5-Hydroxytryptamine receptor 7 modulators and their use as therapeutic agents

Abstract

To provide 5-hydroxytryptamine receptor 7 modulators and their use as therapeutic agents.SOLUTION: Pharmaceutical compositions of the invention comprise functionalized lactone derivatives having a disease-modifying action in treatment of diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. The present invention is directed toward novel 5-hydroxy tryptamine receptor 7 (5- HT7) activity modulators, compounds of formula (I), and hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof. The present invention further relates to compositions comprising an effective amount of one or more compounds according to the present invention and an excipient.SELECTED DRAWING: None

Description

Technical Field

[0001] Statement Regarding Federally Sponsored Research or Development This invention was made with government support under Grant No. HHSN-271-2008-00025-C awarded by the National Institute of Mental Health. The government has certain rights in this invention. Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 474,280, filed on March 21, 2017, which is hereby incorporated by reference in its entirety. Embodiments of the present invention are directed to novel compounds useful as modulators of 5 - hydroxytryptamine receptor 7 (5 - HT7) activity and methods of using the same. Embodiments further target novel chemotypes useful for the treatment of diseases associated with dysregulation of 5 - hydroxytryptamine receptor 7 activity.

Background Art

[0002] Serotonin was discovered in the late 1940s and is present in both the peripheral and central nervous systems (Physiol. Res, 60 (2011) 15 - 25; Psychopharmacology 213 (2011) 167 - 169). Serotonin or 5 - hydroxytryptamine (5 - HT) is a monoamine neurotransmitter of the indolealkylamine group that acts at synapses of nerve cells. Seven families of serotonin receptors have been identified, and at least 20 subpopulations have been cloned based on sequence similarity, signal transduction coupling, and pharmacological properties. The seven families of 5 - HT receptors are 5 - HT 1、 5 - HT2, 5 - HT 3、 5 - HT 4、 5 - HT 5、 5 - HT 6、and named 5-HT7, and these receptors each have a subfamily or subpopulation. The signal transduction mechanisms of all seven families have been studied. Activation of the 5-HT1 receptor and the 5-HT5 receptor decreases intracellular cAMP, while activation of 5-HT2, 5-HT 3、 5-HT4, 5-HT 6、 and 5-HT7 has been found to increase intracellular IP3 and DAG. The 5-HT pathway in the brain is an important target for drug development in CNS disorder areas. This neurotransmitter binds to G protein-coupled receptors and is involved in a wide variety of actions including, for example, cognition, mental state, anxiety, attention, appetite, cardiovascular function, vasoconstriction, sleep (ACS Medicinal Chemistry Letters, 2011, 2, 929-932; Physiological Research, 2011, 60, 15-25), inflammatory bowel disease (IBD) and enteritis (International Application No. 2012058769, Khan, W. I., et. al. Journal of Immunology, 2013, 190, 4795-4804), epilepsy, seizure disorders (Epilepsy Research (2007) 75, 39), drug addiction and alcohol addiction (Hauser, S. R. et. al. Frontiers in Neuroscience, 2015, 8, 1-9).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Summary of the Invention

[0005] The present invention relates to a compound of formula (I) which is a novel 5-hydroxytryptamine receptor 7 (5-HT7) activity regulator, its hydrate, solvate, pharmaceutically acceptable salt, prodrug and complex body, and

Chemical formula

[0006] The present invention further provides Relates to a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

[0007] The present invention also relates to, for example, circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorders, learning disorders, memory disorders, hippocampal signal transduction disorders, sleep disorders, attention deficit / hyperactivity disorder, phobias, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, episodic disorders, drug addiction , and alcohol addiction, related to a method for treating or preventing a disease accompanied by dysregulation of 5-hydroxytryptamine receptor 7 activity, the method comprising administering to a subject an effective amount of a compound or composition according to the invention.

[0008] The present invention still further relates to, for example, circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorders, learning disorders, memory disorders, hippocampal signal transduction disorders, sleep disorders, attention deficit / hyperactivity disorder, phobias, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, episodic disorders, drug addiction, and alcohol addiction, related to a method for treating or preventing a disease accompanied by dysregulation of 5-hydroxytryptamine receptor 7 activity, the method comprising administering to a subject a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

[0009] ​​The present invention also relates to methods for treating or preventing circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulation disorders, learning disorders, memory disorders, hippocampal signal transduction disorders, sleep disorders, attention deficit / hyperactivity disorder, phobias, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, episodic disorders, drug addiction, alcohol addiction, and diseases or conditions associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. The method involves administering to a subject an effective amount of a compound or composition according to the present invention.

[0010] The present invention still further relates to methods for treating or preventing circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulation disorders, learning disorders, memory disorders, hippocampal signal transduction disorders, sleep disorders, attention deficit / hyperactivity disorder, phobias, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, episodic disorders, drug addiction , alcohol addiction, and diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity The method involves administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0011] The present invention also relates to methods for treating or preventing diseases or conditions associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. The method involves administering to a subject an effective amount of a compound or composition according to the present invention.

[0012] The present invention further relates to diseases or conditions associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. or a method for treating or preventing a symptom, the method comprising administering to a subject a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

[0013] The present invention further relates to a process for preparing a 5-hydroxytryptamine receptor 7 modulator of the present invention. For.

[0014] These and other objects, features, and advantages will become apparent to those skilled in the art upon reading the following detailed description and the appended claims. Unless otherwise specified, all percentages, ratios, and proportions in this specification are by weight. Unless otherwise specified, all temperatures are in degrees Celsius (°C). All documents cited are incorporated herein by reference in the relevant part, but the citation of any document should not be construed as an admission that it is prior art relevant to the present invention. In certain embodiments, for example, the following are provided: (Item 1) A compound having the following formula (I),

Chemical formula

Mode for Carrying Out the Invention

[0015] There is evidence suggesting the role of the 5-HT7 receptor in various medical disorders. Modulators of 5-HT7 receptor activity are thought to have beneficial effects in patients suffering from these disorders. These disorders involve dysregulation of 5-HT7, and modulating 5-HT7 receptor activity with therapeutic agents could be a practical approach towards therapeutic relief. Such disorders include, but are not limited to, circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine (Vanhoenacker, P. et al. Trends in Pharmacological Sciences, 2000, 21, 2, 70-77), neuropathic pain, peripheral pain, allodynia (European Patent No. 1875899), thermoregulatory disorders, learning disorders, memory disorders, hippocampal signal transduction disorders, sleep disorders (International Publication No. 20100197700), attention deficit / hyperactivity disorder (ADHD) (International Publication No. 20100069390), phobias, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder (International Publication No. 20040229874), inflammatory bowel disease (IBD), enteritis (International Publication No. 2012058769, Khan, W. I., et. al. Journal of Immunology, 2013, 190, 4795-4804), epilepsy, seizure disorders (Epilepsy Research (2007) 75, 39), drug addiction, and alcohol addiction (Hauser, S. R. et. al. Frontiers in Neuroscience, 2015, 8, 1-9).

[0016] There has been a long-standing need for novel 5-HT7 modulators that would provide therapeutic relief to patients suffering from disorders associated with dysregulation of 5-HT7 receptor 7 activity. The present invention is , which addresses the need to identify novel 5-HT7 modulators capable of treating diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. The present invention relates to circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorders, learning disorders, memory disorders, hippocampal signal transduction disorders, sleep disorders, attention deficit / hyperactivity disorder, phobia, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, seizure disorders, drug addiction, and the need to develop novel therapeutic agents for the treatment and prevention of alcohol addiction.

[0017] The 5-hydroxytryptamine receptor 7 activity modulator of the present invention is 5-hydroxytryptami ne receptor 7 activity-related diseases, such as circadian rhythm disorders, depression, schizophrenia sis, neurogenic inflammation, hypertension, peripheral vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorders, learning disorders, memory disorders, hippocampal signal transduction disorders, sleep disorders, attention deficit / hyperactivity disorder, phobia, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy psy, seizure disorders, drug addiction, and alcohol addiction can be treated and prevented. 5-Hydroxytryptamine receptor 7 has been found to be causally related to many medical disorders, and therefore 5-HT7 receptor activity modulators are thought to have beneficial effects on patients suffering from these diseases. These diseases involve dysregulation of 5-HT7, and modulating 5-HT7 receptor activity with therapeutic agents can be a practical approach towards therapeutic relief. These diseases include, but are not limited to, circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular diseases, migraine (Vanhoenacker, P. et al. Trends in and are considered to have. These diseases involve dysregulation of 5-HT7, and modulating 5-HT7 receptor activity with therapeutic agents can be a practical approach towards therapeutic relief. These diseases include, but are not limited to, circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular diseases, migraine (Vanhoenacker, P. et al. Trends in (Pharmacological Sciences, 2000, 21, 2, 70-77), neuropathic pain, peripheral pain, allodynia (European Patent No. 1875899), thermoregulatory disorder, learning disorder, memory disorder, hippocampal signal transmission disorder, sleep disorder (International Publication No. 20100197700), attention deficit / hyperactivity disorder (ADHD) ( International Publication No. 20100069390), phobia, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder (International Publication No. 20040229874), inflammatory bowel disease (IBD), enteritis (International Publication No. 2012058769), epilepsy, seizure disorder (Epilepsy Research (2007) 75, 39), drug addiction, and alcohol addiction (Hauser, S. R. et. al. Frontiers in Neuroscience, 2015, 8, 1-9) can be mentioned. Although not wishing to be limited to theory, the receptor activity regulator of 5-hydroxytryptamine receptor 7 of the present invention is considered to be able to relieve, remit, or control diseases associated with the dysregulation of 5-hydroxytryptamine receptor 7 activity. Such diseases include, but are not limited to, circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorder, learning disorder, memory disorder, hippocampal signal transmission disorder, sleep disorder, attention deficit / hyperactivity disorder, phobia, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, seizure disorder, drug

[0018] addiction, and alcohol addiction. can be mentioned.

[0019] Throughout this specification, when a composition is described as having, comprising, or including a particular component, or when a process is described as having, comprising, or including a particular process step, the compositions of the present teachings are intended to consist essentially of, or consist of, the recited components, and the processes of the present teachings are also intended to consist essentially of, or consist of, the recited process steps.

[0020] In this specification, when an element or component is stated to be included in and / or selected from a list of recited elements or components, it is to be understood that the element or component may be any one of the recited elements or components, or may be selected from a group consisting of two or more of the recited elements or components.

[0021] As used in this specification, the use of the singular form includes the plural (and vice versa) unless specifically stated otherwise. Further, when the term "about" is used before a quantitative value, the present teachings include the specific quantitative value itself unless specifically stated otherwise.

[0022] It should be understood that the order or sequence of steps for performing a particular act is not important as long as the present teachings are capable of being practiced. Further, two or more steps or acts can be performed simultaneously.

[0023] As used in this specification, the term "halogen" shall mean chlorine, bromine, fluorine, and iodine.

[0024] As used in this specification, unless otherwise specified, "alkyl" and / or "aliphatic" alone or as part of a substituent, represents straight and branched carbon chains having from 1 to 20 carbon atoms, or any number within this range, for example, from 1 to 6 carbon atoms or from 1 to 4 carbon atoms. The specified number of carbon atoms (e.g., C 1-6refers independently to the number of carbon atoms in the alkyl moiety or, for the alkyl moiety of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, etc. can be mentioned. The alkyl group can be optionally substituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, etc. (C 1-6 For substituents having multiple alkyl groups such as (C alkyl)2amino, those alkyl groups may be the same or different.

[0025] As used herein, the terms "alkenyl" and "alkynyl" groups, whether used alone or as part of a substituent, mean straight-chain and branched carbon chains having two or more carbon atoms, preferably 2 to 20 carbon atoms, with the alkenyl chain having at least one double bond in the chain and the alkynyl chain having at least one triple bond in the chain. The alkenyl and alkynyl groups can be optionally substituted. Non-limiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also known as 2-methylethenyl), isopropenyl (also known as 2-methyl ethen-2-yl), buten-4-yl, etc. Non-limiting examples of substituted alkenyl groups include 2-chloroethenyl (also known as 2-chlorovinyl), 4-hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, 7-hydroxy-7- methyloct-3,5-dien-2-yl, etc. Non-limiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also known as propargyl), propin-1-yl, and 2-methyl-hexa-4-yn-1-yl. Non-limiting examples of substituted alkynyl groups include 5-hi droxy, etc. Droxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl, 5- Examples include hydroxy-5-ethylhept-3-ynyl and the like.

[0026] As used herein, "cycloalkyl", whether used alone or as part of another group, is a cycloalkyl group, cycloalkenyl group, or cycloalkynyl group having, for example, 3 to 14 ring carbon atoms, preferably 3 to 7 or 3 to 6 ring carbon atoms, or 3 to 4 ring carbon atoms, and optionally contains one or more (e.g., 1, 2, or 3) double or triple bonds, representing a non-aromatic carbon-containing ring. The cycloalkyl group may be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., including fused, bridged, and / or spiro ring structures), and the carbon atoms may be located inside or outside the ring structure. Any suitable ring position of the cycloalkyl group can be covalently bonded to the defined chemical structure. The cycloalkyl ring may be optionally substituted. Non-limiting examples of cycloalkyl groups include cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cycl obutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octa yl, etc. Hydroindenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl, bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl are included. The term "cycloalkyl" also includes a carbocyclic ring that is a bicyclic hydrocarbon ring, and non-limiting examples thereof include bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

[0027] "Haloalkyl" has a specific number of carbon atoms substituted with one or more halogens and is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups. The haloalkyl group includes perhaloalkyl groups in which all hydrogens of the alkyl group are substituted with halogens (e.g., -CF3, -CF2CF3). The haloalkyl group may optionally be substituted with one or more substituents in addition to the halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl group, dichloroethyl group, trifluoromethyl group, trichloromethyl group, pentafluoroethyl group, and pentachloroethyl group.

[0028] The term "alkoxy" refers to a group of -O-alkyl, where the alkyl group is as defined above and the alkoxy group may optionally be substituted. The term C3-C6 cyclic alkoxy means a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). The C3-C6 cyclic alkoxy group may optionally be substituted.

[0029] The term "haloalkoxy" means a group of -O-haloalkyl, where haloalkyl The Luquil group is as defined above. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and pentafluoroethoxyl.

[0030] The term "aryl", used alone or as part of another group, is defined herein as an unsaturated aromatic monocyclic ring of 6 carbons or an unsaturated aromatic polycyclic ring of 10 - 14 carbons. The aryl ring can be, for example, a phenyl ring or a naphthyl ring, optionally each substituted with one or more moieties that can replace one or more hydrogen atoms. Non-limiting examples of aryl groups include phenyl, naphthylen-1-yl, naphthylen-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluoro rophenyl, 2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaph thylen-1-yl, and 6-cyano-naphthylen-1-yl. The aryl group can include, for example, a phenyl ring or a naphthyl ring fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl) that can be substituted with one or more carbon atoms of the aromatic ring and / or the saturated or partially saturated ring. The term "arylalkyl" or "aralkyl" refers to a -alkyl-aryl group, where the alkyl group and the aryl group are as defined herein. The aralkyl group of the present invention is optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl, and the like.

[0031]

[0032] ​The terms "heterocyclic" and / or "heterocycle" and / or "heterosilyl", whether used alone or as part of another group, refer to one or more rings having from 3 to 20 atoms, where at least one atom of at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and where the ring containing the heteroatom is non-aromatic, as defined for rings. In a heterocyclic group containing two or more fused rings, the non-heteroatom-containing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclic groups have from 3 to 14 ring atoms, 1 to 5 of which are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms of the heterocyclic group can be oxidized. The heterocyclic group can be optionally substituted. (O), or sulfur (S), and where the ring containing the heteroatom is non-aromatic, as defined for rings. In a heterocyclic group containing two or more fused rings, the non-heteroatom-containing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclic groups have from 3 to 14 ring atoms, 1 to 5 of which are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms of the heterocyclic group can be oxidized. The heterocyclic group can be optionally substituted. (O), or sulfur (S), and where the ring containing the heteroatom is non-aromatic, as defined for rings. In a heterocyclic group containing two or more fused rings, the non-heteroatom-containing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclic groups have from 3 to 14 ring atoms, 1 to 5 of which are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms of the heterocyclic group can be oxidized. The heterocyclic group can be optionally substituted.

[0033] Non-limiting examples of heterocyclic units having a single ring include diazinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydroquinoline. Non-limiting examples of bicyclic units having two or more rings include hexahydro-1H-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H-cycloocta[b]pyrrolyl. (O), or sulfur (S), and where the ring containing the heteroatom is non-aromatic, as defined for rings. In a heterocyclic group containing two or more fused rings, the non-heteroatom-containing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclic groups have from 3 to 14 ring atoms, 1 to 5 of which are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms of the heterocyclic group can be oxidized. The heterocyclic group can be optionally substituted. Non-limiting examples of heterocyclic units having a single ring include diazinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydroquinoline. Non-limiting examples of bicyclic units having two or more rings include hexahydro-1H-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H-cycloocta[b]pyrrolyl. (O), or sulfur (S), and where the ring containing the heteroatom is non-aromatic, as defined for rings. In a heterocyclic group containing two or more fused rings, the non-heteroatom-containing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclic groups have from 3 to 14 ring atoms, 1 to 5 of which are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms of the heterocyclic group can be oxidized. The heterocyclic group can be optionally substituted. (O), or sulfur (S), and where the ring containing the heteroatom is non-aromatic, as defined for rings. In a heterocyclic group containing two or more fused rings, the non-heteroatom-containing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclic groups have from 3 to 14 ring atoms, 1 to 5 of which are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms of the heterocyclic group can be oxidized. The heterocyclic group can be optionally substituted.

[0034] The term "heteroaryl", whether used alone or as part of another group, refers to one or more rings having 5 to 20 atoms, with at least one atom in at least one of the rings being a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and at least one of the rings containing the heteroatom being aromatic, as defined herein as a ring. In a heteroaryl group containing two or more fused rings, the non-heteroatom-containing rings may be carbon rings (e.g., 6,7-dihydro-5H-cyclopenta[py]rimidine), or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have 5 to 14 ring atoms and contain 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N atoms or S atoms in the heteroaryl group can be oxidized. The heteroaryl group can also be substituted. Non-limiting examples of heteroaryl rings containing a single ring include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing two or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenz[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl and is defined herein as a ring. In a heteroaryl group containing two or more fused rings, the non-heteroatom-containing rings may be carbon rings (e.g., 6,7-dihydro-5H-cyclopenta[py]rimidine), or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have 5 to 14 ring atoms and contain 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N atoms or S atoms in the heteroaryl group can be oxidized. The heteroaryl group can also be substituted. Non-limiting examples of heteroaryl rings containing a single ring include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing two or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenz[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl and is defined herein as a ring. In a heteroaryl group containing two or more fused rings, the non-heteroatom-containing rings may be carbon rings (e.g., 6,7-dihydro-5H-cyclopenta[py]rimidine), or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have 5 to 14 ring atoms and contain 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N atoms or S atoms in the heteroaryl group can be oxidized. The heteroaryl group can also be substituted. Non-limiting examples of heteroaryl rings containing a single ring include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing two or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenz[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl rings (e.g., 6,7-dihydro-5H-cyclopenta[py]rimidine), or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have 5 to 14 ring atoms and contain 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N atoms or S atoms in the heteroaryl group can be oxidized. The heteroaryl group can also be substituted. Non-limiting examples of heteroaryl rings containing a single ring include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing two or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenz[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl or S atoms in the heteroaryl group can be oxidized. The heteroaryl group can also be substituted. Non-limiting examples of heteroaryl rings containing a single ring include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing two or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenz[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl heteroaryl rings containing a single ring include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing two or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenz[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl Non-limiting examples of heteroaryl rings containing a single ring include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing two or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenz[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl Non-limiting examples of heteroaryl rings containing two or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenz[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl ro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl Examples include nil, 8-hydroxy-quinolinyl, 1H-benzo-[d]imidazol-2(3H)-ononyl, 1H-benzo[d]imidazolyl, and isoquinolinyl.

[0035] One non-limiting example of the above-mentioned heteroaryl group is C1-C5 heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom (preferably 1 to 4 additional ring atoms which are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S). Examples of C1-C5 heteroaryl include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

[0036] Unless otherwise stated, when two substituents combine to form a ring having a predetermined number of ring atoms (e.g., R 2 and R 3 combine with the nitrogen (N) to which they are attached to form a ring having 3 to 7 ring members ), the ring may have carbon atoms and, optionally, one or more (e.g., 1 to 3) additional hetero atoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). The ring may be saturated or partially saturated and may optionally be substituted .

[0037] In the present invention, condensed ring units, spirocyclic rings, bicyclic rings, and the like containing a single heteroatom are considered to belong to the cyclic family corresponding to heteroatom-containing rings. For example, 1,2,3,4-tetrahydroquinoline having the following formula is

Chem.

Chem.

Chem.

[0038] When the term or any of its prefix roots is in the name of a substituent, the name should be construed to include the limitations provided herein. For example, when the term "alkyl" or "aryl" or any of its prefix roots is in the name of a substituent (e.g., arylalkyl, alkylamino), the name should be construed to include the limitations described above for "alkyl" and "aryl".

[0039] The term "substituted" is used throughout this specification. The term "substituted" is defined herein as a moiety having one or more hydrogen atoms substituted with substituents (e.g., 1 to 10) defined below in this specification, whether acyclic or cyclic. It can be. The substituents can replace one or two hydrogen atoms of a single moiety at a time. Further, these substituents can replace two hydrogen atoms attached to two adjacent carbons to form the substituent, i.e., a new moiety or unit. For example, the substitution units in which a single hydrogen atom is replaced include halogen, hydroxyl, etc. The substitution parts of two hydrogen atoms include carbonyl, oxyimino, etc. The substitution parts of two hydrogen atoms of adjacent carbon atoms include epoxy, etc. The term "substituted" is used throughout this specification to indicate that a moiety may have one or more hydrogen atoms replaced by substituents. When a moiety is described as "substituted", any number of hydrogen atoms may be substituted. For example, difluoromethyl is a substituted C1 alkyl, trifluoromethyl is a substituted C1 alkyl, 4-hydroxyphenyl is a substituted aromatic ring, and (N,N-dimethyl -5-amino)octanyl is a substituted C8 alkyl, 3-guanidinopropyl is a substituted C3 alkyl, and 2-carboxypyridinyl is a substituted heteroaryl.

[0040] The variable groups defined herein, for example, the alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, alkoxy groups, aryloxy groups, aryl groups, heterocyclic groups and heteroaryl groups defined herein can be optionally substituted whether used alone or as part of another group. Optionally substituted groups are shown in the same way.

