 3.98 (s, 3H), 3.47 - 3.43 (m, 2H), 2.77 - 2.68 (m, 6H), 1.14 (t, J = 7.2 Hz, 6H). LCMS (ESI+): m / z 258.0 [M+H] + .

[0329] Example 23: Synthesis of N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-propylpropan-1-amine (I-23)

Chemical Structure

[0330] Example 24: Synthesis of N-isopropyl-N-(2-(8-methoxynaphthalen-1-yl)ethyl)propan-2-amine (I-24)

Chemical formula

[0331] Example 25: Synthesis of N-Ethyl-2-(8-methoxynaphthalen-1-yl)-N-methylethan-1-amine (I-25)

Chemical formula

[0332] Example 26: Synthesis of 8-(2-(methyl(ethyl)amino)ethyl)naphthalen-1-ol (I-26)

Chemical Structure

[0333] Example 27: Synthesis of N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-1-amine (I-27) [Chemical formula] Step 1: N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-1-amine (I-27) A solution of 2-(8-methoxynaphthalen-1-yl)acetaldehyde (0.30 g, 1.50 mmol) in CH2Cl2 (9.0 mL) was added with N-methylpropan-1-amine (165 mg, 2.26 mmol) at 0 °C under N2. Then, the reaction mixture was stirred at room temperature for 15 minutes and then cooled to 0 °C. Then, NaBH(OAc)3 (636 mg, 3.0 mmol) was added and the resulting suspension was stirred at room temperature for 12 hours. Then, the reaction mixture was quenched with MeOH (20 mL) and the volatiles were removed in vacuo. The residue was dissolved in CH2Cl2 (20 mL), washed with H2O (5 mL), the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the 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 give the title compound (I-27, 149 mg, 37%) as a brown oil. HPLC purity: 96.6% (220 nm); 1 H NMR (400 MHz, MeOD-d4) δ 7.68 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.28 (d, J = 7.2 Hz, 1H), 6.97 (d, J = 7.6 Hz, 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 = 7.4 Hz, 3H). LCMS (ESI+): m / z 258.0 [M+H] + , 1.6 minutes.

[0334] Example 28: Synthesis of N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (I-28)

Chem.

[0335] Example 29: Synthesis of 8-(2-(methyl(isopropyl)amino)ethyl)naphthalen-1-ol (I-29) [Chemical formula] Step 1: 8-(2-(Methyl(isopropyl)amino)ethyl)naphthalen-1-ol (I-29·HCl) 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 N2 gas, and then heated at 100 °C for 2 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, and the major impurities were first removed from the resulting residue by preparative HPLC (column: Waters Xbridge BEH C18, 100×30 mm×10 μm; 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, 100×30 mm×10 μm; 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 hydrochloride. HPLC purity: 100% (220 nm); 1 H NMR (400 MHz, MeOD-d4) δ 7.72 (d, J = 8.2 Hz, 1H), 7.26 - 7.38 (m, 4H), 6.90 (d, J = 7.4 Hz, 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 = 6.4 Hz, 6H); LCMS (ESI+):m / z 244.2 [M+H] + , 1.94 minutes.

[0336] Example 30: Synthesis of N-(2-(8-methoxynaphthalen-1-yl)ethyl)-N-methylcyclopropanamine (I-30)

Chemical Structure

[0337] Example 31: Synthesis of 8-(2-(cyclopropyl(methyl)amino)ethyl)naphthalen-1-ol (I-31)

Chem.

[0338] Scheme 5: A compound of general formula (I) (wherein Z 1 or Z 4 is N) can be synthesized from an appropriately substituted quinoline according to the general step procedure shown in Scheme 5 or a step procedure similar to the step procedures available to those skilled in the art. R 9The variation in position can be achieved from either a commercially available stock or nucleophilic aromatic substitution conditions such as the specific examples outlined below. Similarly, aryl bromides can be obtained by various methods known to those skilled in the art, and specific examples are outlined below. Alternatively, the aryl bromide may be commercially available. The aryl bromide intermediate is subjected to Heck coupling conditions, followed by alkene reduction to obtain a phthalimide-protected intermediate, which can be removed to obtain an amine analog, which can be alkylated in several ways. One such example is reductive alkylation using formaldehyde, which produces a compound of general formula (I) (exemplified by Example I-8). These steps can also be applied to other appropriately substituted 6,6-aromatic systems.

Chemical formula

[0339] Example 8: Synthesis of 2-(2-methoxyquinolin-8-yl)-N,N-dimethylethan-1-amine (I-8)

Chemical formula

[0340] Step 2: (E)-2-(2-(2-Methoxyquinolin-8-yl)vinyl)isoindoline-1,3-dione (6) A mixture of 8-bromo-2-methoxyquinoline (2.0 g, 8.4 mmol), N-vinylphthalimide (2.18 g, 12.6 mmol), Et3N (3.4 g, 33.6 mmol), tri-o-tolylphosphine (256 mg, 0.84 mmol), and Pd(OAc)2 (189 mg, 0.84 mmol) in DMF (15 mL) was degassed and purged with N2, and then stirred at 110 °C for 14 h. After completion, the reaction mixture was diluted with ACN (50 mL), the insoluble substances were collected by filtration, and the filtrate was discarded. The collected solid was triturated with THF (20 mL), and the remaining insoluble substances were removed by filtration. The filtrate was concentrated in vacuo, and the residue was triturated with CH2Cl2 (5 mL) to give (E)-2-(2-(2-methoxyquinolin-8-yl)vinyl)isoindoline-1,3-dione (960 mg, 35%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 15.2 Hz, 1H), 8.27 (d, J = 15.2 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.93 (dd, J = 5.6, 3.2 Hz, 2H), 7.82 (d, J = 7.2 Hz, 1H), 7.78 (dd, J = 5.6, 3.2 Hz, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.36 - 7.42 (m, 1H), 6.97 (d, J = 8.8 Hz, 1H), 4.23 (s, 3H).

[0341] Step 3: 2-(2-(2-Methoxyquinolin-8-yl)ethyl)isoindoline-1,3-dione (7) 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 argon atmosphere. The suspension was degassed and purged three times with H2, and then stirred at room temperature for 12 hours under H2 (25 psi). After completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give 2-(2-(2-methoxyquinolin-8-yl)ethyl)isoindoline-1,3-dione (0.9 g) as a pale yellow solid, which was used in the next step without further purification.

[0342] Step 4: 2-(2-Methoxyquinolin-8-yl)ethan-1-amine (8) A solution of 2-(2-(2-methoxyquinolin-8-yl)ethyl)isoindoline-1,3-dione (0.8 g) in EtOH (8.0 mL) was treated with hydrazine hydrate (1.51 g, purity 80%, 24.1 mmol) at room temperature. The reaction mixture was then stirred at 80 °C for 12 hours. After completion, the reaction 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 give 2-(2-methoxyquinolin-8-yl)ethan-1-amine (0.4 g, 68% over 2 steps) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 8.0, 1.2 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.29 - 7.35 (m, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.07 (s, 3H), 3.30 - 3.35 (m, 2H), 3.25 - 3.20 (m, 2H).

[0343] Step 5: 2-(2-Methoxyquinolin-8-yl)-N,N-dimethylethan-1-amine (I-8) A solution of 2-(2-methoxyquinolin-8-yl)ethan-1-amine (0.3 g, 1.48 mmol) in CH2Cl2 (5 mL) was treated at 0 °C with AcOH (178 mg, 2.97 mmol), NaBH(OAc)3 (629 mg, 2.97 mmol), and aqueous formaldehyde solution (37 w / w%, 301 mg, 3.71 mmol), and then stirred at room temperature for 2 h. At this point, 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 min) 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% (220 nm); LCMS (ESI+): m / z 231.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.97 (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).

[0344] Scheme 6: General formula (I) wherein Z 4The compound where it is N) can be synthesized from appropriately substituted quinoline according to the step procedure outlined in Scheme 6 or a step procedure similar to those that can be utilized by those skilled in the art. Bromination of the quinoline derivative, followed by Heck coupling, gives an intermediate alkene compound, which is subjected to reduction conditions to give a phthalimide-protected amine. Removal of the phthalimide under standard conditions gives an amine derivative, which can be alkylated in several ways. An example of this is reductive alkylation using formaldehyde, and a compound of general formula (I) (exemplified by Example I-9) is produced. These steps can also be applied to other appropriately substituted 6,6-aromatic systems.

