Novel functionalized lactone as a regulator of 5-hydroxytryptamine receptor 7 and method of using the same

Abstract

Novel selective modifiers of the 5-HT7 receptor are described herein. These selective compounds may be useful for the treatment of CNS and non-CNS indications. The compounds described herein may be selective for targeting the 5-HT7 receptor compared to other receptors and / or may be selective by selectively targeting the 5-HT7 receptor expressed in specific tissues or organs, thereby having effective selectivity through specific splitting profiles of the 5-HT7 modifier.(I)

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 934,985 filed November 13, 2019, the whole of which is incorporated by reference.

[0003] Disclosure of federally funded research

[0004] The present invention was made with government support pursuant to approval number 2R44DK115254-02A1 granted by the National Institute of Diabetes and Gastrointestinal and Kidney Diseases of the United States. The government holds certain rights in the present invention. Background Technology

[0005] Serotonin was discovered in the late 1940s and exists in both the peripheral and central nervous systems [Physiol. Res, 60 (2011) 15-25; Psychopharmacology 213 (2011) 167-169]. Serotonin, or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with an indolealkylamine group that acts at the synapses of nerve cells. Seven distinct groups of serotonin receptors have been identified, and at least 20 subgroups have been cloned based on sequence similarity, signal transduction coupling, and pharmacological properties. The seven groups of 5-HT receptors are 5-HT 1, 5-HT2, 5-HT 3, 5-HT 4, 5-HT 5, 5-HT 6, They are named 5-HT1 and 5-HT5, and each of these receptors has a subgroup or subgroup. The signaling mechanisms for all seven groups have been studied, and while the activation of 5-HT1 and 5-HT5 receptors leads to a decrease in intracellular cAMP, 5-HT2 and 5-HT 3, 5-HT4, 5-HT 6,and 5-HT7 activation is known to result in an increase in intracellular IP3 and DAG. The 5-HT pathway in the brain is an important target for drug development in the field of CNS disorders. This neurotransmitter binds to its G-protein coupled receptor and is associated with a wide range of actions, including, among others, 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 intestinal inflammation (WO 2012058769, Khan, WI et al. [Journal of Immunology, 2013, 190, 4795-4804]), epilepsy, seizure disorders (Epilepsy Research (2007) 75, 39), drug intoxication, and alcohol intoxication (Hauser, SR et al. [Frontiers in Neuroscience, 2015, 8, 1-9]).

[0006] Novel selective modifiers of the 5-HT7 receptor are described herein. These selective compounds may be useful for the treatment of CNS and non-CNS indications. The compounds described herein may be selective for targeting the 5-HT7 receptor compared to other receptors and / or may be selective by selectively targeting the 5-HT7 receptor expressed in specific tissues or organs, thereby having effective selectivity through a specific splitting profile of the 5-HT7 modifier.

[0007] In one embodiment, the present invention is based on the formula (I * Compounds having a structure according to ):

[0008] ( I* ),

[0009] Characterized by compounds including its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes, wherein:

[0010] R 1N It is imidazole, oxazole, isoksazole, , and Selected from a group consisting of; among the formulas

[0011] Each R 4a and R 4b is hydrogen or C1-C7 alkyl; optionally R 4a and R 4b They combine with the atoms to form a ring containing 3 to 7 atoms and optionally oxygen;

[0012] R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of;

[0013] Each R 8a , R 8b , R 8d , R 8g , and R 8i is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms, oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group optionally selected from;

[0014] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl;

[0015] R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls;

[0016] R 4a and R 8a All exist or R 4a and R 8g When all of them are present, these groups arbitrarily combine with the atoms to which they are bonded to form a ring containing 4 to 7 atoms;

[0017] R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0018] Each R AA is independently a C1-C7 linear alkyl;

[0019] Each R 2a is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN;

[0020] a is 0, 1, or 2;

[0021] aa is 0, 1, or 2;

[0022] y 1 is 0, 1, or 2;

[0023] R 5 If is an unsubstituted C1-C7 alkyl or an unsubstituted C3-C7 cycloalkyl, a is 1 or 2.

[0024] In another aspect, the present invention ( I * -N Compounds having a structure according to ):

[0025] ( I*-N ),

[0026] Characterized by compounds including its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes, wherein:

[0027] R 1N-N C6-C 10 Heteroaryl, 5- to 10-membered heteroaryl, , , and Selected from a group consisting of;

[0028] Each R 4a and R 4b is hydrogen or C1-C7 alkyl; optionally R 4a and R 4b They combine with the atoms to form a ring containing 3 to 7 atoms and optionally oxygen;

[0029] R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of;

[0030] Each R 8a , R 8b , R 8d , R 8g , and R 8i is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms, oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group optionally selected from;

[0031] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl;

[0032] R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls;

[0033] R 4a and R 8a All exist or R 4a and R 8g When all of them are present, these groups arbitrarily combine with the atoms to which they are bonded to form a ring containing 4 to 7 atoms;

[0034] R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0035] Each R AA is independently a C1-C7 linear alkyl;

[0036] Each R 2a is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN;

[0037] a is 0, 1, or 2;

[0038] aa is 0, 1, or 2;

[0039] y 1 is 0, 1, or 2;

[0040] R 5 If is an unsubstituted C1-C7 alkyl or an unsubstituted C3-C7 cycloalkyl, a is 1 or 2.

[0041] In the implementation example, the formula ( I* ) or ( I*-N The compound of ) is formula ( I*-1 It has a structure according to ):

[0042] ( I*-1 ),

[0043] It includes its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes.

[0044] In the implementation example, the formula ( I* ) or ( I*-N The compound of ) is formula ( I*-2 It has a structure according to ):

[0045] ( I*-2 )

[0046] It includes its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes.

[0047] In the implementation example, the formula ( I*-N The compound of ) is formula ( I*-3 It has a structure according to ):

[0048] ( I*-3 )

[0049] It includes its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes.

[0050] In an example of implementation, R 1N It is as follows:

[0051] (each of the food) R 8a and R 8b is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms and optionally oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group selected from;R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl);

[0052]

[0053] In an example of implementation, R 1N It is as follows:

[0054] (during the meal) R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls, and 5 to 10 heteroaryls;

[0055] (during the meal, R 8h is an unsubstituted C1-C7 alkyl;

[0056] or

[0057]

[0058] In an example of implementation, R 1N It is as follows:

[0059] or (each of the food) R 8a and R 8b is independently an H or unsubstituted C1-C7 alkyl;

[0060] or (during the meal) R 8d is independently an H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl;

[0061] or (during the meal) R 4a and R 8g Each of the is independently H or an unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl;

[0062] or (during the meal) R 8h is an unsubstituted C1-C7 alkyl;

[0063] or (each of the food) R 8a , R 8b , and R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl;

[0064] (during the meal) R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls, and 5 to 10 heteroaryls;

[0065]

[0066]

[0067]

[0068]

[0069] , or (each of the food) R 8a and R 8b is independently an H or unsubstituted C1-C7 alkyl;

[0070]

[0071] , or (during the meal) R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an independently unsubstituted C1-C7 alkyl;

[0072] or

[0073]

[0074] In an example of implementation, R 1N It is as follows:

[0075]

[0076]

[0077] In an example of implementation, R 1N It is as follows:

[0078] ,

[0079] In another aspect, the present invention ( I Compounds having a structure according to **):

[0080] ( I** )

[0081] Characterized by compounds including its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes, wherein:

[0082] Each R aa and R bb is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl;

[0083] Each R AA is independently a C1-C7 linear alkyl;

[0084] Each R 2a is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN;

[0085] aa is 0, 1, or 2;

[0086] a' It is 1 or 2.

[0087] In an example of implementation, R aa and R bb Each is ethyl.

[0088] In an example of implementation, a is 0 or 1.

[0089] In an example of implementation, a is 1 or 2, and each R AA is methyl.

[0090] In an example of implementation, a' is 1 or 2, and each R AA is methyl.

[0091] In an example of implementation, aa is 0 or 1.

[0092] In an embodiment, each R 2a is independently a halogen.

[0093] In an embodiment, each R 2a is independently -F or -Cl.

[0094] In an embodiment, the C5 carbon of 2-dihydrofuranone is ( R )-has a composition.

[0095] In an embodiment, the C5 carbon of 2-dihydrofuranone is ( R )-has a composition.

[0096] In another aspect, the present invention ( I Compounds having a structure according to ):

[0097] ( I ),

[0098] Characterized by compounds including its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes, wherein:

[0099] Each R a and R b is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl; R a and R b They combine with the atoms to which they are bonded to form a carbon ring having five to seven ring atoms and optionally including a double bond; R a and R b They combine with the atoms they bond to form O, S, SO, SO2, and N R 1 Forming a ring having 6 to 8 ring atoms comprising a moiety selected from the group consisting of;

[0100] A is an N-linked, 5- to 12-membered nitrogen-containing heterocyclyl, wherein the nitrogen-containing heterocyclyl is cyclic or polycyclic and optionally comprises an additional heteroatom selected from O, N, and S, and wherein the non-aromatic nitrogen-containing heterocyclyl is R 2 Including additional energy;

[0101] 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;

[0102] R 2 is a 6- to 10-membered aryl, a 5- to 10-membered nitrogen-containing heteroaryl, and Selected from a group consisting of;

[0103] R 3 It is a 6- to 10-membered aryl or a 5- to 10-membered nitrogen-containing heteroaryl;

[0104] m is 1, 2, or 3;

[0105] n is 1, 2, 3, or 4;

[0106] During the meal A 1,2,3,4-tetrahydroquinol-1-yl, 1,2,3,4-tetrahydroisoquinol-2-yl, octahydropyrrolo[3,4- c ]Pyrrol-1-yl, or in the case of 2,6-diazaspiro[3,3]heptane-1-yl, R a and R b ...cannot all be methyl, ethyl, or phenyl, and R a and R b It cannot be combined to form an unsubstituted C3-C6 cycloalkyl group.

[0107] Chemical formula ( I In an implementation example of ), R a and R b They combine with the atoms to which they bond to form a ring having 6 to 8 ring atoms, wherein one of the ring atoms is O, S, SO, SO2, and N R 1 It is a moiety selected from a group consisting of

[0108] In the implementation example, the formula ( I The compound of ) has one of the following structures:

[0109]

[0110] ceremony ( I In an implementation example of ), R a and R b are all methyl or ethyl, or R a and R b It combines to form unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0111] In the implementation example, the formula ( I The compound of ) has one of the following structures:

[0112]

[0113]

[0114] In the implementation example, the formula ( I Compounds of ) follow one of the following structures:

[0115]

[0116]

[0117]

[0118] ceremony ( I In an implementation example of ), R a and R b It combines with atoms bonded to them to form a ring having 6 to 8 ring atoms.

[0119] In the implementation example, the formula ( I The compound of ) is formula ( IF It has a structure according to ):

[0120] In the implementation example, the formula ( I The compound of ) has a structure according to one of the following formulas:

[0121]

[0122] ceremony ( I In an implementation example of ), A is selected from the group consisting of the following:

[0123]

[0124]

[0125] During the meal

[0126] R 2 phenyl, naphthyl, pyridyl, indolyl, and Selected from a group consisting of;

[0127] R 3 is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl;

[0128] R A is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, Selected from the group consisting of C1-C7 acylamino, mono- or di- C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen;

[0129] a is 0, 1, or 2.

[0130] ceremony ( I In an implementation example of ), A is selected from the group consisting of the following:

[0131]

[0132]

[0133]

[0134] ceremony ( I In an implementation example of ), Ais selected from the group consisting of the following:

[0135]

[0136] ceremony ( I In an implementation example of ), a is 0. Equation ( I In an implementation example of ), a is 1. Equation ( I In an implementation example of ), a is 2.

[0137] ceremony ( I In an implementation example of ), R 1 H, C1-C7 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, imidazole, oxazole, isoxazole,

[0138]

[0139] Selected from a group consisting of;

[0140] Each R 4a , R 4b , R 4c , R 6a , R 6b and R 6c is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0141] R 4a and R 4b They are optionally combined with the atoms to which they are bonded to form a ring containing 3 to 7 atoms and optionally oxygen;

[0142] R 6a and R 6b They are optionally combined with the atoms to which they are bonded to form a ring containing 3 to 7 atoms and optionally oxygen;

[0143] Each R 4d and R 6d is selected from the group consisting of phenyl, benzyl, pyridyl, -CH2(pyridyl), imidazole, and -CH2(imidazole);

[0144] R 5 is hydrogen, C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of;

[0145] R 7 Silver hydrogen, C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NHCONR 8f Selected from a group consisting of;

[0146] Each R 8a , R 8b , R 8d , R 8 , and R 8i g is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0147] R 8a and R 8b is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms and optionally oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group selected from;

[0148] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl;

[0149] R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls;

[0150] R 4a and R 8a All exist or R 4a and R 8g When all of them are present, these groups arbitrarily combine with the atoms to which they are bonded to form a ring containing 4 to 7 atoms;

[0151] R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0152] R 11 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0153] y 1 is 0, 1, or 2;

[0154] y 2 is 0, 1, or 2.

[0155] ceremony ( I In an implementation example of ), R 1 is selected from the group consisting of the following:

[0156]

[0157] ceremony ( I In an implementation example of ), R 1 is selected from the group consisting of the following:

[0158] COOR 5 (R in food 5 is C6-C 10 It is an aryl or a 5- to 10-membered heteroaryl;

[0159] (each of the food) R 8a and R 8b is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms and optionally oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group selected from; R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl);

[0160] (during the meal) R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C10 Selected from the group consisting of aryls, and 5 to 10 heteroaryls;

[0161] (during the meal, R 8h is an unsubstituted C1-C7 alkyl;

[0162] (during the meal) R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls, and 5 to 10 heteroaryls;

[0163] or (each of the food) R 8a and R 8b is independently an H or unsubstituted C1-C7 alkyl;

[0164] (during the meal) R 8d is independently an H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl)

[0165] or (during the meal) R 4a and R 8g Each of the is independently H or an unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl;

[0166]

[0167] (during the meal) R 8h is an unsubstituted C1-C7 alkyl;

[0168] (each of the food) R 8a , R 8b , and R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl;

[0169]

[0170]

[0171] (each of the food) R 8a and R 8b is independently an H or unsubstituted C1-C7 alkyl;

[0172]

[0173] (during the meal) R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an independently unsubstituted C1-C7 alkyl); or

[0174]

[0175] In another aspect, the present invention ( II Compound according to ):

[0176]

[0177] Characterized by compounds including its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes, wherein:

[0178] A 2 Is or And;

[0179] R 2 is a 6- to 10-membered aryl, a 5- to 10-membered nitrogen-containing heteroaryl, and Selected from a group consisting of;

[0180] R 3 It is a 6- to 10-membered aryl or a 5- to 10-membered nitrogen-containing heteroaryl;

[0181] R A is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, Selected from the group consisting of C1-C7 acylamino, mono- or di- C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen;

[0182] a is 0, 1, or 2;

[0183] m is 1, 2, or 3;

[0184] n is 1, 2, 3, or 4;

[0185] R 1' C6-C 10 Aryl, 5- to 6-membered heteroaryl ring,

[0186]

[0187] Selected from a group consisting of;

[0188] Each R 4a , R 4b , R 4c , R 6a , R 6b and R 6c is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0189] R 4a and R 4b They are optionally combined with the atoms to which they are bonded to form a ring containing 3 to 7 atoms and optionally oxygen;

[0190] R 6a and R 6b They are optionally combined with the atoms to which they are bonded to form a ring containing 3 to 7 atoms and optionally oxygen;

[0191] Each R 4d and R 6d is selected from the group consisting of phenyl, benzyl, pyridyl, -CH2(pyridyl), imidazole, and -CH2(imidazole);

[0192] R 5 is hydrogen, C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of;

[0193] R 7 Silver hydrogen, C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NHCONR 8f Selected from a group consisting of;

[0194] Each R 8a , R 8b , R 8d , R 8g , and R 8i is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0195] R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls;

[0196] R 8a and R 8b is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms and optionally oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group selected from;

[0197] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl;

[0198] R 4a and R 8a All exist or R 4a and R 8g When all of them are present, these groups arbitrarily combine with the atoms to which they are bonded to form a ring containing 4 to 7 atoms;

[0199] R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0200] R 11 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0201] y 1 is 0, 1, or 2;

[0202] y 2 is 0, 1, or 2;

[0203] Here A 2 go And, R 2 ga is phenyl, and R 1' this And, y 2 In the case where α is 0 and n is 2, R 7 It is not methyl, CH2SO2CH3, CH2CN, tetrahydropyranyl, phenyl, 4-substituted phenyl, or 5- to 8-membered heteroaryl.

[0204] In the implementation example, the formula ( II Compounds according to ) have one of the following structures:

[0205]

[0206] ceremony ( II In an implementation example of ), R 1' It is as follows:

[0207] COOR 5 (R in food 5 is C6-C 10 It is an aryl or a 5- to 10-membered heteroaryl;

[0208] (each of the food) R 8a and R 8b is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms and optionally oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group selected from; R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl);

[0209] (during the meal) R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls, and 5 to 10 heteroaryls;

[0210] (during the meal, R 8h is an unsubstituted C1-C7 alkyl;

[0211] (during the meal) R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls, and 5 to 10 heteroaryls;

[0212] (each of the food) R 8a andR 8b is independently an H or unsubstituted C1-C7 alkyl;

[0213] (during the meal) R 8d is independently an H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl)

[0214] (during the meal) R 4a and R 8g Each of the is independently H or an unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl;

[0215]

[0216] (during the meal) R 8h is an unsubstituted C1-C7 alkyl;

[0217] (each of the food) R 8a , R 8b , and R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl;

[0218]

[0219]

[0220]

[0221] (each of the food) R 8a and R 8b is independently an H or unsubstituted C1-C7 alkyl;

[0222]

[0223] (during the meal) R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an independently unsubstituted C1-C7 alkyl); or

[0224]

[0225] ceremony ( II In an implementation example of ), A 2 Is am.

[0226] ceremony ( II In an implementation example of ), A 2 Is am.

[0227] ceremony ( II In an implementation example of ), A 2 Is am.

[0228] In the implementation example, the formula ( I ), ( I* ), ( I** ), or ( II The compound of ) is a compound 1 ~ 145 It is any one of the above, and includes its enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, and complex.

[0229] In another aspect, the present invention relates to any compound described herein (e.g., formula ( I ), ( I* ), ( I** ), or ( II It features a pharmaceutical composition comprising a compound according to ) or a pharmaceutically acceptable salt thereof.

[0230] In an embodiment, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0231] In another aspect, the present invention features a method for treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity, said method comprising at least one compound such as that described herein (e.g., formula ( I ), ( I* ), ( I** ), or ( II The method includes the step of administering an effective amount of a compound according to ) or a pharmaceutically acceptable salt thereof to a subject.

[0232] In an embodiment, at least one compound or a pharmaceutically acceptable salt thereof is administered as a composition further comprising at least one excipient.

[0233] In an embodiment, diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity are selected from the group consisting of peripherally selective diseases, neurological diseases, circadian rhythm disorders, depression, schizophrenia, neuroinflammatory disorders, hypertension, peripheral vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulatory disorders, learning disabilities, memory disorders, hippocampal signaling disorders, sleep disorders, attention deficit / hyperactivity disorder, anxiety, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), intestinal inflammation, epilepsy, seizure disorders, drug addiction, alcoholism, breast cancer, liver fibrosis, chronic liver injury, hepatocellular carcinoma, small intestinal neuroendocrine tumor, and lung injury.

[0234] In an embodiment, the disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity is inflammatory bowel disease (IBD) or intestinal inflammation. Specific details for implementing the invention

[0235] definition

[0236] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. Any method and material similar or equivalent to that described herein may be used in the practice and testing of the invention, but exemplary methods, apparatuses, and materials are described below. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing in this document shall be construed as an acknowledgment that the invention is not qualified to precede this disclosure due to prior art.

[0237] As used throughout the specification, where a composition is described as having, including, or containing a specific component, or a process is described as having, including, or containing a specific process step, it should be understood that the composition of this teaching is also composed of or essentially composed of the listed components, and the process of this teaching is composed of or essentially composed of the listed process steps.

[0238] As used throughout this invention, it should be understood that where an element or component is included in and / or selected from the list of elements or components listed, the element or component may be any of the listed elements or components and may be selected from a group consisting of two or more of the listed elements or components.

[0239] In this document, the use of the singular form includes the plural form (and vice versa). Additionally, where the term "about" is used before a quantitative value, this instruction also includes the specific quantitative value itself unless otherwise noted.

[0240] It should be understood that the order of steps or procedures for performing any action is not important, as long as this instruction is feasible. Additionally, two or more steps or actions may be performed simultaneously.

[0241] As used herein, the term "halogen" means chlorine, bromine, fluorine, and iodine.

[0242] As used herein, unless otherwise noted, "alkyl" and / or "aliphatic," used alone or as part of a substituent, refer to linear and branched carbon chains having 1 to 20 carbon atoms or any number within this range, e.g., 1 to 6 carbon atoms or 1 to 4 carbon atoms. The specified number of carbon atoms (e.g., C1-C6) will be referred to independently of 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, Iso -profile, n -butyl, Sekh -butyl, Iso -butyl, Burst - Includes butyl, etc. The alkyl group may not be substituted or may be substituted, and substitution includes substitution with any substituent or combination of substituents described herein. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, etc. In substituents having multiple alkyl groups such as (C1-C6 alkyl)2amino, the alkyl groups may be the same or different.

[0243] As used herein, the terms “alkenyl” and “alkynyl” groups are used alone or as part of a substituent and refer to linear and branched carbon chains having two or more carbon atoms, preferably 2 to 20 carbon atoms, wherein the alkenyl chain has at least one double bond within the chain and the alkynyl chain has at least one triple bond within the chain. The alkenyl and alkynyl groups may be unsubstituted or may be substituted. Non-limiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2-methylethenyl), isopropenyl (also 2-methylethene-2-yl), butene-4-yl, etc. Non-limiting examples of substituted alkenyl groups include 2-chloroethenyl ( also Includes 2-chlorovinyl), 4-hydroxybutene-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, 7-hydroxy-7-methyloct-3,5-diene-2-yl, etc. Non-limiting examples of alkynyl groups are ethinyl, prop-2-inyl ( also It includes propargyl), propin-1-yl, and 2-methyl-hex-4-in-1-yl. Non-limiting examples of substituted alkynyl groups include 5-hydroxy-5-methylhex-3-inyl, 6-hydroxy-6-methylhept-3-in-2-yl, 5-hydroxy-5-ethylhept-3-inyl, etc.

[0244] As used herein, "cycloalkyl" refers to a non-aromatic carbon-containing ring comprising a cyclized alkyl group, an alkenyl group, and an alkynyl group, used alone or as part of another group, i.e., having 3 to 14 cyclic carbon atoms, preferably 3 to 7 or 3 to 6 cyclic carbon atoms, or even 3 to 4 cyclic carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bonds. The cycloalkyl group may be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., condensed, cross-linked, and / or containing a spiro-ring system), and the carbon atoms are located inside or outside the ring system. Any suitable ring position of the cycloalkyl group may be covalently bonded to the defined chemical structure. The cycloalkyl ring may be unsubstituted or may be substituted. Non-limiting examples of cycloalkyl groups include cyclopropyl, 2-methyl-cyclopropyl, cyclopropphenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decarinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1 H -Indenyl, 3a,4,5,6,7,7a-hexahydro-3 H -Indene-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl and dodecahydro-1 H - Includes fluorenyl. The term "cycloalkyl" also includes carbon-cyclic rings that are dicyclic hydrocarbon rings, and, as non-limiting examples, include bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl and bicyclo[3.3.3]undecanyl.

