Novel modulators of serotonin receptor 7 and methods of use thereof

Abstract

The pharmaceutical composition of the present invention comprises a functionalized lactone derivative having a disease ameliorating effect in the treatment of diseases associated with dysregulation of serotonin receptor 7 activity.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a divisional application of the Chinese invention patent application with application number 201780079945.9, application date November 15, 2017, and invention name “Novel modulators of 5-hydroxytryptamine receptor 7 and methods of use thereof”, the original application is a national phase application with international application number PCT / US2017 / 061677, which claims priority to the U.S. provisional patent application with application number 62 / 422,344, filed on November 15, 2016. The entire contents of the application are incorporated by reference.

[0003] Federally Sponsored Research Statement

[0004] The U.S. Government has a paid-up license to this invention and, in limited circumstances, the right to require the patent owner to license others under reasonable terms as provided by Grant No. HHSN-271-2008-00025-C granted by the National Institute of Mental Health. Technical Field

[0005] Embodiments of the present invention are directed to novel compounds useful as modulators of 5-HT7 activity and methods of use thereof. Embodiments are also directed to novel chemotypes useful for treating diseases associated with dysregulation of 5-HT7 activity. Background Art

[0006] Serotonin was discovered in the late 1940s and is present in 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 on the synapses of nerve cells. Seven different serotonin receptor families have been discovered, and at least 20 subgroups have been cloned based on sequence similarity, signal transduction coupling and pharmacological characteristics. The seven 5-HT receptor families are named 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7, and each of these receptors has a subfamily or subgroup. The signal transduction mechanisms of all seven families have been studied, and it is known that activation of 5-HT1 and 5-HT5 receptors results in a decrease in intracellular cAMP, while activation of 5-HT2, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 results in an increase in intracellular IP3 and DAG. The 5-HT pathway in the brain is an important target for drug development in the field of CNS diseases. Neurotransmitters bind to their G protein-coupled receptors and participate in a variety of effects, including cognition, mood, 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 (WO 2012058769, Khan, WI et al., Journal of Immunology, 2013, 190, 4795-4804), epilepsy, epilepsy (Epilepsy Research (2007) 75, 39), drug addiction and alcohol addiction (Hauser, SR et al., Frontiers in Neuroscience, 2015, 8, 1-9), etc. Summary of the invention

[0007] The present invention relates to novel 5-hydroxytryptamine receptor 7 (5-HT7) activity modulators, namely compounds of formula (I),

[0008]

[0009] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0010] A is selected from

[0011] X is selected from O, S, SO, SO2, NR;

[0012] n 1 0, 1, 2;

[0013] n 2 0, 1, 2;

[0014] R is selected from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, COR 2 、CO2R 2a ,CONR 2b R 2c 、SO2NR 2b R 2c and SO2R 2d ;

[0015] R 1a , R 1b , R 1c , R 1d and R 1e is independently selected at each occurrence from H, OH, NO2, halogen, CN, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Straight chain alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Straight chain halogenated alkyl, C 3-7 Branched chain halogenated alkyl, C 1-6 Straight chain halogenated alkoxy, -S(C 1-6 Straight chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 Cycloalkyl), COR 6 、CO2R 7 ,CONR 8a R 8b 、SO2NR 8a R 8b NR 9a R 9b NR 9a COR 10 NR 9a S02R 11 and NR 9a SO2NR 12a R 12b ;

[0016] R 2 Selected from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C3-7 Cycloalkyl;

[0017] R 2a Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0018] R 2b Selected from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0019] R 2c Selected from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0020] R 2d Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Straight chain halogenated alkyl, C 3-7 Branched haloalkyl, -(CH2) q CN, -(CH2) q S02R 13 、-(CH2) q OR 14 ,

[0021] R 3 Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, optionally substituted aryl,

[0022]

[0023] R 4 is an optionally substituted aryl group;

[0024] R 5a and R 5b each independently optionally substituted with aryl;

[0025] R 6 independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0026] R 7 In each occurrence, independently selected from C1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0027] R 8a independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0028] R 8b independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0029] R 9a independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0030] R 9b independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0031] R 10 independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0032] R 11 In each occurrence, independently selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0033] R 12a In each occurrence, independently selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0034] R 12b In each occurrence, independently selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0035] R 13 Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C3-7 Cycloalkyl;

[0036] R 14 Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0037] n is 1, 2 or 3;

[0038] m is 1 or 2;

[0039] and q is 1, 2, or 3;

[0040] The present invention also relates to a composition comprising:

[0041] An effective amount of one or more compounds according to the invention and an excipient.

[0042] The present invention also relates to a method for treating or preventing diseases involving disordered activity of 5-hydroxytryptamine receptor 7, such as circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, temperature regulation disorders, learning disorders, memory disorders, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, epilepsy, drug addiction and alcohol addiction, the method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0043] The present invention also relates to a method for treating or preventing diseases involving dysregulation of 5-hydroxytryptamine receptor 7 activity, including, for example, circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, temperature regulation disorders, learning disorders, memory disorders, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, epilepsy, drug addiction and alcohol addiction, wherein the method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0044] The present invention also relates to a method for treating or preventing a disease or condition associated with circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, temperature regulation disorders, learning disorders, memory disorders, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, epilepsy, drug addiction, alcohol addiction, and diseases involving dysregulation of serotonin receptor 7 activity. The method comprises administering to a subject an effective amount of a compound or composition according to the present invention.

[0045] The present invention also relates to a method for treating or preventing a disease or condition associated with circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, temperature regulation disorders, learning disorders, memory disorders, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, epileptic diseases, drug addiction, alcohol addiction and diseases involving dysregulation of serotonin receptor 7 activity, wherein the method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0046] The present invention also relates to a method for treating or preventing a disease or condition associated with dysregulation of activity of serotonin receptor 7. The method comprises administering to a subject an effective amount of a compound or composition according to the present invention.

[0047] The present invention also relates to a method for treating or preventing a disease or condition associated with dysregulation of serotonin receptor 7 activity, wherein the method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0048] The present invention also relates to a method for preparing the 5-hydroxytryptamine receptor 7 activity modulator of the present invention.

[0049] By reading the following detailed description and the appended claims, the above and other objects, features and advantages will become apparent to those of ordinary skill in the art. Unless otherwise specified, all percentages, ratios and proportions herein are by weight. Unless otherwise specified, all temperatures are in degrees Celsius (° C.). The relevant parts of all cited documents are incorporated herein by reference; the reference to any document should not be construed as an admission that it is prior art with respect to the present invention. DETAILED DESCRIPTION

[0050] There is evidence for a role for the 5-HT7 receptor in a variety of medical conditions. Modulators of 5-HT7 receptor activity may have beneficial effects in patients suffering from these conditions. Diseases in which 5-HT7 dysregulation plays a role and modulation of 5-HT7 receptor activity by therapeutic agents may be a viable approach for therapeutic relief 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 (EP1875899), thermoregulatory disorders, learning disorders, memory disorders, hippocampal signaling disorders, sleep disorders (WO20100197700), attention deficit / hyperactivity disorder (ADHD) (WO20100069390), anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder (WO20040229874), inflammatory bowel disease (IBD), enteritis (WO 2012058769, Khan, WI et al., Journal of Immunology, 2013, 190, 4795-4804), epilepsy, epileptic disorders (Epilepsy Research (2007) 75, 39), drug addiction and alcohol addiction (Hauser, SR et al., Frontiers in Neuroscience, 2015, 8, 1-9).

[0051] Therefore, there is a long-standing need for new 5-HT7 modulators that will provide therapeutic relief to patients suffering from diseases associated with dysregulated 5-HT receptor 7 activity. The present invention addresses the need to identify new 5-HT7 modulators capable of treating diseases associated with dysregulated 5-HT receptor 7 activity. The present invention addresses the need to develop new therapeutic agents for the treatment and prevention of circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, temperature regulation disorders, learning disorders, memory disorders, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, epileptic disorders, drug addiction, and alcohol addiction.

[0052] The 5-hydroxytryptamine receptor 7 activity modulators of the present invention can treat and prevent diseases related to 5-hydroxytryptamine receptor 7 activity disorders, such as circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, temperature regulation disorders, learning disorders, memory disorders, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, epilepsy, drug addiction and alcohol addiction. 5-hydroxytryptamine receptor 7 has been found to play a role in a variety of medical diseases, and therefore, 5-HT7 receptor activity modulators may have beneficial effects on patients suffering from these diseases. Diseases in which 5-HT7 dysregulation plays a role and modulation of 5-HT7 receptor activity by therapeutic agents may be a viable approach for therapeutic relief 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 (EP1875899), thermoregulatory disorders, learning disorders, memory disorders, hippocampal signaling disorders, sleep disorders (WO20100197700), attention deficit / hyperactivity disorder (ADHD) (WO20100069390), anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder (WO20040229874), inflammatory bowel disease (IBD), enteritis (WO 2012058769), epilepsy, epileptic disorders (Epilepsy Research (2007) 75, 39), drug addiction and alcohol addiction (Hauser, SR et al., Frontiers in Neuroscience, 2015, 8, 1-9).

[0053] Without wishing to be bound by theory, it is believed that the 5-hydroxytryptamine receptor 7 receptor activity modulators of the present invention can improve, alleviate or otherwise allow control of diseases associated with dysregulated 5-hydroxytryptamine receptor 7 activity. These diseases include, but are not limited to, circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, temperature regulation disorders, learning disorders, memory disorders, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, epileptic disorders, drug addiction and alcohol addiction.

[0054] Throughout the specification, when compositions are described as having, including, or comprising specific components, or when methods are described as having, including, or comprising specific method steps, it is contemplated that the compositions of the present teachings also consist essentially of or consist of the listed components, and that the methods of the present teachings also consist essentially of or consist of the listed method steps.

[0055] In the application, where an element or component is referred to as being included in and / or selected from the listed elements or components, it should be understood that the element or component can be any one of the listed elements or components, and can be selected from two or more of the listed elements or components.

[0056] Unless expressly stated otherwise, the use of the singular herein includes the plural (and vice versa). In addition, when the term "about" is used before a quantitative value, the present teachings also include the specific quantitative value itself, unless expressly stated otherwise.

[0057] It should be understood that the order of steps or the order in which certain actions are performed is not important as long as the present teachings are still operable. In addition, two or more steps or actions may be performed simultaneously.

[0058] As used herein, the term "halogen" shall mean chlorine, bromine, fluorine and iodine.

[0059] As used herein, unless otherwise indicated, "alkyl" and / or "aliphatic", whether used alone or as part of a substituent group, refers to straight and branched carbon chains having 1 to 20 carbon atoms, or any number within this range (e.g., 1 to 6 carbon atoms or 1 to 4 carbon atoms). 1-6) shall independently refer to the number of carbon atoms in the alkyl portion or to the number of carbon atoms in the alkyl portion of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. Alkyl groups may be optionally substituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, and the like. In substituents having multiple alkyl groups such as (C 1-6 In the amino group, the alkyl groups may be the same or different.

[0060] As used herein, the term "alkenyl" and "alkynyl" groups, whether used alone or as part of a substituent group, refer to straight and branched carbon chains with 2 or more, preferably 2 to 20 carbon atoms, wherein the alkenyl chain has at least one double bond in the chain, and the alkynyl chain has at least one triple bond in the chain. Alkenyl groups and alkynyl groups can be optionally substituted. Non-limiting examples of alkenyl groups include vinyl, 3-propenyl, 1-propenyl (also 2-methylvinyl), isopropenyl (also 2-methylvinyl-2-yl), butene-4-yl, etc. Non-limiting examples of substituted alkenyl groups include 2-chlorovinyl (also 2-chlorovinyl), 4-hydroxybutene-1-yl, 7-hydroxy-7-methyloct-4-ene-2-yl, 7-hydroxy-7-methyloct-3,5-diene-2-yl, etc. The limiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl and 2-methyl-hex-4-yn-1-yl. The limiting examples of substituted alkynyl groups include 5-hydroxy-5-methyl hex-3-ynyl, 6-hydroxy-6-methyl hept-3-yn-2-yl, 5-hydroxy-5-ethyl hept-3-yn-yl etc.

[0061] As used herein, "cycloalkyl", whether used alone or as part of another group, refers to a non-aromatic carbon-containing ring containing, for example, 3 to 14 ring carbon atoms, preferably 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, alkylene and alkynyl groups and optionally containing one or more (e.g., 1, 2 or 3) double or triple bonds. The cycloalkyl group can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged and / or spirocyclic systems), wherein the carbon atoms are located inside or outside the ring system. Any suitable ring position of the cycloalkyl group can be covalently attached to a defined chemical structure. The cycloalkyl ring can be optionally substituted. Non-limiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulyl; bicyclo[6.2.0]decyl, decahydronaphthyl and dodecahydro-1H-fluorenyl. The term "cycloalkyl" also includes carbocycles that are bicyclic hydrocarbon rings, non-limiting examples of which include bicyclo-[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, 1,3-dimethyl[2.2.1]hept-2-yl, bicyclo[2.2.2]octyl, and bicyclo[3.3.3]undecyl.

[0062] "Haloalkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups with a specified number of carbon atoms substituted by one or more halogens.Haloalkyl groups include perhaloalkyl groups, in which all hydrogens of the alkyl group have been replaced by halogens (e.g., -CF3, -CF2CF3). In addition to halogen, haloalkyl may also be optionally substituted by one or more substituents. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl and pentachloroethyl groups.

[0063] The term "alkoxy" refers to group-O-alkyl, wherein the alkyl group is as defined above. The alkoxy group may optionally be substituted. The term C3-C6 cycloalkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyrans). The C3-C6 cycloalkoxy may optionally be substituted.

[0064] The term "haloalkoxy" refers to the group -O-haloalkyl, wherein the haloalkyl group is as defined above. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and pentafluoroethoxy.

[0065] The term "aryl" used alone or as a part of another group is defined as an unsaturated aromatic monocyclic ring of 6 carbon members or an unsaturated aromatic polycyclic ring containing 10 to 14 carbon members in this article. The aryl ring can be, for example, a benzene ring or a naphthalene ring optionally substituted by one or more parts that can replace one or more hydrogen atoms. The non-limiting examples of aryl groups include: phenyl, naphthalene-1-yl, naphthalene-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8-hydroxynaphthalene-2-yl-4,5-dimethoxynaphthalene-1-yl and 6-cyano-naphthalene-1-yl. Aryl groups also include, for example, a benzene or naphthalene ring fused to one or more saturated or partially saturated carbocyclic rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl), which may be substituted at one or more carbon atoms of the aromatic ring and / or the saturated or partially saturated ring.

[0066] The term "arylalkyl" or "aralkyl" refers to the group -alkyl-aryl, wherein the alkyl and aryl groups are as defined herein. The aralkyl groups of the present invention are optionally substituted. Examples of aralkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl, etc.

[0067] The term "heterocycle" and / or "heterocyclyl", whether used alone or as part of another group, is defined herein as one or more rings having 3 to 20 atoms, wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O) or sulfur (S), and the ring containing the heteroatom is non-aromatic. In a heterocyclic group comprising 2 or more fused rings, the ring with a non-heteroatom may be an aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclic groups have 3 to 14 ring atoms, wherein 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O) or sulfur (S). One or more N or S atoms in a heterocyclic group may be oxidized. A heterocyclic group may be optionally substituted.

[0068] Non-limiting examples of heterocyclic units having a single ring include: bisaziridinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl, oxathiazolidinone, oxazolidinone, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-one (valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclic units having 2 or more rings include: hexahydro-1H-pyrrolazinyl, 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, isoindolyl, and decahydro-1H-cycloocta[b]pyrrolyl.

[0069] The term "heteroaryl", whether used alone or as part of another group, is defined herein as one or more rings having 5 to 20 atoms, wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O) or sulfur (S), and at least one of the rings containing heteroatoms is aromatic. In heteroaryl groups comprising 2 or more fused rings, the ring with non-heteroatoms may be a carbocycle (e.g., 6,7-dihydro-5H-cyclopentylpyrimidine) or an aryl (e.g., benzofuranyl, benzothienyl, 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 or S atoms in a heteroaryl group may be oxidized. A heteroaryl group may 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, triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thienyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing 2 or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, 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-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, 1H-benzo[d]imidazol-2(3H)-onyl, 1H-benzo[d]imidazolyl, and isoquinolinyl.

[0070] A non-limiting example of a heteroaryl group as described above is a C1-C5 heteroaryl group having 1 to 5 carbon ring atoms and at least one other ring atom (preferably 1 to 4 other ring atoms as heteroatoms) independently selected from nitrogen (N), oxygen (O) or sulfur (S). Examples of C1-C5 heteroaryl groups include, but are not limited to, triazine, thiazol-2-yl, thiazol-4-yl, imidazole-1-yl, 1H-imidazole-2-yl, 1H-imidazole-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

[0071] Unless otherwise indicated, when two substituents are taken together to form a ring having the indicated number of ring atoms (e.g., R 2 and R 3When taken together 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 heteroatoms independently selected from nitrogen (N), oxygen (O) or sulfur (S). The ring may be saturated or partially saturated and may be optionally substituted.

[0072] For the purposes of this invention, fused ring units containing a single heteroatom, as well as spirocyclic rings, bicyclic rings, etc., will be considered to belong to the cyclic family corresponding to the heteroatom-containing ring. For example, for the purposes of this invention, 1,2,3,4-tetrahydroquinoline having the formula:

[0073]

[0074] For the purposes of the present invention, 6,7-dihydro-5H-cyclopentylpyrimidine has the following formula:

[0075]

[0076] is considered a heteroaryl unit. When a fused ring unit contains heteroatoms in both the saturated and aryl rings, the aryl ring will predominate and be determined as the type of class specified for the ring. For example, for the purposes of this invention, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:

[0077]

[0078] are considered to be heteroaryl units.

[0079] Whenever a term or any of its prefix roots appear in the name of a substituent, the name should be interpreted as including those limitations provided herein. For example, whenever the term "alkyl" or "aryl" or any of their prefix roots appear in the name of a substituent (e.g., arylalkyl, alkylamino), the name should be interpreted as including those limitations given above for "alkyl" and "aryl".

[0080] The term "substituted" is used throughout the specification. The term "substituted" is defined herein as a portion having one or more hydrogen atoms replaced by one or more (e.g., 1 to 10) substituents as defined below, whether acyclic or cyclic. Substituents can replace one or two hydrogen atoms of a single portion at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form the substituent, new portion or unit. For example, the substitution unit requiring a single hydrogen atom replacement includes halogen, hydroxyl, etc. Two hydrogen atom replacements include carbonyl, oxime, etc. Two hydrogen atom replacements from adjacent carbon atoms include epoxy resins, etc. The term "substituted" is used throughout the specification to indicate that a portion may have one or more hydrogen atoms replaced by a substituent. When a portion is described as "substituted", any number of hydrogen atoms can be replaced. For example, difluoromethyl is a substituted C1 alkyl; trifluoromethyl is a substituted C1 alkyl; 4-hydroxyphenyl is a substituted aromatic ring; (N,N-dimethyl-5-amino)octyl is a substituted C8 alkyl; 3-guanidinopropyl is a substituted C3 alkyl; and 2-carboxypyridyl is a substituted heteroaryl.

[0081] Variable groups as defined herein (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle, and heteroaryl groups as defined herein), whether used alone or as part of another group, may be optionally substituted. Optionally substituted groups will be indicated as such.

[0082] The following are non-limiting examples of substituents that may replace a hydrogen atom on a moiety: halogen (chlorine (Cl), bromine (Br), fluorine (F), and iodine (I)), -CN, -NO2, oxygen (=O), -OR 15 ,–SR 15 , –N(R 15 )2. –NR 15 C(O)R 15 , –SO2R 15 , –SO2OR 15 、–SO2N(R 15 )2. –C(O)R 15 , –C(O)OR 15 , –C(O)N(R 15 2. C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-14cycloalkyl, aryl, heterocycle or heteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle and heteroaryl groups is optionally substituted by 1-10 (e.g., 1-6 or 1-4) independently selected from halogen, -CN, -NO2, oxygen and R 15 substituted by a group; wherein R 15 is independently at each occurrence hydrogen, –OR 16 ,–SR 16 , –C(O)R 16 , –C(O)OR 16 , –C(O)N(R 16 2. –SO2R 16 、-S(O)2OR 16 , –N(R 16 )2. –NR 16 C(O)R 16 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, cycloalkyl (e.g., C 3-6 cycloalkyl), aryl, heterocyclic or heteroaryl, or two R 15 The units are taken together with the atoms to which they are bound to form an optionally substituted carbocyclic or heterocyclic ring having 3 to 7 ring atoms; wherein R 16 is independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, cycloalkyl (e.g., C 3-6 cycloalkyl), aryl, heterocyclic or heteroaryl, or two R 16 The units are taken together with the atoms to which they are bonded to form an optionally substituted carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring preferably has 3 to 7 ring atoms.

[0083] In some embodiments, the substituent is selected from

[0084] i)–OR 17 ; for example, –OH, –OCH3, –OCH2CH3, –OCH2CH2CH3;

[0085] ii) – C(O)R 17 ; For example, –COCH3, –COCH2CH3, –COCH2CH2CH3;

[0086] iii) –C(O)OR 17 ; For example, –CO2CH3, –CO2CH2CH3, –CO2CH2CH2CH3;

[0087] iv)–C(O)N(R 17 )2; for example, –CONH2, –CONHCH3, –CON(CH3)2;

[0088] v)–N(R 17 )2; for example, –NH2, –NHCH3, –N(CH3)2, –NH(CH2CH3);

[0089] vi) Halogens: –F, –Cl, –Br and –I;

[0090] vii) – CH e X g ; wherein X is a halogen, m is 0 to 2, and e+g=3; for example, –CH2F, –CHF2, –CF3, –CCl3, or –CBr3;

[0091] viii) – SO2R 17 ; For example, –SO2H, –SO2CH3, –SO2C6H5;

[0092] ix) C1-C6 straight chain, branched or cyclic alkyl;

[0093] x) Cyano

[0094] xi) nitro;

[0095] xii)N(R 17 )C(O)R 17 ;

[0096] xiii) oxygen (=O);

[0097] xiv) heterocyclic ring; and

[0098] xv) heteroaryl.

