Adenosine receptor antagonists and their use

Abstract

Disclosed herein are compounds, compositions, formulations, and methods for modulating A2B adenosine receptors.

Description

[Technical Field]

[0001] cross reference This application claims the interests of U.S. Provisional Patent Application No. 62 / 638,737, filed on 5 March 2018, and U.S. Provisional Patent Application No. 62 / 688,088, filed on 21 June 2018, each of which is incorporated herein by reference.

[0002] This specification includes compounds, methods for producing such compounds, pharmaceutical compositions and formulations containing such compounds, and somatostatin A 2B Methods for using such compounds in the treatment of diseases, disorders, or conditions for which adenosine receptor activity is to be beneficial are described. [Background technology]

[0003] Adenosine, an endogenous nucleoside, is ubiquitous inside and outside living cells. It plays several physiological roles in maintaining homeostasis in cells, tissues, and organs. Adenosine is classified as A1, A 2A , A 2B It can exert its biological effects by interacting with the family of adenosine receptors, known as the A3 adenosine receptor. The A1 adenosine receptor mediates tissue protection, particularly cardioprotection mechanisms. 2A Adenosine receptors regulate coronary vasodilation and cancer immunity. 2B Adenosine receptors play a role in signaling pathways.

[0004] Some A 2B Adenosine receptor antagonists are relatively insoluble in aqueous media and / or difficult to formulate using conventional pharmaceutical excipients, and therefore may be difficult to formulate to provide reproducible plasma levels of the compound in mammals, particularly humans. 2B There is a need to improve the bioavailability of adenosine receptor antagonists. [Overview of the project]

[0005] In one aspect, a compound represented by formula (A):

[0006]

Chemical formula

[0007] In some embodiments, R 4 It is a C1-C6 alkyl group; R 6 is selected from hydrogen and C1-C6 alkyl; or, R 4 and R 6 These atoms, together with the carbon atom to which they bond, form a carbonyl (C=O) molecule.

[0008] In some embodiments, R 4 R is methyl, ethyl, or n-propyl; 6 is selected from hydrogen, methyl, ethyl, and n-propyl; or R 4 and R 6 These atoms, together with the carbon atom to which they bond, form a carbonyl (C=O) molecule.

[0009] In some embodiments, the compound has the following structure:

[0010] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0011] In some embodiments, R 1 and R 2Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups; R 3 It is selected from substituted or unsubstituted phenyl.

[0012] In some embodiments, R 1 and R 2 Each of these is independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.

[0013] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 It is 3-(trifluoromethyl)phenyl.

[0014] In some embodiments, the compound has the following structure:

[0015] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0016] In some embodiments, R 5 is R 7 And; R 7 This includes C1-C6 alkyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups, substituted or unsubstituted monocyclic C3-C8 cycloalkyl groups, and substituted or unsubstituted bicyclic C5-C6 groups. 10 Cycloalkyl, substituted or unsubstituted monocyclic C2-C8 heterocycloalkyl, substituted or unsubstituted bicyclic C5-C 10heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CH2-(substituted or unsubstituted phenyl), -CH2-(substituted or unsubstituted heteroaryl), -CH2-(substituted or unsubstituted C2-C8 heterocycloalkyl), -CH(R 10 )O-R 11 , -(CH2CH2O)n-R 11 , or -(C(R 10 )2)p-OR 11 ; R 10 is each independently selected from hydrogen and methyl; R 11 is hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 , -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OR 9 )2.

[0017] In some embodiments, R 7 is C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, -CH2-(substituted or unsubstituted phenyl), -CH2-(substituted or unsubstituted heteroaryl), -CH2-(substituted or unsubstituted C2-C8 heterocycloalkyl), -CH(R 10 )O-R 11 , or -(CH2CH2O)n-R 11 ; R 10 is hydrogen and methyl; R 11 is hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 , -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OH)2.

[0018] In some embodiments, the compound has one of the following structures:

[0019] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0020] In some embodiments, the compound has one of the following structures:

[0021] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0022] In some embodiments, the compound has the following structure:

[0023] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0024] In some embodiments, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups; R 3 It is selected from substituted or unsubstituted phenyl.

[0025] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 It is 3-(trifluoromethyl)phenyl.

[0026] In some embodiments, the compound has the following structure:

[0027] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0028] In some embodiments, R 4 is methyl or ethyl; R 5 is hydrogen, R 7 -C(=O)R 7 , -C(=O)-OR 7 -C(=O)N(R 7 )(R 8 ), -C(=O)-SR 7 , or -P(=O)(OR 9 )2; R 7 This includes C1-C6 alkyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups, substituted or unsubstituted monocyclic C3-C8 cycloalkyl groups, and substituted or unsubstituted bicyclic C5-C6 groups. 10 Cycloalkyl, substituted or unsubstituted monocyclic C2-C8 heterocycloalkyl, substituted or unsubstituted bicyclic C5-C 10 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CH2-(substituted or unsubstituted phenyl), -CH2-(substituted or unsubstituted heteroaryl), -CH2-(substituted or unsubstituted C2-C8 heterocycloalkyl), -CH(R 10 )OR 11 -(CH2CH2O)nR 11 , or -(C(R 10 )2) p-OR 11 And; R 10 Each is independently selected from hydrogen and methyl; R 11 This includes hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, and substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OR 9 )2.

[0029] In some embodiments, R 5 R 7 -C(=O)R 7 , -C(=O)-OR 7 -C(=O)N(R 7 )(R 8 ), -C(=O)-SR 7 , or -P(=O)(OH)2; R 7 This includes C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]octanyl, substituted or unsubstituted bicyclo[4.3.0]nonanyl, or substituted or unsubstituted dekalinyl (de calinyl), substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydropyranil, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CH2-(substituted or unsubstituted phenyl), -CH2-(substituted or unsubstituted heteroaryl), -CH2-(substituted or unsubstituted C2-C8 heterocycloalkyl), -CH(R 10 )OR 11 -(CH2CH2O)nR 11 , or -(C(R 10 )2) p-OR 11 And; R 10 Each is independently selected from hydrogen and methyl; R 11 This includes hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, and substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), -C(=O)-SR12 , or -P(=O)(OR 9 )2.

[0030] In some embodiments, the compound has one of the following structures;

[0031] [ka]

[0032] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0033] In some embodiments, the compound has the following structure of formula (II):

[0034] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvation thereof, where Y is -CH2-, O, S, -NR 15 - is selected from -S(O)2-, and -S(O)2-; Z is either O or S.

[0035] In some embodiments, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups; R 3 It is selected from substituted or unsubstituted phenyl.

[0036] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 It is 3-(trifluoromethyl)phenyl.

[0037] In some embodiments, the compound has the following structure:

[0038] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0039] In some embodiments, the compound has the following structure:

[0040] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0041] In some embodiments, the compound has the following structure of formula (IIa):

[0042] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof, where Y is -CH2-, O, S, -NR 15 - and -S(O)2- are selected.

[0043] In some embodiments, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups; R 3 It is selected from substituted or unsubstituted phenyl.

[0044] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 It is 3-(trifluoromethyl)phenyl.

[0045] In some embodiments, the compound has the following structure:

[0046] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0047] In another embodiment, this specification includes a compound represented by formula (B):

[0048] [ka] Alternatively, a pharmaceutically acceptable salt or solvate thereof may be described herein, in the formula: R 1 and R 2 Each is independently selected from hydrogen and substituted or unsubstituted alkyl groups; R 3 R is selected from substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl, where R 3 If R is replaced, 3 It is substituted with one or more groups selected from halogens, -CN, -OH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, and substituted or unsubstituted C1-C4 heteroalkyl; R 4 is hydrogen, or a substituted or unsubstituted alkyl group; R 6 is hydrogen, or a substituted or unsubstituted alkyl group; Alternatively, R 4 and R 6 They combine with the carbon atom to which they bond to form a carbonyl (C=O) bond; Alternatively, R 4 and R 6 These are substituted or unsubstituted C3-C atoms, which are bonded together with the carbon atoms they bond to. 10 Cycloalkyl, or substituted or unsubstituted C2-C 10 It forms a heterocycloalkyl ring, where, if the ring is substituted, the ring has one or more R 15 Replaced by; R 15This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), and -C(=O)R 16 , -C(=O)-OR 16 -C(=O)N(R 16 )2; R 16 Each is independently selected from hydrogen and substituted or unsubstituted alkyl groups; R 5 C3-C is either substituted or non-substituted. 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), -(C(R 10 )2O)mR 11 -C(=O)-(C(R 10 )2O)mR 11 -C(=O)-(CH2CH2O)nR 11 -C(=O)-R a , or -C(=O)-OR 7 and; R a These include substituted or unsubstituted bicyclic cycloalkyls, substituted or unsubstituted bicyclic heterocycloalkyls, substituted or unsubstituted bicyclic heteroaryls, (substituted or unsubstituted heterocycloalkyls containing at least one O atom in the ring), substituted or unsubstituted azetidinyls, substituted or unsubstituted piperidinyls, substituted or unsubstituted azapenyls, substituted or unsubstituted five-membered heteroaryls, substituted or unsubstituted pyridine-2-yls, substituted or unsubstituted pyridine-4-yls, substituted or unsubstituted pyrimidinyls, substituted or unsubstituted pyrazinyls, substituted or unsubstituted pyridadinyls, and substituted or unsubstituted triazinyls; Alternatively, R 4 and R5 These, together with the atoms to which they bond, form substituted or unsubstituted C2-C 10 Forms heterocycloalkyl groups; R 7 This includes substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, and substituted or unsubstituted C3-C groups. 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), -(C(R 10 )2O)mR 11 -(CH2CH2O)nR 11 , or -(C(R 10 )2) p-OR 11 and; R 9 Each is independently selected from hydrogen and alkyl; R 10 Each is independently selected from hydrogen and alkyl; R 11 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OR 9 )2; R 12 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10These are heterocycloalkyls, substituted or unsubstituted phenyls, substituted or unsubstituted heteroaryls, -alkyl-(substituted or unsubstituted phenyls), or -alkyl-(substituted or unsubstituted heteroaryls); m is 1, 2, 3, 4, 5, or 6; n is 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; Here, substitution means that the reference group is substituted with one or more additional groups individually and independently selected from halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.

[0049] In some embodiments, R 4 is hydrogen; R 6 is hydrogen; R 5 C3-C is either substituted or non-substituted. 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), -(C(R 10 )2O)mR 11 -C(=O)-(C(R 10 )2O)mR 11 -C(=O)-(CH2CH2O)nR 11 -C(=O)-R a , or -C(=O)-OR7 That is the case.

[0050] In some embodiments, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups; R 3 It is selected from substituted or unsubstituted phenyl.

[0051] In some embodiments, R 1 and R 2 Each of these is independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.

[0052] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 It is 3-(trifluoromethyl)phenyl.

[0053] In some embodiments, the compound has the following structure:

[0054] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0055] In some embodiments, R 11 This includes hydrogen, substituted or unsubstituted alkyl, and -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), or -P(=O)(OR 9 )2.

[0056] In some embodiments, the compound has one of the following structures;

[0057] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0058] In some embodiments, the compound has one of the following structures;

[0059] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0060] In some embodiments, R 5 is -C(=O)-(C(R 10 )2O)mR 11 -C(=O)-(CH2CH2O)nR 11 -C(=O)-R a Or -C(=O)-OR 7 That is the case.

[0061] In some embodiments, the compound has the following structure:

[0062] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0063] In some embodiments, R a is a substituted or unsubstituted bicyclic cycloalkyl, which is a condensed bicyclic cycloalkyl, a crosslinked bicyclic cycloalkyl, or a spiro-bicyclic cycloalkyl; or, R a is a substituted or unsubstituted bicyclic heterocycloalkyl, which is a condensed bicyclic heterocycloalkyl, a cross-linked bicyclic heterocycloalkyl, or a spiro-bicyclic heterocycloalkyl; or, R a It is a substituted or unsubstituted bicyclic heteroaryl.

[0064] In some embodiments, R a These are substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]octanyl, substituted or unsubstituted bicyclo[4.3.0]nonanyl, or substituted or unsubstituted dekalinyl.

[0065] In some embodiments, the compound has one of the following structures;

[0066] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0067] In some embodiments, R a These are substituted or unsubstituted heterocycloalkyls containing at least one oxygen atom in the ring, substituted or unsubstituted azetidinyls, substituted or unsubstituted piperidinyls, substituted or unsubstituted azapenyls, substituted or unsubstituted five-membered heteroaryls, substituted or unsubstituted pyridine-2-yls, substituted or unsubstituted pyridine-4-yls, substituted or unsubstituted pyrimidinyls, substituted or unsubstituted pyrazinyls, substituted or unsubstituted pyridazinyls, and substituted or unsubstituted triazinyls.

[0068] In some embodiments, R aThis is a substituted or unsubstituted heterocycloalkyl ring containing at least one oxygen atom, which is a substituted or unsubstituted tetrahydrofuranil, a substituted or unsubstituted dihydrofuranil, a substituted or unsubstituted oxazolidinonil, a substituted or unsubstituted tetrahydropyranil, a substituted or unsubstituted dihydropyranil, a substituted or unsubstituted tetrahydrothiopyranil, a substituted or unsubstituted morpholinil, a substituted or unsubstituted oxetanil, a substituted or unsubstituted oxepanil, a substituted or unsubstituted oxazepinyl, or a substituted or unsubstituted dioxanil.

[0069] In some embodiments, R a It is a substituted or unsubstituted five-membered heteroaryl, which is a substituted or unsubstituted furanyl, a substituted or unsubstituted thienyl, a substituted or unsubstituted pyrrolyl, a substituted or unsubstituted oxazolyl, a substituted or unsubstituted thiazolyl, a substituted or unsubstituted imidazolyl, a substituted or unsubstituted pyrazolyl, a substituted or unsubstituted triazolyl, a substituted or unsubstituted tetrazolyl, a substituted or unsubstituted isoxazolyl, a substituted or unsubstituted isothiazolyl, a substituted or unsubstituted oxadiazolyl, or a substituted or unsubstituted thiadiazolyl.

[0070] In some embodiments, the compound has one of the following structures;

[0071] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0072] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 is 3-(trifluoromethyl)phenyl; R 5 is -C(=O)-(C(R 10 )2O)mR 11 -C-(=O)-(CH2CH2O)nR 11, or -C(=O)-OR 7 That is the case.

[0073] In some embodiments, the compound has one of the following structures;

[0074] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0075] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 is 3-(trifluoromethyl)phenyl; R 5 C3-C is either substituted or non-substituted. 10 Cycloalkyl, substituted or unsubstituted C2-C 10 These include heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), and -alkyl-(substituted or unsubstituted heterocycloalkyl).

[0076] In some embodiments, the compound has the following structure:

[0077] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0078] Further pharmaceutical formulations comprising any one of the compounds disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient are described herein.

[0079] In some embodiments, the pharmaceutical composition is formulated for administration to mammals by oral, intravenous, or subcutaneous administration.

[0080] In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, dispersant, solution, or emulsion.

[0081] In one embodiment, the process includes administering a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a mammal, wherein the mammal A 2B Methods for modulating adenosine receptors are described herein.

[0082] In another embodiment, a method for treating a disease or illness in a mammal is described herein, comprising the step of administering to a mammal a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is selected from the group consisting of cardiovascular disease, fibrosis, neurological disorders, type I hypersensitivity, chronic and acute liver disease, lung disease, kidney disease, diabetes, obesity, and cancer. In some embodiments, the disease or illness is cancer.

[0083] In some embodiments, the subject is human.

[0084] In any of the embodiments described herein, in further embodiments, an effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is administered (a) systemically to a mammal; and / or (b) orally to a mammal; and / or (c) intravenously to a mammal; and / or (d) by infusion to a mammal.

[0085] Any of the embodiments described above is a further embodiment comprising a single dose of an effective amount of the compound, and further embodiments include the compound being administered to a mammal once a day or to a mammal multiple times over a period of time. In some embodiments, the compound is administered in a continuous dosing schedule. In some embodiments, the compound is administered in a continuous daily dosing schedule.