[0245] "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms, substituted with one or more halogens. The haloalkyl group includes a perhaloalkyl group, where all hydrogens of the alkyl group are substituted with a halogen (e.g., -CF3, -CF2CF3). The haloalkyl group may optionally be substituted with one or more substituents other than a halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

[0246] The term "alkoxy" refers to an -O-alkyl group, and the alkyl group is as defined above. The alkoxy group may be optionally substituted. The term C3-C6 cyclic alkoxy refers to a ring containing three to six carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). The C3-C6 cyclic alkoxy group may be optionally substituted.

[0247] The term "haloalkoxy" refers to -O-haloalkyl, and the haloalkyl group is as defined above. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and pentafluoroethoxy.

[0248] The term “aryl” is used alone or as part of another group and is defined herein as an unsaturated aromatic monocyclic ring of six carbon sources or an unsaturated aromatic polycyclic ring of six to fourteen carbon sources. The aryl group may be unsubstituted or may be substituted. The aryl ring may be, for example, a phenyl or naphthyl ring optionally substituted with one or more moiety capable of substituting 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- Third - Includes butylphenyl, 3-methoxyphenyl, 8-hydroxynaphtylene-2-yl, 4,5-dimethoxynaphtylene-1-yl, and 6-cyano-naphtylene-1-yl. The aryl group also includes a phenyl or naphthyl ring condensed with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl) that may be substituted on one or more carbon atoms of an aromatic and / or saturated or partially saturated ring.

[0249] The terms "arylalkyl" or "aryl-alkyl" refer to an alkyl-aryl group, and the alkyl group and the aryl group are as defined herein. The aryl-alkyl group of the present invention is optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl, etc.

[0250] The terms “heterocyclic” and / or “heterocyclic” and / or “heterocyclyl” are defined herein as one or more rings having 3 to 20 atoms, whether used alone or as part of another group, at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and the ring containing the heteroatom is non-aromatic. In a heterocyclic group comprising two or more condensed rings, the ring containing the non-heteroatom may be an aryl group (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). An exemplary heterocyclic group has 3 to 14 ring atoms, of which 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in the heterocyclic group may be oxidized. Heterocyclic groups may not be substituted or may be substituted.

[0251] Non-limiting examples of heterocyclic units having a single ring include diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isooxazolidinyl, isooxazolillyl, thiazolidinyl, isothiazolyl, isothiazolinyl, oxathiazolidinoyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranil, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranil, tetrahydropyranil, piperidin-2-onyl (valerolactam), and 2,3,4,5-tetrahydro-1 H -Azefinil, 2,3-Dihydro-1 H -Indole, and 1,2,3,4-tetrahydroquinoline are included. Non-limiting examples of heterocyclic units having two or more rings are hexahydro-1 H -Pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1 H -Benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1 H -Indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1 H - Contains cycloocta[b]pyrrolyl.

[0252] The term “heteroaryl” is used alone or as part of another group and is defined herein as one or more rings having 5 to 20 atoms, wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and at least one ring containing the heteroatom is aromatic. In a heteroaryl group comprising two or more condensed rings, the non-heteroatom-containing ring is a carbon ring (e.g., 6,7-dihydro-5 HIt may be -cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). An exemplary heteroaryl group has 5 to 14 ring atoms and contains 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms within the heteroaryl group may be oxidized. The heteroaryl group may be unsubstituted or may be substituted. Non-limiting examples of heteroaryl rings containing a single ring include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1 H - Includes imidazolyl, oxazolyl, furanyl, thiophenyl, pyrimimidinyl, 2-phenylpyriminyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing two or more condensed rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthalidinyl, phenanthridinyl, 7 H -Furinil, 9 H -Purinyl, 6-amino-9 H -Purinyl, 5H-Pyrrol[3,2- d ]Pyrimidinyl, 7 H -pyrrolo[2,3- d ]pyrimidinyl, pyrido[2,3- d ]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1 H -Indolyl, 4,5,6,7-tetrahydro-1- H -Indolyl, Quinoxalinil, 5-Methylquinoxalinil, Quinazolinil, Quinolinil, 8-Hydroxy-quinolinil, 1 H - Includes benzo[d]imidazole-2(3H)-o'nyl, 1H-benzo[d]imidazolyl, and isoquinolinyl.

[0253] One non-limiting example of the aforementioned heteroaryl group is a C1-C5 heteroaryl, which has one to five carbon ring atoms and at least one additional ring atom (preferably one to four additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S). Examples of C1-C5 heteroaryls include triazinyl, thiazole-2-yl, thiazole-4-yl, imidazole-1-yl, 1 H -Imidazole-2-yl, 1 H - Includes, but is not limited to, imidazole-4-yl, isooxazolin-5-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyridine-2-yl, pyridine-3-yl, and pyridine-4-yl.

[0254] Unless otherwise specified, when two substituents combine to form a ring having a specific number of ring atoms (e.g., R 2 and R 3 (where these combine with the attached nitrogen to form a 3 to 7-membered ring), the ring may have carbon atoms and optionally have one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). The ring may be saturated or partially saturated and optionally substituted.

[0255] For the purposes of the present invention, condensed ring units, including spirocyclic rings containing a single heteroatom and bicyclic rings, are also considered to belong to the ring group corresponding to the heteroatom-containing ring. For example, 1,2,3,4-tetrahydroquinoline having the following formula,

[0256]

[0257] For the purposes of the present invention, it is considered as a heterocyclic unit. 6,7-dihydro-5 having the following formula H-Cyclopentapyrimidine is,

[0258]

[0259] For the purposes of the present invention, it is considered as a heteroaryl unit. If a condensed ring unit contains heteroatoms in both the saturated and aryl rings, the aryl ring takes precedence and determines the type of category to which the ring is assigned. For example, 1,2,3,4-tetrahydro-[1,8]naphthiridine having the following formula,

[0260]

[0261] For the purposes of the present invention, it is considered as a heteroaryl unit.

[0262] Whenever a term or one of its prefix roots appears in the name of a substituent, the name shall be interpreted as including the limitations provided herein. For example, if the term "alkyl" or "aryl" or one of its prefix roots appears in the name of a substituent (e.g., arylalkyl, alkylamino), the name shall be interpreted as including the limitations for "alkyl" and "aryl" as set forth above.

[0263] The term “substituted” is used throughout the specification. The term “substituted” is defined herein as a moiety having one or more hydrogen atoms substituted by a substituent or multiple (e.g., 1 to 10) substituents, regardless of whether they are acyclic or cyclic. A substituent may replace one or two hydrogen atoms of a single moiety at a time. Additionally, these substituents may replace two hydrogen atoms on two adjacent carbons to form the aforementioned substituent, new moiety, or unit. For example, a substituted unit requiring a single hydrogen atom replacement includes halogens, hydroxyls, etc. Two hydrogen atom replacements include carbonyls, oxyminoids, etc. Two hydrogen atom replacements from adjacent carbon atoms include epoxyids, etc. The term “substituted” is used throughout the specification and indicates that a moiety may have one or more hydrogen atoms replaced by substituents. When a moiety is described as "substituted," any number of hydrogen atoms may be substituted. For example, difluoromethyl is a substituted C1 alkyl; trifluoromethyl is a substituted C1 alkyl; 4-hydroxyphenyl is a substituted aromatic ring; (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.

[0264] Various groups defined herein, e.g., alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, alkoxy groups, aryloxy groups, aryl groups, heterocyclic groups, and heteroaryl groups, may be used alone or as part of other groups and may be optionally substituted. Optionally substituted groups will be indicated as such.

[0265] The following are non-limiting examples of substituents that may substitute for hydrogen atoms on the moiety: halogens (chlorine (Cl), boron (Br), fluorine (F), and iodine (I)), -CN, -NO2, oxo (=O), -OR', -SR', -N(R')2, -NR'C(O)R', -SO2R', -SO2OR', -SO2N(R')2, -C(O)R', -C(O)OR', -C(O)N(R')2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 14 Cycloalkyl, aryl, heterocyclic, or heteroaryl; wherein each of the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclic, 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'; in each case R' are independently hydrogen, -OR", -SR", -C(O)R", -C(O)OR", -C(O)N(R")2,

[0266] -SO2R", -S(O)2OR", -N(R")2, -NR"C(O)R", C1-C6 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl (e.g., C3-C6 cycloalkyl), aryl, heterocyclic, or heteroaryl, or 2 R' The unit combines with the atom(s) to which it is bonded to form an arbitrarily substituted carbon ring or heteroring having 3 to 7 ring atoms; in each case R" It 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" The unit combines with the atom(s) to which it is bonded to form an arbitrarily substituted carbon ring or heteroring having 3 to 7 ring atoms.

[0267] In some implementations, the substituent is selected from the following:

[0268] i) -OR'"; e.g., -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3;

[0269] ii) -C(O)R'"; ​​e.g., -COCH3, -COCH2CH3, -COCH2CH2CH3;

[0270] iii) -C(O)OR'"; e.g., -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3;

[0271] iv) -C(O)N(R'")2; e.g., -CONH2, -CONHCH3, -CON(CH3)2;

[0272] v) -N(R'")2; e.g., -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3);

[0273] vi) Halogens: -F, -Cl, -Br, and -I;

[0274] vii) -CH e X g (where X is a halogen, m is 0 to 2, and e + g = 3); e.g., -CH2F, -CHF2, -CF3, -CCl3, or -CBr3;

[0275] viii) -SO2R'"; e.g., -SO2H; -SO2CH3; -SO2C6H5;

[0276] ix) C1-C6 linear, branched, or cyclic alkyl;

[0277] x) Cyano

[0278] xi) Nitro;

[0279] xii) N(R'")C(O)R'";

[0280] xiii) Oxo(=O);

[0281] xiv) Heterocyclic; and

[0282] xv) Heteroaryl,

[0283] Here, each R'"It may independently be hydrogen, an optionally substituted C1-C6 linear or branched alkyl (e.g., an optionally substituted C1-C4 linear or branched alkyl), or an optionally substituted C3-C6 cycloalkyl (e.g., an optionally substituted C3-C4 cycloalkyl), or two R"' units may be combined to form a ring comprising 3 to 7 ring atoms. In a given embodiment, each R'" is independently hydrogen, or a C1-C6 linear or branched alkyl optionally substituted with a halogen or C3-C6 cycloalkyl, or a C3-C6 cycloalkyl.

[0284] In various places within this specification, substituents of a compound are disclosed as groups or ranges. This specification is specifically intended to include all individual sub-combinations of these group and range members. For example, the term "C 1-6 "alkyl" is specifically intended to 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 alkyls individually.

[0285] For the purposes of the present invention, the terms “compound,” “analogous,” and “composition of a substance” are equally valid for the 5-hydroxytryptamine receptor 7 activity regulators described herein, including all enantiomer forms, diastereomer forms, salts, etc., and the terms “compound,” “analogous,” and “composition of a substance” are used interchangeably throughout this specification.

[0286] The compounds described herein may contain asymmetric atoms (also referred to as chiral centers), and some compounds may contain one or more asymmetric atoms or centers, thereby producing optical isomers (enantiomers) and diastereomers. The present teachings and the compounds disclosed herein include not only these enantiomers and diastereomers, but also racemic mixtures and resolved enantiomerically pure R and S stereoisomers, as well as other mixtures of said R and S stereoisomers and pharmaceutically acceptable salts thereof. For example, a specific gamma-butyrolactone comprising a substituent at the C5 carbon of a heterocyclic ring is described herein. In any compound or embodiment of the formula described herein, the C5 carbon is ( S It has a )-configuration. In any embodiment of the compound or formula described herein, the C5 carbon is ( R )-composition. Optical isomers may be obtained in pure form by standard procedures known to those skilled in the art, including but not limited to diastereomer salt formation, kinetic splitting, and asymmetric synthesis. The present teaching also includes cis and trans isomers of compounds containing alkenyl moiety (e.g., alkenes and imines). Additionally, the present teaching includes all possible regioisomers and mixtures thereof, the mixtures thereof may 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.

[0287] Pharmaceutically acceptable salts of the compounds of the present teaching that may have an acidic moiety may be formed using organic and inorganic bases. Both mono- and polyanionic salts are considered depending on the number of acidic hydrogens useful for deprotonation. Suitable salts formed with bases include metal salts such as alkali metal or alkaline earth metal salts (e.g., sodium, potassium, or magnesium salts), ammonia salts and organic amine salts such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-lower alkylamines (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-, or dimethylpropylamine), or mono-, di-, or trihydroxy lower alkylamines (e.g., mono-, di-, or triethanolamine). Non-limiting examples of specific inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Internal salts may also be formed. Similarly, if the compounds disclosed herein contain a basic moiety, salts may be formed using organic and inorganic acids. For example, the salt may be formed from the following acids: acetic acid, propionic acid, lactic acid, benzenesulfonic acid, benzoic acid, camphosulfonic acid, citric acid, tartaric acid, succinic acid, dichloroacetic acid, ethenesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromide, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucinous acid, naphthalenesulfonic acid, nitric acid, oxalic acid, parmolic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid, camphosulfonic acid, and other known pharmaceutically acceptable acids.

[0288] Where any variable appears two or more times in any component or any chemical formula, its definition in each case is independent of its definition in all other cases (e.g., N(R9 In )2, each R 9 (They may be identical or different). Combinations of substituents and / or variables are permitted only if such combinations stabilize the compound.

[0289] As used in this institution, the terms "treat," "treating," and "treatment" refer to partially or completely alleviating, suppressing, improving, and / or reducing a condition suspected to be suffered by a patient.

[0290] As used herein, "therapeutically effective" and "effective dose" refer to a substance or amount that induces a desired biological activity or effect.

[0291] Except as mentioned, the terms “subject” or “patient” are used interchangeably to refer to human patients and non-human primates, as well as experimental animals such as rabbits, rats, mice, and other animals. Accordingly, the terms “subject” or “patient” as used herein refer to any mammalian patient or subject to whom the compounds of the present invention may be administered. In exemplary embodiments of the present invention, screening methods are used to identify a subject for treatment according to the method of the present invention, to determine risk factors associated with the targeted or suspected disease or condition, or to determine the state of the pre-existing disease or condition in the subject. Such screening methods include, for example, conventional work to determine risk factors that may be associated with the targeted or suspected disease or condition. In these and other conventional methods, a clinician may select a patient who requires treatment using the method and compounds of the present invention.

[0292] 5-hydroxytryptamine receptor 7 activity regulator

[0293] 5-HT7 activity regulator

[0294] Lactone compounds capable of modulating the activity of 5-hydroxy receptor 7 (5-HT7) are described herein. In particular, the compounds described herein may be selective regulators of the 5-HT7 receptor. In an embodiment, the selective modulation of 5-HT7 includes the selective modulation of 5-HT7 in relation to other receptors. In an embodiment, the selective modulation of 5-HT7 includes, for example, the selective modulation of 5-HT7 expressed in a specific organ or tissue. Accordingly, the compounds described herein may be useful for the treatment of various diseases and pathological conditions (e.g., as described herein).

[0295] In an embodiment of any formula described herein, the C1-C7 alkyl is a C1-C7 linear alkyl. In an embodiment, the C1-C7 alkyl is an unsubstituted C1-C7 linear alkyl. In an embodiment, the C1-C7 alkyl is a substituted C1-C7 linear alkyl (substituted with one, two, three, or more substituents as described herein). In an embodiment, the substituted C1-C7 linear alkyl is a C1-C7 linear perhaloalkyl (e.g., perfluoroalkyl). In an embodiment, the substituted C1-C7 linear alkyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Another exemplary embodiment of a C1-C7 alkyl is described herein.

[0296] In an embodiment of any formula described herein, the C1-C7 alkyl is a C3-C7 branched alkyl. In an embodiment, the C3-C7 branched alkyl is an unsubstituted C3-C7 branched alkyl. In an embodiment, the C3-C7 branched alkyl is a substituted C3-C7 branched alkyl (substituted with one, two, three, or more substituents as described herein). In an embodiment, the substituted C3-C7 branched alkyl is a C3-C7 branched perhaloalkyl (e.g., perfluoroalkyl). In an embodiment, the substituted C3-C7 branched alkyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Another exemplary embodiment of a C3-C7 branched alkyl is described herein.

[0297] In any embodiment of the formula described herein, the cycloalkyl is a C3-C7 or C3-C8 cycloalkyl. In an embodiment, the cycloalkyl is cyclopropyl. In an embodiment, the cycloalkyl is cyclobutyl. In an embodiment, the cycloalkyl is cyclopentyl. In an embodiment, the cycloalkyl is cyclohexyl. In an embodiment, the cycloalkyl is an unsubstituted cycloalkyl (e.g., unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In an embodiment, the cycloalkyl is a substituted cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl comprising 1, 2, 3, 4, or 5 substituents including the exemplary substituents described herein). In an embodiment, the substituted cycloalkyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Another exemplary embodiment of the cycloalkyl is described herein.

[0298] In an embodiment of any formula described herein, C6-C 10The aryl is phenyl. In an embodiment, the phenyl is an unsubstituted phenyl. In an embodiment, the phenyl is a substituted phenyl (e.g., a phenyl having 1, 2, 3, 4, or 5 substituents, including the exemplary substituents described herein). The substituted phenyl group may be attached through any available carbon of the ring, including in a manner as described herein. For example, the phenyl may have a substituent as described herein (e.g., OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2) at the para position of the attachment site to the molecule (e.g., a 4-substituted phenyl group). For example, phenyl may have a substituent as described herein (e.g., OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2) at a meta position (e.g., a 3-substituted phenyl group) of an attachment site to the molecule. For example, phenyl may have a substituent as described herein (e.g., OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2) at an ortho position (e.g., a 2-substituted phenyl group) of an attachment site to the molecule. The phenyl group may have two or more substituents (e.g., 2,3-disubstituted, 2,4-disubstituted, 2,5-disubstituted, 2,6-disubstituted, 3,4-disubstituted, or 3,5-disubstituted phenyl) or three or more substituents (e.g., 2,3,4-trisubstituted, 2,3,5-trisubstituted, 2,3,6-trisubstituted, 2,4,5-trisubstituted, 2,4,6-trisubstituted, 3,4,5-trisubstituted, or 3,4,6-trisubstituted phenyl).In an embodiment, the substituted phenyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Another exemplary embodiment of the phenyl is described herein. In an embodiment, the 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.

[0299] In an embodiment of any formula described herein, C6-C 10The aryl is a naphthyl. In an embodiment, the naphthyl is an unsubstituted naphthyl. In an embodiment, the naphthyl is a substituted naphthyl (e.g., a naphthyl comprising 1, 2, 3, 4, or 5 substituents, including the exemplary substituents described herein). In an embodiment, the naphthyl is attached to the molecule at the C1-position (1-naphthyl). In an embodiment, the naphthyl is attached to the molecule at the C2-position (2-naphthyl). In an embodiment, the naphthyl is attached to the molecule at the C3-position (3-naphthyl). In an embodiment, the naphthyl is attached to the molecule at the C4-position (4-naphthyl). In an embodiment, the naphthyl is attached to the molecule at the C5-position (5-naphthyl). In an embodiment, the naphthyl is attached to the molecule at the C6-position (6-naphthyl). In an embodiment, the naphthyl is attached to the molecule at the C7-position (7-naphthyl). In an embodiment, the naphthyl is attached to the molecule at the C8-position (8-naphthyl). In an embodiment, the substituted naphthyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Another exemplary embodiment of the naphthyl is described herein.

[0300] In any embodiment of the formula described herein, the 5- to 10-membered heteroaryl is imidazolyl. In an embodiment, the imidazolyl is an unsubstituted imidazolyl. In an embodiment, the imidazolyl is a substituted imidazolyl (e.g., an imidazolyl comprising 1, 2, or 3 substituents including the exemplary substituents described herein). In an embodiment, the imidazolyl is an N-linked imidazolyl and is attached to the molecule through the N1 position of the imidazolyl (1-imidazolyl). In an embodiment, the imidazolyl is a C-linked imidazolyl. In an embodiment, the imidazolyl is attached to the molecule through the C2 position of the imidazolyl group (2-imidazolyl). In an embodiment, the imidazolyl is attached to the molecule through the C4 position of the imidazolyl group (4-imidazolyl). In an embodiment, imidazolyl is attached to the molecule through the C5 position of the imidazolyl group (5-imidazolyl). In an embodiment, the substituted imidazolyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. In an embodiment, the substituted imidazolyl is N-methylimidazolyl. Another exemplary embodiment of imidazolyl is described herein.

[0301] In any embodiment of the formula described herein, the 5- to 10-membered heteroaryl is pyrrolyl. In an embodiment, the pyrrolyl is an unsubstituted pyrrolyl. In an embodiment, the pyrrolyl is an N-bonded pyrrolyl and is attached to the molecule through the N1 position of the pyrrolyl (1-pyrrolyl). In an embodiment, the pyrrolyl is a C-bonded pyrrolyl. In an embodiment, the pyrrolyl is attached to the molecule through the C2 position of the pyrrolyl (2-pyrrolyl). In an embodiment, the pyrrolyl is attached to the molecule through the C3 position of the pyrrolyl (3-pyrrolyl). In an embodiment, the pyrrolyl is attached to the molecule through the C4 position of the pyrrolyl (4-pyrrolyl). In an embodiment, the pyrrolyl is attached to the molecule through the C5 position of the pyrrolyl (5-pyrrolyl). In an embodiment, the pyrrolyl is a substituted pyrrolyl (e.g., a pyrrolyl comprising one, two, or three substituents, including the exemplary substituents described herein). In an embodiment, the substituted pyrrolyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Another exemplary embodiment of the pyrrolyl is described herein.

[0302] In any embodiment of the formula described herein, the 5- to 10-membered heteroaryl is an oxazolyl. In an embodiment, the oxazolyl is an unsubstituted oxazolyl. In an embodiment, the oxazolyl is attached to the molecule through the C2 position of the oxazolyl (2-oxazolyl). In an embodiment, the oxazolyl is attached to the molecule through the C3 position of the oxazolyl (3-oxazolyl). In an embodiment, the oxazolyl is attached to the molecule through the C4 position of the oxazolyl (4-oxazolyl). In an embodiment, the oxazolyl is a substituted oxazolyl (e.g., an oxazolyl comprising one or two substituents, including the exemplary substituents described herein). In an embodiment, the substituted oxazolyl comprises one or two substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Another exemplary embodiment of imidazolyl is described herein.

[0303] In any embodiment of the formula described herein, the 5- to 10-membered heteroaryl is tetrazolyl. In an embodiment, the tetrazolyl is unsubstituted tetrazolyl. In an embodiment, the tetrazolyl is substituted tetrazolyl (e.g., N-substituted tetrazolyl comprising the exemplary substituents described herein). Another exemplary embodiment of tetrazolyl is described herein.

[0304] In any embodiment of the formula described herein, the 5- to 10-membered heteroaryl is pyridyl. In an embodiment, pyridyl is unsubstituted pyridyl. In an embodiment, pyridyl is attached to the molecule through the C2 position of pyridyl (2-pyridyl). In an embodiment, pyridyl is attached to the molecule through the C3 position of pyridyl (3-pyridyl). In an embodiment, pyridyl is attached to the molecule through the C4 position of pyridyl (4-pyridyl). In an embodiment, pyridyl is attached to the molecule through the C2 position of pyridyl (5-pyridyl). In an embodiment, pyridyl is attached to the molecule through the C2 position of pyridyl (6-pyridyl). In an embodiment, pyridyl is substituted pyridyl (e.g., pyridyl comprising 1, 2, 3, or 4 substituents, including the exemplary substituents described herein). In an embodiment, the substituted pyridyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Another exemplary embodiment of pyridyl is described herein.

