Novel functionalized lactones as modulators of 5-hydroxytryptamine receptor 7 and methods of use thereof

Abstract

To provide novel functionalized lactones as modulators of 5-hydroxytryptamine receptor 7 and methods of using the same.SOLUTION: Described herein are novel selective modulators of the 5-HT7 receptor. These selective compounds may be useful in the treatment of CNS and non-CNS indications. The compounds described herein can be selective in their targeting of the 5-HT7 receptor compared to other receptors and / or by selectively targeting the 5-HT7 receptor expressed in a particular tissue or organ, whereby there is effective selectivity through a particular partitioning profile of the 5-HT7 modulator.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 934,985, filed November 13, 2019, which is incorporated by reference in its entirety. STATEMENT OF FEDERALLY FUNDED RESEARCH

[0002] This invention is based on the findings of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDD). This invention was made with government support under Grant No. 2R44DK115254-02A1 awarded by the National Institute for Clinical Oncology, the National Institutes of Health ... [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 neuronal synapses. Seven distinct families of serotonin receptors have been identified, and at least 20 subgroups have been cloned based on sequence similarity, signaling binding, and pharmacological properties. The seven 5-HT receptor families are named 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7, and each of these receptors has its own subfamilies or subgroups. The signaling mechanisms of all seven families have been studied, and 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 receptors 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, including cognition, mood, anxiety, attention, appetite, cardiovascular function, vasoconstriction, sleep (ACS Medicinal Chemistry Letters, 2011, 2, 929-932; Physiological Research, 2011, 60, 15-25), inflammatory bowel disease (IBD) and enteritis (WO 2012058769; Khan, WI, et al. Journal of Immunology, 2013, 190, 4795-4804), epilepsy and seizure disorders (Epilepsy Research (2007) 75, 39), and drug and alcohol addiction (Hauser, SR et al. Frontiers in Neuroscience, 2015, 8, 1-9), among others. 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. [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 Summary of the Invention [Means for solving the problem]

[0006] In one aspect, the invention features a compound having a structure according to the following general formula (I*): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: R 1N are imidazoles, oxazoles, isoxazoles, [ka] wherein: R 4a and R 4b are each hydrogen or C1-C7 alkyl, or R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 8a , R 8b , R8d , R 8g , and R 8i are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R AA are each independently a C1-C7 linear alkyl; R 2a are each independently halogen, unsubstituted C1-C7 alkyl, C1-C7 perhaloalkyl, unsubstituted C1-C7 alkoxy, 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 5 is unsubstituted C1-C7 alkyl or unsubstituted C3-C7 cycloalkyl, then a is 1 or 2. In another aspect, the invention features a compound having a structure according to the following general formula (I*-N): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: R 1N-N C6~C 10 Heteroaryl, 5- to 10-membered heteroaryl, [ka] wherein: R 4a and R 4b are each hydrogen or C1-C7 alkyl, or R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8iare each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R AA are each independently a C1-C7 linear alkyl; R 2a are each independently halogen, unsubstituted C1-C7 alkyl, C1-C7 perhaloalkyl, unsubstituted C1-C7 alkoxy, 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 5 is unsubstituted C1-C7 alkyl or unsubstituted C3-C7 cycloalkyl, then a is 1 or 2.

[0007] In embodiments, the compound of general formula (I*) or (I*-N) has a structure according to general formula (I*-1): [ka] Having such a structure, enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are intended to be included.

[0008] In embodiments, the compound of general formula (I*) or (I*-N) has a structure according to general formula (I*-2): [ka] Having such a structure, enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are intended to be included.

[0009] In an embodiment, the compound of general formula (I*-N) has a structure according to general formula (I*-3): [ka] 3. The compound of claim 2 having the structure, including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof.

[0010] In embodiments, R 1N teeth, [ka] In the formula, R 8a and R 8b are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 and R9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; [ka] is.

[0011] In embodiments, R 1N teeth, [ka] In the formula, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; [ka] , where R 8h is an unsubstituted C1-C7 alkyl; or [ka] is.

[0012] In embodiments, R 1N is: [ka] In the formula, R 8a and R 8b are each independently H or unsubstituted C1-C7 alkyl; [ka] In the formula, R 8d are independently H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 4a and R 8gare each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8a , R 8b , and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; [ka] In the formula, R 8a and R 8b are each independently H or unsubstituted C1-C7 alkyl; [ka] In the formula, R 8g are independently H or unsubstituted C1-C7 alkyl, and R 8h are independently unsubstituted C1-C7 alkyl; or [ka]

[0013] In embodiments, R 1N teeth, [ka] is.

[0014] In embodiments, R 1N teeth, [ka] is.

[0015] In another aspect, the invention features a compound having a structure according to the following general formula (I**): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: R aa and R bb are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl; R AA are each independently a C1-C7 linear alkyl; R 2a are each independently halogen, unsubstituted C1-C7 alkyl, C1-C7 perhaloalkyl, unsubstituted C1-C7 alkoxy, C1-C7 perhaloalkoxy, or CN; aa is 0, 1, or 2, and a' is 1 or 2.

[0016] In embodiments, R aa and R bb are ethyl, respectively.

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

[0018] In embodiments, a is 1 or 2 and R AA are each methyl.

[0019] In embodiments, a' is 1 or 2 and R AA are each methyl.

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

[0021] In embodiments, R 2a are each independently a halogen.

[0022] In embodiments, R 2a are each independently -F or -Cl.

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

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

[0025] In another aspect, the invention features a compound having a structure according to the following general formula (I): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: R a and R b are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl, or R a and R b together with the atoms to which they are bonded. to form a carbocyclic ring having 5 to 7 ring atoms, optionally containing a double bond, or R a and R b together with the atoms to which they are attached, are O, S, SO, SO2 and NR 1 forming a ring having 6 to 8 ring atoms containing a moiety selected from the group consisting of A is an N-linked, 5- to 12-membered nitrogen-containing heterocyclyl that is bicyclic or polycyclic and optionally contains additional heteroatoms selected from O, N, and S, and non-aromatic nitrogen-containing heterocyclyls are represented by R2 further comprising a group, R 1 is H, C1-C7 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, a 5- to 6-membered heteroaryl ring, a polar acyl group, or a polar sulfonyl group; R 2 is a 6- to 10-membered aryl, a 5- to 10-membered nitrogen-containing heteroaryl, and [ka] is selected from the group consisting of R 3 is a 6- to 10-membered aryl or a 5- to 10-membered nitrogen-containing heteroaryl, m is 1, 2, or 3, and n is 1, 2, 3, or 4, and wherein R is 1,2,3,4-tetrahydroquinol-1-yl, 1,2,3,4-tetrahydroisoquinol-2-yl, octahydropyrrolo[3,4-c]pyrrol-1-yl, or 2,6-diazaspiro[3.3]heptan-1-yl; a and R b cannot both be methyl, both be ethyl, or both be phenyl, and R a and R b can also not be joined to form an unsubstituted C3-C6 cycloalkyl.

[0026] In embodiments of general formula (I), R a and R b together with the atoms to which they are attached form a ring having 6 to 8 ring atoms, one of which is O, S, SO, SO2, and NR 1 is a moiety selected from the group consisting of:

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

[0028] In embodiments of general formula (I), R a and R b are each methyl or ethyl, or R a and R b are joined to form an unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

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

[0030] In embodiments, the compound of general formula (I) conforms to one of the following structures: [ka]

[0031] In embodiments of general formula (I), R a and R b together with the atoms to which they are attached form a ring having 6 to 8 ring atoms.

[0032] In an embodiment, the compound of general formula (I) has the general formula (IF): [ka] It has a structure according to the following.

[0033] In embodiments, the compound of general formula (I) has a structure according to one of the following general formulas: R: [ka]

[0034] In an embodiment of general formula (I), A is selected from the group consisting of: [ka] During the ceremony, R 2 is phenyl, naphthyl, pyridyl, indolyl, and [ka] is selected from the group consisting of R 3 is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl; R A is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C 1~ C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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, 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 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen; and a is 0, 1, or 2.

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

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

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

[0038] In embodiments of general formula (I), R 1 is H, C1-C7 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, imidazole, oxazole, isoxazole, [ka] is selected from the group consisting of R 4a , R 4b , R 4c , R 6a , R 6b , and R 6c are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; R 6a and R 6b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; R 4d and R 6d are each selected from the group consisting of phenyl, benzyl, pyridyl, —CH2(pyridyl), imidazole, and —CH2(imidazole); R 5 is hydrogen, 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 , SO2R8c , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 7 is hydrogen, 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 , N.R. 8d SO2R 8e , NHCONR 8f is selected from the group consisting of R 8a , R 8b , R 8d , R 8 , and R 8ig are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R 11 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.

[0039] In embodiments of general formula (I), R 1 is selected from the group consisting of: [ka]

[0040] In embodiments of general formula (I), R 1 is selected from the group consisting of: COOR 5 , where R 5 C6~C 10 aryl or 5- to 10-membered heteroaryl; [ka] , where R 8a and R 8b are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 and R 9is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; [ka] In the formula, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; [ka] In the formula, R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; [ka] In the formula, R 8a and R 8b are each independently H or unsubstituted C1-C7 alkyl; [ka] In the formula, R 8d are independently H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8his an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8a , R 8b , and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; [ka] [ka] In the formula, R 8a and R 8b are each independently H or unsubstituted C1-C7 alkyl; [ka] In the formula, R 8g are independently H or unsubstituted C1-C7 alkyl, and R 8h is independently an unsubstituted C1-C7 alkyl, or [ka] is.

[0041] In another aspect, the invention features a compound according to general formula (II): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: A 2 teeth, [ka] and R 2 is a 6- to 10-membered aryl, a 5- to 10-membered nitrogen-containing heteroaryl, and [ka] is selected from the group consisting of R 3 is a 6- to 10-membered aryl or a 5- to 10-membered nitrogen-containing heteroaryl, and R A is C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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, hydroxycarbonyl, 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 5- to 6-membered heterocyclic groups each containing 1 to 4 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 ring, [ka] is selected from the group consisting of R 4a , R 4b , R 4c , R 6a , R 6b , and R 6c are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; R 6a and R 6b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; R 4d and R 6d are each selected from the group consisting of phenyl, benzyl, pyridyl, —CH2(pyridyl), imidazole, and —CH2(imidazole); R 5 is hydrogen, 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 7 is hydrogen, 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 , N.R. 8d SO2R 8e , NHCONR 8fis selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8i are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R 11 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 In the formula, A 2 but [ka] and R 2is phenyl and R 1’ but [ka] and y 2 is 0 and n is 2, R 7 is not methyl, CH2SO2CH3, CH2CN, tetrahydropyranyl, phenyl, 4-substituted phenyl, or 5- to 8-membered heteroaryl.

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

[0043] In an embodiment of general formula (II), R 1’ is: COOR 5 , where R 5 C6~C 10 aryl or 5- to 10-membered heteroaryl; [ka] In the formula, R 8a and R 8b are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 and R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; [ka] In the formula, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10aryl, and 5- to 10-membered heteroaryl; [ka] In the formula, R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; [ka] In the formula, R 8a and R 8b are each independently H or unsubstituted C1-C7 alkyl; [ka] In the formula, R 8d are independently H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8a , R 8b , and R 8gare each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8a and R 8b are each independently H or unsubstituted C1-C7 alkyl; [ka] In the formula, R 8g are independently H or unsubstituted C1-C7 alkyl, and R 8h is independently an unsubstituted C1-C7 alkyl, or [ka] is.

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

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

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

[0047] In embodiments, the compound of general formula (I), (I*), (I**), or (II) is any one of compounds 1-145, including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof. It is one of compounds 1 to 145.

[0048] In another aspect, the invention features a pharmaceutical composition including any compound described herein (e.g., a compound according to general formula (I), (I*), (I**), or (II)), or a pharmaceutically acceptable salt thereof.

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

[0050] In another aspect, the invention features a method for treating a disease associated with dysregulated activity of 5-hydroxytryptamine receptor 7, the method including administering to a subject 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.

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

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

[0053] In embodiments, the disease associated with dysregulated activity of 5-hydroxytryptamine receptor 7 is inflammatory bowel disease (IBD) or enterocolitis. DETAILED DESCRIPTION OF THE INVENTION

[0054] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used to practice or test the present invention, exemplary methods, devices and materials are now described. All technical and patent literature cited herein is incorporated herein by reference in its entirety. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

[0055] Throughout this specification, when a composition is described as having, containing, or comprising particular ingredients, or a method is described as having, containing, or comprising particular method steps, it is intended that the compositions of the present teachings consist essentially of or consist of the recited ingredients, and that the methods of the present teachings also consist essentially of or consist of the recited method steps.

[0056] Throughout this application, when an element or component is described as being included in and / or selected from a recited list of elements or components, the element or component is included in the recited list. It is to be understood that the element or component may be any one of the elements or components, or may be selected from the group consisting of two or more of the listed elements or components.

[0057] As used herein, the use of the singular includes the plural (and vice versa) unless otherwise specified. Furthermore, when the term "about" is used before a quantitative value, the present teachings also include the particular quantitative value itself, unless otherwise specified.

[0058] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0059] As used herein, the term "halogen" is meant to mean chlorine, bromine, fluorine, and iodine.

[0060] As used herein, unless otherwise specified, "alkyl" and / or "aliphatic," whether used alone or as part of a substituent, refer to straight and branched carbon chains having 1 to 20 carbon atoms, or any number within this range, e.g., 1 to 6 carbon atoms or 1 to 4 carbon atoms. A specified number of carbon atoms (e.g., C1-C6) refers independently to the number of carbon atoms within the alkyl moiety or the alkyl portion of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. Alkyl groups can be unsubstituted or substituted, including with any of the 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, and the like. In substituents having multiple alkyl groups, such as (C1-C6 alkyl)2amino, the alkyl groups can be the same or different.

[0061] As used herein, the terms "alkenyl" and "alkynyl," whether used alone or as part of a substituent group, refer to straight 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 and an alkynyl chain has at least one triple bond. Alkenyl and alkynyl groups can 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), buten-4-yl, and the like. Non-limiting examples of substituted alkenyl groups include 2-chloroethenyl (also known as 2-chlorovinyl), 4-hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, 7-hydroxy-7-methyloct-3,5-dien-2-yl, and the like. Non-limiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also known as propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl. Non-limiting examples of substituted alkynyl groups include 5-hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl, 5-hydroxy-5-ethylhept-3-ynyl, and the like.

[0062] As used herein, "cycloalkyl," whether used alone or as part of another group, refers to non-aromatic carbon-containing rings, including cyclized alkyl, alkenyl, and alkynyl groups, e.g., having 3 to 14 ring carbon atoms, preferably 3 to 7 or 3 to 6 ring carbon atoms, or 3 to 4 ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bonds. Cycloalkyl groups include: It may be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, 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 linked to the defined chemical structure. The cycloalkyl ring can 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, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl, bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl. The term "cycloalkyl" also includes carbocyclic rings that are bicyclic hydrocarbon rings, non-limiting examples of which 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] "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens. Haloalkyl groups include perhaloalkyl groups in which all hydrogen atoms on the alkyl group have been replaced with halogens (e.g., -CF3, -CF2CF3). Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogens. 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 alkyl is as defined above. The alkoxy group may be optionally substituted. The term C3-C6 cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). The C3-C6 cyclic alkoxy group may be optionally substituted.

[0065] The term "haloalkoxy" means an -O-haloalkyl group, where haloalkyl is as 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 6-membered, unsaturated, aromatic monocyclic ring or a 6- to 14-membered, unsaturated, aromatic polycyclic ring. Aryl groups can be unsubstituted or substituted. Aryl rings can be, for example, phenyl or naphthyl rings, each optionally substituted with one or more moieties capable of replacing 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. Aryl groups also include, for example, one or more saturated or partially saturated carbocyclic rings, in which one or more carbon atoms of the aromatic ring and / or saturated or partially saturated ring may be substituted (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl). Also included are phenyl or naphthyl rings fused to aryl groups (e.g., indanyl).

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

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

[0069] Non-limiting examples of heterocyclic units having a single ring include diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclic units having 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," whether used alone or as part of another group, is defined herein as one or more rings having 5 to 20 atoms, wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and wherein at least one of the heteroatom-containing rings is aromatic. In heteroaryl groups containing two or more fused rings, the non-heteroatom-containing ring 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 contain 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be unsubstituted or substituted. Non-limiting examples of heteroaryl rings containing a single ring include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing two or more fused 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-methylpyridinyl, and 4-dimethylaminopyridinyl. Examples include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, 1H-benzo-[d]imidazol-2(3H)-onyl, 1H-benzo[d]imidazolyl, and isoquinolinyl.

[0071] One non-limiting example of the heteroaryl group described above is C1-C5 heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom independently selected from nitrogen (N), oxygen (O), or sulfur (S) (preferably 1 to 4 additional ring atoms that are heteroatoms). Examples of C1-C5 heteroaryl include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

[0072] Unless otherwise specified, two substituents taken together form a ring having a specified number of ring atoms (e.g., R 2 and R 3 together with their attached nitrogen (N) form a ring having 3 to 7 ring members, the ring can 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 can be saturated or partially saturated and optionally substituted.

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

[0074] Whenever a term or any of its prefix roots appears in the name of a substituent, that name should be interpreted as including the limitations provided herein. For example, when the term "alkyl" or "aryl" or any of its prefix roots appears in the name of a substituent (e.g., arylalkyl, alkylamino), that name should always be interpreted as including the limitations set forth above for "alkyl" and "aryl."

