Novel functionalized lactone as a regulator of 5-hydroxytryptamine receptor 7 and its method of use

Abstract

This paper describes novel selective modulators of 5-HT7 receptors.These selective compounds can be useful for treating CNS and non-CNS symptoms.Compared to other receptors, the compounds described herein can be selective in targeting 5-HT7 receptors by selectively targeting the 5-HT7 receptors that are expressed in specific tissues or organs, thereby providing effective selectivity through the specific partitioning profile of 5-HT7 modulators. [502] JPEG2023501576000525.jpg2943

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 934,985, filed on 13 November 2019, which is incorporated by reference in its entirety. Statement on research funded by the federal government

[0002] This invention was made possible with government support under grant number 2R44DK115254-02A1 from the National Institute of Diabetes, Digestive and Kidney Disease. The government has certain rights to this invention. [Background technology]

[0003] Serotonin, discovered in the late 1940s, is present in both the peripheral and central nervous systems [Physiol.Res,60(2011)15-25;Psychopharmacology 213(2011)167-169]. Serotonin, also known as 5-hydroxytryptamine (5-HT), is an indolealkylamine monoamine neurotransmitter that acts at the synapses of nerve cells. Seven distinct families of serotonin receptors have been identified, and at least 20 subpopulations have been cloned based on sequence similarity, signal transduction binding, and pharmacological properties. The seven families of 5-HT receptors are named 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7, and each of these receptors further comprises subfamilies or subpopulations. While the signaling mechanisms of all seven families have been studied, it has been found that activation of 5-HT1 and 5-HT5 receptors leads to a decrease in intracellular cAMP, while activation of 5-HT2, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 leads to 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 disorders. This neurotransmitter binds to G protein-coupled receptors and is involved in a wide variety of behaviors, particularly 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 colitis (International Publication No. 2012058769, Khan, WI, et al. Journal of Immunology, 2013, 190, 4795-4804), epilepsy, paroxysmal disorders (Epilepsy Research (2007) 75, 39), drug addiction and alcohol addiction (Hauser, SR et al. Frontiers in Neuroscience, 2015, 8, 1-9). This specification describes novel selective modulators of the 5-HT7 receptor. These selective compounds may be useful in the treatment of CNS and non-CNS symptoms. The compounds described herein may be selective in targeting the 5-HT7 receptor by selectively targeting the 5-HT7 receptor compared to other receptors and / or expressed in specific tissues or organs, thereby exhibiting effective selectivity through a specific partitioning profile of the 5-HT7 modulator. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] International Publication No. 2012058769 [Non-patent literature]

[0005] [Non-Patent Document 1] Physiol.Res,60(2011)15-25 [Non-Patent Document 2] Psychopharmacology 213(2011)167-169 [Non-Patent Document 3] ACS Medicinal Chemistry Letters,2011,2,929-932 [Non-Patent Document 4] Physiological Research,2011,60,15-25 [Non-Patent Document 5] Khan,WI,et al.Journal of Immunology,2013,190,4795-4804 [Non-Patent Document 6] Epilepsy Research (2007) 75,39 [Non-Patent Document 7] Hauser,SRet al.Frontiers in Neuroscience,2015,8,1-9 [Overview of the Initiative]

Means for Solving the Problem

[0006] In one aspect, the present invention features a compound having a structure according to the following general formula (I*),

Chemical formula

Chemical formula

Chemical formula

[0007] In the embodiment, the compound of general formula (I*) or (I*-N) has a structure that conforms to general formula (I*-1), [ka] The structure comprises the enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex.

[0008] In the embodiment, the compound of general formula (I*) or (I*-N) has a structure that conforms to general formula (I*-2), [ka] The structure comprises the enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex.

[0009] In the embodiment, the compound of general formula (I*-N) has a structure that conforms to general formula (I*-3), [ka] The compound according to claim 2, having the structure, wherein the compound comprises an enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex.

[0010] In this embodiment, R 1N teeth, [ka] In the formula, R 8a and R 8b Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 It forms a heterocyle containing 3 to 7 atoms, which contains a group selected from R9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl,

Chemical formula

[0011] In an embodiment, R 1N is

Chemical formula

Chemical formula

Chemical formula

[0012] In an embodiment, R 1N is as follows:

Chemical formula

Chemical formula

Chemical formula

[0013] In this embodiment, R 1N teeth, [ka] That is the case.

[0014] In this embodiment, R 1N teeth, [ka] That is the case.

[0015] In another embodiment, the present invention is characterized by a compound having a structure according to the following general formula (I**): [ka] The formula includes the enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex, in which, R aa and R bb Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl. R AA Each of these is independently a C1-C7 linear alkyl group. R 2a Each of these is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN. aa is 0, 1, or 2, and a' is either 1 or 2.

[0016] In this embodiment, R aa and R bb These are both ethyl compounds.

[0017] In this embodiment, a is either 0 or 1.

[0018] In the embodiment, a is 1 or 2, and R AA Each of these is methyl.

[0019] In the embodiment, a' is 1 or 2, and R AA Each of these is methyl.

[0020] In this embodiment, aa is either 0 or 1.

[0021] In this embodiment, R 2a Each of them is a halogen, independently of the others.

[0022] In this embodiment, R 2a Each of these is independently either -F or -Cl.

[0023] In the embodiment, the C5 carbon of 2-dihydrofuranone has a (R) configuration.

[0024] In the embodiment, the C5 carbon of 2-dihydrofuranone has a (R) configuration.

[0025] In another embodiment, the present invention is characterized by a compound having a structure according to the following general formula (I): [ka] The formula includes the enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex, in which, R a and R b Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl, or R a and R b These, together with the atoms to which they bond, form a cyclic carbon having 5 to 7 ring atoms, optionally containing a double bond, or R a and R b Together with the atoms they bond to, they form O, S, SO, SO2, and NR 1 A ring having 6 to 8 ring atoms is formed, including a portion selected from the group consisting of the following: A is a five- to twelve-membered nitrogen-containing heterocycline with an N bond, the nitrogen-containing heterocycline being bicyclic or polycyclic, and optionally containing further heteroatoms selected from O, N, and S, and non-aromatic nitrogen-containing heterocyclines are R 2 It further includes the base, R 1 These are H, C1-C7 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, five- to six-membered heteroaryl ring, polar acyl group, or polar sulfonyl group. R 2 These include 6- to 10-membered aryls, 5- to 10-membered nitrogen-containing heteroaryls, and [ka] Selected from the group consisting of, R 3 These are 6- to 10-membered aryl compounds or 5- to 10-membered nitrogen-containing heteroaryl compounds. m is 1, 2, or 3, and n is 1, 2, 3, or 4, and also In the formula, if A is 1,2,3,4-tetrahydroquinol-1-yl, 1,2,3,4-tetrahydroisoquinol-2-yl, octahydropyrrolo[3,4-c]pyrrole-1-yl, or 2,6-diazaspiro[3.3]heptan-1-yl, then R a and R b Both cannot be methyl, both ethyl, or both phenyl, R a and R b It is also not possible to form unsubstituted C3-C6 cycloalkyl groups by bonding them together.

[0026] In the embodiment of general formula (I), R a and R b These atoms, together with the atoms they bond to, form a ring with 6 to 8 ring atoms, one of which is O, S, SO, SO2, and NR. 1 This is a part selected from the group consisting of [the specified elements].

[0027] In the embodiment, the compound of general formula (I) has one of the following structures. [ka]

[0028] In the embodiment of general formula (I), R a and R b In all cases, these are either methyl or ethyl, or R a and R b These are bonded to form unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0029] In the embodiment, the compound of general formula (I) has one of the following structures. [ka]

[0030] In the embodiment, the compound of general formula (I) follows one of the following structures: [ka]

[0031] In the embodiment of general formula (I), R a and R b These atoms, together with the atoms they bond to, form a ring with 6 to 8 ring atoms.

[0032] In the embodiment, the compound of general formula (I) is general formula (IF), [ka] It has a structure that follows [the specified format].

[0033] In this embodiment, the compound of general formula (I) has a structure that conforms to one of the following general formulas: [ka]

[0034] In the embodiment of general formula (I), A is selected from the group consisting of the following: [ka] During the ceremony, R 2 phenyl, naphthyl, pyridyl, indolyl, and [ka] Selected from the group consisting of, R 3 It is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl. R A C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C 1~ C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohalalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C 1~ Selected from the group consisting of C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and five-membered to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen, and a is 0, 1, or 2.

[0035] In embodiments of general formula (I), A is selected from the group consisting of: [ka]

[0036] In embodiments of general formula (I), A is selected from the group consisting of: [ka]

[0037] In the embodiment of general formula (I), a is 0. In the embodiment of general formula (I), a is 1. In the embodiment of general formula (I), a is 2.

[0038] In the embodiment of general formula (I), R 1 H, C1-C7 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, imidazole, oxazole, isoxazole, [ka] Selected from the group consisting of, R 4a , R 4b , R 4c , R 6a , R 6b , and R 6c Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 4a and R 4b They optionally, together with the atoms they bond to, form a ring containing 3 to 7 atoms, optionally containing oxygen. R 6a and R 6b They optionally, together with the atoms they bond to, form a ring containing 3 to 7 atoms, optionally containing oxygen. R 4d and R 6d Each is selected from the group consisting of phenyl, benzyl, pyridyl, -CH2(pyridyl), imidazole, and -CH2(imidazole), R 5 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR8d SO2R 8e , NR 8i COOR 8j NHCONR 8f , NR 8g COR 8h , and [ka] Selected from the group consisting of, R 7 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR 8d SO2R 8e NHCONR 8f Selected from the group consisting of, R 8a , R 8b , R 8d , R 8 , and R 8ig Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 Forming a heterocyle containing 3 to 7 atoms, which contains a group selected from the above, R 8c , R 8e , R 8f , and R 8h Each of these is either a C1-C7 alkyl group or a C3-C7 cycloalkyl group. R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, or R4a and R 8a If both exist, or R 4a and R 8g If both are present, these groups optionally combine with the atom to which they bond to form a ring containing 4 to 7 atoms. R 9 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 11 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, y 1 is 0, 1, or 2, and y 2 It is 0, 1, or 2.

[0039] In the embodiment of general formula (I), R 1 The following group is selected: [ka]

[0040] In the embodiment of general formula (I), R 1 The following group is selected: COOR 5 , where R 5 C6~C 10 It is an aryl or a 5- to 10-membered heteroaryl. [ka] , where R 8a and R 8b Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 It forms a heterocyle containing 3 to 7 atoms, which contains a group selected from R 9It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, [ka] In the formula, R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, [ka] In the formula, R 8h These are unsubstituted C1-C7 alkyl groups, [ka] In the formula, R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, [ka] In the formula, R 8a and R 8b Each of these is independently either H or an unsubstituted C1-C7 alkyl group. [ka] In the formula, R 8d These are independently H or unsubstituted C1-C7 alkyl, and R 8e These are unsubstituted C1-C7 alkyl groups, [ka] In the formula, R 4a and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups, [ka] In the formula, R 8hThese are unsubstituted C1-C7 alkyl groups, [ka] In the formula, R 8a , R 8b , and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups, [ka] [ka] In the formula, R 8a and R 8b Each of these is independently either H or an unsubstituted C1-C7 alkyl group. [ka] In the formula, R 8g These are independently H or unsubstituted C1-C7 alkyl, and R 8h These are independently unsubstituted C1-C7 alkyl groups, or [ka] That is the case.

[0041] In another embodiment, the present invention is characterized by a compound according to general formula (II), [ka] The formula includes the enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex, in which, A 2 teeth, [ka] And, R 2 These include 6- to 10-membered aryls, 5- to 10-membered nitrogen-containing heteroaryls, and [ka] Selected from the group consisting of, R 3 These are 6- to 10-membered aryl compounds or 5- to 10-membered nitrogen-containing heteroaryl compounds. R A C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxy Selected from the group consisting of xycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen. a is 0, 1, or 2. m is 1, 2, or 3. n is 1, 2, 3, or 4. R 1’ C6~C 10 Aryl, five- to six-membered heteroaryl rings, [ka] Selected from the group consisting of, R 4a , R 4b , R 4c , R 6a , R 6b , and R 6cEach is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 4a and R 4b They optionally, together with the atoms they bond to, form a ring containing 3 to 7 atoms, optionally containing oxygen. R 6a and R 6b They optionally, together with the atoms they bond to, form a ring containing 3 to 7 atoms, optionally containing oxygen. R 4d and R 6d Each is selected from the group consisting of phenyl, benzyl, pyridyl, -CH2(pyridyl), imidazole, and -CH2(imidazole), R 5 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j NHCONR 8f , NR 8g COR 8h , and [ka] Selected from the group consisting of, R 7 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR8d SO2R 8e NHCONR 8f Selected from the group consisting of, R 8a , R 8b , R 8d , R 8g , and R 8i Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, or R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 Forming a heterocyle containing 3 to 7 atoms, which contains a group selected from the above, R 8c , R 8e , R 8f , and R 8h Each of these is a C1-C7 alkyl or C3-C7 cycloalkyl, or R 4a and R 8a If both exist, or R 4a and R 8g If both are present, these groups optionally combine with the atom to which they bond to form a ring containing 4 to 7 atoms. R 9 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 11 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, y 1 is 0, 1, or 2, and y 2 is 0, 1, or 2, and also In the formula, A 2 but [ka] And R 2 is phenyl, and R 1’ but [ka] And y 2 If is 0 and n is 2, then R 7 It is not methyl, CH2SO2CH3, CH2CN, tetrahydropyranyl, phenyl, 4-substituted phenyl, or a 5- to 8-membered heteroaryl.

[0042] In the embodiment, the compound according to general formula (II) has one of the following structures: [ka]

[0043] In the embodiment of general formula (II), R 1’ The following is true: COOR 5 , where R 5 C6~C 10 It is an aryl or a 5- to 10-membered heteroaryl. [ka] In the formula, R 8a and R 8b Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 It forms a heterocyle containing 3 to 7 atoms, which contains a group selected from R 9 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, [ka] In the formula, R 8jThese are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, [ka] In the formula, R 8h These are unsubstituted C1-C7 alkyl groups, [ka] In the formula, R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, [ka] In the formula, R 8a and R 8b Each of these is independently either H or an unsubstituted C1-C7 alkyl group. [ka] In the formula, R 8d These are independently H or unsubstituted C1-C7 alkyl, and R 8e These are unsubstituted C1-C7 alkyl groups, [ka] In the formula, R 4a and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups, [ka] In the formula, R 8h These are unsubstituted C1-C7 alkyl groups, [ka] In the formula, R 8a , R 8b , and R8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups, [ka] In the formula, R 8a and R 8b Each of these is independently either H or an unsubstituted C1-C7 alkyl group. [ka] In the formula, R 8g These are independently H or unsubstituted C1-C7 alkyl, and R 8h These are independently unsubstituted C1-C7 alkyl groups, or [ka] That is the case.

[0044] In the embodiment of general formula (II), A 2 teeth [ka] That is the case.

[0045] In the embodiment of general formula (II), A 2 teeth [ka] That is the case.

[0046] In the embodiment of general formula (II), A 2 teeth [ka] That is the case.

[0047] In the embodiment, the compound of general formula (I), (I*), (I**), or (II) is one of the compounds 1 to 145, which include its enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex.

[0048] In another embodiment, the present invention is characterized by a pharmaceutical composition comprising any compound described herein (for example, a compound according to general formula (I), (I*), (I**), or (II)) or a pharmaceutically acceptable salt thereof.

[0049] In the embodiment, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0050] In another embodiment, the present invention features a method for treating a disorder associated with dysregulation of the activity of the 5-hydroxytryptamine receptor 7, the method comprising administering an effective amount of at least one compound described herein (e.g., a compound according to general formula (I), (I*), (I**), or (II)) or a pharmaceutically acceptable salt thereof to the subject.

[0051] In the embodiment, the at least one compound or a pharmaceutically acceptable salt thereof is administered in a composition further comprising at least one excipient.

[0052] In the embodiment, diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity are selected from the group consisting of peripherally selective diseases, nervous system diseases, circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular diseases, migraines, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorders, learning disabilities, memory impairment, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), colitis, epilepsy, paroxysmal disorders, drug addiction, alcohol addiction, breast cancer, hepatic fibrosis, chronic liver disease, hepatocellular carcinoma, small intestinal neuroendocrine neoplasms, and lung injury.

[0053] In this embodiment, the disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity is inflammatory bowel disease (IBD) or colitis. [Modes for carrying out the invention]

[0054] definition All technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs, unless otherwise specified. Any methods and materials similar or equivalent to those described herein may be used in carrying out or testing the present invention, but exemplary methods, apparatus and materials are described herein. All technical and patent documents referenced herein are incorporated herein by reference in their entirety. Nothing herein should be construed as meaning that the present invention is not considered to have prior rights on the grounds of prior inventions.

[0055] Throughout this specification, where a composition is described as having, containing, or comprising certain components, or where a method is described as having, containing, or comprising certain steps of a particular method, the compositions of this instruction are intended to consist essentially of the listed components, and the methods of this instruction are also intended to consist essentially of the listed steps of a particular method.

[0056] Throughout this application, where it is stated that an element or component is included in and / or selected from the enumerated list of elements or components, it should be understood that the element or component may be any one of the enumerated elements or components, or may be selected from a group consisting of two or more of the enumerated elements or components.

[0057] In this specification, the use of the singular form includes the plural form unless otherwise specified (and vice versa). Furthermore, when the term “about” is used before a quantitative value, this instruction includes that specific quantitative value itself unless otherwise specified.

[0058] It should be understood that the order or sequence of steps for performing a particular action is not important, as long as this instruction is feasible. Furthermore, two or more steps or actions can be performed simultaneously.

[0059] As used herein, the term "halogen" means chlorine, bromine, fluorine, and iodine.

[0060] Where used herein, unless otherwise specified, “alkyl” and / or “aliphatic” refer to linear 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, whether used alone or as part of a substituent. The specified number of carbon atoms (e.g., C1 to C6) refers independently to the number of carbon atoms in the alkyl moiety or to the alkyl moiety 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, etc. Alkyl groups may be unsubstituted or substituted, including by any substituents and combinations of substituents described herein. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, etc. In substituents having multiple alkyl groups, such as (C1-C6 alkyl)2amino, the alkyl groups may be identical or different.

[0061] As used herein, the terms “alkenyl” and “alkynyl” groups, whether used alone or as part of a substituent, mean linear and branched carbon chains having two or more carbon atoms, preferably 2 to 20 carbon atoms, where an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain. Alkenyl and alkynyl groups may be unsubstituted or substituted. Non-limiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also known as 2-methylethenyl), isopropenyl (also known as 2-methylethen-2-yl), and buten-4-yl. Non-limiting examples of substituted alkenyl groups include 2-chloroethenyl (also known as 2-chlorovinyl), 4-hydroxybuten-1-yl, 7-hydroxy-7-methylocto-4-en-2-yl, and 7-hydroxy-7-methylocto-3,5-dien-2-yl. Non-limiting examples of alkynyl groups include ethinyl, prop-2-inyl (also known as propargyl), propyne-1-yl, and 2-methylhexa-4-in-1-yl. Non-limiting examples of substituted alkynyl groups include 5-hydroxy-5-methylhexa-3-inyl, 6-hydroxy-6-methylhepto-3-in-2-yl, and 5-hydroxy-5-ethylhepto-3-inyl.

[0062] As used herein, "cycloalkyl" refers to a non-aromatic carbon-containing ring, whether used alone or as part of another group, comprising, for example, 3 to 14 ring carbon atoms, preferably 3 to 7 or 3 to 6 ring carbon atoms, or 3 to 4 ring carbon atoms, including cycloalkyl groups, cycloalkenyl groups, and cycloalkynyl groups, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bonds. The cycloalkyl group may be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., including condensed, crosslinked, and / or spiro-ring structures), with the carbon atoms located inside or outside the ring structure. Any suitable ring position of the cycloalkyl group can be covalently bonded to the defined chemical structure. The cycloalkyl ring may be unsubstituted or substituted. Non-limiting examples of cycloalkyl groups include cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, dekalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohexa-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazlenyl, bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl. The term "cycloalkyl" also includes cyclic carbons that are bicyclic hydrocarbon rings, and non-limiting examples include bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

[0063] The term "haloalkyl" is intended to encompass both branched and linear saturated aliphatic hydrocarbon groups having a specific number of carbon atoms, substituted with one or more halogens. Haloalkyls include perhaloalkyl groups in which all hydrogens of the alkyl group are substituted with halogens (e.g., -CF3, -CF2CF3). Haloalkyl groups may optionally be substituted with one or more substituents in addition to the halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

[0064] The term "alkoxy" refers to an -O-alkyl group, where the alkyl group is defined above. The alkoxy group may be optionally substituted. The term C3-C6 cyclic alkoxy means a ring containing 3-6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). The C3-C6 cyclic alkoxy group may be optionally substituted.

[0065] The term "haloalkoxy" refers to an -O-haloalkyl group, where a haloalkyl group is defined above. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and pentafluoroethoxyl.

[0066] The term “aryl,” used alone or as part of another group, is defined herein as a monocyclic unsaturated aromatic ring of six carbon atoms, or a polycyclic unsaturated aromatic ring of six to fourteen carbon atoms. Aryl groups are unsubstituted or substituted. An aryl ring may be, for example, a phenyl ring or a naphthyl ring, each optionally substituted by one or more moieties that can substitute one or more hydrogen atoms. Non-limiting examples of aryl groups include phenyl, naphthylene-1-yl, naphthylene-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-hydroxynaphthylene-2-yl, 4,5-dimethoxynaphthylene-1-yl, and 6-cyano-naphthylene-1-yl. The aryl group also includes a phenyl or naphthyl ring fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl) in which one or more carbon atoms of an aromatic ring and / or a saturated or partially saturated ring may be substituted.

[0067] The terms "arylalkyl" or "aralkyl" refer to an alkyl-aryl group, where alkyl and aryl groups are as defined herein. The aralkyl group of the present invention may be optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and fluorenylmethyl.

[0068] The terms “heterocyclic” and / or “heterocyclic” and / or “heterocylyl” are defined, whether used alone or as part of another group, as one or more rings having 3 to 20 atoms, wherein at least one atom of 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 heterocyclic groups containing two or more fused rings, the non-heteroatom-containing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). An exemplary heterocyclic group has 3 to 14 ring atoms, of which 1 to 5 are independently heteroatoms selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms of a heterocyclic group can be oxidized. Heterocyclic groups may be unsubstituted or substituted.

[0069] Non-restrictive examples of heterocyclic units with monocyclic rings include diazirinyl, azilidinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl, oxathiazolidinyl, oxazolidinyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidine-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydroquinoline. Non-restrictive examples of heterocyclic units with two or more rings include hexahydro-1H-pyrrolidinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H-cycloocta[b]pyrrolyl.

[0070] The term "heteroaryl" is defined herein, whether used alone or as part of another group, as one or more rings having 5 to 20 atoms, wherein at least one atom of at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and at least one of the rings containing the heteroatoms is aromatic. In heteroaryl groups comprising two or more fused rings, the non-heteroatom-containing rings may be carbocyclic (e.g., 6,7-dihydro-5H-cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have 5 to 14 ring atoms and independently contain 1 to 5 ring heteroatoms selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups may be unsubstituted or substituted. Non-limiting examples of heteroaryl rings containing monocyclic rings include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyrimidinyl, and 4-dimethylaminopyrimidinyl. Non-limiting examples of heteroaryl rings containing two or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, synnolinyl, naphthilidinyl, phenanthilidinyl, 7H-prinyl, 9H-prinyl, 6-amino-9H-prinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, and pyri Examples include do[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]imidazole-2(3H)-onyl, 1H-benzo[d]imidazolyl, and isoquinolinyl.