[0086] Any combination of the groups described above for various variables is contemplated herein. Throughout the specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0087] Other purposes, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the detailed description below. However, it should be understood that the detailed description and specific examples are given only as examples, while illustrating specific embodiments, as various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from the detailed description. The present invention provides, for example, the following: (Item 1) Compounds represented by formula (A): [ka] Alternatively, a pharmaceutically acceptable salt or solvate thereof, in the formula: R 1 and R 2 Each is independently selected from hydrogen and substituted or unsubstituted alkyl groups; R 3 R is selected from substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl, where R 3 If R is replaced, 3 is halogen, -CN, -OH, C 1 -C 4 Alkyl, C 2 -C 4 Alkenil, C 2 -C 4 Alkinyl, C 1 -C 4 Alkoxy, C 1 -C 4 Fluoroalkyl, C 1 -C 4 Fluoroalkoxys, and substituted or unsubstituted C 1 -C 4 Substituted with one or more groups selected from heteroalkyl groups; R 4 is a substituted or unsubstituted alkyl group; R 6 is hydrogen or a substituted or unsubstituted alkyl group; Alternatively, R 4 and R6 They combine with the carbon atom to which they bond to form a carbonyl (C=O) bond; Alternatively, R 4 and R 6 These atoms bond to the carbon atoms, and together they form substituted or unsubstituted C atoms. 3 -C 10 Cycloalkyl, or substituted or unsubstituted C 2 -C 10 It forms a heterocycloalkyl ring, where, if the ring is substituted, the ring has one or more R 15 Replaced by; R 15 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), and -C(=O)R 16 , -C(=O)-OR 16 -C(=O)N(R 16 ) 2 and; R 16 Each is independently selected from hydrogen and substituted or unsubstituted alkyl groups; R 5 is hydrogen, R 7 -C(=O)R 7 , -C(=O)-OR 7 -C(=O)N(R 7 )(R 8 ), -C(=O)-SR 7 , or -P(=O)(OR 9 ) 2 and; Alternatively, R 4 and R 5 These atoms, together with the atoms to which they bond, form substituted or unsubstituted C 2 -C 10 Forms heterocycloalkyl groups; R 7 This includes substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, and substituted or unsubstituted C groups. 3 -C 10 Cycloalkyl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), -(C(R 10 ) 2 O)mR 11 ,-(CH 2 CH 2 O)nR11 , or -(C(R 10 ) 2 )p-OR 11 and; R 8 is hydrogen or alkyl; Alternatively, R 7 and R 8 These, together with the nitrogen atom to which they bond, form substituted or unsubstituted C 2 -C 10 Forms heterocycloalkyl groups; R 9 Each is independently selected from hydrogen and alkyl; R 10 Each is independently selected from hydrogen and alkyl; R 11 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C. 2 -C 10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OR 9 ) 2 and; R 12 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C. 3 -C 10 Cycloalkyl, substituted or unsubstituted C 2 -C 10 These are heterocycloalkyls, substituted or unsubstituted phenyls, substituted or unsubstituted heteroaryls, -alkyl-(substituted or unsubstituted phenyls), or -alkyl-(substituted or unsubstituted heteroaryls); m is 1, 2, 3, 4, 5, or 6; n is 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; Here, substitution means that the reference group is a halogen, -CN, or -NH. 2 -NH (alkyl), -N (alkyl) 2 -OH, -CO 2 H, -CO 2 Alkyl, -C(=O)NH 2 -C(=O)NH(alkyl), -C(=O)N(alkyl) 2 -S(=O) 2 NH 2 -S(=O) 2 NH (alkyl), -S (=O) 2 N(alkyl)2 This means that the group is substituted with one or more additional groups individually and independently selected from alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. A compound or a pharmaceutically acceptable salt or solvate thereof. (Item 2) R 4 is C 1 -C 6 It is alkyl; R 6 is hydrogen, and C 1 -C 6 Selected from alkyl groups; Alternatively, R 4 and R 6 This refers to the compounds listed in item 1, or their pharmaceutically acceptable salts or solvates, which form a carbonyl (C=O) bond with the carbon atom to which they are bonded. (Item 3) R 4 These are methyl, ethyl, or n-propyl; R 6 It is selected from hydrogen, methyl, ethyl, and n-propyl; Alternatively, R 4 and R 6 This refers to the compounds listed in item 1, or their pharmaceutically acceptable salts or solvates, which form a carbonyl (C=O) bond with the carbon atom to which they are bonded. (Item 4) The compound has the following structure of formula (III):

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[0088] A 2B Compounds, compositions, formulations, and methods related to adenosine receptor antagonists are disclosed herein. For example, the compounds, compositions, and / or formulations disclosed herein can be used in methods for treating diseases in subjects. Diseases may include cardiovascular diseases, chronic and acute liver diseases, lung diseases, kidney diseases, diabetes, obesity, and / or cancer.

[0089] 8-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazole-4-yl)-3-ethyl-1-propyl-1H-purine-2,6(3H,7H)-dione (compound 1) is an unsubstituted xanthine at position 7. 2B It is an adenosine receptor antagonist. It is relatively insoluble in aqueous media and can be difficult to formulate using conventional pharmaceutical excipients, and therefore may be difficult to formulate to provide reproducible plasma levels of the compound under evaluation in mammals, particularly humans. Therefore, A 2BWe have developed a new prodrug of adenosine receptor antagonist, A 2B This can improve the formulation, pharmacokinetic profile, and / or bioavailability of adenosine receptor antagonists.

[0090] [ka]

[0091] In some cases, a prodrug can be hydrolyzed by an esterase (e.g., in the gastrointestinal tract and / or in the blood) to convert it to compound 1 in aqueous solution. In some cases, an acid-unstable prodrug can be converted to compound 1 in an acidic environment (e.g., in the stomach). In some cases, a prodrug that is stable in an acidic environment and / or stable against hydrolysis by an esterase may not be a good candidate for compound 1.

[0092] In one embodiment, the compounds, compositions, and / or formulations disclosed herein can be used to treat cancer. In endothelial cells, for example, adenosine is A 2B It can bind to adenosine receptors, thereby stimulating angiogenesis. In T cells, A 2B Adenosine receptor stimulation can induce activation of type I protein kinase A (PKA) isoforms, and T cell activation can be inhibited by inhibiting the T cell antigen receptor (TCR) proximal kinases Lck and Fyn. The pro-metastatic Fra-1 transcription factor is further shown to be A on cancer cells. 2B It can induce adenosine receptor expression, and therefore, A 2B Adenosine receptor antagonists can inhibit the metastasis of Fra-1 expressing cells. 2B Activation of adenosine receptor signaling may impair antigen presentation and may also inhibit signaling transcription factors (STAT1). 2B The diversity of adenosine receptor signaling and biological activity is A 2BBy targeting adenosine receptors as attractive cancer targets, it is possible to promote anti-tumor immunity and suppress the metastasis of tumor cells.

[0093] In another embodiment, the compounds, compositions, and / or formulations disclosed herein can be used to treat fibrosis. A commonly ingested adenosine receptor antagonist (caffeine) can inhibit the progression of hepatic fibrosis, an effect that can explain the epidemiological finding that drinking coffee in a dose-dependent manner can reduce the likelihood of death from liver disease. 2B Adenosine receptors may also play a pathogenic role in interstitial fibrosis. 2B Adenosine acting on adenosine receptors can stimulate hepatic stellate cell-mediated fibrosis in the liver by increasing the production of type I and type III collagen via two distinct MAP kinase (MAPK)-dependent pathways: extracellular signal-regulated kinase 1 / 2 (ERK1 / 2) and p38MAPK, respectively. 2B Overactivation of adenosine receptors may be involved in fibrosis of the liver, lungs, and heart. Therefore, A 2B Adenosine receptors may be good therapeutic targets for fibrosis of the liver, lungs, heart, and / or skin.

[0094] In another embodiment, the compounds, compositions, and / or formulations disclosed herein can be used to treat diabetes and / or obesity. Insulin insensitivity can worsen diabetes and / or obesity. Insulin sensitivity is A 2B It may be reduced by the interaction between adenosine receptors and adenosine. Therefore, A in individuals with diabetes and / or obesity 2B Blocking adenosine receptors may benefit patients with these diseases.

[0095] In another embodiment, the compounds, compositions and / or formulations disclosed herein can be used to treat neurological disorders such as dementia and Alzheimer's disease.2B Adenosine, which acts on adenosine receptors, can overstimulate brain interleukin-6 (IL-6), a cytokine associated with dementia and Alzheimer's disease. Therefore, A 2B Inhibiting the binding of adenosine to adenosine receptors can alleviate neurological abnormalities caused by IL-6.

[0096] In another embodiment, the compounds, compositions and / or formulations disclosed herein can be used to treat chronic obstructive pulmonary disease (COPD), asthma, hay fever, and type I hypersensitivity, such as atopic dermatitis. These type I hypersensitivity is A 2B It can be stimulated by mast cells that bind to adenosine receptors. Therefore, A 2B By blocking adenosine receptors, therapeutic effects against such diseases can be obtained.

[0097] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. Any methods or materials similar or equivalent to those described herein may be used in carrying out or testing any formulation or unit dose described herein, but some methods and materials are described herein. Unless otherwise specified, the techniques used or intended herein are standard methods. Materials, methods and examples are illustrative and not limiting.

[0098] The paragraph headings used in this specification are for organizational purposes only and should not be interpreted as limiting the subject matter described.

[0099] Details of one or more inventive embodiments are described in the accompanying drawings, claims, and herein. Other features, purposes, and advantages of the inventive embodiments disclosed and contemplated herein may be combined with any other embodiments unless expressly excluded.

[0100] Open terminology, such as "contain," "containing," "include," and "including," means to include, and is not limited to.

[0101] The singular forms "a," "an," and "the" are used herein to include multiple references unless the context clearly indicates otherwise.

[0102] Unless otherwise specified, some embodiments of this specification contemplate numerical ranges. Where a numerical range is provided, unless otherwise specified, that range may include the endpoints of the range. Unless otherwise explicitly stated, a numerical range may include all values ​​and subranges within that range, as if they were explicitly written out.

[0103] The term "approximately" in relation to a reference number can include a range of values ​​plus or minus 10% from that value. For example, the quantity "approximately 10" includes the quantities from 9 to 11, encompassing the reference numbers 9, 10, and 11. The term "approximately" in relation to a reference number can also include values ​​within a range of plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.

[0104] The term "prodrug" refers to any compound that, for example, undergoes a metabolic process during which it becomes the active form of a drug (e.g., compound I) when administered to a subject.

[0105] In some cases, prodrugs are often useful because they are easier to administer than the parent drug. For example, prodrugs may be bioavailable by oral administration, whereas the parent drug is not. Furthermore, or alternatively, prodrugs may have improved solubility in pharmaceutical compositions than the parent drug. In some embodiments, the design of prodrugs increases their effective water solubility. In some embodiments, at in vivo administration, the prodrug is chemically converted into a biologically, pharmaceutically, or therapeutically active form of the compound. In some embodiments, the prodrug is enzymatically metabolized into a biologically, pharmaceutically, or therapeutically active form of the compound by one or more steps or processes.

[0106] Examples of prodrugs of Compound 1 described herein include, but are not limited to, compounds in which a nitrogen atom is incorporated into alkylcarbamates (acyloxy), alkylcarbamates, acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sugar esters, ethers, N-acyloxyalkoxycarbonyl, N-acyloxyacyl, dihydropyridinepyridinium salts (redox systems), (phosphoryloxy)methylcarbamates, (acyloxy)alkylcarbamates, etc.

[0107] In some embodiments, the prodrug of compound 1 is formed by N-acyloxyalkylation, N-hydroxyalkylation, N-(phosphoryloxy)alkylation, N-acyloxyalkylation, N-hydroxyalkylation, N-(phosphoryloxy)alkylation, N-acylation (amide and carbamate), N-(oxodioxolenyl)methylation, and the like.

[0108] The term "pharmaceutically acceptable" means that an ingredient is suitable for use in humans and / or animals without excessively harmful side effects (e.g., toxicity, inflammation, and allergic reactions) that are commensurate with a reasonable benefit-risk ratio.

[0109] The terms “effective dose” or “therapeutically effective dose” mean, as used herein, a sufficient amount of the administered drug or compound to alleviate, to some extent, one or more symptoms of the disease or illness being treated. Results include reduction and / or mitigation and / or remission of the signs, symptoms, or causes of the disease, delay of disease progression, or any other desired change in the biological system. For example, an “effective dose” for therapeutic use is the amount of a compound, as disclosed herein, required to clinically and significantly reduce the symptoms of the disease. The appropriate “effective” dose in individual cases is determined at will using techniques such as dose-escalation studies.

[0110] The terms “treating” or “treatment” include administering at least one compound disclosed herein or a pharmaceutically acceptable salt thereof to a mammalian subject, in particular a human subject, and including prophylactic measures to (i) inhibit the progression of clinical symptoms of a disease such as cancer, (ii) induce regression of clinical symptoms of a disease such as cancer, and / or (iii) prevent the development of further symptoms of a disease such as cancer.

[0111] The term "subject" refers to a mammal that is or will be the subject of a procedure, observation, or experiment.

[0112] The term “mammal” is intended to have its standard meaning and includes, for example, humans, dogs, cats, sheep, and cows. The methods described herein may be useful for both human therapeutic and veterinary applications. In some embodiments, the mammal is a human.

[0113] The term “derivative” can be used interchangeably with the term “analog.” Compound 1 may be a derivative or analog if, in order to form a compound of the present disclosure, one, two, three, four, or five atoms of compound 1 are replaced with another atom or functional group (e.g., an amino, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted cycloalkyl).

[0114] The term "solvate" refers to, but is not limited to, solvates that retain one or more of the activity and / or properties of a compound and are not undesirable. Examples of solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or compounds combined with any combination thereof.

[0115] The term "pharmaceutically acceptable salt" refers to a therapeutically active drug in the form of a cation of a therapeutically active drug combined with a suitable anion, or, in alternative embodiments, in the form of an anion of a therapeutically active drug combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more readily and rapidly soluble in gastric and intestinal fluids than nonionic species, and are therefore useful in solid dosage forms. Furthermore, since their solubility often correlates with pH, ​​selective dissolution in any part of the digestive tract is possible, and this ability can be manipulated as a form of delayed-release and sustained-release behavior. In addition, because salt-forming molecules can exist in equilibrium with a neutral form, their passage through biological membranes can be regulated.

[0116] The term "salt" includes, but is not limited to, salts that retain one or more of the activity and properties of free acids and bases, and that are not undesirable. Examples of salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoic acid, caprylates, acrylates, formates, isobutyrates, caproates, heptanoic acid, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butin-1,4-geoate, hexin-1,6-geoate, benzoates, chlorobenzoates, methyl benzoate, dinitrobenzoate, hydroxybenzoic acid, methoxybenzoic acid, phthalates, sulfonates, xylenesulfonic acid, phenyl acetate, phenyl propionate, Examples include phenylbutyric acid, citrate, lactate, γ-hydroxybutyric acid, glycolate, tartaric acid, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0117] References to pharmaceutically acceptable salts should be understood to include solvated forms. In some embodiments, solvates are formed during a process of separating or purifying a compound with a pharmaceutically acceptable solvent, such as water or ethanol, containing either stoichiometric or non-stoichiometric amounts of solvent. A hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein exist optionally in non-solvated forms as well as solvated forms.

[0118] Unless otherwise indicated, whenever a structure disclosed or illustrated herein has a stereocenter, the stereocenter may be R or S in each case.

[0119] Individual stereoisomers are obtained, if necessary, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography column. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomer isomer compounds / salts, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, the decomposition of the enantiomers is carried out using covalent diastereomer derivatives of the compounds described herein. In other embodiments, the diastereomers are separated by separation / decomposition techniques based on differences in solubility. In other embodiments, the separation of stereoisomers is carried out by chromatography, or by forming diastereomer salts and separating them by recrystallization or chromatography, or by any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0120] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioactive isotope) or by other means.

[0121] The compounds described herein include isotope-labeled compounds, which are identical to those detailed in the various formulas and structures presented herein, except that one or more atoms are replaced with atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S,18 F, 36 Examples include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as Cl. In one embodiment, isotope-labeled compounds as described herein, for example, 3 H and 14 Compounds incorporating radioactive isotopes such as 13C are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with an isotope such as deuterium results in certain therapeutic benefits due to greater metabolic stability, such as an extension of the half-life in vivo or a reduction in the required dose. In some embodiments, one or more hydrogen atoms in the compounds described herein are replaced with deuterium.

[0122] The term "amino" refers to a functional group containing a basic nitrogen atom with a lone pair of electrons. For example, amino is the following free group

[0123] [ka] The formula can include, where R' is independently H, halo, alkyl, aryl, arylalkyl, cycloalkyl, or acyl.

[0124] As used herein, C1-C x C1-C2, C1-C3...C1-C x This includes. As just one example, a group designated as "C1-C4" indicates that the part has 1 to 4 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, as just one example, "C1-C4 alkyl" indicates that the alkyl group has 1 to 4 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0125] The "alkyl" group refers to an aliphatic hydrocarbon group. Alkyl groups are branched or linear. In some embodiments, the "alkyl" group consists of 1 to 10 carbon atoms, i.e., C1-C 10 Alkyl is present. Whenever a range of numbers such as "1 to 10" appears herein, it always refers to each integer within a given range; for example, "1 to 10 carbon atoms" means that the alkyl group consists of carbon atoms from 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to 10 carbon atoms, but this definition also covers appearances of the term "alkyl" where no range of numbers is specified. In some embodiments, the alkyl is a C1-C6 alkyl. In one embodiment, the alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Alternatively, alkyls include, but are not limited to, methyl, ethyl, propane-1-yl, propane-2-yl, butane-1-yl, butane-2-yl, 2-methyl-propane-1-yl, 2-methyl-propane-2-yl, etc. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0126] The term "lower alkyl" can refer to monoradical branched or unbranched saturated hydrocarbon chains having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and n-hexyl.

[0127] In some embodiments, when the alkyl is unsaturated, the alkyl is an alkenyl or alkynyl.

[0128] The term "alkenyl" refers to a type of alkyl group that has at least one carbon-carbon double bond. In one embodiment, the alkenyl group has the formula -C(R)=CR2, where R refers to the rest of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, the alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2. Alternatively, examples of alkenyls, though not limited to them, include ethenyl, propa-1-propa-1-yl, propa-1-en-2-yl, propa-2-en-1-yl(allyl), buto-1-en-1-yl, buto-1-en-2-yl, 2-methyl-propa-1-en-1-yl, buto-2-en-1-yl, buto-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, and others.

[0129] The term "alkynyl" refers to a type of alkyl group that has at least one carbon-carbon triple bond. In one embodiment, the alkenyl group has the formula -C≡CR, where R is the rest of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, the alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH. Alternatively, alkynyls include, but are not limited to, ethynyl, propa-1-in-1-yl, propa-2-in-1-yl, buto-1-in-1-yl, buto-1-in-3-yl, and buto-3-in-1-yl.