[0041] Non-limiting examples of substituents that can be substituted for hydrogen atoms on a moiety are as follows: halogen (chlorine (Cl), bromine (Br), fluorine (F) and iodine (I)), -CN, -NO2, oxo (=O) , -OR 12 , -SR 12 , -N(R 12 )2, -NR 12 C(O)R 12 , -SO2R 12 , -SO2OR 12 , -SO2N(R 12) 2, -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 12 )2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 2-8 alkenyl, C 2-8 alkynyl, C 3-14 cycloalkyl, aryl, heterocycle or he teroaryl, wherein each group of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle and heteroaryl is optionally substituted with 1 to 10 (e.g., 1 to 6 or 12 1 to 4) groups independently selected from halogen, -CN, -NO2, oxo, and -OR ; R 12 is independently at each occurrence hydrogen, -OR 13 , -SR 13 , -C(O)R 13 , -C(O)OR 13 , -C(O)N(R 13 )2, -SO2R 13 , -S(O)2OR 13 , -N(R 13 )2, -NR 13 C(O)R 13 , C 1-6 a lkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, cycloalkyl (e.g., C 3-6 cycloalkyl), aryl, heterocycle or heteroaryl, or two R 12 units together with the atom to which they are attached optionally form a carbocyclic or heterocyclic ring which is optionally substituted; wherein said carbocyclic or heterocyclic ring has 3 to 7 ring atoms; R 13 is independently at each occurrence hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8Alkynyl, cycloalkyl (e.g., C 3-6 ycloalkyl), aryl, heterocycle or heteroaryl or, or two R 13 units, together with the atoms to which they are attached, optionally form a carbocyclic or heterocyclic ring, where the carbocyclic or heterocyclic ring has 3 to 7 ring atoms.

[0042] In some embodiments, the substituent is i) -OR 14 ; e.g., -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3; ii) -C(O)R 14 ; e.g., -COCH3, -COCH2CH3, -COCH2CH2CH3; iii) -C(O)OR 14 ; e.g., -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3; iv) -C(O)N(R 14 )2; e.g., -CONH2, -CONHCH3, -CON(CH3)2; v) -N(R 14 )2; e.g., -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3); vi) halogen: -F, -Cl, -Br, and -I; vii) -CH e X g ; wherein X is halogen, m is 0 to 2, and e + g = 3; e.g., -CH2F, -CHF2, -CF3, -CCl3, or -CBr3; viii) -SO2R 14 ; e.g., -SO2H; -SO2CH3; -SO2C6H5: ix) C1-C6 linear alkyl, branched alkyl, or cyclic alkyl; x) cyano xi) nitro; xii) N(R 14 )C(O)R 14 ; xiii) oxo (=O); xiv) Complex rings; and xv) Selected from heteroaryl. In the formula, each R 14 is independently hydrogen, optionally substituted C1-C6 linear or branched alkyl (e.g., optionally substituted C1-C4 linear or branched alkyl) , or optionally substituted C3-C6 cycloalkyl (e.g., optionally substituted C3-C4 cycloalkyl); or two R 14 units can combine together to form a ring containing 3 to 7 ring atoms. In certain embodiments, each R 14 is independently hydrogen, or optionally halogen-substituted C1-C6 linear or branched alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl.

[0043] Throughout this specification, substituents of compounds are disclosed in groups or ranges. It is specifically intended that the description include members of such groups and individual subsets of the ranges. For example, the term "C 1-6 alkyl" is specifically intended to individually disclose C1 alkyl, C2 alkyl, C3 alkyl , C4 alkyl, C5 alkyl, C6 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl yl, C1-C3 alkyl, C1-C2 alkyl, C2-C6 alkyl, C2-C5 alkyl, C2-C4 alkyl, C2-C3 alkyl, C3-C6 alkyl, C3-C5 alkyl, C3-C4 alkyl, C4-C6 alkyl, C4-C5 alkyl, and C5-C6 alkyl.

[0044] In the present invention, the terms "compound", "analog", and "composition of matter" all adequately represent the 5-hydroxytryptamine receptor 7 activity regulators described herein, including all enantiomeric forms, diastereomeric forms, salts, etc. of these "compounds The terms ")", "analog", and "composition of matter" are used interchangeably throughout this specification.

[0045] The compounds described herein can contain asymmetric atoms (also referred to as chiral centers), and some compounds can contain one or more asymmetric atoms or centers, which can give rise to optical isomers (enantiomers) and diastereomers. The teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as racemic-separated enantiomerically pure R and S stereoisomers, and other mixtures of R and S stereoisomers with pharmaceutically acceptable salts. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, including but not limited to diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is understood that the present teachings include all possible positional isomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, including but not limited to column chromatography, thin layer chromatography, and high performance liquid chromatography.

[0046] Pharmaceutically acceptable salts of the compounds of the present disclosure can have an acidic moiety and can be formed using organic and inorganic bases. Depending on the number of acidic hydrogens available for deprotonation, both monoanion salts and polyanion salts are contemplated. Suitable salts formed with bases include, for example, metal salts such as alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, or magnesium salts; ammonia salts and organic amine salts such as salts formed using morpholine, thiomorpholine, piperidine, pyrrolidine, mono-lower alkylamines, di-lower alkylamines, or tri-lower alkylamines (e.g., ethyl-tert-butylamine, diethylamine, diisopropylamine, triethylamine, or dimethylpropylamine), or mono-hydroxy lower alkylamines, di-hydroxy lower alkylamines, or tri-hydroxy lower alkylamines (e.g., monoethanolamine, diethanolamine, or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH , NaH2PO4, Na2HPO4, and Na3PO4. Inner salts can also be formed. Similarly, when the compounds disclosed herein contain a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic acid, propionic acid, lactic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, tartaric acid, succinic acid, dichloroacetic acid, ethenesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid, and camphorsulfonic acid, as well as other known pharmaceutically acceptable acids.

[0047] If any variable occurs more than once in any component or any mathematical formula, in each occurrence The definition is independent of the definition in any other occurrence (for example, in N(R 9 ))2, each R 9 may be the same or different). Combinations of substituents and / or variables are permitted only if such combinations result in stable compounds.

[0048] As used herein, the terms “treating,” “being treated,” and “treatment” mean partially or completely alleviating, suppressing, ameliorating, and / or reducing a condition that a patient may suffer from.

[0049] As used herein, “therapeutically effective” and “effective dose” mean a substance or amount that elicits a desired biological activity or effect.

[0050] Unless noted otherwise, the terms “subject” or “patient” are used interchangeably and mean human patients and non-human primates, as well as mammals such as experimental animals and other animals such as rabbits, rats, and mice. Thus, as used herein, the term “subject” or “patient” means any mammalian patient or subject to whom a compound of the invention can be administered. In exemplary embodiments of the invention, to identify a subject patient for treatment by the methods of the invention, a recognized screening method is used to measure risk factors associated with a targeted or suspected disease or condition, or to measure the status of an existing disease or condition of the subject. These screening methods include, for example, conventional diagnostic tests for measuring risk factors that may be associated with a targeted or suspected disease or condition. By these and other conventional methods, a clinician can select patients in need of treatment using the methods and compounds of the invention. 5-Hydroxytryptamine receptor 7 modulators

[0051] The 5-hydroxytryptamine receptor 7 modulators of the present invention include all enantiomeric and diastereomeric forms having the following formula, [Chemical] including its hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex, wherein including its hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex, wherein n is 1, 2, or 3, R 1a and R 1b are each independently selected from the group consisting of hydrogen, C1-6 linear alkyl, and C1-6 branched alkyl, or R 1a and R 1b may together with the atom to which they are attached form a ring having 3 to 7 ring atoms; R 2 is a benzene ring optionally substituted with 0 to 3 R 3 groups that are not hydrogen, a 3-pyridine ring optionally substituted with 0 to 2 R 4 groups that are not hydrogen, and a 2-pyridine ring optionally substituted with 0 to 2 R 4 groups that are not hydrogen, selected from the group consisting of; R 3 is, at each occurrence, hydrogen, OH, NO2, halogen, CN, C 1-6 linear alkyl, C 3-7 branched alkyl, C 3-7 cycloalkyl, C 1-6 linear alkoxy, C 3-7 branched alkoxy, C 3-7 cycloalkoxy, C 1-6 linear haloalkyl, C 3-7 branched haloalkyl, C 1-6 linear haloalkoxy, heterocyclyl, -S(C 1-6 linear alkyl), S(C 3-7 branched alkyl) -S(C 3-7 cycloalkyl), -SO2(C 1-6 linear alkyl), SO2(C 3-7 branched alkyl), -SO2(C 3-7 cycloalkyl), COR5 、 CO2R 6 、 CONR 7a R 7b 、 SO2NR 7a R 7b 、 NR 8a R 8b 、 NR 8a COR 9 、 NR 8a SO2R 10 、 and NR 8a SO2NR 11a R 11b is independently selected from the group consisting of; R 3a 、 R 3b 、 R 3c 、 R 3d 、 and R 3e The term R 3 may be used to designate an individual R R 4 is, at each occurrence, hydrogen, OH, NO2, halogen, CN, C 1-6 linear alkyl, C 3-7 branched alkyl, C 3-7 cycloalkyl, C 1-6 linear alkoxy, C 3-7 branched alkoxy, C 3-7 cycloalkoxy, C 1-6 linear haloalkyl, C 3-7 branched haloalkyl, C 1-6 linear haloalkoxy, heterocyclyl, -S(C 1-6 linear alkyl), S(C 3-7 branched alkyl), -S(C 3-7 cycloalkyl), COR 5 、 CO2R 6 、 CONR 7a R 7b 、 SO2NR 7a R 7b 、 NR 8a R 8b 、 NR 8a COR 9 、 NR 8a SO2R 10 、 and NR 8a SO2NR 11a R11b independently selected from the group consisting of; R 4a 、R 4b 、R 4c 、and R 4d The term may be used to designate the individual R 4 groups on the pyridine ring; R 5 is, at each occurrence, H, C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cyclo alkyl independently selected from the group consisting of; R 6 is, at each occurrence, C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl independently selected from the group consisting of; R 7a is, at each occurrence, H, C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl independently selected from the group consisting of; R 7b is, at each occurrence, H, C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl independently selected from the group consisting of; R 8a is, at each occurrence, H, C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl independently selected from the group consisting of; R 8b is, at each occurrence, H, C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl independently selected from the group consisting of; R 8a and R 8b may together with the atom to which they are attached form a ring having 3 to 7 ring atoms optionally containing oxygen; R9 at each occurrence position, is independently selected from the group consisting of H, C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cyclo alkyl; R 10 at each occurrence position, is independently selected from the group consisting of C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl; ; R 11a at each occurrence position, is independently selected from the group consisting of hydrogen, C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl; and R 11b at each occurrence position, is independently selected from the group consisting of C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl.

[0052] In one embodiment, the present invention includes a compound having the following formula (IIa), its hydrate, solvate, enantiomer, diastereomer, pharmaceutically acceptable salt, and complex: :

Chemical formula

[0053] In one embodiment, the present invention includes compounds having the following formula (IIb), their hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes: :

Chemical formula

[0054] In one embodiment, the present invention includes compounds having the following formula (IIc), their hydrates, solvates ates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes:

Chemical formula

[0055] In one embodiment, the present invention includes a compound having the following formula (III), its hydrate, solvate te, enantiomer, diastereomer, pharmaceutically acceptable salt, and complex.

Chemical formula

[0056] In one embodiment, the present invention includes a compound having the following formula (IIIa), its hydrate, solvate, enantiomer, diastereomer, pharmaceutically acceptable salt, and complex:

Chemical formula

[0057] In one embodiment, the present invention includes a compound having the following formula (IIIb), its hydrate, solvate, enantiomer, diastereomer, pharmaceutically acceptable salt, and complex:

Chemical formula

[0058] In one embodiment, the present invention includes a compound having the following formula (IIIc), its hydrate, solvate, enantiomer, diastereomer, pharmaceutically acceptable salt, and complex:

Chemical formula

[0059] In one embodiment, the present invention includes compounds having the following formula (IV), their hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes. [Chemical formula]

[0060] In one embodiment, the present invention includes compounds having the following formula (IVa), their hydrates, solvates , enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes: [Chemical formula] Wherein: R 3a , R 3b , R 3c , R 3d and R3e At least two of the groups of R are hydrogen, and R 3a , R 3b , R 3c , R 3d and R 3e of the groups of 0 to 3 are independently OH, NO2, halogen, CN, C1-6 linear alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 linear alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 linear haloalkyl, C3-7 branched haloalkyl, C1-6 linear haloalkoxy, heterocyclyl, -S(C1-6 linear alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 linear alkyl), SO2(C3-7 branched alkyl), -SO2(C3-7 cycloalkyl), COR 5 , CO2R 6 , CONR 7a R 7b , SO2NR 7a R 7b , NR 8a R 8b , NR 8a COR 9 , NR 8a SO2R 10 , and NR 8a SO2NR 11a R 11b is selected from the group consisting of.

[0061] In one embodiment, the present invention includes compounds having the following formula (IVb), their hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes.

Chemical formula

[0062] In one embodiment, the present invention includes compounds having the following formula (IVc), their hydrates, solvates , enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes. [Chemical formula] Wherein: R 4a , R 4b , R 4c , and R 4d Among the groups, at least 2 are hydrogen, and R 4a , R 4b , R 4c , and R 4dAmong the 0 to 2 of the groups of the radical, independently, OH, NO2, halogen, CN, C1-6 linear alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 linear alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 linear haloalkyl, C3-7 branched haloalkyl, C1-6 linear haloalkoxy, heterocyclyl, -S(C1-6 linear alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 linear alkyl), SO2(C3-7 branched al kyl), -SO2(C3-7 cycloalkyl), COR 5 、CO2R 6 、CONR 7a R 7b 、SO2NR 7a R 7b 、NR 8a R 8b 、NR 8a COR 9 、NR 8a SO2R 10 、およびNR 8a SO2NR 11a R 11b is selected from the group consisting of.

[0063] In one embodiment, the present invention includes a compound having the following formula (V), its hydrate, solvate , enantiomer, diastereomer, pharmaceutically acceptable salt, and complex.

Chemical formula

[0064] In one embodiment, the present invention includes a compound having the following formula (Va), its hydrate, solvate, enantiomer, diastereomer, pharmaceutically acceptable salt, and complex.

Chemical formula

[0065] In one embodiment, the present invention includes compounds having the following formula (Vb), their hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes.

Chemical formula

[0066] In one embodiment, the present invention includes compounds having the following formula (Vc), hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof. [Chemical formula] In the formula: R 4a , R 4b , R 4c , and R 4d Among the groups, at least 2 are hydrogen, and R 4a , R 4b , R 4c , and R 4dAmong the 0 to 2 groups of the radical, independently, OH, NO2, halogen, CN, C1-6 linear alkyl, C3-7 branched alkyl, C3-7 cycloalkyl, C1-6 linear alkoxy, C3-7 branched alkoxy, C3-7 cycloalkoxy, C1-6 linear haloalkyl, C3-7 branched haloalkyl, C1-6 linear haloalkoxy, heterocyclyl, -S(C1-6 linear alkyl), S(C3-7 branched alkyl), -S(C3-7 cycloalkyl), -SO2(C1-6 linear alkyl), SO2(C3-7 branched al kyl), -SO2(C3-7 cycloalkyl), COR 5 , CO2R 6 , CONR 7a R 7b , SO2NR 7a R 7b , NR 8a R 8b , NR 8a COR 9 , NR 8a SO2R 10 , and NR 8a SO2NR 11a R 11b is selected from the group consisting of.

[0067] In some embodiments, n is 1.

[0068] In some embodiments, n is 2.

[0069] In some embodiments, n is 3.

[0070] In some embodiments, R 1a is hydrogen.

[0071] In some embodiments, R 1a is C 1-6 linear alkyl.

[0072] In some embodiments, R 1a is C 1-6 branched alkyl.

[0073] In some embodiments, R 1b is hydrogen.

[0074] In some embodiments, R 1b is C 1-6 linear alkyl.

[0075] In some embodiments, R 1b is C 1-6 branched alkyl.

[0076] In some embodiments, R 1a and R 1b form a ring having three ring atoms together with the atom to which they are attached to form a ring.

[0077] In some embodiments, R 1a and R 1b form a ring having four ring atoms together with the atom to which they are attached to form a ring.

[0078] In some embodiments, R 1a and R 1b form a ring having five ring atoms together with the atom to which they are attached to form a ring.

[0079] In some embodiments, R 1a and R 1b form a ring having six ring atoms together with the atom to which they are attached to form a ring.

[0080] In some embodiments, R 1a and R 1b form a ring having seven ring atoms together with the atom to which they are attached to form a ring.

[0081] In some embodiments, R 2 is a benzene ring optionally substituted with zero to three R 3 groups that are not hydrogen.

[0082] In some embodiments, R 2is a 3-pyridine ring optionally substituted with 0 to 2 R groups that are not hydrogen. 4

[0083] In some embodiments, R 2 is a 2-pyridine ring optionally substituted with 0 to 2 R groups that are not hydrogen. 4

[0084] In some embodiments, R 3 is hydrogen.

[0085] In some embodiments, R 3 is OH.

[0086] In some embodiments, R 3 is NO2.

[0087] In some embodiments, R 3 is halogen.

[0088] In some embodiments, R 3 is CN.

[0089] In some embodiments, R 3 is C 1-6 linear alkyl.

[0090] In some embodiments, R 3 is C 3-7 branched alkyl.

[0091] In some embodiments, R 3 is C 3-7 cycloalkyl.

[0092] In some embodiments, R 3 is C 1-6 linear alkoxy.

[0093] In some embodiments, R 3 is C 3-7 branched alkoxy.

[0094] ​​In some embodiments, R 3 is C 3-7 cycloalkoxy.

[0095] In some embodiments, R 3 is C 1-6 linear haloalkyl.

[0096] In some embodiments, R 3 is C 3-7 branched haloalkyl.

[0097] In some embodiments, R 3 is C 1-6 linear haloalkoxy.

[0098] In some embodiments, R 3 is -S(C 1-6 linear alkyl).

[0099] In some embodiments, R 3 is -S(C 3-7 branched alkyl).

[0100] In some embodiments, R 3 is -S(C 3-7 cycloalkyl).

[0101] In some embodiments, R 3 is -SO2(C 1-6 linear alkyl).

[0102] In some embodiments, R 3 is -SO2(C 3-7 branched alkyl).

[0103] In some embodiments, R 3 is -SO2(C 3-7 cycloalkyl).

[0104] In some embodiments, R 3 is COR 5 wherein.

[0105] In some embodiments, R 3 is CO2R 6 .

[0106] In some embodiments, R 3 is CONR 7a R 7b .

[0107] In some embodiments, R 3 is SO2NR 7a R 7b .

[0108] In some embodiments, R 3 is NR 8a R 8b .

[0109] In some embodiments, R 3 is NR 8a COR 9 .

[0110] In some embodiments, R 3 is NR 8a SO2R 10 .

[0111] In some embodiments, R 3 is NR 8a SO2NR 11a R 11b .

[0112] In some embodiments, R 3a is hydrogen.

[0113] In some embodiments, R 3a is OH.

[0114] In some embodiments, R 3a is NO2.

[0115] In some embodiments, R 3a is halogen.

[0116] In some embodiments, R3a is CN.

[0117] In some embodiments, R 3a is C 1-6 a linear alkyl.

[0118] In some embodiments, R 3a is C 3-7 a branched alkyl.

[0119] In some embodiments, R 3a is C 3-7 a cycloalkyl.

[0120] In some embodiments, R 3a is C 1-6 a linear alkoxy.

[0121] In some embodiments, R 3a is C 3-7 a branched alkoxy.

[0122] In some embodiments, R 3a is C 3-7 a cycloalkoxy.

[0123] In some embodiments, R 3a is C 1-6 a linear haloalkyl.

[0124] In some embodiments, R 3a is C 3-7 a branched haloalkyl.

[0125] In some embodiments, R 3a is C 1-6 a linear haloalkoxy.

[0126] In some embodiments, R 3a is a heterocyclyl.

[0127] In some embodiments, R 3a is -S(C 1-6 linear alkyl).

[0128] In some embodiments, R 3a is -S(C 3-7 branched alkyl).

[0129] In some embodiments, R 3a is -S(C 3-7 cycloalkyl).

[0130] In some embodiments, R 3a is -SO2(C 1-6 linear alkyl).

[0131] In some embodiments, R 3a is -SO2(C 3-7 branched alkyl).

[0132] In some embodiments, R 3a is -SO2(C 3-7 cycloalkyl).

[0133] In some embodiments, R 3a is COR 5 wherein.

[0134] In some embodiments, R 3a is CO2R 6 wherein.

[0135] In some embodiments, R 3a is CONR 7a R 7b wherein.

[0136] In some embodiments, R 3a is SO2NR 7a R 7b wherein.

[0137] In some embodiments, R 3 is NR 8a R 8b wherein.

[0138] In some embodiments, R 3a is NR8a COR 9 is as follows.

[0139] In some embodiments, R 3a is NR 8a SO2R 10 is as follows.

[0140] In some embodiments, R 3a is NR 8a SO2NR 11a R 11b is as follows.

[0141] In some embodiments, R 3b is hydrogen.

[0142] In some embodiments, R 3b is OH.

[0143] In some embodiments, R 3b is NO2.

[0144] In some embodiments, R 3b is halogen.

[0145] In some embodiments, R 3b is CN.

[0146] In some embodiments, R 3b is C 1-6 linear alkyl.

[0147] In some embodiments, R 3b is C 3-7 branched alkyl.

[0148] In some embodiments, R 3b is C 3-7 cycloalkyl.

[0149] In some embodiments, R 3b is C 1-6 linear alkoxy.

[0150] In some embodiments, R 3b is C 3-7 a branched alkoxy.

[0151] In some embodiments, R 3b is C 3-7 a cycloalkoxy.

[0152] In some embodiments, R 3b is C 1-6 a linear haloalkyl.

[0153] In some embodiments, R 3b is C 3-7 a branched haloalkyl.

[0154] In some embodiments, R 3b is C 1-6 a linear haloalkoxy.

[0155] In some embodiments, R 3b is a heterocyclyl.

[0156] In some embodiments, R 3b is -S(C 1-6 a linear alkyl).

[0157] In some embodiments, R 3b is -S(C 3-7 a branched alkyl).

[0158] In some embodiments, R 3b is -S(C 3-7 a cycloalkyl).

[0159] In some embodiments, R 3b is -SO2(C 1-6 a linear alkyl).

[0160] In some embodiments, R 3b is -SO2(C 3-7 a branched alkyl).

[0161] In some embodiments, R 3b is -SO2(C 3-7 cycloalkyl).

[0162] In some embodiments, R 3b is COR 5 .

[0163] In some embodiments, R 3b is CO2R 6 .

[0164] In some embodiments, R 3b is CONR 7a R 7b .

[0165] In some embodiments, R 3b is SO2NR 7a R 7b .

[0166] In some embodiments, R 3b is NR 8a R 8b .

[0167] In some embodiments, R 3b is NR 8a COR 9 .

[0168] In some embodiments, R 3b is NR 8a SO2R 10 .

[0169] In some embodiments, R 3b is NR 8a SO2NR 11a R 11b .

[0170] In some embodiments, R 3c is hydrogen.

[0171] In some embodiments, R 3c is OH.

[0172] In some embodiments, R 3c is NO2.

[0173] In some embodiments, R 3c is a halogen.

[0174] In some embodiments, R 3c is CN.

[0175] In some embodiments, R 3c is C 1-6 a linear alkyl.

[0176] In some embodiments, R 3c is C 3-7 a branched alkyl.

[0177] In some embodiments, R 3c is C 3-7 a cycloalkyl.

[0178] In some embodiments, R 3c is C 1-6 a linear alkoxy.

[0179] In some embodiments, R 3c is C 3-7 a branched alkoxy.

[0180] In some embodiments, R 3c is C 3-7 a cycloalkoxy.

[0181] In some embodiments, R 3c is C 1-6 a linear haloalkyl.

[0182] In some embodiments, R 3c is C 3-7 a branched haloalkyl.