[0071] One non-limiting example of the heteroaryl group described above is the C1-C5 heteroaryl, which has 1-5 carbocyclic atoms and at least one additional ring atom (preferably 1-4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S). Examples of C1-C5 heteroaryls include, but are not limited to, triazinyl, thiazole-2-yl, thiazole-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, pyridine-2-yl, pyrididine-3-yl, and pyrididine-4-yl.

[0072] Unless otherwise specified, two substituents together form a ring having a predetermined number of ring atoms (for example, R 2 and R 3 If they combine with nitrogen (N) bonded to them 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 optionally be substituted.

[0073] In this invention, fused ring units containing a single heteroatom, as well as spirocyclic rings, bicyclic rings, and similar structures, are considered to belong to the cyclic family corresponding to heteroatom-containing rings. For example, 1,2,3,4-tetrahydroquinoline having the following general formula, [ka] In this invention, it is considered a heterocyclic unit. A 6,7-dihydro-5H-cyclopentapyrimidine having the following general formula is [ka] In this invention, it is considered a heteroaryl unit. When a fused ring unit contains heteroatoms in both the saturated ring and the aryl ring, the aryl ring becomes dominant and determines the classification of the ring type to which it is assigned. For example, 1,2,3,4-tetrahydro-[1,8]naphthyridine, having the following general formula, [ka] In this invention, it is considered a heteroaryl unit.

[0074] Where a term or any of its prefix roots is present in the name of a substituent, that name should always be interpreted as including the limitations provided herein. For example, where the term “alkyl” or “aryl” or any of its prefix roots is present in the name of a substituent (e.g., arylalkyl, alkylamino), that name should always be interpreted as including the limitations given above for “alkyl” and “aryl.”

[0075] The term “substituted” is used throughout this specification. “Substituted” is defined herein as a moiety, whether acyclic or cyclic, having one or more hydrogen atoms substituted by a substituent or several (e.g., 1 to 10) substituents as defined below. These substituents may substitute one or two hydrogen atoms of a single moiety at once. Furthermore, these substituents may substitute two hydrogen atoms attached to two adjacent carbon atoms to form the substituent, i.e., a novel moiety or unit. Examples of substituted units requiring the substitution of a single hydrogen atom include halogens, hydroxyls, etc. Examples of two-hydrogen-atom substitutions include carbonyls, oxyiminos, etc. Examples of two-hydrogen-atom substitutions of adjacent carbon atoms include epoxys, etc. The term “substituted” is used throughout this specification to indicate that a moiety may have one or more hydrogen atoms substituted by a substituent. Where a moiety is described as “substituted,” any number of hydrogen atoms may be substituted. For example, difluoromethyl is a substituted C1 alkyl, trifluoromethyl is a substituted C1 alkyl, 4-hydroxyphenyl is a substituted aromatic ring, (N,N-dimethyl-5-amino)octanyl is a substituted C8 alkyl, 3-guanidinopropyl is a substituted C3 alkyl, and 2-carboxypyridinyl is a substituted heteroaryl.

[0076] The variable groups defined herein, such as alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, alkoxy groups, aryloxy groups, aryl groups, heterocyclic groups, and heteroaryl groups, may be optionally substituted, either alone or as part of another group. The optionally substituted groups are also indicated. The following are non-restrictive examples of substituents that can substitute for a hydrogen atom in a given area: halogens (chlorine (Cl), bromine (Br), fluorine (F), and iodine (I)), -CN, -NO2, oxo (=O), -OR', -SR', -N(R')2, -NR'C(O)R', -SO2R', -SO2OR', -SO2N(R')2, -C(O)R', -C(O)OR', -C(O)N(R')2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 14 Cycloalkyl, aryl, heterocyclic, or heteroaryl, where each alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclic, and heteroaryl group is optionally substituted with 1 to 10 (e.g., 1 to 6 or 1 to 4) groups independently selected from halogen, -CN, -NO2, oxo, and R', where R' is independently, for each occurrence, hydrogen, -OR'', -SR'', -C(O)R'', -C(O)OR'', -C(O)N(R'')2, -SO2R'', -S(O)2OR'', -N(R'')2, -NR''C(O)R'', C1-C6 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl (e.g., Preferably, each instance of R'' is independently a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a cycloalkyl group (e.g., C3-C6 cycloalkyl group), an aryl group, a heterocyclic group, or a heteroaryl group, or two R'' units together with the atom to which they are bonded to form a substituted or heterocyclic group, and the carbocyclic or heterocyclic group has 3-7 ring atoms. In some embodiments, the substituent is i) -OR'''; for example, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3; ii) -C(O)R'''; e.g. -COCH3, -COCH2CH3, -COCH2CH2CH3; iii) -C(O)OR'''; for example, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3; iv) -C(O)N(R''')2; for example, -CONH2, -CONHCH3, -CON(CH3)2; v) -N(R''')2; for example, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3); vi) Halogens: -F, -Cl, -Br, and -I; vii) -CH e X g In the formula, X is a halogen, m is between 0 and 2, and e + g = 3; for example, -CH2F, -CHF2, -CF3, -CCl3, or -CBr3; viii) -SO2R'''; for example, -SO2H;-SO2CH3;-SO2C6H5; ix) C1-C6 linear, branched, or cyclic alkyl groups; x) Cyano; xi) Nitro; xii) N(R''')C(O)R'''; xiii) Oxo (=O); xiv) Complex algebras; and xv) Selected from heteroaryls, In the formula, each R''' is independently hydrogen, an optionally substituted C1-C6 linear or branched alkyl (e.g., an optionally substituted C1-C4 linear or branched alkyl), or an optionally substituted C3-C6 cycloalkyl (e.g., an optionally substituted C3-C4 cycloalkyl), or two R''' units can combine to form a ring containing 3-7 ring atoms. In certain embodiments, each R''' is independently hydrogen, an optionally substituted C1-C6 linear or branched alkyl, or a C3-C6 cycloalkyl.

[0077] Throughout this specification, substituents of compounds are disclosed in groups or ranges. It is particularly intended that the descriptions include members of such groups and individual subsets of those ranges. For example, "C 1~6 The term "alkyl" is specifically intended to independently disclose alkyl groups of 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.

[0078] In this invention, the terms “compound,” “analog,” and “composition of substance” equally and sufficiently represent the 5-hydroxytryptamine receptor 7 activity modifiers described herein, including all enantiomer forms, diastereomer forms, salts, etc., and these terms “compound,” “analog,” and “composition of substance” are used interchangeably throughout this specification.

[0079] The compounds described herein may contain chiral atoms (also called chiral centers), and some compounds may contain one or more chiral atoms or centers, thereby giving rise to optical isomers (enantiomers) and diastereomers. The teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as racemic, separated, enantiomerically pure R and S stereoisomers, and other mixtures of R and S stereoisomers and their pharmaceutically acceptable salts. For example, described herein are certain gamma-butyrolactones having substituents on the C5 carbon of a heterocyclic ring. In any compound or embodiment of the general formula described herein, the C5 carbon has an (S)-isomer. In any compound or embodiment of the general formula described herein, the C5 carbon has an (R)-isomer. Optical isomers can be obtained in their pure form by standard procedures known to those skilled in the art, including but not limited to diastereomer salt formation, kinetic resolution, and asymmetric synthesis. This instruction also covers cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). Naturally, this instruction also covers all possible positional isomers and mixtures thereof, which can be obtained in their 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.

[0080] pharmaceutically acceptable salts of the compounds described herein may have an acidic moiety, but can be formed using organic and inorganic bases. Both monoanionic and polyanionic salts are considered, depending on the number of acidic hydrogens available for deprotonation. Suitable salts formed with bases include metal salts such as alkali metal salts or alkaline earth metal salts, such as sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as salts formed using morpholine, thiomorpholine, piperidine, pyrrolidine, mono-lower alkylamines, di-lower alkylamines, or tri-lower alkylamines (e.g., ethyl-tert-butylamine, diethylamine, diisopropylamine, triethylamine, tributylamine, or dimethylpropylamine), or monohydroxy lower alkylamines, dihydroxy lower alkylamines, or trihydroxy lower alkylamines (e.g., monoethanolamine, diethanolamine, or triethanolamine). Certain non-limiting examples of inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Intramolecular salts can also be formed. Similarly, if the compounds disclosed herein contain a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic acid, propionic acid, lactic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, tartaric acid, succinic acid, dichloroacetic acid, ethensulfonic 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, mucinic acid, naptalenesulfonic 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.

[0081] If any variable appears multiple times in any component or any general expression, its definition in each appearance is independent of its definition in any other appearance (for example, N(R) 9 )2, R 9 Each of these substituents may be the same or different from the other. Combinations of substituents and / or variables are permitted only if such combinations result in a stable compound.

[0082] As used herein, the terms “to treat,” “to treat,” and “treatment” mean to partially or completely alleviate, suppress, improve, and / or reduce a suspected illness in a patient.

[0083] As used herein, “therapeutically effective” and “effective dose” mean the substance or amount that elicits the desired biological activity or effect.

[0084] Unless otherwise noted, the terms “subject” or “patient” are used interchangeably and mean human patients and non-human primates, as well as mammals such as laboratory animals and other animals, including rabbits, rats, and mice. Therefore, as used herein, the terms “subject” or “patient” mean any mammalian patient or subject to which the compounds of the present invention can be administered. In exemplary embodiments of the present invention, to identify a subject patient for treatment by the method of the present invention, a standard screening method is used to measure risk factors associated with the targeted or suspected disease or condition, or to measure the pre-existing disease or condition status of the subject. These screening methods include, for example, conventional precision tests to measure risk factors that may be associated with the targeted or suspected disease or condition. These methods and other conventional methods enable clinicians to select patients who require treatment with the methods and compounds of the present invention. Regulators of 5-hydroxytryptamine receptor 7 activity Regulators of 5-HT7 activity

[0085] This specification describes lactone compounds that can modulate 5-hydroxy receptor 7 (5-HT7) activity. In particular, the compounds described herein may be selective modulators of the 5-HT7 receptor. In embodiments, selective modulation of 5-HT7 includes selectively regulating 5-HT7 compared to other receptors. In embodiments, selective modulation of 5-HT7 includes selectively regulating 5-HT7 expressed in, for example, specific organs and tissues. Therefore, the compounds described herein may be useful in treating a variety of diseases and conditions (e.g., those described herein).

[0086] In any embodiment of the general formula described herein, C1-C7 alkyl is a C1-C7 linear alkyl. In the embodiment, C1-C7 alkyl is an unsubstituted C1-C7 linear alkyl. In the embodiment, C1-C7 alkyl is a substituted C1-C7 linear alkyl (e.g., substituted with one, two, three or more substituents as described herein). In the embodiment, the substituted C1-C7 linear alkyl is a C1-C7 linear perhaloalkyl (e.g., a perfluoroalkyl). In the embodiment, the substituted C1-C7 linear alkyl is OH, OCH3, NH 2、 CN, CH 3、 CF 3、 The C1-C7 alkyl group comprises one, two, or three substituents selected from the group consisting of CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Further exemplary embodiments of C1-C7 alkyl groups are described herein.

[0087] In any embodiment of the general formula described herein, the C1-C7 alkyl is a C3-C7 branched alkyl. In the embodiment, the branched C3-C7 is an unsubstituted C3-C7 branched alkyl. In the embodiment, the C3-C7 branched alkyl is a substituted C3-C7 branched alkyl (e.g., substituted with one, two, three or more substituents as described herein). In the embodiment, the substituted C3-C7 branched alkyl is a C3-C7 branched perhaloalkyl (e.g., a perfluoroalkyl). In the embodiment, the substituted C3-C7 branched alkyl is OH, OCH3, NH 2、 CN, CH 3、 CF 3、 The C3-C7 branched alkyl group comprises one, two, or three substituents selected from the group consisting of CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Further exemplary embodiments of the C3-C7 branched alkyl group are described herein.

[0088] In any embodiment of the general formula described herein, the cycloalkyl is a C3-C7 or C3-C8 cycloalkyl. In an embodiment, the cycloalkyl is cyclopropyl. In an embodiment, the cycloalkyl is cyclobutyl. In an embodiment, the cycloalkyl is cyclopentyl. In an embodiment, the cycloalkyl is cyclohexyl. In an embodiment, the cycloalkyl is an unsubstituted cycloalkyl (e.g., unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In an embodiment, the cycloalkyl is a substituted cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, comprising one, two, three, four, or five substituents, including the exemplary substituents described herein). In an embodiment, the substituted cycloalkyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Further exemplary embodiments of cycloalkyls are described herein.

[0089] In any embodiment of the general formula described herein, C6~C 10 The aryl is phenyl. In embodiments, phenyl is unsubstituted phenyl. In embodiments, phenyl is substituted phenyl (e.g., phenyl containing 1, 2, 3, 4, or 5 substituents, including the exemplary substituents described herein). The substituted phenyl group may be bonded via any available carbon of the ring, including those described herein. For example, phenyl may be bonded para to a bonding site to a molecule (e.g., a 4-substituted phenyl group) with substituents described herein (e.g., OH, OCH3, NH3). 2、 CN, CH3, CF3, CH2CH 3、 The substituents may include isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. In embodiments, phenyl may have substituents described herein (e.g., OH, OCH3, NH2) at the meta position relative to a bond site to a molecule (e.g., a 3-substituted phenyl group). 2、 CN, CH3, CF3, CH2CH 3、 The substituents may include isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. In embodiments, phenyl may have a (2-substituted phenyl group) at the ortho position relative to a bond site to a molecule, as described herein (e.g., OH, OCH3, NH2). 2、 CN, CH3, CF3, CH2CH 3、The phenyl group may have two or more substituents (e.g., 2,3-disubstituted, 2,4-disubstituted, 2,5-disubstituted, 2,6-disubstituted, 3,4-disubstituted, or 3,5-disubstituted phenyl) or three or more substituents (e.g., 2,3,4-trisubstituted, 2,3,5-trisubstituted, 2,3,6-trisubstituted, 2,4,5-trisubstituted, 2,4,6-trisubstituted, 3,4,5-trisubstituted, or 3,4,6-trisubstituted). In embodiments, the substituted phenyl includes one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Further exemplary embodiments of phenyl are described herein. In these embodiments, phenyl is unsubstituted phenyl, 4-OH-phenyl, 3-OH-phenyl, 2-OH-phenyl, 4-OMe-phenyl, 3-OMe-phenyl, 2-OMe-phenyl, 4-CN-phenyl, 3-CN-phenyl, 2-CN-phenyl, 4-Me-phenyl, 3-Me-phenyl, 2-Me-phenyl, 4-Et-phenyl, 3-Et-phenyl, 2-Et-phenyl, 4- i Pr-phenyl, 3- i Pr-phenyl, 2- i These are Pr-phenyl, 4-F-phenyl, 3-F-phenyl, 2-F-phenyl, 4-Cl-phenyl, 3-Cl-phenyl, 2-Cl-phenyl, 4-Br-phenyl, 3-Br-phenyl, 2-Br-phenyl, 4-NH2-phenyl, 3-NH2-phenyl, 2-NH2-phenyl, 4-CF3-phenyl, 3-CF3-phenyl, 2-CF3-phenyl, 2,3-di-Me-phenyl, 2,4-di-Me-phenyl, 2,5-di-Me-phenyl, 2,6-di-Me-phenyl, 4-morpholino-phenyl, 3-morpholino-phenyl, 2-morpholino-phenyl, 4-CN-2-morpholino-phenyl, 4-CH3-2-morpholino-phenyl, or 4-OH-2-morpholino-phenyl.

[0090] In any embodiment of the general formula described herein, C6~C10 The aryl is naphthyl. In embodiments, naphthyl is unsubstituted naphthyl. In embodiments, naphthyl is substituted naphthyl (e.g., naphthyl containing 1, 2, 3, 4, or 5 substituents, including the exemplary substituents described herein). In embodiments, naphthyl is bonded to the molecule at the C1 position (1-naphthyl). In embodiments, naphthyl is bonded to the molecule at the C2 position (2-naphthyl). In embodiments, naphthyl is bonded to the molecule at the C3 position (3-naphthyl). In embodiments, naphthyl is bonded to the molecule at the C4 position (4-naphthyl). In embodiments, naphthyl is bonded to the molecule at the C5 position (5-naphthyl). In embodiments, naphthyl is bonded to the molecule at the C6 position (6-naphthyl). In embodiments, naphthyl is bonded to the molecule at the C7 position (7-naphthyl). In embodiments, naphthyl is bonded to the molecule at the C8 position (8-naphthyl). In embodiments, the substituted naphthyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Further exemplary embodiments of naphthyl are described herein.

[0091] In any embodiment of the general formulas described herein, the 5- to 10-membered heteroaryl is imidazolyl. In embodiments, imidazolyl is unsubstituted imidazolyl. In embodiments, imidazolyl is substituted imidazolyl (e.g., imidazolyl containing 1, 2, or 3 substituents, including the exemplary substituents described herein). In embodiments, imidazolyl is N-linked imidazolyl, which is linked to the molecule via the N1 position of the imidazolyl (1-imidazolyl). In embodiments, imidazolyl is C-linked imidazolyl (imdazolyl). In embodiments, imidazolyl is linked to the molecule via the C2 position of the imidazolyl group (2-imidazolyl). In embodiments, imidazolyl is linked to the molecule via the C4 position of the imidazolyl group (4-imidazolyl). In embodiments, imidazolyl is bonded to the molecule via the C5 position of the imidazolyl group (5-imidazolyl). In embodiments, the substituted imidazolyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. In embodiments, the substituted imidazolyl is N-methylimidazolyl. Further exemplary embodiments of imidazolyl are described herein.

[0092] In any embodiment of the general formulas described herein, a 5- to 10-membered heteroaryl is a pyrrolyl. In embodiments, the pyrrolyl is an unsubstituted pyrrolyl. In embodiments, the pyrrolyl is an N-linked pyrrolyl that binds to the molecule via the N1 position of the pyrrolyl (1-pyrrolyl). In embodiments, the pyrrolyl is a C-linked pyrrolyl. In embodiments, the pyrrolyl binds to the molecule via the C2 position of the pyrrolyl (2-pyrrolyl). In embodiments, the pyrrolyl binds to the molecule via the C3 position of the pyrrolyl (3-pyrrolyl). In embodiments, the pyrrolyl binds to the molecule via the C4 position of the pyrrolyl (4-pyrrolyl). In embodiments, the pyrrolyl binds to the molecule via the C5 position of the pyrrolyl (5-pyrrolyl). In embodiments, the pyrrolyl is a substituted pyrrolyl (e.g., a pyrrolyl containing one, two, or three substituents, including the exemplary substituents described herein). In embodiments, the substituted pyrrolyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Further exemplary embodiments of pyrrolyl are described herein.

[0093] In any embodiment of the general formulas described herein, the 5- to 10-membered heteroaryl is an oxazolyl. In embodiments, the oxazolyl is an unsubstituted oxazolyl. In embodiments, the oxazolyl is bonded to the molecule via the C2 position of the oxazolyl (2-oxazolyl). In embodiments, the oxazolyl is bonded to the molecule via the C3 position of the oxazolyl (3-oxazolyl). In embodiments, the oxazolyl is bonded to the molecule via the C4 position of the oxazolyl (4-oxazolyl). In embodiments, the oxazolyl is a substituted oxazolyl (an oxazolyl comprising one or two substituents, including, for example, the exemplary substituents described herein). In embodiments, the substituted oxazolyl comprises one or two substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Further exemplary embodiments of imidazolyl are described herein.

[0094] In any embodiment of the general formulas described herein, the 5- to 10-membered heteroaryl is a tetrazolyl. In embodiments, the tetrazolyl is an unsubstituted tetrazolyl. In embodiments, the tetrazolyl is a substituted tetrazolyl (e.g., an N-substituted tetrazolyl containing the exemplary substituents described herein). Further exemplary embodiments of the tetrazolyl are described herein.

[0095] In any embodiment of the general formulas described herein, a 5- to 10-membered heteroaryl is a pyridyl. In embodiments, the pyridyl is an unsubstituted pyridyl. In embodiments, the pyridyl is bonded to the molecule via the C2 position (2-pyridyl). In embodiments, the pyridyl is bonded to the molecule via the C3 position (3-pyridyl). In embodiments, the pyridyl is bonded to the molecule via the C4 position (4-pyridyl). In embodiments, the pyridyl is bonded to the molecule via the C2 position (5-pyridyl). In embodiments, the pyridyl is bonded to the molecule via the C2 position (6-pyridyl). In embodiments, the pyridyl is a substituted pyridyl (e.g., a pyridyl containing 1, 2, 3, or 4 substituents, including the exemplary substituents described herein). In embodiments, the substituted pyridyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Further exemplary embodiments of pyridyl are described herein.

[0096] In any embodiment of the general formulas described herein, the 5- to 10-membered heteroaryl is pyrazinyl. In embodiments, pyrazinyl is unsubstituted pyrazinyl. In embodiments, pyrazinyl is 2-pyrazinyl. In embodiments, pyrazinyl is 3-pyrazinyl. In embodiments, pyrazinyl is 5-pyrazinyl. In embodiments, pyrazinyl is 6-pyrazinyl. In embodiments, pyrazinyl is substituted pyrazinyl (e.g., pyrazinyl containing 1, 2, 3, or 4 substituents, including exemplary substituents described herein). In embodiments, substituted pyrazinyl contains 1, 2, or 3 substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Further exemplary embodiments of pyrazinyl are described herein.

[0097] In any embodiment of the general formulas described herein, the 5- to 10-membered heteroaryl is an indolyl. In embodiments, the indolyl is an unsubstituted indolyl. In embodiments, the indolyl is an N-bonded indolyl that binds to the molecule via the N1 position (1-indolyl). In embodiments, the indolyl is a C-bonded indolyl. In embodiments, the indolyl binds to the molecule via the C2 position (2-indolyl). In embodiments, the indolyl binds to the molecule via the C3 position (3-indolyl). In embodiments, the indolyl binds to the molecule via the C4 position (4-indolyl). In embodiments, the indolyl binds to the molecule via the C5 position (5-indolyl). In embodiments, the indolyl binds to the molecule via the C6 position (6-indolyl). In embodiments, the indolyl binds to the molecule via the C7 position (7-indolyl). In embodiments, the indolyl is a substituted indolyl (for example, an indolyl comprising one, two, three, or four substituents, including the exemplary substituents described herein). In embodiments, the substituted indolyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Further exemplary embodiments of the indolyl are described herein.

[0098] In any embodiment of the general formula described herein, the substituents are C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C 1~C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohalalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxycarbonyl, sulfo, halogen, C1-C7 The substituents are selected from the group consisting of alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen. In embodiments, the substituents themselves are unsubstituted. In embodiments, the substituents are selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0099] In any embodiment of the general formula described herein, the C5 carbon of the 2-dihydrofuranone skeleton has a (R)-configuration.

[0100] In any embodiment of the general formula described herein, the C5 carbon of the 2-dihydrofuranone skeleton has an (S)-configuration.

[0101] In any embodiment of the general formula described herein, R A or R AA The substituted carbon has a (R)-configuration.

[0102] In any embodiment of the general formula described herein, R A or R AA The substituted carbon has an (S)-configuration.

[0103] Compounds of general formulas (I*) and (I**) This specification describes compounds of general formula (I*) along with exemplary embodiments of general formula (I*).

[0104] The exemplary general formulas and compounds described herein may also include their hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes.