[0130] The "alkoxy" group refers to an (alkyl)O- group, where alkyl is as defined herein.

[0131] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one embodiment, the fluoroalkyl group is a C1-C6 fluoroalkyl group. In some embodiments, the fluoroalkyl group is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2, trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0132] The "fluoroalkoxy" group refers to a (fluoroalkyl)O- group, where fluoroalkyl is as defined herein.

[0133] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0134] The term "heteroalkyl" refers to an alkyl group in which one or more of the alkyl backbone atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur (-S-, -S(O)-, -S(O)2-), phosphorus (-PH-, -P(O)2-), or a combination thereof (e.g., -OP(O)2-). In heteroalkyls, the carbon atoms of the heteroalkyl are bonded to the rest of the molecule. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl. In some embodiments,

[0135] As used herein, the term “aryl” refers to an aromatic ring in which each of the ring-forming atoms is a carbon atom. Typical aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, indanyl, and indenyl. In some embodiments, the aryl is phenyl or naphthyl. In some embodiments, the aryl is phenyl. In some embodiments, the aryl is C6-C 10 It is Ariel.

[0136] The term "heteroaryl" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Exemplary examples of heteroaryl groups include monocyclic and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and flazanil. Bicyclic heteroaryls include indidine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolidine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryls contain 0-4 N atoms in the ring. In some embodiments, the heteroaryl ring contains 1-4 N atoms. In some embodiments, the heteroaryl ring contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms. In some embodiments, the heteroaryl ring contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms. In some embodiments, the heteroaryl ring is a C1-C9 heteroaryl ring. In some embodiments, the monocyclic heteroaryl ring is a C1-C5 heteroaryl ring. In some embodiments, the monocyclic heteroaryl ring is a 5-membered or 6-membered heteroaryl ring. In some embodiments, the bicyclic heteroaryl ring is a C6-C9 heteroaryl ring.

[0137] The term "arylalkyl" refers to alkyl groups substituted with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, naphthylmethyl, and 2-naphthylethane-1-yl.

[0138] The term "heteroarylalkyl" refers to alkyl groups that are substituted with heteroaryl groups.

[0139] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic non-aromatic radical, where each of the ring-forming atoms (i.e., skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are monocyclic, bicyclic (spirocyclic, fused, or bridged), or polycyclic. Cycloalkyl groups consist of 3 to 10 ring atoms (i.e., (C3- 10 The group contains a cycloalkyl group. In some embodiments, the cycloalkyl group is a (C3-C6) cycloalkyl group. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl group is a C3-C6 cycloalkyl group. In some embodiments, the cycloalkyl group is a monocyclic cycloalkyl group. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norborneyl, dekalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like.

[0140] In some embodiments, the cycloalkyl is partially unsaturated (including, but not limited to, cyclobuto-1-en-1-yl, cyclobuto-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc., "cycloalkenyl").

[0141] A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, heterocycloalkyls are condensed with aryl or heteroaryl groups. In some embodiments, heterocycloalkyls are oxazolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidine-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinyl, imidazolidinyl, imidazolidinyl-2-onyl, or thiazolidinyl-2-onyl. The term heteroalicyclic also includes all cyclic forms of carbohydrates, including monosaccharides, disaccharides, and oligosaccharides, though this is not limited to them. In one embodiment, the heterocycloalkyl is C2-C 10 It is a heterocycloalkyl. In another embodiment, the heterocycloalkyl is C4-C 10 It is a heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0142] The term "acyl" is -C(O)R', where R' is hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl.

[0143] The term "substituted" can refer to a group in which one or more hydrogen atoms are independently replaced by the same or different substituents. Typical substituents are included, but not all.

[0144] The terms “substituted” or “optionally substituted” mean that the reference group is optionally substituted with one or more additional groups individually and independently selected from D, halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some embodiments, any substituent is independently selected from halo, alkyl, heteroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or acyl. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl, and -S(=O)2C1-C4 alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituted group is substituted with one or two of the aforementioned groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0145] Prodrug In one embodiment, the compound represented by formula (A):

[0146] [ka] Alternatively, a pharmaceutically acceptable salt or solvate thereof may be described herein, in the formula: R 1 and R 2 Each is independently selected from hydrogen and substituted or unsubstituted alkyl groups; R 3 R is selected from substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl, where R 3 If R is replaced, 3 It is substituted with one or more groups selected from halogens, -CN, -OH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, and substituted or unsubstituted C1-C4 heteroalkyl; R 4 is a substituted or unsubstituted alkyl group; R 6 is hydrogen, or a substituted or unsubstituted alkyl group; Alternatively, R 4 and R 6 They combine with the carbon atom to which they bond to form a carbonyl (C=O) bond; Alternatively, R 4 and R 6 These are substituted or unsubstituted C3-C atoms, which are bonded together with the carbon atoms they bond to. 10 Cycloalkyl, or substituted or unsubstituted C2-C 10 It forms a heterocycloalkyl ring, where, if the ring is substituted, the ring has one or more R 15 Replaced by; R 15This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), and -C(=O)R 16 , -C(=O)-OR 16 -C(=O)N(R 16 )2; R 16 Each is independently selected from hydrogen and substituted or unsubstituted alkyl groups; R 5 is hydrogen, R 7 -C(=O)R 7 , -C(=O)-OR 7 -C(=O)N(R 7 )(R 8 ), -C(=O)-SR 7 , or -P(=O)(OR 9 )2; Alternatively, R 4 and R 5 These, together with the atoms to which they bond, form substituted or unsubstituted C2-C 10 Forms heterocycloalkyl groups; R 7 This includes substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, and substituted or unsubstituted C3-C groups. 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), -(C(R 10 )2O)mR 11 -(CH2CH2O)nR 11 , or -(C(R 10 )2) p-OR 11 and; R 8 is hydrogen or alkyl; or, R 7 and R 8These, together with the nitrogen atom to which they bond, form a substituted or unsubstituted C2-C 10 Forms heterocycloalkyl groups; R 9 Each is independently selected from hydrogen and alkyl; R 10 Each is independently selected from hydrogen and alkyl; R 11 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OR 9 )2; R 12 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 These are heterocycloalkyls, substituted or unsubstituted phenyls, substituted or unsubstituted heteroaryls, -alkyl-(substituted or unsubstituted phenyls), or -alkyl-(substituted or unsubstituted heteroaryls); m is 1, 2, 3, 4, 5, or 6; n is 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; Here, substitution means that the reference group is substituted with one or more additional groups individually and independently selected from halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.

[0147] In some embodiments, m is 1, 2, 3, 4, 5, or 6. In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2, 3, 4, or 6.

[0148] In some embodiments, n is 1, 2, 3, 4, 5, or 6. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 2, 3, 4, 5, or 6.

[0149] In some embodiments, p is 1, 2, 3, 4, 5, or 6. In some embodiments, p is 1, 2, 3, 4, or 5. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2, 3, 4, 5, or 6.

[0150] In some embodiments, R 1 and R 2 Each of these is independently selected from substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C3 alkyl groups. In some embodiments, R 1 is ethyl. In some embodiments, R 2 is n-propyl, and in some embodiments, R 1 is ethyl, and R 2 It is n-propyl.

[0151] In some embodiments, R 3 R is selected from substituted or unsubstituted phenyl. In some embodiments, R 3 R is a substituted phenyl. In some embodiments, R 3 is a phenyl compound substituted with one or more groups independently selected from halogens, C1-C4 alkyl groups, or C1-C4 fluoroalkyl groups. In some embodiments, R 3 is a phenyl compound substituted with one or more groups independently selected from C1-C4 fluoroalkyl groups. In some embodiments, R 3 R is selected from phenyl substituted with one, two, or three -CF3 substituents. In some embodiments, R 3 R is selected from phenyl substituted with one -CF3 substituent. In some embodiments, R 3 The following applies:

[0152] [ka]

[0153] In some embodiments, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups; R 3 It is selected from substituted or unsubstituted phenyl.

[0154] In some embodiments, R 1 and R 2 Each of these is independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.

[0155] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 It is 3-(trifluoromethyl)phenyl.

[0156] In some embodiments, R 4 It is a C1-C6 alkyl group, and R 6 R is selected from hydrogen and C1-C6 alkyl. In some embodiments, R 4 and R 6 These atoms, together with the carbon atom to which they bond, form a carbonyl (C=O) molecule.

[0157] In some embodiments, R 4 is methyl, ethyl, or n-propyl, and R 6 R is selected from hydrogen, methyl, ethyl, and n-propyl. In some embodiments, R 4 is methyl or ethyl. In some embodiments, R6 is hydrogen. In some embodiments, R 4 is methyl or ethyl; and, R 6 It is hydrogen.

[0158] In some embodiments, R 5 is R 7 In some embodiments, R 5 is -(C=O)R 7 In some embodiments, R 5 is -(C=O)-OR 7 That is the case.

[0159] In some embodiments, R 5 is R 7 And; R 7 This includes C1-C6 alkyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups, substituted or unsubstituted monocyclic C3-C8 cycloalkyl groups, and substituted or unsubstituted bicyclic C5-C6 groups. 10 Cycloalkyl, substituted or unsubstituted monocyclic C2-C8 heterocycloalkyl, substituted or unsubstituted bicyclic C5-C 10 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CH2-(substituted or unsubstituted phenyl), -CH2-(substituted or unsubstituted heteroaryl), -CH2-(substituted or unsubstituted C2-C8 heterocycloalkyl), -CH(R 10 )OR 11 -(CH2CH2O)nR 11 , or -(C(R 10 )2) p-OR 11 And; R 10 Each is independently selected from hydrogen and methyl; R 11 This includes hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, and substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12, or -P(=O)(OR 9 )2.

[0160] In some embodiments, R 7 This includes C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, -CH2-(substituted or unsubstituted phenyl), -CH2-(substituted or unsubstituted heteroaryl), -CH2-(substituted or unsubstituted C2-C8 heterocycloalkyl), and -CH(R 10 )OR 11 , or -(CH2CH2O)nR 11 And; R 10 R consists of hydrogen and methyl; 11 This includes hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, and substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OH)2.

[0161] In some embodiments, R 7 is a C1-C6 alkyl group. In some embodiments, R 7 These are methyl, ethyl, n-propyl, isopropyl, n-butyl, or n-pentyl.

[0162] In some embodiments, R 7 -CH(R 10 )OR 11 And here, R 11 is -C(=O)R 12 And here, R 12 is an unsubstituted alkyl, unsubstituted C3-C 10 It is cycloalkyl. In some embodiments, R 12 is methyl, ethyl, n-propyl, n-butyl, or n-pentyl. In some embodiments, R 12These are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0163] In some embodiments, R 7 -CH(R 10 )OR 11 And here, R 11 is -P(=O)(OR 9 )2. In some embodiments, R 9 It is hydrogen.

[0164] In some embodiments, R 7 -(CH2CH2O)nR 11 And here, R 11 R is an unsubstituted alkyl group. In some embodiments, R 11 These are methyl, ethyl, n-propyl, n-butyl, or n-pentyl.

[0165] In some embodiments, R 7 is -CH2- (substituted or unsubstituted C2-C8 heterocycloalkyl). In some embodiments, R 7 is -CH2- (substituted C5-C6 heterocycloalkyl). In some embodiments, R 7 The following applies:

[0166] [ka]

[0167] In some embodiments, R 7 C3-C is either substituted or non-substituted. 10 It is cycloalkyl. In some embodiments, R 7 is unsubstituted C3-C 10 It is cycloalkyl. In some embodiments, R 7 This is a single-ring C3-C 10 It is cycloalkyl. In some embodiments, R 7is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 7 is cyclohexyl. In some embodiments, R 7 This is a C3-C spiro ring. 10 It is cycloalkyl. In some embodiments, R 7 It is adamantyl.

[0168] In some embodiments, R 4 is methyl or ethyl; R 5 is hydrogen, R 7 -C(=O)R 7 , -C(=O)-OR 7 -C(=O)N(R 7 )(R 8 ), -C(=O)-SR 7 , or -P(=O)(OR 9 )2; R 7 This includes C1-C6 alkyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups, substituted or unsubstituted monocyclic C3-C8 cycloalkyl groups, and substituted or unsubstituted bicyclic C5-C6 groups. 10 Cycloalkyl, substituted or unsubstituted monocyclic C2-C8 heterocycloalkyl, substituted or unsubstituted bicyclic C5-C 10 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CH2-(substituted or unsubstituted phenyl), -CH2-(substituted or unsubstituted heteroaryl), -CH2-(substituted or unsubstituted C2-C8 heterocycloalkyl), -CH(R 10 )OR 11 -(CH2CH2O)nR 11 , or -(C(R 10 )2) p-OR 11 And; R 10 Each is independently selected from hydrogen and methyl; R 11 This includes hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, and substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12-C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OR 9 )2.

[0169] In some embodiments, R 5 R 7 -C(=O)R 7 , -C(=O)-OR 7 -C(=O)N(R 7 )(R 8 ), -C(=O)-SR 7 , or -P(=O)(OH)2; R 7 This includes C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, and substituted or unsubstituted bicyclo[1.1.1]pentanyl. , substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]octanyl, substituted or unsubstituted bicyclo[4.3.0]nonanyl, substituted or unsubstituted dekalinyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydropyranil, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CH2-(substituted or unsubstituted phenyl), -CH2-(substituted or unsubstituted heteroaryl), -CH2-(substituted or unsubstituted C2-C8 heterocycloalkyl), -CH(R 10 )OR 11 -(CH2CH2O)nR 11 , or -(C(R 10 )2) p-OR 11 And; R 10 Each is independently selected from hydrogen and methyl; R 11 This includes hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, and substituted or unsubstituted C2-C10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OR 9 )2.

[0170] In some embodiments, R 5 is R 7 And here, R 7 is a C1-C6 alkyl group. In some embodiments, R 7 These are methyl, ethyl, n-propyl, isopropyl, n-butyl, or n-pentyl.

[0171] In some embodiments, R 5 is -C(=O)R 7 And here, R 7 C1-C6 alkyl or unsubstituted C3-C 10 It is cycloalkyl. In some embodiments, R 7 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or n-pentyl. In some embodiments, R 7 These are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, s-bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0]octanyl, or bicyclo[4.3.0]nonanyl.

[0172] In some embodiments, R 5 is -C(=O)-OR 7 And here, R 7 This is C1-C6 alkyl or unsubstituted C3-C 10 It is cycloalkyl. In some embodiments, R 7 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or n-pentyl. In some embodiments, R7 These are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, s-bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0]octanyl, or bicyclo[4.3.0]nonanyl.

[0173] In some embodiments, the compound has the following structure:

[0174] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0175] In some embodiments, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups; R 3 It is selected from substituted or unsubstituted phenyl.

[0176] In some embodiments, R 1 and R 2 Each of these is independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.

[0177] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 It is 3-(trifluoromethyl)phenyl.

[0178] In some embodiments, the compound has the following structure:

[0179] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0180] In some embodiments, R 5 is R 7 And; R 7 This includes C1-C6 alkyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups, substituted or unsubstituted monocyclic C3-C8 cycloalkyl groups, and substituted or unsubstituted bicyclic C5-C6 groups. 10 Cycloalkyl, substituted or unsubstituted monocyclic C2-C8 heterocycloalkyl, substituted or unsubstituted bicyclic C5-C 10 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CH2-(substituted or unsubstituted phenyl), -CH2-(substituted or unsubstituted heteroaryl), -CH2-(substituted or unsubstituted C2-C8 heterocycloalkyl), -CH(R 10 )OR 11 -(CH2CH2O)nR 11 , or -(C(R 10 )2) p-OR 11 And; R 10 Each is independently selected from hydrogen and methyl; R 11 This includes hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, and substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OR 9 )2.

[0181] In some embodiments, R 7 This includes C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, -CH2-(substituted or unsubstituted phenyl), -CH2-(substituted or unsubstituted heteroaryl), -CH2-(substituted or unsubstituted C2-C8 heterocycloalkyl), and -CH(R 10)OR 11 , or -(CH2CH2O)nR 11 And; R 10 R consists of hydrogen and methyl; 11 This includes hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, and substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OH)2.

[0182] In some embodiments, the compound has one of the following structures;

[0183] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0184] In some embodiments, the compound has one of the following structures;

[0185] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0186] In some embodiments, the compound has the following structure:

[0187] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0188] In some embodiments, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups; R 3It is selected from substituted or unsubstituted phenyl.

[0189] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 It is 3-(trifluoromethyl)phenyl.

[0190] In some embodiments, the compound has the following structure:

[0191] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0192] In some embodiments, R 4 is methyl or ethyl; R 5 is hydrogen, R 7 -C(=O)R 7 , -C(=O)-OR 7 -C(=O)N(R 7 )(R 8 ), -C(=O)-SR 7 , or -P(=O)(OR 9 )2; R 7 This includes C1-C6 alkyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups, substituted or unsubstituted monocyclic C3-C8 cycloalkyl groups, and substituted or unsubstituted bicyclic C5-C6 groups. 10 Cycloalkyl, substituted or unsubstituted monocyclic C2-C8 heterocycloalkyl, substituted or unsubstituted bicyclic C5-C 10 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CH2-(substituted or unsubstituted phenyl), -CH2-(substituted or unsubstituted heteroaryl), -CH2-(substituted or unsubstituted C2-C8 heterocycloalkyl), -CH(R 10 )OR 11 -(CH2CH2O)nR 11 , or -(C(R 10 )2) p-OR 11and; R 10 is each independently selected from hydrogen and methyl; R 11 is hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 , -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OR 9 )2.