Chemical formula

[0345] Example 9: Synthesis of 2-(3-methoxyquinolin-5-yl)-N,N-dimethylethane-1-amine (I-9)

Chemical formula

[0346] Step 2: (E)-2-(2-(3-Methoxyquinolin-5-yl)vinyl)isoindoline-1,3-dione (11) A mixture of 5-bromo-3-methoxyquinoline (1.0 g, 4.2 mmol), N-vinylphthalimide (1.09 g, 6.3 mmol), Et3N (1.7 g, 16.8 mmol), tri-o-tolylphosphine (128 mg, 0.42 mmol), and Pd(OAc)2 (94 mg, 0.42 mmol) in DMF (7 mL) was degassed and purged with N2 three times, and then stirred at 115 °C for 16 h under N2. After completion, the reaction mixture was diluted with ACN (50 mL), the insoluble substances were collected by filtration, and the filtrate was discarded. The collected solid was washed with THF (20 mL), and the remaining insoluble substances were removed by filtration. The filtrate was concentrated in vacuo, and the residue was triturated with CH2Cl2 (3.0 mL) to give the title compound (400 mg) as a yellow solid, which was used in the next step without further purification.

[0347] Step 3: 2-(2-(3-Methoxyquinolin-5-yl)ethyl)isoindoline-1,3-dione (12) 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 argon. The suspension was degassed and purged with H2 three times, and then stirred at room temperature for 12 h under H2 (25 psi). After 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, which was used in the next step without further purification.

[0348] Step 4: 2-(3-Methoxyquinolin-5-yl)ethan-1-amine (13) 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 room temperature. Then, the reaction mixture was stirred at 80 °C for 12 h. After completion, the reaction was filtered and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc (5.0 mL), washed with H2O (5.0 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (110 mg, 13% over 3 steps) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 2.8 Hz, 1H), 7.47 - 7.53 (m, 1H), 7.37 - 7.42 (m, 1H), 3.98 (s, 3H), 3.19 (m, 4H).

[0349] Step 5: 2-(3-Methoxyquinolin-5-yl)-N,N-dimethylethan-1-amine (I-9) A solution of 2-(3-methoxyquinolin-5-yl)ethan-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 solution (37 w / w%, 110 mg, 1.36 mmol) at 0 °C, and then stirred at room temperature for 2 h. 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 min) to give the title compound (I-9, 26 mg, 21%) as a yellow oil. HPLC purity: 96.0% (220 nm); LCMS (ESI+): m / z 231.1 [M+H] + ; 11H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.48 (m, 1H), 7.39 (d, J = 7.2 Hz, 1H), 3.98 (s, 3H), 3.18 - 3.26 (m, 2H), 2.62 - 2.69 (m, 2H), 2.39 (s, 6H).

[0350] Scheme 7: The compounds of general formula (I) can be synthesized from appropriately substituted cyclic ketones according to the step procedures outlined in Scheme 7 or step procedures similar to those that can be utilized by those skilled in the art. 3,4-Dihydronaphthalen-1(2H)-one having an appropriate aromatic substitution pattern can be reacted with the phosphonate carbanion of triethyl phosphonate generated in situ using a strong base, and the corresponding substituted cyclohexene can be obtained after elimination. The substituted cyclohexene can be oxidized with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) to obtain the corresponding 6,6-aromatic system, which can undergo hydrolysis to obtain a carboxylic acid. Subsequently, the carboxylic acid can be reduced to obtain an alcohol, which can then be converted to an alkyl bromide and alkylated with an appropriately substituted amine to obtain a compound of general formula (I) (exemplified by Example I-32). Alternatively, the carboxylic acid can be activated and reacted directly with an appropriately substituted amine to obtain an amide, which can be reduced to the desired tertiary amine to obtain a compound of general formula (I) (exemplified by Examples I-33, I-34, I-35, I-37, and I-39).

Chemical formula

[0351] Example 32: Synthesis of 2-(7-chloronaphthalen-1-yl)-N,N-dimethylethane-1-amine (I-32)

Chemical formula

[0352] Step 2: Ethyl 2-(7-chloronaphthalen-1-yl)acetate (21) DDQ (3.59 g, 15.8 mmol) was added portionwise to a stirred solution of ethyl (7-chloro-3,4-dihydro-1-naphthyl) acetate (3.3 g, 13.2 mmol) in CH2Cl2 (50 mL). Stirring was continued for 4 h, at which point the reaction mass was filtered and the residue was washed with Et2O (3 × 20 mL). The combined filtrates were concentrated under reduced pressure and the resulting crude material was purified by column chromatography to afford ethyl (7-chloro-1-naphthyl) acetate (3.0 g, 92%) as a colorless oil. 1 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 2.0 Hz, 1H), 7.90 - 7.76 (m, 2H), 7.48 - 7.43 (m, 3H), 4.20 (q, J = 7.1 Hz, 2H), 4.04 (s, 2H), 1.28 (t, J = 7.1 Hz, 3H).

[0353] Step 3: 2-(7-Chloronaphthalen-1-yl)acetic acid (22) A solution of LiOH (867 mg, 36.2 mmol) in H2O (10 mL) was added to a suspension of ethyl (7-chloro-1-naphthyl) acetate (3.0 g, 12.1 mmol) and TBAB (0.12 mmol) in THF (10 mL). Stirring was continued at room temperature for 12 h, at which point the solution was concentrated under reduced pressure and washed with Et2O (2 × 25 mL). Concentrated HCl (32% aqueous solution) was added to acidify the aqueous layer 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), dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound (2 g, 96%) as a white crystalline solid. 1 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 2.0 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.50 - 7.41 (m, 3H), 4.07 (s, 2H).

[0354] Step 4: 2-(7-Chloronaphthalen-1-yl)ethan-1-ol (23) A stirred solution of (7-chloro-1-naphthyl)acetic acid (2.22 g, 10.1 mmol) in THF (20 mL) was treated with LiAlH4 (1.53 g, 40 mmol) at 0 °C, and the resulting suspension was warmed to room temperature. Stirring was continued at this temperature for 6 h, at which point the reaction mass was cooled to 0 °C and treated successively with H2O (1.5 mL), NaOH (15% aqueous solution, 1.5 mL), and H2O (4.5 mL), and then filtered through a pad of Celite. The residue was washed with THF (3 × 50 mL), and the combined filtrates were concentrated under reduced pressure. The crude oil thus obtained was purified by column chromatography (SiO2, 10-40% EtOAc / hexane (v / v)) to afford the desired compound (1.7 g, 82%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.51 - 7.34 (m, 3H), 3.98 (t, J = 6.7 Hz, 3H), 3.30 (t, J = 6.7 Hz, 2H).

[0355] Step 5: 1-(2-Bromoethyl)-7-chloronaphthalene (24) To a flask containing triphenylphosphine (3.95 g, 15.1 mmol) was added a dry CH2Cl2 (17.4 mL) solution of 2-(7-chloro-1-naphthyl)ethan-1-ol (2.08 g, 10.1 mmol) and CBr4 (2.12 g, 6.39 mmol) under an N2 atmosphere. The resulting mixture was stirred at 40 °C for 18 h. Et2O (29 mL) was added, and the resulting suspension was stirred at room temperature for 30 min. The resulting brown precipitate was filtered and washed with Et2O. The filtrate was concentrated under reduced pressure, and the crude product was purified by flash chromatography (SiO2, 0-5% EtOAc / hexane (v / v)) to afford 1-(2-bromoethyl)-7-chloronaphthalene (2.21 g, 82%) as a colorless oil. 11H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.78 (dd, J = 7.6, 2.0 Hz, 1H), 7.50 - 7.39 (m, 3H), 3.70 (ddd, J = 7.9, 6.9, 1.4 Hz, 2H), 3.61 (ddd, J = 8.8, 6.9, 1.3 Hz, 2H). 13 13C NMR (101 MHz, CDCl3) δ 134.2, 132.4, 132.3, 132.2, 130.6, 128.0, 127.6, 126.7, 125.8, 122.3, 36.4, 31.7.

[0356] Step 6: 2-(7-Chloronaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-32·HCl) A suspension of 1-(2-bromoethyl)-7-chloronaphthalene (150 mg, 0.56 mmol) and K2CO3 (154 mg, 1.11 mmol) was treated with 2 M Me2NH / THF solution (620 μL, 1.23 mmol) at room temperature. Then, the reaction mass was heated to 70 °C for 8 h, diluted with H2O (15 mL), and extracted with EtOAc (3 × 25 mL). The combined organic extracts were then washed successively with H2O (3 × 25 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting oil was purified by column chromatography (SiO2, 1 - 10% MeOH / NH3 in CH2Cl2) to give the title compound (85 mg) as a colorless oil. This oil was converted to the HCl salt according to the general procedure A, giving crystalline needles, which 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); 11H NMR (400 MHz, DMSO-d6) δ 10.88 - 10.83 (m, 1H), 8.29 (d, J = 1.9 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.95 - 7.86 (m, 1H), 7.57 (dd, J = 8.7, 2.0 Hz, 1H), 7.54 - 7.51 (m, 2H), 3.54 - 3.41 (m, 2H), 3.36 - 3.27 (m, 2H), 2.88 (d, J = 4.9 Hz, 6H). 13 13C NMR (101 MHz, DMSO-d6) δ 132.7, 132.1, 131.9, 131.5, 130.9, 128.0, 127.5, 126.6, 126.2, 122.6, 56.4, 42.0, 26.9.