[0105] In one embodiment, the present invention is characterized by a compound having a structure according to the following general formula (I*): [ka] The formula includes the enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex, in which, R 1N These include imidazole, oxazole, isoxazole, [ka] Selected from the group consisting of, in the formula, R 4a and R 4b Each is either hydrogen or a C1-C7 alkyl group, or R 4a and R 4b They optionally, together with the atoms they bond to, form a ring containing 3 to 7 atoms, optionally containing oxygen. R 5 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j NHCONR 8f , NR8g COR 8h , and [ka] Selected from the group consisting of, R 8a , R 8b , R 8d , R 8g , and R 8i Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 Forming a heterocyle containing 3 to 7 atoms, which contains a group selected from the above, R 8c , R 8e , R 8f , and R 8h Each of these is either a C1-C7 alkyl group or a C3-C7 cycloalkyl group. R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, or R 4a and R 8a If both exist, or R 4a and R 8g If both are present, these groups optionally combine with the atom to which they bond to form a ring containing 4 to 7 atoms. R 9 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R AA Each of these is independently a C1-C7 linear alkyl group. R 2a Each of these is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN. a is 0, 1, or 2. aa is 0, 1, or 2, and y 1 It is 0, 1, or 2.

[0106] In another embodiment, the present invention is characterized by a compound having a structure according to the following general formula (I*-N): [ka] The formula includes the enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex, in which, R 1N-N C6~C 10 Heteroaryls, 5-member to 10-member heteroaryls, [ka] Selected from the group consisting of, in the formula, R 4a and R 4b Each is either hydrogen or a C1-C7 alkyl group, or R 4a and R 4b They optionally, together with the atoms they bond to, form a ring containing 3 to 7 atoms, optionally containing oxygen. R 5 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j NHCONR 8f , NR 8g COR 8h , and [ka] Selected from the group consisting of, R 8a , R 8b , R 8d , R 8g , and R 8i Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 Forming a heterocyle containing 3 to 7 atoms, which contains a group selected from the above, R 8c , R 8e , R 8f , and R 8h Each of these is either a C1-C7 alkyl group or a C3-C7 cycloalkyl group. R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, or R 4a and R 8a If both exist, or R 4a and R 8g If both are present, these groups optionally combine with the atom to which they bond to form a ring containing 4 to 7 atoms. R 9 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R AA Each of these is independently a C1-C7 linear alkyl group. R 2a Each of these is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN. a is 0, 1, or 2. aa is 0, 1, or 2. y 1 is 0, 1, or 2, and In the formula, R 5If a is an unsubstituted C1-C7 alkyl or an unsubstituted C3-C7 cycloalkyl, then a is 1 or 2.

[0107] In this embodiment, R 5 If a is an unsubstituted C1-C7 alkyl or an unsubstituted C3-C7 cycloalkyl, then a is 1 or 2.

[0108] In the embodiment, the compound according to general formula (I*) has a structure according to the following general formula, [ka] In the formula, R 1N , R AA , R 2a , aa, and a are subject to any aspect or embodiment described herein.

[0109] In the embodiment, the compound according to general formula (I*) has a structure according to the following general formula, [ka] In the formula, R 1N , R AA , R 2a , aa, and a are subject to any aspect or embodiment described herein.

[0110] In the embodiment, the compound according to the general formula (I*-N) has a structure according to the following general formula, [ka] In the formula, R 1N-N , R AA , R 2a , aa, and a are subject to any aspect or embodiment described herein.

[0111] In the embodiment, the compound according to the general formula (I*-N) has a structure according to the following general formula, [ka] In the formula, R 1N-N, R AA , R 2a , aa, and a are subject to any aspect or embodiment described herein.

[0112] In this embodiment, R AA Each of these is independently a C1-C7 linear alkyl group. In the embodiment, R AA Each of them is independently methyl.

[0113] In the embodiment, a is 0. In the embodiment, a is 1. In the embodiment, a is 2. In the embodiment, a is not 0. In the embodiment, a excludes 0. In the embodiment, a is 0 or 1. In the embodiment, a is 1 or 2.

[0114] In this embodiment, R 2a Each of these is independently a halogen. In this embodiment, R 2a Each of these is independently F. In this embodiment, R 2a Each of them is independently Cl.

[0115] In this embodiment, aa is 0. In this embodiment, aa is 1. In this embodiment, aa is 2. In this embodiment, aa is 1 or 2.

[0116] In this embodiment, R 1N These include imidazole, oxazole, isoxazole, [ka] Selected from the group consisting of, in the formula, R 4a and R 4b Each is either hydrogen or a C1-C7 alkyl group, or R 4a and R 4b They optionally, together with the atoms they bond to, form a ring containing 3 to 7 atoms, optionally containing oxygen. R 5C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j NHCONR 8f , NR 8g COR 8h , and [ka] Selected from the group consisting of, R 8a , R 8b , R 8d , R 8g , and R 8i Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 Forming a heterocyle containing 3 to 7 atoms, which contains a group selected from the above, R 8c , R 8e , R 8f , and R 8h Each of these is either a C1-C7 alkyl group or a C3-C7 cycloalkyl group. R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, or R 4a and R 8a If both exist, or R 4a and R 8gIf both are present, these groups optionally combine with the atom to which they bond to form a ring containing 4 to 7 atoms. R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, and y 1 It is 0, 1, or 2.

[0117] In this embodiment, R 1N-N C6~C 10 Heteroaryls, 5-member to 10-member heteroaryls, [ka] Selected from the group consisting of, in the formula, R 4a and R 4b Each is either hydrogen or a C1-C7 alkyl group, or R 4a and R 4b They optionally, together with the atoms they bond to, form a ring containing 3 to 7 atoms, optionally containing oxygen. R 5 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j NHCONR 8f , NR 8g COR 8h , and [ka] Selected from the group consisting of, R 8a , R 8b , R 8d , R 8g, and R 8i Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 Forming a heterocyle containing 3 to 7 atoms, which contains a group selected from the above, R 8c , R 8e , R 8f , and R 8h Each of these is either a C1-C7 alkyl group or a C3-C7 cycloalkyl group. R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, or R 4a and R 8a If both exist, or R 4a and R 8g If both are present, these groups optionally combine with the atom to which they bond to form a ring containing 4 to 7 atoms. R 9 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 11 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, and y 1 It is 0, 1, or 2.

[0118] In this embodiment, R 5 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR8d SO2R 8e , NR 8i COOR 8j NHCONR 8f , NR 8g COR 8h , and [ka] Selected from the group consisting of. In this embodiment, R 5 This excludes unsubstituted C1-C7 alkyl groups. In the embodiment, R 5 This excludes unsubstituted C3-C7 cycloalkyl groups.

[0119] In this embodiment, R 1N teeth, [ka] In this embodiment, R 1N-N teeth, [ka] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0120] In this embodiment, R 1N teeth, [ka] In this embodiment, R 1N-N teeth, [ka] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0121] In this embodiment, R 1N-N teeth, [ka] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0122] In this embodiment, y 1 is 0, and R 1 is COR 5 In this embodiment, R 5 is pyridyl. In the embodiment, R 5 is pyridazine. In the embodiment, R 5 is a C1-C7 alkyl group. In the embodiment, R 5 is a C3-C7 cycloalkyl group. In this embodiment, R 5 is a C1-C7 haloalkyl group. In the embodiment, R 5 is a C3-C7 cyclohaloalkyl group. In the embodiment, R 5 is a C1-C7 fluoroalkyl group. In the embodiment, R 5 These are C3-C7 cyclofluoroalkyl groups.

[0123] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0124] In this embodiment, R 4a H is H. In this embodiment, R 4b H is H. In this embodiment, R 4a and R 4b Both are H. In the embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0125] In this embodiment, R 5 is pyridyl. In the embodiment, R 5 is pyridazine. In the embodiment, R 5is a C1-C7 alkyl group. In the embodiment, R 5 is a C3-C7 cycloalkyl group. In this embodiment, R 5 is a C1-C7 haloalkyl group. In the embodiment, R 5 is a C3-C7 cyclohaloalkyl group. In the embodiment, R 5 is a C1-C7 fluoroalkyl group. In the embodiment, R 5 is a C3-C7 cyclofluoroalkyl group. In the embodiment, R 5 is an unsubstituted C1-C7 alkyl group. In the embodiment, R 5 R is a substituted C1-C7 alkyl group (e.g., including amino substituents such as -NH2, -NHCH3, or -N(CH3)2). In embodiments, R 5 R is phenyl. In this embodiment, R 5 R is an unsubstituted phenyl compound. In this embodiment, R 5 is a substituted phenyl. In the embodiment, R 5 , NR 8a R 8b In this embodiment, R 5 SO2R 8c In this embodiment, R 5 , NR 8d SO2R 8e In this embodiment, R 5 , NR 8i COOR 8j In this embodiment, R 5 , NHCONR 8f In this embodiment, R 5 , NR 8g COR 8h In this embodiment, R 5 It is not an unsubstituted C1-C7 alkyl group.

[0126] In this embodiment, R 11 is hydrogen. In this embodiment, R 11 is a C1-C7 alkyl group (e.g., methyl). In the embodiment, R 11 These are C3-C7 cycloalkyl groups.

[0127] In this embodiment, R1N or R 1N-N teeth, [ka] And in the formula, R 4a , R 4b , and y 1 This applies according to any aspect or embodiment described herein. Z a is CH2 or O, Z a If it is CH2, then p 1 +p 2 is 1, 2, 3, or 4, and Z a If p is O, 1 +p 2 is 1, 2, 3, or 4, and also p 1 and p 2 Both are not 0.

[0128] In this embodiment, R 4a and R 4b These, together with the atoms to which they bond, form a cyclic carbon containing 3 to 7 atoms. In the embodiment, R 4a and R 4b These atoms, together with the atoms they bond to, form an oxygen-containing ring containing 3 to 7 atoms.

[0129] In this embodiment, R 1N or R 1N-N teeth [ka] And in the formula, Z b is CH2 or O, Z b If it is CH2, then p 1 +p 2 is 1, 2, 3, or 4, Z b If p is O, 1 +p 2 is 1, 2, 3, or 4, and also p1 and p 2 Both are not 0, R 5 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j NHCONR 8f , NR 8g COR 8h , and [ka] Selected from the group consisting of, R 8a , R 8b , R 8d , R 8g , R 8i , and R 9 Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 Forming a heterocyle containing 3 to 7 atoms, which contains a group selected from the above, R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, R 8c , R 8e , R 8f , and R 8h These are, respectively, C1-C7 alkyl or C3-C7 cycloalkyl.

[0130] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 4a , R 4b , and y 1 This applies according to any aspect or embodiment described herein. R 10a and R 10b These are independently H, C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, and SO2R 8e COOR 8j CONR 8f , and COR 8h Selected from the group consisting of, R 10a and R 10b At least one of these is selected from the group consisting of H, C1-C7 linear alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl. R 8e , R 8f , and R 8h Each of these is selected from the group consisting of H, C1-C7 linear alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl.

[0131] In this embodiment, R 1N-N is a urea group (for example, [ka] )

[0132] In this embodiment, R 1N or R 1N-N is a carbamate group (for example, [ka] ) is. In this embodiment, R 1N is an aminoacyl group (for example, [ka] ) is. In this embodiment, R 1N is an alkylacyl group (for example, [ka] ) is. In this embodiment, R 1N or R 1N-N is an arrow. In this embodiment, R 1N is a heteroaryl (for example, [ka] ) is. In this embodiment, R 1N This is a heteroaryl compound containing an acyl group (for example, [ka] )

[0133] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 8a and R 8b Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 It forms a heterocyle containing 3 to 7 atoms, which contains a group selected from R 9 The element is selected from the group consisting of hydrogen, C1-C7 alkyl groups, and C3-C7 cycloalkyl groups.

[0134] In this embodiment, R 1N or R 1N-N teeth [ka] And in the formula, uu is either 1 or 2.

[0135] In this embodiment, R 1N or R 1N-N teeth, [ka] That is the case.

[0136] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 The group is selected from aryls and heteroaryls consisting of 5- to 10 members.

[0137] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 8h These are unsubstituted C1-C7 alkyl groups.

[0138] In this embodiment, R 1N or R 1N-N teeth, [ka] That is the case.

[0139] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 8a and R 8b Each of these is independently either H or an unsubstituted C1-C7 alkyl group.

[0140] In this embodiment, R1N or R 1N-N teeth, [ka] And in the formula, R 8d These are independently H or unsubstituted C1-C7 alkyl, and R 8e These are unsubstituted C1-C7 alkyl groups.

[0141] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 4a and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups.

[0142] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 4a and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups.

[0143] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 4a and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups.

[0144] In this embodiment, R 1N or R1N-N teeth, [ka] And in the formula, R 8h These are unsubstituted C1-C7 alkyl groups.

[0145] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 8h These are unsubstituted C1-C7 alkyl groups.

[0146] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 8h These are unsubstituted C1-C7 alkyl groups.

[0147] In this embodiment, R 1N or R 1N-N teeth, [ka] That is the case.

[0148] In this embodiment, R 1N or R 1N-N teeth, [ka] That is the case.

[0149] In this embodiment, R 1N or R 1N-N teeth, [ka] That is the case.

[0150] In this embodiment, R1N or R 1N-N teeth, [ka] And in the formula, R 8a , R 8b , and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups.

[0151] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 The group is selected from aryls and heteroaryls consisting of 5- to 10 members.

[0152] In this embodiment, R 1N or R 1N-N teeth, [ka] That is the case.

[0153] In this embodiment, R 1N or R 1N-N teeth, [ka] That is the case.

[0154] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 8a and R 8b Each of these is independently either H or an unsubstituted C1-C7 alkyl group.

[0155] In this embodiment, R 1N or R 1N-N teeth, [ka] And in the formula, R 8g These are independently H or unsubstituted C1-C7 alkyl, and R 8h These are independently unsubstituted C1-C7 alkyl groups.

[0156] In this embodiment, R 1N or R 1N-N teeth, [ka] That is the case.

[0157] In this embodiment, R 1N or R 1N-N teeth, [ka] That is the case.

[0158] In this embodiment, R 1N or R 1N-N teeth, [ka] That is the case.

[0159] In the embodiment, the compound according to general formula (I*) or (I*-N) has the following structure: [ka] In the formula, R 5 , R 4a , R 4b , R 2a , R AA , y 1 , aa, and a respectively conform to any aspect or embodiment described herein.

[0160] In the embodiment, the compound according to general formula (I*) or (I*-N) has the following structure: [ka] In the formula, R 5 , R 4a , R 4b , R 2a , R AA , y 1 , aa, and a respectively conform to any aspect or embodiment described herein.

[0161] In the embodiment, the compound according to the general formula (I*-N) has the following structure: [ka] In the formula, R 5 , R 11 , R 4a , R 4b , R 2a , R AA , y 1 , aa, and a respectively conform to any aspect or embodiment described herein.

[0162] In the embodiment, a compound according to general formula (I*-1), (I*-2), or (I*-3) has one of the following structures: [ka] During the ceremony, R 5 , R 11 , R 4a , R 4b , R 2a , R AA , y 1 , aa, and a respectively conform to any aspect or embodiment described herein.

[0163] In another embodiment, the present invention is characterized by a compound having a structure according to the following general formula (I**): [ka] The formula includes the enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex, in which, R aa and R bb Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl. R AA Each of these is independently a C1-C7 linear alkyl group. R 2a Each of these is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN. a' is either 1 or 2, and aa is 0, 1, or 2.

[0164] In the embodiment, the compound according to general formula (I**) has a structure according to the following general formula, [ka] In the formula, R aa , R bb , R AA , R 2a , aa, and a' are according to any aspect or embodiment described herein.

[0165] In the embodiment, the compound according to general formula (I**) has a structure according to the following general formula, [ka] In the formula, R aa , R bb , R AA , R 2a , aa, and a' are according to any aspect or embodiment described herein.

[0166] In this embodiment, R AA Each of these is independently a C1-C7 linear alkyl group. In the embodiment, R AA Each of them is independently methyl.

[0167] In the embodiment, a' is 1. In the embodiment, a' is 2. In the embodiment, a' is 1 or 2.

[0168] In this embodiment, R 2a Each of these is independently a halogen. In this embodiment, R 2a Each of these is independently F. In this embodiment, R 2a Each of them is independently Cl.

[0169] In this embodiment, aa is 0. In this embodiment, aa is 1. In this embodiment, aa is 2. In this embodiment, aa is 1 or 2.

[0170] In this embodiment, R aa is a C1-C7 linear alkyl group. In the embodiment, R aa is a C3-C7 branched alkyl group. In the embodiment, R aa is ethyl. In the embodiment, R bb is a C1-C7 linear alkyl group. In the embodiment, R bb is a C3-C7 branched alkyl group. In the embodiment, R bb is ethyl. In the embodiment, R aa and R bb These are both ethyl compounds.

[0171] Compounds of general formula (I) In one embodiment, the present invention is characterized by a compound having a structure according to the following general formula (I): [ka] The formula includes the enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex, in which, R a and R b Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl, or R a and R bThese, together with the atoms to which they bond, form a cyclic carbon having 5 to 7 ring atoms, optionally containing a double bond, or R a and R b Together with the atoms they bond to, they form O, S, SO, SO2, and NR 1 A ring having 6 to 8 ring atoms is formed, including a portion selected from the group consisting of the following: A is a five- to twelve-membered nitrogen-containing heterocycline with an N bond, which is bicyclic or polycyclic and optionally contains further heteroatoms selected from O, N, and S, and non-aromatic nitrogen-containing heterocyclines are R 2 It further includes the base, R 1 These are H, C1-C7 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, five- to six-membered heteroaryl ring, polar acyl group, or polar sulfonyl group. R 2 These include 6- to 10-membered aryls, 5- to 10-membered nitrogen-containing heteroaryls, and [ka] Selected from the group consisting of, R 3 These are 6- to 10-membered aryl compounds or 5- to 10-membered nitrogen-containing heteroaryl compounds. m is 1, 2, or 3, and n is 1, 2, 3, or 4.

[0172] In the embodiment, if A is 1,2,3,4-tetrahydroquinol-1-yl, 1,2,3,4-tetrahydroisoquinol-2-yl, octahydropyrrolo[3,4-c]pyrrole-1-yl, or 2,6-diazaspiro[3.3]heptan-1-yl, then R a and R b Both cannot be methyl, both ethyl, or both phenyl, R a and R b It is also not possible to form unsubstituted C3-C6 cycloalkyl groups by bonding them together.

[0173] In the embodiment, A is not 1,2,3,4-tetrahydroquinol-1-yl, 1,2,3,4-tetrahydroisoquinol-2-yl, octahydropyrrolo[3,4-c]pyrrole-1-yl, or 2,6-diazaspiro[3.3]heptan-1-yl. In the embodiment, A excludes 1,2,3,4-tetrahydroquinol-1-yl, 1,2,3,4-tetrahydroisoquinol-2-yl, octahydropyrrolo[3,4-c]pyrrole-1-yl, or 2,6-diazaspiro[3.3]heptan-1-yl.

[0174] In this embodiment, R a and R b These atoms, together with the atoms they bond to, form a ring with 6 to 8 ring atoms, one of which is O, S, SO, SO2, and NR. 1 This is a part selected from the group consisting of [the specified elements].

[0175] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula, [ka] In the formula, R a , R b A, n, and n are subject to any aspect or embodiment described herein.

[0176] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula, [ka] In the formula, R a , R b A, n, and n are subject to any aspect or embodiment described herein.

[0177] In this embodiment, R a and R b Each of these is methyl.

[0178] In this embodiment, R aand R b Each of them is ethyl.

[0179] In this embodiment, R a and R b By bonding these, unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is formed. In the embodiment, R a and R b By bonding, an unsubstituted cyclopropyl is formed. In the embodiment, R a and R b By bonding, an unsubstituted cyclobutyl is formed. In the embodiment, R a and R b By bonding, an unsubstituted cyclopentyl is formed. In the embodiment, R a and R b These are bonded together to form an unsubstituted cyclohexyl.

[0180] In this embodiment, R a and R b Together with the atoms they bond to, NR 1 It forms a ring having 6 to 8 ring atoms, including the part that is [the specified part].

[0181] In this embodiment, R a and R b They are combined, [ka] It forms a group.

[0182] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0183] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0184] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0185] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0186] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0187] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0188] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0189] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0190] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0191] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0192] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0193] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0194] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0195] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0196] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0197] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0198] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0199] In the embodiment, the compound according to general formula (I) has a structure according to the following general formula. [ka] In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3.

[0200] In this embodiment, A is selected from the group consisting of the following: [ka] During the ceremony, R 2 phenyl, naphthyl, pyridyl, indolyl, and [ka] Selected from the group consisting of, R 3 It is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl. R A C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxy Selected from the group consisting of five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from cyclocarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and oxygen, sulfur, and nitrogen, and a is 0, 1, or 2.

[0201] In this embodiment, a is 0.

[0202] In this embodiment, a is 1.

[0203] In this embodiment, a is 2.

[0204] In the embodiment, A is selected from the group consisting of the following: [ka]

[0205] In this embodiment, A is [ka] That is the case.

[0206] In this embodiment, A is [ka] That is the case.

[0207] In this embodiment, A is [ka] That is the case.

[0208] In this embodiment, A is [ka] That is the case.

[0209] In this embodiment, A is [ka] That is the case.

[0210] In this embodiment, A is [ka] That is the case.

[0211] In this embodiment, A is [ka] That is the case.

[0212] In this embodiment, A is [ka] That is the case.

[0213] In this embodiment, A is [ka] That is the case.

[0214] In this embodiment, A is [ka] That is the case.

[0215] In this embodiment, A is [ka] That is the case.

[0216] In this embodiment, A is [ka] That is the case.

[0217] In this embodiment, A is [ka] That is the case.

[0218] In this embodiment, A is [ka] That is the case.

[0219] In this embodiment, A is [ka] That is the case.

[0220] In this embodiment, A is [ka] That is the case.

[0221] In this embodiment, A is [ka] That is the case.

[0222] In this embodiment, A is [ka] That is the case.

[0223] In this embodiment, A is [ka] That is the case.

[0224] In this embodiment, A is [ka] That is the case.

[0225] In this embodiment, A is [ka] That is the case.

[0226] In this embodiment, A is [ka] That is the case.

[0227] In this embodiment, A is [ka] That is the case.

[0228] In this embodiment, A is [ka] That is the case.

[0229] In this embodiment, A is [ka] That is the case.

[0230] In this embodiment, A is [ka] That is the case.

[0231] In this embodiment, A is [ka] That is the case.

[0232] In this embodiment, A is [ka] That is the case.

[0233] In this embodiment, A is [ka] That is the case.

[0234] In this embodiment, A is [ka] That is the case.

[0235] In this embodiment, A is [ka] That is the case.

[0236] In this embodiment, A is [ka] That is the case.

[0237] In this embodiment, A is [ka] That is the case.

[0238] In this embodiment, A is [ka] That is the case.

[0239] In this embodiment, A is [ka] That is the case.

[0240] In embodiments of general formula (I), A is selected from the group consisting of: [ka]

[0241] In this embodiment, a is 0.

[0242] In this embodiment, a is 1.

[0243] In this embodiment, a is 2.

[0244] In this embodiment, A is [ka] That is the case.

[0245] In this embodiment, A is [ka] That is the case.

[0246] In this embodiment, A is [ka] That is the case.

[0247] In this embodiment, A is [ka] That is the case.