[0305] In any embodiment of the formula described herein, the 5- to 10-membered heteroaryl is pyrazinyl. In an embodiment, the pyrazinyl is unsubstituted pyrazinyl. In an embodiment, the pyrazinyl is 2-pyrazinyl. In an embodiment, the pyrazinyl is 3-pyrazinyl. In an embodiment, the pyrazinyl is 5-pyrazinyl. In an embodiment, the pyrazinyl is 6-pyrazinyl. In an embodiment, the pyrazinyl is substituted pyrazinyl (e.g., a pyrazinyl comprising 1, 2, 3, or 4 substituents, including the exemplary substituents described herein). In an embodiment, the substituted pyrazinyl comprises one, two, or three substituents selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. Another exemplary embodiment of pyrazinyl is described herein.

[0306] In any embodiment of the formula described herein, the 5- to 10-membered heteroaryl is an indolyl. In an embodiment, the indolyl is an unsubstituted indolyl. In an embodiment, the indolyl is an N-linked indolyl and is attached to the molecule through the N1 position of the indolyl (1-indolyl). In an embodiment, the indolyl is a C-linked indolyl. In an embodiment, the indolyl is attached to the molecule through the C2 position of the indolyl (2-indolyl). In an embodiment, the indolyl is attached to the molecule through the C3 position of the indolyl (3-indolyl). In an embodiment, the indolyl is attached to the molecule through the C4 position of the indolyl (4-indolyl). In an embodiment, the indolyl is attached to the molecule through the C5 position of the indolyl (5-indolyl). In an embodiment, the indolyl is attached to the molecule through the C6 position of the indolyl (6-indolyl). In an embodiment, the indolyl is attached to the molecule through the C7 position of the indolyl (7-indolyl). In an embodiment, the indolyl is a substituted indolyl (e.g., an indolyl comprising 1, 2, 3, or 4 substituents, including the exemplary substituents described herein). In an embodiment, the substituted indolyl comprises 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. Another exemplary embodiment of the indolyl is described herein.

[0307] In any embodiment of the formula described herein, the substituent is selected from the group consisting of: C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, C1-C7 acylamino, modo- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, arylcarbonyl, and 5- to 6-membered heterocyclic groups each containing 4 heteroatoms selected from oxygen, sulfur, and nitrogen. In an embodiment, the substituent is not substituted itself. In an embodiment, the substituent is selected from the group consisting of OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0308] In any embodiment of the formula described herein, the C5 carbon of the 2-dihydrofuranone core is ( R )-has a composition.

[0309] In any embodiment of the formula described herein, the C5 carbon of the 2-dihydrofuranone core is ( S )-has a composition.

[0310] In any embodiment of the formula described herein, R A or R AA The carbon substituted with ( R )-has a composition.

[0311] In any embodiment of the formula described herein, R A or R AA The carbon substituted with ( S )-has a composition.

[0312] ceremony ( I* ) and ( I** ) compound

[0313] ceremony ( I* The compound of ) is formula ( I* ) is described herein with exemplary embodiments.

[0314] The exemplary formulas and compounds described herein may also include their hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

[0315] In one embodiment, the present invention ( I* Compounds having a structure according to )

[0316] ( I* ),

[0317] Characterized by compounds including its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes, wherein:

[0318] R 1N It is imidazole, oxazole, isoksazole, , and Selected from a group consisting of; among the formulas

[0319] Each R 4a and R 4b is hydrogen or C1-C7 alkyl; optionally R 4a and R 4b They combine with the atoms to form a ring containing 3 to 7 atoms and optionally oxygen;

[0320] R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of;

[0321] Each R 8a , R 8b , R 8d , R 8g , and R 8i is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms, oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group optionally selected from;

[0322] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl;

[0323] R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10Selected from the group consisting of aryls and 5 to 10 heteroaryls;

[0324] R 4a and R 8a All exist or R 4a and R 8g When all of them are present, these groups arbitrarily combine with the atoms to which they are bonded to form a ring containing 4 to 7 atoms;

[0325] R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0326] Each R AA is independently a C1-C7 linear alkyl;

[0327] Each R 2a is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN;

[0328] a is 0, 1, or 2;

[0329] aa is 0, 1, or 2;

[0330] y 1 is 0, 1, or 2.

[0331] In another aspect, the present invention ( I * -N Compounds having a structure according to ):

[0332] ( I*-N ),

[0333] Characterized by compounds including its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes, wherein:

[0334] R 1N-N C6-C 10 Heteroaryl, 5- to 10-membered heteroaryl, , , and Selected from a group consisting of;

[0335] Each R 4a and R 4b is hydrogen or C1-C7 alkyl; optionally R 4a and R 4b They combine with the atoms to form a ring containing 3 to 7 atoms and optionally oxygen;

[0336] R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of;

[0337] Each R 8a , R 8b , R 8d , R 8g , and R 8i is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a andR 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms, oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group optionally selected from;

[0338] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl;

[0339] R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls;

[0340] R 4a and R 8a All exist or R 4a and R 8g When all of them are present, these groups arbitrarily combine with the atoms to which they are bonded to form a ring containing 4 to 7 atoms;

[0341] R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0342] Each R AA is independently a C1-C7 linear alkyl;

[0343] Each R 2a is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN;

[0344] a is 0, 1, or 2;

[0345] aa is 0, 1, or 2;

[0346] y 1 is 0, 1, or 2;

[0347] R 5 If is an unsubstituted C1-C7 alkyl or an unsubstituted C3-C7 cycloalkyl, a is 1 or 2.

[0348] In an example of implementation, R 5 is an unsubstituted C1-C7 alkyl or an unsubstituted C3-C7 cycloalkyl, and a is 1 or 2.

[0349] In the implementation example, the formula ( I* Compounds according to ) have a structure according to the following formula and

[0350] ( I*-R ), during food R 1N , R AA , R 2a , aa , and a It follows any mode or embodiment as described herein.

[0351] In the implementation example, the formula ( I* Compounds according to ) have a structure according to the following formula and

[0352] ( I*-S ), during food R 1N , R AA , R 2a , aa , and a It follows any mode or embodiment as described herein.

[0353] In the implementation example, the formula ( I*-N Compounds according to ) have a structure according to the following formula and

[0354] ( I*-NR ), during food R 1N-N , R AA , R 2a , aa , and a It follows any mode or embodiment as described herein.

[0355] In the implementation example, the formula ( I*-N Compounds according to ) have a structure according to the following formula and

[0356] ( I*-NS ), during food R 1N-N , R AA , R 2a , aa , and a It follows any mode or embodiment as described herein.

[0357] In an example of implementation, Each R AA is independently a C1-C7 linear alkyl. In an embodiment, each R AA is independently methyl.

[0358] In an example of implementation, a is 0. In the implementation example, a is 1. In the implementation example, a is 2. In the implementation example, a is not 0. In the implementation example, a is excluding 0. In an example implementation, a is 0 or 1. In an example implementation, a is 1 or 2.

[0359] In an embodiment, each R 2a is independently a halogen. In an embodiment, Each R 2a is independently F. In an example implementation, Each R 2a is independently Cl.

[0360] In an example of implementation, aa is 0. In the implementation example, aa is 1. In the implementation example, aa is 2. In the implementation example, aa is 1 or 2.

[0361] In an example of implementation, R 1N It is imidazole, oxazole, isooxazole, , and Selected from a group consisting of; among the formulas

[0362] Each R 4a and R 4b is hydrogen or C1-C7 alkyl; optionally R 4a and R 4b They combine with the atoms to form a ring containing 3 to 7 atoms and optionally oxygen;

[0363] R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of;

[0364] Each R 8a , R 8b , R 8d , R 8g , and R 8i is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms, oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group optionally selected from;

[0365] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl;

[0366] R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls;

[0367] R 4a and R 8a All exist or R 4a and R 8g When all of them are present, these groups arbitrarily combine with the atoms to which they are bonded to form a ring containing 4 to 7 atoms;

[0368] R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0369] y 1 is 0, 1, or 2.

[0370] In an example of implementation,R 1N-N C6-C 10 Heteroaryl, 5- to 10-membered heteroaryl, , , and Selected from a group consisting of;

[0371] Each R 4a and R 4b is hydrogen or C1-C7 alkyl; optionally R 4a and R 4b They combine with the atoms to form a ring containing 3 to 7 atoms and optionally oxygen;

[0372] R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of;

[0373] Each R 8a , R 8b , R 8d , R 8g , and R 8i is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms, oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group optionally selected from;

[0374] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl;

[0375] R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls;

[0376] R 4a and R 8a All exist or R 4a and R 8g When all of them are present, these groups arbitrarily combine with the atoms to which they are bonded to form a ring containing 4 to 7 atoms;

[0377] R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0378] R 11 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0379] y 1 is 0, 1, or 2.

[0380] In an example of implementation, R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and It is selected from a group consisting of. In an embodiment, R 5 ... excludes unsubstituted C1-C7 alkyl groups. In an embodiment, R 5 It excludes unsubstituted C3-C7 cycloalkyl groups.

[0381] In an example of implementation, R 1N silver is. In the implementation example, R 1N-N silver is. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0382] In an example of implementation, R 1N silver is. In the implementation example, R 1N-N silver is. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0383] In an example of implementation, R 1N-N silver is. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0384] In an example of implementation, y 1 is 0, and R 1 COR 5 is. In the implementation example, R 5 is Piridil. In the implementation example, R 5 is Piridazine. In the embodiment, R 5 is a C1-C7 alkyl. In an embodiment, R 5 is a C3-C7 cycloalkyl. In an embodiment, R 5 is a C1-C7 haloalkyl. In an embodiment, R 5 is a C3-C7 cyclohaloalkyl. In an embodiment, R 5 is a C1-C7 fluoroalkyl. In an embodiment, R 5 is a C3-C7 cyclofluoroalkyl.

[0385] In an example of implementation, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0386] In an example of implementation, R 4a is H. In the embodiment, R 4b is H. In the embodiment, R 4a and R 4b All are H. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0387] In an example of implementation, R 5 is Piridil. In the implementation example, R 5 is Piridazine. In the embodiment, R 5 is a C1-C7 alkyl. In an embodiment, R 5 is a C3-C7 cycloalkyl. In an embodiment, R 5 is a C1-C7 haloalkyl. In an embodiment, R 5 is a C3-C7 cyclohaloalkyl. In an embodiment, R 5 is a C1-C7 fluoroalkyl. In an embodiment, R 5 is a C3-C7 cyclofluoroalkyl. In an embodiment, R 5 is an unsubstituted C1-C7 alkyl. In an embodiment, R 5 is a substituted C1-C7 alkyl (containing amino substituents such as -NH2, -NHCH3, or -N(CH3)2). In an embodiment, R 5 is phenyl. In an embodiment, R 5 is an unsubstituted phenyl. In an embodiment, R 5 is a substituted phenyl. In an embodiment, R 5 is NR 8a R 8b is. In the implementation example, R 5 is SO2R 8c is. In the implementation example, R 5 is NR 8d SO2R 8e is. In the implementation example, R 5 is NR 8i COOR 8jis. In the implementation example, R 5 NHCONR 8f is. In the implementation example, R 5 is NR 8g COR 8h is. In the implementation example, R 5 is not an unsubstituted C1-C7 alkyl.

[0388] In an example of implementation, R 11 It is hydrogen. In an embodiment, R 11 is a C1-C7 alkyl (e.g., methyl). In an embodiment, R 11 It is a C3-C7 cycloalkyl.

[0389] In an example of implementation, R 1N or R 1N-N silver

[0390] is, and among the food

[0391] R 4a , R 4b , and y 1 is according to any mode or embodiment described herein;

[0392] Z a CH2 or O and;

[0393] Z a If is CH2, p 1 + p 2 is 1, 2, 3, or 4;

[0394] Z a If is O, p 1 + p 2 is 1, 2, 3, or 4 and; p 1 and p 2 Both are not 0.

[0395] In an example of implementation,R 4a and R 4b These combine with the atoms to which they are bonded to form a carbon ring containing 3 to 7 atoms. In an embodiment, R 4a and R 4b These combine with the atoms to form an oxygen-containing ring containing 3 to 7 atoms.

[0396] In an example of implementation, R 1N or R 1N-N silver is, and among the food

[0397] Z b CH2 or O and;

[0398] Z b If is CH2, p 1 + p 2 is 1, 2, 3, or 4;

[0399] Z b If is O, p 1 + p 2 is 1, 2, 3, or 4 and; p 1 and p 2 Neither of them is 0;

[0400] R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR8g COR 8h , and Selected from a group consisting of;

[0401] Each R 8a , R 8b , R 8d , R 8g , R 8i , and R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0402] R 8a and R 8b is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms and optionally oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group selected from;

[0403] R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls, and 5 to 10 heteroaryls;

[0404] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl.

[0405] In an example of implementation, R 1N or R 1N-N silver

[0406] is, and among the food

[0407] R 4a , R 4b , andy 1 is according to any mode or embodiment described herein;

[0408] R 10a and R 10b is H, C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, SO2R 8e , COOR 8j , CONR 8f , and COR 8h Independently selected from a group consisting of;

[0409] R 10a and R 10b At least one of them is selected from the group consisting of H, C1-C7 linear alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl;

[0410] Each R 8e , R 8f , and R 8h is selected from the group consisting of H, C1-C7 linear alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl.

[0411] In an example of implementation, R 1N-N ureagi (e.g. )am.

[0412] In an example of implementation, R 1N or R 1N-N It is a carbamate group (e.g., ) is. In the implementation example, R 1N It has an aminoacyl group (e.g., ) is. In the implementation example, R 1N alkylacyl groups (e.g., or ) is. In the implementation example, R 1N or R 1N-N It is an aryl. In the embodiment, R 1N is a heteroaryl (e.g., ) is. In the implementation example, R 1N Eun Asilgi (e.g.: It is a heteroaryl containing ).

[0413] In an example of implementation, R 1N or R 1N-N silver and, each of the expressions R 8a and R 8b is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms, oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group arbitrarily selected from; R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl.

[0414] In an example of implementation, R 1N or R 1N-N silver And, in the expression, uu is 1 or 2.

[0415] In an example of implementation, R 1N or R 1N-N silver am.

[0416] In an example of implementation, R 1N or R 1N-N silver is, and among the food R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C10 It is selected from the group consisting of aryls and 5 to 10 heteroaryls.

[0417] In an example of implementation, R 1N or R 1N-N silver is, and among the food R 8h is an unsubstituted C1-C7 alkyl.

[0418] In an example of implementation, R 1N or R 1N-N silver or am.

[0419] In an example of implementation, R 1N or R 1N-N silver and, each of the expressions R 8a and R 8b is independently H or an unsubstituted C1-C7 alkyl.

[0420] In an example of implementation, R 1N or R 1N-N silver is, and among the food R 8d is independently an H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl.

[0421] In an example of implementation, R 1N or R 1N-N silver is, and among the food R 4a and R 8g Each is independently an H or unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl.

[0422] In an example of implementation,R 1N or R 1N-N silver is, and among the food R 4a and R 8g Each is independently an H or unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl.

[0423] In an example of implementation, R 1N or R 1N-N silver is, and among the food R 4a and R 8g Each is independently an H or unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl.

[0424] In an example of implementation, R 1N or R 1N-N silver is, and among the food R 8h is an unsubstituted C1-C7 alkyl.

[0425] In an example of implementation, R 1N or R 1N-N silver is, and among the food R 8h is an unsubstituted C1-C7 alkyl.

[0426] In an example of implementation, R 1N or R 1N-N silver is, and among the food R 8h is an unsubstituted C1-C7 alkyl.

[0427] In an example of implementation, R 1N or R 1N-N silver am.

[0428] In an example of implementation, R 1N or R 1N-N silver am.

[0429] In an example of implementation, R 1N or R 1N-N silver am.

[0430] In an example of implementation, R 1N or R 1N-N silver and, each of the expressions R 8a , R 8b , and R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0431] In an example of implementation, R 1N or R 1N-N silver is, and among the food R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 It is selected from the group consisting of aryls and 5 to 10 heteroaryls.

[0432] In an example of implementation, R 1N or R 1N-N silver am.

[0433] In an example of implementation, R 1N or R 1N-N silver am.

[0434] In an example of implementation, R 1N or R 1N-N silver and, each of the expressions R 8a and R 8b is independently H or an unsubstituted C1-C7 alkyl.

[0435] In an example of implementation, R 1N or R 1N-N silver is, and among the food R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an independently unsubstituted C1-C7 alkyl.

[0436] In an example of implementation, R 1N or R 1N-N silver am.

[0437] In an example of implementation, R 1N or R 1N-N silver am.

[0438] In an example of implementation, R 1N or R 1N-N silver am.

[0439] In the implementation example, the formula ( I* ) or ( I*-N The compound according to ) has the following structure

[0440] ( I*-1 ), each of the expressions R 5 , R 4a , R 4b , R 2a , R AA ,y 1 , aa , and a It follows any mode or embodiment as described herein.

[0441] In the implementation example, the formula ( I* ) or ( I*-N The compound according to ) has the following structure

[0442] ( I*-2 ), each of the expressions R 5 , R 4a , R 4b , R 2a , R AA , y 1 , aa , and a It follows any mode or embodiment as described herein.

[0443] In the implementation example, the formula ( I*-N The compound according to ) has the following structure

[0444] ( I*-3 ), each of the expressions R 5 , R 11 , R 4a , R 4b , R 2a , R AA , y 1 , aa , and a It follows any mode or embodiment as described herein.

[0445] In the implementation example, the formula ( I*-1 ), ( I*-2 ), or ( I*-3Compounds according to ) have one of the following structures, and

[0446] ( I*-1' ),

[0447] ( I*-1" ),

[0448] ( I*-2' ),

[0449] ( I*-2" ),

[0450] ( I*-3' ),

[0451] ( I*-3" ), during food

[0452] Each R 5 , R 11 , R 4a , R 4b , R 2a , R AA , y 1 , aa , and a It follows any mode or embodiment as described herein.

[0453] In another aspect, the present invention ( I** Compounds having a structure according to )

[0454] ( I**)

[0455] Characterized by compounds including its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes, wherein:

[0456] Each R aa and R bb is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl;

[0457] Each R AA is independently a C1-C7 linear alkyl;

[0458] Each R 2a is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN;

[0459] a' is 1 or 2 and;

[0460] aa is 0, 1, or 2.

[0461] In the implementation example, the formula ( I** Compounds according to ) have a structure according to the following formula and

[0462] ( I**-R ), during food R aa , R bb , R AA , R 2a , aa , and a ' is in accordance with any mode or embodiment as described herein.

[0463] In the implementation example, the formula ( I** Compounds according to ) have a structure according to the following formula and

[0464] ( I**-S ), during food R aa , R bb , R AA , R 2a , aa , and a ' is in accordance with any mode or embodiment as described herein.

[0465] In an example of implementation, Each R AA is independently a C1-C7 linear alkyl. In an embodiment, each R AA is independently methyl.

[0466] In an example of implementation, a' is 1. In the implementation example, a' It is 2. In the implementation example, a' It is 1 or 2.

[0467] In an embodiment, each R 2a is independently a halogen. In an embodiment, Each R 2a is independently F. In an example implementation, Each R 2a is independently Cl.

[0468] In an example of implementation, aa is 0. In the implementation example, aa is 1. In the implementation example, aa is 2. In the implementation example, aa is 1 or 2.

[0469] In an example of implementation, R aa is a C1-C7 linear alkyl. In an embodiment, R aa is a C3-C7 branched alkyl. In an embodiment, R aa is ethyl. In an embodiment, R bb is a C1-C7 linear alkyl. In an embodiment, R bb is a C3-C7 branched alkyl. In an embodiment, R bb is ethyl. In the embodiment R aa and R bb Each is ethyl.

[0470] Compound of Formula (I)

[0471] In one embodiment, the present invention ( I Compounds having a structure according to )

[0472] ( I ),

[0473] Characterized by compounds including its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes, wherein:

[0474] Each R a and R b is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl; R a and R b They combine with the atoms to which they are bonded to form a carbon ring having five to seven ring atoms and optionally including a double bond; R a and R b They combine with the atoms they bond to form O, S, SO, SO2, and N R 1 Forming a ring having 6 to 8 ring atoms comprising a moiety selected from the group consisting of;

[0475] A is an N-bonded 5- to 12-membered nitrogen-containing heterocyclyl, said nitrogen-containing heterocyclyl is cyclic or polycyclic and optionally comprises additional heteroatoms selected from O, N, and S, and the non-aromatic nitrogen-containing heterocyclyl is R 2 Including additional energy;

[0476] 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;

[0477] R 2 is a 6- to 10-membered aryl, a 5- to 10-membered nitrogen-containing heteroaryl, and Selected from a group consisting of;

[0478] R 3 It is a 6- to 10-membered aryl or a 5- to 10-membered nitrogen-containing heteroaryl;

[0479] m is 1, 2, or 3;

[0480] n It is 1, 2, 3, or 4.

[0481] In an example of implementation, A 1,2,3,4-tetrahydroquinol-1-yl, 1,2,3,4-tetrahydroisoquinol-2-yl, octahydropyrrolo[3,4- c ]Pyrrol-1-yl, or in the case of 2,6-diazaspiro[3,3]heptane-1-yl, R a and R b ...cannot all be methyl, ethyl, or phenyl, and R a and R b It cannot be combined to form an unsubstituted C3-C6 cycloalkyl.

[0482] In an example of implementation, A is 1,2,3,4-tetrahydroquinol-1-yl, 1,2,3,4-tetrahydroisoquinol-2-yl, octahydropyrrolo[3,4- c ] It is not pyrrole-1-yl or 2,6-diazaspiro[3,3]heptane-1-yl. In an embodiment, A is 1,2,3,4-tetrahydroquinol-1-yl, 1,2,3,4-tetrahydroisoquinol-2-yl, octahydropyrrolo[3,4- c ]Excluding pyrrole-1-yl, or 2,6-diazaspiro[3,3]heptane-1-yl.

[0483] In an example of implementation, R a and R b They combine with the atoms to which they bond to form a ring having 6 to 8 ring atoms, where one of the ring atoms is O, S, SO, SO2, and N R 1 It is a moiety selected from a group consisting of

[0484] In an embodiment, the compound according to formula (I) has a structure according to the following formula.

[0485] ( I' ), during food R a , R b , A , and n It follows any mode or embodiment as described herein.

[0486] In an embodiment, the compound according to formula (I) has a structure according to the following formula.

[0487] ( I" ), during food R a , R b , A , and n It follows any mode or embodiment as described herein.

[0488] In an embodiment, each R a and R b is methyl.

[0489] In an embodiment, each R a and R b is ethyl.

[0490] In an example of implementation, R a and R b It combines to form an unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In an embodiment, R a and R b It combines to form an unsubstituted cyclopropyl. In an embodiment, R a and R b It combines to form an unsubstituted cyclobutyl. In an embodiment, R a and R b It combines to form an unsubstituted cyclopentyl. In an embodiment, R a and R b It combines to form an unsubstituted cyclohexyl.

[0491] In an example of implementation, R a and R b It combines with the atoms to which they bond, and N R 1 It forms a ring having 6 to 8 ring atoms containing a moiety.

[0492] In an example of implementation, R a and R b is combined It forms popularity.

[0493] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0494] ( IA ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0495] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0496] ( IA' ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0497] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0498] ( IA" ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0499] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0500] ( IB ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0501] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0502] ( IB' ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0503] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0504] ( IB" ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0505] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0506] ( IC ). In an implementation example, n is 1. In the implementation example,n It is 2. In the implementation example, n It is 3.

[0507] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0508] ( IC' ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0509] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0510] ( IC" ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0511] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0512] ( ID ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0513] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0514] ( ID' ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0515] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0516] ( ID" ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0517] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0518] ( IE ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0519] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0520] ( IE' ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0521] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0522] ( IE" ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0523] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0524] ( IF ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0525] In the implementation example, the formula ( ICompounds according to ) have a structure according to the following formula:

[0526] ( IF' ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0527] In the implementation example, the formula ( I Compounds according to ) have a structure according to the following formula:

[0528] ( IF ). In an implementation example, n is 1. In the implementation example, n It is 2. In the implementation example, n It is 3.