[0099] Each R 17 R is independently hydrogen, optionally substituted C1-C6 straight or branched alkyl (e.g., optionally substituted C1-C4 straight or branched alkyl), or optionally substituted C3-C6 cycloalkyl (e.g., optionally substituted C3-C4 cycloalkyl); or two R 17 The units can be joined together to form a ring containing 3-7 ring atoms. 17 are independently hydrogen, C1-C6 linear or branched alkyl optionally substituted by halogen or C3-C6 cycloalkyl, or C3-C6 cycloalkyl.

[0100] At various places in this specification, substituents of compounds are disclosed in the form of groups or ranges. Specifically, the description includes every individual subcombination of members in these groups and ranges. For example, the term "C1-6 The term “alkyl” is specifically intended to disclose individually C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0101] For the purposes of the present invention, the terms "compound", "analog" and "composition of matter" also represent the 5-hydroxytryptamine receptor 7 activity modulators described herein, including all enantiomeric forms, diastereomeric forms of salts, etc., and the terms "compound", "analog" and "composition of matter" can be used interchangeably in this specification.

[0102] The compounds described herein may contain asymmetric atoms (also referred to as chiral centers), and some compounds may contain one or more asymmetric atoms or centers, thus producing optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as racemic and resolved enantiomerically pure R and S stereoisomers, and other mixtures of R and S stereoisomers and pharmaceutically acceptable salts thereof. 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 should also be understood that the present teachings encompass all possible regioisomers 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.

[0103] Organic bases and inorganic bases can be used to form pharmaceutically acceptable salts of the compounds of the present teachings, which may have an acidic part. Monoanionic salts and polyanionic salts can be envisioned, depending on the number of acidic hydrogens that can be used for deprotonation. Suitable salts formed with alkalis include 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 morpholine, thiomorpholine, piperidine, pyrrolidine, mono, di or tri-lower alkylamines (e.g., ethyl-tert-butylamine, diethylamine, diisopropylamine, triethylamine, tributylamine or dimethylpropylamine), or monohydroxy, dihydroxy or trihydroxy lower alkylamines (e.g., monoethanolamine, diethanolamine or triethanolamine). The specific non-limiting examples of inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4 and Na3PO4. Internal salts can also be formed. Similarly, when the compounds disclosed herein contain a basic moiety, organic and inorganic acids can be used to form salts. 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, vinylsulfonic 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.

[0104] When any variable occurs more than one time in any constituent or in any formula, its definition on each occurrence is independent of its definition at all other occurrences (e.g., in N(R 9 )2, each R 9 Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0105] As used herein, the term "treat" refers to partially or completely alleviating, inhibiting, ameliorating and / or relieving a condition that a patient is suspected of suffering from.

[0106] As used herein, "therapeutically effective" and "effective dose" refer to a substance or amount that elicits a desired biological activity or effect.

[0107] Unless otherwise indicated, the terms "subject" or "patient" are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats and mice, and other animals. Therefore, the terms "subject" or "patient" as used herein mean any mammalian patient or subject to which the compounds of the present invention can be administered. In an exemplary embodiment of the present invention, in order to identify a subject to be treated according to the method of the present invention, a recognized screening method is used to determine the risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in the subject. These screening methods include, for example, routine examinations to determine the risk factors that may be associated with a targeted or suspected disease or condition. These and other conventional methods enable clinicians to select patients in need of treatment using the methods and compounds of the present invention.

[0108] 5-HT receptor 7 activity modulators

[0109] The 5-hydroxytryptamine receptor 7 activity modulators of the present invention include salts of all enantiomeric and diastereomeric forms having the following formula:

[0110]

[0111] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0112] A is selected from

[0113] X is selected from O, S, SO, SO2, NR;

[0114] n 1 0, 1, 2;

[0115] n 2 0, 1, 2;

[0116] R is selected from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl,

[0117] COR 2 、CO2R 2a ,CONR 2b R 2c 、SO2NR 2b R 2c and SO2R 2d ;

[0118] R 1a , R 1b , R 1c , R 1d and R 1eis independently selected at each occurrence from H, OH, NO2, halogen, CN, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Straight chain alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Straight chain halogenated alkyl, C 3-7 Branched chain halogenated alkyl, C 1-6 Straight chain halogenated alkoxy, -S(C 1-6 Straight chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 Cycloalkyl), COR 6 、CO2R 7 ,CONR 8a R 8b 、SO2NR 8a R 8b NR 9a R 9b NR 9a COR 10 NR 9a S02R 11 and NR 9a SO2NR 12a R 12b ;

[0119] R 2 Selected from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0120] R 2a Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0121] R 2b Selected from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0122] R 2c Selected from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0123] R 2d Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C3-7 Cycloalkyl, C 1-6 Straight chain halogenated alkyl, C 3-7 Branched haloalkyl, -(CH2) q CN, -(CH2) q S02R 13 、-(CH2) q OR 14 ,

[0124] R 3 Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, optionally substituted aryl,

[0125]

[0126] R 4 is an optionally substituted aryl group;

[0127] R 5a and R 5b each independently optionally substituted with aryl;

[0128] R 6 independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0129] R 7 In each occurrence, independently selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0130] R 8a independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0131] R 8b independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0132] R 9a independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0133] R 9b independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0134] R 10 independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0135] R 11 In each occurrence, independently selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0136] R 12a In each occurrence, independently selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0137] R 12b In each occurrence, independently selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0138] R 13 Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0139] R 14 Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl;

[0140] n is 1, 2 or 3;

[0141] m is 1 or 2;

[0142] and q is 1, 2, or 3;

[0143] Embodiments of the present invention include compounds having formula (II):

[0144]

[0145] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0146] Embodiments of the present invention include compounds having formula (III):

[0147]

[0148] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0149] Embodiments of the present invention include compounds having formula (IV):

[0150]

[0151] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0152] Embodiments of the present invention include compounds having formula (V):

[0153]

[0154] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0155] Embodiments of the present invention include compounds having formula (VI):

[0156]

[0157] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0158] Embodiments of the present invention include compounds having formula (VII):

[0159]

[0160] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0161] Embodiments of the present invention include compounds having formula (VIII):

[0162]

[0163] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0164] Embodiments of the present invention include compounds having formula (IX):

[0165]

[0166] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0167] Embodiments of the present invention include compounds having formula (X):

[0168]

[0169] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0170] Embodiments of the present invention include compounds having formula (XI):

[0171]

[0172] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0173] Embodiments of the present invention include compounds having formula (XII):

[0174]

[0175] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0176] Embodiments of the present invention include compounds having formula (XIII):

[0177]

[0178] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0179] Embodiments of the present invention include compounds having formula (XIV):

[0180]

[0181] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0182] Embodiments of the present invention include compounds having formula (XV):

[0183]

[0184] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0185] Embodiments of the present invention include compounds having formula (XVI):

[0186]

[0187] This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts and complexes thereof.

[0188] In some embodiments, A is

[0189] In some embodiments, A is

[0190] In some embodiments, A is

[0191] In some embodiments, A is

[0192] In some embodiments, A is

[0193] In some embodiments, X is O.

[0194] In some embodiments, X is S.

[0195] In some embodiments, X is SO.

[0196] In some embodiments, X is SO2.

[0197] In some embodiments, X is NR

[0198] In some embodiments, n 1 is 0.

[0199] In some embodiments, n 1 is 1.

[0200] In some embodiments, n 1 is 2.

[0201] In some embodiments, n 2 is 0.

[0202] In some embodiments, n 2 is 1.

[0203] In some embodiments, n 2 is 2.

[0204] In some embodiments, R is H.

[0205] In some embodiments, R is C 1-6 Straight chain alkyl.

[0206] In some embodiments, R is C 3-7 Branched chain alkyl.

[0207] In some embodiments, R is C 3-7 Cycloalkyl.

[0208] In some embodiments, R is

[0209] In some embodiments, R is COR 2 .

[0210] In some embodiments, R is CO2R 2a .

[0211] In some embodiments, R is CONR 2b R 2c .

[0212] In some embodiments, R is SO2NR 2b R 2c .

[0213] In some embodiments, R is SO2R 2d .

[0214] In some embodiments, R 1a For H.

[0215] In some embodiments, R 1a For OH.

[0216] In some embodiments, R 1a For NO2.

[0217] In some embodiments, R 1a It is a halogen.

[0218] In some embodiments, R 1a For CN.

[0219] In some embodiments, R 1a C 1-6 Straight chain alkyl.

[0220] In some embodiments, R 1a C 3-7 Branched chain alkyl.

[0221] In some embodiments, R 1a C 3-7 Cycloalkyl.

[0222] In some embodiments, R 1a C 1-6 Straight chain alkoxy.

[0223] In some embodiments, R 1a C 3-7 Branched chain alkoxy.

[0224] In some embodiments, R 1a C 3-7 Cycloalkoxy.

[0225] In some embodiments, R 1a C 1-6 Straight chain halogenated alkyl.

[0226] In some embodiments, R 1a C 3-7 Branched chain haloalkyl.

[0227] In some embodiments, R 1a C 1-6 Straight chain haloalkoxy.

[0228] In some embodiments, R 1a -S(C 1-6 Straight chain alkyl).

[0229] In some embodiments, R 1a S(C 3-7 branched chain alkyl).

[0230] In some embodiments, R 1a -S(C 3-7 cycloalkyl).

[0231] In some embodiments, R 1a COR 6 .

[0232] In some embodiments, R 1a For CO2R 7 .

[0233] In some embodiments, R 1a CONR 8a R 8b .

[0234] In some embodiments, R 1a For SO2NR 8a R 8b .

[0235] In some embodiments, R 1a NR 9a R 9b .

[0236] In some embodiments, R 1a NR 9a COR 10 .

[0237] In some embodiments, R 1a NR 9a S02R 11 .

[0238] In some embodiments, R1a NR 9a SO2NR 12a R 12b .

[0239] In some embodiments, R 1b For H.

[0240] In some embodiments, R 1b For OH.

[0241] In some embodiments, R 1b For NO2.

[0242] In some embodiments, R 1b It is a halogen.

[0243] In some embodiments, R 1b For CN.

[0244] In some embodiments, R 1b C 1-6 Straight chain alkyl.

[0245] In some embodiments, R 1b C 3-7 Branched chain alkyl.

[0246] In some embodiments, R 1b C 3-7 Cycloalkyl.

[0247] In some embodiments, R 1b C 1-6 Straight chain alkoxy.

[0248] In some embodiments, R 1b C 3-7 Branched chain alkoxy.

[0249] In some embodiments, R 1b C 3-7 Cycloalkoxy.

[0250] In some embodiments, R 1b C 1-6 Straight chain halogenated alkyl.

[0251] In some embodiments, R 1b C 3-7 Branched chain haloalkyl.

[0252] In some embodiments, R 1b C 1-6 Straight chain haloalkoxy.

[0253] In some embodiments, R 1b-S(C 1-6 Straight chain alkyl).

[0254] In some embodiments, R 1b S(C 3-7 branched chain alkyl).

[0255] In some embodiments, R 1b -S(C 3-7 cycloalkyl).

[0256] In some embodiments, R 1b COR 6 .

[0257] In some embodiments, R 1b For CO2R 7 .

[0258] In some embodiments, R 1b CONR 8a R 8b .

[0259] In some embodiments, R 1b For SO2NR 8a R 8b .

[0260] In some embodiments, R 1b NR 9a R 9b .

[0261] In some embodiments, R 1b NR 9a COR 10 .

[0262] In some embodiments, R 1b NR 9a S02R 11 .

[0263] In some embodiments, R 1b NR 9a SO2NR 12a R 12b .

[0264] In some embodiments, R 1c For H.

[0265] In some embodiments, R 1c For OH.

[0266] In some embodiments, R 1c For NO2.

[0267] In some embodiments, R 1c It is a halogen.

[0268] In some embodiments, R 1c For CN.

[0269] In some embodiments, R 1c C 1-6 Straight chain alkyl.

[0270] In some embodiments, R 1c C 3-7 Branched chain alkyl.

[0271] In some embodiments, R 1c C 3-7 Cycloalkyl.

[0272] In some embodiments, R 1c C 1-6 Straight chain alkoxy.

[0273] In some embodiments, R 1c C 3-7 Branched chain alkoxy.

[0274] In some embodiments, R 1c C 3-7 Cycloalkoxy.

[0275] In some embodiments, R 1c C 1-6 Straight chain halogenated alkyl.

[0276] In some embodiments, R 1c C 3-7 Branched chain haloalkyl.

[0277] In some embodiments, R 1c C 1-6 Straight chain haloalkoxy.

[0278] In some embodiments, R 1c -S(C 1-6 Straight chain alkyl).

[0279] In some embodiments, R 1c S(C 3-7 branched chain alkyl).

[0280] In some embodiments, R 1c -S(C 3-7 cycloalkyl).

[0281] In some embodiments, R 1c COR 6 .

[0282] In some embodiments, R 1c For CO2R 7 .

[0283] In some embodiments, R 1c CONR 8a R 8b .

[0284] In some embodiments, R 1c For SO2NR 8a R 8b .

[0285] In some embodiments, R 1c NR 9a R 9b .

[0286] In some embodiments, R 1c NR 9a COR 10 .

[0287] In some embodiments, R 1c NR 9a S02R 11 .

[0288] In some embodiments, R 1c NR 9a SO2NR 12a R 12b .

[0289] In some embodiments, R 1d For H.

[0290] In some embodiments, R 1d For OH.

[0291] In some embodiments, R 1d For NO2.

[0292] In some embodiments, R 1d It is a halogen.

[0293] In some embodiments, R 1d For CN.

[0294] In some embodiments, R 1d C 1-6 Straight chain alkyl.

[0295] In some embodiments, R 1d C 3-7 Branched chain alkyl.

[0296] In some embodiments, R 1d C 3-7 Cycloalkyl.

[0297] In some embodiments, R 1d C 1-6 Straight chain alkoxy.

[0298] In some embodiments, R 1d C 3-7 Branched chain alkoxy.

[0299] In some embodiments, R 1d C 3-7 Cycloalkoxy.

[0300] In some embodiments, R 1d C 1-6 Straight chain halogenated alkyl.

[0301] In some embodiments, R 1d C 3-7 Branched chain haloalkyl.

[0302] In some embodiments, R 1d C 1-6 Straight chain haloalkoxy.

[0303] In some embodiments, R 1d -S(C 1-6 Straight chain alkyl).

[0304] In some embodiments, R 1d S(C 3-7 branched chain alkyl).

[0305] In some embodiments, R 1d -S(C 3-7 cycloalkyl).

[0306] In some embodiments, R 1d COR 6 .

[0307] In some embodiments, R 1d For CO2R 7 .

[0308] In some embodiments, R 1d CONR 8a R 8b .

[0309] In some embodiments, R 1d For SO2NR 8a R 8b .

[0310] In some embodiments, R 1d NR 9a R 9b .

[0311] In some embodiments, R 1d NR 9a COR 10 .

[0312] In some embodiments, R 1d NR 9a S02R 11 .

[0313] In some embodiments, R 1d NR 9a SO2NR 12a R 12b .

[0314] In some embodiments, R 1e For H.

[0315] In some embodiments, R 1e For OH.

[0316] In some embodiments, R 1e For NO2.

[0317] In some embodiments, R 1e It is a halogen.

[0318] In some embodiments, R 1e For CN.

[0319] In some embodiments, R 1e C 1-6 Straight chain alkyl.

[0320] In some embodiments, R 1e C 3-7 Branched chain alkyl.

[0321] In some embodiments, R 1e C 3-7 Cycloalkyl.

[0322] In some embodiments, R 1e C 1-6 Straight chain alkoxy.

[0323] In some embodiments, R 1e C 3-7 Branched chain alkoxy.

[0324] In some embodiments, R 1e C 3-7Cycloalkoxy.

[0325] In some embodiments, R 1e C 1-6 Straight chain halogenated alkyl.

[0326] In some embodiments, R 1e C 3-7 Branched chain haloalkyl.

[0327] In some embodiments, R 1e C 1-6 Straight chain haloalkoxy.

[0328] In some embodiments, R 1e -S(C 1-6 Straight chain alkyl).

[0329] In some embodiments, R 1e S(C 3-7 branched chain alkyl).

[0330] In some embodiments, R 1e -S(C 3-7 cycloalkyl).

[0331] In some embodiments, R 1e COR 6 .

[0332] In some embodiments, R 1e For CO2R 7 .

[0333] In some embodiments, R 1e CONR 8a R 8b .

[0334] In some embodiments, R 1e For SO2NR 8a R 8b .

[0335] In some embodiments, R 1e NR 9a R 9b .

[0336] In some embodiments, R 1e NR 9a COR 10 .

[0337] In some embodiments, R 1e NR 9a S02R 11 .

[0338] In some embodiments, R 1e NR 9a SO2NR 12a R 12b .

[0339] In some embodiments, R 2 For H.

[0340] In some embodiments, R 2 C 1-6 Straight chain alkyl.

[0341] In some embodiments, R 2 C 3-7 Branched chain alkyl.

[0342] In some embodiments, R 2 C 3-7 Cycloalkyl.

[0343] In some embodiments, R 2a C 1-6 Straight chain alkyl.

[0344] In some embodiments, R 2a C 3-7 Branched chain alkyl.

[0345] In some embodiments, R 2a C 3-7 Cycloalkyl.

[0346] In some embodiments, R 2b For H.

[0347] In some embodiments, R 2b C 1-6 Straight chain alkyl.

[0348] In some embodiments, R 2b C 3-7 Branched chain alkyl.

[0349] In some embodiments, R 2b C 3-7 Cycloalkyl.

[0350] In some embodiments, R 2c For H.

[0351] In some embodiments, R 2c C 1-6 Straight chain alkyl.

[0352] In some embodiments, R 2c C 3-7 Branched chain alkyl.

[0353] In some embodiments, R 2c C 3-7 Cycloalkyl.

[0354] In some embodiments, R 2d C 1-6 Straight chain alkyl.

[0355] In some embodiments, R 2d C 3-7 Branched chain alkyl.

[0356] In some embodiments, R 2d C 3-7 Cycloalkyl.

[0357] In some embodiments, R 2d C 1-6 Straight chain halogenated alkyl.

[0358] In some embodiments, R 2d C 3-7 Branched chain haloalkyl.

[0359] In some embodiments, R 2d -(CH2) q CN.

[0360] In some embodiments, R 2d -(CH2) q S02R 13 .

[0361] In some embodiments, R 2d -(CH2) q OR 14 .

[0362] In some embodiments, R 2d for

[0363] In some embodiments, R 2d for

[0364] In some embodiments, R 2d for

[0365] In some embodiments, R 2d for

[0366] In some embodiments, R 2d for

[0367] In some embodiments, R 2d for

[0368] In some embodiments, R 2d for

[0369] In some embodiments, R 2d for

[0370] In some embodiments, R 2d for

[0371] In some embodiments, R 2d for

[0372] In some embodiments, R 2d for

[0373] In some embodiments, R 2d for

[0374] In some embodiments, R 3 C 1-6 Straight chain alkyl.

[0375] In some embodiments, R 3 C 3-7 Branched chain alkyl.

[0376] In some embodiments, R 3 C 3-7 Cycloalkyl.

[0377] In some embodiments, R 3 is an optionally substituted aryl group.

[0378] In some embodiments, R 3 It is phenyl.

[0379] In some embodiments, R 3 is an aryl group optionally substituted by 1 to 4 units independently selected from OH, NO2, halogen, CN, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Straight chain alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Straight chain halogenated alkyl, C 3-7 Branched chain halogenated alkyl, C 1-6Straight chain halogenated alkoxy, -S(C 1-6 Straight chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 Cycloalkyl), COR 6 、CO2R 7 ,CONR 8a R 8b 、SO2NR 8a R 8b NR 9a R 9b NR 9a COR 10 NR 9a S02R 11 NR 9a SO2NR 12a R 12b ,

[0380] In some embodiments, R 3 for

[0381] In some embodiments, R 3 for

[0382] In some embodiments, R 3 for

[0383] In some embodiments, R 3 for

[0384] In some embodiments, R 3 for

[0385] In some embodiments, R 3 for

[0386] In some embodiments, R 3 for

[0387] In some embodiments, R 3 for

[0388] In some embodiments, R 3 for

[0389] In some embodiments, R 3 for

[0390] In some embodiments, R4 is an optionally substituted aryl group.

[0391] In some embodiments, R 4 is an optionally substituted aryl group substituted by 1 to 4 units independently selected from OH, NO2, halogen, CN, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Straight chain alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Straight chain halogenated alkyl, C 3-7 Branched chain halogenated alkyl, C 1-6 Straight chain halogenated alkoxy, -S(C 1-6 Straight chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 Cycloalkyl), COR 6 、CO2R 7 ,CONR 8a R 8b 、SO2NR 8a R 8b NR 9a R 9b NR 9a COR 10 NR 9a S02R 11 NR 9a SO2NR 12a R 12b ,

[0392] In some embodiments, R 5 is an optionally substituted aryl group.

[0393] In some embodiments, R 5 is an optionally substituted aryl group.

[0394] In some embodiments, R 6 For H.

[0395] In some embodiments, R 6 C 1-6 Straight chain alkyl.