[0183] In some embodiments, R 3c is C 1-6 a linear haloalkoxy.

[0184] In some embodiments, R 3c is a heterocycle.

[0185] In some embodiments, R 3c is -S(C 1-6 linear alkyl).

[0186] In some embodiments, R 3c is -S(C 3-7 branched alkyl).

[0187] In some embodiments, R 3c is -S(C 3-7 cycloalkyl).

[0188] In some embodiments, R 3c is -SO2(C 1-6 linear alkyl).

[0189] In some embodiments, R 3c is -SO2(C 3-7 branched alkyl).

[0190] In some embodiments, R 3c is -SO2(C 3-7 cycloalkyl).

[0191] In some embodiments, R 3c is COR 5 wherein.

[0192] In some embodiments, R 3c is CO2R 6 wherein.

[0193] In some embodiments, R 3c is CONR 7a R 7b wherein.

[0194] In some embodiments, R 3c is SO2NR 7a R 7bis.

[0195] In some embodiments, R 3c is NR 8a R 8b is.

[0196] In some embodiments, R 3c is NR 8a COR 9 is.

[0197] In some embodiments, R 3c is NR 8a SO2R 10 is.

[0198] In some embodiments, R 3c is NR 8a SO2NR 11a R 11b is.

[0199] In some embodiments, R 3d is hydrogen.

[0200] In some embodiments, R 3d is OH.

[0201] In some embodiments, R 3d is NO2.

[0202] In some embodiments, R 3d is halogen.

[0203] In some embodiments, R 3d is CN.

[0204] In some embodiments, R 3d is C 1-6 linear alkyl.

[0205] In some embodiments, R 3d is C 3-7 branched alkyl.

[0206] In some embodiments, R3d is C 3-7 and is cycloalkyl.

[0207] In some embodiments, R 3d is C 1-6 and is linear alkoxy.

[0208] In some embodiments, R 3d is C 3-7 and is branched alkoxy.

[0209] In some embodiments, R 3d is C 3-7 and is cycloalkoxy.

[0210] In some embodiments, R 3d is C 1-6 and is linear haloalkyl.

[0211] In some embodiments, R 3d is C 3-7 and is branched haloalkyl.

[0212] In some embodiments, R 3d is C 1-6 and is linear haloalkoxy.

[0213] In some embodiments, R 3d is heterocyclyl.

[0214] In some embodiments, R 3d is -S(C 1-6 and is linear alkyl).

[0215] In some embodiments, R 3d is -S(C 3-7 and is branched alkyl).

[0216] In some embodiments, R 3d is -S(C 3-7 and is cycloalkyl).

[0217] In some embodiments, R 3dis -SO2(C 1-6 linear alkyl).

[0218] In some embodiments, R 3d is -SO2(C 3-7 branched alkyl).

[0219] In some embodiments, R 3d is -SO2(C 3-7 cycloalkyl).

[0220] In some embodiments, R 3d is COR 5 .

[0221] In some embodiments, R 3d is CO2R 6 .

[0222] In some embodiments, R 3d is CONR 7a R 7b .

[0223] In some embodiments, R 3d is SO2NR 7a R 7b .

[0224] In some embodiments, R 3d is NR 8a R 8b .

[0225] In some embodiments, R 3d is NR 8a COR 9 .

[0226] In some embodiments, R 3d is NR 8a SO2R 10 .

[0227] In some embodiments, R 3d is NR 8a SO2NR 11a R 11b .

[0228] In some embodiments, R 3e is hydrogen.

[0229] In some embodiments, R 3e is OH.

[0230] In some embodiments, R 3e is NO2.

[0231] In some embodiments, R 3e is a halogen.

[0232] In some embodiments, R 3e is CN.

[0233] In some embodiments, R 3e is C 1-6 a linear alkyl.

[0234] In some embodiments, R 3e is C 3-7 a branched alkyl.

[0235] In some embodiments, R 3e is C 3-7 a cycloalkyl.

[0236] In some embodiments, R 3e is C 1-6 a linear alkoxy.

[0237] In some embodiments, R 3e is C 3-7 a branched alkoxy.

[0238] In some embodiments, R 3e is C 3-7 a cycloalkoxy.

[0239] In some embodiments, R 3e is C 1-6 a linear haloalkyl.

[0240] In some embodiments, R 3e is C 3-7 branched haloalkyl.

[0241] In some embodiments, R 3e is C 1-6 linear haloalkoxy.

[0242] In some embodiments, R 3e is heterocyclyl.

[0243] In some embodiments, R 3e is -S(C 1-6 linear alkyl).

[0244] In some embodiments, R 3e is -S(C 3-7 branched alkyl).

[0245] In some embodiments, R 3e is -S(C 3-7 cycloalkyl).

[0246] In some embodiments, R 3e is -SO2(C 1-6 linear alkyl).

[0247] In some embodiments, R 3e is -SO2(C 3-7 branched alkyl).

[0248] In some embodiments, R 3e is -SO2(C 3-7 cycloalkyl).

[0249] In some embodiments, R 3e is COR 5 .

[0250] In some embodiments, R 3e is CO2R 6 .

[0251] In some embodiments, R 3e is CONR 7a R 7b .

[0252] In some embodiments, R 3e is SO2NR 7a R 7b .

[0253] In some embodiments, R 3e is NR 8a R 8b .

[0254] In some embodiments, R 3e is NR 8a COR 9 .

[0255] In some embodiments, R 3e is NR 8a SO2R 10 .

[0256] In some embodiments, R 3e is NR 8a SO2NR 11a R 11b .

[0257] In some embodiments, R 4 is hydrogen.

[0258] In some embodiments, R 4 is OH.

[0259] In some embodiments, R 4 is NO2.

[0260] In some embodiments, R 4 is halogen.

[0261] In some embodiments, R 4 is CN.

[0262] In some embodiments, R 4is C 1-6 is a linear alkyl group.

[0263] In some embodiments, R 4 is C 3-7 is a branched alkyl group.

[0264] In some embodiments, R 4 is C 3-7 is a cycloalkyl group.

[0265] In some embodiments, R 4 is C 1-6 is a linear alkoxy group.

[0266] In some embodiments, R 4 is C 3-7 is a branched alkoxy group.

[0267] In some embodiments, R 4 is C 3-7 is a cycloalkoxy group.

[0268] In some embodiments, R 4 is C 1-6 is a linear haloalkyl group.

[0269] In some embodiments, R 4 is C 3-7 is a branched haloalkyl group.

[0270] In some embodiments, R 4 is C 1-6 is a linear haloalkoxy group.

[0271] In some embodiments, R 4 is -S(C 1-6 linear alkyl).

[0272] In some embodiments, R 4 is -S(C 3-7 branched alkyl).

[0273] In some embodiments, R 4is -S(C 3-7 cycloalkyl).

[0274] In some embodiments, R 4 is -SO2(C 1-6 linear alkyl).

[0275] In some embodiments, R 4 is -SO2(C 3-7 branched alkyl).

[0276] In some embodiments, R 4 is -SO2(C 3-7 cycloalkyl).

[0277] In some embodiments, R 4 is COR 5 .

[0278] In some embodiments, R 4 is CO2R 6 .

[0279] In some embodiments, R 4 is CONR 7a R 7b .

[0280] In some embodiments, R 4 is SO2NR 7a R 7b .

[0281] In some embodiments, R 4 is NR 8a R 8b .

[0282] In some embodiments, R 4 is NR 8a COR 9 .

[0283] In some embodiments, R 4 is NR 8a SO2R 10 .

[0284] In some embodiments, R 4 is NR 8a SO2NR 11a R 11b .

[0285] In some embodiments, R 4a is hydrogen.

[0286] In some embodiments, R 4a is OH.

[0287] In some embodiments, R 4a is NO2.

[0288] In some embodiments, R 4a is halogen.

[0289] In some embodiments, R 4a is CN.

[0290] In some embodiments, R 4a is C 1-6 a linear alkyl.

[0291] In some embodiments, R 4a is C 3-7 a branched alkyl.

[0292] In some embodiments, R 4a is C 3-7 a cycloalkyl.

[0293] In some embodiments, R 4a is C 1-6 a linear alkoxy.

[0294] In some embodiments, R 4a is C 3-7 a branched alkoxy.

[0295] In some embodiments, R 4a is C 3-7 a cycloalkoxy.

[0296] In some embodiments, R 4a is C 1-6 a linear haloalkyl.

[0297] In some embodiments, R 4a is C 3-7 a branched haloalkyl.

[0298] In some embodiments, R 4a is C 1-6 a linear haloalkoxy.

[0299] In some embodiments, R 4a is -S(C 1-6 a linear alkyl).

[0300] In some embodiments, R 4a is -S(C 3-7 a branched alkyl).

[0301] In some embodiments, R 4a is -S(C 3-7 a cycloalkyl).

[0302] In some embodiments, R 4a is -SO2(C 1-6 a linear alkyl).

[0303] In some embodiments, R 4a is -SO2(C 3-7 a branched alkyl).

[0304] In some embodiments, R 4a is -SO2(C 3-7 a cycloalkyl).

[0305] In some embodiments, R 4a is COR 5 wherein.

[0306] In some embodiments, R 4a is CO2R 6 wherein.

[0307] In some embodiments, R 4a is CONR 7a R 7b .

[0308] In some embodiments, R 4 is SO2NR 7a R 7b .

[0309] In some embodiments, R 4a is NR 8a R 8b .

[0310] In some embodiments, R 4a is NR 8a COR 9 .

[0311] In some embodiments, R 4a is NR 8a SO2R 10 .

[0312] In some embodiments, R 4a is NR 8a SO2NR 11a R 11b .

[0313] In some embodiments, R 4b is hydrogen.

[0314] In some embodiments, R 4b is OH.

[0315] In some embodiments, R 4b is NO2.

[0316] In some embodiments, R 4b is halogen.

[0317] In some embodiments, R 4b is CN.

[0318] In some embodiments, R 4b is a C 1-6 linear alkyl.

[0319] In some embodiments, R 4b is a C 3-7 branched alkyl.

[0320] In some embodiments, R 4b is a C 3-7 cycloalkyl.

[0321] In some embodiments, R 4b is a C 1-6 linear alkoxy.

[0322] In some embodiments, R 4b is a C 3-7 branched alkoxy.

[0323] In some embodiments, R 4b is a C 3-7 cycloalkoxy.

[0324] In some embodiments, R 4b is a C 1-6 linear haloalkyl.

[0325] In some embodiments, R 4b is a C 3-7 branched haloalkyl.

[0326] In some embodiments, R 4b is a C 1-6 linear haloalkoxy.

[0327] In some embodiments, R 4b is -S(C 1-6 linear alkyl).

[0328] In some embodiments, R 4b is -S(C 3-7 branched alkyl).

[0329] In some embodiments, R 4b is -S(C 3-7 cycloalkyl).

[0330] In some embodiments, R 4b is -SO2(C 1-6 linear alkyl).

[0331] In some embodiments, R 4b is -SO2(C 3-7 branched alkyl).

[0332] In some embodiments, R 4b is -SO2(C 3-7 cycloalkyl).

[0333] In some embodiments, R 4b is COR 5 ).

[0334] In some embodiments, R 4b is CO2R 6 ).

[0335] In some embodiments, R 4b is CONR 7a R 7b ).

[0336] In some embodiments, R 4b is SO2NR 7a R 7b ).

[0337] In some embodiments, R 4b is NR 8a R 8b ).

[0338] In some embodiments, R 4b is NR 8a COR 9 ).

[0339] In some embodiments, R 4b is NR 8a SO2R 10It is.

[0340] In some embodiments, R 4b is NR 8a SO2NR 11a R 11b It is.

[0341] In some embodiments, R 4c is hydrogen.

[0342] In some embodiments, R 4c is OH.

[0343] In some embodiments, R 4c is NO2.

[0344] In some embodiments, R 4c is a halogen.

[0345] In some embodiments, R 4c is CN.

[0346] In some embodiments, R 4c is C 1-6 a linear alkyl.

[0347] In some embodiments, R 4c is C 3-7 a branched alkyl.

[0348] In some embodiments, R 4c is C 3-7 a cycloalkyl.

[0349] In some embodiments, R 4c is C 1-6 a linear alkoxy.

[0350] In some embodiments, R 4c is C 3-7 a branched alkoxy.

[0351] In some embodiments, R 4c is C 3-7It is cycloalkoxy.

[0352] In some embodiments, R 4c is C 1-6 linear haloalkyl.

[0353] In some embodiments, R 4c is C 3-7 branched haloalkyl.

[0354] In some embodiments, R 4c is C 1-6 linear haloalkoxy.

[0355] In some embodiments, R 4c is -S(C 1-6 linear alkyl).

[0356] In some embodiments, R 4c is -S(C 3-7 branched alkyl).

[0357] In some embodiments, R 4c is -S(C 3-7 cycloalkyl).

[0358] In some embodiments, R 4c is -SO2(C 1-6 linear alkyl).

[0359] In some embodiments, R 4c is -SO2(C 3-7 branched alkyl).

[0360] In some embodiments, R 4c is -SO2(C 3-7 cycloalkyl).

[0361] In some embodiments, R 4c is COR 5 wherein.

[0362] In some embodiments, R 4cis CO2R 6 is.

[0363] In some embodiments, R 4c is CONR 7a R 7b is.

[0364] In some embodiments, R 4c is SO2NR 7a R 7b is.

[0365] In some embodiments, R 4c is NR 8a R 8b is.

[0366] In some embodiments, R 4c is NR 8a COR 9 is.

[0367] In some embodiments, R 4c is NR 8a SO2R 10 is.

[0368] In some embodiments, R 4c is NR 8a SO2NR 11a R 11b is.

[0369] In some embodiments, R 4d is hydrogen.

[0370] In some embodiments, R 4d is OH.

[0371] In some embodiments, R 4d is NO2.

[0372] In some embodiments, R 4d is halogen.

[0373] In some embodiments, R 4d is CN.

[0374] In some embodiments, R 4d is C 1-6 a straight-chain alkyl.

[0375] In some embodiments, R 4d is C 3-7 a branched-chain alkyl.

[0376] In some embodiments, R 4d is C 3-7 a cycloalkyl.

[0377] In some embodiments, R 4d is C 1-6 a straight-chain alkoxy.

[0378] In some embodiments, R 4d is C 3-7 a branched-chain alkoxy.

[0379] In some embodiments, R 4d is C 3-7 a cycloalkoxy.

[0380] In some embodiments, R 4d is C 1-6 a straight-chain haloalkyl.

[0381] In some embodiments, R 4d is C 3-7 a branched-chain haloalkyl.

[0382] In some embodiments, R 4d is C 1-6 a straight-chain haloalkoxy.

[0383] In some embodiments, R 4d is -S(C 1-6 a straight-chain alkyl).

[0384] In some embodiments, R 4d is -S(C 3-7 a branched-chain alkyl).

[0385] In some embodiments, R 4d is -S(C 3-7 cycloalkyl).

[0386] In some embodiments, R 4d is -SO2(C 1-6 linear alkyl).

[0387] In some embodiments, R 4d is -SO2(C 3-7 branched alkyl).

[0388] In some embodiments, R 4d is -SO2(C 3-7 cycloalkyl).

[0389] In some embodiments, R 4d is COR 5 .

[0390] In some embodiments, R 4d is CO2R 6 .

[0391] In some embodiments, R 4d is CONR 7a R 7b .

[0392] In some embodiments, R 4d is SO2NR 7a R 7b .

[0393] In some embodiments, R 4d is NR 8a R 8b .

[0394] In some embodiments, R 4d is NR 8a COR 9 .

[0395] In some embodiments, R 4d is NR8a SO2R 10 is as follows.

[0396] In some embodiments, R 4d is NR 8a SO2NR 11a R 11b is as follows.

[0397] In some embodiments, R 5 is hydrogen.

[0398] In some embodiments, R 5 is C 1-6 linear alkyl.

[0399] In some embodiments, R 5 is C 3-7 branched alkyl.

[0400] In some embodiments, R 5 is C 3-7 cycloalkyl.

[0401] In some embodiments, R 6 is C 1-6 linear alkyl.

[0402] In some embodiments, R 6 is C 3-7 branched alkyl.

[0403] In some embodiments, R 6 is C 3-7 cycloalkyl.

[0404] In some embodiments, R 7a is hydrogen.

[0405] In some embodiments, R 7a is C 1-6 linear alkyl.

[0406] In some embodiments, R 7a is C 3-7 branched alkyl.

[0407] In some embodiments, R 7a is C 3-7 cycloalkyl.

[0408] In some embodiments, R 7b is hydrogen.

[0409] In some embodiments, R 7b is C 1-6 linear alkyl.

[0410] In some embodiments, R 7b is C 3-7 branched alkyl.

[0411] In some embodiments, R 7b is C 3-7 cycloalkyl.

[0412] In some embodiments, R 8a is hydrogen.

[0413] In some embodiments, R 8a is C 1-6 linear alkyl.

[0414] In some embodiments, R 8a is C 3-7 branched alkyl.

[0415] In some embodiments, R 8a is C 3-7 cycloalkyl.

[0416] In some embodiments, R 8b is hydrogen.

[0417] In some embodiments, R 8b is C 1-6 linear alkyl.

[0418] In some embodiments, R 8b is C 3-7It is a branched alkyl.

[0419] In some embodiments, R 8b is C 3-7 cycloalkyl.

[0420] In some embodiments, R 8a and R 8b together with the atom to which they are attached have a ring formed by three ring atoms.

[0421] In some embodiments, R 8a and R 8b together with the atom to which they are attached have a ring formed by four ring atoms.

[0422] In some embodiments, R 8a and R 8b together with the atom to which they are attached have a ring formed by five ring atoms.

[0423] In some embodiments, R 8a and R 8b together with the atom to which they are attached form a ring having six ring atoms optionally containing oxygen.

[0424] In some embodiments, R 8a and R 8b together with the atom to which they are attached form a ring having seven ring atoms optionally containing oxygen.

[0425] In some embodiments, R 9 is hydrogen.

[0426] In some embodiments, R 9 is C 1-6 linear alkyl.

[0427] In some embodiments, R 9 is C 3-7 branched alkyl.

[0428] In some embodiments, R 9 is C 3-7 cycloalkyl.

[0429] In some embodiments, R 10 is C 1-6 linear alkyl.

[0430] In some embodiments, R 10 is C 3-7 branched alkyl.

[0431] In some embodiments, R 10 is C 3-7 cycloalkyl.

[0432] In some embodiments, R 11a is hydrogen.

[0433] In some embodiments, R 11a is C 1-6 linear alkyl.

[0434] In some embodiments, R 11a is C 3-7 branched alkyl.

[0435] In some embodiments, R 11a is C 3-7 cycloalkyl.

[0436] In some embodiments, R 11b is hydrogen.

[0437] In some embodiments, R 11b is C 1-6 linear alkyl.

[0438] In some embodiments, R 11b is C 3-7 branched alkyl.

[0439] In some embodiments, R 11b is C 3-7 cycloalkyl.

[0440] Examples of the compounds of the present invention include, but are not limited to, the following compounds or their pharmaceutically acceptable forms: (R)-3,3-Diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3-(2-(5-(2-Isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2-Isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3,3-Diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-2-(5-(2-(4,4-Diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydro pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (S)-2-(5-(2-(4,4-Diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydro pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (R)-3-(5-(2-(4,4-Diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydro pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (S)-3-(5-(2-(4,4-Diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydro pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (R)-4-(5-(2-(4,4-Diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydro pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (S)-4-(5-(2-(4,4-Diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydro pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (R)-3,3-Diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2 (1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one.

[0441] Exemplary embodiments include a compound having the following formula (I) or a pharmaceutically acceptable salt form thereof:

Chemical formula

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

[0442] Exemplary embodiments include compounds having the following formula (VI) or pharmaceutically acceptable salt forms thereof:

Chemical Formula

Table 2-1

Table 2-2

Table 2-3

[0443] Exemplary embodiments include compounds having the following formula (VII) or pharmaceutically acceptable salt forms thereof: :

Chemical Formula

Table 3-1

Table 3-2

Table 3-3

[0444] Exemplary embodiments include compounds having the following formula (VIII) or pharmaceutically acceptable salt forms thereof:

Chemical Formula

Table 4-1

Table 4-2

[0445] Exemplary embodiments include compounds having the following formula (IX) or pharmaceutically acceptable salt forms thereof:

Chemical formula

Table 5-1

Table 5-2

[0446] Exemplary embodiments include compounds having the following formula (II) or pharmaceutically acceptable salt forms thereof:

Chemical formula

Table 6-1

Table 6-2

Table 6-3

Table 6-4

Table 6-5

Table 6-6

[0447] Exemplary embodiments include compounds having the following formula (X) or pharmaceutically acceptable salt forms thereof: :

Chemical formula

Table 7-1

Table 7-2

[0448] Exemplary embodiments include compounds having the following formula (XI) or pharmaceutically acceptable salt forms thereof:

Chemical formula

Table 8-1

Table 8-2

Table 8-3

[0449] Exemplary embodiments include compounds having the following formula (XII) or pharmaceutically acceptable salt forms thereof:

Chemical formula

Table 9-1

Table 9-2

Table 9-3

[0450] Exemplary embodiments include compounds having the following formula (XIII) or pharmaceutically acceptable salt forms thereof:

Chemical formula

Table 10-1

Table 10-2

[0451] For the purpose of showing the manner in which the compounds of the present invention are named and referred to herein, a compound having the following formula:

Chemical formula

[0452] In the present invention, for example, a compound represented by the following racemic formula

Chemical formula

Chemical formula

Chemical formula

[0453] In all of the embodiments provided herein, examples of any suitable substituents are not intended to limit the claims. The compounds of the present invention may include any of the substituents provided herein or combinations of substituents. Process for preparing a 5-hydroxytryptamine receptor 7 activity regulator of the present invention

[0454] The present invention further relates to a process for preparing a 5-hydroxytryptamine receptor 7 activity regulator of the present invention for.

[0455] The compounds of the present disclosure can be prepared from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, following the procedures outlined herein, using standard synthetic methods and procedures known to those of ordinary skill in the art. Standard synthetic methods and procedures for the preparation of organic molecules and for the conversion and manipulation of functional groups can be readily obtained from the relevant scientific literature or from standard textbooks in the field. Of course, other process conditions can be used as well, unless otherwise stated, even when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. The optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those of ordinary skill in the art using routine optimization procedures. Those of ordinary skill in the field of organic synthesis will recognize that they can vary the nature and order of the presented synthetic steps for the purpose of optimizing the formation of the compounds described herein.

[0456] The processes described herein can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic methods such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, etc., or by chromatography such as high performance liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin layer chromatography (TLC).

[0457] The preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemical properties of protecting groups are described, for example, in Greene et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference for all purposes.

[0458] The reactions or processes described herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents typically do not substantially react with the reactants, intermediates, and / or products at the temperature at which the reaction is carried out, i.e., in the range of temperatures from the freezing temperature to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or in a mixture of two or more solvents. Depending on the particular reaction step, a solvent suitable for the particular reaction step can be selected.

[0459] The compounds of these teachings can be prepared by methods known in the art of organic chemistry. The reagents used to prepare the compounds of these teachings are commercially available or can be prepared by standard procedures described in the literature. For example, the compounds of the present invention can be prepared according to the methods illustrated in the general synthetic scheme: General synthetic scheme for the preparation of compounds

[0460] The reagents used in the preparation of the compounds of the present invention are commercially available or can be prepared by standard procedures described in the literature. According to the present invention, the compounds of this classification can be produced by one of the following reaction schemes.