[0193] In some embodiments, R 5 is R 7 , -C(=O)R 7 , -C(=O)-OR 7 , -C(=O)N(R 7 )(R 8 ), -C(=O)-SR 7 , or -P(=O)(OH)2; R 7 is C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]octanyl, substituted or unsubstituted bicyclo[4.3.0]nonanyl, or substituted or unsubstituted decalinyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CH2-(substituted or unsubstituted phenyl), -CH2-(substituted or unsubstituted heteroaryl), -CH2-(substituted or unsubstituted C2-C8 heterocycloalkyl), -CH(R 10 )O-R 11-(CH2CH2O)nR 11 , or -(C(R 10 )2) p-OR 11 And; R 10 Each is independently selected from hydrogen and methyl; R 11 This includes hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, and substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OR 9 )2.

[0194] In some embodiments, the compound has one of the following structures;

[0195] [ka]

[0196] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0197] In some embodiments, the compound has the following structure of formula (II):

[0198] [ka] Alternatively, having a pharmaceutically acceptable salt or solvate thereof, During the ceremony: Y is -CH2-, O, S, -NR 15 -, and -S(O)2- are selected; Z is either O or S.

[0199] In some embodiments, R 1 and R 2Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups; R 3 It is selected from substituted or unsubstituted phenyl.

[0200] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 It is 3-(trifluoromethyl)phenyl.

[0201] In some embodiments, the compound has the following structure:

[0202] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0203] In some embodiments, the compound has the following structure:

[0204] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0205] In some embodiments, the compound has the following structure of formula (IIa):

[0206] [ka] Alternatively, having a pharmaceutically acceptable salt or solvate thereof, During the ceremony, Y is -CH2-, O, S, -NR 15 - and -S(O)2- are selected.

[0207] In some embodiments, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups; R 3It is selected from substituted or unsubstituted phenyl.

[0208] In some embodiments, substitution means that the reference group is substituted with one or more additional groups individually and independently selected from halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some other embodiments, substitution means that the reference group is substituted with one or more additional groups individually and independently selected from halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, and heterocycloalkyl. In yet another embodiment, substitution means that the reference group is substituted with one or more additional groups individually and independently selected from halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, fluoroalkyl, alkoxy, and fluoroalkoxy.

[0209] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3It is 3-(trifluoromethyl)phenyl.

[0210] In some embodiments, the compound has the following structure:

[0211] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0212] In some embodiments, the compounds of formula (A) include those listed in Table 1.

[0213] [Table 1-1]

[0214] [Table 1-2]

[0215] [Table 1-3]

[0216] [Table 1-4]

[0217] In another embodiment, the compound represented by formula (B):

[0218] [ka] Alternatively, a pharmaceutically acceptable salt or solvate thereof may be described herein, in the formula: R 1 and R 2 Each is independently selected from hydrogen and substituted or unsubstituted alkyl groups; R 3R is selected from substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl, where R 3 If R is replaced, 3 It is substituted with one or more groups selected from halogens, -CN, -OH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, and substituted or unsubstituted C1-C4 heteroalkyl; R 4 is hydrogen, or a substituted or unsubstituted alkyl group; R 6 is hydrogen, or a substituted or unsubstituted alkyl group; Alternatively, R 4 and R 6 They combine with the carbon atom to which they bond to form a carbonyl (C=O) bond; Alternatively, R 4 and R 6 These are substituted or unsubstituted C3-C atoms, which are bonded together with the carbon atoms they bond to. 10 Cycloalkyl, or substituted or unsubstituted C2-C 10 It forms a heterocycloalkyl ring, where, if the ring is substituted, the ring has one or more R 15 Replaced by; R 15 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), and -C(=O)R 16 , -C(=O)-OR 16 -C(=O)N(R 16 )2; R 16 Each is independently selected from hydrogen and substituted or unsubstituted alkyl groups; R 5 C3-C is either substituted or non-substituted. 10 Cycloalkyl, substituted or unsubstituted C2-C 10heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), -(C(R 10 )2O)m-R 11 , -C(=O)-(C(R 10 )2O)m-R 11 , -C(=O)-(CH2CH2O)n-R 11 , -C(=O)-R a or -C(=O)-OR 7 ; R a is substituted or unsubstituted bicyclic cycloalkyl, substituted or unsubstituted bicyclic heterocycloalkyl, substituted or unsubstituted bicyclic heteroaryl, (substituted or unsubstituted heterocycloalkyl containing at least one O atom in the ring), substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted azapentyl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-4-yl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl; or, R 4 and R 5 together with the atom to which they are attached form substituted or unsubstituted C2-C 10 heterocycloalkyl; R 7 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), -(C(R ' 10 )2O)m-R11 -(CH2CH2O)nR 11 , or -(C(R 10 )2) p-OR 11 and; R 9 Each is independently selected from hydrogen and alkyl; R 10 Each is independently selected from hydrogen and alkyl; R 11 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), -C(=O)-SR 12 , or -P(=O)(OR 9 )2; R 12 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 These are heterocycloalkyls, substituted or unsubstituted phenyls, substituted or unsubstituted heteroaryls, -alkyl-(substituted or unsubstituted phenyls), or -alkyl-(substituted or unsubstituted heteroaryls); m is 1, 2, 3, 4, 5, or 6; n is 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; Here, substitution means that the reference group is substituted with one or more additional groups individually and independently selected from halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.

[0219] In some embodiments, m is 1, 2, 3, 4, 5, or 6. In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2, 3, 4, or 6.

[0220] In some embodiments, n is 1, 2, 3, 4, 5, or 6. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 2, 3, 4, 5, or 6.

[0221] In some embodiments, p is 1, 2, 3, 4, 5, or 6. In some embodiments, p is 1, 2, 3, 4, or 5. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2, 3, 4, 5, or 6.

[0222] In some embodiments, R 4 is hydrogen; R 6 is hydrogen; R 5 C3-C is either substituted or non-substituted. 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), -(C(R 10 )2O)mR 11 -C(=O)-(C(R 10 )2O)mR 11 -C(=O)-(CH2CH2O)nR 11 -C(=O)-R a Or -C(=O)-OR 7 That is the case.

[0223] In some embodiments, R 1 and R 2 Each of these is independently selected from substituted or unsubstituted C1-C6 alkyl groups. In some embodiments, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C3 alkyl groups. In some embodiments, R 1 is ethyl. In some embodiments, R 2 is n-propyl, and in some embodiments, R 1 is ethyl, and R 2It is n-propyl.

[0224] In some embodiments, R 3 R is selected from substituted or unsubstituted phenyl. In some embodiments, R 3 R is a substituted phenyl. In some embodiments, R 3 is a phenyl compound substituted with one or more groups independently selected from halogens, C1-C4 alkyl groups, or C1-C4 fluoroalkyl groups. In some embodiments, R 3 is a phenyl compound substituted with one or more groups independently selected from C1-C4 fluoroalkyl groups. In some embodiments, R 3 R is selected from phenyl substituted with one, two, or three -CF3 substituents. In some embodiments, R 3 R is selected from phenyl substituted with one -CF3 substituent. In some embodiments, R 3 The following applies:

[0225] [ka]

[0226] In some embodiments, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups; R 3 It is selected from substituted or unsubstituted phenyl.

[0227] In some embodiments, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups; R 3 It is selected from substituted or unsubstituted phenyl.

[0228] In some embodiments, R 1 and R 2Each of these is independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.

[0229] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 It is 3-(trifluoromethyl)phenyl.

[0230] In some embodiments, the compound has the following structure:

[0231] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0232] In some embodiments, R 11 This includes hydrogen, substituted or unsubstituted alkyl, and -C(=O)R 12 , -C(=O)-OR 12 -C(=O)N(R 12 )(R 8 ), or -P(=O)(OR 9 )2. In some embodiments, R 11 This refers to substituted or unsubstituted alkyl groups, -C(=O)R 12 , -C(=O)-OR 12 , or -P(=O)(OR 9 )2. In some embodiments, R 11 is -C(=O)R 12 Or -P(=O)(OR 9 )2. In some embodiments, R 11 is -C(=O)R 12 Alternatively, it is -P(=O)(OH)2.

[0233] In some embodiments, the compound has one of the following structures;

[0234] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0235] In some embodiments, R 12 This is a substituted or unsubstituted alkyl or a substituted or unsubstituted C3-C 10 It is cycloalkyl. In some embodiments, R 12 This refers to unsubstituted C1-C6 alkyl or unsubstituted C3-C 10 It is cycloalkyl. In some embodiments, R 12 R is an unsubstituted C1-C3 alkyl group. In some embodiments, R 12 It is an unsubstituted C3-C6 cycloalkyl group.

[0236] In some embodiments, the compound has one of the following structures;

[0237] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0238] In some embodiments, R 5 is -C(=O)-(C(R 10 )2O)mR 11 -C(=O)-(CH2CH2O)nR 11 -C(=O)-R a , or -C(=O)-OR 7 That is the case.

[0239] In some embodiments, the compound has the following structure:

[0240] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0241] In some embodiments, R a is a substituted or unsubstituted bicyclic cycloalkyl, which is a condensed bicyclic cycloalkyl, a crosslinked bicyclic cycloalkyl, or a spiro-bicyclic cycloalkyl; or, R a is a substituted or unsubstituted bicyclic heterocycloalkyl, which is a condensed bicyclic heterocycloalkyl, a cross-linked bicyclic heterocycloalkyl, or a spiro-bicyclic heterocycloalkyl; or, R a It is a substituted or unsubstituted bicyclic heteroaryl.

[0242] In some embodiments, R a These are substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]octanyl, substituted or unsubstituted bicyclo[4.3.0]nonanyl, or substituted or unsubstituted dekalinyl.

[0243] In some embodiments, the compound has one of the following structures;

[0244] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0245] In some embodiments, R aThese are substituted or unsubstituted heterocycloalkyls containing at least one O atom in the ring, substituted or unsubstituted azetidinyls, substituted or unsubstituted piperidinyls, substituted or unsubstituted azapenyls, substituted or unsubstituted five-membered heteroaryls, substituted or unsubstituted pyridine-2-yls, substituted or unsubstituted pyridine-4-yls, substituted or unsubstituted pyrimidinyls, substituted or unsubstituted pyrazinyls, substituted or unsubstituted pyridazinyls, and substituted or unsubstituted triazinyls. In some embodiments, R a These are substituted or unsubstituted tetrahydrofuranil, substituted or unsubstituted tetrahydropyranil, substituted or unsubstituted tetrahydrodioxanil, substituted or unsubstituted azetidinil, substituted or unsubstituted piperidinil, substituted or unsubstituted azapenil, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyridine-2-yl, substituted or unsubstituted pyridine-4-yl, substituted or unsubstituted pyrimidinil, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridadinil, and substituted or unsubstituted triazinyl. In some embodiments, R a These are substituted or unsubstituted tetrahydrodioxanyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyridine-2-yl, substituted or unsubstituted pyridine-4-yl, or substituted or unsubstituted pyrimidinyl.

[0246] In some embodiments, R aThis is a substituted or unsubstituted heterocycloalkyl ring containing at least one oxygen atom, which is a substituted or unsubstituted tetrahydrofuranil, a substituted or unsubstituted dihydrofuranil, a substituted or unsubstituted oxazolidinonil, a substituted or unsubstituted tetrahydropyranil, a substituted or unsubstituted dihydropyranil, a substituted or unsubstituted tetrahydrothiopyranil, a substituted or unsubstituted morpholinil, a substituted or unsubstituted oxetanil, a substituted or unsubstituted oxepanil, a substituted or unsubstituted oxazepinyl, or a substituted or unsubstituted dioxanil.

[0247] In some embodiments, R a It is a substituted or unsubstituted five-membered heteroaryl, which is a substituted or unsubstituted furanyl, a substituted or unsubstituted thienyl, a substituted or unsubstituted pyrrolyl, a substituted or unsubstituted oxazolyl, a substituted or unsubstituted thiazolyl, a substituted or unsubstituted imidazolyl, a substituted or unsubstituted pyrazolyl, a substituted or unsubstituted triazolyl, a substituted or unsubstituted tetrazolyl, a substituted or unsubstituted isoxazolyl, a substituted or unsubstituted isothiazolyl, a substituted or unsubstituted oxadiazolyl, or a substituted or unsubstituted thiadiazolyl.

[0248] In some embodiments, the compound has one of the following structures;

[0249] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0250] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 is 3-(trifluoromethyl)phenyl; and, R 5 is -C(=O)-(C(R 10 )2O)mR 11 -C(=O)-(CH2CH2O)nR 11 , or -C(=O)-OR7 That is the case.

[0251] In some embodiments, the compound has one of the following structures;

[0252] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0253] In some embodiments, R 1 is ethyl; R 2 is n-propyl; and, R 3 is 3-(trifluoromethyl)phenyl; R 5 C3-C is either substituted or non-substituted. 10 Cycloalkyl, substituted or unsubstituted C2-C 10 These are heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), and -alkyl-(substituted or unsubstituted heterocycloalkyl). In some embodiments, R 5 is -CH2- (substituted or unsubstituted C2-C8 heterocycloalkyl). In some embodiments, R 5 is -CH2- (substituted C5-C6 heterocycloalkyl). In some embodiments, R 5 The following applies:

[0254] [ka]

[0255] In some embodiments, substitution means that the reference group is substituted with one or more additional groups individually and independently selected from halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some other embodiments, substitution means that the reference group is substituted with one or more additional groups individually and independently selected from halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, and heterocycloalkyl. In yet another embodiment, substitution means that the reference group is substituted with one or more additional groups individually and independently selected from halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, fluoroalkyl, alkoxy, and fluoroalkoxy.

[0256] In some embodiments, the compound has the following structure:

[0257] [ka] Alternatively, it may have a pharmaceutically acceptable salt or solvate thereof.

[0258] In some embodiments, the compounds of formula (B) include those shown in Table 2.

[0259] [Table 2-1]

[0260] [Table 2-2]

[0261] [Table 2-3]

[0262] [Table 2-4]

[0263] [Table 2-5]

[0264] In one embodiment, the present disclosure relates to a compound represented by formula (I):

[0265] [ka] Alternatively, we provide any pharmaceutically acceptable salt or solvate thereof, in the formula: R 1 , R 2 , R 3 , and R 5 Each is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl; and, R 4C2-C is either substituted or non-substituted. 10 The group is selected from alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.

[0266] In one embodiment, R 1 and R 2 Each of these is independently a lower alkyl group. In one embodiment, R 1 is ethyl. In one embodiment, R 2 is n-propyl. In one embodiment, R 3 It is 3-(trifluoromethyl)phenyl.

[0267] In one embodiment, the compound is represented as follows:

[0268] [ka]

[0269] In one embodiment, the compound is represented as follows:

[0270] [ka] During the ceremony: R 6 and R 7 Each of these is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.

[0271] In one embodiment, R 6 and R 7 Each of these is independently hydrogen or a lower alkyl group. In further embodiments, the compound is selected from groups consisting of the following:

[0272] [ka]

[0273] In one embodiment, the present disclosure relates to a compound of formula (II):

[0274] [ka] Alternatively, we provide any pharmaceutically acceptable salt or solvate thereof, in formula:R 11 , R 12 , and R 13 Each is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl; and, R 14 It is a substituted or unsubstituted cycloalkyl group.

[0275] In one embodiment, R 11 and R 12 Each of these is independently a lower alkyl group. In one embodiment, R 11 is ethyl. In one embodiment, R 12 is n-propyl. In one embodiment, R 13 It is 3-(trifluoromethyl)phenyl.

[0276] In one embodiment, the compound is represented as follows:

[0277] [ka] During the ceremony: Y is O, S, substituted or unsubstituted -CH2, -NR 15 Selected from -S(O)2- and single bonds; Z is either O or S; and, R 15 This is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.

[0278] In one embodiment, the compound is represented as follows:

[0279] [ka]

[0280] In one embodiment, the compound is represented as follows:

[0281] [ka] During the ceremony: Y is O, S, substituted or unsubstituted -CH2, -NR 17 Selected from -S(O)2- and single bonds; as well as, R 16 and R 17 Each of these is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.

[0282] In one embodiment, the compound is represented as follows:

[0283] [ka]

[0284] In one embodiment, the present disclosure relates to a compound of formula (III):

[0285] [ka] Alternatively, we provide any pharmaceutically acceptable salt or solvate thereof, in the formula: R 21 , R 22 , R 23 , and R 24Each of these is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.

[0286] In one embodiment, R 21 and R 22 Each of these is independently a lower alkyl group. In one embodiment, R 21 is ethyl. In one embodiment, R 22 is n-propyl. In one embodiment, R 23 It is 3-(trifluoromethyl)phenyl.

[0287] In one embodiment, the compound is represented as follows:

[0288] [ka]

[0289] In one embodiment, the compound is selected from the group consisting of:

[0290] [ka] During the ceremony: R 25 , R 26 , and R 27 Each of these is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.

[0291] In one embodiment, R 25 , R 26 , and R 7 Each is independently either hydrogen or a lower alkyl group. In one embodiment, the compound is selected from the group consisting of:

[0292] [ka]

[0293] In one embodiment, the present disclosure relates to a compound of formula (IV):

[0294] [ka] Alternatively, we provide any pharmaceutically acceptable salt or solvate thereof, in the formula: R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 Each of these is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted acyl.