[0529] In an example of implementation, A is selected from the group consisting of the following:

[0530]

[0531]

[0532]

[0533] During the meal

[0534] R 2 phenyl, naphthyl, pyridyl, indolyl, and Selected from a group consisting of;

[0535] R 3 is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl;

[0536] R A is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, Selected from the group consisting of C1-C7 acylamino, modo- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen;

[0537] a is 0, 1, or 2.

[0538] In an example of implementation, a is 0.

[0539] In an example of implementation, a is 1.

[0540] In an example of implementation, a is 2.

[0541] In an example of implementation, A is selected from the group consisting of the following:

[0542]

[0543]

[0544] In an example of implementation, A Is am.

[0545] In an example of implementation, A Is am.

[0546] In an example of implementation, A Is am.

[0547] In an example of implementation, A Is am.

[0548] In an example of implementation, A Is am.

[0549] In an example of implementation, A Is am.

[0550] In an example of implementation, A Is am.

[0551] In an example of implementation, A Is am.

[0552] In an example of implementation, A Is am.

[0553] In an example of implementation, A Is am.

[0554] In an example of implementation, A Is am.

[0555] In an example of implementation, A Is am.

[0556] In an example of implementation, A Is am.

[0557] In an example of implementation, A Is am.

[0558] In an example of implementation, A Is am.

[0559] In an example of implementation, A Is am.

[0560] In an example of implementation, A Is am.

[0561] In an example of implementation, A Is am.

[0562] In an example of implementation, A Is am.

[0563] In an example of implementation, A Is am.

[0564] In an example of implementation, A Is am.

[0565] In an example of implementation, A Is am.

[0566] In an example of implementation, A Is am.

[0567] In an example of implementation, A Is am.

[0568] In an example of implementation, A Is am.

[0569] In an example of implementation, A Is am.

[0570] In an example of implementation, A Is am.

[0571] In an example of implementation, A Is am.

[0572] In an example of implementation, A Is am.

[0573] In an example of implementation, A Is am.

[0574] In an example of implementation, A Is am.

[0575] In an example of implementation, A Is am.

[0576] In an example of implementation, A Is am.

[0577] In an example of implementation, A Is am.

[0578] In an example of implementation, A Is am.

[0579] ceremony (I In an implementation example of ), A is selected from the group consisting of the following:

[0580]

[0581] In an example of implementation, a is 0.

[0582] In an example of implementation, a is 1.

[0583] In an example of implementation, a is 2.

[0584] In an example of implementation, A Is am.

[0585] In an example of implementation, A Is am.

[0586] In an example of implementation, A Is am.

[0587] In an example of implementation, A Is am.

[0588] In an example of implementation, R 2 is phenyl. In an embodiment, R 2 is an unsubstituted phenyl. In an embodiment, R 2 is a phenyl comprising at least one halogen substituent (e.g., at least one substituent that is chloro or fluoro). In an embodiment, R 2 is a fluorophenyl (e.g., 2-, 3-, or 4-fluorophenyl), difluorophenyl, chlorophenyl (e.g., 2-, 3-, or 4-chlorophenyl), dichlorophenyl, or chlorofluorophenyl. In an embodiment, R 2 is OH, OCH3, NH2, CN, It is a phenyl substituted by 1, 2, or 3 groups (e.g., 1 or 2 groups) selected from CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0589] In an example of implementation, R 2 is naphthyl. In an embodiment, R 2 is an unsubstituted naphthyl. In an embodiment, R 2 is a naphthyl comprising at least one halogen substituent (e.g., at least one chloro or fluoro substituent). In an embodiment, R 2 is a naphthyl substituted by one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0590] In an example of implementation, R 2 is Piridil. In the implementation example, R 2 is 2-pyridyl. In an example implementation, R 2 is 3-pyridyl. In an implementation example, R 2 is 4-pyridyl. In the implementation example, R 2 is an unsubstituted pyridil. In the implementation example, R 2 is a pyridyl comprising at least one halogen substituent (e.g., at least one chloro or fluoro substituent). In an embodiment, R 2 is a pyridyl substituted by 1, 2, or 3 groups (e.g., 1 or 2 groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0591] In an example of implementation, R 2 is indolil. In an embodiment, R 2 is an unsubstituted indolyl. In an embodiment, R 2 is an indolyl comprising at least one halogen substituent (e.g., at least one chloro or fluoro substituent). In an embodiment, R 2 is an indolyl substituted by one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0592] In an example of implementation, R 2 is phenyl, naphthyl, pyridyl, or am.

[0593] In an example of implementation, R 2 Is is, and among the food aa is 0, 1, 2, or 3, and each R 2a is any substituent independently described herein. In an embodiment, each R 2a is independently selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. In an embodiment, each R 2a is independently selected from the group consisting of the following: C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkinyl, 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, A 5- to 6-membered heterocyclic group each containing 1 to 4 heteroatoms selected from amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and oxygen, sulfur, and nitrogen.

[0594] In an example of implementation, R 2 Is is. In an example, m is 1. In an example, m is 2. In an example, m is 3.

[0595] In an example of implementation, R 3 is phenyl. In an embodiment, R 3 is an unsubstituted phenyl. In an embodiment, R 3 is a phenyl comprising at least one halogen substituent (e.g., at least one chloro or fluoro substituent). In an embodiment, R 3 is fluorophenyl (e.g., 2-, 3-, or 4-fluorophenyl), difluorophenyl, chlorophenyl (e.g., 2-, 3-, or 4-chlorophenyl), dichlorophenyl, or chlorofluorophenyl. In an embodiment, R 3 OH, OCH3, NH2, CN, It is a phenyl substituted by 1, 2, or 3 groups (e.g., 1 or 2 groups) selected from CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0596] In an example of implementation, R 3 It is naphthyl. In an embodiment, R 3 is unsubstituted naphthyl. In an embodiment, R 3 is a naphthyl comprising at least one halogen substituent (e.g., at least one chloro or fluoro substituent). In an embodiment, R 3 It is a naphthyl substituted by one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0597] In an example of implementation, R 3 It is Piridil. In the implementation example, R 3 It is 2-pyridyl. In an example implementation, R 3 It is 3-pyridyl. In the implementation example, R 3 It is 4-pyridyl. In the implementation example, R 3 is an unsubstituted pyridil. In an example implementation, R 3 is a pyridyl comprising at least one halogen substituent (e.g., at least one chloro or fluoro substituent). In an embodiment, R 3 It is a pyridyl substituted by one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0598] In an example of implementation, R 3 It is indolyl. In an embodiment, R 3 is an unsubstituted indolyl. In an embodiment, R 3 is an indolyl comprising at least one halogen substituent (e.g., at least one chloro or fluoro substituent). In an embodiment, R 3 It is an indolyl substituted by one, two, or three groups (e.g., one or two groups) selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2.

[0599] In an example of implementation, R 3 It is phenyl, naphthyl, or pyridyl.

[0600] In an example of implementation, R 3 silver is, and among the food aa is 0, 1, 2, or 3, and each R 3a is any substituent independently described herein. In an embodiment, each R 3a is independently selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. In an embodiment, each R 3a is independently selected from the group consisting of the following: C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkinyl, 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, A 5- to 6-membered heterocyclic group each containing 1 to 4 heteroatoms selected from amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and oxygen, sulfur, and nitrogen.

[0601] In a specific implementation example, A Is is, and among the food R 2a is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, Selected from the group consisting of C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen;R A is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, aralkyl, nitro, hydroxy, mercapdo, oxo, thioxo, cyano, carba, carboxyl, C1-C7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, aryltio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, Selected from the group consisting of C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen; a is independently 0, 1, or 2.

[0602] In an example of implementation, R 1 C6-C 10 It is Aril.

[0603] In an example of implementation, R 1 It is a 5- to 6-membered heteroaryl ring. In an embodiment, R 1 is imidazolyl (e.g., unsubstituted imidazolyl or N-methylimidazolyl). In an embodiment, R 1 It is oxazolil (for example, It is an unsubstituted oxazolyl. In an embodiment, R 1 is isooxazolyl (e.g., unsubstituted oxazolyl).

[0604] In an example of implementation, R 1 silver is, and among the food X is O, NH, or NCH3, and aa1 is 0, 1, or 2, and R 1a is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, It is selected from the group consisting of C1-C7 acylamino, modo- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen.

[0605] In an example of implementation, R 1 silver It is selected from a group consisting of. In an embodiment, R 1 silver am.

[0606] In an example of implementation, R 1 It is a polar acyl group (e.g.,

[0607]

[0608] ) is. In the implementation example, R 1 ... is an acyl moiety comprising a C1-C7 alkyl group, a C3-C7 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), a C1-C7 haloalkyl group, a C3-C7 cycloalkyl group (e.g., cyclopropyl, cyclohalopropyl, cyclohalobutyl, cyclohalopenyl, or cyclohalohexyl), a quaternary to 6-membered oxygen-containing heterocyclyl (e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or oxazalidonone), or a quaternary to 6-membered nitrogen-containing heterocyclyl (e.g., azetidinyl, pyrrolidinyl, or piperidinyl), wherein the group is an amino group (e.g., -NH2, monoalkylamino (e.g., -NHMe), or dialkylamino (e.g., -NMe2)), an acetamido group (e.g., It comprises a substituent that is -NHCOMe or NMeCOMe), a carbamate group (e.g., -NHCO2Me or -NMeCO2Me), an alkylsulfonamido group (e.g., -NHSO2Me or -NMeSO2Me), or a 5- to 10-membered nitrogen-containing heterocyclic group (e.g., tetrazolyl, imidazolyl, N-methylimidazolyl, pyridyl, or pyridazinyl). In an embodiment, R 1 is an alkylacyl group (e.g., -C(O)(C1-C7alkyl) or -C(O)(C3-C7cycloalkyl)). In an embodiment, R 1 ... excludes unsubstituted alkylacyl groups (e.g., -C(O)(C1-C7alkyl) or -C(O)(C3-C7cycloalkyl)). In an embodiment, R 1 polar sulfonyl groups (e.g., subgroups such as those further described herein) or ) is. In the implementation example, R 1 is a sulfonyl moiety comprising a C1-C7 alkyl group, a C3-C7 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), a C1-C7 haloalkyl group, a C3-C7 cycloalkyl group (e.g., cyclopropyl, cyclohalopropyl, cyclohalobutyl, cyclohalopenyl, or cyclohalohexyl), a quaternary to 6-membered oxygen-containing heterocyclyl (e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or oxazalidonone), or a quaternary to 6-membered nitrogen-containing heterocyclyl (e.g., azetidinyl, pyrrolidinyl, or piperidinyl), wherein the group is an amino group (e.g., -NH2, monoalkylamino (e.g., -NHMe), or dialkylamino (e.g., -NMe2)), an acetamido group (e.g., It includes a substituent that is -NHCOMe or NMeCOMe), an alkylsulfonamido group (e.g., -NHSO2Me or -NMeSO2Me), or a 5- to 10-membered nitrogen-containing heterocyclic group (e.g., tetrazolyl, imidazolyl, N-methylimidazolyl, pyridyl, or pyridazinyl).

[0609] In an example of implementation, R 1 is selected from the group consisting of the following:

[0610]

[0611]

[0612] Each R 4a , R 4b , R 4c , R 6a , R 6b , and R 6c is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 4a and R 4b They may optionally combine with the atoms to which they are bonded to form a ring containing 3 to 7 atoms and optionally oxygen; R 6a and R 6b They are optionally combined with the atoms to which they are bonded to form a ring containing 3 to 7 atoms and optionally oxygen;

[0613] Each R 4d and R 6d is selected from the group consisting of phenyl, benzyl, pyridyl, -CH2(pyridyl), imidazole, and -CH2(imidazole);

[0614] R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of;

[0615] R 7 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e, NHCONR 8f Selected from a group consisting of;

[0616] Each R 8a , R 8b , R 8d , R 8g , and R 8i is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms, oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group optionally selected from;

[0617] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl;

[0618] R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls;

[0619] R 4a and R 8a All exist or R 4a and R 8g When all of them are present, these groups arbitrarily combine with the atoms to which they are bonded to form a ring containing 4 to 7 atoms;

[0620] R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0621] R 11 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0622] y 1 is 0, 1, or 2;

[0623] y 2 is 0, 1, or 2.

[0624] In an example of implementation, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0625] In an example of implementation, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0626] In an example of implementation, R 4a is H. In the embodiment, R 4b is H. In the embodiment, R 4a and R 4b All are H. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0627] In an example of implementation, R 4a and R 4b These combine with the atoms to which they are bonded to form a carbon ring containing 3 to 7 atoms. In an embodiment,R 4a and R 4b These combine with the atoms to form an oxygen-containing ring containing 3 to 7 atoms.

[0628] In an example of implementation, R 4c is H. In the embodiment, R 4d is phenyl. In an embodiment, R 4d is benzyl. In an embodiment, R 4d is Piridil. In the implementation example, R 4d is -CH2(pyridyl). In the implementation example, R 4d is imidazole. In an embodiment, R 4d is -CH2(imidazole). In an embodiment, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0629] In an example of implementation, R 6a is H. In the embodiment, R 6b is H. In the embodiment, R 6a and R 6b All are H. In the implementation example, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0630] In an example of implementation, R 46 and R 6b These combine with the atoms to which they are bonded to form a carbon ring containing 3 to 7 atoms. In an embodiment, R 6a andR bb These combine with the atoms to form an oxygen-containing ring containing 3 to 7 atoms.

[0631] In an example of implementation, R 6c is H. In the embodiment, R 6d is phenyl. In an embodiment, R 6d is benzyl. In an embodiment, R 6d is Piridil. In the implementation example, R 6d is -CH2(pyridyl). In the implementation example, R 6d is imidazole. In an embodiment, R 6d is -CH2(imidazole). In an embodiment, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0632] In an example of implementation, R 5 is Piridil. In the implementation example, R 5 is Piridazine. In the embodiment, R 5 is a C1-C7 alkyl. In an embodiment, R 5 is a C3-C7 cycloalkyl. In an embodiment, R 5 is a C1-C7 haloalkyl. In an embodiment, R 5 is a C3-C7 cyclohaloalkyl. In an embodiment, R 5 is a C1-C7 fluoroalkyl. In an embodiment, R 5 is a C3-C7 cyclofluoroalkyl. In an embodiment, R 5 is an unsubstituted C1-C7 alkyl. In an embodiment, R 5 is a substituted C1-C7 alkyl (containing amino substituents such as -NH2, -NHCH3, or -N(CH3)2). In an embodiment, R 5 is phenyl. In an embodiment, R 5 is phenyl. In an embodiment, R 5 is an unsubstituted phenyl. In an embodiment, R 5 is a substituted phenyl. In an embodiment, R 5 is NR 8a R 8b is. In the implementation example, R 5 is SO2R 8c is. In the implementation example, R 5 is NR 8d SO2R 8e is. In the implementation example, R 5 is NR 8i COOR 8j is. In the implementation example, R 5 NHCONR 8f is. In the implementation example, R 5 is NR 8g COR 8h is. In the implementation example, R 5 is not an unsubstituted C1-C7 alkyl.

[0633] In an example of implementation, R 7 It is Piridil. In the implementation example, R 7 It is a minced lute. In the embodiment, R 7 is a C1-C7 alkyl. In an embodiment, R 7 is a C3-C7 cycloalkyl. In an embodiment, R 7 is a C1-C7 haloalkyl. In an embodiment, R 7 is a C3-C7 cyclohaloalkyl. In an embodiment, R 7 is a C1-C7 fluoroalkyl. In an embodiment, R 7 is a C3-C7 cyclofluoroalkyl. In an embodiment, R 7 is an unsubstituted C1-C7 alkyl. In an embodiment, R 7 is a substituted C1-C7 alkyl. In an embodiment, R 7 is phenyl. In an embodiment, R 7 is phenyl. In an embodiment, R 7 is an unsubstituted phenyl. In an embodiment, R 7 is a substituted phenyl. In an embodiment, R 7 NR 8a R 8b is. In the implementation example, R 7 SO2R 8c is. In the implementation example, R 7 NR 8d SO2R 8e is. In the implementation example, R 7 NHCONR 8f is. In the implementation example, R 7 is not an unsubstituted C1-C7 alkyl.

[0634] In an example of implementation, R 4d Is

[0635]

[0636] Selected from a group consisting of, and among the R 4bb is H or CH3, and a1 is 1 or 2, and each R 4a is any substituent independently described herein. In an embodiment, each R 4aa is independently selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. In an embodiment, each R 4aa is independently selected from the group consisting of the following: C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkinyl, 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, A 5- to 6-membered heterocyclic group each containing 1 to 4 heteroatoms selected from amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and oxygen, sulfur, and nitrogen.

[0637] In an example of implementation, R 6d Is

[0638]

[0639] Selected from a group consisting of, and among the R 6bb is H or CH3, and a1 is 1 or 2, and each R 6aa is any substituent independently described herein. In an embodiment, each R 6aa is independently selected from OH, OCH3, NH2, CN, CH3, CF3, CH2CH3, isopropyl, F, Cl, Br, morpholino, CO2H, CO2CH3, and CO2NH2. In an embodiment, each R 6aa is independently selected from the group consisting of the following: C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkinyl, 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, A 5- to 6-membered heterocyclic group each containing 1 to 4 heteroatoms selected from amino, C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and oxygen, sulfur, and nitrogen.

[0640] In an example of implementation, R 1 silver is. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0641] In an example of implementation, R 1 silver is. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0642] In an example of implementation, R 1 silver is. In the implementation example, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0643] In an example of implementation, R 1 silver is. In the implementation example, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0644] In an example of implementation, R 1 silver is. In the implementation example, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0645] In an example of implementation, R 1 silver is. In the implementation example, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0646] In an example of implementation, R 1 silver is. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0647] In an example of implementation, R 1 silver is. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0648] In an example of implementation, y 1 is 0, and R 1 COR 5 is. In the implementation example, R 5 is Piridil. In the implementation example, R 5 is Piridazine. In the embodiment, R 5 is a C1-C7 alkyl. In an embodiment, R 5 is a C3-C7 cycloalkyl. In an embodiment, R 5 is a C1-C7 haloalkyl. In an embodiment, R 5 is a C3-C7 cyclohaloalkyl. In an embodiment, R 5 is a C1-C7 fluoroalkyl. In an embodiment, R 5 is a C3-C7 cyclofluoroalkyl.

[0649] In an example of implementation, R 11 It is hydrogen. In an embodiment, R 11 is a C1-C7 alkyl (e.g., methyl). In an embodiment, R 11 It is a C3-C7 cycloalkyl.

[0650] In an example of implementation, R 1 silver

[0651] is, and among the food

[0652] R 4a , R 4b , and y 1 is according to any mode or embodiment described herein;

[0653] Z a CH2 or O and;

[0654] Z a If is CH2, p 1 + p 2 is 1, 2, 3, or 4;

[0655] Z a If is O, p 1 + p 2 is 1, 2, 3, or 4 and; p 1 and p 2 Both are not 0.

[0656] In an example of implementation, R 1 silver is, and among the food

[0657] Z b CH2 or O and;

[0658] Z b If is CH2, p 1 + p 2 is 1, 2, 3, or 4;

[0659] Z b If is O, p 1 + p 2 is 1, 2, 3, or 4 and; p 1 and p 2 Neither of them is 0;

[0660] R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R8b , SO2R 8c , NR 8d SO2R 8e , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of;

[0661] Each R 8a , R 8b , R 8d , R 8g , and R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0662] R 8a and R 8b is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms and optionally oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group selected from;

[0663] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl.

[0664] In an example of implementation, R 1 silver is, and among the food

[0665] Z c CH2 or O and;

[0666] Z c If is CH2, p 1 + p 2 is 1, 2, 3, or 4;

[0667] Z c If is O, p 1 + p 2 is 1, 2, 3, or 4 and; p 1 and p 2 Neither of them is 0;

[0668] R 7 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NHCONR 8f Selected from a group consisting of;

[0669] Each R 8a , R 8b , R 8d , R 8g , and R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0670] R 8a and R 8b is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms and optionally oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group selected from;

[0671] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl.

[0672] In an example of implementation, R 1 silver

[0673] is, and among the food

[0674] R 10a and R 10b is H, C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, SO2R 8e , COOR 8j , CONR 8f , and COR 8h Independently selected from a group consisting of;

[0675] R 10a and R 10b At least one of them is selected from the group consisting of H, C1-C7 linear alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl;

[0676] Each R 8e , R 8f , and R 8h is selected from the group consisting of H, C1-C7 linear alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl;

[0677] R 8j is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C6-C 10 It is selected from the group consisting of aryls and 5 to 10 heteroaryls.

[0678] In an example of implementation, R 1 COOR 5 and, here R 5 is C6-C 10 It is an aryl or a 5- to 10-membered heteroaryl.

[0679] In an example of implementation, R 1 silver and, each of the expressions R 8a and R 8b is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms, oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group arbitrarily selected from; R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl.

[0680] In an example of implementation, R 1 silver And, in the expression, uu is 1 or 2.

[0681] In an example of implementation, R 1 silver is, and among the food R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 It is selected from the group consisting of aryls and 5 to 10 heteroaryls.

[0682] In an example of implementation, R 1 silver is, and among the food R 8h is an unsubstituted C1-C7 alkyl.

[0683] In an example of implementation, R 1 silver is, and among the food R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 It is selected from the group consisting of aryls and 5 to 10 heteroaryls.

[0684] In an example of implementation, R 1 silver and, each of the expressions R 8a and R 8b is independently H or an unsubstituted C1-C7 alkyl.

[0685] In an example of implementation, R 1 silver is, and among the food R 8d is independently an H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl.

[0686] In an example of implementation, R 1 silver is, and among the food R 4a and R 8g Each is independently an H or unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl.

[0687] In an example of implementation, R 1 silver is, and among the food R 4a and R 8g Each is independently an H or unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl.

[0688] In an example of implementation, R 1 silver is, and among the food R 4a and R 8g Each is independently an H or unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl.

[0689] In an example of implementation, R 1 silver is, and among the foodR 8h is an unsubstituted C1-C7 alkyl.

[0690] In an example of implementation, R 1 silver is, and among the food R 8h is an unsubstituted C1-C7 alkyl.

[0691] In an example of implementation, R 1 silver is, and among the food R 8h is an unsubstituted C1-C7 alkyl.

[0692] In an example of implementation, R 1 silver am.

[0693] In an example of implementation, R 1 silver am.

[0694] In an example of implementation, R 1 silver am.

[0695] In an example of implementation, R 1 silver and, each of the expressions R 8a , R 8b , and R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0696] In an example of implementation, R 1 silver or am.

[0697] In an example of implementation, R 1 silver or am.

[0698] In an example of implementation, R 1 silver am.

[0699] In an example of implementation, R 1 silver am.

[0700] In an example of implementation, R 1 silver am.

[0701] In an example of implementation, R 1 silver or am.

[0702] In an example of implementation, R 1 silver am.

[0703] In an example of implementation, R 1 silver and, each of the expressions R 8a and R 8b is independently H or an unsubstituted C1-C7 alkyl.

[0704] In an example of implementation, R 1 silver is, and among the food R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an independently unsubstituted C1-C7 alkyl.

[0705] In an example of implementation, R 1 silver am.