[0396] In some embodiments, R 6 C 3-7 Branched chain alkyl.

[0397] In some embodiments, R 6 C 3-7 Cycloalkyl.

[0398] In some embodiments, R 7 C 1-6 Straight chain alkyl.

[0399] In some embodiments, R 7 C 3-7 Branched chain alkyl.

[0400] In some embodiments, R 7 C 3-7 Cycloalkyl.

[0401] In some embodiments, R 8a For H.

[0402] In some embodiments, R 8a C 1-6 Straight chain alkyl.

[0403] In some embodiments, R 8a C 3-7 Branched chain alkyl.

[0404] In some embodiments, R 8a C 3-7 Cycloalkyl.

[0405] In some embodiments, R 8b For H.

[0406] In some embodiments, R 8b C 1-6 Straight chain alkyl.

[0407] In some embodiments, R 8b C 3-7 Branched chain alkyl.

[0408] In some embodiments, R 8b C 3-7 Cycloalkyl.

[0409] In some embodiments, R 9a For H.

[0410] In some embodiments, R 9a C 1-6 Straight chain alkyl.

[0411] In some embodiments, R 9a C 3-7 Branched chain alkyl.

[0412] In some embodiments, R 9a C 3-7 Cycloalkyl.

[0413] In some embodiments, R9b For H.

[0414] In some embodiments, R 9b C 1-6 Straight chain alkyl.

[0415] In some embodiments, R 9b C 3-7 Branched chain alkyl.

[0416] In some embodiments, R 9b C 3-7 Cycloalkyl.

[0417] In some embodiments, R 10 For H.

[0418] In some embodiments, R 10 C 1-6 Straight chain alkyl.

[0419] In some embodiments, R 10 C 3-7 Branched chain alkyl.

[0420] In some embodiments, R 10 C 3-7 Cycloalkyl.

[0421] In some embodiments, R 11 C 1-6 Straight chain alkyl.

[0422] In some embodiments, R 11 C 3-7 Branched chain alkyl.

[0423] In some embodiments, R 11 C 3-7 Cycloalkyl.

[0424] In some embodiments, R 10 C 1-6 Straight chain alkyl.

[0425] In some embodiments, R 10 C 3-7 Branched chain alkyl.

[0426] In some embodiments, R 10 C 3-7 Cycloalkyl.

[0427] In some embodiments, R 12a C 1-6 Straight chain alkyl.

[0428] In some embodiments, R12a C 3-7 Branched chain alkyl.

[0429] In some embodiments, R 12a C 3-7 Cycloalkyl.

[0430] In some embodiments, R 12b C 1-6 Straight chain alkyl.

[0431] In some embodiments, R 12b C 3-7 Branched chain alkyl.

[0432] In some embodiments, R 12b C 3-7 Cycloalkyl.

[0433] In some embodiments, R 13 C 1-6 Straight chain alkyl.

[0434] In some embodiments, R 13 C 3-7 Branched chain alkyl.

[0435] In some embodiments, R 13 C 3-7 Cycloalkyl.

[0436] In some embodiments, R 14 C 1-6 Straight chain alkyl.

[0437] In some embodiments, R 14 C 3-7 Branched chain alkyl.

[0438] In some embodiments, R 14 C 3-7 Cycloalkyl.

[0439] In some embodiments, n is 1.

[0440] In some embodiments, n is 2.

[0441] In some embodiments, n is 3.

[0442] In some embodiments, m is 1.

[0443] In some embodiments, m is 2.

[0444] In some embodiments, q is 1.

[0445] In some embodiments, q is 2.

[0446] In some embodiments, q is 3.

[0447] Exemplary embodiments include compounds having formula (XVII)

[0448]

[0449] or a pharmaceutically acceptable salt form thereof, as defined in Table 1 below.

[0450] Table 1

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469] Exemplary embodiments include compounds having formula (XVIII)

[0470] or a pharmaceutically acceptable salt form thereof, as defined in Table 2 below.

[0471] Table 2

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491] Exemplary embodiments include compounds having formula (XIX)

[0492] or a pharmaceutically acceptable salt form thereof, as defined in Table 3 below.

[0493] Table 3

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505] Exemplary embodiments include compounds having formula (XX)

[0506] or a pharmaceutically acceptable salt form thereof, as defined in Table 4 below.

[0507] Table 4

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519] Exemplary embodiments include compounds having formula (XXI)

[0520]

[0521] or a pharmaceutically acceptable salt form thereof, as defined in Table 5 below.

[0522] Table 5

[0523]

[0524] Exemplary embodiments include compounds having formula (XXII)

[0525]

[0526] or a pharmaceutically acceptable salt form thereof, as defined in Table 6 below.

[0527] Table 6

[0528] Entry n R <![CDATA[R 1a ]]> <![CDATA[R 1b ]]> <![CDATA[R 1c ]]> <![CDATA[R 1d ]]> 1 1 H H H H H 2 2 H H H H H 3 3 H H H H H 4 1 Me H H H H 5 2 Me H H H H 6 3 Me H H H H 7 1 <![CDATA[CH2Ph]]> H H H H 8 2 <![CDATA[CH2Ph]]> H H H H 9 3 <![CDATA[CH2Ph]]> H H H H 10 1 COMe H H H H 11 2 COMe H H H H 12 3 COMe H H H H 13 1 <![CDATA[CO2Me]]> H H H H 14 2 <![CDATA[CO2Me]]> H H H H 15 3 <![CDATA[CO2Me]]> H H H H 16 1 <![CDATA[CO2tBu]]> H H H H 17 2 <![CDATA[CO2tBu]]> H H H H 18 3 <![CDATA[CO2tBu]]> H H H H 19 1 CONHMe H H H H 20 2 CONHMe H H H H 21 3 CONHMe H H H H 22 1 <![CDATA[SO2Me]]> H H H H 23 2 <![CDATA[SO2Me]]> H H H H 24 3 <![CDATA[SO2Me]]> H H H H 25 1 <![CDATA[SO2NH2]]> H H H H 26 2 <![CDATA[SO2NH2]]> H H H H 27 3 <![CDATA[SO2NH2]]> H H H H

[0529] Exemplary embodiments include compounds having formula (XXIII)

[0530]

[0531] or a pharmaceutically acceptable salt form thereof, as defined in Table 7 below.

[0532] Table 7

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541] Exemplary embodiments include compounds having formula (XXIV)

[0542]

[0543] or a pharmaceutically acceptable salt form thereof, as defined in Table 8 below.

[0544] Table 8

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553] Exemplary embodiments include compounds having formula (XXV)

[0554]

[0555] or a pharmaceutically acceptable salt thereof, as defined in Table 9 below

[0556] Table 9

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567] Exemplary embodiments include compounds having formula (XXVI)

[0568]

[0569] or a pharmaceutically acceptable salt form thereof, as defined in Table 10 below.

[0570] Table 10

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581] To illustrate the manner in which the compounds of the present invention are named and referred to herein, a compound having the formula:

[0582]

[0583] The chemical name is 8-(methylsulfonyl)-3-(2-(4-phenylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one.

[0584] To illustrate the manner in which the compounds of the present invention are named and referred to herein, a compound having the formula:

[0585]

[0586] The chemical name is 8-(methylsulfonyl)-3-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one.

[0587] For the purposes of this invention, compounds described by the racemic form, for example:

[0588]

[0589] will also represent the following formula:

[0590]

[0591] Or the following:

[0592]

[0593] Any of the two enantiomers or mixtures thereof, or, in the case of a second chiral center, all diastereomers.

[0594] In all embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention.The compounds of the invention may contain any substituent or combination of substituents provided herein.

[0595] Method for preparing the 5-hydroxytryptamine receptor 7 activity modulator of the present invention

[0596] The present invention also relates to a method for preparing the 5-hydroxytryptamine receptor 7 activity modulator of the present invention.

[0597] The compounds of the present teachings can be prepared from commercially available raw materials, compounds known in the literature, or easily prepared intermediates by using standard synthetic methods and procedures known to those skilled in the art according to the procedures outlined herein. Standard synthetic methods and procedures for preparing organic molecules and functional group transformations and operations can be easily obtained from relevant scientific literature or standard textbooks in the field. It should be understood that, in the case of typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise stated. The optimal reaction conditions may vary with the specific reactants or solvents used, but these conditions may be determined by conventional optimization procedures by those skilled in the art. Those skilled in the art of organic synthesis will recognize that in order to optimize the formation of the compounds described herein, the nature and order of the proposed synthesis steps may be changed.

[0598] The methods described herein can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin layer chromatography (TLC).

[0599] The preparation of compounds may involve the protection and deprotection of various chemical groups. Those skilled in the art can easily determine the need for protection and deprotection and the selection of appropriate protecting groups. The chemical properties of protecting groups can be found in, for example, Greene et al., Protective Groups in Organic Synthesis, 2nd edition (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference for all purposes.

[0600] The reactions or methods described herein can be carried out in a suitable solvent, which can be easily selected by a person skilled in the art of organic synthesis. Suitable solvents are generally substantially non-reactive with reactants, intermediates and / or products at a temperature at which the reaction is carried out, which temperature can be within the range of the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in a solvent or in a mixture of more than one solvent. Depending on the specific reaction steps, a solvent suitable for a particular reaction step can be selected.

[0601] The compounds of these teachings can be prepared by methods known in the field of organic chemistry. The reagents used to prepare the compounds of these teachings can be 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 shown in the general synthesis scheme:

[0602] General synthetic schemes for preparing compounds

[0603] The reagents used to prepare the compounds of the present invention are either commercially available or can be prepared by standard procedures described in the literature. According to the present invention, the compounds in the genus can be prepared by one of the following reaction schemes.

[0604] Compounds of the present disclosure can be prepared according to the methods outlined in Schemes 1-x.

[0605]

[0606] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, etc., in the presence of a solvent such as ethanol, methanol, isopropanol, tetrahydrofuran, 1,4-dioxane, dichloromethane, N,N-dimethylformamide, etc., optionally by heating, optionally by microwave irradiation, a suitably substituted compound of formula (1), a known compound or a compound prepared by a known method (wherein X 1 C 1-6In 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., in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, etc., the compound of formula (2) is reacted with a compound of formula (3), a known compound or a compound prepared by a known method (wherein LG is a leaving group, such as chlorine, bromine, iodine, mesylate, tosylate, etc.) to obtain a compound of formula (4). Then, in the presence of an acid such as sulfuric acid, hydrochloric acid, etc., in the presence of acetic acid, and optionally in an organic solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (4) is treated with paraformaldehyde to obtain a compound of formula (5). Next, in a solvent such as water, methanol, ethanol, isopropanol, etc., optionally by heating, the compound of formula (5) is treated with a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., and then in a solvent such as water, methanol, ethanol, isopropanol, etc., it is treated with an acid such as sulfuric acid, hydrochloric acid, etc., to obtain a compound of formula (6). In the presence of imidazole, in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (6) is reacted with tert-butyldimethylsilyl chloride to obtain a compound of formula (7). Alternatively, in the presence of a base such as pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, etc., in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (6) is reacted with tert-butyldimethylsilyl trifluoromethanesulfonate to obtain a compound of formula (7).

[0607]

[0608] In the presence of a palladium catalyst such as palladium on carbon, palladium on barium sulfate, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), palladium on carbon, bis (acetonitrile) palladium dichloride (II), etc., in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, etc., the compound of formula (7) is reacted with hydrogen to obtain a compound of formula (8). In the presence of a base such as pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, etc., in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (8) is reacted with di-tert-butyl dicarbonate to obtain a compound of formula (9). In the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (9) is reacted with tetra-n-butylammonium fluoride to obtain a compound of formula (10).

[0609]

[0610] The compound of formula (10) is treated with carbon tetrabromide in the presence of triphenylphosphine in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (11). In the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (11) is reacted with a compound of formula (12), a known compound or a compound prepared by a known method to obtain a compound of formula (13). The compound of formula (13) is reacted with an acid such as trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, etc., optionally in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (14).

[0611]

[0612] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (14) is reacted with a compound of formula (15), a known compound or a compound prepared by a known method to obtain a compound of formula (16).

[0613]

[0614] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (14) is reacted with a compound of formula (17), a known compound or a compound prepared by a known method to obtain a compound of formula (18).

[0615]

[0616] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (14) is reacted with a compound of formula (19), a known compound or a compound prepared by a known method to obtain a compound of formula (20).

[0617]

[0618] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (14) is reacted with a compound of formula (21), a known compound or a compound prepared by a known method to obtain a compound of formula (22).

[0619]

[0620] The compound of formula (14) is reacted with a compound of formula (23), a known compound or a compound prepared by a known method in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (24).

[0621]

[0622] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (14) is reacted with a compound of formula (25), a known compound or a compound prepared by a known method to obtain a compound of formula (26).

[0623]

[0624] 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., in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, etc., a suitably substituted compound of formula (27), a known compound, or a compound prepared by a known method (wherein X 1 C 1-6 alkyl) is reacted with a compound of formula (28), a known compound or a compound prepared by a known method (wherein LG is a leaving group, such as chloro, bromo, iodo, mesylate, tosylate, etc.), thereby obtaining a compound of formula (29). Then, in the presence of an acid such as sulfuric acid, hydrochloric acid, etc., in the presence of acetic acid, and optionally in an organic solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (29) is treated with paraformaldehyde to obtain a compound of formula (30). Next, in a solvent such as water, methanol, ethanol, isopropanol, etc., optionally by heating, the compound of formula (30) is treated with a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., and then in a solvent such as water, methanol, ethanol, isopropanol, etc., it is treated with an acid such as sulfuric acid, hydrochloric acid, etc., thereby obtaining a compound of formula (31). The compound of formula (31) is treated with carbon tetrabromide in the presence of triphenylphosphine in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (32). In the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (32) is reacted with a compound of formula (33), a known compound or a compound prepared by a known method to obtain a compound of formula (34).

[0625]

[0626] Then, in the presence of a base such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., in the presence of a solvent such as tetrahydrofuran, ether, 1,4-dioxane, etc., the compound of formula (29) is reacted with iodine to obtain a compound of formula (35). 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 by heating, optionally by microwave irradiation, the compound of formula (35) is reacted with a compound of formula (36), a known compound or a compound prepared by a known method to obtain a compound of formula (37).

[0627]

[0628] Then, in the presence of a base such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., in the presence of a solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane, etc., the compound of formula (4) is reacted with iodine to obtain a compound of formula (38). 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 by heating, optionally by microwave irradiation, the compound of formula (38) is reacted with a compound of formula (39), a known compound or a compound prepared by a known method to obtain a compound of formula (40). In the presence of a palladium catalyst such as palladium on carbon, palladium on barium sulfate, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), palladium on carbon, bis (acetonitrile) palladium dichloride (II), etc., in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, etc., the compound of formula (40) is reacted with hydrogen to obtain a compound of formula (41).

[0629]

[0630] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (41) is reacted with a compound of formula (42), a known compound or a compound prepared by a known method to obtain a compound of formula (43).

[0631]

[0632] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (41) is reacted with a compound of formula (44), a known compound or a compound prepared by a known method to obtain a compound of formula (45).

[0633]

[0634] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (41) is reacted with a compound of formula (46), a known compound or a compound prepared by a known method to obtain a compound of formula (47).

[0635]

[0636] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (41) is reacted with a compound of formula (48), a known compound or a compound prepared by a known method to obtain a compound of formula (49).

[0637]

[0638] The compound of formula (41) is reacted with a compound of formula (50), a known compound or a compound prepared by a known method in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (51).

[0639]

[0640] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (41) is reacted with a compound of formula (52), a known compound or a compound prepared by a known method to obtain a compound of formula (53).

[0641]

[0642] In the presence of sodium periodate, in a solvent such as acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (4) is reacted with ruthenium chloride to obtain a compound of formula (54). In the presence of a solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (54) is reacted with a compound of formula (55), a known compound or a compound prepared by a known method (wherein X 2 halogen) to obtain a compound of formula (56). In the presence of sodium periodate, in a solvent such as acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (56) is reacted with ruthenium chloride to obtain a compound of formula (57). In a solvent such as methanol, ethanol, isopropanol, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (57) is reacted with a reducing agent such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, etc. to obtain a compound of formula (58). In the presence of triphenylphosphine, in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (58) is treated with carbon tetrabromide to obtain a compound of formula (59). In the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (59) is reacted with a compound of formula (60), a known compound or a compound prepared by a known method to obtain a compound of formula (61).

[0643]

[0644] The compound of formula (62) is then converted to the compound of formula (63) using methods known to those skilled in the art, wherein LG is mesylate, tosylate, nitrobenzenesulfonate, etc. Thus, the compound of formula (62) is treated with a sulfonyl chloride such as methanesulfonyl chloride, tosylate, p-nitrobenzenesulfonyl chloride, etc. in the presence of a base such as triethylamine, diisopropylamine, pyridine, 2,6-lutidine, etc., in an organic solvent such as dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, etc., to give the compound of formula (63). In the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (63) is reacted with a compound of formula (64), a known compound or a compound prepared by a known method to obtain a compound of formula (65).

[0645]

[0646] In the presence of sodium periodate, in a solvent such as acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (4) is reacted with ruthenium chloride to obtain a compound of formula (66). In the presence of a solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (66) is reacted with a compound of formula (67), a known compound or a compound prepared by a known method (wherein X 2is halogen) to obtain a compound of formula (68). In the presence of sodium periodate, in a solvent such as acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (68) is reacted with ruthenium chloride to obtain a compound of formula (69). In a solvent such as methanol, ethanol, isopropanol, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (69) is reacted with a reducing agent such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, etc. to obtain a compound of formula (70). In the presence of imidazole, in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (70) is reacted with tert-butyldimethylsilyl chloride to obtain a compound of formula (71). Alternatively, the compound of formula (70) is reacted with tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of a base such as pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, and the like, in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (71).

[0647]

[0648] In the presence of a palladium catalyst such as palladium on carbon, palladium on barium sulfate, palladium (II) acetate, tetrakis(triphenylphosphine)palladium (0), dichlorobis(triphenylphosphine)palladium (II), palladium on carbon, bis(acetonitrile)palladium (II) dichloride, etc., in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, etc., the compound of formula (71) is reacted with hydrogen to obtain a compound of formula (72). In the presence of a base such as pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, etc., in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (72) is reacted with di-tert-butyl dicarbonate to obtain a compound of formula (73). The compound of formula (73) is reacted with tetra-n-butylammonium fluoride in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (74).

[0649]

[0650] The compound of formula (74) is treated with carbon tetrabromide in the presence of triphenylphosphine in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (75). In the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (75) is reacted with a compound of formula (76), a known compound or a compound prepared by a known method to obtain a compound of formula (77). Optionally, in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (77) is reacted with an acid such as trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, etc. to obtain a compound of formula (78).

[0651]

[0652] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (78) is reacted with a compound of formula (79), a known compound or a compound prepared by a known method to obtain a compound of formula (80).

[0653]

[0654] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (78) is reacted with a compound of formula (81), a known compound or a compound prepared by a known method to obtain a compound of formula (82).

[0655]

[0656] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (78) is reacted with a compound of formula (83), a known compound or a compound prepared by a known method to obtain a compound of formula (84).

[0657]

[0658] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (78) is reacted with a compound of formula (85), a known compound or a compound prepared by a known method to obtain a compound of formula (86).

[0659]

[0660] The compound of formula (78) is reacted with a compound of formula (87), a known compound or a compound prepared by a known method in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (88).

[0661]

[0662] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (78) is reacted with a compound of formula (89), a known compound or a compound prepared by a known method to obtain a compound of formula (90).

[0663]

[0664] Diethanolamine (91) is reacted with 4-nitrobenzenesulfonyl chloride (NosCl) in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as tetrahydrofuran, 1,4-dioxane, dichloromethane, etc., to obtain a compound of formula (92). Then, the compound of formula (92) is reacted with a compound of formula (93), a known compound or a compound prepared by a known method in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as acetonitrile, methanol, ethanol, dimethylformamide, optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (94). In the presence of a base such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., in the presence of a solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane, acetonitrile, etc., optionally in the presence of dimethyl sulfoxide, optionally by heating, optionally by microwave irradiation, the compound of formula (94) is reacted with thiophenol to obtain a compound of formula (95).

[0665]

[0666] In the presence of a base such as sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, etc., optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, etc., in the presence of a palladium catalyst such as palladium acetate (II), tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), palladium on carbon, bis (acetonitrile) dichloropalladium (II), tris (dibenzylideneacetone) dipalladium (0), etc., in the presence of a solvent such as toluene, benzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (96), a known compound or a compound prepared by a known method is reacted with a compound of formula (97), a known compound or a compound prepared by a known method (wherein X 3 Selected from chlorine, bromine, iodine and methane trifluorosulfonate) to obtain a compound of formula (98). Optionally in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (98) is reacted with an acid such as trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, etc., to obtain a compound of formula (99).

[0667]

[0668] In the presence of a base such as sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, etc., optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, etc., in the presence of a palladium catalyst such as palladium acetate (II), tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), palladium on carbon, bis (acetonitrile) dichloropalladium (II), tris (dibenzylideneacetone) dipalladium (0), etc., in the presence of a solvent such as toluene, benzene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, etc., optionally by heating, optionally by microwave irradiation, reacting a compound of formula (100), a known compound or a compound prepared by a known method with a compound of formula (101), a known compound or a compound prepared by a known method (wherein X 3 The compound of formula (102) is reacted with an acid such as trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, etc., optionally in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (103).

[0669]

[0670] In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, etc., optionally by heating, optionally by microwave irradiation, a compound of formula (104), a known compound or a compound prepared by a known method (wherein X 4 C 1-6 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., in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, etc., the compound of formula (105) is reacted with a compound of formula (106), a known compound or a compound prepared by a known method (wherein LG 1 is a leaving group, such as chloro, bromo, iodo, methanesulfonate, toluenesulfonate, etc.), thereby obtaining a compound of formula (107).