[0075] The term "substituted" is used throughout this specification. The term "substituted" is defined herein as a moiety, whether acyclic or cyclic, having one or more hydrogen atoms substituted with a substituent or several (e.g., 1 to 10) substituents as defined herein below. The substituents can replace one or two hydrogen atoms of a single moiety at a time. Furthermore, these substituents can replace two hydrogen atoms attached to two adjacent carbons to form the substituent, i.e., a new moiety or unit. For example, substituted units requiring the replacement of a single hydrogen atom include halogen, hydroxyl, etc. Replacements of two hydrogen atoms include carbonyl, oximino, etc. Replacements of two hydrogen atoms on adjacent carbon atoms include epoxy, etc. The term "substituted" is used throughout this specification to indicate that a moiety can have one or more hydrogen atoms replaced by a substituent. When a moiety is described as "substituted," any number of hydrogen atoms can be replaced. For example, difluoromethyl is a substituted C1 alkyl, trifluoromethyl is a substituted C1 alkyl, 4-hydroxyphenyl is a substituted aromatic ring, (N,N-dimethyl-5-amino)octanyl is a substituted C8 alkyl, 3-guanidinopropyl is a substituted C3 alkyl, and 2-carboxypyridinyl is a substituted heteroaryl.

[0076] Variable groups defined herein, such as alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocyclic, and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups are also designated. The following are non-limiting examples of substituents that can replace a hydrogen atom of a moiety: halogen (chlorine (Cl), bromine (Br), fluorine (F), and iodine (I)), —CN, —NO2, oxo (═O), —OR′, —SR′, —N(R′)2, —NR′C(O)R′, —S02R′, —S02OR′, —SON(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-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 alkyl, C3-C6 haloalkyl, C3-C6 alkoxy, C2-C8 alkyl, C2-C8 haloalkyl, C3-C6 alkoxy, C2-C8 alkyl, C2-C8 haloalkyl, C3-C6 haloalkyl, C3-C6 haloalkyl, C3-C6 haloalkyl, C3-C6 haloalkoxy, C2-C8 haloalkyl, C2-C8 haloalkyl, C3-C8 haloalkoxy, C2-C8 haloalkyl, C2-C8 haloalkoxy ... 14 cycloalkyl, aryl, heterocycle, or heteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups 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′, wherein R′ at each occurrence is independently selected from hydrogen, —OR″, —SR″, —C(O)R″, —C(O)OR″, —C(O)N(R″)2, —S02R″, —S(O)2OR″, —N(R″)2, —NR″C(O)R″, C1-C6 alkyl, C1-C6 haloalkyl, or two R' units together with the atom to which they are attached form an optionally substituted carbocyclic or heterocyclic ring having from 3 to 7 ring atoms, wherein R" at each occurrence is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl (e.g., C3-C6 cycloalkyl), aryl, heterocyclic, or heteroaryl; or two R" units together with the atom to which they are attached form an optionally substituted carbocyclic or heterocyclic ring having from 3 to 7 ring atoms, wherein R" at each occurrence is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl (e.g., C3-C6 cycloalkyl), aryl, heterocyclic, or heteroaryl; These preferably form an optionally substituted carbocyclic or heterocyclic ring, and the carbocyclic or heterocyclic ring has 3 to 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'''; e.g., -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3; iv) -C(O)N(R''')2; e.g., -CONH2, -CONHCH3, -CON(CH3)2; v) -N(R''')2; e.g., -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3); vi) Halogens: -F, -Cl, -Br, and -I; vii) -CH e X g where X is a halogen, m is 0-2, and e+g=3; for example, —CH2F, —CHF2, —CF3, —CCl3, or —CBr3; viii) -SO2R'''; e.g., -SO2H; -SO2CH3; -SO2C6H5; ix) C1-C6 linear, branched, or cyclic alkyl; x) cyano; xi) nitro; xii) N(R''')C(O)R''; xiii) oxo(=O); xiv) heterocycles; and xv) heteroaryl; wherein each R'" is independently hydrogen, an optionally substituted C1-C6 straight chain or branched alkyl (e.g., an optionally substituted C1-C4 straight chain or branched alkyl), or an optionally substituted C3-C6 cycloalkyl (e.g., an optionally substituted C3-C4 cycloalkyl), or two R"" units can be joined to form a ring containing from 3 to 7 ring atoms. In certain embodiments, each R'" is independently hydrogen, a C1-C6 straight chain or branched alkyl optionally substituted with halogen or C3-C6 cycloalkyl, or a C3-C6 cycloalkyl.

[0077] At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description also include individual subsets of such group members and ranges. For example, "C 1~6 The term "alkyl" is specifically intended to independently disclose C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0078] As used herein, the terms "compound," "analog," and "composition of matter" equally adequately refer to the 5-hydroxytryptamine receptor 7 modulators described herein, including all enantiomeric forms, diastereomeric forms, salts, etc., and the terms "compound," "analog," and "composition of matter" are used interchangeably throughout this specification.

[0079] The compounds described herein may contain asymmetric atoms (also called chiral centers), and some compounds may contain one or more asymmetric atoms or centers, thereby Optical isomers (enantiomers) and diastereomers can result. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as racemic, resolved, enantiomerically pure R and S stereoisomers, and other mixtures of R and S stereoisomers and pharmaceutically acceptable salts thereof. For example, described herein are certain gamma-butyrolactones containing a substituent at the C5 carbon of the heterocycle. In any compound or general formula embodiment described herein, the C5 carbon has the (S)-configuration. In any compound or general formula embodiment described herein, the C5 carbon has the (R)-configuration. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, including, but not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis- and trans-isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible positional isomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, including, but not limited to, column chromatography, thin layer chromatography, and high performance liquid chromatography.

[0080] Pharmaceutically acceptable salts of the compounds of the present teachings, which may have an acidic moiety, can be formed using organic and inorganic bases. Depending on the number of acidic hydrogens available for deprotonation, both monoanionic and polyanionic salts are considered. Suitable salts formed with bases include metal salts, such as alkali metal salts or alkaline earth metal salts, for example, sodium salts, potassium salts, or magnesium salts; ammonia salts and organic amine salts, such as salts formed with morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-lower alkylamines (e.g., ethyl-tert-butylamine, diethylamine, diisopropylamine, triethylamine, tributylamine, or dimethylpropylamine), or mono-, di-, or tri-hydroxy-lower alkylamines (e.g., monoethanolamine, diethanolamine, or triethanolamine). Specific, non-limiting examples of inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Internal salts can also be formed. Similarly, when the compounds disclosed herein contain a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic acid, propionic acid, lactic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, tartaric acid, succinic acid, dichloroacetic acid, ethenesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, napthalenesulfonic 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] When any variable occurs more than one time in any constituent or in any general formula, its definition on each occurrence is independent of its definition at every other occurrence (e.g., N(R 9 )2, R 9 (each may be the same or different from the other). Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0082] As used herein, the terms "treat" and "treating" and "treatment" mean to partially or completely alleviate, suppress, improve, and / or relieve a condition from which a patient is suspected to suffer.

[0083] As used herein, "therapeutically effective" and "effective dose" refer to a substance or amount that elicits a desired biological activity or effect.

[0084] Except where noted, the terms "subject" or "patient" are used interchangeably and refer to mammals, such as human patients and non-human primates, as well as laboratory and other animals, such as rabbits, rats, and mice. Thus, as used herein, the term "subject" or "patient" refers to any mammalian patient or subject to which a compound of the present invention can be administered. In exemplary embodiments of the present invention, to identify target patients for treatment with the methods of the present invention, recognized screening methods are used to measure risk factors associated with the targeted or suspected disease or condition, or to measure the subject's existing disease or condition status. These screening methods include, for example, conventional workups to measure risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow clinicians to select patients in need of treatment using the methods and compounds of the present invention. Modulators of 5-hydroxytryptamine receptor 7 activity Regulators of 5-HT7 activity

[0085] Described herein are lactone compounds capable of modulating 5-hydroxylase receptor 7 (5-HT7) activity. In particular, the compounds described herein can be selective modulators of the 5-HT7 receptor. In embodiments, selective modulation of 5-HT7 includes selectively modulating 5-HT7 relative to other receptors. In embodiments, selective modulation of 5-HT7 includes, for example, selectively modulating 5-HT7 expressed in specific organs and tissues. Thus, the compounds described herein can be useful in treating various diseases and conditions (e.g., as described herein).

[0086] In embodiments of any of the general formulas described herein, the C1-C7 alkyl is a C1-C7 straight chain alkyl. In embodiments, the C1-C7 alkyl is an unsubstituted C1-C7 straight chain alkyl. In embodiments, the C1-C7 alkyl is a substituted C1-C7 straight chain alkyl (e.g., substituted with one, two, three, or more substituents described herein). In embodiments, the substituted C1-C7 straight chain alkyl is a C1-C7 straight chain perhaloalkyl (e.g., perfluoroalkyl). In embodiments, the substituted C1-C7 straight chain alkyl is OH, OCH3, NH 2、 CN, CH 3、 CF 3、 and includes 1, 2, or 3 substituents selected from the group consisting of CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Still other exemplary embodiments of C1-C7 alkyl are described herein.

[0087] In embodiments of any of the general formulas described herein, the C1-C7 alkyl is a C3-C7 branched alkyl. In embodiments, the branched C3-C7 is an unsubstituted C3-C7 branched alkyl. In embodiments, the C3-C7 branched alkyl is a substituted C3-C7 branched alkyl (e.g., substituted with one, two, three, or more substituents described herein). In embodiments, the substituted C3-C7 branched alkyl is a C3-C7 branched perhaloalkyl (e.g., perfluoroalkyl ...), such as OH, OCH3, NH 2、 CN, CH 3、 CF 3、 and includes 1, 2, or 3 substituents selected from the group consisting of CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Still other exemplary embodiments of C3-C7 branched alkyls are described herein.

[0088] In embodiments of any of the general formulae described herein, cycloalkyl is C3-C7 or C3-C8 cycloalkyl. In embodiments, cycloalkyl is cyclopropyl. In embodiments, the cycloalkyl is cyclobutyl. In embodiments, the cycloalkyl is cyclopentyl. In embodiments, the cycloalkyl is cyclohexyl. In embodiments, the cycloalkyl is unsubstituted cycloalkyl (e.g., unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In embodiments, the cycloalkyl is substituted cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl containing 1, 2, 3, 4, or 5 substituents, including exemplary substituents described herein). In embodiments, the substituted cycloalkyl 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. Still other exemplary embodiments of cycloalkyl are described herein.

[0089] In any of the general formula embodiments described herein, C6-C 10 Aryl is phenyl. In embodiments, the phenyl is unsubstituted phenyl. In embodiments, the phenyl is substituted phenyl (e.g., phenyl containing 1, 2, 3, 4, or 5 substituents, including exemplary substituents described herein). Substituted phenyl groups can be attached through any available carbon of the ring, including those described herein. For example, phenyl can contain a substituent described herein (e.g., OH, OCH, NH) in the para position relative to the point of attachment to a molecule (e.g., a 4-substituted phenyl group). 2、 CN, CH3, CF3, CH2CH 3、 isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH). In embodiments, the phenyl can have a substituent described herein (e.g., OH, OCH, NH) in the meta position relative to the point of attachment to a molecule (e.g., a 3-substituted phenyl group). 2、 CN, CH3, CF3, CH2CH 3、 isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH). In embodiments, the phenyl can have a substituent described herein (e.g., OH, OCH, NH) at the ortho position relative to the point of attachment to a molecule (a 2-substituted phenyl group). 2、 CN, CH3, CF3, CH2CH 3、isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH). The phenyl group can 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, OCH, NH, CN, CH, CF, CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH. Further exemplary embodiments of phenyl are described herein. In 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 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 of the general formula embodiments described herein, C6-C10 Aryl is napthyl. In embodiments, napthyl is unsubstituted napthyl. In embodiments, napthyl is substituted napthyl (e.g., napthyl containing 1, 2, 3, 4, or 5 substituents, including exemplary substituents described herein). In embodiments, naphthyl is attached to the molecule at the C1-position (1-naphthyl). In embodiments, naphthyl is attached to the molecule at the C2-position (2-naphthyl). In embodiments, naphthyl is attached to the molecule at the C3-position (3-naphthyl). In embodiments, naphthyl is attached to the molecule at the C4-position (4-naphthyl). In embodiments, naphthyl is attached to the molecule at the C5-position (5-naphthyl). In embodiments, naphthyl is attached to the molecule at the C6-position (6-naphthyl). In embodiments, naphthyl is attached to the molecule at the C7-position (7-naphthyl). In embodiments, naphthyl is attached to the molecule at the C8-position (8-naphthyl). In embodiments, substituted naphthyl 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. Still other exemplary embodiments of napthyl are described herein.

[0091] In embodiments of any of the general formulae described herein, the 5- to 10-membered heteroaryl is imidazolyl. In embodiments, the imidazolyl is unsubstituted imidazolyl. In embodiments, the imidazolyl is substituted imidazolyl (e.g., imidazolyl containing 1, 2, or 3 substituents, including exemplary substituents described herein). In embodiments, the imidazolyl is an N-linked imidazolyl, attached to the molecule through the N1 position of the imidazolyl (1-imidazolyl). In embodiments, the imidazolyl is a C-linked imdazolyl. In embodiments, the imidazolyl is attached to the molecule through the C2 position of the imidazolyl group (2-imidazolyl). In embodiments, the imidazolyl is attached to the molecule through the C4 position of the imidazolyl group (4-imidazolyl). In embodiments, the imidazolyl is attached to the molecule through the C5 position of the imidazolyl group (5-imidazolyl). In embodiments, the substituted imidazolyl includes one, two, or three substituents selected from the group consisting of OH, OCH, NH, CN, CH, CF, CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH. In embodiments, the substituted imidazolyl is N-methylimidazolyl. Still other exemplary embodiments of imidazolyl are described herein.

[0092] In embodiments of any of the general formulas described herein, the 5- to 10-membered heteroaryl is pyrrolyl. In embodiments, the pyrrolyl is unsubstituted pyrrolyl. In embodiments, the pyrrolyl is an N-linked pyrrolyl, attached to the molecule through the N1 position of the pyrrolyl (1-pyrrolyl). In embodiments, the pyrrolyl is a C-linked pyrrolyl. In embodiments, the pyrrolyl is attached to the molecule through the C2 position of the pyrrolyl (2-pyrrolyl). In embodiments, the pyrrolyl is attached to the molecule through the C3 position of the pyrrolyl (3-pyrrolyl). In embodiments, the pyrrolyl is attached to the molecule through the C4 position of the pyrrolyl (4-pyrrolyl). In embodiments, the pyrrolyl is attached to the molecule through the C5 position of the pyrrolyl (5-pyrrolyl). In embodiments, the pyrrolyl is a substituted pyrrolyl (e.g., a pyrrolyl containing 1, 2, or 3 substituents, including exemplary substituents described herein). In embodiments, a substituted pyrrolyl includes one, two, or three substituents selected from the group consisting of OH, OCH, NH, CN, CH, CF, CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH. Still other exemplary embodiments of pyrrolyl are described herein.

[0093] In an embodiment of any of the general formulas described herein, the 5- to 10-membered heteroaryl is oxazolyl. In an embodiment, the oxazolyl is unsubstituted oxazolyl. In embodiments, the oxazolyl is attached to the molecule through the C2 position of the oxazolyl (2-oxazolyl). In embodiments, the oxazolyl is attached to the molecule through the C3 position of the oxazolyl (3-oxazolyl). In embodiments, the oxazolyl is attached to the molecule through the C4 position of the oxazolyl (4-oxazolyl). In embodiments, the oxazolyl is a substituted oxazolyl (e.g., an oxazolyl containing one or two substituents, including exemplary substituents described herein). In embodiments, the substituted oxazolyl contains 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. Still other exemplary embodiments of imidazolyl are described herein.

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

[0095] In embodiments of any of the general formulas described herein, the 5- to 10-membered heteroaryl is pyridyl. In embodiments, the pyridyl is unsubstituted pyridyl. In embodiments, the pyridyl is attached to the molecule through the C2 position (2-pyridyl). In embodiments, the pyridyl is attached to the molecule through the C3 position (3-pyridyl). In embodiments, the pyridyl is attached to the molecule through the C4 position (4-pyridyl). In embodiments, the pyridyl is attached to the molecule through the C2 position (5-pyridyl). In embodiments, the pyridyl is attached to the molecule through the C2 position (6-pyridyl). In embodiments, the pyridyl is substituted pyridyl (e.g., pyridyl containing 1, 2, 3, or 4 substituents, including exemplary substituents described herein). In embodiments, the substituted pyridyl comprises one, two, or three substituents selected from the group consisting of OH, OCH, NH, CN, CH, CF, CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH. Still other exemplary embodiments of pyridyl are described herein.

[0096] In embodiments of any of the general formulas described herein, the 5- to 10-membered heteroaryl is pyrazinyl. In embodiments, the pyrazinyl is unsubstituted pyrazinyl. In embodiments, the pyrazinyl is 2-pyrazinyl. In embodiments, the pyrazinyl is 3-pyrazinyl. In embodiments, the pyrazinyl is 5-pyrazinyl. In embodiments, the pyrazinyl is 6-pyrazinyl. In embodiments, the pyrazinyl is substituted pyrazinyl (e.g., pyrazinyl containing 1, 2, 3, or 4 substituents, including exemplary substituents described herein). In embodiments, the 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. Still other exemplary embodiments of pyrazinyl are described herein.

[0097] In embodiments of any of the general formulas described herein, the 5- to 10-membered heteroaryl is indolyl. In embodiments, the indolyl is unsubstituted indolyl. In embodiments, the indolyl is N-linked indolyl, attached to the molecule through the N1 position of the indolyl (1-indolyl). In embodiments, the indolyl is C-linked indolyl. In embodiments, the indolyl is attached to the molecule through the C2 position (2-indolyl). In embodiments, the indolyl is attached to the molecule through the C3 position (3-indolyl). In embodiments, the indolyl is attached to the molecule through the C4 position (4-indolyl). In embodiments, the indolyl is attached to the molecule through the C5 position (5-indolyl). In embodiments, the indolyl is attached to the molecule through the C6 position (5-indolyl). In embodiments, the indolyl is attached to the molecule through the C6 position (6-indolyl). In embodiments, the indolyl is attached to the molecule through the C7 position (7-indolyl). In embodiments, the indolyl is a substituted indolyl (e.g., an indolyl containing 1, 2, 3, or 4 substituents, including exemplary substituents described herein). In embodiments, the substituted indolyl 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. Still other exemplary embodiments of indolyl are described herein.