[0706] Compound of Formula (II)

[0707] In one embodiment, the present invention ( II Compounds having a structure according to ):

[0708]

[0709] Characterized by compounds including its enantiomers, diastereomers, hydrides, solvates, pharmaceutically acceptable salts, and complexes, wherein:

[0710] A 2 Is And;

[0711] R 2 is a 6- to 10-membered aryl, a 5- to 10-membered nitrogen-containing heteroaryl, and Selected from a group consisting of;

[0712] R 3 It is a 6- to 10-membered aryl or a 5- to 10-membered nitrogen-containing heteroaryl;

[0713] m is 1, 2, or 3;

[0714] n is 1, 2, 3, or 4;

[0715] R 1' C6-C 10 Aryl, 5- to 6-membered heteroaryl ring,

[0716]

[0717] Selected from a group consisting of;

[0718] Each R 4a , R 4b , R 4c , R 6a , R 6b and R 6c is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0719] R 4a andR 4b They are optionally combined with the atoms to which they are bonded to form a ring containing 3 to 7 atoms and optionally oxygen;

[0720] R 6a and R 6b They are optionally combined with the atoms to which they are bonded to form a ring containing 3 to 7 atoms and optionally oxygen;

[0721] Each R 4d and R 6d is selected from the group consisting of phenyl, benzyl, pyridyl, -CH2(pyridyl), imidazole, and -CH2(imidazole);

[0722] R 5 is hydrogen, C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of;

[0723] R 7 Silver hydrogen, C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R8b , SO2R 8c , NR 8d SO2R 8e , NHCONR 8f Selected from a group consisting of;

[0724] Each R 8a , R 8b , R 8d , R 8g , and R 8i is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0725] R 8a and R 8b is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms and optionally oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group selected from;

[0726] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl;

[0727] R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls;

[0728] R 4a and R 8a All exist, or R 4a and R 8g When all of them are present, these groups arbitrarily combine with the atoms to which they are bonded to form a ring containing 4 to 7 atoms;

[0729] R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0730] R 11 It is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0731] R A is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, Selected from the group consisting of C1-C7 acylamino, mono- or di- C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen;

[0732] a is 0, 1, or 2;

[0733] y 1 is 0, 1, or 2;

[0734] y 2 is 0, 1, or 2.

[0735] In an example of implementation, A 2 go And, R 2 ga is phenyl, and R1' this And, y 2 In the case where α is 0 and n is 2, R 7 It is not methyl, CH2SO2CH3, CH2CN, tetrahydropyranyl, phenyl, 4-substituted phenyl, or 5- to 8-membered heteroaryl.

[0736] In the implementation example, the formula ( II The compound according to ) is formula ( II' ) or expression ( II" It has a structure according to ):

[0737]

[0738] In an example of implementation, A 2 Is am.

[0739] In an example of implementation, A 2 Is am.

[0740] In an example of implementation, A 2 Is am.

[0741] In an example of implementation, R A is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, It is selected from the group consisting of C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen. In an embodiment, R A is unsubstituted C 1- It is a -C7 alkyl. In an embodiment, R A is methyl.

[0742] In an example of implementation, a is 0. In the implementation example, a is 1. In the implementation example, a is 2. In the implementation example, a is not 0. In the implementation example, a is excluding 0. In an example implementation, a is 0 or 1. In an example implementation, a is 1 or 2.

[0743] In an example of implementation, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0744] In an example of implementation, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0745] In an example of implementation, R 4a is H. In the embodiment, R 4b is H. In the embodiment, R 4a and R 4b All are H. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0746] In an example of implementation, R 4a and R 4b These combine with the atoms to which they are bonded to form a carbon ring containing 3 to 7 atoms. In an embodiment, R 4a and R 4b These combine with the atoms to form an oxygen-containing ring containing 3 to 7 atoms.

[0747] In an example of implementation, R 4c is H. In the embodiment, R 4d is phenyl. In an embodiment, R 4d is benzyl. In an embodiment, R 4d is Piridil. In the implementation example, R 4d is -CH2(pyridyl). In the implementation example, R 4d is imidazole. In an embodiment, R 4d is -CH2(imidazole). In an embodiment, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example,y 1 It is 2.

[0748] In an example of implementation, R 6a is H. In the embodiment, R 6b is H. In the embodiment, R 6a and R 6b All are H. In the implementation example, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0749] In some implementations, R 6a and R 6b It combines with atoms bonded to them to form a carbon ring containing 3 to 7 atoms. In some embodiments, R 6a and R 6b It combines with atoms bonded to them to form an oxygen-containing ring containing 3 to 7 atoms.

[0750] In an example of implementation, R 6c is H. In the embodiment, R 6d is phenyl. In an embodiment, R 6d is benzyl. In an embodiment, R 6d is Piridil. In the implementation example, R 6d is -CH2(pyridyl). In the implementation example, R 6d is imidazole. In an embodiment, R 6d is -CH2(imidazole). In an embodiment, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0751] In an example of implementation, R 5 is Piridil. In the implementation example, R 5 is Piridazine. In the embodiment, R 5 is a C1-C7 alkyl. In an embodiment, R 5 is a C3-C7 cycloalkyl. In an embodiment, R 5 is a C1-C7 haloalkyl. In an embodiment, R 5 is a C3-C7 cyclohaloalkyl. In an embodiment, R 5 is a C1-C7 fluoroalkyl. In an embodiment, R 5 is a C3-C7 cyclofluoroalkyl. In an embodiment, R 5 is an unsubstituted C1-C7 alkyl. In an embodiment, R 5 is a substituted C1-C7 alkyl (containing amino substituents such as -NH2, -NHCH3, or -N(CH3)2). In an embodiment, R 5 is phenyl. In an embodiment, R 5 is phenyl. In an embodiment, R 5 is an unsubstituted phenyl. In an embodiment, R 5 is a substituted phenyl. In an embodiment, R 5 is NR 8a R 8b is. In the implementation example, R 5 is SO2R 8c is. In the implementation example, R 5 is NR 8d SO2R 8e is. In the implementation example, R 5 is NR 8i COOR 8jis. In the implementation example, R 5 NHCONR 8f is. In the implementation example, R 5 is NR 8g COR 8h is. In the implementation example, R 5 is not an unsubstituted C1-C7 alkyl.

[0752] In an example of implementation, R 7 It is Piridil. In the implementation example, R 7 It is a minced lute. In the embodiment, R 7 is a C1-C7 alkyl. In an embodiment, R 7 is a C3-C7 cycloalkyl. In an embodiment, R 7 is a C1-C7 haloalkyl. In an embodiment, R 7 is a C3-C7 cyclohaloalkyl. In an embodiment, R 7 is a C1-C7 fluoroalkyl. In an embodiment, R 7 is a C3-C7 cyclofluoroalkyl. In an embodiment, R 7 is an unsubstituted C1-C7 alkyl. In an embodiment, R 7 is a substituted C1-C7 alkyl. In an embodiment, R 7 is phenyl. In an embodiment, R 7 is phenyl. In an embodiment, R 7 is an unsubstituted phenyl. In an embodiment, R 7 is a substituted phenyl. In an embodiment, R 7 NR 8a R 8b is. In the implementation example, R 7 SO2R 8c is. In the implementation example, R 7 NR 8d SO2R 8e is. In the implementation example, R 7 NHCONR 8f is. In the implementation example, R 7 is not an unsubstituted C1-C7 alkyl.

[0753] In an example of implementation, R 1' It is a 5- to 6-membered heteroaryl ring. In an embodiment, R 1' is imidazolyl (e.g., unsubstituted imidazolyl or N-methylimidazolyl). In an embodiment, R 1 It is oxazolil (for example, It is an unsubstituted oxazolyl. In an embodiment, R 1 is isooxazolyl (e.g., unsubstituted oxazolyl).

[0754] In an example of implementation, R 1' silver is, and in the food X is O, NH, or NCH3, and aa1 is 0, 1, or 2, and R 1a is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C1-C7 linear alkoxy, C3-C7 branched alkoxy, C3-C7 cycloalkoxy, aryloxy, C1-C7 linear haloalkyl, C3-C7 branched haloalkyl, C3-C7 cyclohaloalkyl, C2-C7 alkenyl, C2-C7 cycloalkenyl, C2-C7 alkynyl, aryl, arylalkyl, nitro, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C1-C7 alkoxycarbonyl, sulfo, halogen, C1-C7 alkylthio, arylthio, C1-C7 alkylsulfinyl, arylsulfinyl, C1-C7 alkylsulfonyl, arylsulfonyl, amino, It is selected from the group consisting of C1-C7 acylamino, mono- or di-C1-C7 alkylamino, C3-C7 cycloalkylamino, arylamino, C2-C7 acyl, aryl carbonyl, and 5- to 6-membered heterocyclic groups each containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen.

[0755] In an example of implementation, R 1' silver It is selected from a group consisting of. In an embodiment, R 1 silver am.

[0756] In an example of implementation, R 1' silver is. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0757] In an example of implementation, R 1' silver is. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0758] In an example of implementation,R 1' silver is. In the implementation example, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0759] In an example of implementation, R 1' silver is. In the implementation example, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0760] In an example of implementation, R 1' silver is. In the implementation example, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0761] In an example of implementation, R 1' silver is. In the implementation example, y 2 is 0. In the implementation example, y 2 is 1. In the implementation example, y 2 is 2.

[0762] In an example of implementation, R 1' silver is. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0763] In an example of implementation, R 1' silver is. In the implementation example, y 1 is 0. In the implementation example, y 1 is 1. In the implementation example, y 1 It is 2.

[0764] In an example of implementation, y 1 is 0, and R 1' COR 5 is. In the implementation example, R 5 is Piridil. In the implementation example, R 5 is Piridazine. In the embodiment, R 5 is a C1-C7 alkyl. In an embodiment, R 5 is a C3-C7 cycloalkyl. In an embodiment, R 5 is a C1-C7 haloalkyl. In an embodiment, R 5 is a C3-C7 cyclohaloalkyl. In an embodiment, R 5 is a C1-C7 fluoroalkyl. In an embodiment, R 5 is a C3-C7 cyclofluoroalkyl.

[0765] In an example of implementation, R 11 It is hydrogen. In an embodiment, R 11 is a C1-C7 alkyl (e.g., methyl). In an embodiment, R 11 It is a C3-C7 cycloalkyl.

[0766] In an example of implementation, R 1' silver

[0767] is, and among the food

[0768] R 4a , R 4b , and y 1 is according to any mode or embodiment described herein;

[0769] Z a CH2 or O and;

[0770] Z a If is CH2, p 1 + p 2 is 1, 2, 3, or 4;

[0771] Z a If is O, p 1 + p 2 is 1, 2, 3, or 4 and; p 1 and p 2 Both are not 0.

[0772] In an example of implementation, R 1' silver is, and among the food

[0773] Z b CH2 or O and;

[0774] Z b If is CH2, p 1 + p 2 is 1, 2, 3, or 4;

[0775] Z b If is O, p 1 + p 2 is 1, 2, 3, or 4 and; p 1 and p 2 Neither of them is 0;

[0776] R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R8b , SO2R 8c , NR 8d SO2R 8e , NHCONR 8f , Selected from a group consisting of;

[0777] Each R 8a , R 8b , R 8d , R 8g , and R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0778] R 8a and R 8b is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms and optionally oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group selected from;

[0779] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl.

[0780] In an example of implementation, R 1' silver is, and among the food

[0781] Z c CH2 or O and;

[0782] Z c If is CH2, p 1 + p 2 is 1, 2, 3, or 4;

[0783] Z c If is O, p1 + p 2 is 1, 2, 3, or 4 and; p 1 and p 2 Neither of them is 0;

[0784] R 7 C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NHCONR 8f Selected from a group consisting of;

[0785] Each R 8a , R 8b , R 8d , R 8g , and R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl;

[0786] R 8a and R 8b is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms and optionally oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group selected from;

[0787] Each R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl.

[0788] In an example of implementation, R 1' silver is, and among the food

[0789] R 10a and R 10b is H, C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, SO2R 8e , COOR 8j , CONR 8f , and COR 8h Independently selected from a group consisting of;

[0790] R 10a and R 10b At least one of them is selected from the group consisting of H, C1-C7 linear alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl;

[0791] Each R 8e , R 8f , and R 8h is selected from the group consisting of H, C1-C7 linear alkyl, C3-C7 branched alkyl, and C3-C7 cycloalkyl;

[0792] R 8j is C1-C7 linear alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C6-C 10 It is selected from the group consisting of aryls and 5 to 10 heteroaryls.

[0793] In an example of implementation, R 1' COOR 5 and, among the equations, R 5 is C6-C 10 It is an aryl or a 5- to 10-membered heteroaryl.

[0794] In an example of implementation, R 1' silver and, each of the expressions R 8a andR 8b is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It is optionally combined with the atoms to which they are bonded to contain 3 to 7 atoms and optionally oxygen, sulfur, and NR 9 Forming a heterocyclic ring containing a group selected from; R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl.

[0795] In an example of implementation, R 1' silver And, in the expression, uu is 1 or 2.

[0796] In an example of implementation, R 1' silver is, and among the food R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 It is selected from the group consisting of aryls and 5 to 10 heteroaryls.

[0797] In an example of implementation, R 1' silver is, and among the food R 8h is an unsubstituted C1-C7 alkyl.

[0798] In an example of implementation, R 1' silver is, and among the food R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 It is selected from the group consisting of aryls and 5 to 10 heteroaryls.

[0799] In an example of implementation, R 1 silver and, each of the expressions R 8a andR 8b is independently H or an unsubstituted C1-C7 alkyl.

[0800] In an example of implementation, R 1' silver is, and among the food R 8d is independently an H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl.

[0801] In an example of implementation, R 1' silver is, and among the food R 4a and R 8g Each is independently an H or unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl.

[0802] In an example of implementation, R 1' silver is, and among the food R 4a and R 8g Each is independently an H or unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl.

[0803] In an example of implementation, R 1' silver is, and among the food R 4a and R 8g Each is independently an H or unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl.

[0804] In an example of implementation, R 1' silver is, and among the food R 8h is an unsubstituted C1-C7 alkyl.

[0805] In an example of implementation, R 1' silver is, and among the food R 8h is an unsubstituted C1-C7 alkyl.

[0806] In an example of implementation, R 1' silver is, and among the food R 8h is an unsubstituted C1-C7 alkyl.

[0807] In an example of implementation, R 1' silver am.

[0808] In an example of implementation, R 1' silver am.

[0809] In an example of implementation, R 1' silver am.

[0810] In an example of implementation, R 1' silver and, each of the expressions R 8a , R 8b , and R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl.

[0811] In an example of implementation, R 1' silver or am.

[0812] In an example of implementation, R 1' silver or am.

[0813] In an example of implementation, R 1' silver am.

[0814] In an example of implementation, R 1' silver am.

[0815] In an example of implementation, R 1' silver am.

[0816] In an example of implementation, R 1' silver or am.

[0817] In an example of implementation, R 1' silver am.

[0818] In an example of implementation, R 1' silver and, each of the expressions R 8a and R 8b is independently H or an unsubstituted C1-C7 alkyl.

[0819] In an example of implementation, R 1' silver is, and among the food R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an independently unsubstituted C1-C7 alkyl.

[0820] In an example of implementation, R 1' silver am.

[0821] Compounds with chemical formulas (A) to (AAA)

[0822] ceremony ( I ), (I*), (I**), or ( II Another compound of ) is of the same formula as described herein ( A )~( AAAIt includes any one of the compounds, wherein any variable may follow any mode or embodiment as described herein.

[0823] Additional exemplary formulas and compounds described herein may also include their hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes.

[0824] For example, in any one of the formulas described herein (e.g., formulas (I), (I*), (I**), (II) and any one of formulas (A) to (AAA)), the C5 carbon of 2-dihydrofuranone is ( R )-has a composition.

[0825] Alternatively, in any one of the formulas described herein (e.g., formulas (I), (I*), (I**), (II) and any one of formulas (A) through (AAA)), the C5 carbon of 2-dihydrofuranone is ( S )-has a composition.

[0826] In the implementation example, the formula ( A A compound having a structure according to ) is provided herein:

[0827] ( A ), during food R a , R b , A , n , and Aril It follows any mode and embodiment described herein.

[0828] In the implementation example, the formula ( B A compound having a structure according to ) is provided herein:

[0829] ( B ), during food Q 1 is 1 or 2, and Q 2 is 1 or 2, and A and nIt follows any mode and embodiment described herein.

[0830] In the implementation example, the formula ( C A compound having a structure according to ) is provided herein:

[0831] ( C ), during food Q 1 is 1 or 2, and Q 2 is 1 or 2, and A and n It follows any mode and embodiment described herein.

[0832] In the implementation example, the formula ( D A compound having a structure according to ) is provided herein:

[0833] ( D ), during food Q 1 is 1 or 2, and Q 2 is 1 or 2, and A and n It follows any mode and embodiment described herein.

[0834] In the implementation example, the formula ( E A compound having a structure according to ) is provided herein:

[0835] ( E ), during food Q 1 is 1 or 2, and Q 2 is 1 or 2, and A and n It follows any mode and embodiment described herein.

[0836] In the implementation example, the formula ( F A compound having a structure according to ) is provided herein:

[0837] ( F ), during food Q 1 is 1 or 2, andQ 2 is 1 or 2, and A and n It follows any mode and embodiment described herein.

[0838] In the implementation example, the formula ( G A compound having a structure according to ) is provided herein:

[0839] ( G ), during food Q 1 is 1 or 2, and Q 2 is 1 or 2, and A and n It follows any mode and embodiment described herein.

[0840] In the implementation example, the formula ( H A compound having a structure according to ) is provided herein:

[0841] ( H ), during food Q 1 is 1 or 2, and Q 2 is 1 or 2, and R 1 , A , and n It follows any mode and embodiment described herein.

[0842] In a specific implementation example, the formula ( J A compound having a structure according to ) is provided herein:

[0843] ( J ), during food R a and R b is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl;

[0844] R 2 is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl;

[0845] R 3 It is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl.

[0846] In a specific implementation example, the formula ( K A compound having a structure according to ) is provided herein:

[0847] ( K ), during food

[0848] R 2 is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl;

[0849] R 3 It is selected from the group consisting of phenyl, naphthyl, pyridyl, and indolyl.

[0850] In an example of implementation, A compound containing a unit is provided herein, and among the formula L A is described herein A It is an arbitrary basis for . In an implementation example, L A Is

[0851]

[0852] It is selected from a group consisting of.

[0853] In the implementation example, the formula ( L A compound having a structure according to ) is provided herein:

[0854] ( L ), during food R 2a , aa , L A , n , R 4a , R 4b , y 1 ,R 10a , and R 10b It follows any mode and embodiment described herein.

[0855] In the implementation example, the formula ( M A compound having a structure according to ) is provided herein:

[0856] ( M ), during food R 2a , aa , n , R 4a , R 4b , y 1 , R 10a , and R 10b It follows any mode and embodiment described herein.

[0857] In the implementation example, the formula ( N A compound having a structure according to ) is provided herein:

[0858] ( N ), during food R 2a , aa , L A , n , R 4a , R 4b , y 1 , Z 1 , p 1 , and p 2 It follows any mode and embodiment described herein.

[0859] In the implementation example, the formula ( O A compound having a structure according to ) is provided herein:

[0860] ( O ), during food R 2a , aa , n , R 4a , R 4b , y 1 , Z 1 , p 1 , and p 2 It follows any mode and embodiment described herein.

[0861] In the implementation example, the formula ( P A compound having a structure according to ) is provided herein:

[0862] ( P ), during food R 2a , aa , L A , n , X , and R 1a It follows any mode and embodiment described herein.

[0863] In the implementation example, the formula ( Q A compound having a structure according to ) is provided herein:

[0864] ( Q ), during food R 2a , aa , n , X , and R 1a It follows any mode and embodiment described herein.

[0865] In the implementation example, the formula ( R A compound having a structure according to ) is provided herein:

[0866] ( R ), during food R 2a , aa , L A , n ,Z b , p 1 , p 2 , and R 10a , and R 10b It follows any mode and embodiment described herein.

[0867] In the implementation example, the formula ( S A compound having a structure according to ) is provided herein:

[0868] ( S ), during food R 2a , aa , n , Z b , p 1 , p 2 , and R 10a , and R 10b It follows any mode and embodiment described herein.

[0869] In the implementation example, the formula ( T A compound having a structure according to ) is provided herein:

[0870] ( T ), during food p 1 is 1, 2, 3, or 4, and R 2a , aa , L A , n , R 4b , and R 8h It follows any mode and embodiment described herein.

[0871] In the implementation example, the formula ( U A compound having a structure according to ) is provided herein:

[0872] ( U ), among the foods p 1is 1, 2, 3, or 4, and R 2a , aa , n , R 4b , and R 8h It follows any mode and embodiment described herein.

[0873] In the implementation example, the formula ( V A compound having a structure according to ) is provided herein:

[0874] ( V ), during food R 2a , aa , L A , n , R 4a , R 4b , and y 1 It follows any mode and embodiment described herein.

[0875] In the implementation example, the formula ( W A compound having a structure according to ) is provided herein:

[0876] ( W ), during food R 2a , aa , n , R 4a , R 4b , and y 1 It follows any mode and embodiment described herein.

[0877] In the implementation example, the formula ( X A compound having a structure according to ) is provided herein:

[0878] ( X ), during food R 5N is selected from H, C1-C7 linear alkyl, and C3-C7 branched alkyl, and R 2a , aa , L A , n , R 4a , R 4b , and y 1 It follows any mode and embodiment described herein.

[0879] In the implementation example, the formula ( Y A compound having a structure according to ) is provided herein:

[0880] ( Y ), during food R 5N is selected from H, C1-C7 linear alkyl, and C3-C7 branched alkyl, and R 2a , aa , n , R 4a , R 4b , and y 1 It follows any mode and embodiment described herein.

[0881] In the implementation example, the formula ( Z A compound having a structure according to ) is provided herein:

[0882] ( Z ), during food R 5a is pyridil or pyridazine, and R 2a , aa , L A , and n It follows any mode and embodiment described herein.

[0883] In the implementation example, the formula ( AA A compound having a structure according to ) is provided herein:

[0884] ( AA ), during food R 5a is pyridil or pyridazine, andR 2a , aa , and n It follows any mode and embodiment described herein.

[0885] In the implementation example, the formula ( BB A compound having a structure according to ) is provided herein:

[0886] ( BB ), during food R 5b is a C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 fluoroalkyl, or C3-C7 cyclofluoroalkyl, and R 2a , aa , L A , and n It follows any mode and embodiment described herein.

[0887] In the implementation example, the formula ( CC A compound having a structure according to ) is provided herein:

[0888] ( CC ), during food R 5b is a C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 fluoroalkyl, or C3-C7 cyclofluoroalkyl, and R 2a , aa , and n It follows any mode and embodiment described herein.

[0889] In the implementation example, the formula ( DD A compound having a structure according to ) is provided herein:

[0890] ( DD ), during food R 2 , n , R a , and R b It follows any mode and embodiment described herein.

[0891] In the implementation example, the formula ( EE A compound having a structure according to ) is provided herein:

[0892] ( EE ), during food R 2 and n It follows any mode and embodiment described herein.

[0893] In the implementation example, the formula ( FF A compound having a structure according to ) is provided herein:

[0894] ( FF ), during food R 2 and n It follows any mode and embodiment described herein.

[0895] In the implementation example, the formula ( GG A compound having a structure according to ) is provided herein:

[0896] ( GG ), during food R 2 and n It follows any mode and embodiment described herein.

[0897] In the implementation example, the formula ( HH A compound having a structure according to ) is provided herein:

[0898] ( HH ), during food R 2 and n It follows any mode and embodiment described herein.

[0899] In the implementation example, the formula ( JJ A compound having a structure according to ) is provided herein:

[0900] ( JJ ), during food R 1 , R 2 , and nIt follows any mode and embodiment described herein.

[0901] In the implementation example, the formula ( KK A compound having a structure according to ) is provided herein:

[0902] ( KK ), during food R 1 , R 2a , a , and n It follows any mode and embodiment described herein.

[0903] In the implementation example, the formula ( LL A compound having a structure according to ) is provided herein:

[0904] ( LL ), during food R 1 , R 2a , a , and n It follows any mode and embodiment described herein.

[0905] In the implementation example, the formula ( MM A compound having a structure according to ) is provided herein:

[0906] ( MM ), during food R 1 , R 2a , aa , and n It follows any mode and embodiment described herein.