[0671]

[0672] The compound of formula (107) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, etc. in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, etc., optionally in the presence of water, optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (108). Then, in the presence of a base such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., in the presence of a solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane, etc., the compound of formula (108) is reacted with iodine to obtain a compound of formula (109).

[0673]

[0674] 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 by heating, optionally by microwave irradiation, a compound of formula (109) is reacted with a compound of formula (110), a known compound or a compound prepared by a known method to obtain a compound of formula (111). Optionally, in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (111) is reacted with an acid such as trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, etc., to obtain a compound of formula (112).

[0675]

[0676] In the presence of sodium periodate, in a solvent such as acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (113) is reacted with ruthenium chloride to obtain a compound of formula (114). In the presence of a solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (114) is reacted with a compound of formula (115), a known compound or a compound prepared by a known method (wherein X 5is halogen) to obtain a compound of formula (116). In the presence of sodium periodate, in a solvent such as acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (116) is reacted with ruthenium chloride to obtain a compound of formula (117). In a solvent such as methanol, ethanol, isopropanol, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (117) is reacted with a reducing agent such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, etc. to obtain a compound of formula (118).

[0677]

[0678] In the presence of a palladium catalyst such as palladium on carbon, palladium on barium sulfate, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), palladium on carbon, bis (acetonitrile) palladium dichloride (II), etc., in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, etc., the compound of formula (7) is reacted with hydrogen to obtain a compound of formula (119). The compound of formula (119) is reacted with a compound of formula (15), a known compound or a compound prepared by a known method in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (120). The compound of formula (120) is reacted with tetra-n-butylammonium fluoride in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (121). The compound of formula (121) is treated with carbon tetrabromide in the presence of triphenylphosphine in the presence of a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, to obtain a compound of formula (122). In the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, etc., optionally by heating, optionally by microwave irradiation, the compound of formula (122) is reacted with a compound of formula (12), a known compound or a compound prepared by a known method to obtain a compound of formula (123).

[0679] The examples provided below provide representative methods for preparing exemplary compounds of the invention. One skilled in the art will know how to substitute appropriate reagents, starting materials and purification methods known to those skilled in the art in order to prepare the compounds of the invention.

[0680] Example

[0681] The practice of the present invention is illustrated by the following non-limiting examples. The examples provided below provide representative methods for preparing exemplary compounds of the present invention. Those skilled in the art will know how to replace appropriate reagents, raw materials and purification methods known to those skilled in the art to prepare the compounds of the present invention.

[0682] In the following examples, the spectral characteristics of the samples were obtained on a Varian Mercury 300-MHz NMR. 1 H-NMR Spectra. Purity (%) and mass spectral data were determined using an Alliance 2695 HPLC / MS (Waters Symmetry C18, 4.6 x 75 mm, 3.5 μm) equipped with a 2996 diode array detector from 210-400 nm.

[0683]

[0684] Example 1: Preparation of 1-benzylpiperidine-4-carboxylic acid ethyl ester: Benzyl bromide (7.07 g, mmol, 1.3 equiv) was added dropwise to a solution of ethylpiperidine-4-carboxylic acid ethyl ester (5.0 g, 31.8 mmol, 1.0 equiv) and ethanol (15.0 mL) at 0 ° C. Then, triethylamine (1.06 g, 10.5 mmol, 1.5 equiv) was added at once at 0 ° C. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reactants were concentrated in vacuo to remove the ethanol present. The resulting residue was suspended in a mixture of ethyl acetate: deionized water (20 mL: 20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2x10 mL). The combined extracts were dried over Na2SO4, then filtered through a silica gel plug and washed with ethyl acetate. The filtrate was concentrated in vacuo to give the product, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ7.41-7.20(m,5H),4.14(q,J=7.2Hz,2H),3.51(s,2H),2.87(dt,J=3.5,11.8Hz,2H) ,2.29(m,1H),2.04(td,J=2.5,11.4Hz,2H),1.95-1.85(m,2H),1.85-1.70(m,2H),1.26(t,J=7.1Hz,3H).

[0685]

[0686] Example 2: Preparation of 4-allyltetrahydro-2H-pyran-4-carboxylic acid methyl ester: The reaction was carried out in an oven-dried glassware under a nitrogen atmosphere. At -78 ° C, a 5 mL anhydrous THF solution of tetrahydro-2H-pyran-4-carboxylic acid methyl ester (0.5 g, 3.47 mmol, 1.0 equivalent) was added dropwise to a solution of lithium diisopropylamide (1 M, 1.20 equivalents) in anhydrous tetrahydrofuran (4.16 mL) over 0.5 hours. The mixture was stirred at this temperature for 1 hour, and then allyl bromide (0.457 g, 3.78 mmol, 1.1 equivalents) was added dropwise. Within 1 hour, the reaction mixture was warmed to room temperature. The reaction was quenched with 10% HCl (while cooling in an ice bath) until it was acidic (pH = 2). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3x10 mL). The extracts were dried over Na2SO4 and then concentrated in vacuo to give the product which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ5.68-5.52(m,1H),5.03-4.91(m,2H),3.75(dt,J=3.7,11.8Hz,2H),3.63(s ,3H),3.37(td,J=2.1,11.6Hz,2H),2.21(d,J=7.4Hz,2H),2.03-1.95(m,2H),1.53-1.40(m,2H).

[0687]

[0688] Example 3: Preparation of 4-allyl-1-benzylpiperidine-4-carboxylic acid ethyl ester: The reaction was carried out in an oven-dried glassware under a nitrogen atmosphere. At -78 ° C, a solution of 1-benzylpiperidine-4-carboxylic acid ethyl ester (6.24 g, 26.7 mmol, 1.0 equivalent) and anhydrous THF (50 mL) was added dropwise in anhydrous tetrahydrofuran (29.3 mL) solution of lithium diisopropylamide (1 M, 1.10 equivalent) over 0.5 hours. The mixture was stirred at this temperature for 1 hour, and then allyl iodide (6.73 g, 3.78 mmol, 1.5 equivalent) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated NH4Cl aqueous solution until neutral pH (cooled in an ice bath at the same time). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2x50 mL). The combined extracts were dried over Na2SO4, then filtered through a silica gel plug and washed with ethyl acetate. The filtrate was concentrated in vacuo to give the product which was used in the next step without further purification. 1H NMR (400MHz, CDCl3) δ7.37-7.20(m,5H),5.78-5.62(m,1H),5.10-4.97(m,2H),4.17(q,J=7.1Hz,2H),3.47(s ,2H),2.78-2.64(m,2H),2.28(d,J=7.4Hz,2H),2.18-2.03(m,4H),1.61-1.46(m,2H),1.26(t,J=7.1Hz,3H).

[0689]

[0690] Example 4: Preparation of 3-(2-hydroxyethyl)-2,8-dioxaspiro[4.5]dec-1-one: A mixture of glacial acetic acid (10.9 g, 180 mmol, 53.6 equiv), paraformaldehyde (0.309 g, 10.3 mmol, 3.0 equiv) and H2SO4 (0.191 g, 1.95 mmol, 0.57 equiv) was stirred at 70 ° C for 30 min, and 4-allyltetrahydro-2H-pyran-4-carboxylic acid methyl ester (0.632 g, 3.43 mmol, 1.0 equiv) was added dropwise over 10 min. The reaction mixture was then kept at 70 to 80 ° C and stirred overnight. Acetic acid was removed under reduced pressure and the reaction was quenched with 10% NaHCO3 solution. The mixture was then extracted with ethyl acetate (3x10 mL), and the combined organic phases were concentrated in vacuo to give a crude oil. The crude oil was used in the next step without further purification.

[0691] The mixture of crude oil (715mg) and 30% NaOH (2.86g NaOH, 4x crude oil) aqueous solution was refluxed for 2 hours. The mixture was cooled in an ice bath and an excess of 30% H2SO4 was added until it was acidic (pH < 2). The resulting mixture was extracted with ethyl acetate (3x25mL), and the combined organic phases were washed with 10% NaHCO3, (50mL), brine (50mL), dried over Na2SO4 and concentrated in vacuo to give a crude product which was used in the next step without further purification. 1H NMR (400MHz, CDCl3) δ4.57(m,1H),3.91(dt,J=4.5,11.8Hz,1H),3.79(dt,J=4.5,12.0Hz,1H),3.66(t,J=6.0Hz,2H),3.54-3.44(m,1H),3 .43-3.34(m,1H),3.13(b,1H),2.41(dd,J=6.1,13.2Hz,1H),2.01-1.91(m,1H),1.89-1.64(m,4H),1.54-1.44(m,1H),1.42-1.33(m,1H).

[0692]

[0693] Example 5: Preparation of 8-benzyl-3-(2-hydroxyethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: A mixture of glacial acetic acid (78.1 g, 1.3 mmol, 53.6 equiv), paraformaldehyde (2.21 g, 73.5 mmol, 3.0 equiv) and H2SO4 (3.63 g, 37 mmol, 1.5 equiv) was stirred at 70°C for 30 min, and 4-allyl-1-benzylpiperidine-4-carboxylic acid ethyl ester (7.03 g, 24.5 mmol, 1.0 equiv) was added dropwise over 10 min. The reaction mixture was then kept at 70 to 80°C and stirred overnight. Acetic acid was removed under reduced pressure and the reaction was quenched with 10% NaHCO3 solution. The mixture was then extracted with ethyl acetate (3x40 mL), and the combined organic phases were concentrated in vacuo to give a crude oil. The crude oil was used in the next step without further purification.

[0694] The mixture of crude oil (7.07 mg) and 30% NaOH (28 g NaOH, 4x crude oil) aqueous solution was refluxed for 2 hours. The mixture was cooled in an ice bath and an excess of 30% H2SO4 was added until it was acidic (pH < 2). The resulting mixture was neutralized (pH = 8-9) with saturated NaHCO3 aqueous solution, then extracted with ethyl acetate (3x100 mL), and the combined organic phases were dried over Na2SO4 and concentrated in vacuo to give a crude product, which was used in the next step without further purification. 1H NMR (400MHz, CDCl3) δ7.39-7.22(m,5H),4.65(m,1H),3.83(t,J=5.6Hz,2H),3.54(s,2H),2.95-2.84(m,1H),2.83-2. 73(m,1H),2.42(dd,J=6.1,13.0Hz,1H),2.30-2.07(m,4H),2.00-1.84(m,3H),1.75-1.59(m,2H),1.58-1.48(m,1H).

[0695]

[0696] Example 6: Preparation of 8-benzyl-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: To a solution of 8-benzyl-3-(2-hydroxyethyl)-2-oxa-8-azaspiro[4.5]dec-1-one (10.0 g, 34.6 mmol, 1.0 equiv), imidazole (2.47 g, 36.3 mmol, 1.05 equiv) and dichloromethane (70 mL) was added a solution of tert-butyldimethylsilyl chloride (1 M, 5.47 g, 36.3 mmol, 1.05 equiv) in dichloromethane (36.3 mL). The reaction was stirred at room temperature for 2 hours and then quenched with deionized water (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2x50 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give the crude product, which was further purified by column chromatography (ethyl acetate / hexanes, 0% to 20%). 1 H NMR (400MHz, CDCl3) δ7.32-7.11(m,5H),4.52(m,1H),3.73-3.65(m,2H),3.46( s,2H),2.87-2.76(m,1H),2.72(dt,J=4.5,11.8Hz,1H),2.31(dd,J=6.2,12.9H z,1H),2.22-2.08(m,1H),2.08-1.97(m,2H),1.91-1.70(m,3H),1.62(dd,J=9. 8,12.8Hz,1H),1.59-1.50(m,1H),1.49-1.38(m,1H),0.83(s,9H),0.00(s,6H).

[0697]

[0698] Example 7: Preparation of tert-butyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: A mixture of 8-benzyl-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one (4.77 g, 11.8 mmol, 1 eq), Pd / C (954 mg, 20 wt%) and MeOH (79 mL) was stirred at room temperature overnight under 1 atm H2 (inflated balloon). The mixture was filtered through a plug of celite, washed with MeOH (50 mL) and concentrated in vacuo to give a crude oil. The crude oil (3.78 g) was dissolved in dichloromethane (79 mL) and cooled to 0 ° C, followed by the addition of di-tert-butyl dicarbonate (2.83 g, 13.0 mmol, 1.1 equivalents) and trimethylamine (1.8 g, 17.7 mmol, 1.5 equivalents). The reaction was warmed to room temperature and stirred for 45 min. At this point, the reaction was diluted with saturated NaHCO3 aqueous solution, then extracted with ethyl acetate (3x50 mL), and the combined organic phases were dried over Na2SO4 and concentrated in vacuo to give a crude product, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ4.57(m,1H),3.91(b,1H),3.77(b,1H),3.73-3.66(m,2H),3.17-3.05(m,1H),3.04-2.93(m,1H),2.31(d d,J=6.2,13.0Hz,1H),1.96-1.81(m,2H),1.81-1.64(m,3H),1.59-1.48(m,1H),1.48-1.32(m,10H),0.83(s,9H),0.00(s,6H).

[0699]

[0700] Example 8: Preparation of tert-butyl 3-(2-hydroxyethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: To a solution of tert-butyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (4.88 g, 11.8 mmol, 1 eq) and THF (70 mL) was added tetra-n-butylammonium fluoride (3.24 g, 12.4 mmol, 1.05 eq); THF (10 mL) was used to complete the transfer. The resulting solution was stirred at room temperature for 30 min and then concentrated in vacuo to give the crude product, which was further purified by column chromatography (MeOH / DCM, 0% to 10%). 1H NMR (400MHz, CDCl3) δ4.67(m,1H),3.95(dt,J=5.0,13.6Hz,1H),3.87-3.73(m,3H),3.23-3.10(m,1H),3.09-2.98( m,1H),2.39(dd,J=6.0,13.0Hz,1H),1.99-1.84(m,4H),1.83-1.68(m,2H),1.63-1.53(m,1H),1.53-1.36(m,10H).

[0701]

[0702] Example 9: Preparation of 3-(2-bromoethyl)-2,8-dioxaspiro[4.5]dec-1-one: A solution of 3-(2-hydroxyethyl)-2,8-dioxaspiro[4.5]dec-1-one (0.320 g, 1.60 mmol, 1 eq) and THF (15 mL) was cooled to 0 ° C, and triphenylphosphine (0.630 g, 2.4 mmol, 1.5 eq) and carbon tetrabromide (0.795 g, 2.4 mmol, 1.5 eq) were added to the solution in sequence. The reaction solution was allowed to warm to room temperature and stirred overnight. The resulting mixture was then filtered and concentrated in vacuo to give a crude mixture. The mixture was suspended in ether (50 mL) and filtered twice with ether to wash the filter cake. The final filtrate was vacuum loaded onto diatomaceous earth and further purified by column chromatography (ethyl acetate / hexane, 0% to 40%). 1 H NMR (400MHz, CDCl3) δ4.67(m,1H),4.04(dt,J=4.6,11.8Hz,1H),3.91(dt,J=4.6,12.1Hz,1H),3.60(m,1H),3.56-3.45(m,3H),2 .50(dd,J=6.1,12.9Hz,1H),2.30-2.02(m,3H),1.91(m,1H),1.76(dd,J=9.8,13.0Hz,1H),1.64-1.55(m,1H),1.52-1.44(m,1H).

[0703]

[0704] Example 10: Preparation of tert-butyl 3-(2-bromoethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: The title compound was prepared according to the procedure for 3-(2-bromoethyl)-2,8-dioxaspiro[4.5]decane-1-one, except that tert-butyl 3-(2-hydroxyethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was used instead of 3-(2-hydroxyethyl)-2,8-dioxaspiro[4.5]decane-1-one: 1 H NMR(400MHz, CDCl3) δ4.68(m,1H),3.97(dt,J=5.0,13.5Hz,1H),3.83(dt,J=5.0,13 .7Hz,1H),3.54(dd,J=5.3,7.5Hz,2H),3.27-3.14(m,1H),3.13-3.01(m,1H),2.42(d d,J=6.0,13.0Hz,1H),2.31-2.20(m,1H),2.20-2.09(m,1H),2.01-1.90(m,1H),1.8 9-1.78(m,1H),1.74(dd,J=9.8,12.8Hz,1H),1.66-1.56(m,1H),1.54-1.36(m,10H).

[0705]

[0706] Example 11: Preparation of 8-benzyl-3-(2-bromoethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate: A solution of 3-(2-hydroxyethyl)-2,8-dioxaspiro[4.5]dec-1-one (2.07 g, 7.16 mmol, 1 eq) and THF (70 mL) was cooled to 0 ° C, and triphenylphosphine (2.83 g, 10.8 mmol, 1.5 eq) and carbon tetrabromide (3.58 g, 10.8 mmol, 1.5 eq) were added to the solution in sequence. The reaction solution was allowed to warm to room temperature and stirred overnight. The resulting mixture was then filtered and concentrated in vacuo to give a crude mixture. The mixture was suspended in ether (50 mL) and filtered twice with ether to wash the filter cake. The final filtrate was vacuum loaded onto diatomaceous earth and further purified by column chromatography on a C18 column. (ACN / H2O, 0% to 100%, with 0.1% formic acid). 1H NMR(400MHz,MeOD)δ7.53(b,2H),7.47(b,3H),4.75(m,1H),4.27(s,2H),3.64-3.47(m,3H),3.34(m, 1H),3.19(b,1H),3.08(b,1H),2.52(m,1H),2.35-2.15(m,3H),2.15-1.97(m,2H),1.96-1.81(m,2H).

[0707]

[0708] Example 12: Preparation of 3-(2-(4-phenylpiperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one: A solution of 3-(2-bromoethyl)-2,8-dioxaspiro[4.5]decan-1-one (0.050 g, 0.190 mmol, 1 eq), THF (4 mL) and 1-phenylpiperazine (0.065 g, 0.399 mmol, 2.1 eq) was stirred at 60° C. for 3 days. 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% to 10%). 1 HNMR (400MHz, CDCl3) δ7.27(m,2H),6.93(d,J=8.3Hz,2H),6.86(t,J=7.3Hz,1H),4.58(m,1 H),4.06(dt,J=4.6,11.9Hz,1H),3.93(dt,J=4.6,12.0Hz,1H),3.61(m,1H),3.51(m,1H),3. 21(t,J=5.0Hz,4H),2.70-2.52(m,6H),2.47(dd,J=6.0,12.8Hz,1H),2.11(m,1H),2.01-1.8 3(m,3H),1.79(dd,J=9.7,13.1Hz,1H),1.65-1.54(m,1H),1.54-1.45(m,1H); MS(LC / MS,M+H + ):344.8.

[0709]

[0710] Example 13: Preparation of 3-(2-(4-(4-(hydroxyphenyl)piperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure used for 3-(2-(4-phenylpiperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]dec-1-one, except that 4-(piperazin-1-yl)phenol was used instead of 1-phenylpiperazine: 1HNMR (400MHz, CDCl3) δ6.74(d,J=8.9Hz,2H),6.63(d,J=8.9Hz,2H),4.45(m,1H),3.97(d t,J=4.6,11.8Hz,1H),3.83(dt,J=4.5,12.3Hz,1H),3.51(m,1H),3.42(m,1H),3.00(t,J =4.7Hz,4H),2.67-2.42(m,6H),2.35(dd,J=6.1,12.1Hz,1H),2.00(m,1H),1.92-1.74(m ,3H),1.67(dd,J=9.6,12.9Hz,1H),1.52-1.43(m,1H),1.43-1.34(m,1H); MS(LC / MS,M+H + ):360.8.

[0711]

[0712] Example 14: Preparation of 8-benzyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: A solution of 8-benzyl-3-(2-bromoethyl)-2-oxa-8-azaspiro[4.5]decan-1-one carboxylate (0.545 g, 1.37 mmol, 1 eq), THF (13.7 mL), 1-(p-tolyl)piperazine (0.507 g, 2.88 mmol, 2.1 eq) and triethylamine (0.107 g, 1.5 mmol, 1.1 eq) was heated and stirred at 60° C. for 3 days. 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% to 10%). 1 H NMR (400MHz, CDCl3) δ7.39-7.23(m,5H),7.10(d,J=8.3Hz,2H),6.87(d,J=8.6Hz, 2H),4.53(m,1H),3.54(s,2H),3.17(t,J=5.0Hz,4H),2.95-2.85(m,1H),2.84-2. 75(m,1H),2.70-2.49(m,6H),2.40(dd,J=6.2,12.8Hz,1H),2.30(s,3H),2.27-2. 05(m,3H),2.01-1.79(m,3H),1.76-1.58(m,2H),1.58-1.46(m,1H); MS(LC / MS,M+H + ):447.8.

[0713]

[0714] Example 15: Preparation of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: A mixture of 8-benzyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one (445 mg, 0.993 mmol, 1 eq), Pd / C (90 mg, 20 wt%) and EtOH (6.6 mL) was stirred at room temperature for 48 h under 1 atm H (inflated balloon). The mixture was filtered through a plug of celite, washed with MeOH (50 mL) and concentrated in vacuo to give a crude oil. 1 H NMR(400MHz,MeOD)δ6.95(d,J=8.2Hz,2H),6.77(d,J=8.5Hz,2H),4.56(m,1 H),3.47(m,1H),3.28-3.18(m,1H),3.17-3.09(m,1H),3.08-2.96(m,5H),2 .66-2.46(m,6H),2.42(dd,J=6.0,13.0Hz,1H),2.14(s,3H),2.10-2.00(m, 1H),2.00-1.91(m,1H),1.91-1.80(m,4H),1.80-1.70(m,1H); MS(LC / MS,M+H + ):357.8.