[0461] The compounds of the present disclosure can be prepared according to any of the processes outlined in Schemes 1-5 below.

Chemical formula

[0462] Therefore, the appropriately substituted compound (1) is a known compound or a compound prepared by a known method, and a compound of formula (2) which is a compound prepared by a known compound or a known method, for example, palladium acetate, palladium bis(triphenylphosphine) dichloride, palladium tetrakis(triphenylphosphine), bis(acetonitrile) dichloropalladium [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dium, tris(dibenzylideneacetone) dipalladium(0) and other palladium catalysts in the presence of, for example, potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide and other bases, optionally in the presence of organic bases such as triethylamine, diisopropylethylamine, pyridine, etc., optionally in the presence of bis(diphenylphosphino) derivative compounds such as 2,2'-bis (diphenylphosphino)-1,1'-binaphthalene, 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl, 1,1'-binaphthalene-2,2'-diyl)bis[bis(3,5-dimethylphenyl )phosphine], 5,5'-bis[di(3,5-xylyl)phosphino]-4,4'-bi-1,3-benzodioxole, 5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole )phosphine], 5,5'-bis[di(3,5-xylyl)phosphino]-4,4'-bi-1,3-benzodioxole, 5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole and other bis(diphenylphosphino) derivative compounds Below, in a solvent such as toluene, benzene, xylene, 1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., react while optionally heating and optionally irradiating with microwaves to obtain the compound of formula (3). The compound of formula (3) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. in the presence of an organic solvent such as methylene chloride, dichloroethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, etc. optionally to obtain the compound of formula (4). Obtain. [Chemical formula]

[0463] The appropriately substituted compound (5) is a known compound or a compound prepared by a known method, and the compound of formula (6) which is a compound prepared by a known compound or a known method, in the presence of a palladium catalyst such as palladium acetate, palladium bis(triphenylphosphine) dichloride, palladium tetrakis(triphenylphosphine), bis(acetonitrile) dichloropalladium [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium, tris(dibenzylideneacetone) dipalladium(0), etc., for example, in the presence of a base such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, etc., optionally in the presence of an organic base such as triethylamine, diisopropylethylamine, pyridine, etc., optionally such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl, 1,1'-binaphthalene-2,2'-diyl)bis[bis(3,5-dimethylphenyl)phosphine] compound, and in the presence of a palladium catalyst such as palladium acetate, palladium bis(triphenylphosphine) dichloride, palladium tetrakis(triphenylphosphine), bis(acetonitrile) dichloropalladium [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium, tris(dibenzylideneacetone) dipalladium(0), etc., for example, in the presence of a base such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, etc., optionally in the presence of an organic base such as triethylamine, diisopropylethylamine, pyridine, etc., optionally such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl, 1,1'-binaphthalene-2,2'-diyl)bis[bis(3,5-dimethylphenyl)phosphine] such as in the presence of a palladium catalyst such as palladium acetate, palladium bis(triphenylphosphine) dichloride, palladium tetrakis(triphenylphosphine), bis(acetonitrile) dichloropalladium [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium, tris(dibenzylideneacetone) dipalladium(0), etc., for example, in the presence of a base such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, etc., optionally in the presence of an organic base such as triethylamine, diisopropylethylamine, pyridine, etc., optionally such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl, 1,1'-binaphthalene-2,2'-diyl)bis[bis(3,5-dimethylphenyl)phosphine] such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, etc., optionally in the presence of an organic base such as triethylamine, diisopropylethylamine, pyridine, etc., optionally such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl, 1,1'-binaphthalene-2,2'-diyl)bis[bis(3,5-dimethylphenyl)phosphine] phosphino)-1,1'-binaphthalene, 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl, 1,1'-binaphthalene-2,2'-diyl)bis[bis(3,5-dimethylphenyl)phosphine] , 5,5'-bis[di(3,5-xylyl)phosphino]-4,4'-bi-1,3-benzodioxole, 5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3- In the presence of a bis(diphenylphosphino) derivative compound such as , in a solvent such as toluene, benzene, xylene, 1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., the reaction is carried out optionally with heating and optionally with microwave irradiation to obtain the compound of formula (7). The compound of formula (7) is reacted with hydrogen in a solvent such as methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, etc. in the presence of a palladium catalyst such as palladium on carbon, palladium on celite, palladium barium sulfate, palladium acetate, palladium bis(triphenylphosphine) dichloride, palladium tetrakis(triphenylphosphine), etc. to obtain the compound of formula (8).

Chemical formula

[0464] The properly substituted compound of formula (9) is a known compound or a compound prepared by a known method, wherein X is, for example, chlorine, bromine, iodine, mesylate, tosylate, etc. ​The compound of formula (10) as a leaving group is reacted in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, etc. in the presence of a base such as lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, etc. to obtain the compound of formula (11). Next, the compound of formula (11) is treated with paraformaldehyde in an organic solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, etc. optionally in the presence of an acid such as sulfuric acid, hydrochloric acid, etc. and optionally in the presence of acetic acid, optionally with heating and optionally with microwave irradiation to obtain the compound of formula (12). Next, the compound of formula (12) is treated with a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. in a solvent such as water, methanol, ethanol, isopropanol, etc. optionally with heating, and then treated with an acid such as sulfuric acid, hydrochloric acid, etc. in a solvent such as water, methanol, ethanol, isopropanol, etc. to obtain the compound of formula (13). Subsequently, the compound of formula (13) is converted to the compound of formula (14) using a method known to those skilled in the art. In the formula, LG is a leaving group such as mesylate, tosylate, nosylate, bromine, etc. Therefore, the compound of formula (13) is treated with a sulfonyl chloride such as methanesulfonyl chloride, toluenesulfonyl chloride, p-nitrophenylsulfonyl chloride, etc. in an organic solvent such as methylene chloride, dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, etc. in the presence of a base such as triethylamine, diisopropylamine, pyridine, 2,6-lutidine, etc. to obtain the compound of formula (14). Alternatively, the compound of formula (13) is treated in the presence of triphenylphosphine in an organic solvent such as methylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, In a solvent such as tetrahydrofuran or 1,4-dioxane, while optionally heating and optionally irradiating with microwaves, treat with carbon tetrabromide to obtain the compound of formula (14).

[0465] The compound of formula (14) is reacted in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, etc., optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, etc., optionally while irradiating with microwaves and optionally heating, with a compound of formula (15) which is a known compound or a compound prepared by a known method, to obtain the compound of formula (16).

Chemical formula

[0466] The appropriately substituted compound of formula (17) is a known compound or a compound prepared by a known method, wherein X is a leaving group such as chlorine, bromine, iodine, mesylate, tosylate, etc. of formula (18), and, for example, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, n-butyllithium, sec-butyllithium, tert-butyllithium ​In the presence of a base such as a mu, the reaction is carried out in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, etc. to obtain a compound of formula (19). Next, the compound of formula (19) is treated with paraformaldehyde in an organic solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, etc. in the presence of an acid such as sulfuric acid or hydrochloric acid and in the presence of acetic acid, optionally with heating and optionally with microwave irradiation, to obtain a compound of formula (20). Next, the compound of formula (20) is treated with a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. in a solvent such as water, methanol, ethanol, isopropanol, etc., optionally with heating, and then treated with an acid such as sulfuric acid, hydrochloric acid, etc. in a solvent such as water, methanol, ethanol, isopropanol, etc., optionally with heating, to obtain a compound of formula (21). Subsequently, the compound of formula (21) is converted to a compound of formula (22) using a method known to those skilled in the art. In the formula, LG is a leaving group such as mesylate, tosylate, nosylate, bromine, etc. Therefore, the compound of formula (21) is treated with a sulfonyl chloride such as methanesulfonyl chloride, toluenesulfonyl chloride, p-nitrophenylsulfonyl chloride, etc. in an organic solvent such as methylene chloride, dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, etc. in the presence of a base such as triethylamine, diisopropylamine, pyridine, 2,6-lutidine, etc. to obtain a compound of formula (22). Alternatively, the compound of formula (21) is treated with carbon tetrabromide in a solvent such as methylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, etc. in the presence of triphenylphosphine, optionally with heating and optionally with microwave irradiation, to obtain a compound of formula (22). Of formula (22) The compound is reacted, in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, etc., optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, etc., and optionally using microwave irradiation, while optionally heating, with a compound of formula (23) which is a known compound or a compound prepared by a known method, to obtain a compound of formula (24).

Chemical formula

[0467] The compound of formula (25) is reacted, in the presence of a solvent such as methanol, ethanol, isopropanol, water, etc., with a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, etc., while optionally heating and optionally with microwave irradiation, to obtain a compound of formula (26). Then, the compound of formula (26) is reacted with iodine in the presence of a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate, sodium carbonate, potassium carbonate, lithium hydrogen carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., and in the presence of a solvent such as tetrahydrofuran, ethyl ether, 1,4-dioxane, etc., to obtain a compound of formula (27). The compound of formula (27) is reacted, in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, etc., optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, etc., and optionally using microwave irradiation, while optionally heating but not, with a compound of formula (28) which is a known compound or a compound prepared by a known method, to obtain a compound of formula (29).

Chemical formula

[0468] ​The compound of formula (30) is reacted with ruthenium chloride in the presence of sodium periodate in a solvent such as acetonitrile, methanol, ethanol, isopropanol, etc. to obtain the compound of formula (31). The compound of formula (31) is reacted with the compound of formula (32), which is a known compound or a compound prepared by a known method, in the presence of a solvent such as ethyl ether, tetrahydrofuran, 1,4-dioxane, etc. to obtain the compound of formula (33). The compound of formula (33) is reacted with ruthenium chloride in the presence of sodium periodate in a solvent such as acetonitrile, methanol, ethanol, isopropanol, etc. to obtain the compound of formula (34). The compound of formula (34) is reacted with a reducing agent such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, etc. in a solvent such as methanol, ethanol, isopropanol, acetonitrile, etc. to obtain the compound of formula (35). Subsequently, the formula The compound of formula (35) is converted to the compound of formula (36) using methods known to those skilled in the art. In the formula, LG is a leaving group such as mesylate, tosylate, nosylate, bromine, etc. Thus, the compound of formula (35) is treated with a sulfonyl chloride such as methanesulfonyl chloride, toluenesulfonyl chloride, p-nitrophenylsulfonyl chloride, etc. in an organic solvent such as methylene chloride, dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, etc. in the presence of a base such as triethylamine, diisopropylamine, pyridine, 2,6-lutidine, etc. to obtain the compound of formula (36). Alternatively, the compound of formula (35) is treated with carbon tetrabromide in a solvent such as methylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, etc. in the presence of triphenylphosphine, optionally with heating, optionally with microwave irradiation, to obtain the compound of formula (36). The compound of formula (36) is reacted with a compound of formula (37), which is a known compound or a compound prepared by a known method, in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, etc., optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, etc., optionally with microwave irradiation, optionally with heating, to obtain the compound of formula (38). The compound of formula (38) is obtained by reacting it with a compound of formula (37), which is a known compound or a compound prepared by a known method, in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, etc., optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, etc., optionally with microwave irradiation, optionally with heating.

[0469] The examples provided below offer representative methods for preparing exemplary compounds of the present invention. Those skilled in the art will know how to alternatively use appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds of the present invention.

Examples

[0470] The implementation of the present invention is shown by the following non-limiting examples. The examples provided below offer representative methods for preparing exemplary compounds of the present invention. Those skilled in the art will know how to alternatively use appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds of the present invention.

[0471] In the following examples, 1 The 1H-NMR spectra were obtained on a Varian Mercury 300-MHz NMR. Purity (%) and mass spectral data were measured by a Waters Alliance 2695 HPLC / MS (Waters Symmetry C18, 4.6×75 mm, 3.5 μm) equipped with a 2996 diode array detector from 210 nm to 400 nm. The spectral data were measured.

[0472] In the following examples, 1 The 1H-NMR spectra were obtained on a Varian Mercury 300-MHz NMR. Purity (%) and mass spectral data were measured by a Waters Alliance 2695 HPLC / MS (Waters Symmetry C18, 4.6×75 mm, 3.5 μm) equipped with a 2996 diode array detector from 210 nm to 400 nm. The spectral data were measured. [Chemical formula]

[0473] Example 1: Preparation of methyl 2,2-dimethylpent-4-enoate: This reaction was carried out under a nitrogen atmosphere It was carried out in an oven-dried glass product. Methyl isobutyrate (3.32 g, 32.6 mmol, 1.0 equivalent) was added dropwise to a stirred solution of freshly prepared lithium diisopropylamide (1 M, 1.10 equivalents) in 35 ml of anhydrous tetrahydrofuran at -78 °C over 0.5 h. The mixture was stirred at this temperature for 30 min, then allyl bromide (5.35 g, 44.0 mmol) and hexamethyl phosphoramide (HMPA) (2.91 g, 16.3 mmol) were added dropwise over 0.5 h. The reaction mi xture was stirred at room temperature overnight and quenched with 10% HCl (while cooling in an ice bath) until acidic (pH = 2). The organic layer was separated and the aqueous layer was extracted with hexane (3 × 100 mL). The extract was washed with 10% NaHCO3 (200 mL) and brine (200 mL). The solution was then dried over MgSO4, concentrated in vacuo, and distilled to obtain the pure product. 1 1H NMR (400 MHz, CDCl3) δ 5.73 (dd, J = 9.4, 17.7, 1H), 5.04 (dd, J = 1.9, 13.5, 2H), 4.12 (q, J = 7.1, 2H), 2.28 (d, J = 7.4, 2H), 1.25 (t, J = 7.1, 3H), 1.17 (s, 6H); 13 13C NMR (101 MHz, CDCl3) δ 177.42, 134.42, 117.88, 77.68, 77.36, 77.04, 60.35, 44.91, 42.25, 24.92, 14.35

[0474] The following compounds can be prepared by the procedure of methyl 2,2-dimethylpent-4-enoate. One of ordinary skill in the art would know how to substitute appropriate reagents, starting materials, and purification methods known to those of ordinary skill in the art to prepare the compounds presented herein.

Chemical formula

[0475] ​ Example 2: Preparation of ethyl 2,2 - diethylpent - 4 - enoate: The title compound was prepared according to the procedure for methyl 2,2 - dimethylpent - 4 - enoate. However, ethyl 2 - ethyl - butyrate and methyl isobutyrate were replaced. with ethyl 2 - ethyl - butyrate and methyl isobutyrate replaced. 1 H NMR (300 MHz, CDCl3) δ 5.68 (dd, J = 9.9, 17.2, 1H), 5.16 - 4.97 (m, 2H), 4.14 (q, J = 7.1, 2H), 2.33 (d, J = 7.4, 2H), 1.59 (dt, J = 6.5, 7.5, 5H), 1.26 (t, J = 7.1, 3H), 0.80 (t, J = 7.5, 6H)

Chemical Structure

[0476] Example 3: Preparation of 1 - allylcyclobutanecarboxylic acid: This reaction was carried out in an oven - dried glassware under a nitrogen atmosphere. To a well - stirred solution of freshly prepared lithium diisopropylamide (1M, 10.76 mmol, 2.30 equivalents) in 107 ml of anhydrous tetrahydrofuran, cyclobutanecarboxylic acid (4.68 g, 46.8 mmol, 1.0 equivalent) was added dropwise at 0 °C for 0.5 h. The mixture was heated to 50 °C for 6 h, then cooled to 0 °C, and then NaI (0.697 g, 4.68 mmol, 0.1 equivalent) was added in one portion, and a mixture of allyl bromide (7.58 g, 63.2 mmol, 1.35 equivalents) and HMPA (4.18 g, 23.4 mmol, 0.5 equivalent) was added dropwise over 0.5 h. The reaction mixture was stirred at room temperature overnight and quenched with 10% HCl (while cooling in an ice bath) until acidic (pH = 2). The organic layer was separated, and the aqueous layer was extracted with ether (3 × 250 mL). The organic layers were combined, washed with brine. Then the solution was dried over MgSO4 and concentrated in vacuo to obtain a crude oil, which was then purified by flash chromatography (eluent: hexane / ethyl acetate = 50 / 1 to 20 / 1). The pure product was obtained as a colorless liquid. Purified through flash chromatography (silica; ethyl acetate / hexane, 1% - 10%) Performed. 1 H NMR (400 MHz, CDCl3) δ 5.77 (ddt, J = 7.1, 10.2, 17.2, 1H), 5.17 - 4.99 (m, 2H), 2.59 - 2.38 (m, 4H), 2.07 - 1.84 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 184.04, 133.90, 118.19, 47.20, 41.74, 29.57, 15.65; Rf, 0.43 (hexane:ethyl acetate 10:1); HRMS (CI): [M+H], C8H 13 Calculated value of O2 141.0916; Measured value 141.0911.

[0477] The following compounds can be prepared by the procedure of 1 - allylcyclobutanecarboxylic acid. Those skilled in the art will know how to alternatively use appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein. Would know.

Chemical formula

[0478] Example 4: Preparation of 1 - allylcyclopentanecarboxylic acid: The title compound was prepared according to the procedure of 1 - allylcyclobutanecarboxylic acid, except that cyclopentanecarboxylic acid and cyclobutanecarboxylic acid were replaced. 1 H NMR (400 MHz, CDCl3) δ 5.77 (ddt, J = 7.2, 10.2, 17.4, 1H), 5.17 - 4.94 (m, 2H), 2.38 (d, J = 7.2, 2H), 2.20 - 2.02 (m, 2H), 1.79 - 1.47 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 184.94, 134.96, 118.02, 53.75, 42.96, 35.89, 25.47. Rf, 0.50 (hexane: ethyl acetate 10:1); HRMS (CI): [M+H], C9H 15 Calculated value of O2 155.1072; measured value 155.1068. [Chemical formula]

[0479] Example 5: Preparation of 1-allylcyclohexanecarboxylic acid: The title compound was prepared according to the procedure of 1-allylcyclobutanecarboxylic acid, except that cyclohexanecarboxylic acid and cyclobutanecarboxylic acid were replaced. 1 1H NMR (400 MHz, CDCl3) δ 12.13 (broad band, 1H), 5.83 - 5.63 (m, 1H), 5.12 - 5.00 (m, 2H), 2.27 (m, 2H), 2.04 (m, 2H), 1.66 - 1.50 (m, 3H), 1.49 - 1.33 (m, 2H), 1.33 - 1.17 (m, 3H). [Chemical formula]

[0480] Example 6: Preparation of 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: A mixture of glacial acetic acid (28.6 g, 477 mmol, 53.6 equivalents), paraformaldehyde (0.80 g, 26.7 mmol, 3.0 equivalents) and H2SO4 (0.5 g, 4.45 mmol, 0.57 equivalents) was stirred at 70 °C for 30 minutes, then 2,2- Methyl dimethylpent-4-enoate (1.26 g, 8.9 mmol, 1.0 eq) was added dropwise over 10 minutes. Then, the reaction mixture was maintained at 70 - 80 °C and stirred overnight. Acetic acid was removed under reduced pressure, and the reaction was quenched with 10% NaHCO3 solution. Subsequently, the mixture was extracted with ethyl acetate (3 × 50 mL), and the combined organic layers were concentrated under vacuum to obtain a crude oil. The crude oil was used in the next step without further purification.

[0481] A mixture of the crude oil (200 mg, 1.0 mmol, 1 eq) and an aqueous solution of 30% NaOH (800 mg NaOH, 20 mmol, 20 eq) was refluxed for 2 hours. The mixture was cooled in an ice bath, and excess 30% H2SO4 was added until acidic (pH < 2 ). The resulting mixture was extracted with ethyl acetate (3 x 25 mL), and the combined organic layers were washed with 10% NaHCO3 (50 mL), brine (50 mL), dried over MgSO4, and concentrated in vacuo to obtain a crude product, which was further purified by column chromatography (ethyl acetate / hexane, 10% - 60%). 1 1H NMR (400 MHz, CDCl3) δ 4.70 - 4.60 (m, 1H), 3.90 - 3.78 (m, 2H), 2.22 (dd, J = 5.9, 12.7, 1H), 1.98 - 1.87 (m, 2H), 1.80 (dd, J = 5.9, 12.7, 1H), 1.28 (d, J = 4.8, 6H). 13 13C NMR (101 MHz, CDCl3) δ 182.26, 75.01, 59.58, 43.93, 40.62, 38.69, 25.31, 24.61; Rf, 0.34 (hexane:ethyl acetate 1:1); Anal. Calcd for C8H 14 O3: C, 60.74; H, 8.92; Found: C, 60.47; H, 8.86.

[0482] The following compound is of 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one It can be prepared by the procedure. A person skilled in the art will know how to alternatively use appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein.

Chemical Structure

[0483] Example 7: Preparation of 3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one: Ethyl 2,2-diethylpenta-4-enoate was used instead of methyl 2,2-dimethylpenta-4-enoate Except for this replacement, following the procedure of 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one the title compound was prepared: 1 H NMR (400 MHz, CDCl3) δ 4.62 (dtd, J = 5.3, 7.3, 9.5, 1H), 3.78 (t, J = 6.1, 2H), 3.20 (s, 1H), 2.19 (dd, J = 6.8, 13.1, 1H), 1.97 - 1.81 (m, 3H), 1.70 - 1.56 (m, 4H), 0.93 (dt, J = 7.5, 20.7, 6H); 13 C NMR (101 MHz, CDCl3) δ 181.46, 75.10, 58.91, 48.77, 39.13, 37.76, 29.21, 28.30, 8.83, 8.73; Rf, 0.36 ( hexane:ethyl acetate 5:2); Analytical. C 10 H 18 Calculated values for C

Chemical Structure

[0484] Example 8: Preparation of 7-(2-hydroxyethyl)-6-oxaspiro[3.4]octan-5-one: Except for replacing 1-allylcyclobutanecarboxylic acid and methyl 2,2-dimethylpent-4-enoate, the title compound was prepared in accordance with the procedure for 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: H NMR (400 MHz, CDCl3) δ 4.60 - 4.50 (m, 1H), 3.82 (t, J = 5.9, 2H), 2.61 - 2.40 (m, 3H), 2.19 - 1.96 (m, 5H). 1.92 - 1.85 (m, 2H); C NMR (101 MHz, CDCl3) δ 181.25, 75.46, 59.66, 44.62, 42.42, 38.47, 31.95, 29.64, 16.79; Rf, 0.40 (hexane:ethyl acetate 1 1:2); Calculated value for C9H 13 O3 is 171.1021; Found 171.1016. 1:2); C9H 15 O3's calculated value is 171.1021; Measured value is 171.1016.

Chemical formula

[0485] Example 9: Preparation of 3-(2-hydroxyethyl)-2-oxaspiro[4.4]nonan-1-one: Except for replacing 1-allylcyclopentanecarboxylic acid and methyl 2,2-dimethylpent-4-enoate, the title compound was prepared in accordance with the procedure for 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: H NMR (400 MHz, CDCl3) δ 4.65 - 4.56 (m, 1H), 3.84 - 3.76 (m, 2H), 2.74 (s, 1H), 2.28 (dd, J = 5.8, 12.6, 1H), 2.20 - 2.10 (m, 1H), 2.00 - 1.56 (m, 10H); C NMR (101 MHz, CDCl3) 1 H NMR (400 MHz, CDCl3) δ 4.65 - 4.56 (m, 1H), 3.84 - 3.76 (m, 2H), 2.74 (s, 1H), 2.28 (dd, J = 5.8, 12.6, 1H), 2.20 - 2.10 (m, 1H), 2.00 - 1.56 (m, 10H); 13 C NMR (101 MHz, CDCl3) δ 183.02, 75.77, 59.20, 50.35, 43.41, 38.41, 37.49, 36.93, 25.67, 25.58; Rf, 0.46 (hexane:ethyl acetate 1:2); HRMS (CI): [M+H], C 10 H 17 Calculated value of O3 185.1178; measured value 185.1171.