[0907] In the implementation example, the formula ( NN A compound having a structure according to ) is provided herein:

[0908] ( NN ), during food X , R 2a , n It follows any mode and embodiment described herein.

[0909] In the implementation example, the formula ( OO A compound having a structure according to ) is provided herein:

[0910] ( OO ), during food R 2 , n , R 6a , R 6b , and R 7 It follows any mode and embodiment described herein.

[0911] In the implementation example, the formula ( PP A compound having a structure according to ) is provided herein:

[0912] ( PP ), during food R 2 , n , R 6c , R 6d , and R 7 It follows any mode and embodiment described herein.

[0913] In the implementation example, the formula ( QQ A compound having a structure according to ) is provided herein:

[0914] ( QQ ), during food R 8h , R 2a , R 4a , R A , a , aa , and n is as described herein for any chemical formula, mode, or embodiment. In an embodiment, R 8h is an unsubstituted C1-C7 alkyl (e.g., methyl). In an embodiment, R 4a is hydrogen or an unsubstituted C1-C7 alkyl (e.g., R 4a is hydrogen or methyl, ethyl, or isopropyl). In an embodiment, n It is 2. In the implementation example, aa is 1 or 2. In an example implementation, aa is 1. In the embodiment, each R 2a is a halogen (e.g., -F and / or -Cl). In an embodiment, a is 0 or 1. In an example implementation, R A When exists, R A is an unsubstituted C1-C7 alkyl (e.g., methyl). In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( R It has a )-configuration. In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( S )-has a configuration. In an example implementation, R 4a The carbon substituted with ( R )-has a configuration. In an example implementation, R 4a The carbon substituted with ( S )-has a configuration. In an example implementation, R A The carbon substituted with ( R )-has a configuration. In an example implementation, R A The carbon substituted with ( S )-has a composition.

[0915] In the implementation example, the formula ( RR A compound having a structure according to ) is provided herein:

[0916] ( RR ), during food R 8e , R 2a , a , and n is as described herein for any chemical formula, mode, or embodiment. In an embodiment,R 8e is an unsubstituted C1-C7 alkyl (e.g., methyl). In an embodiment, n It is 2. In the implementation example, aa is 1 or 2. In an example implementation, aa is 1. In the embodiment, each R 2a is a halogen (e.g., -F and / or -Cl). In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( R It has a )-configuration. In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( S )-has a composition.

[0917] In the implementation example, the formula ( SS A compound having a structure according to ) is provided herein:

[0918] ( SS ), during food R 2a , R A , a , aa , and n ...is as described in any expression, modality, or embodiment described herein. In an embodiment, n It is 2. In the implementation example, aa is 0, 1, or 2. In an example implementation, aa is 0. In the implementation example, aa is 1. In the embodiment, each R 2a is a halogen (e.g., -F and / or -Cl). In an embodiment, a is 1. In the implementation example, R A is a C1-C7 alkyl (e.g., methyl). In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( R It has a )-configuration. In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( S )-has a configuration. In an example implementation, R A The carbon substituted with ( R)-has a configuration. In an example implementation, R A The carbon substituted with ( S )-has a composition.

[0919] In the implementation example, the formula ( TT A compound having a structure according to ) is provided herein:

[0920] ( TT ), during food R 2a , R A , R 5 , a , aa , and n ...is as described herein for any expression, mode, or embodiment. In an embodiment, R 5 is an unsubstituted C1-C7 alkyl (e.g., methyl or ethyl). In an embodiment, n is 2. In an embodiment, a is 0 or 1. In an example implementation, R A is a C1-C7 alkyl (e.g., methyl). In an embodiment, aa is 1. In the implementation example, aa is 0, 1, or 2. In an example implementation, aa is 0. In the implementation example, aa is 1. In the embodiment, each R 2a is a halogen (e.g., -F and / or -Cl). In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( R It has a )-configuration. In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( S )-has a configuration. In an example implementation, R A The carbon substituted with ( R )-has a configuration. In an example implementation, R A The carbon substituted with ( S )-has a composition.

[0921] In the implementation example, the formula ( UU A compound having a structure according to ) is provided herein:

[0922] ( UU ), during food R 5 , R A , R 2a , a , aa , and n ...is as described herein for any expression, mode, or embodiment. In an embodiment, R 5 is an unsubstituted C1-C7 alkyl (e.g., methyl, ethyl, isopropyl). In an embodiment, R 5 is a C1-C7 haloalkyl (e.g., CH2CF3). In an embodiment, n It is 2. In the implementation example, aa is 1 or 2. In an example implementation, aa is 1. In the embodiment, each R 2a is a halogen (e.g., -F and / or -Cl). In an embodiment, a is 0 or 1. In an example implementation, R A When exists, R A is an unsubstituted C1-C7 alkyl (e.g., methyl). In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( R It has a )-configuration. In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( S )-has a configuration. In an example implementation, R A The carbon substituted with ( R )-has a configuration. In an example implementation, R A The carbon substituted with ( S )-has a composition.

[0923] In the implementation example, the formula ( VV A compound having a structure according to ) is provided herein:

[0924] ( VV ), during food R A , R 2a , a , aa , and n ...is as described herein for any expression, mode, or embodiment. In an embodiment, n It is 2. In the implementation example, aa is 1 or 2. In an example implementation, aa is 1. In the embodiment, each R 2a is a halogen (e.g., -F and / or -Cl). In an embodiment, a is 0 or 1. In an example implementation, R A When exists, R A is an unsubstituted C1-C7 alkyl (e.g., methyl). In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( R It has a )-configuration. In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( S )-has a configuration. In an example implementation, R A The carbon substituted with ( R )-has a configuration. In an example implementation, R A The carbon substituted with ( S )-has a composition.

[0925] In the implementation example, the formula ( WW A compound having a structure according to ) is provided herein:

[0926] ( WW ), during food R 8j , R 2a , R A , a , aa , and n ...is as described herein for any expression, mode, or embodiment. In an embodiment,R 8j is an unsubstituted C1-C7 alkyl (e.g., methyl or ethyl). In an embodiment, n It is 2. In the implementation example, aa is 1 or 2. In an example implementation, aa is 1. In the embodiment, each R 2a is a halogen (e.g., -F and / or -Cl). In an embodiment, a is 0 or 1. In an example implementation, R A When exists, R A is an unsubstituted C1-C7 alkyl (e.g., methyl). In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( R It has a )-configuration. In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( S )-has a configuration. In an example implementation, R A The carbon substituted with ( R )-has a configuration. In an example implementation, R A The carbon substituted with ( S )-has a composition.

[0927] In the implementation example, the formula ( XX A compound having a structure according to ) is provided herein:

[0928] ( XX ), during food R A , R 2a , a , aa , and n ...is as described herein for any expression, mode, or embodiment. In an embodiment, n It is 2. In the implementation example, aa is 1 or 2. In an example implementation, aa is 1. In the embodiment, each R 2a is a halogen (e.g., -F and / or -Cl). In an embodiment,a is 0 or 1. In an example implementation, R A When exists, R A is an unsubstituted C1-C7 alkyl (e.g., methyl). In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( R It has a )-configuration. In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( S )-has a configuration. In an example implementation, R A The carbon substituted with ( R )-has a configuration. In an example implementation, R A The carbon substituted with ( S )-has a composition.

[0929] In the implementation example, the formula ( YY A compound having a structure according to ) is provided herein:

[0930] ( YY ), during food R A , R 2a , a , aa , and n ...is as described herein for any expression, mode, or embodiment. In an embodiment, n It is 2. In the implementation example, aa is 1 or 2. In an example implementation, aa is 1. In the embodiment, each R 2a is a halogen (e.g., -F and / or -Cl). In an embodiment, a is 0 or 1. In an example implementation, R A When exists, R A is an unsubstituted C1-C7 alkyl (e.g., methyl). In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( R It has a )-configuration. In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( S)-has a configuration. In an example implementation, R A The carbon substituted with ( R )-has a configuration. In an example implementation, R A The carbon substituted with ( S )-has a composition.

[0931] In the implementation example, the formula ( ZZ A compound having a structure according to ) is provided herein:

[0932] ( ZZ ), during food R A , R 2a , R 8a , R 8b , a , aa , and n ...is as described herein for any expression, mode, or embodiment. In an embodiment, R 8a is hydrogen or an unsubstituted C1-C7 alkyl (e.g., methyl). In an embodiment, R 8b is hydrogen or an unsubstituted C1-C7 alkyl (e.g., methyl). In an embodiment, n It is 2. In the implementation example, aa is 1 or 2. In an example implementation, aa is 1. In the embodiment, each R 2a is a halogen (e.g., -F and / or -Cl). In an embodiment, a is 0 or 1. In an example implementation, R A When exists, R A is an unsubstituted C1-C7 alkyl (e.g., methyl). In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( R It has a )-configuration. In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( S )-has a configuration. In an example implementation, R A The carbon substituted with ( R )-has a configuration. In an example implementation, R A The carbon substituted with ( S )-has a composition.

[0933] In the implementation example, the formula ( AAA A compound having a structure according to ) is provided herein:

[0934] ( AAA ), during food R A , R 2a , R 8a , R 8b , a , aa , and n ...is as described herein for any expression, mode, or embodiment. In an embodiment, uu is 1 or 2. In an example implementation, n It is 2. In the implementation example, aa is 1 or 2. In an example implementation, aa is 1. In the embodiment, each R 2a is a halogen (e.g., -F and / or -Cl). In an embodiment, a is 0 or 1. In an example implementation, R A When exists, R A is an unsubstituted C1-C7 alkyl (e.g., methyl). In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( R It has a )-configuration. In an embodiment, the C5 carbon of the 2-dihydrofuranone core is ( S )-has a configuration. In an example implementation, R A The carbon substituted with ( R )-has a configuration. In an example implementation, R A The carbon substituted with ( S )-has a composition.

[0935] Exemplary compounds

[0936] Formulas described herein (e.g., formula ( I ), ( I* ), ( I** ), or ( II ), for example, formula ( A )~( AAA An exemplary compound according to any one of ) is Table 1 Compounds such as those described in 1 ~ 145 Includes

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959] General synthesis method for the preparation of 5-HT7 regulators

[0960] The reagents used in the preparation of the compounds of the present invention may be commercially available or may be prepared by standard procedures described in the literature. According to the present invention, compounds of this class may be produced by one of the following reaction schemes.

[0961] The compounds disclosed herein are International Application No. PCT / US2017 / 061677 filed November 15, 2017; International Application No. PCT / US2013 / 071926 filed November 26, 2013; International Application No. PCT / US2014 / 023400 filed March 11, 2014; International Application No. PCT / US2015 / 049303 filed September 10, 2015; International Application No. PCT / US2016 / 031780 filed May 11, 2016; International Application No. PCT / US2018 / 022581 filed March 15, 2018; It may be manufactured by the methods described in international application PCT / US2018 / 022574 filed on March 15, 2018, the full contents of each of which are incorporated herein by reference.

[0962] Additionally, certain exemplary methods Reaction Equations 1 to 4 It is described in [the document]. In these reaction schemes, any variable within any structure may follow any mode or embodiment as described herein.

[0963] Reaction Equation 1.

[0964]

[0965] A binder such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is present, optionally hydroxybenzotriazole is present, optionally 1-hydroxy-7-azabenzotriazole is present, optionally bases such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, N,N-diisopropylethylamine, pyridine are present, and N-methyl-2-pyrrolidone, N,N-dimethylformamide, Formula ( a1 A compound of formula () which is a known compound or a compound prepared by a known method a5 React with a compound of ), heat optionally, and irradiate with microwaves to formula ( a2 A compound of ) is obtained. 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., of formula ( a2 A compound according to ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., heated optionally, and optionally irradiated with microwaves by formula ( a3 Obtain a compound of ).

[0966] In the presence of bases such as triethylamine, diisopropylethylamine, pyridine, etc., in solvents such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., formula ( a3A compound of formula () which is a known compound or a compound prepared by a known method a4-1 React with a compound of ), heat optionally, and irradiate with microwaves to formula ( a4-1a ) obtains a compound of formula ( a3 A compound of formula () which is a known compound or a compound prepared by a known method a4-2 React with the compound of ) (X in the formula 1 (is chlorine), heated arbitrarily, and irradiated with microwaves arbitrarily to formula ( a4-2a Obtain a compound of ). Alternatively, a binder such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is present, optionally hydroxybenzotriazole is present, optionally 1-hydroxy-7-azabenzotriazole is present, optionally bases such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine are present, and N-methyl-2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, Formula (in the presence of solvents such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, etc. a3 A compound of formula () which is a known compound or a compound prepared by a known method a4-2 React with the compound of ) (X in the formula 1(is OH), heated arbitrarily, and irradiated with microwaves arbitrarily, formula ( a4-2a Obtain a compound of ).

[0967] Alternatively, in the presence of bases such as triethylamine, diisopropylethylamine, pyridine, etc., in solvents such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., formula ( a3 A compound of formula () which is a known compound or a compound prepared by a known method a4-3 React with a compound of ) (where X in the formula is selected from the group consisting of iodine, boron, chlorine, methanesulfonate, and para-tolylsulfonate), optionally heat, and optionally irradiate with microwaves to formula ( a4-3a Obtain a compound of ).

[0968] Reaction Equation 2.

[0969]

[0970] A binder such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is present, optionally hydroxybenzotriazole is present, optionally 1-hydroxy-7-azabenzotriazole is present, optionally bases such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, N,N-diisopropylethylamine, pyridine are present, and N-methyl-2-pyrrolidone, N,N-dimethylformamide, Formula ( a1A compound of formula () which is a known compound or a compound prepared by a known method a9 React with a compound of ), heat optionally, and irradiate with microwaves to formula ( a6 A compound of ) is obtained. 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., of formula ( a6 A compound according to ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., heated optionally, and optionally irradiated with microwaves by formula ( a7 A compound of ) is obtained. In the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc., in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., of formula ( a7 A compound of formula () which is a known compound or a compound prepared by a known method a8-1 React with a compound of ), heat optionally, and irradiate with microwaves to formula ( a8-1a ) obtains a compound of formula ( a7 A compound of formula () which is a known compound or a compound prepared by a known method a8-2 React with the compound of ) (X in the formula 1 (is chlorine), heated arbitrarily, and irradiated with microwaves arbitrarily to formula ( a8-2aObtain a compound of ). Alternatively, a binder such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is present, optionally hydroxybenzotriazole is present, optionally 1-hydroxy-7-azabenzotriazole is present, optionally bases such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine are present, and N-methyl-2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, Formula (in the presence of solvents such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, etc. a7 A compound of formula () which is a known compound or a compound prepared by a known method a8-2 React with the compound of ) (X in the formula 1 (is OH), heated arbitrarily, and irradiated with microwaves arbitrarily, formula ( a4-8a Obtain a compound of ).

[0971] Alternatively, in the presence of bases such as triethylamine, diisopropylethylamine, pyridine, etc., in solvents such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, etc., formula ( a7 A compound of formula () which is a known compound or a compound prepared by a known method a8-3 React with a compound of ) (where X in the formula is selected from the group consisting of iodine, boron, chlorine, methanesulfonate, and para-tolylsulfonate), optionally heat, and optionally irradiate with microwaves to formula ( a8-3a Obtain a compound of ).

[0972] Reaction Equation 3.

[0973]

[0974] Palladium catalysts such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium (0), dichlorobis(triphenylphosphine)palladium (II), carbon-attached palladium, bis(acetonitrile)dichloropalladium (II) are present, and 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′-diisopropoxybiphenyl, Organic phosphines such as 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)-2-amine, etc. are present, and optionally sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, In the presence of bases such as pyridine, 2,6-dimethylpyridine, etc., in solvents such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., formula ( a1 A compound of formula () which is a known compound or a compound prepared by a known method a10React with a compound of ) (where X in the formula is selected from the group consisting of iodine, boron, chlorine, methanesulfonate, and para-tolylsulfonate), optionally heat, and optionally irradiate with microwaves to formula ( a10-1 Obtain a compound of ).

[0975] Reaction Equation 4.

[0976]

[0977] A binder such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is present, optionally hydroxybenzotriazole is present, optionally 1-hydroxy-7-azabenzotriazole is present, optionally bases such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, N,N-diisopropylethylamine, pyridine are present, and N-methyl-2-pyrrolidone, N,N-dimethylformamide, Formula ( a1 A compound of formula () which is a known compound or a compound prepared by a known method a12 React with a compound of ), heat optionally, and irradiate with microwaves to formula ( a11 Obtain a compound of ).

[0978] Treatment methods

[0979] In an embodiment, the compound described herein is a selective regulator of the serotonin 5-HT7 receptor. In some embodiments, the compound described herein may bind more strongly to the serotonin 5-HT7 receptor compared to other targets (e.g., other serotonin receptors). In an embodiment, the compound described herein may selectively bind to the serotonin 5-HT7 receptor in a specific tissue or organ.

[0980] For example, the compounds described herein can selectively bind to serotonin 5-HT7 receptors in the intestines of subjects. Therefore, the compounds described herein can be used to treat or prevent inflammatory bowel disease (IBD) or intestinal inflammation.

[0981] In other embodiments, the compounds described herein may have properties particularly beneficial for the effective treatment of (e.g., any one of the diseases or conditions described herein). For example, in the treatment of CNS or psychiatric disorders, the compounds described herein may exhibit effective blood-brain barrier permeability. Or, in the treatment of non-CNS or non-psychiatric disorders, the compounds described herein will not have high blood-brain barrier permeability (e.g., inaccurate effects will be reduced). Without being bound by theory, the molecular elements of the compounds may be an effective strategy for achieving desired biological targeting.

[0982] There is evidence suggesting a role for the 5-HT7 receptor in numerous medical disorders. Regulators of 5-HT7 receptor activity may have beneficial effects on patients suffering from these disorders. Disorders in which 5-HT7 dysregulation plays a role and modulation of 5-HT7 receptor activity by therapeutic agents may be a viable approach for therapeutic relief include circadian rhythm disorders, depression, schizophrenia, neuroinflammation, hypertension, peripheral vascular disease, migraine (Vanhoenacker, P. et al., Trends in Pharmacological Sciences, 2000, 21, 2, 70-77), neuropathic pain, peripheral pain, allodynia (EP1875899), thermoregulatory disorders, learning disabilities, memory disorders, hippocampal signaling disorders, sleep disorders (WO20100197700), attention deficit / hyperactivity disorder (ADHD) (WO20100069390), anxiety, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder (WO20040229874), and inflammatory bowel disease. Disease (IBD), intestinal inflammation (WO 2012058769, Khan, WI et al., Journal of Immunology, 2013, 190, 4795-4804), epilepsy, seizure disorder (Epilepsy Research (2007) 75, 39), drug addiction and alcoholism (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, ZXMolecular Oncology, 2016, 10, 195-212), small intestinal neuroendocrine tumors (Modlin, IM Cancer Science, 2013, 104, 7, 844-855), and lung injury (Halici, Z. Immunology, 2013, 1271-1283.), including but not limited to these.

[0983] There has long been a need for a new 5-HT7 modulator to provide therapeutic relief to patients suffering from diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. The present invention addresses the need to identify a novel 5-HT7 modulator capable of treating diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. The present invention addresses the need for the development of new therapeutic agents for the treatment and prevention of circadian rhythm disorders, depression, schizophrenia, neuroinflammatory disorders, 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, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), intestinal inflammation, epilepsy, seizure disorders, drug addiction, alcoholism, breast cancer, liver fibrosis, chronic liver injury, hepatocellular carcinoma, small intestinal neuroendocrine tumors, and lung injury.

[0984] The 5-hydroxytryptamine receptor 7 activity modulator of the present invention can treat or prevent diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity, such as, for example, circadian rhythm disorders, depression, schizophrenia, neuroinflammatory disorders, 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, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), intestinal inflammation, epilepsy, seizure disorders, drug addiction, alcoholism, breast cancer, liver fibrosis, chronic liver damage, hepatocellular carcinoma, small intestinal neuroendocrine tumor, and lung damage. Since 5-hydroxytryptamine receptor 7 has been found to play a role in numerous medical disorders, 5-HT7 receptor activity modulators may provide beneficial effects to patients suffering from these disorders. Disorders in which 5-HT7 dysregulation plays a role and modulation of 5-HT7 receptor activity by therapeutic agents may be a viable approach for therapeutic relief include circadian rhythm disorders, depression, schizophrenia, neuroinflammation, hypertension, peripheral vascular disease, and migraine (Vanhoenacker, P.Literature by et al. [Trends in Pharmacological Sciences, 2000, 21, 2, 70-77]), neuropathic pain, peripheral pain, allodynia (EP1875899), thermoregulatory disorders, learning disabilities, memory disorders, hippocampal signaling disorders, sleep disorders (WO20100197700), attention deficit / hyperactivity disorder (ADHD) (WO20100069390), anxiety, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder (WO20040229874), inflammatory bowel disease (IBD), intestinal inflammation (WO 2012058769), epilepsy, seizure disorders (Epilepsy Research (2007) 75, 39), drug addiction and alcoholism (Literature by Hauser, SR et al. [Frontiers in Neuroscience, 2015, 8, 1-9]), breast cancer (Gautam, J.'s literature [Molecular Cancer, 2016, 15, 75, 1-14], Gautam, J.'s literature [Breast Cancer Research and Treatment, 2017, 161, 29-40]), liver fibrosis, chronic liver injury (Halici, Z.'s literature [International Immunopharmacology, 2017, 43, 227-235]), hepatocellular carcinoma (Bian, ZX's literature [Molecular Oncology, 2016, 10, 195-212]), small intestine neuroendocrine tumor (Modlin, IM's literature [Cancer Science, 2013, 104, 7, 844-855]), and lung injury (Halici, Z.'s literature [Immunology, 2013, Includes, but not limited to, 1271-1283]).

[0985] Without being bound by theory, it is believed that the 5-hydroxytryptamine receptor 7 receptor activity modulator of the present invention can improve, attenuate, or otherwise modulate diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. Diseases include, but are not limited to, circadian rhythm disorders, depression, schizophrenia, neuroinflammatory disorders, 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, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), intestinal inflammation, epilepsy, seizure disorders, drug addiction, alcoholism, breast cancer, liver fibrosis, chronic liver injury, hepatocellular carcinoma, small intestinal neuroendocrine tumor, and lung injury.

[0986] In some embodiments, the disease is depression, schizophrenia, anxiety, or bipolar disorder. In some embodiments, the disease is depression. In some embodiments, the disease is schizophrenia. In some embodiments, the disease is anxiety. In some embodiments, the disease is bipolar disorder.

[0987] In some embodiments, the disorder is attention deficit / hyperactivity disorder.

[0988] In some embodiments, the disorder is avoidant personality disorder.

[0989] In some embodiments, the disorder is seasonal affective disorder.

[0990] In some embodiments, the disease is a circadian rhythm disorder or a hippocampal signaling disorder. In some embodiments, the disease is a circadian rhythm disorder. In some embodiments, the disease is a hippocampal signaling disorder.

[0991] In some embodiments, the disease is neuroinflammatory.

[0992] In some embodiments, the disease is neuropathic pain, peripheral pain, or allodynia. In some embodiments, the disease is neuropathic pain. In some embodiments, the disease is peripheral pain. In some embodiments, the disease is allodynia.

[0993] In some embodiments, the disease is a migraine.

[0994] In some embodiments, the disease is epilepsy or a seizure disorder. In some embodiments, the disease is epilepsy. In some embodiments, the disease is a seizure disorder.

[0995] In some embodiments, the disease is a learning disability or a memory disorder. In some embodiments, the disease is a learning disability. In some embodiments, the disease is a memory disorder.

[0996] In some embodiments, the disease is an eating disorder.

[0997] In some embodiments, the disease is drug addiction or alcohol addiction.

[0998] In some embodiments, the disease is a sleep disorder.