[0715]

[0716] Example 16: Preparation of methyl 1-oxo-3-(2-(4-(p-tolyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: A solution of 3-(2-(4-(p-tolyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one (0.05 g, 0.14 mmol, 1 eq), dichloromethane (2 mL) and triethylamine (0.44 g, 0.41 mmol, 3 eq) was cooled to 0°C and methyl chloroformate (0.027 g, 0.28 mmol, 2 eq) was added to the solution. The reaction solution was allowed to warm to room temperature and stirred for 3 hours. The reaction was diluted with dichloromethane and vacuum loaded onto diatomaceous earth and further purified by column chromatography on a C18 column. (ACN / H2O, 0% to 100%, containing 0.1% formic acid). The resulting formate salt was dissolved in MeOH (2 mL) and Amberlite IRA-400 (OH) resin was added. The mixture was stirred at room temperature for 30 minutes, then filtered and concentrated in vacuo to give the pure free radical product. 1H NMR (400MHz, CDCl3) δ7.08(d,J=8.4Hz,2H),6.85(d,J=8.6Hz,2H),4.59(m,1H),4.02(b,1H),3.85(b,1H),3.72(s,3H),3.35-3.24(m,1H) ),3.23-3.10(m,5H),2.71-2.50(m,6H),2.38(dd,J=6.0,12.8Hz,1H),2.28(s,3H),2.07-1.72(m,5H),1.69-1.47(m,2H); MS(LC / MS,M+H + ):415.8.

[0717]

[0718] Example 17: Preparation of 8-acetyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The title compound was prepared according to the procedure used for methyl 1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that acetic anhydride was used instead of methyl chloroformate: 1 H NMR (400MHz, CDCl3) δ7.08(d,J=8.3Hz,2H),6.85(d,J=8.5Hz,2H),4.60(m,1H),4.19(m,0.5H),4.04-3.84(m,1H),3.72(m,0.5H),3.45-3.22(m, 2H),3.15(t,J=4.8Hz,4H),2.70-2.49(m,6H),2.43-2.32(m,1H),2.27( s,3H),2.10(s,3H),2.05-1.72(m,5H),1.69-1.49(m,2H); MS(LC / MS,M+H + ):399.8.

[0719]

[0720] Example 18: Preparation of N-methyl-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxamide: The title compound was prepared according to the procedure used for methyl 1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that N-methyl-1H-imidazole-1-carboxamide was used instead of methyl chloroformate: 1H NMR (400MHz, MeOD) δ6.96(d,J=8.3Hz,2H),6.78(d,J=8.2Hz,2H),4.52(m,1H),3.79(dt,J=4.7,13.8Hz,1H),3.68(dt,J=4.5,13.8Hz,1H),3.22 (m,1H),3.16-2.86(m,6H),2.63(s,3H),2.59-2.36(m,7H),2.15(s,3H) ,1.91-1.67(m,3H),1.66-1.50(m,2H),1.50-1.38(m,1H); MS(LC / MS,M+H + ):414.8.

[0721]

[0722] Example 20: Preparation of tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: A mixture of tert-butyl 3-(2-bromoethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.500 g, 1.38 mmol, 1 eq), ACN (7 mL), 1-(2-isopropylphenyl)piperazine (0.337 g, 1.65 mmol, 1.2 eq) and KCO (0.954 g, 6.9 mmol, 5 eq) was heated and stirred at 80° C. for 3 days. 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% to 10%). 1 H NMR (400MHz, CDCl3) δ7.16 (dd, J=1.6, 7.4Hz, 1H), 7.09-6.94 (m, 3H), 4.49 (m, 1H) ,3.89(b,1H),3.75(b,1H),3.40(sep,J=6.9Hz,1H),3.09(m,1H),2.98(m,1H),2. 81(t,J=4.6Hz,4H),2.65-2.39(m,5H),2.30(dd,J=6.1,12.8Hz,1H),1.99-1.60( m,5H),1.51(m,1H),1.46-1.29(m,11H),1.12(s,3H),1.10(s,6H); MS(LC / MS,M+H + ):485.8

[0723]

[0724] Example 21: Preparation of tert-butyl 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: The title compound was prepared according to the procedure for tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that 1,2,3,4-tetrahydroisoquinoline hydrochloride was used instead of 1-(2-isopropylphenyl)piperazine: 1 HNMR(400MHz, CDCl3)δ7.07-6.96(m,3H),6.95-6.87(m,1H),4.53(m,1H),3.87 (b,1H),3.72(b,1H),3.60-3.46(m,2H),3.06(m,1H),2.95(m,1H),2.80(t,J=5 .8Hz,2H),2.64(t,J=6.0Hz,2H),2.58(t,J=7.3Hz,2H),2.28(dd,J=6.1,12.9H z,1H),1.97-1.75(m,3H),1.74-1.58(m,2H),1.54-1.26(m,11H); MS(LC / MS,M+H + ):414.8

[0725]

[0726] Example 22: Preparation of tert-butyl 1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: A solution of tert-butyl 3-(2-bromoethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.5 g, 4.11 mmol, 1.1 eq), THF (36 mL), 1-(p-tolyl)piperazine (0.660 g, 3.74 mmol, 1 eq) and triethylamine (0.416 g, 4.11 mmol, 1.1 eq) was heated and stirred at 70° C. for 3 days. 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% to 10%). 1H NMR (400MHz, CDCl3) δ7.05(d,J=8.3Hz,2H),6.82(d,J=8.5Hz,2H),4.55(m,1H),3.96(m,1H),3.81(m,1H),3.22-2.98(m,6H),2 .67-2.45(m,6H),2.36(dd,J=6.2,12.9Hz,1H),2.25(s,3H),2.00-1.66(m,5H),1.57(m,1H),1.53-1.34(m,10H); MS(LC / MS,M+H + ):457.8

[0727]

[0728] Example 23: Preparation of tert-butyl 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: A solution of tert-butyl 3-(2-bromoethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.5 g, 1.38 mmol, 1 equiv), THF (12 mL), 2-methyl-7-(piperazin-1-yl)-1H-benzo[d]imidazole (0.549 g, 1.65 mmol, 1.2 equiv) and triethylamine (0.500 g, 4.95 mmol, 3.5 equiv) was heated at 70°C and stirred for 3 days. The resulting mixture was then filtered and concentrated in vacuo to give a crude residue which was first purified by column chromatography (methanol / dichloromethane, 0% to 10%). The resulting fractions were further purified by column chromatography on a C18 column. (ACN / H2O, 0% to 100%, containing 0.1% NH4OH) 1 H NMR (400MHz, CDCl3) δ7.16-6.97(m,2H),6.65(m,1H),4.54(m,1H),3.98(m,1H),3.83(m,1H),3.40(b,4H),3.17(t,J=11.1Hz,1H),3.06 (t,J=11.5Hz,1H),2.68-2.42(m,9H),2.36(dd,J=6.2,13.0Hz,1H),1.99-1.66(m,5H),1.58(m,1H),1.54-1.33(m,10H); MS(LC / MS,M+H + ):497.8

[0729]

[0730] Example 24: Preparation of tert-butyl 3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: The title compound was prepared according to the procedure used for tert-butyl 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that 4-(2-(piperazin-1-yl)phenyl)morpholine was used in place of 2-methyl-7-(piperazin-1-yl)-1H-benzo[d]imidazole: 1 H NMR (400MHz, CDCl3) δ6.94-6.87(m,2H),6.87-6.78(m,2H),4.51(m,1H),3.90(m,1H),3.81-3.66(m,5H),3.34-2.84(m,1 0H),2.67-2.37(m,6H),2.31(dd,J=6.2,12.9Hz,1H),1.93-1.59(m,5H),1.52(m,1H),1.47-1.30(m,10H); MS(LC / MS,M+H + ):528.8

[0731]

[0732] Example 25: Preparation of 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: To a solution of tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.450 g, 0.930 mol, 1 eq.) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) at 0°C. The reaction was stirred at room temperature for 30 min, then diluted with MeOH and concentrated in vacuo to give the product as a TFA salt. The resulting TFA salt was dissolved in MeOH (2 mL) and Amberlite IRA-400(OH) resin was added. The mixture was stirred at room temperature for 30 minutes, then filtered and concentrated in vacuo to give the pure free radical product. 1H NMR (400MHz, MeOD) δ7.16(d,J=7.5Hz,1H),7.07-6.93(m,3H),4.50(m,1H),3.44(sep,J=6.9Hz,1H),2.99(dt,J=4.3,12.6Hz,1H),2.89(dt,J=4.3, 13.2Hz,1H),2.82(t,J=4.7Hz,4H),2.74-2.37(m,9H),1.91-1.78(m,3H) ,1.77-1.50(m,3H),1.42(m,1H),1.12(s,3H),1.10(s,3H); MS(LC / MS,M+H + ):385.8

[0733]

[0734] Example 26: Preparation of 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one, except that tert-butyl 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was used instead of tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: 1 H NMR (400MHz, MeOD) δ7.18-7.09(m,3H),7.09-7.03(m,1H),4.64(m,1H),3.68(s,2H),3.25(dt,J=5.0,13.1Hz,1H),3.10(dt,J=5.0,13.4Hz ,1H),2.99-2.88(m,3H),2.85-2.61(m,5H),2.55(dd,J=6.1,12.9Hz,1H),2.09-1.95(m,3H),1.90-1.70(m,3H),1.63(m,1H); MS(LC / MS,M+H + ):314.8

[0735]

[0736] Example 27: Preparation of 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate: A solution of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one (0.05 g, 0.14 mmol, 1 eq), dichloromethane (2 mL) and triethylamine (0.44 g, 0.41 mmol, 3 eq) was cooled to 0°C and methanesulfonyl chloride (0.032 g, 0.28 mmol, 2 eq) was added to the solution. The reaction solution was allowed to warm to room temperature and stirred for 3 hours. The reaction was diluted with dichloromethane and vacuum loaded onto celite and further purified by column chromatography on a C18 column. (ACN / H2O, 0% to 100%, with 0.1% formic acid). 1 H NMR (400MHz, DMSO) δ7.01(d,J=8.5Hz,2H),6.82(d,J=8.5Hz,2H),4.59(m,1H),3.58-3.45(m,1H),3.44-3.33(m,1H), 3.13-2.95(m,5H),2.88(s,3H),2.86-2.78(m,1H),2.62-2.31(m,7H),2.19(s,3H),1.97-1.57(m,7H); MS(LC / MS,M+H + ):435.8

[0737]

[0738] Example 28: Preparation of 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]dec-1-one carboxylate: The title compound was prepared according to the procedure used for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one carboxylate, except that 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one was used instead of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: 1H NMR(400MHz,MeOD)δ7.34-7.27(m,1H),7.23-7.08(m,3H),4.67(m,1H),3.7 0(dt,J=4.8,12.3Hz,1H),3.61-3.47(m,2H),3.40-3.09(m,11H),3.04(m,1 H),2.88(s,3H),2.56(dd,J=6.4,12.8Hz,1H),2.29-2.10(m,2H),2.05(m,1 H),1.96-1.80(m,3H),1.75(m,1H),1.24(s,3H),1.22(s,3H); MS(LC / MS,M+H + ):463.7

[0739]

[0740] Example 29: Preparation of 8-(methylsulfonyl)-3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one carboxylate: The title compound was prepared according to the procedure used for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one carboxylate, except that 3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one was used instead of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: 1 H NMR (400MHz, MeOD) δ7.13-6.90(m,4H),4.67(m,1H),3.86(t,J=4.6Hz,4H),3.70(dt,J=4.7,12.3Hz,1H),3.61-3.08(m,16H),3.04 (m,1H),2.88(s,3H),2.56(dd,J=5.9,13.0Hz,1H),2.29-2.11(m,2H),2.05(m,1H),1.97-1.81(m,3H),1.75(m,1H); MS(LC / MS,M+H + ):507.2

[0741]

[0742] Example 30: Preparation of 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one carboxylate: The title compound was prepared according to the procedure used for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one carboxylate, except that 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one was used instead of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: 1 H NMR (400MHz, MeOD) δ7.47-7.26(m,2H),7.04(d,J=6.7Hz,1H),4.69(m,1H),3.79-3.28(m,12H),3.14(m,1H),3.01(m,1H),2.87(s,3 H),2.79(s,3H),2.58(dd,J=5.9,12.9Hz,1H),2.38-2.14(m,2H),2.12-1.98(m,1H),1.96-1.80(m,3H),1.75(m,1H); MS(LC / MS,M+H + ):476.2

[0743]

[0744] Example 31: Preparation of 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one carboxylate: The title compound was prepared according to the procedure used for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one carboxylate, except that 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one was used instead of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: 1H NMR(400MHz,MeOD)δ7.31-7.21(m,3H),7.20-7.15(m,1H),4.67(m,1H),4.26(s, 2H),3.70(dt,J=4.9,12.3Hz,1H),3.53(dt,J=5.2,12.5Hz,1H),3.39(t,J=6.2H z,2H),3.31-3.10(m,5H),3.03(m,1H),2.88(s,3H),2.56(dd,J=6.0,12.9Hz,1H ),2.30-2.12(m,2H),2.05(m,1H),1.97-1.80(m,3H),1.75(m,1H); MS(LC / MS,M+H + ):392.7.

[0745]

[0746] Example 32: Preparation of 8-(phenylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that benzenesulfonyl chloride was used instead of methanesulfonyl chloride, and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 HNMR(400MHz, CDCl3)δ7.69(m,2H),7.53(m,1H),7.46(m,2H),7.00(d,J=8.3H z,2H),6.75(d,J=8.5Hz,2H),4.44(m,1H),3.46(m,1H),3.22(m,1H),3.10(t, J=4.7Hz,4H),2.97(m,1H),2.87(m,1H),2.75-2.44(m,6H),2.19(s,3H),2.12 (dd,J=6.1,13.0Hz,1H),2.02-1.77(m,4H),1.72-1.53(m,3H); MS(LC / MS,M+H + ):498.2.

[0747]

[0748] Example 33: Preparation of 8-((4-methoxyphenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that 4-methoxybenzenesulfonyl chloride was used instead of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 H NMR (400MHz, CDCl3) δ7.62(d,J=9.0Hz,2H),6.99(d,J=8.3Hz,2H),6.91(d,J=8.9 Hz,2H),6.75(d,J=8.6Hz,2H),4.45(m,1H),3.80(s,3H),3.42(m,1H),3.18(m,1H) ,3.04(t,J=4.9Hz,4H),2.95(m,1H),2.86(m,1H),2.57-2.39(m,6H),2.19(s,3H), 2.11(dd,J=6.1,12.9Hz,1H),2.01-1.86(m,2H),1.86-1.50(m,5H); MS(LC / MS,M+H + ):528.2.

[0749]

[0750] Example 34: Preparation of 8-((4-chlorophenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that 4-chlorobenzenesulfonyl chloride was used instead of methanesulfonyl chloride, and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1H NMR (400MHz, CDCl3) δ7.56(d,J=8.6Hz,2H),7.37(d,J=8.5Hz,2H),6.93(d,J=8.4Hz ,2H),6.69(d,J=8.6Hz,2H),4.40(m,1H),3.37(m,1H),3.10(m,1H),3.02(t,J=4.7H z,4H),2.96(m,1H),2.87(m,1H),2.59-2.34(m,6H),2.13(s,3H),2.06(dd,J=5.9,1 2.9Hz,1H),1.95-1.81(m,2H),1.81-1.67(m,2H),1.66-1.49(m,3H); MS(LC / MS,M+H + ):532.2.

[0751]

[0752] Example 35: Preparation of 8-((tetrahydro-2H-pyran-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that tetrahydro-2H-pyran-4-sulfonyl chloride was used instead of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 H NMR (400MHz, CDCl3) δ7.08(d,J=8.3Hz,2H),6.84(d,J=8.5Hz,2H),4.60(m,1H),4.08(dd,J=3.6,11.5Hz,2H),3.80(m,1H),3.57-3.42(m, 4H),3.41-3.30(m,3H),3.22-3.06(m,5H),2.69-2.47(m,6H),2.30(dd,J=6.1,12.9Hz,1H),2.27(s,3H),2.03-1.65(m,9H); MS(LC / MS,M+H + ):506.2.

[0753]

[0754] Example 36: Preparation of 8-(thiophene-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that thiophene-2-sulfonyl chloride was used instead of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 H NMR (400MHz, CDCl3) δ7.53 (dd, J=1.2, 5.0Hz, 1H), 7.46 (dd, 1.3, 3.8Hz, 1H), 7.06 (dd, J= 3.8,5.0Hz,1H),6.99(d,J=8.4Hz,2H),6.75(d,J=8.5Hz,2H),4.46(m,1H),3.49(m,1H),3 .24(m,1H),3.12-2.97(m,5H),2.92(m,1H),2.61-2.41(m,6H),2.19(s,3H),2.14(dd,J= 6.0,13.0Hz,1H),2.04-1.88(m,2H),1.88-1.73(m,2H),1.73-1.57(m,3H); MS(LC / MS,M+H + ):504.1.

[0755]

[0756] Example 37: Preparation of 4-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-onecarboxylate, except that 4-cyanobenzenesulfonyl chloride was used instead of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1H NMR (400MHz, CDCl3) δ7.89(d,J=8.1Hz,2H),7.85(d,7.8Hz,2H),7.08(d,J=8.2Hz,2H),6.84(d,J=8.5Hz,2H),4.57(m,1H),3.53(m,1H),3.24 (m,2H),3.20-3.07(m,5H),2.68-2.48(m,6H),2.28(s,3H),2.21(dd,J=6.0,13.0Hz,1H),2.08-1.97(m,2H),1.97-1.65(m,5H); MS(LC / MS,M+H + ):523.2.

[0757]

[0758] Example 38: Preparation of 8-((6-chloroimidazo[2,1-b]thiazol-5-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride was used instead of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 H NMR (400MHz, CDCl3) δ7.90(d,J=4.5Hz,1H),7.11-7.02(m,3H),6.84(d,J=8.6Hz,2H),4.57(m,1H),3.74(m,1H),3.52(m,1H),3.26(m, 1H),3.20-3.06(m,5H),2.67-2.47(m,6H),2.32-2.21(m,4H),2.13-1.97(m,2H),1.97-1.82(m,2H),1.82-1.65(m,3H); MS(LC / MS,M+H + ):578.1.

[0759]

[0760] Example 39: Preparation of 8-(((methylsulfonyl)methyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that (methylsulfonyl)methanesulfonyl chloride was used in place of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 H NMR(400MHz, CDCl3) δ7.09(d,J=8.3Hz,2H),6.86(d,J=8.6Hz,2H),4.61(m ,1H),4.45(s,2H),3.89(m,1H),3.66(m,1H),3.45(m,1H),3.34(m,1H),3. 23(s,3H),3.17(t,J=4.9Hz,4H),2.73-2.52(m,6H),2.37(dd,J=6.1,12.9 Hz,1H),2.28(s,3H),2.15-1.85(m,4H),1.85-1.65(m,3H); MS(LC / MS,M+H + ):514.2.

[0761]

[0762] Example 40: Preparation of 2-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)acetonitrile: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-onecarboxylate, except that cyanomethanesulfonyl chloride was used instead of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1H NMR (400MHz, CDCl3) δ7.09(d,J=8.3Hz,2H),6.86(d,J=8.5Hz,2H),4.64(m,1H),4.02-3.91(m,3H),3.69(m,1H),3.58(m,1H),3.48(m,1H),3.18(t, J=4.9Hz,4H),2.73-2.54(m,6H),2.34(dd,J=6.1,13.0Hz,1H),2.29(s,3H ),2.13-2.02(m,2H),2.02-1.89(m,2H),1.89-1.71(m,3H); MS(LC / MS,M+H + ):461.2.