[0248] In this embodiment, R 2 R is phenyl. In this embodiment, R 2 R is an unsubstituted phenyl compound. In this embodiment, R 2 is a phenyl compound containing at least one halogen substituent (for example, at least one substituent which is a chloro or fluoro group). In embodiments, R 2 These are fluorophenyl (e.g., 2-, 3-, or 4-fluorophenyl), difluorophenyl, chlorophenyl (e.g., 2-, 3-, or 4-chlorophenyl), dichlorophenyl, and chlorofluorophenyl. In embodiments, R 2 This is a phenyl molecule substituted with one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0249] In this embodiment, R 2 is naphthyl. In this embodiment, R 2 is an unsubstituted naphthyl. In this embodiment, R 2 is a naphthyl containing at least one halogen substituent (for example, at least one substituent which is a chloro or fluoro group). In embodiments, R2 is naphthyl substituted by one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0250] In an embodiment, R 2 is pyridyl. In an embodiment, R 2 is 2-pyridyl. In an embodiment, R 2 is 3-pyridyl. In an embodiment, R 2 is 4-pyridyl. In an embodiment, R 2 is unsubstituted pyridyl. In an embodiment, R 2 is pyridyl containing at least one halogen substituent (e.g., at least one substituent that is a chloro or fluoro group). In an embodiment, R 2 is pyridyl substituted by one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0251] In an embodiment, R 2 is indolyl. In an embodiment, R 2 is unsubstituted indolyl. In an embodiment, R 2 is indolyl containing at least one halogen substituent (e.g., at least one substituent that is a chloro or fluoro group). In an embodiment, R 2 is indolyl substituted by one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0252] In an embodiment, R 2 is phenyl, naphthyl, pyridyl or

Chemical formula

[0253] In this embodiment, R 2 teeth, [ka] And in the formula, aa is 0, 1, 2, or 3, and each R 2a R is independently any substituent described herein. In embodiments, R 2a These are independently OH, OCH3, NH2, CN, CH3, and CF. 3、 Selected from CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. In embodiments, R 2a Each of these independently comprises C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C The group is selected from the group consisting of 7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen.

[0254] In this embodiment, R 2 teeth, [ka] In this embodiment, m is 1. In this embodiment, m is 2. In this embodiment, m is 3.

[0255] In this embodiment, R 3 R is phenyl. In this embodiment, R 3 R is an unsubstituted phenyl compound. In this embodiment, R 3 is a phenyl compound containing at least one halogen substituent (for example, at least one substituent which is a chloro or fluoro group). In embodiments, R 3 These are fluorophenyl (e.g., 2-, 3-, or 4-fluorophenyl), difluorophenyl, chlorophenyl (e.g., 2-, 3-, or 4-chlorophenyl), dichlorophenyl, and chlorofluorophenyl. In embodiments, R 3 This is a phenyl molecule substituted with one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0256] In this embodiment, R 3 is naphthyl. In this embodiment, R 3 is an unsubstituted naphthyl. In this embodiment, R 3 is a naphthyl containing at least one halogen substituent (for example, at least one substituent which is a chloro or fluoro group). In embodiments, R 3 This is a naphthyl substituted with one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0257] In this embodiment, R 3 is pyridyl. In the embodiment, R 3 is 2-pyridyl. In the embodiment, R 3 is 3-pyridyl. In the embodiment, R 3is 4-pyridyl. In the embodiment, R 3 is an unsubstituted pyridyl. In the embodiment, R 3 is a pyridyl containing at least one halogen substituent (for example, at least one substituent which is a chloro or fluoro group). In embodiments, R 3 This is a pyridyl substituted with one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0258] In this embodiment, R 3 This is an indrill. In this embodiment, R 3 This is a non-substituting indolyl. In this embodiment, R 3 is an indolyl comprising at least one halogen substituent (for example, at least one substituent which is a chloro or fluoro group). In embodiments, R 3 This is an indolyl substituted with one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0259] In this embodiment, R 3 These are phenyl, naphthyl, or pyridyl.

[0260] In this embodiment, R 3 teeth, [ka] And in the formula, aa is 0, 1, 2, or 3, and each R 3a R is independently any substituent described herein. In embodiments, R 3a These are independently OH, OCH3, NH2, CN, CH3, and CF. 3、Selected from CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. In embodiments, R 3a Each of these independently comprises C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C The group is selected from the group consisting of 7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen.

[0261] In a particular embodiment, A is [ka] And in the formula, R 2aC1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxy Selected from the group consisting of xicarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen, R A C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxycarbonyl, sulfo The group is selected from halogens, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl groups, and five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen, and a is independently 0, 1, or 2.

[0262] In this embodiment, R 1 C6~C 10 It is Ariel.

[0263] In this embodiment, R 1 R is a five- to six-membered heteroaryl ring. In the embodiment, R 1 is imidazolyl (e.g., unsubstituted imidazolyl or N-methylimidazolyl). In embodiments, R 1 is an oxazolyl (e.g., an unsubstituted oxazolyl). In the embodiment, R 1 This is isoxazolyl (e.g., unsubstituted oxazolyl).

[0264] In this embodiment, R 1 teeth [ka] In the formula, X is O, NH, or NCH3, aa1 is 0, 1, or 2, and R 1a C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxy The group is selected from xicarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen.

[0265] In this embodiment, R 1 teeth, [ka] Selected from the group consisting of. In this embodiment, R 1 teeth, [ka] That is the case.

[0266] In this embodiment, R 1 is a polar acyl group (for example, the substructure is [ka] ) is. In this embodiment, R 1 These include C1-C7 alkyl groups, C3-C7 cycoalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), C1-C7 haloalkyl groups, C3-C7 cycohaloalkyl groups (e.g., cyclohalopropyl, cyclohalobutyl, cyclohalopentyl, or cyclohalohexyl), 4-6 membered oxygen-containing heterocyclines (e.g., oxetanyl, tetrahydrofuranil, tetrahydropyranil, or oxazalidonone), or 4-6 membered nitrogen-containing heterocyclines (e.g., azetidinyl, pyrrolidinyl, An acyl moiety comprising (or piperidinyl), wherein the group comprises substituents that are amino groups (e.g., -NH2, monoalkylamino (e.g., -NHMe), or dialkylamino (e.g., -NMe2)), acetamide groups (e.g., -NHCOMe or NMeCOMe), carbamate groups (e.g., -NHCO2Me or -NMeCO2Me), alkylsulfonamide groups (e.g., -NHSO2Me or -NMeSO2Me), or 5- to 10-membered nitrogen-containing heterocyclines (e.g., tetrazolyl, imidazolyl, N-methylimidazolyl, pyridyl, or pyridazinyl). In embodiments, R 1 is an alkylacyl group (e.g., -C(O)(C1-C7 alkyl) or -C(O)(C3-C7 cycloalkyl)). In the embodiment, R1 Unsubstituted alkylacyl groups (e.g., -C(O)(C1-C7 alkyl) or -C(O)(C3-C7 cycloalkyl)) are excluded. In the embodiment, R 1 This is a polar sulfonyl group (for example, a substructure as further described herein). [ka] ) is. In this embodiment, R 1 These include C1-C7 alkyl groups, C3-C7 cycoalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), C1-C7 haloalkyl groups, C3-C7 cycohaloalkyl groups (e.g., cyclohalopropyl, cyclohalobutyl, cyclohalopentyl, or cyclohalohexyl), 4-6 membered oxygen-containing heterocyclines (e.g., oxetanyl, tetrahydrofuranil, tetrahydropyranil, or oxazalidonone), or 4-6 membered nitrogen-containing heterocyclines (e.g., The sulfonyl moiety comprises azetidinyl, pyrrolidinyl, or piperidinyl, wherein the group includes substituents that are amino groups (e.g., -NH2, monoalkylamino (e.g., -NHMe), or dialkylamino (e.g., -NMe2)), acetamide groups (e.g., -NHCOMe or NMeCOMe), alkylsulfonamide groups (e.g., -NHSO2Me or -NMeSO2Me), or 5- to 10-membered nitrogen-containing heterocyclines (e.g., tetrazolyl, imidazolyl, N-methylimidazolyl, pyridyl, or pyridazinyl).

[0267] In this embodiment, R 1 teeth, [ka] Selected from the group consisting of, R 4a , R 4b , R 4c , R 6a , R 6b , and R6c is each independently selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 4a and R 4b optionally together with the atom to which they are attached form a 3- to 7-membered ring optionally containing oxygen, or R 6a and R 6b optionally together with the atom to which they are attached form a 3- to 7-membered ring optionally containing oxygen, R 4d and R 6d are each independently selected from the group consisting of phenyl, benzyl, pyridyl, -CH2(pyridyl), imidazole, and -CH2(imidazole), R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohaloalkoxy, C6-C 10 aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO₂R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and

Chemical formula

[0268] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y1 The answer is 2.

[0269] In this embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0270] In this embodiment, R 4a H is H. In this embodiment, R 4b H is H. In this embodiment, R 4a and R 4b Both are H. In the embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0271] In this embodiment, R 4a and R 4b These, together with the atoms to which they bond, form a cyclic carbon containing 3 to 7 atoms. In the embodiment, R 4a and R 4b These atoms, together with the atoms they bond to, form an oxygen-containing ring containing 3 to 7 atoms.

[0272] In this embodiment, R 4c is H. In this embodiment, R 4d R is phenyl. In the embodiment, R 4d is benzyl. In the embodiment, R 4d is pyridyl. In the embodiment, R 4d is -CH2 (pyridyl). In the embodiment, R 4d is an imidazole. In this embodiment, R 4d is -CH2 (imidazole). In the embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0273] In this embodiment, R 6a H is H. In this embodiment, R6b H is H. In this embodiment, R 6a and R 6b Both are H. In the embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0274] In this embodiment, R 46 and R 6b These, together with the atoms to which they bond, form a cyclic carbon containing 3 to 7 atoms. In the embodiment, R 6a and R bb These atoms, together with the atoms they bond to, form an oxygen-containing ring containing 3 to 7 atoms.

[0275] In this embodiment, R 6c is H. In this embodiment, R 6d R is phenyl. In the embodiment, R 6d is benzyl. In the embodiment, R 6d is pyridyl. In the embodiment, R 6d is -CH2 (pyridyl). In the embodiment, R 6d is an imidazole. In this embodiment, R 6d is -CH2 (imidazole). In the embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0276] In this embodiment, R 5 is pyridyl. In the embodiment, R 5 is pyridazine. In the embodiment, R 5 is a C1-C7 alkyl group. In the embodiment, R 5 is a C3-C7 cycloalkyl group. In this embodiment, R 5 is a C1-C7 haloalkyl group. In the embodiment, R 5 is a C3-C7 cyclohaloalkyl group. In the embodiment, R 5is a C1-C7 fluoroalkyl group. In the embodiment, R 5 is a C3-C7 cyclofluoroalkyl group. In the embodiment, R 5 is an unsubstituted C1-C7 alkyl group. In the embodiment, R 5 R is a substituted C1-C7 alkyl group (e.g., including amino substituents such as -NH2, -NHCH3, or -N(CH3)2). In embodiments, R 5 R is phenyl. In this embodiment, R 5 R is phenyl. In this embodiment, R 5 R is an unsubstituted phenyl compound. In this embodiment, R 5 is a substituted phenyl. In the embodiment, R 5 , NR 8a R 8b In this embodiment, R 5 SO2R 8c In this embodiment, R 5 , NR 8d SO2R 8e In this embodiment, R 5 , NR 8i COOR 8j In this embodiment, R 5 , NHCONR 8f In this embodiment, R 5 , NR 8g COR 8h In this embodiment, R 5 It is not an unsubstituted C1-C7 alkyl group.

[0277] In this embodiment, R 7 is pyridyl. In the embodiment, R 7 is pyridazine. In the embodiment, R 7 is a C1-C7 alkyl group. In the embodiment, R 7 is a C3-C7 cycloalkyl group. In this embodiment, R 7 is a C1-C7 haloalkyl group. In the embodiment, R 7 is a C3-C7 cyclohaloalkyl group. In the embodiment, R 7 is a C1-C7 fluoroalkyl group. In the embodiment, R 7is a C3-C7 cyclofluoroalkyl group. In the embodiment, R 7 is an unsubstituted C1-C7 alkyl group. In the embodiment, R 7 is a substituted C1-C7 alkyl group. In the embodiment, R 7 R is phenyl. In this embodiment, R 7 R is phenyl. In this embodiment, R 7 R is an unsubstituted phenyl compound. In this embodiment, R 7 is a substituted phenyl. In the embodiment, R 7 , NR 8a R 8b In this embodiment, R 7 SO2R 8c In this embodiment, R 7 , NR 8d SO2R 8e In this embodiment, R 7 , NHCONR 8f In this embodiment, R 7 It is not an unsubstituted C1-C7 alkyl group.

[0278] In this embodiment, R 4d teeth, [ka] Selected from the group consisting of, in the formula, R 4bb is H or CH3, a1 is 1 or 2, and each R 4aa R is independently any substituent described herein. In embodiments, R 4aa These are independently OH, OCH3, NH2, CN, CH3, and CF. 3、 Selected from CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. In embodiments, R 4aaEach of these independently comprises C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C The group is selected from the group consisting of 7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen.

[0279] In this embodiment, R 6d teeth, [ka] Selected from the group consisting of, in the formula, R 6bb is H or CH3, a1 is 1 or 2, and each R 6aa R is independently any substituent described herein. In embodiments, R 6aa These are independently OH, OCH3, NH2, CN, CH3, and CF. 3、 Selected from CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. In embodiments, R 6aaEach of these independently comprises C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C The group is selected from the group consisting of 7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen.

[0280] In this embodiment, R 1 teeth, [ka] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0281] In this embodiment, R 1 teeth, [ka] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0282] In this embodiment, R 1 teeth, [ka] In this embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0283] In this embodiment, R 1 teeth, [ka] In this embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0284] In this embodiment, R 1 teeth, [ka] In this embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0285] In this embodiment, R 1 teeth, [ka] In this embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0286] In this embodiment, R 1 teeth, [ka] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0287] In this embodiment, R 1 teeth, [ka] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0288] In this embodiment, y 1 is 0, and R 1 is COR 5 In this embodiment, R 5 is pyridyl. In the embodiment, R 5 is pyridazine. In the embodiment, R 5 is a C1-C7 alkyl group. In the embodiment, R 5 is a C3-C7 cycloalkyl group. In this embodiment, R 5 is a C1-C7 haloalkyl group. In the embodiment, R 5 is a C3-C7 cyclohaloalkyl group. In the embodiment, R 5 is a C1-C7 fluoroalkyl group. In the embodiment, R 5 These are C3-C7 cyclofluoroalkyl groups.

[0289] In this embodiment, R 11 is hydrogen. In this embodiment, R 11 is a C1-C7 alkyl group (e.g., methyl). In the embodiment, R 11 These are C3-C7 cycloalkyl groups.

[0290] In this embodiment, R 1 teeth, [ka] And in the formula, R 4a , R 4b , and y 1 This applies according to any aspect or embodiment described herein. Z a is CH2 or O, Z a If it is CH2, then p 1 +p 2 is 1, 2, 3, or 4, and Z a If p is O, 1 +p 2 is 1, 2, 3, or 4, and also p 1 and p 2 Both are not 0.

[0291] In this embodiment, R 1 teeth, [ka] And in the formula, Z b is CH2 or O, Z b If it is CH2, then p 1 +p 2 is 1, 2, 3, or 4, Z b If p is O, 1 +p 2 is 1, 2, 3, or 4, and also p 1 and p 2 Both are not 0, R 5 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR 8d SO2R 8e NHCONR 8f , NR 8g COR 8h , and [ka] Selected from the group consisting of, R 8a , R 8b , R 8d , R 8g , and R 9 Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 Forming a heterocyle containing 3 to 7 atoms, which contains a group selected from the above, R 8c , R 8e , R 8f , and R 8h These are, respectively, C1-C7 alkyl or C3-C7 cycloalkyl.

[0292] In this embodiment, R 1 teeth, [ka] And in the formula, Z c is CH2 or O, Z c If it is CH2, then p 1 +p 2 is 1, 2, 3, or 4, Z c If p is O, 1 +p 2 is 1, 2, 3, or 4, and also p 1 and p 2 Both are not 0, R 7 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c, NR 8d SO2R 8e NHCONR 8f Selected from the group consisting of, R 8a , R 8b , R 8d , R 8g , and R 9 Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 Forming a heterocyle containing 3 to 7 atoms, which contains a group selected from the above, R 8c , R 8e , R 8f , and R 8h These are, respectively, C1-C7 alkyl or C3-C7 cycloalkyl.

[0293] In this embodiment, R 1 teeth, [ka] And in the formula, R 10a and R 10b These are independently H, C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, and SO2R 8e COOR 8j CONR 8f , and COR 8h Selected from the group consisting of, R 10a and R 10b At least one of these is selected from the group consisting of H, C1-C7 linear alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl. R 8e , R 8f , and R 8h Each is selected from the group consisting of H, C1-C7 linear alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl, and R 8j C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C6-C 10 The group is selected from aryls and heteroaryls consisting of 5- to 10 members.

[0294] In this embodiment, R 1 COOR 5 And in the formula, R 5 C6~C 10 They are aryl or 5- to 10-membered heteroaryls.

[0295] In this embodiment, R 1 teeth, [ka] And in the formula, R 8a and R 8b Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 It forms a heterocyle containing 3 to 7 atoms, which contains a group selected from R 9 The element is selected from the group consisting of hydrogen, C1-C7 alkyl groups, and C3-C7 cycloalkyl groups.

[0296] In this embodiment, R 1 teeth, [ka] And in the formula, uu is either 1 or 2.

[0297] In this embodiment, R 1 teeth, [ka] And in the formula, R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C10 The group is selected from aryls and heteroaryls consisting of 5- to 10 members.

[0298] In this embodiment, R 1 teeth, [ka] And in the formula, R 8h These are unsubstituted C1-C7 alkyl groups.

[0299] In this embodiment, R 1 teeth, [ka] And in the formula, R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 The group is selected from aryls and heteroaryls consisting of 5- to 10 members.

[0300] In this embodiment, R 1 teeth, [ka] And in the formula, R 8a and R 8b Each of these is independently either H or an unsubstituted C1-C7 alkyl group.

[0301] In this embodiment, R 1 teeth, [ka] And in the formula, R 8d These are independently H or unsubstituted C1-C7 alkyl, and R 8e These are unsubstituted C1-C7 alkyl groups.

[0302] In this embodiment, R 1 teeth, [ka] And in the formula, R4a and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups.

[0303] In this embodiment, R 1 teeth, [ka] And in the formula, R 4a and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups.

[0304] In this embodiment, R 1 teeth, [ka] And in the formula, R 4a and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups.

[0305] In this embodiment, R 1 teeth, [ka] And in the formula, R 8h These are unsubstituted C1-C7 alkyl groups.

[0306] In this embodiment, R 1 teeth, [ka] And in the formula, R 8h These are unsubstituted C1-C7 alkyl groups.

[0307] In this embodiment, R 1 teeth, [ka] And in the formula, R 8h These are unsubstituted C1-C7 alkyl groups.

[0308] In one embodiment, R 1 teeth, [ka] That is the case.

[0309] In one embodiment, R 1 teeth, [ka] That is the case.

[0310] In one embodiment, R 1 teeth, [ka] That is the case.

[0311] In this embodiment, R 1 teeth, [ka] And in the formula, R 8a , R 8b , and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups.

[0312] In this embodiment, R 1 teeth, [ka] That is the case.

[0313] In this embodiment, R 1 teeth, [ka] That is the case.

[0314] In this embodiment, R 1 teeth, [ka] That is the case.

[0315] In this embodiment, R 1 teeth, [ka] That is the case.

[0316] In this embodiment, R 1 teeth, [ka] That is the case.

[0317] In this embodiment, R 1 teeth, [ka] That is the case.

[0318] In this embodiment, R 1 teeth, [ka] That is the case.

[0319] In this embodiment, R 1 teeth, [ka] And in the formula, R 8a and R 8b Each of these is independently either H or an unsubstituted C1-C7 alkyl group.

[0320] In this embodiment, R 1 teeth, [ka] And in the formula, R 8g These are independently H or unsubstituted C1-C7 alkyl, and R 8h These are independently unsubstituted C1-C7 alkyl groups.

[0321] In this embodiment, R 1 teeth, [ka] That is the case.

[0322] Compounds of general formula (II) In one embodiment, the present invention is characterized by a compound having a structure according to the following general formula (II): [ka] The formula includes the enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex, in which, A 2 teeth, [ka] And, R 2 These include 6- to 10-membered aryls, 5- to 10-membered nitrogen-containing heteroaryls, and [ka] Selected from the group consisting of, R 3 These are 6- to 10-membered aryl compounds or 5- to 10-membered nitrogen-containing heteroaryl compounds. m is 1, 2, or 3. n is 1, 2, 3, or 4. R 1’ C6~C 10 Aryl, five- to six-membered heteroaryl rings, [ka] Selected from the group consisting of, R 4a , R4b , R 4c , R 6a , R 6b , and R 6c Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 4a and R 4b They optionally, together with the atoms they bond to, form a ring containing 3 to 7 atoms, optionally containing oxygen. R 6a and R 6b They optionally, together with the atoms they bond to, form a ring containing 3 to 7 atoms, optionally containing oxygen. R 4d and R 6d Each is selected from the group consisting of phenyl, benzyl, pyridyl, -CH2(pyridyl), imidazole, and -CH2(imidazole), R 5 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j NHCONR 8f , NR 8g COR 8h , and [ka] Selected from the group consisting of, R 7 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR 8d SO2R 8e NHCONR 8f Selected from the group consisting of, R 8a , R 8b , R 8d , R 8g , and R 8i Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 Forming a heterocyle containing 3 to 7 atoms, which contains a group selected from the above, R 8c , R 8e , R 8f , and R 8h Each of these is either a C1-C7 alkyl group or a C3-C7 cycloalkyl group. R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, or R 4a and R 8a If both exist, or R 4a and R 8g If both are present, these groups optionally combine with the atom to which they bond to form a ring containing 4 to 7 atoms. R 9 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 11 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R AC1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxy Selected from the group consisting of xicarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen, a is 0, 1, or 2. y 1 is 0, 1, or 2, and y 2 It is 0, 1, or 2.

[0323] In this embodiment, A 2 but [ka] And R 2 is phenyl, and R 1’ but [ka] And y 2 If is 0 and n is 2, then R 7 It is not methyl, CH2SO2CH3, CH2CN, tetrahydropyranyl, phenyl, 4-substituted phenyl, or a 5- to 8-membered heteroaryl.

[0324] In the embodiment, the compound according to general formula (II) has a structure according to general formula (II') or general formula (II''). [ka]

[0325] In this embodiment, A 2 teeth, [ka] That is the case.

[0326] In this embodiment, A 2 teeth, [ka] That is the case.

[0327] In this embodiment, A 2 teeth, [ka] That is the case.

[0328] In this embodiment, R AC1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxy The group is selected from xicarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen. In embodiments, R A is an unsubstituted C1-C7 alkyl group. In the embodiment, R A It is methyl.

[0329] In the embodiment, a is 0. In the embodiment, a is 1. In the embodiment, a is 2. In the embodiment, a is not 0. In the embodiment, a excludes 0. In the embodiment, a is 0 or 1. In the embodiment, a is 1 or 2.

[0330] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0331] In this embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0332] In this embodiment, R 4aH is H. In this embodiment, R 4b H is H. In this embodiment, R 4a and R 4b Both are H. In the embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0333] In this embodiment, R 4a and R 4b These, together with the atoms to which they bond, form a cyclic carbon containing 3 to 7 atoms. In the embodiment, R 4a and R 4b These atoms, together with the atoms they bond to, form an oxygen-containing ring containing 3 to 7 atoms.

[0334] In this embodiment, R 4c is H. In this embodiment, R 4d R is phenyl. In the embodiment, R 4d is benzyl. In the embodiment, R 4d is pyridyl. In the embodiment, R 4d is -CH2 (pyridyl). In the embodiment, R 4d is an imidazole. In this embodiment, R 4d is -CH2 (imidazole). In the embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0335] In this embodiment, R 6a H is H. In this embodiment, R 6b H is H. In this embodiment, R 6a and R 6b Both are H. In the embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0336] In this embodiment, R6a and R 6b These, together with the atoms to which they bond, form a cyclic carbon containing 3 to 7 atoms. In the embodiment, R 6a and R 6b These atoms, together with the atoms they bond to, form an oxygen-containing ring containing 3 to 7 atoms.