[0999] In some embodiments, the disease is hypertension or peripheral vascular disease. In some embodiments, the disease is hypertension. In some embodiments, the disease is peripheral vascular disease.

[1000] In some embodiments, the disease is a thermoregulatory disorder.

[1001] In some embodiments, the condition is premature ejaculation.

[1002] In some embodiments, the disease is premenstrual syndrome or premenstrual dysphoric disorder. In some embodiments, the disease is premenstrual syndrome. In some embodiments, the disease is premenstrual dysphoric disorder.

[1003] In some embodiments, the disease is inflammatory bowel disease (IBD) or intestinal inflammation. In some embodiments, the disease is inflammatory bowel disease (IBD). In some embodiments, the disease is intestinal inflammation.

[1004] In some embodiments, the disease is breast cancer.

[1005] In some embodiments, the disease is liver fibrosis, chronic liver injury, or hepatocellular carcinoma. In some embodiments, the disease is liver fibrosis. In some embodiments, the disease is chronic liver injury. In some embodiments, the disease is hepatocellular carcinoma.

[1006] In some embodiments, the disease is a small intestinal neuroendocrine tumor.

[1007] In some embodiments, the disease is lung damage.

[1008] In some embodiments, the disease is inflammatory bowel disease (IBD).

[1009] Formulation (pharmaceutical composition) of 5-HT7 regulator

[1010] The present invention also relates to a composition or formulation comprising a 5-hydroxytryptamine receptor 7 activity modulator according to the present invention. Generally, the composition of the present invention comprises an effective amount of one or more compounds of the present disclosure and salts thereof that are effective in providing modulation of 5-hydroxytryptamine receptor 7 activity; and one or more excipients.

[1011] For the purposes of the present invention, the terms “excipient” and “carrier” are used interchangeably throughout the description of the present invention, and these terms are defined herein as “ingredients used in the practice of formulating safe and effective pharmaceutical compositions.”

[1012] The compounder will understand that excipients are primarily used to deliver safe, stable, and functional drugs, acting not only as part of an overall transporter for delivery but also as a means to achieve effective absorption of the active ingredient by the recipient. Excipients may serve a simple and direct role as inactive fillers, or, as used herein, may be part of a pH stabilization system or coating to ensure the safe delivery of the aforementioned ingredient to the stomach. The compounder may also take advantage of the fact that the compounds of the present invention improve cellular efficacy, pharmacokinetic properties, as well as oral bioavailability.

[1013] The present teaching also provides a pharmaceutical composition 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, for example, Remington's Pharmaceutical Sciences, It may be manufactured according to pharmaceutically acceptable procedures, such as those described in the 17th edition, edited by Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985) (the full disclosure is incorporated herein by reference for all purposes). As used herein, “pharmaceuticalally acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not interact adversely with the active ingredient. Thus, the pharmaceutically acceptable carrier is compatible with other ingredients in the formulation and is biologically acceptable. The supplementary active ingredient may also be included in the pharmaceutical composition.

[1014] The compounds of this teaching may be administered orally or parenterally, without mixing with other substances or in combination with conventional pharmaceutical carriers. Applicable solid carriers may also comprise one or more substances capable of acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, lubricants, compression aids, binders or tablet-dissolving agents, or encapsulating materials. The compounds may be formulated in a conventional manner, for example, in a manner similar to that used for known 5-hydroxytryptamine receptor 7 activity modifiers. Oral formulations containing the compounds disclosed herein may include any conventionally used oral administration forms, including tablets, capsules, buccal forms, lozenges, and oral liquids, suspensions, or solutions. In powders, the carrier may be a finely ground solid, which is mixed with the finely ground compound. In tablets, the compounds disclosed herein may be mixed with a carrier having the necessary compression properties in appropriate proportions and compressed into a desired shape and size. Powders and tablets can contain up to 99% of the compound.

[1015] The capsule may contain a mixture of one or more compounds disclosed herein having pharmaceutically acceptable starch (e.g., corn, sweet potato, or tapioca starch), sugars, artificial sweeteners, powdered cellulose (e.g., crystalline and microcrystalline cellulose), inactive filler(s) such as wheat flour, gelatin, gum, etc., and / or diluent(s).

[1016] A useful tablet formulation may be prepared by conventional compression, wet granulation, or dry granulation methods and may contain, but is not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low-melting point waxes, and ion exchange resins, pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents, or Stabilizers may be used. 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, cetosteal alcohol, cetomacrogol emulsifying wax, sorbitan ester, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine. In this invention, oral formulations may utilize standard delayed-release or time-release formulations to alter the absorption of the compound(s). Oral formulations may also consist of administering the compound disclosed herein in water or fruit juice containing a suitable solubilizer or emulsifier as needed.

[1017] Liquid carriers may be used to prepare solutions, suspensions, emulsions, syrups, and elixirs for inhalation delivery. Compounds of this teaching may be dissolved or suspended in pharmaceutically acceptable liquid carriers, such as water, organic solvents, or mixtures thereof, or in pharmaceutically acceptable oils or fats. Liquid carriers may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colorings, viscosity modifiers, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (containing additives as described herein, for example, cellulose derivatives such as sodium carboxymethyl cellulose solution), alcohols (monohydric and polyhydric alcohols, including glycols, for example) and their derivatives, and oils (for example, fractionated palm oil and peanut oil). For parenteral administration, the carrier may be an oily ester such as ethyl oleate and isopropyl myristate. A sterile liquid carrier is used in a sterile liquid form composition for parenteral administration. A liquid carrier for a pressurized composition may be a halogenated hydrocarbon or another pharmaceutically acceptable propellant.

[1018] Liquid pharmaceutical compositions, which are sterile solutions or sterile suspensions, may be used, for example, by intramuscular, intraperitoneal, or subcutaneous injection. Sterile solutions may also be administered intravenously. Compositions for oral administration may be in liquid or solid form.

[1019] Preferably, the pharmaceutical composition is in the form of a unit dose, e.g., a tablet, capsule, powder, solution, suspension, emulsion, granule, or suppository. In this form, the pharmaceutical composition may be subdivided into unit dose(s) containing an appropriate amount of the compound. The unit dose form may be a packaged composition, e.g., packeted powders, vials, ampoules, pre-filled syringes, or liquid-containing pouches. Alternatively, the unit dose form may be the capsule or tablet itself, or a package of an appropriate number of such compositions. These unit dose forms may contain about 1 mg / kg of the compound to about 500 mg / kg of the compound and may be provided as a single dose or two or more doses. These doses may be administered in any manner useful for delivering the compound(s) into the recipient's bloodstream, including oral, via implant, parenteral (including intravenous, intraperitoneal, and subcutaneous injection), rectal, vaginal, and transdermal administration.

[1020] It should be understood that when administered for the treatment or suppression of a specific disease state or disorder, the effective dosage may vary depending on the specific compound used, the mode of administration, and the severity of the condition being treated, as well as various physical factors relevant to the individual being treated. For therapeutic use, the compounds of this teaching may be provided to patients already suffering from the disease in an amount sufficient to cure or at least partially improve the symptoms of the disease and its complications. The dosage used for the treatment of a specific individual should generally be determined subjectively by the attending physician. Relevant variables include the patient's size, age, and response pattern, as well as specific conditions and states.

[1021] In some cases, it may be desirable to administer the compound directly into the patient's airway using a device such as, but not limited to, a metered-dose inhaler, a respiratory inhaler, a multi-dose dry powder inhaler, a pump, a squeeze-acting nebulizer, an aerosol dispenser, or an aerosol nebulizer. For administration by intranasal or bronchial inhalation, the compounds of this teaching may be formulated as a liquid composition, a solid composition, or an aerosol composition. A liquid composition may, by example, comprise one or more compounds of this teaching dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents, and may be administered, for example, by a pump or a squeeze-acting nebulizer. The solvent may be, for example, isotonic saline or bacteriostatic water. The solid composition may be a powder formulation comprising one or more compounds of this teaching mixed with, for example, lactose or other inert powder permitted for bronchial use, and may be administered, for example, by an aerosol dispenser or device that delivers the solid composition for inhalation by breaking or perforating a capsule surrounding the solid composition. The aerosol composition may, for example, comprise one or more compounds of this teaching, a propellant, a surfactant, and a co-solvent, and may be administered, for example, by a metered device. The propellant may be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other physiologically and environmentally acceptable propellant.

[1022] The compounds described herein may be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or pharmaceutically acceptable salts, hydrates, or esters thereof may be prepared in water appropriately mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions may also be prepared in oil with glycerol, liquid polyethylene glycol, and mixtures thereof. Under normal conditions of storage and use, these formulations typically contain preservatives to inhibit microbial growth.

[1023] Pharmaceutical forms suitable for injection may include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In some embodiments, these forms are sterile and have a viscosity that allows them to flow through a syringe. These forms are preferably stable under manufacturing and storage conditions and can be preserved from the action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), a suitable mixture thereof, and vegetable oil.

[1024] The compounds described herein may be administered transdermally, that is, through the inner lining of body passages including epithelial and mucosal tissues and the surface of the body. Such administration may be carried out using the compounds of this teaching, their pharmaceutically acceptable salts, hydrates, or esters as lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[1025] Transdermal administration may be performed via a transdermal patch containing a carrier that contains a compound such as the compound disclosed herein, may be inert to the compound, may be non-toxic to the skin, and may allow the delivery of the compound for systemic absorption into the bloodstream through the skin. The carrier may take various forms, such as creams and ointments, pastes, gels, and occlusion devices. Creams and ointments may be viscous liquids or semi-solid emulsifiers of the oil-in-water or water-in-oil type. Pastes composed of absorbent powders dispersed in petroleum or hydrophilic petroleum containing such compounds may also be suitable. Various occlusion devices, such as semi-permeable membranes covering reservoirs containing compounds with or without a carrier, or matrices containing the compound, may be used to release the compound into the bloodstream. Other occlusion devices are known in the literature.

[1026] The compounds described herein may be administered rectally or vaginally in the form of conventional suppositories. Suppository formulations may be prepared from traditional materials comprising cocoa butter and glycerin, with or without added wax to modify the melting point of the suppository. Water-soluble suppository bases, such as polyethylene glycol of various molecular weights, may also be used.

[1027] Lipid formulations or nanocapsules may be used to introduce the compounds of the present teaching into host cells in vitro or in vivo. Lipid formulations and nanocapsules may be prepared by methods known in the art.

[1028] To increase the efficacy of the compound of the present teaching, it may be desirable to use the compound in combination with other agents effective in treating the target disease. For example, other active compounds effective in treating the target disease (i.e., other active ingredients or agents) may be administered together with the compound of the present teaching. Other agents may be administered simultaneously with or at different times from the compound disclosed herein.

[1029] The compounds of the present teaching may be useful for the treatment or inhibition of pathological conditions or disorders in mammals, e.g., human subjects. Accordingly, the present teaching provides a method for treating or inhibiting pathological conditions or disorders by providing a compound of the present teaching to a mammal in combination or combination with a pharmaceutically acceptable carrier, comprising a pharmaceutical composition containing a pharmaceutically acceptable salt or one or more compounds of the present teaching. The compounds of the present teaching may be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of pathological conditions or disorders.

[1030] 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 and one or more excipients according to the present invention, about 0.01 mg to about 100 mg of one or more compounds of the present disclosure and one or more excipients according to the present invention, and about 0.1 mg to about 10 mg of one or more compounds of the present disclosure and one or more excipients according to the present invention.

[1031] example

[1032] The implementation of the present invention is illustrated by the following non-limiting embodiments.

[1033] Synthesis of the 5-HT7 regulator

[1034] The compounds of the present invention may be prepared by methods known in the art. Exemplary methods include International Application No. PCT / US2017 / 061677 filed November 15, 2017; International Application No. PCT / US2013 / 071926 filed November 26, 2013; International Application No. PCT / US2014 / 023400 filed March 11, 2014; International Application No. PCT / US2015 / 049303 filed September 10, 2015; International Application No. PCT / US2016 / 031780 filed May 11, 2016; and International Application No. PCT / US2018 / 022581 filed March 15, 2018. and disclosed in international application PCT / US2018 / 022574 filed on March 15, 2018.

[1035] The examples provided below provide a representative method for preparing an exemplary compound of the present invention. Those skilled in the art will recognize methods to substitute suitable reagents, starting materials, and purification methods known to those skilled in the art for preparing the compound of the present invention.

[1036] Synthesis and Characterization of Intermediates

[1037]

[1038] Preparation of tert-butyl (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: 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 equivalent) and (S)-1-(4-fluorophenyl)-3-methylpiperazine (1.35 g, 6.95 mmol, 2.1 equivalents) were added to a small vial, and then both were dissolved in acetonitrile (33 mL). Then, K2CO3 (1.14 g, 8.2 mmol, 2.5 equivalents) was added, and the reaction mixture was stirred overnight at 80°C, followed by cooling to 23°C. The mixture was filtered, washed with acetonitrile, and the filtrate concentrated under vacuum to obtain an unpurified product, which was further purified by column chromatography (MeOH / methylene chloride, 0%–10%). LC / MS [M+H] = m / z 476.2

[1039]

[1040] Preparation of tert-butyl (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: The compound of the title was prepared according to the procedure for tert-butyl (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that 1-(4-fluorophenyl)piperazine was substituted with (S)-1-(4-fluorophenyl)-3-methylpiperazine. LC / MS [M+H] = m / z 462.2

[1041]

[1042] Preparation of tert-butyl (R)-3-(2-((R)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: The compound of the title was prepared according to the procedure for tert-butyl (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that (R)-1-(4-fluorophenyl)-3-methylpiperazine was substituted with (S)-1-(4-fluorophenyl)-3-methylpiperazine. LC / MS [M+H] = m / z 476.2

[1043]

[1044] Preparation of tert-butyl (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: The compound of the title was prepared according to the procedure for tert-butyl (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that 1-(3-chlorophenyl)piperazine was substituted with (S)-1-(4-fluorophenyl)-3-methylpiperazine. LC / MS [M+H] = m / z 478.2

[1045]

[1046] Preparation of (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: Acetyl chloride (1.2 mL) was added to methanol (3 mL) to prepare a 6 M HCl solution in methanol. Tert-butyl (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.127 g, 0.267 mmol, 1.0 equivalent) was dissolved in a prepared 6 M methanol-HCl solution (3 mL) and stirred at 23°C for 30 minutes. Afterward, the mixture was diluted with methanol and concentrated under vacuum to obtain the crude product as a 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 under vacuum to obtain the crude product. LC / MS [M+H] = m / z 376.2

[1047]

[1048] Preparation of (R)-3-(2-((R)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is, except that tert-butyl (R)-3-(2-((R)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate is substituted with tert-butyl (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, It was prepared according to the procedure for (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one. LC / MS [M+H] = m / z 376.2

[1049]

[1050] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is, except that tert-butyl (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate is substituted with tert-butyl (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, It was prepared according to the procedure for (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one. LC / MS [M+H] = m / z 362.2

[1051]

[1052] Preparation of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is, except that tert-butyl (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate is substituted with tert-butyl (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, It was prepared according to the procedure for (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one. LC / MS [M+H] = m / z 378.2

[1053]

[1054] Preparation of tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate: This reaction was carried out in an oven-dried glass vessel under a nitrogen atmosphere. N-(tert-butoxycarbonyl)glycine (13.8 mg, 0.078 mmol, 1.05 equivalents) was added to a small vial and dissolved in dimethylformamide (700 μL). Next, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (31.3 mg, 0.082 mmol, 1.1 equivalents) and N,N-diisopropylethylamine (39 mg, 0.3 mmol, 4 equivalents) were added, and the resulting solution was stirred at 23°C for 15 minutes. In separate vials, a solution of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride (33.3 mg, 0.074 mmol, 1.0 equivalent), dimethylformamide (300 μL), and N,N-diisopropylethylamine (17.3 mg, 0.13 mmol, 2.2 equivalents) was prepared. The two solutions were combined and stirred at 23°C for 30 minutes, then diluted with methanol (5 mL) and concentrated under vacuum. The resulting residue was quenched in saturated NaHCO3 (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layer was dried with Na2SO4 and concentrated under vacuum to obtain an unrefined product, which was further purified by column chromatography (methanol / dichloromethane, 0%–10%). LC / MS [M+H] = m / z 535.3

[1055]

[1056] Preparation of Tert-Butyl (R)-(2-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate: The compound of the title is tert-butyl except that (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride. It was prepared according to the procedure for (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate. LC / MS [M+H] = m / z 519.3

[1057]

[1058] Preparation of tert-butyl ((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxopropane-2-yl)carbamate: The compound of the title is formed by substituting (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride and (tert-butoxycarbonyl)-L-alanine Except for substitution with N-(tert-butoxycarbonyl)glycine, it was prepared according to the procedure for tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate. LC / MS [M+H] = m / z 533.3

[1059]

[1060] Preparation of tert-butyl ((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxobutane-2-yl)carbamate: The compound of the title is formed by substituting (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride and (S)-2-((tert-butoxycarbonyl)amino)butanoic acid Except for substitution with N-(tert-butoxycarbonyl)glycine, it was prepared according to the procedure for tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate. LC / MS [M+H] = m / z 547.3

[1061]

[1062] Preparation of tert-butyl ((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutane-2-yl)carbamate: The compound of the title is formed by substituting (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride and (tert-butoxycarbonyl)-L-valine Except for substitution with N-(tert-butoxycarbonyl)glycine, it was prepared according to the procedure for tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate. LC / MS [M+H] = m / z 561.3

[1063]

[1064] Preparation of tert-butyl ((S)-1-((R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxopropane-2-yl)carbamate: The compound of the title, (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one, is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride and (tert-butoxycarbonyl)-L-alanine Except for substitution with N-(tert-butoxycarbonyl)glycine, it was prepared according to the procedure for tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate. LC / MS [M+H] = m / z 547.3

[1065]

[1066] Preparation of tert-butyl (R)-(1-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-methyl-1-oxopropane-2-yl)carbamate: The compound of the title was prepared according to the procedure for tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that 2-(boc-amino)isobutyric acid was substituted with N-(tert-butoxycarbonyl)glycine. LC / MS [M+H] = m / z 563.3

[1067]

[1068] Preparation of tert-butyl (R)-(1-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropane-2-yl)carbamate: The compound of the title, except that (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one and 2-(boc-amino)isobutyric acid is substituted with N-(tert-butoxycarbonyl)glycine, Tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate was prepared according to the procedure. LC / MS [M+H] = m / z 547.3

[1069] Synthesis and Characterization of 5-HT7 Regulators

[1070]

[1071] Preparation of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride: Acetyl chloride (6 mL) was added to methanol (15 mL) to prepare a 6 M HCl solution in methanol. Tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate (0.607 g, 0.119 mmol, 1.0 equivalent) was dissolved in a prepared 6 M methanol-HCl solution (13 mL), stirred at 23°C for 45 minutes, diluted with methanol, and concentrated under vacuum to obtain the crude product as a diHCl salt. LC / MS [M+H] = m / z 435.2

[1072]

[1073] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride: The compound of the title is, except that tert-butyl (R)-(2-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate is substituted with tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride was prepared according to the procedure. LC / MS [M+H] = m / z 419.2

[1074]

[1075] Preparation of (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide: A solution of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride (31.6 mg, 0.062 mmol, 1 equivalent), dichloromethane (1.5 mL), and triethylamine (28.5 mg, 0.24 mmol, 4 equivalents) was cooled to 0°C, and then acetyl chloride (5.0 mg, 0.062 mmol, 1 equivalent) was added to the solution. The reaction solution was heated to 23°C and stirred for 15 minutes. The reaction product was diluted with methanol (approx. 2 mL), concentrated under vacuum, and further purified by column chromatography using a C18 column (ACN / H2O, 0%–100%, w / 0.1% NH4OH). LC / MS [M+H] = m / z 477.2

[1076]

[1077] Preparation of (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide: The compound of the title, except that (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride, (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide was prepared according to the procedure. LC / MS [M+H] = m / z 461.2

[1078]

[1079] Preparation of (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)methanesulfonamide: A solution of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride (431 mg, 0.845 mmol, 1 equivalent), dichloromethane (17 mL), and triethylamine (516 mg, 5.1 mmol, 6 equivalents) was cooled to 0°C, and then methanesulfonyl chloride (117 mg, 1.02 mmol, 1.2 equivalents) was added to the solution. The reaction solution was heated to 23°C and stirred for 15 minutes. The reaction product was diluted with methanol (approx. 10 mL), concentrated under vacuum, and further purified by column chromatography using a C18 column (ACN / H2O, 0%–100%, w / 0.1% NH4OH). LC / MS [M+H] = m / z 513.2

[1080]

[1081] Preparation of (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)methanesulfonamide: The compound of the title is, except that (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride, (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)methanesulfonamide was prepared according to the procedure. LC / MS [M+H] = m / z 497.2

[1082]

[1083] Preparation of (R)-8-(2-amino-2-methylpropaneoil)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is tert-butyl (R)-(1-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropane-2-yl)carbamate as tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate Except for substitution, it was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride. Additionally, the product was free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration under vacuum to obtain the product. LC / MS [M+H] = m / z 447.2

[1084]

[1085] Preparation of (R)-8-(2-amino-2-methylpropaneoil)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azspiro[4.5]decane-1-one: The compound of the title is tert-butyl (R)-(1-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-methyl-1-oxopropane-2-yl)carbamate. It was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride, except that it was substituted with (R)-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride. Additionally, the product was free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration under vacuum to obtain the product. LC / MS [M+H] = m / z 463.2

[1086]

[1087] Preparation of (R)-N-(1-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropane-2-yl)acetamide: The compound of the title, except that (R)-8-(2-amino-2-methylpropaneoil)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide was prepared according to the procedure. LC / MS [M+H] = m / z 488.2

[1088]

[1089] Preparation of (R)-N-(1-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropane-2-yl)acetamide: The compound of the title, except that (R)-8-(2-amino-2-methylpropaneoil)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide was prepared according to the procedure. LC / MS [M+H] = m / z 504.2

[1090]

[1091] Preparation of (R)-N-(1-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropane-2-yl)pivalamide: The compound of the title is, except that (R)-8-(2-amino-2-methylpropaneoil)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)pivalamide was prepared according to the procedure. LC / MS [M+H] = m / z 531.3

[1092]

[1093] Preparation of (R)-N-(1-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-methyl-1-oxopropane-2-yl)pivalamide: The compound of the title, except that (R)-8-(2-amino-2-methylpropaneoil)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)pivalamide was prepared according to the procedure. LC / MS [M+H] = m / z 547.3

[1094]

[1095] Preparation of (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)pivalamide: This reaction was carried out in an oven-dried glass vessel under a nitrogen atmosphere. Sodium pivalate (21.8 mg, 0.17 mmol, 1.05 equivalents) was added to a small vial and dissolved in dimethylformamide (1.5 mL). Next, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (70 mg, 0.18 mmol, 1.1 equivalents) and N,N-diisopropylethylamine (86.3 mg, 0.67 mmol, 4 equivalents) were added, and the resulting solution was stirred at 23°C for 15 minutes. In separate vials, a solution of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride (81.2 mg, 0.16 mmol, 1.0 equivalent), dimethylformamide (400 μL), and N,N-diisopropylethylamine (48 mg, 0.37 mmol, 2.2 equivalents) was prepared. The two solutions were combined and stirred at 23°C for 30 minutes, then diluted with methanol (5 mL) and concentrated under vacuum. The resulting residue was quenched in saturated NaHCO3 (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layer was dried with Na2SO4 and concentrated under vacuum to obtain an unrefined product, which was further purified by column chromatography using a C18 column (ACN / H2O, 0%–100%, w / 0.1% NH4OH). LC / MS [M+H] = m / z 503.3

[1096]

[1097] Preparation of (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)pivalamide: The compound of the title, except that (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride is substituted with (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride, (R)-N-(2-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)pivalamide was prepared according to the procedure. LC / MS [M+H] = m / z 519.3