[0098] In any of the general formula embodiments described herein, the substituents can be C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C 1~C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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, 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 5- to 6-membered heterocyclic groups, each containing 1 to 4 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 of the general formula embodiments described herein, the C5 carbon of the 2-dihydrofuranone backbone has the (R)-configuration.

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

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

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

[0103] Compounds of general formula (I*) and (I**) Described herein are compounds of general formula (I*), as well as exemplary embodiments of general formula (I*).

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

[0105] In one aspect, the invention features a compound having a structure according to the following general formula (I*): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: R 1N are imidazoles, oxazoles, isoxazoles, [ka] wherein: R 4a and R 4b are each hydrogen or C1-C7 alkyl, or R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R.8g COR 8h , and [ka] is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8i are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R AA are each independently a C1-C7 linear alkyl; R 2a are each independently selected from halogen, unsubstituted C1-C7 alkyl, C1-C7 perhalogen alkyl, unsubstituted C1-C7 alkoxy, C1-C7 perhaloalkoxy, or CN; a is 0, 1, or 2; aa is 0, 1, or 2, and y 1 is 0, 1, or 2.

[0106] In another aspect, the invention features a compound having a structure according to the following general formula (I*-N): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: R 1N-N C6~C 10 Heteroaryl, 5- to 10-membered heteroaryl, [ka] wherein: R 4a and R 4b are each hydrogen or C1-C7 alkyl, or R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8i are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R AA are each independently a C1-C7 linear alkyl; R 2a are each independently halogen, unsubstituted C1-C7 alkyl, C1-C7 perhaloalkyl, unsubstituted C1-C7 alkoxy, 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, R5 is unsubstituted C1-C7 alkyl or unsubstituted C3-C7 cycloalkyl, then a is 1 or 2.

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

[0108] In embodiments, 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 according to any aspect or embodiment described herein.

[0109] In embodiments, 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 according to any aspect or embodiment described herein.

[0110] In embodiments, the compound according to 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 according to any aspect or embodiment described herein.

[0111] In embodiments, the compound according to general formula (I*-N) has a structure according to the following general formula: [ka] In the formula, R1N-N , R AA , R 2a , aa, and a according to any aspect or embodiment described herein.

[0112] In embodiments, R AA are each independently a C1-C7 straight chain alkyl. AA Each is independently methyl.

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

[0114] In embodiments, R 2a Each is independently halogen. 2a are each independently F. In an embodiment, R 2a are each independently Cl.

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

[0116] In embodiments, R 1N are imidazoles, oxazoles, isoxazoles, [ka] wherein: R 4a and R 4b are each hydrogen or C1-C7 alkyl, or R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; R 5is 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8i are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 4a and R 8a If both exist, or R 4a and R 8gwhen both are present, these groups, optionally together with the atoms to which they are attached, 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 is 0, 1, or 2.

[0117] In embodiments, R 1N-N C6~C 10 Heteroaryl, 5- to 10-membered heteroaryl, [ka] wherein: R 4a and R 4b are each hydrogen or C1-C7 alkyl, or R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 8a , R 8b , R 8d , R 8g, and R 8i are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R 11 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, and y 1 is 0, 1, or 2.

[0118] In embodiments, 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 , N.R.8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] In embodiments, R 5 excludes unsubstituted C1-C7 alkyl. In embodiments, R 5 excludes unsubstituted C3-C7 cycloalkyl.

[0119] In embodiments, R 1N teeth, [ka] In an embodiment, R 1N-N teeth, [ka] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0120] In embodiments, R 1N teeth, [ka] In an embodiment, R 1N-N teeth, [ka] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0121] In embodiments, R 1N-N teeth, [ka] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0122] In an embodiment, y 1 is 0 and R 1 is COR 5 In an embodiment, R 5 is pyridyl. In embodiments, R 5 is pyridazine. In embodiments, R 5 is C1-C7 alkyl. In an embodiment, R 5 is C3-C7 cycloalkyl. In an embodiment, R 5 is C1-C7 haloalkyl. In embodiments, R 5 is C3-C7 cyclohaloalkyl. In embodiments, R 5 is C1-C7 fluoroalkyl. In an embodiment, R 5 is a C3-C7 cyclofluoroalkyl.

[0123] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0124] In embodiments, R 4a is H. In an embodiment, R 4b is H. In an embodiment, R 4a and R 4b are both H. In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

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

[0126] In embodiments, R 11 is hydrogen. In embodiments, R 11 is C1-C7 alkyl (e.g., methyl). In embodiments, R 11 is a C3-C7 cycloalkyl.

[0127] In embodiments, R 1N or R 1N-N teeth, [ka] where: R 4a , R 4b , and y 1 According to any aspect or embodiment described herein, Z a is CH2 or O, Z a If is CH2, p 1 +p 2 is 1, 2, 3, or 4, and Z a If is O, then p 1 +p 2 is 1, 2, 3, or 4, and p 1 and p 2 Both are non-zero.

[0128] In embodiments, R 4a and R 4b are taken together with the atoms to which they are attached to form a carbocyclic ring containing from 3 to 7 atoms. In embodiments, R 4a and R 4b together with the atoms to which they are attached form an oxygen-containing ring containing 3 to 7 atoms.

[0129] In embodiments, R 1N or R 1N-N teeth [ka] where: Z b is CH2 or O, Z b If is CH2, p 1 +p 2 is 1, 2, 3, or 4, Z b If is O, then p 1 +p 2is 1, 2, 3, or 4, and p 1 and p 2 are not both 0, 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , R 8i , and R 9 are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl.

[0130] In embodiments, R 1N or R 1N-N teeth, [ka] where: R 4a , R 4b , and y 1 According to any aspect or embodiment described herein, R 10a and R 10b are independently H, C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, SO2R 8e , COOR 8j ,CONR 8f , and C.O.R. 8h and R 10a and R 10b at least one of is selected from the group consisting of H, C1-C7 straight chain alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl; R 8e , R 8f , and R 8h are each selected from the group consisting of H, C1-C7 straight chain alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl.

[0131] In embodiments, R 1N-N is a urea group (e.g., [ka] )

[0132] In embodiments, R 1N or R 1N-N is a carbamate group (e.g., [ka] In an embodiment, R 1N is an aminoacyl group (e.g., [ka] In an embodiment, R 1N is an alkyl acyl group (e.g., [ka] In an embodiment, R 1N or R 1N-N is aryl. In embodiments, R 1N is a heteroaryl (e.g., [ka] In an embodiment, R 1N is a heteroaryl containing an acyl group (e.g., [ka] )

[0133] In embodiments, R 1N or R 1N-N teeth, [ka] where R 8a and R 8b are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 and R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl.

[0134] In embodiments, R 1N or R 1N-N teeth [ka] where uu is 1 or 2.

[0135] In embodiments, R 1N or R 1N-N teeth, [ka] is.

[0136] In embodiments, R 1N or R 1N-N teeth, [ka] where R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0137] In embodiments, R 1N or R 1N-N teeth, [ka] where R 8h is an unsubstituted C1-C7 alkyl.

[0138] In embodiments, R 1N or R 1N-N teeth, [ka] is.

[0139] In embodiments, R 1N or R 1N-N teeth, [ka] where R 8a and R 8b is each independently H or unsubstituted C1-C7 alkyl.

[0140] In embodiments, R 1N or R 1N-N teeth, [ka] where R 8d are independently H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl.

[0141] In embodiments, R 1N or R 1N-N teeth, [ka] where R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0142] In embodiments, R 1N or R 1N-N teeth, [ka] where R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0143] In embodiments, R 1N or R 1N-N teeth, [ka] where R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0144] In embodiments, R1N or R 1N-N teeth, [ka] where R 8h is an unsubstituted C1-C7 alkyl.

[0145] In embodiments, R 1N or R 1N-N teeth, [ka] where R 8h is an unsubstituted C1-C7 alkyl.

[0146] In embodiments, R 1N or R 1N-N teeth, [ka] where R 8h is an unsubstituted C1-C7 alkyl.

[0147] In embodiments, R 1N or R 1N-N teeth, [ka] is.

[0148] In embodiments, R 1N or R 1N-N teeth, [ka] is.

[0149] In embodiments, R 1N or R 1N-N teeth, [ka] is.

[0150] In embodiments, R 1N or R 1N-N teeth, [ka] where R 8a , R 8b , and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0151] In embodiments, R 1N or R 1N-N teeth, [ka] where R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0152] In embodiments, R 1N or R 1N-N teeth, [ka] is.

[0153] In embodiments, R 1N or R 1N-N teeth, [ka] is.

[0154] In embodiments, R 1N or R 1N-N teeth, [ka] where R 8a and R 8b is each independently H or unsubstituted C1-C7 alkyl.

[0155] In embodiments, R 1N or R 1N-N teeth, [ka] where R 8g are independently H or unsubstituted C1-C7 alkyl, and R 8h is independently unsubstituted C1-C7 alkyl.

[0156] In embodiments, R 1N or R 1N-N teeth, [ka] is.

[0157] In embodiments, R 1N or R 1N-N teeth, [ka] is.

[0158] In embodiments, R 1N or R 1N-N teeth, [ka] is.

[0159] In embodiments, 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 each according to any aspect or embodiment described herein.

[0160] In embodiments, 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 each according to any aspect or embodiment described herein.

[0161] In an embodiment, the compound according to 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 each according to any aspect or embodiment described herein.

[0162] In embodiments, the 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 each according to any aspect or embodiment described herein.

[0163] In another aspect, the invention features a compound having a structure according to the following general formula (I**): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: R aa and R bb are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl; R AA are each independently a C1-C7 linear alkyl; R 2a are each independently halogen, unsubstituted C1-C7 alkyl, C1-C7 perhaloalkyl, unsubstituted C1-C7 alkoxy, C1-C7 perhaloalkoxy, or CN; a' is 1 or 2, and aa is 0, 1, or 2.

[0164] In embodiments, 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 embodiments, 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 embodiments, R AA are each independently a C1-C7 straight chain alkyl. AA Each is independently methyl.

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

[0168] In embodiments, R 2a Each is independently halogen. 2a are each independently F. In an embodiment, R 2a are each independently Cl.

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

[0170] In embodiments, R aa is a C1-C7 straight chain alkyl. aa is a C3-C7 branched alkyl. In embodiments, R aa is ethyl. In embodiments, R bb is a C1-C7 straight chain alkyl. bb is a C3-C7 branched alkyl. In embodiments, R bb is ethyl. In embodiments, R aa and R bb are ethyl, respectively.

[0171] Compounds of general formula (I) In one aspect, the invention features a compound having a structure according to the following general formula (I): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: R a and R b are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl, or R a and R btogether with the atoms to which they are attached form a carbocyclic ring having 5 to 7 ring atoms, optionally containing a double bond, or R a and R b together with the atoms to which they are attached, are O, S, SO, SO2 and NR 1 forming a ring having 6 to 8 ring atoms containing a moiety selected from the group consisting of A is an N-linked, 5- to 12-membered nitrogen-containing heterocyclyl that is bicyclic or polycyclic and optionally contains an additional heteroatom selected from O, N, and S, and a non-aromatic nitrogen-containing heterocyclyl is R 2 further comprising a group, R 1 is H, C1-C7 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, a 5- to 6-membered heteroaryl ring, a polar acyl group, or a polar sulfonyl group; R 2 is a 6- to 10-membered aryl, a 5- to 10-membered nitrogen-containing heteroaryl, and [ka] is selected from the group consisting of R 3 is a 6- to 10-membered aryl or a 5- to 10-membered nitrogen-containing heteroaryl; m is 1, 2, or 3; and n is 1, 2, 3, or 4.

[0172] In embodiments, when A is 1,2,3,4-tetrahydroquinol-1-yl, 1,2,3,4-tetrahydroisoquinol-2-yl, octahydropyrrolo[3,4-c]pyrrol-1-yl, or 2,6-diazaspiro[3.3]heptan-1-yl, R a and R b cannot both be methyl, both be ethyl, or both be phenyl, and R a and R b can also not be joined to form an unsubstituted C3-C6 cycloalkyl.

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

[0174] In embodiments, R a and R b together with the atoms to which they are attached form a ring having 6 to 8 ring atoms, one of which is O, S, SO, SO2, and NR 1 is a moiety selected from the group consisting of:

[0175] In embodiments, 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, and n are according to any aspect or embodiment described herein.

[0176] In embodiments, 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, and n are according to any aspect or embodiment described herein.

[0177] In embodiments, R a and R b are each methyl.

[0178] In embodiments, R aand R b are each ethyl.

[0179] In embodiments, R a and R b are joined to form an unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. a and R b is attached to form an unsubstituted cyclopropyl. a and R b is attached to form an unsubstituted cyclobutyl. a and R b is attached to form an unsubstituted cyclopentyl. a and R b Combine them to create a non Forms a substituted cyclohexyl.

[0180] In embodiments, R a and R b together with the atoms to which they are attached, form NR 1 Forms a ring having 6 to 8 ring atoms, including a moiety

[0181] In embodiments, R a and R b is combined with [ka] This forms a group which is

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0200] In embodiments, A is selected from the group consisting of: [ka] During the ceremony, R 2 is phenyl, naphthyl, pyridyl, indolyl, and [ka] is selected from the group consisting of R 3 is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl; R A is C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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, 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 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen; a is 0, 1, or 2.

[0201] In an embodiment, a is 0.

[0202] In an embodiment, a is 1.

[0203] In an embodiment, a is 2.

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

[0205] In an embodiment, A is [ka] is.

[0206] In an embodiment, A is [ka] is.

[0207] In an embodiment, A is [ka] is.

[0208] In an embodiment, A is [ka] is.

[0209] In an embodiment, A is [ka] is.

[0210] In an embodiment, A is [ka] is.

[0211] In an embodiment, A is [ka] is.

[0212] In an embodiment, A is [ka] is.

[0213] In an embodiment, A is [ka] is.

[0214] In an embodiment, A is [ka] is.

[0215] In an embodiment, A is [ka] is.

[0216] In an embodiment, A is [ka] is.

[0217] In an embodiment, A is [ka] is.

[0218] In an embodiment, A is [ka] is.

[0219] In an embodiment, A is [ka] is.

[0220] In an embodiment, A is [ka] is.

[0221] In an embodiment, A is [ka] is.

[0222] In an embodiment, A is [ka] is.

[0223] In an embodiment, A is [ka] is.

[0224] In an embodiment, A is [ka] is.

[0225] In an embodiment, A is [ka] is.

[0226] In an embodiment, A is [ka] is.

[0227] In an embodiment, A is [ka] is.

[0228] In an embodiment, A is [ka] is.

[0229] In an embodiment, A is [ka] is.

[0230] In an embodiment, A is [ka] is.

[0231] In an embodiment, A is [ka] is.

[0232] In an embodiment, A is [ka] is.

[0233] In an embodiment, A is [ka] is.

[0234] In an embodiment, A is [ka] is.

[0235] In an embodiment, A is [ka] is.

[0236] In an embodiment, A is [ka] is.

[0237] In an embodiment, A is [ka] is.

[0238] In an embodiment, A is [ka] is.

[0239] In an embodiment, A is [ka] is.

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

[0241] In an embodiment, a is 0.

[0242] In an embodiment, a is 1.

[0243] In an embodiment, a is 2.

[0244] In an embodiment, A is [ka] is.

[0245] In an embodiment, A is [ka] is.

[0246] In an embodiment, A is [ka] is.

[0247] In an embodiment, A is [ka] is.

[0248] In embodiments, R 2 is phenyl. In embodiments, R 2 is unsubstituted phenyl. In embodiments, R 2 is phenyl containing at least one halogen substituent (e.g., at least one substituent that is a chloro or fluoro group). 2 is fluorophenyl (e.g., 2-, 3-, or 4-fluorophenyl), difluorophenyl, chlorophenyl (e.g., 2-, 3-, or 4-chlorophenyl), dichlorophenyl, chlorofluorophenyl. 2 is 1, 2, or 3 selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2; and phenyl substituted with one group (eg, one or two groups).

[0249] In embodiments, R 2 is naphthyl. In embodiments, R 2 is unsubstituted naphthyl. In embodiments, R 2is naphthyl containing at least one halogen substituent (e.g., at least one substituent that is a chloro or fluoro group). 2 is naphthyl substituted with one, two, or three groups (e.g., one or two groups) selected from OH, OCH, NH, CN, CH, CF, CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH.

[0250] In embodiments, R 2 is pyridyl. In embodiments, R 2 is 2-pyridyl. In embodiments, R 2 is 3-pyridyl. In embodiments, R 2 is 4-pyridyl. In embodiments, R 2 is unsubstituted pyridyl. In embodiments, R 2 is pyridyl containing at least one halogen substituent (e.g., at least one substituent that is a chloro or fluoro group). 2 is pyridyl substituted with one, two, or three groups (e.g., one or two groups) selected from OH, OCH, NH, CN, CH, CF, CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH.

[0251] In embodiments, R 2 is indolyl. In embodiments, R 2 is an unsubstituted indolyl. In embodiments, R 2 is an indolyl that includes at least one halogen substituent (e.g., at least one substituent that is a chloro or fluoro group). 2 is indolyl substituted with one, two, or three groups (e.g., one or two groups) selected from OH, OCH, NH, CN, CH, CF, CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH.