Chem.

[0486] Example 10: Preparation of 3-(2-hydroxyethyl)-2-oxaspiro[4.5]decan-1-one: Except that 1-allylcyclohexanecarboxylic acid and methyl 2,2-dimethylpenta-4-enoate were replaced, according to the procedure for 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one, the title compound was prepared: 1 H NMR (400 MHz, CDCl3) δ 4.62 (m, 1H), 3.82 (t, J = 5.9, 2H), 2.43 (dd, J = 6.2, 12.9, 1H), 2.22 (s, 1H), 2.00 - 1.17 (m, 13H). 13 C NMR (101 MHz, CDCl3) δ 181.96, 75.37, 59.55, 45.13, 39.88, 38.91, 34.54, 31.71, 25.57, 22.42, 22.36; Rf, 0.46 (hexane:ethyl acetate 1:2); Analytical. C 11 H 18 Calculated value of O3: C, 66.64; H, 9.15; Measured value: C, 66.48; H, 9.17.

Chem.

[0487] Example 11: Preparation of 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate: 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one To a stirred solution of (0.316 g, 2 mmol, 1.0 eq) of 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one and Et3N (0.152 g, 1.5 mmol, 1.5 eq) in anhydrous dichloromethane, a solution of p-TosCl (0.475 g, 2.5 mmol, 1.25 eq) in dichloromethane was added dropwise at 0 °C The resulting mixture was stirred at 0 °C for 1 h and then stirred overnight at room temperature. The reaction mixture was then diluted with dichloromethane (50 mL), washed with 10% HCl, brine, dried over MgSO4 and concentrated in vacuo to give a yellowish oil. The crude product was then purified by flash chromatography (silica gel; ethyl acetate / hexane, 0% - 40%) to give the desired tosylate. 1 1H NMR (300 MHz, CDCl3) δ 7.72 (m, 2H), 7.29 (m, 2H), 4.39 (m, 1H), 4.10 (m, 2H), 2.38 (s, 3H), 2.09 (m, 1H), 1.93 (m, 2H), 1.65 (m, 1H), 1.16 (d, J = 4.8, 6H); 13 13C NMR (101 MHz, CDCl3) 13 13C NMR (101 MHz, CDCl3) δ 181.26, 145.16, 132.53, 130.03, 127.84, 77.68, 77.36, 77.04, 72.93, 66.83, 42.99, 40.23, 34.97, 24.82, 24.12, 21.57; HRMS (CI): [M+H] 313.1; Anal. Calcd for C 15 H 20 O5S: C, 57.67; H, 6.45; Found: C, 57.85; H, 6.63.

[0488] The following compounds can be prepared by the procedure of 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate. Those skilled in the art will know how to alternatively use appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein. [Chemical formula]

[0489] Example 12: Preparation of 2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate: The title compound was prepared according to the procedure of 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate, except that 3,3-diethyl-5-(2-hydroxyethyl)dihydro furan-2(3H)-one and 5-(2-hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one were replaced. 1 H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.55 - 4.33 (m, 1H), 4.14 (dd, J = 6.5, 13.3 Hz, 3H), 2.46 (s, 3H), 2.21 - 1.84 (m, 3H), 1.83 - 1.68 (m, 1H), 1.58 (t, J = 7.4 Hz, 4H), 0.89 (dt, J = 7.5, 18.0 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 180.33, 145.30, 132.72, 130.15, 128.03, 77.68, 77.36, 77.04, 73.18, 66.95, 48.67, 37.53, 35.82, 29.14, 28.23, 21.76, 8.81, 8.74. Analytical. C 17 H 24Calculated values for O5S: C, 59.98; H, 7.11; Measured values: C, 60.27; H, 7.25.

Chem.

[0490] Example 13: Preparation of 2-(5-oxo-6-oxaspiro[3.4]octan-7-yl)ethyl 4-methylbenzenesulfonate: The title compound was prepared according to the procedure for 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate, except that 7-(2-hydroxyethyl)-6-oxaspiro [3.4]octan-5-one and 5-(2-hydroxyethyl)-3,3-dimethyl-dihydro-furan-2-one were used instead. 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.37 (tdd, J = 8.8, 6.0, 4.3 Hz, 1H), 4.21 - 4.05 (m, 2H), 2.57 - 2.32 (m, 6H), 2.19 - 1.82 (m, 7H); 13 C NMR (101 MHz, CDCl3) δ 180.41, 145.24, 132.68, 130.10, 128.02, 73.38, 66.76, 44.33, 41.79, 35.10, 31.72, 29.28, 21.76, 16.51.

Chem.

[0491] Example 14: Preparation of 2-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)ethyl 4-methylbenzenesulfonate: The title compound was prepared according to the procedure of 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate, except that 3-(2-hydroxyethyl)-2-oxaspiro[4.4]nonan-1-one and 5-(2-hydroxyethyl)-3,3-dimethyl-dihydro-furan-2-one were replaced. It was prepared according to the procedure of 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate, except for the replaced points. 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.51 - 4.35 (m, 1H), 4.25 - 4.06 (m, 2H), 2.45 (s, 3H), 2.28 - 2.08 (m, 2H), 2.08 - 1.91 (m, 2H), 1.87 - 1.52 (m, 9H); 13 C NMR (101 MHz, CDCl3) δ 181.90, 145.26, 132.76, 130.12, 128.07, 73.71, 66.85, 50.19, 43.07, 37.44, 36.81, 35.19, 25.61, 25.50, 21.79.

Chemical formula

[0492] Example 15: Preparation of 2-(1-oxo-2-oxaspiro[4.5]decane-3-yl)ethyl 4-methylbenzenesulfonate: The title compound was prepared according to the procedure of 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate, except that 3-(2-hydroxyethyl)-2-oxaspiro[4.5]decane-1-one and 5-(2-hydroxyethyl)-3,3-dimethyl-dihydro-furan-2-one were replaced. It was prepared according to the procedure of 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate, except for the replaced points. 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.51 - 4.38 (m, 1H), 4.26 - 4.12 (m, 2H), 2.45 (s, 3H), 2.36 (dd, J = 12.9, 6.2 Hz, 1H), 2.12 - 1.87 (m, 2H), 1.85 - 1.68 (m, 3H), 1.65 - 1.50 (m, 5H), 1.43 - 1.14 (m, 3H); 13 C NMR (101 MHz, CDCl3) δ 180.97, 145.2 7, 132.76, 130.12, 128.07, 73.28, 66.85, 44.96, 39.48, 35.58, 34.35, 31.52, 25.37, 22.23, 22.16, 21.80.

Chem.

[0493] Example 16: Preparation of 2,2 - diethylpenta - 4 - enoic acid: Ethyl 2,2 - diethylpenta - 4 - enoate (0.2 g, 0.28 mmol) was mixed with NaOH (0.4 g, 10 mmol), MeOH (2.5 mL) and H2O (2.5 mL) in a microwave vial. Then the mixture was heated in a microwave reactor at 160 °C for 2 hours. Then the mixture was acidified with 10% HCl and washed with ether (3 x 30 ml). The combined organic phases were dried over MgSO4 and concentrated under vacuum to obtain the crude product, which was used in the next step without further purification.

Chem.

[0494] Example 17: Preparation of 3,3 - diethyl - 5 - (iodomethyl)dihydrofuran - 2(3H) - one: 2,2 - di Ethyl penta-4-enoate (1.77 g, 11.67 mmol) was stirred with tetrahydrofuran (34 mL), ether (12 mL), and saturated NaHCO3 solution (57 mL). The mixture was shielded from light. I2 was dissolved in 12 mL of tetrahydro rofuran and added to the mixture all at once at 0 °C. The mixture was stirred at room temperature overnight. Sat urated sodium thiosulfate was added to the mixture to quench the reaction. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by flash chromatography (silica gel; ethyl acetate / hexane, 0% - 25%). 1 1H NMR (400 MHz, CDCl3) δ 4.42 (dtd, J = 9.0, 7.3, 4.6 Hz, 1H), 3.41 (dd, J = 10.2, 4.6 Hz, 1H), 3.23 (dd, J = 10.2, 7.5 Hz, 1H), 2.25 (dd, J = 13.3, 6.9 Hz, 1H), 1.86 (dd, J = 13.3, 9.1 Hz, 1H), 1.63 (m, 4H), 0.94 (dt, J = 10.4, 7.5 Hz, 6H). MS (LC / MS, M+H + ): 283.0

[0495] The following compounds can be prepared according to the procedure of 3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one. Those skilled in the art will know how to alternatively use appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein.

Chemical formula

[0496] Example 18: Preparation of 3-(iodomethyl)-2-oxaspiro[4.4]nonan-1-one: The title compound It was prepared according to the procedure of 3,3 - diethyl - 5-(iodomethyl)dihydrofuran - 2(3H)-one, except that 1 - allylcyclopentanecarboxylic acid and 2,2 - diethylpent - 4 - enoic acid were replaced. Except for this point, it was prepared according to the procedure of 3,3 - diethyl - 5-(iodomethyl)dihydrofuran - 2(3H)-one. 1 H NMR (400 MHz, CDCl3) δ 4.48 - 4.34 (m, 1H), 3.39 (dd, J = 10.2, 4.9 Hz, 1H), 3.23 (dd, J = 10.2, 7.5 Hz, 1H), 2.35 (dd, J = 12.9, 6.1 Hz, 1H), 2.20 - 2.04 (m, 1H), 1.93 - 1.54 (m, 8H); 13 C NMR (101 MHz, CDCl3) δ 181.57, 75.96, 50.71, 43.44, 37.84, 36 .89, 25.45, 25.36, 7.02; MS (LC / MS, M+H + ): 281.0

Chemical Structure

[0497] Example 19: Preparation of 3-(iodomethyl)-2 - oxaspiro[4.5]decan - 1 - one: The title compound It was prepared according to the procedure of 3,3 - diethyl - 5-(iodomethyl)dihydrofuran - 2(3H)-one, except that 1 - allylcyclohexanecarboxylic acid and 2,2 - diethylpent - 4 - enoic acid were replaced. Except for this point, it was prepared according to the procedure of 3,3 - diethyl - 5-(iodomethyl)dihydrofuran - 2(3H)-one. 1 H NMR (400 MHz, CDCl3) δ 4.42 (dtd, J = 9.2, 6.9, 4.6 Hz, 1H), 3.41 (dd, J = 10.3, 4.6 Hz, 1H), 3.26 (dd, J = 10.2, 7.3 Hz, 1H), 2.50 (dd, J = 13.1, 6.5 Hz, 1H), 1.85 - 1.49 (m, 8H), 1.44 - 1.20 (m, 3H); MS (LC / MS, M+H+ ): 295.0

Chem.

[0498] Example 20: Preparation of 3-Hydroxy-2-oxaspiro[4.4]nonan-1-one: 1-Allylcyclo Pentanecarboxylic acid (10.93 g, 71 mmol, 1 equiv), a stock solution of RuCl3 (0.514 g, 0.035 M aqueous solution, 0.035 equiv) and a stirred solution of CH3CN (500 mL) were added NaIO4 (30.8 g, 142 mmol, 2.04 equiv) portionwise over 30 minutes at room temperature. The suspension was stirred for an additional 30 minutes at room temperature. The reaction mixture was quenched with saturated aqueous Na2S2O3 and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel; ethyl acetate / hexane, 10% - 50%) to give the desired product. 1 H NMR (400 MHz, CDCl3) δ 5.87 (s, 1H), 5.28 (s, 1H), 2.06 (dd, J = 35.1, 28.9 Hz, 4H), 1.90 - 1.44 (m, 6H); 13 C NMR (101 MHz, CDCl3) δ 183.20, 49.58, 43.94, 38.28, 25.42.

[0499] The following compounds can be prepared by the procedure of 3-Hydroxy-2-oxaspiro[4.4]nonan-1-one Those skilled in the art will know how to alternatively use appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein.

Chem.

[0500] Example 21: Preparation of 3-Hydroxy-2-oxaspiro[4.5]decan-1-one: 1-Allylcyclo The title compound was prepared according to the procedure for 3-hydroxy-2-oxaspiro[4.4]nonan-1-one, except that 1-allylcyclohexanecarboxylic acid and 1-allylcyclopentanecarboxylic acid were replaced: 1 H NMR (400 MHz, CDCl3) δ 5.86 (t, J = 4.5 Hz, 1H), 4.47 (broad , 1H), 2.18 (m, 2H), 1.83 - 1.43 (m, 7H), 1.32 (d, J = 5.8 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 181.91, 96.88, 44.52, 40.54, 34.06, 25.28, 22.23.

Chemical formula

[0501] Example 22: Preparation of 3-(But-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one: This reaction was carried out in a freshly oven-dried glass product under a nitrogen atmosphere. 3-Hydroxy-2-oxaspiro[4.4]nonan-1-one (5.0 g, 32.0 mmol, 1.0 equivalent) was added dropwise to a well-stirred solution of freshly prepared but-1-enemagnesium bromide Grignard reagent (96 mmol, 1 M, 3 equivalents) in anhydrous ether at 0 °C over 0.5 h. The reaction mixture was stirred at room temperature overnight and quenched with 10% HCl (while cooling in an ice bath) until acidic (pH = 2 ). The organic layer was separated, and water The layer was extracted with ethyl acetate (3 × 200 mL). The extract was washed with 10% NaHCO3 (100 mL) and brine (200 mL). The solution was then dried over MgSO4 and concentrated in vacuo, and purified by flash column chromatography (silica gel; ethyl acetate / hexane, 0% - 25%) to obtain the desired product. 1 H NMR (400 MHz, CDCl3) δ 5.79 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.15 - 4.88 (m, 2H), 4.36 (ddt, J = 9.7, 7.9, 5.5 Hz, 1H), 2.18 (m, 4H), 1.93 - 1.46 (m, 10H); 13 C NMR (101 MHz, CDCl3) δ 182.55, 137.26, 115.62, 77.19, 50.28, 43.24, 37.51, 36.91, 34.83, 29.70, 25.56, 25.47.

[0502] The following compounds can be prepared according to the procedure of 3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one Those skilled in the art will know how to alternatively use appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein.

Chemical formula

[0503] Example 23: Preparation of 3-(but-3-en-1-yl)-2-oxaspiro[4.5]decan-1-one: Title The compound was prepared according to the procedure of 3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one, except that 3-hydroxy-2-oxaspiro[4.5]decan-1-one and 3-hydroxy-2-oxaspiro[4.4]nonan-1-one were replaced. ​1 1H NMR (400 MHz, CDCl3) δ 5.80 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.17 - 4.89 (m, 2H), 4.48 - 4.31 (m, 1H), 2.36 (dd, J = 12.9, 6.3 Hz, 1H), 2.30 - 2.08 (m, 2H), 1.87 - 1.17 (m, 13H); 13 13C NMR (101 MHz, CDCl3) δ 181.68, 137.31, 115.67, 76.77, 45.04, 39.55, 35.31, 34.43, 31.70, 29.75, 25.42, 22.29, 22.22

Chemical formula

[0504] Example 24: Preparation of 3-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)propyl 4-methylbenzenesulfonate: To a stirred solution of 3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one (0.194 g, 1 mmol, 1 equiv), RuCl3 stock solution (7.2 mg, 0.035 M aqueous solution, 0.035 equiv) and CH3CN (6 mL), NaIO4 (434 mg, 2.04 mmol, 2.04 equiv) was added portionwise at room temperature over 5 minutes in several portions. The suspension was stirred at room temperature for an additional 30 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude aldehyde was used in the next step without further purification. This reaction was carried out in an oven-dried glassware under a nitrogen atmosphere. To a well-stirred solution of the crude aldehyde (0.196 g, 1 mmol, 1 equiv) in anhydrous methanol, NaBH4 (74 mg, 2.0 mmol) was added.

[0505] This reaction was carried out in an oven-dried glassware under a nitrogen atmosphere. To a well-stirred solution of the crude aldehyde (0.196 g, 1 mmol, 1 equiv) in anhydrous methanol, NaBH4 (74 mg, 2.0 mmol) , 2 equivalents) was added to the mixed solution at 0 °C all at once. The reaction mixture was further stirred at room temperature for 1 hour and quenched with brine (while cooling in an ice bath). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). Subsequently, the combined organic layers were dried over MgSO4 and concentrated in vacuo . The crude alcohol was used in the next step without further purification.

[0506] To a stirred solution of the crude alcohol (0.396 g, 2 mmol, 1.0 equivalent) and triethylamine (0.303 g, 3 mmol, 1.5 equivalents) in anhydrous dichloromethane was added dropwise at 0 °C a solution of p-TosCl (0.475 g, 2.5 mmol, 1.25 equivalents) in dich loromethane. The resulting mixture was stirred at 0 °C for 1 hour and then stirred overnight at room temperature. Subsequently, the reaction mixture was diluted with dichloromethane (50 mL), washed with 10% HCl, brine , dried over MgSO4, and concentrated in vacuo to afford a yellowish oil. Then , this crude product was purified by flash chromatography (silica gel; ethyl acetate / hexane, 0% - 40%) to give the desired tosylate. 1 1H NMR (400 MHz, CDCl3) δ 7.82 - 7.71 (m, 2H), 7.35 (m, 2H), 4.37 - 4.23 (m, 1H), 4.06 (qdd, J = 10.0, 6.7, 5.2 Hz, 2H), 2.45 (s, 3H), 2.15 (m, 2H), 1.92 - 1.50 (m, 12H); 13 13C NMR (101 MHz, CDCl3) δ 182.29, 145.03, 133.05, 130.04, 128.00, 76.90, 69.91, 50.24, 43.20, 37.53, 36.92, 31.74, 25.59, 25.49, 25.37, 21.76.

[0507] The following compound can be prepared by the procedure of 3-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)propyl 4-methylbenzenesulfonate. Those skilled in the art will know how to alternatively use appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds presented herein. [Chemical formula]

[0508] Example 25: Preparation of 3-(1-oxo-2-oxaspiro[4.5]decan-3-yl)propyl 4-methylbenzenesulfonate: The title compound was prepared following the procedure of 3-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)propyl 4-methylbenzenesulfonate, except that 3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one was replaced with 3-(but-3-en-1-yl)-2-oxaspiro[4.5]decan-1-one. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.39 - 4.26 (m, 1H), 4.16 - 3.97 (m, 2H), 2.44 (s, 3H), 2.32 (dt, J = 15.8, 7.9 Hz, 1H), 1.98 - 1.13 (m, 16H); 13 C NMR (101 MHz, CDCl3) δ 181.36, 145.03, 133.05, 130.03, 127.99, 76.46, 69.91, 44.97, 39.54, 34.40, 32.15, 31.68, 25.37, 25.36, 22.25, 22.18, 21.76 [Chemical formula] ​​​

[0509] Example 26: Preparation of 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one: To a solution of 3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one (8.03 g, 43.0 mmol, 1 equiv) in tetrahydrofuran (143 mL) was added triphenylphosphine (16.94 g, 64.6 mmol, 1.5 equiv). The resulting solution was cooled to 0 °C and carbon tetrabromide (21.44 g, 64.6 mmol, 1.5 equiv) was added all at once. The reaction mixture was stirred at 22 °C overnight. The reaction mixture was diluted with ether and filtered and concentrated in vacuo over celite and further purified by column chromatography (ethyl acetate / hexanes, 0% - 30%, solid load). 1 H NMR (400 MHz, CDCl3) δ4.60 (m, 1H), 3.53 (dd, J = 5.5, 7.6 Hz, 2H), 2.27-2.07 (m, 3H), 1.82 (dd, J = 9.3, 13.0 Hz, 1H), 1.69-1.57 (m, 4H), 0.93 (dt, J = 7.5, 25.7 Hz, 6H).

Chemical formula

[0510] Example 27: Preparation of 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one, except that 3-(2-hydroxyethyl)-2-oxaspiro[4.5]decan-1-one was used in place of 3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one. 11H NMR (400 MHz, CDCl3) δ4.61 (m, 1H), 3.53 (dd, J = 5.5, 7.6 Hz, 2H), 2.44 (dd, J = 6.4, 12.9 Hz, 1H), 2.29 - 2.07 (m, 2H), 1.88 - 1.70 (m, 3H), 1.69 - 1.54 (m, 4HzH), 1.53 - 1.44 (m, 1H), 1.44 - 1.18 (m, 3H).

Chem.

[0511] Example 28: Preparation of 5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one: 5-(2-Bromoethyl)-3,3-diethyl dihydrofuran-2(3H)-one (0.400 g, 1.53 mmol, 1 equiv), acetonitrile (8 mL), 2-benzyl octahydropyrrolo[3,4-c]pyrrole (0.340 g, 1.68 mmol, 1.1 equiv) and K2CO3 (1.05 g , 7.65 mmol, 5 equiv) were heated and stirred at 80 °C for 24 h. The resulting mixture was then filtered and concentrated in vacuo to give a crude residue, which was further purified by column chromatography (methanol / dichloromethane, 0% - 10%). 1 1H NMR (400 MHz, CDCl3) δ7.25 - 7.14 (m, 4H), 7.14 - 7.06 (m, 1H), 4.38 (m, 1H), 3.46 (s, 2H), 2.64 - 2.48 (m, 6H), 2.48 - 2.38 (m, 2H), 2.28 - 2.13 (m, 4H), 2.02 (dd, J = 6.8, 13.0 Hz, 1H), 1.87 - 1.59 (m, 3H), 1.58 - 1.44 (m, 4H), 0.83 (dt, J = 7.3, 21.4 Hz, 6H); MS (LC / MS, M+H + ): m / z 371.2

Chem.

[0512] Example 29: Preparation of 3-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one: 3-(2-Bromoethyl)-2-oxaspiro[4.5] decan-1-one and 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one were placed except for the replacement point, and the title compound was prepared according to the procedure of 5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)eth yl)-3,3-diethyldihydrofuran-2(3H)-one. 1 H NMR (400 MHz, CDCl3) δ7.26 - 7.17 (m, 4H), 7.17 - 7.10 (m, 1H), 4.40 (m, 1H), 3.50 (s, 2H), 2.69 - 2.52 (m, 6H), 2.49 (t, J = 7.4 Hz, 2H), 2.30 (dd, J = 6.3, 12.8 Hz, 1H), 2.27 - 2.16 (m, 4H), 1.88 - 1.61 (m, 5H), 1.61 - 1.45 (m, 4H), 1.44 - 1.37 (m, 1H), 1.36 - 1.07 (m, 3H); MS (LC / MS, M + H + ): m / z 383.2

Chem.