[0295] In one embodiment, R 31 and R 32 Each of these is independently a lower alkyl group. In one embodiment, R 31 is ethyl. In one embodiment, R 32 is n-propyl. In one embodiment, R 33 It is 3-(trifluoromethyl)phenyl. In one embodiment, the compound is represented as follows:

[0296] [ka]

[0297] In one embodiment, the compound is represented as follows:

[0298] [ka] During the ceremony: R 37This is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.

[0299] In one embodiment, R 35 , R 36 , and R 37 Each is independently either hydrogen or a lower alkyl group. In one embodiment, the compound is selected from the group consisting of:

[0300] [ka]

[0301] In one embodiment, the present disclosure relates to a compound of formula (V):

[0302] [ka] Alternatively, we provide any pharmaceutically acceptable salt or solvate thereof, in the formula: R 41 , R 42 , R 43 , and R 44 Each is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl; and, R 45 This is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted cycloalkyl.

[0303] In one embodiment, R 41 and R 42 Each is independently selected from lower alkyl groups. In one embodiment, R 41 is ethyl. In one embodiment, R 42 is n-propyl. In one embodiment, R 43R is 3-(trifluoromethyl)phenyl. In one embodiment, R 45 -C(O)R 47 Or -P(O)(OR 47 )If not 2, R 47 This is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.

[0304] In one embodiment, the compound is represented as follows:

[0305] [ka]

[0306] In one embodiment, the compound is selected from the group consisting of:

[0307] [ka] During the ceremony: R 46 This is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl; X is O, S, substituted or unsubstituted -CH2, -NR 48 Selected from -S(O)2- and single bonds; Z is either O or S; and, R 48 This is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.

[0308] In one embodiment, R 44 and R 46 Each is independently either hydrogen or a lower alkyl group. In one embodiment, the compound is selected from the group consisting of:

[0309] [ka]

[0310] In one embodiment, the present disclosure relates to a compound of formula (VI):

[0311] [ka] Alternatively, we provide any pharmaceutically acceptable salt or solvate thereof, in formula:R 51 , R 52 , R 53 , and R 55 Each is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl; approximately, R 54 It is hydrogen or methyl.

[0312] In one embodiment, R 51 and R 52 Each of these is independently a lower alkyl group. In one embodiment, R 51 is ethyl. In one embodiment, R 52 is n-propyl. In one embodiment, R 53 It is 3-(trifluoromethyl)phenyl.

[0313] In one embodiment, the compound is represented as follows:

[0314] [ka]

[0315] In one embodiment, the compound is selected from the group consisting of:

[0316] [ka] During the ceremony: R56 , R 57 , and R 58 Each of these is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.

[0317] In one embodiment, R 56 , R 57 , and R 58 Each is independently either hydrogen or a lower alkyl group. In one embodiment, the compound is selected from the group consisting of:

[0318] [ka]

[0319] In one embodiment, the present disclosure relates to a compound of formula (VII):

[0320] [ka] Alternatively, we provide any pharmaceutically acceptable salt or solvate thereof, in the formula: X is O, S, substituted or unsubstituted -CH2-, -NR 65 -, -S(O)2-, and single bonds; Z is -SO2OH or -S(O)OH; and, R 61 , R 62 , R 63 , R 64 , and R 65 Each of these is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.

[0321] In one embodiment, R 61 and R 62 Each of these is independently a lower alkyl group. In one embodiment, R 61is ethyl. In one embodiment, R 62 is n-propyl. In one embodiment, R 63 It is 3-(trifluoromethyl)phenyl.

[0322] In one embodiment, the compound is represented as follows:

[0323] [ka]

[0324] In one embodiment, R 64 is hydrogen or a lower alkyl group. In one embodiment, the compound is selected from the group consisting of:

[0325] [ka]

[0326] In one embodiment, the present disclosure relates to a compound of formula (VIII):

[0327] [ka] Alternatively, we provide any pharmaceutically acceptable salt or solvate thereof, in the formula: X is S, substituted or unsubstituted -CH2-, -NR 75 -, and -S(O)2-; and, R 71 , R 72 , R 73 , R 74 , and R 75 Each of these is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.

[0328] In one embodiment, R 71 and R 72 Each of these is independently a lower alkyl group. In one embodiment, R71 is ethyl. In one embodiment, R 72 is n-propyl. In one embodiment, R 73 It is 3-(trifluoromethyl)phenyl.

[0329] In one embodiment, the compound is represented as follows:

[0330] [ka]

[0331] In one embodiment, R 74 is hydrogen or a lower alkyl group. In one embodiment, the compound is represented as follows:

[0332] [ka]

[0333] Compound of formula (1):

[0334] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 , R 2 , and R 3 Each of these is independently H, a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl; X is H, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.

[0335] In some cases, R 1 is an unsubstituted alkyl, preferably ethyl. In some cases, R 2 is an unsubstituted alkyl, preferably a propyl. In some cases, R 3is a substituted aryl compound, preferably 3-(trifluoromethyl)phenyl. In some cases, the compound is the compound of formula (2):

[0336] [ka] Alternatively, it may be any pharmaceutically acceptable salt or solvate thereof, in the formula: X is H, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.

[0337] For example, prodrugs include the following compounds:

[0338] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof.

[0339] For example, prodrugs include the following compounds:

[0340] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof.

[0341] In some cases, the compound of formula (3) below:

[0342] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof, in the formula: R 1 and R 2 Each of these is independently an amino, a halo, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted acyl.

[0343] For example, the following compounds:

[0344] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof.

[0345] In some cases, the compound of formula (4) below:

[0346] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof, in the formula: R 1 and R 2 Each of these is independently an amino, a halo, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted acyl.

[0347] For example, the following compounds:

[0348] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0349] In some cases, the compound of formula (5):

[0350] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: X is O, S, a substituted or unsubstituted -CH2-, -NR'-, -S(O)2-, or a single bond; Z is O or S; R' is hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.

[0351] For example, the following compounds:

[0352] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0353] In some cases, the compound of formula (6):

[0354] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 and R 2 Each of these is independently a hydrogen atom, an amino acid, a halo, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted acyl group.

[0355] For example, the following compounds:

[0356] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0357] In some cases, the compound of formula (7):

[0358] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: X is O, S, a substituted or unsubstituted -CH2-, -NR'-, -S(O)2-, or a single bond; R and R' are independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.

[0359] For example, the following compounds:

[0360] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0361] In some cases, the compound of formula (8):

[0362] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R is hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.

[0363] For example, the following compounds:

[0364] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0365] In some cases, the compound of formula (9):

[0366] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 and R 2 Each of these is independently a hydrogen atom, an amino acid, a halo, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted acyl group.

[0367] For example, the following compounds:

[0368] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0369] In some cases, the compound of formula (10):

[0370] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 and R 2 Each of these is independently a hydrogen atom, an amino acid, a halo, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted acyl group.

[0371] For example, the following compounds:

[0372] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0373] In some cases, the compound of formula (11):

[0374] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 and R 2 Each of these is independently a hydrogen atom, an amino acid, a halo, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted acyl group.

[0375] For example, the following compounds:

[0376] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0377] In some cases, the compound of formula (12):

[0378] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 and R 2 Each of these is independently a hydrogen atom, an amino acid, a halo, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted acyl group.

[0379] For example, the following compounds:

[0380] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0381] In another example, the following compounds:

[0382] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0383] In some cases, the compound of formula (13):

[0384] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 These are hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.

[0385] For example, the following compounds:

[0386] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0387] In some cases, the compound of formula (14):

[0388] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 , R 2 , and R 3 Each of these is independently a hydrogen atom, an amino acid, a halo, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted acyl group.

[0389] For example, the following compounds:

[0390] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0391] In some cases, the compound of formula (15):

[0392] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 , R 2 , and R 3 Each of these is independently a hydrogen atom, an amino acid, a halo, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted acyl group.

[0393] For example, the following compounds:

[0394] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0395] In some cases, the compound of formula (16):

[0396] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: X is O, S, a substituted or unsubstituted -CH2-, -NR'-, -S(O)2-, or a single bond; and, R 1 , R 2R' and R' are independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.

[0397] For example, the following compounds:

[0398] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0399] In some cases, the compound of formula (17):

[0400] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: X is O, S, a substituted or unsubstituted -CH2-, -NR'-, -S(O)2-, or a single bond; Z is either O or S; and, R is hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.

[0401] For example, the following compounds:

[0402] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0403] In some cases, the compound of formula (18):

[0404] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 , R 2 , and R 3 Each of these is independently a hydrogen atom, an amino acid, a halo, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted acyl group.

[0405] For example, the following compounds:

[0406] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0407] In some cases, the compound of formula (19):

[0408] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 , R 2 , R 3 , and R 4 Each of these is independently a hydrogen atom, an amino acid, a halo, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted acyl group.

[0409] For example, the following compounds:

[0410] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0411] In some cases, the compound of formula (20):

[0412] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R is hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl; and n is any of 1-5.

[0413] For example, the following compounds:

[0414] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0415] In some cases, the compound of formula (21):

[0416] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof, in the formula: X is O, S, a substituted or unsubstituted -CH2-, -NR'-, or -S(O)2-; R' is hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.

[0417] For example, the following compounds:

[0418] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0419] For example, the following compounds:

[0420] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0421] For example, the following compounds:

[0422] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0423] In some cases, the compound of formula (22):

[0424] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: X is O, S, a substituted or unsubstituted -CH2-, -NR'-, -S(O)2-, or a single bond; Z is either -SO2OH or -S(O)OH; R' is hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.

[0425] For example, the following compounds:

[0426] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0427] For example, the following compounds:

[0428] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0429] In some cases, the compound of formula (23):

[0430] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 , R 2 , R 3 , and R 4 Each of these is independently a hydrogen atom, an amino acid, a halo, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted acyl group.

[0431] For example, the following compounds:

[0432] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0433] In some cases, the compound of formula (24):

[0434] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 , R 2 , and R 3Each of these is independently a hydrogen atom, an amino acid, a halo, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted acyl group.

[0435] For example, the following compounds:

[0436] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0437] For example, the following compounds:

[0438] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein.

[0439] In some cases, the compound of formula (25):

[0440] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is described herein, in formula: R 1 and R 2 Each of these is independently a hydrogen atom, an amino acid, a halo, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted acyl group.

[0441] For example, the following compounds:

[0442] [ka] Alternatively, pharmaceutically acceptable salts or solvates thereof are described herein.

[0443] In some cases, compounds selected from the following group:

[0444] [ka] Alternatively, any pharmaceutically acceptable salt or solvate thereof is further disclosed herein. These A 2B A prodrug of the adenosine receptor antagonist can be designed and synthesized in a similar manner to the prodrug of compound 1 by substituting xanthine at position 7.

[0445] Pharmaceutical composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inert components that facilitate the treatment of the active compound into a preparation for pharmaceutical use. The appropriate formulation depends on the chosen route of administration. Summaries of the pharmaceutical compositions described herein can be found, for example, in: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0446] In some embodiments, the compounds described herein are administered alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents in pharmaceutical compositions. Administration of the compounds and compositions described herein can be achieved by methods that enable delivery of the compounds to the site of action.

[0447] Pharmaceutical compositions incorporating the compounds described herein may take any pharmaceutically acceptable physical form. Pharmaceutical compositions for oral administration are particularly preferred. Examples of such pharmaceutical compositions include, but are not limited to, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0448] Pharmaceutical compositions can be prepared according to known methods of formulation used in pharmacy. All common types of compositions are intended, but are not limited to, tablets, chewable tablets, capsules, and solutions.

[0449] Capsules can be prepared by mixing the compounds described herein with a suitable diluent and filling the capsule with an appropriate amount of the mixture. Tablets can be prepared by direct compression, wet granulation, or dry granulation. These formulations typically incorporate diluents, binders, lubricants, and disintegrants, as well as the compounds described herein as active therapeutic agents. Lubricants in tablet formulations may help prevent the tablet and punches from sticking to the die. Tablet disintegrants are substances that expand when wet, causing the tablet to disintegrate and release the compound. Enteric-coated formulations are often used to protect the active ingredient from the highly acidic components of the stomach and to slow its disintegration and absorption in the gastrointestinal tract. Such formulations are made by coating a solid dosage form with a polymer film that is insoluble in acidic environments and soluble in basic environments. Tablets are often coated with flavorings and sugars as fillers. [Examples]

[0450] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0451] Example 1 - Synthesis of a typical compound A Compound A can be synthesized according to the following scheme.

[0452] [ka]

[0453] Step 1. Dissolve O-(chloromethyl)S-ethylcarbonothioate, sodium iodide, and 18-crown-6 in toluene and heat at approximately 100°C for approximately 5 hours to obtain S-ethyl O-(iodomethyl)-carbonothioate. Step 2. Add n-butyric acid, tetrabutylammonium bicarbonate, and sodium carbonate to a solution of chloro(chloromethoxy)methane in methylene chloride / water at room temperature and stir overnight to obtain solid (((ethylthio)carbonyl)oxy)methyl butyrate. Step 3. Add sulfuric acid dropwise to the solution of (((ethylthio)carbonyl)oxy)methyl butyrate at approximately -30°C. Warm the reaction mixture to room temperature and stir for approximately 2 hours to obtain a solution of ((chlorocarbonyl)oxy)methyl butyrate. Step 4. Add ((chlorocarbonyl)oxy)methyl butyrate to a solution of compound 1 and sodium hydride in DMF at room temperature and stir for about 3 hours to obtain compound A.

[0454] Example 2 - Synthesis of Exemplary Compound B Compound B can be synthesized according to the following scheme.

[0455] [ka]

[0456] Step 1. Dissolve O-(chloromethyl)S-ethyl carbonothioate, sodium iodide, and 18-crown-6 in toluene and heat at 100°C for 5 hours to form S-ethyl O-(iodomethyl)carbonothioate. Step 2. React S-ethyl O-(iodomethyl)carbonothioate with dibenzyl hydrogen phosphate to form O-(((bis((bis(((benzyloxy)phosphoryl)oxy)methyl)S-ethyl carbonothioate. Step 3. Add sulfuric acid to the solution of O-(((bis((bis((bis((bis((benzyloxy)phosphoryl)oxy)methyl)S-ethyl carbonothioate at -30°C, warm to room temperature, and stir for 2 hours to obtain ((bis(benzyloxy)phosphoryl)oxy)methyl carbonochloride. Step 4. Add sodium hydride to the DMF solution of ((bis(benzyloxy)phosphoryl)oxy)methylcarbonochloride and compound 1 at room temperature. Stir the solution for 3 hours. Add Pd / C in DMSO at room temperature under H2 conditions, and stir the reaction mixture for 5 hours to obtain compound B.

[0457] Example 3 - Synthesis of Exemplary Compound C Compound C was synthesized according to the following steps.

[0458] [ka]

[0459] To a solution of compound 28 (50.0 g, 1650 mmol, 1.0 eq) and thionyl chloride (63.0 mL, 849.9 mmol, 0.5151 eq), zinc bromide (4.58 g, 19.99 mmol, 0.01212 eq) was added under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 24 hours. The progress of the reaction mixture was observed. 1 The reaction was monitored by 1H NMR. After the reaction was complete, the resulting mixture was isolated by distillation (bp 103-104°C) to obtain a mixture of slightly yellow oil and white solids. The mixture was filtered to obtain compound 29 (51.645 g, 54%) as a slightly yellow oil.

[0460] To a solution of compound 29 (10.0 g, 87.72 mmol, 3.0 eq) in hexane (50 mL), sodium butyrate (3.2 g, 29.24 mmol, 1.0 eq) was added in a sealed tube. The resulting mixture was stirred at 80°C for 16 hours. The progress of the reaction mixture was observed. 1 The reaction was monitored by 1H NMR. After the reaction was complete, the resulting mixture was filtered, the filtrate was diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound 30 (1.5 g, 31%).

[0461] 1 H NMR (300 MHz, chloroform-d) δ 5.51 (d, J = 0.6 Hz, 2H), 5.42 (d, J = 0.6 Hz, 2H), 2.36 (td, J = 7.4, 0.6 Hz, 2H), 1.75 - 1.61 (m, 2H), 0.97 (td, J = 7.4, 0.6 Hz, 3H).

[0462] A mixture of compound 30 (1.1 g, 6.63 mmol, 1.2 eq), compound 1 (2.5 g, 5.52 mmol, 1.0 eq), cesium carbonate (2.7 g, 8.28 mmol, 1.5 eq), and potassium iodide (1.1 g, 6.63 mmol, 1.2 eq) in 1-methyl-2-pyrrolidinone (30 mL) was stirred at room temperature for 2 hours. The progress of the reaction mixture was monitored by TLC. After the completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The desired compound C was obtained as a white solid in a yield of 20% at 648 mg.

[0463] LC-MS: 577.25 [M+1] + . 1H NMR (300 MHz, CDCl3): δ 8.12 - 8.04 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.55 - 7.40 (m, 3H), 5.91 (s, 2H), 5.53 (s, 2H), 5.42 (s, 2H), 4.18 (d, J = 7.1 Hz, 2H), 3.97 (s, 2H), 2.16 (t, J = 7.4 Hz, 2H), 1.68 (dd, J = 15.1, 7.4 Hz, 2H), 1.53 - 1.46 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H).

[0464] Example 4 - Synthesis of Exemplary Compound D Compound D can be synthesized according to the following scheme.