[0252] In embodiments, R 2 is phenyl, naphthyl, pyridyl or [ka] is.

[0253] In embodiments, R 2 teeth, [ka] wherein aa is 0, 1, 2, or 3, and each R 2a are independently any substituent described herein. In embodiments, R 2a are each independently OH, OCH3, NH2, CN, CH3, and CF 3、 In embodiments, R is selected from CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH. 2a each independently represents C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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, or carboxyl , C1-C7 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 5- or 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen.

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

[0255] In embodiments, R 3 is phenyl. In embodiments, R 3 is unsubstituted phenyl. In embodiments, R 3 is phenyl containing at least one halogen substituent (e.g., at least one substituent that is a chloro or fluoro group). 3 is fluorophenyl (e.g., 2-, 3-, or 4-fluorophenyl), difluorophenyl, chlorophenyl (e.g., 2-, 3-, or 4-chlorophenyl), dichlorophenyl, chlorofluorophenyl. 3 is phenyl substituted with one, two, or three groups (e.g., one or two groups) selected from OH, OCH, NH, CN, CH, CF, CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH.

[0256] In embodiments, R 3 is naphthyl. In embodiments, R 3 is unsubstituted naphthyl. In embodiments, R 3 is naphthyl containing at least one halogen substituent (e.g., at least one substituent that is a chloro or fluoro group). 3 is naphthyl substituted with one, two, or three groups (e.g., one or two groups) selected from OH, OCH, NH, CN, CH, CF, CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH.

[0257] In embodiments, R 3 is pyridyl. In embodiments, R 3is 2-pyridyl. In embodiments, R 3 is 3-pyridyl. In embodiments, R 3 is 4-pyridyl. In embodiments, R 3 is unsubstituted pyridyl. In embodiments, R 3 is pyridyl containing at least one halogen substituent (e.g., at least one substituent that is a chloro or fluoro group). 3 is pyridyl substituted with one, two, or three groups (e.g., one or two groups) selected from OH, OCH, NH, CN, CH, CF, CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH.

[0258] In embodiments, R 3 is indolyl. In embodiments, R 3 is an unsubstituted indolyl. In embodiments, R 3 is an indolyl that includes at least one halogen substituent (e.g., at least one substituent that is a chloro or fluoro group). 3 is indolyl substituted with one, two, or three groups (e.g., one or two groups) selected from OH, OCH, NH, CN, CH, CF, CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH.

[0259] In embodiments, R 3 is phenyl, naphthyl, or pyridyl.

[0260] In embodiments, R 3 teeth, [ka] wherein aa is 0, 1, 2, or 3, and each R 3a are independently any substituent described herein. In embodiments, R 3aare each independently OH, OCH3, NH2, CN, CH3, and CF 3、 In embodiments, R is selected from CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH. 3a are each independently C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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 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 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen.

[0261] In certain embodiments, A is [ka] where R 2ais C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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, R is selected from the group consisting of hydroxycarbonyl, 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 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen; A is C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cycloalkoxy, cycloalkoxy, aryl ... and a is independently 0, 1, or 2.

[0262] In embodiments, R 1 C6~C 10 It is aryl.

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

[0264] In embodiments, R 1 teeth [ka] wherein X is O, NH, or NCH3, aa1 is 0, 1, or 2, and R 1a is C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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, and 5- or 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen.

[0265] In embodiments, R1 teeth, [ka] In embodiments, R 1 teeth, [ka] is.

[0266] In embodiments, R 1 is a polar acyl group (e.g., the partial structure is [ka] In an embodiment, R 1 is a C1-C7 alkyl group, a C3-C7 cycoalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), a C1-C7 haloalkyl group, a C3-C7 cycohaloalkyl group (e.g., cyclohalopropyl, cyclohalobutyl, cyclohalopentyl, or cyclohalohexyl), a 4-6-membered oxygen-containing heterocyclyl (e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or oxazalidonone), or a 4-6-membered nitrogen-containing heterocyclyl (e.g., azetidinyl, pyrrolidinyl, or piperidinyl), which groups contain a substituent that is an amino group (e.g., —NH, monoalkylamino (e.g., —NHMe), or dialkylamino (e.g., —NMe)), an acetamide group (e.g., —NHCOMe or —NMeCOMe), a carbamate group (e.g., —NHCOMe or —NMeCOMe), an alkylsulfonamide group (e.g., —NHSOMe or —NMeSOMe), or a 5- to 10-membered nitrogen-containing heterocyclyl (e.g., tetrazolyl, imidazolyl, N-methylimidazolyl, pyridyl, or pyridazinyl). In embodiments, R 1is an alkyl acyl group (e.g., —C(O)(C1-C7 alkyl) or —C(O)(C3-C7 cycloalkyl)). In embodiments, R 1 excludes unsubstituted alkyl acyl groups (e.g., —C(O)(C1-C7 alkyl) or —C(O)(C3-C7 cycloalkyl)). 1 is a polar sulfonyl group (e.g., a moiety such as, as further described herein, [ka] In an embodiment, R 1 is a C1-C7 alkyl group, a C3-C7 cycoalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), a C1-C7 haloalkyl group, a C3-C7 cycohaloalkyl group (e.g., cyclohalopropyl, cyclohalobutyl, cyclohalopentyl, or cyclohalohexyl), a 4-6 membered oxygen-containing heterocyclyl (e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or oxazalidonone), a sulfonyl moiety containing an amino group (e.g., -NH2, monoalkylamino (e.g., -NHMe), or dialkylamino (e.g., -NMe2)), an acetamide group (e.g., -NHCOMe or NMeCOMe), an alkylsulfonamide group (e.g., -NHSO2Me or -NMeSO2Me), or a 5- to 10-membered nitrogen-containing heterocyclyl (e.g., azetidinyl, pyrrolidinyl, or piperidinyl); terocycyle) (e.g., tetrazolyl, imidazolyl, N-methylimidazolyl, pyridyl, or pyridazinyl).

[0267] In embodiments, R 1 teeth, [ka] is selected from the group consisting of R4a , R 4b , R 4c , R 6a , R 6b , and R 6c are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen, or R 6a and R 6b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; R 4d and R 6d are each 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 7 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 10Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , N.R. 8d SO2R 8e , NHCONR 8f is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8i are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are C1-C7 alkyl or C3- C7 cycloalkyl, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R 11 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.

[0268] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0269] In an embodiment, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

[0270] In embodiments, R 4a is H. In an embodiment, R 4b is H. In an embodiment, R 4a and R 4b are both H. In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0271] In embodiments, R 4a and R 4b are taken together with the atoms to which they are attached to form a carbocyclic ring containing from 3 to 7 atoms. In embodiments, R 4a and R 4b together with the atoms to which they are attached form an oxygen-containing ring containing 3 to 7 atoms.

[0272] In embodiments, R 4c is H. In an embodiment, R 4d is phenyl. In embodiments, R 4d is benzyl. In embodiments, R 4d is pyridyl. In embodiments, R 4d is —CH (pyridyl). In embodiments, R 4d is imidazole. In embodiments, R 4d is —CH (imidazole). In embodiments, y 1 is 0. In an embodiment, y 1is 1. In an embodiment, y 1 is 2.

[0273] In embodiments, R 6a is H. In an embodiment, R 6b is H. In an embodiment, R 6a and R 6b are both H. In an embodiment, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

[0274] In embodiments, R 46 and R 6b are taken together with the atoms to which they are attached to form a carbocyclic ring containing from 3 to 7 atoms. In embodiments, R 6a and R bb together with the atoms to which they are attached form an oxygen-containing ring containing 3 to 7 atoms.

[0275] In embodiments, R 6c is H. In an embodiment, R 6d is phenyl. In embodiments, R 6d is benzyl. In embodiments, R 6d is pyridyl. In embodiments, R 6d is —CH (pyridyl). In embodiments, R 6d is imidazole. In embodiments, R 6d is —CH (imidazole). In embodiments, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

[0276] In embodiments, R 5 is pyridyl. In embodiments, R 5 is pyridazine. In embodiments, R 5 is C1-C7 alkyl. In an embodiment, R 5 is C3-C7 cycloalkyl. In an embodiment, R5 is C1-C7 haloalkyl. In this state, R 5 is C3-C7 cyclohaloalkyl. In embodiments, R 5 is C1-C7 fluoroalkyl. In an embodiment, R 5 is C3-C7 cyclofluoroalkyl. In an embodiment, R 5 is an unsubstituted C1-C7 alkyl. In embodiments, R 5 is a substituted C1-C7 alkyl (e.g., containing an amino substituent such as -NH2, -NHCH3, or -N(CH3)2). 5 is phenyl. In embodiments, R 5 is phenyl. In embodiments, R 5 is unsubstituted phenyl. In embodiments, R 5 is a substituted phenyl. In embodiments, R 5 is NR 8a R 8b In an embodiment, R 5 is SO2R 8c In an embodiment, R 5 is NR 8d SO2R 8e In an embodiment, R 5 is NR 8i COOR 8j In an embodiment, R 5 NHCONR 8f In an embodiment, R 5 is NR 8g COR 8h In an embodiment, R 5 is not unsubstituted C1-C7 alkyl.

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

[0278] In embodiments, R 4d teeth, [ka] wherein R 4bb is H or CH3, a1 is 1 or 2, and each R 4aa are independently any substituent described herein. In embodiments, R 4aa are each independently OH, OCH3, NH2, CN, CH3, and CF 3、 In embodiments, R is selected from CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH. 4aaeach independently represents C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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, 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 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.

[0279] In embodiments, R 6d teeth, [ka] wherein R 6bb is H or CH3, a1 is 1 or 2, and each R 6aa are independently any substituent described herein. In embodiments, R 6aa are each independently OH, OCH3, NH2, CN, CH3, and CF 3、 In embodiments, R is selected from CHCH, isopropyl, F, Cl, Br, morpholino, COH, COCH, and CONH. 6aaare each independently C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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 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 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen.

[0280] In embodiments, R 1 teeth, [ka] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0281] In embodiments, R 1 teeth, [ka] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0282] In embodiments, R 1 teeth, [ka] In an embodiment, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

[0283] In embodiments, R 1 teeth, [ka] In an embodiment, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

[0284] In embodiments, R 1 teeth, [ka] In an embodiment, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

[0285] In embodiments, R 1 teeth, [ka] In an embodiment, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

[0286] In embodiments, R 1 teeth, [ka] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0287] In embodiments, R 1 teeth, [ka] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0288] In an embodiment, y 1 is 0 and R 1 is COR 5 In an embodiment, R 5 is pyridyl. In embodiments, R 5 is pyridazine. In embodiments, R 5 is C1-C7 alkyl. In an embodiment, R 5 is C3-C7 cycloalkyl. In an embodiment, R 5 is C1-C7 haloalkyl. In embodiments, R 5 is C3-C7 cyclohaloalkyl. In embodiments, R 5 is C1-C7 fluoroalkyl. In an embodiment, R 5 is a C3-C7 cyclofluoroalkyl.

[0289] In embodiments, R 11 is hydrogen. In embodiments, R 11 is C1-C7 alkyl (e.g., methyl). In embodiments, R 11 is a C3-C7 cycloalkyl.

[0290] In embodiments, R 1 teeth, [ka] where: R 4a , R 4b , and y 1 According to any aspect or embodiment described herein, Z a is CH2 or O, Z a If is CH2, p 1 +p 2 is 1, 2, 3, or 4, and Z a If is O, then p 1 +p 2 is 1, 2, 3, or 4, and p 1 and p 2 Both are non-zero.

[0291] In embodiments, R 1 teeth, [ka] where: Z b is CH2 or O, Z b If is CH2, p 1 +p 2 is 1, 2, 3, or 4, Z b If is O, then p 1 +p 2 is 1, 2, 3, or 4, and p 1 and p 2 are not both 0, 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 , N.R. 8d SO2R 8e , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 9 are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl.

[0292] In embodiments, R 1 teeth, [ka] where: Z c is CH2 or O, Z c If is CH2, p 1 +p 2 is 1, 2, 3, or 4, Z c If is O, then p 1 +p 2 is 1, 2, 3, or 4, and p 1 and p 2 are not both 0, R 7 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 , SO2R8c , N.R. 8d SO2R 8e , NHCONR 8f is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 9 are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl.

[0293] In embodiments, R 1 teeth, [ka] where: R 10a and R 10b are independently H, C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, SO2R 8e , COOR 8j ,CONR 8f , and C.O.R. 8h and R 10a and R 10b at least one of is selected from the group consisting of H, C1-C7 straight chain alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl; R 8e , R 8f , and R 8hare each selected from the group consisting of H, C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, and R 8j is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0294] In embodiments, R 1 COOR 5 where R 5 C6~C 10 It is aryl or 5- to 10-membered heteroaryl.

[0295] In embodiments, R 1 teeth, [ka] where R 8a and R 8b are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 and R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl.

[0296] In embodiments, R 1 teeth, [ka] where uu is 1 or 2.

[0297] In embodiments, R 1 teeth, [ka] where R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0298] In embodiments, R 1 teeth, [ka] where R 8h is an unsubstituted C1-C7 alkyl.

[0299] In embodiments, R 1 teeth, [ka] where R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0300] In embodiments, R 1 teeth, [ka] where R 8a and R 8b is each independently H or unsubstituted C1-C7 alkyl.

[0301] In embodiments, R 1 teeth, [ka] where R 8d are independently H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl.

[0302] In embodiments, R 1 teeth, [ka] where R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0303] In embodiments, R 1 teeth, [ka] where R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0304] In embodiments, R 1 teeth, [ka] where R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0305] In embodiments, R 1 teeth, [ka] where R 8h is an unsubstituted C1-C7 alkyl.

[0306] In embodiments, R 1 teeth, [ka] where R 8h is an unsubstituted C1-C7 alkyl.

[0307] In embodiments, R 1 teeth, [ka] where R 8h is an unsubstituted C1-C7 alkyl.

[0308] In embodiments, R 1 teeth, [ka] is.

[0309] In embodiments, R 1 teeth, [ka] is.

[0310] In embodiments, R 1 teeth, [ka] is.

[0311] In embodiments, R 1 teeth, [ka] where R 8a , R 8b , and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0312] In embodiments, R 1 teeth, [ka] is.

[0313] In embodiments, R 1 teeth, [ka] is.

[0314] In embodiments, R 1 teeth, [ka] is.

[0315] In embodiments, R 1 teeth, [ka] is.

[0316] In embodiments, R 1 teeth, [ka] is.

[0317] In embodiments, R 1 teeth, [ka] is.

[0318] In embodiments, R 1 teeth, [ka] is.

[0319] In embodiments, R 1 teeth, [ka] where R 8a and R 8b is each independently H or unsubstituted C1-C7 alkyl.

[0320] In embodiments, R 1 teeth, [ka] where R 8g are independently H or unsubstituted C1-C7 alkyl, and R 8h is independently unsubstituted C1-C7 alkyl.

[0321] In embodiments, R 1 teeth, [ka] is.

[0322] Compounds of general formula (II) In one aspect, the invention features a compound having a structure according to the following general formula (II): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: A 2 teeth, [ka] and R 2 is a 6- to 10-membered aryl, a 5- to 10-membered nitrogen-containing heteroaryl, and [ka] is selected from the group consisting of R 3 is a 6- to 10-membered aryl or a 5- to 10-membered nitrogen-containing heteroaryl, and m is 1, 2, or 3; n is 1, 2, 3, or 4; R 1’ C6~C 10 Aryl, five- to six-membered heteroaryl ring, [ka] is selected from the group consisting of R 4a , R 4b , R 4c , R 6a , R 6b , and R 6c are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; R 6a and R 6b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; R 4d and R 6d are each selected from the group consisting of phenyl, benzyl, pyridyl, —CH2(pyridyl), imidazole, and —CH2(imidazole); R 5 is hydrogen, 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 7is hydrogen, 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 , N.R. 8d SO2R 8e , NHCONR 8f is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8i are hydrogen, C1-C7 alkyl and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R11 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R A is C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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, hydroxycarbonyl, 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 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen; a is 0, 1, or 2; y 1 is 0, 1, or 2, and y 2 is 0, 1, or 2.

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

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

[0325] In an embodiment, A 2 teeth, [ka] is.

[0326] In an embodiment, A 2 teeth, [ka] is.

[0327] In an embodiment, A 2 teeth, [ka] is.

[0328] In embodiments, R Ais C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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, In an embodiment, R is selected from the group consisting of hydroxycarbonyl, 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 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen. A is an unsubstituted C1-C7 alkyl. In embodiments, R A is methyl.

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

[0330] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0331] In an embodiment, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

[0332] In embodiments, R 4ais H. In an embodiment, R 4b is H. In an embodiment, R 4a and R 4b are both H. In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0333] In embodiments, R 4a and R 4b are taken together with the atoms to which they are attached to form a carbocyclic ring containing from 3 to 7 atoms. In embodiments, R 4a and R 4b together with the atoms to which they are attached form an oxygen-containing ring containing 3 to 7 atoms.

[0334] In embodiments, R 4c is H. In an embodiment, R 4d is phenyl. In embodiments, R 4d is benzyl. In embodiments, R 4d is pyridyl. In embodiments, R 4d is —CH (pyridyl). In embodiments, R 4d is imidazole. In embodiments, R 4d is —CH (imidazole). In embodiments, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0335] In embodiments, R 6a is H. In an embodiment, R 6b is H. In an embodiment, R 6a and R 6b are both H. In an embodiment, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

[0336] In embodiments, R6a and R 6b are taken together with the atoms to which they are attached to form a carbocyclic ring containing from 3 to 7 atoms. In embodiments, R 6a and R 6b together with the atoms to which they are attached form an oxygen-containing ring containing 3 to 7 atoms.