[0337] In this embodiment, R 6c is H. In this embodiment, R 6d R is phenyl. In the embodiment, R 6d is benzyl. In the embodiment, R 6d is pyridyl. In the embodiment, R 6d is -CH2 (pyridyl). In the embodiment, R 6d is an imidazole. In this embodiment, R 6d is -CH2 (imidazole). In the embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0338] In this embodiment, R 5 is pyridyl. In the embodiment, R 5 is pyridazine. In the embodiment, R 5 is a C1-C7 alkyl group. In the embodiment, R 5 is a C3-C7 cycloalkyl group. In this embodiment, R 5 is a C1-C7 haloalkyl group. In the embodiment, R 5 is a C3-C7 cyclohaloalkyl group. In the embodiment, R 5 is a C1-C7 fluoroalkyl group. In the embodiment, R 5 is a C3-C7 cyclofluoroalkyl group. In the embodiment, R 5 is an unsubstituted C1-C7 alkyl group. In the embodiment, R 5 R is a substituted C1-C7 alkyl group (e.g., including amino substituents such as -NH2, -NHCH3, or -N(CH3)2). In embodiments, R 5 R is phenyl. In this embodiment, R5 R is phenyl. In this embodiment, R 5 R is an unsubstituted phenyl compound. In this embodiment, R 5 is a substituted phenyl. In the embodiment, R 5 , NR 8a R 8b In this embodiment, R 5 SO2R 8c In this embodiment, R 5 , NR 8d SO2R 8e In this embodiment, R 5 , NR 8i COOR 8j In this embodiment, R 5 , NHCONR 8f In this embodiment, R 5 , NR 8g COR 8h In this embodiment, R 5 It is not an unsubstituted C1-C7 alkyl group.

[0339] In this embodiment, R 7 is pyridyl. In the embodiment, R 7 is pyridazine. In the embodiment, R 7 is a C1-C7 alkyl group. In the embodiment, R 7 is a C3-C7 cycloalkyl group. In this embodiment, R 7 is a C1-C7 haloalkyl group. In the embodiment, R 7 is a C3-C7 cyclohaloalkyl group. In the embodiment, R 7 is a C1-C7 fluoroalkyl group. In the embodiment, R 7 is a C3-C7 cyclofluoroalkyl group. In the embodiment, R 7 is an unsubstituted C1-C7 alkyl group. In the embodiment, R 7 is a substituted C1-C7 alkyl group. In the embodiment, R 7 R is phenyl. In this embodiment, R 7 R is phenyl. In this embodiment, R 7 R is an unsubstituted phenyl compound. In this embodiment, R 7is a substituted phenyl. In the embodiment, R 7 , NR 8a R 8b In this embodiment, R 7 SO2R 8c In this embodiment, R 7 , NR 8d SO2R 8e In this embodiment, R 7 , NHCONR 8f In this embodiment, R 7 It is not an unsubstituted C1-C7 alkyl group.

[0340] In this embodiment, R 1’ R is a 5- to 6-membered heteroaryl ring. In the embodiment, R 1’ is imidazolyl (e.g., unsubstituted imidazolyl or N-methylimidazolyl). In embodiments, R 1 is an oxazolyl (e.g., an unsubstituted oxazolyl). In the embodiment, R 1 This is isoxazolyl (e.g., unsubstituted oxazolyl).

[0341] In this embodiment, R 1’ teeth, [ka] In the formula, X is O, NH, or NCH3, aa1 is 0, 1, or 2, and R 1aC1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxy The group is selected from xicarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and five- to six-membered heterocyclic groups each containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen.

[0342] In this embodiment, R 1’ teeth, [ka] Selected from the group consisting of. In this embodiment, R 1 teeth, [ka] That is the case.

[0343] In this embodiment, R 1’ teeth, [ka] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0344] In this embodiment, R 1’ teeth, [ka] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0345] In this embodiment, R 1’ teeth, [ka] In this embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0346] In this embodiment, R 1’ teeth, [ka] In this embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0347] In this embodiment, R 1’ teeth, [ka] In this embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y 2 The answer is 2.

[0348] In this embodiment, R 1’ teeth, [ka] In this embodiment, y 2 is 0. In this embodiment, y 2 is 1. In this embodiment, y2 The answer is 2.

[0349] In this embodiment, R 1’ teeth, [ka] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0350] In this embodiment, R 1’ teeth, [ka] In this embodiment, y 1 is 0. In this embodiment, y 1 is 1. In this embodiment, y 1 The answer is 2.

[0351] In this embodiment, y 1 is 0, and R 1’ is COR 5 In this embodiment, R 5 is pyridyl. In the embodiment, R 5 is pyridazine. In the embodiment, R 5 is a C1-C7 alkyl group. In the embodiment, R 5 is a C3-C7 cycloalkyl group. In this embodiment, R 5 is a C1-C7 haloalkyl group. In the embodiment, R 5 is a C3-C7 cyclohaloalkyl group. In the embodiment, R 5 is a C1-C7 fluoroalkyl group. In the embodiment, R 5 These are C3-C7 cyclofluoroalkyl groups.

[0352] In this embodiment, R 11 is hydrogen. In this embodiment, R 11 is a C1-C7 alkyl group (e.g., methyl). In the embodiment, R 11These are C3-C7 cycloalkyl groups.

[0353] In this embodiment, R 1’ teeth, [ka] And in the formula, R 4a , R 4b , and y 1 This applies according to any aspect or embodiment described herein. Z a is CH2 or O, Z a If it is CH2, then p 1 +p 2 is 1, 2, 3, or 4, and Z a If p is O, 1 +p 2 is 1, 2, 3, or 4, and also p 1 and p 2 Both are not 0.

[0354] In this embodiment, R 1’ teeth, [ka] And in the formula, Z b is CH2 or O, Z b If it is CH2, then p 1 +p 2 is 1, 2, 3, or 4, Z b If p is O, 1 +p 2 is 1, 2, 3, or 4, and also p 1 and p 2 Both are not 0, R 5C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR 8d SO2R 8e NHCONR 8f , NR 8g COR 8h , and [ka] Selected from the group consisting of, R 8a , R 8b , R 8d , R 8g , and R 9 Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 Forming a heterocyle containing 3 to 7 atoms, which contains a group selected from the above, R 8c , R 8e , R 8f , and R 8h These are, respectively, C1-C7 alkyl or C3-C7 cycloalkyl.

[0355] In this embodiment, R 1’ teeth, [ka] And in the formula, Z c is CH2 or O, Z c If it is CH2, then p 1 +p 2is 1, 2, 3, or 4, Z c If p is O, 1 +p 2 is 1, 2, 3, or 4, and also p 1 and p 2 Both are not 0, R 7 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohaloalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryls, CN, NR 8a R 8b SO2R 8c , NR 8d SO2R 8e NHCONR 8f Selected from the group consisting of, R 8a , R 8b , R 8d , R 8g , and R 9 Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 Forming a heterocyle containing 3 to 7 atoms, which contains a group selected from the above, R 8c , R 8e , R 8f , and R 8h These are, respectively, C1-C7 alkyl or C3-C7 cycloalkyl.

[0356] In this embodiment, R 1’ teeth, [ka] And in the formula, R 10a and R 10bThese are independently H, C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, and SO2R 8e COOR 8j CONR 8f , and COR 8h Selected from the group consisting of, R 10a and R 10b At least one of these is selected from the group consisting of H, C1-C7 linear alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl. R 8e , R 8f , and R 8h Each is selected from the group consisting of H, C1-C7 linear alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl. R 8j C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C6-C 10 The group is selected from aryls and heteroaryls consisting of 5- to 10 members.

[0357] In this embodiment, R 1’ COOR 5 And in the formula, R 5 C6~C 10 They are aryl or 5- to 10-membered heteroaryls.

[0358] In this embodiment, R 1’ teeth, [ka] And in the formula, R 8a and R 8b Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b They may optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR 9 It forms a heterocyle containing 3 to 7 atoms, which contains a group selected from R 9The element is selected from the group consisting of hydrogen, C1-C7 alkyl groups, and C3-C7 cycloalkyl groups.

[0359] In this embodiment, R 1’ teeth, [ka] And in the formula, uu is either 1 or 2.

[0360] In this embodiment, R 1’ teeth, [ka] And in the formula, R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 The group is selected from aryls and heteroaryls consisting of 5- to 10 members.

[0361] In this embodiment, R 1’ teeth, [ka] And in the formula, R 8h These are unsubstituted C1-C7 alkyl groups.

[0362] In this embodiment, R 1’ teeth, [ka] And in the formula, R 8j These are C1-C7 alkyl, C3-C7 cycloalkyl, and C6-C 10 The group is selected from aryls and heteroaryls consisting of 5- to 10 members.

[0363] In this embodiment, R 1 teeth, [ka] And in the formula, R 8a and R 8bEach of these is independently either H or an unsubstituted C1-C7 alkyl group.

[0364] In this embodiment, R 1’ teeth, [ka] And in the formula, R 8d These are independently H or unsubstituted C1-C7 alkyl, and R 8e These are unsubstituted C1-C7 alkyl groups.

[0365] In this embodiment, R 1’ teeth, [ka] And in the formula, R 4a and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups.

[0366] In this embodiment, R 1’ teeth, [ka] And in the formula, R 4a and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups.

[0367] In this embodiment, R 1’ teeth, [ka] And in the formula, R 4a and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups.

[0368] In this embodiment, R 1’teeth, [ka] And in the formula, R 8h These are unsubstituted C1-C7 alkyl groups.

[0369] In this embodiment, R 1’ teeth, [ka] And in the formula, R 8h These are unsubstituted C1-C7 alkyl groups.

[0370] In this embodiment, R 1’ teeth, [ka] And in the formula, R 8h These are unsubstituted C1-C7 alkyl groups.

[0371] In this embodiment, R 1’ teeth, [ka] That is the case.

[0372] In this embodiment, R 1’ teeth, [ka] That is the case.

[0373] In this embodiment, R 1’ teeth,

[0374] [ka] That is the case.

[0375] In this embodiment, R 1’ teeth, [ka] And in the formula, R 8a , R 8b , and R 8g Each of them is independently H or an unsubstituted C1-C7 alkyl, and R 8h These are unsubstituted C1-C7 alkyl groups.

[0376] In this embodiment, R 1’ teeth, [ka] That is the case.

[0377] In this embodiment, R 1’ teeth, [ka] That is the case.

[0378] In this embodiment, R 1’ teeth, [ka] That is the case.

[0379] In this embodiment, R 1’ teeth, [ka] That is the case.

[0380] In this embodiment, R 1’ teeth, [ka] That is the case.

[0381] In this embodiment, R 1’ teeth, [ka] That is the case.

[0382] In this embodiment, R 1’ teeth, [ka] That is the case.

[0383] In this embodiment, R 1’ teeth, [ka] And in the formula, R 8a and R 8b Each of these is independently either H or an unsubstituted C1-C7 alkyl group.

[0384] In this embodiment, R 1’ teeth, [ka] And in the formula, R 8g These are independently H or unsubstituted C1-C7 alkyl, and R 8h These are independently unsubstituted C1-C7 alkyl groups.

[0385] In this embodiment, R 1’ teeth, [ka] That is the case.

[0386] Compounds of general formula (A) to (AAA) Further compounds of general formula (I), (I*), (I**), or (II) include any one compound of general formula (A) to (AAA) described herein, and all variables may be in any form or embodiment described herein.

[0387] Further exemplary general formulas and compounds described herein may also include their hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes.

[0388] For example, in any of the general formulas described herein (e.g., any of general formulas (I), (I*), (I**), (II), and any of general formulas (A) to (AAA), the C5 carbon of 2-dihydrofuranone has an (R) configuration.

[0389] Alternatively, in any of the general formulas described herein (for example, any of general formulas (I), (I*), (I**), (II), and any of general formulas (A) to (AAA), the C5 carbon of 2-dihydrofuranone has an (S)-configuration.

[0390] In embodiments, the following compounds having a structure according to the general formula (A) are provided herein: [ka] In the formula, R a , R b A, n, and aryl are as described herein in any aspect and embodiment.

[0391] In embodiments, the following compounds having a structure according to general formula (B) are provided herein: [ka] In the formula, Q 1 Q is either 1 or 2. 2 is 1 or 2, and A and n are as described herein in any aspect and embodiment.

[0392] In embodiments, the following compounds having a structure according to the general formula (C) are provided herein: [ka] In the formula, Q 1 Q is either 1 or 2. 2 is 1 or 2, and A and n are as described herein in any aspect and embodiment.

[0393] In the embodiments described herein, compounds having a structure according to the following general formula (D) are provided: [ka] In the formula, Q 1 Q is either 1 or 2. 2 is 1 or 2, and A and n are as described herein in any aspect and embodiment.

[0394] In embodiments, the following compounds having a structure according to the general formula (E) are provided herein: [ka] In the formula, Q 1 Q is either 1 or 2. 2 is 1 or 2, and A and n are as described herein in any aspect and embodiment.

[0395] In embodiments, the following compounds having a structure according to the general formula (F) are provided herein: [ka] In the formula, Q 1 Q is either 1 or 2. 2 is 1 or 2, and A and n are as described herein in any aspect and embodiment.

[0396] In embodiments, the following compounds having a structure according to the general formula (G) are provided herein: [ka] In the formula, Q 1 Q is either 1 or 2. 2 is 1 or 2, and A and n are as described herein in any aspect and embodiment.

[0397] In embodiments, the following compounds having a structure according to the general formula (H) are provided herein: [ka] In the formula, Q 1 Q is either 1 or 2. 2 is 1 or 2, and R 1 A and n are as described herein in any aspect and embodiment.

[0398] In certain embodiments, the Specified herein provides compounds having a structure according to the following general formula (J): [ka] R a and R b Each is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl. R 2 It is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl, and R 3 The compound is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl.

[0399] In certain embodiments, the Specified herein provides compounds having a structure according to the following general formula (K): [ka] During the ceremony, R 2 It is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl, and R 3 The compound is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl.

[0400] In the embodiments described herein, [ka] A compound containing the unit is provided, in the formula L Ais any group relating to A as described herein. In embodiments, L A teeth, [ka] It is selected from the group consisting of the following.

[0401] In embodiments, the following compounds having a structure according to the general formula (L) are provided herein: [ka] In the formula, R 2a , aa, L A , n, R 4a , R 4b , y 1 , R 10a , and R 10b This is as described in any aspect and embodiment of this specification.

[0402] In embodiments, the following compounds having a structure according to the general formula (M) are provided herein: [ka] In the formula, R 2a aa, n, R 4a , R 4b , y 1 , R 10a , and R 10b This is as described in any aspect and embodiment of this specification.

[0403] In embodiments, the following compounds having a structure according to the general formula (N) are provided herein: [ka] In the formula, R 2a , aa, L A , n, R 4a , R 4b , y 1 , Z 1 , p 1 , and p 2This is as described in any aspect and embodiment of this specification.

[0404] In the embodiments described herein, compounds having a structure according to the following general formula (O) are provided: [ka] In the formula, R 2a aa, n, R 4a , R 4b , y 1 , Z 1 , p 1 , and p 2 This is as described in any aspect and embodiment of this specification.

[0405] In the embodiments described herein, compounds having a structure according to the following general formula (P) are provided: [ka] In the formula, R 2a , aa, L A , n, X, and R 1a This is as described in any aspect and embodiment of this specification.

[0406] In embodiments, the following compounds having a structure according to the general formula (Q) are provided herein: [ka] In the formula, R 2a aa, n, X, and R 1a This is as described in any aspect and embodiment of this specification.

[0407] In embodiments, the following compounds having a structure according to the general formula (R) are provided herein: [ka] In the formula, R 2a , aa, L A , n, Z b , p1 , p 2 , and R 10a , and R 10b This is as described in any aspect and embodiment of this specification.

[0408] In embodiments, the following compounds having a structure according to the general formula (S) are provided herein: [ka] In the formula, R 2a aa, n, Z b , p 1 , p 2 , and R 10a , and R 10b This is as described in any aspect and embodiment of this specification.

[0409] In the embodiments described herein, compounds having a structure according to the following general formula (T) are provided: [ka] In the formula, p 1 is 1, 2, 3, or 4, and also R 2a , aa, L A , n, R 4b , and R 8h This is as described in any aspect and embodiment of this specification.

[0410] In embodiments, the following compounds having a structure according to the general formula (U) are provided herein: [ka] In the formula, p 1 is 1, 2, 3, or 4, and also R 2a aa, n, R 4b , and R 8h This is as described in any aspect and embodiment of this specification.

[0411] In embodiments, the following compounds having a structure according to the general formula (V) are provided herein: [ka] In the formula, R 2a , aa, L A , n, R 4a , R 4b , and y 1 This is as described in any aspect and embodiment of this specification.

[0412] In embodiments, the following compounds having a structure according to the general formula (W) are provided herein: [ka] In the formula, R 2a aa, n, R 4a , R 4b , and y 1 This is as described in any aspect and embodiment of this specification.

[0413] In embodiments, the following compounds having a structure according to the general formula (X) are provided herein: [ka] In the formula, R 5N The group is selected from H, C1-C7 linear alkyl, and C3-C7 branched alkyl, and R 2a , aa, L A , n, R 4a , R 4b , and y 1 This is as described in any aspect and embodiment of this specification.

[0414] In embodiments, the following compounds having a structure according to the general formula (Y) are provided herein: [ka] In the formula, R 5NThe group is selected from H, C1-C7 linear alkyl, and C3-C7 branched alkyl, and R 2a aa, n, R 4a , R 4b , and y 1 This is as described in any aspect and embodiment of this specification.

[0415] In embodiments, the following compounds having a structure according to the general formula (Z) are provided herein: [ka] In the formula, R 5a It is pyridyl or pyridazine, and also R 2a , aa, L A , and n are as described herein in any aspect and embodiment.

[0416] In embodiments, the following compounds having a structure according to the general formula (AA) are provided herein: [ka] In the formula, R 5a It is pyridyl or pyridazine, and also R 2a , aa, and n are as described herein in any aspect and embodiment.

[0417] In embodiments, the following compounds having a structure according to the general formula (BB) are provided herein: [ka] In the formula, R 5b is a C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 fluoroalkyl, or C3-C7 cyclofluoroalkyl, and also R 2a , aa, L A , and n are as described herein in any aspect and embodiment.

[0418] In embodiments, the following compounds having a structure according to the general formula (CC) are provided herein: [ka] In the formula, R 5b is a C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 fluoroalkyl, or C3-C7 cyclofluoroalkyl, and also R 2a , aa, and n are as described herein in any aspect and embodiment.

[0419] In embodiments, the following compounds having a structure according to the general formula (DD) are provided herein: [ka] In the formula, R 2 , n, R a , and R b This is as described in any aspect and embodiment of this specification.

[0420] In the embodiments described herein, compounds having a structure according to the following general formula (EE) are provided: [ka] In the formula, R 2 and n are as described herein in any aspect and embodiment.

[0421] In embodiments, the following compounds having a structure according to the general formula (FF) are provided herein: [ka] In the formula, R 2 and n are as described herein in any aspect and embodiment.

[0422] In embodiments, the following compounds having a structure according to the general formula (GG) are provided herein: [ka] In the formula, R 2 and n are as described herein in any aspect and embodiment.

[0423] In the embodiments herein, compounds having a structure according to the following general formula (HH) are provided: [ka] In the formula, R 2 and n are as described herein in any aspect and embodiment.

[0424] In embodiments, the following compounds having a structure according to the general formula (JJ) are provided herein. [ka] In the formula, R 1 , R 2 , and n are as described herein in any aspect and embodiment.

[0425] In embodiments, the following compounds having a structure according to the general formula (KK) are provided herein: [ka] In the formula, R 1 , R 2a , a, and n are as described herein in any aspect and embodiment.

[0426] In embodiments, the following compounds having a structure according to the general formula (LL) are provided herein: [ka] In the formula, R 1 , R 2a , a, and n are as described herein in any aspect and embodiment.

[0427] In embodiments, the following compounds having a structure according to the general formula (MM) are provided herein: [ka] In the formula, R 1 , R 2a , aa, and n are as described herein in any aspect and embodiment.

[0428] In embodiments, the following compounds having a structure according to the general formula (NN) are provided herein: [ka] In the formula, X, R 2a n is as described in any aspect and embodiment of this specification.

[0429] In embodiments, the following compounds having a structure according to the general formula (OO) are provided herein: [ka] In the formula, R 2 , n, R 6a , R 6b , and R 7 This is as described in any aspect and embodiment of this specification.

[0430] In embodiments, the following compounds having a structure according to the general formula (PP) are provided herein: [ka] In the formula, R 2 , n, R 6c , R 6d , and R 7 This is as described in any aspect and embodiment of this specification.

[0431] In embodiments, the following compounds having a structure according to the general formula (QQ) are provided herein. [ka] In the formula, R 8h , R 2a , R 4a , R A , a, aa, and n are as described in relation to any general formula, aspect, or embodiment described herein. In embodiments, R 8h is an unsubstituted C1-C7 alkyl group (e.g., methyl). In the embodiment, R 4a is hydrogen or an unsubstituted C1-C7 alkyl group (for example, R 4a (is hydrogen or methyl, ethyl, or isopropyl). In embodiments, n is 2. In embodiments, aa is 1 or 2. In embodiments, aa is 1. In embodiments, R 2a Each of these is a halogen (e.g., -F and / or -Cl). In the embodiment, a is 0 or 1. In the embodiment, R A If present, is an unsubstituted C1-C7 alkyl (e.g., methyl). In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (R) configuration. In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (S) configuration. In the embodiment, R 4a The carbon substituted with has a (R) configuration. In the embodiment, R 4a The substituted carbon has a (S)-configuration. In the embodiment, R A The carbon substituted with has a (R) configuration. In the embodiment, R A The substituted carbon has a (S)- configuration.

[0432] In embodiments, the following compounds having a structure according to the general formula (RR) are provided herein: [ka] In the formula, R 8e , R 2a , a, and n are as described with respect to any general formula, aspect, or embodiment described herein. In embodiments, R 8eis an unsubstituted C1-C7 alkyl (e.g., methyl). In the embodiment, n is 2. In the embodiment, aa is 1 or 2. In the embodiment, aa is 1. In the embodiment, R 2a These are halogens (e.g., -F and / or -Cl). In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has a (R)-configuration. In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (S)-configuration.

[0433] In the embodiments described herein, compounds having a structure according to the following general formula (SS) are provided: [ka] In the formula, R 2a , R A , a, aa, and n are as described in relation to any general formula, aspect, or embodiment described herein. In embodiments, n is 2. In embodiments, aa is 0, 1, or 2. In embodiments, aa is 0. In embodiments, aa is 1. In embodiments, R 2a Each of these is a halogen (e.g., -F and / or -Cl). In the embodiment, a is 1. In the embodiment, R A is a C1-C7 alkyl group (e.g., methyl). In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (R) configuration. In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (S) configuration. In the embodiment, R A The carbon substituted with has a (R) configuration. In the embodiment, R A The substituted carbon has a (S)- configuration.

[0434] In embodiments, the following compounds having a structure according to the general formula (TT) are provided herein: [ka] In the formula, R 2a , R A , R 5, a, aa, and n are as described in relation to any general formula, aspect, or embodiment described herein. In embodiments, R 5 is an unsubstituted C1-C7 alkyl (e.g., methyl or ethyl). In the embodiment, n is 2. In the embodiment, a is 0 or 1. In the embodiment, R A is a C1-C7 alkyl group (e.g., methyl). In the embodiment, aa is 1. In the embodiment, aa is 0, 1, or 2. In the embodiment, aa is 0. In the embodiment, aa is 1. In the embodiment, R 2a Each is a halogen (e.g., -F and / or -Cl). In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (R)-configuration. In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (S)-configuration. In the embodiment, R A The carbon substituted with has a (R) configuration. In the embodiment, R A The substituted carbon has a (S)- configuration.