[0513] Example 30: Preparation of 3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: 5-(2-(5-Benzylhexahydropyrrolo[3,4-c]pi rrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one (540 mg, 1.46 mmol , 1 equivalent), a mixed solution of Pd / C (108 mg, 20 wt%) and MeOH (5.0 mL) was stirred at 22 °C for 3 days under 1 atm of H2 (filled balloon). The mixed solution was filtered through a Celite plug, washed with MeOH (50 mL), and concentrated in vacuo to obtain a crude product, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ4.42 (m, 1H), 2.83 (b, 1H), 2.69 (m, 2H), 2.55 - 2.39 (m, 4H), 2.33 (m, 2H), 2.26 (t, J = 7.0 Hz, 2H), 2.14 (dd, J = 1.7, 9.0 Hz, 2H), 1.91 (dd, J = 6.7, 13.0 Hz, 1H), 1.71 - 1.47 (m, 3H), 1.45 - 1.32 (m, 4H), 0.69 (dt, J = 7.4, 19.2 Hz, 6H); MS (LC / MS, M+H + ): m / z 281.2.

Chemical Structure

[0514] Example 31: Preparation of 3-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxa spiro[4.5]decan-1-one: The title compound was prepared according to the procedure of 3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except that 3-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one and 5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one were replaced. 1 H NMR (400 MHz, CDCl3) δ 4.55 (m, 1H), 2.94 (m, 2H), 2.82 - 2.63 (m, 5H), 2.63 - 2.46 (m, 3H), 2.42 (m, 2H), 1.97 - 1.60 (m, 8H), 1.59 - 1.43 (m, 3H), 1.43 - 1.22 (m, 4H); MS (LC / MS, M + H + ): m / z 293.2

Chem.

[0515] Example 32: Preparation of 1-(benzyloxy)-2-bromobenzene: To a solution of 2-bromophenol (1.0 g , 5.78 mmol, 1.01 equiv) in acetonitrile (14 mL) were added benzyl bromide (0.975 g, 5.7 mmol, 1.0 equiv) and K2CO3 (1.09 g, 7.87 mmol, 1.38 equiv). The mixture was stirred at 22 °C overnight. The reaction mixture was filtered and concentrated in vacuo to give a crude residue, which was further purified by column chromatography (hexane / ethyl acetate, 0% - 10%). The reaction solution was filtered and concentrated in vacuo to obtain a crude residue, which was further purified by column chromatography (hexane / ethyl acetate, 0% - 10%). 1 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 1.6, 7.8 Hz, 1H), 7.51 (m, 2H), 7.42 ( t, J = 7.6 Hz, 2H), 7.35 (m, 1H), 7.29 - 7.22 (m, 1H), 6.97 (dd, J = 1.2 8.3 Hz, 1H), 6.88 (td, J = 1.3, 7.6 Hz, 1H), 5.19 (s, 2H).

Chem.

[0516] Example 33: Preparation of 1-(benzyloxy)-3-bromobenzene: 3-Bromophenol and 2-b The procedure for 1-(benzyloxy)-2-bromobenzene was repeated except that 2-bromophenol was substituted. The title compound was prepared accordingly: 1 H NMR (400 MHz, CDCl3) δ7.50-7.34 (m, 5H), 7.23-7.10 (m, 3H), 6.95 (m, 1H), 5.08 (s, 2H). [ka]

[0517] Example 34: Preparation of 1-(benzyloxy)-4-bromobenzene: 4-Bromophenol and 2-Bromo The procedure for 1-(benzyloxy)-2-bromobenzene was repeated except that 2-bromophenol was substituted. The title compound was prepared accordingly: 1 H NMR (400 MHz, CDCl3) δ7.51-7.33 (m, 7H), 6.91 (d, J= 9.1 Hz, 2H), 5.08 (s, 2H). [ka]

[0518] Example 35: Preparation of 4-(2-bromophenyl)morpholine: The reaction was carried out under a nitrogen atmosphere. The reaction was carried out in a bromine-dried glassware. To a solution of 1,2-dibromobenzene (1.0 g, 4.24 mmol, 1.0 equiv.) and morpholine (0.370 g, 4.24 mmol, 1.0 equiv.) in anhydrous toluene (10.6 mL) was added in the following order: Pd2(dba)3 (0.097 g, 5 mol%), BINAP (0.197 g, 7.5 mol%), and NaOtBu (0.448 g, 5.08 mmol, 1.2 equiv.). The resulting mixture was allowed to stir at 80 °C under a N2 sweep overnight. The reaction mixture was cooled to 22 °C and then filtered through a Celite plug. The filtrate was collected and concentrated in vacuo to give the crude residue, which was further purified by column chromatography (hexanes / ethyl acetate, 0% to 20%).1 1H NMR (400 MHz, CDCl3) δ7.55 (doublet of doublets, J = 1.5, 7.9 Hz, 1H), 7.25 (triplet of doublets, J = 1.4, 7.8 Hz, 1H), 7.00 (doublet of doublets, J = 1.4, 8.0 Hz, 1H), 6.89 (triplet of doublets, J = 1.4, 7.7 Hz, 1H), 3.83 (multiplet, 4H), 2.99 (multiplet, 4H); MS (LC / MS, M+H + ): m / z 241.9, 243.8.

Chem.

[0519] Example 36: Preparation of tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate : The title compound was prepared according to the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except that tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and the hemioxylate of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate were used, and 1-bromo-2-methylbenzene and bromobenzene were replaced. hemioxylate) was replaced, and 1-bromo-2-methylbenzene and bromobenzene were replaced, except that tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and the hemioxylate of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate were used, and 1-bromo-2-methylbenzene and bromobenzene were replaced. 1 1H NMR (400 MHz, CDCl3) δ7.18 - 7.10 (multiplet, 2H), 6.96 - 6.89 (multiplet, 2H), 3.69 (broad, 2H), 3.36 (broad, 2H), 3.18 (broad, 2H), 3.05 (broad, 2H), 2.91 (broad, 2H), 2.33 (singlet, 3H), 1.52 (singlet, 9H); MS (LC / MS, M+H + ): m / z 303.2

Chem.

[0520] Example 37: tert-Butyl 5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate Preparation: The title compound was prepared according to the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except that tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and the hemioxylate of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate were replaced, and 1-bromo-3-methylbenzene and bromobenzene were replaced. 1 H NMR (400 MHz, CDCl3) δ 7.17 (t, J = 7.8 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6.46 - 6.37 (m, 2H), 3.68 (b, 2H), 3.52 (b, 2H), 3.42 (m, 1H), 3.29 (m, 1H), 3.23 (m, 2H), 2.97 (b, 2H), 2.38 (s, 3H), 1.54 (s, 9H); MS (LC / MS, M + H + ): m / z 303.2 [Chemical formula]

[0521] Example 38: tert-Butyl 5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate Preparation: The title compound was prepared according to the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except that tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and the hemioxylate of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate were replaced, and 1-bromo-4-methylbenzene and bromobenzene were replaced. 11H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 8.1 Hz, 2H), 6.52 (d, J = 8.5 Hz, 2H), 3.68 (m, 2H), 3.57 (b, 2H), 3.42 (m, 1H), 3.28 (m, 1H), 3.21 (m, 2H), 3.00 (b, 2H), 2.30 (s, 3H), 1.51 (s, 9H); MS (LC / MS, M+H + ): m / z 303.2.

Chem.

[0522] Example 39: Preparation of tert-Butyl 5-(2-Methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: The title compound was prepared according to the procedure for tert-Butyl 6-Phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except that tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was replaced and 1-Bromo-2-methoxybenzene and Bromobenzene were replaced with the hemioxylate of tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate. 1 1H NMR (400 MHz, CDCl3) δ 6.91 - 6.78 (m, 3H), 6.76 - 6.67 (m, 1H), 3.80 (s, 3H), 3.61 (b, 2H), 3.45 (b, 2H), 3.40 - 3.22 (m, 2H), 3.14 (b, 2H), 2.90 (b, 2H), 1.46 (s, 9H); MS (LC / MS, M+H + ): m / z 319.2.

Chem.

[0523] Example 40: Preparation of tert-Butyl 5-(3-Methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate were replaced, and 1-bromo-3-methoxybenzene and bromobenzene were replaced. The title compound was prepared according to the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except for these replacements. 1 H NMR (400 MHz, CDCl3) δ7.13 (t, J = 8.1 Hz, 1H), 6.29 (dd, J = 2.2, 8.1 Hz, 1H), 6.18 (dd, J = 1.8, 8.1 Hz, 1H), 6.10 (t, J = 2.2 Hz, 1H), 3.79 (s, 3H), 3.63 (m, 2H), 3.50 (m, 2H), 3.37 (m, 1H), 3.30 - 3.11 (m, 3H), 2.95 (b, 2H), 1.48 (s, 9H); MS (LC / MS, M+H + ): m / z 319.2 [Chemical formula]

[0524] Example 41: Preparation of tert-Butyl 5-(4-Methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate were replaced, and 1-bromo-4-methoxybenzene and bromobenzene were replaced. The title compound was prepared according to the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except for these replacements. 11H NMR (400 MHz, CDCl3) δ6.83 (d, J = 9.0 Hz, 2H), 6.50 (d, J = 9.0 Hz, 2H), 3.73 (s, 3H), 3.62 (m, 2H), 3.48 - 3.29 (m, 3H), 3.23 (m, 1H), 3.12 (dd, J = 3.5, 9.3 Hz, 2H), 2.93 (b, 2H), 1.46 (s, 9H); MS (LC / MS, M + H + ): m / z 319.2.

Chem.

[0525] Example 42: Preparation of tert - butyl 5-(2 - cyanophenyl)hexahydropyrrolo[3,4 - c]pyrrole - 2(1H)-carboxylate: Replace tert - butyl 2,6 - diazaspiro[3.3]heptane - 2 - carboxylate hemioxylate with tert - butyl hexahydropyrrolo[3,4 - c]pyrrole - 2(1H)-carboxylate, and replace 2 - bromobenzonitrile and bromobenzene except at the replaced points, and prepare the title compound according to the procedure of tert - butyl 6 - phenyl - 2,6 - diazaspiro[3.3]heptane - 2 - carboxylate. 1 1H NMR (400 MHz, CDCl3) δ7.39 (dd, J = 1.6, 7.8 Hz, 1H), 7.30 (m, 1H), 6.66 (t, J = 7.5 Hz, 1H), 6.59 (d, J = 8.5 Hz, 1H), 3.80 (m, 2H), 3.61 (m, 2H), 3.52 (m, 1H), 3.44 (m, 1H), 3.28 (m, 2H), 2.95 (b, 2H), 1.42 (s, 9H); MS (LC / MS, M + H + ): m / z 314.2.

Chem.

[0526] Example 43: Preparation of tert-Butyl 5-(3-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxylate were replaced, and bromobenzene and 3-bromobenzonitrile were used. The title compound was prepared according to the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except for the replacement of 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxylate with tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and the replacement of bromobenzene with 3-bromobenzonitrile. 1 H NMR (400 MHz, CDCl3) δ7.22 (m, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.71 - 6.64 (m, 2H), 3.62 (m, 2H), 3.49 (m, 2H), 3.31 (m, 1H), 3.23 (m, 1H), 3.16 (dd, J = 3.9, 9.7 Hz, 2H), 2.99 (b, 2H), 1.42 (s, 9H); MS (LC / MS, M+H + ): m / z 314.2

Chemical formula

[0527] Example 44: Preparation of tert-Butyl 5-(4-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxylate were replaced, and bromobenzene and 4-bromobenzonitrile were used. The title compound was prepared according to the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except for the replacement of 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxylate with tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and the replacement of bromobenzene with 4-bromobenzonitrile. 11H NMR (400 MHz, CDCl3) δ7.35 (d, J = 8.9 Hz, 2H), 6.41 (d, J = 8.9 Hz, 2H), 3.57 (m, 2H), 3.50 (m, 2H), 3.26 (m, 1H), 3.21 - 3.06 (m, 3H), 2.95 (b, 2H), 1.37 (s, 9H); MS (LC / MS, M + H + ): m / z 314.2.

Chem.

[0528] Example 45: Preparation of tert - butyl 5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4 - c]pyrrole - 2(1H)-carboxylate: tert - butyl hexahydropyrrolo[3,4 - c]pyrrole - 2(1H)-carboxylate was replaced with tert - butyl 2,6 - diazaspiro[3.3]heptane - 2 - carboxylate hemioxylate, and 1 - (benzyloxy)-2 - bromobenzene was replaced with bromobenzene. The title compound was prepared according to the procedure for tert - butyl 6 - phenyl - 2,6 - diazaspiro[3.3]heptane - 2 - carboxylate, except for these replacements. 1 1H NMR (400 MHz, CDCl3) δ7.36 - 7.23 (m, 4H), 7.20 (m, 1H), 6.79 (m, 2H), 6.72 (m, 1H), 6.65 (m, 1H), 4.94 (s, 2H), 3.50 (b, 2H), 3.33 (m, 2H), 3.27 - 3.02 (m, 3H), 2.76 (b, 2H), 1.35 (s, 9H); MS (LC / MS, M + H + ): m / z 395.2.

Chem.

[0529] Example 46: Preparation of tert-Butyl 5-(3-(Benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbo nic acid tert-butyl ester was replaced with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxylate, and 1-(benzyloxy)-3-bromobenzene and bromobenzene were replaced. The title compound was prepared according to the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except for these replacements. 1 H NMR (400 MHz, CDCl3) δ7.47 (m, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.34 (m, 1H), 7.17 (t, J = 8.2 Hz, 1H), 6.39 (dd, J = 1.7, 8.0 Hz, 1H), 6.23 (m, 2H), 5.08 (s, 2H), 3.66 (m, 2H), 3.53 (m, 2H), 3.40 (m, 1H), 3.33 - 3.14 (m, 3H), 2.99 (b, 2H), 1.49 (s, 9H); MS (LC / MS, M+H + ): m / z 395.2.

Chemical Structure

[0530] Example 47: Preparation of tert-Butyl 5-(4-(Benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbo tert-Butyl phosphate was replaced with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxylate, and 1-(benzyloxy)-4-bromobenzene and bromobenzene were replaced. The title compound was prepared according to the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except for the above replacements. 1 H NMR (400 MHz, CDCl3) δ7.46 (m, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.34 (m, 1H), 6.95 (d, J = 9.0 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 5.03 (s, 2H), 3.67 (b, 2H), 3.47 (b, 2H), 3.40 (m, 1H), 3.28 (m, 1H), 3.18 (dd, J = 3.4, 9.3 Hz, 2H), 2.99 (b, 2H), 1.50 (s, 9H); MS (LC / MS, M+H + ): m / z 395.2.

Chemical Structure

[0531] Example 48: Preparation of tert-butyl 5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was replaced with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxylate, and 4-(2-bromophenyl)morpholine and bromobenzene were replaced. The title compound was prepared according to the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except for the above replacements. boxylate, except for the above replacements. The title compound was prepared according to the procedure for tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except for the above replacements. 11H NMR (400 MHz, CDCl3) δ 7.04 - 6.89 (m, 3H), 6.85 (d, J = 7.8 Hz, 1H), 3.85 (t, J = 4.5 Hz, 4H), 3.62 (b, 2H), 3.48 - 3.21 (m, 6H), 3.04 (t, J = 4.5 Hz, 4H), 2.92 (b, 2H), 1.48 (s, 9H); MS (LC / MS, M + H + ): m / z 374.2.

Chem.

[0532] Example 49: Preparation of 2-Benzyl-5-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole: Following the procedure of tert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except replacing 2-benzyl octahydropyrrolo[3,4-c]pyrrole and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxylate, and replacing 1-bromo-2-isopropylbenzene and bromobenzene, the title compound was prepared. The product was purified by column chromatography (dichloromethane / MeOH, 0% - 5%). 1 1H NMR (400 MHz, CDCl3) δ 7.54 - 7.33 (m, 6H), 7.32 - 7.11 (m, 3H), 3.77 (s, 2H), 3.65 (sept, J = 6.9 Hz, 1H), 3.15 (m, 2H), 3.09 - 2.99 (m, 4H), 2.96 (m, 2H), 2.47 (dd, J = 4.9, 8.8 Hz, 2H), 1.39 (d, J = 6.9 Hz, 9H); MS (LC / MS, M + H + ): m / z 321.2.

Chem.

[0533] Example 50: Preparation of 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: 5-(o-tolyl)he xahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl (0.490 g, 1.62 mmol, 1 equivalent) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at 0 °C. After stirring the reaction mixture at 22 °C for 30 minutes, it was diluted with MeOH and concentrated in vacuo to give the product as the TFA salt The salt was then suspended in saturated NaHCO3 solution and the free product was extracted with methylene chloride (3 x 15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the product as the free base: MS (LC / MS, M+H + ): m / z 203.2. [Chemical formula]

[0534] Example 51: Preparation of 2-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole: 5-(m-tolyl)he xahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl and 5-(m-tolyl)hex xahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl were replaced, the title compound was prepared according to the procedure for 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole. MS (LC / MS, M+H + ): m / z 203.2. [Chemical formula]

[0535] Example 52: Preparation of 2-(p-tolyl)octahydropyrrolo[3,4-c]pyrrole: 5-(p-tolyl)he The title compound was prepared according to the procedure of 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except that xahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate were replaced. MS (LC / MS, M+H + ): m / z 203.2

Chemical formula

[0536] Example 53: Preparation of 2-(2-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole: tert-Butyl 5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate were used, except that the tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was replaced. The title compound was prepared according to the procedure of 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole. MS (LC / MS, M+H + ): m / z 219.2.

Chemical formula

[0537] Example 54: Preparation of 2-(4-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole: tert-Butyl 5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate were used, except that the tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was replaced. The title compound was prepared according to the procedure of 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole. MS (LC / MS, M+H + ): m / z 219.2.

Chemical formula

[0538] Example 55: Preparation of 3-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: Except for replacing 5-(3-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl and 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl with those in the procedure of 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, the title compound was prepared. MS (LC / MS, M+H ): m / z 214.2 + ): m / z 214.2

Chemical Structure

[0539] Example 56: Preparation of 4-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: Except for replacing 5-(4-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl and 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl with those in the procedure of 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, the title compound was prepared. MS (LC / MS, M+H ): m / z 214.2 + ): m / z 214.2.

Chemical Structure

[0540] Example 57: 2-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride Preparation: To a 0 °C solution of tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.408 g, 1.30 mmol, 1 eq) in MeOH (1 mL) was added 1 M methanolic HCl (3 mL). After stirring the reaction mixture at 22 °C overnight, it was diluted with MeOH and concentrated in vacuo to obtain the product as the HCl salt. MS (LC / MS, M+H + ): m / z 214.2.

Chemical Structure

[0541] Example 58: Preparation of 2-(3-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride : The title compound was prepared according to the procedure for 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride, except that tert-butyl 5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate were replaced. MS (LC / MS, M+H ): m / z + ): m / z 219.2.

Chemical Structure

[0542] Example 59: 2-(2-(Benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrole salt Preparation of the hydrochloride salt: The title compound was prepared according to the procedure for 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride, except that tert-butyl 5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate were used instead. MS (LC / MS, M+H + ): m / z 295.2.

Chemical Structure

[0543] Example 60: 2-(3-(Benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride Preparation of the hydrochloride salt: The title compound was prepared according to the procedure for 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride, except that tert-butyl 5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate were used instead. MS (LC / MS, M+H + ): m / z 295.2.

Chemical Structure

[0544] Example 61: 2-(4-(Benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride Preparation of the hydrochloride salt: The title compound was prepared according to the procedure for 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride, except that tert-butyl 5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate were used instead. MS (L C / MS, M+H + ): m / z 295.2.

Chem.

[0545] Example 62: Preparation of 4-(2-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)morpholine hydrochloride: The title compound was prepared according to the procedure for 2-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride, except that 5-(2-Morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl and 5-(2-Cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl were replaced. MS (LC / MS, M+H + ): m / z 274.2.

Chem.

[0546] Example 63: Preparation of 2-(2-Isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole: To a dried round-bottom flask was added 0.04 g of 10% Pd / C (20 wt%) and moistened with a small amount of ethyl acetate. Next, a solution of 2-Benzyl-5-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole (0.20 g, 0.624 mmol, 1 equiv) in MeOH (2.1 mL) was slowly added to the round-bottom flask containing Pd / C. Then the system was flushed three times with H2 using a balloon filled with H2 . The reaction solution was stirred at room temperature for 5 days under 1 atm of H2. The Pd / C was removed by filtration through a plug of celite . The filtrate was concentrated in vacuo to give a crude oil of 2-(2-Isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole, which was used in the next step without further purification . MS (LC / MS, M+H + ): m / z 231.2. [Chemical formula]

[0547] Example 64: Preparation of 3,3 - diethyl - 5 - (2 - (5 - (2 - isopropylphenyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H) - yl)ethyl)dihydrofuran - 2(3H) - one: 2 - (2 - isopropyl phenyl)octahydropyrrolo[3,4 - c]pyrrole and 2 - phenyl - 2,6 - diazaspiro[3.3]heptane trifluoroacetate were replaced, and the title compound was prepared according to the procedure of 3,3 - diethyl - 5 - (2 - (6 - phenyl - 2,6 - diazaspiro[3.3]heptan - 2 - yl)ethyl)dihydrofuran - 2(3H) - one except for the above - mentioned replacement: [The title compound was prepared: 1 H NMR (400 MHz, CDCl3) δ7.18 (dd, J = 1.5, 7.4 Hz, 1H), 7.10 - 6.90 (m, 3H), 4.43 (m, 1H), 3.38(sept, J = 6.9 Hz, 1H) , 3.01 - 2.84 (m, 4H), 2.83 - 2.66 (m, 4H), 2.52 (t, J = 6.8 Hz, 2H), 2.19 (m, 2H), 2.06 (dd, J = 6.8, 13.1 Hz, 1H), 1.91 - 1.67 (m, 3H), 1.63 - 1.44 (m, 4H), 1.15 (d, J = 6.9 Hz, 6H), 0.86 (dt, J = 7.3, 19.3 Hz, 6H); MS (LC / MS, M + H + ): m / z 399.2. [Chemical formula]

[0548] Example 65: Preparation of 3-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxospiro[4.5]decan-1-one: Replace 3-(2-bromoethyl)-2-oxospiro[4.5]decan-1-one and 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one, and replace 2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyr role and 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate, and prepare the title compound according to the procedure of 3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)e thyl)dihydrofuran-2(3H)-one: 1 H NMR (400 MHz, CDCl3) δ7.18 (dd, J = 1.5, 7.0 Hz, 1H), 7.09 - 6.94 (m, 3H), 4.44 (m, 1H), 3.37(sept, J = 6.8 Hz, 1H), 2.99 - 2.83 (m, 4H), 2.82 - 2.66 (m, 4H), 2.52 (t, J = 7.2 Hz, 2H), 2.32 (dd, J = 6.3, 12.7 Hz, 1H), 2.24 - 2.12 (m, 2H), 1.93 - 1.81 (m, 1H), 1.80 - 1.46 (m, 8H), 1.46 - 1.37 (m, 1H), 1.37 - 1.04 (m, 9H) MS (LC / MS, M+H + ): m / z 411.2.