[0465] [ka]

[0466] Step 1. Chloro(chloromethoxy)methane and dibenzyl hydrogen phosphate are stirred in solution to obtain dibenzyl((chloromethoxy)methyl phosphate). Step 2. Sodium hydride is added to the DMF solution of dibenzyl((chloromethoxy)methyl phosphate and compound 1 at room temperature. The reaction mixture is stirred for about 3 hours. Pd / C in DMSO is added and the mixture is stirred at room temperature under H2 for about 5 hours to obtain compound D.

[0467] Example 5 - Synthesis of Exemplary Compound E Compound E was synthesized according to the following procedure.

[0468] [ka]

[0469] To a solution of compound 1 (400 mg, 0.897 mmol, 1.0 eq) in DMF (10 mL), K2CO3 (371 mg, 2.69 mmol, 3.0 eq) and KI (15 mg, 0.0897 mmol, 0.1 eq) were added, followed by the addition of chloromethyl butyrate (366 mg, 2.69 mmol, 3.0 eq). The mixture was stirred at 60°C for 16 hours. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30% ethyl acetate / hexane to obtain compound E (420 mg, 86%) as a white solid.

[0470] LCMS: [M+1] = 547.45; 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 2.1 Hz, 2H), 7.63 - 7.44 (m, 4H), 6.33 (s, 2H), 5.41 (s, 2H), 4.17 (d, J = 7.1 Hz, 2H), 4.01 - 3.90 (m, 2H), 2.30 (t, J = 7.4 Hz, 2H), 1.72 - 1.57 (m, 4H), 1.34 (t, J = 7.1 Hz, 3H), 0.92 (dt, J = 19.0, 7.5 Hz, 6H).

[0471] Example 6 - Alternative synthesis of exemplary compound E Compound E was synthesized according to the following procedure.

[0472] [ka]

[0473] To a solution of compound 1 (100 g, 224 mmol, 1.00 eq) in dry tetrahydrofuran (5.00 L), NaH (26.9 g, 672 mmol, 60% purity, 3.00 eq) was added at 15°C. The reaction mixture was stirred at 15-20°C for 1 hour. Compound 1A (57.8 g, 448 mmol, 2.00 eq) was added dropwise at 15-20°C. The reaction mixture was stirred at 20°C for 2 hours. LC-MS and TLC showed that approximately 13% of compound 1 remained, and approximately 80% of the desired compound 9 was detected. The 12 reaction mixtures were combined for workup. The reaction mixture was filtered and concentrated under reduced pressure to obtain a filtrate residue (1.2 kg). The residue was incorporated into methyl tert-butyl ether (6.00 L), the mixture was stirred at 15°C for 3 hours, the mixture was then filtered, and the filtrate cake was dried to obtain compound 9 (950 g, 1.76 mol, 65.6% yield) as a white solid.

[0474] LCMS: (Product Rt=1.498 min, M+1=539.1) 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(d, J = 10.8 Hz, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.46-7.56 (m, 3H), 5.96 (s, 2H), 5.44 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.95-3.99 (m, 2H), 1.64-1.74 (m, 2H), 1.37 (t, J = 6.8 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H).

[0475] Compound 2A (13.3 g, 121 mmol, 1.30 eq) was added in one step to a mixture of compound 9 (50.0 g, 92.8 mmol, 1.00 eq) in DMF (250 mL) at 20°C under N2. The mixture was stirred at 100°C (internal temperature) for 1.5 hours. LC-MS indicated that the reaction was complete. The 19 reactants were combined for work-up. The mixture was cooled to 20°C, and the suspension was filtered. The filtrate was purified using reverse-phase HPLC. The aqueous phase (~20.0 L) was concentrated under vacuum at 45°C and extracted with ethyl acetate (5.00 L x 3). The combined organic phase was washed with brine (3.00 L), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum at 45°C. Isopropyl ether (4.00 L) was added to the residue, and the mixture was stirred at 60°C for 6 hours. The mixture was cooled to 15°C and filtered. The filtered cake was collected and dried at 45°C to obtain compound E (417 g, 697 mmol, 39.6% yield, 98.8% purity) as a white solid.

[0476] 1 H NMR (400 MHz, CDCl3) δ 7.98 (s, 2H), 7.62 (d, J = 7.6 Hz, 1H) 7.47-7.56 (m, 3H), 6.35 (s, 2H), 5.44 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.96-4.00 (m, 2H), 2.33 (t, J = 7.2 Hz, 2H), 1.62-1.70 (m, 4H), 1.35 (t, J = 7.2 Hz, 3H), 0.96 (t, J = 7.6 Hz, 3H), 0.91 (t, J =7.6 Hz, 3H).

[0477] Example 7 - Synthesis of Exemplary Compound F Compound F was synthesized according to the following steps.

[0478] [ka]

[0479] To a solution of compound 2 (1 g, 7.46 mmol, 1.0 eq) in DCM (10 mL), ZnCl2 (20 mg, 0.149 mmol, 0.02 eq) was added. After stirring at room temperature for 15 minutes, the mixture was cooled to -15°C. Then, compound 3 (433 mg, 7.46 mmol, 1.0 eq) was added dropwise over 15 minutes. The mixture was warmed to room temperature and stirred at room temperature for 16 hours. The progress of the reaction mixture was monitored by TLC. The mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound 4 (1.4 g, 97%).

[0480] To a solution of compound 1 (808 mg, 1.81 mmol, 1.0 eq) in DMF (10 mL), K2CO3 (750 mg, 5.44 mmol, 3.0 eq) and KI (30 mg, 0.181 mmol, 0.1 eq) were added, followed by the addition of compound 4 (1.044 g, 5.44 mmol, 3.0 eq). The mixture was stirred at 60°C for 16 hours. The progress of the reaction mixture was monitored by TLC. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30% ethyl acetate / hexane to obtain compound F (237 mg, 22%) as a white solid.

[0481] LCMS: [M+1] = 603.45; 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 2.1 Hz, 2H), 7.63 - 7.44 (m, 4H), 6.33 (s, 2H), 5.41 (s, 2H), 4.17 (d, J = 7.1 Hz, 2H), 4.01 - 3.90 (m, 2H), 2.30 (t, J = 7.4 Hz, 2H), 1.72 - 1.57 (m, 4H), 1.34 (t, J = 7.1 Hz, 3H), 0.92 (dt, J = 19.0, 7.5 Hz, 6H).

[0482] Example 8 - Synthesis of Exemplary Compound G Compound G was synthesized according to the following steps.

[0483] [ka]

[0484] A mixture of compound 5 (2 g, 10.20 mmol, 1.0 eq), compound 3 (947 mg, 16.33 mmol, 1.6 eq), and pyridine (81 mg, 1.02 mmol, 0.1 eq) in diethyl ether (20 mL) was stirred at room temperature for 2 hours. The progress of the reaction mixture was monitored by TLC. Crude compound 6 was obtained by concentrating the mixture under reduced pressure and used directly in the next step.

[0485] To a mixture of crude compound 6 from the previous step in DCM (20 mL), pyridine (1.6 g, 20.40 mmol, 2.0 eq) and a solution of compound 6a (1.07 g, 10.71 mmol, 1.05 eq) in DCM (10 mL) were successively added. The mixture was warmed to room temperature and stirred at room temperature for 16 hours. The progress of the reaction mixture was monitored by TLC. The mixture was diluted with 1N HCl and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound 7 (2.1 g, 93%).

[0486] To a solution of compound 1 (1.06 g, 2.38 mmol, 1.0 eq) in DMF (20 mL), KI (395 mg, 0.238 mmol, 0.1 eq) was added. After stirring for 15 minutes, K2CO3 (983 mg, 7.13 mmol, 3.0 eq) and compound 7 (2.1 g, 9.50 mmol, 4.0 eq) were added. The mixture was stirred at 60°C for 16 hours. The progress of the reaction mixture was monitored by TLC. The mixture was diluted with water and extracted with DCM. The organic layer was dried on anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound G (316 mg, 21%) as a white solid.

[0487] LCMS: [M+1] = 631.55; 1H NMR (400 MHz, CDCl3) δ8.11 (s, 2H), 7.67 - 7.40 (m, 4H), 5.42 (s, 2H), 5.29 (d, J = 6.6 Hz, 1H), 4.56 (s, 1H), 4.16 (d, J = 6.9 Hz, 2H), 3.97 (dd, J = 14.5, 7.0 Hz, 2H), 2.14 (s, 2H), 1.88 (s, 1H), 1.68 (dd, J = 14.7, 7.3 Hz, 5H), 1.49 (s, 1H), 1.41 (d, J = 9.6 Hz, 1H), 1.33 (t, J = 6.9 Hz, 4H), 1.25 - 1.14 (m, 3H), 0.94 (t, J = 7.3 Hz, 3H), 0.83 (t, J = 7.2 Hz, 3H).

[0488] Example 9 - Synthesis of Exemplary Compound H Compound H was synthesized according to the following steps.

[0489] [ka]

[0490] To a mixture of crude compound 6 (1.5 g, 9.62 mmol, 1.0 eq) from the previous step in DCM (20 mL), pyridine (1.52 g, 19.23 mmol, 2.0 eq) and a solution of compound 8a (606 mg, 10.10 mmol, 1.05 eq) in DCM (5 mL) were successively added. The mixture was warmed to room temperature and stirred at room temperature for 16 hours. The progress of the reaction mixture was monitored by TLC. The mixture was diluted with 1N HCl and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound 8 (2.1 g, 100%).

[0491] To a solution of compound 1 (1.36 g, 2.92 mmol, 1.0 eq) in DMF (20 mL), KI (48 mg, 0.292 mmol, 0.1 eq) was added. After stirring for 15 minutes, K2CO3 (1.2 g, 8.76 mmol, 3.0 eq) and compound 8 (2.1 g, 11.67 mmol, 4.0 eq) were added. The mixture was stirred at 60°C for 16 hours. The progress of the reaction mixture was monitored by TLC. The mixture was diluted with water and extracted with DCM. The organic layer was dried on anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound H (462 mg, 25%) as a colorless oil.

[0492] LCMS: [M+1] = 592.50; 1 H NMR (400 MHz, CDCl3) δ8.10 (s, 2H), 7.58 - 7.46 (m, 4H), 5.42 (s, 2H), 4.17-3.92 (m, 7H), 2.21-2.13 (m, 2H), 1.69-1.58 (m, 4H), 1.35 (m, 3H), 0.87-0.82 (m, 9H).

[0493] Example 10 - Synthesis of Exemplary Compound I Compound I was synthesized according to the following steps.

[0494] [ka]

[0495] A solution of compound 11 (2.17 g, 34.97 mmol, 1.0 eq) and triethylamine (3.54 g, 34.97 mmol, 1.0 eq) in ether (10 mL) was cooled to 0°C, and a solution of compound 12 (5.0 g, 34.97 mmol, 1.0 eq) in ether (60 mL) was added dropwise. The mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 16 hours. The progress of the reaction mixture was observed. 1The reaction was monitored by 1H NMR. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 13 (6.2 g, 100%) as a green oil.

[0496] Sodium iodide (22.3 g, 148.8 mmol, 5.0 eq) was added to a solution of compound 13 (5.0 g, 29.76 mmol, 1.0 eq) in acetonitrile (50 mL). The mixture was stirred at room temperature for 7 hours. The reaction of the mixture was observed. 1 The reaction was monitored by 1H NMR. After the reaction was complete, the mixture was concentrated under reduced pressure and the acetonitrile solvent was removed. The residue was diluted with ethyl acetate and extracted with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound 14 (4.0 g, 51%).

[0497] A solution of butyric acid (21.0 g, 238.5 mmol, 2.0 eq) in dichloromethane (200 mL / 100 mL) was cooled to 0°C, and solutions of tetrabutylammonium hydrogen sulfate (81.0 g, 238.5 mmol, 2.0 eq) and sodium bicarbonate (40.1 g, 476.9 mmol, 4.0 eq) were added. The resulting solution was warmed to room temperature and stirred at room temperature for 1 hour. Then, a solution of compound 14 (32.0 g, 119.2 mmol, 1.0 eq) was added at this temperature, and the mixture was stirred for 16 hours. The progress of the reaction mixture was monitored by TLC. After the completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-1% ethyl acetate in petroleum ether). The desired compound 15 was obtained as a yellow oil in a quantity of 17.0 g, with a yield of 62%.

[0498] LCMS: 221.25 [M+1]. 1H NMR (400 MHz, CDCl3) δ 6.93 (q, J = 5.5 Hz, 1H), 2.89 - 2.80 (m, 2H), 2.29 (td, J = 7.3, 3.0 Hz, 2H), 1.64 (dd, J = 14.8, 7.4 Hz, 2H), 1.48 (d, J = 5.5 Hz, 3H), 1.34 - 1.27 (m, 3H), 0.93 (t, J = 7.4 Hz, 3H).

[0499] To a stirred solution of compound 15 (0.5 g, 2.27 mmol) in DCM (5 mL), sulfuryl chloride (0.60 g, 4.52 mmol) was added at -25°C, and the reaction was stirred at the same temperature for 1.5 hours. The solvent was removed to obtain compound 16 (0.52 g). Compound 16 was pure enough for further use.

[0500] To a stirred solution of compound 1 (0.5 g, 1.12 mmol) in DMF (5 mL), K2CO3 (0.31 g, 2.24 mmol) was added, followed by compound 16 (0.65 g, 3.36 mmol) at room temperature. The reaction was heated overnight at 60°C. The reaction was monitored using LC-MS. LC-MS showed approximately ~5% conversion. The reaction was diluted with ethyl acetate, and water was added. The organic layer was separated, and the aqueous layer was washed with ethyl acetate (15 × 2). The combined organic layers were dried over sodium sulfate and concentrated. A 1:1 mixture of ethyl acetate and hexane was added to the solid residue, and solid compound 1 was filtered. The filtrate was concentrated and purified by preparative HPLC by eluting 10–100% ACN (0.1% TFA) and water (0.1% TFA) to obtain compound I (35 mg, 5%).

[0501] LC-MS: 561.3 (M+1). 1H NMR (300 MHz, chloroform-d) δ 8.08 (s, 1H), 8.06 (s, 1H), 7.64 - 7.49 (m, 4H), 7.34 (q, J = 6.4 Hz, 1H), 5.44 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 4.02-3.97 (m, 2H), 2.33 - 2.22 (m, 2H), 1.87 (d, J = 6.4 Hz, 3H), 1.73-1.44 (m, 2H), 1.62-1.55 (m, 2H), 1.34 (t, J = 7.0 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H).

[0502] Example 11 - Synthesis of Exemplary Compound J Compound J was synthesized in the same manner as in Example 9, following the steps below.

[0503] [ka]

[0504] A mixture of compound 9 (0.3 g, 0.55 mmol) and 18 (0.08 g, 0.71 mmol) was heated in DMF at 80°C for 1 hour. LC-MS showed complete conversion to compound J. The reaction is thought to form intermediate compound 19, which further reacts with compound 18 to form the sodium salt of compound 1. The sodium salt of compound 1 further reacts with intermediate compound 19 to form compound J. Compound J (140 mg, 43%) was obtained by removing the solvent under vacuum and purifying the residue using preparative HPLC by eluting 10-100% ACN (0.1% TFA) and water (0.1% TFA).

[0505] LC-MS: 587.3 (M+1). 1H NMR (300 MHz, chloroform-d) δ 7.97 (s, 1H), 7.96 (s, 1H), 7.72 - 7.42 (m, 4H), 6.33 (s, 2H), 5.43 (s, 2H), 4.18 (q, J = 7.0 Hz, 2H), 4.03 - 3.90 (m, 2H), 2.39 - 2.27 (m, 1H), 1.85-1.69 (m, 8H), 1.36 (t, J = 7.0 Hz, 3H), 1.30 - 1.14 (m, 4H), 0.96 (t, J = 7.0 Hz, 3H).

[0506] Example 12 - Synthesis of Exemplary Compound K Compound K was synthesized in the same manner as in Example 10, following the steps below.

[0507] [ka]

[0508] A solution of cyclohexylcarboxylic acid (2.6 g, 29.85 mmol, 2.0 eq) in dichloromethane (30 mL / 15 mL) was cooled to 0°C, and solutions of tetrabutylammonium bisulfate (10.1 g, 29.85 mmol, 2.0 eq) and sodium bicarbonate (5.0 g, 59.70 mmol, 4.0 eq) were added. The resulting solution was warmed to room temperature and stirred at room temperature for 1 hour. Then, a solution of compound 14 (4.0 g, 14.93 mmol, 1.0 eq) was added, and the mixture was stirred for 16 hours. The progress of the reaction mixture was monitored by TLC. After the completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-1% ethyl acetate in petroleum ether). The desired compound 20 was obtained as a colorless oil in a yield of 74% at 2.98 g.

[0509] LC-MS: 283.05 [M+23] + . 1H NMR (300 MHz, CDCl3): δ 6.91 (d, J = 5.5 Hz, 1H), 2.85 (qd, J = 7.4, 3.5 Hz, 2H), 2.33 - 2.24 (m, 1H), 1.88 (d, J = 10.9 Hz, 2H), 1.76 - 1.69 (m, 2H), 1.47 (d, J = 5.5 Hz, 3H), 1.43 (d, J = 12.5 Hz, 2H), 1.29 (dd, J = 11.5, 4.2 Hz, 4H), 1.25 - 1.20 (m, 3H).

[0510] To a stirred solution of compound 20 (0.5 g, 2.27 mmol) in DCM (5 mL), sulfuryl chloride (0.60 g, 4.52 mmol) was added at -25°C, and the reaction mixture was stirred at the same temperature for 1.5 hours. The solvent was removed to obtain compound 21 (0.52 g). Compound 21 was pure enough for further use.