[0435] In embodiments, the following compounds having a structure according to the general formula (UU) are provided herein: [ka] In the formula, R 5 , R A , R 2a , a, aa, and n are as described in relation to any general formula, aspect, or embodiment described herein. In embodiments, R 5 is an unsubstituted C1-C7 alkyl group (e.g., methyl, ethyl, isopropyl). In the embodiment, R 5 is a C1-C7 haloalkyl group (e.g., CH2CF3). In the embodiment, n is 2. In the embodiment, aa is 1 or 2. In the embodiment, aa is 1. In the embodiment, R 2a Each of these is a halogen (e.g., -F and / or -Cl). In the embodiment, a is 0 or 1. In the embodiment, R AIf present, is an unsubstituted C1-C7 alkyl (e.g., methyl). In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (R) configuration. In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (S) configuration. In the embodiment, R A The carbon substituted with has a (R) configuration. In the embodiment, R A The substituted carbon has a (S)- configuration.

[0436] In embodiments, the following compounds having a structure according to the general formula (VV) are provided herein: [ka] In the formula, R A , R 2a , a, aa, and n are as described in relation to any general formula, aspect, or embodiment described herein. In embodiments, n is 2. In embodiments, aa is 1 or 2. In embodiments, aa is 1. In embodiments, R 2a Each of these is a halogen (e.g., -F and / or -Cl). In the embodiment, a is 0 or 1. In the embodiment, R A If present, is an unsubstituted C1-C7 alkyl (e.g., methyl). In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (R) configuration. In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (S) configuration. In the embodiment, R A The carbon substituted with has a (R) configuration. In the embodiment, R A The substituted carbon has a (S)- configuration.

[0437] In embodiments, the following compounds having a structure according to the general formula (WW) are provided herein: [ka] In the formula, R 8j , R 2a , R A, a, aa, and n are as described in relation to any general formula, aspect, or embodiment described herein. In embodiments, R 8j is an unsubstituted C1-C7 alkyl (e.g., methyl or ethyl). In the embodiment, n is 2. In the embodiment, aa is 1 or 2. In the embodiment, aa is 1. In the embodiment, R 2a Each of these is a halogen (e.g., -F and / or -Cl). In the embodiment, a is 0 or 1. In the embodiment, R A If present, is an unsubstituted C1-C7 alkyl (e.g., methyl). In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (R) configuration. In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (S) configuration. In the embodiment, R A The carbon substituted with has a (R) configuration. In the embodiment, R A The substituted carbon has a (S)- configuration.

[0438] In embodiments, the following compounds having a structure according to the general formula (XX) are provided herein: [ka] In the formula, R A , R 2a , a, aa, and n are as described in relation to any general formula, aspect, or embodiment described herein. In embodiments, n is 2. In embodiments, aa is 1 or 2. In embodiments, aa is 1. In embodiments, R 2a Each of these is a halogen (e.g., -F and / or -Cl). In the embodiment, a is 0 or 1. In the embodiment, R A If present, is an unsubstituted C1-C7 alkyl (e.g., methyl). In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (R) configuration. In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (S) configuration. In the embodiment, R A The carbon substituted with has a (R) configuration. In the embodiment, R AThe substituted carbon has a (S)- configuration.

[0439] In the embodiments described herein, compounds having a structure according to the following general formula (YY) are provided: [ka] In the formula, R A , R 2a , a, aa, and n are as described in relation to any general formula, aspect, or embodiment described herein. In embodiments, n is 2. In embodiments, aa is 1 or 2. In embodiments, aa is 1. In embodiments, R 2a Each of these is a halogen (e.g., -F and / or -Cl). In the embodiment, a is 0 or 1. In the embodiment, R A If present, is an unsubstituted C1-C7 alkyl (e.g., methyl). In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (R) configuration. In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (S) configuration. In the embodiment, R A The carbon substituted with has a (R) configuration. In the embodiment, R A The substituted carbon has a (S)- configuration.

[0440] In embodiments, the following compounds having a structure according to the general formula (ZZ) are provided herein: [ka] In the formula, R A , R 2a , R 8a , R 8b , a, aa, and n are as described in relation to any general formula, aspect, or embodiment described herein. In embodiments, R 8a R is hydrogen or an unsubstituted C1-C7 alkyl group (e.g., methyl). In the embodiment, R 8bis hydrogen or an unsubstituted C1-C7 alkyl (e.g., methyl). In the embodiment, n is 2. In the embodiment, aa is 1 or 2. In the embodiment, aa is 1. In the embodiment, R 2a Each of these is a halogen (e.g., -F and / or -Cl). In the embodiment, a is 0 or 1. In the embodiment, R A If present, is an unsubstituted C1-C7 alkyl (e.g., methyl). In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (R) configuration. In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (S) configuration. In the embodiment, R A The carbon substituted with has a (R) configuration. In the embodiment, R A The substituted carbon has a (S)- configuration.

[0441] In embodiments, the following compounds having a structure according to the general formula (AAA) are provided herein: [ka] , where R A , R 2a , R 8a , R 8b , a, aa, and n are as described in relation to any general formula, aspect, or embodiment described herein. In embodiments, uu is 1 or 2. In embodiments, n is 2. In embodiments, aa is 1 or 2. In embodiments, aa is 1. In embodiments, R 2a Each of these is a halogen (e.g., -F and / or -Cl). In the embodiment, a is 0 or 1. In the embodiment, R A If present, is an unsubstituted C1-C7 alkyl (e.g., methyl). In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (R) configuration. In the embodiment, the C5 carbon of the 2-dihydrofuranone skeleton has an (S) configuration. In the embodiment, R A The carbon substituted with has a (R) configuration. In the embodiment, R A The substituted carbon has a (S)- configuration.

[0442] Exemplary Compounds Exemplary compounds conforming to the general formulas described herein (for example, those conforming to general formulas (I), (I*), (I**), or (II), such as any of general formulas (A) to (AAA)) include compounds 1 to 145, as shown in Table 1. Table 1: Exemplary Compounds [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22] General synthetic methods for the preparation of 5-HT7 regulators

[0443] The reagents used in the preparation of the compounds of the present invention are commercially available or can be prepared by standard procedures described in the literature. According to the present invention, the compounds of this classification can be produced by one of the following reaction schemes.

[0444] The compounds disclosed herein are those described in International Patent Application PCT / US2017 / 061677, filed November 15, 2017; International Patent Application PCT / US2013 / 071926, filed November 26, 2013; International Patent Application PCT / US2014 / 023400, filed March 11, 2014; and International Patent Application PCT / US2015 / 049303, filed September 10, 2015. It is possible to prepare this by the methods described in International Patent Application No. PCT / US2016 / 031780 filed on 11 May 2016, International Patent Application No. PCT / US2018 / 022581 filed on 15 March 2018, and International Patent Application No. PCT / US2018 / 022574 filed on 15 March 2018, each of which is incorporated herein by reference in its entirety.

[0445] Furthermore, specific exemplary methods are described in Schemes 1-4. In these schemes, the variables within any structure may conform to any aspect or embodiment described herein. Scheme 1. [ka]

[0446] Compounds of general formula (a1) are converted in the presence of coupling agents such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, optionally in the presence of hydroxybenzotriazole, optionally in the presence of 1-hydroxy-7-azabenzotriazole, and optionally, for example, sodium carbonate, potassium carbonate, lithium carbonate, heavy carbon The compound of general formula (a2) is obtained by reacting a known compound of general formula (a5) or a compound prepared by a known method with a known compound in the presence of a base such as sodium acid, potassium bicarbonate, lithium bicarbonate, triethylamine, N,N-diisopropylethylamine, or pyridine, with a solvent such as N-methyl-2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, or 1,2-dimethoxyethane, optionally by heating or optionally by microwave irradiation. Compounds conforming to general formula (a2) are reacted with acids such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid in a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane, methanol, ethanol, 1,2-dimethoxyethane, N,N-dimethylformamide, or N,N-dimethylacetamide, optionally by heating or optionally by microwave irradiation, to obtain compounds conforming to general formula (a3). The compound of general formula (a3) ​​is reacted with a known compound of general formula (a4-1) or a compound prepared by a known method, in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, or acetonitrile, optionally by heating and optionally by microwave irradiation, to obtain the compound of general formula (a4-1a). Alternatively, a compound of general formula (a3) ​​may be transformed into a compound of general formula (a4-2) by heating, optionally by microwave irradiation, in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, or acetonitrile, optionally by heating, optionally by microwave irradiation, wherein the compound of general formula (a4-2) is formed by X in the formula. 1The compound of general formula (a4-2a) is reacted with a known compound or a compound prepared by a known method, where is chlorine, to obtain the compound of general formula (a4-2a). Alternatively, the compound of general formula (a3) ​​is reacted with a coupling agent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, optionally in the presence of hydroxybenzotriazole, and optionally with 1-hydroxy-7-azabenzotriazole In the presence of a solvent such as a steroid, optionally in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or 2,6-dimethylpyridine, optionally in the presence of a solvent such as N-methyl-2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, or 1,2-dimethoxyethane, optionally by heating, optionally by microwave irradiation, a compound of general formula (a4-2), wherein X 1 The compound with the general formula (a4-2a) is obtained by reacting it with a known compound or a compound prepared by a known method, where the compound is OH.

[0447] Alternatively, a compound of general formula (a3) ​​may be reacted with a compound of general formula (a4-3a), which is a known compound or a compound prepared by a known method, in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, or acetonitrile, optionally by heating or optionally by microwave irradiation, to obtain a compound of general formula (a4-3a). Scheme 2. [ka] The compound of general formula (a1) is used in the presence of a coupling agent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, optionally in the presence of hydroxybenzotriazole, optionally in the presence of 1-hydroxy-7-azabenzotriazole, and optionally, for example, sodium carbonate, potassium carbonate, lithium carbonate, bicarbonate. The compound of general formula (a6) is obtained by reacting a known compound of general formula (a9) or a compound prepared by a known method with a known compound in the presence of a base such as sodium, potassium bicarbonate, lithium bicarbonate, triethylamine, N,N-diisopropylethylamine, or pyridine, and a solvent such as N-methyl-2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, or 1,2-dimethoxyethane, optionally by heating or optionally by microwave irradiation. Compounds conforming to general formula (a6) are reacted with acids such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid in a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane, methanol, ethanol, 1,2-dimethoxyethane, N,N-dimethylformamide, and N,N-dimethylacetamide, optionally by heating and optionally by microwave irradiation, to obtain compounds conforming to general formula (a7).The compound of general formula (a7) is reacted with a known compound of general formula (a8-1) or a compound prepared by a known method, in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, or acetonitrile, optionally by heating and optionally by microwave irradiation, to obtain the compound of general formula (a8-1a). Alternatively, a compound of general formula (a7) may be transformed into a compound of general formula (a8-2), where X is present, in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, or acetonitrile, optionally by heating or optionally by microwave irradiation. 1The compound of general formula (a8-2a) is reacted with a known compound or a compound prepared by a known method, where is chlorine, to obtain the compound of general formula (a8-2a). Alternatively, the compound of general formula (a7) is reacted with a coupling agent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, optionally in the presence of hydroxybenzotriazole, and optionally with 1-hydroxy-7-azabenzotriazole In the presence of a solvent such as a steroid, optionally in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or 2,6-dimethylpyridine, optionally in the presence of a solvent such as N-methyl-2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, or 1,2-dimethoxyethane, optionally by heating, optionally by microwave irradiation, a compound of general formula (a8-2), wherein X 1 The compound with the general formula (a4-8a) is obtained by reacting it with a known compound or a compound prepared by a known method, where the compound is OH.

[0448] Alternatively, a compound of general formula (a7) may be reacted with a compound of general formula (a8-3a), which is a known compound or a compound prepared by a known method, in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, or acetonitrile, optionally by heating or optionally by microwave irradiation, to obtain a compound of general formula (a8-3a). Scheme 3. [ka]

[0449] Compounds of general formula (a1) are converted in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(O), dichlorobis(triphenylphosphine)palladium(II), palladium carbon, or bis(acetonitrile)dichloropalladium(II), for example, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-disic Rohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl Lu-1,1'-biphenyl, sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine In the presence of organophosphines such as, optionally, in the presence of bases such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, for example, tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,In a solvent such as 2-dimethoxyethane, optionally by heating and optionally by microwave irradiation, a compound of general formula (a10) is reacted with a known compound prepared by a known method, wherein X is selected from the group consisting of iodine, bromine, chlorine, methanesulfonate, and para-tolylsufonate, to obtain a compound of general formula (a10-1). Scheme 4. [ka]

[0450] Compounds of general formula (a1) are coupled in the presence of coupling agents such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, optionally in the presence of hydroxybenzotriazole, optionally in the presence of 1-hydroxy-7-azabenzotriazole, and optionally, for example, sodium carbonate, potassium carbonate, lithium carbonate, and bicarbonate. The compound of general formula (a11) is obtained by reacting a known compound of general formula (a12) or a compound prepared by a known method with a known compound in the presence of a base such as sodium, potassium bicarbonate, lithium bicarbonate, triethylamine, N,N-diisopropylethylamine, or pyridine, with a solvent such as N-methyl-2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, or 1,2-dimethoxyethane, optionally by heating or optionally by microwave irradiation.

[0451] Treatment method In embodiments, the compounds described herein are selective modulators of the serotonin 5-HT7 receptor. In embodiments, the compounds described herein can bind more strongly to the serotonin 5-HT7 receptor compared to other targets (e.g., other serotonin receptors). In embodiments, the compounds described herein can selectively bind to the serotonin 5-HT7 receptor in specific tissues or organs.

[0452] For example, the compounds described herein may selectively bind to serotonin 5-HT7 receptors in the target intestine. Therefore, the compounds described herein may be used to treat or prevent inflammatory bowel disease (IBD) or colitis.

[0453] In other embodiments, the compounds described herein may have properties particularly advantageous for effective therapy (for example, for any of the diseases or symptoms described herein). For example, in the treatment of CNS or psychiatric disorders, the compounds described herein may exhibit advantageously effective blood-brain barrier permeability. Alternatively, in the treatment of non-CNS disorders or non-psychiatric disorders, the compounds described herein may not exhibit high blood-brain barrier permeability (for example, resulting in reduced off-target effects). While not limited to theory, the molecular elements of a compound may be an effective strategy for achieving desired biological targeting.

[0454] Evidence suggests a role for the 5-HT7 receptor in various medical disorders. 5-HT7 receptor activity regulators are thought to have beneficial effects on patients suffering from these disorders.Disorders affected by 5-HT7 dysregulation, where modulation of 5-HT7 receptor activity by therapeutic agents may be a viable therapeutic approach, include circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine (Vanhoenacker, P. et al. Trends in Pharmacological Sciences, 2000, 21, 2, 70-77), neuropathic pain, peripheral pain, allodynia (European Patent Application Publication No. 1875899 (EP1875899)), thermoregulatory disorders, learning disabilities, memory impairment, hippocampal signaling disorders, sleep disorders (International Publication No. 20100197700), attention deficit / hyperactivity disorder (ADHD) (International Publication No. 20100069390), anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, and premenstrual dysphonia. Disorder), seasonal affective disorder, bipolar disorder (International Publication No. 20040229874), inflammatory bowel disease (IBD), colitis (International Publication No. 2012058769, Khan, WI, et al. Journal of Immunology, 2013, 190, 4795-4804), epilepsy, paroxysmal disorder (Epilepsy Research (2007) 75, 39), drug addiction, alcohol addiction (Hauser, S et al. Frontiers in Neuroscience, 2015, 8, 1-9), breast cancer (Gautam, J. Molecular Cancer, 2016, 15, 75, 1-14, Gautam, J. Breast Cancer Research and Treatment, 2017, 161, 29-40), hepatic fibrosis, chronic liver disease (Halici, Z. International Examples include, but are not limited to, Immunopharmacology (2017, 43, 227-235), hepatocellular carcinoma (Bian, ZX Molecular Oncology, 2016, 10, 195-212), small intestinal neuroendocrine tumors (Modlin, IM Cancer Science, 2013, 104, 7, 844-855), and lung injury (Halici, Z. Immunology, 2013, 1271-1283).

[0455] There has long been a need for novel 5-HT7 modulators that would provide therapeutic relief in patients suffering from diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. This invention addresses the need to identify novel 5-HT7 modulators that can treat diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. This invention addresses the need to develop novel therapeutic agents for the treatment and prevention of circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraines, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorders, learning disabilities, memory impairment, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), colitis, epilepsy, paroxysmal disorders, drug addiction, alcohol addiction, breast cancer, hepatic fibrosis, chronic liver disease, hepatocellular carcinoma, small intestinal neuroendocrine tumors, and lung injury.

[0456] The 5-hydroxytryptamine receptor 7 activity regulator of the present invention can treat and prevent diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity, such as circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorders, learning disabilities, memory impairment, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), colitis, epilepsy, seizure disorders, drug addiction, alcohol addiction, breast cancer, hepatic fibrosis, chronic liver disease, hepatocellular carcinoma, small intestinal neuroendocrine tumors, and lung injury. The 5-hydroxytryptamine receptor 7 has been shown to be causally associated with many medical disorders, and therefore, 5-HT7 receptor activity regulators are thought to have beneficial effects on patients suffering from these diseases.Disorders affected by 5-HT7 dysregulation, where modulation of 5-HT7 receptor activity by therapeutic agents may be a viable therapeutic approach, include circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine (Vanhoenacker, P. et al. Trends in Pharmacological Sciences, 2000, 21, 2, 70-77), neuropathic pain, peripheral pain, allodynia (European Patent Application Publication No. 1875899 (EP1875899)), thermoregulatory disorders, learning disabilities, memory impairment, hippocampal signaling disorders, sleep disorders (International Publication No. 20100197700), attention deficit / hyperactivity disorder (ADHD) (International Publication No. 20100069390), anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, and premenstrual dysphonia. Disorders, seasonal affective disorder, bipolar disorder (International Publication No. 20040229874), inflammatory bowel disease (IBD), colitis (International Publication No. 2012058769), epilepsy, paroxysmal disorders (Epilepsy Research (2007) 75, 39), drug addiction, alcohol addiction (Hauser, S et al. Frontiers in Neuroscience, 2015, 8, 1-9), breast cancer (Gautam, J. Molecular Cancer, 2016, 15, 75, 1-14, Gautam, J. Breast Cancer Research and Treatment, 2017, 161, 29-40), hepatic fibrosis, chronic liver disease (Halici, Z. International Immunopharmacology, 2017, 43, 227-235), hepatocellular carcinoma (Bian, ZX Molecular Examples include, but are not limited to, those of small intestinal neuroendocrine tumors (Oncology, 2016, 10, 195-212), small intestinal neuroendocrine tumors (Modlin, IMCancer Science, 2013, 104, 7, 844-855), and lung injuries (Halici, Z. Immunology, 2013, 1271-1283).

[0457] While not intended to be limited to theory, the 5-hydroxytryptamine receptor 7 receptor activity modifiers of the present invention are thought to be able to alleviate, remit, or control diseases associated with dysregulation of 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, thermoregulatory disorders, learning disabilities, memory impairment, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), colitis, epilepsy, paroxysmal disorders, drug addiction, alcohol addiction, breast cancer, hepatic fibrosis, chronic liver disease, hepatocellular carcinoma, small intestinal neuroendocrine tumors, and lung injury.

[0458] In the embodiments, the disorder is depression, schizophrenia, anxiety disorder, or bipolar disorder. In the embodiments, the disorder is depression. In the embodiments, the disorder is schizophrenia. In the embodiments, the disorder is anxiety disorder. In the embodiments, the disorder is bipolar disorder.

[0459] In this embodiment, the disorder is attention-deficit / hyperactivity disorder.

[0460] In this embodiment, the disorder is avoidant personality disorder.

[0461] In this embodiment, the disorder is seasonal affective disorder.

[0462] In this embodiment, the disease is a circadian rhythm disorder or a hippocampal signaling disorder. In this embodiment, the disease is a circadian rhythm disorder. In this embodiment, the disease is a hippocampal signaling disorder.

[0463] In this embodiment, the disease is neurogenic inflammation.

[0464] In the embodiment, the disease is neuropathic pain, peripheral pain, or allodynia. In the embodiment, the disease is neuropathic pain. In the embodiment, the disease is peripheral pain. In the embodiment, the disease is allodynia.

[0465] In this embodiment, the disease is a migraine.

[0466] In this embodiment, the disease is epilepsy or a seizure disorder. In this embodiment, the disease is epilepsy. In this embodiment, the disease is a seizure disorder.

[0467] In this embodiment, the disorder is a learning disability or a memory disorder. In this embodiment, the disorder is a learning disability. In this embodiment, the disorder is a memory disorder.

[0468] In this embodiment, the disease is an eating disorder.

[0469] In this embodiment, the disorder is either drug addiction or alcohol addiction.

[0470] In this embodiment, the disorder is a sleep disorder.

[0471] In the embodiment, the disease is hypertension or peripheral vascular disease. In the embodiment, the disease is hypertension. In the embodiment, the disease is peripheral vascular disease.

[0472] In this embodiment, the disease is a thermoregulatory disorder.

[0473] In this embodiment, the disease is premature ejaculation.

[0474] In the embodiments, the disease is premenstrual syndrome or premenstrual dysphonic disorder. In the embodiments, the disease is premenstrual syndrome. In the embodiments, the disease is premenstrual dysphonic disorder.

[0475] In the embodiment, the disease is inflammatory bowel disease (IBD) or colitis. In the embodiment, the disease is inflammatory bowel disease (IBD). In the embodiment, the disease is colitis.

[0476] In one embodiment, the disease is breast cancer.

[0477] In the embodiment, the disease is hepatic fibrosis, chronic liver injury, or hepatocellular carcinoma. In the embodiment, the disease is hepatic fibrosis. In the embodiment, the disease is chronic liver injury. In the embodiment, the disease is hepatocellular carcinoma.

[0478] In this embodiment, the disease is a small intestinal neuroendocrine tumor.

[0479] In this embodiment, the disease is lung injury.

[0480] In this embodiment, the disease is inflammatory bowel disease (IBD).

[0481] Preparations of 5-HT7 regulatory factors (pharmaceutical compositions) The present invention also relates to compositions or formulations comprising the 5-hydroxytryptamine receptor 7 activity modifiers of the present invention. Generally, the compositions of the present invention comprise an effective amount of one or more compounds of the present disclosure and salts thereof, and one or more excipients, which are effective in providing modulation of 5-hydroxytryptamine receptor 7 activity.

[0482] In this invention, the terms “excipient” and “carrier” are used interchangeably throughout the description of this invention, and are defined herein as “components used in the practice of formulating safe and effective pharmaceutical compositions.”

[0483] The compounder understands that excipients, by their use, first and foremost, help in the safe, stable, and functional delivery of pharmaceuticals, serving not only as part of the overall delivery vehicle but also as a means of effectively facilitating the absorption of the active ingredient by the recipient. Excipients can play a simple, direct role, as inert fillers do, or, as used herein, they can partially act as a pH stabilizer or coating to ensure the safe and reliable delivery of the ingredient to the stomach. The compounder can also take advantage of the fact that the compounds of the present invention have improved cytotoxicity, pharmacokinetic properties, and even improved oral bioavailability.

[0484] This instruction also provides pharmaceutical compositions comprising at least one of the compounds 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, e.g., Remington's Pharmaceutical Sciences, 17 th Preparations may also be made according to acceptable pharmaceutical procedures, such as those described in edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), and the entire disclosure of that document is incorporated herein by reference for all purposes. As used herein, “pharmaceutically acceptable” means a substance that is acceptable for use in pharmaceutical applications from a toxicological standpoint and does not adversely affect the active ingredient. Thus, a pharmaceutically acceptable carrier is a carrier that is compatible with the other components of the formulation and is also bioacceptable. Auxiliary active ingredients may also be incorporated into the pharmaceutical composition.