[0337] In embodiments, R 6c is H. In an embodiment, R 6d is phenyl. In embodiments, R 6d is benzyl. In embodiments, R 6d is pyridyl. In embodiments, R 6d is —CH (pyridyl). In embodiments, R 6d is imidazole. In embodiments, R 6d is —CH (imidazole). In embodiments, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

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

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

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

[0341] In embodiments, R 1’ teeth, [ka] wherein X is O, NH, or NCH3, aa1 is 0, 1, or 2, and R 1ais C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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, and 5- or 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen.

[0342] In embodiments, R 1’ teeth, [ka] In embodiments, R 1 teeth, [ka] is.

[0343] In embodiments, R 1’ teeth, [ka] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0344] In embodiments, R 1’ teeth, [ka] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0345] In embodiments, R 1’ teeth, [ka] In an embodiment, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

[0346] In embodiments, R 1’ teeth, [ka] In an embodiment, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

[0347] In embodiments, R 1’ teeth, [ka] In an embodiment, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y 2 is 2.

[0348] In embodiments, R 1’ teeth, [ka] In an embodiment, y 2 is 0. In an embodiment, y 2 is 1. In an embodiment, y2 is 2.

[0349] In embodiments, R 1’ teeth, [ka] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0350] In embodiments, R 1’ teeth, [ka] In an embodiment, y 1 is 0. In an embodiment, y 1 is 1. In an embodiment, y 1 is 2.

[0351] In an embodiment, y 1 is 0 and R 1’ is COR 5 In an embodiment, R 5 is pyridyl. In embodiments, R 5 is pyridazine. In embodiments, R 5 is C1-C7 alkyl. In an embodiment, R 5 is C3-C7 cycloalkyl. In an embodiment, R 5 is C1-C7 haloalkyl. In embodiments, R 5 is C3-C7 cyclohaloalkyl. In embodiments, R 5 is C1-C7 fluoroalkyl. In an embodiment, R 5 is a C3-C7 cyclofluoroalkyl.

[0352] In embodiments, R 11 is hydrogen. In embodiments, R 11 is C1-C7 alkyl (e.g., methyl). In embodiments, R 11is a C3-C7 cycloalkyl.

[0353] In embodiments, R 1’ teeth, [ka] where: R 4a , R 4b , and y 1 may be prepared according to any aspect or embodiment described herein. stomach, Z a is CH2 or O, Z a If is CH2, p 1 +p 2 is 1, 2, 3, or 4, and Z a If is O, then p 1 +p 2 is 1, 2, 3, or 4, and p 1 and p 2 Both are non-zero.

[0354] In embodiments, R 1’ teeth, [ka] where: Z b is CH2 or O, Z b If is CH2, p 1 +p 2 is 1, 2, 3, or 4, Z b If is O, then p 1 +p 2 is 1, 2, 3, or 4, and p 1 and p 2 are not both 0, R 5is 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 , N.R. 8d SO2R 8e , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 9 are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl.

[0355] In embodiments, R 1’ teeth, [ka] where: Z c is CH2 or O, Z c If is CH2, p 1 +p 2is 1, 2, 3, or 4, Z c If is O, then p 1 +p 2 is 1, 2, 3, or 4, and p 1 and p 2 are not both 0, R 7 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 , N.R. 8d SO2R 8e , NHCONR 8f is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 9 are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl.

[0356] In embodiments, R 1’ teeth, [ka] where: R 10a and R 10bare independently H, C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, SO2R 8e , COOR 8j ,CONR 8f , and C.O.R. 8h and R 10a and R 10b at least one of is selected from the group consisting of H, C1-C7 straight chain alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl; R 8e , R 8f , and R 8h are each selected from the group consisting of H, C1-C7 straight chain alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl; R 8j is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0357] In embodiments, R 1’ COOR 5 where R 5 C6~C 10 It is aryl or 5- to 10-membered heteroaryl.

[0358] In embodiments, R 1’ teeth, [ka] where R 8a and R 8b are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 and R 9is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl.

[0359] In embodiments, R 1’ teeth, [ka] where uu is 1 or 2.

[0360] In embodiments, R 1’ teeth, [ka] where R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0361] In embodiments, R 1’ teeth, [ka] where R 8h is an unsubstituted C1-C7 alkyl.

[0362] In embodiments, R 1’ teeth, [ka] where R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0363] In embodiments, R 1 teeth, [ka] where R 8a and R 8bis each independently H or unsubstituted C1-C7 alkyl.

[0364] In embodiments, R 1’ teeth, [ka] where R 8d are independently H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl.

[0365] In embodiments, R 1’ teeth, [ka] where R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0366] In embodiments, R 1’ teeth, [ka] where R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0367] In embodiments, R 1’ teeth, [ka] where R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0368] In embodiments, R 1’teeth, [ka] where R 8h is an unsubstituted C1-C7 alkyl.

[0369] In embodiments, R 1’ teeth, [ka] where R 8h is an unsubstituted C1-C7 alkyl.

[0370] In embodiments, R 1’ teeth, [ka] where R 8h is an unsubstituted C1-C7 alkyl.

[0371] In embodiments, R 1’ teeth, [ka] is.

[0372] In embodiments, R 1’ teeth, [ka] is.

[0373] In embodiments, R 1’ teeth,

[0374] [ka] is.

[0375] In embodiments, R 1’ teeth, [ka] where R 8a , R 8b , and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0376] In embodiments, R 1’ teeth, [ka] is.

[0377] In embodiments, R 1’ teeth, [ka] is.

[0378] In embodiments, R 1’ teeth, [ka] is.

[0379] In embodiments, R 1’ teeth, [ka] is.

[0380] In embodiments, R 1’ teeth, [ka] is.

[0381] In embodiments, R 1’ teeth, [ka] is.

[0382] In embodiments, R 1’ teeth, [ka] is.

[0383] In embodiments, R 1’ teeth, [ka] where R 8a and R 8b is each independently H or unsubstituted C1-C7 alkyl.

[0384] In embodiments, R 1’ teeth, [ka] where R 8g are independently H or unsubstituted C1-C7 alkyl, and R 8h is independently unsubstituted C1-C7 alkyl.

[0385] In embodiments, R 1’ teeth, [ka] is.

[0386] Compounds of general formulas (A) to (AAA) Still further compounds of general formula (I), (I*), (I**), or (II) include compounds of any one of general formulas (A)-(AAA) described herein, where any variable can be according to any aspect or embodiment described herein.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0400] In embodiments, herein: [ka] Compounds are provided that include units, wherein LA is any group described herein for A. In embodiments, L A teeth, [ka] is selected from the group consisting of:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0432] In embodiments, provided herein are compounds having a structure according to the following general formula (RR): [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 unsubstituted C1-C7 alkyl (e.g., methyl). In embodiments, n is 2. In embodiments, aa is 1 or 2. In embodiments, aa is 1. In embodiments, R 2a are each halogen (e.g., —F and / or —Cl). In embodiments, the C5 carbon of the 2-dihydrofuranone skeleton has the (R)-configuration. In embodiments, the C5 carbon of the 2-dihydrofuranone skeleton has the (S)-configuration.

[0433] In embodiments, provided herein are compounds having a structure according to the following general formula (SS): [ka] In the formula, R 2a , R A , a, aa, and n are as described with respect 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 In embodiments, a is 1. In embodiments, R A teeth , C1-C7 alkyl (e.g., methyl). In embodiments, the C5 carbon of the 2-dihydrofuranone skeleton has the (R)-configuration. In embodiments, the C5 carbon of the 2-dihydrofuranone skeleton has the (S)-configuration. In embodiments, R A The carbon substituted with has the (R)-configuration. A The carbon substituted with has the (S)-configuration.

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

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

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

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

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

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

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

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

[0442] Exemplary Compounds Exemplary compounds according to the general formulas described herein (e.g., according to general formula (I), (I*), (I**), or (II), e.g., any of general formulas (A)-(AAA)) include compounds 1-145 as set forth 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 modulators

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

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

[0445] Additionally, certain exemplary methods are described in Schemes 1-4. In these schemes, the variables within any structure can be according to any aspect or embodiment described herein. Scheme 1. [ka]

[0446] The compound of general formula (a1) can be 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 a hydroxybenzotriazole, optionally in the presence of 1-hydroxy-7-azabenzotriazole, and optionally in the presence of a coupling agent such as sodium carbonate, potassium carbonate, lithium carbonate, bicarbonate, In the presence of a base such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, N,N-diisopropylethylamine, or pyridine, 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 with heating and optionally with microwave irradiation, a compound of general formula (a2) is obtained by reacting the compound of general formula (a2) with a known compound of general formula (a5) or a compound prepared by a known method. The compound according to general formula (a2) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. in a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane, methanol, ethanol, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, etc., optionally with heating, optionally with microwave irradiation, to give a compound of general formula (a3). The compound of general formula (a3) ​​is reacted 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 with heating. Alternatively, the compound of general formula (a3) ​​can be reacted with a known compound of general formula (a4-1) or a compound prepared by a known method, optionally by microwave irradiation, to give a compound of general formula (a4-1a). Alternatively, the compound of general formula (a3) ​​can be reacted with a known compound of general formula (a4-1a), optionally by microwave irradiation, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, optionally by heating, to give a compound of general formula (a4-2), wherein X 1 is chlorine to give a compound of general formula (a4-2a). Alternatively, the compound of general formula (a3) ​​can be reacted with a known compound or a compound prepared by a known method, 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 a hydroxybenzotriazole, and optionally with 1-hydroxy-7-azabenzotriazoline. in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and 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, 1,2-dimethoxyethane, and optionally by heating and optionally by microwave irradiation, to give a compound of general formula (a4-2), wherein X 1 is OH, to give a compound of general formula (a4-2a).

[0447] Alternatively, a compound of general formula (a3) ​​can be reacted with a compound of general formula (a4-3), wherein X is selected from the group consisting of iodine, bromine, chlorine, methanesulfonate, and para-tolylsulfonate, 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 with heating and optionally with microwave irradiation, to obtain a compound of general formula (a4-3a). Scheme 2. [ka] The compound of general formula (a1) can be reacted with a hydroxybenzotriazole in the presence of a coupling agent such as, for example, 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 a hydroxybenzotriazole, optionally in the presence of 1-hydroxy-7-azabenzotriazole, optionally with a hydroxybenzotriazole such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, bicarbonate, In the presence of a base such as sodium, potassium bicarbonate, lithium bicarbonate, triethylamine, N,N-diisopropylethylamine, pyridine, and the like, 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, 1,2-dimethoxyethane, and the like, optionally with heating and optionally with microwave irradiation, a compound of general formula (a6) is obtained by reacting with a known compound of general formula (a9) or a compound prepared by a known method. A compound according to general formula (a6) is reacted with an acid 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 with heating and / or microwave irradiation, to give a compound of general formula (a7). A 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 a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, or N,N-dimethylacetamide, optionally with heating and / or microwave irradiation, in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine, optionally with heating and / or microwave irradiation, to give a compound of general formula (a8-1a). Alternatively, the compound of general formula (a7) can be converted into a compound of general formula (a8-2), wherein X is a group represented by the formula (a8-3), 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 with heating and optionally with microwave irradiation. 1 is chlorine to give a compound of general formula (a8-2a). Alternatively, the compound of general formula (a7) can be reacted with a known compound or a compound prepared by a known method, 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 a hydroxybenzotriazole, and optionally with 1-hydroxy-7-azabenzotriazoline. in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and 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, 1,2-dimethoxyethane, and optionally by heating and optionally by microwave irradiation, to give a compound of general formula (a8-2), wherein X 1 is OH, to give a compound of general formula (a4-8a).

[0448] Alternatively, a compound of general formula (a7) can be reacted with a compound of general formula (a8-3), where X is selected from the group consisting of iodine, bromine, chlorine, methanesulfonate, and para-tolylsulfonate, 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 with heating and optionally with microwave irradiation, to obtain a compound of general formula (a8-3a). Scheme 3. [ka]

[0449] The compound of general formula (a1) can be reacted in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, or bis(acetonitrile)dichloropalladium(II) to produce, for example, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropanol, 2'-(di-tert-butylphosphino)-N,N-dimethyl-(1,1'-biphenyl)-2-amine, optionally in the presence of an organophosphine such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, hydroxide In the presence of a base such as sodium, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, or 2,6-dimethylpyridine, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, or 1,2-dimethoxyethane, optionally with heating and optionally with microwave irradiation, a compound of general formula (a10) in which X is selected from the group consisting of iodine, bromine, chlorine, methanesulfonate, and para-tolylsufonate is reacted with a known compound prepared by a known method to obtain a compound of general formula (a10-1). Scheme 4. [ka]

[0450] The compound of general formula (a1) can be reacted with a hydroxybenzotriazole 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 a hydroxybenzotriazole, optionally in the presence of 1-hydroxy-7-azabenzotriazole, optionally in the presence of a hydroxybenzotriazole such as sodium carbonate, potassium carbonate, lithium carbonate, bicarbonate, or the like. In the presence of a base such as sodium, potassium bicarbonate, lithium bicarbonate, triethylamine, N,N-diisopropylethylamine, or pyridine, 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 with heating and optionally with microwave irradiation, a compound of general formula (a11) is obtained by reacting with a known compound of general formula (a12) or a compound prepared by a known method.

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

[0452] For example, the compounds described herein can selectively bind serotonin 5-HT7 receptors in the intestine of a subject.Therefore, the compounds described herein can be used to treat or prevent inflammatory bowel disease (IBD) or intestinal inflammation.

[0453] In other embodiments, the compounds described herein may have particularly advantageous properties for effective therapy (e.g., of any of the diseases or conditions described herein). For example, in the treatment of CNS or psychiatric disorders, the compounds described herein may advantageously exhibit effective blood-brain barrier permeability. Alternatively, in the treatment of non-CNS or non-psychiatric disorders, the compounds described herein will not have high blood-brain barrier permeability (e.g., will have reduced off-target effects). Without being bound by theory, the molecular elements of the compounds may be an effective strategy for achieving desired biological targeting.

[0454] Evidence suggests a role for the 5-HT7 receptor in a variety of medical disorders, and modulators of 5-HT7 receptor activity are thought to have beneficial effects on patients suffering from these disorders. Disorders in which 5-HT7 dysregulation is impacted and in which modulation of 5-HT7 receptor activity by therapeutic agents may be a viable approach for therapeutic relief 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 disorders, hippocampal signaling disorders, sleep disorders (WO20100197700), attention deficit / hyperactivity disorder (ADHD) (WO20100069390), anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, and premenstrual dysphonia. disorder), seasonal affective disorder, bipolar disorder (WO 20040229874), inflammatory bowel disease (IBD), enteritis (WO 2012058769, Khan, WI, et al. Journal of Immunology, 2013, 190, 4795-4804), epilepsy, seizure disorders (Epilepsy Research (2007) 75, 39), drug addiction, alcohol addiction (Hauser, SR 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), liver fibrosis, chronic liver injury (Halici, Z. International Immunopharmacology, 2017, 43, 227-235), hepatocellular carcinoma (Bian, Z. Molecular Oncology, 2016, 10, 195-212), small intestinal neuroendocrine tumors (Modlin, I. M. 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 will provide therapeutic relief to patients suffering from disorders associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. The present invention addresses the need to identify novel 5-HT7 modulators that can treat disorders associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. The present invention relates to a therapeutic approach for treating disorders associated with dysregulation of 5-hydroxytryptamine receptor 7 activity, including circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorders, learning disabilities, memory disorders, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphonia, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, and seizures. The present invention addresses the need to develop novel therapeutic agents for the treatment and prevention of epilepsy, seizure disorders, drug addiction, alcohol addiction, breast cancer, liver fibrosis, chronic liver damage, hepatocellular carcinoma, small intestinal neuroendocrine tumors, and lung injury.

[0456] The 5-hydroxytryptamine receptor 7 activity modulators 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 disorders, hippocampal signal transduction 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), enteritis, epilepsy, seizure disorders, drug addiction, alcohol addiction, breast cancer, liver fibrosis, chronic liver damage, 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 modulators may have beneficial effects on patients suffering from these diseases.Disorders in which 5-HT7 dysregulation is impacted and in which modulation of 5-HT7 receptor activity by therapeutic agents may be a viable approach for therapeutic relief 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 disorders, hippocampal signaling disorders, sleep disorders (WO20100197700), attention deficit / hyperactivity disorder (ADHD) (WO20100069390), anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, and premenstrual dysphonia. disorder), seasonal affective disorder, bipolar disorder (WO 20040229874), inflammatory bowel disease (IBD), enteritis (WO 2012058769), epilepsy, seizure disorders (Epilepsy Research (2007) 75, 39), drug addiction, alcohol addiction (Hauser, SR 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), liver fibrosis, chronic liver damage (Halici, Z. International Immunopharmacology, 2017, 43, 227-235), hepatocellular carcinoma (Bian, ZX Molecular Oncology, 2016, 10, 195-212), small intestinal neuroendocrine tumors (Modlin, I. M. Cancer Science, 2013, 104, 7, 844-855), and lung injury (Halici, Z. Immunology, 2013, 1271-1283).

[0457] Without wishing to be limited by theory, it is believed that the 5-hydroxytryptamine receptor 7 receptor activity modulators of the present invention can alleviate, ameliorate, or control diseases associated with dysregulated 5-hydroxytryptamine receptor 7 activity, including, but not limited to, circadian rhythm disorders, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorders, learning disorders, memory disorders, hippocampal signaling disorders, sleep disorders, attention-deficit / hyperactivity disorder, anxiety disorders, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphonia, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, seizure disorders, drug addiction, alcohol addiction, breast cancer, liver fibrosis, chronic liver damage, hepatocellular carcinoma, small intestinal neuroendocrine tumors, and lung injury.

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

[0459] In embodiments, the disease is attention deficit / hyperactivity disorder.

[0460] In embodiments, the disease is avoidant personality disorder.