Chemical formula

[0549] Example 66: Preparation of 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: 5-(2-Bromoethyl)-3,3-diethyl Dihydrofuran-2(3H)-one (0.075 g, 0.301 mmol, 1 equiv), acetonitrile (3 mL), 2-(o- tolyl)octahydropyrrolo[3,4-c]pyrrole (0.073 g, 0.361 mmol, 1.2 equiv) and N,N-diisopropylethylamine (0.116 g, 0.903 mmol, 3 equiv) were irradiated with microwave at 120 °C for 4 h. The resulting solution was concentrated in vacuo to give a crude residue, which was first purified by column chromatography (methanol / dichloromethane, 0% - 10%). 1 H NMR (400 MHz, CDCl3) δ7.15 (m, 2H), 6.96 (m, 2H), 4.50 (m, 1H), 3.08 - 2.92 (m, 6H), 2.86 (b, 2H), 2.60 (t, J = 6.9 Hz, 2H), 2.37 - 2.24 (m, 5H), 2.14 (dd, J = 6.7, 13.0 Hz, 1H), 1.99 - 1.75 (m, 3H), 1.64 (m, 4H), 0.94 (dt, J = 7.4, 18.1 Hz, 6H); MS (LC / MS, M+H + ): m / z 371.2.

Chemical formula

[0550] Example 67: Preparation of 3,3-diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl)ethyl)dihydrofuran-2(3H)-one: The title compound was prepared according to the procedure of 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except that 2-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole was used in place of 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole. 11H NMR (400 MHz, CDCl3) δ 7.13 (t, J = 8.0 Hz, 1H), 6.58 (d, J = 7.4 Hz, 1H), 6.53 - 6.45 (m, 2H), 4.47 (m, 1H), 3.37 (m, 2H), 3.18 (dt, J = 2.8, 9.4 Hz, 2H), 2.95 (b, 2H), 2.86 (m, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.41 (dd, J = 4.0, 8.9 Hz, 2H), 2.33 (s, 3H), 2.12 (dd, J = 6.6, 13.0 Hz, 1H), 1.97 - 1.73 (m, 3H), 1.62 (q, J = 7.5 Hz, 4H), 0.92 (dt, J = 7.5, 14.8 Hz, 6H); MS (LC / MS, M + H + ): m / z 371.2.

Chem.

[0551] Example 68: Preparation of 3,3 - diethyl - 5-(2-(5-(p - tolyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)dihydrofuran - 2(3H)-one: The title compound was prepared according to the procedure for 3,3 - diethyl - 5-(2-(5-(o - tolyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)dihydrofuran - 2(3H)-one, except that 2-(p - tolyl)octahydropyrrolo[3,4 - c]pyrrole and 2-(o - tolyl)octahydropyrrolo[3,4 - c]pyrrole were replaced. 1H) δ 6.89 (d, J = 8.4 Hz, 2H), 6.45 (d, J = 8.4 Hz, 2H), 4.32 (m, 1H), 3.17 (m, 2H), 2.99 (dt, J = 3.0, 9.2 Hz, 2H), 2.78 (b, 2H), 2.70 (m, 2H), 2.42 (t, J = 6.9 Hz, 2H), 2.42 (dd, J = 4.0, 8.8 Hz, 2H), 2.11 (s, 3H), 2.97 (dd, J = 6.8, 13.0 Hz, 1H), 1.81 - 1.57 (m, 3H), 1.45 (q, J = 7.2 Hz, 4H), 0.76 (dt, J = 7.5, 14.7 Hz, 6H); MS (LC / MS, M + H + ): m / z 371.2.

Chem.

[0552] Example 69: Preparation of 2-(5-(2-(4,4 - diethyl - 5 - oxotetrahydrofuran - 2 - yl)ethyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)benzonitrile: 2-(Hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)benzonitrile hydrochloride and, except that 2-(o - tolyl)octahydropyrrolo[3,4 - c]pyrrole was replaced, according to the procedure of 3,3 - diethyl - 5-(2-(5-(o - tolyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)dihydrofuran - 2(3H)-one the title compound was prepared. H NMR (400 MHz, CDCl3) δ7.45 (dd, J = 1.5, 7.6 Hz, 1H), 7.36 (m, 1H), 6.81 - 6.68 (m, 2H), 4.45 (m, 1H), 3.62 (m, 2H), 3.45 (td, J = 2.0, 8.6 Hz, 2H), 2.92 (b, 2H), 2.74 (m, 2H), 2.63 - 2.53 (m, 2H), 2.52 - 2.46 (m, 2H), 2.11 (dd, J = 6.8, 13.0 Hz, 1H), 1.94 - 1.70 (m, 3H), 1.58 (qd, J = 2.6, 7.4 Hz, 4H), 0.88 (dt, J= 1 7.5, 14.7 Hz, 6H); MS (LC / MS, M + H ): m / z 371.2. 7.3, 14.8 Hz, 6H); MS (LC / MS, M+H + ): m / z 382.2.

Chem.

[0553] Example 70: Preparation of 3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: 3-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile and 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole were replaced, except for the point where 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole was replaced, and the title compound was prepared according to the procedure of 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one. 1 H NMR (400) δ7.26 (m, 1H), 6.95 (d, J = 7.5 Hz, 1H), 6.82 - 6.75 (m, 2H), 4.44 (m, 1H), 3.44 (t, J = 8.7 Hz, 2H), 3.15 (dt, J = 3.8, 9.4 Hz, 2H), 2.98 (b, 2H), 2.73 (m, 2H), 2.57 (t, J = 7.0 Hz, 2H), 2.50 (dd, J = 3.1, 9.1 Hz, 2H), 2.10 (dd, J = 6.8, 12.9 Hz, 1H), 1.94 - 1.70 (m, 3H), 1.59 (q, J = 7.3 Hz, 4H), 0.89 (dt, J = 5.4, 14.9 Hz, 6H); ): m / z 382.2.

Chem.

[0554] ​​​Example 71: Preparation of 4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: 4-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile was used, and the title compound was prepared according to the procedure of 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except that 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole was replaced with 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole. 1 H NMR (400 MHz, CDCl3) δ7.44 (d, J = 8.9 Hz, 2H), 6.54 (d, J = 8.7 Hz, 2H), 4.44 (m, 1H), 3.55 (t, J = 9.0 Hz, 2H), 3.23 (dt, J = 3.6, 9.9 Hz, 2H), 3.00 (b, 2H), 2.72 (m, 2H), 2.64 - 2.50 (m, 4H), 2.10 (dd, J = 6.7, 13.1 Hz, 1H), 1.94 - 1.71 (m, 3H), 1.59 (q, J = 7.5 Hz, 4H), 0.89 (dt, J = 5.1, 14.9 Hz, 6H); MS (LC / MS, M+H

Chemical Structure

[0555] Example 72: Preparation of 3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: The title compound was prepared according to the procedure of 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except that 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole was replaced with 2-(2-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole. Performed. 1 H NMR (400 MHz, CDCl3) δ6.83 - 6.61 (m, 4H), 4.34 (m, 1H), 3.71 (s, 3H), 3.23 (q, J = 7.5 Hz, 2H), 2.86 (m, 2H), 2.72 (b, 2H), 2.58 (b, 2H), 2.44 (m, 2H), 2.31 (dt, J = 3.2, 8.8 Hz, 2H), 1.98 (dd, J = 6.8, 13.1 Hz, 1H), 1.84 - 1.73 (m, 1H), 1.73 - 1.58 (m, 2H), 1.47 (qd, J = 1.5, 7.5 Hz, 4H), 0.77 (dt, J = 7.3, 15.8 Hz, 6H); MS (LC / MS, M + H + ): m / z 387.2. [Chemical formula]

[0556] Example 73: Preparation of 3,3 - diethyl - 5-(2-(5-(3 - methoxyphenyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)dihydrofuran - 2(3H)-one: The title compound was prepared according to the procedure of 3,3 - diethyl - 5-(2-(5-(o - tolyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)dihydrofuran - 2(3H)-one, except that 2-(3 - methoxyphenyl)octahydropyrrolo[3,4 - c]pyrrole and 2-(o - tolyl)octahydropyrrolo[3,4 - c]pyrrole were replaced. 1 H NMR (400 MHz, CDCl3) δ7.14 (t, J = 8.2 Hz, 1H), 6.30 (m, 2H), 6.20 (t, J = 2.2 Hz, 1H), 4.46 (m, 1H), 3.79 (s, 3H), 3.38 (t, J = 8.2 Hz, 2H), 3.17 (dt, J = 3.0, 9.5 Hz, 2H), 2.94 (b, 2H), 2.86 - 2.77 (m, 2H), 2.57 (t, J = 7.1 Hz, 2H), 2.42 (dd, J = 3.9, 9.0 Hz, 2H), 2.11 (dd, J = 6.8, 13.0 Hz, 1H), 1.95 - 1.72 (m, 3H), 1.61 (qd, J = 1.5, 7.5 Hz, 4H), 0.91 (dt, J = 7.4, 14.8 Hz, 6H); ): m / z 387.2. [Chemical formula]

[0557] Example 74: Preparation of 3,3 - diethyl - 5-(2-(5-(4 - methoxyphenyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)dihydrofuran - 2(3H)-one: The title compound was prepared according to the procedure for 3,3 - diethyl - 5-(2-(5-(o - tolyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)dihydrofuran - 2(3H)-one, except that 2-(4 - methoxyphenyl)octahydropyrrolo[3,4 - c]pyrrole and 2-(o - tolyl)octahydropyrrolo[3,4 - c]pyrrole were replaced. 1 1H NMR (400 MHz, CDCl3) δ6.83 (d, J = 9.0 Hz, 2H), 6.65 (d, J = 9.0 Hz, 2H), 4.46 (m, 1H), 3.76 (s, 3H), 3.28 (m, 2H), 3.10 (dt, J = 3.2, 9.1 Hz, 2H), 2.92 (b, 2H), 2.84 (b, 2H), 2.63 - 2.51 (m, 2H), 2.39 (dd, J = 4.0, 8.7 Hz, 2H), 2.11 (dd, J = 6.8, 13.0 Hz, 1H), 1.97 - 1.71 (m, 3H), 1.61 (qd, J = 1.3, 7.4 Hz, 4H), 0.91 (dt, J= 7.3, 14.8 Hz, 6H); MS (LC / MS, M + H

Chem.

[0558] Example 75: Preparation of 3,3 - diethyl - 5-(2-(5-(2 - morpholinophenyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)dihydrofuran - 2(3H)-one 4-(2-(Hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)phenyl)morpholine hydrochloride and 2-(o - tolyl)octahydropyrrolo[3,4 - c]pyrrole were used instead, and the title compound was prepared according to the procedure of 3,3 - diethyl - 5-(2-(5-(o - tolyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)dihydrofuran - 2(3H)-one in sequence. 1 1H NMR (400 MHz, CDCl3) δ7.05 - 6.94 (m, 3H), 6.91 - 6.83 (m, 1H), 4.49 (m, 1H) 3.85 (t, J = 4.7 Hz, 4H), 3.68 - 3.42 (m, 4H), 3.22 - 2.84 (m, 10H), 2.61 (b, 2H), 2.30 (b, 1H), 2.19 (dd, J = 6.7, 13.2 Hz, 1H), 2.05 - 1.90 (m, 1H), 1.84 (dd, J = 9.3, 13.2 Hz, 1H), 1.67 - 1.56 (m, 4H), 0.91 (dt, J = 7.3, 16.5 Hz, 6H); MS (LC / MS, M + H + ): m / z 442.2.

Chem.

[0559] Example 76: 5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole Preparation of 2-(2-(benzoyl)-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one (O-tolyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride and 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, except that hexahydropyrrolo[3,4-c]pyrrole is replaced. The title compound was prepared according to the procedure. 1 H NMR (400 MHz, CDCl3) δ7.46-7.29 (m, 5H), 7.01-6.86 (m, 3H), 6.81 (dd, J= 1.4, 7.7 Hz, 1H), 5.03 (s, 2H), 4.43 (m, 1H), 3.61 (b, 2H), 3.36 (t, J= 10.6 Hz, 2H), 3.17-2.97 (m, 3H), 2.91 (td, J= 5.3, 12.2 Hz, 1H), 2.86-2.73 (m, 2H), 2.58-2.37 (m, 2H), 2.30 (m, 1H), 2.17 (dd, J= 6.7, 13.1 Hz, 1H), 1.92-1.73 (m, 2H), 1.61 (q, J= 7.4 Hz, 4H), 0.91 (dt, J= 7.0, 13.9 Hz, 6H); MS (LC / MS, M+H + ): m / z 463.2. [ka]

[0560] Example 78: 5-(2-(5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole Preparation of 3,3 - diethyl - 5 - (2 - (5 - (o - tolyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H) - yl)ethyl)dihydrofuran - 2(3H) - one: 2 - (3 - (benzy loxy)phenyl)octahydropyrrolo[3,4 - c]pyrrole hydrochloride and 2 - (o - tolyl)octa hydropyrrolo[3,4 - c]pyrrole were used, except that 2 - (o - tolyl)octa hydropyrrolo[3,4 - c]pyrrole was replaced. The title compound was prepared according to the procedure of 3,3 - diethyl - 5 - (2 - (5 - (o - tolyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H) - yl)ethyl)dihydrofuran - 2(3H) - one. 1 1H NMR (400 MHz, CDCl3) δ7.39 - 7.33 (m, 2H), 7.33 - 7.26 (m, 2H), 7.26 - 7.20 (m, 1H), 7.05 (m, 1H), 6.29 (dd, J = 1.7, 8.1 Hz, 1H), 6.24 - 6.18 (m, 2H), 4.96 (s, 2H), 4.37 (m, 1H), 3.28 (m, 2H), 3.08 (dt, J = 2.9, 9.3 Hz, 2H), 2.93 - 2.81 (m, 2H), 2.81 - 2.69 (m, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.33 (dd, J 3.9, 8.9 Hz, 2H), 2.02 (dd, J = 6.7, 13.0 Hz, 1H), 1.87 - 1.63 (m, 3H), 1.52 (qd, J = 1.2, 7.4 Hz, 4H), 0.82 (dt, J = 7.4, 14.9 Hz, 6H); MS (LC / MS, M + H + ): m / z 463.2.

Chemical Structure

[0561] Example 79: 5 - (2 - (5 - (4 - (benzyloxy)phenyl)hexahydropyrrolo[3,4 - c]pyrrol Preparation of ethyl 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: 2-(4-(benzy loxy)phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride and 2-(o-tolyl)octa hydropyrrolo[3,4-c]pyrrole were used, except that 2-(o-tolyl)octa hydropyrrolo[3,4-c]pyrrole was replaced. The title compound was prepared according to the procedure of 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one. 1 1H NMR (400 MHz, CDCl3) δ7.37 - 7.31 (m, 2H), 7.31 - 7.25 (m, 2H), 7.24 - 7.18 (m, 1H), 6.81 (d, J = 9.0 Hz, 2H), 6.55 (d, J = 9.0 Hz, 2H), 4.92 (s, 2H), 4.37 (m, 1H), 3.19 (m, 2H), 3.01 (dt, J = 3.1, 9.3 Hz, 2H), 2.89 - 2.80 (m, 2H), 2.80 - 2.70 (m, 2H), 2.48 (t, J = 6.9 Hz, 2H), 2.29 (dd, J 3.9, 8.6 Hz, 2H), 2.02 (dd, J = 6.7, 13.1 Hz, 1H), 1.87 - 1.62 (m, 3H), 1.52 (q, J = 7.3 Hz, 4H), 0.82 (dt, J = 7.5, 14.5 Hz, 6H); MS (LC / MS, M+H + ): m / z 463.2. [Chemical formula]

[0562] Example 80: Preparation of 3,3 - Diethyl - 5 - (2 - (5 - (2 - hydroxyphenyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H) - yl)ethyl)dihydrofuran - 2(3H) - one: In a dry RBF, 0.013 g of 10% Pd / C (20 wt%) was added and moistened with a small amount of ethyl acetate. Next, a solution of 5 - (2 - (5 - (2 - (benzyloxy)phenyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H) - yl)ethyl) - 3,3 - diethyl dihydrofuran - 2(3H) - one (0.065 g, 0.140 mmol, 1 equiv) in MeOH (1.5 mL) was slowly added to the RBF containing Pd / C. Then, the system was flushed three times with H2 using a balloon filled with H2. The reaction mixture was stirred at room temperature overnight under 1 atm of H2 The Pd / C was removed by filtration through a Celite plug. The filtrate was concentrated in vacuo to give a crude residue, which was first purified by column chromatography (methanol / dichloromethane, 0% - 10%) purified. 1 1H NMR (400 MHz, CDCl3) δ7.13 (dd, J = 1.3, 7.8 Hz, 1H), 7.05 (td, J = 1.3, 7.7 Hz, 1H), 6.93 (dd, J = 1.3, 8.1 Hz, 1H), 6. 85 (td, J = 1.4, 7.7 Hz, 1H), 4.52 (m, 1H), 3.12 - 3.00 (m, 2H), 2.98 - 2.74 (m, 6H), 2.65 (t, J = 7.3 Hz, 2H), 2.58 - 2.46 (m, 2H), 2.16 (dd, J = 6.7, 13.1 Hz, 1H), 2.00 - 1.76 (m, 3H), 1.64 (q, J = 7.5 Hz, 4H), 0.95 (dt, J = 7.4, 22.8 Hz, 6H);): m / z 373.2.

Chemical Structure

[0563] Example 81: Preparation of 3,3-Diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: 5-(2-(5-(3-(Benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyl dihydrofuran-2(3H)-one and 5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one were replaced, except that the title compound was prepared according to the procedure of 3,3-Diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one. compound was prepared. 1 H NMR (400 MHz, CDCl3) δ6.85 (t, J = 8.1 Hz, 1H), 6.00 (td, J = 1.8, 7.6 Hz, 2H), 5.91 (t, J = 2.3 Hz, 1H), 4.24 (m, 1H), 3.18 - 3.05 (m, 2H), 2.97 (d, J = 9.2 Hz, 2H), 2.83 - 2.64 (m, 4H), 2.44 (t, J = 7.3 Hz, 2H), 2.25 (m, 2H), 1.91 (dd, J = 6.7, 13.1 Hz, 1H), 1.77 - 1.53 (m, 3H), 1.40 (q, J = 7.4 Hz, 4H), 0.70 (dt, J = 7.4, 15.6 Hz, 6H); MS (LC / MS, M+H + ): m / z 373.2.

Chemical Structure

[0564] ​​Example 82: Preparation of 3,3 - diethyl - 5-(2-(5-(4 - hydroxyphenyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)dihydrofuran - 2(3H)-one trifluoroacetate: 5-(2-(5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl) ethyl)-3,3 - diethyldihydrofuran - 2(3H)-one and 5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)-3,3 - diethyldihydrofuran - 2(3H)-one were replaced, and except that the reaction time was extended to 3 days, 3,3 - diethyl - 5-(2-(5-(2 - hydroxyphenyl)hexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)di hydrofuran - 2(3H)-one was prepared according to the procedure of the title compound. The second purification through column chromatography (acetonitrile / water, 0% - 100%, w / 0.1% TFA) on a C18 column was required: 1 H NMR (400 MHz, MeOD) δ6.78 - 6.67 (m, 4H), 4.54 (m, 1H), 3.69 (b, 2H), 3.45 (dd, J = 7.2, 9.6 Hz, 2H), 3.40 - 3.09 (m, 6H), 2.98 (m, 2H), 2.28 (dd, J = 6.7, 13.2 Hz, 1H), 2.20 - 1.97 (m, 2H), 1.91 (dd, J = 9.4, 13.2 Hz, 1H), 1.74 - 1.52 (m, 4H), 0.94 (dt, J = 5.0, 14.9 Hz, 6H); MS (LC / MS, M + H + ): m / z 373.2.

Chemical Structure

[0565] Example 83: Preparation of 3,3 - diethyl - 5-(2-(5 - phenylhexahydropyrrolo[3,4 - c]pyrrol - 2(1H)-yl)ethyl)dihydrofuran - 2(3H)-one: 2 - phenyloctahydropyrrolo[3,4 - c]pyrrole dihydrochloride and 2 - phenyl - 2,6 - diazaspiro[3.3]heptane trifluoro The title compound was prepared according to the procedure of 3,3 - diethyl - 5-(2-(6 - phenyl - 2,6 - diazaspiro[3.3]heptan - 2 - yl)ethyl)dihydrofuran - 2(3H)-one, except that 2 - phenyl - 2,6 - diazaspiro[3.3]heptane trifluoro acetate was replaced: 1 H NMR (400 MHz, CDCl3) δ7.14 (m, 2H), 6.64 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.5 Hz, 2H), 4.37 (m, 1H), 3.29 (t, J = 8.1 Hz, 2H), 3.08 (dt, J = 2.7, 9.3 Hz, 2H), 2.92 - 2.79 (b, 2H), 2.78 - 2.65 (m, 2H), 2.47 (t, J = 6.9 Hz, 2H), 2.32 (dd, J = 4.0, 8.9 Hz, 2H), 2.02 (dd, J = 6.7, 13.1 Hz, 1H), 1.87 - 1.61 (m, 3H), 1.51 (q, J = 7.3 Hz, 4H), 0.81 (dt, J = 7.5, 13.9 Hz, 6H); MS (LC / MS, M + H + ): m / z 357.2 Formulation

[0566] The present invention also relates to a composition or formulation comprising a 5 - hydroxytryptamine receptor 7 activity regulator of the present invention. Generally, the composition of the present invention comprises an effective amount of one or more compounds of the present disclosure and salts thereof that are effective in providing regulation of 5 - hydroxytryptamine receptor 7 activity, and one or more excipients.

[0567] ​In the present invention, the terms "excipient" and "carrier" are used interchangeably throughout the description of the present invention and are defined herein as "components used in the formulation of a safe and effective pharmaceutical composition."

[0568] The formulator understands that by using excipients, they first serve to deliver a safe, stable, and functional pharmaceutical product, not only as part of the overall delivery vehicle but also as a means to effectively absorb the active ingredient into the recipient. Excipients can serve a simple and direct role similar to an inert filler, or as used herein, an excipient may partially serve as a pH stabilizing means or a coating to safely and reliably deliver the component to the stomach. The formulator also understands that the compounds of the present invention can take advantage of improved cellular efficacy, pharmacokinetic properties, and even improved oral bioavailability.

[0569] The present teachings also provide pharmaceutical compositions comprising at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and may be prepared according to acceptable pharmaceutical procedures such as those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), the entire disclosure of which is incorporated herein by reference for all purposes. As used herein, "pharmaceutically acceptable" refers to substances that are acceptable for use in pharmaceutical applications from a toxicological perspective and do not have an adverse effect on the active ingredient. Thus, a pharmaceutically acceptable carrier is compatible with the other ingredients in the formulation and is biologically acceptable. Auxiliary active ingredients may also be incorporated into the pharmaceutical composition.

[0570] The compounds of the present disclosure can be administered orally or parenterally, either as such or in combination with conventional pharmaceutical carriers. Suitable solid carriers may include one or more substances that can also function as flavoring agents, lubricants, solubilizing agents, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrants, or encapsulating materials. The compounds can be formulated by conventional methods, for example, in a manner similar to the methods used for known 5-hydroxytryptamine receptor 7 modulators. Oral formulations containing the compounds disclosed herein can include any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges, and oral liquids, suspensions or solutions. In the case of powders, the carrier may be a finely divided solid which will be a mixture with the finely divided compound. In the case of tablets, the compounds disclosed herein can be mixed with a carrier having the necessary compression characteristics in suitable ratios and compressed into the desired shape and size. Powders and tablets can contain up to 99% of the compound. Capsules can contain a mixture of one or more of the compounds disclosed herein with an inert filler and / or diluent, such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweeteners, powdered celluloses (e.g., crystalline cellulose and microcrystalline cellulose), wheat flour, gelatin, gums, etc.