[0357] Example 33: Synthesis of N-Ethyl-N-methyl-2-(naphthalen-1-yl)ethan-1-amine (I-33) [Chemical formula] Step 1: N-Ethyl-N-methyl-2-(naphthalen-1-yl)ethan-1-amine (I-33·Fum) 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 1 drop of DMF. Stirring was continued for 1 h, at which point the reaction was concentrated under a stream of N2 gas. The resulting yellow oil was then redissolved in CH2Cl2 (10 mL), cooled to 0 °C, treated with N-methylethylamine (201 mg, 3.4 mmol), followed by dropwise addition of triethylamine (0.79 mL, 5.66 mmol), and stirring was continued for 3 h. The reaction was then diluted with H2O (25 mL), and the phases were separated. The organic phase was washed with NaHCO3 (saturated aqueous solution, 25 mL), followed by brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting residue was triturated with Et2O (10 mL), filtered to give a white powder, which was dissolved in anhydrous THF (25 mL), cooled to 0 °C, treated portionwise with LiAlH4 (166 mg, 4.38 mmol), and the resulting suspension was then heated to reflux for 4 h. The reaction was then cooled to 0 °C, quenched by sequential dropwise addition of H2O (0.15 mL), NaOH (0.15 mL, 15% aqueous solution), and H2O (1 mL), followed by addition of MgSO4 (1 g). The suspension was then filtered through a Celite pad, and the residue was washed with THF (2 × 25 mL). The combined filtrates were concentrated under reduced pressure, and the crude oil was purified by flash column chromatography (SiO2, 0-5% MeOH / NH3 (v / v) in CH2Cl2) to give the title compound (85 mg) as a colorless oil. The free base was converted to the fumarate salt according to the general procedure B, affording a white crystalline product, which was identified as the title compound (I-33·Fum, 0.1 g, 80%). HPLC purity: 96.0% (254 nm); 11H NMR (400 MHz, DMSO-d6) δ 8.13 (ddd, J = 7.9, 1.7, 0.7 Hz, 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 = 7.2 Hz, 2H), 2.59 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 167.9, 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.

[0358] Example 34: Synthesis of N-methyl-N-(2-(naphthalen-1-yl)ethyl)propan-2-amine (I-34)

Chemical formula

[0359] Example 35: Synthesis of N-(2-(7-chloronaphthalen-1-yl)ethyl)-N-methylcyclopropanamine (I-35)

Chemical formula

[0360] Step 2: N-(2-(7-chloronaphthalen-1-yl)ethyl)-N-methylcyclopropanamine (I-35·mal) A stirred solution of 2-(7-chloronaphthalen-1-yl)-N-cyclopropyl-N-methylacetamide (0.3 g, 1.10 mmol) in THF (10 mL) was treated portionwise with LiAlH4 (166 mg, 4.38 mmol) at 0 °C under an inert atmosphere, and the resulting suspension was then heated to reflux for 4 h. The reaction was then cooled to 0 °C and quenched by the sequential addition of H2O (0.15 mL), NaOH (0.15 mL, 15% aqueous solution), and H2O (1 mL), followed by the addition of MgSO4 (1 g). The suspension was then filtered through a pad of celite and the residue was washed with THF (2 × 25 mL). The combined filtrates were concentrated under reduced pressure and the crude oil was purified by flash column chromatography (SiO2, 0 - 5% MeOH / NH3 (v / v) in CH2Cl2) to afford the title compound (174 mg) as 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 cooled to 0 °C overnight. The white crystalline precipitate was collected by suction filtration, the residue was washed with cold Et2O (2 × 10 mL), and air dried to afford the title compound as the maleate (I-35.mal, 112 mg, 27%). HPLC purity: 95% (280 nm); 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.92 (dq, J = 8.1, 4.0 Hz, 1H), 7.59 (dd, J = 8.8, 2.1 Hz, 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). 13 C NMR (101 MHz, DMSO-d6) δ 167.6, 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.

[0361] Example 37: Synthesis of N-benzyl-2-(naphthalen-1-yl)ethan-1-amine (I-37) [Chemical formula] Step 1: N-benzyl-2-(7-chloronaphthalen-1-yl)acetamide (26) 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 1 drop of DMF. Stirring was continued for 1 hour, and at this point, the reaction mixture was concentrated under a stream of N2 gas. Subsequently, the resulting yellow oil was redissolved in CH2Cl2 (10 mL), cooled to 0 °C, treated with benzylamine (364 mg, 3.40 mmol), and then triethylamine (0.79 mL, 5.66 mmol) was added dropwise. Stirring was continued for 3 hours. Then, the reaction mixture was diluted with H2O (25 mL), and the phases were separated. The organic phase was washed with NaHCO3 (saturated aqueous solution, 25 mL), followed by brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography (SiO2, 0 - 50% EtOAc / hexane (v / v)) to give the title compound (410 mg, 57%) as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (t, J = 6.0 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.88 (dd, J = 7.3, 2.1 Hz, 1H), 7.58 - 7.46 (m, 3H), 7.35 - 7.19 (m, 5H), 4.30 (d, J = 5.9 Hz, 2H), 3.98 (s, 2H).

[0362] Step 2: N-benzyl-2-(naphthalen-1-yl)ethan-1-amine (I-37·HCl) A stirred solution of N-benzyl-2-(7-chloronaphthalen-1-yl)acetamide (0.35 g, 1.13 mmol) in THF (10 mL) was treated portionwise with LiAlH4 (172 mg, 4.52 mmol) at 0 °C under an inert atmosphere, and the resulting suspension was then heated to reflux for 4 h. The reaction was then cooled to 0 °C and quenched by the sequential addition of H2O (0.15 mL), NaOH (0.15 mL, 15% aqueous solution), and H2O (1 mL), followed by the addition of MgSO4 (1 g). The suspension was then filtered through a pad of celite and the residue was washed with THF (2 × 25 mL). The combined filtrates were concentrated under reduced pressure and the crude oil was purified by flash column chromatography (SiO2, 0 - 5% MeOH / NH3 (v / v) in CH2Cl2) to afford the title compound (114 mg) as a colorless oil. The resulting oil was converted to the HCl salt according to general procedure A. The white crystalline precipitate was collected by suction filtration, the residue was washed with cold Et2O (2 × 10 mL) and air dried to afford the title compound as the HCl salt (I-37.HCl, 60 mg, 16%). HPLC purity: 92% (280 nm); 1 H NMR (400 MHz, DMSO-d6) δ 9.73 - 9.61 (br. s, 2H), 8.24 - 8.18 (m, 1H), 8.01 - 7.93 (m, 1H), 7.86 (dd, J = 8.1, 1.3 Hz, 1H), 7.67 - 7.52 (m, 4H), 7.56 - 7.44 (m, 2H), 7.49 - 7.38 (m, 4H), 4.22 (t, J = 5.9 Hz, 2H), 3.57 - 3.48 (m, 2H), 3.25 - 3.15 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 134.0, 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.

[0363] Scheme 8: The compounds of general formula (I) can be synthesized from appropriately substituted cyclic ketones according to the step procedures outlined in Scheme 8 or step procedures similar to those that can be utilized by a person skilled in the art. Alternatively, as shown in Scheme 8, 3,4-dihydronaphthalen-1(2H)-one having an appropriate aromatic substitution pattern can be reacted with cyanoacetic acid, and the corresponding substituted cyclohexene can be obtained after elimination. The substituted cyclohexene can be oxidized with various oxidizing agents, such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), to obtain the corresponding 6,6-aromatic system. The nitrile can be reduced to obtain a primary amine, which can then be subjected to reductive N-alkylation with an appropriate aldehyde to obtain the compounds of general formula (I) (exemplified by Examples I-38, I-42, I-50, I-52, and I-53).

Chemical formula

[0364] Example 53: Synthesis of 2-(7-fluoronaphthalen-1-yl)ethan-1-amine (I-53)

Chemical formula

[0365] Step 2: 2-(7-Fluoronaphthalen-1-yl)acetonitrile (32) A sealed pressure tube containing a solution of (7-fluoro-3,4-dihydro-1-naphthyl)acetonitrile (1.0 g, 5.34 mmol) and DDQ (purity 98%, 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 silica plug and eluted with CH2Cl2. The combined filtrates were concentrated under a stream of N2 gas, and the residue was purified by flash chromatography (0%-40% CH2Cl2 in hexane) to give the title compound (570 mg, 58%) as orange crystals. 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (dd, J = 9.0, 6.1 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.82 (dd, J = 11.3, 2.5 Hz, 1H), 7.65 (d, J = 7.1 Hz, 1H), 7.56 - 7.43 (m, 2H), 4.47 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.5 (d, J = 244.6 Hz), 131.7 (d, J = 9.3 Hz), 131.5 (d, J = 9.1 Hz), 130.5, 128.5, 127.4, 127.1 (d, J = 5.6 Hz), 125.1 (d, J = 2.5 Hz), 118.9, 116.4 (d, J = 25.2 Hz), 107.3 (d, J = 21.8 Hz), 20.6.