[0485] The compounds of this instruction can be administered orally or parenterally, either as is or in combination with conventional pharmaceutical carriers. Applicable solid carriers may include one or more substances that can also function as flavoring agents, lubricants, solubilizers, suspending agents, fillers, lubricants, compression aids, binders or tablet disintegrants, or encapsulating materials. The compounds can be formulated in conventional methods, for example, in a manner similar to those used for known 5-hydroxytryptamine receptor 7 activity modulators. Oral formulations containing the compounds disclosed herein may include any conventionally used oral forms, including tablets, capsules, buccal forms, lozenges, and oral liquids, suspensions or solutions. In the case of powders, the carrier may be finely divided solids or a mixture with the finely divided compounds. In the case of tablets, the compounds disclosed herein can be mixed in appropriate ratios with a carrier having the required compression properties and compressed to the desired shape and size. Powders and tablets may contain up to 99% of the compound.

[0486] Capsules may comprise a mixture of one or more compounds disclosed herein with an inert filler and / or diluent, such as pharmaceutically acceptable starch (e.g., corn, potato, or tapioca starch), sugars, artificial sweeteners, powdered cellulose (e.g., crystalline cellulose and microcrystalline cellulose), wheat flour, gelatin, gum, etc.

[0487] Useful tablet formulations can be prepared by conventional compression, wet granulation, or dry granulation methods, and may use pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents, or stabilizers. Examples of these include, but are not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low-melting-point waxes, and ion-exchange resins. Surface modifiers include nonionic and anionic surface modifiers. Typical examples of surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, aluminum magnesium silicate, and triethanolamine. The oral formulations herein can be modified by utilizing standard delayed-release or sustained-release formulations to alter the absorption of the compounds. Oral formulations may also consist of administering the compounds disclosed herein in water or fruit juice, which may include a suitable solubilizer or emulsifier as needed.

[0488] Liquid carriers can be used to prepare solutions, suspensions, emulsions, syrups, and elixirs, and can also be used for inhalation delivery. The compounds of this teaching may be dissolved or suspended in water, organic solvents, or mixtures thereof, or in pharmaceutically acceptable liquid carriers such as pharmaceutically acceptable oils or fats. Liquid carriers may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers, and osmotic pressure modifiers. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (in particular, including the additives described herein, e.g., cellulose derivatives such as carboxymethylcellulose sodium solution), alcohols (including monohydric alcohols and polyhydric alcohols such as glycols) and their derivatives, and oils (e.g., coconut fractionated oil and peanut oil). For parenteral administration, the carrier may be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid-form compositions for parenteral administration. Liquid carriers for pressurized compositions may be halogenated hydrocarbons or other pharmaceutically acceptable sprays.

[0489] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be used, for example, for intramuscular, intraperitoneal, or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be in either liquid or solid form.

[0490] The pharmaceutical composition is preferably in the form of a unit dosage form, such as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such dosage forms, the pharmaceutical composition may be further divided into unit doses containing an appropriate amount of the compound. The unit dosage form may be a packaged composition, such as powders in a sachet, vials, ampoules, pre-filled syringes, or sachets containing liquid. Alternatively, the unit dosage form may be the capsule or tablet itself, or an appropriate number of any composition in packaged form. Such a unit dosage form may contain about 1 mg / kg to about 500 mg / kg of the compound and may be administered in a single dose or in two or more doses. Such doses may be administered by any method useful for introducing the compound into the recipient's bloodstream, such as orally, via implantation, parenterally (including intravenous, intraperitoneal, and subcutaneous injections), rectally, vaginally, and percutaneously.

[0491] When administered for the treatment or suppression of a specific disease state or disorder, it is understood that the effective dosage may vary depending on the specific compound used, the method of administration, the severity of the symptoms being treated, and various physical factors associated with the individual being treated. For therapeutic use, the compounds described in this instruction may be provided to patients already suffering from a disease in an amount sufficient to cure or at least partially improve the symptoms of that disease and its complications. The dosage to be used for the treatment of a particular individual should typically be subjectively determined by the attending physician. Involved variability factors include the specific symptoms and their condition, as well as the patient's size, age, and response pattern.

[0492] In some cases, it may be desirable to directly administer the compounds into the patient's airways using devices such as metered-dose inhalers, respiratory inhalers, multi-dose dry powder inhalers, pumps, compressive-actuated spray dispensers, aerosol dispensers, and aerosol nebulizers, but not limited to these. For administration by intranasal or intrabronchial inhalation, the compounds of this instruction may be formulated into liquid compositions, solid compositions, or aerosol compositions. A liquid composition may, for example, contain one or more compounds of this instruction dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and may be administered, for example, using a pump or a compressive-actuated spray dispenser. The solvent may be, for example, isotonic saline or bacteriostatic water. A solid composition may, for example, be a powder preparation containing one or more compounds of this instruction, which is mixed with lactose or other inactive powders that can be used in the bronchi. The solid composition may also be administered, for example, by an aerosol dispenser, or by a device that breaks or punctures a capsule enclosing the solid composition and delivers the solid composition for inhalation. The aerosol composition may, for example, comprise one or more of the compounds, sprays, surfactants, and cosolvents described herein, and may be administered, for example, using a quantification device. The spray may be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other physiologically and environmentally acceptable spray.

[0493] The compounds described herein may be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or their pharmaceutically acceptable salts, hydrates, or esters can be prepared as aqueous solutions by appropriately mixing them with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared with glycerol, liquid polyethylene glycol, and mixtures thereof in oils. Under normal storage and use conditions, these preparations typically contain preservatives to inhibit microbial growth.

[0494] Pharmaceutical forms suitable for injection may include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions. In some embodiments, the dosage form can be sterile and, due to its viscosity, can flow through a syringe. Preferably, the dosage form is stable under manufacturing and storage conditions and can be protected from contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerin, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0495] The compounds described herein can be administered transdermally, that is, across the body surface and across the inner layers of the body's tubules, including epithelial and mucous membrane tissues. Such administration can be carried out using the compounds described herein, including their pharmaceutically acceptable salts, hydrates, or esters, in the form of lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[0496] Transdermal administration can be carried out using a transdermal patch containing a compound, such as the compounds disclosed herein, and a carrier that may be inert to the compound, harmless to the skin, and capable of delivering the compound into the bloodstream for systemic absorption via the skin. The carrier may take any number of forms, such as creams and ointments, pastes, gels, and occlusive devices. Creams and ointments may be viscous liquids or semi-fluid emulsions of either oil-in-water or water-in-oil type. Pastes consisting of an absorbable powder containing the compound dispersed in petroleum or hydrophilic petroleum may also be preferred. The compound can be released into the bloodstream using various occlusive devices, such as a semipermeable membrane covering a storage portion containing the compound with or without a carrier, or a substrate containing the compound. Other occlusive devices are known in the literature.

[0497] The compounds described herein can be administered rectally or vaginally in the form of conventional suppositories. Suppository formulations can be made from conventional materials, including cocoa butter, with or without the addition of waxes that alter the melting point of the suppository and glycerin. Water-soluble suppository bases, such as polyethylene glycol of various molecular weights, can also be used.

[0498] The compounds described herein can be introduced into host cells in vitro or in vivo using lipid formulations or nanocapsules. Lipid formulations and nanocapsules can be prepared by methods known in the art.

[0499] To enhance the efficacy of the compound described herein, it may be desirable to combine the compound with other agents effective in treating the target disease. For example, other active compounds (i.e., other active ingredients or agents) effective in treating the target disease may be administered together with the compound described herein. Such other agents may be administered simultaneously with or at a different time from the compound disclosed herein.

[0500] The compounds described herein may be useful for treating or suppressing medical conditions or disorders in mammals, such as humans. Therefore, this instruction provides a method for treating or suppressing a medical condition or disorder by administering a pharmaceutical composition containing one or more of the compounds described herein (including their pharmaceutically acceptable salts) in combination with or in association with a pharmaceutically acceptable carrier to a mammal. The compounds described herein may be administered alone, in combination with other therapeutically effective compounds, or in combination with a therapeutic method for treating or suppressing the medical condition or disorder.

[0501] Non-limiting examples of compositions according to the present invention include one or more compounds of the present disclosure and one or more excipients in amounts of about 0.001 mg to about 1000 mg, one or more compounds of the present disclosure and one or more excipients in amounts of about 0.01 mg to about 100 mg, and one or more compounds of the present disclosure and one or more excipients in amounts of about 0.1 mg to about 10 mg.

[0502] Example The embodiment of the present invention is shown by the following non-limiting examples. [Examples]

[0503] Synthesis of 5-HT7 regulators The compounds of the present invention may be prepared by methods known in the art. Exemplary methods are disclosed in International Patent Application PCT / US2017 / 061677 filed November 15, 2017; International Patent Application PCT / US2013 / 071926 filed November 26, 2013; International Patent Application PCT / US2014 / 023400 filed March 11, 2014; International Patent Application PCT / US2015 / 049303 filed September 10, 2015; International Patent Application PCT / US2016 / 031780 filed May 11, 2016; International Patent Application PCT / US2018 / 022581 filed March 15, 2018; and International Patent Application PCT / US2018 / 022574 filed March 15, 2018.

[0504] The examples provided below offer typical methods for preparing exemplary compounds of the present invention. Those skilled in the art will know how to alternatively use suitable reagents, starting materials, and purification methods known to those skilled in the art to prepare the compounds of the present invention. Synthesis and characterization of intermediates [ka]

[0505] Preparation of tert-butyl(R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: 1.5 g, 3.31 mmol, 1 equivalent of tert-butyl(R)-1-oxo-3-(2-(tosyloxy)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate and 1.35 g, 6.95 mmol, 2.1 equivalents of (S)-1-(4-fluorophenyl)-3-methylpiperazine were added to a small vial, and both were then dissolved in acetonitrile (33 mL). Next, K2CO3 (1.14 g, 8.2 mmol, 2.5 equivalents) was added, and the reaction mixture was stirred overnight at 80°C, then cooled to 23°C. The mixture was filtered, washed with acetonitrile, and the filtrate was concentrated under vacuum to obtain the crude product, which was further purified by column chromatography (MeOH / methylene chloride, 0%~10%). LC / MS[M+H]=m / z 476.2 [ka]

[0506] Preparation of tert-butyl(R)-3-(2-(4-(4-fluorophenyl)piperazine-1-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(R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that 1-(4-fluorophenyl)piperazine was used instead of (S)-1-(4-fluorophenyl)-3-methylpiperazine. LC / MS[M+H]=m / z 462.2 [ka]

[0507] Preparation of tert-butyl(R)-3-(2-((R)-4-(4-fluorophenyl)-2-methylpiperazine-1-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(R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that (R)-1-(4-fluorophenyl)-3-methylpiperazine was used instead of (S)-1-(4-fluorophenyl)-3-methylpiperazine. LC / MS[M+H]=m / z 476.2 [ka]

[0508] Preparation of tert-butyl(R)-3-(2-(4-(3-chlorophenyl)piperazine-1-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(R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that 1-(3-chlorophenyl)piperazine was used instead of (S)-1-(4-fluorophenyl)-3-methylpiperazine. LC / MS[M+H]=m / z 478.2 [ka]

[0509] Preparation of (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: 6M HCl in methanol solution was prepared by adding acetyl chloride (1.2 mL) to methanol (3 mL). tert-butyl(R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.127 g, 0.267 mmol, 1.0 equivalent) was dissolved in the prepared 6M methanol-HCl solution (3 mL), stirred at 23°C for 30 minutes, diluted with methanol, and concentrated under vacuum to produce the crude product as diHCl salt. The product was liberated by stirring in methanol with Amberlite IRN-78 base resin for 15 minutes, followed by filtration and concentration under vacuum to obtain the crude product, LC / MS[M+H]=m / z 376.2. [ka]

[0510] Preparation of (R)-3-(2-((R)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: tert-butyl(R) is used instead of tert-butyl(R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate. The title compound was prepared according to the procedure for (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one, except that the salt -3-(2-((R)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one was used. LC / MS[M+H]=m / z 376.2 [ka]

[0511] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: Instead of tert-butyl(R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, use tert-butyl(R The title compound was prepared according to the procedure for (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-one, except that the salt ((R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one was used. LC / MS[M+H]=m / z 362.2 [ka]

[0512] Preparation of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: Instead of tert-butyl(R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, use tert-butyl(R The title compound was prepared according to the procedure for (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one, except that the salt ((R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one was used. LC / MS[M+H]=m / z 378.2 [ka]

[0513] Preparation of tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate: This reaction was carried out under a nitrogen atmosphere in oven-dried glassware. N-(tert-butoxycarbonyl)glycine (13.8 mg, 0.078 mmol, 1.05 equivalents) was added to a small vial and dissolved in dimethylformamide (700 μL). Next, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (31.3 mg, 0.082 mmol, 1.1 equivalents) and N,N-diisopropylethylamine (39 mg, 0.3 mmol, 4 equivalents) were added, and the resulting solution was stirred at 23°C for 15 minutes. In a separate vial, a solution was prepared consisting of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride (33.3 mg, 0.074 mmol, 1.0 equivalent), dimethylformamide (300 μL), and N,N-diisopropylethylamine (17.3 mg, 0.13 mmol, 2.2 equivalents). Both solutions were combined and stirred at 23°C for 30 minutes. Then, the mixture was diluted with methanol (5 mL) and concentrated under vacuum. The resulting residue was suspended in saturated NaHCO3 (5 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum to obtain the crude product, which was further purified by column chromatography (methanol / dichloromethane, 0%~10%). LC / MS[M+H]=m / z 535.3 [ka]

[0514] Preparation of tert-butyl(R)-(2-(3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate: (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride instead of (R)-3-(2-(4 The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that was used. LC / MS[M+H]=m / z 519.3 [ka]

[0515] Preparation of tert-butyl((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxopropan-2-yl)carbamate: (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride instead of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl) The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that tert-butyl(R)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride was used and (tert-butoxycarbonyl)-L-alanine was used instead of N-(tert-butoxycarbonyl)glycine. LC / MS[M+H]=m / z 533.3 [ka]

[0516] Preparation of tert-butyl((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)carbamate: (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride instead of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)- The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that 2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride was used and (S)-2-((tert-butoxycarbonyl)amino)butanoic acid was used instead of N-(tert-butoxycarbonyl)glycine. LC / MS[M+H]=m / z 547.3 [ka]

[0517] Preparation of tert-butyl((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)carbamate: (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride instead of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl) The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that (tert-butoxycarbonyl)-L-valine was used instead of (tert-butoxycarbonyl)glycine. LC / MS[M+H]=m / z 561.3 [ka]

[0518] Preparation of tert-butyl((S)-1-((R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxopropan-2-yl)carbamate: (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methyl The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate was used, except that (tert-butoxycarbonyl)-L-alanine was used instead of N-(tert-butoxycarbonyl)glycine. LC / MS[M+H]=m / z 547.3 [ka]

[0519] Preparation of tert-butyl(R)-(1-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropan-2-yl)carbamate: The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that 2-(boc-amino)isobutyric acid was used instead of N-(tert-butoxycarbonyl)glycine. LC / MS[M+H]=m / z 563.3 [ka]

[0520] Preparation of tert-butyl(R)-(1-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-methyl-1-oxopropan-2-yl)carbamate: (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one instead of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1 The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate was used and 2-(boc-amino)isobutyric acid was used instead of N-(tert-butoxycarbonyl)glycine. LC / MS[M+H]=m / z 547.3 Synthesis and characterization of 5-HT7 regulators [ka]

[0521] Preparation of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride: 6M HCl in methanol solution was prepared by adding acetyl chloride (6 mL) to methanol (15 mL). tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate (0.607 g, 0.119 mmol, 1.0 equivalent) was dissolved in the prepared 6M methanol-HCl solution (13 mL), stirred at 23°C for 45 minutes, diluted with methanol, and concentrated under vacuum to produce the crude product as diHCl salt. LC / MS[M+H]=m / z 435.2 [ka]

[0522] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride: Instead of tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, use tert-butyl(R The title compound was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride. LC / MS[M+H]=m / z 419.2 [ka]

[0523] Preparation of (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide: A solution of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride (31.6 mg, 0.062 mmol, 1 equivalent), dichloromethane (1.5 mL), and triethylamine (28.5 mg, 0.24 mmol, 4 equivalents) was cooled to 0°C, and then acetyl chloride (5.0 mg, 0.062 mmol, 1 equivalent) was added to this solution. The reaction solution was heated to 23°C and stirred for 15 minutes. The reaction mixture was diluted with methanol (approximately 2 mL), concentrated under vacuum, and further purified by column chromatography on a C18 column (ACN / H2O, 0%~100%, containing 0.1% NH4OH). LC / MS[M+H]=m / z 477.2 [ka]

[0524] Preparation of (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide: (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride instead of (R)-3-(2-(4 The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that (4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that (4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide. LC / MS[M+H]=m / z 461.2 [ka]

[0525] Preparation of (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)methanesulfonamide: A solution of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride (431 mg, 0.845 mmol, 1 equivalent), dichloromethane (17 mL), and triethylamine (516 mg, 5.1 mmol, 6 equivalents) was cooled to 0°C, and then methanesulfonyl chloride (117 mg, 1.02 mmol, 1.2 equivalents) was added to this solution. The reaction solution was heated to 23°C and stirred for 15 minutes. The reaction mixture was diluted with methanol (approximately 10 mL), concentrated under vacuum, and further purified by column chromatography on a C18 column (ACN / H2O, 0%~100%, containing 0.1% NH4OH). LC / MS[M+H]=m / z 513.2 [ka]

[0526] Preparation of (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)methanesulfonamide: Instead of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxaspiro[4.5]decane-1-one dihydrochloride, (R)-3-(2-( The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride), except that 4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)methanesulfonamide, except that 4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)methanesulfonamide. LC / MS[M+H]=m / z 497.2 [ka]

[0527] Preparation of (R)-8-(2-amino-2-methylpropanoyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate instead of tert-butyl(R) The title compound was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropan-2-yl)carbamate, except that -(1-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride was used. Furthermore, the product was liberated by stirring in methanol with Amberlite IRN-78 base resin for 15 minutes, followed by filtration and concentration under vacuum to obtain the product. LC / MS[M+H]=m / z 447.2 [ka]

[0528] Preparation of (R)-8-(2-amino-2-methylpropanoyl)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: Instead of tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, use tert-butyl(R) The title compound was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropan-2-yl)carbamate, except that -(1-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride was used. Furthermore, the product was liberated by stirring in methanol with Amberlite IRN-78 base resin for 15 minutes, followed by filtration and concentration under vacuum to obtain the product. LC / MS[M+H]=m / z 463.2 [ka]

[0529] Preparation of (R)-N-(1-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropan-2-yl)acetamide: Instead of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxaspiro[4.5]decane-1-one dihydrochloride, use (R)-8-(2-A The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that mino-2-methylpropanoyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxo-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that mino-2-methylpropanoyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide. LC / MS[M+H]=m / z 488.2 [ka]

[0530] Preparation of (R)-N-(1-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropan-2-yl)acetamide: Instead of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, use (R)-8-(2-A The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that mino-2-methylpropanoyl)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-2-oxo-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that mino-2-methylpropanoyl)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide. LC / MS[M+H]=m / z 504.2 [ka]

[0531] Preparation of (R)-N-(1-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropan-2-yl)pivalamide: Instead of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxaspiro[4.5]decane-1-one dihydrochloride, (R)-8-(2-A The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)pivalamide, except that mino-2-methylpropanoyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)pivalamide. LC / MS[M+H]=m / z 531.3 [ka]

[0532] Preparation of (R)-N-(1-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropan-2-yl)pivalamide: Instead of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxaspiro[4.5]decane-1-one dihydrochloride, (R)-8-(2-A The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)pivalamide, except that mino-2-methylpropanoyl)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-2-oxo-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)pivalamide. LC / MS[M+H]=m / z 547.3 [ka]

[0533] Preparation of (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)pivalamide: This reaction was carried out under a nitrogen atmosphere in oven-dried glassware. Sodium pivalate (21.8 mg, 0.17 mmol, 1.05 equivalents) was added to a small vial and dissolved in dimethylformamide (1.5 mL). Next, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (70 mg, 0.18 mmol, 1.1 equivalents) and N,N-diisopropylethylamine (86.3 mg, 0.67 mmol, 4 equivalents) were added, and the resulting solution was stirred at 23°C for 15 minutes. In a separate vial, a solution was prepared consisting of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride (81.2 mg, 0.16 mmol, 1.0 equivalent), dimethylformamide (400 μL), and N,N-diisopropylethylamine (48 mg, 0.37 mmol, 2.2 equivalents). Both solutions were combined and stirred at 23°C for 30 minutes. The mixture was then diluted with methanol (5 mL) and concentrated under vacuum. The resulting residue was suspended in saturated NaHCO3 (5 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum to obtain the crude product, which was further purified by column chromatography on a C18 column (ACN / H2O, 0%~100%, containing 0.1% NH4OH). LC / MS[M+H]=m / z 503.3 [ka]

[0534] Preparation of (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)pivalamide: Instead of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxaspiro[4.5]decane-1-one dihydrochloride, (R)-3-(2-( The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-1-one dihydrochloride), except that 4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)pivalamide. LC / MS[M+H]=m / z 519.3 [ka]

[0535] Preparation of (R)-8-(dimethylglycyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride instead of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that -8-azaspiro[4.5]decane-1-one was used and N,N-dimethylglycine was used instead of N-(tert-butoxycarbonyl)glycine. Furthermore, the purification method was replaced by column chromatography on a C18 column (ACN / H2O, 0%~100%, containing 0.1% NH4OH). LC / MS[M+H]=m / z 447.3 [ka]

[0536] Preparation of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-(dimethylglycyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, except that N,N-dimethylglycine was used instead of N-(tert-butoxycarbonyl)glycine. Furthermore, the purification method was replaced by column chromatography on a C18 column (ACN / H2O, 0%~100%, containing 0.1% NH4OH). LC / MS[M+H]=m / z 463.3 [ka]

[0537] Preparation of (R)-8-(2-(dimethylamino)-2-methylpropanoyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride instead of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2- The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that oxa-8-azaspiro[4.5]decane-1-one was used and 2-(dimethylamino)-2-methylpropanoic acid was used instead of N-(tert-butoxycarbonyl)glycine. Furthermore, the purification method was replaced by column chromatography on a C18 column (ACN / H2O, 0%~100%, containing 0.1% NH4OH). LC / MS[M+H]=m / z 475.3 [ka]

[0538] Preparation of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-(2-(dimethylamino)-2-methylpropanoyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, except that 2-(dimethylamino)-2-methylpropanoic acid was used instead of N-(tert-butoxycarbonyl)glycine. Furthermore, the purification method was replaced by column chromatography on a C18 column (ACN / H2O, 0%~100%, containing 0.1% NH4OH). LC / MS[M+H]=m / z 491.3 [ka]

[0539] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(2-morpholinoacetyl)-2-oxa-8-azaspiro[4.5]decan-1-one: (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride instead of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2- The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that xa-8-azaspiro[4.5]decane-1-one was used and morpholine-4-ylacetic acid was used instead of N-(tert-butoxycarbonyl)glycine. Furthermore, the purification method was replaced by column chromatography on a C18 column (ACN / H2O, 0%~100%, containing 0.1% NH4OH). LC / MS[M+H]=m / z 489.3 [ka]

[0540] Preparation of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-(2-morpholinoacetyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, except that morpholine-4-ylacetic acid was used instead of N-(tert-butoxycarbonyl)glycine. Furthermore, the purification method was replaced by column chromatography on a C18 column (ACN / H2O, 0%~100%, containing 0.1% NH4OH). LC / MS[M+H]=m / z 505.3 [ka]