[0571]

[0572] ​Useful tablet formulations can be prepared by conventional compression methods, wet granulation methods or dry granulation methods, and pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents or stabilizers can be used. Examples of these include, but are not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, saccharides, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicate, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting point wax, and ion exchange resin. Surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine. The oral formulations herein can vary the absorption of the compound using standard delayed release or sustained release formulations. Oral formulation can also consist of dosing the compounds disclosed herein into water or fruit juice containing appropriate solubilizing or emulsifying agents as needed.

[0573] The liquid carrier can be used to prepare solutions, suspensions, emulsions, syrups, and elixirs, and can also be used for inhalation delivery. The compounds of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier can include other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, dyes, viscosity regulators, stabilizers, and osmotic pressure regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (especially including additives described herein, such as cellulose derivatives such as sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols such as glycols) and their derivatives, and oils (such as fractionated coconut oil and peanut oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. It can be. The sterile liquid carrier is used in a sterile liquid form composition for parenteral administration. The liquid carrier for a pressurized composition can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0574] A liquid pharmaceutical composition that is a sterile solution or suspension can be utilized, for example, for intramuscular, intraperitoneal, or subcutaneous injection. The sterile solution can also be administered intravenously. The composition for oral administration can be in either liquid or solid form.

[0575] The pharmaceutical composition is preferably in a unit dosage form such as, for example, tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such dosage forms, the pharmaceutical composition can be further divided into unit doses containing an appropriate amount of the compound. The unit dosage form can be, for example, a packaged composition such as a powder in a sachet, a vial, an ampoule, a pre-filled syringe, or a sachet containing a liquid. Alternatively, the unit dosage form can be the capsule or tablet itself, or any appropriate number of the packaged form of the composition. Such unit dosage forms can contain from about 1 mg / kg to about 500 mg / kg of the compound and can be administered as a single dose or multiple doses. Such doses can be administered, for example, orally, via an implant tablet, parenterally (including intravenous injection, intraperitoneal injection, and subcutaneous injection), rectally, vaginally, and transdermally, in any manner useful for introducing the compound into the bloodstream of the recipient.

[0576] It is understood that when administered for the treatment or suppression of a particular disease state or disorder, the effective dosage can vary depending on the particular compound used, the method of administration, and the severity of the symptoms being treated, as well as various physical factors related to the individual being treated. In therapeutic use, the compounds of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a particular individual will customarily have to be determined subjectively by the attending physician. The variables involved include the particular symptoms and their condition, as well as the size, age, and response pattern of the patient.

[0577] In certain cases, it may be desirable to administer the compounds directly to the patient's airway using devices such as, but not limited to, metered dose inhalers, respiratory inhalers, multi-dose dry powder inhalers, pumps, squeeze sprayers, aerosol dispensers, and aerosol sprayers. For administration by inhalation into the nasal cavity or bronchus, the compounds of the present teachings can be formulated into liquid compositions, solid compositions, or aerosol compositions. Liquid compositions include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered, for example, using a pump or squeeze sprayer. The solvent can be, for example, isotonic saline or bacteriostatic water. Solid compositions can be, by way of illustration, powder preparations containing one or more compounds of the present teachings, which preparations are mixed with lactose or other inert powders that can be used in the bronchus. Also, the composition can be administered, for example, by an aerosol dispenser or by a device that breaks or punctures a capsule enclosing the solid composition and delivers the solid composition by inhalation. Aerosol compositions can include, by way of illustration, one or more compounds of the present teachings, a propellant, a surfactant, and a co-solvent and can be administered, for example, using a metering device. The propellant can be a chlorofluorocarbon (CFC), a hydrofluoro alkane (HFA), or other propellant that is physiologically and environmentally acceptable and can be used.

[0578] The compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or their pharmaceutically acceptable salts, hydrates, or esters can be prepared as aqueous solutions by appropriately mixing them with surfactants such as hydroxypropylcellulose. Also, dispersions can be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oils. Under normal storage and use conditions, these preparations generally contain preservatives to inhibit the growth of microorganisms.

[0579] Pharmaceutical forms suitable for injection may include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions. In some embodiments, the form can be sterilized and, by virtue of its viscosity, can flow through a syringe. The form is preferably stable under the conditions of manufacture and storage and can be protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium including water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0580] The compounds described herein can be administered transdermally, i.e., across the body surface and inside the body's passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings (including their pharmaceutically acceptable salts, hydrates, or esters) in the form of lotions, creams, foams, patches, suspensions, solutions, and suppositories (such as rectal and vaginal).

[0581] Transdermal administration can be effected by using a transdermal patch containing a compound such as a compound disclosed herein, and a carrier that is inert to the compound, harmless to the skin, and capable of delivering the compound through the skin for systemic absorption into the bloodstream. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. Creams and ointments can be either water-in-oil or oil-in-water viscous liquid or semisolid emulsions. Pastes consisting of absorbent powders dispersed in petrolatum or hydrophilic petrolatum containing the compound can also be suitable. The compound can be released into the bloodstream using various occlusive devices such as a semipermeable membrane covering a reservoir containing the compound with or without the carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

[0582] The compounds described in this specification can be administered rectally or vaginally in the form of conventional suppositories. Suppository formulations can be made from conventional materials including cocoa butter, with or without the addition of waxes that change the melting point of the suppository and glycerin. Water-soluble suppository bases such as polyethylene glycols of various molecular weights can also be used.

[0583] Lipid formulations or nanocapsules can be used to introduce the compounds of the present teachings into host cells in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

[0584] To enhance the effectiveness of the compounds of the present teachings, it may be desirable to combine the compounds with other agents effective in the treatment of the target disease. For example, other active compounds (i.e., other active ingredients or agents) effective in the treatment of the target disease can be co-administered with the compounds of the present teachings. The other agents can be administered simultaneously with or at different times from the compounds disclosed herein.

[0585] The compounds of the present teachings can be useful in the treatment or suppression of pathological conditions or disorders in mammals, such as human subjects. Accordingly, the present teachings provide a method of treating or suppressing a pathological condition or disorder by administering to a mammal a pharmaceutical composition comprising a compound of the present teachings (including its pharmaceutically acceptable salts), or one or more compounds of the present teachings in combination or association with a pharmaceutically acceptable carrier. The compounds of the present teachings can be administered alone, or in combination with other therapeutically effective compounds, or a method of treatment for treating or suppressing the pathological condition or disorder.

[0586] Non-limiting examples of the compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more compounds according to the present invention disclosed herein and one or more excipients, from about 0.01 mg to about 100 mg of one or more compounds according to the present invention disclosed herein and one or more excipients, from about 0.1 mg to about 10 mg of one or more compounds according to the present invention disclosed herein and one or more excipients, from about 0.1 mg to about 10 mg of one or more compounds according to the present invention disclosed herein and one or more excipients. The above compounds and one or more excipients may be mentioned. Procedure

[0587] In the evaluation and selection of a compound as a 5-hydroxytryptamine receptor 7 modulator the following procedure can be used. Radioligand binding assay for serotonin 5-HT7 receptor, Method 1:

[0588] A solution of the compound of the present disclosure to be tested is prepared as a 1 mg / ml stock solution dissolved in Assay Buffer or DMSO according to its solubility. Also, a similar stock solution of the reference compound chlorpromazine is prepared as a positive control. Eleven dilutions (5× assay concentration) of the compound of the present disclosure and chlorpromazine are prepared in Assay Buffer by serial dilution to obtain final corresponding assay concentrations in the range of 10 pM to 10 μM.

[0589] 5 nM of 3 [3H]LSD (lysergic acid diethylamide) stock solution concentration is prepared in 50 mM Tris-HCl, 10 mM MgCl2, 1 mM EDTA, pH 7.4 (Assay Buffer). Aliquots (50 μl) of the radioligand are dispensed into the wells of a 96-well plate containing 100 μl of Assay Buffer. Aliquots (50 μl) of each serial dilution of the test compound of the present disclosure and the chlorpromazine positive control reference compound are added.

[0590] Membrane fractions (50 μL) of cells expressing recombinant 5-HT7 receptor are dispensed into each well. The membrane is It is prepared from a stable transfected cell line expressing the 5HT7 receptor cultured on a 10 cm plate. This culture is carried out by recovering the monolayer rinsed with PBS, resuspending and lysing it in cooled hypotonic 50 mM Tris-HCl (pH 7.4), centrifuging at 20,000×g, discarding the supernatant, and storing at -80 °C. The membrane preparation is resuspended in 3 mL of cooled Assay Buffer and homogenized by passing it several times through a 26-gauge needle before use in the assay.

[0591] After incubating 250 μl of the reaction mixture at room temperature for 1.5 h, it is collected by rapid filtration on a 96-well filter mat treated with 0.3% polyethyleneimine using a Filtermate Harvester. To reduce non-specific binding, four rapid 500 μl washes are performed using cooled Assay Buffer. After drying the filter mat, scintillant is added to the filter and the radioactivity remaining on the filter is counted using a Microbeta scintillation counter. The raw data (dpm) representing total radioligand binding (i.e., specific + non-specific binding) is plotted as a function of the logarithm of the molar concentration of the competitor (i.e., test compound or reference compound). Non-linear regression of the normalized (i.e., the ratio of radioligand binding compared to that observed in the absence of the test compound or reference compound) raw data is performed using Prism 4.0 (GraphPad Software) with a built-in three-parameter logistic model representing the binding of the ligand competitor to the radioligand-labeled site:

[0592] y = bottom + [(top - bottom) / (1 + 10x-logIC )] 50 where bottom is the residual radioligand binding measured in the presence of 10 μM reference compound, i.e., i.e., non-specific binding), and the upper part is equal to the total radioligand binding observed in the absence of the competitor. log IC 50 (i.e., the logarithm of the ligand concentration that reduces the radioligand binding by 50%) is estimated from the data, and Ki is obtained from the Cheng-Prusoff approximation using this value: Ki = IC 50 / (1 + [ligand] / KD) where [ligand] is equal to the assay radioligand concentration and KD is equal to the binding constant of the radioligand for the target receptor.

[0593] In addition, the compounds of the present disclosure are screened at a single concentration of 10 μM using the same method as described for the test of radiolabeled binding to the serotonin 5HT7 receptor, 3 and the inhibition rate of [H]LSD binding is calculated. Radiolabeled binding assay for serotonin 5-HT7 receptor, Method 2:

[0594] A solution of the compound of the present disclosure to be tested is prepared as a 1 mg / ml stock solution dissolved in Assay Buffer or DMSO depending on its solubility. Also, a similar stock solution of the reference compound chlorpromazine is prepared as a positive control. Eleven dilutions (5× assay concentration) of the compound of the present disclosure and chlorpromazine are prepared in Assay Buffer by serial dilution to obtain final corresponding assay concentrations in the range of 10 pM to 10 μM.

[0595] 5 nM of 3 [H]-5-hydroxytryptamine ( 3 [H]-5HT) stock solution concentration is prepared in 50 mM Tris-HCl, 10 mM MgCl2, 1 mM EDTA, pH 7.4 (Assay Buffer). Aliquots (50 μl) of the radioligand are dispensed into the wells of a 96-well plate containing 100 μl of Assay Buffer. Aliquots (50 μl) of each serial dilution of the test compound of the present disclosure and the chlorpromazine positive control reference compound are added.

[0596] Aliquot 50 μL of the membrane fraction of cells expressing recombinant 5HT7 receptor into each well. The membrane is prepared from a stable transfected cell line expressing 5HT7 receptor cultured on a 10 cm plate. This culture is performed by collecting the monolayer rinsed with PBS, resuspending and lysing it in chilled hypotonic 50 mM Tris-HCl (pH 7.4), centrifuging at 20,000 × g, discarding the supernatant, and storing at -80 °C. The prepared membrane is resuspended in 3 mL of chilled Assay Buffer and homogenized by passing it several times through a 26-gauge needle before use in the assay.

[0597] Incubate 250 μL of the reaction mixture at room temperature for 1.5 h, then collect it by rapid filtration on a 96-well filtermat treated with 0.3% polyethyleneimine using a 96-well Filtermate Harvester Star. Perform four rapid 500 μL washes with chilled Assay Buffer to reduce non-specific binding. After drying the filtermat, add scintillant to the filter and count the radioactivity remaining on the filter using a Microbeta scintillation counter. Plot the raw data (dpm) representing total radioligand binding (i.e., specific + non-specific binding) as a function of the logarithm of the molar concentration of the competitor (i.e., test compound or reference compound). Perform non-linear regression of the normalized (i.e., the ratio of radioligand binding observed in the absence of the test compound or reference compound) raw data using the built-in 3-parameter logistic model representing the binding of the ligand competitor to the radioligand-labeled site using Prism 4.0 (GraphPad Software):

[0598] y = Bottom + [(Top - Bottom) / (1 + 10x - logIC 50 50 50 50 )] Here, the bottom is equal to the residual radioligand binding measured in the presence of 10 μM of the reference compound (i.e., non-specific binding), and the top is equal to the total radioligand binding observed in the absence of the competitor. The log IC (i.e., the logarithm of the ligand concentration that reduces radioligand binding by 50%) is estimated from the data and used to obtain Ki from the Cheng-Prusoff approximation: 50 (i.e., the logarithm of the ligand concentration that reduces radioligand binding by 50%) is estimated from the data and used to obtain Ki from the Cheng-Prusoff approximation: Ki = IC Ki = IC 50 / (1 + [ligand] / KD) where [ligand] is equal to the assay radioligand concentration and KD is equal to the binding constant of the radioligand for the target receptor.

[0599] Also, the compounds of the present disclosure are screened at a single concentration of 10 μM using the same method as described for the test of radiolabeled binding to the serotonin 5HT7 receptor to calculate the inhibition rate of 3 H]-5HT binding.

[0600] The results of representative compounds according to the present invention are listed in Table 11. Table 11: Results of radiolabeled binding assay of serotonin 5HT7 receptor for exemplary compounds of the present disclosure

Table 11-1

Table 11-2

Table 11-3

[0601] Functional serotonin 5HT7 assay, Method 1:

[0602] A cell line stably expressing the human 5HT7 receptor is assayed (40,000 cells per well) 48 hours before in Dulbecco's modified Eagle's medium (DMEM) containing 5% dialyzed serum. The cells were seeded onto a 96-well poly-L-lysine-coated plate. Twenty hours before the assay, the medium was Change to serum-free DMEM. On the day of the assay, wash and replace the DMEM with 30 μl of assay buffer (1× Krebs-Ringer glucose bicarbonate buffer, 0.75 mM IBMX, pH 7.4). Incubations are carried out in a humidified incubator at 37°C (Celsius). Cells are then stimulated by adding 30 μl of a 2× dilution of a compound of the disclosure or chlorpromazine (final concentrations ranging from 0.1 nM to 10 μM, each concentration assayed in triplicate). A positive control (100 μM forskolin) is also included. cAMP is allowed to accumulate for 15 minutes before the buffer is removed and cells are lysed with Cell Lysis Buffer (CatchPoint cAMP Assay Kit, Molecular Devices). Lysates are then transferred to 96-well glass-bottom plates coated with goat anti-rabbit IgG and adsorbed with rabbit anti-cAMP (Molecular Devices). After a 5-minute incubation, Horseradish peroxidase-cAMP conjugate (Molecular Devices) was added and the chamber was Incubate at room temperature for 2 hours. Then wash three times with Wash Buffer (Molecular Devices). After washing, Stoplight Red substrate (Molecular Devices) reconstituted in Substrate Buffer (Molecular Devices) containing freshly added 1 mM H2O2 is added and fluorescence is measured after 15 min incubation at room temperature (excitation 510-545 nm, emission 565-625 nm). For each assay, a cAMP calibration curve is generated and a no-lysate and no-antibody control is also included.

[0603] For the agonist assay, the raw data (maximum fluorescence, fluorescence units) for each concentration of the compound of the present disclosure or chlorpromazine is normalized against the fluorescence of the basal (vehicle-derived) (recording how many times increased relative to the basal), and plotted as a logarithmic function of the molar concentration of the drug (i.e., the test compound or reference compound ). Non-linear regression of the normalized data is performed in Prism 4.0 (GraphPad Software) using a built-in three-parameter logistic model (i.e., sigmoidal concentration response) representing agonist-induced activation of a single receptor population: That is: y = Bottom + [(Top - Bottom) / (1 + 10^(x - logEC50))] Here, Bottom is equal to the best-fit basal fluorescence, and Top is equal to the best-fit maximum fluorescence induced by the compound of the present disclosure or chlorpromazine. log EC 50 (i.e., the logarithm of the drug concentration at which a 50% fluorescence increase of the maximum fluorescence observed for the compound of the present disclosure or chlorpromazine is seen) is estimated from the data, and EC (agonist potency) is obtained. To obtain an estimate of the relative efficacy (relative Emax) of the test compound, its best-fit Top is compared to that of chlorpromazine and expressed as a ratio to chlorpromazine (the relative Emax of the reference agonist is 1.00). 50

[0604] To confirm whether the compound of the present disclosure is an antagonist, a representative example of double addition is used. First, 30 μl of the compound of the present disclosure (20 μM) is added (final concentration 10 μM) and incubated for 15 minutes. Then, 30 μl of chlorpromazine (3X; EC 90 ) is added (a ​The final concentration of the gonist is EC30), and cAMP is accumulated for 15 minutes. Next, the sample is processed for cAMP measurement as detailed above. The measured value of chlorpromazine-induced cAMP accumulation is compared with the signal induced by chlorpromazine after adding the vehicle instead of the test compound and expressed as a ratio. Subsequently, "hits" (compounds that suppress at least 50% of the increase in fluorescence induced by chlorpromazine normalized to the baseline) are characterized by modified Schild analysis.

[0605] For modified Schild analysis, a set of chlorpromazine concentration-response isotherms is generated in the absence of the test compound and in the presence of stepwise concentrations of the test compound (added 15 minutes before the reference agonist). In theory, a compound that is a competitive antagonist causes a rightward shift of the agonist concentration-response isotherm without decreasing the maximum response to the agonist (i.e., competitive antagonism). On the other hand, factors such as non-competitive antagonism, hemiequilibria, and / or pre-receptors may result in apparent persistent antagonism. To account for such deviations, the modified Lew-Angus method is applied to confirm the effectiveness of the antagonist (Christopoulos et al., 1999). Briefly, the equipotent concentration of the agonist (the concentration of the agonist that elicits a response equal to the EC 25% of the agonist control curve) is plotted as a function of the concentration of the compound of the present disclosure present in the wells in which the concentration was measured. Nonlinear regression of the baseline-normalized data is performed in Prism 4.0 using the following equation: pEC25% = -log([B] + 10-pK) - log c where EC25% is equal to the concentration of the agonist that elicits a response equal to 25% of the maximum agonist control curve response, [B] is equal to the antagonist concentration; K, c, and s are fitting parameters. The parameter s is equal to the Schild slope factor. If s does not differ significantly from 1, pK is equal to pKB. Otherwise, pA2 is calculated (pA2 = pK / s). The parameter c is equal to the ratio EC 25% / [B]. Functional Efficacy Assay for 5-HT7 Receptor Method 2:

[0606] The functional efficacy of the compounds of the present disclosure on the 5-HT7 serotonin receptor was measured in a cell-based cAMP enzyme fragment complementation assay using the HitHunter cAMP assay (DiscoveRx). Cells stably expressing the human 5HT7 receptor were plated at 4000 cells / well in 96-well plates 16 - 20 hours prior to assay in growth medium (Ultraculture medium, 2 mM GlutaMax and 1 mg / mL G418). Serial dilutions of the agonist, 5-carboxamidotryptamine (5-CT), were prepared in the final concentration range of 10 μM to 10 nM. The compounds of the present disclosure were prepared in 3-fold serial dilutions to obtain a final concentration range of 10 μM to 0.1 nM. The compounds of the present disclosure were evaluated for agonist activity in the absence of 5-CT and antagonist activity in the presence of 5-CT. For the cAMP assay, the protocol was followed according to the instructions provided by the supplier. Briefly, the cells were incubated with the compounds of the present disclosure at 37 °C for 30 minutes before adding the EC concentration of 5-CT. After an additional 30 minutes, the cAMP antibody / cell lysis solution was added (20 μL / well) and incubated at room temperature for 60 minutes. The cAMP XS and EA reagents were added (20 μL / well) and incubated at room temperature for 2 70 hours. Luminescence was read on an Envision Multilabel plate reader.

[0607] The disclosure of each patent, patent application, and publication cited herein is hereby incorporated by reference in its entirety.

[0608] ​Although the present invention has been disclosed with reference to specific embodiments, it will be apparent that other embodiments and modifications of the present invention can be devised by those skilled in the art without departing from the true spirit and scope of the invention. It is intended that the appended claims be construed to include all such embodiments and equivalent modifications.

Claims

1. A composition for treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity, comprising an effective amount of at least one compound having the following formula (I): 【Chemical 1】 (including its pharmaceutically acceptable salts), characterized by being administered to a subject, wherein: n is 2, R 1ａ and R 1ｂ are each independently C 1-6 a linear alkyl, or R 1ａ and R 1ｂ may together with the atom to which they are attached form a cycloalkyl ring having 3 to 7 ring atoms; R 2 is a benzene ring optionally substituted with a group R which is not hydrogen and has 0 to 3 hydrogens; 3 ​ R 3 is, at each occurrence position, independently selected from the group consisting of OH, CN, C 1-6 linear alkyl, C 3-7 branched alkyl, C 1-6 linear alkoxy, heterocyclyl; and R 3ａ 、 R 3ｂ 、 R 3ｃ 、 R 3ｄ 、 and R 3ｅ The terms R 3 groups may be used to specify the individual R Composition.

2. A composition for treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity according to claim 1, wherein the compound having formula (I) is a compound having the following formula (IIa): (including an effective amount of its pharmaceutically acceptable salts), wherein: n is 2; and R 3a 、R 3b 、R 3c 、R 3d and R 3e Of the groups of R 3a 、R 3b 、R 3c 、R 3d and R 3e Among them, 0 to 3 are independently selected from the group consisting of OH, CN, C 1-6 linear alkyl, C 3-7 branched alkyl, C 1-6 linear alkoxy, heterocyclyl, a composition.

3. R 1ａ and R 1ｂ each independently is C 1-6 a straight-chain alkyl, a composition for treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity according to claim 1 or 2. The composition according to claim 3, wherein R1a and R1b are each independently ethyl.

5. R 1ａ and R 1ｂ forms, together with the atoms to which they are attached, a cycloalkyl ring having 3 to 7 ring atoms, a composition for treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity according to claim 1 or 2.

6. A composition for treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity according to claim 1, wherein the at least one compound is (R)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (S)-3-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one; (R)-3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-2-(5-(2-(4,4-Diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (S)-2-(5-(2-(4,4-Diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (R)-3-(5-(2-(4,4-Diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (S)-3-(5-(2-(4,4-Diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (R)-4-(5-(2-(4,4-Diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (S)-4-(5-(2-(4,4-Diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile; (R)-3,3-Diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (R)-3,3-Diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one; (S)-3,3-Diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one, or a composition comprising at least one of these pharmaceutically acceptable salts.

7. A composition for treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity according to claim 1, further comprising at least one excipient.

8. A composition for treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity according to any one of claims 1 to 7, wherein the disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity is inflammatory bowel disease, circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorder, learning disorder, memory disorder, hippocampal signal transduction disorder, sleep disorder, attention deficit / hyperactivity disorder, phobia, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, or bipolar disorder.

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