[0366] Step 3: 2-(7-Fluoronaphthalen-1-yl)ethan-1-amine hydrochloride (I-53·HCl) A solution of (7-fluoro-1-naphthyl)acetonitrile (500 mg, 2.70 mmol) in anhydrous THF (20 mL) was cooled in an ice bath and treated portionwise with LiAlH4 (205 mg, 5.40 mmol). The resulting suspension was stirred under reflux for 16 h. The reaction was then cooled in an ice bath and treated with additional LiAlH4 (300 mg, 8.10 mmol) and refluxed for a further 8 h. The reaction was then cooled in an ice bath and quenched with H2O (0.8 mL), 15% aqueous NaOH (0.8 mL), and H2O (2.4 mL). The suspension was then stirred with anhydrous Na2SO4 for 30 min, filtered through a plug of celite, and the filter cake was washed several times with hot THF. The combined filtrates were concentrated in vacuo and the residue was purified by flash chromatography (0.1%-5% MeOH / NH3 in CH2Cl2) to give the title compound as a yellow oil. HCl (35% aqueous solution) was added to acidify a solution of this oil in CHCl3 (50 mL) and iPrOH (1 mL), and Et2O was added until turbidity persisted. When this was cooled to 0 °C for 18 h, the title compound (250 mg, 41%) precipitated as the white crystalline hydrochloride salt. 1 1H qNMR purity: 98.4% (ERETIC); 1 1H NMR (400 MHz, DMSO-d6) δ 8.23 (br. s, 3H), 8.05 (dd, J = 9.0, 6.1 Hz, 1H), 7.96 (dd, J = 11.6, 2.5 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.56 - 7.36 (m, 3H), 3.41 - 3.29 (m, 2H), 3.14 - 2.99 (m, 2H). 13 13C NMR (101 MHz, DMSO-d6) δ 160.5 (d, J = 243.6 Hz), 133.2 (d, J = 5.7 Hz), 132.3 (d, J = 8.8 Hz), 131.7 (d, J = 9.3 Hz), 130.7, 128.1, 127.4, 125.1 (d, J = 2.2 Hz), 116.0 (d, J = 25.3 Hz), 107.3 (d, J = 21.3 Hz), 39.4, 30.2.

[0367] Example 38: Synthesis of 2-(7-Fluoronaphthalen-1-yl)-N,N-dimethylethane-1-amine (I-38)

Chemical Structure

[0368] Step 2: 2-(7-Fluoronaphthalen-1-yl)-N,N-dimethylethane-1-amine fumarate (I-38·Fum) 2-(7-Fluoronaphthalen-1-yl)-N,N-dimethylethane-1-amine (135 mg, 0.62 mmol) was formulated as the fumarate salt according to General Procedure B to give the title compound (65 mg, 31%) as off-white crystals. 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (dd, J = 9.0, 6.1 Hz, 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 (101 MHz, DMSO-d6) δ 167.2, 160.3 (d, J = 243.4 Hz), 134.7, 134.7, 132.3 (d, J = 8.7 Hz), 131.6 (d, J = 9.3 Hz), 130.6, 127.7, 127.0, 125.0 (d, J = 2.3 Hz), 115.8 (d, J = 25.4 Hz), 107.3 (d, J = 21.2 Hz), 58.1, 43.4, 28.7.

[0369] Scheme 9: The compounds of general formula (I) can be synthesized from appropriately substituted cyclic ketones according to the step procedures outlined in Scheme 8 or step procedures similar to those that can be utilized by a person skilled in the art. Alternatively, as shown in Scheme 9, 3,4-dihydronaphthalen-1(2H)-one having an appropriate aromatic substitution pattern can be subjected to the Horner-Wadsworth-Emmons reaction to generate a cyclohexene analog, and after oxidation, a naphthyl acetate intermediate is obtained. Naphthylacetic acid derivatives are produced by ester hydrolysis and can be subjected to an amidation reaction as described previously (Scheme 2). The resulting amide can be reduced using a number of methods that can be utilized by a person skilled in the art, including but not limited to borane-dimethyl sulfide complex or lithium aluminum hydride. This makes it possible to obtain appropriate amine compounds of general formula (I) (exemplified by Examples I-39, I-40, and I-41).

Chem.

[0370] Example 39: Synthesis of N-Ethyl-2-(7-fluoronaphthalen-1-yl)-N-methylethan-1-amine (I-39)

Chem.

[0371] Step 2: Ethyl 2-(7-fluoronaphthalen-1-yl)acetate (35) A mixture of ethyl 2-(7-fluoro-3,4-dihydronaphthalen-1-yl)acetate (4.10 g, 17.5 mmol), 10% palladium on carbon (3.73 g, 3.5 mmol), and d-limonene (57 mL) was stirred at 180 °C for 2 hours, at which point strong gas evolution was observed. After cooling, the mixture was then diluted with EtOAc (100 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and then purified by flash chromatography (SiO2, 0 - 5% EtOAc / hexane) to afford the title compound (1.6 g, 39%) as a yellow oil. 1 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, J = 9.0, 5.9 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.62 (dd, J = 11.2, 2.4 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.27 (ddd, J = 9.0, 8.2, 2.5 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 4.00 (s, 2H), 1.24 (t, J = 7.1 Hz, 3H).

[0372] Step 4: 2-(7-Fluoronaphthalen-1-yl)acetic acid (36) A solution of ethyl 2-(7-fluoronaphthalen-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 nitrogen stream 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 afford the title compound (1.21 g, 86%) as a yellow oil. 11H NMR (400 MHz, CDCl3): δ 7.86 (dd, J = 9.0, 5.9 Hz, 1H), 7.80 (dt, J = 8.0, 1.2 Hz, 1H), 7.58 (dd, J = 11.0, 2.5 Hz, 1H), 7.46 - 7.43 (m, 1H), 7.42 - 7.36 (m, 1H), 7.28 (ddd, J = 9.0, 8.2, 2.4 Hz, 1H), 4.03 (s, 2H).

[0373] Step 4: N-Ethyl-2-(7-fluoronaphthalen-1-yl)-N-methylacetamide (37) To a solution of 2-(7-fluoronaphthalen-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-tetramethylisouronium hexafluorophosphate (1.56 g, 4.11 mmol) in DMF (4.0 mL), iPr2NEt (1.06 g, 8.23 mmol), and then MeNHEt (146 mg, 2.47 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h. Then the reaction 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 / hexane) to give the title compound (368 mg, 73%) as a yellow oil. 1 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, J = 9.0, 5.9 Hz, 1H), 7.80 - 7.71 (m, 1H), 7.56 (dd, J = 11.7, 2.5 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.27 (ddd, J = 8.8, 8.1, 2.5 Hz, 1H), 4.06 (s, 2H), 3.35 - 3.55 (m, 2H), 3.01 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H).

[0374] Step 5: N-Ethyl-2-(7-fluoronaphthalen-1-yl)-N-methylethan-1-amine (I-39) 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 dropwise a 2 M borane-dimethyl sulfide complex / THF solution (3.0 mL, 6.0 mmol), and the mixture was stirred at 60 °C for 1 h. After cooling, the mixture was carefully treated with 6 M aqueous HCl (2.0 mL), followed by MeOH (4.0 mL), and then stirred under reflux for 1 h. After cooling, the volatiles were removed under a stream of N2 gas, and the remaining aqueous phase was extracted with Et2O (2 × 10 mL), which was 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 1H NMR (400 MHz, CDCl3): δ 7.84 (dd, J = 9.0, 5.9 Hz, 1H), 7.71 (dd, J = 7.1, 2.4 Hz, 1H), 7.66 (dd, J = 11.3, 2.5 Hz, 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 = 7.2 Hz, 2H), 2.41 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H).

[0375] Step 6: N-Ethyl-2-(7-fluoronaphthalen-1-yl)-N-methylethan-1-amine fumarate (I-39·Fum) N-Ethyl-2-(7-fluoronaphthalen-1-yl)-N-methylethan-1-amine (219 mg, 0.95 mmol) was formulated as the fumarate salt according to General Procedure B to afford the title compound (117 mg, 36%) as white crystals. HPLC purity: 99.8% (254 nm); 1 H NMR (400 MHz, DMSO-d6): δ 8.03 (dd, J = 9.0, 6.1 Hz, 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 = 7.2 Hz, 2H), 2.56 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6): δ 167.1, 160.3 (d, J = 243.5 Hz), 134.8 (d, J = 5.9 Hz), 134.6, 132.3 (d, J = 8.8 Hz), 131.6 (d, J = 9.4 Hz), 130.6, 127.7, 126.9, 125.0 (d, J = 2.8 Hz), 115.8 (d, J = 25.2 Hz), 107.3 (d, J = 21.3 Hz), 55.9, 50.1, 39.6, 28.4, 10.5.