[0541] Preparation of N-((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxopropan-2-yl)acetamide: Instead of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, (R)-8 The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that -(L-alanyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxaspiro[4.5]decane-1-one was used. LC / MS[M+H]=m / z 475.2 [ka]

[0542] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-nicotinoyl-2-oxa-8-azaspiro[4.5]decan-1-one: (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride instead of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl) The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)methanesulfonamide, except that (til)-2-oxa-8-azaspiro[4.5]decane-1-one was used and nicotinoyl chloride hydrochloride was used instead of methanesulfonyl chloride. LC / MS[M+H]=m / z 467.2 [ka]

[0543] Preparation of (R)-8-(2-(1H-tetrazole-5-yl)acetyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate: The title compound was prepared according to the procedure for (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(pyridazin-3-carbonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, except that 2H-tetrazole-5-acetic acid was used instead of 3-pyridazinecarboxylic acid. Furthermore, the purification method was replaced by column chromatography on a C18 column (ACN / H2O, 0%~100%, containing 0.1% HCOOH). LC / MS[M+H]=m / z 472.2

[0544] [ka]

[0545] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-(2-(2-oxoxazolidine-3-yl)acetyl)-2-oxa-8-azaspiro[4.5]decan-1-one: (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride instead of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride The title compound was prepared according to the procedure for tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that xa-8-azaspiro[4.5]decane-1-one was used and (2-oxo-1,3-oxazolidine-3-yl)acetic acid was used instead of N-(tert-butoxycarbonyl)glycine. Furthermore, the purification method was replaced by column chromatography on a C18 column (ACN / H2O, 0%~100%, containing 0.1% NH4OH). LC / MS[M+H]=m / z 489.3 [ka]

[0546] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(pyridazin-3-carbonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: This reaction was carried out under a nitrogen atmosphere in oven-dried glassware. 3-pyridazinecarboxylic acid (14.3 mg, 0.115 mmol, 1.9 equivalents) was added to a small vial and dissolved in dimethylacetamide (500 μL). Subsequently, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (55.8 mg, 0.291 mmol, 4.8 equivalents), 1-benzotriazole (39.3 mg, 0.291 mmol, 4.8 equivalents), and N-methylmorpholine (59 mg, 0.584 mmol, 9.6 equivalents) were added, and the resulting solution was stirred at 23°C for 15 minutes. Next, (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one (21.9 mg, 0.0607 mmol, 1 equivalent) was added using dimethylacetamide (150 μL) to assist the transfer. The resulting solution was stirred at 23°C for 30 minutes, then diluted with methanol (5 mL) and concentrated under vacuum. The resulting residue was suspended in saturated NaHCO3 (5 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum to obtain the crude product, which was further purified by column chromatography on a C18 column (ACN / H2O, 0%~100%, containing 0.1% NH4OH). LC / MS[M+H]=m / z 468.2 [ka]

[0547] Preparation of (R)-8-acetyl-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: Instead of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride, (R)-3-(2-((S)-4- The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that (4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that (4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide. LC / MS[M+H]=m / z 418.2 [ka]

[0548] Preparation of N-((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)acetamide: Instead of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, use (R)-8-((S) The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that (-2-aminobutanoyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxo-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that (-2-aminobutanoyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxo-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide. LC / MS[M+H]=m / z 489.2 [ka]

[0549] Preparation of N-((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)acetamide: Instead of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, (R The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that (R)-8-(L-valyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide. LC / MS[M+H]=m / z 502.2 [ka]

[0550] Preparation of methyl(R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride instead of (R)-3-(2-((S)-4-(4-fluorophenyl) The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that (-2-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide was used, except that methyl chloroformate was used instead of acetyl chloride. LC / MS[M+H]=m / z 434.2 [ka]

[0551] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(isoxazole-3-yl)-2-oxa-8-azaspiro[4.5]decan-1-one: This reaction was carried out in oven-dried glassware under a nitrogen atmosphere. To a solution of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one (1.0 g, 2.76 mmol, 1.0 equivalent) and 3-bromoisoxazole (0.614 g, 4.15 mmol, 1.5 equivalents) in anhydrous toluene (10.6 mL), the following were added in this order. Pd2(dba)3 (0.063 g, 5 mol%), BINAP (0.127 g, 7.5 mol%), triethylamine (0.698 g, 6.6 mmol, 2.5 equivalents), and NaOtBu (0.291 g, 3.3 mmol, 1.2 equivalents). The resulting mixture was stirred overnight at 80°C under a stream of N2. The reaction mixture was cooled to room temperature and then filtered through a Celite plug. The recovered filtrate was concentrated under vacuum to obtain a crude residue, which was further purified by column chromatography (dichloromethane / methanol, 0%~10%). LC / MS[M+H]=m / z 429.3 [ka]

[0552] Preparation of methyl(R)-(2-(3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate: (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride instead of (R)-3-(2-(4-(4-fluorophenyl) The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride and methyl chloroformate instead of acetyl chloride. LC / MS[M+H]=m / z 477.2 [ka]

[0553] Preparation of (R)-3,3-diethyl-5-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)dihydrofuran-2(3H)-one: The title compound was prepared following the procedure for tert-butyl(R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-carboxylate, except that (R)-2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate was used instead of tert-butyl(R)-1-oxo-3-(2-(tosyloxy)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate. LC / MS[M+H]=m / z 363.2 [ka]

[0554] Preparation of N-((S)-1-((R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxopropan-2-yl)acetamide: Instead of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, (R)-8 The title compound was prepared according to the procedure for (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxaspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide, except that -(L-alanyl)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxaspiro[4.5]decane-1-one was used. LC / MS[M+H]=m / z 489.2 [ka]

[0555] Preparation of (R)-8-(L-alanyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: Instead of tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, use tert-butyl((S)-1-( The title compound was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxopropan-2-yl)carbamate, except that (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride. Furthermore, the product was liberated by stirring in methanol with Amberlite IRN-78 base resin for 15 minutes, followed by filtration and concentration under vacuum to obtain the product. LC / MS[M+H]=m / z 433.2 [ka]

[0556] Preparation of (R)-8-((S)-2-aminobutanoyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: tert-butyl((S)-butyl((S) The title compound was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)carbamate, except that (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride. The product was further liberated by stirring in methanol with Amberlite IRN-78 base resin for 15 minutes, followed by filtration and concentration under vacuum to obtain the product, LC / MS[M+H]=m / z 447.2. [ka]

[0557] Preparation of (R)-8-(L-valyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: Instead of tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, use tert-butyl((S)-1-((R) The title compound was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)carbamate, except that (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride. Furthermore, the product was liberated by stirring in methanol with Amberlite IRN-78 base resin for 15 minutes, followed by filtration and concentration under vacuum to produce the product, LC / MS[M+H]=m / z 461.2. [ka]

[0558] Preparation of (R)-8-(L-alanyl)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: Instead of tert-butyl(R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, use tert-butyl((S)-1-( The title compound was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxopropan-2-yl)carbamate, except that (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride. The product was then liberated by stirring in methanol with Amberlite IRN-78 base resin for 15 minutes, followed by filtration and concentration under vacuum to obtain the product, LC / MS[M+H]=m / z 447.2.

[0559] Biochemical tests The biological activity of the compounds described herein can be measured according to methods known in the art, including those described in International Patent Application PCT / US19 / 31824, which is incorporated herein by reference in its entirety. Exemplary assays are described herein.

[0560] method 1 Radiolabeled conjugation (IC 50 and K I ) A solution of the compound of this disclosure, which is the test subject, is prepared as a 1 mg / ml stock solution dissolved in assay buffer or DMSO, depending on its solubility. A similar stock solution of chlorpromazine, the reference compound, is also prepared as a positive control. Eleven dilutions (5× assay concentrations) of the compound of this disclosure and chlorpromazine are prepared in assay buffer by serial dilution to obtain the corresponding final assay concentrations in the range of 10 pM to 10 μM.

[0561] The stock solution concentration is 5 nM [ 3 Prepare [H]LSD (lysergic acid diethylamide) with 50 mM Tris-HCl, 10 mM MgCl2, 1 mM EDTA, pH 7.4 (assay buffer). Dispense aliquots (50 μl) of the radioactive ligand into the wells of a 96-well plate containing 100 μl of assay buffer. Add 50 μl aliquots of serially diluted duplicates of the test compound of this disclosure and the chlorpromazine-positive control reference compound.

[0562] Dispense 50 μL of the membrane fraction of cells expressing recombinant 5-HT7 receptor into each well. The membrane is prepared from a stably transfected cell line expressing 5-HT7 receptor cultured on a 10 cm plate. This is done by rinsing the monolayer with PBS, collecting it, resuspending and dissolving it in chilled hypotonic 50 mM Tris-HCl, pH 7.4, centrifugating at 20,000 × g, decanting the supernatant, and storing it at -80°C. Resuspend this membrane preparation in 3 mL of chilled assay buffer, homogenize it by passing it several times through a 26 gauge needle, and then use it in the assay.

[0563] 250 μl of the reaction mixture is incubated at room temperature for 1.5 hours, then collected by rapid filtration using a 96-well Filtermate harvester on a 96-well filter mat treated with 0.3% polyethyleneimine. To reduce nonspecific binding, four rapid washes of 500 μl each are performed with cooled assay buffer. After drying the filter mat, scintillant is added to the filter, and the radioactivity remaining on the filter is counted using a Microbeta scintillation counter. The raw data representing total radioligand binding (dpm) (i.e., specific + nonspecific binding) is plotted as a logarithmic function of the molar concentration of the competitor (i.e., the test compound or reference compound). A nonlinear regression of the normalized (i.e., percentage of radioligand binding compared to binding observed in the absence of the test compound or reference compound) raw data is performed using a built-in 3-parameter logistic model representing the binding of ligand competitors to the radioligand label site, in Prism 4.0 (GraphPad Software). y=bottom+[(top-bottom) / (1+10x-logIC 50 )] Here, bottom is equal to the residual radioactive ligand binding (i.e., nonspecific binding) measured in the presence of a 10 μM reference compound, and top is equal to the total radioactive ligand binding observed in the absence of competitors, i.e., log IC2. 50 (That is, the logarithm of the ligand concentration that reduces radioactive ligand binding by 50%) is estimated from the data, and the Cheng-Prusoff approximation is applied to obtain Ki: Ki=IC 50 / (1+[ligand] / KD) Here, [ligand] is equal to the assay radioactive ligand concentration, and KD is equal to the affinity constant of the radioactive ligand for the target receptor.

[0564] Functional data (K b ) The functional efficacy of the compounds disclosed herein on the 5-HT7 serotonin receptor was measured by a cell-based cAMP enzyme fragment complementation assay using the HitHunter cAMP assay (DiscoveRx). Cells stably expressing the human 5HT7 receptor were seeded at 4000 cells / well in 96-well plates 16–20 hours prior to the assay in growth medium (Ultraculture medium, 2 mM GlutaMax and G418 1 mg / mL). Serial dilutions of the agonist 5-hydroxytryptamine (5-HT) were prepared in a final concentration range of 10 μm to 10 nM. The compounds disclosed herein were prepared in 3-fold serial dilutions to obtain a final concentration range of 10 μM to 0.1 nM. The compounds disclosed herein were tested for agonist activity in the absence of 5-HT and antagonist activity in the presence of 5-HT. For the cAMP assay, the protocol was performed according to the instructions provided by the supplier. In short, the cells are incubated with the compound of this disclosure at 37°C for 30 minutes, and then EC 70 Add 5-HT at a concentration. After another 30 minutes, add cAMP antibody / cell lysate (20 μL / well) and incubate at room temperature for 60 minutes. Add cAMP XS+EA reagent (20 μL / well) and incubate at room temperature for 2 hours. Luminescence was read using an Envision Multilabel plate reader.

[0565] Exemplary K for specific compounds that conform to the general formulas described herein (e.g., conforming to general formulas (I) to (II), such as any of general formulas (A) to (AAA)). i and K b The data is given in Table 1.

[0566] While several embodiments of the present invention have been described, it is evident that the basic embodiments may be modified to provide other embodiments utilizing the compounds, methods, and processes of the present invention. Therefore, it will be understood that the scope of the present invention is defined not by the specific embodiments presented herein as examples, but by the appended claims. The present invention provides, for example, the following items: (Item 1) A compound having a structure that follows general formula (I*),

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Claims

1. A compound having a structure that conforms to general formula (I*), 【Chemistry 427】 This includes the enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof. During the ceremony, R １Ｎ It is selected from the group consisting of imidazole, oxazole, and isoxazole. R ＡＡ Each of them is independent, C １ ~C ７ It is a linear alkyl group, R ２ａ each independently represents a halogen, unsubstituted C １ to C ７ alkyl, C １ to C ７ perhaloalkyl, unsubstituted C １ to C ７ alkoxy, C １ to C ７ perhaloalkoxy, or CN, and a is 0, 1, or 2, and aa is either 1 or 2. compound.

2. A compound having a structure that conforms to general formula (I*), 【Chemical 504】 This includes the enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof. During the ceremony, R １Ｎ teeth, 【Chemical 505】 And in the formula, R ４ａ and R ４ｂ These are hydrogen or C, respectively. １ ~C ７ Alkyl, or R ４ａ and R ４ｂ They optionally, together with the atoms to which they bond, form a ring containing 3 to 7 atoms, optionally containing oxygen. R ５ C １ ~C ７ Alkyl, C ３ ~C ７ Cycloalkyl, C １ ~C ７ Alkoxy, C ３ ~C ７ Cycloalkoxy, C １ ~C ７ Haloalkyl, C ３ ~C ７ Cyclohaloalkyl, C １ ~C ７ Haloalkoxy, C ３ ~C ７ Cyclohaloalkoxy, C ６ ~C １０ Aryl, 5- to 10-membered heteroaryl, CN, NR ８ａ R ８ｂ SO ２ R ８ｃ , NR ８ｄ SO ２ R ８ｅ , NR ８ｉ COOR ８ｊ NHCONR ８ｆ , NR ８ｇ COR ８ｈ , and 【Chemical 506】 Selected from the group consisting of, R ８ａ , R ８ｂ , R ８ｄ , R ８ｇ , and R ８ｉ These are hydrogen and C, respectively. １ ~C ７ Alkyl and C ３ ~C ７ Selected from the group consisting of cycloalkyl groups, or R ８ａ and R ８ｂ They optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR ９ Forming a heterocyle containing 3 to 7 atoms and a group selected from the above, R ８ｃ , R ８ｅ , R ８ｆ , and R ８ｈ These are C １ ~C ７ Alkyl or C ３ ~C ７ It is a cycloalkyl, R ８ｊ C １ ~C ７ Alkyl, C ３ ~C ７ Cycloalkyl, C ６ ~C １０ Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, or R ４ａ and R ８ａ If both exist, or R ４ａ and R ８ｇ If both are present, these groups optionally combine with the atom to which they bond to form a ring containing 4 to 7 atoms. R ９ is hydrogen, C １ ~C ７ Alkyl and C ３ ~C ７ Selected from the group consisting of cycloalkyl groups, R ＡＡ is each independently a C １ -C ７ linear alkyl, R ２ａ is each, independently, halogen, unsubstituted C １ to C ７ alkyl, C １ to C ７ perhaloalkyl, unsubstituted C １ to C ７ alkoxy, C １ to C ７ perhaloalkoxy, or CN, and a is either 1 or 2, aa is 1 or 2, and y １ is 0, 1, or 2. compound.

3. A compound having a structure that conforms to general formula (I*), 【Chemical 507】 This includes the enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof. During the ceremony, R １Ｎ teeth, 【Chemical 508】 And in the formula, R ４ａ and R ４ｂ These are hydrogen or C, respectively. １ ~C ７ Alkyl, or R ４ａ and R ４ｂ They optionally, together with the atoms to which they bond, form a ring containing 3 to 7 atoms, optionally containing oxygen. R ５ C １ ~C ７ Alkyl, C ３ ~C ７ Cycloalkyl, C １ ~C ７ Alkoxy, C ３ ~C ７ Cycloalkoxy, C １ ~C ７ Haloalkyl, C ３ ~C ７ Cyclohaloalkyl, C １ ~C ７ Haloalkoxy, C ３ ~C ７ Cyclohaloalkoxy, C ６ ~C １０ Aryl, 5- to 10-membered heteroaryl, CN, NR ８ａ R ８ｂ SO ２ R ８ｃ , NR ８ｄ SO ２ R ８ｅ , NR ８ｉ COOR ８ｊ NHCONR ８ｆ , NR ８ｇ COR ８ｈ , and 【Chemical 509】 Selected from the group consisting of, R ８ａ , R ８ｂ , R ８ｄ , R ８ｇ , and R ８ｉ These are hydrogen and C, respectively. １ ~C ７ Alkyl and C ３ ~C ７ Selected from the group consisting of cycloalkyl groups, or R ８ａ and R ８ｂ They optionally combine with the atoms they bond to, optionally oxygen, sulfur, and NR ９ Forming a heterocyle containing 3 to 7 atoms and a group selected from the above, R ８ｃ , R ８ｅ , R ８ｆ , and R ８ｈ These are C １ ~C ７ Alkyl or C ３ ~C ７ It is a cycloalkyl, R ８ｊ C １ ~C ７ Alkyl, C ３ ~C ７ Cycloalkyl, C ６ ~C １０ Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, or R ４ａ and R ８ａ If both exist, or R ４ａ and R ８ｇ If both are present, these groups optionally combine with the atom to which they bond to form a ring containing 4 to 7 atoms. R ９ is hydrogen, C １ ~C ７ Alkyl and C ３ ~C ７ Selected from the group consisting of cycloalkyl groups, R ＡＡ Each of them is independent, C １ ~C ７ It is a linear alkyl group, R ２ａ These are, independently, halogen and unsubstituted C. １ ~C ７ Alkyl, C １ ~C ７ Perhaloalkyl, unsubstituted C １ ~C ７ Alkoxy, C １ ~C ７ It is a perhalalkoxy or CN. a is either 1 or 2, aa is 1 or 2, and y １ It is either 1 or 2. compound.

4. R １Ｎ teeth, 【Chemical 440】 The compound according to claim 2.

5. R １Ｎ The compound according to claim 3 is as follows: 【Chemistry 441】 In the formula, R ８ａ and R ８ｂ Each of these is independently either H or unsubstituted C. １ ~C ７ It is alkyl, 【Chemistry 442】 In the formula, R ８ｄ These are independently H or unsubstituted C １ ~C ７ It is alkyl, and also R ８ｅ is unsubstituted C １ ~C ７ It is alkyl, 【Chemistry 443】 In the formula, R ４ａ and R ８ｇ Each of these is independently either H or unsubstituted C. １ ~C ７ It is alkyl, and also R ８ｈ is unsubstituted C １ ~C ７ It is alkyl, 【Chemistry 444】 In the formula, R ８ｈ is unsubstituted C １ ~C ７ It is alkyl, 【Chemistry 445】 In the formula, R ８ａ , R ８ｂ , and R ８ｇ Each of these is independently either H or unsubstituted C. １ ~C ７ It is alkyl, and also R ８ｈ is unsubstituted C １ ~C ７ It is alkyl, 【Chemistry 446】 In the formula, R ８ｊ C １ ~C ７ Alkyl, C ３ ~C ７ Cycloalkyl, C ６ ~C １０ Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, 【Chemistry 447】 In the formula, R ８ａ and R ８ｂ Each of these is independently either H or unsubstituted C. １ ~C ７ It is alkyl, 【Chemistry 448】 In the formula, R ８ｇ These are independently H or unsubstituted C １ ~C ７ It is alkyl, and also R ８ｈ Independently, non-substituted C １ ~C ７ It is alkyl, or 【Chemistry 449】

6. R １Ｎ teeth, 【Chemical 510】 The compound according to claim 3.

7. R １Ｎ teeth, 【Chemical 511】 The compound according to claim 1.

8. A compound having a structure that conforms to the general formula (I**), 【Chemistry 452】 The formula includes the enantiomer, diastereomer, hydrate, solvate, and pharmaceutically acceptable salt thereof, in which, R ａａ and R ｂｂ These are hydrogen and C, respectively. １ ~C ７ Alkyl and C ３ ~C ７ Selected from the group consisting of branched alkyl groups, R ＡＡ Each of them is independent, C １ ~C ７ It is a linear alkyl group, R ２ａ These are, independently, halogen and unsubstituted C. １ ~C ７ Alkyl, C １ ~C ７ Perhaloalkyl, unsubstituted C １ ~C ７ Alkoxy, C １ ~C ７ It is a perhalalkoxy or CN. aa is 1 or 2, and a' is a compound that is 1 or 2.

9. R ａａ and R ｂｂ The compound according to claim 8, wherein each of them is ethyl.

10. The compound according to claim 1, wherein a is 0 or 1.

11. a is 1 or 2, and R ＡＡ The compound according to claim 1, wherein each of them is methyl.

12. R ＡＡ The compound according to claim 2, wherein each of them is methyl.

13. R ＡＡ The compound according to claim 3, wherein each of them is methyl.

14. R ＡＡ The compound according to claim 8, wherein each of them is methyl.

15. R ２ａ The compound according to claim 1, wherein each of them is independently a halogen.

16. R ２ａ The compound according to claim 2, wherein each of them is independently a halogen.

17. R ２ａ The compound according to claim 3, wherein each of them is independently a halogen.

18. R ２ａ The compound according to claim 15, wherein each of them is independently -F or -Cl.

19. R ２ａ The compound according to claim 16, wherein each of them is independently -F or -Cl.

20. R ２ａ The compound according to claim 17, wherein each of them is independently -F or -Cl.

21. The compound according to claim 1, wherein the C5 carbon of the 2-dihydrofuranone has a (R)-configuration.

22. The compound according to claim 2, wherein the C5 carbon of the 2-dihydrofuranone has an (R) configuration.

23. The compound according to claim 3, wherein the C5 carbon of the 2-dihydrofuranone has an (R)-configuration.

24. The compound according to claim 8, wherein the C5 carbon of the 2-dihydrofuranone has an (R)-configuration.

25. The compound according to claim 1, wherein the C5 carbon of the 2-dihydrofuranone has an (S)-configuration.

26. The compound according to claim 2, wherein the C5 carbon of the 2-dihydrofuranone has an (S)-configuration.

27. The compound according to claim 3, wherein the C5 carbon of the 2-dihydrofuranone has an (S)-configuration.

28. The compound according to claim 8, wherein the C5 carbon of the 2-dihydrofuranone has an (S)-configuration.

29. The aforementioned compound, 【Chemical 512】 【Chemical 513】 【Chemical Formula 514】 (This includes its enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts.) A compound according to claim 1, selected from the group consisting of the following.

30. The aforementioned compound, 【Chemical 515】 【Chemical 516】 (This includes its enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts.) A compound according to claim 2, selected from the group consisting of the following.

31. The aforementioned compound, 【Chemical 536】 【Chemical Formula 537】 【Chemical 538】 (This includes its enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts.) A compound according to claim 3, selected from the group consisting of the following. 【Request Item 32】 【Chemistry 539】 (This includes its enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts.) A compound selected from the group consisting of the following.

33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof.

34. The pharmaceutical composition according to claim 33, further comprising at least one pharmaceutically acceptable excipient.

35. A composition comprising a compound according to any one of claims 1 to 32 for treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity.

36. The aforementioned diseases related to dysregulation of the activity of 5-hydroxytryptamine receptor 7 include peripherally selective diseases, neurological disorders, circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular diseases, migraines, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorders, learning disabilities, memory impairment, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, and premenstrual dysphonia. The composition according to claim 35, selected from the group consisting of disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, seizure disorder, drug addiction, alcohol addiction, breast cancer, hepatic fibrosis, chronic liver disease, hepatocellular carcinoma, small intestinal neuroendocrine tumor, and lung injury.

37. The composition according to claim 35, wherein the disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity is inflammatory bowel disease (IBD) or colitis.

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