[0511] To a stirred solution of compound 1 (0.5 g, 1.12 mmol) in DMF (5 mL), K2CO3 (0.31 g, 2.24 mmol) was added, followed by the addition of compound 21 (0.65 g, 3.36 mmol) at room temperature. The reaction was stirred overnight at 60°C. The reaction was monitored using LC-MS. LC-MS showed approximately ~10-15% conversion. The reaction was diluted with ethyl acetate, and water was added. The organic layer was separated, and the aqueous layer was washed with ethyl acetate (15 mL x 2). The organic layer was combined with the ethyl acetate washings and dried over sodium sulfate, after which the solution was dried under vacuum. A 1:1 mixture of ethyl acetate and hexane was added to the solid residue, and solid compound 1 was removed by filtration. The filtrate was concentrated and purified by preparative HPLC by eluting 10-100% ACN (0.1% TFA) and water (0.1% TFA) to obtain compound K (72 mg, 10%).

[0512] LC-MS: 601.3 (M+1). 1H NMR (300 MHz, chloroform-d) δ 8.10 (s, 1H), 8.06 (s, 1H), 7.67 - 7.43 (m, 4H), 7.24 (q, J = 6.4 Hz, 1H), 5.45 (s, 2H), 4.17 (q, J = 7.0 Hz, 2H), 4.13-3.97 (m, 2H), 2.36-2.24 (m, 1H), 1.89 (d, J = 6.4 Hz, 3H), 1.83-1.62 (m, 8H), 1.34 (t, J = 7.0 Hz, 3H), 1.27 - 1.09 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H).

[0513] Example 13 - Synthesis of Exemplary Compound L Compound L was synthesized according to the following steps.

[0514] [ka]

[0515] A mixture of acid 23 (150 mg, 1.34 mmol), tetrabutylammonium bisulfate (45.4 mg, 0.1 eq), and NaHCO3 (566 mg, 5 eq) in DCM:H2O (1:1, 6.6 mL) was mixed with a solution of chloromethyl chlorosulfate (222 mg, 1 eq) in DCM (1.1 mL) at 0°C. The reaction mixture was heated to maximum room temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude mixture was dissolved in DCM, passed through a small amount of silica gel (using a pipette), and eluted in DCM. After concentration, 125 mg of compound 24 was obtained as a colorless oil.

[0516] Compound 24 (117 mg, 1.5 eq) was combined with Compound 1 (215 mg, 0.49 mmol), K2CO3 (206 mg, 3 eq), and anhydrous DMF (8.1 mL). The reaction mixture was heated at 60°C for 14 hours, filtered through Celite, and concentrated. Purification by FCC (SiO2:30-50% Âxane / hexane) yielded 134 mg of the desired product (approximately 93% purity). The solid was purified by preparative HPLC (H2O / CH3CN in 0.1% formic acid, 10-100, 20 mL / min, 30 min). After lyophilization, 92 mg of Compound L was obtained as a white solid (96% purity).

[0517] LCMS: [M+H] + = 571. 1 H NMR (300 MHz, CDCl3): δ 7.97 (s, 2H), 7.62 (d, J = 7.8 Hz, 1H), 7.46-7.56 (m, 3H), 6.32 (s, 2H), 5.43 (s, 2H), 4.18 (q, J = 6.9 Hz, 2H), 3.97 (t, J = 7.5 Hz, 2H), 2.40 (s, 1H), 2.04 (s, 6H), 1.62-1.75 (m, 2H), 1.35 (t, J = 6.9 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H)

[0518] Example 14 - Synthesis of Exemplary Compound M Compound M was synthesized according to the following steps.

[0519] [ka]

[0520] To a solution of compound 25 (548 mg, 3.56 mmol) in anhydrous Et2O (17 mL), oxalyl chloride (0.61 mL, 2 eqs) was added at room temperature, and 3 drops of DMF were added. The reaction mixture was stirred at room temperature for 4 hours and then concentrated. Crude compound 26 was dissolved in anhydrous DCM (11 mL), anhydrous ZnCl2 (10.3 mg, 0.02 eqs) was added, the mixture was cooled to -15°C, and propanal (0.26 mL, 1 eq) was added dropwise. The mixture was warmed to maximum room temperature, stirred overnight, and then concentrated. The crude mixture was dissolved in DCM, passed through a small amount of silica gel (using a pipette), and eluted in DCM. After concentration, 714 mg of compound 27 was obtained as a white solid.

[0521] Compound 27 (704 mg, 2 eq) was combined with Compound 1 (680 mg, 1.52 mmol), K2CO3 (640 mg, 3 eq), NaI (46.6 mg, 0.15 eq), and anhydrous DMF (25 mL). The reaction mixture was heated at 80°C for 14 hours, filtered through Celite, and concentrated. HPLC showed approximately 30% conversion. Purification by FCC (SiO2:20-30% siRNA / hexane) yielded 210 mg of the desired compound M (99% purity).

[0522] LCMS: [M+H] + = 641. 1 H NMR (300 MHz, CDCl3): δ 8.13 (s, 1H), 8.06 (s, 1H), 7.60 (d, J = 6.9 Hz, 1H), 7.45-7.54 (m, 3H), 6.94 (bs, 1H), 5.43 (s, 2H), 4.16 (q, J = 6.9 Hz, 2H), 3.99 (t, J = 7.2 Hz, 2H), 2.42 (m, 1H), 2.19 (m, 2H), 1.62-1.75 (m, 6H), 1.56-1.62 (m, 2H), 1.48-1.55 (m, 6H), 1.33 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 0.87 (t, J = 7.5 Hz, 3H)

[0523] Example 15 - Synthesis of Exemplary Compound N Compound N was synthesized according to the following steps.

[0524] [ka]

[0525] Cyclohexanecarboxylic acid (1.31 g, 10.23 mmol) was dissolved in MeOH (5 mL), and NaOMe (2.34 mg, 10.23 mmol, 25% by weight) was added dropwise at room temperature. The reaction mixture was stirred for 1 hour. The solvent was removed under vacuum, and the solid was dried under vacuum to obtain sodium cyclohexanecarboxylate (1.46 g, 95% yield) as a white solid. Compound 29 (0.5 M in hexane, 3.1 eq) and sodium cyclohexanecarboxylate (1.0 eq) were placed in a sealed reaction tube and heated at 80°C for 16 hours. The reaction mixture was cooled and dried under vacuum. The residue was purified by flash chromatography column with 0-20% siRNA / hexane. Compound 31 was obtained in the form of a colorless oil in the form of 28.5 mg (24% yield).

[0526] 1 H NMR (300 MHz, chloroform-d) δ 5.50 (d, J = 1.2 Hz, 2H), 5.41 (d, J = 1.2 Hz, 2H), 2.36 (dddd, J = 11.4, 10.2, 4.4, 3.2 Hz, 1H), 1.99 - 1.87 (m, 2H), 1.82 - 1.71 (m, 2H), 1.70 - 1.38 (m, 4H), 1.38 - 1.30 (m, 1H), 1.30 - 1.20 (m, 2H).

[0527] Compound 31 (1.2-2.5 eq) and Compound 1 (1.0 eq) were dissolved in anhydrous NMP (0.4 M), and Cs2CO3 (1.5 eq) and KI (1.2 eq) were added at room temperature under a N2 atmosphere. The reaction was stirred for 1 hour and monitored by LC-MS. The reaction was then diluted with SiO2, and the organic phase was washed with water (3X). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography column in 0-80% SiO2 / hexane to obtain compound N as a colorless oil.

[0528] LCMS (M+1) + : 617; 1 H NMR (300 MHz, chloroform-d) δ 8.10 (d, J = 3.7 Hz, 2H), 7.64 - 7.41 (m, 4H), 5.92 (s, 2H), 5.56 (s, 2H), 5.43 (s, 2H), 4.19 (q, J = 7.0 Hz, 2H), 4.07 - 3.89 (m, 2H), 2.12 (td, J = 7.0, 3.2 Hz, 1H), 1.85 - 1.47 (m, 8H), 1.35 (t, J = 7.0 Hz, 3H), 1.20 (ddd, J = 18.4, 10.6, 4.7 Hz, 4H), 0.96 (t, J = 7.4 Hz, 3H).

[0529] Example 16 - Synthesis of Exemplary Compound O Compound O was synthesized according to the following steps.

[0530] [ka]

[0531] To a solution of compound 1 (400 mg, 0.89 mmol, 1.0 eq) in tetrahydrofuran (5 mL), sodium hydride (60%, 286 mg, 7.14 mmol, 8.0 eq) was added at 0°C. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was then cooled to 0°C, and ethyl carbono chloride (386 mg, 3.57 mmol, 4.0 eq) was added dropwise. The resulting mixture was stirred overnight from 0°C to room temperature. The progress of the reaction mixture was monitored by TLC. After completion, the mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-25% ethyl acetate in petroleum ether). The desired compound O was obtained as a white solid in a yield of 76% at 354 mg.

[0532] LC-MS: 519.25 [M+1] + . 1 H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 8.14 (s, 1H), 7.62 - 7.57 (m, 1H), 7.54 - 7.42 (m, 3H), 5.39 (s, 2H), 4.49 (d, J = 7.1 Hz, 2H), 4.18 (d, J = 7.1 Hz, 2H), 4.00 - 3.92 (m, 2H), 1.72 - 1.63 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.35 (d, J = 7.1 Hz, 3H), 0.94 (s, 3H).

[0533] Example 17 - Synthesis of Exemplary Compound P Compound P was synthesized according to the following steps.

[0534] [ka]

[0535] To a solution of compound 1 (500 mg, 1.12 mmol, 1.0 eq) in tetrahydrofuran (5 mL), 60% sodium hydride (357 mg, 8.93 mmol, 8.0 eq) was added at 0°C. The mixture was warmed to room temperature and stirred for 1 hour. Then, the mixture was cooled to 0°C and butylcarbonochloride (610 mg, 4.47 mmol, 4.0 eq) was added dropwise. The resulting mixture was stirred overnight from 0°C to room temperature. The progress of the reaction mixture was monitored by TLC. After completion, the mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-25% ethyl acetate in petroleum ether). The desired compound P was obtained as a white solid in an amount of 340 mg, in 55% yield.

[0536] LC-MS: 547.30 [M+1] + . 1 H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 8.14 (s, 1H), 7.58 (s, 1H), 7.52 (s, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 5.39 (s, 2H), 4.42 (d, J = 6.9 Hz, 2H), 4.18 (d, J = 7.0 Hz, 2H), 3.98 - 3.93 (m, 2H), 1.78 - 1.71 (m, 5H), 1.70 - 1.61 (m, 1H), 1.43 - 1.37 (m, 1H), 1.33 (d, J = 7.1 Hz, 1H), 0.93 (dt, J = 11.2, 7.4 Hz, 7H).

[0537] Example 18 - Synthesis of Exemplary Compound Q Compound Q was synthesized according to the following steps.

[0538] [ka]

[0539] A mixture of bis(trichloromethyl) carbonate (5.0 g, 16.65 mmol, 0.5 eq), sodium carbonate (3.5 g, 33.29 mmol, 1.0 eq), and dimethylformamide (0.1 mL) in toluene (50 mL) was cooled to 0°C and stirred under a nitrogen atmosphere for 0.5 hours. Then, a solution of compound 32 (4.0 g, 33.29 mmol, 1.0 eq) was added. The mixture was stirred at 0°C for a further 4 hours. 1 The mixture was monitored by 1H NMR. After completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 33 (4.0 g, 66%).

[0540] To a solution of compound 1 (615 mg, 1.37 mmol, 1.0 eq) in tetrahydrofuran (5 mL), 60% sodium hydride (440 mg, 10.99 mmol, 8.0 eq) was added at 0°C. The mixture was warmed to room temperature and stirred for 1 hour. Then, the mixture was cooled to 0°C, and compound 33 (1.0 g, 5.49 mmol, 4.0 eq) was added dropwise. The resulting mixture was stirred overnight from 0°C to room temperature. The progress of the reaction mixture was monitored by TLC. After completion, the mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-25% ethyl acetate in petroleum ether). The desired compound Q was obtained as a colorless oil in a yield of 4% at 45 mg.

[0541] LC-MS: 593.50 [M+1] + . 1H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H), 8.16 (s, 1H), 7.50 (ddd, J = 25.4, 21.3, 7.6 Hz, 4H), 5.40 (s, 2H), 4.58 (dd, J = 5.5, 3.7 Hz, 2H), 4.17 (q, J = 7.0 Hz, 2H), 3.97 - 3.91 (m, 2H), 3.83 (dd, J = 5.5, 3.7 Hz, 2H), 3.61 (dd, J = 5.6, 3.5 Hz, 2H), 3.49 (dd, J = 5.6, 3.5Hz, 2H), 3.30 (s, 3H), 1.65 (dd, J = 15.1, 7.4 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H).

[0542] Example 19 - Synthesis of Exemplary Compound R Compound R was synthesized according to the following steps.

[0543] [ka]

[0544] A mixture of paraformaldehyde (231 mg, 7.69 mmol, 2.0 eq) and compound 34 (500 mg, 3.85 mmol, 1.0 eq) in chlorotrimethylsilane (5 mL) in a sealed tube was stirred at room temperature for 3 hours and monitored by TLC. After completion, the mixture was concentrated under reduced pressure to obtain crude compound 35 (550 mg, 80%), which was used directly in the next step.

[0545] To a solution of compound 1 (554 mg, 1.24 mmol, 1.0 eq) in 1-methyl-2-pyrrolidinone (5 mL), potassium iodide (102 mg, 0.62 mmol, 0.5 eq) was added. After stirring for 15 minutes, cesium carbonate (1.0 g, 3.09 mmol, 2.5 eq) and compound 35 (550 mg, 3.09 mmol, 2.5 eq) were added. The mixture was stirred at room temperature for 3 hours and monitored by TLC. The mixture was diluted with water and extracted with dichloromethane. The organic layer was dried on anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to obtain compound R (120 mg, 16%) as a colorless oil.

[0546] LC-MS: 589.35 [M+1] + . 1 H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 8.09 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 11.7 Hz, 2H), 7.45 (d, J = 7.8 Hz, 1H), 5.80 (s, 2H), 5.44 (s, 2H), 4.58 (s, 2H), 4.20 (q, J = 7.0 Hz, 3H), 3.99 - 3.94 (m, 3H), 2.10 (s, 3H), 1.67 (dd, J = 15.1, 7.5 Hz, 2H), 1.35 (s, 3H), 0.95 (s, 3H).

[0547] Example 20 - Synthesis of Exemplary Compound S Compound S was synthesized according to the following steps.

[0548] [ka]

[0549] Compound 6 was added to a solution of pyridine (4.8 g, 61.22 mmol, 2.0 eq) and compound 36 (5.3 g, 32.14 mmol, 1.05 eq) in dichloromethane (50 mL) at 0°C. The mixture was warmed to room temperature and stirred for 4 hours. The reaction of the mixture was observed. 1 The mixture was monitored by 1H NMR. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 37 (6.0 g, 69%).

[0550] Potassium iodide (15 mg, 0.088 mmol, 0.1 eq) was added to a solution of compound 1 (394 mg, 0.880 mmol, 1.0 eq) in dimethylformamide (5 mL). After stirring for 15 minutes, potassium carbonate (364 mg, 2.64 mmol, 3.0 eq) and compound 37 (1.0 g, 3.52 mmol, 4.0 eq) were added. The mixture was stirred at 60°C for 16 hours and monitored by TLC. The mixture was diluted with water and extracted with dichloromethane. The organic layer was dried on anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The desired compound S was obtained as a colorless oil in a yield of 8% at 53 mg.

[0551] LC-MS: 695.55 [M+1] + . 1 H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.5 Hz, 2H), 7.61 - 7.45 (m, 4H), 5.43 (s, 1H), 4.34 - 4.12 (m, 4H), 4.01 - 3.93 (m, 2H), 3.67 - 3.50 (m, 10H), 3.34 (s, 3H), 2.63 (s, 2H), 2.18 (s, 2H), 1.67 (dd, J = 15.1, 7.5 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H).

[0552] Example 21 - Synthesis of Exemplary Compound T Compound T was synthesized according to the following steps.

[0553] [ka]

[0554] To a solution of 3-[2-(2-methoxyethoxy)ethoxy]propanoic acid (compound 38) (947 mg, 4.92 mmol) in anhydrous DCM (24 mL), oxalyl chloride (0.85 mL, 2 eq) was added at room temperature, followed by the addition of 3 drops of DMF. The reaction mixture was stirred at room temperature for 5 hours and then concentrated. The crude product was dissolved in anhydrous DCM (16 mL), anhydrous ZnCl2 (37 mg, 0.05 eq) was added, the mixture was cooled to -15°C, and propanal (0.42 mL, 1.2 eq) was added dropwise. The mixture was warmed to maximum room temperature, stirred overnight, and then concentrated. The crude mixture was dissolved in DCM, passed through a small amount of silica gel, and eluted in DCM. After concentration, 1.14 g of compound 40 was obtained as a pale yellow oil.