[0376] Example 40: Synthesis of N-(2-(7-fluoronaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (I-40)

Chemical Structure

[0377] Step 2: N-(2-(7-Fluoronaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (I-40) 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 dropwise 2M borane-dimethyl sulfide complex / THF solution (3.6 mL, 7.18 mmol), and the mixture was stirred at 60 °C for 1 h. After cooling, the mixture was carefully treated with 6M aqueous HCl (2.0 mL), followed by MeOH (4.0 mL), and then stirred under reflux for 1 h. After cooling, the volatiles were removed under a stream of N2 gas, and the remaining aqueous phase was extracted with Et2O (2 × 10 mL), which was 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 afford the title compound (208 mg, 47%) as a clear oil. 1 H NMR (400 MHz, CDCl3): δ 7.84 (dd, J = 9.0, 5.9 Hz, 1H), 7.72 (dd, J = 7.8, 1.4 Hz, 1H), 7.67 (dd, J = 11.3, 2.5 Hz, 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 = 6.6 Hz, 6H).

[0378] Step 3: N-(2-(7-Fluoronaphthalen-1-yl)ethyl)-N-methylpropan-2-amine fumarate (I-40·Fum) N-(2-(7-Fluoronaphthalen-1-yl)ethyl)-N-methylpropan-2-amine (208 mg, 0.85 mmol) was formulated as the fumarate salt according to General Procedure B to afford the title compound (118 mg, 39%) as white crystals. HPLC purity: 99.2% (254 nm); 11H NMR (400 MHz, DMSO-d6): δ 8.03 (dd, J = 9.0, 6.1 Hz, 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 = 6.6 Hz, 6H); 13 13C NMR (101 MHz, DMSO-d6): δ 166.9, 160.4 (d, J = 243.5 Hz), 134.5, 132.3 (d, J = 8.8 Hz), 131.6 (d, J = 9.2 Hz), 130.6, 127.9, 127.0, 125.0 (d, J = 2.1 Hz), 115.8 (d, J = 25.2 Hz), 115.8 (d, J = 25.2 Hz), 107.3 (d, J = 21.3 Hz), 54.4, 53.0, 34.9, 28.8, 16.6。

[0379] Example 41: Synthesis of N-(2-(7-Fluoronaphthalen-1-yl)ethyl)-N-methylcyclopropanamine (I-41)

Chemical Structure

[0380] Step 2: N-(2-(7-fluoronaphthalen-1-yl)ethyl)-N-methylcyclopropanamine (I-41) 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 dropwise 2M borane-dimethyl sulfide complex / THF solution (2.9 mL, 5.77 mmol), and the mixture was stirred at 60 °C for 1 h. After cooling, the mixture was carefully treated with 6M aqueous HCl (2.0 mL), followed by MeOH (4.0 mL), and then stirred under reflux for 1 h. After cooling, the volatiles were removed under a stream of N2 gas, and the remaining aqueous phase was extracted with Et2O (2 × 10 mL), which was 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 (400 MHz, CDCl3) δ 7.84 (dd, J = 9.0, 5.9 Hz, 1H), 7.71 (dd, J = 7.4, 2.1 Hz, 1H), 7.67 (dd, J = 11.4, 2.5 Hz, 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 = 6.3 Hz, 4H).

[0381] Step 3: N-(2-(7-Fluoronaphthalen-1-yl)ethyl)-N-methylcyclopropanamine fumarate (I-41·Fum) N-(2-(7-Fluoronaphthalen-1-yl)ethyl)-N-methylcyclopropanamine (154 mg, 0.63 mmol) was formulated as the fumarate salt according to General Procedure B to give the title compound (90 mg, 34%) as white crystals. HPLC purity: 99.9% (254 nm); 11H NMR (400 MHz, DMSO-d6): δ 7.84 (dd, J = 9.0, 5.9 Hz, 1H), 7.71 (dd, J = 7.4, 2.1 Hz, 1H), 7.67 (dd, J = 11.4, 2.5 Hz, 1H), 7.42 - 7.32 (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 = 6.3 Hz, 4H); 13 13C NMR (101 MHz, DMSO-d6): δ 166.1, 160.2 (d, J = 243.3 Hz), 136.1 (d, J = 5.7 Hz), 134.1, 132.3 (d, J = 8.4 Hz), 131.6 (d, J = 9.2 Hz), 130.6, 127.4, 126.5, 125.0 (d, J = 2.8 Hz), 115.7 (d, J = 25.1 Hz), 107.1 (d, J = 21.2 Hz), 58.0, 42.0, 37.9, 29.6, 6.4。

[0382] Example 42: Synthesis of N-benzyl-2-(7-fluoronaphthalen-1-yl)ethan-1-amine (I-42)

Chemical formula

[0383] Step 2: N-Benzyl-2-(7-fluoronaphthalen-1-yl)ethan-1-amine fumarate (I-42·Fum) N-Benzyl-2-(7-fluoronaphthalen-1-yl)ethan-1-amine (56 mg, 0.20 mmol) was formulated as a fumarate salt according to General Procedure B to give the title compound (51 mg, 65%) as white crystals. HPLC purity: 99.8% (254 nm); 1 H NMR (400 MHz, DMSO-d6): δ 8.02 (dd, J = 9.0, 6.1 Hz, 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); 1313C NMR (101 MHz, DMSO-d6): δ 167.3, 160.4 (d, J = 243.2 Hz), 134.8, 134.7, 132.3 (d, J = 9.0 Hz), 136.5, 132.4, 131.6 (d, J = 9.2 Hz), 130.6, 128.9, 128.4, 127.7 (d, J = 4.4 Hz), 127.0, 125.0 (d, J = 2.2 Hz), 115.8 (d, J = 25.3 Hz), 107.3 (d, J = 21.2 Hz), 51.2, 48.1, 30.9。

[0384] Example 52: Synthesis of 2-(5-methoxynaphthalen-1-yl)ethan-1-amine (I-52) [Chemical formula] Step 1: 2-(5-Methoxy-3,4-dihydronaphthalen-1-yl)acetonitrile (59) To a solution of 5-methoxy-3,4-dihydronaphthalen-1(2H)-one (8.0 g, 45.4 mmol) in toluene (60 mL) were 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 h. After cooling to room temperature, the reaction was diluted with EtOAc (120 mL) and then washed with 0.5 M aqueous NaOH (80 mL), followed by saturated aqueous NaHCO3 (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 afford 2-(5-methoxy-3,4-dihydronaphthalen-1-yl)acetonitrile (3.75 g, 41%) as a pale yellow crystalline solid. 11H NMR (400 MHz, CDCl3): δ 7.20 (ddt, J = 8.5, 7.8, 0.7 Hz, 1H), 6.85 (dd, J = 8.3, 1.0 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.27 (tt, J = 4.6, 1.6 Hz, 1H), 3.84 (s, 3H), 3.47 (q, J = 1.8 Hz, 2H), 2.80 (t, J = 8.3 Hz, 2H), 2.32 (tdt, J = 8.2, 4.6, 1.9 Hz, 2H).

[0385] Step 2: 2-(5-Methoxynaphthalen-1-yl)acetonitrile (60) To a solution of 2-(5-methoxy-3,4-dihydronaphthalen-1-yl)acetonitrile (2.05 g, 10.3 mmol) in DCE (60 mL) was added DDQ (3.04 g, 13.4 mmol), and the mixture was stirred at 100 °C for 14 h under N2 gas. Then, the reaction was diluted with EtOAc (120 mL), filtered through a pad of celite, and the residue was washed with EtOAc (2 × 25 mL). The combined filtrates were then washed with saturated aqueous Na2CO3 (2 × 100 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The dark brown residue was purified by flash chromatography (SiO2, 0 - 20% EtOAc in hexane) and the isolated material (1.30 g) was recrystallized from EtOAc / hexane to give 2-(5-methoxynaphthalen-1-yl)acetonitrile (895 mg, 44%) as fine white needles. 1 1H NMR (400 MHz, CDCl3): δ 8.36 - 8.28 (m, 1H), 7.61 (dq, J = 7.1, 1.0 Hz, 1H), 7.56 - 7.38 (m, 3H), 6.90 (dd, J = 7.6, 0.9 Hz, 1H), 4.12 (br s, 2H), 4.02 (s, 3H); 1313C NMR (400 MHz, CDCl3): δ 156.3, 132.0, 127.4, 127.1, 126.1, 125.5, 124.9, 123.2, 117.9, 114.7, 104.6, 55.8, 22.2。