[0763]

[0764] Example 41: Preparation of 8-(propylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that 1-propanesulfonyl chloride was used instead of methanesulfonyl chloride, and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 HNMR (400MHz, CDCl3) δ7.09(d,J=8.3Hz,2H),6.85(d,J=8.4Hz,2H),4.61(m,1H),3.73(m,1H),3.48-3.35(m,2H),3.34-3.25(m,1H),3.16(t,J= 4.8Hz, 4H), 2.92 (m, 2H), 2.69-2.50 (m, 6H), 2.30 (dd, J=6.0, 12.9Hz, 1H), 2.28 (s, 3H), 2.07-1.65 (m, 9H), 1.07 (t, J=7.4Hz, 3H); MS (LC / MS, M+H + ):464

[0765]

[0766] Example 42: Preparation of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((trifluoromethyl)sulfonyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that trifluoromethanesulfonyl chloride was used instead of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 H NMR (400MHz, CDCl3) δ6.96(d,J=8.3Hz,2H),6.72(d,J=8.5Hz,2H),4.50(m,1H),3.87(m,1H),3.70-3.23(b,3H),3.03(t,J=4 .9Hz,4H),2.56-2.38(m,6H),2.19(dd,J=6.2,12.9Hz,1H),2.15(s,3H),1.98-1.86(m,2H),1.86-1.52(m,5H); MS(LC / MS,M+H + ):490

[0767]

[0768] Example 43: Preparation of 8-(isopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that 2-propanesulfonyl chloride was used instead of methanesulfonyl chloride, and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 H NMR (400MHz, CDCl3) δ6.95(d,J=8.2Hz,2H),6.72(d,J=8.6Hz,2H),4.47(m,1H),3.67(m,1H),3.44(m,1H),3.35(m,1H),3.25(m,1H), 3.12-2.94(m,5H),2.58-2.36(m,6H),2.18(dd,J=6.0,12.9Hz,1H),2.14(s,3H),1.92-1.71(m,4H),1.71-1.45(m,3H); MS(LC / MS,M+H + ):464

[0769]

[0770] Example 44: Preparation of 8-(cyclopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that cyclopropylsulfonyl chloride was used instead of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 HNMR(400MHz, CDCl3)δ7.08(d,J=8.3Hz,2H),6.85(d,J=8.5Hz,2H),4.61(m,1H),3.78(m,1H),3.50(m,1H),3.37(m,1H),3.28(m,1H),3.16(t, J=4.9Hz,4H),2.70-2.50(m,6H),2.36-2.25(m,5H),2.10-1.98(m,2H),1.98-1.65(m,5H),1.23-1.11(m,2H),1.07-0.95(m,2H); MS (LC / MS, M+H + ):462

[0771]

[0772] Example 45: Preparation of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((3,3,3-trifluoropropyl)sulfonyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that 3,3,3-trifluoropropane-1-sulfonyl chloride was used instead of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 H NMR (400MHz, CDCl3) δ6.95(d,J=8.3Hz,2H),6.72(d,J=8.5Hz,2H),4.49(m,1H),3.64(m,1H),3.38-3.27(m,2H),3.23(m,1H),3.0 9-2.93(m,6H),2.59-2.36(m,8H),2.17(dd,J=5.9,13.0Hz,1H),2.15(s,3H),1.96-1.85(m,2H),1.85-1.56(m,5H); MS(LC / MS,M+H+ ):518

[0773]

[0774] Example 46: Preparation of 8-(isobutylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that isobutanesulfonyl chloride was used instead of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 H NMR(400MHz, CDCl3)δ7.08(d,J=8.3Hz,2H),6.85(d,J=8.5Hz,2H),4.61(m,1H),3.70(m,1H),3.45-3.33(m,2H),3.29(m,1H)3.16(t,J=4.8Hz,4H ),2.79(dd,J=2.2,6.6Hz,2H),2.70-2.49(m,6H),2.37-2.20(m,5H),2.07-1.97(m,2H),1.97-1.67(m,5H),1.12(d,J=6.7Hz,6H); MS(LC / MS,M+H + ):478

[0775]

[0776] Example 47: Preparation of 8-(cyclopentylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that cyclopentanesulfonyl chloride was used instead of methanesulfonyl chloride, and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1H NMR (400MHz, CDCl3) δ6.95(d,J=8.3Hz,2H),6.72(d,J=8.6Hz,2H),4.47(m,1H),3.64(m,1H),3.42-3.22(m,3H),3.18(m,1 H)3.03(t,J=4.9Hz,4H),2.57-2.37(m,6H),2.18(dd,J=6.1,12.9Hz,1H),2.15(s,3H),1.95-1.42(m,15H); MS(LC / MS,M+H + ):490

[0777]

[0778] Example 48: Preparation of 8-(cyclohexylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that cyclohexanesulfonyl chloride was used instead of methanesulfonyl chloride, and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 H NMR(400MHz, CDCl3) δ6.95(d,J=8.3Hz,2H),6.72(d,J=8.4Hz,2H),4.47(m,1H),3.66(m,1H) ,3.38(m,1H),3.27(m,1H),3.18(m,1H),3.03(t,J=4.9Hz,4H),2.77(tt,J=3.4,12.0Hz,1H) ,2.59-2.36(m,6H),2.19(dd,J=6.0,12.9Hz,1H),2.15(s,3H),2.06-1.94(b,2H),1.91-1.7 2(m,6H),1.72-1.49(m,4H),1.37(qd,J=3.3,12.3Hz,2H),1.23-0.99(m,3H); MS(LC / MS,M+H + ):504

[0779]

[0780] Example 49: Preparation of 8-(ethylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that ethanesulfonyl chloride was used instead of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 HNMR(400MHz, CDCl3)δ7.08(d,J=8.2Hz,2H),6.85(d,J=8.6Hz,2H),4.61(m, 1H),3.75(m,1H),3.51-3.35(m,2H),3.30(m,1H),3.15(t,J=4.9Hz,4H),2.98 (q,J=7.4Hz,2H),2.70-2.48(m,6H),2.31(dd,J=6.2,13.0Hz,1H),2.28(s,3 H),2.07-1.96(m,2H),1.96-1.66(m,5),1.38(t,J=7.4Hz,3H); MS(LC / MS,M+H + ):450

[0781]

[0782] Example 50: Preparation of 8-(pyridin-3-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that pyridine-3-sulfonyl chloride was used instead of methanesulfonyl chloride, and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1H NMR (400MHz, CDCl3) δ9.00 (d, J=2.3Hz, 1H), 8.84 (dd, J=1.5, 4.8Hz, 1H), 8.06 (dt, J=1 .9,8.0Hz,1H),7.5(dd,J=4.9,7.9Hz,1H),7.08(d,J=8.3Hz,2H),6.84(d,J=8.5Hz,2H) ,4.55(m,1H),3.56(m,1H),3.29(m,1H),3.24-3.05(m,6H),2.66-2.47(m,6H),2.27(s ,3H)2.09(dd,J=6.0,13.0Hz,1H),2.09-1.96(m,2H),1.96-1.64(m,5H); MS(LC / MS,M+H + ):499

[0783]

[0784] Example 51: Preparation of 8-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that 1-methyl-1H-pyrazole-4-sulfonyl chloride was used instead of methanesulfonyl chloride, and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 H NMR (400MHz, CDCl3) δ7.75 (s, 1H), 7.71 (s, 1H), 7.07 (d, J = 8.4Hz, 2H), 6.84 ( d,J=8.6Hz,2H),4.55(m,1H),3.95(s,3H),3.48(m,1H),3.23(m,1H),3.13(t, J=4.9Hz,4H),3.02(m,1H),2.93(m,1H),2.67-2.48(m,6H),2.27(s,3H),2.22 (dd,J=6.1,12.9Hz,1H),2.11-1.96(m,2H),1.96-1.64(m,5H); MS(LC / MS,M+H + ):502

[0785]

[0786] Example 52: Preparation of 8-((1H-imidazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-onecarboxylate: The title compound was prepared according to the procedure used for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-onecarboxylate, except that 1H-imidazole-4-sulfonyl chloride was used instead of methanesulfonyl chloride: 1 H NMR (400MHz, MeOD) δ7.88(s,1H),7.74(s,1H),7.09(d,J=8.4Hz,2H),6.90(d,J=8.4Hz,2H),4.58(b,1H),3.67(m,1H),3.53(m,1H),3.40-3.05(m, 10H),2.99(m,1H),2.85(m,1H),2.38(dd,J=5.7,12.9Hz,1H),2.26(s,3H ),2.19-1.91(m,3H),1.90-1.72(m,3H),1.72-1.58(m,1H); MS(LC / MS,M+H + ):488

[0787]

[0788] Example 53: Preparation of 8-(furan-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-1-one formate, except that furan-2-sulfonyl chloride was used instead of methanesulfonyl chloride and the title compound was purified by column chromatography on silica gel. (MeOH / DCM, 0% to 10%): 1 H NMR (400MHz, CDCl3) δ7.59(s,1H),7.07(d,J=8.4Hz,2H),7.02(d,J=3.4Hz,1H),6.84(d,J=8.4Hz,2H),6.52(dd,J=1.7,3.3Hz,1H),4.56(m,1H),3. 70(m,1H),3.47(m,1H),3.24(m,1H),3.19-3.07(m,5H),2.68-2.46(m,6H ),2.33-2.18(m,4H),2.07-1.79(m,4H),1.79-1.60(m,3H); MS(LC / MS,M+H + ):488

[0789]

[0790] Example 54: Preparation of 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: A mixture of 8-benzyl-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one (3.25 g, 8.04 mmol, 1 eq), Pd / C (0.65 g, 20 wt %) and MeOH (54 mL) was stirred at room temperature overnight under 1 atm H2 (inflated balloon). The mixture was filtered through a plug of celite, washed with MeOH (50 mL) and concentrated in vacuo to give a crude oil. The crude oil (2.43 g) was dissolved in dichloromethane (50 mL) and triethylamine (5.55 mL, 38.8 mmol, 5 eq) was added. Cool to 0°C and add methanesulfonyl chloride (2.83 g, 13.0 mmol, 1.1 equiv). Warm the reaction to room temperature and stir for 30 min. At this point, dilute the reaction with deionized water and then extract with dichloromethane (3 x 50 mL), and the combined organic phases are dried over Na2SO4 and concentrated in vacuo to give the crude product, which is further purified by column chromatography (EtOAc / DCM, 0% to 10%). 1 H NMR (400MHz, CDCl3) δ4.61(m,1H),3.75-3.65(m,2H),3.60(m,1H),3.37-3.18(m,3H),2.75(s,3H ), 2.21 (dd, J = 6.0, 13.0Hz, 1H), 2.02-1.91 (m, 2H), 1.91-1.62 (m, 5H), 0.83 (s, 9H), 0.00 (s, 6H).

[0791]

[0792] Example 55: Preparation of 3-(2-hydroxyethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The title compound was prepared according to the procedure used for tert-butyl 3-(2-hydroxyethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was used. Oxa-8-azaspiro[4.5]decan-1-one was used instead of tert-butyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, and the product was purified by column chromatography initially on a C18 column (ACN / H2O, 0% to 100%, containing 0.1% formic acid) and then on a silica gel column (MeOH / DCM, 0% to 10%). 1 H NMR (400MHz, CDCl3) δ4.73 (m, 1H), 3.84 (t, J = 5.5Hz, 2H), 3.68 (m, 1H), 3.41-3.32 (m, 2H), 3. 29(m,1H),2.83(s,3H),2.33(dd,J=6.0,13.0Hz,1H),2.10-2.00(m,2H),2.10-1.71(m,6H).

[0793]

[0794] Example 56: Preparation of 3-(2-bromoethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]dec-1-one: A solution of 3-(2-hydroxyethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]dec-1-one (0.890 g, 3.21 mmol, 1 eq) and dichloromethane (12 mL) was cooled to 0°C, and triphenylphosphine (1.26 g, 4.81 mmol, 1.5 eq) and carbon tetrabromide (1.6 g, 4.81 mmol, 1.5 eq) were added to the solution in sequence. The reaction solution was allowed to warm to room temperature and maintained for 4 hours. The resulting mixture was then filtered and concentrated in vacuo to give a crude mixture. The mixture was suspended in diethyl ether (50 mL) and filtered twice using diethyl ether to wash the filter cake. The final filtrate was vacuum loaded onto celite and further purified by column chromatography (EtOAc / DCM, 0% to 40%). 1H NMR(400MHz,MeOD)δ4.72(m,1H),3.67(m,1H),3.54(dd,J=5.3,7.6Hz,2H),3.44-3.25(m,3H),2.82(s,3H) ,2.34(dd,J=6.0,12.9Hz,1H),2.31-2.21(m,1H),2.21-2.10(m,1H),2.10-1.98(m,2H),1.88-1.71(m,3H).

[0795]

[0796] Example 57: Preparation of 3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]dec-1-one: 3-(2-bromoethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]dec-1-one (50 mg, 0.147 mmol, 1 eq), 1-(4-methoxyphenyl)-piperazine (59.33 mg, 0.308 mmol, 2.1 eq) and acetonitrile (2 mL) were microwaved at 120° C. for 1 hour. The solvent was then evaporated in vacuo and the product was suspended in 15 mL of saturated NaHCO and extracted in dichloromethane (3×15 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give a crude mixture which was then dissolved in dichloromethane and purified by column chromatography (methanol / dichloromethane, 0% to 10%). 1 H NMR (400MHz, CDCl3) δ7.4(d,J=9.2Hz,2H),6.5(d,J=9.2Hz,2H),4.61(m,1H),3.77(s,3H),3.67(m,1H),3.36(m,2H),3.29(m,1H),3.1(t ,J=7.1Hz,4H),2.8(s,3H),2.62(m,4H),2.56(t,J=7.1Hz,2H),2.29(dd,J=7.2,6Hz,1H),2.05(m,2H),1.99-1.71(m,6H); MS(LC / MS,M+H + ):452.

[0797]

[0798] Example 58: Preparation of 3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared and purified according to the procedure used for 3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, except that 1-(4-trifluoromethylphenyl)-piperazine was used instead of 1-(4-methoxyphenyl)-piperazine. 1 HNMR(400MHz, CDCl3)δ7.5(d,J=8.76Hz,2H),6.94(d,J=8.7Hz,2H),4.64(m,1H),3.68(m,1H),3..46-3.28(m,7H ),2.83(s,3H),2.67-2.55(m,6H),2.3(dd,J=7.1,6.1Hz,1H),2.11-2.01(m,2H),2.0-1.74(m,5H); MS(LC / MS,M+H + ):490

[0799]

[0800] Example 59: Preparation of 4-(4-(2-(8-(methylsulfonyl)-1-oxo-2-oxa-8-azaspiro[4.5]dec-3-yl)ethyl)piperazin-1-yl)benzonitrile: The title compound was prepared and purified according to the procedure used for 3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, except that triethylamine (0.06 mL, 0.44 mmol, 3 equiv) was added to the microwave treatment mixture and 1-(4-cyanophenyl)-piperazine was used instead of 1-(4-methoxyphenyl)-piperazine. 1 H NMR (400MHz, CDCl3) δ7.49(d,J=8.4Hz,2H),6.85(d,J=8.4Hz,2H),4.61(m,1H),3.65(m,1H),3.43-3.26(m,7H ),2.81(s,3H),2.64-2.52(m,6H),2.28(dd,J=6.8,5.9Hz,1H),2.02(m,2H),1.96-1.74(m,5H); MS(LC / MS,M+H + ):447

[0801]

[0802] Example 60: Preparation of 8-(methylsulfonyl)-3-(2-(4-(4-nitrophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared and purified according to the procedure used for 3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, except that it was microwaved at 120°C for 1.5 hours and 1-(4-nitrophenyl)-piperazine was used instead of 1-(4-methoxyphenyl)-piperazine. 1 H NMR (400MHz, CDCl3) δ8.13(d,J=9.3Hz,2H),6.82(d,J=9.3Hz,2H),4.62(m,1H),3.66(m,1H),3.46-3.36(m,4H),3.36-3. 28(m,3H),2.8(s,3H),2.67-2.5(b,6H),2.28(dd,J=6.8,5.9Hz,1H),2.08-1.98(m,2H),1.95-1.72(m,5H); MS(LC / MS,M+H + ):467

[0803]

[0804] Example 61: Preparation of 3-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared and purified according to the procedure used for 3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, except that it was microwaved at 120°C for 2 hours and 1-(4-chlorophenyl)-piperazine was used instead of 1-(4-methoxyphenyl)-piperazine. 1 H NMR (400MHz, CDCl3) δ7.19(d,J=8.9Hz,2H),6.82(d,J=8.9Hz,2H),4.6(m,1H),3.65(m,1H),3.42-3.26(m,3H),3.15(t,J= 4.9Hz, 4H), 2.8 (s, 3H), 2.66-2.52 (m, 6H), 2.27 (dd, J=6.8, 5.9Hz, 1H), 2.07-1.98 (m, 2H), 1.97-1.7 (m, 5H); MS (LC / MS, M+H + ):456

[0805]

[0806] Example 62: Preparation of 3-(2-(4-(4-iodophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared and purified according to the procedure used for 3-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, except that 1-(4-iodophenyl)-piperazine was used instead of 1-(4-methoxyphenyl)-piperazine. 1 H NMR (400MHz, CDCl3) δ7.49(d,J=8.8Hz,2H),6.65(d,J=8.8Hz,2H),4.58(m,1H),3.64(m,1H),3.4-3.24(m,3H),3.15(t,J =4.8Hz,4H),2.79(s,3H),2.62-2.5(m,6H),2.26(dd,J=6.8,6Hz,1H),2.0-1.96(m,2H),1.95-1.69(m,5H); MS(LC / MS,M+H + ):548

[0807]

[0808] Example 63: Preparation of 3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared and purified according to the procedure used for 3-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, except that 1-(4-fluorophenyl)-piperazine was used instead of 1-(4-methoxyphenyl)-piperazine. 1 H NMR (400MHz, CDCl3) δ6.94(m,2H),6.85(m,2H),4.59(m,1H),3.65(m,1H),3.4-3.24(m,3H),3.1(t,J=4.8Hz, 4H), 2.8 (s, 3H), 2.65-2.5 (m, 6H), 2.27 (dd, J=6.7, 5.9Hz, 1H), 2.0 (m, 2H), 1.97-1.69 (m, 5H); MS (LC / MS, M+H + ):440.

[0809]

[0810] Preparation of 3-morpholino-4-nitrobenzonitrile: A solution of 3-fluoro-4-nitrobenzonitrile (0.6 g, 3.61 mmol, 1 eq.) and morpholine (0.629 g, 7.22 mmol, 2 eq.) in dimethyl sulfoxide (6.57 mL) was heated at 60 °C for 4 hours. The reaction solution was diluted with water 20 mL and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give a crude product which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ7.82 (d, J=8.3Hz, 1H), 7.40 (d, J=1.5Hz, 1H), 7.33 (dd, J=1.6, 8.3Hz, 1H), 3.86 (m, 4H), 3.11 (m, 4H); MS (LC / MS, M+H + ):234

[0811]

[0812] Preparation of 4-(5-methyl-2-nitrophenyl)morpholine: The title compound was prepared according to the procedure for 3-morpholino-4-nitrobenzonitrile except using 2-fluoro-4-methyl-1-nitrobenzene in place of 3-fluoro-4-nitrobenzonitrile. 1 H NMR (400MHz, CDCl3) δ7.76 (d, J=8.2Hz, 1H), 6.93 (b, 1H), 6.88 (d, J=8.3Hz, 1H), 3.86 (m, 4H), 3.06 (m, 4H), 2.40 (s, 3H); MS (LC / MS, M+H + ):223

[0813]

[0814] Preparation of 3-morpholino-4-nitrophenol: The title compound was prepared according to the procedure used for 3-morpholino-4-nitrobenzonitrile except substituting 3-fluoro-4-nitrophenol for 3-fluoro-4-nitrobenzonitrile. 1 HNMR(400MHz,MeOD)δ7.90(d,J=9.0Hz,1H),6.56(d,J=2.4Hz,1H),6.49(dd,J=2.5,9.0Hz,1H),3.83(m,4H),3.02(m,4H); MS(LC / MS,M+H + ):225

[0815]

[0816] Preparation of 4-(2-nitro-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)morpholine: A solution of 3-morpholino-4-nitrophenol (1.34 g, 5.98 mmol, 1 eq), 2-(trimethylsilyl)ethoxymethyl chloride (1.05 g, 6.28 mmol, 1.05 eq) and N,N-diisopropylethylamine (2.31 g, 17.9 mmol, 3 eq) in dichloromethane (30.0 mL) was stirred at 25 °C for 16 hours. The reaction solution was diluted with 40 mL of water and extracted with dichloromethane (3 x 40 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give the crude product, which was used in the next step without further purification. 1 HNMR (400MHz, CDCl3) δ7.93 (d, J = 9.7Hz, 1H), 6.68 (m, 2H), 5.24 (s, 2H), 3.85 (m, 4H), 3.74 (m, 2H), 3.04 (m, 4H), 0.94 (m, 2H), 0.00 (s, 9H); MS (LC / MS, M+H) + ):355

[0817]

[0818] Preparation of 4-(5-methyl-2-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)phenyl)morpholine: A mixture of 4-(5-methyl-2-nitrophenyl)morpholine (1.58 g, 7.11 mmol, 1 eq), Pd / C (316 mg, 20 wt%) and methanol (72 mL) was stirred at 25° C. under 1 atm H (inflated balloon) for 48 h. The mixture was filtered through a plug of celite, washed with methanol (50 mL) and concentrated in vacuo to give the crude intermediate 4-methyl-2-morpholinoaniline.