[0461] In embodiments, the disease is seasonal affective disorder.

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

[0463] In embodiments, the disease is neurogenic inflammation.

[0464] In embodiments, the condition is neuropathic pain, peripheral pain, or allodynia. In embodiments, the condition is neuropathic pain. In embodiments, the condition is peripheral pain. In embodiments, the condition is allodynia.

[0465] In an embodiment, the disease is migraine.

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

[0467] In embodiments, the disorder is a learning or memory disorder. In embodiments, the disorder is a learning disorder. In embodiments, the disorder is a memory disorder.

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

[0469] In embodiments, the disease is drug addiction or alcohol addiction.

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

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

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

[0473] In an embodiment, the condition is premature ejaculation.

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

[0475] In embodiments, the disease is inflammatory bowel disease (IBD) or enteritis. In embodiments, the disease is inflammatory bowel disease (IBD). In embodiments, the disease is enteritis.

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

[0477] In embodiments, the disease is liver fibrosis, chronic liver damage, or hepatocellular carcinoma. In embodiments, the disease is liver fibrosis. In embodiments, the disease is chronic liver damage. In embodiments, the disease is hepatocellular carcinoma.

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

[0479] In embodiments, the disease is lung injury.

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

[0481] Formulations of 5-HT7 modulators (pharmaceutical compositions) The present invention also relates to compositions or formulations comprising the 5-hydroxytryptamine receptor 7 activity modulators 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 in accordance with the present invention that are effective in providing modulation of 5-hydroxytryptamine receptor 7 activity, and one or more excipients.

[0482] In the present invention, the terms "excipient" and "carrier" are used interchangeably throughout the description of the present invention, and the term is defined herein as "an ingredient used in the practice of formulating a safe and effective pharmaceutical composition."

[0483] Formulators understand that the use of excipients primarily aids in the delivery of safe, stable, and functional pharmaceutical agents, serving not only as part of the overall delivery vehicle but also as a means for the effective absorption of the active ingredient by the recipient. Excipients can play a simple and straightforward role, such as inert fillers, or, as used herein, excipients can act in part as pH stabilizing agents or coatings to ensure safe delivery of ingredients to the stomach. Formulators can also take advantage of the compounds of the present invention, which have improved cellular efficacy, pharmacokinetic properties, and even improved oral bioavailability.

[0484] The present teachings also provide pharmaceutical compositions comprising at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and are described, for example, in Remington's Pharmaceutical Sciences, 17 th The compositions may be prepared in accordance with acceptable pharmaceutical procedures, such as those described in "Pharmaceutical Preparations," ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), the entire disclosure of which is incorporated herein by reference for all purposes. As used herein, "pharmaceutically acceptable" refers to 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 one that is compatible with other ingredients contained in the formulation and is biologically acceptable. Supplementary active ingredients may also be incorporated into the pharmaceutical composition.

[0485] The compounds of the present teachings can be administered orally or parenterally, either directly or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances that can also function as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents, or encapsulating materials. The compounds can be formulated in conventional ways, for example, in a manner similar to that used for known 5-hydroxytryptamine receptor 7 modulators. Oral formulations containing the compounds disclosed herein include tablets, capsules, buccal forms, troches, lozenges, and oral preparations. It can comprise any oral form that has been conventionally used, including liquid, suspension or solution.For powder, carrier can be a finely divided solid, and be mixed with finely divided compound.For tablet, compound disclosed herein can be mixed with carrier that has necessary compression properties in appropriate ratio, and compressed into desired shape and size.Powder and tablet can contain up to 99% compound.

[0486] Capsules may contain a mixture of one or more compounds disclosed herein with inert fillers and / or diluents, such as pharmaceutically acceptable starches (e.g., corn, potato, or tapioca starch), sugars, artificial sweeteners, powdered cellulose (e.g., crystalline and microcrystalline cellulose), flour, gelatin, gums, and the like.

[0487] Useful tablet formulations can be prepared by conventional compression, wet granulation, or dry granulation methods and may contain pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents, or stabilizers, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, 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 waxes, and ion exchange resins. Surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearal alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphate salts, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delayed-release or sustained-release formulations to alter the absorption of the compounds. Oral formulations can also consist of administering the compounds disclosed herein in water or fruit juice, optionally containing appropriate solubilizers or emulsifiers.

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

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

[0490] The pharmaceutical composition is preferably in unit dosage form, such as, for example, tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such dosage forms, the pharmaceutical composition may be subdivided into unit doses containing appropriate amounts of the compound. The unit dosage form may be a packaged composition, such as, for example, packeted powders, vials, ampoules, prefilled syringes, or sachets containing liquids. Alternatively, the unit dosage form may be a capsule or tablet itself, or any appropriate number of compositions in packaged form. Such unit dosage forms may contain from about 1 mg / kg to about 500 mg / kg of the compound and may be given 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, for example, orally, via implantation, parenterally (including intravenous, intraperitoneal, and subcutaneous injections), rectally, vaginally, or transdermally.

[0491] When administered for the treatment or suppression of a specific disease state or disorder, it is understood that the effective dosage can vary depending on the specific compound used, the method of administration, and the severity of the symptoms being treated, as well as various physical factors related to the individual being treated.In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.The dosage to be used in the treatment of a specific individual must usually be subjectively determined by the attending physician.The variables involved include the specific symptoms and their condition, as well as the size, age, and response pattern of the patient.

[0492] In some cases, it may be desirable to administer the compound directly to a patient's respiratory tract using devices such as, but not limited to, metered-dose inhalers, breath-actuated inhalers, multi-dose dry powder inhalers, pumps, squeeze-activated atomizer dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, compounds of the present teachings can be formulated into liquid, solid, or aerosol compositions. Liquid compositions, illustratively, can contain one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered, for example, using a pump or a squeeze-activated atomizer dispenser. The solvent can be, for example, isotonic saline or bacteriostatic water. Solid compositions, illustratively, can be powder preparations containing one or more compounds of the present teachings, mixed with lactose or other inert powders that can be used intrabronchially. The solid compositions can 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. Illustratively, the aerosol composition may include one or more compounds of the present teachings, a propellant, a surfactant, and a cosolvent, and can be administered, for example, using a metered-dose device. The propellant can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other physiologically and environmentally acceptable propellant.

[0493] The compounds described herein can be administered parenterally or intraperitoneally.These compounds or their pharmaceutically acceptable salts, hydrates, or esters can be prepared as aqueous solutions or suspensions by appropriately mixing with surfactants such as hydroxypropyl cellulose.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oils.Under normal storage and use conditions, these preparations usually contain preservatives to prevent the growth of microorganisms.

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

[0495] The compounds described herein can be administered transdermally, i.e., across the surface of the body and across the inner linings of bodily passages, including epithelial and mucosal tissues. Such administration can be carried out using compounds of the present teachings, including their pharmaceutically acceptable salts, hydrates, or esters, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[0496] Transdermal administration can be achieved by using a transdermal patch containing a compound, such as the compounds disclosed herein, and a carrier that can be inert to the compound, be non-toxic to the skin, and deliver the compound through the skin into the bloodstream for systemic absorption.The carrier can take any number of forms, such as creams and ointments, pastes, gels, and occlusive devices.Creams and ointments can be viscous liquids or semi-fluid emulsions, either oil-in-water or water-in-oil.Pastes consisting of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable.Various occlusive devices can be used to release the compound into the bloodstream, such as a semi-permeable membrane covering a reservoir containing the compound, with or without a carrier, or a matrix containing the compound.Other occlusive devices are known in the literature.

[0497] The compound described herein can be administered rectally or vaginally in the form of conventional suppositories.Suppository preparations can be made from conventional materials, including cocoa butter, with or without the addition of wax and glycerin, which change the melting point of suppository.Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

[0498] Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

[0499] To enhance the effectiveness of a compound of the present teachings, it may be desirable to combine the compound with another agent effective in treating the target disease. For example, another active compound (i.e., another active ingredient or agent) effective in treating the target disease can be administered together with a compound of the present teachings. The other agent can be administered at the same time as the compound disclosed herein or at a different time.

[0500] Compounds of the present teachings can be useful for treating or preventing a disease state or disorder in a mammal, e.g., a human subject. Accordingly, the present teachings provide methods for treating or preventing a disease state or disorder by administering to a mammal a compound of the present teachings (including pharmaceutically acceptable salts thereof) or a pharmaceutical composition comprising one or more compounds of the present teachings in combination or association with a pharmaceutically acceptable carrier. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapeutic methods for treating or preventing the disease state or disorder.

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

[0502] Example The practice of the present invention is illustrated by the following non-limiting examples. [Example]

[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 No. PCT / US2017 / 061677, filed November 15, 2017, International Patent Application No. PCT / US2013 / 071926, filed November 26, 2013, International Patent Application No. PCT / US2014 / 023400, filed March 11, 2014, International Patent Application No. PCT / US2015 / 049303, filed September 10, 2015, International Patent Application No. PCT / US2016 / 031780, filed May 11, 2016, International Patent Application No. PCT / US2018 / 022581, filed March 15, 2018, and International Patent Application No. PCT / US2018 / 022574, filed March 15, 2018.

[0504] The examples provided below provide representative methods for preparing exemplary compounds of the invention. One of ordinary skill in the art would know how to substitute the appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare compounds of the invention. Synthesis and characterization of intermediates [ka]

[0505] Preparation 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: To a small vial was added tert-butyl (R)-1-oxo-3-(2-(tosyloxy)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.5 g, 3.31 mmol, 1 equiv.) and (S)-1-(4-fluorophenyl)-3-methylpiperazine (1.35 g, 6.95 mmol, 2.1 equiv.), and both were then dissolved in acetonitrile (33 mL). K2CO3 (1.14 g, 8.2 mmol, 2.5 equiv) was then added and the reaction was allowed to stir at 80 °C overnight and then cooled to 23 °C. The mixture was filtered, washed with acetonitrile, and the filtrate was concentrated in vacuo to give 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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: tert-butyl (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine) except that 1-(4-fluorophenyl)piperazine was used instead of (S)-1-(4-fluorophenyl)-3-methylpiperazine The title compound was prepared according to the procedure for (1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate. LC / MS [M+H] = m / z 462.2 [ka]

[0507] Preparation of tert-butyl (R)-3-(2-((R)-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 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, 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)piperazin-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-methylpiperazin-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-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: A 6 M 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-methylpiperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.127 g, 0.2 The hydroxybenzoate (67 mmol, 1.0 equiv.) was dissolved in the prepared 6 M methanolic HCl solution (3 mL) and stirred at 23° C. for 30 minutes, then diluted with methanol and concentrated in vacuo to yield the crude product as the dihydrochloride (diHCl) salt. The product was free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration in vacuo to yield 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]decan-1-one: 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 instead of 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]decan-1-one, except using -3-(2-((R)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate. 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]decan-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, 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]decan-1-one, except using (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate. 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]decan-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, 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]decan-1-one, except using (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate. 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-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate: The reaction was carried out in oven-dried glassware under a nitrogen atmosphere. To a small vial was added N-(tert-butoxycarbonyl)glycine (13.8 mg, 0.078 mmol, 1.05 equiv.) and dissolved in dimethylformamide (700 μL). Subsequently, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (31.3 mg, 0.082 mmol, 1.1 equiv.) and N,N-diisopropylethylamine (39 mg, 0.3 mmol, 4 equiv.) were added, and the resulting solution was allowed to stir for 15 minutes at 23° C. In a separate vial, a solution of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride (33.3 mg, 0.074 mmol, 1.0 equiv.), dimethylformamide (300 μL), and N,N-diisopropylethylamine (17.3 mg, 0.13 mmol, 2.2 equiv.) was prepared. Both solutions were combined and stirred at 23 °C for 30 min, then diluted with methanol (5 mL) and concentrated in vacuo. The resulting residue was suspended in saturated NaHCO (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give 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]decan-8-yl)-2-oxoethyl)carbamate: (R)-3-(2-(4-(4-fluorophenyl)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-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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, except using tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-2-oxo-8-azaspiro[4.5]decan-1-one dihydrochloride. LC / MS [M+H] = m / z 519.3 [ka]

[0515] Preparation of tert-butyl ((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-1-oxopropan-2-yl)carbamate: (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride was replaced with (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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, except that (tert-butoxycarbonyl)-2-oxa-8-azaspiro[4.5]decan-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]decan-8-yl)-1-oxobutan-2-yl)carbamate: (R)-3-(2-(4-(4-fluorophenyl)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)- 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-oxa-8-azaspiro[4.5]decan-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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)carbamate: (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride was replaced with (R)-3-(2-(4-(4-fluorophenyl)piperazin-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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, except that (3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate was used, except that (3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate was used instead of N-(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-methylpiperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-1-oxopropan-2-yl)carbamate: (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride instead of (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]decan-8-yl)-2-oxoethyl)carbamate, except that (piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one was used and (tert-butoxycarbonyl)-L-alanine was used instead of N-(tert-butoxycarbonyl)glycine. LC / MS [M+H] = m / z 547.3 [ka]

[0519] tert-Butyl (R)-(1-(3-(2-(4-(3-chlorophenyl)piperazine) Preparation 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-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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-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)piperazin-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-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one instead of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-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-(tert-butoxycarbonyl)glycine was replaced with N-(tert-butoxycarbonyl)glycine, and 2-(boc-amino)isobutyric acid was used. LC / MS [M+H] = m / z 547.3 Synthesis and characterization of 5-HT7 modulators [ka]

[0521] Preparation of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride: A 6 M 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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate (0.607 g, 0.119 mmol, 1.0 equiv.) was dissolved in the 6 M methanolic HCl solution (13 mL) and stirred at 23 °C for 45 minutes, then diluted with methanol and concentrated in vacuo to yield the crude product as the dihydrochloride (diHCl) salt. LC / MS [M+H] = m / z 435.2 [ka]

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

[0523] Preparation of (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)acetamide: A solution of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride (31.6 mg, 0.062 mmol, 1 equiv.), dichloromethane (1.5 mL), and triethylamine (28.5 mg, 0.24 mmol, 4 equiv.) was cooled to 0° C., and acetyl chloride (5.0 mg, 0.062 mmol, 1 equiv.) was added to the solution. The reaction mixture was warmed to 23° C. and stirred for 15 minutes. The reaction was diluted with methanol (approximately 2 mL), concentrated in vacuo, and further purified by column chromatography on a C18 column (ACN / H2O, 0% to 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]decan-8-yl)-2-oxoethyl)acetamide: (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[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-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)acetamide, except that (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride was used instead of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride. 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]decan-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]decan-1-one dihydrochloride (431 mg, 0.845 mmol, 1 equiv.), dichloromethane (17 mL), and triethylamine (516 mg, 5.1 mmol, 6 equiv.) was cooled to 0° C., and methanesulfonyl chloride (117 mg, 1.02 mmol, 1.2 equiv.) was added to the solution. The reaction mixture was warmed to 23° C. and stirred for 15 minutes. The reaction was diluted with methanol (approximately 10 mL), concentrated in vacuo, and further purified by column chromatography on a C18 column (ACN / H2O, 0% to 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-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)methanesulfonamide: Instead of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride, use (R)-3-(2-( 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]decan-8-yl)-2-oxoethyl)methanesulfonamide, except 4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride was used. 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: Use 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)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride, except using -(1-(3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-methyl-1-oxopropan-2-yl)carbamate. The product was then free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration in vacuo to yield 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, tert-butyl (R) The title compound was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride, except that -(1-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-methyl-1-oxopropan-2-yl)carbamate was used. The product was then free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration in vacuo to yield the product. LC / MS [M+H] = m / z 463.2 [ka]

[0529] Preparation of (R)-N-(1-(3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-methyl-1-oxopropan-2-yl)acetamide: Instead of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride, (R)-8-(2-azaspiro[4.5]decan-1-one dihydrochloride was used. 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]decan-8-yl)-2-oxoethyl)acetamide, except using (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-methyl-1-oxopropan-2-yl)acetamide: Instead of (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride, (R)-8-(2-azaspiro[4.5]decan-1-one dihydrochloride was used. 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]decan-8-yl)-2-oxoethyl)acetamide, except using (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-methyl-1-oxopropan-2-yl)pivalamide: (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2 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-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)pivalamide, except that (R)-8-(2-amino-2-methylpropanoyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride was used. LC / MS [M+H] = m / z 531.3 [ka]

[0532] Preparation of (R)-N-(1-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-methyl-1-oxopropan-2-yl)pivalamide: Instead of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride, (R)-8-(2-methyl-1-oxopropan-2-yl)pivalamide was used. 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-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)pivalamide, except using (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-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-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)pivalamide: The reaction was carried out in oven-dried glassware under a nitrogen atmosphere. To a small vial was added sodium pivalate (21.8 mg, 0.17 mmol, 1.05 equiv.) and dissolved in dimethylformamide (1.5 mL). Subsequently, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (70 mg, 0.18 mmol, 1.1 equiv.) and N,N-diisopropylethylamine (86.3 mg, 0.67 mmol, 4 equiv.) were added, and the resulting solution was allowed to stir for 15 minutes at 23° C. In a separate vial, a solution of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride (81.2 mg, 0.16 mmol, 1.0 equiv.), dimethylformamide (400 μL), and N,N-diisopropylethylamine (48 mg, 0.37 mmol, 2.2 equiv.) was prepared. Both solutions were combined and stirred at 23° C. for 30 min, then diluted with methanol (5 mL) and concentrated in vacuo. The resulting residue was suspended in saturated NaHCO (5 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 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-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)pivalamide: Instead of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride, (R)-3-(2-( 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-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)pivalamide, except 4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride was used. 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-(4-fluorophenyl)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]decan-8-yl)-2-oxoethyl)carbamate, except that 8-azaspiro[4.5]decan-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 / HO, 0% to 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 / HO, 0% to 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-(4-fluorophenyl)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]decan-8-yl)-2-oxoethyl)carbamate, except that oxa-8-azaspiro[4.5]decan-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 / HO, 0% to 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 / HO, 0% to 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-(4-fluorophenyl)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-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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, except that 2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate was used instead of N-(tert-butoxycarbonyl)glycine. Furthermore, the purification method was replaced by column chromatography on a C18 column (ACN / HO, 0% to 100%, containing 0.1% NH4OH). LC / MS [M+H] = m / z 489.3 [ka]