[1098]

[1099] Preparation of (R)-8-(dimethylglycyl)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one, except that (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride is substituted and N,N-dimethylglycine is substituted with N-(tert-butoxycarbonyl)glycine, except that tert-butyl It was prepared according to the procedure for (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate. Additionally, the above purification method was replaced with column chromatography using a C18 column (ACN / H2O, 0% to 100%, w / 0.1% NH4OH). LC / MS [M+H] = m / z 447.3

[1100]

[1101] Preparation of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-(dimethylglycyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title was prepared according to the procedure for tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that N,N-dimethylglycine was substituted with N-(tert-butoxycarbonyl)glycine. Additionally, the above purification method was replaced with column chromatography using a C18 column (ACN / H2O, 0% to 100%, w / 0.1% NH4OH). LC / MS [M+H] = m / z 463.3

[1102]

[1103] Preparation of (R)-8-(2-(dimethylamino)-2-methylpropaneoil)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is, except that (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride and 2-(dimethylamino)-2-methylpropanoic acid is substituted with N-(tert-butoxycarbonyl)glycine, tert-butyl It was prepared according to the procedure for (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate. Additionally, the above purification method was replaced with column chromatography using a C18 column (ACN / H2O, 0% to 100%, w / 0.1% NH4OH). LC / MS [M+H] = m / z 475.3

[1104]

[1105] Preparation of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-(2-(dimethylamino)-2-methylpropaneoil)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title was prepared according to the procedure for tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that 2-(dimethylamino)-2-methylpropanoic acid was substituted with N-(tert-butoxycarbonyl)glycine. Additionally, the above purification method was replaced with column chromatography using a C18 column. (ACN / H2O, 0% ~ 100%, w / 0.1% NH4OH). LC / MS [M+H] = m / z 491.3

[1106]

[1107] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-(2-mopolinoacetyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one, except that (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride is substituted and morpholin-4-yl acetic acid is substituted with N-(tert-butoxycarbonyl)glycine, except that tert-butyl It was prepared according to the procedure for (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate. Additionally, the above purification method was replaced with column chromatography using a C18 column (ACN / H2O, 0% to 100%, w / 0.1% NH4OH). LC / MS [M+H] = m / z 489.3

[1108]

[1109] Preparation of (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-(2-morpholine-oacetyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title was prepared according to the procedure for tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, except that morpholine-4-yl acetic acid was substituted with N-(tert-butoxycarbonyl)glycine. Additionally, the above purification method was replaced with column chromatography using a C18 column (ACN / H2O, 0% to 100%, w / 0.1% NH4OH). LC / MS [M+H] = m / z 505.3

[1110]

[1111] Preparation of N-((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-1-oxopropane-2-yl)acetamide: The compound of the title is, except that (R)-8-(L-alanyl)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride, (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide was prepared according to the procedure. LC / MS [M+H] = m / z 475.2

[1112]

[1113] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-nicotineoil-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is, except that (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride and nicotineoil chloride is substituted with methanesulfonyl chloride, (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)methanesulfonamide was prepared according to the procedure. LC / MS [M+H] = m / z 467.2

[1114]

[1115] Preparation of (R)-8-(2-(1H-tetrazole-5-yl)acetyl)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one formate: The title compound is, 2 H It was prepared according to the procedure for (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-(pyridazine-3-carbonyl)-2-oxa-8-azaspiro[4.5]decane-1-one, except that tetrazole-5-acetic acid was substituted with 3-pyridazine carboxylic acid. Additionally, the above purification method was replaced with column chromatography using a C18 column (ACN / H2O, 0% to 100%, w / 0.1% HCOOH). LC / MS [M+H] = m / z 472.2

[1116]

[1117] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-(2-(2-oxo-oxazolidin-3-yl)acetyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is obtained by substituting (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride and substituting (2-oxo-1,3-oxazolidin-3-yl)acetic acid with N-(tert-butoxycarbonyl)glycine Except for, it was prepared according to the procedure for tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate. Additionally, the above purification method was replaced with column chromatography using a C18 column (ACN / H2O, 0% to 100%, w / 0.1% NH4OH). LC / MS [M+H] = m / z 489.3

[1118]

[1119] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-(pyridazine-3-carbonyl)-2-oxa-8-azaspiro[4.5]decane-1-one: This reaction was carried out in an oven-dried glass vessel under a nitrogen atmosphere. 3-pyridazine carboxylic acid (14.3 mg, 0.115 mmol, 1.9 equivalents) was added to a small vial and dissolved in dimethylacetamide (500 μL). Then, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (55.8 mg, 0.291 mmol, 4.8 equivalents), 1-benzotriazole (39.3 mg, 0.291 mmol, 4.8 equivalents), and N-methylmorpholine (59 mg, 0.584 mmol, 9.6 equivalents) were added, and the resulting solution was stirred at 23°C for 15 minutes. Subsequently, (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one (21.9 mg, 0.0607 mmol, 1 equivalent) was added using dimethylacetamide (150 μL) to aid delivery. The resulting solution was stirred at 23°C for 30 minutes, then diluted with methanol (5 mL) and concentrated under vacuum. The resulting residue was quenched in saturated NaHCO3 (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layer was dried with Na2SO4 and concentrated under vacuum to obtain an unpurified product, which was further purified by column chromatography using a C18 column (ACN / H2O, 0%–100%, w / 0.1% NH4OH). LC / MS [M+H] = m / z 468.2

[1120]

[1121] Preparation of (R)-8-acetyl-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is, except that (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide was prepared according to the procedure. LC / MS [M+H] = m / z 418.2

[1122]

[1123] Preparation of N-((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxobutane-2-yl)acetamide: The compound of the title is, except that (R)-8-((S)-2-aminobutaneoil)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide was prepared according to the procedure. LC / MS [M+H] = m / z 489.2

[1124]

[1125] Preparation of N-((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutane-2-yl)acetamide: The compound of the title, except that (R)-8-(L-valyl)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide was prepared according to the procedure. LC / MS [M+H] = m / z 502.2

[1126]

[1127] Preparation of methyl (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: The compound of the title is, except that (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride and methyl chloroformate is substituted with acetyl chloride, (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide was prepared according to the procedure. LC / MS [M+H] = m / z 434.2

[1128]

[1129] Preparation of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-(isoxazole-3-yl)-2-oxa-8-azaspiro[4.5]decane-1-one: This reaction was carried out in an oven-dried glass vessel under a nitrogen atmosphere. The following substances were added in the following order to a solution of (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one (1.0 g, 2.76 mmol, 1.0 equivalent) and 3-bromoisoxazole (0.614 g, 4.15 mmol, 1.5 equivalent) in anhydrous toluene (10.6 mL): Pd2(dba)3 (0.063 g, 5 mol %), BINAP (0.127 g, 7.5 mol %), triethylamine (0.698 g, 6.6 mmol, 2.5 equivalent), and NaOtBu (0.291 g, 3.3 mmol, 1.2 equivalent). The resulting mixture was stirred overnight at 80°C while sweeping with N2. The reaction mixture was cooled to RT and then filtered through a Celite plug. The collected filtrate was concentrated under vacuum to obtain an unrefined residue, which was further purified by column chromatography (dichloromethane / methanol, 0%–10%). LC / MS [M+H] = m / z 429.3

[1130]

[1131] Preparation of methyl (R)-(2-(3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate: The compound of the title is, except that (R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride and methyl chloroformate is substituted with acetyl chloride, (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide was prepared according to the procedure. LC / MS [M+H] = m / z 477.2

[1132]

[1133] Preparation of (R)-3,3-diethyl-5-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)dihydrofuran-2(3H)-one: The compound of the title was prepared according to the procedure for tert-butyl (R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except that (R)-2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate was substituted with 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

[1134]

[1135] Preparation of N-((S)-1-((R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxopropane-2-yl)acetamide: The compound of the title, except that (R)-8-(L-alanyl)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one is substituted with (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride, (R)-N-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-8-yl)-2-oxoethyl)acetamide was prepared according to the procedure. LC / MS [M+H] = m / z 489.2

[1136]

[1137] Preparation of (R)-8-(L-alanyl)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is, except that tert-butyl ((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxopropane-2-yl)carbamate is substituted with tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate, It was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride. Additionally, the product was free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration under vacuum to obtain the product. LC / MS [M+H] = m / z 433.2

[1138]

[1139] Preparation of (R)-8-((S)-2-aminobutaneoil)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is tert-butyl ((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxobutane-2-yl)carbamate as tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate Except for substitution, it was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride. Additionally, the product was free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration under vacuum to obtain the product. LC / MS [M+H] = m / z 447.2

[1140]

[1141] Preparation of (R)-8-(L-valyl)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is obtained by substituting tert-butyl ((S)-1-((R)-3-(2-(4-(4-fluorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutane-2-yl)carbamate with tert-butyl (R)-(2-(3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-2-oxoethyl)carbamate Except for, it was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azaspiro[4.5]decane-1-one dihydrochloride. Additionally, the product was free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration under vacuum to obtain the product. LC / MS [M+H] = m / z 461.2

[1142]

[1143] Preparation of (R)-8-(L-alanyl)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-1-one: The compound of the title is tert-butyl ((S)-1-((R)-3-(2-((S)-4-(4-fluorophenyl)-2-methylpiperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-yl)-1-oxopropane-2-yl)carbamate. It was prepared according to the procedure for (R)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-1-oxo-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride, except that it was substituted with (R)-(2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl)-8-glycyl-2-oxa-8-azspiro[4.5]decane-1-one dihydrochloride. Additionally, the product was free-based by stirring with Amberlite IRN-78 base resin in methanol for 15 minutes, followed by filtration and concentration under vacuum to obtain the product. LC / MS [M+H] = m / z 447.2

[1144] Biochemical research

[1145] The biological activity of the compounds described herein may be determined by methods known in the art, including that described in International Application No. PCT / US19 / 31824, the whole of which is incorporated herein by reference. Exemplary tests are described herein.

[1146] method

[1147] 1 Radiolabeling (IC) 50 and K I )

[1148] A solution of the compound of the present disclosure to be tested is prepared as a 1 mg / mL stock in assay buffer or DMSO according to its solubility. A similar stock of the reference compound chlorpromazine is also prepared as a positive control. Eleven dilutions (5 x assay concentrations) of the compound of the present disclosure and chlorpromazine are prepared in serial dilutions in assay buffer to yield a final corresponding assay concentration in the range of 10 pM to 10 μM.

[1149] 5 nM [ 3 A stock concentrate of [H]LSD (diethylamide resergylic acid) is prepared in 50 mM Tris-HCl, 10 mM MgCl2, 1 mM EDTA, pH 7.4 (test buffer). An aliquot (50 μl) of the radioactive ligand is dispensed into wells of a 96-well plate containing 100 μl of test buffer. An overlapping 50 μl aliquot of serial dilutions of the test compound of the present disclosure and the chlorpromazine positive control reference compound is added.

[1150] Dispense the membrane fraction (50 μL) of cells expressing the recombinant 5-HT7 receptor into each well. The membrane is prepared by harvesting a PBS-washed monolayer from a stably transfected cell line expressing the 5-HT7 receptor cultured in a 10 cm plate, resuspending and lysing it in cooled hypotonic 50 mM Tris-HCl, pH 7.4, and 20,000 x g It is prepared by centrifugation, decanting the supernatant, and storing at -80°C, and this membrane product is resuspended in 3 mL of cooled assay buffer, homogenized through multiple channels using a 26 gauge needle, and then used for assay.

[1151] After incubating 250 μl of the reaction mixture at room temperature for 1.5 hours, it is harvested by rapid filtration onto a 96-well filter mat treated with 0.3% polyethyleneimine using a 96-well Filtermate harvester. Four rapid washes of 500 μl with cooled assay buffer are performed to reduce non-specific binding. After drying the filter mat, scintillation is applied to the filter, and the radioactivity retained on the filter is counted using a micro-beta scintillation counter.

[1152] Raw data (dpm), representing total radioactive ligand binding (i.e., specific + non-specific binding), is expressed as a logarithmic function of the molar concentration of competitors (i.e., test or reference compounds). Nonlinear regression of the normalized (i.e., percentage of radioactive ligand binding compared to that observed in the absence of test or reference compounds) raw data was performed in Prism 4.0 (GraphPad software) using an embedded 3-parameter logistic model representing ligand competition for binding to radioactive ligand-marker sites.

[1153] y = minimum + [(maximum - minimum) / (1 + 10x-logIC 50 )]

[1154] In the equation, the lowest value is equal to the residual radioactive ligand binding measured in the presence of a 10 μM reference compound (i.e., non-specific binding), and the highest value is equal to the total radioactive ligand binding observed in the absence of competitors. Accordingly, log IC 50 (i.e., the logarithm of the ligand concentration that reduces radioligand binding by 50%) is estimated from the data and is used to obtain Ki by applying the Cheng-Prusoff approximation:

[1155] K i = IC 50 / (1 + [ligand] / K D)

[1156] (In the formula, [ligand] is equal to the concentration of the radioactive ligand, and KD is equal to the affinity constant of the radioligand for the target receptor).

[1157] Sensory data (K b )

[1158] The sensory efficacy of the compound of the present disclosure against the 5-HT7 serotonin receptor was measured using the HitHunter cAMP assay (DiscoveRx) as a cell-based cAMP enzyme fragment complement assay. 16 to 20 hours prior to the assay, cells stably expressing the human 5HT7 receptor were plated at 4,000 cells / well in growth medium (superculture medium, 2 mM GlutaMax, and G418 1 mg / mL) in 96-well plates. Serial dilutions of the agonist 5-hydroxytryptamine (5-HT) were prepared in a final concentration range of 10 μM to 10 nM. The compound of the present disclosure was prepared in 3-fold serial dilutions to obtain a final concentration range of 10 μM to 0.1 nM. The compound of the present disclosure was tested for agonist activity in the absence of 5-HT and for antagonist activity in the presence of 5-HT. For the cAMP assay, the protocol was followed according to the instructions provided by the supplier. Briefly, after incubating cells with the compound of the present disclosure at 37°C for 30 minutes, EC 70 Add 5-HT at a certain concentration. After another 30 minutes, add cAMP antibody / cell lysis solution (20 μL / well) and incubate at room temperature for 60 minutes. Add cAMP XS + EA reagent (20 μL / well) and incubate at room temperature for 2 hours. Luminescence is read using an Envision multi-label plate reader.

[1159] According to the formula described herein (e.g., formula ( I )~( II ), for example, formula ( A )~( AAA Exemplary K for a specified compound (according to ) i and K b The data Table 1 It is provided in.

[1160] Although numerous embodiments of the present invention have been described, it is evident that other embodiments utilizing the compounds, methods, and processes of the present invention can be provided by modifying the basic embodiments. Accordingly, it will be understood that the scope of the present invention should be defined by the appended claims rather than by the specific embodiments expressed herein by way of example.

Claims

Claim 1 ceremony ( I* A compound having a structure according to ), or its enantiomer, diastereomer, hydride, solvate, or pharmaceutically acceptable salt, ( I* ), during the meal: R 1N is selected from the group consisting of imidazole, oxazole, and isoxazole; each R AA is independently a C1-C7 linear alkyl; each of R 2a is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN; a is 0, 1, or 2; aa is 1 or 2. Claim 2 ceremony ( I* A compound having a structure according to ), or its enantiomer, diastereomer, hydride, solvate, or pharmaceutically acceptable salt, ( I* ), during the meal: R 1N silver and; among the expressions R 4a and R 4b is hydrogen or C1-C7 alkyl; R 4a and R 4b It optionally combines with the atoms to which they bond to form a ring containing 3 to 7 atoms and optionally containing oxygen; R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of; each of R 8a , R 8b , R 8d , R 8g , and R 8i is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It optionally combines with atoms to which they bond, containing 3 to 7 atoms, oxygen, sulfur, and No. 9 Forming a heterocyclic ring selectively containing a group selected from; and each of R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl; R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls; R 4a and R 8a All exist or R 4a and R 8g When all of them are present, these groups optionally combine with the atoms to which they are bonded to form a ring containing 4 to 7 atoms; R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; each of R AA is independently a C1-C7 linear alkyl; each of R 2a is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN; a is 1 or 2 and; aa is 1 or 2 and; y 1 is 0, 1, or 2. Claim 3 ceremony ( I* A compound having a structure according to ), or its enantiomer, diastereomer, hydride, solvate, or pharmaceutically acceptable salt, ( I* ), during the meal: R 1N silver and; among the expressions R 4a and R 4b is hydrogen or C1-C7 alkyl; R 4a and R 4b It optionally combines with the atoms to which they bond to form a ring containing 3 to 7 atoms and optionally containing oxygen; R 5 is C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxy, C3-C7 cycloalkoxy, C1-C7 haloalkyl, C3-C7 cyclohalalkyl, C1-C7 haloalkoxy, C3-C7 cyclohalalkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, CN, NR 8a R 8b , SO2R 8c , NR 8d SO2R 8e , NR 8i COOR 8j , NHCONR 8f , NR 8g COR 8h , and Selected from a group consisting of; each of R 8a , R 8b , R 8d , R 8g , and R 8i is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; R 8a and R 8b It optionally combines with atoms to which they bond, containing 3 to 7 atoms, oxygen, sulfur, and No. 9 Forming a heterocyclic ring selectively containing a group selected from; and each of R 8c , R 8e , R 8f and R 8h is a C1-C7 alkyl or C3-C7 cycloalkyl; R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls; R 4a and R 8a All exist or R 4a and R 8g When all of them are present, these groups optionally combine with the atoms to which they are bonded to form a ring containing 4 to 7 atoms; R 9 is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 cycloalkyl; each of R AA is independently a C1-C7 linear alkyl; each of R 2a is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN; a is 1 or 2 and; aa is 1 or 2 and; y 1 It is 1 or 2. Claim 4 In paragraph 2, R 1N silver: Phosphorus, compound. Claim 5 In paragraph 3, R 1N silver: or (each of the food) R 8a and R 8b is independently an H or unsubstituted C1-C7 alkyl; or (during the meal) R 8d is independently an H or unsubstituted C1-C7 alkyl, and R 8e is an unsubstituted C1-C7 alkyl; or (during the meal) R 4a and R 8g Each of the is independently H or an unsubstituted C1-C7 alkyl; R 8h is an unsubstituted C1-C7 alkyl; or (during the meal) R 8h is an unsubstituted C1-C7 alkyl; or (each of the food) R 8a , R 8b , and R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an unsubstituted C1-C7 alkyl; (during the meal) R 8j is C1-C7 alkyl, C3-C7 cycloalkyl, C6-C 10 Selected from the group consisting of aryls, and 5 to 10 heteroaryls; , or (each of the food) R 8a and R 8b is independently an H or unsubstituted C1-C7 alkyl; , or (during the meal) R 8g is independently an H or unsubstituted C1-C7 alkyl, and R 8h is an independently unsubstituted C1-C7 alkyl); or Phosphorus, compound. Claim 6 In paragraph 3, R 1N silver: or Phosphorus, compound. Claim 7 In paragraph 1, R 1N silver: or Phosphorus, compound. Claim 8 ceremony ( I** A compound having a structure according to ), or its enantiomer, diastereomer, hydride, solvate, or pharmaceutically acceptable salt, ( I** ) Among: each R aa and R bb is selected from the group consisting of hydrogen, C1-C7 alkyl, and C3-C7 branched alkyl; each of R AA is independently a C1-C7 linear alkyl; each of R 2a is independently a halogen, an unsubstituted C1-C7 alkyl, a C1-C7 perhaloalkyl, an unsubstituted C1-C7 alkoxy, a C1-C7 perhaloalkoxy, or CN; aa is 1 or 2 and; a' A compound consisting of 1 or 2. Claim 9 In paragraph 8, R aa and R bb ethyl, respectively, and compounds. Claim 10 In paragraph 1, a A compound that is 0 or 1. Claim 11 In paragraph 1, a is 1 or 2, and each R AA is a methyl compound. Claim 12 In paragraph 2, each R AA is a methyl compound. Claim 13 In Paragraph 3, each R AA is a methyl compound. Claim 14 In Paragraph 8, each R AA is a methyl compound. Claim 15 In paragraph 1, each R 2a is a compound that is independently a halogen. Claim 16 In paragraph 2, each R 2a is a compound that is independently a halogen. Claim 17 In Paragraph 3, each R 2a is a compound that is independently a halogen. Claim 18 In Paragraph 15, each R 2a A compound that is independently -F or -Cl. Claim 19 In Paragraph 16, each R 2a A compound that is independently -F or -Cl. Claim 20 In Paragraph 17, each R 2a A compound that is independently -F or -Cl. Claim 21 In paragraph 1, the C5 carbon of 2-dihydrofuranone is ( R A compound having a )-composition. Claim 22 In paragraph 2, the C5 carbon of 2-dihydrofuranone is ( R A compound having a )-composition. Claim 23 In paragraph 3, the C5 carbon of 2-dihydrofuranone is ( R A compound having a )-composition. Claim 24 In paragraph 8, the C5 carbon of 2-dihydrofuranone is ( R A compound having a )-composition. Claim 25 In paragraph 1, the C5 carbon of 2-dihydrofuranone is ( S A compound having a )-composition. Claim 26 In paragraph 2, the C5 carbon of 2-dihydrofuranone is ( S A compound having a )-composition. Claim 27 In paragraph 3, the C5 carbon of 2-dihydrofuranone is ( S A compound having a )-composition. Claim 28 In paragraph 8, the C5 carbon of 2-dihydrofuranone is ( S A compound having a )-composition. Claim 29 In claim 1, a compound selected from the group comprising the following compounds, their enantiomers, diastereomers, hydrides, solvates, and pharmaceutically acceptable salts: . Claim 30 In paragraph 2, a compound selected from the group comprising the following compounds, their enantiomers, diastereomers, hydrides, solvates, and pharmaceutically acceptable salts: . Claim 31 In paragraph 3, a compound selected from the group comprising the following compounds, their enantiomers, diastereomers, hydrides, solvates, and pharmaceutically acceptable salts: . Claim 32 A compound selected from the group comprising the following compounds, their enantiomers, diastereomers, hydrides, solvates, and pharmaceutically acceptable salts: . Claim 33 A pharmaceutical composition comprising a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, for treating a disease selected from the group consisting of peripherally selective diseases, neurological diseases, 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, avoidant personality disorder, premature ejaculation, eating disorders, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), intestinal inflammation, epilepsy, seizure disorders, drug addiction, alcoholism, breast cancer, liver fibrosis, chronic liver injury, hepatocellular carcinoma, small intestinal neuroendocrine tumor, and lung injury. Claim 34 A pharmaceutical composition according to claim 33, further comprising at least one pharmaceutically acceptable excipient. Claim 35 A pharmaceutical composition for use in a method for treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity, comprising at least one compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, wherein the method comprises the step of administering an effective amount of said at least one compound or a pharmaceutically acceptable salt thereof to a subject, wherein the disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity is a peripheral nerve selective disease, a neurological disease, a circadian rhythm disorder, depression, schizophrenia, neuroinflammatory disease, 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, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), intestinal inflammation, epilepsy, seizure disorder, drug intoxication, alcohol A pharmaceutical composition selected from the group consisting of poisoning, breast cancer, liver fibrosis, chronic liver injury, hepatocellular carcinoma, small intestine neuroendocrine tumor, and lung injury. Claim 36 A pharmaceutical composition according to claim 35, wherein at least one compound or a pharmaceutically acceptable salt thereof is administered as a composition further comprising at least one excipient. Claim 37 A pharmaceutical composition according to claim 35, wherein the disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity is inflammatory bowel disease (IBD) or intestinal inflammation. Claim 38 delete Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete Claim 43 delete Claim 44 delete Claim 45 delete Claim 46 delete Claim 47 delete

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