[0819] (((4-nitrophenyl)sulfonyl)azanediyl)bis(ethane-2,1-diyl)bis(4-nitrobenzenesulfonate) (1.0 g, 1.5 mmol, 1 eq.), 4-methyl-2-morpholinoaniline (0.346 g, 1.8 mmol, 1.2 eq.), N,N-diisopropylethylamine (1.55 g, 12.0 mmol, 4 eq.) and acetonitrile (4.7 mL) were mixed in a microwave reaction vial (10 mL) equipped with a non-invasive vial cap. The reaction vial containing the mixture was reacted at 175 °C for 1 hour in a microwave treatment. After 1 hour, the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with HCl (10%, 3x30 mL) and saturated NaHCO3 (40 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to give the crude product. The title compound was purified by column chromatography on a silica gel column. (ethyl acetate / dichloromethane, 0% to 10%): 1 H NMR(400MHz, CDCl3) δ8.44(d,J=8.9Hz,2H),8.02(d,J=9.0Hz,2H),6.82(m,2H),6.74 (b,1H),3.71(t,J=4.2Hz,4H),3.24(b,8H),3.05(m,4H),2.29(s,3H);MS(LC / MS,M+H + ):447

[0820]

[0821] Preparation of 3-morpholino-4-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)benzonitrile: The title compound was prepared according to the procedure for 4-(5-methyl-2-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)phenyl)morpholine, except that 3-morpholino-4-nitrobenzonitrile was used in place of 4-(5-methyl-2-nitrophenyl)morpholine and 4-amino-3-morpholinobenzonitrile was used in place of 4-methyl-2-morpholinoaniline. 1 H NMR (400MHz, CDCl3) δ8.43(d,J=8.8Hz,2H),8.01(d,J=8.8Hz,2H),7.30(dd,J=1.8,8.2Hz,1H),7.14(d,J=1.8Hz, 1H), 6.90 (d, J = 8.3Hz, 1H), 3.73 (t, J = 4.5Hz, 4H), 3.36 (m, 4H), 3.26 (m, 4H), 3.02 (t, J = 4.3Hz, 4H); MS (LC / MS, M+H + ):458

[0822]

[0823]

[0136] Preparation of 4-(2-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)morpholine: The title compound was prepared according to the procedure for 4-(5-methyl-2-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)phenyl)morpholine, except that 4-(2-nitro-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)morpholine was used in place of 4-(5-methyl-2-nitrophenyl)morpholine and 2-morpholino-4-((2-(trimethylsilyl)ethoxy)methoxy)aniline was used in place of 4-methyl-2-morpholinoaniline. 1 H NMR (400MHz, CDCl3) δ8.41(d,J=8.8Hz,2H),8.01(d,J=8.7Hz,2H),6.80(d,J=8.7Hz,1H),6.67(dd,J=2.7,8.7Hz,1H),6.60(d,J=2.6Hz ,1H),5.14(s,2H),3.74(m,2H).3.68(t,J=4.4Hz,4H),3.23(b,4H),3.16(b,4H),3.03(b,4H),0.95(m,2H),0.00(s,9H); MS(LC / MS,M+H + ):579

[0824]

[0825] Preparation of 4-(5-methyl-2-(piperazin-1-yl)phenyl)morpholine: Potassium carbonate (1.5 g, 10.8 mmol, 12 eq) was added to a mixture of acetonitrile and dimethyl sulfoxide (CH3CN / DMSO 49:1, 2.4 mL) and heated to 50°C. Benzothiophenol (0.988 g, 8.96 mmol, 10 eq) was added dropwise to the mixture via a syringe under stirring. After 30 minutes, a solution of 4-(5-methyl-2-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)phenyl)morpholine (0.410 g, 0.896 mmol, 1 eq) in acetonitrile and dimethyl sulfoxide (acetonitrile / dimethyl sulfoxide 49:1, 4.5 mL) was added dropwise. The reaction mixture was stirred for 3 hours, quenched with excess NaOH solution (40%) and concentrated under reduced pressure. With dichloromethane (5x30mL) extraction residue, and with organic phase at MgSO4 upper drying and vacuum concentration, obtain crude oil.By reverse phase chromatography (acetonitrile water solution, gradient is 1% to 100%, contains 0.1% formic acid) purification of this oily matter, obtain the formate of required piperazine.Salt is dissolved in dichloromethane, with saturated NaHCO3 solution washing, and organic phase is vacuum concentrated, obtain product. 1H NMR (400MHz, CDCl3) δ6.87-6.76 (m, 2H), 6.71 (s, 1H), 3.84 (t, J = 4.5Hz, 4H), 3.18 (b, 4H), 3.07 (b, 4H), 2.98 (b, 4H), 2.29 (s, 3H); MS (LC / MS, M+H + ):262

[0826]

[0827] Preparation of 3-morpholino-4-(piperazin-1-yl)benzonitrile: The title compound was prepared according to the procedure for 4-(5-methyl-2-(piperazin-1-yl)phenyl)morpholine, except that 3-morpholino-4-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)benzonitrile was used in place of 4-(5-methyl-2-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)phenyl)morpholine. 1 H NMR (400MHz, CDCl3) δ7.24 (dd, J=1.8, 8.2Hz, 1H), 7.08 (d, J=1.8Hz, 1H), 6.88 (d, J=8. 4Hz,1H),3.81(t,J=4.6Hz,4H),3.21(b,4H),3.11(b,4H),3.00(b,4H); MS(LC / MS,M+H + ):273

[0828]

[0829] Preparation of 4-(2-(piperazin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)morpholine: The title compound was prepared according to the procedure for 4-(5-methyl-2-(piperazin-1-yl)phenyl)morpholine, except that 4-(2-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)morpholine was used in place of 4-(5-methyl-2-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)phenyl)morpholine. 1 H NMR (400MHz, CDCl3) δ6.83(d,J=8.6Hz,1H),6.67(dd,J=2.7,8.5Hz,1H),6.59(d,J=2.8Hz,1H),3.82( t,J=4.7Hz,4H),3.74(m,2H),3.18(b,4H),3.10-2.92(b,8H),0.95(m,2H),0.00(s,9H); MS(LC / MS,M+H + ):394

[0830]

[0831] Preparation of tert-butyl 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: A solution of tert-butyl 3-(2-bromoethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.05 g, 0.138 mmol, 1 eq), 4-(5-methyl-2-(piperazin-1-yl)phenyl)morpholine (0.044 g, 0.166 mmol, 1.2 eq) and triethylamine (0.070 g, 0.69 mmol, 5 eq) in acetonitrile (2 mL) was microwaved at 120 °C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product. The title compound was purified by column chromatography on silica gel. (Methanol / dichloromethane, 0% to 10%) 1 H NMR (400MHz, CDCl3) δ6.87-6.76(m,2H),6.71(s,1H),4.59(m,1H),3.98(m,1H),3.90-3.73(m,5H),3.31-2.94(m,10H),2.70 -2.47(m,6H),2.39(dd,J=6.2,12.8Hz,1H),2.28(s,3H),2.03-1.70(m,5H),1.60(m,1H),1.55-1.38(m,10H); MS(LC / MS,M+H + ):543

[0832]

[0833] Preparation of tert-butyl 3-(2-(4-(4-cyano-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: The title compound was prepared according to the procedure used for tert-butyl 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that 3-morpholino-4-(piperazin-1-yl)benzonitrile was used in place of 4-(5-methyl-2-(piperazin-1-yl)phenyl)morpholine. 1H NMR (400MHz, CDCl3) δ7.26(dd,J=1.8,8.3Hz,1H),7.09(d,J=1.6Hz,1H),6.89(d,J=8.3Hz,1H),4.57(m,1H),3.96(m,1H),3.89-3.73(m,5H ),3.40-2.98(m,10H),2.72-2.45(m,6H),2.37(dd,J=6.1,12.8Hz,1H),2.03-1.67(m,5H),1.58(m,1H),1.54-1.38(m,10H); MS(LC / MS,M+H + ):554

[0834]

[0835] Preparation of 8-(methylsulfonyl)-3-(2-(4-(2-morpholino-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure used for tert-butyl 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate The invention relates to a product of the invention, except that 4-(2-(piperazin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)morpholine is used instead of 4-(5-methyl-2-(piperazin-1-yl)phenyl)morpholine, and 3-(2-bromoethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one is used instead of tert-butyl 3-(2-bromoethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate. 1 HNMR (400MHz, CDCl3) δ6.83 (d, J=8.6Hz, 1H), 6.66 (dd, J=2.7, 8.6Hz, 1H), 6.59 (d, J= 2.7Hz,1H),5.14(s,2H),4.61(m,1H),3.81(t,J=4.4Hz,4H),3.74(m,2H),3.66(m,1H ),3.35(m,2H),3.26(m,1H),3.21-2.94(b,8H),2.80(s,3H),2.70-2.41(m,6H),2.30 (dd,J=5.6,12.9Hz,1H),2.08-1.67(m,7H),0.95(m,2H),0.00(s,9H); MS(LC / MS,M+H + ):653

[0836]

[0837] Preparation of 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazine-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decane-1-one: A solution of tert-butyl 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.077 g, 0.142 mol, 1 equivalent) in trifluoroacetic acid: dichloromethane (1:3, 2 mL) was stirred at 25 ° C for 30 minutes. The reaction solution was diluted with methanol (2 mL) and concentrated in vacuo to give a crude intermediate in the form of a trifluoroacetate salt. The resulting material was dissolved in dichloromethane (10 mL) and washed with saturated NaHCO3 aqueous solution (10 mL). The aqueous layer was backwashed with dichloromethane (2 x 10 mL) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the crude intermediate as the free base.

[0838] The obtained free base (0.052 g, 0.114 mmol, 1 eq) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C, and trimethylamine (0.058 g, 0.57 mmol, 5 eq) and methanesulfonyl chloride (0.026, 0.228 mmol, 2 eq) were added. The reaction solution was stirred at 25 ° C for 30 minutes and then concentrated in vacuo to give a crude solid. The title compound was purified by column chromatography on a silica gel column. (Methanol / dichloromethane, 0% to 10%) 1 H NMR (400MHz, CDCl3) δ6.79-6.68(m,2H),6.64(s,1H),4.54(m,1H),3.75(t,J=4.4Hz,4H),3.59(m,1H),3.37-2.88 (b,11H),2.74(s,3H),2.69-2.33(b,6H),2.27-2.16(m,4H),2.02-1.92(m,2H),1.92-1.62(m,5H); MS(LC / MS,M+H + ):521

[0839]

[0840] Preparation of 4-(4-(2-(8-(methylsulfonyl)-1-oxo-2-oxa-8-azaspiro[4.5]dec-3-yl)ethyl)piperazin-1-yl)-3-morpholinobenzonitrile: Prepare according to the procedure for 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one. Prepare the title compound except replacing 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate with tert-butyl 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate. 1 H NMR (400MHz, CDCl3) δ7.29(dd,J=1.8,8.3Hz,1H),7.12(d,J=1.7Hz,1H),6.91(d,J=8.3Hz,1H),4.63(m,1H),3.85(t,J=4.3Hz,4H),3.67(m, 1H),3.55-2.96(b,11H),2.83(s,3H),2.75-2.40(b,6H),2.30(dd,J=6.0,12.9Hz,1H),2.12-1.99(m,2H),1.99-1.71(m,5H); MS(LC / MS,M+H) + ):532

[0841]

[0842] Preparation of 3-(2-(4-(4-hydroxy-2-morpholinophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: 8-(methylsulfonyl)-3-(2-(4-(2-morpholino-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one (0.190 g, 0.291 mmol, 1 eq) was added to a vial and dissolved in hexamethylphosphoramide (1.5 mL). Tetra-n-butylammonium fluoride trihydrate (0.230 g, 0.873 mmol, 3 eq) was added, followed by 300 mg of The reaction mixture was stirred at 60 °C for 48 hours, then filtered and concentrated in vacuo to give a crude oil. The title compound was purified by column chromatography on silica gel. (methanol / dichloromethane, 0% to 10%) 1H NMR (400MHz, CDCl3) δ6.70(d,J=9.2Hz,1H),6.40-6.32(m,2H),4.53(m,1H),3.75(t,J=4.3Hz,4H),3.58(m,1H),3.38-2.84 (b,11H),2.74(s,3H),2.70-2.33(b,6H),2.21(dd,J=5.9,12.8Hz,1H),2.01-1.80(m,4H),1.79-1.60(m,3H); MS(LC / MS,M+H + ):523.

[0843] preparation

[0844] The present invention also relates to a composition or formulation comprising a 5-hydroxytryptamine receptor 7 activity modulator according to the present invention. Generally speaking, the composition of the present invention comprises: an effective amount of one or more disclosed compounds and salts thereof according to the present invention, which can effectively provide modulation of 5-hydroxytryptamine receptor 7 activity; and one or more excipients.

[0845] For the purposes of the present invention, the terms "excipient" and "carrier" are used interchangeably in the specification of the present invention, and the terms are defined herein as "ingredients used in the practice of formulating safe and effective pharmaceutical compositions."

[0846] Formulators should understand that excipients are primarily used to provide safe, stable and functional drugs, not only as a part of the entire delivery vehicle, but also as a means of achieving effective absorption of the recipient of the active ingredient. Excipients can work simply and directly like inert fillers, or excipients as used herein can be part of a pH stabilizing system or coating to ensure that the ingredients are safely delivered to the stomach. Formulators can also take advantage of the fact that the compounds of this invention have improved cellular efficacy, pharmacokinetic properties, and improved oral bioavailability.

[0847] 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 can be prepared according to acceptable pharmaceutical methods, such as those described in Remington's Pharmaceutical Sciences, 17th edition, 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 a substance that can be used for pharmaceutical applications from a toxicological perspective and does not interact adversely with active ingredients. Therefore, a pharmaceutically acceptable carrier is a carrier that is compatible with other ingredients in a formulation and is biologically acceptable. Supplementary active ingredients can also be incorporated into pharmaceutical compositions.

[0848] The compounds of the present teachings can be administered orally or parenterally, alone or in combination with conventional pharmaceutical carriers. Applicable solid carriers may include one or more substances that may also be used as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents, or encapsulating materials. The compounds can be formulated in a conventional manner, for example, in a manner similar to that used for known 5-hydroxytryptamine receptor 7 activity modulators. Oral formulations containing the compounds disclosed herein may include any commonly used oral forms, including tablets, capsules, oral dosage forms, lozenges, pastilles and oral liquids, suspensions or solutions. In powders, the carrier may be a finely divided solid, which is a mixture with a finely divided compound. In tablets, the compounds disclosed herein may be mixed with a carrier having the necessary compression properties in a suitable proportion and pressed into the desired shape and size. Powders and tablets may contain up to 99% of the compound.

[0849] Capsules may contain a mixture of one or more compounds disclosed herein with inert fillers and / or diluents such as pharmaceutically acceptable starch (e.g., corn, potato or tapioca starch), sugars, artificial sweeteners, powdered cellulose (e.g., crystalline and microcrystalline cellulose), flours, gelatin, gums, and the like.

[0850] Tablet formulations available can be prepared by conventional compression, wet granulation or dry granulation methods, and use pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents or stabilizers, including but not limited to magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinyl pyrrolidine, alginic acid, gum arabic, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting 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, cetearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium lauryl sulfate, magnesium aluminum silicate, and triethanolamine. The oral formulations herein may use standard delayed or extended release formulations to alter the absorption of the compound. The oral formulations may also include administering the compounds disclosed herein in water or juice, containing appropriate solubilizers or emulsifiers as needed.

[0851] Liquid carriers can be used to prepare solutions, suspensions, emulsions, syrups, elixirs and for inhalation delivery. The compounds of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent or a mixture of the two or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers and osmotic regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (especially containing additives as described herein, such as cellulose derivatives, such as sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyols, such as diols) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, the carrier can be an oily ester, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions in sterile liquid form for parenteral administration. The liquid carrier for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0852] Liquid pharmaceutical compositions (which are sterile solutions or suspensions) can be used, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in liquid or solid form.

[0853] Preferably, the pharmaceutical composition is a unit dosage form in the form of tablets, capsules, powders, solutions, suspensions, emulsions, granules or suppositories. In this form, the pharmaceutical composition can be subdivided into unit doses containing an appropriate amount of compound. The unit dosage form can be a packaged composition, such as a packaged powder, vial, ampoule, pre-filled syringe or a pouch containing a liquid. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be any such composition of an appropriate number of packaged forms. This unit dosage form can contain about 1 mg / kg compound to about 500 mg / kg compound, and can be administered in a single dose or two or more doses. These doses can be used in any manner that can be used to guide the compound to the recipient's bloodstream, including oral, via implants, parenteral (including intravenous, intraperitoneal and subcutaneous injections), rectal, vaginal and transdermal.

[0854] When used to treat or inhibit a specific disease state or condition, it should be understood that the effective dose can vary according to the specific compound used, the mode of administration, the severity of the condition being treated, and various physical factors associated with the individual being treated. In therapeutic applications, the compound of the present teachings can be applied to a patient who has suffered from the disease in an amount sufficient to cure or at least partially improve the symptoms of the disease or its complications. The dosage used to treat a specific individual must usually be determined subjectively by the attending physician. The variables involved include the patient's specific condition and its state, as well as body size, age, and reaction pattern.

[0855] In some cases, it is desirable to use devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multi-dose dry powder inhalers, pumps, squeeze-actuated atomizing spray dispensers, aerosol dispensers, and aerosol sprayers to apply the compound directly to the patient's airway. For administration by intranasal or intrabronchial inhalation, the compound of the present teaching content can be formulated into a liquid composition, a solid composition, or an aerosol composition. For example, a liquid composition may include one or more compounds of the present teaching content dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents, and may be administered by, for example, a pump or an squeeze-actuated atomizing spray dispenser. The solvent may be, for example, isotonic saline or antibacterial water. For example, a solid composition may be a powder preparation containing one or more compounds of the present teaching content mixed with lactose or other inert powders that can be used for intrabronchial use, and may be administered by, for example, an aerosol dispenser or a device that can destroy or pierce a capsule that encapsulates a solid composition and delivers a solid composition for inhalation. For example, an aerosol composition may include one or more compounds of the present teaching content, a propellant, a surfactant, and a cosolvent, and may be administered by, for example, a metering device. The propellant may be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other physiologically and environmentally acceptable propellant.

[0856] 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 in water appropriately mixed with a surfactant such as hydroxypropylcellulose. Dispersants can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under normal storage and use conditions, these preparations typically contain preservatives to inhibit the growth of microorganisms.

[0857] The pharmaceutical form suitable for injection can include sterile aqueous solution or dispersion and sterile powder for the temporary preparation of sterile injectable solution or dispersion. In some embodiments, the form can be sterile and its viscosity allows it to flow through the syringe. The form is preferably stable under manufacturing and storage conditions, and can prevent the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetable oil.

[0858] The compounds described herein can be administered transdermally, i.e., through the surface of the body and the inner linings of body passages, including epithelial and mucosal tissues. Such administration can be performed using the compounds of the present teachings (including pharmaceutically acceptable salts, hydrates or esters thereof) in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal).

[0859] Transdermal administration can be accomplished by using a transdermal patch containing a compound (e.g., a compound disclosed herein) and a carrier that may be inert to the compound and nontoxic to the skin, and can allow the compound to be delivered for systemic absorption into the bloodstream via the skin. The carrier can take any number of forms, such as creams and ointments, pastes, gels, and occlusive devices. Creams and ointments can be viscous liquids or semisolid emulsions of the oil-in-water or water-in-oil type. Pastes composed of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the compound may also be suitable. Various occlusive devices can be used to release the compound into the bloodstream, such as a semipermeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

[0860] The compounds described herein can be administered rectally or vaginally in the form of conventional suppositories. Suppository formulations can be made from traditional materials (including cocoa butter with or without wax added to change the melting point of the suppository) and glycerol. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

[0861] Lipid formulations or nanocapsules can be used to introduce 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.

[0862] In order to increase the effectiveness of the compounds of the present teachings, it is desirable to combine the compounds with other agents that can effectively treat the target disease. For example, other active compounds (i.e., other active ingredients or agents) that can effectively treat the target disease can be administered together with the compounds of the present teachings. Other agents can be administered simultaneously or at different times with the compounds disclosed herein.

[0863] The compounds of the present teachings can be used to treat or inhibit pathological conditions or disorders in mammals (e.g., human subjects). Therefore, the present teachings provide methods for treating or inhibiting pathological conditions or disorders by providing to mammals compounds of the present teachings (including pharmaceutically acceptable salts thereof) or pharmaceutical compositions comprising one or more compounds of the present teachings in combination or association with a pharmaceutically acceptable carrier. The compounds of the present invention can be administered alone or in combination with other therapeutically effective compounds or therapies for treating or inhibiting pathological conditions or disorders.

[0864] Non-limiting examples of compositions according to the present invention include about 0.001 mg to about 1000 mg of one or more compounds according to the present invention and one or more excipients; about 0.01 mg to about 100 mg of one or more compounds according to the present invention and one or more excipients; and about 0.1 mg to about 10 mg of one or more compounds according to the present invention and one or more excipients.

[0865] Process

[0866] The following procedure can be used to evaluate and select compounds as modulators of serotonin receptor 7 activity.

[0867] Radiolabeled Binding Studies at Serotonin 5HT7 Receptors, Method 1:

[0868] Solutions of the disclosed compounds to be tested were prepared as 1 mg / ml stock solutions in assay buffer or DMSO, depending on their solubility. A similar stock solution of the reference compound chlorpromazine was also prepared as a positive control. Eleven dilutions (5x assay concentration) of the disclosed compounds and chlorpromazine were prepared in assay buffer by serial dilution to give final corresponding assay concentrations in the range of 10 pM to 10 μM.

[0869] A stock concentration of 5 nM was prepared in 50 mM Tris-HCl, 10 mM MgCl2, 1 mM EDTA (pH 7.4, assay buffer) 3 H]LSD (lysergic acid diethylamide). Aliquots (50 μl) of the radioligand were dispensed into wells of a 96-well plate containing 100 μl of assay buffer. Serial dilutions of the disclosed test compounds and the chlorpromazine positive control reference compound were added in duplicate in 50 μl aliquots.

[0870] The membrane fraction (50 μL) of cells expressing the recombinant 5HT7 receptor was distributed to each well. Membranes were prepared from a stably transfected cell line expressing the 5HT7 receptor cultured on 10 cm plates by collecting monolayer cells rinsed with PBS, resuspending and lysing in frozen hypotonic 50 mM Tris-HCl (pH 7.4), centrifuging at 20,000 x g, decanting the supernatant and storing at -80°C; the membrane preparation was resuspended in 3 ml of frozen assay buffer and homogenized by several passages through a 26-gauge needle before use in the assay.

[0871] 250 μl of the reaction was incubated at room temperature for 1.5 hours and then collected by rapid filtration onto a 0.3% polyethyleneimine treated 96-well filter mat using a 96-well Filtermate harvester. Four rapid 500 μl washes with chilled assay buffer were performed to reduce nonspecific binding. The filter mat was dried and scintillant was then added to the filter and the radioactivity retained on the filter was counted in a Microbeta scintillation counter.

[0872] Raw data (dpm) representing total radioligand binding (i.e., specific and nonspecific binding) were plotted as a function of the logarithm of the molar concentration of the competitor (i.e., test or reference compound). Nonlinear regression of the normalized (i.e., percent radioligand binding compared to that observed in the absence of test or reference compound) raw data was performed in Prism 4.0 (GraphPad Software) using a built-in three-parameter logistic model describing ligand competition binding to radioligand-labeled sites:

[0873] y = bottom + [(top - bottom) / (1 + 10x - logIC 50 )]

[0874] where the bottom equals the residual radioligand binding (i.e., nonspecific binding) measured in the presence of 10 μM reference compound and the top equals the total radioligand binding observed in the absence of competitor. Thus, the log IC is estimated from the data 50 (i.e., the logarithm of the ligand concentration that reduces radioligand binding by 50%) and is used to obtain Ki by applying the Cheng-Prusoff approximation:

[0875] Ki=IC 50 / (1+[ligand] / KD)

[0876] where [ligand] equals the assayed radioligand concentration and KD equals the affinity constant of the radioligand for the target receptor.