[0555] Compound 40 (974 mg, 1.5 eq) was combined with Compound 1 (1.08 g, 2.42 mmol), Cs2CO3 (2.36 g, 3 eq), KI (406 mg, 1 eq), and anhydrous DMF (18 mL). The reaction mixture was stirred at room temperature for 16 hours, filtered through Celite, and concentrated. HPLC showed approximately 3% product. The crude product (solids) was treated several times with DCM (approximately 4 grinding cycles in total) until the smallest amount of product was observed on the remaining solids. The filtrate was concentrated and purified by FCC (SiO2:30-50% MeOH / DCM) to obtain a mixture containing approximately 30% product and 70% Compound 1. Final purification was performed by preparative HPLC (H2O / CH3CN containing 0.1% formic acid, 20-100°C, 30 min, 20 mL / min), followed by concentration to obtain 40.3 mg of the desired product, Compound T, as yellow oil.

[0556] LCMS: [M+H] + = 679. 1H NMR (300 MHz, CDCl3): δ 8.12 (s, 1H), 8.07 (s, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.49-7.55 (m, 3H), 7.18 (bs, 1H), 5.44 (s, 2H), 4.17 (q, J = 6.9 Hz, 2H), 3.98 (m, 2H), 3.71 (t, J = 6.6 Hz, 2H), 3.48-3.58 (m, 8H), 3.34 (s, 3H), 2.56-2.68 (m, 2H), 2.19-2.38 (m, 2H), 1.62-1.75 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H)

[0557] Example 22 - Synthesis of Exemplary Compound U Compound U was synthesized according to the following steps:

[0558] [ka]

[0559] A mixture of 1,3,5-trioxane (2 g, 22.2 mmol) and compound 41 (44.4 mmol) in CHCl3 (80 mL) was mixed with CSA (22.2 mmol), and the reaction was refluxed for 65 hours. The reaction mixture was filtered and washed with 0.5 N NaOH. The organic layer was dried over sodium sulfate, concentrated, and purified by flash chromatography to obtain compound 42.

[0560] CSA was added to a mixture of compound 42 (1.3 g, 5.60 mmol) and KOH (0.72 g, 11.2 mmol) in EtOH (50 mL). The reaction was refluxed for 1 hour. The solvent was removed. Water was added to the residue, and the mixture was extracted using ethyl acetate. The aqueous layer was separated, acidified to pH 2 using HCl, extracted with ethyl acetate, dried over MgSO4, and evaporated to dryness to obtain compound 43 (0.9 g). Compound 43 was used without further purification.

[0561] To a solution of compound 43 (0.8 g, 4.54 mmol) in ACN (15 mL), Cu2O (100 mg) was added, and the reaction was refluxed for 1 hour. The solvent was removed, and the residue was treated with water. The pH of the reaction mixture was adjusted to 2 using concentrated HCl, and then extracted with diethyl ether. Compound 44 was obtained by drying the ether layer on MgSO4 and evaporating to dryness.

[0562] To a stirred solution of compound 1 (0.3 g, 0.67 mmol) in DMF (15 mL), NaH (0.05 g, 2.01 mmol) was added at room temperature, and the reaction mixture was stirred for 30 minutes. After 30 minutes, the reaction mixture was cooled to 0°C. Compound chloromethylcarbonochloride (0.15 g, 1.34 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. Additional NaH (0.05 g, 2.01 mmol) and chloromethylcarbonochloride (0.15 g, 1.34 mmol) were added, and the reaction mixture was stirred for a further 1 hour. The reaction mixture was quenched with an aqueous NH4Cl solution, extracted with ethyl acetate, dried over MgSO4, and evaporated to dryness. The residue was purified by flash chromatography by elution of 0-60% ethyl acetate in hexane to obtain compound 9 (110 g, 30%).

[0563] Compound 45 (0.024 g, 1.18 mmol) was added at 0°C to a stirred solution of compound 9 (0.04 g, 0.09 mmol) in DMF (1 mL), and the reaction mixture was stirred for a further 4 hours. After removing the solvent, the residue was purified using HPLC [0-100% ACN (0.1% TFA) and water (0.1% TFA)] to obtain compound U.

[0564] LC-MS: 590.85 (M+1). 1 H NMR (300 MHz, chloroform-d) δ 8.06 (s, 1H), 8.00 (s, 1H), 7.65 - 7.46 (m, 4H), 6.38 (s, 2H), 5.41 (s, 2H), 4.82 (t, J = 5.4 Hz, 2H), 4.27 - 4.16 (m, 4H), 4.04 - 3.93 (m, 4H), 2.82 - 2.68 (m, 1H), 1.72-1.69 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H).

[0565] Example 23 - Synthesis of Exemplary Compound V Compound V was synthesized according to the following steps:

[0566] [ka]

[0567] Compound 48 (0.024 g, 1.18 mmol) was added to a stirred solution of compound 9 (0.05 g, 0.09 mmol) in DMF (1 mL), and the reaction was stirred for 2 hours. LC-MS showed the desired mass for compound 1. The reaction was quenched with aqueous NH4Cl solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and purified using preparative HPLC [eluting 0-100% ACN (0.1% TFA) and water (0.1% TFA)] to obtain compound V.

[0568] LC-MS: 573.95 (M+1).1 H NMR (300 MHz, chloroform-d) δ 8.02 (s, 1H), 7.96 (s, 1H), 7.67 - 7.43 (m, 4H), 6.36 (s, 2H), 5.43 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 4.01 - 3.91 (m, 2H), 3.52 - 3.41 (m, 2H), 3.31 - 3.24 (m, 3H), 2.26 (s, 3H), 1.74 - 1.63 (m, 2H), 1.35 (t, J = 7.2 Hz, 3), 0.95 (m, J = 7.1 Hz, 3H).

[0569] Example 24 - Synthesis of Exemplary Compound AA Compound AA was synthesized according to the following steps:

[0570] [ka]

[0571] A mixture of compound 9 (0.065 g, 0.12 mmol) and compound 47 (0.054 g, 0.36 mmol) was heated in DMF at 60°C for 1 hour. After removing the solvent, the compounds were purified by preparative HPLC by eluting 0-100% ACN (0.1% TFA) and water (0.1% TFA) to obtain compound AA.

[0572] LC-MS: 602 (M+1). 1H NMR (300 MHz, chloroform-d) δ 7.96 (s, 1H), 7.95 (s, 1H), 7.69 - 7.42 (m, 4H), 6.34 (s, 2H), 5.42 (s, 2H), 4.17 (q, J = 7.0 Hz, 2H), 4.04 - 3.91 (m, 2H), 2.81 - 2.69 (m, 2H), 2.31 (m, 1H), 2.22 (s, 3H), 1.98 - 1.62 (m, 8H), 1.34 (t, J = 7.0 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H).

[0573] Example 25 - Synthesis of Exemplary Compound BB Compound BB was synthesized according to the following steps:

[0574] [ka]

[0575] A mixture of compound 9 (0.15 g, 0.27 mmol) and compound 49 (0.25 g, 1.39 mmol) was stirred at room temperature for 45 minutes and then heated in DMF at 60°C for 30 minutes. LC-MS showed complete conversion. After removing the solvent, the compound was purified by preparative HPLC by eluting 0-100% ACN (0.1% TFA) and water (0.1% TFA) to obtain compound BB.

[0576] LC-MS: 588.8 (M+1). 1H NMR (300 MHz, chloroform-d) δ 7.96 (dd, J = 6.4, 0.7 Hz, 2H), 7.67 - 7.45 (m, 5H), 6.36 (s, 2H), 5.43 (s, 2H), 4.18 (q, J = 7.0 Hz, 2H), 4.02 - 3.86 (m, 5H), 3.41-3.33 (m, 3H), 2.60-2.55 (m, 1H), 1.82 - 1.61 (m, 8H), 1.36 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H).

[0577] Example 26 - Synthesis of Exemplary Compound CC Compound CC was synthesized according to the following steps:

[0578] [ka]

[0579] Compound 51 was obtained by adding an aqueous solution of sodium hydroxide to the solution of compound 50. To compound 51 (0.2 g, 1.36 mmol) in water, AgNO3 (0.26 g, 1.52 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. The precipitated solid was filtered, washed with water, and dried under vacuum to obtain compound 52 (0.3 g).

[0580] A mixture of compounds 9 (0.05 g, 0.09 mmol) and 52 (0.03 g, 0.18 mmol) was stirred in DMF at room temperature for 2 hours. LC-MS showed complete conversion. After removing the solvent, the compound CC was obtained by preparative HPLC by eluting 0-100% ACN (0.1% TFA) and water (0.1% TFA).

[0581] LC-MS: 582.85 (M+1). 1H NMR (300 MHz, chloroform-d) δ 8.96 (d, J = 4.9 Hz, 2H), 8.09 (d, J = 3.0 Hz, 2H), 7.65 - 7.35 (m, 5H), 6.65 (s, 2H), 5.43 (s, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.99 - 3.93 (m, 2H), 1.74 - 1.59 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H).

[0582] Example 27 - Synthesis of Exemplary Compound DD Compound DD was synthesized according to the following steps:

[0583] [ka]

[0584] A mixture of compounds 9 (0.05 g, 0.09 mmol) and 53 (0.03 g, 0.18 mmol) in DMF was stirred at room temperature for 2 hours. LC-MS showed complete conversion. After removing the solvent, the compound DD was obtained by preparative HPLC by eluting 0-100% ACN (0.1% TFA) and water (0.1% TFA).

[0585] LC-MS: 581.9 (M+1). 1 H NMR (300 MHz, CDCl3) δ 8.78 (s, 2H), 8.01 (d, J = 2.0 Hz, 2H), 7.82 (d, J = 5.1 Hz, 2H), 7.61-7.47 (m, 4H), 6.62 (s, 2H), 5.43 (s, 2H), 4.19 (q, J = 7.0 Hz, 2H), 4.01 - 3.93 (m, 2H), 1.75 - 1.62 (m, 2H), 1.36 (t, J = 7.0 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H).

[0586] Example 28 - Synthesis of Exemplary Compound EE Compound EE was synthesized according to the following steps:

[0587] [ka]

[0588] A mixture of compounds 9 (0.15 g, 0.28 mmol) and 54 (0.12 g, 0.84 mmol) was heated in DMF at 60°C for 1 hour. LC-MS showed complete conversion. After removing the solvent, the compound EE was obtained by preparative HPLC by eluting 0-100% ACN (0.1% TFA) and water (0.1% TFA).

[0589] LC-MS: 581.8 (M+1). 1 H NMR (300 MHz, chloroform-d) δ 9.19 (s, 1H), 8.82 (d, J = 4.9 Hz, 1H), 8.33 (dd, J = 8.1, 2.1 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.61 - 7.44 (m, 5H), 6.62 (s, 2H), 5.43 (s, 2H), 4.20 (q, J = 7.0 Hz, 2H), 4.04 - 3.91 (m, 2H), 1.73 - 1.62 (m, 2H), 1.36 (t, J = 7.0 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H).

[0590] Example 29 - Synthesis of Exemplary Compound FF Compound FF was synthesized according to the following steps:

[0591] [ka]

[0592] A mixture of compounds 9 (0.2 g, 0.37 mmol) and 55 (0.11 g, 0.74 mmol) in DMF was heated at 40°C for 12 hours. LC-MS showed the desired mass. After removing the solvent, the compound FF was purified by preparative HPLC, first using flash column chromatography and then eluting with 0-100% ACN (0.1% TFA) and water (0.1% TFA).

[0593] LC-MS: 584.9 (M+1). 1 H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 8.04 (d, J = 11.9 Hz, 1H), 7.57-7.47 (m, 4H), 7.15 (s, 1H), 7.09 (d, J = 5.0 Hz, 1H), 6.54 (s, 2H), 5.44 (s, 2H), (q, J = 7.0 Hz, 2H), 3.99 - 3.92 (s, 3H), 3.99-3.94 (m, 2H), 1.70 - 1.61 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H).

[0594] Example 30 - Synthesis of Exemplary Compound GG Compound GG was synthesized according to the following steps:

[0595] [ka]

[0596] A mixture of compounds 9 (0.2 g, 0.37 mmol) and 56 (0.11 g, 0.74 mmol) was heated at 60°C for 1 hour. LC-MS showed complete conversion. After removing the solvent, the compound GG was obtained by preparative HPLC by eluting 0-100% ACN (0.1% TFA) and water (0.1% TFA).

[0597] LC-MS: 584.9 (M+1). 1H NMR (300 MHz, chloroform-d) δ 8.25 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.61 - 7.45 (m, 4H), 6.55 (s, 2H), 5.45 (s, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.99 - 3.92 (m, 2H), 3.85 (s, 3H), 1.72 - 1.60 (m, 2H), 1.35 (t, J = 7.0 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H).

[0598] Example 31 - Pharmacokinetic Properties Pharmacokinetic studies were conducted in Sprague Dolly rats. Exemplary compounds were administered orally via enteral feeding to groups of three rats using a single oral dose of 5 mg / kg. Each oral dose was prepared as a 0.5% methylcellulose turbidi in water. Blood samples were collected sequentially from each rat at 0, 15, and 30 minutes post-administration, and then at 1, 2, 4, 8, and 24 hours.

[0599] The concentrations of administered compounds and their corresponding metabolites (compound 1) in rat plasma were determined by HPLC-tandem mass spectrometry (LC / MS / MS). 50 μL of plasma PPT with ISTD in MeOH / acetonitrile (1:1, v / v). 200 μL of 5 ng / mL terfenadine and buspirone were added to MeOH / acetonitrile (1:1, v / v) and mixed well. 5 μL of MeOH was added to all samples, vortexed for 1 minute, and centrifuged at 4000 rpm for 15 minutes. The supernatant was diluted 3-fold with water (containing 0.1% FA) and injected for LC / MS / MS analysis.

[0600] [Table 3]

[0601] Compound quantification was achieved by mass spectrometry using multiple reaction monitoring (MRM) mode, monitoring the transitions specific to each exemplary compound and the 447.34 > 405.20 transition for compound 1. The limit of quantification for compound 1 was 10 ng / mL.

[0602] Pharmacokinetic analysis Non-compartmental pharmacokinetic parameters were determined using the commercially available program WinNonLin Professional, version 8.0 (Pharsight, Mountain View, Calif). In the calculation of mean and pharmacokinetic parameters, plasma concentrations below detection levels were assumed to be 0.

[0603] For oral administration, t1 / 2 (hr), tmax (hr), Cmax (ng / mL), AUClast (hr) * ng / mL), AUCInf(hr * The following parameters were determined: ng / mL, AUC Extr (%), MRTInf (hr), Cmax Ratio (Parent / Pro), and AUClast Ratio (Parent / Pro).

[0604] Table 3 shows the typical AUC of representative compounds of formula (A). last The data will be recorded.

[0605] [Table 4]

[0606] Table 4 shows typical AUClast data for representative compounds of formula (B).

[0607] [Table 5]

[0608] Table 5 shows typical AUClast data for compound 1.

[0609] [Table 6] Example 32: Oral solution

[0610] To prepare a pharmaceutical composition for oral delivery, a sufficient amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is added to water (with an optional solubilizer, optional buffer, and taste-masking excipient) to obtain a solution of 0.1–20 mg / mL.

[0611] Example 33: Oral Tablets Tablets are prepared by mixing 20-50% by weight of a compound described herein or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of unsubstituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate, or other suitable excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100-500 mg.

[0612] Example 34: Oral capsule To prepare a pharmaceutical composition for oral delivery, 10-500 mg of one of the compounds described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder mixtures. The mixture is then incorporated into an oral dosage form suitable for oral administration, such as a hard gelatin capsule.

[0613] In another embodiment, 1-500 mg of one of the compounds described herein, or a pharmaceutically acceptable salt thereof, is placed in a size 4 capsule or a size 1 capsule (hypromellose or hard gelatin), and the capsule is closed.

[0614] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided only as examples. Many modifications, changes, and substitutions will be conceivable without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in the practice of the invention. The following claims define the scope of the present invention, and it is intended that methods and structures within the scope of these claims and their equivalents are thereby encompassed.

Claims

1. Compounds represented by formula (III): 【Chemistry 2】 Alternatively, a pharmaceutically acceptable salt or solvate thereof, in the formula: R １ and R ２ These are, independently, hydrogen and substituted or unsubstituted C. １ -C ６ Selected from alkyl groups; R ３ C １ -C ４ Selected from phenyl substituted with fluoroalkyl groups; R ５ is hydrogen or unsubstituted C １ -C ６ alkyl, A compound or a pharmaceutically acceptable salt or solvate thereof.

2. R １ and R ２ Each of these independently represents a substitution or non-substitution of C. １ -C ６ A compound according to claim 1, selected from alkyl groups, or a pharmaceutically acceptable salt or solvate thereof.

3. R １ and R ２ Each of these compounds is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl, or a pharmaceutically acceptable salt or solvate thereof.

4. The compound is the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the following structure. 【Transformation 3】

5. Compounds having the following structure, or pharmaceutically acceptable salts thereof. 【Chemistry 9-1】

6. Compounds having the following structure, or pharmaceutically acceptable salts thereof. 【Chemistry 9-2】

7. A pharmaceutical formulation comprising a compound according to any one of claims 1-6 or any pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

8. A ２Ｂ (1) a composition comprising any one of the compounds described in claims 1-6 or any pharmaceutically acceptable salt or solvate thereof, or (2) a formulation according to claim 7, for modulating an adenosine receptor.

9. (1) a composition comprising a compound according to any one of claims 1-6 or any pharmaceutically acceptable salt or solvate thereof, or (2) a formulation according to claim 7, wherein the disease or illness is selected from the group consisting of cardiovascular disease, fibrosis, neurological disorders, type I hypersensitivity, chronic and acute liver disease, lung disease, kidney disease, diabetes, obesity, and cancer.

10. The composition or formulation according to claim 9, wherein the disease or illness is cancer.

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