[0386] Step 3: 2-(5-Methoxynaphthalen-1-yl)ethan-1-amine (I-52) Under a N2 atmosphere, LiAlH4 (861 mg, 22.7 mmol) was added portionwise to anhydrous THF (30 mL) at 0 °C. While maintaining at 0 °C, a solution of 2-(5-methoxynaphthalen-1-yl)acetonitrile (895 mg, 4.54 mmol) in anhydrous THF (10 mL) was added dropwise, and the mixture was stirred overnight at room temperature under a N2 atmosphere. The reaction mixture was cooled on an ice / water bath, and cold H2O (1 mL), followed by 15% aqueous NaOH (1 mL) and H2O (3 mL) were slowly added to quench. The mixture was filtered through a Celite pad and then washed thoroughly with THF. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO2, 2-10% MeOH / NH3 in CH2Cl2) to give 2-(5-methoxynaphthalen-1-yl)ethan-1-amine (153 mg, 17%) as a white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 8.04 (ddd, J = 7.9, 1.9, 0.8 Hz, 1H), 7.66 (dt, J = 8.6, 0.9 Hz, 1H), 7.45 (dd, J = 8.6, 7.6 Hz, 1H), 7.42 - 7.35 (m, 2H), 6.97 (d, J = 7.9 Hz, 1H), 3.96 (s, 3H), 3.10 (dd, J = 8.5, 6.4 Hz, 2H), 2.85 (dd, J = 8.3, 6.6 Hz, 2H)。

[0387] Step 4: 2-(5-Methoxynaphthalen-1-yl)ethan-1-amine hydrochloride (I-52·HCl) 2-(5-Methoxynaphthalen-1-yl)ethan-1-amine (59 mg, 0.29 mmol) was formulated as the hydrochloride salt according to General Procedure A and isolated as white crystals (43 mg, 62%). 1 1H qNMR purity: 96.0% (ERETIC). 1 1H NMR (400 MHz, DMSO-d6): δ 8.23 (s, 3H), 8.14 - 8.08 (m, 1H), 7.72 (dt, J = 8.6, 0.9 Hz, 1H), 7.50 (dd, J = 8.6, 7.7 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.01 (dd, J = 7.8, 0.8 Hz, 1H), 3.97 (s, 3H), 3.41 - 3.32 (m, 2H), 3.11 - 3.02 (m, 2H). 13 13C NMR (101 MHz, DMSO-d6): δ 155.4, 133.2, 132.3, 127.4, 126.6, 125.3, 124.9, 120.8, 115.6, 104.4, 55.7, 30.5.

[0388] Example 50: 2-(5-Methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine (I-50)

Chemical Structure

[0389] Step 2: 2-(5-Methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine fumarate (I-50·Fum) 2-(5-Methoxynaphthalen-1-yl)-N,N-dimethylethan-1-amine (53 mg, 0.45 mmol) was formulated as the fumarate salt according to the general procedure B and isolated as white crystals (36 mg, 69%). 1 1H qNMR purity: 98.6% (ERETIC); 1 1H NMR (400 MHz, DMSO-d6): δ 8.12 - 8.03 (m, 1H), 7.66 (dt, J = 8.6, 0.8 Hz, 1H), 7.47 (dd, J = 8.6, 7.7 Hz, 1H), 7.45 - 7.38 (m, 2H), 6.99 (dd, J = 7.8, 0.8 Hz, 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); 1313C NMR (101 MHz, DMSO-d6): δ 167.2, 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。

[0390] Example 51: Functional assay for 5-HT 2A , 5-HT 2B , and 5-HT 2C receptor The activities in 5-HT2A, 5-HT2B, and 5-HT2C receptors were determined according to their standard protocols using the FLIPR Ca 2+ flux assay by WuXi AppTec Co., Ltd. (Hong Kong) Discovery Biology Unit. Briefly, stably transfected cells expressing the receptor of interest (HEK293 for 5-HT2A and 5-HT2C, CHO-K1 for 5-HT2B) were grown, placed in 384-well plates, and incubated overnight at 37 °C and 5% CO2. A 250 mM stock solution of probenecid in FLIPR Calcium Assay Buffer (10 mL) was freshly prepared and combined with the fluorescent dye (Fluo-4 Direct) to give a final assay concentration of 2.5 mM. The reference compound was serially diluted 4-fold, and the screening compound was serially diluted 3-fold in 100% DMSO for 10 points using Agilent Bravo, and 750 nL was added to the 384-well compound plate together with 30 μL of assay buffer using Echo. Then, the fluorescent dye was added to the assay plate together with the assay buffer to make the final volume 40 μL. The cell plate was incubated at 37 °C and 5% CO2 for 50 minutes and placed into FLIPR Tetra together with the compound plate. Then, 10 μL of the 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.

Table 2-1

Table 2-2

[0391] Example 49: In Vivo Pharmacokinetics Experiment This investigation was conducted using procedures established in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes, and the test protocol was reviewed and approved by the Monash Institute of Pharmaceutical Sciences Animal Ethics Committee.

[0392] The systemic exposure of the selected examples was investigated in male C57BL / 6 mice weighing 22.3 - 26.2 g that were not fasted. The mice had free access to food and water throughout the pre - dosing and post - dosing sampling periods.

[0393] On the dosing day, formulations of each compound were prepared by dissolving the solid compound in phosphate - buffered saline (50 mM) using a vortex to create a colorless solution (pH 6.1 - 6.3) for each compound.

[0394] The compounds were administered to the mice by IP injection (10 mL / kg dosing volume via a 27G needle; n = 9 mice per compound), and blood samples were collected at 5 and 30 minutes, 1 hour, 2 hours, and 4 hours post - dosing (n = 3 mice per time point per compound). A maximum of three blood samples were obtained from each mouse, and plasma samples were collected via submandibular bleeding (approx. 120 μL). Once collected, the blood samples were immediately centrifuged, the supernatant plasma was removed, and stored at - 80 °C until analysis by LCMS. In addition, at 5 and 30 minutes and 4 hours post - dosing, immediately after blood collection, the whole brain was rapidly removed from the cadaver. The whole brain was blotted to remove excess blood, placed in a pre - weighed polypropylene vial, and weighed. The brain was snap - frozen in dry ice and then stored frozen (-80 °C) until analysis.

[0395] Overview of the biological analysis method: 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).

[0396] The test compound standard solution was diluted from a concentrated stock solution (1 mg / mL in DMSO) using 50% acetonitrile / water solution (v / v), and the calibration curve was prepared in a matrix adapted to the test samples.

[0397] Plasma: The plasma calibration curve was prepared by spiking an aliquot of blank mouse plasma (25 μL) with the test compound standard solution (5 μL) and the internal standard solution (5 μL of diazepam, 5 μg / mL in 50% acetonitrile in water). The test plasma sample (25 μL) was thawed, mixed, and then spiked with the internal standard solution (5 μL). Plasma protein precipitation was performed by adding acetonitrile (3-fold volume ratio) and thorough vortex mixing. The sample was centrifuged for 3 minutes (RCF = 9391×g), and the supernatant (90 μL) was recovered for analysis.

[0398] Tissue: Pre-weighed tissue samples (brain) were homogenized using a glass rod in a buffer containing an EDTA / potassium fluoride solution (0.1 M / 4 mg / mL) as a stabilization cocktail to minimize the potential for ex vivo degradation (3 mL cocktail / g tissue). The tissue homogenate was briefly centrifuged for 10 seconds (RCF = 79 × g) to separate the foam layer, and then 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 standard (10 μL) and internal standard (10 μL). Investigational samples were prepared similarly, except that acetonitrile (10 μL) was added instead of the solution standard to maintain the same volume. Protein precipitation was performed by adding three volumes of acetonitrile, followed by vortex mixing and centrifugation (RCF = 9391 × g) for 3 minutes, and the supernatant was recovered for analysis.

[0399] Analysis of replicates: Triplicate analytical replicate (AR) samples were prepared in the same manner as the standards for each sample type at three concentrations (50, 500, and 2,000 ng / mL), and the repeated injections of these ARs were included throughout the analytical run to evaluate assay performance. Extraction of the test compound from the standards and ARs was performed as described above.

[0400] All test samples were quantified within the calibration range of the assay, and the assay performance for ARs was considered acceptable. The stability of each test compound was confirmed in the homogenate during sample processing (15 minutes). [Table 3]

[0401] The maximum plasma concentration of I-7 after IP administration at 10 mg / kg is shown in Table 3. Comprehensive pharmacokinetic data including brain penetration information are shown in Figure 1 and / or Table 4. [Table 4]

Table 5

[0402] Example 54: Biotelemetry and Head Twitch Response (HTR) Experiment Mice (C57BL / 6J males) were purchased at 5 - 6 weeks of age from Jackson Laboratory (Bar Harbor, ME, USA) and acclimated for at least 1 - 2 weeks in the Intramural Research Program (IRP) of NIDA, an animal research facility in Baltimore, MD, USA. The animal facility was fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care, and all procedures were approved by the Animal Care and Use Committee of the NIDA IRP. During acclimation, mice were grouped at 3 - 5 per cage and housed on a 12 - hour light - dark cycle, with lights on at 0700h, throughout the study. Food and water were available ad libitum except during each test. For each test drug, a cohort of 20 - 24 mice was used. Mice were subjected to experimental tests once every 1 - 2 weeks over a 2 - 3 - month period to complete dose - effect curves and antagonist experiments. To avoid tolerance to the effects of repeated drug administration, a minimum of 7 days was utilized between treatments. All drug doses are expressed as the weight of salt dissolved in 0.9% saline vehicle. Mice were first tested in a dose - response study to evaluate the effects of each compound at subcutaneous doses of 0.03 - 30 mg / kg and then tested in antagonist reversal studies utilizing pretreatment with M100907 and WAY100635. All experiments were conducted between 0900 - 1700 local time during the light phase because the sensitivity of rodents to other tryptamine psychedelics is diurnal and maximal HTR is observed in the middle of the light phase. Experiments were also conducted during the light phase to avoid potential effects of melatonin receptor activity on HTR, as melatonin and related agonists are known to reduce DOI - induced HTR in rats. For each experiment, mice were acclimated to the test chamber in their home cage for at least 1 hour prior to the experimental session.The locomotor test sessions were performed in a TruScan mouse locomotor arena (Coulbourn Instruments, Holliston, MA, USA) equipped with a photobeam array and modified with a cylindrical insert and a transparent floor useful for detecting mouse HTRs.