[0877] Using the same method described for radiolabeled binding studies at the serotonin 5HT7 receptor, the compounds of the present disclosure were screened at a single concentration of 10 μM to determine [ 3 H] Percent inhibition of LSD binding.

[0878] Radiolabeled Binding Studies at Serotonin 5-HT7 Receptors, Method 2:

[0879] Solutions of the disclosed compounds to be tested were prepared as 1 mg / ml stock solutions in assay buffer or DMSO, depending on their solubility. A similar stock solution of the reference compound chlorpromazine was also prepared as a positive control. Eleven dilutions (5x assay concentration) of the disclosed compounds and chlorpromazine were prepared in assay buffer by serial dilution to give final corresponding assay concentrations in the range of 10 pM to 10 μM.

[0880] A stock concentration of 5 nM was prepared in 50 mM Tris-HCl, 10 mM MgCl2, 1 mM EDTA (pH 7.4, assay buffer) 3 H]-5-hydroxytryptamine ([ 3 Aliquots (50 μl) of the radioligand were dispensed into wells of a 96-well plate containing 100 μl of assay buffer. Serial dilutions of the disclosed test compounds and the chlorpromazine positive control reference compound were added in duplicate in 50 μl aliquots.

[0881] The membrane fraction (50 μL) of cells expressing the recombinant 5HT7 receptor was distributed to each well. Membranes were prepared from a stably transfected cell line expressing the 5HT7 receptor cultured on 10 cm plates by collecting monolayer cells rinsed with PBS, resuspending and lysing in frozen hypotonic 50 mM Tris-HCl (pH 7.4), centrifuging at 20,000 x g, decanting the supernatant and storing at -80°C; the membrane preparation was resuspended in 3 ml of frozen assay buffer and homogenized by several passages through a 26-gauge needle before use in the assay.

[0882] 250 μl of the reaction was incubated at room temperature for 1.5 hours and then collected by rapid filtration onto a 0.3% polyethyleneimine treated 96-well filter mat using a 96-well Filtermate harvester. Four rapid 500 μl washes with chilled assay buffer were performed to reduce nonspecific binding. The filter mat was dried and scintillant was then added to the filter and the radioactivity retained on the filter was counted in a Microbeta scintillation counter.

[0883] Raw data (dpm) representing total radioligand binding (i.e., specific and nonspecific binding) were plotted as a function of the logarithm of the molar concentration of the competitor (i.e., test or reference compound). Nonlinear regression of the normalized (i.e., percent radioligand binding compared to that observed in the absence of test or reference compound) raw data was performed in Prism 4.0 (GraphPad Software) using a built-in three-parameter logistic model describing ligand competition binding to radioligand-labeled sites:

[0884] y = bottom + [(top - bottom) / (1 + 10x - logIC 50 )]

[0885] where the bottom equals the residual radioligand binding (i.e., nonspecific binding) measured in the presence of 10 μM reference compound and the top equals the total radioligand binding observed in the absence of competitor. Thus, the log IC is estimated from the data 50 (i.e., the logarithm of the ligand concentration that reduces radioligand binding by 50%) and is used to obtain Ki by applying the Cheng-Prusoff approximation:

[0886] Ki=IC 50 / (1+[ligand] / KD)

[0887] where [ligand] equals the assayed radioligand concentration and KD equals the affinity constant of the radioligand for the target receptor.

[0888] Using the same method described for radiolabeled binding studies at the serotonin 5HT7 receptor, the compounds of the present disclosure were screened at a single concentration of 10 μM to determine [ 3 H]-Percent inhibition of 5HT binding.

[0889] Results for representative compounds according to the invention are listed in Table 11.

[0890] Table 11: Radiolabeled Binding Studies of Serotonin 5HT7 Receptor Results for Exemplary Compounds of the Disclosure

[0891]

[0892]

[0893]

[0894]

[0895] ND = Not Determined

[0896] Functional serotonin 5HT7 assay, method 1:

[0897] In Dulbecco's modified Eagle medium (DMEM) containing 5% dialyzed serum, a cell line stably expressing the human 5HT7 receptor was seeded into a 96-well poly-L-lysine coated plate (40,000 cells per well) 48 hours before the assay. Twenty hours before the assay, the medium was replaced with serum-free DMEM. On the day of the assay, the DMEM was washed and replaced with 30 μl of assay buffer (1X Krebs-Ringer bicarbonate glucose buffer, 0.75 mM IBMX, pH 7.4). Pre-incubation was performed for 10 minutes in a humidified incubator at 37 degrees Celsius. Then, cells were stimulated by adding 30 μl of 2X diluted compounds of the present disclosure or chlorpromazine (final concentration range of 0.1 nM to 10 μM, each concentration was measured in triplicate). A positive control (100 μM forskolin) was also included. The accumulation of cAMP was allowed to continue for 15 min, after which the buffer was removed and the cells were lysed with cell lysis buffer (CatchPoint cAMP Assay Kit, Molecular Devices). Next, the lysate was transferred to a 96-well glass bottom plate coated with goat anti-rabbit IgG and adsorbed with rabbit anti-cAMP (Molecular Devices). After incubation for 5 minutes, horseradish peroxidase-cAMP conjugate (Molecular Devices) was added and incubated for 2 hours at room temperature. Then, after washing three times with wash buffer (Molecular Devices), Stoplight Red substrate (Molecular Devices) reconstructed in substrate buffer (Molecular Devices) containing newly added 1 mM H2O2 was added, and fluorescence (excitation 510-545 nm, emission 565-625 nm) was measured after incubation for 15 minutes at room temperature. For each assay, a cAMP calibration curve was generated, and controls without lysate and antibody were included.

[0898] For agonist testing, raw data (maximum fluorescence, fluorescence units) for each concentration of a disclosed compound or chlorpromazine were normalized to basal (vehicle stimulated) fluorescence (reported as fold increase over basal) and plotted as a function of the logarithm of the molar concentration of the drug (i.e., test or reference compound). Nonlinear regression of the normalized data was performed in Prism 4.0 (GraphPad software) using a built-in three-parameter logistic model describing the activation of a receptor population by agonist stimulation (i.e., sigmoidal concentration-response):

[0899] y = bottom + [(top - bottom) / (1 + 10x - logEC50)]

[0900] where the bottom equals the best fit basal fluorescence and the top equals the best fit maximum fluorescence stimulated by a disclosed compound or chlorpromazine. Thus, the log EC was estimated from the data 50 (i.e., the logarithm of the drug concentration that increases the fluorescence by 50% of the maximum fluorescence observed for the compound of the present invention or chlorpromazine), and the EC 50 (Agonist potency). To obtain an estimate of the relative potency of the test compound (Rel. Emax), its best fit top was compared to chlorpromazine and expressed as a ratio to chlorpromazine (Rel. Emax of the reference agonist is 1.00).

[0901] To determine whether the compounds of the present disclosure are antagonists, a double addition paradigm was used. First, 30 μl of the compounds of the present disclosure (20 μM) (10 μM final concentration) were added and incubated for 15 minutes. Then, 30 μl of chlorpromazine (3X; EC 90 ) (final concentration of agonist is EC30) and cAMP accumulation is allowed to proceed for 15 minutes. Samples are then processed as described above for cAMP measurement. Measurements of chlorpromazine-induced cAMP accumulation are compared to the signal elicited by chlorpromazine after addition of vehicle rather than test compound and expressed as a ratio. "Hits" (compounds that antagonize chlorpromazine, stimulating an increase in baseline normalized fluorescence of at least 50%) are then characterized by modified Schild analysis.

[0902] For the modified Schild analysis, a series of chlorpromazine concentration-response isotherms were generated in the absence and presence of graded concentrations of the test compound (added 15 minutes before the reference agonist). In theory, a compound that acts as a competitive antagonist causes a right-handed shift in the agonist concentration-response isotherm without reducing the maximum response to the agonist (i.e., surmountable antagonism). However, sometimes, factors such as non-competitive antagonism, half-equilibrium, and / or receptor reserve can lead to apparently insurmountable antagonism. To account for this deviation, we applied a modified Lew-Angus method to determine antagonist potency (Christopoulos et al., 1999). In short, the equivalent agonist concentration (the agonist concentration that causes a response equal to the EC of the agonist control curve) is converted to the isotherm. 25％ ) are plotted as a function of the concentration of the disclosed compound present in the wells in which they were measured. Nonlinear regression of the baseline normalized data was performed in Prism 4.0 using the following equation:

[0903] pEC25%=-log([B]+10-pK)-log c

[0904] Where EC25% is equal to the agonist concentration that causes a response equal to 25% of the maximum agonist control curve response, and [B] is equal to the antagonist concentration; K, c, and s are fitting parameters. Parameter s is equal to the Schild slope factor. If s is not much different from unity, pK is equal to pKB; otherwise, pA2 is calculated (pA2 = pK / s). Parameter c is equal to EC 25％ / [B] ratio.

[0905] 5-HT7 Receptor Efficacy Assay, Method 2:

[0906] In a cell-based cAMP enzyme fragment complementation assay, the HitHunter cAMP assay (DiscoveRx) was used to measure the efficacy of the disclosed compounds on the 5-HT7 serotonin receptor. Cells stably expressing the human 5HT7 receptor were seeded in 96-well plates at 4000 cells / well 16-20 hours before the assay in growth medium (Ultraculture medium, 2mM GlutaMax and G418 1mg / mL). Serial dilutions of the agonist 5-carboxamidotryptamine (5-CT) were prepared with a final concentration range of 10μM to 10nM. The disclosed compounds were prepared in 3-fold serial dilutions to obtain a final concentration range of 10μM to 0.1nM. The agonist activity and antagonist activity of the disclosed compounds in the absence of 5-CT were tested in the presence of 5-CT. For the cAMP assay, the protocol was followed according to the instructions provided by the supplier. In short, after adding EC 70 Before adding 5-CT at a concentration of 1:1, cells were incubated with the compounds of the present disclosure at 37°C for 30 minutes. After another 30 minutes, cAMP antibody / cell lysate (20 μL / well) was added and incubated at room temperature for 60 minutes. cAMP XS+EA reagent (20 μL / well) was added and incubated at room temperature for 2 hours. Luminescence values ​​were read on an Envision Multilabel plate reader.

[0907] The disclosures of each of the patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.

[0908] Although the present invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of the present invention may be designed by others skilled in the art without departing from the true spirit and scope of the present invention. The appended claims are intended to be understood to include all such embodiments and equivalent variations.

Claims

1. A compound having formula (I): Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: A is selected from X is selected from O, S, SO, SO2, NR; n 1 is 0, 1, 2; n 2 is 0, 1, 2; R is selected from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, COR 2 、CO2R 2a ,CONR 2b R 2c 、SO2NR 2b R 2c and SO2R 2d ; R 1a , R 1b , R 1c , R 1d and R 1e is independently selected at each occurrence from H, OH, NO2, halogen, CN, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Straight chain alkoxy, C 3-7 Branched alkoxy, C 3-7 Cycloalkoxy, C 1-6 Straight chain halogenated alkyl, C 3-7 Branched chain halogenated alkyl, C 1-6 Straight chain halogenated alkoxy, -S(C 1-6 Straight chain alkyl), S(C 3-7 Branched alkyl), -S(C 3-7 Cycloalkyl), COR 6 、CO2R 7 ,CONR 8a R 8b 、SO2NR 8a R 8b NR 9a R 9b NR 9a COR 10 NR 9a S02R 11 and NR 9a SO2NR 12a R 12b ; R 2 Selected from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 2a Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 2b Selected from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 2c Selected from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 2d Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, C 1-6 Straight chain halogenated alkyl, C 3-7 Branched haloalkyl, -(CH2) q CN, -(CH2) q S02R 13 、-(CH2) q OR 14 , R 3 Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl, C 3-7 Cycloalkyl, optionally substituted aryl, R 4 is an optionally substituted aryl group; R 5a and R 5b each independently optionally substituted with aryl; R 6 independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 7 In each occurrence, independently selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 8a independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 8b independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 9a independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 9b independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 10 independently selected at each occurrence from H, C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 11 In each occurrence, independently selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 12a In each occurrence, independently selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 12b In each occurrence, independently selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 13 Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; R 14 Selected from C 1-6 Straight chain alkyl, C 3-7 Branched alkyl and C 3-7 Cycloalkyl; n is 1, 2 or 3; m is 1 or 2; And q is 1, 2 or 3.

2. The compound according to claim 1, which has formula (II): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

3. The compound according to claim 1, which has formula (III): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

4. The compound according to claim 1, which has formula (IV): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

5. The compound according to claim 1, which has formula (V): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

6. The compound according to claim 1, which has formula (VI): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

7. The compound according to claim 1, which has formula (VII): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

8. The compound according to claim 1, which has formula (VIII): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

9. The compound according to claim 1, which has the formula (IX): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

10. The compound according to claim 1, which has formula (X): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

11. The compound according to claim 1, which has the formula (XI): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

12. The compound according to claim 1, which has the formula (XII): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

13. The compound according to claim 1, which has the formula (XIII): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

14. The compound according to claim 1, which has the formula (XIV): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

15. The compound according to claim 1, which has formula (XV): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

16. The compound according to claim 1, which has the formula (XVI): This includes hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs and complexes thereof.

17. The compound according to claim 1, wherein the compound is selected from: (R)-3-(2-(4-phenylpiperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-(hydroxyphenyl)piperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, (R)-8-Benzyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(p-Tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid methyl ester, (R)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-8-acetyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-N-methyl-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxamide, (R)-tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-tert-butyl 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, (R)-tert-butyl 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-tert-butyl 3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(methylsulfonyl)-3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(phenylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((4-methoxyphenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((4-chlorophenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((tetrahydro-2H-pyran-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(Thiophen-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-4-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile, (R)-8-((6-chloroimidazo[2,1-b]thiazol-5-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(((methylsulfonyl)methyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, and (R)-2-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)acetonitrile, (R)-8-(propylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((trifluoromethyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(isopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(cyclopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((3,3,3-trifluoropropyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(isobutylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(cyclopentylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(cyclohexylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(ethylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(pyridin-3-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((1H-imidazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(Furan-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-4-(4-(2-(8-(methylsulfonyl)-1-oxo-2-oxa-8-azaspiro[4.5]dec-3-yl)ethyl)piperazin-1-yl)benzonitrile, (R)-8-(methylsulfonyl)-3-(2-(4-(4-nitrophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-iodophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-phenylpiperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-(hydroxyphenyl)piperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, (S)-8-Benzyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(p-Tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid methyl ester, (S)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-8-Acetyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-N-methyl-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxamide, (S)-tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-tert-butyl 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, (S)-tert-butyl 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-tert-butyl 3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(methylsulfonyl)-3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(phenylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((4-methoxyphenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((4-chlorophenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((tetrahydro-2H-pyran-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(Thiophen-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-4-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile, (S)-8-((6-chloroimidazo[2,1-b]thiazol-5-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(((methylsulfonyl)methyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, and (S)-2-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)acetonitrile, (S)-8-(propylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((trifluoromethyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(isopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(cyclopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((3,3,3-trifluoropropyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(isobutylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(cyclopentylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(cyclohexylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(ethylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(pyridin-3-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((1H-imidazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(Furan-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-4-(4-(2-(8-(methylsulfonyl)-1-oxo-2-oxa-8-azaspiro[4.5]dec-3-yl)ethyl)piperazin-1-yl)benzonitrile, (S)-8-(Methylsulfonyl)-3-(2-(4-(4-nitrophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-iodophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, or a pharmaceutically acceptable form thereof.

18. A composition comprising an effective amount of at least one compound according to claim 1.

19. The composition of claim 18, further comprising at least one excipient.

20. The composition of claim 19, wherein the at least one compound is at least one member comprising: (R)-3-(2-(4-phenylpiperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-(hydroxyphenyl)piperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, (R)-8-Benzyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(p-Tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid methyl ester, (R)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-8-acetyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-N-methyl-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxamide, (R)-tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-tert-butyl 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, (R)-tert-butyl 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-tert-butyl 3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(methylsulfonyl)-3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(phenylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((4-methoxyphenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((4-chlorophenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((tetrahydro-2H-pyran-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(Thiophen-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-4-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile, (R)-8-((6-chloroimidazo[2,1-b]thiazol-5-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(((methylsulfonyl)methyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, and (R)-2-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)acetonitrile, (R)-8-(propylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((trifluoromethyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(isopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(cyclopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((3,3,3-trifluoropropyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(isobutylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(cyclopentylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(cyclohexylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(ethylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(pyridin-3-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((1H-imidazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(Furan-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-4-(4-(2-(8-(methylsulfonyl)-1-oxo-2-oxa-8-azaspiro[4.5]dec-3-yl)ethyl)piperazin-1-yl)benzonitrile, (R)-8-(methylsulfonyl)-3-(2-(4-(4-nitrophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-iodophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-phenylpiperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-(hydroxyphenyl)piperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, (S)-8-Benzyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(p-Tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid methyl ester, (S)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-8-Acetyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-N-methyl-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxamide, (S)-tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-tert-butyl 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, (S)-tert-butyl 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-tert-butyl 3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(methylsulfonyl)-3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(phenylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((4-methoxyphenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((4-chlorophenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((tetrahydro-2H-pyran-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(Thiophen-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-4-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile, (S)-8-((6-chloroimidazo[2,1-b]thiazol-5-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(((methylsulfonyl)methyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, and (S)-2-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)acetonitrile, (S)-8-(propylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((trifluoromethyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(isopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(cyclopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((3,3,3-trifluoropropyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(isobutylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(cyclopentylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(cyclohexylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(ethylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(pyridin-3-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((1H-imidazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(Furan-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-4-(4-(2-(8-(methylsulfonyl)-1-oxo-2-oxa-8-azaspiro[4.5]dec-3-yl)ethyl)piperazin-1-yl)benzonitrile, (S)-8-(Methylsulfonyl)-3-(2-(4-(4-nitrophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-iodophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, or a pharmaceutically acceptable form thereof.

21. A method of treating a disease associated with dysregulated serotonin receptor 7 activity, the method comprising administering to a subject an effective amount of at least one compound according to claim 1 to treat the disease.

22. The method of claim 21, wherein the at least one compound is administered in the form of a composition further comprising at least one excipient.

23. The method of claim 21, wherein the at least one compound is at least one member of the group consisting of: (R)-3-(2-(4-phenylpiperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-(hydroxyphenyl)piperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, (R)-8-Benzyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(p-Tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid methyl ester, (R)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-8-acetyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-N-methyl-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxamide, (R)-tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-tert-butyl 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, (R)-tert-butyl 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-tert-butyl 3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (R)-3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(methylsulfonyl)-3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(phenylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((4-methoxyphenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((4-chlorophenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((tetrahydro-2H-pyran-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(Thiophen-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-4-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile, (R)-8-((6-chloroimidazo[2,1-b]thiazol-5-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(((methylsulfonyl)methyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, and (R)-2-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)acetonitrile, (R)-8-(propylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((trifluoromethyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(isopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(cyclopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((3,3,3-trifluoropropyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(isobutylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(cyclopentylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(cyclohexylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(ethylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(pyridin-3-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-((1H-imidazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-8-(Furan-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-4-(4-(2-(8-(methylsulfonyl)-1-oxo-2-oxa-8-azaspiro[4.5]dec-3-yl)ethyl)piperazin-1-yl)benzonitrile, (R)-8-(methylsulfonyl)-3-(2-(4-(4-nitrophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-iodophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-phenylpiperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-(hydroxyphenyl)piperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, (S)-8-Benzyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(p-Tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid methyl ester, (S)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-8-Acetyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-N-methyl-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxamide, (S)-tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-tert-butyl 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, (S)-tert-butyl 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-tert-butyl 3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, (S)-3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(methylsulfonyl)-3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(phenylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((4-methoxyphenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((4-chlorophenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((tetrahydro-2H-pyran-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(Thiophen-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-4-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)benzonitrile, (S)-8-((6-chloroimidazo[2,1-b]thiazol-5-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(((methylsulfonyl)methyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, and (S)-2-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl)acetonitrile, (S)-8-(propylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((trifluoromethyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(isopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(cyclopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((3,3,3-trifluoropropyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(isobutylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(cyclopentylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(cyclohexylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(ethylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(pyridin-3-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-((1H-imidazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-8-(Furan-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-4-(4-(2-(8-(methylsulfonyl)-1-oxo-2-oxa-8-azaspiro[4.5]dec-3-yl)ethyl)piperazin-1-yl)benzonitrile, (S)-8-(Methylsulfonyl)-3-(2-(4-(4-nitrophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-iodophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, (S)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, or a pharmaceutically acceptable form thereof.

24. The method of claim 21, wherein the disease associated with dysregulation of 5-HT receptor 7 activity comprises: Inflammatory bowel disease, circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, temperature regulation disorders, learning disorders, memory disorders, hippocampal signaling disorders, sleep disorders, attention-deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, or bipolar disorder.

25. The method of claim 22, wherein the disease associated with dysregulation of 5-HT receptor 7 activity comprises: Inflammatory bowel disease, circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, temperature regulation disorders, learning disorders, memory disorders, hippocampal signaling disorders, sleep disorders, attention-deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, or bipolar disorder.

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