[0540] Preparation of (R)-3-(2-(4-(3-chlorophenyl)piperazin-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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, except that morpholin-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 / HO, 0% to 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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-1-oxopropan-2-yl)acetamide: (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa 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]decan-8-yl)-2-oxoethyl)acetamide, except that (R)-8-(L-alanyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one was used instead of (R)-8-(L-alanyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride. LC / MS [M+H] = m / z 475.2 [ka]

[0542] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-nicotinoyl-2-oxa-8-azaspiro[4.5]decan-1-one: (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride instead of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride 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]decan-8-yl)-2-oxoethyl)methanesulfonamide, except using (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)methanesulfonamide, and using nicotinoyl chloride hydrochloride instead of methanesulfonyl chloride. LC / MS [M+H] = m / z 467.2 [ka]

[0543] Preparation of (R)-8-(2-(1H-tetrazol-5-yl)acetyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate salt: The title compound was prepared according to the procedure for (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(pyridazine-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 / HO, 0% to 100%, containing 0.1% HCOOH). LC / MS [M+H] = m / z 472.2

[0544] [ka]

[0545] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(2-(2-oxooxazolidin-3-yl)acetyl)-2-oxa-8-azaspiro[4.5]decan-1-one: (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one instead of (R)-3-(2-(4-(3-chlorophenyl)piperazin-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)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)carbamate, except that 2-oxo-8-azaspiro[4.5]decan-1-one was used and (2-oxo-1,3-oxazolidin-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 / HO, 0% to 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-(pyridazine-3-carbonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: This reaction was carried out in oven-dried glassware under a nitrogen atmosphere. 3-Pyridazinecarboxylic acid (14.3 mg, 0.115 mmol, 1.9 equiv.) 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 equiv.), 1-benzotriazole (39.3 mg, 0.291 mmol, 4.8 equiv.), and N-methylmorpholine (59 mg, 0.584 mmol, 9.6 equiv.) were added, and the resulting solution was stirred at 23 °C for 15 min. Subsequently, (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 equiv.) was added using dimethylacetamide (150 μL) to aid in the transfer. The resulting solution was stirred at 23 °C for 30 min, then diluted with methanol (5 mL) and concentrated in vacuo. The resulting residue was suspended in saturated NaHCO (5 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give the crude product, which was further purified by column chromatography on a C column (ACN / H O, 0% to 100%, containing 0.1% NH OH). LC / MS [M+H] = m / z 468.2 [ka]

[0547] Preparation of (R)-8-acetyl-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: Instead of (R)-3-(2-(4-(3-chlorophenyl)piperazin-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-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)acetamide, except using (4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one. 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]decan-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]decan-1-one dihydrochloride, (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-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)acetamide, except using (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-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]decan-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]decan-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]decan-8-yl)-2-oxoethyl)acetamide, except using -8-(L-valyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one. LC / MS [M+H]=m / z 502.2 [ka]

[0550] Preparation of methyl (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride instead of (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride 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]decan-8-yl)-2-oxoethyl)acetamide, except using (R)—N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)acetamide, and ... [ka]

[0551] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(isoxazol-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 equiv.) and 3-bromoisoxazole (0.614 g, 4.15 mmol, 1.5 equiv.) in anhydrous toluene (10.6 mL) was added the following 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 equiv.), and NaOtBu (0.291 g, 3.3 mmol, 1.2 equiv.). The resulting mixture was stirred at 80 °C overnight under N2. The reaction mixture was cooled to room temperature and then filtered through a plug of Celite. The collected filtrate was concentrated in vacuo to give a crude residue, which was further purified by column chromatography (dichloromethane / methanol, 0% to 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]decan-8-yl)-2-oxoethyl)carbamate: (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride instead of (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride 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]decan-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]decan-8-yl)-2-oxoethyl)acetamide was used ... instead of (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)acetamide was used instead of (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)acetamide was used instead of (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-2-oxoethyl)acetamide) was used instead of (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-1- [ka]

[0553] Preparation of (R)-3,3-diethyl-5-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)dihydrofuran-2(3H)-one: The title compound was prepared according to the procedure for 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, 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-methylpiperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-1-oxopropan-2-yl)acetamide: Alternative to (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride 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]decan-8-yl)-2-oxoethyl)acetamide, except using (R)-8-(L-alanyl)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one. 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: tert-butyl ((S)-1-( The title compound was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride, except that (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-1-oxopropan-2-yl)carbamate was used. The product was then free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration in vacuo to yield 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)-2-aminobutanoyl)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2-oxo-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 The title compound was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride, except that (R)-3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-1-oxobutan-2-yl)carbamate was used. The product was then free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration in vacuo to yield 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: tert-butyl ((S)-1-((R)) 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 The title compound was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride, except that -3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)carbamate was used. The product was then free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration in vacuo to yield 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-methylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: Use tert-butyl ((S)-1-( The title compound was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decan-1-one dihydrochloride, except that (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)-1-oxopropan-2-yl)carbamate was used. The product was then free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration in vacuo to yield the product, LC / MS [M+H] = m / z 447.2.

[0559] Biochemical testing 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 No. 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 ) The solution of the compound of the present disclosure to be tested is prepared as a stock solution of 1 mg / ml in assay buffer or DMSO depending on its solubility.A similar stock solution of the reference compound chlorpromazine is also prepared as a positive control.Eleven dilutions (5x assay concentration) of the compound of the present disclosure and chlorpromazine are prepared in assay buffer by serial dilution to obtain the corresponding final assay concentration ranging from 10 pM to 10 μM.

[0561] Stock concentration is 5 nM [ 3 [H]LSD (lysergic acid diethylamide) is prepared in 50 mM Tris-HCl, 10 mM MgCl, 1 mM EDTA, pH 7.4 (assay buffer). Aliquots (50 μl) of the radioligand are dispensed into wells of a 96-well plate containing 100 μl of assay buffer. Duplicate 50 μl aliquots of serial dilutions of each of the test compounds of the present disclosure and the chlorpromazine positive control reference compound are added.

[0562] Membrane fractions (50 μL) from cells expressing recombinant 5-HT7 receptors were dispensed into each well. Membranes were prepared from stably transfected cell lines expressing 5-HT7 receptors grown on 10 cm plates by harvesting the monolayers, rinsing with PBS, resuspending and lysing them in chilled hypotonic 50 mM Tris-HCl, pH 7.4, centrifuging at 20,000 × g, decanting the supernatant, and storing at -80 °C. The membrane preparations were resuspended in 3 mL of chilled assay buffer and homogenized by passing them through a 26-gauge needle several times before use in the assay.

[0563] The 250 μl reactions are incubated for 1.5 hours at room temperature and then harvested by rapid filtration onto 0.3% polyethyleneimine-treated 96-well filtermats using a 96-well Filtermate harvester. Four rapid 500 μl washes with chilled assay buffer are performed to reduce nonspecific binding. After drying the filtermats, scintillant is added to the filters and the radioactivity retained on the filters is counted in a Microbeta scintillation counter. The raw data (dpm) representing total radioligand binding (i.e., specific + nonspecific binding) are plotted as a function of the logarithm of the molar concentration of competitor (i.e., test or reference compound). Nonlinear regression of the normalized (i.e., percentage of radioligand binding compared to binding observed in the absence of test or reference compound) raw data is performed in Prism 4.0 (GraphPad Software) using a built-in three-parameter logistic model describing binding of the ligand competitor to the radioligand-labeled site: y=bottom+[(top-bottom) / (1+10x-logIC 50 )] where bottom is equal to the residual radioligand binding (i.e., nonspecific binding) measured in the presence of 10 μM of reference compound, and top is equal to the total radioligand binding observed in the absence of competitor, i.e., log IC 50 (i.e., the logarithm of the ligand concentration that reduces radioligand binding by 50%) is estimated from the data and used to obtain K by applying the Cheng-Prusoff approximation: Ki=IC 50 / (1+[ligand] / KD) where [ligand] equals the assay radioligand concentration and KD equals the affinity constant of the radioligand for the target receptor.

[0564] Functional Data (K b ) The functional efficacy of compounds of the present disclosure on the 5-HT7 serotonin receptor was measured in a cell-based cAMP enzyme fragment complementation assay using the HitHunter cAMP assay (DiscoveRx). Cells stably expressing the human 5HT7 receptor were 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 1 mg / mL G418). Serial dilutions of the agonist 5-hydroxytryptamine (5-HT) were prepared, ranging in final concentrations from 10 μM to 10 nM. Compounds of the present disclosure were prepared in 3-fold serial dilutions, resulting in a final concentration range of 10 μM to 0.1 nM. Compounds of the present disclosure 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. Briefly, cells were incubated with compounds of the present disclosure for 30 minutes at 37°C, followed by EC 70 After an additional 30 minutes, cAMP antibody / cell lysis solution was added (20 μL / well) and incubated at room temperature for 60 minutes. cAMP XS+EA reagent was added (20 μL / well) and incubated at room temperature for 2 hours. Luminescence was read on an Envision Multilabel plate reader.

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

[0566] While several embodiments of the present invention have been described, it will be apparent that the basic examples may be modified to provide other embodiments that utilize the compounds, methods, and processes of the present invention. It will therefore be understood that the scope of the present invention is defined by the appended claims rather than by the specific embodiments that have been represented by way of example herein. The present invention provides, for example, the following items. (Item 1) A compound having a structure according to general formula (I*): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: R 1N are imidazoles, oxazoles, isoxazoles, [ka] wherein: R 4a and R 4b are each hydrogen or C1-C7 alkyl, or R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8iare each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R AA are each independently a C1-C7 linear alkyl; R 2a are each independently halogen, unsubstituted C1-C7 alkyl, C1-C7 perhaloalkyl, unsubstituted C1-C7 alkoxy, 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 5 is unsubstituted C1-C7 alkyl or unsubstituted C3-C7 cycloalkyl, then a is 1 or 2. (Item 2) A compound having a structure according to general formula (I*-N): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: R 1N-N C6~C 10 Heteroaryl, 5- to 10-membered heteroaryl, [ka] wherein: R 4a and R 4b are each hydrogen or C1-C7 alkyl, or R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8iare each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R AA are each independently a C1-C7 linear alkyl; R 2a are each independently halogen, unsubstituted C1-C7 alkyl, C1-C7 perhaloalkyl, unsubstituted C1-C7 alkoxy, 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 5 is unsubstituted C1-C7 alkyl or unsubstituted C3-C7 cycloalkyl, then a is 1 or 2. (Item 3) It has a structure according to general formula (I*-1): [ka] 3. The compound of claim 1 or 2 having the structure above, including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof. (Item 4) It has a structure according to general formula (I*-2): [ka] 3. The compound of claim 1 or 2 having the structure above, including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof. (Item 5) It has a structure according to general formula (I*-3): [ka] Item 3. The compound of item 2 having the structure above, including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof. (Item 6) R 1N teeth, [ka] In the formula, R 8a and R 8b are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 and R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; [ka] Item 1. The compound according to item 1, (Item 7) R 1N teeth, [ka] In the formula, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; [ka] In the formula, R 8h is an unsubstituted C1-C7 alkyl; or [ka] Item 1. The compound according to item 1, (Item 8) R 1N is the compound according to item 1, which is: [ka] In the formula, R 8a and R 8b are each independently H or unsubstituted C1-C7 alkyl; [ka] In the formula, R 8d are independently H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8a , R 8b , and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; [ka] In the formula, R 8a and R 8b are each independently H or unsubstituted C1-C7 alkyl; [ka] In the formula, R 8g are independently H or unsubstituted C1-C7 alkyl, and R 8h are independently unsubstituted C1-C7 alkyl; or [ka] (Item 9) R 1N teeth, [ka] Item 1. The compound according to item 1, (Item 10) R 1N teeth, [ka] Item 1. The compound according to item 1, (Item 11) A compound having a structure according to general formula (I**): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: R aa and R bb are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl; R AA are each independently a C1-C7 linear alkyl; R 2a are each independently halogen, unsubstituted C1-C7 alkyl, C1-C7 perhaloalkyl, unsubstituted C1-C7 alkoxy, C1-C7 perhaloalkoxy, or CN; aa is 0, 1, or 2, and a' is 1 or 2. (Item 12) R aa and R bb and each is ethyl. (Item 13) 11. The compound according to any one of items 1 to 10, wherein a is 0 or 1. (Item 14) a is 1 or 2, and R AA 11. The compound according to any one of items 1 to 10, wherein each is methyl. (Item 15) a' is 1 or 2, and R AA 13. The compound according to any one of items 11 to 12, wherein each is methyl. (Item 16) 16. The compound according to any one of items 1 to 15, wherein aa is 1 or 2. (Item 17) R 2a Item 17. The compound according to item 16, wherein each is independently halogen. (Item 18) R 2a is each independently -F or -Cl. (Item 19) 19. The compound according to any one of items 1 to 18, wherein the C5 carbon of the 2-dihydrofuranone has the (R)-configuration. (Item 20) 19. The compound according to any one of items 1 to 18, wherein the C5 carbon of the 2-dihydrofuranone has an (S)-configuration. (Item 21) A compound having a structure according to general formula (I): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: R a and R b are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl, or R a and R b together with the atoms to which they are attached form a carbocyclic ring having 5 to 7 ring atoms, optionally containing a double bond, or R a and R b together with the atoms to which they are attached, are O, S, SO, SO2 and NR 1 forming a ring having 6 to 8 ring atoms containing a moiety selected from the group consisting of A is an N-linked, 5- to 12-membered nitrogen-containing heterocyclyl that is bicyclic or polycyclic and optionally contains additional heteroatoms selected from O, N, and S, and non-aromatic nitrogen-containing heterocyclyls are represented by R 2 further comprising a group, R 1is H, C1-C7 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, a 5- to 6-membered heteroaryl ring, a polar acyl group, or a polar sulfonyl group; R 2 is a 6- to 10-membered aryl, a 5- to 10-membered nitrogen-containing heteroaryl, and [ka] is selected from the group consisting of R 3 is a 6- to 10-membered aryl or a 5- to 10-membered nitrogen-containing heteroaryl; m is 1, 2, or 3; and n is 1, 2, 3, or 4, and wherein R is 1,2,3,4-tetrahydroquinol-1-yl, 1,2,3,4-tetrahydroisoquinol-2-yl, octahydropyrrolo[3,4-c]pyrrol-1-yl, or 2,6-diazaspiro[3.3]heptan-1-yl; a and R b cannot both be methyl, both be ethyl, or both be phenyl, and R a and R b can also not be bonded to form an unsubstituted C3-C6 cycloalkyl. (Item 22) 22. The compound according to item 21, having one of the following structures: [ka] (Item 23) R a and R b are both methyl or ethyl, or R a and R b is attached to form an unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (Item 24) Item 23, the compound having one of the following structures: [ka] (Item 25) 25. The compound according to item 24, having one of the following structures: [ka] (Item 26) R a and R b together with the atom to which they are attached form a ring having 6 to 8 ring atoms. (Item 27) 27. The compound according to item 26, having a structure according to general formula (IF): [ka] . (Item 28) Item 26, a compound having a structure according to one of the following general formulas: [ka] . (Item 29) A, [ka] is selected from the group consisting of During the ceremony, R 2 is phenyl, naphthyl, pyridyl, indolyl, and [ka] is selected from the group consisting of R 3 is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl; R A is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C 1~C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, o xo, 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 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen; and 29. The compound according to any one of items 21 to 28, wherein a is independently 0, 1, or 2. (Item 30) A, [ka] 30. The compound according to item 29, selected from the group consisting of: (Item 31) A, [ka] 30. The compound according to item 29, selected from the group consisting of: (Item 32) R 1 is H, C1-C7 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, imidazole, oxazole, isoxazole, [ka] is selected from the group consisting of R 4a , R 4b , R 4c, R 6a , R 6b , and R 6c are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; R 6a and R 6b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; R 4d and R 6d are each selected from the group consisting of phenyl, benzyl, pyridyl, —CH2(pyridyl), imidazole, and —CH2(imidazole); R 5 is hydrogen, 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 7 is hydrogen, 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, NR8a R 8b , SO2R 8c , N.R. 8d SO2R 8e , NHCONR 8f is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8i are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R 11 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; y 1 is 0, 1, or 2, and y 2The compound according to any one of items 21 to 31, wherein is 0, 1, or 2. (Item 33) R 1 but, [ka] 33. The compound according to item 32, selected from the group consisting of: (Item 34) R 1 but, COOR 5 , where R 5 C6~C 10 aryl or 5- to 10-membered heteroaryl; [ka] In the formula, R 8a and R 8b are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b is optional, together with the atoms to which they are bonded, optionally oxygen, sulfur and NR 9 and R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; [ka] In the formula, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; [ka] In the formula, R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; [ka] In the formula, R 8a and R 8b are each independently H or unsubstituted C1-C7 alkyl; [ka] In the formula, R 8d are independently H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8a , R 8b , and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8a and R 8b are each independently H or unsubstituted C1-C7 alkyl; [ka] In the formula, R 8g are independently H or unsubstituted C1-C7 alkyl, and R 8h is independently an unsubstituted C1-C7 alkyl, or [ka] 34. The compound according to item 32 or 33, wherein (Item 35) A compound having a structure according to general formula (II): [ka] Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and complexes thereof are included, wherein: A 2 teeth, [ka] and R 2 is a 6- to 10-membered aryl, a 5- to 10-membered nitrogen-containing heteroaryl, and [ka] is selected from the group consisting of R 3 is a 6- to 10-membered aryl or a 5- to 10-membered nitrogen-containing heteroaryl; R Ais C1-C7 straight chain alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 straight chain alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 straight chain 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, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C selected from the group consisting of C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen; a is 0, 1, or 2, and m is 1, 2, or 3; n is 1, 2, 3, or 4; R 1’ C6~C 10 Aryl, five- to six-membered heteroaryl ring, [ka] is selected from the group consisting of R 4a , R 4b , R 4c , R 6a , R 6b , and R 6c are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 4a and R 4b optionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; R 6a and R 6boptionally, together with the atoms to which they are attached, form a ring containing 3 to 7 atoms, optionally containing oxygen; R 4d and R 6d are each selected from the group consisting of phenyl, benzyl, pyridyl, —CH2(pyridyl), imidazole, and —CH2(imidazole); R 5 is hydrogen, 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 , N.R. 8d SO2R 8e , N.R. 8i COOR 8j , NHCONR 8f , N.R. 8g COR 8h , and [ka] is selected from the group consisting of R 7 is hydrogen, 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 , N.R. 8d SO2R 8e , NHCONR 8f is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8i are hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; or R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 forming a heterocycle containing 3 to 7 atoms, containing a group selected from R 8c , R 8e , R 8f , and R 8h are each C1-C7 alkyl or C3-C7 cycloalkyl, or R 4a and R 8a If both exist, or R 4a and R 8g when both are present, these groups, optionally together with the atoms to which they are attached, 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; R 11 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 In the formula, A 2 but [ka] and R 2 is phenyl and R 1’ but [ka] and y 2is 0 and n is 2, R 7 is not methyl, CH2SO2CH3, CH2CN, tetrahydropyranyl, phenyl, 4-substituted phenyl, or 5- to 8-membered heteroaryl. (Item 36) The compound according to item 35, having one of the following structures: [ka] . (Item 37) R 1’ but, COOR 5 , where R 5 C6~C 10 aryl or 5- to 10-membered heteroaryl; [ka] In the formula, R 8a and R 8b are each selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl, or R 8a and R 8b optionally, together with the atoms to which they are attached, optionally oxygen, sulfur, and NR 9 and R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; [ka] In the formula, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; [ka] In the formula, R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; [ka] In the formula, R 8a and R 8b are each independently H or unsubstituted C1-C7 alkyl; [ka] In the formula, R 8d are independently H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 4a and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8a , R 8b , and R 8g are each independently H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; [ka] In the formula, R 8a and R 8bare each independently H or unsubstituted C1-C7 alkyl; [ka] In the formula, R 8g are independently H or unsubstituted C1-C7 alkyl, and R 8h is independently an unsubstituted C1-C7 alkyl, or [ka] 37. The compound according to item 35 or 36, wherein (Item 38) A 2 but [ka] 38. The compound according to any one of items 35 to 37, wherein (Item 39) A 2 but [ka] 38. The compound according to any one of items 35 to 37, wherein (Item 40) A 2 but [ka] 38. The compound according to any one of items 35 to 37, wherein (Item 41) A compound selected from the group consisting of compounds 1 to 145, or a pharmaceutically acceptable salt thereof. (Item 42) 42. A pharmaceutical composition comprising a compound according to any one of items 1 to 41, or a pharmaceutically acceptable salt thereof. (Item 43) 43. The pharmaceutical composition according to item 42, further comprising at least one pharmaceutically acceptable excipient. (Item 44) 42. A method for treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity, the method comprising administering to a subject an effective amount of at least one compound according to any one of items 1 to 41, or a pharmaceutically acceptable salt thereof. (Item 45) 45. The method of claim 44, wherein the at least one compound, or a pharmaceutically acceptable salt thereof, is administered in a composition further comprising at least one excipient. (Item 46) 46. ​​The method of claim 44 or 45, wherein the disease associated with dysregulated 5-hydroxytryptamine receptor 7 activity is selected from the group consisting of peripherally selective disease, nervous system disease, circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorder, learning disability, memory disorder, hippocampal signaling disorder, sleep disorder, attention deficit / hyperactivity disorder, anxiety disorder, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), enteritis, epilepsy, seizure disorder, drug addiction, alcohol addiction, breast cancer, liver fibrosis, chronic liver disease, hepatocellular carcinoma, small intestinal neuroendocrine tumor, and lung injury. (Item 47) 46. ​​The method according to item 44 or 45, wherein the disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity is inflammatory bowel disease (IBD) or enterocolitis.