[0403] Subcutaneous temperature transponder implantation. At least 1 week before the start of the experiment, mice received a subcutaneous implanted temperature transponder (14×2 mm, model IPTT-300, Bio Medic Data Systems, Inc., Seaford, DE, USA) under short-term isoflurane anesthesia. Mice were singly housed after implantation for the remainder of the investigation to protect the transponder from removal by cage mates. Temperature was determined non-invasively using a hand-held receiver sensitive to the signal emitted from the implanted transponder.

[0404] Before each experiment, the body weight and body temperature of the mice were recorded. Subsequently, the mice were placed in the laboratory for adaptation. In the dose-response investigation, after a brief 5-minute adaptation, the body temperature of the mice was recorded for baseline measurement, the mice received a subcutaneous injection of the test substance or vehicle, and the animals were returned to the test arena for 30 minutes. During the session, spontaneous locomotor activity was monitored via photobeam tracking of movement in the horizontal plane, and the distance traveled in centimeters was obtained. Mouse HTRs were monitored by analysis of GoPro Hero Black 7 video recordings (120 frames / second and 960p resolution) using a commercially available software package from Clever Sys Inc. (Reston, VA, USA). Post-treatment body temperature values of 82 were also recorded, and the temperature data were expressed as changes from the pre-treatment baseline.

[0405] In the antagonist reversal experiment, mice received a subcutaneous injection of either a receptor antagonist or vehicle and were returned to the laboratory for 30 minutes. During this period, spontaneous motor activity was monitored to examine the potential effects of antagonist treatment on general behavior or movement. Thirty minutes after antagonist administration, mice were given the test drug or vehicle and returned to the chamber for an additional 30-minute video recording for analysis.

[0406] 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 from the ascending phase of the curve for HTR measurements. For mouse studies, one-way analysis of variance with Dunnett's post hoc test was used to compare all conditions to the vehicle control (0 or 0.0) in dose–response and antagonist experiments. The time-course drug effects for all parameters in mouse studies are shown for reference. Mean HTR counts, distance moved, and temperature change for each condition were used for statistical comparison. Alpha was set at 0.05 for all analyses.

Claims

1. Equation (I): 【Chemistry 1】 Compounds thereof, or pharmaceutically acceptable salts, solvates, tautomers, N-oxides, stereoisomers, metabolites, polymorphs, and / or prodrugs thereof, During the ceremony, 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 haloalkenyl, C ２～６ alkynyl, C ２～６ haloalkynyl, C ３～８ cycloalkyl, C ４～１４ alkylenecycloalkyl, C ３ -C ８ heterocycloalkyl, C ４ -C １４ alkylenheterocycloalkyl, C ６～１２ aryl, C ７～１８ alkylenearyl, C ５～１０ heteroaryl, and C ６～１６ alkylenheteroaryl, respectively independently selected from Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３ ~C ８ Heterocycloalkyl, C ４ ~C １４ Alkylene heterocycloalkyl, C ６～１２ Ariel, C ７～１８ Alkylenearyl, C ５～１０ Heteroaryls, and C ６～１６ Alkylene heteroaryls, halogens, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ４ , C(O)N(R ４ ) ２ , OR ４ , N(R ４ ) ２ NO ２ , SR ４ , and SO ２ R ４ Each substituent is optionally substituted with one or more substituents independently selected from the given set. Said C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３ ~C ８ Heterocycloalkyl, C ４ ~C １４ Alkylene heterocycloalkyl, C ６～１２ Ariel, C ７～１８ Alkylenearyl, C ５～１０ Heteroaryls, and C ６～１６ Alkylene heteroaryl, (O), C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyls, as well as O, S, N, S(O), SO ２ , and NR ４ C containing one or two ring heteroparts selected from ３～６ Each substituent is further optionally substituted with substituents independently selected from heterocycloalkyl groups. Alternatively, R １ and R ２ However, together with the nitrogen atoms to which these are bonded, they form O, S, S(O), SO ２ , N, and NR ４ C comprising one or two additional ring heteroparts selected from ３～８ Forms heterocycloalkyl groups, Said C ３～８ heterocycloalkyl is halogen, (O), CN, C １～８ alkoxy, C １～８ alkylamino, C １～８ alkylsulfonyl, CO ２ R ４ , C(O)N(R ４ ), ２ OR ４ , N(R ４ ), ２ , NO ２ , SR ４ , SO ２ R ４ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ haloalkenyl, C ２～６ alkynyl, C ２～６ haloalkynyl, C １～８ alkylamino, C １～８ alkylsulfonyl, C ３～６ cycloalkyl, and O, S, N, S(O), SO ２ , and NR ４ and is further optionally substituted with a substituent selected from C ３～６ heterocycloalkyl containing one or two ring hetero moieties selected from R ３ However, hydrogen, C １～６ Alkyl, C ３～８ Cycloalkyl, or C ４～１４ Selected from alkylene cycloalkyl, Alternatively, R ３ and R １ and R ２ One of them, together with the atom to which they are bonded, C ３～１２ Forms heterocycloalkyl groups, Said C ３～１２ Heterocycloalkyl groups include halogens, (O), CN, and C. １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ４ , C(O)N(R ４ ) ２ , OR ４ , N(R ４ ) ２ NO ２ , SR ４ SO ２ R ４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyls, as well as O, S, N, S(O), SO ２ , and NR ４ C containing one or two ring heteroparts selected from ３～６ It is further optionally substituted with substituents selected from heterocycloalkyl groups. Each R ４ However, hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～７ Cycloalkyls, as well as O, S, S(O), SO ２ , N, and NR ５ C containing one or two ring heteroparts selected from ３～７ Independently selected from heterocycloalkyls, Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～７ Cycloalkyl, and C ３～７ Heterocycloalkyls are halogens, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ５ , C(O)N(R ５ ) ２ , OR ５ , N(R ５ ) ２ NO ２ , SR ５ , and SO ２ R ５ Each substituent is optionally substituted with one or more substituents independently selected from the given set. Said C ３ ~C ７ Cycloalkyl and C ３～７ Heterocycloalkyl groups are (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyls, as well as O, S, S(O), SO ２ , N, and NR ５ C containing one or two ring heteroparts selected from ３～６ Each substituent is further optionally substituted with substituents independently selected from heterocycloalkyl groups. Each R ５ However, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ５～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ Selected independently from heteroaryls, Said C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ５～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ Heteroaryls are halogens, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ C(O)NH ２ , C(O)N(CH ３ ) ２ C(O)NHCH ３ OH, NH ２ , N (CH ３ ) ２ , NHCH ３ NO ２ SH, SCH ３ SO ２ CH ３ EN SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyls, as well as O, S, S(O), SO ２ , N, NH, and NCH ３ C containing one or two ring heteroparts selected from ３～６ Each substituent is optionally substituted with one or more substituents independently selected from heterocycloalkyl groups. L is C １～４ Alkylene, C ２ ~C ４ Alkenylene and C ２ ~C ４ Selected from alkynylenes, Z １ However, CR ８ or N, Z ４ However, CR １１ or N, R ８ , R ９ , and R １１ However, hydrogen, halogen, CN, OR １３ , N(R １３ ) ２ , SR １３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２ ~C ６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C １～６ Alkylamine, C １～６ Alkoxy, C １～６ Haloalkoxy, CO ２ R 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 OSO ２ R 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 SO ２ R 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 NO ２ , C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkylene heterocycloalkyl, C ６～１２ Ariel, C ７～１８ Alkylenearyl, C ５～１０ Heteroaryl, C ４～１６ Each was independently selected from alkylene heteroaryls, Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２ ~C ６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C １～６ Alkylamine, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkylene heterocycloalkyl, C ６～１２ Ariel, C ７～１８ Alkylenearyl, C ５～１０ Heteroaryls, and C ４～１６ Alkylene heteroaryls, halogens, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １３ , C(O)N(R １３ ) ２ , OR １３ , N(R １３ ) ２ NO ２ , SR １３ , and SO ２ R １３ It is optionally substituted with one or more substituents independently selected from the above, Said C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkylene heterocycloalkyl, C ６～１２ Ariel, C ７～１８ Alkylenearyl, C ５～１０ Heteroaryls, and C ４～１６ Alkylene heteroaryl, (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyls, as well as O, S, S(O), SO ２ , N, and NR １３ C containing one or two ring heteroparts selected from ３～６ Each substituent is further optionally substituted with a substituent selected from heterocycloalkyl groups. Each R １３ However, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkylene heterocycloalkyl, C ６～１２ Ariel, C ７～１８ Alkylenearyl, C ５～１０ Heteroaryls, and C ６～１６ Independently selected from alkylene heteroaryls, Said C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkylene heterocycloalkyl, C ６～１２ Ariel, C ７～１８ Alkylenearyl, C ５～１０ Heteroaryls, and C ６～１６ Alkylene heteroaryls, halogens, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ C(O)NH ２ , C(O)N(CH ３ ) ２ C(O)NHCH ３ OH, NH ２ , N (CH ３ ) ２ , NHCH ３ NO ２ SH, SCH ３ SO ２ CH ３ EN SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyls, as well as O, S, S(O), SO ２ , N, NH, and NCH ３ C containing one or two ring heteroparts selected from ３～６ Compounds of formula (I), or pharmaceutically acceptable salts, solvates, tautomers, N-oxides, stereoisomers, metabolites, polymorphs, and / or prodrugs thereof, each optionally substituted with one or more substituents independently selected from heterocycloalkyl groups.