Claims

1. A compound having a structure according to general formula (I*): 【Chemical 503】 Enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof, wherein: R 1N is imidazole, oxazole, isoxazole, 【Chemical 504】 wherein: R 4a and R 4b are each hydrogen or C 1 -C 7 alkyl, or R 4a and R 4b optionally together with the atoms to which they are attached form a ring containing from 3 to 7 atoms, optionally containing oxygen; R 5 is 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 505】 is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8i are each selected from the group consisting of hydrogen, C 1 -C 7 alkyl, and C 3 -C 7 cycloalkyl, or R 8a and R 8b optionally together with the atom to which they are attached form a heterocyl containing from 3 to 7 atoms, optionally containing a group selected from oxygen, sulfur, and NR 9 ; R 8c , R 8e , R 8f , and R 8h are each C 1 -C 7 alkyl or C 3 -C 7 cycloalkyl; R 8j is selected from the group consisting of C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; or when both R 4a and R 8a are present, or when both R 4a and R 8g are present, these groups may optionally be joined together with the atoms to which they are attached to form a ring containing 4 to 7 atoms; R 9 is selected from the group consisting of hydrogen, C 1 -C 7 alkyl, and C 3 -C 7 cycloalkyl; Each R AA is independently a C 1 -C 7 straight chain alkyl; each R 2a is independently halogen, unsubstituted C 1 -C 7 alkyl, C 1 -C 7 perhaloalkyl, unsubstituted C 1 -C 7 alkoxy, C 1 -C 7 perhaloalkoxy, or CN; a is 0, 1, or 2; aa is 0, 1, or 2; A compound wherein y 1 is 1 or 2.

2. A compound having a structure according to general formula (I*-N): 【Chemical 506】 Enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof, wherein: R 1N-N is C 6 -C 10 heteroaryl, 5- to 10-membered heteroaryl; 【Chemical 507】 wherein: R 4a and R 4b are each hydrogen or C 1 -C 7 alkyl, or R 4a and R 4b optionally together with the atoms to which they are attached form a ring containing from 3 to 7 atoms, optionally containing oxygen; R 5 is 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 508】 is selected from the group consisting of R 8a , R 8b , R 8d , R 8g , and R 8i are each selected from the group consisting of hydrogen, C 1 -C 7 alkyl, and C 3 -C 7 cycloalkyl, or R 8a and R 8b optionally together with the atom to which they are attached form a heterocyl containing from 3 to 7 atoms, optionally containing a group selected from oxygen, sulfur, and NR 9 ; R 8c , R 8e , R 8f , and R 8h are each C 1 -C 7 alkyl or C 3 -C 7 cycloalkyl; R 8j is selected from the group consisting of C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; or when both R 4a and R 8a are present, or when both R 4a and R 8g are present, these groups may optionally be joined together with the atoms to which they are attached to form a ring containing 4 to 7 atoms; R 9 is selected from the group consisting of hydrogen, C 1 -C 7 alkyl, and C 3 -C 7 cycloalkyl; Each R AA is independently a C 1 -C 7 straight chain alkyl; each R 2a is independently halogen, unsubstituted C 1 -C 7 alkyl, C 1 -C 7 perhaloalkyl, unsubstituted C 1 -C 7 alkoxy, C 1 -C 7 perhaloalkoxy, or CN; a is 0, 1, or 2; aa is 0, 1, or 2; A compound wherein y 1 is 1 or 2.

3. A compound having a structure according to general formula (I*-1): 【Chemical 509】 10. The compound of claim 1 having the structure, including enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof.

4. A compound having a structure according to general formula (I*-2): 【Chemical 510】 10. The compound of claim 1 having the structure, including enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof.

5. R 1N is 【Chemical 511】 wherein R 8j is selected from the group consisting of C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; 【Chemical 512】 wherein R 8h is unsubstituted C 1 -C 7 alkyl; or 【Chemical Formula 513】 2. The compound of claim 1, wherein:

6. The compound of claim 1, wherein R 1N is: 【Chemical Formula 514】 wherein R 8a and R 8b are each independently H or unsubstituted C 1 -C 7 alkyl; 【Chemical 515】 wherein R 8d is independently H or unsubstituted C 1 -C 7 alkyl, and R 8e is unsubstituted C 1 -C 7 alkyl; 【Chemical 516】 wherein R 4a and R 8g are each independently H or unsubstituted C 1 -C 7 alkyl, and R 8h is unsubstituted C 1 -C 7 alkyl; 【Chemical 517】 wherein R 8h is unsubstituted C 1 -C 7 alkyl; 【Chemical 518】 wherein R 8a , R 8b , and R 8g are each independently H or unsubstituted C 1 -C 7 alkyl, and R 8h is unsubstituted C 1 -C 7 alkyl; 【Chemical Formula 519】 wherein R 8j is selected from the group consisting of C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; 【Chemical 520】 wherein R 8a and R 8b are each independently H or unsubstituted C 1 -C 7 alkyl; 【Chem.521】 wherein R 8g is independently H or unsubstituted C 1 -C 7 alkyl, and R 8h is independently unsubstituted C 1 -C 7 alkyl; or 【Chemical 522】 。

7. R 1N is 【Chemical 523】 2. The compound of claim 1, wherein:

8. R 1N is 【Chemical 524】 2. The compound of claim 1, wherein:

9. A compound having a structure according to general formula (I**), 【Chemical 525】 Enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof, wherein: R aa and R bb are each selected from the group consisting of hydrogen, C 1 -C 7 alkyl, and C 3 -C 7 branched alkyl; Each R AA is independently a C 1 -C 7 straight chain alkyl; each R 2a is independently halogen, unsubstituted C 1 -C 7 alkyl, C 1 -C 7 perhaloalkyl, unsubstituted C 1 -C 7 alkoxy, C 1 -C 7 perhaloalkoxy, or CN; aa is 0, 1, or 2, and a' is 1 or 2.

10. The compound of claim 9, wherein R aa and R bb are each ethyl.

11. The compound of claim 1, wherein a is 0 or 1.

12. The compound of claim 1, wherein a is 1 or 2 and each R AA is methyl.

13. The compound of claim 1, wherein a' is 1 or 2, and each R AA is methyl.

14. The compound described in claim 1, wherein aa is 1 or 2.

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

16. The compound of claim 1, wherein each R 2a is independently —F or —Cl.

17. The compound of claim 1, wherein the C5 carbon of the 2-dihydrofuranone has an (R)-configuration.

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

19. A compound having a structure according to general formula (I): 【Chemical 526】 Enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof, wherein: R a and R b are each selected from the group consisting of hydrogen, C 1 -C 7 alkyl, and C 3 -C 7 branched alkyl, or R a and R b together with the atom to which they are attached form a carbocyclic ring having 5 to 7 ring atoms, optionally containing a double bond, or R a and R b together with the atom to which they are attached form a ring having 6 to 8 ring atoms that contains a moiety selected from the group consisting of O, S, SO, SO 2 and NR 1 ; A is an N-linked 5- to 12-membered nitrogen-containing heterocyclyl that is bicyclic or polycyclic and optionally contains an additional heteroatom selected from O, N, and S, and non-aromatic nitrogen-containing heterocyclyl further contains an R 2 group; R 1 is H, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, phenyl, benzyl, a 5- to 6-membered heteroaryl ring, a polar acyl group, or a polar sulfonyl group; R 2 is a 6- to 10-membered aryl, a 5- to 10-membered nitrogen-containing heteroaryl, and 【Chemical 527】 is selected from the group consisting of R 3 is a 6- to 10-membered aryl or a 5- to 10-membered nitrogen-containing heteroaryl; m is 1, 2, or 3; and n is 1, 2, 3, or 4; and Compounds of the formula: wherein when A is 1,2,3,4-tetrahydroquinol-1-yl, 1,2,3,4-tetrahydroisoquinol-2-yl, octahydropyrrolo[3,4-c]pyrrol-1-yl, or 2,6-diazaspiro[3.3]heptan-1-yl, R a and R b cannot both be methyl, both ethyl, or both phenyl, and R a and R b cannot be joined to form unsubstituted C 3 -C 6 cycloalkyl.

20. A compound having a structure according to general formula (II): 【Chemical 528】 Enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof, wherein: A2 is 【Chemical 529】 and R 2 is a 6- to 10-membered aryl, a 5- to 10-membered nitrogen-containing heteroaryl, and 【Chemical 530】 is selected from the group consisting of R 3 is a 6- to 10-membered aryl or a 5- to 10-membered nitrogen-containing heteroaryl; R A is C 1 to C 7 straight chain alkyl, C 3 to C 7 branched alkyl, C 3 to C 7 cycloalkyl, C 1 to C 7 straight chain alkoxy, C 3 to C 7 branched alkoxy, C 3 to C 7 cycloalkoxy, aryloxy, C 1 to C 7 straight chain haloalkyl, C 3 to C 7 branched haloalkyl, C 3 to C 7 cyclohaloalkyl, C 2 to C 7 alkenyl, C 2 to C 7 cycloalkenyl, C 2 to C 7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C 1 to C 7 alkoxycarbonyl, sulfo, halogen, C 1 to C 7 alkylthio, arylthio, C 1 to C 7 alkylsulfinyl, arylsulfinyl, C 1 to C 7 selected from the group consisting of alkylsulfonyl, arylsulfonyl, amino, C 1 -C 7 acylamino, mono- or di-C 1 -C 7 alkylamino, C 3 -C 7 cycloalkylamino, arylamino, C 2 -C 7 acyl, arylcarbonyl, and 5- to 6-membered heterocyclic groups each containing from 1 to 4 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′ is a C 6 -C 10 aryl, a 5- to 6-membered heteroaryl ring; 【Chemistry 531】 is selected from the group consisting of R 4a , R 4b , R 4c , R 6a , R 6b , and R 6c are each selected from the group consisting of hydrogen, C 1 -C 7 alkyl, and C 3 -C 7 cycloalkyl; R 4a and R 4b optionally together with the atoms to which they are attached form a ring containing 3 to 7 atoms, optionally containing oxygen; R 6a and R 6b optionally together with the atoms to which they are attached form a ring containing 3 to 7 atoms, optionally containing oxygen; R 4d and R 6d are each selected from the group consisting of phenyl, benzyl, pyridyl, —CH 2 (pyridyl), imidazole, and —CH 2 (imidazole); R 5 is hydrogen, 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 532】 is selected from the group consisting of R 7 is selected from the group consisting of hydrogen, 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 , NHCONR 8f ; R 8a , R 8b , R 8d , R 8g , and R 8i are each selected from the group consisting of hydrogen, C 1 -C 7 alkyl, and C 3 -C 7 cycloalkyl; or R 8j is selected from the group consisting of C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; or R 8a and R 8b optionally together with the atom to which they are attached form a heterocyl containing from 3 to 7 atoms, optionally containing a group selected from oxygen, sulfur and NR 9 ; R 8c , R 8e , R 8f , and R 8h are each C 1 -C 7 alkyl or C 3 -C 7 cycloalkyl; or when both R 4a and R 8a are present, or when both R 4a and R 8g are present, these groups may optionally be joined together with the atoms to which they are attached to form a ring containing 4 to 7 atoms; R 9 is selected from the group consisting of hydrogen, C 1 -C 7 alkyl, and C 3 -C 7 cycloalkyl; R 11 is selected from the group consisting of hydrogen, C 1 -C 7 alkyl, and C 3 -C 7 cycloalkyl; y 1 is 1 or 2, and y 2 is 0, 1, or 2; and In the formula, A 2 is 【Chemical 533】 wherein R 2 is phenyl and R 1′ is 【Chemistry 534】 and when y 2 is 0 and n is 2, then R 7 is not methyl, CH 2 SO 2 CH 3 , CH 2 CN, tetrahydropyranyl, phenyl, 4-substituted phenyl, or 5- to 8-membered heteroaryl.

21. The compound of claim 1, 【Chemical 535】 【Chemical 536】 【Chemical Formula 537】 【Chemical 538】 【Chemical 539】 【Chemical 540】 【Chemistry 541】 【Chemistry 542】 【Chemistry 543】 【Chemical 544】 【Chemical 545】 【Chemical 546】 【Chemical 547】 【Chemical 548】 【Chemistry 549】 (including enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof) 2. The compound of claim 1 selected from the group consisting of:

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof.

23. The pharmaceutical composition of claim 22, further comprising at least one pharmaceutically acceptable excipient.

24. A composition for treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity, comprising a compound described in any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof.

25. The composition of claim 24, wherein the composition is administered in combination with at least one excipient.

26. The disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity is selected from the group consisting of peripherally selective disease, nervous system disease, circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral vascular disease, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorder, learning disability, memory disorder, hippocampal signaling disorder, sleep disorder, attention deficit / hyperactivity disorder, anxiety disorder, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, and premenstrual dysphonia.

25. The composition of claim 24, wherein the therapeutic agent is selected from the group consisting of: inflammatory bowel disease (IBD), enteritis, epilepsy, seizure disorders, drug addiction, alcohol addiction, breast cancer, liver fibrosis, chronic liver injury, hepatocellular carcinoma, small intestinal neuroendocrine tumors, and lung injury.

27. ​​The composition described in claim 24, wherein the disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity is inflammatory bowel disease (IBD) or enteritis.

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