2. R １ and R ２ However, hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～８ Cycloalkyl, C ７～１８ Alkylenearyl and C ４～１４ The compound according to claim 1, each independently selected from alkylenecycloalkyl groups.

3. R １ and R ２ However, hydrogen, C １～４ Alkyl, C ３～４ Cycloalkyl, and C ７～８ The compound according to claim 2, each independently selected from alkylenearyl compounds.

4. R １ and R ２ However, together with the nitrogen to which these are bound, the following occurs: 【Chemistry 2】 The compound according to claim 1, which forms any one of the following.

5. R １ and R ２ However, together with the nitrogen atom to which these are bonded, C ３～６ Form a heterocycloalkyl group, and the C ３～６ Heterocycloalkyls are halogens, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ４ , C(O)N(R ４ ) ２ , OR ４ , N(R ４ ) ２ NO ２ , SR ４ and SO ２ R ４ , (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyls, as well as O, S, N, S(O), SO ２ , and NR ４ C containing one or two ring heteroparts selected from ３～６ It is optionally substituted with one or more substituents independently selected from heterocycloalkyl groups, where R ４ The compound according to claim 1, as defined in claim 1.

6. R ３ The compound according to claim 1, wherein the compound is hydrogen.

7. R ３ and R １ and R ２ One of them, together with the atom to which they are bonded, C ３～８ Form a heterocycloalkyl group, and the C ３～８ Heterocycloalkyl groups include halogens, (O), CN, and C. １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ４ , C(O)N(R ４ ) ２ , OR ４ , N(R ４ ) ２ NO ２ , SR ４ SO ２ R ４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyls, as well as O, S, N, S(O), SO ２ , and NR ４ C containing one or two ring heteroparts selected from ３～６ It is further optionally substituted with substituents selected from heterocycloalkyl groups, where R ４ The compound according to claim 1, as defined in claim 1.

8. R ８ , R ９ , and R １１ However, hydrogen, halogen, CN, OR １３ , N(R １３ ) ２ , SR １３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２ ~C ６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C １～６ Alkylamine, C １～６ Alkoxy, C １～６ Haloalkoxy, CO ２ R １３ , C(O)N(R １３ ) ２ OC(O)R １３ OSO ２ R １３ , OP(O)(OR １３ ) ２ , OC １～６ Alkylene P(O)(OR) １３ ) ２ S(O)R １３ SO ２ R １３ , N(R １３ ) ２ NO ２ , C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkylene heterocycloalkyl, C ６～１２ Ariel, C ７～１８ Alkylenearyl, C ５～１０ Heteroaryl, C ４～１６ Each was independently selected from alkylene heteroaryls, Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２ ~C ６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C １～６ Alkylamine, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkylene heterocycloalkyl, C ６～１２ Ariel, C ７～１８ Alkylenearyl, C ５～１０ Heteroaryls, and C ４～１６ Alkylene heteroaryls, halogens, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ C(O)NH ２ , C(O)N(CH ３ ) ２ C(O)NHCH ３ OH, NH ２ , N (CH ３ ) ２ NO ２ , NHCH ３ SH, SCH ３ SO ２ CH ３ , and SOCH ３ It is optionally substituted with one or more substituents independently selected from the above, Said C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkylene heterocycloalkyl, C ６～１２ Ariel, C ７～１８ Alkylenearyl, C ５～１０ Heteroaryls, and C ４～１６ Alkylene heteroaryl, (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Haloalkenil, C ２～６ Alkinyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyls, as well as O, S, S(O), SO ２ , N, NH, and NCH ３ C containing one or two ring heteroparts selected from ３～６ Each substituent is further optionally substituted with a substituent selected from heterocycloalkyl groups. In the formula, R １３ The compound according to claim 1, as defined in claim 1.

9. R ８ , R ９ , and R １１ If one of these is present, then halogen, CN, C １～６ Alkyl, C １～６ Haloalkyl and OR １３ Each is independently selected from, and in the formula, R １３ However, hydrogen, C １～６ Alkyl and C １～６ Selected from haloalkyl, R ８ , R ９ , and R １１ The compound according to claim 8, wherein the other of these is hydrogen.

10. R ８ , R ９ , and R １１ If one of these is present, it may be fluoro, chloro, hydroxy, or OCH ３ And R ８ , R ９ , and R １１ The compound according to claim 9, wherein the other of these is hydrogen.

11. L is C １～４ The compound according to claim 1, wherein it is an alkylene.

12. The compound according to claim 11, wherein L is methylene.

13. Equation (Ia): 【Transformation 3】 It has, in the formula, R １ , R ２ , R ３ , R ８ , R ９ , and R １１ The compound according to claim 1, wherein it is defined as any one of claims 1 to 10.

14. Z １ The compound according to claim 1, wherein is N.

15. Formula (Ib): 【Chemistry 4】 It has, in the formula, R １ , R ２ , R ３ , R ９ , and R １１ The compound according to claim 14, wherein it is defined as any one of claims 1 to 10.

16. Z ４ The compound according to claim 1, wherein is N.

17. Formula (Ic): 【Transformation 5】 It has, in the formula, R １ , R ２ , R ３ , R ８ , and R ９ The compound according to claim 16, wherein it is defined as any one of claims 1 to 10.

18. below: 【Chemistry 6-1】 【Chemistry 6-2】 One of the following, The compound according to claim 1, or selected from pharmaceutically acceptable salts, solvates, tautomers, N-oxides, stereoisomers, metabolites, polymorphs, and / or prodrugs thereof.

19. A pharmaceutical product 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. To treat diseases, disorders, or conditions related to the activity of serotonin receptors, and / or To treat mental illness, and / or, To treat diseases, disorders, or conditions of the central nervous system (CNS), and / or To treat diseases, disorders, or conditions of the nervous system, and / or To increase neural plasticity, and / or, Increases dendritic spine density. A pharmaceutical product selected from one or more of the following: A pharmaceutical product 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.

22. A pharmaceutical product according to claim 21 for treating a disease, disorder, or condition related to the activity of serotonin receptors, wherein the pharmaceutical product is administered in combination with another agent useful for treating the disease, disorder, or condition, or the pharmaceutical product further comprises another agent useful for treating the disease, disorder, or condition.

23. A pharmaceutical product according to claim 21 for treating mental illness, The pharmaceutical product according to claim 21, wherein the mental 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 reaction syndrome, dissociative disorders, depersonalization disorders, factitious disorders, sexual and gender disorders, somatic symptom disorders, hallucinations, delusions, mental disorders, and combinations thereof.

24. A pharmaceutical product according to claim 21 for treating a disease, disorder, or condition of the central nervous system (CNS), or for treating a disease, disorder, or condition of the nervous system, The aforementioned diseases, disorders, or conditions of the CNS and / or diseases, disorders, or conditions of the nervous system include neurodevelopmental disorders and neurodegenerative diseases such as Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia; cognitive impairment, Parkinson's disease, and Parkinsonian dementia, as well as corticobasal degeneration and Parkinson's disease-related disorders such as supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; brittle X syndrome; Angelman syndrome; hereditary ataxia; neuro-otology. A medicinal product according to claim 21, selected from neurological disorders and oculomotor disorders; neurodegenerative diseases of the retina, amyotrophic lateral sclerosis; tardive dyskinesia; hyperactivity disorder; 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; bulimia nervosa, trichotillomania, dermatopruriticism, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology, as well as combinations thereof, of the nervous system.

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